U.S. patent number 10,683,302 [Application Number 16/308,739] was granted by the patent office on 2020-06-16 for inhibitors of the menin-mll interaction.This patent grant is currently assigned to VITAE PHARMACEUTICALS, LLC. The grantee listed for this patent is VITAE PHARMACEUTICALS, LLC. Invention is credited to Salvacion Cacatian, David A. Claremon, Lawrence Wayne Dillard, Chengguo Dong, Yi Fan, Travis L. Houston, Lanqi Jia, Stephen D. Lotesta, Andrew Marcus, Angel Morales-Ramos, Stephan D. Parent, Suresh B. Singh, Shankar Venkatraman, Jing Yuan, Yajun Zheng, Linghang Zhuang.
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| United States Patent | 10,683,302 |
| Cacatian , et al. | June 16, 2020 |
Inhibitors of the menin-MLL interaction
Abstract
The present invention is directed to inhibitors of theinteraction of menin with MLL and MLL fusion proteins,pharmaceutical compositions containing the same, and their use inthe treatment of cancer and other diseases mediated by themenin-MLL interaction.
| Inventors: | Cacatian; Salvacion(Conshohocken, PA), Claremon; David A. (Maple Glen, PA),Dillard; Lawrence Wayne (Yardley, PA), Dong; Chengguo(Staten Island, NY), Fan; Yi (Doylestown, PA), Jia;Lanqi (Horsham, PA), Lotesta; Stephen D. (Burlington,NJ), Marcus; Andrew (Media, PA), Morales-Ramos; Angel(Blue Bell, PA), Singh; Suresh B. (Kendall Park, NJ),Venkatraman; Shankar (Lansdale, PA), Yuan; Jing(Lansdale, PA), Zheng; Yajun (Hockessin, DE), Zhuang;Linghang (Chalfont, PA), Parent; Stephan D. (WestLafayette, IN), Houston; Travis L. (Lafayette, IN) | ||||||||||
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| Applicant: |
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| Assignee: | VITAE PHARMACEUTICALS, LLC(Madison, NJ) | ||||||||||
| FamilyID: | 59325631 | ||||||||||
| Appl.No.: | 16/308,739 | ||||||||||
| Filed: | June 8, 2017 | ||||||||||
| PCTFiled: | June 08, 2017 | ||||||||||
| PCT No.: | PCT/US2017/036506 | ||||||||||
| 371(c)(1),(2),(4) Date: | December 10, 2018 | ||||||||||
| PCTPub. No.: | WO2017/214367 | ||||||||||
| PCTPub. Date: | December 14, 2017 |
Prior Publication Data
| DocumentIdentifier | Publication Date | |
|---|---|---|
| US 20190144459 A1 | May 16, 2019 | |
Related U.S. Patent Documents
| ApplicationNumber | Filing Date | Patent Number | Issue Date | ||
|---|---|---|---|---|---|
| 62348496 | Jun 10, 2016 | ||||
| Current U.S.Class: | 1/1 |
| Current CPCClass: | C07D403/04(20130101); C07F 9/6561(20130101); C07D491/107(20130101); A61P 35/02(20180101); C07D491/10(20130101); C07D 405/14(20130101); C07D471/10(20130101); C07D 487/10(20130101); C07D403/14(20130101); C07B 2200/13(20130101) |
| Current InternationalClass: | C07D405/14(20060101); C07D 471/10(20060101); C07D487/10(20060101); C07D 491/10(20060101); C07D403/14(20060101); C07D 403/04(20060101); A61P35/02(20060101); C07F 9/6561(20060101); C07D491/107(20060101) |
Foreign Patent Documents
| WO 2009/137733 | Nov 2009 | WO | |||
| WO 2014/164543 | Oct 2014 | WO | |||
| WO 2015/191701 | Dec 2015 | WO | |||
Other References
Borkin et al. "Pharmacologic Inhibition of the Menin-MLLInteraction Blocks Progression of MLL Leukemia In Vivo", CancerCell, vol. 27, p. 589-602 (2015). cited by applicant .
Chamberlain et al. "Menin determines K-RAS proliferative outputs inendocrine cells", The Journal of Clinical Investigation, vol. 124,No. 9, p. 4093-4101 (2014). cited by applicant .
Cierpicki T. et al. "Challenges and opportunities in targeting themenin-MLL interaction", Future Med. Chem. vol. 6, No. 4, p. 447-462(2014). cited by applicant .
Grembecka J. et al. "Menin-MLL inhibitors reverse oncogenicactivity of MLL fusion proteins in leukemia", Nature ChemicalBiology, vol. 8, p. 277-284 (2012). cited by applicant .
Kress et al. "Chemistry of Pyrimidine. 2. Synthesis of PyrimidineJV-Oxides and 4-Pyrimidinones by Reaction of 5-SubstitutedPyrimidines with Peracids. Evidence for Covalent Hydrates asReaction Intermediates", J. Org. Chem., vol. 50, p. 3073-3076(1985). cited by applicant .
Maiti D. et al. "Cu-Catalyzed Arylation of Phenols: Synthesis ofSterically Hindered and Heteroaryl Diaryl Ethers", J. Org. Chem.vol. 75, p. 1791-1794 (2010). cited by applicant .
Malik R. et al. "Targeting the MLL complex in castration-resistantprostate cancer", Nature Medicine, vol. 21, No. 4, p. 344-354(2015). cited by applicant .
Salvi L. et al. "A New Biarylphosphine Ligand for the Pd-CatalyzedSynthesis of Diaryl Ethers under Mild Conditions", Organic Letters,vol. 14, No. 1, p. 170-173 (2012). cited by applicant .
Shi A. et al. "Structural insights into inhibition of the bivalentmenin-MLL interaction by small molecules in leukemia", Blood, vol.120, No. 23, 2012, pp. 4461-4469. cited by applicant .
Yang Y. et al. "Reversal of preexisting hyperglycemia in diabeticmice by acute deletion of the Men1 gene", PNAS, vol. 107, No. 47,p. 20358-20363 (2010). cited by applicant .
Yokoyama A. et al. "The Menin Tumor Suppressor Protein Is anEssential Oncogenic Cofactor for MLL-Associated Leukemogenesis",Cell, vol. 123, p. 207-218, (2005). cited by applicant.
Primary Examiner: Kifle; Bruck
Attorney, Agent or Firm: Cooley LLP Erlacher; Heidi A.Owens; Eric A.
Parent Case Text
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a national stage application, filed under 35U.S.C. 371, of PCT Application No. PCT/US2017/036506 filed Jun. 8,2017, which claims the benefit of U.S. Provisional Application No.62/348,496 filed Jun. 10, 2016, which are incorporated by referenceherein in their entireties.
Claims
What is claimed is:
1. A compound of Formula I: ##STR00562## or a pharmaceuticallyacceptable salt thereof, wherein: A, B, D, and E are eachindependently selected from --C(R.sup.A1)(R.sup.A2)--,--C(R.sup.A1)(R.sup.A2)--C(R.sup.A1)(R.sup.A2)--,--C(R.sup.A1)(R.sup.A2)--O--, --C(R.sup.A1)(R.sup.A2)--NR.sup.A3--,--C(.dbd.O)--, --C(R.sup.A1)(R.sup.A2)--C(.dbd.O)--, and--N.dbd.C(NH.sub.2)-- wherein no more than one of A, B, D, and E is--C(R.sup.A1)(R.sup.A2)--O--, --C(R.sup.A1)(R.sup.A2)--NR.sup.A3--,--C(R.sup.A1)(R.sup.A2)--C(.dbd.O)--, --C(.dbd.O)--, or--N.dbd.C(NH.sub.2)--; U is N or CR.sup.U, wherein R.sup.U is H,halo, CN, OH, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, amino, C.sub.1-4alkyl amino, or C.sub.2-8 dialkylamino; W is N or CR.sup.W, whereinR.sup.W is H, halo, CN, OH, C.sub.1-4 alkyl, C.sub.1-4 alkoxy,amino, C.sub.1-4 alkyl amino, or C.sub.2-8 dialkylamino; X is N orCR.sup.X, wherein R.sup.X is H, halo, CN, OH, C.sub.1-4 alkyl,C.sub.1-4 alkoxy, amino, C.sub.1-4 alkyl amino, or C.sub.2-8dialkylamino, wherein when X is N, the atom of L that is directlybonded with X is other than N, O, or S; L is selected from--C.sub.1-6 alkylene- and --(C.sub.1-4 alkylene).sub.a-Q-(C.sub.1-4alkylene).sub.b-, wherein the C.sub.1-6 alkylene group and anyC.sub.1-4 alkylene group of the --(C.sub.1-4alkylene).sub.a-Q-(C.sub.1-4 alkylene).sub.b-group is optionallysubstituted with 1, 2, or 3 substituents independently selectedfrom halo, CN, OH, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-3haloalkyl, C.sub.1-3 haloalkoxy, amino, C.sub.1-3 alkylamino, anddi(C.sub.1-3 alkyl)amino; Q is --O--, --S--, --S(.dbd.O)--,--S(.dbd.O).sub.2--, --C(.dbd.O)--, --C(.dbd.O)NR.sup.q1--,--C(.dbd.O)O--, --OC(.dbd.O)NR.sup.q1--, --NR.sup.q1--,--NR.sup.q1C(.dbd.O)O--, --NR.sup.q1C(.dbd.O)NR.sup.q1--,--S(.dbd.O).sub.2NR.sup.q1--, --C(.dbd.NR.sup.q2)--, or--C(.dbd.NR.sup.q2)--NR.sup.q1--, wherein each R.sup.q1 isindependently selected from H or C.sub.1-6 alkyl, and wherein eachR.sup.q2 is independently selected from H, C.sub.1-6 alkyl, and CN;Cy is a linking C.sub.6-14 aryl, C.sub.3-18 cycloalkyl, 5-16membered heteroaryl, or 4-18 membered heterocycle group, each ofwhich is optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R.sup.Cy, wherein the heteroaryl orheterocycle has 1-3 rings and 1-4 heteroatoms independentlyselected from nitrogen, sulfur, and oxygen; each R.sup.Cy isindependently selected from halo, C.sub.1-6 alkyl, C.sub.1-4haloalkyl, C.sub.1-4 cyanoalkyl, C.sub.2-6 alkenyl, C.sub.2-6alkynyl, C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycle, CN, NO.sub.2, OR.sup.a1,SR.sup.a1, C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1,OC(O)R.sup.b1, OC(O)NR.sup.c1R.sup.d1,C(.dbd.NR.sup.e1)NR.sup.c1R.sup.d1,NR.sup.c1C(.dbd.NR.sup.e1)NR.sup.c1R.sup.d1, NR.sup.c1R.sup.d1,NR.sup.c1C(O)R.sup.b1, NR.sup.c1C(O)OR.sup.a1,NR.sup.c1C(O)NR.sup.c1R.sup.d1, NR.sup.c1S(O)R.sup.b1,NR.sup.c1S(O).sub.2R.sup.b1, NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1,S(O)R.sup.b1, S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1, andS(O).sub.2NR.sup.c1R.sup.d1, wherein said C.sub.1-6 alkyl,C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.6-10 aryl, C.sub.3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycleare each optionally substituted by 1, 2, 3, or 4 substituentsindependently selected from CN, NO.sub.2, OR.sup.a1, SR.sup.a1,C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1, OC(O)R.sup.b1,OC(O)NR.sup.c1R.sup.d1, C(.dbd.NR.sup.e1)NR.sup.c1R.sup.d1,NR.sup.c1C(.dbd.NR.sup.e1)NR.sup.c1R.sup.d1, NR.sup.c1R.sup.d1,NR.sup.c1C(O)R.sup.b1, NR.sup.c1C(O)OR.sup.a1,NR.sup.c1C(O)NR.sup.c1R.sup.d1, NR.sup.c1S(O)R.sup.b1,NR.sup.c1S(O).sub.2R.sup.b1, NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1,S(O)R.sup.b1, S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1, andS(O).sub.2NR.sup.c1R.sup.d1, wherein the heteroaryl or heterocyclehas 1-3 rings and 1-4 heteroatoms independently selected fromnitrogen, sulfur, and oxygen; R.sup.1 is H, Cy.sup.1, halo,C.sub.1-6 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 cyanoalkyl,C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, CN, NO.sub.2, OR.sup.a2,SR.sup.a2, C(O)R.sup.b2, C(O)NR.sup.c2R.sup.d2, C(O)OR.sup.a2,OC(O)R.sup.b2, OC(O)NR.sup.c2R.sup.d2,C(.dbd.NR.sup.e2)NR.sup.c2R.sup.d2,NR.sup.c2C(.dbd.NR.sup.e2)NR.sup.c2R.sup.d2, NR.sup.c2R.sup.d2,NR.sup.c2C(O)R.sup.b2, NR.sup.c2C(O)OR.sup.a2,NR.sup.c2C(O)NR.sup.c2R.sup.d2, NR.sup.c2S(O)R.sup.b2,NR.sup.c2S(O).sub.2R.sup.b2, NR.sup.c2S(O).sub.2NR.sup.c2R.sup.d2,S(O)R.sup.b2, S(O)NR.sup.c2R.sup.d2, S(O).sub.2R.sup.b2 andS(O).sub.2NR.sup.c2R.sup.d2, wherein said C.sub.1-6 alkyl,C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are each optionallysubstituted by 1, 2, 3, or 4 substituents independently selectedfrom halo, CN, NO.sub.2, OR.sup.a2, SR.sup.a2, C(O)R.sup.b2,C(O)NR.sup.c2R.sup.d2, C(O)OR.sup.a2, OC(O)R.sup.b2,OC(O)NR.sup.c2R.sup.d2, C(.dbd.NR.sup.e2)NR.sup.c2R.sup.d2,NR.sup.c2C(.dbd.NR.sup.e2)NR.sup.c2R.sup.d2, NR.sup.c2R.sup.d2,NR.sup.c2C(O)R.sup.b2, NR.sup.c2C(O)OR.sup.a2,NR.sup.c2C(O)NR.sup.c2R.sup.d2, NR.sup.c2S(O)R.sup.b2,NR.sup.c2S(O).sub.2R.sup.b2, NR.sup.c2S(O).sub.2NR.sup.c2R.sup.d2,S(O)R.sup.b2, S(O)NR.sup.c2R.sup.d2, S(O).sub.2R.sup.b2, andS(O).sub.2NR.sup.c2R.sup.d2; Y is O, S, CR.sup.Y1R.sup.Y2 orNR.sup.Y3, wherein R.sup.Y1, R.sup.Y2, and R.sup.Y3 are eachindependently selected from H and C.sub.1-4 alkyl; Z is Cy.sup.2,halo, C.sub.1-6 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 cyanoalkyl,C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, CN, NO.sub.2, OR.sup.a3,SR.sup.a3, C(O)R.sup.b3, C(O)NR.sup.c3R.sup.d3, C(O)OR.sup.a3,OC(O)R.sup.b3, OC(O)NR.sup.c3R.sup.d3,C(.dbd.NR.sup.e3)NR.sup.c3R.sup.d3,NR.sup.c3C(.dbd.NR.sup.e3)NR.sup.c3R.sup.d3, NR.sup.c3R.sup.d3,NR.sup.c3C(O)R.sup.b3, NR.sup.c3C(O)OR.sup.a3,NR.sup.c3C(O)NR.sup.c3R.sup.d3, NR.sup.c3S(O)R.sup.b3,NR.sup.c3S(O).sub.2R.sup.b3, NR.sup.c3S(O).sub.2NR.sup.c3R.sup.d3,S(O)R.sup.b3, S(O)NR.sup.c3R.sup.d3, S(O).sub.2R.sup.b3,S(O).sub.2NR.sup.c3R.sup.d3, and P(O)R.sup.c3R.sup.d3 wherein saidC.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are eachoptionally substituted by 1, 2, 3, or 4 substituents independentlyselected from Cy.sup.2, halo, CN, NO.sub.2, CN, NO.sub.2,OR.sup.a3, SR.sup.a3, C(O)R.sup.b3, C(O)NR.sup.c3R.sup.d3,C(O)OR.sup.a3, OC(O)R.sup.b3, OC(O)NR.sup.c3R.sup.d3,C(.dbd.NR.sup.e3)NR.sup.c3R.sup.d3,NR.sup.c3C(.dbd.NR.sup.e3)NR.sup.c3R.sup.d3, NR.sup.c3R.sup.d3,NR.sup.c3C(O)R.sup.b3, NR.sup.c3C(O)OR.sup.a3,NR.sup.c3C(O)NR.sup.c3R.sup.d3, NR.sup.c3S(O)R.sup.b3,NR.sup.c3S(O).sub.2R.sup.b3, NR.sup.c3S(O).sub.2NR.sup.c3R.sup.d3,S(O)R.sup.b3, S(O)NR.sup.c3R.sup.d3, S(O).sub.2R.sup.b3, andS(O).sub.2NR.sup.c3R.sup.d3; each R.sup.2 and R.sup.3 isindependently selected from H, halo, C.sub.1-6 alkyl, C.sub.1-4haloalkyl, C.sub.1-4 cyanoalkyl, C.sub.2-6 alkenyl, C.sub.2-6alkynyl, CN, NO.sub.2, OR.sup.a4, SR.sup.a4, C(O)R.sup.b4,C(O)NR.sup.c4R.sup.d4, C(O)OR.sup.a4, OC(O)R.sup.b4,OC(O)NR.sup.c4R.sup.d4, C(.dbd.NR.sup.e4)NR.sup.c4R.sup.d4,NR.sup.c4C(.dbd.NR.sup.e4)NR.sup.c4R.sup.d4, NR.sup.c4R.sup.d4,NR.sup.c4C(O)R.sup.b4, NR.sup.c4C(O)OR.sup.a4,NR.sup.c4C(O)NR.sup.c4R.sup.d4, NR.sup.c4S(O)R.sup.b4,NR.sup.c4S(O).sub.2R.sup.b4, NR.sup.c4S(O).sub.2NR.sup.c4R.sup.d4,S(O)R.sup.b4, S(O)NR.sup.c4R.sup.d4, S(O).sub.2R.sup.b4, andS(O).sub.2NR.sup.c4R.sup.d4, wherein said C.sub.1-6 alkyl,C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are each optionallysubstituted by 1, 2, 3, or 4 substituents independently selectedfrom halo, CN, NO.sub.2, OR.sup.a4, SR.sup.a4, C(O)R.sup.b4,C(O)NR.sup.c4R.sup.d4, C(O)OR.sup.a4, OC(O)R.sup.b4,OC(O)NR.sup.c4R.sup.d4, C(.dbd.NR.sup.e4)NR.sup.c4R.sup.d4,NR.sup.4C(.dbd.NR.sup.e4)NR.sup.c4R.sup.d4, NR.sup.c4R.sup.d4,NR.sup.4C(O)R.sup.b4, NR.sup.4C(O)OR.sup.a4,NR.sup.c4C(O)NR.sup.c4R.sup.d4, NR.sup.c4S(O)R.sup.b4,NR.sup.c4S(O).sub.2R.sup.b4, NR.sup.c4S(O).sub.2NR.sup.c4R.sup.d4,S(O)R.sup.b4, S(O)NR.sup.c4R.sup.d4, S(O).sub.2R.sup.b4, andS(O).sub.2NR.sup.c4R.sup.d4; each R.sup.A1 is independentlyselected from H, halo, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4haloalkyl, C.sub.1-4 haloalkoxy, amino, C.sub.1-4 alkylamino,C.sub.2-8 dialkylamino, CN, NO.sub.2, and OH; each R.sup.A2 isindependently selected from H, halo, C.sub.1-4 alkyl, C.sub.1-4alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy, amino, C.sub.1-4alkylamino, C.sub.2-8 dialkylamino, CN, NO.sub.2, and OH; eachR.sup.A3 is independently selected from H, C.sub.1-4 alkyl,C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C(O)R.sup.z, andC(O)OR.sup.z, wherein said C.sub.1-4 alkyl is optionallysubstituted by phenyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, CN,NO.sub.2, or OH; R.sup.z is H, C.sub.1-4 alkyl, or phenyl; eachCy.sup.1 is independently selected from C.sub.6-14 aryl, C.sub.3-18cycloalkyl, 5-16 membered heteroaryl, and 4-18 memberedheterocycle, each of which is optionally substituted with 1, 2, 3,or 4 substituents independently selected from R.sup.Cy1, whereinthe heteroaryl or heterocycle has 1-3 rings and 1-4 heteroatomsindependently selected from nitrogen, sulfur, and oxygen; eachCy.sup.2 is independently selected from C.sub.6-14 aryl, C.sub.3-18cycloalkyl, 5-16 membered heteroaryl, and 4-18 memberedheterocycle, each of which is optionally substituted with 1, 2, 3,or 4 substituents independently selected from R.sup.Cy2, whereinthe heteroaryl or has 1-3 rings and 1-4 heteroatoms independentlyselected from nitrogen, sulfur, and oxygen; each R.sup.Cy1 andR.sup.Cy2 is independently selected from halo, C.sub.1-6 alkyl,C.sub.1-4 haloalkyl, C.sub.1-4 cyanoalkyl, C.sub.2-6 alkenyl,C.sub.2-6 alkynyl, phenyl, C.sub.3-7 cycloalkyl, 5-6 memberedheteroaryl, and 4-7 membered heterocycle, CN, NO.sub.2, OR.sup.a5,SR.sup.a5, C(O)R.sup.b5, C(O)NR.sup.c5R.sup.d5, C(O)OR.sup.a5,OC(O)R.sup.b5, OC(O)NR.sup.c5R.sup.d5,C(.dbd.NR.sup.e5)NR.sup.c5R.sup.d5,NR.sup.c5C(.dbd.NR.sup.e5)NR.sup.c5R.sup.d5, NR.sup.c5R.sup.d5,NR.sup.c5C(O)R.sup.b5, NR.sup.c5C(O)OR.sup.a5,NR.sup.c5C(O)NR.sup.c5R.sup.d5, NR.sup.c5S(O)R.sup.b5,NR.sup.c5S(O).sub.2R.sup.b5, NR.sup.c5S(O).sub.2NR.sup.c5R.sup.d5,S(O)R.sup.b5, S(O)NR.sup.c5R.sup.d5, S(O).sub.2R.sup.b5, andS(O).sub.2NR.sup.C5R.sup.d5, wherein said C.sub.1-6 alkyl,C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, phenyl, C.sub.3-7 cycloalkyl,5-6 membered heteroaryl, and 4-7 membered heterocycle are eachoptionally substituted by 1, 2, 3, or 4 substituents independentlyselected from CN, NO.sub.2, OR.sup.a5, SR.sup.a5, C(O)R.sup.b5,C(O)NR.sup.c5R.sup.d5, C(O)OR.sup.a5, OC(O)R.sup.b5,OC(O)NR.sup.c5R.sup.d5, C(.dbd.NR.sup.e5)NR.sup.c5R.sup.d5,NR.sup.c5C(.dbd.NR.sup.e5)NR.sup.c5R.sup.d5, NR.sup.c5R.sup.d5,NR.sup.c5C(O)R.sup.b5, NR.sup.c5C(O)OR.sup.a5,NR.sup.c5C(O)NR.sup.c5R.sup.d5 NR.sup.c5S(O)R.sup.b5,NR.sup.c5S(O).sub.2R.sup.b5, NR.sup.c5S(O).sub.2NR.sup.c5R.sup.d5,S(O)R.sup.b5, S(O)NR.sup.c5R.sup.d5, S(O).sub.2R.sup.b5, andS(O).sub.2NR.sup.c5R.sup.d5, wherein the heteroaryl or heterocyclehas 1-3 rings and 1-4 heteroatoms independently selected fromnitrogen, sulfur, and oxygen; each R.sup.a1, R.sup.b1, R.sup.c1,R.sup.d1, R.sup.a2, R.sup.b2, R.sup.c2, R.sup.d2, R.sup.a3,R.sup.b3, R.sup.c3, R.sup.d3, R.sup.a4, R.sup.b4, R.sup.c4,R.sup.d4, R.sup.a5, R.sup.b5, R.sup.c5, and R.sup.d5 isindependently selected from H, C.sub.1-6 alkyl, C.sub.1-4haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.6-10 aryl,C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycle, C.sub.6-10 aryl-C.sub.1-6 alkyl, C.sub.3-10cycloalkyl-C.sub.1-6 alkyl, (5-10 membered heteroaryl)-C.sub.1-6alkyl, and (4-10 membered heterocycle)-C.sub.1-6 alkyl, whereinsaid C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycle, C.sub.6-10 aryl-C.sub.1-6 alkyl,C.sub.3-10 cycloalky-C.sub.1-6 alkyl, (5-10 memberedheteroaryl)-C.sub.1-6 alkyl, and (4-10 memberedheterocycle)-C.sub.1-6 alkyl are each optionally substituted with1, 2, 3, 4, or 5 substituents independently selected from R.sup.g,wherein the heteroaryl or heterocycle has 1-3 rings and 1-4heteroatoms independently selected from nitrogen, sulfur, andoxygen; each R.sup.e1, R.sup.e2, R.sup.e3, R.sup.e4, and R.sup.e5is independently selected from H, C.sub.1-4 alkyl, and CN; eachR.sup.g is independently selected from the group consisting of OH,NO.sub.2, CN, halo, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6alkynyl, C.sub.1-4 haloalkyl, C.sub.1-6 alkoxy, C.sub.1-6haloalkoxy, cyano-C.sub.1-3 alkyl, HO--C.sub.1-3 alkyl, amino,C.sub.1-6 alkylamino, di(C.sub.1-6 alkyl)amino, thiol, C.sub.1-6alkylthio, C.sub.1-6 alkylsulfinyl, C.sub.1-6 alkylsulfonyl,carboxy, aminocarbonyl, C.sub.1-6 alkylcarbonyl, and C.sub.1-6alkoxycarbonyl; n is 0 or 1; m is 0 or 1; p is 0, 1, 2, or 3; q is0, 1, or 2; a is 0 or 1; and b is 0 or 1, wherein any cycloalkyl orheterocycle group is optionally further substituted by 1 or 2 oxogroups.
2. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein Y is O or NR.sup.Y3.
3. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein U is N or CR.sup.U.
4. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein W is N or CR.sup.W.
5. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein X is N or CR.sup.X.
6. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein A, B, D, and E are each independently selectedfrom --C(R.sup.A1)(R.sup.A2)-- or--C(R.sup.A1)(R.sup.A2)--C(R.sup.A1)(R.sup.A2)--.
7. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein A, B, D, and E are each independently selectedfrom --CH.sub.2-- or --CH.sub.2--CH.sub.2--.
8. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein the spiro moiety represented by the below formula:##STR00563## wherein e and f indicate points of attachment to theremainder of the molecule, is selected from: ##STR00564##
9. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein the spiro moiety is represented by the belowformula: ##STR00565## wherein e and f indicate points of attachmentto the remainder of the molecule, is selected from:##STR00566##
10. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein L is selected from --C.sub.1-6 alkylene-optionally substituted with 1, 2, or 3 substituents independentlyselected from halo, CN, OH, C.sub.1-3 alkyl, C.sub.1-3 alkoxy,C.sub.1-3 haloalkyl, C.sub.1-3 haloalkoxy, amino, C.sub.1-3alkylamino, and di(C.sub.1-3 alkyl)amino.
11. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein L is selected from methylene, ethylene, and--CH.sub.2--CH(OH)--.
12. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein L is methylene.
13. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein L is selected from --(C.sub.1-4alkylene).sub.a-Q-(C.sub.1-4 alkylene).sub.b-, wherein anyC.sub.1-4 alkylene group of the --(C.sub.1-4alkylene).sub.a-Q-(C.sub.1-4 alkylene).sub.b- group is optionallysubstituted with 1, 2, or 3 substituents independently selectedfrom halo, CN, OH, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-3haloalkyl, C.sub.1-3 haloalkoxy, amino, C.sub.1-3 alkylamino, anddi(C.sub.1-3 alkyl)amino.
14. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein L is selected from --C(O)--CH.sub.2--,--C(O)--CH.sub.2--CH.sub.2--, C(O), --NH--CH.sub.2--, NH,--C(O)--CH(NH.sub.2)--, --NH--CH(CH.sub.3)--,--N(CH.sub.3)--C(O)--, N(CH.sub.3)--CH.sub.2--,--CH.sub.2--CH.sub.2--O--, and --C(O)--NH--.
15. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein Cy is a linking phenyl, C.sub.3-18 cycloalkyl,5-10 membered heteroaryl, or 4-9 membered heterocycle group, eachof which is optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R.sup.Cy, wherein the heteroaryl orheterocycle has 1 or 2 rings and 1-3 heteroatoms independentlyselected from nitrogen, sulfur, and oxygen.
16. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein Cy is a linking group having the formula:##STR00567## ##STR00568## each of which is optionally substitutedwith 1, 2, 3, or 4 substituents independently selected fromR.sup.Cy.
17. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein Cy is a linking group having the formula:##STR00569##
18. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein Z is Cy.sup.2 or C(O)NR.sup.c3R.sup.d3.
19. The compound of claim 1, or a pharmaceutically acceptable saltthereof, having Formula IIa, IIb, IIIa, or IIIb: ##STR00570##
20. The compound of claim 1, or a pharmaceutically acceptable saltthereof, having Formula IVa, IVb, IVc, IVd, IVe, or IVf:##STR00571## ##STR00572##
21. The compound of claim 1, wherein the compound is selected from:5-fluoro-N,N-diisopropyl-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol--5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide;N-ethyl-5-fluoro-N-isopropyl-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imid-azol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)benzami-de;5-fluoro-2-((4-(7-((1-(2-hydroxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]im-idazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-N,N--diisopropylbenzamide;N-ethyl-5-fluoro-2-((4-(7-((1-(2-hydroxyethyl)-2-oxo-2,3-dihydro-1H-benzo-[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)--N-isopropylbenzamide;5-fluoro-N-(2-hydroxyethyl)-N-isopropyl-2-((4-(7-((2-oxo-2,3-dihydro-1H-b-enzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)-oxy)benzamide;5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide;5-fluoro-N,N-diisopropyl-2-((4-(7-(((1s,4s)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide;5-((7-(5-(2-(amino(cyclopentyl)methyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,-7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one;5-((7-(5-(2-(cyclopentyl(dimethylamino)methyl)-4-fluorophenoxy)pyrimidin--4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazo-l-2-one;N-(cyclopentyl(5-fluoro-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]i-midazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)phen-yl)methyl)acetamide;6-((7-(5-(4-fluoro-2-(1-hydroxy-2-methylpropyl)phenoxy)pyrimidin-4-yl)-2,-7-diazaspiro[4.4]nonan-2-yl)methyl)-3,3-dimethylindolin-2-one;6-((7-(5-(4-fluoro-2-isobutyrylphenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4-]nonan-2-yl)methyl)-3-methyl-2-oxoindoline-3-carbonitrile;5-fluoro-2-((4-(6-(3-(4-fluorophenyl)propanoyl)-2,6-diazaspiro[3.4]octan-2-yl)pyrimidin-5-yl)oxy)-N,N-diisopropylbenzamide;5-((7-(5-(4-fluoro-2-(1-isopropyl-1H-pyrazol-5-yl)phenoxy)pyrimidin-4-yl)--3-oxo-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one-;N-(4-fluoro-2-(5-isopropyl-3-methylisoxazol-4-yl)phenyl)-4-(6-((tetrahyd-ro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-amine;4-(5-fluoro-2-((4-(6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.-3]heptan-2-yl)pyrimidin-5-yl)oxy)phenyl)-5-isopropyl-3-methylisoxazole;N-(5-fluoro-2'-isopropyl-[1,1'-biphenyl]-2-yl)-4-(6-((tetrahydro-2H-pyran--4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-amine;5-fluoro-2-((4-(2-(2-hydroxy-2-methylpropyl)-2,7-diazaspiro[3.5]nonan-7-y-l)pyrimidin-5-yl)amino)-N,N-diisopropylbenzamide;5-((7-(5-(2-(dimethylphosphoryl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diaz-aspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one;2-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-N-(4--fluorobenzyl)-5-oxa-2-azaspiro[3.4]octan-7-amine;4-(((2-(5-((5-fluoro-2'-isopropyl-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl-)-5-oxa-2-azaspiro[3.4]octan-7-yl)amino)methyl)benzonitrile;7-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-N-(4--fluorobenzyl)-1-oxa-7-azaspiro[4.4]nonan-3-amine;5-fluoro-N-isopropyl-N-methyl-2-((4-(7-(((1r,4r)-4-(methylcarbamoyl)cyclo-hexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide;2-((4-(7-amino-7-(4-cyanobenzyl)-2-azaspiro[4.4]nonan-2-yl)pyrimidin-5-yl-)oxy)-5-fluoro-N,N-diisopropylbenzamide;5-fluoro-2-((4-(7-hydroxy-8-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-methyl)-2-azaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-N,N-diisopropylbenza-mide;2-((4-(7-amino-8-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl-)-2-azaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbe-nzamide;5-fluoro-2-((4-(8-(4-fluorobenzyl)-7-(2-hydroxyethyl)-2,7-diazasp-iro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-N,N-diisopropylbenzamide;6-((7-(5-(2-chloro-4-fluorophenoxy)pyrimidin-4-yl)-2-azaspiro[4.4]nonan-2--yl)methyl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one;5-((7-(3-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyridin-4-yl)-2,7--diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one;5-((7-(5-(2-(3-cyclopropyl-1-methyl-6-oxo-1,6-dihydropyridin-2-yl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4-]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one;N-(5-fluoro-2'-isopropyl-[1,1'-biphenyl]-2-yl)-4-(6-((tetrahydro-2H-pyran--4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-amine;2-(5-((4',5-difluoro-2'-(2-fluoropropan-2-yl)-[1,1'-biphenyl]-2-yl)oxy)py-rimidin-4-yl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]hept-ane;5-fluoro-N-isopropyl-2-((4-(6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6--diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)benzenesulfonamide;5-((7-(5-(4-fluoro-2-(2-methoxybutan-2-yl)phenoxy)pyrimidin-4-yl)-2,7-dia-zaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one;5-((7-(5-(4-fluoro-2-(3-hydroxypentan-3-yl)phenoxy)pyrimidin-4-yl)-2,7-di-azaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one;2-(5-fluoro-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)--2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)phenyl)-N-methylcyclopro-pane carboxamide;5-((7-(5-(4-fluoro-2-(3-hydroxy-3-methylbutyl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol--2(3H)-one; methyl2-(5-fluoro-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)--2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)phenyl)cyclopropanecarbo-xylate;2-(5-fluoro-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)phenyl)-N-methylc-yclopropane carboxamide;6-((2-(5-(2-chloro-4-fluorophenoxy)pyrimidin-4-yl)-2,6-diazaspiro[3.4]oct-an-6-yl)methyl)-3,3-dimethylindolin-2-one;2-(6-(5-(2-chloro-4-fluorophenoxy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]hept-ane-2-carbonyl)-2,3-dihydro-1H-indene-5-sulfonamide;5-((7-(5-((5-fluoro-2'-isopropyl-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol--2(3H)-one;5-((7-(5-((5-fluoro-2'-isopropyl-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)--2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one;2-cyclopropyl-5'-fluoro-2'-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol--5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-[1,1'-biph-enyl]-4-carbonitrile;2-cyclopropyl-5'-fluoro-2'-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol--5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-[1,1'-biph-enyl]-4-carboxamide;2-cyclopropyl-5'-fluoro-2'-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol--5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-[1,1'-biph-enyl]-4-carboxylic acid;2-cyclopropyl-5'-fluoro-N,N-dimethyl-2'-((4-(7-((2-oxo-2,3-dihydro-1H-ben-zo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)ox-y)-[1,1'-biphenyl]-4-carboxamide;5-((7-(2-chloro-5-(4-fluoro-2-(1-isopropyl-1H-pyrazol-5-yl)phenoxy)pyrimi-din-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imi-dazol-2-one;5-((7-(5-((4,5-difluoro-2'-isopropyl-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4--yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one;5'-fluoro-2-methyl-2'-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl-)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-[1,1'-biphenyl]--4-carbonitrile;5-((7-(5-((2'-cyclopropyl-5-fluoro-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-y-l)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one;5-((7-(5-((5-fluoro-2'-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)oxy)pyrimid-in-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-o-ne;5'-fluoro-2,6-dimethyl-2'-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidaz-ol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-[1,1'-bi-phenyl]-4-carbonitrile;2-cyclopropyl-3',5'-difluoro-2'-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imi-dazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-[1,1'--biphenyl]-4-carbonitrile;5-((7-(5-(4-fluoro-2-(2-isopropyl-1H-imidazol-1-yl)phenoxy)pyrimidin-4-yl-)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one;5-((7-(5-(2-(cyclopropylmethoxy)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diaz-aspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one;ethyl2-(7-(5-((4'-cyano-2'-cyclopropyl-5-fluoro-[1,1'-biphenyl]-2-yl)oxy)pyrim-idin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)thiazole-4-carboxylate;2-(7-(5-((4'-cyano-2'-cyclopropyl-5-fluoro-[1,1'-biphenyl]-2-yl)oxy)pyrim-idin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)thiazole-4-carboxylicacid;2-(7-(5-((4'-cyano-2'-cyclopropyl-5-fluoro-[1,1'-biphenyl]-2-yl)oxy)pyrim-idin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)-N-methylthiazole-4-carboxamide;2-(7-(5-((4'-cyano-2'-cyclopropyl-5-fluoro-[1,1'-biphenyl]-2-yl)oxy)pyrim-idin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)-N,N-dimethylthiazole-4-carboxami-de;7-benzyl-2-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin--4-yl)-2-azaspiro[4.4]nonane;5-((7-(5-((5-fluoro-2'-(1-hydroxyethyl)-[1,1'-biphenyl]-2-yl)oxy)pyrimidi-n-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-on-e;5-fluoro-N-isopropyl-N-methyl-2-((4-(7-(3-(2-oxooxazolidin-3-yl)benzyl)--2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide;5-fluoro-N-isopropyl-N-methyl-2-((4-(7-(4-(2-oxooxazolidin-3-yl)benzyl)-2-,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide;5-((7-(5-((5-fluoro-2'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-2-yl)oxy)py-rimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol-2(-3H)-one; 2-(1,4-dioxaspiro[40.5]decan-8-ylmethyl)-6-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane;4-((6-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-2-,6-diazaspiro [3.3]heptan-2-yl) methyl)cyclohexanol;2-cyclopropyl-5'-fluoro-2'-((4-(6-((4-hydroxycyclohexyl)methyl)-2,6-diaza-spiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)-[1,1'-biphenyl]-4-carbonitrile;2-(5-((5-fluoro-2'-(1-methoxyethyl)-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4--yl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane;5-(5-fluoro-2-((4-(6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[30.3]heptan-2-yl)pyrimidin-5-yl)oxy)phenyl)-2,3-dihydro-1H-inden-2-amine;5-((7-(5-((5-fluoro-2'-(1-hydroxypropan-2-yl)-[1,1'-biphenyl]-2-yl)oxy)py-rimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol-2(-3H)-one;5-((7-(5-(4-fluoro-2-(morpholinomethyl)phenoxy)pyrimidin-4-yl)-2,-7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one;1-(7-(5-((2'-ethyl-5-fluoro-[1,1'-biphenyl]-2-yl)amino)pyrimidin-4-yl)-2,-7-diazaspiro[3 0.5]nonan-2-yl)-2-methylpropan-2-ol;1-((6-(5-(4-fluoro-2-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)phe-noxy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)cyclohexan-1-ol-;N-(2-amino-2-oxoethyl)-N-(5-fluoro-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo-[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-phenyl)isobutyramide; N-(5-fluoro-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[30.5]nonan-2-yl)pyrimidin-5-yl)oxy)phenyl)propane-2-sulfonamide;tert-butyl7-(5-(4-fluoro-2-(N-methylisobutyramido)phenoxy)pyrimidin-4-yl)-2,7-diaza-spiro[4.4]nonane-2-carboxylate;N-(5-fluoro-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)--2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)phenyl)-N-methylisobutyr-amide;5-((7-(5-(4-fluoro-2-isobutylphenoxy)pyrimidin-4-yl)-2,7-diazaspiro-[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one;2-(3-((2'-ethyl-5-fluoro-[1,1'-biphenyl]-2-yl)methyl)pyridin-4-yl)-6-((te-trahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane;N-((1r,4r)-4-((2-(5-(2-(3-cyclopropyl-1-methyl-6-oxo-1,6-dihydropyridin-2--yl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)-cyclohexyl)-2,2,2-trifluoroacetamide;N-(4-((2-(5-(2-(3-cyclopropyl-1-methyl-6-oxo-1,6-dihydropyridin-2-yl)-4-f-luorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)cyclohex-yl)methanesulfonamide; 5-((7-(5-(2-(3-cyclopropyl-1-methyl-6-oxo-1,6-dihydropyridin-2-yl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4-]nonan-2-yl)methyl)-1-(2-hydroxyethyl)-1H-benzo[d]imidazol-2(3H)-one;(1r,4r)-4-(2-(6-(5-(2-(2-cyclopropylpyridin-3-yl)-4-fluorophenoxy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)cyclohexan-1-amine;tert-butyl((1r,4r)-4-(((2-(5-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenoxy)pyrimi-din-4-yl)-2-azaspiro[3.3]heptan-6-yl)amino)methyl)cyclohexyl)carbamate;tert-butyl((1r,4r)-4-((2-(5-(2-(N-ethylisobutyramido)-4-fluorophenoxy)pyrimidin-4-y-l)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)cyclohexyl) carbamate;methyl((1r,4r)-4-((2-(5-(2-(N-ethylisobutyramido)-4-fluorophenoxy)pyrimidin-4-y-l)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)cyclohexyl)carbamate;N-ethyl-N-(5-fluoro-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohexyl)me-thyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)phenyl)isobutyramide;2-((4-(6-(2-((1r,4r)-4-(3,3-dimethylbutanamido)cyclohexyl)ethyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-y-l)oxy)-5-fluoro-N,N-diisopropyl benzamide; tert-butyl((1r,4r)-4-(2-(6-(5-(2-(2-cyclopropylpyridin-3-yl)-4-fluorophenoxy)pyrimi-din-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)cyclohexyl)carbamate;5-fluoro-2-((4-(7-(2-hydroxy-2-methylpropyl)-2,7-diazaspiro[3.5]nonan-2-y-l)pyrimidin-5-yl)oxy)-N,N-diisopropylbenzamide;2-((4-(7-((3-cyano-3-methyl-2-oxoindolin-6-yl)methyl)-2,7-diazaspiro[4.4]-nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide;methylethyl(5-fluoro-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)meth-yl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)phenyl)carbamate;5-fluoro-2-((4-(7-((1-(2-hydroxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imida-zol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-N-isopr-opyl-N-methylbenzamide;5-fluoro-N-isopropyl-N-methyl-2-((4-(6-((tetrahydro-2H-pyran-4-yl)amino)--2-azaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)benzamide;5-fluoro-N-isopropyl-N-methyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyc-lohexyl) methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide; tert-butyl((1r,4r)-4-((2-(5-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenoxy)pyrimid-in-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)cyclohexyl)carbamate;methyl((1r,4r)-4-((2-(5-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenoxy)pyrimid-in-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)cyclohexyl)carbamate;N-(tert-butyl)-2-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimi-din-4-yl)-2-azaspiro[3.4]octan-6-amine;2-((4-(7-(((1r,4r)-4-(3,3-dimethylureido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide;5-fluoro-2-((4-(7-((4-hydroxycyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan--2-yl)pyrimidin-5-yl)oxy)-N,N-diisopropylbenzamide;5-fluoro-2-((4-(6-((4-hydroxycyclohexyl)methyl)-2,6-diazaspiro[3.4]octan--2-yl)pyrimidin-5-yl)oxy)-N,N-diisopropylbenzamide;2-((4-(7-((1,4-dioxaspiro[4.5]decan-8-yl)methyl)-2,7-diazaspiro[3.5]nonan--2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide;5-fluoro-N,N-diisopropyl-2-((4-(7-((tetrahydro-2H-pyran-4-yl)methyl)-2,7--diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide;5-fluoro-N,N-diisopropyl-2-((4-(6-neopentyl-2,6-diazaspiro[3.4]octan-2-yl-)pyrimidin-5-yl)oxy)benzamide;2-((4-(6-(cyclopropylmethyl)-2,6-diazaspiro[3.4]octan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide;2-((4-(6-(6-cyano-1,2,3,4-tetrahydronaphthalen-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)pyrimidin-5-yl)oxy)-5-fluo-ro-N,N-diisopropyl benzamide;5-fluoro-N,N-diisopropyl-2-((4-(6-(2-((1r,4r)-4-pivalamidocyclohexyl)ethy-l)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)benzamide;N-(2-((4-(6-(cyclohexylmethyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro phenyl)-N-ethylisobutyramide;N-ethyl-5-fluoro-N-isopropyl-2-((4-(7-((1-methyl-2-oxo-2,3-dihydro-1H-ben-zo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)ox-y)benzamide;2-(5-(2-(cyclopentyloxy)-4-fluorophenoxy)pyrimidin-4-yl)-7-((tetrahydro-2-
H-pyran-4-yl) methyl)-2,7-diazaspiro[4.4]nonane;2-(5-(2-cyclopropoxy-4-fluorophenoxy)pyrimidin-4-yl)-7-((tetrahydro-2H-pyran-4-yl)methyl)-2,7-diazaspiro[4.4]nonane;N-ethyl-N-(5-fluoro-2-((4-(7-((tetrahydro-2H-pyran-4-yl)methyl)-2,7-diaza-spiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)phenyl)isobutyramide;5-fluoro-N,N-diisopropyl-2-((4-(6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6--diazaspiro[3.4]octan-2-yl)pyrimidin-5-yl)oxy)benzamide;5-fluoro-N,N-diisopropyl-2-((4-(6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6--diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)benzamide;2-((4-(6-(2-(4-cyanophenyl)acetyl)-2,6-diazaspiro[3.4]octan-2-yl)pyrimidi-n-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide;5-fluoro-2-((4-(6-(6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2,6-diazas-piro[3.4]octan-2-yl)pyrimidin-5-yl)oxy)-N,N-diisopropylbenzamide;tert-butyl((1r,4r)-4-(2-(6-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4--yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)cyclohexyl)carbamate;2-((4-(6-(2-(4-cyanophenyl)acetyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimid-in-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide;N-ethyl-N-(5-fluoro-2-((4-(6-(5-(methylsulfonyl)-2,3-dihydro-1H-indene-2--carbonyl)-2,6diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)phenyl)isobutyr-amide;3-(((2-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin--4-yl)-2-azaspiro[3.3]heptan-6-yl)amino)methyl)bicyclo[1.1.1]pentane-1-carb-onitrile;N-ethyl-N-(5-fluoro-2-((4-(6-(2-(4-(methylsulfonyl)phenyl)acetyl-)-2,6-diazaspiro[3.3]heptan-2-yl) pyrimidin-5-yl)oxy)phenyl)isobutyramide;N-(2-((4-(6-(5-bromo-2,3-dihydro-1H-indene-2-carbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)-5-fluorophenyl)-N-ethylisobutyramide-;N-ethyl-N-(5-fluoro-2-((4-(6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diaz-aspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy) phenyl)isobutyramide;N-cyclopropyl-5-fluoro-N-isopropyl-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[-d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)b-enzamide;2-((4-(7-((1-(2-acetamidoethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imi-dazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-flu-oro-N-isopropyl-N-methylbenzamide;2-((4-(7-((1-(2-(dimethylamino)ethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidaz-ol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro--N-isopropyl-N-methylbenzamide;2-((4-(7-((3-cyano-3-methyl-2-oxoindolin-6-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropyl-N-methylbenzamid-e;5-((7-(5-(4-fluoro-2-(1-isopropyl-1H-pyrazol-5-yl)phenoxy)-2-methylpyri-midin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]i-midazol-2-one;2-((4-(2-(2-(4-cyanophenyl)acetyl)-2,6-diazaspiro[3.4]octan-6-yl)pyrimidi-n-5-yl)oxy)-5-fluoro-N-isopropyl-N-methylbenzamide;2-((4-(7-((1-ethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7--diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropyl-N-meth-ylbenzamide;5-fluoro-N-isopropyl-2-((4-(7-((1-(2-methoxyethyl)-2-oxo-2,3-dihydro-1H-b-enzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)-oxy)-N-methyl benzamide;4-(2-(6-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)--2,6-diazaspiro[3.4]octan-2-yl)-2-oxoethyl)benzonitrile;5-((7-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-2-,7-diazaspiro[4.4]nonan-2-yl)methyl)-1-(2-methoxyethyl)-1,3-dihydro-2H-ben-zo[d]imidazol-2-one;1-(6-(5-(4-fluoro-2-(4-isopropylpyrimidin-4-yl)-2,6-diazaspiro[3.3]heptan--2-yl)-2-(6-methoxypyridin-3-yl)ethan-1-one;6-(2-(6-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)--2,6-diazaspiro[3.3]heptan-2-yl)-2-oxoethyl)-3,3-dimethylindolin-2-one;tert-butyl((1r,4r)-4-(2-(6-(5-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenoxy)pyrim-idin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)cyclohexyl)carbamate;5-((7-(5-(4-fluoro-2-((isopropyl(methyl)amino)methyl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl-)-1,3-dihydro-2H-benzo[d]imidazol-2-one;N-ethyl-N-(5-fluoro-2-((4-(6-isobutyl-2,6-diazaspiro[3.4]octan-2-yl)pyrimidin-5-yl)oxy)phenyl)isobutyramide;N-(2-((4-(6-((4,4-difluorocyclohexyl)methyl)-2,6-diazaspiro[3.4]octan-2-y-l)pyrimidin-5-yl)oxy)-5-fluorophenyl)-N-ethylisobutyramide;tert-butyl ((1r,4r)-4-(2-(6-(5-(4-fluoro-2-(N-methylisobutyramido)phenoxy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethyl) cyclohexyl)carbamate;2-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-7-(6--fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-5-oxa-2-azaspiro[3.4]octane;4-(((2-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)--2-azaspiro[3.3]heptan-6-yl)amino)methyl)-1-methylcyclohexane-1-carbonitril-e;4-(1-((2-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4--yl)-2-azaspiro[3.3]heptan-6-yl)amino)ethyl)benzonitrile;5-fluoro-N-isopropyl-N-methyl-2-((4-(7-(4-(2-oxooxazolidin-3-yl)benzyl)-2-,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide;N-((1r,4r)-4-(2-(6-(5-((4'-cyano-2'-cyclopropyl-5-fluoro-[1,1'-biphenyl]--2-yl)oxy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)cyclohexyl)a-cetamide; methyl(5-fluoro-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2-,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)phenyl)(isopropyl)carbamat-e;2-((4-(7-((1H-indazol-6-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimi-din-5-yl)oxy)-5-fluoro-N-isopropyl-N-methylbenzamide;2-((4-(7-((3-cyano-1H-indazol-6-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)-pyrimidin-5-yl)oxy)-5-fluoro-N-isopropyl-N-methylbenzamide;tert-butyl((1r,4r)-4-((7-(5-(2-(cyclopentyloxy)-4-fluorophenoxy)pyrimidin-4-yl)-2,7--diazaspiro[4.4]nonan-2-yl)methyl)cyclohexyl)carbamate;4-((2-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-2--azaspiro[3.3]heptan-6-yl)amino)-1-methylcyclohexanecarbonitrile;4-(2-(2-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)--2,6-diazaspiro[3.4]octan-6-yl)-2-oxoethyl)benzonitrile;5-((7-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-2-,7-diazaspiro[4.4]nonan-2-yl)methyl)-1-methyl-1,3-dihydro-2H-benzo[d]imida-zol-2-one;2-cyclopropyl-5'-fluoro-2'-((4-(6-((4-hydroxycyclohexyl)methyl)--2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)-[1,1'-biphenyl]-4-carbonitrile;4-(((2-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)--2-azaspiro[3.3]heptan-6-yl)amino)methyl)benzonitrile;5-((7-(5-(2-(2,5-dimethylpyrrolidine-1-carbonyl)-4-fluorophenoxy)pyrimidi-n-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imida-zol-2-one;5-((7-(5-(4-fluoro-2-(pyrrolidine-1-carbonyl)phenoxy)pyrimidin--4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one;5-((7-(5-(4-fluoro-2-(morpholine-4-carbonyl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one;N-ethyl-N-(5-fluoro-2-((4-(6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diaza-spiro[3.4]octan-2-yl)pyrimidin-5-yl)oxy)phenyl)isobutyramide;7-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-N-(4--fluorobenzyl)-1-oxa-7-azaspiro[4.4]nonan-3-amine;N-(2-((4-(6-(cyclohexylmethyl)-2,6-diazaspiro[3.4]octan-2-yl)pyrimidin-5--yl)oxy)-5-fluorophenyl)-N-ethylisobutyramide;N-benzyl-2-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4--yl)-5-oxa-2-azaspiro[3.4]octan-7-amine;5-((7-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-2-,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one-;5-((7-(5-((5-fluoro-2'-(prop-1-en-2-yl)-[1,1'-biphenyl]-2-yl)oxy)pyrimid-in-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imid-azol-2-one;2-(5-(4-fluoro-2-(2-isopropoxypyridin-3-yl)phenoxy)pyrimidin-4-yl)-6-((te-trahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane;5-fluoro-N-isopropyl-N-methyl-2-((4-(7-((1-methyl-2-oxo-2,3-dihydro-1H-be-nzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)o-xy)benzamide; ethyl(5-fluoro-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2-,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)phenyl)(methyl)carbamate;N-cyclopropyl-5-fluoro-N-methyl-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]i-midazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)benz-amide;5-fluoro-N-methyl-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol--5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-N-phenylben-zamide;2-((4-(6-(cyclohexylmethyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimid-in-5-yl)oxy)-5-fluoro-N-isopropyl-N-methylbenzamide;2-(5-(2-(cyclopentyloxy)-4-fluorophenoxy)pyrimidin-4-yl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]h-eptane;2-cyclopropyl-5'-fluoro-2'-((4-(7-((2-oxo-2,3-dihydrobenzo[d]oxazo-l-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-[1,1'-bip-henyl]-4-carbonitrile; methyl(3-((7-(5-((4'-cyano-2'-cyclopropyl-5-fluoro-[1,1'-biphenyl]-2-yl)oxy)pyr-imidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)phenyl)carbamate;2'-((4-(7-((1H-benzo[d][1,2,3]triazol-6-yl)methyl)-2,7-diazaspiro[4.4]non-an-2-yl)pyrimidin-5-yl)oxy)-2-cyclopropyl-5'-fluoro-[1,1'-biphenyl]-4-carb-onitrile;N-(2-chloro-4-((7-(5-((4'-cyano-2'-cyclopropyl-5-fluoro-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methy-l)phenyl)acetamide; N,N-diethyl-5-fluoro-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)meth-yl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide;5-fluoro-N-isopropyl-N-methyl-2-((4-(7-((2-oxo-2,3-dihydrobenzo[d]oxazol--5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide;N-(tert-butyl)-5-fluoro-N-methyl-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]-imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)ben-zamide;1-(7-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4--yl)-2,7-diazaspiro[4.4]nonan-2-yl)-2-methylpropan-2-ol;2-(5-(2-(2-cyclopropylpyridin-3-yl)-4-fluorophenoxy)pyrimidin-4-yl)-6-((t-etrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane;6-((7-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-2-,7-diazaspiro[4.4]nonan-2-yl)methyl)-3,3-dimethylindolin-2-one;6-((7-(5-(2-(2-cyclopropylpyridin-3-yl)-4-fluorophenoxy)pyrimidin-4-yl)-2-,7-diazaspiro[4.4]nonan-2-yl)methyl)-3,3-dimethylindolin-2-one;5-((7-(5-(2-(2-cyclopropylpyridin-3-yl)-4-fluorophenoxy)pyrimidin-4-yl)-2-,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one-;4-(((2-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)--5-oxa-2-azaspiro[3 0.4]octan-7-yl)(methyl)amino)methyl)benzonitrile;6-((7-(5-(4-fluoro-2-(2,2,2-trifluoroethoxy)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-3,3-dimethy-lindolin-2-one;5-fluoro-N-isopropyl-N-methyl-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imi-dazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)benzam-ide;N-(cyclohexylmethyl)-2-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phen-oxy)pyrimidin-4-yl)-5-oxa-2-azaspiro[3.4]octan-7-amine;N-(5-fluoro-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)--2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)phenyl)-N-(2-hydroxyethy-l)isobutyramide;N-ethyl-N-(5-fluoro-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl-)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)phenyl)isobutyra-mide;N-(5-fluoro-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)me-thyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)phenyl)-N-(2,2,2-tr-ifluoroethyl)isobutyramide;N-((1r,4r)-4-((7-(5-((4'-cyano-2'-cyclopropyl-5-fluoro-[1,1'-biphenyl]-2--yl)oxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)cyclohexyl)ace-tamide; tert-butyl((1r,4r)-4-(2-(6-(5-((4'-cyano-2'-cyclopropyl-5-fluoro-[1,1'-biphenyl]-2--yl)oxy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)cyclohexyl)car-bamate;5-((7-(5-(4-fluoro-2-(5-isopropylthiazol-4-yl)phenoxy)pyrimidin-4--yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol--2-one;N-((1s,4s)-4-((7-(5-((4'-cyano-2'-cyclopropyl-5-fluoro-[1,1'-biphen-yl]-2-yl)oxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)cyclohex-yl)acetamide;2-cyclopropyl-2'-((4-(7-((1-ethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5--yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5'-fluoro-[1-,1'-biphenyl]-4-carbonitrile;3-((7-(5-(2-(cyclopentyloxy)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspi-ro[4.4]nonan-2-yl)methyl)-1H-indole-6-carbonitrile;6-((7-(5-(2-(cyclopentyloxy)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspi-ro[4.4]nonan-2-yl)methyl)-3,3-dimethylindolin-2-one;2-((4-(7-((6-cyano-1H-indol-3-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)py-rimidin-5-yl)oxy)-5-fluoro-N-isopropyl-N-methylbenzamide;2-cyclopropyl-5'-fluoro-2'-((4-(7-(4-(2-oxopyrrolidin-1-yl)benzyl)-2,7-di-azaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-[1,1'-biphenyl]-4-carbonitril-e;2-cyclopropyl-5'-fluoro-2'-((4-(7-((2-oxoindolin-6-yl)methyl)-2,7-diaza-spiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-[1,1'-biphenyl]-4-carbonitrile;6-((7-(5-(4-fluoro-2-(1-isopropyl-1H-pyrazol-5-yl)phenoxy)pyrimidin-4-yl)--2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d][1,2,3]triazole;2-cyclopropyl-3',5'-difluoro-2'-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imi-dazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-[1,1'--biphenyl]-4-carbonitrile;3-((7-(5-(2-(cyclopropylmethoxy)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diaz-aspiro[4.4]nonan-2-yl)methyl)-1H-indole-6-carboxamide;3-((7-(5-(2-(cyclopropylmethoxy)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diaz-aspiro[4.4]nonan-2-yl)methyl)-1H-indole-6-carbonitrile;2-((4-(7-((3,3-dimethyl-2-oxoindolin-6-yl)methyl)-2,7-diazaspiro[4.4]nona-n-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropyl-N-methylbenzamide;2'-((4-(6-(4-cyanophenethyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-y-l)oxy)-2-cyclopropyl-5'-fluoro-[1,1'-biphenyl]-4-carbonitrile;2-cyclopropyl-5'-fluoro-2'-((4-(7-((2-oxoindolin-5-yl)methyl)-2,7-diazasp-iro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-[1,1'-biphenyl]-4-carbonitrile;2-cyclopropyl-2'-((4-(7-((3,3-dimethyl-2-oxoindolin-6-yl)methyl)-2,7-diaz-aspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5'-fluoro-[1,1'-biphenyl]-4-carb-onitrile;2-amino-2-cyclohexyl-1-(7-(5-(4-fluoro-2-(1-isopropyl-1H-pyrazol--5-yl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)ethanone;methyl(5-fluoro-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)me-thyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)phenyl)(methyl)carb-amate; 5-((7-(5-(2-(benzyloxy)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one;5-((7-(5-(4-fluoro-2-methoxyphenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]no-nan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one;5-fluoro-N-isopropyl-N-methyl-2-((4-(7-((3-oxo-3,4-dihydro-2H-benzo[b][1,-4]oxazin-6-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)ben-zamide;5-((7-(5-(4-fluoro-2-(2-methylpyrrolidine-1-carbonyl)phenoxy)pyrim-idin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one;5-((7-(5-(2-((1s,4s)-7-azabicyclo[2.2.1]heptane-7-carbonyl)-4-fluoropheno-xy) pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one;5-((7-(5-((2'-(1,1-difluoroethyl)-5-fluoro-[1,1'-biphenyl]-2-yl)oxy)pyrim-idin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]im-idazol-2-one;2-cyclopropyl-5'-fluoro-2'-((4-(6-((4-hydroxytetrahydro-2H-pyran-4-yl)met-hyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)-[1,1'-biphenyl]-4--carbonitrile;2-cyclopropyl-5'-fluoro-2'-((4-(6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6--diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)-[1,1'-biphenyl]-4-carbonit-rile;5-fluoro-N-isopropyl-N-methyl-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[-d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)b-enzamide;5-((7-(5-(4-fluoro-2-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol--5-yl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-di-
hydro-2H-benzo[d]imidazol-2-one;5-((7-(5-(4-fluoro-2-(2-isopropyl-5-oxopyrrolidin-1-yl)phenoxy)pyrimidin--4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazo-l-2-one;(1r,4r)-4-((7-(5-((5-fluoro-2'-isopropyl-[1,1'-biphenyl]-2-yl)oxy-)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)cyclohexan-1-amine;tert-butyl((1r,4r)-4-((7-(5-((5-fluoro-2'-isopropyl-[1,1'-biphenyl]-2-yl)oxy)pyrimi-din-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)cyclohexyl)carbamate;N-(4-((7-(5-((5-fluoro-2'-isopropyl-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4--yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)phenyl)acetamide;5-fluoro-N-isopropyl-N-methyl-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imi-dazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)benzen-esulfonamide; ethyl5'-fluoro-2'-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)--2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-[1,1'-biphenyl]-2-carbox-ylate;5-((7-(5-(4-fluoro-2-(4-isopropylthiazol-5-yl)phenoxy)pyrimidin-4-y-l)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2--one;5-fluoro-N-isopropyl-N-methyl-2-((4-(6-((tetrahydro-2H-pyran-4-yl)me-thyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)benzamide;5'-fluoro-2-methyl-2'-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl-)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-[1,1'-biphenyl]--4-carbonitrile;4-(2-(6-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)--2,6-diazaspiro[3.3]heptan-2-yl)-2-oxoethyl)benzonitrile;4-(2-(6-(5-((5-fluoro-2'-isopropyl-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-y-l)-2,6-diazaspiro[3.3]heptan-2-yl)-2-oxoethyl)benzonitrile;1-(6-(5-((5-fluoro-2'-isopropyl-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)--2,6-diazaspiro[3.3]heptan-2-yl)-2-(4-(methylsulfonyl)phenyl)ethan-1-one;5'-fluoro-2-methyl-2'-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl-)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-[1,1'-biphenyl]--3-carbonitrile;2-((3,3-difluorocyclohexyl)methyl)-6-(5-(4-fluoro-2-(1-isopropyl-1H-pyraz-ol-5-yl)phenoxy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane;2-((3,3-difluorocyclohexyl)methyl)-6-(5-(4-fluoro-2-(4-isopropylpyrimidin--5-yl)phenoxy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane;4-(((2-(5-(4-fluoro-2-(1-isopropyl-1H-pyrazol-5-yl)phenoxy)pyrimidin-4-yl-)-5-oxa-2-azaspiro[3.4]octan-7-yl)amino)methyl)benzonitrile;5-((7-(5-(2-(2-ethylpyridin-3-yl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one;5-((7-(5-(4-fluoro-2-isopentylphenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]-nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one;5-((7-(5-(4-fluoro-2-isobutylphenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]n-onan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one;5-((7-(5-(4-fluoro-2-(1-isopropyl-1H-pyrazol-5-yl)phenoxy)pyrimidin-4-yl)--2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-o-ne;2-(5-((5-fluoro-2'-isopropyl-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)--6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane;N-ethyl-5-fluoro-N-isopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cycl-ohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide;5-fluoro-N,N-diisopropyl-2-((4-(6-((tetrahydro-2H-pyran-4-yl)amino)-2-aza-spiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)benzamide;5-fluoro-N,N-diisopropyl-2-((4-(6-(methyl(tetrahydro-2H-pyran-4-yl)amino)--2-azaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)benzamide;tert-butyl((1r,4r)-4-((7-(5-((2-(diisopropylcarbamoyl)-4-fluorophenyl)amino)pyrimid-in-4-yl)-2,7-diazaspiro [3.5]nonan-2-yl)methyl) cyclohexyl)carbamate;1-((6-(5-((5-fluoro-2'-isopropyl-[1,1'-biphenyl]-2-yl)amino)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)cyclohexan-1-ol;5-((7-(5-((5-fluoro-2'-isopropyl-[1,1'-biphenyl]-2-yl)amino)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one;N-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenyl)-4-(6-((tetrahydro-2H-pyr-an-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-amine;N-(5-fluoro-2'-isopropoxy-[1,1'-biphenyl]-2-yl)-4-(2-isobutyl-2,7-diazasp-iro[3.5]nonan-7-yl)pyrimidin-5-amine;N-(5-fluoro-2'-isopropyl-[1,1'-biphenyl]-2-yl)-4-(2-isobutyl-2,7-diazaspi-ro[3.5]nonan-7-yl)pyrimidin-5-amine;N-(2'-ethyl-5-fluoro-[1,1'-biphenyl]-2-yl)-4-(2-isobutyl-2,7-diazaspiro[3-.5]nonan-7-yl)pyrimidin-5-amine;5-fluoro-N,N-diisopropyl-2-((4-(2-(4-(methylsulfonamido)cyclohexyl)-2,7-d-iazaspiro[3.5]nonan-7-yl)pyrimidin-5-yl)amino)benzamide;5-((7-(3-((5-fluoro-2'-isopropyl-[1,1'-biphenyl]-2-yl)oxy)pyridin-4-yl)-2-,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one-;2'-((4-(7-amino-7-benzyl-2-azaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-2--cyclopropyl-5'-fluoro-[1, 1'-biphenyl]-4-carbonitrile; tert-butyl((1r,4r)-4-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-y-l)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)cyclohexyl)carbamate;2-((4-(3-(4-acetamidobenzyl)-2-amino-4-oxo-1,3,7-triazaspiro[4.4]non-1-en--7-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropyl-N-methylbenzamide;andN-ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)-2,7-dia-zaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide;or a pharmaceutically acceptable salt thereof.
22. The compound of claim 1, which is5-fluoro-N,N-diisopropyl-2-((4-(7-(((r,4r)-4-(methylsulfonamido)cyclohexy-l)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamideorN-ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)-2,7-dia-zaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide,or a pharmaceutically acceptable salt thereof.
23. A pharmaceutically acceptable salt of the compound of claim 22,wherein the salt is a bis-methanesulfonic acid salt, abis-hydrochloric acid salt, or a sesquifumaric acid salt.
24. A crystalline form of the salt of claim 23.
25. The crystalline form of claim 24, which is substantiallyanhydrous.
26. The crystalline form of claim 24, which is hydrated orsolvated.
27. The crystalline form of claim 24, which is a monohydrate.
28. A pharmaceutical composition comprising a compound of claim 1,or a pharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable carrier.
Description
TECHNICAL FIELD
The present invention is directed to inhibitors of the interactionof menin with MLL and MLL fusion proteins, pharmaceuticalcompositions containing the same, and their use in the treatment ofcancer and other diseases mediated by the menin-MLLinteraction.
BACKGROUND
The mixed-lineage leukemia (MLL) protein is a histonemethyltransferase that is mutated in clinically and biologicallydistinctive subsets of acute leukemia. Rearranged mixed lineageleukemia (MLL-r) involves recurrent translocations of the 11q23chromosome locus which lead to an aggressive form of acute leukemiawith limited therapeutic options. These translocations target theMLL gene creating an oncogenic fusion protein comprising theamino-terminus of MLL fused in frame with more than 60 differentfusion protein partners. Menin, a ubiquitously expressed, nuclearprotein encoded by the multiple endocrine neoplasia type 1 (MEN1)tumor suppressor gene, has a high affinity binding interaction withMLL fusion proteins and is an essential co-factor of oncogenicMLL-r fusion proteins (Yokoyama et al., 2005, Cell, 123:207-18;Cierpicki & Grembecka, 2014, Future Med. Chem., 6:447-462).Disruption of this interaction leads to selective growth inhibitionand apoptosis of MLL-r leukemia cells both in vitro (Grembecka etal., 2012, Nat. Chem. Biol., 8:277-284) and in vivo (Yokoyama etal., 2005, op. cit.; Borkin et al., 2015, Cancer Cell,27:589-602).
The menin-MLL complex plays a role in castration-resistant/advancedprostate cancer, and a menin-MLL inhibitor has been shown to reducetumor growth in vivo (Malik et al., 2015, Nat. Med., 21:344-352).Additionally, a menin-MLL inhibitor has been shown to enhance human.beta. cell proliferation (Chamberlain et al., 2014, J. Clin.Invest., 124:4093-4101), supporting a role for inhibitors of themenin-MLL interaction in the treatment of diabetes (Yang et al.,2010, Proc Natl Acad Sci USA., 107:20358-20363). The interactionbetween menin and MLL or MLL fusion proteins is an attractivetarget for therapeutic intervention, and there is a need for novelagents that inhibit the menin-MLL interaction for the treatment ofvarious diseases and conditions, including leukemia, other cancersand diabetes.
SUMMARY
The present invention provides inhibitors of the menin-MLLinteraction, such as a compound of Formula I:
##STR00001## or a pharmaceutically acceptable salt thereof, whereinconstituent variables are defined herein.
The present invention further provides a pharmaceutical compositioncomprising a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceuticallyacceptable carrier.
The present invention further provides pharmaceutically acceptablesalt forms of the compounds of Formula I.
The present invention further provides crystalline forms of thecompounds of Formula I.
The present invention further provides a method of inhibiting theinteraction between menin and MLL comprising contacting the meninand MLL with a compound of Formula I, or a pharmaceuticallyacceptable salt thereof.
The present invention further provides a method of treating cancerin a patient comprising administering to the patient atherapeutically effective amount of a compound of Formula I, or apharmaceutically acceptable salt thereof.
The present invention further provides a method of treating insulinresistance, pre-diabetes, diabetes, risk of diabetes, orhyperglycemia in a patient comprising administering to the patienta therapeutically effective amount of a compound of Formula I, or apharmaceutically acceptable salt thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows an XRPD pattern characteristic ofN-ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)-2,7-dia-zaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide.
FIG. 2 shows an XRPD pattern characteristic ofN-ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5--yl)oxy)-5-fluoro-N-isopropylbenzamide sesquifumaric acid salt.
FIG. 3 shows an XRPD pattern characteristic ofN-ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)-2,7-dia-zaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamidebis-methanesulfonic acid salt.
FIG. 4 shows an XRPD pattern characteristic ofN-ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)-2,7-dia-zaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamidebis-hydrochloric acid salt.
FIG. 5 shows an XRPD pattern characteristic of5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide.
FIG. 6 shows an XRPD pattern characteristic of5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidebis-methanesulfonic acid salt.
FIG. 7 shows an XRPD pattern characteristic of5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidesesquifumaric acid salt.
FIG. 8 shows an XRPD pattern characteristic of5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidebis-hydrochloric acid salt.
FIG. 9 shows XRPD pattern characteristics of5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidesesquifumaric acid salt, crystalline Form A, Form B, Form C+Form A,Form D, Form, E, and Form F.
FIG. 10 shows an XRPD pattern characteristic of5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidesesquifumaric acid salt, crystalline Form A.
FIG. 11 shows a DSC thermogram characteristic of5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidesesquifumaric acid salt, crystalline Form A.
FIG. 12 shows a TGA thermogram characteristic of5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidesesquifumaric acid salt, crystalline Form A.
FIG. 13 shows a DVS pattern characteristic of5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidesesquifumaric acid salt, crystalline Form A.
FIG. 14 shows variable temperature (VT)-XRPD patternscharacteristic of5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidesesquifumaric acid salt, crystalline Form A.
FIG. 15 shows an XRPD pattern characteristic of5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidesesquifumaric acid salt, crystalline Form B.
FIG. 16 shows XRPD patterns characteristic of5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidefumaric acid salt, crystalline Form B and Form D isolated from ascale-up preparation as a slurry (top trace; Form B), a wet cakeafter vacuum filtration (middle trace; Form B), and after dryingthe wet cake at 45.degree. C. overnight (bottom trace; Form D).
FIG. 17 shows a DSC thermogram characteristic of5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidesesquifumaric acid salt, crystalline Form D.
FIG. 18 shows a TGA thermogram characteristic of5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidesesquifumaric acid salt, crystalline Form D.
FIG. 19 shows a DSC thermogram characteristic of5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidesesquifumaric acid salt, crystalline Form F.
FIGS. 20-21 show ORTEP representations of5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidebis-methanesulfonic acid salt with 50% probability thermalellipsoids.
FIG. 22 shows an ORTEP representation of5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidesesquifumaric acid salt with 50% probability thermalellipsoids.
FIG. 23 shows an XRPD pattern characteristic of5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidesesquifumaric acid salt, crystalline Form D.
DETAILED DESCRIPTION
The present invention provides inhibitors of the menin-MLLinteraction, such as a compound of Formula I:
##STR00002## or a pharmaceutically acceptable salt thereof,wherein:
A, B, D, and E are each independently selected from--C(R.sup.A1)(R.sup.A2)--,--C(R.sup.A1)(R.sup.A2)--C(R.sup.A1)(R.sup.A2)--,--C(R.sup.A1)(R.sup.A2)--O--, --C(R.sup.A1)(R.sup.A2)--NR.sup.S3--,--C(.dbd.O)--, --C(R.sup.A1)(R.sup.A2)--C(.dbd.O)--, and--N.dbd.C(NH.sub.2)-- wherein no more than one of A, B, D, and E is--C(R.sup.A1)(R.sup.A2)--O--, --C(R.sup.A1)(R.sup.A2)--NR.sup.A3--,--C(R.sup.A1)(R.sup.A2)--C(.dbd.O)--, --C(.dbd.O)--, or--N.dbd.C(NH.sub.2)--;
U is N or CR.sup.U, wherein R.sup.U is H, halo, CN, OH, C.sub.1-4alkyl, C.sub.1-4 alkoxy, amino, C.sub.1-4 alkyl amino, or C.sub.2-8dialkylamino;
W is N or CR.sup.W, wherein R.sup.W is H, halo, CN, OH, C.sub.1-4alkyl, C.sub.1-4 alkoxy, amino, C.sub.1-4 alkyl amino, or C.sub.2-8dialkylamino;
X is N or CR.sup.X, wherein R.sup.X is H, halo, CN, OH, C.sub.1-4alkyl, C.sub.1-4 alkoxy, amino, C.sub.1-4 alkyl amino, or C.sub.2-8dialkylamino, wherein when X is N, the atom of L that is directlybonded with X is other than N, O, or S;
L is selected from --C.sub.1-6 alkylene- and --(C.sub.1-4alkylene).sub.a-Q-(C.sub.1-4 alkylene).sub.b-, wherein theC.sub.1-6 alkylene group and any C.sub.1-4 alkylene group of the--(C.sub.1-4 alkylene).sub.a-Q-(C.sub.1-4 alkylene).sub.b- group isoptionally substituted with 1, 2, or 3 substituents independentlyselected from halo, CN, OH, C.sub.1-3 alkyl, C.sub.1-3 alkoxy,C.sub.1-3 haloalkyl, C.sub.1-3 haloalkoxy, amino, C.sub.1-3alkylamino, and di(C.sub.1-3 alkyl)amino;
Q is --O--, --S--, --S(.dbd.O)--, --S(.dbd.O).sub.2--,--C(.dbd.O)--, --C(.dbd.O)NR.sup.q1--, --C(.dbd.O)O--,--OC(.dbd.O)NR.sup.q1--, --NR.sup.q1--, --NR.sup.q1C(.dbd.O)O--,--NR.sup.q1C(.dbd.O)NR.sup.q1--, --S(.dbd.O).sub.2NR.sup.q1--,--C(.dbd.NR.sup.q2)--, or --C(.dbd.NR.sup.q2)--NR.sup.q1--, whereineach R.sup.q1 is independently selected from H or C.sub.1-6 alkyl,and wherein each R.sup.q2 is independently selected from H,C.sub.1-6 alkyl, and CN;
Cy is a linking C.sub.6-14 aryl, C.sub.3-18 cycloalkyl, 5-16membered heteroaryl, or 4-18 membered heterocycloalkyl group, eachof which is optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R.sup.Cy;
each R.sup.Cy is independently selected from halo, C.sub.1-6 alkyl,C.sub.1-4 haloalkyl, C.sub.1-4 cyanoalkyl, C.sub.2-6 alkenyl,C.sub.2-6 alkynyl, C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO.sub.2,OR.sup.a1, SR.sup.a1, C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1,C(O)OR.sup.a1, OC(O)R.sup.b1, OC(O)NR.sup.c1R.sup.d1,C(.dbd.NR.sup.e1)NR.sup.c1R.sup.d1,NR.sup.c1C(.dbd.NR.sup.e1)NR.sup.c1R.sup.d1, NR.sup.c1R.sup.d1,NR.sup.c1C(O)R.sup.b1, NR.sup.c1C(O)OR.sup.a1,NR.sup.c1C(O)NR.sup.c1R.sup.d1, NR.sup.c1S(O)R.sup.b1,NR.sup.c1S(O).sub.2R.sup.b1, NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1,S(O)R.sup.b1, S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1, andS(O).sub.2NR.sup.c1R.sup.d1, wherein said C.sub.1-6 alkyl,C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.6-10 aryl, C.sub.3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 memberedheterocycloalkyl are each optionally substituted by 1, 2, 3, or 4substituents independently selected from CN, NO.sub.2, OR.sup.a1,SR.sup.a1, C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1,OC(O)R.sup.b1, OC(O)NR.sup.c1R.sup.d1,C(.dbd.NR.sup.e1)NR.sup.c1R.sup.d1,NR.sup.c1C(.dbd.NR.sup.e1)NR.sup.c1R.sup.d1, NR.sup.c1R.sup.d1,NR.sup.c1C(O)R.sup.b1, NR.sup.c1C(O)OR.sup.a1,NR.sup.c1C(O)NR.sup.c1R.sup.d1, NR.sup.c1S(O)R.sup.b1,NR.sup.c1S(O).sub.2R.sup.b1, NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1,S(O)R.sup.b1, S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1, andS(O).sub.2NR.sup.c1R.sup.d1;
R.sup.1 is H, Cy.sup.1, halo, C.sub.1-6 alkyl, C.sub.1-4 haloalkyl,C.sub.1-4 cyanoalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, CN,NO.sub.2, OR.sup.a2, SR.sup.a2, C(O)R.sup.b2,C(O)NR.sup.c2R.sup.d2, C(O)OR.sup.a2, OC(O)R.sup.b2,OC(O)NR.sup.c2R.sup.d2, C(.dbd.NR.sup.e2)NR.sup.c2R.sup.d2,NR.sup.c2C(.dbd.NR.sup.e2)NR.sup.c2R.sup.d2, NR.sup.c2R.sup.d2,NR.sup.c2C(O)R.sup.b2. NR.sup.c2C(O)OR.sup.a2,NR.sup.c2C(O)NR.sup.c2R.sup.d2, NR.sup.c2S(O)R.sup.b2,NR.sup.c2S(O).sub.2R.sup.b2, NR.sup.c2S(O).sub.2NR.sup.c2R.sup.d2,S(O)R.sup.b2, S(O)NR.sup.c2R.sup.d2, S(O).sub.2R.sup.b2 andS(O).sub.2NR.sup.c2R.sup.d2, wherein said C.sub.1-6 alkyl,C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are each optionallysubstituted by 1, 2, 3, or 4 substituents independently selectedfrom halo, CN, NO.sub.2, OR.sup.a2, SR.sup.a2, C(O)R.sup.b2,C(O)NR.sup.c2R.sup.d2, C(O)OR.sup.a2, OC(O)R.sup.b2,OC(O)NR.sup.c2R.sup.d2, C(.dbd.NR.sup.e2)NR.sup.c2R.sup.d2,NR.sup.c2C(.dbd.NR.sup.e2)NR.sup.c2R.sup.d2, NR.sup.c2R.sup.d2,NR.sup.c2C(O)R.sup.b2, NR.sup.c2C(O)OR.sup.a2,NR.sup.c2C(O)NR.sup.c2R.sup.d2, NR.sup.c2S(O)R.sup.b2,NR.sup.c2S(O).sub.2R.sup.b2, NR.sup.c2S(O).sub.2NR.sup.c2R.sup.d2,S(O)R.sup.b2, S(O)NR.sup.c2R.sup.d2, S(O).sub.2R.sup.b2, andS(O).sub.2NR.sup.c2R.sup.d2;
Y is O, S, CR.sup.Y1R.sup.Y2 or NR.sup.Y3, wherein R.sup.Y1,R.sup.Y2, and R.sup.Y3 are each independently selected from H andC.sub.1-4 alkyl;
Z is Cy.sup.2, halo, C.sub.1-6 alkyl, C.sub.1-4 haloalkyl,C.sub.1-4 cyanoalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, CN,NO.sub.2, OR.sup.a3, SR.sup.a3, C(O)R.sup.b3,C(O)NR.sup.c3R.sup.d3, C(O)OR.sup.a3, OC(O)R.sup.b3,OC(O)NR.sup.c3R.sup.d3, C(.dbd.NR.sup.e3)NR.sup.c3R.sup.d3,NR.sup.c3C(.dbd.NR.sup.e3)NR.sup.c3R.sup.d3, NR.sup.c3R.sup.d3,NR.sup.c3C(O)R.sup.b3, NR.sup.c3C(O)OR.sup.a3,NR.sup.c3C(O)NR.sup.c3R.sup.d3, NR.sup.c3S(O)R.sup.b3,NR.sup.c3S(O).sub.2R.sup.b3, NR.sup.c3S(O).sub.2NR.sup.c3R.sup.d3,S(O)R.sup.b3, S(O)NR.sup.c3R.sup.d3, S(O).sub.2R.sup.b3,S(O).sub.2NR.sup.c3R.sup.d3, and P(O)R.sup.c3R.sup.d3 wherein saidC.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are eachoptionally substituted by 1, 2, 3, or 4 substituents independentlyselected from Cy.sup.2, halo, CN, NO.sub.2, CN, NO.sub.2,OR.sup.a3, SR.sup.a3, C(O)R.sup.b3, C(O)NR.sup.c3R.sup.d3,C(O)OR.sup.a3, OC(O)R.sup.b3, OC(O)NR.sup.c3R.sup.d3,C(.dbd.NR.sup.e3)NR.sup.c3R.sup.d3,NR.sup.c3C(.dbd.NR.sup.e3)NR.sup.c3R.sup.d3, NR.sup.c3R.sup.d3,NR.sup.c3C(O)R.sup.b3, NR.sup.c3C(O)OR.sup.a3,NR.sup.c3C(O)NR.sup.c3R.sup.d3, NR.sup.c3S(O)R.sup.b3,NR.sup.c3S(O).sub.2R.sup.b3, NR.sup.c3S(O).sub.2NR.sup.c3R.sup.d3,S(O)R.sup.b3, S(O)NR.sup.c3R.sup.d3, S(O).sub.2R.sup.b3, andS(O).sub.2NR.sup.c3R.sup.d3;
each R.sup.2 and R.sup.3 is independently selected from H, halo,C.sub.1-6 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 cyanoalkyl,C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, CN, NO.sub.2, OR.sup.a4,SR.sup.a4, C(O)R.sup.b4, C(O)NR.sup.c4R.sup.d4, C(O)OR.sup.a4,OC(O)R.sup.b4, OC(O)NR.sup.c4R.sup.d4,C(.dbd.NR.sup.e4)NR.sup.c4R.sup.d4,NR.sup.c4C(.dbd.NR.sup.e4)NR.sup.c4R.sup.d4, NR.sup.c4R.sup.d4,NR.sup.c4C(O)R.sup.b4, NR.sup.c4C(O)OR.sup.a4,NR.sup.c4C(O)NR.sup.c4R.sup.d4, NR.sup.c4S(O)R.sup.b4,NR.sup.c4S(O).sub.2R.sup.b4, NR.sup.c4S(O).sub.2NR.sup.c4R.sup.d4,S(O)R.sup.b4, S(O)NR.sup.c4R.sup.d4, S(O).sub.2R.sup.b4, andS(O).sub.2NR.sup.c4R.sup.d4, wherein said C.sub.1-6 alkyl,C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are each optionallysubstituted by 1, 2, 3, or 4 substituents independently selectedfrom halo, CN, NO.sub.2, OR.sup.a4, SR.sup.a4, C(O)R.sup.b4,C(O)NR.sup.c4R.sup.d4, C(O)OR.sup.a4, OC(O)R.sup.b4,OC(O)NR.sup.c4R.sup.d4, C(.dbd.NR.sup.e4)NR.sup.c4R.sup.d4,NR.sup.c4C(.dbd.NR.sup.e4)NR.sup.c4R.sup.d4, NR.sup.c4R.sup.d4,NR.sup.c4C(O)R.sup.b4, NR.sup.c4C(O)OR.sup.a4,NR.sup.c4C(O)NR.sup.c4R.sup.d4, NR.sup.c4S(O)R.sup.b4,NR.sup.c4S(O).sub.2R.sup.b4, NR.sup.c4S(O).sub.2NR.sup.c4R.sup.d4,S(O)R.sup.b4, S(O)NR.sup.c4R.sup.d4, S(O).sub.2R.sup.b4, andS(O).sub.2NR.sup.c4R.sup.d4;
each R.sup.A1 is independently selected from H, halo, C.sub.1-4alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy,amino, C.sub.1-4 alkylamino, C.sub.2-8 dialkylamino, CN, NO.sub.2,and OH;
each R.sup.A2 is independently selected from H, halo, C.sub.1-4alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy,amino, C.sub.1-4 alkylamino, C.sub.2-8 dialkylamino, CN, NO.sub.2,and OH;
each R.sup.A3 is independently selected from H, C.sub.1-4 alkyl,C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C(O)R.sup.z, andC(O)OR.sup.z, wherein said C.sub.1-4 alkyl is optionallysubstituted by phenyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, CN,NO.sub.2, or OH;
R.sup.z is H, C.sub.1-4 alkyl, or phenyl;
each Cy.sup.1 is independently selected from C.sub.6-14 aryl,C.sub.3-18 cycloalkyl, 5-16 membered heteroaryl, and 4-18 memberedheterocycloalkyl, each of which is optionally substituted with 1,2, 3, or 4 substituents independently selected from R.sup.Cy1;
each Cy.sup.2 is independently selected from C.sub.6-14 aryl,C.sub.3-18 cycloalkyl, 5-16 membered heteroaryl, and 4-18 memberedheterocycloalkyl, each of which is optionally substituted with 1,2, 3, or 4 substituents independently selected from R.sup.Cy2;
each R.sup.Cy1 and R.sup.Cy2 is independently selected from halo,C.sub.1-6 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 cyanoalkyl,C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, phenyl, C.sub.3-7 cycloalkyl,5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl, CN,NO.sub.2, OR.sup.a5, SR.sup.a5, C(O)R.sup.b5,C(O)NR.sup.c5R.sup.d5, C(O)OR.sup.a5, OC(O)R.sup.b5,OC(O)NR.sup.c5R.sup.d5, C(.dbd.NR.sup.e5)NR.sup.c5R.sup.d5,NR.sup.c5C(.dbd.NR.sup.e5)NR.sup.c5R.sup.d5, NR.sup.c5R.sup.d5,NR.sup.c5C(O)R.sup.b5, NR.sup.c5C(O)OR.sup.a5,NR.sup.c5C(O)NR.sup.c5R.sup.d5, NR.sup.c5S(O)R.sup.b5,NR.sup.c5S(O).sub.2R.sup.b5, NR.sup.c5S(O).sub.2NR.sup.c5R.sup.d5,S(O)R.sup.b5, S(O)NR.sup.c5R.sup.d5, S(O).sub.2R.sup.b5, andS(O).sub.2NR.sup.c5R.sup.d5, wherein said C.sub.1-6 alkyl,C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, phenyl, C.sub.3-7 cycloalkyl,5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are eachoptionally substituted by 1, 2, 3, or 4 substituents independentlyselected from CN, NO.sub.2, OR.sup.a5, SR.sup.a5, C(O)R.sup.b5,C(O)NR.sup.c5R.sup.d5, C(O)OR.sup.a5, OC(O)R.sup.b5,OC(O)NR.sup.c5R.sup.d5, C(.dbd.NR.sup.e5)NR.sup.c5R.sup.d5,NR.sup.c5C(.dbd.NR.sup.e5)NR.sup.c5R.sup.d5, NR.sup.c5R.sup.d5,NR.sup.c5C(O)R.sup.b5, NR.sup.c5C(O)OR.sup.a5,NR.sup.c5C(O)NR.sup.c5R.sup.d5, NR.sup.c5S(O)R.sup.b5,NR.sup.c5S(O).sub.2R.sup.b5, NR.sup.c5S(O).sub.2NR.sup.c5R.sup.d5,S(O)R.sup.b5, S(O)NR.sup.c5R.sup.d5, S(O).sub.2R.sup.b5, andS(O).sub.2NR.sup.c5R.sup.d5;
each R.sup.a1, R.sup.b1, R.sup.c1, R.sup.d1, R.sup.a2, R.sup.b2,R.sup.c2, R.sup.d2, R.sup.a3, R.sup.b3, R.sup.c3, R.sup.d3,R.sup.a4, R.sup.b4, R.sup.c4, R.sup.d4, R.sup.a5, R.sup.b5,R.sup.c5, and R.sup.d5 is independently selected from H, C.sub.1-6alkyl, C.sub.1-4 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-6 alkyl,C.sub.3-10 cycloalkyl-C.sub.1-6 alkyl, (5-10 memberedheteroaryl)-C.sub.1-6 alkyl, and (4-10 memberedheterocycloalkyl)-C.sub.1-6 alkyl, wherein said C.sub.1-6 alkyl,C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.6-10 aryl, C.sub.3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C.sub.6-10 aryl-C.sub.1-6 alkyl, C.sub.3-10cycloalky-C.sub.1-6 alkyl, (5-10 membered heteroaryl)-C.sub.1-6alkyl, and (4-10 membered heterocycloalkyl)-C.sub.1-6 alkyl areeach optionally substituted with 1, 2, 3, 4, or 5 substituentsindependently selected from R.sup.g;
each R.sup.e1, R.sup.e2, R.sup.e3, R.sup.e4, and R.sup.e5 isindependently selected from H, C.sub.1-4 alkyl, and CN;
each R.sup.g is independently selected from the group consisting ofOH, NO.sub.2, CN, halo, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,C.sub.2-6 alkynyl, C.sub.1-4 haloalkyl, C.sub.1-6 alkoxy, C.sub.1-6haloalkoxy, cyano-C.sub.1-3 alkyl, HO--C.sub.1-3 alkyl, amino,C.sub.1-6 alkylamino, di(C.sub.1-6 alkyl)amino, thiol, C.sub.1-6alkylthio, C.sub.1-6 alkylsulfinyl, C.sub.1-6 alkylsulfonyl,carboxy, aminocarbonyl, C.sub.1-6 alkylcarbonyl, and C.sub.1-6alkoxycarbonyl;
n is 0 or 1;
m is 0 or 1;
p is 0, 1, 2, or 3;
q is 0, 1, or 2;
a is 0 or 1; and
b is 0 or 1,
wherein any cycloalkyl or heterocycloalkyl group is optionallyfurther substituted by 1 or 2 oxo groups.
In some embodiments, Y is O.
In some embodiments, Y is NR.sup.Y3. In some embodiments, Y isNH.
In some embodiments, U is CR.sup.U. In some embodiments, U isCH.
In some embodiments, W is N.
In some embodiments, W is CR.sup.W. In some embodiments, W isCH.
In some embodiments, X is N.
In some embodiments, X is CR.sup.X. In some embodiments, X isselected from CH or CNH.sub.2.
In some embodiments, A, B, D, and E are each independently selectedfrom --C(R.sup.A1)(R.sup.A2)--,--C(R.sup.A1)(R.sup.A2)--C(R.sup.A1)(R.sup.A2)--,--C(R.sup.A1)(R.sup.A2)--O--, --C(R.sup.A1)(R.sup.A2)--C(.dbd.O)--,and --C(.dbd.O)--, wherein no more than one of A, B, D, and E is--C(R.sup.A1)(R.sup.A2)--O--, --C(R.sup.A1)(R.sup.A2)--C(.dbd.O)--,or --C(.dbd.O)--.
In some embodiments, A, B, D, and E are each independently selectedfrom --C(R.sup.A1)(R.sup.A2)--,--C(R.sup.A1)(R.sup.A2)--C(R.sup.A1)(R.sup.A2)--, and--C(R.sup.A1)(R.sup.A2)--O--, wherein no more than one of A, B, D,and E is --C(R.sup.A1)(R.sup.A2)--O--.
In some embodiments, A, B, D, and E are each independently selectedfrom --C(R.sup.A1)(R.sup.A2)-- or--C(R.sup.A1)(R.sup.A2)--C(R.sup.A1)(R.sup.A2)--.
In some embodiments, each R.sup.A1 and R.sup.A2 are independentlyselected from H, OH, and NH.sub.2.
In some embodiments, A, B, D, and E are each independently selectedfrom --CH.sub.2--, --CH.sub.2--CH.sub.2--, and --CH.sub.2O--.
In some embodiments, A, B, D, and E are each independently selectedfrom --CH.sub.2-- or --CH.sub.2--CH.sub.2--.
In some embodiments, the spiro moiety represented by the belowformula:
##STR00003## wherein e and f indicate points of attachment to theremainder of the molecule, is selected from:
##STR00004## ##STR00005##
In some embodiments, the spiro moiety represented by the belowformula:
##STR00006## wherein e and f indicate points of attachment to theremainder of the molecule, is selected from:
##STR00007##
In some embodiments, the spiro moiety represented by the belowformula:
##STR00008## wherein e and f indicate points of attachment to theremainder of the molecule, is selected from:
##STR00009##
In some embodiments, L is selected from --C.sub.1-6 alkylene-optionally substituted with 1, 2, or 3 substituents independentlyselected from halo, CN, OH, C.sub.1-3 alkyl, C.sub.1-3 alkoxy,C.sub.1-3 haloalkyl, C.sub.1-3 haloalkoxy, amino, C.sub.1-3alkylamino, and di(C.sub.1-3 alkyl)amino.
In some embodiments, L is selected from methylene, ethylene, and--CH.sub.2--CH(OH)--.
In some embodiments, L is methylene.
In some embodiments, L is selected from --(C.sub.1-4alkylene).sub.a-Q-(C.sub.1-4 alkylene).sub.b-, wherein anyC.sub.1-4 alkylene group of the --(C.sub.1-4alkylene).sub.a-Q-(C.sub.1-4 alkylene).sub.b- group is optionallysubstituted with 1, 2, or 3 substituents independently selectedfrom halo, CN, OH, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-3haloalkyl, C.sub.1-3 haloalkoxy, amino, C.sub.1-3 alkylamino, anddi(C.sub.1-3 alkyl)amino.
In some embodiments, a is 1.
In some embodiments, a is 0.
In some embodiments, b is 1.
In some embodiments, b is 0.
In some embodiments, a and b are each 1.
In some embodiments, a and b are each 0.
In some embodiments, a is 1 and b is 0.
In some embodiments, a is 0 and b is 1.
In some embodiments, L is selected from --C(O)--CH.sub.2--,--C(O)--CH.sub.2--CH.sub.2--, C(O), --NH--CH.sub.2--, NH,--C(O)--CH(NH.sub.2)--, --NH--CH(CH.sub.3)--,--N(CH.sub.3)--C(O)--, N(CH.sub.3)--CH.sub.2--,--CH.sub.2--CH.sub.2--O--, and --C(O)--NH--.
In some embodiments, Cy is a linking phenyl, C.sub.3-18 cycloalkyl,5-10 membered heteroaryl, or 4-9 membered heterocycloalkyl group,each of which is optionally substituted with 1, 2, 3, or 4substituents independently selected from R.sup.Cy.
In some embodiments, Cy is a linking phenyl, C.sub.3-18 cycloalkyl,5-10 membered heteroaryl, or 4-9 membered heterocycloalkyl group,each of which is optionally substituted with 1, 2, 3, or 4substituents independently selected from R.sup.Cy.
In some embodiments, Cy is a linking group having the formula:
##STR00010## ##STR00011## each of which is optionally substitutedwith 1, 2, 3, or 4 substituents independently selected fromR.sup.Cy.
In some embodiments, Cy is a linking group having the formula:
##STR00012##
In some embodiments, Z is Cy.sup.2 or C(O)NR.sup.c3R.sup.d3.
In some embodiments, each Cy.sup.2 is independently selected fromC.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,and 4-10 membered heterocycloalkyl, each of which is optionallysubstituted with 1, 2, 3, or 4 substituents independently selectedfrom R.sup.Cy2.
In some embodiments, each Cy.sup.2 is independently selected fromphenyl, C.sub.3-10 cycloalkyl, 5-6 membered heteroaryl, and 4-6membered heterocycloalkyl, each of which is optionally substitutedwith 1, 2, 3, or 4 substituents independently selected fromR.sup.Cy2.
In some embodiments, n is 0.
In some embodiments, n is 1.
In some embodiments, m is 0.
In some embodiments, m is 1.
In some embodiments, p is 0.
In some embodiments, p is 1.
In some embodiments, q is 0.
In some embodiments, q is 1.
In some embodiments, the compound of Formula I, or apharmaceutically acceptable salt thereof, is a compound of FormulaIIa, IIb, IIIa, or IIIb:
##STR00013## or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula I, or apharmaceutically acceptable salt thereof, is a compound of FormulaIVa, IVb, IVc, IVd, IVe, or IVf:
##STR00014## ##STR00015## or a pharmaceutically acceptable saltthereof.
In some embodiments, the compound or pharmaceutically acceptablesalt of the compound of Formula I provided herein is crystalline.As used herein, "crystalline" or "crystalline form" is meant torefer to a certain lattice configuration of a crystallinesubstance. Different crystalline forms of the same substancetypically have different crystalline lattices (e.g., unit cells)which are attributed to different physical properties that arecharacteristic of each of the crystalline forms. In some instances,different lattice configurations have different water or solventcontent.
Different crystalline forms of the same compound or salt can havedifferent bulk properties relating to, for example, hygroscopicity,solubility, stability, and the like. Forms with high melting pointsoften have good thermodynamic stability which is advantageous inprolonging shelf-life drug formulations containing the solid form.Forms with lower melting points often are less thermodynamicallystable, but are advantageous in that they have increased watersolubility, translating to increased drug bioavailability. Formsthat are weakly hygroscopic are desirable for their stability toheat and humidity and are resistant to degradation during longstorage.
The different crystalline forms can be identified by solid statecharacterization methods such as by X-ray powder diffraction(XRPD). Other characterization methods such as differentialscanning calorimetry (DSC), thermogravimetric analysis (TGA),dynamic vapor sorption (DVS), and the like further help identifythe form as well as help determine stability and solvent/watercontent.
An XRPD pattern of reflections (peaks) is typically considered afingerprint of a particular crystalline form. It is well known thatthe relative intensities of the XRPD peaks can widely varydepending on, inter alia, the sample preparation technique, crystalsize distribution, various filters used, the sample mountingprocedure, and the particular instrument employed. In someinstances, new peaks may be observed or existing peaks maydisappear, depending on the type of the instrument or the settings.As used herein, the term "peak" refers to a reflection having arelative height/intensity of at least about 5% of the maximum peakheight/intensity. Moreover, instrument variation and other factorscan affect the 2-theta values. Thus, peak assignments, such asthose reported herein, can vary by plus or minus about 0.2.degree.(2-theta), and the term "substantially" and "about" as used in thecontext of XRPD herein is meant to encompass the above-mentionedvariations.
In the same way, temperature readings in connection with DSC, TGA,or other thermal experiments can vary about .+-.3.degree. C.depending on the instrument, particular settings, samplepreparation, etc. Accordingly, a crystalline form reported hereinhaving a DSC thermogram "substantially" as shown in any of theFigures or the term "about" is understood to accommodate suchvariation.
The present invention provides crystalline forms of certaincompounds, or salts thereof. In some embodiments, the compound ofFormula I is5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide,or a pharmaceutically acceptable salt thereof.
In some embodiments, the present invention provides crystalline the5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidecharacterized, for example, by an XRPD profile substantially asshown in FIG. 5.
In some embodiments, crystalline5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidehas at least one, at least two, at least three, or at least fourXRPD peaks, in terms of 2-theta, selected from about 6.2.degree.,about 8.3.degree., about 16.1.degree., about 16.6.degree., about17.3.degree., about 19.0.degree., about 23.5.degree., about25.3.degree., and about 26.9.degree..
In some embodiments, crystalline5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidehas at least one, at least two, at least three, or at least fourXRPD peaks, in terms of 2-theta, selected from about 6.2.degree.,about 8.3.degree., about 16.1.degree., about 16.6.degree., andabout 19.0.degree..
In some embodiments, the5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidecan be isolated as a bis-methanesulfonic acid salt which can becrystalline having an XRPD profile substantially as shown in FIG.6.
In some embodiments, the crystalline form of the5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidebis-methanesulfonic acid salt has at least one, at least two, atleast three, or at least four XRPD peaks, in terms of 2-theta,selected from about 5.6.degree., about 8.8.degree., about10.2.degree., about 12.6.degree., about 13.8.degree., about15.3.degree., about 16.2.degree., about 16.8.degree., about17.6.degree., about 18.6.degree., about 20.3.degree., about20.9.degree., about 21.2.degree., about 22.7.degree., and about24.6.degree..
In some embodiments, the crystalline form of the5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidebis-methanesulfonic acid salt has at least one, at least two, atleast three, or at least four XRPD peaks, in terms of 2-theta,selected from about 5.6.degree., about 8.8.degree., about10.2.degree., about 12.6.degree., about 13.8.degree., about15.3.degree., about 16.2.degree., about 16.8.degree., about17.6.degree., about 18.6.degree., about 20.3.degree..
In some embodiments, the5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidecan be isolated as a bis-hydrochloric acid salt which can becrystalline having an XRPD profile substantially as shown in FIG.8.
In some embodiments, the5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidecan be isolated as a fumaric acid salt, such as a sesquifumaricacid salt which can be crystalline. The crystalline sesquifumaricacid salt can be hydrated (e.g., a monohydrate), solvated (e.g.,contains solvent other than water), or anhydrous and unsolvated. Insome embodiments, the crystalline form of the sesquifumaric acidsalt is substantially anhydrous or substantially unsolvated. Insome embodiments, the crystalline form of the sesquifumaric acidsalt is hydrated or solvated. In some embodiments, the crystallineform of the sesquifumaric acid salt is hydrated. In someembodiments, the crystalline form of the sesquifumaric acid salt isa monohydrate.
In some embodiments, the crystalline form of the5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidesesquifumaric acid salt has an XRPD profile substantially as shownin FIG. 7.
In some embodiments, the crystalline form of the5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidesesquifumaric acid salt has at least one, at least two, at leastthree, or at least four XRPD peaks, in terms of 2-theta, selectedfrom about 2.9.degree., about 5.8.degree., about 8.7.degree., about13.2.degree., about 16.0.degree., about 17.6.degree., about19.1.degree., about 20.3.degree., about 20.4.degree., about20.8.degree., about 21.8.degree., about 22.9.degree., about23.0.degree., about 23.3.degree., about 24.9.degree., and about26.0.degree..
In some embodiments, the crystalline form of the5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidesesquifumaric acid salt has at least one, at least two, at leastthree, or at least four XRPD peaks, in terms of 2-theta, selectedfrom about 2.9.degree., about 5.8.degree., about 8.7.degree., about13.2.degree., about 16.0.degree., about 17.6.degree., about19.1.degree., about 20.3.degree., about 20.4.degree., about20.8.degree., about 21.8.degree., about 23.0.degree., about23.3.degree., about 24.9.degree., and about 26.0.degree..
In some embodiments, the crystalline form of the5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidesesquifumaric acid salt has at least one, at least two, at leastthree, or at least four XRPD peaks, in terms of 2-theta, selectedfrom about 2.9.degree., about 5.8.degree., about 8.7.degree., about13.2.degree., about 16.0.degree., about 19.1.degree., about21.8.degree., about 24.9.degree., and about 26.0.degree..
In some embodiments, the crystalline form of the5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidesesquifumaric acid salt has at least one, at least two, at leastthree, or at least four XRPD peaks, in terms of 2-theta, selectedfrom about 2.9.degree., about 5.8.degree., about 8.7.degree., about13.2.degree., about 16.0.degree., about 19.1.degree., and about21.8.degree..
In some embodiments, the crystalline form of the5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidesesquifumaric acid salt is selected from crystalline Form A,crystalline Form B, crystalline Form C, crystalline Form D,crystalline Form E, and crystalline Form F.
In some embodiments, crystalline Form A of the5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidesesquifumaric acid salt monohydrate has an XRPD profilesubstantially as shown in FIG. 10.
In some embodiments, crystalline Form A of the5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidesesquifumaric acid salt has at least one, at least two, at leastthree, or at least four XRPD peaks, in terms of 2-theta, selectedfrom about 5.8.degree., about 13.2.degree., about 15.9.degree.,about 19.2.degree., about 20.3.degree., about 21.8.degree., about23.0.degree., and about 23.3.degree..
In some embodiments, crystalline Form A of the5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidesesquifumaric acid salt monohydrate is characterized by a DSCthermogram having an endothermic peak at about 183.degree. C.
In some embodiments, crystalline Form A of the5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidesesquifumaric acid salt monohydrate is characterized by athermographic analysis (TGA) substantially as shown in FIG. 12.
In some embodiments, crystalline Form A of the5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidesesquifumaric acid salt monohydrate is characterized by a dynamicvapor sorption analysis substantially as shown in FIG. 13.
In some embodiments, crystalline Form B of the5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidesesquifumaric acid salt has an XRPD profile substantially as shownin FIG. 15.
In some embodiments, crystalline Form B of the5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidesesquifumaric acid salt has at least one, at least two, at leastthree, or at least four XRPD peaks, in terms of 2-theta, selectedfrom about 6.2.degree., about 7.8.degree., about 8.5.degree., about10.9.degree., about 12.6.degree., about 13.2.degree., about13.5.degree., about 16.1.degree., about 19.0.degree., about19.3.degree., about 21.2.degree., about 21.4.degree., and about21.6.degree..
In some embodiments, crystalline Form D of the5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidesesquifumaric acid salt has an XRPD profile substantially as shownin FIG. 23.
In some embodiments, crystalline Form D of the5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidesesquifumaric acid salt has at least one, at least two, at leastthree, or at least four XRPD peaks, in terms of 2-theta, selectedfrom about 7.2.degree., about 8.5.degree., about 11.8.degree.,about 14.5.degree., about 16.0.degree., about 17.4.degree., about19.3.degree., about 19.7.degree., and about 21.8.degree..
In some embodiments, crystalline Form D of the5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidesesquifumaric acid salt is characterized by a DSC thermogram havingan endothermic peak at about 167.degree. C.
In some embodiments, crystalline Form D of the5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidesesquifumaric acid salt is characterized by a thermographicanalysis (TGA) substantially as shown in FIG. 18.
In some embodiments, crystalline Form E of the5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidesesquifumaric acid salt has an XRPD profile substantially as shownin FIG. 9.
In some embodiments, the crystalline Form F of the5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidesesquifumaric acid salt has an XRPD profile substantially as shownin FIG. 9.
In some embodiments, the crystalline Form F of the5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidesesquifumaric acid salt is characterized by a thermographicanalysis (TGA) substantially as shown in FIG. 18.
In some embodiments, the5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamideis a benzenesulfonic acid salt (besylate) which can becrystalline.
In some embodiments, the5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamideis a naphthalenedisulfonic acid (napadisylate) salt which can becrystalline. In some embodiments, the5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamideis a naphthalene-1,5-disulfonic acid salt which can becrystalline.
In some embodiments, the5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamideis a toluenesulfonic acid (tosylate) salt which can becrystalline.
The present invention further provides crystalline forms of thecompoundN-ethyl-2-((4-(7-(((r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)-2,7-diaz-aspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide,or a pharmaceutically acceptable salt thereof.
In some embodiments, the present invention provides a crystallineform ofN-ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)-2,7-dia-zaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide,having, for example, an XRPD profile substantially as shown in FIG.1.
In some embodiments, the crystalline form ofN-ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)-2,7-dia-zaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamidehas at least one, at least two, at least three, or at least fourXRPD peaks, in terms of 2-theta, selected from about 9.7.degree.,about 11.6.degree., about 12.6.degree., about 16.6.degree., about17.5.degree., about 18.8.degree., about 19.2.degree., about19.8.degree., about 21.0.degree., and about 25.3.degree..
In some embodiments, theN-ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)-2,7-dia-zaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamidecan be isolated as a fumaric acid salt, such as a sesquifumaricacid salt, which can be crystalline. In some embodiments, thecrystalline form of the sesquifumaric acid salt is substantiallyanhydrous. In some embodiments, the crystalline form of thesesquifumaric acid salt is hydrated or solvated. In someembodiments, the crystalline form of the sesquifumaric acid salt ishydrated. In some embodiments, the crystalline form of thesesquifumaric acid salt is a monohydrate.
In some embodiments, the crystalline form of theN-ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)-2,7-dia-zaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamidesesquifumaric acid salt has an XRPD profile substantially as shownin FIG. 2.
In some embodiments, the crystalline form of theN-ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)-2,7-dia-zaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamidesesquifumaric acid salt has at least one, at least two, at leastthree, or at least four XRPD peaks, in terms of 2-theta, selectedfrom about 5.8.degree., about 8.7.degree., about 13.2.degree.,about 16.0.degree., about 17.4.degree., about 17.6.degree., about19.1.degree., about 20.3.degree., about 21.8.degree., about23.0.degree., about 23.3.degree., about 24.9.degree., and about26.0.degree..
In some embodiments, the crystalline form of theN-ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)-2,7-dia-zaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamidesesquifumaric acid salt has at least one, at least two, at leastthree, or at least four XRPD peaks, in terms of 2-theta, selectedfrom about 5.8.degree., about 8.7.degree., about 13.2.degree.,about 16.0.degree., about 17.4.degree., about 17.6.degree., about19.1.degree., about 20.3.degree., about 21.8.degree., and about23.0.theta..
In some embodiments, the crystalline form of theN-ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)-2,7-dia-zaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamidesesquifumaric acid salt has at least one, at least two, at leastthree, or at least four XRPD peaks, in terms of 2-theta, selectedfrom about 5.8.degree., about 8.7.degree., about 13.2.degree.,about 16.0.degree., about 17.4.degree., about 17.6.degree., andabout 19.1.theta..
In some embodiments, theN-ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)-2,7-dia-zaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamideis a bis-methanesulfonic acid salt which can be crystalline,having, for example, an XRPD profile substantially as shown in FIG.3.
In some embodiments, the crystalline form of theN-ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)-2,7-dia-zaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamidebis-methanesulfonic acid salt has at least one, at least two, atleast three, or at least four XRPD peaks, in terms of 2-theta,selected from about 5.6.degree., about 11.0.degree., about13.3.degree., about 16.7.degree., about 20.1.degree., about20.9.degree., about 22.1.degree., about 23.6.degree., about24.9.degree., and about 29.6.theta..
In some embodiments, the crystalline form of theN-ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)-2,7-dia-zaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamidebis-methanesulfonic acid salt has at least one XRPD peak, in termsof 2-theta, selected from about 5.6.degree. and about16.7.degree..
In some embodiments, theN-ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)-2,7-dia-zaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamideis a bis-hydrochloric acid salt which can be crystalline, having,for example, an XRPD profile substantially as shown in FIG. 4.
In some embodiments, the crystalline form of theN-ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)-2,7-dia-zaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamidebis-hydrochloric acid salt has at least one, at least two, at leastthree, or at least four XRPD peaks, in terms of 2-theta, selectedfrom about 4.7.degree., about 10.7.degree., about 13.4.degree.,about 15.9.degree., about 17.0.degree., about 19.5.degree., about20.1.degree., about 23.8.degree., about 25.8.degree., and about28.1.degree..
In some embodiments, the crystalline form of theN-ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)-2,7-dia-zaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamidebis-hydrochloric acid salt has at least one or two XRPD peaks, interms of 2-theta, selected from about 4.7.degree., about17.0.degree., and about 19.5.degree..
It is appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments,can also be provided in combination in a single embodiment.Conversely, various features of the invention which are, forbrevity, described in the context of a single embodiment, can alsobe provided separately or in any suitable subcombination.
As used herein, the phrase "optionally substituted" meansunsubstituted or substituted. As used herein, the term"substituted" means that a hydrogen atom is removed and replaced bya substituent. The term "substituted" may also mean that twohydrogen atoms are removed and replaced by a divalent substituentsuch as an oxo or sulfide group. It is to be understood thatsubstitution at a given atom is limited by valency.
At various places in the present specification, substituents ofcompounds of the invention are disclosed in groups or in ranges. Itis specifically intended that the invention include each and everyindividual subcombination of the members of such groups and ranges.For example, the term "C.sub.1-6 alkyl" is specifically intended toindividually disclose methyl, ethyl, C.sub.3 alkyl, C.sub.4 alkyl,C.sub.5 alkyl, and C.sub.6 alkyl.
The term "z-membered" (where z is an integer) typically describesthe number of ring-forming atoms in a moiety where the number ofring-forming atoms is z. For example, piperidinyl is an example ofa 6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring, and 1, 2, 3, 4-tetrahydro-naphthalene is anexample of a 10-membered cycloalkyl group.
At various places in the present specification, linkingsubstituents are described. It is specifically intended that eachlinking substituent include both the forward and backward forms ofthe linking substituent. For example, --NR(CR'R'').sub.n-- includesboth --NR(CR'R'').sub.n-- and --(CR'R'').sub.nNR--. Where thestructure clearly requires a linking group, the Markush variableslisted for that group are understood to be linking groups. Forexample, if the structure requires a linking group and the Markushgroup definition for that variable lists "alkyl" or "aryl" then itis understood that the "alkyl" or "aryl" represents a linkingalkylene group or arylene group, respectively.
At various places in the present specification various aryl,heteroaryl, cycloalkyl, and heterocycloalkyl rings are described.Unless otherwise specified, these rings can be attached to the restof the molecule at any ring member as permitted by valency. Forexample, the term "a pyridine ring" or "pyridinyl" may refer to apyridin-2-yl, pyridin-3-yl, or pyridin-4-yl ring.
For compounds of the invention in which a variable appears morethan once, each variable can be a different moiety independentlyselected from the group defining the variable. For example, where astructure is described having two R groups that are simultaneouslypresent on the same compound, the two R groups can representdifferent moieties independently selected from the group definedfor R.
As used herein, the term "C.sub.i-j alkyl," employed alone or incombination with other terms, refers to a saturated hydrocarbongroup that may be straight-chain or branched, having i to jcarbons. In some embodiments, the alkyl group contains from 1 to 6carbon atoms, or from 1 to 4 carbon atoms, or from 1 to 3 carbonatoms. Examples of alkyl moieties include, but are not limited to,chemical groups such as methyl, ethyl, n-propyl, isopropyl,n-butyl, s-butyl, and t-butyl. In some embodiments, where an alkylgroup is a linking group, it may be referred to as "C.sub.i-jalkylene."
As used herein, the term "C.sub.i-j alkoxy," employed alone or incombination with other terms, refers to a group of formula--O-alkyl, wherein the alkyl group has i to j carbons. Examplealkoxy groups include methoxy, ethoxy, and propoxy (e.g., n-propoxyand isopropoxy). In some embodiments, the alkyl group has 1 to 3carbon atoms.
As used herein, "C.sub.i-j alkenyl," employed alone or incombination with other terms, refers to an unsaturated hydrocarbongroup having one or more double carbon-carbon bonds and having i toj carbons. In some embodiments, the alkenyl moiety contains 2 to 6or 2 to 4 carbon atoms. Example alkenyl groups include, but are notlimited to, ethenyl, n-propenyl, isopropenyl, n-butenyl,sec-butenyl, and the like.
As used herein, "C.sub.i-j alkynyl," employed alone or incombination with other terms, refers to an unsaturated hydrocarbongroup having one or more triple carbon-carbon bonds and having i toj carbons. Example alkynyl groups include, but are not limited to,ethynyl, propyn-1-yl, propyn-2-yl, and the like. In someembodiments, the alkynyl moiety contains 2 to 6 or 2 to 4 carbonatoms.
As used herein, the term "C.sub.i-j alkylamino," employed alone orin combination with other terms, refers to a group of formula--NH(alkyl), wherein the alkyl group has i to j carbon atoms. Insome embodiments, the alkyl group has 1 to 6 or 1 to 4 carbonatoms.
As used herein, the term "di-C.sub.i-j-alkylamino," employed aloneor in combination with other terms, refers to a group of formula--N(alkyl).sub.2, wherein each of the two alkyl groups has,independently, i to j carbon atoms. In some embodiments, each alkylgroup independently has 1 to 6 or 1 to 4 carbon atoms. In someembodiments, the dialkylamino group is --N(C.sub.1-4 alkyl).sub.2such as, for example, dimethylamino or diethylamino.
As used herein, the term "C.sub.i-j alkylthio," employed alone orin combination with other terms, refers to a group of formula--S-alkyl, wherein the alkyl group has i to j carbon atoms. In someembodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. Insome embodiments, the alkylthio group is C.sub.1-4 alkylthio suchas, for example, methylthio or ethylthio.
As used herein, the term "thiol," employed alone or in combinationwith other terms, refers to --SH.
As used herein, the term "amino," employed alone or in combinationwith other terms, refers to a group of formula --NH.sub.2.
As used herein, "C.sub.i-j haloalkoxy," employed alone or incombination with other terms, refers to a group of formula--O-haloalkyl having i to j carbon atoms. An example haloalkoxygroup is OCF.sub.3. An additional example haloalkoxy group isOCHF.sub.2. In some embodiments, the haloalkoxy group isfluorinated only. In some embodiments, the alkyl group has 1 to 6or 1 to 4 carbon atoms. In some embodiments, the haloalkoxy groupis C.sub.1-4 haloalkoxy.
As used herein, the term "halo," employed alone or in combinationwith other terms, refers to a halogen atom selected from F, Cl, Ior Br. In some embodiments, "halo" refers to a halogen atomselected from F, Cl, or Br. In some embodiments, the halosubstituent is F.
As used herein, the term "C.sub.i-j haloalkyl," employed alone orin combination with other terms, refers to an alkyl group havingfrom one halogen atom to 2s+1 halogen atoms which may be the sameor different, where "s" is the number of carbon atoms in the alkylgroup, wherein the alkyl group has i to j carbon atoms. In someembodiments, the haloalkyl group is fluorinated only. In someembodiments, the haloalkyl group is fluoromethyl, difluoromethyl,or trifluoromethyl. In some embodiments, the haloalkyl group istrifluoromethyl. In some embodiments, the haloalkyl group is2,2,2-trifluoroethyl. In some embodiments, the haloalkyl group is2,2-difluoroethyl. In some embodiments, the haloalkyl group has 1to 6 or 1 to 4 carbon atoms.
As used herein, "C.sub.i-j cyanoalkyl," employed alone or incombination with other terms, refers to a group of formulaCN--(C.sub.i-j alkyl)-.
As used herein, the term "aryl," employed alone or in combinationwith other terms, refers to a monocyclic or polycyclic (e.g.,having 2, 3 or 4 fused rings) aromatic hydrocarbon, such as, butnot limited to, phenyl, 1-naphthyl, 2-naphthyl, anthracenyl,phenanthrenyl, and the like. In some embodiments, aryl isC.sub.6-10 aryl. In some embodiments, aryl is C.sub.6-14 aryl. Insome embodiments, the aryl group is a naphthalene ring or phenylring. In some embodiments, the aryl group is phenyl.
As used herein, the term "C.sub.i-j cycloalkyl," employed alone orin combination with other terms, refers to a non-aromatic cyclichydrocarbon moiety having i to j ring-forming carbon atoms, whichmay optionally contain one or more alkenylene groups as part of thering structure. Cycloalkyl groups can include mono- or polycyclicring systems. Polycyclic ring systems can include fused ringsystems and spirocycles. Also included in the definition ofcycloalkyl are moieties that have one or more aromatic rings fused(i.e., having a bond in common with) to the cycloalkyl ring, forexample, benzo or pyrido derivatives of cyclopentane, cyclopentene,cyclohexane, and the like. A heterocycloalkyl group that includes afused aromatic (e.g., aryl or heteroaryl) moiety can be attached tothe molecule through an atom from either the aromatic ornon-aromatic portion. One or more ring-forming carbon atoms of acycloalkyl group can be oxidized to form carbonyl linkages. In someembodiments, cycloalkyl is C.sub.3-10 cycloalkyl, C.sub.3-7cycloalkyl, or C.sub.5-6 cycloalkyl. Exemplary cycloalkyl groupsinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl,cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, and the like.Further exemplary cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl. Additional examplecycloalkyl groups, where the cycloalkyl group has a fused aryl orheteroaryl moiety, include tetrahydronaphthalen-2-yl,2,3-dihydro-1H-inden-2-yl; 2,3,4,9-tetrahydro-1H-carbazol-7-yl;2,6,7,8-tetrahydrobenzo[cd]indazol-4-yl; and5,6,7,8,9,10-hexahydrocyclohepta[b]indol-3-yl.
As used herein, the term "heteroaryl," employed alone or incombination with other terms, refers to a monocyclic or polycyclic(e.g., having 2, 3 or 4 fused rings) aromatic heterocylic moiety,having one or more heteroatom ring members selected from nitrogen,sulfur and oxygen. In some embodiments, the heteroaryl group has 1,2, 3, or 4 heteroatom ring members. In some embodiments, theheteroaryl group has 1, 2, or 3 heteroatom ring members. In someembodiments, the heteroaryl group has 1 or 2 heteroatom ringmembers. In some embodiments, the heteroaryl group has 1 heteroatomring member. In some embodiments, the heteroaryl group is 5- to10-membered or 5- to 6-membered. In some embodiments, theheteroaryl group is 5-membered. In some embodiments, the heteroarylgroup is 6-membered. In some embodiments, the heteroaryl group is9- or 10-membered bicyclic. In some embodiments, the heteroaryl is9-member bicyclic. When the heteroaryl group contains more than oneheteroatom ring member, the heteroatoms may be the same ordifferent. The nitrogen atoms in the ring(s) of the heteroarylgroup can be oxidized to form N-oxides. Example heteroaryl groupsinclude, but are not limited to, pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, pyrrolyl, pyrazolyl, azolyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, imidazolyl, furanyl, thiophenyl,triazolyl, tetrazolyl, thiadiazolyl, quinolinyl, isoquinolinyl,indolyl, benzothiopheneyl, benzofuranyl, benzisoxazolyl,benzoimidazolyl, imidazo[1, 2-b]thiazolyl, purinyl, triazinyl, andthe like. In some embodiments, the heteroaryl group is9H-carbazol-2-yl; 1H-benzo[d]imidazol-6-yl; 1H-indol-6-yl;1H-indazol-6-yl; 2H-indazol-4-yl; 1H-benzo[d][1,2,3]triazol-6-yl;benzo[d]oxazol-2-yl; quinolin-6-yl; or benzo[d]thiazol-2-yl.
As used herein, the term "heterocycloalkyl," employed alone or incombination with other terms, refers to a non-aromatic heterocyclicring system, which may optionally contain one or more unsaturationsas part of the ring structure, and which has at least oneheteroatom ring member independently selected from nitrogen, sulfurand oxygen. In some embodiments, the heterocycloalkyl group has 1,2, 3, or 4 heteroatom ring members. In some embodiments, theheterocycloalkyl group has 1, 2, or 3 heteroatom ring members. Insome embodiments, the heterocycloalkyl group has 1 or 2 heteroatomring members. In some embodiments, the heterocycloalkyl group has 1heteroatom ring member. When the heterocycloalkyl group containsmore than one heteroatom in the ring, the heteroatoms may be thesame or different. Example ring-forming members include CH,CH.sub.2, C(O), N, NH, O, S, S(O), and S(O).sub.2. Heterocycloalkylgroups can include mono- or polycyclic (e.g., having 2, 3 or 4fused rings) ring systems. Polycyclic rings can include both fusedsystems and spirocycles. Also included in the definition ofheterocycloalkyl are moieties that have one or more aromatic ringsfused (i.e., having a bond in common with) to the non-aromaticring, for example, 1, 2, 3, 4-tetrahydro-quinoline,dihydrobenzofuran and the like. A heterocycloalkyl group thatincludes a fused aromatic moiety can be attached to the moleculethrough an atom from either the aromatic or non-aromatic portion.The carbon atoms or heteroatoms in the ring(s) of theheterocycloalkyl group can be oxidized to form a carbonyl,sulfinyl, or sulfonyl group (or other oxidized linkage) or anitrogen atom can be quaternized. In some embodiments,heterocycloalkyl is 5- to 10-membered, 4- to 10-membered, 4- to7-membered, 5-membered, or 6-membered. Examples of heterocycloalkylgroups include 1, 2, 3, 4-tetrahydro-quinolinyl,dihydrobenzofuranyl, azetidinyl, azepanyl, pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, andpyranyl. Examples of heterocycloalkyl groups that include one ormore fused aromatic groups (e.g., aryl or heteroaryl) includeN-(2'-oxospiro[cyclohexane-1,3'-indolin]-6'-yl;1,2,3,4-tetrahydroisoquinolin-6-yl;2,3-dihydro-1H-benzo[d]imidazol-5-yl;1,3-dihydrospiro[indene-2,3'-indolin]-6'-yl;2,3-dihydrobenzo[d]oxazol-5-yl; 1,2-dihydroquinolin-7-yl;indolin-6-yl; spiro[cyclopentane-1,3'-indolin]-6'-yl;spiro[cyclohexane-1,3'-indolin]-6'-yl; chroman-6-yl;3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl; andbenzo[d][1,3]dioxol-5-yl.
As used herein, the term "arylalkyl," employed alone or incombination with other terms, refers to an alkyl group substitutedby an aryl group.
As used herein, the term "cycloalkylalkyl," employed alone or incombination with other terms, refers to an alkyl group substitutedby a cycloalkyl group.
As used herein, the term "heteroarylalkyl," employed alone or incombination with other terms, refers to an alkyl group substitutedby a heteroaryl group.
As used herein, the term "hetercycloalkylalkyl," employed alone orin combination with other terms, refers to an alkyl groupsubstituted by a heterocycloalkyl group.
As used herein, the term "C.sub.i-j alkylsulfinyl," employed aloneor in combination with other terms, refers to a group of formulat--S(.dbd.O)--(C.sub.i-j alkyl).
As used herein, the term "C.sub.i-j alkylsulfinyl," employed aloneor in combination with other terms, refers to a group of formulat--S(.dbd.O).sub.2--(C.sub.i-j alkyl).
As used herein, the term "carboxy," employed alone or incombination with other terms, refers to a --C(.dbd.O)OH group.
As used herein, the term "C.sub.i-j alkylcarbonyl," employed aloneor in combination with other terms, refers to a group of formula--C(.dbd.O)--(C.sub.i-j alkyl).
As used herein, the term "C.sub.i-j alkoxycarbonyl," employed aloneor in combination with other terms, refers to a group of formula--C(.dbd.O)O--(C.sub.i-j alkyl).
As used herein, the term "aminocarbonyl," employed alone or incombination with other terms, refers to a group of formula--C(.dbd.O)NH.sub.2.
The compounds described herein can be asymmetric (e.g., having oneor more stereocenters). All stereoisomers, such as enantiomers anddiastereoisomers, are intended unless otherwise indicated. Where acompound name or structure is silent with respect to thestereochemistry of a stereocenter, all possible configurations atthe stereocenter are intended. Compounds of the present inventionthat contain asymmetrically substituted carbon atoms can beisolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically inactive startingmaterials are known in the art, such as by resolution of racemicmixtures or by stereoselective synthesis. Geometric isomers ofolefins, C.dbd.N double bonds, and the like can also be present inthe compounds described herein, and all such stable isomers arecontemplated in the present invention. Cis and trans geometricisomers of the compounds of the present invention are described andmay be isolated as a mixture of isomers or as separated isomericforms.
When the compounds of the invention contain a chiral center, thecompounds can be any of the possible stereoisomers. In compoundswith a single chiral center, the stereochemistry of the chiralcenter can be (R) or (S). In compounds with two chiral centers, thestereochemistry of the chiral centers can each be independently (R)or (S) so the configuration of the chiral centers can be (R) and(R), (R) and (S); (S) and (R), or (S) and (S). In compounds withthree chiral centers, the stereochemistry each of the three chiralcenters can each be independently (R) or (S) so the configurationof the chiral centers can be (R), (R) and (R); (R), (R) and (S);(R), (S) and (R); (R), (S) and (S); (S), (R) and (R); (S), (R) and(S); (S), (S) and (R); or (S), (S) and (S).
Resolution of racemic mixtures of compounds can be carried out byany of numerous methods known in the art. An example methodincludes fractional recrystallization using a chiral resolving acidwhich is an optically active, salt-forming organic acid. Suitableresolving agents for fractional recrystallization methods are, forexample, optically active acids, such as the D and L forms oftartaric acid, diacetyltartaric acid, dibenzoyltartaric acid,mandelic acid, malic acid, lactic acid or the various opticallyactive camphorsulfonic acids such as .beta.-camphorsulfonic acid.Other resolving agents suitable for fractional crystallizationmethods include stereoisomerically pure forms of.alpha.-methylbenzylamine (e.g., S and R forms, ordiastereoisomerically pure forms), 2-phenylglycinol, norephedrine,ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.
Resolution of racemic mixtures can also be carried out by elutionon a column packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent compositioncan be determined by one skilled in the art.
When a disclosed compound is named or depicted without indicatingthe stereochemistry of one or more stereocenters, each of thestereoisomers resulting from the possible stereochemistries at theundefined stereocenter(s) are intended to be encompassed. Forexample, if a stereocenter is not designated as R or S, then eitheror both are intended.
Compounds of the invention also include tautomeric forms.Tautomeric forms result from the swapping of a single bond with anadjacent double bond together with the concomitant migration of aproton. Tautomeric forms include prototropic tautomers which areisomeric protonation states having the same empirical formula andtotal charge. Example prototropic tautomers include ketone-enolpairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidicacid pairs, enamine-imine pairs, and annular forms where a protoncan occupy two or more positions of a heterocyclic system, forexample, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1, 2, 4-triazole,1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms canbe in equilibrium or sterically locked into one form by appropriatesubstitution.
Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different massnumbers. Isotopes of constituent atoms of the compounds of theinvention can be present in natural or non-natural abundance.Examples of isotopes of hydrogen include deuterium and tritium. Insome embodiments, the compounds of the invention are deuterated,meaning at least one deuterium atom is present in the place of ahydrogen atom. In some embodiments, 1, 2, 3, 4, 5, 6, 7, or 8hydrogens in a compound of the invention are replaced by deuterium.Methods for replacing hydrogen with deuterium in a molecule areknown in the art.
The term "compound" as used herein is meant to include allstereoisomers, geometric isomers, tautomers, and isotopes of thestructures depicted. Compounds herein identified by name orstructure as one particular tautomeric form are intended to includeother tautomeric forms unless otherwise specified (e.g., in thecase of purine rings, unless otherwise indicated, when the compoundname or structure has the 9H tautomer, it is understood that the 7Htautomer is also encompassed).
All compounds, and pharmaceutically acceptable salts thereof, canbe found together with other substances such as water and solvents(e.g., hydrates and solvates) or can be isolated.
In some embodiments, the compounds of the invention, or saltsthereof, or crystalline forms of any of the aforementioned, arepurified or substantially isolated. By "substantially isolated" ismeant that the compound is at least partially or substantiallyseparated from the environment in which it was formed or detected.Partial separation can include, for example, a composition enrichedin a compound of the invention. Substantial separation can includecompositions containing at least about 50%, at least about 60%, atleast about 70%, at least about 80%, at least about 90%, at leastabout 95%, at least about 97%, or at least about 99% by weight ofthe compounds of the invention, or salt thereof. In someembodiments, the compounds of the invention, or salts thereof, orcrystalline forms of any of the aforementioned, can be preparedwith a purity of about 75% or more, 80% or more, 85% or more, 90%or more, 95% or more, 98% or more, or 99% or more.
The phrase "pharmaceutically acceptable" is employed herein torefer to those compounds, materials, compositions, and/or dosageforms which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of human beings andanimals without excessive toxicity, irritation, allergic response,or other problem or complication, commensurate with a reasonablebenefit/risk ratio.
The expressions, "ambient temperature" and "room temperature," asused herein, are understood in the art, and refer generally to atemperature, e.g., a reaction temperature, that is about thetemperature of the room in which the reaction is carried out, forexample, a temperature from about 20.degree. C. to about 30.degree.C.
The present invention also includes pharmaceutically acceptablesalts of the compounds described herein. As used herein,"pharmaceutically acceptable salts" refers to derivatives of thedisclosed compounds wherein the parent compound is modified byconverting an existing acid or base moiety to its salt form.Examples of pharmaceutically acceptable salts include, but are notlimited to, mineral or organic acid salts of basic residues such asamines; alkali or organic salts of acidic residues such ascarboxylic acids; and the like. The pharmaceutically acceptablesalts of the present invention include the conventional non-toxicsalts of the parent compound formed, for example, from non-toxicinorganic or organic acids. The pharmaceutically acceptable saltsof the present invention can be synthesized from the parentcompound which contains a basic or acidic moiety by conventionalchemical methods. Generally, such salts can be prepared by reactingthe free acid or base forms of these compounds with astoichiometric amount of the appropriate base or acid in water orin an organic solvent, or in a mixture of the two; generally,non-aqueous media like ether, ethyl acetate, alcohols (e.g.,methanol, ethanol, iso-propanol, or butanol) or acetonitrile (MeCN)are preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17.sup.th Ed., (Mack Publishing Company,Easton, 1985), p. 1418, Berge et al., J. Pharm. Sci., 1977, 66(1),1-19, and in Stahl et al., Handbook of Pharmaceutical Salts:Properties, Selection, and Use, (Wiley, 2002).
As used herein the terms "subject" and "patient" may be usedinterchangeably, and means a mammal in need of treatment, e.g.,companion animals (e.g., dogs, cats, and the like), farm animals(e.g., cows, pigs, horses, sheep, goats and the like) andlaboratory animals (e.g., rats, mice, guinea pigs and the like).Typically, the subject or patient is a human in need oftreatment.
Synthesis
Compounds of the invention, including salts thereof, can beprepared using known organic synthesis techniques and can besynthesized according to any of numerous possible syntheticroutes.
The reactions for preparing compounds of the invention can becarried out in suitable solvents which can be readily selected byone of skill in the art of organic synthesis. Suitable solvents canbe substantially non-reactive with the starting materials(reactants), the intermediates, or products at the temperatures atwhich the reactions are carried out, e.g., temperatures which canrange from the solvent's freezing temperature to the solvent'sboiling temperature. A given reaction can be carried out in onesolvent or a mixture of more than one solvent. Depending on theparticular reaction step, suitable solvents for a particularreaction step can be selected by the skilled artisan.
Preparation of compounds of the invention can involve theprotection and deprotection of various chemical groups. The needfor protection and deprotection, and the selection of appropriateprotecting groups ("Pg"), can be readily determined by one skilledin the art. The chemistry of protecting groups ("Pg") can be found,for example, in P. G. M. Wuts and T. W. Greene, Protective Groupsin Organic Synthesis, 4.sup.th Ed., Wiley & Sons, Inc., NewYork (2006), which is incorporated herein by reference in itsentirety.
Compounds of the invention can be prepared employing conventionalmethods that utilize readily available reagents and startingmaterials. The reagents used in the preparation of theintermediates of this invention can be either commercially obtainedor can be prepared by standard procedures described in theliterature. Various technologies such as solid phase chemistry,microwave chemistry or flow chemistry etc., can also be utilized tosynthesize intermediates or final compounds. Furthermore, othermethods of preparing compounds of the invention will be readilyapparent to person of ordinary skill in the art in light of thefollowing reaction and schemes and examples. Unless otherwiseindicated all the variables are defined below. Suitable method ofsynthesis are described in the following references: March,Advanced Organic Chemistry, 3.sup.rd edition, John Wiley &Sons, 1985; Greene and Wuts, Protective Groups in OrganicChemistry, 2.sup.nd edition, John Wiley & Sons 1991; andLarock, Comprehensive Organic Transformations, 4.sup.th edition,VCH publishers Inc., 1989. Furthermore, in any one synthesis, oneor more of the reagents, intermediates or chemicals may be used inexcess amount to ensure the completion of reaction. Suitablereaction temperatures generally range from about 0.degree. C. toabout the boiling point of the solvent. More typically,temperatures are sufficiently high to allow refluxing, for example,about 68.degree. C. for tetrahydrofuran. In some cases, such asmicrowave conditions, the temperature of the reaction may exceedthe boiling point of the solvent.
The compounds of the invention can be synthesized by the methodsdescribed in Schemes 1-3 below. Many of the synthetic steps arewell described in as in F. A. Carey, R. J. Sundberg, AdvancedOrganic Chemistry, 2.sup.nd ed., Plenum publication in 1983. Thesynthesis of various hydroxyl-substituted heterocycles is welldocumented in the literature and can be synthesized by knownliterature methods. The general synthesis of useful heterocyclicrings are referenced in The Handbook of Heterocyclic Chemistry,Alan R. Katritzky; Pergamon Press, NY, USA, 1st ed. 1986. Thedepicted intermediates may also be available as commercial reagentsfrom numerous vendors.
##STR00016##
The compounds of the invention can be synthesized by numerousmethods, based on retro synthetic analysis of final targets.Exemplary methods are shown in routes A, B & C.
Route A:
This method involves coupling of amine Intermediate I with variousaldehydes, amines, acids, aryl halides, and the like. The aldehydesand ketones can be condensed with Intermediate I by reductiveamination. This method involves reaction of aldehydes or ketoneswith amine in presence of a reducing agent (e.g., sodiumcyanoborohydride or triacetoxy sodium cyanoborohydride). Variousalternative methods for reaction of amines with aldehyde andketones under reductive conditions are well known in the art. Forexample, these reactions can be performed in various protic andaprotic solvents and at temperatures from -78.degree. C. torefluxing conditions. One method involves reaction of amines withaldehydes or ketones in solvents such as, for example, methanol,ethanol, tetrahydrofuran, dichloromethane or 1,2-dichloroethane ora combination thereof in presence of a reducing agent (e.g.,triacetoxy sodium borohydride or sodium cyanoborohydride) betweenRT and refluxing conditions in the presence or absence of microwavereactor.
Route B:
This method involves the coupling of Intermediate II withIntermediate III. The Intermediate II (W.dbd.NH) can besynthesized, for example, from various spirocyclic amines usingknown synthetic procedures as described in literature and bymethods known to a person skilled in the art. For example,Intermediate III can be synthesized by any of the various methodsdescribed below. The leaving group (LVG) can be any suitable groupsuch as, for example, a halogen, mesylate, tosylate, or any othergroups that can be suitable for nucleophilic substitution catalyzedby base or by metal catalyzed displacement (e.g., copper,palladium, and the like). These methods are well described inHandbook of Reagents for Organic Synthesis, Catalyst Components forCoupling Reactions; Gary Molander, 1st. edition, 2013; John Wiley& sons. One method involves reaction of halo derivatives ofIntermediate III with amine under protic or aprotic solvents in thepresence of organic or inorganic base at elevated temperature. Anadditional example involves treatment of chloro derivatives ofIntermediate III with an amine in an aprotic solvent (e.g., DMF orDMSO) in the presence of organic base (e.g., triethylamine orpyridine) at elevated temperatures. For compounds of IntermediateII where W is carbon the reaction can be performed, for example, bya cross coupling reaction of vinyl boronates of spiroamines withIntermediate III, followed by hydrogenation to yield carbonanalogs.
Route C:
The final compound can be synthesized from Intermediate IV byfunctional group modification. The functional group may be, forexample, an acid, alcohol, amine, aryl halide, and the like. Thisreaction utilizes amines with various acylating agents (e.g., acylchloride, sulfonyl chloride, isocyanates, and the like).Alternatively, functional groups such as acid can be converted toamides. Aryl halides can be converted to the desired product usingconventional methods known for other functional groups and many ofthese functional group transformations are well known in literatureand described in "Comprehensive Organic Transformations: A Guide toFunctional Group Preparations" by Richard C. Larock, Edition 2,1999, Wiley & Sons. One functional group transformationinvolves reaction of an amine with various acylating agents (e.g.,acyl chloride or sulfonyl chloride) in the presence of an aproticsolvent and base. Another example involves reaction of an aminewith sulfonyl chloride in dichloromethane in the presence of anorganic base (e.g., pyridine, trimethylamine, and the like).
##STR00017##
Intermediate I can be synthesized by numerous methods as depictedin Scheme 2. Exemplary methods are shown in routes D, E &F.
Route D:
The method employed in route D is analogous to the method employedin route B (Scheme 1). For spirodiamines, one of the aminefunctionalities may be selectively protected so as to perform thereaction in a regioselective manner. The protecting groups arechosen such that they can be compatible with other functionalgroups and their transformations, and can be removed selectively.Various amine protecting groups are well known in literature andare well documented in Greene's Protective Groups in OrganicSynthesis by Peter G. M. Wuts & Theodora W. Greene; 4thEdition; 2006, Wiley-Interscience. Commonly used amine protectinggroup include, for example, tert-butoxycarbonyl which is cleavedunder acidic condition in aprotic solvents. One example methodcomprises the use of trifluoroacetic acid or hydrochloride gas inaprotic solvents (e.g., 1,4-dioxane, dichloromethane, and the like)at RT.
Route E:
The functional group Fg of Intermediate V can undergo variousfunctional group transformation to prepare Intermediate I. Suchtransformations are well documented in the literature, for example,as in Advanced Organic Chemistry: Reactions, Mechanisms, andStructure, by Jerry March, Wiley-Interscience; 6 edition 2007. Anexample reaction involves the cross coupling of an aryl halide(e.g., where Fg is a halogen) of Intermediate V with variousboronates, tin reagents, and the like. These cross couplingreactions can be effected with various metal catalysts (e.g.,copper, palladium, rhodium, and the like) in a variety ofprotic/aprotic solvents or combination thereof, in the presence ofinorganic or organic bases at temperatures varying from RT toelevated temperatures. An optional microwave reactor may also beused. An example method involves reaction of a chloro- orbromo-derivative of Intermediate V with an aryl Suzuki reagent inthe presence of a palladium catalyst in various solvents (e.g.,DMF, toluene/water, and the like) at elevated temperature inpresence of inorganic base (e.g., cesium carbonate or potassiumphosphate). In certain cases further functionalization can beperformed to arrive at the desired compound. For example, an Fghalo group in Intermediate V can be converted into an acid andfurther converted into an amide, alcohol, ether, and the like.Similarly, the Fg halo group of Intermediate V can be convertedinto a cyano group, which can be further converted into otherfunctional groups as is well known in the art.
Route F:
This method involves reactions of phenols, thiols, anilines with3-halopyridines or 5-halo pyrimidine using metal mediatedreactions. The nucelophilic displacement of 3-halopyridines or5-halo pyrimidine by phenols, anilines and aryl thiols are wellknown in literature as described, for example, in Copper-MediatedCross-Coupling Reactions by Gwilherm Evano & Nicolas Blanchardby John Wiley & Sons, Edition 1, 2013. For example,Intermediate VII can be synthesized from a 3,4-di halopyridine or a4,5-dihalo pyrimidine by reaction with a spiroamine using methodssimilar to that described in Route B. Additionally, the carbonanalog can be synthesized, for example, by cross coupling reactionof Intermediate VII with various alkyl zinc halides in the presenceof metal catalyst as described in "Applied Cross-CouplingReactions" by Yasushi Nishihara Springer Science Edition 1, 2013.An example method involves reaction of benzyl zinc bromide withpalladium catalyst in an aprotic solvent (e.g., diethylether ortetrahydrofuran) at elevated temperature in the presence or absenceof a microwave reactor. Fluoro substituted phenols, anilines, andthiols are well known in literature and can be synthesized byvarious methods known to one skilled in the art.
Various methods are available for synthesis of Intermediate IIIcontaining a pyrimide-phenol ether. Some of the methods areillustrated in Scheme 3, Routes A and B
##STR00018##
Scheme 3, Route A involves reaction of a phenol with a 2-haloacetate. This method is well known in literature and described, forexample, in Journal of Medicinal Chemistry (1980), 23(9), 1026-31.This reaction is achieved by converting a phenol into thecorresponding phenolate by reaction with a metal hydride in anaprotic solvent (e.g., DMF, THF, and the like). One exampleinvolves reaction of phenol with sodium hydride in an aproticsolvents (e.g., DMF), followed by addition of methylchloroacetatein the same pot at temperature varying from -78.degree. C. to RT.The 2-phenoxyacetate intermediate is further condensed withformaldehyde in presence of a metal hydride (e.g., NaH) in anaprotic solvent as described in the first step. This intermediateis then reacted with thiourea in a protic solvent (e.g., alcohol)under elevated temperature to yield 2-thiopyrimidine intermediate.The thiopyrimidine can be reduced to pyrimidine or converted to2-substituted pyrimidine by various synthetic routes known in theliterature. An example method involves reduction of thiopyrimidineto pyrimidine under metal catalyzed hydrogenation conditions (e.g.,nickel in a protic solvent such as ethanol, and the like). The4-pyrimidone intermediate can then be converted to a4-halopyrimidone by reaction with a chlorinating solvent (e.g.,thionyl chloride, phosphorousoxy trichloride, and the like) eitherneat or in an aprotic solvent (e.g., toluene, THF, and the like) atelevated temperature. Alternatively the 4-pyrimidone can be reactedwith a sulfonyl chloride (e.g., methane sulfonyl chloride ortrifluoromethane sulfonyl chloride) to generate a sulfonate as aleaving group suitable for nucleophilic displacement, which can befurther utilized in preparing the desired compounds as describedherein in Schemes 1 and 2.
##STR00019##
The first step in Scheme 3, Route B, involves the coupling ofphenol with 5-halopyrimidine as described, for example, in OrganicLetters, 14(1), 170-173; 2012, or in Journal of Organic Chemistry,75(5), 1791-1794; 2010. The resulting pyrimidine can then beoxidized with a peracid in an aprotic solvent at RT to yield apyrimidine N-oxide. An example method involves reaction ofpyrimdine ether with meta-perchloro perbenzoic acid in ahalogenated solvent (e.g., dichloromethane, 1,2-dichloroethane, andthe like) as described in J. Org. Chem., 1985, 50 (17), pp3073-3076. The crude intermediate can be further treated withphosphorousoxytrichloride or phosphorous pentachloride to yieldIntermediate III as described in Int. Patent Appl. No., WO2009/137733.
Methods of Use
The compounds of the invention are inhibitors of the interaction ofmenin with MLL and MLL fusion proteins. In some embodiments, thepresent invention is directed to a method of inhibiting theinteraction between menin and MLL or an MLL fusion protein bycontacting menin and MLL or the MLL fusion protein with a compoundof the invention. The contacting can be carried out in vitro or invivo. In some embodiments, the compounds of the invention can bindto menin, thereby interfering with the binding of MLL to menin. Insome embodiments, the present invention provides a method ofinhibiting the activity of menin by contacting menin with acompound of the invention in the presence of MLL or an MLL fusionprotein. In further embodiments, the present invention provides amethod of inhibiting the binding of MLL or an MLL fusion protein tomenin, comprising contacting menin with a compound of the inventionin the presence of the MLL or MLL fusion protein.
The compounds of the invention are also useful in treating diseasesassociated with the menin-MLL interaction or menin-MLL fusionprotein interaction. For example, diseases and conditions treatableaccording to the methods of the invention include cancer, such asleukemia, and other diseases or disorders mediated by the menin-MLLinteraction or menin-MLL fusion protein interaction such asdiabetes.
Accordingly, the compounds of the invention are believed to beeffective against a broad range of cancers, including, but notlimited to, hematological cancer (e.g., leukemia and lymphoma),bladder cancer, brain cancer (e.g., glioma, diffuse intrinsicpontine glioma (DIPG)), breast cancer (e.g., triple-negative breastcancer, estrogen-receptor-positive breast cancer (i.e., ER+ breastcancer)), colorectal cancer, cervical cancer, gastrointestinalcancer (e.g., colorectal carcinoma, gastric cancer), genitourinarycancer, head and neck cancer, liver cancer, lung cancer, melanoma,ovarian cancer, pancreatic cancer, prostate cancer (e.g.,castration resistant prostate cancer), renal cancer (e.g., renalcell carcinoma), skin cancer, thyroid cancer (e.g., papillarythyroid carcinoma), testicular cancer, sarcoma (e.g., Ewing'ssarcoma), and AIDS-related cancers. In some embodiments, the canceris associated with a rearranged MLL gene. In some embodiments, thepathophysiology of the cancer is dependent on the MLL gene. In someembodiments, the cancer is associated with mutant p53gain-of-function.
In some embodiments, the specific cancers that may be treated bythe compounds, compositions and methods described herein includecardiac cancers, such as for example, sarcoma (e.g., angiosarcoma,fibrosarcoma, rhabdomyosarcoma, and liposarcoma), myxoma,rhabdomyoma, fibroma, lipoma and teratoma; lung cancers, including,for example, bronchogenic carcinoma (e.g., squamous cell,undifferentiated small cell, undifferentiated large cell, andadenocarcinoma), alveolar and bronchiolar carcinoma, bronchialadenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma,non-small cell lung cancer, small cell lung cancer, bronchialadenomas/carcinoids, and pleuropulmonary blastoma; gastrointestinalcancer, including, for example, cancers of the esophagus (e.g.,squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, andlymphoma), cancers of the stomach (e.g., carcinoma, lymphoma, andleiomyosarcoma), cancers of the pancreas (e.g., ductaladenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoidtumors, and vipoma), cancers of the small bowel (e.g.,adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma,leiomyoma, hemangioma, lipoma, neurofibroma, and fibroma), cancersof the large bowel or colon, (e.g., adenocarcinoma, tubularadenoma, villous adenoma, hamartoma, and leiomyoma), and othercancers of the digestive tract (e.g., anal cancer, anorectalcancer, appendix cancer, cancer of the anal canal, cancer of thetongue, gallbladder cancer, gastrointestinal stromal tumor (GIST),colon cancer, colorectal cancer, extrahepatic bile duct cancer,intrahepatic bile duct cancer, rectal cancer, and small intestinecancer); genitourinary tract cancers, including, for example,cancers of the kidney (e.g., adenocarcinoma, Wilm's tumor(nephroblastoma), lymphoma, and leukemia), cancers of the bladderand urethra (e.g., squamous cell carcinoma, transitional cellcarcinoma, and adenocarcinoma), cancers of the prostate (e.g.,adenocarcinoma and sarcoma), cancers of the testis, (e.g.,seminoma, teratoma, embryonal carcinoma, teratocarcinoma,choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma,fibroadenoma, adenomatoid tumors, and lipoma), as well astransitional cell cancer, transitional cell cancer of the renalpelvis and ureter and other urinary organs, urethral cancer, andurinary bladder cancer; liver cancers, including, for example,hepatoma (e.g., hepatocellular carcinoma), cholangiocarcinoma,hepatoblastoma, angiosarcoma, hepatocellular adenoma, andhemangioma; bone cancers, including, for example, osteogenicsarcoma (osteosarcoma), fibrosarcoma, malignant fibroushistiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma(reticulum cell sarcoma), multiple myeloma, malignant giant celltumor chordoma, osteochrondroma (osteocartilaginous exostoses),benign chondroma, chondroblastoma, chondromyxofibroma, osteoidosteoma and giant cell tumors; nervous system cancers, including,for example, cancers of the skull (e.g., osteoma, hemangioma,granuloma, xanthoma, and osteitis deformans); cancers of themeninges (e.g., meningioma, meningiosarcoma, and gliomatosis);cancers of the brain (e.g., astrocytoma, medulloblastoma, glioma,ependymoma, germinoma (pinealoma), glioblastoma multiforme,oligodendroglioma, schwannoma, retinoblastoma, and congenitaltumors); cancers of the spinal cord (e.g., neurofibroma,meningioma, glioma, and sarcoma), and other nervous system cancers(e.g., brain stem glioma, diffuse intrinsic pontine glioma (DIPG),brain tumor, central nervous system cancer, cerebellar astrocytoma,cerebral astrocytoma/malignant glioma, childhood cerebellarastrocytoma, childhood cerebral astrocytoma, primary centralnervous system lymphoma, visual pathway and hypothalamic glioma,nervous system lymphoma, supratentorial primitive neuroectodeimaltumors, pineoblastoma and supratentorial primitive neuroectodermaltumors); gynecological cancers, including, for example, cancers ofthe uterus (e.g., endometrial carcinoma), cancers of the cervix(e.g., cervical carcinoma, and pre tumor cervical dysplasia),cancers of the ovaries (e.g., ovarian carcinoma, including serouscystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiedcarcinoma, granulosa thecal cell tumors, Sertoli Leydig celltumors, dysgerminoma, and malignant teratoma), cancers of the vulva(e.g., squamous cell carcinoma, intraepithelial carcinoma,adenocarcinoma, fibrosarcoma, and melanoma), cancers of the vagin*(e.g., clear cell carcinoma, squamous cell carcinoma, botryoidsarcoma, and embryonal rhabdomyosarcoma), and cancers of thefallopian tubes (e.g., carcinoma); other reproductive tractcancers, including, for example, endometrial cancer, endometrialuterine cancer, germ cell tumor, gestational trophoblastic tumor,gestational trophoblastic tumor glioma, ovarian epithelial cancer,ovarian germ cell tumor, ovarian low malignant potential tumor,penile cancer, vagin*l cancer, vulvar cancer, extracranial germcell tumor, extragonadal germ cell tumor, uterine cancer, uterinecorpus cancer, uterine sarcoma; lymphatic and hematologic cancers,including, for example, cancers of the blood (e.g., acute myeloidleukemia (AML), chronic myeloid leukemia (CML), acute lymphoblasticleukemia (ALL), chronic lymphoblastic leukemia, chronic lymphocyticleukemia, myeloproliferative diseases, multiple myeloma, andmyelodysplastic syndrome, Hodgkin's lymphoma, non Hodgkin'slymphoma (malignant lymphoma) and Waldenstrom's macroglobulinemia),and other lymphatic or hematologic cancers including, for example,childhood leukemia, myeloproliferative disorders (e.g., primarymyelofibrosis), plasma cell neoplasm/multiple myeloma,myelodysplasia, myelodysplastic syndrome, cutaneous T-celllymphoma, lymphoid neoplasm, AIDS-related lymphoma, thymoma,thymoma and thymic carcinoma, mycosis fungoides, and SezarySyndrome; skin cancers, including, for example, malignant melanoma,basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma,moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids,psoriasis, merkel cell carcinoma, merkel cell skin carcinoma,melanoma, and carcinoid tumor; adrenal gland cancers, including,for example, neuroblastoma; other cancers associated with theendocrine system including, for example, adrenocortical carcinoma,multiple endocrine neoplasia (e.g., multiple endocrine neoplasiatype I), multiple endocrine neoplasia syndrome, parathyroid cancer,pituitary tumor, pheochromocytoma, islet cell pancreatic cancer,and islet cell tumors); connective tissue cancer (e.g., bonecancer, bone and joint cancer, osteosarcoma and malignant fibroushistiocytoma); cancer associated with the head, neck, and mouth(e.g., head and neck cancer, paranasal sinus and nasal cavitycancer, metastatic squamous neck cancer, mouth cancer, throatcancer, esophageal cancer, laryngeal cancer, pharyngeal cancer,hypopharyngeal cancer, lip and oral cavity cancer, nasopharyngealcancer, oral cancer, oropharyngeal cancer, and salivary glandcancer); and cancer associated with the eye (e.g., ocular cancer,intraocular melanoma). In some embodiments, the cancer is Ewing'ssarcoma.
In some embodiments, the cancer is a hematological cancer such asleukemia or lymphoma. Example leukemia and lymphomas treatable bythe compounds of the invention include mixed lineage leukemia(MLL), MLL-related leukemia, MLL-associated leukemia, MLL-positiveleukemia, MLL-induced leukemia, rearranged mixed lineage leukemia(MLL-r), leukemia associated with a MLL rearrangement or arearrangement of the MLL gene, acute leukemia, chronic leukemia,indolent leukemia, lymphoblastic leukemia, lymphocytic leukemia,myeloid leukemia, myelogenous leukemia, childhood leukemia, acutelymphocytic leukemia (ALL) (also referred to as acute lymphoblasticleukemia or acute lymphoid leukemia), acute myeloid leukemia (AML)(also referred to as acute myelogenous leukemia or acutemyeloblastic leukemia), acute granulocytic leukemia, acutenonlymphocytic leukemia, chronic lymphocytic leukemia (CLL) (alsoreferred to as chronic lymphoblastic leukemia), chronic myelogenousleukemia (CML) (also referred to as chronic myeloid leukemia),therapy related leukemia, myelodysplastic syndrome (MDS),myeloproliferative disease (MPD) (such as primary myelofibrosis(PMF)), myeloproliferative neoplasia (MPN), plasma cell neoplasm,multiple myeloma, myelodysplasia, cutaneous T-cell lymphoma,lymphoid neoplasm, AIDS-related lymphoma, thymoma, thymiccarcinoma, mycosis fungoides, Alibert-Bazin syndrome, granulomafungoides, Sezary Syndrome, hairy cell leukemia, T-cellprolymphocytic leukemia (T-PLL), large granular lymphocyticleukemia, meningeal leukemia, leukemic leptomeningitis, leukemicmeningitis, multiple myeloma, Hodgkin's lymphoma, non Hodgkin'slymphoma (malignant lymphoma), and Waldenstrom's macroglobulinemia.In some embodiments, the acute myeloid leukemia (AML) is abstractnucleophosmin (NPM1)-mutated acute myeloid leukemia (i.e.,NPM1.sup.mut acute myloid leukemia).
In particular embodiments, compounds of the invention are used totreat leukemia associated with a MLL rearrangement, acutelymphocytic leukemia associated with a MLL rearrangement, acutelymphoblastic leukemia associated with a MLL rearrangement, acutelymphoid leukemia associated with a MLL rearrangement, acutemyeloid leukemia associated with a MLL rearrangement, acutemyelogenous leukemia associated with a MLL rearrangement, or acutemyeloblastic leukemia associated with a MLL rearrangement. As usedherein, "MLL rearrangement" means a rearrangement of the MLLgene.
In some embodiments, diseases and conditions treatable withcompounds of the invention include insulin resistance,pre-diabetes, diabetes (e.g., Type 2 diabetes or Type 1 diabetes),and risk of diabetes. In some embodiments, diseases and conditionstreatable with compounds of the invention include hyperglycemia. Insome embodiments, the hyperglycemia is associated with diabetes,such as Type 2 diabetes. In some embodiments, compounds of theinvention are used to treat loss of response to other anti-diabeticagents and/or reduced beta cell function in a patient or subject.In some embodiments, compounds of the invention are used to restoreresponse to other anti-diabetic agents and/or to restore beta cellfunction and/or to reduce the need for insulin in a patient orsubject. In some embodiments, compounds of the invention are usedto reduce insulin resistance, reduce the risk of diabetes, orreduce increases in blood glucose caused by a statin in a subjecttaking a statin. In some embodiments, compounds of the inventionare used to treat diabetes in a subject taking a statin or toprevent diabetes in a subject taking a statin. Methods of theinvention include decreasing, reducing, inhibiting, suppressing,limiting or controlling in the patient elevated blood glucoselevels. In further aspects, methods of the invention includeincreasing, stimulating, enhancing, promoting, inducing oractivating in the subject insulin sensitivity. Statins include, butare not limited to atorvastatin, cerivastatin, fluvastatin,lovastatin, mevastatin, pitavastatin, pravastatin, rousuvastatinand simvastatin.
In some embodiments, a patient is treated with (e.g., administered)a compound of the present invention in an amount sufficient totreat or ameliorate one or more of the diseases and conditionsrecited above (e.g., a therapeutically effective amount). Thecompounds of the invention may also be useful in the prevention ofone or more of the diseases recited therein.
Combination Therapy
The invention further relates to a combination therapy for treatinga disease or a disorder described herein. In some embodiments, thecombination therapy comprises administering at least one compoundof the present invention in combination with one or more otherpharmaceutically active agents for treating cancer or otherdisorders mediated by menin/MLL. In some embodiments, thecombination therapy comprises administering at least one compoundof the present invention in combination with one or more otherpharmaceutically active agents, such as for the treatment ofcancer. The pharmaceutically active agents can be combined with acompound of the invention in a single dosage form, or thetherapeutics can be administered simultaneously or sequentially asseparate dosage forms.
The compounds according to the invention may also be used incombination with immunotherapies, including but not limited tocell-based therapies, antibody therapies and cytokine therapies,for the treatment of a disease or disorder disclosed herein.
In certain embodiments, compounds according to the invention areused in combination with one or more passive immunotherapies,including but not limited to naked monoclonal antibody drugs andconjugated monoclonal antibody drugs. Examples of naked monoclonalantibody drugs that can be used include, but are not limited torituximab (Rituxan.RTM.), an antibody against the CD20 antigen;trastuzumab (Herceptin.RTM.), an antibody against the HER2 protein;alemtuzumab (Lemtrada.RTM., Campath.RTM.), an antibody against theCD52 antigen; cetuximab (Erbitux.RTM.), an antibody against theEGFR protein; and bevacizumab (Avastin.RTM.) which is ananti-angiogenesis inhibitor of VEGF protein.
Examples of conjugated monoclonal antibodies that can be usedinclude, but are not limited to, radiolabeled antibody ibritumomabtiuxetan (Zevalin.RTM.); radiolabeled antibody tositumomab(Bexxar.RTM.); and immunotoxin gemtuzumab ozogamicin(Mylotarg.RTM.) which contains calicheamicin; BL22, an anti-CD22monoclonal antibody-immunotoxin conjugate; radiolabeled antibodiessuch as OncoScint.RTM. and ProstaScint.RTM.; brentuximab vedotin(Adcetris.RTM.); ado-trastuzumab emtansine (Kadcyla.RTM., alsocalled TDM-1).
Further examples of therapeutic antibodies that can be usedinclude, but are not limited to, REOPRO.RTM. (abciximab), anantibody against the glycoprotein IIb/IIIa receptor on platelets;ZENAPAX.RTM. (daclizumab) an immunosuppressive, humanized anti-CD25monoclonal antibody; PANOREX.TM., a murine anti-17-IA cell surfaceantigen IgG2a antibody; BEC2, a murine anti-idiotype (GD3 epitope)IgG antibody; IMC-C225, a chimeric anti-EGFR IgG antibody;VITAXIN.TM. a humanized anti-.alpha.V.beta.3 integrin antibody;Campath 1H/LDP-03, a humanized anti CD52 IgG1 antibody; Smart M195,a humanized anti-CD33 IgG antibody; LYMPHOCIDE.TM., a humanizedanti-CD22 IgG antibody; LYMPHOCIDE.TM. Y-90; Lymphoscan;Nuvion.RTM. (against CD3; CM3, a humanized anti-ICAM3 antibody;IDEC-114 a primatized anti-CD80 antibody; IDEC-131 a humanizedanti-CD40L antibody; IDEC-151 a primatized anti-CD4 antibody;IDEC-152 a primatized anti-CD23 antibody; SMART anti-CD3, ahumanized anti-CD3 IgG; 5G1.1, a humanized anti-complement factor 5(C5) antibody; D2E7, a humanized anti-TNF-.alpha. antibody; CDP870,a humanized anti-TNF-.alpha. Fab fragment; IDEC-151, a primatizedanti-CD4 IgG1 antibody; MDX-CD4, a human anti-CD4 IgG antibody;CD20-streptdavidin (+biotin-yttrium 90); CDP571, a humanizedanti-TNF-.alpha. IgG4 antibody; LDP-02, a humanizedanti-.alpha.4.beta.7 antibody; OrthoClone OKT4A, a humanizedanti-CD4 IgG antibody; ANTOVA.TM., a humanized anti-CD40L IgGantibody; ANTEGREN.TM., a humanized anti-VLA-4 IgG antibody; andCAT-152, a human anti-TGF-.beta..sub.2 antibody.
In certain embodiments, compounds according to the invention areused in combination with one or more targeted immunotherapiescontaining toxins but not an antibody, including but not limited todenileukin diftitox (Ontak.RTM.), IL-2 linked to diphtheriatoxin.
The compounds according to the invention may also be used incombination with adjuvant immunotherapies for the treatment of adisease or disorder disclosed herein. Such adjuvant immunotherapiesinclude, but are not limited to, cytokines, such asgranulocyte-macrophage colony-stimulating factor (GM-CSF),granulocyte-colony stimulating factor (G-CSF), macrophageinflammatory protein (MIP)-1-alpha, interleukins (including IL-1,IL-2, IL-4, IL-6, IL-7, IL-12, IL-15, IL-18, IL-21, and IL-27),tumor necrosis factors (including TNF-alpha), and interferons(including IFN-alpha, IFN-beta, and IFN-gamma); aluminum hydroxide(alum); Bacille Calmette-Guerin (BCG); Keyhole limpet hemocyanin(KLH); Incomplete Freund's adjuvant (IFA); QS-21; DETOX;Levamisole; and Dinitrophenyl (DNP), and combinations thereof, suchas, for example, combinations of interleukins, for example IL-2,with other cytokines, such as IFN-alpha.
In certain embodiments, compounds according to the invention areused in combination with vaccine therapy, including but not limitedto autologous and allogeneic tumor cell vaccines, antigen vaccines(including polyvalent antigen vaccines), dendritic cell vaccines,and viral vaccines.
In another embodiment, the present disclosure comprisesadministering to a subject with cancer an effective amount of acompound of the invention and one or more additional anti-cancertherapies selected from: surgery, anti-cancer agents/drugs,biological therapy, radiation therapy, anti-angiogenesis therapy,immunotherapy, adoptive transfer of effector cells, gene therapy orhormonal therapy. Examples of anti-cancer agents/drugs aredescribed below.
In some embodiments, the anti-cancer agents/drug is, for example,adriamycin, aactinomycin, bleomycin, vinblastine, cisplatin,acivicin; aclarubicin; acodazole hydrochloride; acronine;adozelesin; aldesleukin; altretamine; ambomycin; ametantroneacetate; aminoglutethimide; amsacrine; anastrozole; anthramycin;asparaginase; asperlin; azacitidine; azetepa; azotomycin;batimastat; benzodepa; bicalutamide; bisantrene hydrochloride;bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinarsodium; bropirimine; busulfan; cactinomycin; calusterone;caracemide; carbetimer; carboplatin; carmustine; carubicinhydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin;cladribine; crisnatol mesylate; cyclophosphamide; cytarabine;dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin;dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin;doxorubicin hydrochloride; droloxifene; droloxifene citrate;dromostanolone propionate; duazomycin; edatrexate; eflornithinehydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine;epirubicin hydrochloride; erbulozole; esorubicin hydrochloride;estramustine; estramustine phosphate sodium; etanidazole;etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride;fazarabine; fenretinide; floxuridine; fludarabine phosphate;fluorouracil; flurocitabine; fosquidone; fostriecin sodium;gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicinhydrochloride; ifosfamide; ilmofosine; iproplatin; irinotecanhydrochloride; lanreotide acetate; letrozole; leuprolide acetate;liarozole hydrochloride; lometrexol sodium; lomustine; losoxantronehydrochloride; masoprocol; maytansine; mechlorethaminehydrochloride; megestrol acetate; melengestrol acetate; melphalan;menogaril; mercaptopurine; methotrexate; methotrexate sodium;metoprine; meturedepa; mitindomide; mitocarcin; mitocromin;mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantronehydrochloride; mycophenolic acid; nocodazole; nogalamycin;ormaplatin; oxisuran; pegaspargase; peliomycin; pentamustine;peplomycin sulfate; perfosfamide; pipobroman; piposulfan;piroxantrone hydrochloride; plicamycin; plomestane; porfimersodium; porfiromycin; prednimustine; procarbazine hydrochloride;puromycin; puromycin hydrochloride; pyrazofurin; riboprine;rogletimide; safingol; safingol hydrochloride; semustine;simtrazene; sparfosate sodium; sparsomycin; spirogermaniumhydrochloride; spiromustine; spiroplatin; streptonigrin;streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur;teloxantrone hydrochloride; temoporfin; teniposide; teroxirone;testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin;tirapazamine; toremifene citrate; trestolone acetate; triciribinephosphate; trimetrexate; trimetrexate glucuronate; triptorelin;tubulozole hydrochloride; uracil mustard; uredepa; vapreotide;verteporfin; vinblastine sulfate; vincristine sulfate; vindesine;vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicinhydrochloride; palbociclib; Yervoy.RTM. (ipilimumab); Mekinist.TM.(trametinib); peginterferon alfa-2b, recombinant interferonalfa-2b; Sylatron.TM. (peginterferon alfa-2b); Tafinlar.RTM.(dabrafenib); Zelboraf.RTM. (vemurafenib); or nivolumab.
The compounds according to the present invention can beadministered in combination with existing methods of treatingcancers, for example by chemotherapy, irradiation, or surgery.Thus, there is further provided a method of treating cancercomprising administering an effective amount of a compound of theinvention, or a pharmaceutically acceptable salt form thereof, to asubject in need of such treatment, wherein an effective amount ofat least one additional cancer chemotherapeutic agent isadministered to the subject. Examples of suitable cancerchemotherapeutic agents include any of: abarelix, ado-trastuzumabemtansine, aldesleukin, alemtuzumab, alitretinoin, allopurinol,altretamine, anastrozole, arsenic trioxide, asparaginase,azacitidine, bevacizumab, bexarotene, bleomycin, bortezombi,bortezomib, busulfan intravenous, busulfan oral, calusterone,capecitabine, carboplatin, carmustine, cetuximab, chlorambucil,cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine,dacarbazine, dactinomycin, dalteparin sodium, dasatinib,daunorubicin, decitabine, denileukin, denileukin diftitox,dexrazoxane, docetaxel, doxorubicin, dromostanolone propionate,eculizumab, emtansine, epirubicin, eribulin, erlotinib,estramustine, etoposide phosphate, etoposide, everolimus,exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine,fluorouracil, fruquintinib, fulvestrant, gefitinib, gemcitabine,gemtuzumab ozogamicin, goserelin acetate, histrelin acetate,ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib mesylate,interferon alfa 2a, irinotecan, ixabepilone, lapatinib ditosylate,lenalidomide, letrozole, leucovorin, leuprolide acetate,levamisole, lomustine, meclorethamine, megestrol acetate,melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycin C,mitotane, mitoxantrone, nandrolone phenpropionate, nelarabine,nofetumomab, oxaliplatin, pacl*taxel, pacl*taxel albumin-stabilizednanoparticle formulation, pamidronate, panitumumab, pegaspargase,pegfilgrastim, pemetrexed disodium, pentostatin, pertuzuma,pipobroman, plicamycin, procarbazine, quinacrine, rasburicase,rituximab, sorafenib, streptozocin, sulfatinib, sunitinib,sunitinib maleate, tamoxifen, temozolomide, teniposide,testolactone, thalidomide, thioguanine, thiotepa, topotecan,toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard,valrubicin, vinblastine, vincristine, vinorelbine, volitinib,vorinostat, and zoledronate.
In particular embodiments, compounds according to the invention areused in combination with one or more anti-cancer agent selectedfrom methotrexate, pacl*taxel albumin-stabilized nanoparticleformulation, ado-trastuzumab emtansine, eribulin, doxorubicin,fluorouracil, everolimus, anastrozole, pamidronate disodium,exemestane, capecitabine, cyclophosphamide, docetaxel, epirubicin,toremifene, fulvestrant, letrozole, gemcitabine, gemcitabinehydrochloride, goserelin acetate, trastuzumab, ixabepilone,lapatinib ditosylate, megestrol acetate, tamoxifen citrate,pamidronate disodium, palbociclib, and pertuzumab for the treatmentof breast cancer.
Other anti-cancer agents/drugs include, but are not limited to:20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone;aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin;ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine;aminolevulinic acid; amrubicin; amsacrine; anagrelide;andrographolide; angiogenesis inhibitors; antagonist D; antagonistG; antarelix; anti-dorsalizing morphogenetic protein-1;antiandrogen; antiestrogen; antineoplaston; antisenseoligonucleotides; aphidicolin glycinate; apoptosis gene modulators;apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; argininedeaminase; asulacrine; atamestane; atrimustine; axinastatin 1;axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine;baccatin III derivatives; balanol; batimastat; BCR/ABL antagonists;benzochlorins; benzoylstaurosporine; beta lactam derivatives;beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor;bicalutamide; bisantrene; bisaziridinylspermine; bisnafide;bistratene A; bizelesin; breflate; bropirimine; budotitane;buthionine sulfoximine; calcipotriol; calphostin C; camptothecinderivatives; canarypox IL-2; capecitabine;carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN700; cartilage derived inhibitor; carzelesin; casein kinaseinhibitors; castanospermine; cecropin B; cetrorelix; chlorins;chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin;cladribine; clomifene analogues; clotrimazole; collismycin A;collismycin B; combretastatin A4; combretastatin analogue;conagenin; crambescidin 816; crisnatol; cryptophycin 8;cryptophycin A derivatives; curacin A; cyclin-dependent kinaseinhibitors; cyclopentanthraquinones; cycloplatam; cypemycin;cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab;decitabine; dehydrodidemnin B; deslorelin; dexamethasone;dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B;didox; diethylnorspermine; dihydro-5-azacytidine; 9-dioxamycin;diphenyl spiromustine; docosanol; dolasetron; doxifluridine;droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine;edelfosine; edrecolomab; eflornithine; elemene; emitefur;epirubicin; epristeride; estramustine analogue; estrogen agonists;estrogen antagonists; etanidazole; etoposide phosphate; fadrozole;fazarabine; fenretinide; filgrastim; finasteride; flavopiridol;flezelastine; fluasterone; fludarabine; fluorodaunorunicinhydrochloride; forfenimex; formestane; fostriecin; fotemustine;gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;gelatinase inhibitors; gemcitabine; glutathione inhibitors;hepsulfam; heregulin; hexamethylene bisacetamide; hypericin;ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine;ilomastat; imidazoacridones; imiquimod; immunostimulant peptides;insulin-like growth factor-1 receptor inhibitor; iobenguane;iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine;isobengazole; isohom*ohalicondrin B; itasetron; jasplakinolide;kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin;lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemiainhibiting factor; leuprolide+estrogen+progesterone; leuprorelin;levamisole; liarozole; linear polyamine analogue; lipophilicdisaccharide peptide; lipophilic platinum compounds; lissoclinamide7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone;lovastatin; loxoribine; lurtotecan; lutetium texaphyrin;lysofylline; lytic peptides; maitansine; mannostatin A; marimastat;masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinaseinhibitors; menogaril; merbarone; meterelin; methioninase;metoclopramide; MIF inhibitor; mifepristone; miltefosine;mirimostim; mismatched double stranded RNA; mitoguazone;mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblastgrowth factor-saporin; mitoxantrone; mofarotene; molgramostim;monoclonal antibody, human chorionic gonadotrophin; monophosphoryllipid A+myobacterium cell wall sk; mopidamol; multiple drugresistance gene inhibitor; multiple tumor suppressor 1-basedtherapy; mustard anticancer agent; mycaperoxide B; mycobacterialcell wall extract; myriaporone; N-acetyldinaline; N-substitutedbenzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin;naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid;neutral endopeptidase; nilutamide; nisamycin; nitric oxidemodulators; nitroxide antioxidant; nitrullyn; O6-benzylguanine;octreotide; okicenone; oligonucleotides; onapristone; ondansetron;ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone;oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronicacid; panaxytriol; panomifene; parabactin; pazelliptine;pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin;pentrozole; perflubron; perfosfamide; perillyl alcohol;phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil;pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A;placetin B; plasminogen activator inhibitor; platinum complex;platinum compounds; platinum-triamine complex; porfimer sodium;porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2;proteasome inhibitors; protein A-based immune modulator; proteinkinase C inhibitors; microalgal; protein tyrosine phosphataseinhibitors; purine nucleoside phosphorylase inhibitors; purpurins;pyrazoloacridine; pyridoxylated hemoglobin polyoxyethyleneconjugate; raf antagonists; raltitrexed; ramosetron; ras farnesylprotein transferase inhibitors; ras inhibitors; ras-GAP inhibitor;retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin;ribozymes; RII retinamide; rogletimide; rohitukine; romurtide;roquinimex; rubiginone B1; ruboxyl; safingol; saintopin; SarCNU;sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescencederived inhibitor 1; sense oligonucleotides; signal transductioninhibitors; signal transduction modulators; single chainantigen-binding protein; sizofiran; sobuzoxane; sodium borocaptate;sodium phenylacetate; solverol; somatomedin binding protein;sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin;spongistatin 1; squalamine; stem cell inhibitor; stem-cell divisioninhibitors; stipiamide; stromelysin inhibitors; sulfinosine;superactive vasoactive intestinal peptide antagonist; suradista;suramin; swainsonine; synthetic glycosaminoglycans; tallimustine;tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium;tegafur; tellurapyrylium; telomerase inhibitors; temoporfin;temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;thaliblastine; thiocoraline; thrombopoietin; thrombopoietinmimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan;thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine;titanocene bichloride; topsentin; toremifene; totipotent stem cellfactor; translation inhibitors; tretinoin; triacetyluridine;triciribine; trimetrexate; triptorelin; tropisetron; turosteride;tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex;urogenital sinus-derived growth inhibitory factor; urokinasereceptor antagonists; vapreotide; variolin B; vector system,erythrocyte gene therapy; velaresol; veramine; verdins;verteporfin; vinorelbine; vinxaltine; vitaxin; zanoterone;zilascorb; zinostatin stimalamer; 5-fluorouracil; andleucovorin.
In some embodiments, the anti-cancer agent/drug is an agent thatstabilizes microtubules. As used herein, a "microtubulinstabilizer" means an anti-cancer agent/drug which acts by arrestingcells in the G2-M phases due to stabilization of microtubules.Examples of microtubulin stabilizers include Acl*tAXEL.RTM. andTaxol.RTM. analogues. Additional examples of microtubulinstabilizers include without limitation the following marketed drugsand drugs in development: Discodermolide (also known asNVP-XX-A-296); Epothilones (such as Epothilone A, Epothilone B,Epothilone C (also known as desoxyepothilone A or dEpoA);Epothilone D (also referred to as KOS-862, dEpoB, anddesoxyepothilone B); Epothilone E; Epothilone F; Epothilone BN-oxide; Epothilone A N-oxide; 16-aza-epothilone B;21-aminoepothilone B (also known as BMS-310705);21-hydroxyepothilone D (also known as Desoxyepothilone F anddEpoF), 26-fluoroepothilone); FR-182877 (Fujisawa, also known asWS-9885B), BSF-223651 (BASF, also known as ILX-651 and LU-223651);AC-7739 (Ajinomoto, also known as AVE-8063A and CS-39.HCl); AC-7700(Ajinomoto, also known as AVE-8062, AVE-8062A, CS-39-L-Ser.HCl, andRPR-258062A); Fijianolide B; Laulimalide; Caribaeoside;Caribaeolin; Taccalonolide; Eleutherobin; Sarcodictyin;Laulimalide; Dictyostatin-1; Jatrophane esters; and analogs andderivatives thereof.
In another embodiment, the anti-cancer agent/drug is an agent thatinhibits microtubules. As used herein, a "microtubulin inhibitor"means an anti-cancer agent which acts by inhibiting tubulinpolymerization or microtubule assembly. Examples of microtubulininhibitors include without limitation the following marketed drugsand drugs in development: Erbulozole (also known as R-55104);Dolastatin 10 (also known as DLS-10 and NSC-376128); Mivobulinisethionate (also known as CI-980); Vincristine; NSC-639829;ABT-751 (Abbott, also known as E-7010); Altorhyrtins (such asAltorhyrtin A and Altorhyrtin C); Spongistatins (such asSpongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4,Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8, andSpongistatin 9); Cemadotin hydrochloride (also known as LU-103793and NSC-D-669356); Auristatin PE (also known as NSC-654663);Soblidotin (also known as TZT-1027), LS-4559-P (Pharmacia, alsoknown as LS-4577); LS-4578 (Pharmacia, also known as LS-477-P);LS-4477 (Pharmacia), LS-4559 (Pharmacia); RPR-112378 (Aventis);Vincristine sulfate; DZ-3358 (Daiichi); GS-164 (Takeda); GS-198(Takeda); KAR-2 (Hungarian Academy of Sciences); SAH-49960(Lilly/Novartis); SDZ-268970 (Lilly/Novartis); AM-97 (Armad/KyowaHakko); AM-132 (Armad); AM-138 (Armad/Kyowa Hakko); IDN-5005(Indena); Cryptophycin 52 (also known as LY-355703); Vitilevuamide;Tubulysin A; Canadensol; Centaureidin (also known as NSC-106969);T-138067 (Tularik, also known as T-67, TL-138067 and TI-138067);COBRA-1 (Parker Hughes Institute, also known as DDE-261 andWHI-261); H10 (Kansas State University); H16 (Kansas StateUniversity); Oncocidin A1 (also known as BTO--956 and DIME);DDE-313 (Parker Hughes Institute); SPA-2 (Parker Hughes Institute);SPA-1 (Parker Hughes Institute, also known as SPIKET-P); 3-IAABU(Cytoskeleton/Mt. Sinai School of Medicine, also known as MF-569);Narcosine (also known as NSC-5366); Nascapine, D-24851 (AstaMedica), A-105972 (Abbott); Hemiasterlin; 3-BAABU (Cytoskeleton/Mt.Sinai School of Medicine, also known as MF-191); TMPN (ArizonaState University); Vanadocene acetylacetonate; T-138026 (Tularik);Monsatrol; Inanocine (also known as NSC-698666); 3-IAABE(Cytoskeleton/Mt. Sinai School of Medicine); A-204197 (Abbott);T-607 (Tularik, also known as T-900607); RPR-115781 (Aventis);Eleutherobins (such as Desmethyleleutherobin, Desaetyleleutherobin,Isoeleutherobin A, and Z-Eleutherobin); Halichondrin B; D-64131(Asta Medica); D-68144 (Asta Medica); Diazonamide A; A-293620(Abbott); NPI-2350 (Nereus); TUB-245 (Aventis); A-259754 (Abbott);Diozostatin; (-)-Phenylahistin (also known as NSCL-96F037); D-68838(Asta Medica); D-68836 (Asta Medica); Myoseverin B; D-43411(Zentaris, also known as D-81862); A-289099 (Abbott); A-318315(Abbott); HTI-286 (also known as SPA-110, trifluoroacetate salt)(Wyeth); D-82317 (Zentaris); D-82318 (Zentaris); SC-12983 (NCI);Resverastatin phosphate sodium; BPR-0Y-007 (National HealthResearch Institutes); SSR-250411 (Sanofi); Combretastatin A4;eribulin (Halaven.RTM.); and analogs and derivatives thereof.
In further embodiments, compounds according to the invention areused in combination with one or more alkylating agents,antimetabolites, natural products, or hormones.
Examples of alkylating agents useful in the methods of theinvention include but are not limited to, nitrogen mustards (e.g.,mechloroethamine, cyclophosphamide, chlorambucil, melphalan, etc.),ethylenimine and methylmelamines (e.g., hexamethlymelamine,thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g.,carmustine, lomusitne, semustine, streptozocin, etc.), or triazenes(decarbazine, etc.).
Examples of antimetabolites useful in the methods of the inventioninclude but are not limited to folic acid analog (e.g.,methotrexate), or pyrimidine analogs (e.g., fluorouracil,floxouridine, cytarabine), and purine analogs (e.g.,mercaptopurine, thioguanine, pentostatin). Examples of naturalproducts useful in the methods of the invention include but are notlimited to vinca alkaloids (e.g., vinblastin, vincristine),epipodophyllotoxins (e.g., etoposide, teniposide), antibiotics(e.g., actinomycin D, daunorubicin, doxorubicin, bleomycin,plicamycin, mitomycin) or enzymes (e.g., L-asparaginase).
Examples of hormones and antagonists useful for the treatment ofcancer include but are not limited to adrenocorticosteroids (e.g.,prednisone), progestins (e.g., hydroxyprogesterone caproate,megestrol acetate, medroxyprogesterone acetate), estrogens (e.g.,diethlystilbestrol, ethinyl estradiol), antiestrogen (e.g.,tamoxifen), androgens (e.g., testosterone propionate,fluoxymesterone), antiandrogen (e.g., flutamide), and gonadotropinreleasing hormone analog (e.g., leuprolide).
Other agents that can be used in combination with the compounds ofthe invention for the treatment of cancer include platinumcoordination complexes (e.g., cisplatin, carboblatin),anthracenedione (e.g., mitoxantrone), substituted urea (e.g.,hydroxyurea), methyl hydrazine derivative (e.g., procarbazine), andadrenocortical suppressant (e.g., mitotane, aminoglutethimide).Other anti-cancer agents/drugs that can be used in combination withthe compounds of the invention include, but are not limited to,liver X receptor (LXR) modulators, including LXR agonists and LXRbeta-selective agonists; aryl hydrocarbon receptor (AhR)inhibitors; inhibitors of the enzyme poly ADP ribose polymerase(PARP), including olaparib, iniparib, rucaparib, veliparib;inhibitors of vascular endothelial growth factor (VEGF) receptortyrosine kinases, including cediranib; programmed cell deathprotein 1 (PD-1) inhibitors, including nivolumab (Bristol-MyersSquibb Co.) and pembrolizumab (Merck & Co., Inc.; MK-3475); MEKinhibitors, including cobimetinib; B-Raf enzyme inhibitors,including vemurafenib; cytotoxic T lymphocyte antigen (CTLA-4)inhibitors, including tremelimumab; programmed death-ligand 1(PD-L1) inhibitors, including MEDI4736 (AstraZeneca); inhibitors ofthe Wnt pathway; inhibitors of epidermal growth factor receptor(EGFR) including AZD9291 (AstraZeneca), erlotinib, gefitinib,panitumumab, and cetuximab; adenosine A2A receptor inhibitors;adenosine A2B receptor inhibitors; colony-stimulating factor-1receptor (CSF1R) inhibitors, including PLX3397 (Plexxikon), andinhibitors of CD73.
The compounds of the invention can be used in combination with oneor more therapeutic strategies including immune checkpointinhibitors, including inhibitors of PD-1, PD-L1, and CTLA-4.
The compounds of the invention can be used in combination with oneor more anti-cancer agents selected from MCL-1 inhibitors, e.g.,hom*oharringtonin (HHT) and omacetaxine; BCL-2 inhibitors, e.g.,venetoclax (ABT-199), navitoclax (ABT-263), ABT-737, gossypol(AT-101), apogossypolone (ApoG2) and obatoclax; selectiveinhibitors of nuclear export (SINEs), e.g., selinexor(KPT-330).
In particular embodiments, the compounds of the invention are usedin combination with one or more anti-cancer agents selected frommethotrexate (Abitrexate.RTM.; Folex.RTM.; Folex PFS.RTM.;Mexate.RTM.; Mexate-AQ.RTM.); nelarabine (Arranon.RTM.);blinatumomab (Blincyto.RTM.); rubidomycin hydrochloride ordaunorubicin hydrochloride (Cerubidine.RTM.); cyclophosphamide(Clafen.RTM.; Cytoxan.RTM.; Neosar.RTM.); clofarabine(Clofarex.RTM.; Clolar.RTM.); cytarabine (Cytosar-U.RTM.; TarabinePFS.RTM.); dasatinib (Sprycel.RTM.); doxorubicin hydrochloride;asparaginase Erwinia chrysanthemi (Erwinaze); imatinib mesylate(Gleevec.RTM.); ponatinib hydrochloride (Iclusig.RTM.);mercaptopurine (Purinethol; Purixan); pegaspargase (Oncaspar.RTM.);prednisone; vincristine sulfate (Oncovin.RTM., Vincasar PFS.RTM.,Vincrex.RTM.); vincristine sulfate liposome (Marqibo.RTM.);hyper-CVAD (fractionated cyclophosphamide, vincristine, adriamycin,and dexamethasone); arsenic trioxide (Trisenox.RTM.); idarubicinhydrochloride (Idamycin.RTM.); mitoxantrone hydrochloride;thioguanine (Tabloid.RTM.); ADE (cytarabine, daunorubicin, andetoposide); alemtuzumab (Lemtrada.RTM., Campath.RTM.); chlorambucil(Ambochlorin.RTM., Amboclorin.RTM., Leukeran.RTM.,Linfolizin.RTM.); ofatumumab (Arzerra.RTM.); bendamustinehydrochloride (Treanda.RTM.); fludarabine phosphate (Fludara.RTM.);obinutuzumab (Gazyva.RTM.); ibrutinib (Imbruvica.RTM.); idelalisib(Zydelig.RTM.); mechlorethamine hydrochloride (Mustargen.RTM.);rituximab (Rituxan.RTM.); chlorambucil-prednisone; CVP(cyclophosphamide, vincristine, and prednisone); bosutinib(Bosulif.RTM.); busulfan (Busulfex.RTM.; Myleran.RTM.); omacetaxinemepesuccinate (Synribo.RTM.); nilotinib (Tasigna.RTM.); Intron.RTM.A (recombinant interferon Alfa-2b); DOT1L inhibitors, includingEPZ-5676 (Epizyme, Inc.); and inhibitors of bromodomain andextra-terminal motif (BET) proteins (BET inhibitors), includingMS417, JQ1, I-BET 762, and I-BET 151 for the treatment ofleukemia.
Compounds of the invention can be used in combination with one ormore other agents or therapies for the treatment of insulinresistance, pre-diabetes, diabetes (e.g., Type 2 diabetes or Type 1diabetes), and risk of diabetes, including but not limited toinsulins and insulin analogues, such as Humulin.RTM. (EIi Lilly),Lantus.RTM. (Sanofi Aventis), Novolin.RTM. (Novo Nordisk), andExubera.RTM. (Pfizer); Avandamet.RTM. (metformin HCl androsiglitazone maleate, GSK); Avandaryl.RTM. (glimepiride androsiglitazone maleate, GSK); Metaglip.RTM. (glipizide and metforminHCl, Bristol Myers Squibb); Glucovance.RTM. (glyburide andmetformin HCl, Bristol Myers Squibb); PPAR gamma agonists, such asAvandia.RTM. (rosiglitizone maleate, GSK) and Actos.RTM.(pioglitazone hydrochloride, Takeda/Eli Lilly); sulfonylureas, suchas Amaryl.RTM. (glimepiride, Sanofi Aventis), Diabeta.RTM.(glyburide, Sanofi Aventis), Micronase.RTM./Glynase.RTM.(glyburide, Pfizer), and Glucotrol.RTM./Glucotrol XL.RTM.(glipizide, Pfizer); meglitinides, such asPrandin.RTM./NovoNorm.RTM. (repaglinide, Novo Nordisk),Starlix.RTM. (nateglinide, Novartis), and Glufast.RTM.(mitiglinide, Takeda); biguanides, such asGlucophase.RTM./Glucophase XR.RTM. (metformin HCl, Bristol MyersSquibb) and Glumetza.RTM. (metformin HCl, Depomed);thiazolidinediones; amylin analogs; GLP-1 analogs; DPP-IVinhibitors such as Januvia.RTM. (sitagliptin, Merck) andGalvus.RTM. (vildagliptin, Novartis); PTB-1 B inhibitors; proteinkinase inhibitors (including AMP-activated protein kinaseinhibitors); glucagon antagonists, glycogen synthase kinase-3 betainhibitors; glucose-6-phoshatase inhibitors; glycogen phosphorylaseinhibitors; sodium glucose co-transporter inhibitors; andalpha-glucosidase inhibitors, such as Glycet.RTM. (miglitol,Pfizer); statins, fibrates, and Zetia.RTM. (ezetimibe);alpha-blockers; beta-blockers; calcium channel blockers; diuretics;angiotensin converting enzyme (ACE) inhibitors; dual ACE andneutral endopeptidase (NEP) inhibitors; angiotensin-receptorblockers (ARBs); aldosterone synthase inhibitors;aldosterone-receptor antagonists; endothelin receptor antagonists;orlistat; phentermine; sibutramine; Acomplia.RTM. (rimonabant);thiazolidinediones (e.g., rosiglitazone, pioglitazone); SGLT 2inhibitors (e.g., dapagliflozin, remogliflozin etabonate,sergliflozin, canagliflozin, and1-chloro-4-(.beta.-D-glucopyranos-1-yl)-2-[4-(('S)-tetrahydrofuran-3-ylox-y)-benzyl]-benzene); PPAR-gamma-agonists (e.g., Gl 262570) andantagonists; PPAR-gamma/alpha modulators (e.g., KRP 297);alpha-glucosidase inhibitors (e.g., acarbose, voglibose); DPPIVinhibitors (e.g., Januvia.RTM. (sitagliptin),Galvus.RTM./Zomelis.RTM. (vildagliptin), Onglyza.RTM.(saxagliptin), Nesina.RTM./Vipidia.RTM. (alogliptin), andTradjenta.RTM./Trajenta.RTM. (linagliptin)); alpha2-antagonists;glucagon-like protein-1 (GLP-1) receptor agonists and analogues(e.g., exendin-4); amylin; inhibitors of proteintyrosinephosphatase 1; substances that affect deregulated glucoseproduction in the liver, e.g., inhibitors of glucose-6-phosphatase,or fructose-1,6-bisphosphatase, glycogen phosphorylase; glucagonreceptor antagonists; inhibitors of phosphoenol pyruvatecarboxykinase; glycogen synthase kinase and gluco*kinase activators;lipid lowering agents such as HMG-CoA-reductase inhibitors (e.g.,simvastatin, atorvastatin); fibrates (e.g., bezafibrate,fenofibrate), nicotinic acid and the derivatives thereof,PPAR-alpha agonists, PPAR-delta agonists; ACAT inhibitors (e.g.,avasimibe); cholesterol absorption inhibitors such as ezetimibe;bile acid-binding substances such as cholestyramine; inhibitors ofileac bile acid transport; HDL-raising compounds such as CETPinhibitors and ABC1 regulators; active substances for treatingobesity such as sibutramine and tetrahydrolipostatin; SDRIs;axokine; leptin; leptin mimetics; antagonists of the cannabinoid 1receptor; and MCH-1 receptor antagonists; MC4 receptor agonists;NPY5 and NPY2 antagonists; beta3 adrenergic agonists such asSB-418790 and AD-9677; agonists of the 5HT2c receptor;GABA-receptor antagonists; Na-channel blockers; topiramate;protein-kinase C inhibitors; advanced glycation end productinhibitors; and aldose reductase inhibitors.
Pharmaceutical Formulations, Administration, and Dosage Forms
When employed as pharmaceuticals, the compounds of the inventioncan be administered in the form of a pharmaceutical compositionwhich refers to a combination of a compound of the invention, orits pharmaceutically acceptable salt, and at least onepharmaceutically acceptable carrier. These compositions can beprepared in a manner well known in the pharmaceutical art, and canbe administered by a variety of routes, depending upon whetherlocal or systemic treatment is desired and upon the area to betreated. Administration may be topical (including ophthalmic and tomucous membranes including intranasal, vagin*l and rectaldelivery), pulmonary (e.g., by inhalation or insufflation ofpowders or aerosols, including by nebulizer; intratracheal,intranasal, epidermal and transdermal), ocular, oral or parenteral.Methods for ocular delivery can include topical administration (eyedrops), subconjunctival, periocular or intravitreal injection orintroduction by balloon catheter or ophthalmic inserts surgicallyplaced in the conjunctival sac. Parenteral administration includesintravenous, intraarterial, subcutaneous, intraperitoneal, orintramuscular injection or infusion; or intracranial, e.g.,intrathecal or intraventricular, administration. Parenteraladministration can be in the form of a single bolus dose, or maybe, for example, by a continuous perfusion pump. Pharmaceuticalcompositions and formulations for topical administration mayinclude transdermal patches, ointments, lotions, creams, gels,drops, suppositories, sprays, liquids and powders. Conventionalpharmaceutical carriers, aqueous, powder or oily bases, thickenersand the like may be necessary or desirable.
This invention also includes pharmaceutical compositions whichcontain, as the active ingredient, one or more of the compounds ofthe invention above in combination with one or morepharmaceutically acceptable carriers. In making the compositions ofthe invention, the active ingredient is typically mixed with anexcipient, diluted by an excipient or enclosed within such acarrier in the form of, for example, a capsule, sachet, paper, orother container. When the excipient serves as a diluent, it can bea solid, semi-solid, or liquid material, which acts as a vehicle,carrier or medium for the active ingredient. Thus, the compositionscan be in the form of tablets, pills, powders, lozenges, sachets,cachets, elixirs, suspensions, emulsions, solutions, syrups,aerosols (as a solid or in a liquid medium), ointments containing,for example, up to 10% by weight of the active compound, soft andhard gelatin capsules, suppositories, sterile injectable solutions,and sterile packaged powders.
Compounds or compositions described herein may be administered to apatient using any amount and any route of administration effectivefor treating or lessening the severity of one or more of thediseases and conditions described herein. The exact amount requiredwill vary from subject to subject, depending on the species, age,and general condition of the subject, the severity of theinfection, disease or disorder, the particular agent, its mode ofadministration, and the like. Provided compounds are preferablyformulated in a particular unit dosage form for ease ofadministration and uniformity of dosage. The expression "unitdosage form" as used herein refers to a physically discrete unit ofa*gent appropriate for the patient to be treated.
The therapeutic dosage of the compounds of the present inventioncan vary according to, for example, the particular use for whichthe treatment is made, the manner of administration of thecompound, the health and condition of the patient, and the judgmentof the prescribing physician. The proportion or concentration of acompound of the invention in a pharmaceutical composition can varydepending upon a number of factors including dosage, chemicalcharacteristics (e.g., hydrophobicity), and the route ofadministration. For example, the compounds of the invention can beprovided in an aqueous physiological buffer solution containingabout 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 .mu.g/kgto about 1 g/kg of body weight per day. In some embodiments, thedose range is from about 0.01 mg/kg to about 100 mg/kg of bodyweight per day. The dosage is likely to depend on such variables asthe type and extent of progression of the disease or disorder, theoverall health status of the particular patient, the relativebiological efficacy of the compound selected, formulation of theexcipient, and its route of administration. Effective doses can beextrapolated from dose-response curves derived from in vitro oranimal model test systems.
EXAMPLES
As depicted in the Examples below, compounds of the invention wereprepared and isolated according to the following generalprocedures. It will be appreciated that, although the generalmethods may depict the synthesis of certain compounds of thepresent invention, the following general methods, and other methodsknown to one of ordinary skill in the art, can be applied to allcompounds and subclasses and species of each of these compounds, asdescribed herein.
Microwave reactions were performed in a CEM reactor using discoverySP system. Where NMR data are presented, spectra were obtained in aVarian-400 (400 MHz). Spectra are reported as ppm downfield fromtetramethylsilane with the number of proton, multiplicities and, incertain instances, coupling constants indicated parentheticallyalong with reference to deuterated solvent. Compounds were alsopurified by ISCO flash chromatography system utilizing standardmethods described in the manual.
Compounds were purified by acidic, basic, or neutral preparativeHPLC method as described below in HPLC Methods A to G.
Preparative RP-HPLC Method A:
RP-HPLC (C-18, Boston Green ODS 150*30 mm*5 .mu.m; eluent-gradient:water+0.1% TFA/acetonitrile=81:19 to 51:49)
Mobile phase A: water+0.1% TFA; Mobile phase B: CH.sub.3CN; Flowrate: 30 mL/min; Detection: UV 220 nm/254 nm; Column: Boston GreenODS 150*30 mm*5 .mu.m; Column temperature: 30.degree. C.
TABLE-US-00001 Time in min % A % B 0.00 81 19 8.00 51 49 8.20 0 10010.00 0 100
Preparative RP-HPLC Method B:
RP-HPLC (C-18, Phenomenex Synergi C18 250*21.2 mm*4 .mu.m;eluent-gradient: water+0.1% TFA/acetonitrile=75:25 to 45:55).
Mobile phase A: water+0.1% TFA; Mobile phase B: CH.sub.3CN; Flowrate: 25 mL/min; Detection: UV 220 nm/254 nm; Column: PhenomenexSynergi C18 250*21.2 mm*4 .mu.m; Column temperature: 30.degree.C.
TABLE-US-00002 Time in min % A % B 0.00 75 25 10.00 45 55 10.20 0100 12.00 0 100
Preparative RP-HPLC Method C:
RP-HPLC (C-18, Phenomenex Synergi C18 250*21.2 mm*4 .mu.m;eluent-gradient: water+0.05% HCl/acetonitrile=82:18 to 52:48).
Mobile phase A: water with 0.05% HCl; Mobile phase B: CH.sub.3CN;Flow rate: 30 mL/min; Detection: UV 220 nm/254 nm; Column:Phenomenex Gemini 150*30 mm*4 .mu.m; Column temperature: 30.degree.C.
TABLE-US-00003 Time in min % A % B 0.00 82 18 8.00 52 48 8.20 0 10010.00 0 100
Preparative RP-HPLC Method D:
RP-HPLC (C-18, Phenomenex Gemini 150*25 mm*10 .mu.m;eluent-gradient: water+0.05% ammonia hydroxide/acetonitrile=30:70to 0:100).
Mobile phase A: water with 0.05% ammonia hydroxide; Mobile phase B:CH.sub.3CN; Flow rate: 25 mL/min; Detection: UV 220 nm/254 nm;Column: Phenomenex Gemini 150*25 mm*10 .mu.m; Column temperature:30.degree. C.
TABLE-US-00004 Time in min % A % B 0.00 30 70 8.00 0 100 8.20 0 10010.00 0 100
Preparative RP-HPLC Method E:
Mobile phase A: water with 0.1% TFA; Mobile phase B: acetonitrilewith 0.1% TFA; Flow rate: 25 mL/min; Detection: UV 220 nm/254 nm;Column: C-18 Synergi Max-RP 150*30 mm*4 .mu.m; Column temperature:30.degree. C.
TABLE-US-00005 Time in min % A % B 0.00 90 10 12.00 60 40 12.20 1090 13.5 90 10
Neutral Preparative HPLC Method F:
Mobile phase A: water
Mobile phase B: CH.sub.3CN
Flow rate: 120 mL/min
Detection: UV 220 nm/254 nm
Column: Phenomenex Synergi Max-RP 250*50 mm*10 um
Column temperature: 30.degree. C.
TABLE-US-00006 Time in min % A % B 0.00 80 20 23.00 35 65 23.20 0100 26.00 0 100
Preparative HPLC Method G:
Mobile phase A: water (10 mM NH.sub.4HCO.sub.3)
Mobile phase B: CH.sub.3CN
Flow rate: 25 mL/min
Detection: UV 220 nm/254 nm
Column: Xtimate C18 150*25 mm*5 um
Column temperature: 30.degree. C.
TABLE-US-00007 Time in min % A % B 0.00 72 28 10.00 52 48 10.20 0100 13.00 0 100
LCMS data were obtained by utilizing the following chromatographicconditions:
LCMS Method A:
HPLC System: Waters ACQUITY; Column: Waters ACQUITY CSH.TM. C18 1.7.mu.M. Guard column: Waters Assy. Frit, 0.2 M, 2.1 mm; Columntemperature: 40.degree. C.
Mobile Phase: A: TFA: Water (1:1000, v:v); Mobile phase B: TFA: ACN(1:1000, v:v); Flow Rate: 0.65 mL/min; Injection Volume: 2 .mu.L;Acquisition time: approximately 1.5 min.
Gradient Program:
TABLE-US-00008 Time (min) B % 0.00 10 1.0 90 1.20 10
Mass Spectrometer: Waters SQD; Ionization: Positive ElectrosprayIonization (ESI); Mode Scan (100-1400 m/z in every 0.2 second); ESCapillary Voltage: 3.5 kV; ES Cone Voltage: 25 V.
Source Temperature: 120.degree. C.; Desolvation Temperature:500.degree. C.; Desolvation Gas Flow: Nitrogen Setting 650 (L/h);Cone Gas Flow: Nitrogen Setting 50 (L/h).
LCMS Method B:
HPLC System: Waters ACQUITY; Column: Waters ACQUITY CSH.TM. C18 1.7.mu.M. Guard column: Waters Assy. Frit, 0.2 .mu.M, 2.1 mm; Columntem: 40.degree. C.
Mobile Phase: A: TFA: Water (1:1000, v:v); Mobile phase B: TFA: ACN(1:1000, v:v); Flow Rate: 0.65 mL/min; Injection Volume: 2 .mu.L;Acquisition time: approximately 1.5 min.
TABLE-US-00009 Time (min) B % 0.00 10 2 90 2.20 90
Mass Spectrometer: Waters SQD; Ionization: Positive ElectrosprayIonization (ESI); Mode Scan (100-1400 m/z in every 0.2 second); ESCapillary Voltage: 3.5 kV; ES Cone Voltage: 25 v.
Source Temperature: 120.degree. C.; Desolvation Temperature:500.degree. C.; Desolvation Gas Flow: Nitrogen Setting 650 (L/h);Cone Gas Flow: Nitrogen Setting 50 (L/h).
LCMS Method C:
TABLE-US-00010 Column MERCK, RP-18e 25-2 mm Mobile Phase A: water(4L) + TFA(1.5 mL) B: acetonitrile(4 L) + TFA(0.75 mL) TIME (min) B %0 5 0.7 95 1.1 95 1.11 5 1.5 5 Flow Rate 1.5 mL/min wavelength UV220, 224 nm Oven Temp 50.degree. C. MS ionization ESI
LCMS Method D:
TABLE-US-00011 Column Xbrige Shield RP-18, 5 .mu.m, 2.1*50 mmMobile Phase A: water(1 L) + NH.sub.3H.sub.2O(0.5 mL) B:acetonitrile TIME(min) B % 0 10 2 80 2.48 80 2.49 10 3 10 Flow Rate1.0 mL/min wavelength UV 220 nm Oven Temp 30.degree. C. MSionization ESI
LCMS Method E:
TABLE-US-00012 Column Xtimate C18 2.1*30 mm, 3 .mu.m Mobile PhaseA: water(4 L) + TFA(1.5 mL) B: acetonitrile(4 L) + TFA(0.75 mL)TIME(min) B % 0 10 0.9 80 1.5 80 1.51 10 2 10 Flow Rate 1.2 mL/minwavelength UV 220 nm Oven Temp 50.degree. C. MS ionization ESI
LCMS Method F:
TABLE-US-00013 Column Xtimate C18 2.1*30 mm, 3 .mu.m Mobile PhaseA: water(4 L) + TFA(1.5 mL) B: acetonitrile(4 L) + TFA(0.75 mL)TIME(min) B % 0 0 0.9 60 1.5 60 1.51 0 2 0 Flow Rate 1.2 mL/minwavelength UV 220 nm Oven Temp 50.degree. C. MS ionization ESI
LCMS Method G:
HPLC System: Waters ACQUITY; Column: Waters ACQUITY CSH.TM. C18 1.7.mu.M. Guard column: Waters Assy. Frit, 0.2 .mu.M, 2.1 mm; Columntem: 40.degree. C.
Mobile Phase: A: TFA: Water (1:1000, v:v); Mobile phase B: TFA: ACN(1:1000, v:v); Flow Rate: 1 mL/min; Injection Volume: 2 .mu.L;Acquisition time: approximately 115 min.
TABLE-US-00014 Time in min B % 0.1 10 2.0 10 14 90 15 90 16 10
Mass Spectrometer: Waters SQD; Ionization: Positive ElectrosprayIonization (ESI); Mode Scan (100-1400 m/z in every 0.2 second); ESCapillary Voltage: 3.5 kV; ES Cone Voltage: 25 v.
Source Temperature: 120.degree. C.; Desolvation Temperature:500.degree. C.; Desolvation Gas Flow: Nitrogen Setting 650 (L/h);Cone Gas Flow: Nitrogen Setting 50 (L/h).
The following are Supercritical Fluid Chromatography (SFC)separation methods for racemic compounds.
Method A
Instrument: Thar SFC 80; Column: AD 250 mm*30 mm, 5 .mu.m; Mobilephase: A: Supercritical CO.sub.2, B: IPA (0.05% DEA), A:B=80:20 at60 mL/min; Column Temp: 38.degree. C.; Nozzle Pressure: 100 Bar;Nozzle Temp: 60.degree. C.; Evaporator Temp: 20.degree. C.; TrimmerTemp: 25.degree. C.; Wavelength: 220 nm.
Method B
Instrument: SFC MG2; Column: OJ 250 mm*30 mm, 5 .mu.m; Mobilephase: A: Supercritical CO.sub.2, B: MeOH (0.05% DEA), A:B=90:10 at70 mL/min; Column Temp: 38.degree. C.; Nozzle Pressure: 100 BarNozzle Temp: 60.degree. C.; Evaporator Temp: 20.degree. C.; TrimmerTemp: 25.degree. C.; Wavelength: 220 nm.
The following are SFC analytical (anal.) methods utilized tocharacterize final compounds.
SFC Anal. Method A: Instrument: Thar SFC 80; Column: AD_H 4 mm*40mm, 5 .mu.m; Mobile phase: A: Supercritical CO.sub.2, B: IPA (0.05%DEA), A:B=80:20 at 4 mL/min; 3 min run, Column Temp: 38.degree. C.;Nozzle Pressure: 100 Bar; Nozzle Temp: 60.degree. C.; EvaporatorTemp: 20.degree. C.; Trimmer Temp: 25.degree. C.; Wavelength: 220nm.
SFC Anal. Method B: Instrument: Thar SFC 80; Column: AD_H 4 mm*40mm, 5 .mu.m; Mobile phase: A: Supercritical CO.sub.2, B: IPA (0.05%DEA), A:B=80:20 at 2.4 mL/min; 10 min run, Column Temp: 38.degree.C.; Nozzle Pressure: 100 Bar; Nozzle Temp: 60.degree. C.;Evaporator Temp: 20.degree. C.; Trimmer Temp: 25.degree. C.;Wavelength: 220 nm.
SFC Anal. Method C: Instrument: Thar SFC 80; Column: AD_H 4 mm*40mm, 5 .mu.m; Mobile phase: A: Supercritical CO.sub.2, B: IPA (0.05%DEA), A:B=80:20 at 2.8 mL/min; 13 min run, Column Temp: 38.degree.C.; Nozzle Pressure: 100 Bar; Nozzle Temp: 60.degree. C.;Evaporator Temp: 20.degree. C.; Trimmer Temp: 25.degree. C.;Wavelength: 220 nm.
SFC Anal. Method D: Instrument: Thar SFC 80; Column: AD-3, 5 mm*40mm, 5 m; Mobile phase: A: Supercritical CO.sub.2, B: IPA (0.05%DEA), A:B=80:20 at 25 mL/min; 5 min run, Column Temp: 38.degree.C.; Nozzle Pressure: 100 Bar; Nozzle Temp: 60.degree. C.;Evaporator Temp: 20.degree. C.; Trimmer Temp: 25.degree. C.;Wavelength: 220 nm.
X-Ray Powder Diffraction (XRPD) Method A
Rigaku MiniFlex 600 X-ray diffractometer with a high speed D/teXdetector was used under the following conditions: 40 kV, 15 mA, CuK-alpha radiation (wavelength=1.54 .ANG.). The 2-theta scanningrange was 3-45.degree. and the scanning rate was10.degree./min.
X-Ray Powder Diffraction (XRPD) Method B
TABLE-US-00015 Parameter Value Instrument Rigaku SmartLab SystemGeometry Reflection BB X-ray Tube copper Monochromatization betafilter Detector D'teX PSD Voltage (kV) 40.00 Current (mA) 44.00Start Angle (2.theta.) 2.00 End Angle (2.theta.) 70.00 Step Size(2.theta.) 0.04 Scan Speed (2.theta.) 3.00 Slits (S0 deg, S1 deg,S3 mm) 1/3, 4, 13 Measurement Type symmetric .theta.:2.theta.Sample Holder Si low-background Sample Rotation (RPM) 75
X-Ray Powder Diffraction (XRPD) Method C Transmission Geometry
XRPD patterns were collected with a PANalytical X'Pert PRO MPDdiffractometer using an incident beam of Cu radiation producedusing an Optix long, fine-focus source. An elliptically gradedmultilayer mirror was used to focus Cu K.alpha. X-rays through thespecimen and onto the detector. Prior to the analysis, a siliconspecimen (NIST SRM 640e) was analyzed to verify the observedposition of the Si-111 peak was consistent with the NIST-certifiedposition. A specimen of the sample was placed between 3-.mu.m-thickfilms and analyzed in transmission geometry. A beam-stop, shortantiscatter extension, and antiscatter knife edge were used tominimize the background generated by air. Soller slits for theincident and diffracted beams were used to minimize broadening fromaxial divergence. Diffraction patterns were collected using ascanning position-sensitive detector (X'Celerator) located 240 mmfrom the specimen and Data Collector software v.2.2b.
Reflection Geometry
XRPD patterns were collected with a PANalytical X'Pert PRO MPDdiffractometer using an incident beam of Cu K.alpha. radiationproduced using a long, fine-focus source and a nickel filter. Thediffractometer was configured using the symmetric Bragg-Brentanogeometry. Prior to the analysis, a silicon specimen (NIST SRM 640e)was analyzed to verify the observed position of the Si-111 peak wasconsistent with the NIST-certified position. A specimen of thesample was prepared as a thin, circular layer centered on a siliconzero-background substrate. Antiscatter slits (SS) were used tominimize the background generated by air. Soller slits for theincident and diffracted beams were used to minimize broadening fromaxial divergence. Diffraction patterns were collected using ascanning position-sensitive detector (X'Celerator) located 240 mmfrom the sample and Data Collector software v.2.2b.
Differential Scanning Calorimetry (DSC)
DSC measurements were performed using a TA Instruments 2920differential scanning calorimeter. Temperature calibration wasperformed using NIST-traceable indium metal.
Dynamic Vapor Sorption/Desorpotion (DVS)
Moisture sorption/desorption data were collected on a VTI SGA-100Vapor Sorption Analyzer. NaCl and PVP were used as calibrationstandards. Samples were not dried prior to analysis. Sorption anddesorption data were collected over a range from 5% to 95% RH at10% RH increments under a nitrogen purge. The equilibrium criterionused for analysis was less than 0.0100% weight change in 5 minuteswith a maximum equilibration time of 3 hours. Data were notcorrected for the initial moisture content of the samples.
Thermal Gravimetric Analysis (TGA)
TG analyses were performed using a TA Instruments Q5000 IRthermogravimetric analyzer. Temperature calibration was performedusing nickel and ALUMEL.TM.. Each sample was prepared in a platinumpan and the furnace was heated under nitrogen.
The invention is illustrated by the following examples, in whichthe following abbreviations may be employed:
TABLE-US-00016 Abbreviation Meaning ACN acetonitrile BOP(benzotriazol-1-yloxy)tris(dimethylamino)phosphoniumhexafluorophosphate BTC bis(trichloromethyl) carbonate DCE1,2-dichloroethane DCM methylene chloride DIEA diisopropylethylamine DMA dimethyl acetamide DMF dimethyl formamide dppf1,1-bis(diphenylphosphino)ferrocene DSC differential scanningcalorimetry DVS dynamic vapor sorption/desorption EDXenergy-dispersive X-ray spectroscopy EtN triethylamine EtOAc ethylacetate EtOH ethanol h hour(s) HATU1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium3-oxid hexafluorophosphate. HBTU2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate HCl hydrochloric acid HPLC high performanceliquid chromatography Im imidazaole KI potassium iodide K3PO4Potassium phosphate LCMS liquid chromatography-massspectorphotmetry min minute(s) Me methyl mL milliliters mmolmillimoles mg milligram NaBH.sub.3CN sodium cyanoborohydride PLMpolarized light microscopy RP reverse phase RT room temperature SFCsupercritical fluid chromatography SPhos Gen 2Chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II), t.sub.R;t.sub.r, R.sub.t, retention time TBAF tetra butyl ammonium fluorideTBDMS tert butyl dimethyl silyl TEA triethylamine TFAtrifluoroacetic acid THF tetrahydrofuran TGA thermogravimetricanalysis TLC thin layer chromatography XPhosdicyclohexyphosphino-2',4',6' triiso-propyl-1,1'-biphenyl XRPDX-ray powder diffraction
Intermediate 1
5-(2-bromo-4-fluorophenoxy)-4-chloropyrimidine
##STR00020##
Step 1: Ethyl 2-(2-bromo-4-fluorophenoxy)acetate
##STR00021##
To solution of 2-bromo-4-fluorophenol (250 g, 1.31 mol) inCH.sub.3CN (2 L) was added K.sub.2CO.sub.3 (270 g, 1.97 mol) andethyl 2-bromoacetate (219 g, 1.31 mol). The suspension was heatedat 90.degree. C. for 1.5 h. The mixture was filtered and thefiltrate was concentrated to give crude ethyl2-(2-bromo-4-fluorophenoxy)acetate as a brown oil, which was useddirectly in next step. Yield: 312 g; .sup.1H NMR (CDCl.sub.3):.delta. 7.32 (dd, J=7.6, 3.2 Hz, 1H), 6.95-6.97 (m, 1H), 6.82 (dd,J=8.8, 4.4 Hz, 1H), 4.66 (s, 2H), 4.27 (q, J=7.2 Hz, 2H), 1.31 (t,J=7.2 Hz, 3H). .sup.1F NMR (CDCl.sub.3): .delta. -120.06 (s,1F).
Step 2.5-(2-bromo-4-fluorophenoxy)-2-thioxo-2,3-dihydropyrimidin-4(1H)-on-e
##STR00022##
To a solution of ethyl 2-(2-bromo-4-fluorophenoxy)acetate (100 g)in anhydrous THF (2 L) was added ethyl formate (108 g) and NaH (20g) at 0.degree. C. The mixture was stirred at 35-45.degree. C. for18 h. The solvent was removed under vacuum and anhydrous EtOH (2 L)and thiourea (25 g, 324.8 mmol) were added and stirred at90.degree. C. for 16 h. The mixture was concentrated and dilutedwith water (2 L) and extracted with petroleum ether:ethyl acetate(10:1; 500 mL.times.3). The aqueous layer was acidified to pH=4 byaq. HCl (1N, 200 mL) and white solid was precipitated. The mixturewas filtered and the resulting filter cake was dried to give crude5-(2-bromo-4-fluorophenoxy)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one(62 g) as a with solid, which was used directly in next stepwithout purification. Yield: 62 g; LCMS method C: R.sub.t=0.638min; (M+H).sup.+=316.9, 318.9 (chlorine isotopes).
Step 3: 5-(2-bromo-4-fluorophenoxy)pyrimidin-4-ol
##STR00023##
To a solution of5-(2-bromo-4-fluorophenoxy)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one(62 g) in anhydrous EtOH (1.5 L) was added Raney Ni (62 g) and themixture was heated at reflux for 6 h. The solvent was removed undervacuum and anhydrous EtOH (2 L) was added. The mixture was filteredand filtrate stock was concentrated to give crude5-(2-bromo-4-fluorophenoxy)pyrimidin-4-ol as a grey solid. Yield:55 g. LCMS method C: R.sub.t=0.619 min, (M+H).sup.+=284.9 287.0(chlorine isotopes).
Step 4: 5-(2-bromo-4-fluorophenoxy)-4-chloropyrimidine
To a solution of 5-(2-bromo-4-fluorophenoxy)pyrimidin-4-ol (55 g)in SOCl.sub.2 (500 mL) was added anhydrous DMF (5 mL). The mixturewas heated at 70.degree. C. for 4 h. The mixture was concentrated,dissolved with DCM (500 mL), then poured into saturated NaHCO.sub.3(aq) (500 mL) and stirred at RT for 2 h. The organic layer wasseparated, dried over Na.sub.2SO.sub.4, filtered, and concentrated.The residue was then purified by ISCO column on silica gel (from100% petroleum ether to EtOAc:petroleum ether=9:1) to give5-(2-bromo-4-fluorophenoxy)-4-chloropyrimidine as a light yellowsolid. Yield: 32 g. LCMS method C: R.sub.t=0.858 min,(M+H).sup.+=302.9, 304.9 (chlorine & bromine isotopes); .sup.1HNMR (CDCl.sub.3): .delta. 8.77 (s, 1H), 8.07 (s, 1H), 7.45 (dd,J=7.6 3.2 Hz, 1H), 7.06-7.12 (m, 2H). .sup.1F NMR (CDCl.sub.3):.delta. -113.64 (s, 1F).
Intermediates 2-10a
The following intermediates were prepared according to theprocedure described for Intermediate 1.
TABLE-US-00017 TABLE 1 Intermediates 2-10a. Mass peak(s) R.sub.fvalue Int. No. Name Structural formula Yield (M + H).sup.+ orR.sub.t 2 4-chloro-5- (2,6- dichloro-4- fluorophen- oxy)pyrimi-dine ##STR00024## 87% 294.9, 296.9 R.sub.t = 0.828 LCMS method C.sup.1H NMR (CDCl.sub.3): .delta. 8.75 (s, 1H), 7.88 (s, 1H), 7.26(s, 1H), 7.24 (s, 1H). .sup.19F NMR: (CDCl.sub.3): .delta. -110.54(s, 1F). 3 4-chloro-5- (2-chloro- 3,4- difluorophen- oxy)pyrimi-dine ##STR00025## 42% 277.0, 279.0 0.994 min LCMS method C .sup.1HNMR (CDCl.sub.3): .delta. 8.81 (s, 1H), 8.17 (s, 1H), 7.10-7.20 (m,1H), 6.80-6.85 (m, 1H). .sup.19F NMR: (CDCl.sub.3): .delta.-132.37, -136.57. 4 4-chloro-5- (4-fluoro- 2- (trifluoro-methyl)phen- oxy) pyrimidine ##STR00026## 32% 292.9 0.886 min inLCMS method C .sup.1H NMR (CDCl.sub.3): .delta. 8.80 (s, 1H), 8.26(s, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.15-7.25 (m, 1H), 6.81-6.95 (m,1H). .sup.19F NMR: (CDCl.sub.3): .delta. -62.00~-62.29,-114.92~-114.95. 5 ethyl 2-(2- chloro-4- (trifluorometh- yl)phen-oxy)acetate ##STR00027## 15% 308.8, 310.8 0.854 min in LCMS methodC 6 4-chloro-5- (4-fluoro- 2- (trifluorometh- yl)phen- oxy)pyrimidine ##STR00028## 36% 276.8, 278.8 0.834 min in LCMS method C.sup.1H NMR (CDCl.sub.3): .delta. 8.79 (s, 1H), 8.15 (s, 1H), 7.55(d, J = 2.0 Hz, 1H), 7.30 (dd, J = 8.8 2.4 Hz, 1H), 6.99 (d, J =8.8 Hz, 1H). 7 4-chloro-5- (4-fluoro- 2- (trifluoro- methyl)phen-oxy) pyrimidine ##STR00029## 14% 320.8, 322.8 0.878 min in LCMSmethod C 8 4-chloro-5- (2-bromo- 3,4- difluorophen- oxy) pyrimidine##STR00030## 31% 321.0, 323.1 1.645 min in LCMS method C 9 5-(2-bormo- 4,5difluoro- phenoxy)- 4chloro- pyrimidine ##STR00031## 31%320.8, 322.8 1.025 min in LCMS method C 10 4-chloro-5- (2-chloro-3- (trifluorometh- yl)phen- oxy) pyrimidine ##STR00032## 25% 309.1,310.9 0.841 min in LCMS method C .sup.1H NMR (CD.sub.3OD): .delta.8.82 (s, 1 H), 8.40 (s, 1 H), 7.70 (d, J = 8.0 Hz, 1 H), 7.54 (t, J= 8.0 Hz, 1 H) 7.39 (d, J = 8.0 Hz, 1 H). .sup.19F NMR(CD.sub.3OD): .delta. -63.82 (m, 3 F). 10a 4-chloro-5- (2-chloro-4- fluorophen- oxy)pyrimi- dine ##STR00033## 45% 258.1, 260.1 0.829min in LCMS method C
Intermediate 11
tert-Butyl7-(5-(2-bromo-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.-4]nonane-2-carboxylate
##STR00034##
A solution of 5-(2-bromo-4-fluorophenoxy)-4-chloropyrimidine(Intermediate 1, 4 g, 13.18 mmol), tert-butyl2,7-diazaspiro[4.4]nonane-2-carboxylate (3.0 g, 13.18 mmol) andK.sub.2CO.sub.3 (7.3 g, 52.72 mmol) in CH.sub.3CN (100 mL) wasstirred at 95.degree. C. for 8 h. The solid was filtered off andthe filtrate was concentrated under reduced pressure. The residuewas purified by column chromatography on silica gel (eluting withpetroleum ether:ethyl acetate=10:1 to 3:2) to afford tert-butyl7-(5-(2-bromo-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2--carboxylate (Intermediate 11) as a yellow oil. Yield: 9.5 g; HPLCmethod C: R.sub.t=0.749 min; (M+H).sup.+=493.0 495.1 (bromineisotopes); .sup.1H NMR (CD.sub.3OD): .delta. 8.29 (s, 1H), 7.66 (s,1H), 7.54 (d, J=2.8 Hz, 1H), 7-16 (d, J=6.0 Hz, 1H), 6.96 (d, J=4.8Hz, 1H), 3.67-3.81 (t, 4H), 3.37 (s, 2H), 3.23-3.27 (m, 2H),1.87-1.96 (t, 4H), 1.44 (s, 9H). .sup.19F NMR (CD.sub.3OD): .delta.-119.01.
Intermediates 12-19
The following intermediates were prepared according to theprocedure described for Intermediate 11.
TABLE-US-00018 TABLE 2 Intermediates 12-19 Mass peak(s) R.sub.fvalue Int. No. Name Structural formula Yield (M + H).sup.+ orR.sub.t 12 7-(5-(2,6- dichloro-4- fluorophenoxy) pyrimidin-4-yl)-2,7- diazaspiro[4.4] nonane-2- carboxylate ##STR00035## 80%483.0, 485.0 0.775 in LCMS method C 13 tert-butyl-6- (5-(2-chloro-4- fluorophenoxy) pyrimidin- 4-yl)-2,6- diazaspiro[3.4] octane-2-carboxylate ##STR00036## 86% 467.3, 469.3 1.023 min in LCMS methodC .sup.1H NMR (CDCl.sub.3): .delta. 8.44 (s, 1H), 7.83 (s, 1H),7.00-7.10 (m, 1H), 6.45-6.55 (m, 1H), 3.55-3.90 (m, 4H), 3.20-3.50(m, 4H), 1.80-2.00 (m, 4H), 1.45 (s, 9H). .sup.19F NMR: (CDCl.sub.3400 MHz): .delta. -133.24~-133.47, -140.23~-140.44. 14 tert-butyl7- (5-(4-fluoro- 2- (trifluorometh- yl)phenoxy)pyri- midin-4-yl)-2,7- diazaspiro[4.4] nonane-2- carboxylate ##STR00037## 85%483.1 0.821 min in LCMS method C .sup.1H NMR (CD.sub.3OD): .delta.8.30-8.40 (m, 1H), 7.80 (s, 1H), 7.55 (dd, J = 8.0 2.8 Hz, 1H),7.36-7.40 (m, 1H), 6.91- 7.00 (m, 1H), 3.70-3.88 (m, 2H), 3.55-3.69(m, 2H), 3.32- 3.50 (m, 2H), 3.15-3.29 (m, 2H), 1.84-2.00 (m, 4H),1.45 (d, J = 3.6 Hz, 9H). .sup.19F NMR: (CD.sub.3OD): .delta.-63.9~-63.53, -120.02~-120.32. 15 tert-butyl 7- (5-(2-chloro- 4-(trifluorometh- yl)phenoxy) pyrimidin-4- yl)-2,7- diazaspiro[4.4]nonane-2- carboxylate ##STR00038## 70% 499.3, 502.3 (chlorineisotopes) 0.819 min in LCMS method E .sup.1H NMR (CDCl.sub.3):.delta. 8.49 (s, 1 H), 7.94 (s, 1 H), 7.76 (s, 1 H), 7.47 (d, J =8.4 Hz, 1 H), 6.80-6.82 (m, 1 H), 3.65- 3.76 (m, 2 H), 3.57-3.60(m, 2 H), 3.41-3.47 (m, 2 H), 3.23-3.32 (m, 2 H), 1.85-1.92 (m, 4H), 1.46 (s, 9 H). .sup.19F NMR: (CDCl.sub.3): .delta. -62.09. 16tert-butyl 7- (5-(2,4- dichlorophen- oxy)pyrimidin- 4-yl)-2,7-diazaspiro[4.4] nonane-2- carboxylate ##STR00039## 94% (M + H)+ =464.9, 466.9 (chlorine isotopes) 0.788 min in LCMS method C .sup.1HNMR (CDCl.sub.3): .delta. 8.44 (s, 1H), 7.84 (s, 1H), 7.48 (s, 1H),7.19 (d, J = 8.4 2.4 Hz, 1H), 6.72 (d, J = 8.0 Hz, 1H), 3.60-3.80(m, 4H), 3.25-3.46 (m, 4H), 1.87-1.93 (m, 4H), 1.46 (s, 9H). 17tert-butyl7- (5-(2-bromo- 4,6- difluorophenoxy) pyrimidin-4-yl)-2,7- diazaspiro[4.4] nonane-2- carboxylate ##STR00040## 90%(M + H)+ = 513.1, 515.1 (bromine isotopes) 0.762 min in LCMS methodC 18 tert-butyl7- (5-(2-bromo- 4,5- difluorophenoxy) pyrimidin-4-yl)-2,7- diazaspiro[4.4] nonane-2- carboxylate ##STR00041## 90%(M + H)+ = 510.9, 512.9, (bromine isotopes) 0.823 min in LCMSmethod C 19 tert-butyl 7- (5-(2-chloro- 3- (trifluorometh-yl)phenoxy) pyrimidin-4- yl)-2,7- diazaspiro [4.4]nonane-2-carboxylate ##STR00042## 74% (M + H)+ = 499.3, 501.3 (chlorineisotopes) 1.060 min in LCMS method D .sup.1H NMR (CD.sub.3OD):.delta. 8.38 (s, 1 H), 7.86 (s, 1 H), 7.47- 7.60 (m, 2 H), 7.18 (s,1 H), 3.80-3.84 (m, 2 H), 3.61-3.67 (m, 2 H), 3.44-3.52 (m, 2 H),3.24-3.27 (m, 2 H), 1.89- 1.99 (m, 4H), 1.46-1.48 (m, 9 H)..sup.19F NMR (CD.sub.3OD): .delta. -63.71 (m, 3 F).
Intermediate 20
tert-butyl6-(5-(2-bromo-4-fluorophenoxy)pyrimidin-4-yl)-2,6-diazaspiro[3.-3]heptane-2-carboxylate
##STR00043##
To a solution of 5-(2-bromo-4-fluorophenoxy)-4-chloropyrimidine(Intermediate 1, 5.55 g, 18.4 mmol) in CH.sub.3CN (80 mL) was addedtert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (3.62 g, 18.4mmol) and Na.sub.2CO.sub.3 (3.89 g, 36.74 mmol). The mixture wasstirred at 90-95.degree. C. for 16 h. The mixture was filtered andthe filtrate was concentrated. The residue was purified by silicagel column chromatography (petroleum ether:ethyl acetate=0:1) togive tert-butyl6-(5-(2-bromo-4-fluorophenoxy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane--2-carboxylate as a yellow solid. Yield: 6.5 g; HPLC method C:R.sub.t=0.742 min, (M+H).sup.+=465.0, 467.0 (bromine isotopes).
Intermediates 20a-25
The following intermediates were prepared according to theprocedure described for Intermediate 20.
TABLE-US-00019 TABLE 3 Intermediates 20a-25 Mass peak(s) R.sub.fvalue Int. No. Name Structure Yield (M + H).sup.+ or R.sub.t 20atert-butyl 6-(5- (2-chloro-4- fluorophenoxy) pyrimidin-4- yl)-2,6-diazaspiro[3.3] heptane-2- carboxylate ##STR00044## 70% 421.1,423.1 0.701 min in LCMS method C 21 tert-butyl(2-(5- (2-bromo-4-fluorophenoxy) pyrimidin-4- yl)-2-azaspiro [3.3]heptan-6-yl)carbamate ##STR00045## 76% 478.9, 480.9 0.696 min in LCMS methodC 22 2-(5-(2- bromo-4- fluorophenoxy) pyrimidin-4- yl)-2-aza-spiro[3.3]heptan- 6-one ##STR00046## 55 378.1, 380.1 0.721 min inLCMS method C 23 tert-butyl 2-(5- (2-bromo-4- fluorophenoxy)pyrimidin-4- yl)-2,7- diazaspiro[3.5] nonane-7- carboxylate##STR00047## 82% 493.0, 495.0 0.696 min in LCMS method C 24tert-butyl2-(5- (2-bromo-4- fluorophenoxy) pyrimidin-4- yl)-2,6-diazaspiro[3.4] octane-6- carboxylate ##STR00048## 90% 478.9, 480.90.725 min in LCMS method C 24A tert-butyl2-(5- (2-bromo-4-fluorophenoxy) pyrimidin-4- yl)-2,6- diazaspiro[3.4] octane-6-carboxylate ##STR00049## 90% 435.1 437.1 0.713 min in LCMS method C25 tert-butyl6-(5- (2-bromo-4- fluorophenoxy) pyrimidin-4- yl)-2,6-diazaspiro[3.4] octane-2- carboxylate ##STR00050## 78% 479.0, 481.00.716 min in LCMS method C
Intermediate 26
2-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-2,7-di-azaspiro[4.4]nonane
##STR00051##
Step 1: tert-butyl7-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-2,7-d-iazaspiro[4.4]nonane-2-carboxylate
##STR00052##
To a suspension of tert-butyl7-(5-(2-bromo-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2--carboxylate (Intermediate 11, 200 mg, 0.40 mmol),(4-isopropylpyrimidin-5-yl)boronic acid (130 mg, 0.80 mmol) andK.sub.3PO.sub.4 (170 mg, 0.80 mmol) in dioxane (6 mL) and H.sub.2O(2 mL) was added Sphos palladacycle (14.4 mg, 0.02 mmol) underN.sub.2 atmosphere and the mixture was stirred at 90.degree. C. for16 h. The reaction mixture was washed with water (80 mL) andextracted with EtOAc (3.times.50 mL), the organic layers were driedover anhydrous Na.sub.2SO.sub.4, filtered, and concentrated underreduced pressure. The residue was purified by preparative TLC onsilica gel (petroleum ether:EtOAc=1:1, R.sub.f=0.25) to givetert-butyl7-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-2,7-d-iazaspiro[4.4] nonane-2-carboxylate as a white solid. Yield: 110mg; HPLC method C: R.sub.t=0.759 min; (M+H).sup.+=535.2.
Step 2: 2-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane
To a solution of tert-butyl7-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-2,7-d-iazaspiro[4.4]nonane-2-carboxylate (100 mg, 1.87 mmol) inCH.sub.2Cl.sub.2 (3 mL) was added TFA (1 mL). The mixture wasstirred at 20-25.degree. C. for 2 h. Then the reaction mixture wasneutralized with NH.sub.3--H.sub.2O (pH=8) and washed with water(80 mL) and extracted with CH.sub.2Cl.sub.2 (3.times.50 mL). Theorganic layers were dried over anhydrous Na.sub.2SO.sub.4,filtered, and concentrated in vacuo to give crude2-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)--2,7-diazaspiro[4.4]nonane as a yellow solid which was used in thenext step without further purification. Yield: 90 mg; HPLC methodC: R.sub.t=0.575 min; (M+H).sup.+=435.2.
Intermediates 27-32
The following intermediates were prepared according to theprocedure described for Intermediate 26.
TABLE-US-00020 TABLE 4 Intermediates 27-32 Mass peak(s) R.sub.fvalue Int No. Name Structure Yield (M + H).sup.+ or R.sub.t 272-(5-(4-fluoro-2- (4- isopropylpyrimidin- 5-yl)phenoxy)pyrimidin-4-yl)- 2,6-diaza- spiro[3.3]heptane ##STR00053## 59%407.0 0.566 min in LCMS method C 28 (6-(5-(4-fluoro-2- (4-isopropylpyrimidin- 5-yl)phenoxy) pyrimidin-4-yl)- 2,6-diazaspiro[3.4]octane ##STR00054## 90% 421.2 1.941 min in LCMSmethod D .sup.1H NMR (MeOD): .delta. 9.12 (s, 1 H), 8.63-8.65 (m, 1H), 8.26 (s, 1 H), 7.77 (s, 1 H), 7.25-7.30 (m, 2 H), 7.02- 7.05(m, 1 H) 3.58-3.74 (m, 8 H), 3.09-3.14 (m, 1 H), 2.05-2.16 (m, 2H), 1.24 (d, J = 6.8 Hz, 6 H). .sup.19F NMR (MeOD): .delta.-120.40. 29 2-(5-(4-fluoro-2- (4- isopropylpyrimidin- 5-yl)phenoxy)pyrimidin-4-yl)-2- azaspiro[3.3]heptan- 6-amine ##STR00055## 74%421.0 0.565 min in LCMS method C 30 2-(5-((5-fluoro-2'-isopropyl-[1,1'- biphenyl]-2- yl)oxy)pyrimidin- 4-yl)-2,6-diazaspiro[3.3] heptane ##STR00056## 78% 405.1 0.617 min in LCMSmethod C 31 2'-((4-(2,7-diaza- spiro[4.4]nonan- 2-yl)pyrimidin-5-yl)oxy)-2- cyclopropyl-5'- fluoro-[1,1'- biphenyl]-4-carbonitrile ##STR00057## 77% 456.2 0.639 min in LCMS method C 31a2-(5-(4-fluoro-2- (1-isopropyl-1H- pyrazol-5- yl)phenoxy)pyrimidin-4-yl)- 2,7-diaza- spiro[4.4]nonane ##STR00058## 70% 423.20.539 min in LCMS method C 31b 2-(5-(4-fluoro-2- (4-isopropylpyrimidin- 5- yl)phenoxy)pyrimi- din-4-yl)-2,7-di-azaspiro[3.5]nonane ##STR00059## 58 435.2 0.551 min in LCMS methodC 31c 2-(5-(2-(2- cyclopropylpyridin- 3-yl)-4- fluorophenoxy)pyrimidin-4-yl)- 2,6-diaza- spiro[3.3]heptane ##STR00060## 50%404.2 0.532 min in LCMS method C 32 2'-((4-(2,6-diaza-spiro[3.3]heptan- 2-yl)pyrimidin- 5-yl)oxy)-2- cyclopropyl-5'-fluoro-[1,1'- biphenyl]-4- carbonitrile ##STR00061## 49% 428.00.615 min in in LCMS method C
Intermediate 33
2-((4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopro-pyl-N-methylbenzamide
##STR00062##
Step 1. tert-butyl7-(5-(4-fluoro-2-(methoxycarbonyl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[-4.4]nonane-2-carboxylate
##STR00063##
To a solution of tert-butyl7-(5-(2-bromo-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2--carboxylate (Intermediate 11, 9.5 g, 19.31 mmol) andPd(dppf)Cl.sub.2 (7.1 g, 9.66 mmol) was added in Et.sub.3N (13.4mL) and MeOH (100 mL). Then the reaction mixture was stirred at65.degree. C. under CO (50 Psi) for about 16 h. The reaction wasfiltered through Celite and concentrated under reduced pressure toafford the residue which was purified by column chromatography onsilica gel (eluting with DCM:MeOH=1:0.about.10:1) to affordtert-butyl7-(5-(4-fluoro-2-(methoxycarbonyl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[-4.4]nonane-2-carboxylate as brown oil. Yield: 9.0 g; LC-MS methodE: R.sub.t=0.914 min; (M+H).sup.+=473.2.
Step 2.2-((4-(7-(tert-butoxycarbonyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrim-idin-5-yl)oxy)-5-fluorobenzoic Acid
##STR00064##
To a solution of tert-butyl7-(5-(4-fluoro-2-(methoxycarbonyl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[-4.4]nonane-2-carboxylate (3.3 g, 6.99 mmol) in MeOH (30 mL), THF(30 mL) and H.sub.2O (10 mL) was added KOH (0.78 g, 13.98 mmol).The mixture was stirred at 13-23.degree. C. for 16 h. The mixturewas concentrated, and adjusted to pH=3-4 with aqueous HCl (3mol/L). The mixture was extracted with EtOAc (3.times.50 mL), andthe combined organic layers were washed with brine (50 mL),directed over Na.sub.2SO.sub.4, filtered and concentrated to givecrude2-((4-(7-(tert-butoxycarbonyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5--yl)oxy)-5-fluorobenzoic acid as a brown solid, which was useddirectly without further purification. Yield: 3.2 g; LCMS Method C:R.sub.t=0.702 min, (M+H).sup.+=459.0. .sup.1H NMR (DMSO-d.sub.6):.delta. 8.30 (s, 1H), 7.39-7.69 (m, 3H), 6.95-7.05 (m, 1H),3.60-3.72 (m, 5H), 3.17 (s, 3H), 1.77-1.88 (m, 4H), 1.38 (s, 9H)..sup.19F NMR (DMSO-d.sub.6): .delta. -119.13.
Step 3. tert-butyl7-(5-(4-fluoro-2-isopropyl(methyl)carbamoyl)phenoxy)pyrimidin-4-yl)-2,7-d-iazaspiro[4.4]nonane-2-carboxylate
##STR00065##
To a solution of2-((4-(7-(tert-butoxycarbonyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5--yl)oxy)-5-fluorobenzoic acid (2.9 g, 5.45 mmol) andN-methylpropan-2-amine (0.6 g, 8.18 mmol) in DCM (100 mL) was addedHATU (3.1 g, 8.18 mmol) and DIPEA (2.1 g, 16.3 mmol). The mixturewas stirred at 13-21.degree. C. for 16 h. The mixture wasconcentrated, and the residue was purified by neutral preparativeHPLC to give tert-butyl7-(5-(4-fluoro-2-isopropyl(methyl)carbamoyl)phenoxy)pyrimidin-4-yl)-2,7-d-iazaspiro[4.4]nonane-2-carboxylate. Yield: 2.1 g; LCMS method E:R.sub.t=0.731 min (M+H).sup.+=514.1. .sup.1H NMR (DMSO-d.sub.6):.delta. 8.30-8.33 (m, 1H), 7.77-7.82 (m, 1H), 7.19-7.29 (m, 2H),6.87-6.97 (m, 1H), 4.67 (s, 1H), 3.56-3.78 (m, 6H), 3.15-3.17 (m,2H), 2.67-2.83 (m, 3H), 1.79-1.84 (m, 4H), 1.38 (s, 9H), 1.06-1.11(m, 6H). .sup.19F NMR (DMSO-d.sub.6): .delta. -111.36.
Step 4.2-((4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro--N-isopropyl-N-methylbenzamide
To a solution of tert-butyl7-(5-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenoxy)pyrimidin-4-yl)-2,7--diazaspiro[4.4]nonane-2-carboxylate (1 g, 1.95 mmol) in anhydrousDCM (10 mL) was added HCl-MeOH (2 mL, 4 mol/L in MeOH) slowly at0.degree. C. under N.sub.2. The reaction was stirred at17-23.degree. C. for 16 h. The mixture was adjusted topH=11.about.12 with aq. NaOH (1 mol/L) then was extracted withEtOAc (50 mL.times.3). The combined organic layers were washed withbrine (50 mL), dried over Na.sub.2SO.sub.4, filtered, andconcentrated under reduced pressure to give crude2-((4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopr-opyl-N-methylbenzamide as a brown solid. Yield: 0.8 g (95% crude);LCMS method C: R.sub.t=0.508 min, (M+H).sup.+=414.0.
Intermediates 35-39
The following intermediates were prepared according to theprocedure provided for Intermediate 33.
TABLE-US-00021 TABLE 5 Intermediates 35-39 Mass peak(s) R.sub.fvalue Int. No. Name Structure Yield (M + H).sup.+ or R.sub.t 352-((4-(2,6- diazaspiro[3.5] octan-2- yl)pyrimidin- 5-yl)oxy)-5-fluoro-N- isopropyl-N- methylbenzamide ##STR00066## 77% 400.0 0.420min in LCMS method C 36 2-((4-(2,7- diazaspiro[3.5] nonan-2-yl)pyrimidin- 5-yl)oxy)-5- fluoro-N- isopropyl-N- methylbenzamide##STR00067## 81% 414.3 0.827 min in LCMS method F .sup.1H NMR(CD.sub.3OD): .delta. 8.22-8.27 (m, 1H), 7.70-7.80 (m, 1H),6.94-7.22 (m, 3H), 4.77-4.79 (m, 1H), 3.90-4.01 (m, 4H), 2.77-3.31(m, 7H), 1.84-1.86 (m, 4H), 1.15-1.28 (m, 6H). .sup.19F NMR(CD.sub.3OD): .delta. -115.01. 37 2-((4-(2,6- diazaspiro[3.4]octan-6- yl)pyrimidin- 5-yl)oxy)-5- fluoro-N- isopropyl-N-methylbenzamide ##STR00068## 54% 400.2 1.850 min in LCMS Method D.sup.1H NMR (CD.sub.3OD): .delta. 8.25-8.35 (m, 1 H), 7.75-7.91 (m,1 H), 7.15-7.25 (m, 2 H), 6.85-7.00 (m, 1 H), 3.60-4.05 (m, 9 H),2.80-3.00 (m, 3 H), 2.15-2.25 (m, 2 H), 1.00-1.30 (m, 6 H)..sup.19F NMR (CD.sub.3OD): .delta. -120.13~-120.73. 38 2-((4-(6-amino-2-aza- spiro[3.3]heptan- 2- yl)pyrimidin- 5-yl)oxy)-5-fluoro-N- isopropyl-N- methylbenzamide ##STR00069## 37% 399.8 1.45min in LCMS Method D 39 ((4-(2,6- diazaspiro[3.3] heptan-2-yl)pyrimidin- 5-yl)oxy)-5- fluoro-N- isopropyl-N- methylbenzamide##STR00070## 35% 386.1 1.42 min in LCMS Method D
Intermediate 40
2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbaldehyde
##STR00071##
To a suspension of2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile (10 g, 57.75mmol) in HCO.sub.2H (187 mL) and H.sub.2O (63 mL) was added Ni--Alalloy (6.19 g, 144.38 mmol) in portions. Then the mixture wasstirred at 90.degree. C. for 16 h. The reaction mixture wasfiltered and the filtrate was washed with EtOH and concentratedunder reduced pressure. The residue was washed with water (150 mL)and filtered. The filter cake was dried under reduced pressure togive 2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbaldehyde as agrey white solid. Yield: 9.1 g (97.2%); LCMS method D:R.sub.t=1.404 min, (M+H).sup.+=163.0. .sup.1H NMR (CD.sub.3OD):.delta. 9.87 (s, 1H), 7.65 (dd, J=8.4, 1.2 Hz, 1H), 7.55 (s, 1H),7.19 (d, J=8.0 Hz, 1H).
Intermediate 41
2-((4-chloropyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide
##STR00072##
Step 1. Methyl 5-fluoro-2-methoxybenzoate
##STR00073##
To a solution of 5-fluoro-2-hydroxybenzoic acid (100 g, 641 mmol)in acetone (1000 mL) was added K.sub.2CO.sub.3 (190 g, 1380 mmol)and MeI (268.3 g, 1890 mmol). The mixture was stirred at 50.degree.C. for 16 h. The mixture was filtered and concentrated underreduced pressure. The residue was mixed with EtOAc (500 mL) andwashed with H.sub.2O (3.times.300 mL). The organic layer was thendried over anhydrous Na.sub.2SO.sub.4, filtered, and concentratedunder reduced pressure. The residue was purified by columnchromatography on silica gel eluting with petroleum ether:ethylacetate=20:1 to afford methyl 5-fluoro-2-methoxybenzoate. Yield: 78g (66%). .sup.1H NMR (CDCl.sub.3): .delta. 7.50 (dd, J=3.6 Hz, 8.8Hz, 1H), 7.17-7.18 (m, 1H), 6.92 (dd, J=4.0 Hz, 8.8 Hz 1H), 3.89(s, 3H), 3.88 (s, 3H).
Step 2. 5-fluoro-2-methoxybenzoic Acid
##STR00074##
To a solution of methyl 5-fluoro-2-methoxybenzoate (25 g, 135.9mmol) in MeOH (250 mL) and H.sub.2O (50 mL) was added KOH (25 g,446.4 mmol). The mixture was stirred at 60.degree. C. for 3 h. Themixture was then adjusted to pH 3-4 by 2N HCl solution andconcentrated to remove MeOH under reduced pressure. The residue wasmixed with EtOAc (200 mL) and washed with H.sub.2O (2.times.200mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4,filtered, and concentrated under reduced pressure to afford crude5-fluoro-2-methoxybenzoic acid as a white solid, which was used fornext step without further purification. Yield: 23 g.
Step 3. 5-fluoro-N,N-diisopropyl-2-methoxybenzamide
##STR00075##
To a solution of 5-fluoro-2-methoxybenzoic acid (20 g, 117.6 mmol)and diisopropylamine (23.8 g, 235.6 mmol) in anhydrousCH.sub.2Cl.sub.2 (300 mL) was added DIEA (22.8 g, 176.7 mmol) andHATU (53.6 g, 141.4 mmol) at 0.degree. C. The mixture was stirredat 25.degree. C. for 16 h. The mixture was then washed withH.sub.2O (3.times.200 mL). The organic layer was dried overanhydrous Na.sub.2SO.sub.4, filtered, and concentrated underreduced pressure. The residue was purified by column chromatographyon silica gel eluting with petroleum ether:ethyl acetate=5:1 toafford 5-fluoro-N,N-diisopropyl-2-methoxybenzamide as a whitesolid. Yield: 22 g. LCMS method C: R.sub.t value: 0.785 min,(M+H).sup.+=254.0.
Step 4. 5-fluoro-2-hydroxy-N,N-diisopropylbenzamide
##STR00076##
To a solution of 5-fluoro-N,N-diisopropyl-2-methoxybenzamide (15 g,59.3 mmol) in anhydrous CH.sub.2Cl.sub.2 (250 mL) was added withBBr.sub.3 (11 mL, 116.6 mmol) dropwise at -70.degree. C. Themixture was stirred at 5.degree. C. for 16 h. The reaction mixturewas quenched with MeOH (30 mL) slowly at -78.degree. C. andadjusted to pH 7-8 with sat. NaHCO.sub.3 solution. The mixture wasextracted with EtOAc (2.times.300 mL). The combined organic layerswere dried over anhydrous Na.sub.2SO.sub.4, filtered, andconcentrated under reduced pressure. The residue was purified bycolumn chromatography on silica gel eluting with petroleumether:ethyl acetate=4:1 to afford5-fluoro-2-hydroxy-N,N-diisopropylbenzamide as a white solid.Yield: 11 g. LCMS method C: R.sub.t=0.744 min;(M+H).sup.+=240.0.
Step 5. 5-fluoro-N,N-diisopropyl-2-pyrimidin-5-yloxy)benzamide
##STR00077##
To a solution of 5-fluoro-2-hydroxy-N,N-diisopropylbenzamide (11.0g, 46.0 mmol) and 5-bromopyrimidine (21.8 g, 138.0 mmol) inanhydrous DMF (300 mL) was added Cs.sub.2CO.sub.3 (45.0 g, 138.0mmol). The mixture was stirred at 130.degree. C. for 16 h. Themixture was added to EtOAc (500 mL) and washed with H.sub.2O(3.times.300 mL). The organic layer was dried over anhydrousNa.sub.2SO.sub.4, filtered, and concentrated under reducedpressure. The residue was purified by column chromatography onsilica gel eluting with petroleum ether:ethyl acetate=3:1 to afford5-fluoro-N,N-diisopropyl-2-(pyrimidin-5-yloxy)benzamide as a whitesolid. Yield: 14 g (97%) LCMS method C: R.sub.t=0.731 min;(M+H).sup.+=317.9.
Step 6.5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidine-1-oxide
##STR00078##
To a solution of5-fluoro-N,N-diisopropyl-2-(pyrimidin-5-yloxy)benzamide (14 g, 44.2mmol) in anhydrous CH.sub.2Cl.sub.2 (400 mL) was added m-CPBA (27g, 132.7 mmol). The mixture was stirred at 10.degree. C. for 16 h.The reaction mixture was quenched with sat. Na.sub.2SO.sub.3solution (200 mL) and washed with NaHCO.sub.3 (2.times.200 mL). Theorganic layer was dried over anhydrous Na.sub.2CO.sub.3, filtered,and concentrated under reduced pressure to afford crude5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidine 1-oxide as apale yellow solid, which was used for next step without furtherpurification. Yield: 16 g (109%). LCMS method C: R.sub.t=0.705 min,(M+H).sup.+=333.9.
Step 7.2-((4-chloropyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide
To a solution of Et.sub.3N (7.3 g, 72.3 mmol) in CHCl.sub.3 (30 mL)was added POCl.sub.3 (12.5 g, 81.7 mmol) at 0.degree. C. Then themixture was added to a solution of5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidine-1-oxide(16.0 g, 48.0 mmol) in CHCl.sub.3 (270 mL) slowly at 0.degree. C.The mixture was stirred at 65.degree. C. for 16 h. The mixture wasthen slowly added to a sat. NaHCO.sub.3 solution (500 mL) and thepH was adjusted to 7-8 by sat. NaHCO.sub.3 solution. The mixturewas extracted with ethyl acetate (2.times.300 mL). The combinedorganic layers were dried over anhydrous Na.sub.2SO.sub.4,filtered, and concentrated under reduced pressure. The residue waspurified by column chromatography on silica gel eluting withpetroleum ether:ethyl acetate=5:1 to afford2-((4-chloropyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide(6 g) as a yellow solid. HPLC method C: R.sub.t=0.735 min,(M+H).sup.+=351.9. .sup.1H NMR (CDCl.sub.3): .delta. 8.71 (s, 1H),8.21 (s, 1H), 7.02-7.12 (m, 3H), 3.73-3.80 (m, 1H), 3.46-3.53 (m,1H), 1.49 (d, J=6.8 Hz, 3H), 1.34 (d, J=6.8 Hz, 3H), 1.26 (d, J=6.4Hz, 3H), 1.14 (d, J=6.8 Hz, 3H). .sup.19F NMR (CDCl.sub.3): .delta.-114.5.
Intermediate 41a
2-((4-(2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-dii-sopropylbenzamide
##STR00079##
The title compound was synthesized from Intermediate 41 andtert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate by methoddescribed for preparing Intermediate 20. LCMS--Method C: 0.620 min,(M+H).sup.+=413.2.
Intermediates 41b-41f
The following intermediates were prepared according to theprocedure described for Intermediates 41 and 41a.
TABLE-US-00022 TABLE 6 Intermediates 42b-42f Mass R.sub.f valueInt. No. Name Structure Yield peak(s) or R.sub.t 41b 2-((4-(2,6-diazaspiro[3.4] octan-2- yl)pyrimidin-5- yl)oxy)-5- fluoro-N,N-diisopropyl benzamide ##STR00080## 77% (M + H).sup.+ = 428.0 0.520min in LCMS method C 41c 2-((4-(2,6- diazaspiro[3.4] octan-6-yl)pyrimidin-5- yl)oxy)-5- fluoro-N,N- diisopropyl- benzamide##STR00081## 54% (M + H).sup.+ = 428.2 1.45 min in LCMS Method D41d 2-((4-(6- amino- 2azaspiro[3.3] heptan-2- yl)pyrimidin-5-yl)oxy)-5- fluoro-N,N- diisopropyl- benzamide ##STR00082## 37% (M +H).sup.+ = 428.2 1.42 min in LCMS Method D 41e 2-((4-(2,6-diazaspiro[3.4] octan-2- yl)pyrimidin-5- yl)oxy)-N- ethyl-5-fluoro-N-isopropyl- benzamide ##STR00083## 70% (M + H).sup.+ = 414.1 0.512min in LCMS method C 41f 2-((4-(2,7- diazaspiro[3.5] nonan-2-yl)pyrimidin-5- yl)oxy)-N- ethyl-5-fluoro- N-isopropyl- benzamide##STR00084## 54% (M + H).sup.+ = 428.2 1.36 min in LCMS MethodD
Intermediates 42 and 42c.1-(2-hydroxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbaldehydeand 2-(5-formyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethylformate
##STR00085##
Step 1. 4-((2-hydroxyethyl)amino)-3-nitrobenzonitrile
##STR00086##
To a solution of 4-fluoro-3-nitrobenzonitrile (15 g, 90.4 mmol) and2-aminoethanol (11.0 g, 180.7 mmol) in anhydrous DMF (600 mL) wasadded K.sub.2CO.sub.3 (37.4 g, 271.2 mmol) under N.sub.2, then thereaction mixture was stirred at 25.degree. C. for 2 h. The reactionmixture was filtered and the filtrate was concentrated underreduced pressure. The residue was washed with H.sub.2O (100 mL) andthe mixture was extracted with EtOAc (3.times.500 mL). The organiclayers were washed with brine (20 mL), dried over anhydrousNa.sub.2SO.sub.4, filtered, and concentrated to afford4-((2-hydroxyethyl)amino)-3-nitrobenzonitrile. The residue was usedfor the next step without further purification as a yellow solid.Yield: 17.3 g. LCMS method E: R.sub.t=1.016 min;(M+H).sup.+=207.9.
Step 2. 3-amino-4-((2-hydroxyethyl)amino)benzonitrile
##STR00087##
To a solution of 4-((2-hydroxyethyl)amino)-3-nitrobenzonitrile(17.3 g, 83.6 mmol) in EtOH (800 mL) and H.sub.2O (400 mL) wereadded Fe (23.4 g, 418.0 mmol) and NH.sub.4Cl (44.8 g, 836.0 mmol)under N.sub.2. The reaction mixture was stirred at 80.degree. C.for 2 h. The reaction mixture was filtered and the filtrate wasconcentrated under reduced pressure. The residue was dissolved inEtOAc (500 mL), washed with H.sub.2O (2.times.100 mL), brine (20mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, andconcentrated to afford3-amino-4-((2-hydroxyethyl)amino)benzonitrile. The residue was usedfor the next step without further purification as a brown redsolid. Yield: 11.6 g. LCMS Method D: R.sub.t=0.941 min;(M+H).sup.+=178.2.
Step 3.3-amino-4-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)benzonitri-le
##STR00088##
To a solution of 3-amino-4-((2-hydroxyethyl)amino)benzonitrile(11.6 g, 65.46 mmol) and tert-butylchlorodimethylsilane (11.84 g,78.55 mmol) in anhydrous DMF (300 mL) was added imidazole (11.14 g,163.65 mmol), then the reaction was stirred at 35.degree. C. for 16h. The reaction mixture was filtered and the filtrate wasconcentrated under reduced pressure. The reaction mixture was addedto water (1000 mL) and extracted with EtOAc (3.times.500 mL). Theorganic layer was washed with brine (100 mL), dried over anhydrousNa.sub.2SO.sub.4, filtered, and concentrated under reduced pressureto afford3-amino-4-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)benzonitrileas a black oil, which was used for the next step without furtherpurification. Yield: 25 g. LCMS method C: R.sub.t=0.878 min;(M+H).sup.+=292.1.
Step 4.1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-oxo-2,3-dihydro-1H-ben-zo[d]imidazole-5-carbonitrile
##STR00089##
To a solution of3-amino-4-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)benzonitrile(14 g, 48.1 mmol) in anhydrous THF (400 mL) was added a solution ofBTC (28.5 g, 96.2 mmol) at 0.degree. C. Then Et.sub.3N (33 mL) wasadded dropwise to the mixture under at 0.degree. C. After addition,the reaction was stirred at 25.degree. C. for 2 h. The reaction waspoured into sat. aq. NaHCO.sub.3 (500 mL), extracted with EtOAc(3.times.300 mL). The organic layer was washed with brine, driedover anhydrous Na.sub.2SO.sub.4, filtered, and concentrated. Theresidue was purified by column chromatograph on silica gel (elutingwith petroleum ether:EtOAc=5:1 to 1:1) to afford1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile.Yield: 4.8 g (31%). LCMS method F: R.sub.t=1.378 min,(M+H).sup.+=318.3 .sup.1H NMR (CDCl.sub.3): .delta. 10.06 (brs,1H), 7.31 (d, J=8.4 Hz, 1H), 7.16 (s, 1H), 7.11 (d, J=8.0 Hz, 1H),3.94-3.96 (m, 2H), 3.83-3.85 (m, 2H), 0.67 (s, 9H), -0.198 (s,6H).
Step 5.1-(2-hydroxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbal-dehyde and2-(5-formyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethylfor-mate
##STR00090##
To a solution of1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-oxo-2,3-dihydro-1H-benzo[d]im-idazole-5-carbonitrile (6.1 g, 19.2 mmol) in HCOOH (120 mL) andH.sub.2O (40 mL) was added Ni--Al (8.27 g, 96.2 mmol) underN.sub.2, then the reaction mixture was stirred at 90.degree. C. for16 h. The reaction mixture was then filtered and the filtrate wasconcentrated under reduced pressure. The residue was purified bycolumn chromatograph on silica gel (eluting with DCM:MeOH=10:1) toafford1-(2-hydroxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbaldehydeas a white solid and2-(5-formyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethylformate as a yellow solid.
Intermediate 42.
2-(5-formyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethylformate: Yield: 1.7 g (27%). LCMS method F: R.sub.t=0.858 min;(M+H).sup.+=235.2 .sup.1H NMR (DMSO-d.sub.6): .delta. 11.27 (brs,1H), 9.87 (s, 1H), 8.12 (s, 1H), 7.63 (dd, J=8.0, 1.2 Hz, 1H), 7.42(s, 1H), 7.37 (d, J=8.0 Hz, 1H), 4.35-4.38 (m, 2H), 4.12-4.14 (m,2H).
Intermediate 42c.
1-(2-hydroxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbaldehyde:Yield: 1.5 g (27%). LCMS method F: R.sub.t=0.788 min;(M+H).sup.+=207.2 .sup.1H NMR (DMSO-d.sub.6): .delta. 11.20 (brs,1H), 9.86 (s, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.40 (s, 1H), 7.31 (d,J=8.0 Hz, 1H), 4.86 (s, 1H), 3.85-3.86 (m, 2H), 3.63-3.65 (m,2H).
Intermediate 42a
1-(2-methoxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbaldehyde
##STR00091##
The title product was prepared according to the procedure providedfor Intermediate 41 starting with 2-methoxyethan-1-amine. LCMSmethod F: R.sub.t=0.828 min; (M+H).sup.+=221.2.
Intermediate 42b
1-ethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbaldehyde
##STR00092##
The title product was prepared according to the procedure providedfor Intermediate 41, starting with ethylamine LCMS method F:R.sub.t=0.868 min; (M+H).sup.+=191.2.
Intermediate 43
2-((4-chloropyrimidin-5-yl)oxy)-5-fluoro-N-isopropyl-N-methylbenzamide
##STR00093##
Step 1. 5-(2-bromo-4-fluorophenoxy)pyrimidine
##STR00094##
To a solution of 2-bromo-4-fluorophenol (6 g, 31.41 mmol) and5-bromopyrimidine (5.7 g, 36.12 mmol) in anhydrous DMF (60 mL) wasadded Cs.sub.2CO.sub.3 (30.7 g, 94.23 mmol) under N.sub.2. Thereaction mixture was stirred at 130.degree. C. for 16 h. Thereaction mixture was then filtered through a Celite and dilutedwith H.sub.2O (60 mL). The mixture was extracted with EtOAc(3.times.100 mL). The combined organic layers were washed withbrine (3.times.100 mL), dried over anhydrous Na.sub.2SO.sub.4,filtered, and concentrated under reduced pressure to give5-(2-bromo-4-fluorophenoxy)pyrimidine as brown oil which was usedfor next step directly. Yield: 6.5 g. LCMS method F: R.sub.t=0.969min, (M+H).sup.+=269.1.
Step 2.5-fluoro-N-isopropyl-N-methyl-2-(pyrimidin-5-yloxy)benzamide
##STR00095##
To a solution of 5-(2-bromo-4-fluorophenoxy)pyrimidine (5.5 g,crude, 20.45 mmol) and N-methylpropan-2-amine (12 g, 163.60 mmol)in anhydrous DMF (60 mL) was added Pd(dppf)Cl.sub.2 (3 g, 4.09mmol) and Et.sub.3N (14 mL, 102.25 mmol, d=0.726 g/mL) under COatmosphere. The reaction was stirred at 80.degree. C. for 20 h with50 psi. The reaction was concentrated under reduced pressure toafford the residue which was purified by column chromatography onsilica gel (eluting with petroleum ether:EtOAc=10:1 to 1:1) to give5-fluoro-N-isopropyl-N-methyl-2-(pyrimidin-5-yloxy)benzamide as abrown oil. Yield: 3.5 g. LCMS method E: R.sub.t=0.700 min;(M+H).sup.+=290.1.
Step 3.5-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenoxy)pyrimidine-1-oxi-de
##STR00096##
To a solution of5-fluoro-N-isopropyl-N-methyl-2-(pyrimidin-5-yloxy)benzamide (1.8g, 6.22 mmol) in anhydrous CH.sub.2Cl.sub.2 (80 mL) was addedm-CPBA (2.6 g, 15.55 mmol) under N.sub.2. The reaction was stirredat 11-20.degree. C. for 30 h. The reaction was quenched with sat.NaHSO.sub.3 solution (100 mL), extracted with CH.sub.2Cl.sub.2(3.times.100 mL). The combined organic layers were washed with sat.NaHCO.sub.3 solution (3.times.100 mL), brine (3.times.100 mL),dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentratedunder reduced pressure to give 5-(4-fluoro-2(isopropyl(methyl)carbamoyl)-phenoxy)pyrimidine-1-oxide as a yellowsolid which was used for next step directly. Yield: 1.6 g; LCMSmethod F: R.sub.t=0.886 min; (M+H).sup.+=306.1.
Step 4.2-((4-chloropyrimidin-5-yl)oxy)-5-fluoro-N-isopropyl-N-methylbenza-mide
##STR00097##
To a solution of Et.sub.3N (1.1 mL, 7.86 mmol, d=0.726 g/mL) andPOCl.sub.3 (1.2 g, 7.86 mmol) in CHCl.sub.3 (5 mL) was added5-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenoxy)pyrimidine-1-oxide(1.6 g, 5.24 mmol) in CHCl.sub.3 (15 mL) slowly under N.sub.2. Themixture reaction was stirred at 65.degree. C. for 16 h. Thereaction mixture was then quenched with sat. NaHCO.sub.3 solution(100 mL) and extracted with CH.sub.2Cl.sub.2 (3.times.80 mL). Thecombined organic layers were washed with brine (3.times.80 mL),dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentratedunder reduced pressure to afford a residue which was purified bycolumn chromatography on silica gel (eluting with petroleumether:EtOAc=20:1 to 3:1) to give2-((4-chloropyrimidin-5-yl)oxy)-5-fluoro-N-isopropyl-N-methylbenzamideas a yellow solid. Yield: 470 mg. LCMS method E: R.sub.t=0.982 min;(M+H).sup.+=324.2.
Intermediate 43a
5-(2-(benzyloxy)-4-fluorophenoxy)-4-chloropyrimidine
##STR00098##
The title product was synthesized according to the proceduredescribed for Intermediate 43, starting from2-(benzyloxy)-4-fluorophenol. LCMS method B: R.sub.t=2.13 min;(M+H).sup.+=313.3 .sup.1H NMR (CDCl.sub.3, 400 MHz): .delta. 8.66(s, 1H), 8.03 (s, 1H), 7.32-7.27 (m, 3H), 7.19-7.15 (m, 3H),6.84-6.81 (m, 1H), 6.76-6.71 (m, 1H), 5.02 (s, 2H).
Intermediate 43b
tert-Butyl7-(5-(4-fluoro-2-hydroxyphenoxy)pyrimidin-4-yl)-2,7-diazaspiro[-4.4]nonane-2-carboxylate
##STR00099##
Step 1. tert-butyl7-(5-(2-(benzyloxy)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]no-nane-2-carboxylate
##STR00100##
A solution of 5-(2-(benzyloxy)-4-fluorophenoxy)-4-chloropyrimidine(0.80 mmol) and tert-butyl 2,7-diazaspiro[4.4]nonane-2-carboxylate(218 mg, 0.96 mmol) in .sup.iPrOH (2 mL) was added Hunig's base(285 .mu.L, 1.60 mmol). The reaction mixture was heated in themicrowave reactor at 120.degree. C. for 90 min. After cooling toRT, the mixture was diluted with H.sub.2O (10 mL) and extractedwith EtOAc (3.times.15 mL). The organic layer was washed withbrine, dried over Na.sub.2SO.sub.4, and concentrated under vacuum.The crude product was purified by flash chromatography over silicagel eluting with 3% MeOH/DCM to afford 170 mg tert-butyl7-(5-(2-(benzyloxy)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]no-nane-2-carboxylate as an orange oil. LCMS method B: R.sub.t=1.71min; (M+H).sup.+=521.7.
Step 2. tert-butyl7-(5-(4-fluoro-2-hydroxyphenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane--2-carboxylate
To a solution of tert-butyl7-(5-(2-(benzyloxy)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]no-nane-2-carboxylate (160 mg, 0.3 mmol) in MeOH (5 mL) was addedpalladium on carbon (5% dry basis, 33 mg, 30 .mu.mol). The mixturewas stirred at RT under the atmosphere of a hydrogen balloon for 3h and filtered through a celite pad. The filtrate was thenconcentrated under reduced pressure. The crude product was useddirectly for the next step reaction without further purification.LCMS method B: R.sub.t=1.56 min; (M+H).sup.+=431.
Intermediate 44
N-(2-(5-formyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethyl)acetamide
##STR00101##
Step 1. N-(2-((4-cyano-2-nitrophenyl)amino)ethyl)acetamide
##STR00102##
To a solution of 4-fluoro-3-nitrobenzonitrile (200 mg, 1.2 mmol)and N-(2-aminoethyl)acetamide (245 mg, 2.4 mmol) in anhydrous DMF(10 mL) was added K.sub.2CO.sub.3 (496 mg, 3.6 mmol) under N.sub.2,then the reaction mixture was stirred at 14-20.degree. C. for 4 h.The reaction mixture was filtered and the filtrate was concentratedunder reduced pressure. The residue was then extracted withH.sub.2O (10 mL) and EtOAc (3.times.20 mL). The organic layers werewashed with brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4,filtered, and concentrated to affordN-(2-((4-cyano-2-nitrophenyl)amino)ethyl)acetamide. The residue wasused for the next step without further purification as a yellowsolid. Yield: 250 mg. LCMS method D: R.sub.t=1.256 min,(M+H).sup.+=249.1.
Step 2. N-(2-((2-amino-4-cyanophenyl)amino)ethyl)acetamide
##STR00103##
To a solution of N-(2-((4-cyano-2-nitrophenyl)amino)ethyl)acetamide(250 mg, 1.0 mmol) in EtOH (10 mL) and H.sub.2O (5 mL) was added Fe(280 mg, 5.0 mmol) and NH.sub.4Cl (530 mg, 10 mmol) under N.sub.2.The reaction mixture was stirred at 80.degree. C. for 2 h. Thereaction mixture was then filtered and the filtrate wasconcentrated under reduced pressure. The residue was extracted withH.sub.2O (10 mL) and EtOAc (20 mL). The organic layer was washedwith brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4,filtered, and concentrated to affordN-(2-((2-amino-4-cyanophenyl)amino)ethyl)acetamide. The residue wasused for the next step without further purification as a brownsolid. Yield: 200 mg. LCMS method F: R.sub.t=0.992 min,(M+H).sup.+=219.1.
Step 3.N-(2-(5-cyano-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethyl)ace-tamide
##STR00104##
To a solution of N-(2-((2-amino-4-cyanophenyl)amino)ethyl)acetamide(10 mg, 0.046 mmol) in anhydrous THF (4 mL) was added Et.sub.3N(0.5 mL), then a solution of BTC (27 mg, 0.092 mmol) in anhydrousTHF (2 mL) was added dropwise to the mixture at 0.degree. C. Afteraddition, the reaction mixture was stirred at 3-14.degree. C. for12 h. The reaction mixture was extracted with H.sub.2O (5 mL) andEtOAc (20 mL.times.3). The organic layers were washed with brine(20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, andconcentrated. The residue was purified by column chromatography onsilica gel (eluting with CH.sub.2Cl.sub.2: MeOH=1:0 to 10:1) toaffordN-(2-(5-cyano-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethyl)acetamideas a brown oil. Yield: 20 mg. LCMS method F: R.sub.t=1.175 min;(M+H).sup.+=245.2.
Step 4.N-(2-(5-formyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethyl)ac-etamide
To a solution ofN-(2-(5-cyano-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethyl)acetamide(20 mg, 0.082 mmol) in HCOOH (3 mL) and H.sub.2O (1 mL) was addedNi--Al (35 mg, 0.41 mmol), then the reaction was stirred at90.degree. C. for 12 h. The reaction was filtered and the filtratewas concentrated under reduced pressure to affordN-(2-(5-formyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethyl)acetamide(15 mg, 92% purity, 75%). The residue was used for the next stepwithout further purification as a brown solid. Yield: 15 mg. LCMSmethod F: R.sub.t=R.sub.t value: 0.773 min; (M+H).sup.+=248.1.
Intermediate 44a
1-(2-(dimethylamino)ethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbal-dehyde
##STR00105##
The title product was synthesized according to the proceduredescribed for Intermediate 44 starting withN1,N1-dimethylethane-1,2-diamine and 4-fluoro-3-nitrobenzonitrile.LCMS method F: R.sub.t=0.773 min; (M+H).sup.+=233.1.
Intermediate 45
3,3-dimethyl-2-oxoindoline-6-carbaldehyde
##STR00106##
To a solution of 6-bromo-3,3-dimethylindolin-2-one (502 mg, 2.09mmol) in DMF (10 mL) under N.sub.2 atmosphere was addedPd(OAc).sub.2 (14 mg, 0.063 mmol), N-formyl saccharin (662 mg, 3.14mmol), dppb (39 mg, 0.094 mmol), Na.sub.2CO.sub.3 (315 mg, 3.16mmol) and Et.sub.3SiH (316 mg, 2.72 mmol). The resulting mixturewas heated to 80.degree. C. for 16 h. The reaction mixture wasdiluted with EtOAc, washed with H.sub.2O, brine, dried overanhydrous Na.sub.2SO.sub.4, and filtered. The filtrate was thenconcentrated to dryness. The residue was purified by flashchromatography to afford 70 mg of3,3-dimethyl-2-oxoindoline-6-carbaldehyde. LCMS method B:R.sub.t=1.63 min; (M+H).sup.+=190.
Intermediate 46
6-formyl-3-methyl-2-oxoindoline-3-carbonitrile
##STR00107##
Step 1. Methyl4-(2-cyano-1-ethoxy-1-oxopropan-2-yl)-3-nitrobenzoate
##STR00108##
To a 60% suspension of sodium hydride (2.0 g, 50 mmol) in dry DMF(50 mL) at 0.degree. C. was added ethyl 2-cyanoacetate (5.33 mL, 50mmol) dropwise and the reaction mixture was stirred for anadditional 30 min at 0.degree. C. To the resulting gray suspensionwas added methyl 4-fluoro-3-nitrobenzoate (7.97 g, 40 mmol) at0.degree. C. The resulting deep red mixture was stirred at0.degree. C. for 30 min and warmed to RT over 2 h. The reactionmixture was cooled to 0.degree. C., and MeI (7.8 mL) was added,followed by KOtBu (8.4 g, 75 mmol). After the addition, the mixturewas stirred for 2 days at RT and subsequently quenched with aqueousNH.sub.4Cl solution. The resulting mixture was then extracted withEtOAc twice. The organic layers were combined and washed withH.sub.2O and brine successively, and dried over anhydrous sodiumsulfate, filtered, and concentrated. The residue was purified byflash-chromatography to afford methyl4-(2-cyano-1-ethoxy-1-oxopropan-2-yl)-3-nitrobenzoate. Yield 6.04g. LCMS method B: R.sub.t=1.63 min.
Step 2. Methyl 3-cyano-3-methyl-2-oxoindoline-6-carboxylate
##STR00109##
To a solution of methyl4-(2-cyano-1-ethoxy-1-oxopropan-2-yl)-3-nitrobenzoate (6.039 g,19.72 mmol) in EtOH (60 mL) was added saturated aqueous NH.sub.4Clsolution (15 mL) and iron powder (5.803 g, 98.61 mmol). The mixturewas heated to reflux overnight. The mixture was then cooled to RTand filtered through a short pad of Celite and subsequently washedwith EtOAc. The filtrate was washed with H.sub.2O, brine, driedover anhydrous sodium sulfate, filtered, and concentrated. Theresidue was purified by flash-chromatography to afford methyl3-cyano-3-methyl-2-oxoindoline-6-carboxylate. Yield 4.404 g. LCMSmethod B: R.sub.t=1.07 min; (M+H).sup.+=231.
Step 3. 6-(Hydroxymethyl)-3-methyl-2-oxoindoline-3-carbonitrile
##STR00110##
To a solution of methyl3-cyano-3-methyl-2-oxoindoline-6-carboxylate (2.101 g, 9.12 mmol)in dry THF (40 mL) under N.sub.2 atmosphere was added a solution ofLiBH.sub.4 (9.1 mL, 18.2 mmol), followed by MeOH (0.2 mL). Themixture was heated to reflux for 2 h and subsequently quenched withaqueous NH.sub.4Cl solution. The mixture was then extracted twicewith EtOAc. The organic layers were combined and washed withH.sub.2O and brine successively, dried over anhydrous sodiumsulfate, filtered, and concentrated. The residue was purified byflash-chromatography to afford6-(hydroxymethyl)-3-methyl-2-oxoindoline-3-carbonitrile. Yield 1.42g. LCMS method B: R.sub.t=0.79 min; (M+H).sup.+=203.1.
Step 4. 6-formyl-3-methyl-2-oxoindoline-3-carbonitrile
To a solution of6-(hydroxymethyl)-3-methyl-2-oxoindoline-3-carbonitrile (0.597 g,2.95 mmol) in DCM was added active MnO.sub.2 (2.57 g, 29.56 mmol).The mixture was stirred at RT overnight and then filtered through ashort pad of Celite. The filtrate was concentrated to removesolvent. The residue was purified by flash-chromatography to afford6-formyl-3-methyl-2-oxoindoline-3-carbonitrile. Yield 0.347 g. LCMSmethod B: R.sub.t=1.25 min, (M+H).sup.+=201.1.
Intermediate 47
N-((1r,4r)-4-formylcyclohexyl)methanesulfonamide
##STR00111##
Step 1. Methyl(1r,4r)-4-(methylsulfonamido)cyclohexane-1-carboxylate
##STR00112##
A mixture of methyl (1r,4r)-4-aminocyclohexane-1-carboxylatehydrochloride (50 g, 0.259 mol) and Et.sub.3N (130.8 g, 1.295 mol)in anhydrous CH.sub.2Cl.sub.2 (2000 mL) was stirred RT for 20 min.MsCl (29.8 g, 0.259 mol) was added dropwise at 0.degree. C. underN.sub.2 and the mixture was stirred at 0.degree. C. for 2 h. TheDCM reaction mixture was washed with H.sub.2O (3.times.800 mL) andbrine (800 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered andconcentrated under reduced pressure. The mixture was purified bycolumn chromatography on silica gel eluting with petroleumether:EtOAc=2:1 to 1:1 (adding 25 mL of CH.sub.2Cl.sub.2 in 1 L ofpetroleum ether/ethyl acetate for the eluent) to afford methyl(1r,4r)-4-(methylsulfonamido)cyclohexane-1-carboxylate (58 g,89.5%) as a white solid. .sup.1H NMR (CDCl.sub.3): .delta. 4.45 (d,J=7.6 Hz, 1H), 3.69 (s, 3H), 3.29-3.23 (m, 1H), 2.98 (s, 3H),2.24-2.13 (m, 1H), 2.11-2.09 (m, 2H), 2.05-2.02 (m, 2H), 1.55-1.51(m, 2H), 1.29-1.26 (m, 2H).
Step 2. N-((1r,4r)-4-formylcyclohexyl)methanesulfonamide
##STR00113##
Methyl (1r,4r)-4-(methylsulfonamido)cyclohexane-1-carboxylate (20g, 85.11 mmol) in anhydrous toluene (500 mL) was stirred at40.degree. C. for 30 min under N.sub.2. The resulting solution wascooled to -70.degree. C. (internal temperature). A solution ofDIBAL-H (1 M in toluene, 180 mL, 180 mmol) was added dropwisewithin 110 min under N.sub.2 (keeping the internal temperaturebelow -70.degree. C.). After addition, the mixture was stirredvigorously at -70.degree. C. for 4 h. MeOH (30 mL) was thencarefully added dropwise over a 30 min period (keeping the internaltemperature below -70.degree. C.). After being stirred for 10 min,sat. Rochelle salt solution (600 mL) was added at -70.degree. C.and the mixture was warmed to RT. EtOAc (300 mL) was added and themixture stirred at RT for 16 h. The mixture was separated and theaqueous layer was extracted with EtOAc (3.times.400 mL). Thecombined organic layers were washed with brine (3.times.500 mL),dried over anhydrous Na.sub.2SO.sub.4, filtered and concentratedunder reduced pressure to afford crudeN-((1r,4r)-4-formylcyclohexyl)methanesulfonamide (19 grams) whichwas used for next step without further purification. .sup.1H NMR(CDCl.sub.3): .delta. 9.65 (s, 0.035H), 9.62 (s, 1H), 4.40-4.39 (m,1H), 3.28-3.25 (m, 1H), 2.98 (s, 3H), 2.18-2.03 (m, 5H), 1.38-1.28(m, 4H).
Step 3. Sodium(R)-hydroxy((1r,4R)-4-(methylsulfonamido)cyclohexyl)methanesulfonate
##STR00114##
To a solution of crudeN-((1r,4r)-4-formylcyclohexyl)methanesulfonamide (19 grams) in THF(200 mL) was added aq. NaHSO.sub.3 solution (4 M, 110 mL) over a 10min period at 45.degree. C. After being stirred at 45.degree. C.for 30 min, the mixture was cooled to RT and stirred for another 1h. The resulting white precipitate was filtered and the filter cakewas washed with THF (3.times.50 mL) and dried under high vacuum toafford sodium(R)-hydroxy((1r,4R)-4-(methylsulfonamido)cyclohexyl)methanesulfonate(16.5 g, 55% over Step 2-3) as a white solid, which was used fornext step without further purification. .sup.1H NMR (DMSO-d.sub.6):.delta. 9.90 (s, 0.17H), 6.91 (d, J=7.2 Hz, 1H), 4.98 (d, J=5.2 Hz,1H), 3.65 (t, J=4.4 Hz, 1H), 2.97-2.95 (m, 1H), 2.89 (d, J=6.8 Hz,3H), 2.06-2.03 (m, 1H), 1.86-1.81 (m, 3H), 1.61 (brs, 1H),1.23-1.06 (m, 4H).
Step 4. N-((1r,4r)-4-formylcyclohexyl)methanesulfonamide
To a mixture of sodium(R)-hydroxy((1r,4R)-4-(methylsulfonamido)cyclohexyl)methanesulfonate(16.5 g, 53.4 mmol) in CH.sub.2Cl.sub.2 (160 mL) was added aq.Na.sub.2CO.sub.3 solution (1M, 160 mL). The mixture was stirred atRT for 30 min. The mixture was separated and the aqueous layer wasextracted with CH.sub.2Cl.sub.2 (3.times.80 mL). The combinedorganic layers were washed with brine (300 mL), dried overanhydrous Na.sub.2SO.sub.4, filtered and concentrated under reducedpressure to afford crudeN-((1r,4r)-4-formylcyclohexyl)methanesulfonamide (7.5 g, 69%) as awhite solid, which was used for next step without furtherpurification. .sup.1H NMR (CDCl.sub.3): .delta. 9.66 (s, 0.021H),9.62 (s, 1H), 4.38 (brs, 1H), 3.30-3.25 (m, 1H), 2.98 (s, 3H),2.18-2.14 (m, 3H), 2.05-2.01 (m, 2H), 1.42-1.30 (m, 4H).
Intermediate 48
Methyl 2-((4-chloropyrimidin-5-yl)oxy)-5-fluorobenzoate
##STR00115##
Step 1: Ethyl 2-(2-bromo-4-fluorophenoxy)acetate
##STR00116##
To solution of 2-bromo-4-fluorophenol (250 g, 1.31 mol) in MeCN (2L) was added K.sub.2CO.sub.3 (270 g, 1.97 mol) and ethyl2-bromoacetate (219 g, 1.31 mol). The suspension was heated at90.degree. C. for 1.5 h. The mixture was filtered and the filtratewas concentrated to give crude ethyl2-(2-bromo-4-fluorophenoxy)acetate as a brown oil, which was useddirectly in next step (312 g); .sup.1H NMR (CDCl.sub.3): .delta.7.32 (dd, J=7.6, 3.2 Hz, 1H), 6.95-6.97 (m, 1H), 6.82 (dd, J=8.8,4.4 Hz, 1H), 4.66 (s, 2H), 4.27 (q, J=7.2 Hz, 2H), 1.31 (t, J=7.2Hz, 3H); .sup.1F NMR (CDCl.sub.3): .delta. -120.06 (s, 1F).
Step 2:5-(2-Bromo-4-fluorophenoxy)-2-thioxo-2,3-dihydropyrimidin-4(1H)-on-e
##STR00117##
To a solution of ethyl 2-(2-bromo-4-fluorophenoxy)acetate (100 g)in anhydrous THF (2 L) was added ethyl formate (108 g) and NaH (20g) at 0.degree. C. The mixture was stirred at 35-45.degree. C. for18 h. The solvent was removed under vacuum and anhydrous EtOH (2 L)and thiourea (25 g, 324.8 mmol) were added and the mixture wasstirred at 90.degree. C. for 16 h. The mixture was concentrated anddiluted with water (2 L) and extracted with petroleum ether:ethylacetate (10:1; 500 mL.times.3). The aqueous layer was acidified topH=4 by aq. HCl (1N, 200 mL) and a white solid was precipitated.The mixture was filtered and the resulting filter cake was dried togive crude5-(2-bromo-4-fluorophenoxy)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one(62 g) as a white solid, which was used directly in the next stepwithout purification; LCMS method C: R.sub.t=0.638 min;(M+H).sup.+=316.9, 318.9 (chlorine isotopes).
Step 3: 5-(2-Bromo-4-fluorophenoxy)pyrimidin-4-ol
##STR00118##
To a solution of5-(2-bromo-4-fluorophenoxy)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one(62 g) in anhydrous EtOH (1.5 L) was added Raney Ni (62 g), and themixture was heated at reflux for 6 h. The solvent was removed undervacuum and anhydrous EtOH (2 L) was added. The mixture was filteredand the filtrate was concentrated to give crude5-(2-bromo-4-fluorophenoxy)pyrimidin-4-ol as a grey solid (55 g);LCMS method C: R.sub.t=0.62 min, (M+H).sup.+=284.9, 287.0 (bromineisotopes).
Step 4: Methyl5-fluoro-2-((4-hydroxypyrimidin-5-yl)oxy)benzoate
##STR00119##
To a solution of 5-(2-bromo-4-fluorophenoxy)pyrimidin-4-ol (60 g,0.17 mol) in DMF (100 mL) and MeOH (150 mL) was added TEA (25.5 g,0.252 mol) and Pd(dppf)Cl.sub.2 (12.4 g, 0.017 mol). The resultingreaction mixture was stirred under 50 PSI of CO at 80.degree. C.for 24 h. The mixture was then concentrated, diluted with H.sub.2O(300 mL), and extracted with DCM/MeOH (10:1) (200 mL.times.3). Thecombined organic layers were dried over Na.sub.2SO.sub.4, filtered,and concentrated to give the crude product, which was washed withethyl acetate (100 mL). The filter cake was dried to afford crudemethyl 5-fluoro-2-((4-hydroxypyrimidin-5-yl)oxy)benzoate as a brownsolid (20 g, 45%); LCMS method C: R.sub.t=0.56 min;(M+H).sup.+=264.9.
Step 5: Methyl 2-((4-chloropyrimidin-5-yl)oxy)-5-fluorobenzoate
To a solution of crude methyl5-fluoro-2-((4-hydroxypyrimidin-5-yl)oxy)benzoate (11 g, 42 mmol)in SOCl.sub.2 (5 mL) was added DMF (0.5 mL). The resulting mixturewas heated at 70.degree. C. for 2 h. The mixture was concentratedto give the residue which was dissolved into DCM (100 mL) andH.sub.2O (100 mL). The mixture was neutralized with saturatedNaHCO.sub.3 (50 mL). The separated organic layer was dried overNa.sub.2SO.sub.4, filtered, and concentrated, and the residue waspurified by chromatography column (petroleum ether:ethylacetate=5:1-1:1) to afford methyl2-((4-chloropyrimidin-5-yl)oxy)-5-fluorobenzoate as a brown solid(8.3 g, 57%); LCMS method C: R.sub.t=0.74 min;(M+H).sup.+=283.5.
Intermediate 49
5-Fluoro-2-(pyrimidin-5-yloxy)benzoic Acid
##STR00120##
Step 1: 5-(2-Bromo-4-fluorophenoxy)pyrimidine
##STR00121##
A 100-L jacketed reactor was charged with 2-bromo-4-fluorophenol(11.00 kg, 57.59 moles), 5-bromopyrimidine (9.43 kg, 59.32 moles),cesium carbonate (24.39 kg, 74.87 moles), and DMA (66.00 L), andthe mixture was heated to 115-125.degree. C. over 2.5 h. The batchwas then stirred at 120.degree. C. over 4 days. The internaltemperature of the batch was then adjusted to 20-30.degree. C. Oncethe batch was cooled it was partitioned between deionized water(132.00 L) and MTBE (44.00 L) in a 250 L Schott reactor. Thereactor contents were agitated at RT for 30 min. After this time,the agitation was stopped and the layer separation was allowed tooccur. The top organic layer was removed and placed in a separatecontainer. A total of four MTBE extractions were performed. TheMTBE extracts were combined and washed with 2 N sodium hydroxide(22.00 L), then by 0.5 M citric acid solution (11.00 L), andfinally by 5 wt % sodium bicarbonate solution (11.00 L). The MTBEsolution was concentrated using a rotary evaporator (25 in. Hgvacuum, 40.degree. C. water bath). The residue was passed through awiped film evaporator (WFE) system to remove volatiles (MTBE) and aportion of remaining 5-bromopyrimidine. The conditions for WFEdistillation were as follows: the first pass--vacuum 10-15 in. Hg,wiper speed 600 rpm, jacket temperature 150-160.degree. C.,addition rate 4 mL/min; the second pass--vacuum 0.7 Torr, wiperspeed 600 rpm, jacket temperature 160-170.degree. C., addition rate4 mL/min. The product 5-(2-bromo-4-fluorophenoxy)-pyrimidine wasisolated in 45% yield (7.15 kg) with HPLC purity 95.3% (AUC).
Step 2: Methyl 5-fluoro-2-(pyrimidin-5-yloxy)benzoate
##STR00122##
A 80-L jacketed stainless steel reactor was charged with palladiumcatalyst (Pd(dppf)Cl.sub.2 DCM complex) (1.00 kg, 1.22 moles),5-(2-bromo-4-fluorophenoxy)pyrimidine (8.54 kg, 31.59 moles), TEA(6.38 kg, 63.18 moles), and methanol (42.50 L). The reactor waspurged with nitrogen (3 times up to 50 psig of nitrogen pressure)and then with carbon monoxide gas (3 times up to 50 psig of carbonmonoxide). The reactor internal temperature was adjusted to65-75.degree. C. over 75 min. Once at temperature, the vesselinternal pressure was adjusted to 50 psig with carbon monoxide gas.The reactor contents were stirred at the specified temperature andpressure for at least 34 h. After this time, the reaction mixturewas cooled to 15-25.degree. C. and was purged with nitrogen threetimes with 50 psig pressure to afford a methanolic solutioncontaining methyl 5-fluoro-2-(pyrimidin-5-yloxy)benzoate. The batchwas filtered over a Celite.TM. pad to remove the palladiumcatalyst.
Step 3: 5-Fluoro-2-(pyrimidin-5-yloxy)benzoic Acid
The methanolic solution containing compound methyl5-fluoro-2-(pyrimidin-5-yloxy)benzoate from Step 2 was placed in a100-L jacketed glass reactor and was diluted with water (17.00 L).After this, 50 wt % sodium hydroxide aqueous solution (10.11 kg,126.36 moles) was added, keeping the batch internal temperature at35-45.degree. C. Once the addition was complete, the temperaturewas adjusted to 35-45.degree. C., and the batch was stirred for atleast 14 h. The reaction volume was decreased by vacuumdistillation from 87 to 33 liters (27 in. Hg vacuum was achieved;at the end the batch temperature was 32.4.degree. C.). The batchwas then diluted with water (42.5 L), cooled to 20-30.degree. C.,and was filtered through a Celite.TM. pad to remove the catalyst.The aqueous layer was extracted two times with MTBE (17 L). Thebatch was adjusted to pH=2 using 6 M hydrochloric acid (about 17L), keeping the internal batch temperature at 10-20.degree. C. Oncethe acid addition was complete, the batch was cooled to0-10.degree. C. and filtered over a polypropylene cloth using afilter/dryer. The filter cake was washed with water (17.00 L) anddried under stream of nitrogen at 40-45.degree. C. over severaldays until the water level was 0.3 wt % by KF analysis. The productwas isolated in 102% yield (7.57 kg) with a HPLC purity of 97.5%(AUC) and 94 wt % purity by NMR analysis.
Intermediate 50
((1r,4r)-4-(Ethylsulfonamido)cyclohexyl)methyl4-methylbenzenesulfonate
##STR00123##
Step 1: Methyl(1r,4r)-4-(ethylsulfonamido)cyclohexane-1-carboxylate
##STR00124##
A solution of methyl (1r,4r)-4-aminocyclohexane-1-carboxylatehydrochloride (120 g, 0.62 mol) and Et.sub.3N (346 mL, 2.48 mol) inanhydrous DCM (2.5 L) was stirred at RT for 30 min. Ethanesulfonylchloride (80.6 g, 0.63 mol) was added dropwise over 30 min to thereaction mixture at 0-5.degree. C. After addition, the mixture wasstirred at 0.degree. C. for 3 h. The mixture was quenched withwater (250 mL) at 0.degree. C. After partition, the organic layerwas washed with H.sub.2O (600 mL, 5 volumes) and 1 N HCl(2.times.600 mL, 2.times.5 volumes), H.sub.2O (600 mL, 5 volumes)and brine (600 mL, 5 volumes), dried over anhydrousNa.sub.2SO.sub.4, filtered, and concentrated under reduced pressureto afford crude methyl(1r,4r)-4-(ethylsulfonamido)cyclohexane-1-carboxylate (117.6 g,76%) as a light yellow solid, which was used for the next stepwithout further purification. .sup.1H NMR (CDCl.sub.3 400 MHz):.delta. 4.36 (d, J=8.0 Hz, 1H), 3.67 (s, 3H), 3.29-3.22 (m, 1H),3.04 (q, J=7.6 Hz, 2H), 2.25-2.21 (m, 1H), 2.15-2.09 (m, 2H),2.08-2.01 (m, 2H), 1.58-1.51 (m, 2H), 1.39-1.25 (m, 5H).
Step 2.N-((1r,4r)-4-(hydroxymethyl)cyclohexyl)ethanesulfonamide
##STR00125##
To a solution of crude methyl(1r,4r)-4-(ethylsulfonamido)cyclohexane-1-carboxylate (100 g, 402mmol) in anhydrous THF (1 L) was added LiAlH.sub.4 (403 mL, 403mmol, 1 M in THF) dropwise at 0-5.degree. C. under N.sub.2 overabout 1 h. The mixture was then stirred at 0.degree. C. for 2 hunder N.sub.2. Additional LiAlH.sub.4 (40 mL, 40 mmol, 1 Min THF)was then added to the reaction mixture. The mixture was stirred at0.degree. C. for 1 h under N.sub.2. The mixture was quenched with20% NaCl solution (20 mL) slowly at 0.degree. C. and diluted withTHF (500 mL, 5 volumes). The mixture was warmed to 15.degree. C.and stirred for 15 min. The mixture was filtered and rinsed withTHF (2.times.200 mL). The filter cake was suspended within THF (1L, 10 volumes) for 30 min. The suspension was filtered and rinsedwith THF (2.times.200 mL). The filter cake suspension andfiltration was repeated twice in THF (1 L, 10 volumes), and wasthen rinsed with THF (2.times.200 mL). The combined filtrate wasdried over anhydrous Na.sub.2SO.sub.4, concentrated under reducedpressure to afford crudeN-((1r,4r)-4-(hydroxymethyl)cyclohexyl)ethanesulfonamide (72 g,81%) as a white solid, which was used for the next step withoutfurther purification; .sup.1H NMR (CDCl.sub.3 400 MHz): .delta.4.23 (d, J=8.0 Hz, 1H), 3.46 (t, J=6.4 Hz, 2H), 3.25-3.18 (m, 1 H),3.04 (q, J=7.6 Hz, 2H), 2.11-2.07 (m, 2H), 1.88-1.84 (m, 2H),1.46-1.35 (m, 4H), 1.29-1.24 (m, 2H), 1.09-1.00 (m, 2H).
Step 3: ((1r,4r)-4-(Ethylsulfonamido)cyclohexyl)methyl4-methylbenzenesulfonate
To a solution of crudeN-((1r,4r)-4-(hydroxymethyl)cyclohexyl)ethanesulfonamide (30 g, 136mmol) in anhydrous DCM (300 mL) was added TsCl (25.84 g, 136 mmol),DMAP (1.66 g, 13.6 mmol) and Et.sub.3N (41.2 g, 408 mmol). Themixture was stirred at 10.degree. C. for 6 h under N.sub.2. Themixture was then quenched with H.sub.2O (200 mL). After partition,the organic layer was washed with H.sub.2O (2.times.150 mL) andbrine (150 mL), dried over anhydrous Na.sub.2SO.sub.4, andconcentrated under reduced pressure. The residue was purified bycolumn chromatography on silica gel eluting with petroleumether/ethyl acetate=1/0.about.2/1 to give((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl4-methylbenzenesulfonate (37 g, 73%) as a white solid; .sup.1H NMR(CDCl.sub.3 400 MHz): .delta. 7.78 (d, J=8.4 Hz, 2H), 7.35 (d,J=8.8 Hz, 2H), 4.23 (d, J=7.6 Hz, 1H), 3.81 (d, J=6.4 Hz, 2H),3.19-3.14 (m, 1H), 3.01 (q, J=7.6 Hz, 2H), 2.46 (s, 3H), 2.09-2.03(m, 2H), 1.79-1.74 (m, 2H), 1.66-1.56 (m, 1H), 1.35 (t, J=7.6 Hz,3H), 1.28-1.18 (m, 2H), 1.09-1.01 (m, 2H).
Example 1
5-fluoro-N,N-diisopropyl-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol--5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide(Racemic Mixture)
##STR00126##
Step 1. tert-butyl7-(5-(4-fluoro-2-(methoxycarbonyl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[-4.4]nonane-2-carboxylate
##STR00127##
To a solution of tert-butyl7-(5-(2-bromo-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2--carboxylate (Intermediate 11, 900 mg, 1.82 mmol) andPd(dppf)Cl.sub.2 (134 mg, 0.18 mmol) were added in Et.sub.3N (3 mL)and MeOH (20 mL). Then the reaction mixture was stirred at65.degree. C. under CO (50 psi) for about 16 h. The reactionmixture was filtered through a Celite pad, and concentrated underreduced pressure to afford the residue which was purified by columnchromatography on silica gel (eluting withdichloromethane:methanol=1:0.about.0:1) to afford tert-butyl7-(5-(4-fluoro-2-(methoxycarbonyl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[-4.4]nonane-2-carboxylate as a light yellow oil. Yield: 850 mg. LCMSmethod C: R.sub.t=0.739 min; (M+H).sup.+=473.2.
Step 2.2-((4-(7-(tert-butoxycarbonyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrim-idin-5-yl)oxy)-5-fluorobenzoic Acid
##STR00128##
To a mixture of tert-butyl7-(5-(4-fluoro-2-(methoxycarbonyl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[-4.4]nonane-2-carboxylate (850 mg, 1.79 mmol) and NaOH (143 mg, 3.58mmol) was added MeOH (10 mL) and H.sub.2O (2 mL) under N.sub.2. Thereaction mixture was stirred at 21-27.degree. C. for 12 h. Thesolvent was removed under reduced pressure to afford the residue.Then, 1N HCl was added to adjust the solution to pH 5-6 and EtOAc(10 mL) was added. The organic layer was concentrated under reducedpressure to afford2-((4-(7-(tert-butoxycarbonyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5--yl)oxy)-5-fluorobenzoic acid. Yield: 700 mg (85%). LCMS method C:R.sub.t=0.705 min (M+H).sup.+=459.2.
Step 3. tert-butyl7-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazas-piro[4.4]nonane-2-carboxylate
##STR00129##
To a solution of2-((4-(7-(tert-butoxycarbonyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5--yl)oxy)-5-fluorobenzoic acid (800 mg, 1.746 mmol) in anhydrousCH.sub.2Cl.sub.2 (15 mL) were added HATU (553 mg, 1.455 mmol) andDIEA (677 mg, 5.238 mmol) under N.sub.2, and the reaction mixturewas stirred at 9-20.degree. C. for 30 min. Then diisopropylamine(265 mg, 2.619 mmol) was added to the solution and the reactionmixture was stirred at 9-20.degree. C. for 12 h. The solvent wasthen removed under reduced pressure. The resulting residue waspurified by column chromatography on silica gel (eluting withCH.sub.2Cl.sub.2:MeOH=1:0.about.10:1) to afford tert-butyl7-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazas-piro[4.4]nonane-2-carboxylate as brown oil. Yield: 900 mg. LCMSmethod F: R.sub.t=1.238 min; (M+H).sup.+=542.4.
Step 4.2-((4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro--N,N-diisopropylbenzamide
##STR00130##
To a solution of tert-butyl7-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazas-piro[4.4]nonane-2-carboxylate (900 mg, 1.67 mmol) in anhydrousCH.sub.2Cl.sub.2 (25 mL) was added TFA (5 mL) under N.sub.2. Thereaction mixture was stirred at 10-22.degree. C. for 2 h. Thesolvent was then removed under reduced pressure. The resultingresidue was adjusted to pH to 9-10 using 10% NaOH. Then the mixturewas extracted with CH.sub.2Cl.sub.2 (20 mL.times.3). The organiclayers were washed with brine (20 mL), dried over anhydrousNa.sub.2SO.sub.4, filtered and concentrated under reduced pressureto afford2-((4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-dii-sopropylbenzamide. The residue was used for the next step withoutfurther purification, as a brown oil. Yield: 730 mg. LCMS method F:R.sub.t=0.888 min; (M+H).sup.+=442.4.
Step 5.5-fluoro-N,N-diisopropyl-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]i-midazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)benz-amide
To a mixture of2-((4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-dii-sopropylbenzamide (730 mg, 1.654 mmol),2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbaldehyde (Intermediate40, 536 mg, 3.308 mmol) and 4 .ANG.-molecular sieves (100 mg) wasadded anhydrous MeOH (20 mL), then the reaction was stirred at60.degree. C. for 30 min under N.sub.2. Then NaBH.sub.3CN (513 mg,8.270 mmol) was added to the solution and the reaction mixture wasstirred at 60.degree. C. for 4 h. The reaction mixture was thenfiltered and concentrated under reduced pressure. The resultingresidue was diluted with MeOH (15 mL) and the mixture was purifiedby preparative RP-HPLC method C (HCl) to afford compound5-fluoro-N,N-diisopropyl-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d-]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)be-nzamide as a white solid. Yield: 540 mg (55%). LCMS method C:R.sub.t=0.931; (M+H).sup.+=588.5. .sup.1H NMR (CD.sub.3OD): .delta.8.30-8.38 (m, 1H), 7.62-7.84 (m, 1H), 6.86-7.15 (m, 6H), 4.22-4.30(m, 3H), 3.20-4.03 (m, 9H), 1.87-2.04 (m, 5H), 0.81-1.30 (m, 11H)..sup.19F NMR (CD.sub.3OD): .delta. -117.14.
Examples 1A and 1B
5-fluoro-N,N-diisopropyl-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol--5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide(Isomers 1 and 2)
##STR00131##
The racemic compound of Example 1 was separated by SFC method A toafford two isomers.
Isomer 1 (Example 1A): LCMS method C: R.sub.t=0.931;(M+H).sup.+=588.5. .sup.1H NMR (CD.sub.3OD): .delta. 8.54-8.61 (m,1H), 7.86-8.09 (m, 1H), 7.20-7.31 (m, 5H), 7.15 (d, J=36.4 Hz, 1H),4.41-4.51 (m, 3H), 3.40-4.02 (m, 9H), 2.15-2.25 (m, 4H), 1.06-1.48(m, 12H). .sup.19F NMR (CD.sub.3OD): .delta. -117.11. SFC Anal.Method A: t.sub.R=0.569 min, ee=100%.
Isomer 2 (Example 1B): LCMS method C: R.sub.t=0.930;(M+H).sup.+=588.5. .sup.1H NMR (CD.sub.3OD): .delta. 8.58-8.65 (m,1H), 7.90-8.14 (m, 1H), 7.25-7.35 (m, 5H), 7.18 (d, J=44.8 Hz, 1H),4.45-4.54 (m, 3H), 3.43-4.06 (m, 9H), 2.18-2.30 (m, 4H), 1.10-1.52(m, 12H). .sup.19F NMR (CD.sub.3OD 400 MHz): .delta. -117.10. SFCAnal. Method A: t.sub.R=0.809 min, ee=98.87%.
Example 2
N-ethyl-5-fluoro-N-isopropyl-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imida-zol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)benzamid-e (Racemic Mixture)
##STR00132##
The title product was synthesized by the method described inExample 1. In step 3, N-isopropyl-N-ethyl amine was utilized. LCMSmethod B: R.sub.t=1.164; (M+H).sup.+=574.1.
Examples 2A and 2B
N-ethyl-5-fluoro-N-isopropyl-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imida-zol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)benzamid-e (Isomers 1-2)
##STR00133##
The racemic compound of Example 2 was separated by SFC method A toafford two isomers.
Isomer 1 (Example 2A): Yield: 92.5 mg. LCMS method E: R.sub.t=1.132min; (M+H).sup.+=574.3 .sup.1H NMR (CD.sub.3OD): .delta.8.20-8.29(m, 1H), 7.72-7.80 (m, 1H), 6.85-7.16 (m, 6H), 4.35-4.41 (m, 1H),3.45-3.89 (m, 8H), 3.12-3.23 (m, 1H), 2.50-2.71 (m, 4H), 1.76-1.96(m, 4H), 1.05-1.27 (m, 8H). .sup.19F NMR (CD.sub.3OD):.delta.-120.380. SFC Anal. Method A: t.sub.R=0.722 min,ee=100%.
Isomer 2 (Example 2B): Yield: 115.8 mg. LCMS method E:R.sub.t=1.121 min; (M+H).sup.+=574.3. .sup.1H NMR (CD.sub.3OD):.delta.8.21-8.29 (m, 1H), 7.71-7.80 (m, 1H), 6.85-7.16 (m, 6H),4.35-4.42 (m, 1H), 3.45-3.90 (m, 8H), 3.15-3.23 (m, 1H), 2.48-2.71(m, 4H), 1.76-1.96 (m, 4H), 1.05-1.27 (m, 8H). .sup.19F NMR(CD.sub.3OD): .delta.-120.390. SFC Anal. Method A: t.sub.R=1.455min, ee=99.65%.
Examples 3A and 3B
5-fluoro-2-((4-(7-((1-(2-hydroxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidaz-ol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-N,N-diis-opropylbenzamide (Isomers 1-2)
##STR00134##
To a solution of2-((4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-dii-sopropylbenzamide (70 mg, 0.16 mmol) and1-(2-hydroxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbaldehyde(Intermediate 42c, 33 mg, 0.16 mmol) in anhydrous MeOH (3 mL) wasadded NaBH.sub.3CN (50 mg, 0.80 mmol) under N.sub.2. The reactionwas stirred at 55.degree. C. for 16 h. The reaction wasconcentrated under reduced pressure to afford the residue which waspurified by silica gel chromatography (CH.sub.2Cl.sub.2:MeOH=10:1), and further purified by preparative SFC method B andRP-HPLC method E to give the compound as two isomers.
Isomer 1 (Example 3A): White solid. LCMS method E: R.sub.t=0.736min (M+H).sup.+=632.4. .sup.1H NMR (CD.sub.3OD): .delta. 8.28 (s,1H), 7.80 (d, J=2.4 Hz, 1H), 6.89-7.15 (m, 5H), 6.89-6.90 (m, 1H),3.99 (t, J=5.6 Hz, 2H), 3.55-3.85 (m, 10H), 2.52-2.72 (m, 4H),1.84-1.96 (m, 4H), 1.54 (dd, J=2.4, 6.8 Hz, 3H), 1.43 (t, J=4.8 Hz,3H), 1.19 (d, J=3.2 Hz, 3H), 1.32 (t, J=4.8 Hz, 3H). .sup.19F NMR(CD.sub.3OD): .delta. -120.25-120.33. SFC Anal. Method B:t.sub.R=7.26 min, ee=100%.
Isomer 2 (Example 3B): White solid. LCMS method E: R.sub.t=0.738min. (M+H).sup.+=632.4. .sup.1H NMR (CD.sub.3OD): .delta. 8.28 (s,1H), 7.80 (d, J=2.4 Hz, 1H), 6.89-7.15 (m, 5H), 6.89-6.90 (m, 1H),3.99 (t, J=5.6 Hz, 2H), 3.55-3.85 (m, 10H), 2.52-2.72 (m, 4H),1.84-1.96 (m, 4H), 1.54 (dd, J=2.4, 6.8 Hz, 3H), 1.43 (t, J=4.8 Hz,3H), 1.19 (d, J=3.2 Hz, 3H), 1.32 (t, J=4.8 Hz, 3H). .sup.19F NMR(CD.sub.3OD): .delta. -120.27-120.35. SFC Anal. Method B:t.sub.R=7.92 min, ee=97.04%.
Example 4
N-ethyl-5-fluoro-2-((4-(7-((1-(2-hydroxyethyl)-2-oxo-2,3-dihydro-1H-benzo[-d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)--N-isopropylbenzamide
##STR00135##
To a solution of2-((4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro--N-isopropylbenzamide (prepared as an intermediate during thesynthesis of Example 2, 100 mg, 0.23 mmol) in anhydrous MeOH (10mL) was added1-(2-hydroxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbaldehyde(Intermediate 42c, 72 mg, 0.35 mmol), and was stirred for 5 minunder N.sub.2. Then NaBH.sub.3CN (71 mg, 1.15 mmol) was added andthe mixture was stirred at 65.degree. C. for 2 h. The reactionmixture, with an additional 20 mg of2-((4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro--N-isopropylbenzamide, was concentrated under reduced pressure toafford the residue which was purified by column chromatograph onsilica gel (eluting with dichloromethane:methanol=20:1 to 10:1) togiveN-ethyl-5-fluoro-2-((4-(7-((1-(2-hydroxyethyl)-2-oxo-2,3-dihydro-1H-benzo-[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)--N-isopropylbenzamide as a yellow oil. Yield: 70 mg. LCMS method C:R.sub.t=0.583 min; (M+H).sup.+=618.1.
Examples 4A and 4B
N-ethyl-5-fluoro-2-((4-(7-((1-(2-hydroxyethyl)-2-oxo-2,3-dihydro-1H-benzo[-d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)--N-isopropylbenzamide (Isomers 1-2)
##STR00136##
An amount of 70 mg ofN-ethyl-5-fluoro-2-((4-(7-((1-(2-hydroxyethyl)-2-oxo-2,3-dihydro-1H-benzo-[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)--N-isopropylbenzamide (Example 4) was separated with SFC method Ato give Isomers 1 and 2 as white solids.
Isomer 1 (Example 4A):
Yield: 8.70 mg. R.sub.t=1.14 min; (M+H).sup.+=618.3. .sup.1H NMR(CD.sub.3OD): .delta.8.27-8.29 (m, 1H), 7.78-7.82 (m, 1H),6.89-7.18 (m, 6H), 3.33-4.01 (m, 13H), 2.48-2.75 (m, 4H), 1.75-1.96(m, 4H), 1.05-1.26 (m, 9H). .sup.19F NMR (CD.sub.3OD):.delta.-120.390. SFC Anal. Method C: t.sub.R=1.870 min,ee=98.60%.
Isomer 2 (Example 4B):
Yield: 9.2 mg. LCMS method E: R.sub.t=R.sub.t value: 1.140 min;(M+H).sup.+=618.3. .sup.1H NMR (CD.sub.3OD): .delta.8.25-8.31 (m,1H), 7.76-7.25 (m, 1H), 6.85-7.20 (m, 6H), 3.48-4.00 (m, 13H),2.48-2.75 (m, 4H), 1.75-1.96 (m, 4H), 1.05-1.33 (m, 9H). .sup.19FNMR (CD.sub.3OD): .delta.-120.398. SFC Anal. Method C:t.sub.R=2.922 min, ee=99.43%.
Example 5
5-fluoro-N-(2-hydroxyethyl)-N-isopropyl-2-((4-(7-((2-oxo-2,3-dihydro-1H-be-nzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)o-xy)benzamide
##STR00137##
Step 1. tert-butyl7-(5-(2-((2-((tert-butyldimethylsilyl)oxy)ethyl)(isopropyl)carbamoyl)-4-f-luorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate
##STR00138##
To a solution of2-((4-(7-(tert-butoxycarbonyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5--yl)oxy)-5-fluorobenzoic acid (Intermediate 33, Step 2, 50 mg,0.1092 mmol) in anhydrous DMF (3 mL) was addedN-(2-((tert-butyldimethylsilyl)oxy)ethyl)propan-2-amine (36 mg,0.1637 mmol), HATU (83 mg, 0.2183 mmol) and DIEA (28 mg, 0.2183mmol) and the mixture was stirred at 16.degree. C. for 6 h underN.sub.2. The mixture was then diluted with EtOAc (20 mL) and washedwith brine (3.times.20 mL). The organic layer was dried overanhydrous Na.sub.2SO.sub.4, filtered and concentrated under reducedpressure. The residue was purified by preparative TLC with EtOAc toafford tert-butyl7-(5-(2-((2-((tert-butyldimethylsilyl)oxy)ethyl)(isopropyl)carbamoyl)-4-f-luorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylateas a yellow oil. Yield: 50 mg. LCMS method C: R.sub.t=0.851 min,(M+H).sup.+=658.1.
Step 2.2-((4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro--N-(2-hydroxyethyl)-N-isopropylbenzamide
##STR00139##
To a solution of tert-butyl7-(5-(2-((2-((tert-butyldimethylsilyl)oxy)ethyl)(isopropyl)carbamoyl)-4-f-luorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate(50 mg, 0.0761 mmol) in CH.sub.2Cl.sub.2 (4 mL) was added TFA (1mL) and the mixture was stirred at 16.degree. C. for 3 h. Themixture was then concentrated under reduced pressure. The residuewas adjusted to pH=8-9 with sat. NaHCO.sub.3 solution and dilutedwith water (15 mL). The aqueous layer was extracted withCH.sub.2Cl: .sup.iPrOH (3:1, 3.times.20 mL). The combined organiclayers were dried over anhydrous Na.sub.2SO.sub.4, filtered andconcentrated under reduced pressure to give crude2-((4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-(2-hy-droxyethyl)-N-isopropylbenzamide as a yellow oil, which was usedfor the next step directly without further purification. Yield: 34mg.
Step 3.5-fluoro-N-(2-hydroxyethyl)-N-isopropyl-2-((4-(7-((2-oxo-2,3-dihyd-ro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidi-n-5-yl)oxy)benzamide
To a solution of2-((4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-(2-hy-droxyethyl)-N-isopropylbenzamide (34 mg, 0.0761 mmol) in anhydrousMeOH (3 mL) was added2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbaldehyde (Intermediate40, 25 mg, 0.1522 mmol) and NaBH.sub.3CN (24 mg, 0.3805 mmol). Themixture was stirred at 60.degree. C. for 16 h under N.sub.2. LCMSshowed that the reaction was completed. The mixture wasconcentrated under reduced pressure and purified directly byRP-HPLC method D to give5-fluoro-N-(2-hydroxyethyl)-N-isopropyl-2-((4-(7-((2-oxo-2,3-dihydro-1H-b-enzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)-oxy)benzamide as a pale yellow solid. Yield: 10.00 mg. LCMS methodC: R.sub.t=0.560 min, (M+H).sup.+=590.2 .sup.1H NMR (CDCl.sub.3):.delta. 10.35-10.15 (m, 0.5H), 9.75-9.60 (m, 0.5H), 9.01-8.77 (m,1H), 8.36 (s, 1H), 7.81-7.70 (m, 1H), 7.35-7.25 (m, 0.5H),7.18-7.08 (m, 0.5H), 7.05-6.90 (m, 2H), 6.89-6.75 (m, 2H),6.65-6.50 (m, 1H), 4.05-3.25 (m, 12H), 2.97-2.25 (m, 4H), 2.12-1.85(m, 4H), 1.30-1.07 (m, 6H). .sup.19F NMR (CDCl.sub.3): .delta.-119.3.
Example 6A
5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohexy-l)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide
##STR00140##
Step 1. tert-butyl2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazas-piro[3.5]nonane-7-carboxylate
##STR00141##
A mixture of2-((4-chloropyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide(Intermediate 41, 1.8 g, 5.13 mmol), tert-butyl2,7-diazaspiro[3.5]nonane-7-carboxylate (1.35 g, 5.13 mmol) andDIEA (1.32 g, 10.26 mmol) in .sup.iPrOH (20 mL) was stirred at70.degree. C. for 16 h. After concentration, the mixture waspurified directly by column chromatography on silica gel elutingwith petroleum ether:ethyl acetate=3:7 to afford tert-butyl2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazas-piro[3.5]nonane-7-carboxylate as a yellow oil. Yield: 2.9 g. LCMSmethod E: R.sub.t=0.767 min; (M+H).sup.+=542.2
Step 2:2-((4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro--N,N-diisopropylbenzamide
##STR00142##
The solution of tert-butyl2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazas-piro[3.5]nonane-7-carboxylate (2.9 g, 5.35 mmol) in anhydrousCH.sub.2Cl.sub.2 (30 mL) was added TFA (10 mL) and the mixture wasstirred at 25.degree. C. for 2 h. The mixture was then concentratedunder reduced pressure and to the residue was added 30% aqueousNaOH solution to a pH=11-12. The aqueous layer was then extractedwith CH.sub.2Cl.sub.2/.sup.iPrOH (4/1, 3.times.30 mL). The combinedorganic layers were dried over anhydrous Na.sub.2SO.sub.4, filteredand concentrated under reduced pressure to afford crude2-((4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-dii-sopropylbenzamide as a yellow solid, which was used for next stepwithout further purification. Yield: 2.3 g. LCMS method C:R.sub.t=0.584 min, (M+H).sup.+=442.1.
Step 3: tert-butyl((1r,4r)-4-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-y-l)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)cyclohexyl)carbamate(Example 99A)
##STR00143##
To a solution of2-((4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-dii-sopropylbenzamide (2.3 g, 5.20 mmol) in anhydrous MeOH (50 mL) wasadjusted to pH 6-7 by AcOH. Then tert-butyl((1r,4r)-4-formylcyclohexyl)carbamate (1.3 g, 5.72 mmol) was added.After being stirred at 25.degree. C. for 5 min, NaBH.sub.3CN (656mg, 10.41 mmol) was added and the mixture was stirred at 70.degree.C. for 1 h. The mixture was then concentrated under reducedpressure. The residue was dissolved with EtOAc (50 mL) and washedwith H.sub.2O (2.times.30 mL). The organic layer was dried overanhydrous Na.sub.2SO.sub.4, filtered and concentrated under reducedpressure. The residue was purified by column chromatography onsilica gel eluting with petroleum ether:ethyl acetate=3:7 to affordtert-butyl ((1r,4r)-4-((2-(5-(2-(diisopropylcarbamoyl)-4fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)cycloh-exyl)carbamate as a white solid. Yield: 3.0 g. LCMS method C:R.sub.t=0.929 min; (M+H).sup.+=653.3.
Step 4:2-((4-(7-(((1r,4r)-4-aminocyclohexyl)methyl)-2,7-diazaspiro[3.5]no-nan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide
##STR00144##
To a solution of tert-butyl((1r,4r)-4-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-y-l)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)cyclohexyl)carbamate (3 g,4.60 mmol) in anhydrous ethyl CH.sub.2Cl.sub.2 (30 mL) was addedwith TFA (10 mL) and the mixture was stirred at 25.degree. C. for 2h. The mixture was then concentrated under reduced pressure toafford crude2-((4-(7-(((1r,4r)-4-aminocyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-y-l)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide as a paleyellow oil, which was used for next step without furtherpurification. Yield: 4.0 g. LCMS method C: R.sub.t=0.513 min;(M+H).sup.+=553.2.
Step 5:(5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)-cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzam-ide)
##STR00145##
To a solution of2-((4-(7-(((1r,4r)-4-aminocyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-y-l)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide (3.6 g,crude, about 4.14 mmol) and Et.sub.3N (2.47 g, 24.0 mmol) inanhydrous CH.sub.2Cl.sub.2 (50 mL) was added MsCl (844 mg, 7.34mmol) dropwise at 0.degree. C. under N.sub.2 and the mixture wasstirred at 0.degree. C. for 2 h. The mixture was then washed withH.sub.2O (3.times.50 mL) and brine (50 mL). The organic layer wasdried over anhydrous Na.sub.2SO.sub.4, filtered and concentratedunder reduced pressure. The residue was purified by columnchromatography on silica gel eluting withCH.sub.2Cl.sub.2:CH.sub.3OH=19:1 to afford5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamideas a white solid, which was purified by RP-HPLC method D to afford5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamideas a white solid. Yield: 1.59 g. LCMS method C: R.sub.t=0.565 min;(M+H).sup.+=631.1. .sup.1H NMR (CDCl.sub.3): .delta. 8.27 (s, 1H),8.78 (s, 1H), 7.17-7.15 (m, 2H), 7.03-6.99 (m, 1H), 4.06-4.03 (m,2H), 3.96-3.89 (m, 2H), 3.87-3.84 (m, 1H), 3.66-3.63 (m, 1H),3.34-3.32 (m, 1H), 3.20-3.15 (m, 1H), 2.95 (s, 3H), 2.55-2.51 (m,3H), 2.33-2.30 (m, 2H), 2.06-2.04 (m, 2H), 1.89-1.87 (m, 6H), 1.56(d, J=6.8 Hz, 4H), 1.48 (d, J=6.8 Hz, 3H), 1.33-1.30 (m, 2H), 1.20(d, J=6.8 Hz, 3H), 1.13 (d, J=6.4 Hz, 3H), 1.08-1.07 (m, 2H)..sup.19F NMR (CDCl.sub.3): .delta. -119.7.
Examples 6A-6B
Alternative Synthesis of5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide(Example 6A) and5-fluoro-N,N-diisopropyl-2-((4-(7-(((1s,4s)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide(Example 6B)
##STR00146##
To a solution of2-((4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-dii-sopropylbenzamide (Example 6A, Step 2, 11 g, 24.9 mmol) inanhydrous CH.sub.2Cl.sub.2 (170 mL) was added Intermediate 47 (7.5g, 36.6 mmol). The mixture was stirred at RT for 15 min andNaBH(OAc).sub.3 (7.2 g, 33.9 mmol) was added in portions over 5min. The mixture was stirred at RT for another 2 h. The mixture waswashed with H.sub.2O (3.times.100 mL) and brine (100 mL), driedover anhydrous Na.sub.2SO.sub.4, filtered and concentrated underreduced pressure. The residue was purified by column chromatographyon silica gel eluting with CH.sub.2Cl.sub.2/CH.sub.3OH=24/1 to 10/1to afford the title compound as the free base with a trans:cisratio of 97:3. LC-MS Method D t.sub.R=0.555 min, MS (m/z 631.3[M+H].sup.+ The trans and cis isomers were separated by SFC methodA.
Trans-isomer (Example 6A):
LC-MS Method E t.sub.R=3.881 min, m/z 631.3 [M+H].sup.+. Isomer SFCt.sub.R=4.430 min in 10 min chromatography (Column: OD-3; MethodName: OD-3_EtOH/diethylamine_5_40_25 mL, trans=100%). .sup.1H NMR(CD.sub.3OD): .delta. 8.22 (s, 1H), 7.73 (s, 1H), 7.23-7.10 (m,2H), 7.01-6.95 (m, 1H), 4.08-3.80 (m, 5H), 3.68-3.56 (m, 1H),3.20-3.07 (m, 1H), 2.92 (s, 3H), 2.48-2.25 (m, 4H), 2.13 (d, J=6.4Hz, 2H), 2.06-1.96 (m, 2H), 1.91-1.76 (m, 6H), 1.53 (d, J=6.8 Hz,3H), 1.51-1.45 (m, 1H), 1.45 (d, J=6.8 Hz, 3H), 1.35-1.24 (m, 2H),1.17 (d, J=6.8 Hz, 3H), 1.09 (d, J=6.4 Hz, 3H), 1.06-0.98 (m, 2H)..sup.19F NMR (CDCl.sub.3): .delta. -119.711.
Cis-isomer (Example 6B):
LC-MS method D: t.sub.R=0.582 minm/z 631.1 [M+H].sup.+. Isomer SFCt.sub.R=4.461 min in 10 min chromatography (Column: OD-3; MethodName: OD-3_EtOH/diethylamine_5_40_25 mL, trans/cis=2.1%/97.9%)..sup.1H NMR (CDCl.sub.3): .delta. 8.36 (s, 1H), 7.75 (s, 1H),7.05-6.96 (m, 2H), 6.80-6.71 (m, 1H), 4.40-4.30 (m, 1H), 4.05-3.75(m, 5H), 3.70-3.60 (m, 1H), 3.55-3.45 (m, 1H), 2.96 (s, 3H),2.45-2.09 (m, 6H), 1.85-1.65 (m, 10H), 1.60-1.45 (m, 7H), 1.44-1.19(m, 2H), 1.13 (d, J=6.8 Hz, 3H), 1.09 (d, J=6.8 Hz, 3H). .sup.19FNMR (CDCl.sub.3): .delta. -118.583.
Example 7
5-((7-(5-(2-(amino(cyclopentyl)methyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7--diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one
##STR00147##
Step 1: tert-Butyl7-(5-(2-(1-((tert-butylsulfinyl)amino)ethyl)-4-fluorophenoxy)pyrimidin-4--yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate
##STR00148##
To a solution of tert-butyl7-(5-(2-bromo-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2--carboxylate (Intermediate 11, 407 mg, 0.83 mmol) and(E)-N-(cyclopentylmethylene)-2-methylpropane-2-sulfinamide (249 mg,1.24 mmol) in anhydrous THE (6 mL) was added 1.6 M BuLi solution inhexane (0.78 mL, 1.24 mmol) dropwise under N.sub.2 atmosphere at-78.degree. C. After the addition, the mixture was stirred foranother 30 min before quenching with aq. NH.sub.4Cl solution. Thereaction mixture was extracted twice with EtOAc and the combinedorganic phase was washed with H.sub.2O, dried over anhydrousNa.sub.2SO.sub.4, filtered and evaporated under reduced pressure.The residue was purified by flash chromatography using DCM/MeOH aseluent to yield 461 mg of the desired product tert-butyl7-(5-(2-(1-((tert-butylsulfinyl)amino)ethyl)-4-fluorophenoxy)pyrimidin-4--yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate. LCMS method B:R.sub.t=1.32 min, (M+H).sup.+=616.3.
Step 2:N-((2-((4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-flu-orophenyl)(cyclopentyl)methyl)-2-methylpropane-2-sulfinamide
##STR00149##
To a solution of tert-butyl7-(5-(2-(1-((tert-butylsulfinyl)amino)ethyl)-4-fluorophenoxy)pyrimidin-4--yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (61 mg, 0.099 mmol) inDCM (6 mL) was added TFA (0.3 mL). The mixture was stirred 16 h atRT. The reaction mixture was diluted with EtOAc, washed withaqueous NaHCO.sub.3 solution and brine successively, dried overanhydrous Na.sub.2SO.sub.4, filtered and evaporated under reducedpressure to afford 37 mg of crude product, which was used in thenext step without further purification.
Step 3:N-(cyclopentyl(5-fluoro-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]im-idazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)pheny-l)methyl)-2-methylpropane-2-sulfinamide
##STR00150##
To a solution ofN-((2-((4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluorophen-yl)(cyclopentyl)methyl)-2-methylpropane-2-sulfinamide (37 mg, 0.072mmol) in MeOH (2 mL) was added2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbaldehyde (Intermediate40, 14 mg, 0.086 mmol) and NaBH.sub.3CN (9 mg, 0.14 mmol). Thesuspension was stirred at RT for 24 h. Solvent was removed underreduced pressure. The residue was used for next step withoutfurther purification.
Step 4:5-((7-(5-(2-(amino(cyclopentyl)methyl)-4-fluorophenoxy)pyrimidin-4--yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol--2-one
Above crude product was dissolved in MeOH (1 mL) and 4 MHCl/dioxane (3 ml). The solution was stirred at RT for 30 minbefore solvents was removed under reduced pressure. The residue waspurified by RP-HPLC method A to afford5-((7-(5-(2-(amino(cyclopentyl)methyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,-7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one.LCMS method A: R.sub.t=0.15 min, (M+H).sup.+=558.3. .sup.1H NMR(CD.sub.3OD) .delta.: 8.57 (s, 1H), 7.83 (m, 1H), 7.41 (m, 1H),7.26-7.17 (m, 4H), 7.09 (d, J=7.6 Hz, 1H), 4.42 (m, 2H), 4.07 (m,4H), 3.64-3.34 (m, 4H), 2.48 (m, 1H), 2.22-2.03 (m, 5H), 1.78-1.48(m, 6H), 1.39 (d, J=6.4 Hz, 1H).
Example 8
5-((7-(5-(2-(cyclopentyl(dimethylamino)methyl)-4-fluorophenoxy)pyrimidin-4--yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol--2-one
##STR00151##
To a solution of5-((7-(5-(2-(amino(cyclopentyl)methyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,-7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-onetri-TFA salt (Example 7, 8.7 mg, 0.01 mmol) in DCM (2 mL) was addedTEA (1 drop), paraformadehyde (4 mg), followed byNaBH.sub.3(OAc).sub.3 (9 mg, 0.04 mmol). The mixture was stirredovernight at RT before the solvent was removed under reducedpressure. The residue was purified by RP-HPLC method A to affordthe titled compound. LCMS method A: R.sub.t=0.53 min,(M+H).sup.+=586.3. .sup.1H NMR (CD.sub.3OD) .delta.: .delta.: 8.57(s, 1H), 7.83 (m, 1H), 7.61 (m, 1H), 7.36 (m, 1H), 7.26 (m, 1H),7.21 (s, 1H), 7.18 (d, J=8.0 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H), 4.43(m, 2H), 4.14 (m, 2H), 3.62-3.45 (m, 3H), 2.84 (s, 6H), 2.20-2.06(m, 5H), 1.76 (m, 2H), 1.62-1.47 (m, 4H), 0.99 (m, 1H).
Example 9
N-(cyclopentyl(5-fluoro-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5--yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)phenyl)methyl-)acetamide
##STR00152##
The title product was synthesized by acylating the compound ofExample 7 with acetic anhydride in pyridine. The final product waspurified by RP-HPLC method A. LCMS method A: R.sub.t=0.53 min,(M+H).sup.+=600.3.
Example 10
6-((7-(5-(4-fluoro-2-(1-hydroxy-2-methylpropyl)phenoxy)pyrimidin-4-yl)-2,7--diazaspiro[4.4]nonan-2-yl)methyl)-3,3-dimethylindolin-2-one
##STR00153##
Step 1:1-(2-((4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluo-rophenyl)-2-methylpropan-1-ol
##STR00154##
To a solution of tert-butyl7-(5-(2-bromo-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2--carboxylate (Intermediate 11, 526 mg, 1.065 mmol) andN-methoxy-N-methylisobutyramide (268 mg, 2.04 mmol) in dry THF (6mL) under N.sub.2 atmosphere at -78.degree. C. was added 1.6 M BuLi(0.7 mL, 1.067 mmol) dropwise. After the addition, the reactionmixture was stirred for another 10 min before quenched with aqueousNH.sub.4Cl solution. The resulting mixture was extracted withEtOAc, washed with H.sub.2O, brine, dried over anhydrousNa.sub.2SO.sub.4 and filtered. The filtrate was concentrated todryness. The residue was purified by flash chromatography to afford249 mg of tert-butyl7-(5-(4-fluoro-2-isobutyrylphenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]non-ane-2-carboxylate (Intermediate 41b). LCMS Method B: t.sub.R: 1.76min, (M+H).sup.+=485.3
To a cold solution of Intermediate 41b (83 mg, 0.17 mmol) inTHF/MeOH (2/0.5 mL) at 0.degree. C. was added NaBH.sub.4 (20 mg,0.53 mmol). The mixture was stirred for another 20 min and quenchedwith acetone. The solvent was removed to give the crude product.The crude product was then dissolved in MeOH (1 mL) 4 M HCl/dioxane(0.5 mL) was added and the mixture was stirred for 30 min. Thesolvents were removed under reduced pressure to afford crudeproduct as the bis-HCl salt.
Step 2:6-((7-(5-(4-fluoro-2-(1-hydroxy-2-methylpropyl)phenoxy)pyrimidin-4--yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-3,3-dimethylindolin-2-one
The crude product from Step 1 was dissolved in DCM (1 mL)containing TEA (0.1 mL). Solvent was then removed under reducedprocedure. The resulting residue was dissolved in DCM (2 mL). Tothis solution was added Intermediate 45 (32 mg, 0.17 mmol) andNaBH(OAc).sub.3 (72 mg, 0.34 mmol) and the mixture was stirred for30 min. The solvents were removed and the residue was purified bypreparative HPLC method A to afford the titled compound as a TFAsalt. LCMS method A: R.sub.t=075 min, (M+H).sup.+=560.3. .sup.1HNMR (CD.sub.3OD) .delta.: 8.53 (s, 1H), 7.58 (s, 1H), 7.36-7.10 (m,6H), 4.53-3.78 (m, 11H), 2.22 (m, 4H), 1.96 (m, 1H), 1.34 (s, 6H),1.00 (d, J=6.8 Hz, 3H), 0.84 (d, J=6.8 Hz, 3H).
Example 11
6-((7-(5-(4-fluoro-2-isobutyrylphenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]-nonan-2-yl)methyl)-3-methyl-2-oxoindoline-3-carbonitrile
##STR00155##
The title compound was synthesized from tert-butyl7-(5-(4-fluoro-2-isobutyrylphenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]non-ane-2-carboxylate (Intermediate 41b), by the method described forstep 2 and 3 in the synthesis of Example 10. In step 3,6-formyl-3-methyl-2-oxoindoline-3-carbonitrile was utilized. LCMSmethod A: R.sub.t=0.57 min, (M+H).sup.+=569.3.
Example 12
5-fluoro-2-((4-(6-(3-(4-fluorophenyl)propanoyl)-2,6-diazaspiro[3.4]octan-2--yl)pyrimidin-5-yl)oxy)-N,N-diisopropylbenzamide
##STR00156##
To a solution of Intermediate 41b (10 mg, 0.02 mmol),3-(4-fluorophenyl)propanoic acid (10 mg, 0.06 mmol) andiPr.sub.2NEt (0.02 mL, 0.11 mmol) in DMF (2 mL) was added HATU (12mg, 0.03 mmol) at RT and the reaction mixture was stirred for 1 hat RT. EtOAc (5 mL) and H.sub.2O (2 mL) were added for the workup.The EtOAc layer was dried using Na.sub.2SO.sub.4 and evaporated.The crude residue was purified by ISCO flash column chromatography(eluting with 10% MeOH in DCM) to afford5-fluoro-2-((4-(6-(3-(4-fluorophenyl)propanoyl)-2,6-diazaspiro[3.4]octan--2-yl)pyrimidin-5-yl)oxy)-N,N-diisopropylbenzamide as the free base.LCMS Method G: t.sub.R=6.728 min, MS (ESI) m/z 578.56 [M+H].sup.+..sup.1H NMR (CD.sub.3OD): .delta. 8.45 (s, 1H), 7.72 (s, 1H),7.25-7.17 (m, 5H), 6.93 (t, J=8.4 Hz, 2H), 4.65-4.20 (m, 4H),3.77-3.72 (m, 1H), 3.60-3.56 (m, 3H), 3.44-3.40 (m, 2H), 2.85 (t,J=7.6 Hz, 2H), 2.55 (t, J=7.6 Hz, 2H), 2.16-2.10 (m, 2H), 1.46 (d,J=6.4 Hz, 3H), 1.37)d, J=6.4 Hz, 3H), 1.15 (d, J=6.4 Hz, 3H), 1.03(d, J=6.4 Hz, 3H).
Example 13
5-((7-(5-(4-fluoro-2-(1-isopropyl-1H-pyrazol-5-yl)phenoxy)pyrimidin-4-yl)--3-oxo-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one
##STR00157##
Step 1: 2, 7-diazaspiro[4.4]nonan-3-one
##STR00158##
To solution of tert-butyl8-oxo-2,7-diazaspiro[4.4]nonane-2-carboxylate (1 g, 4.2 mmol) inanhydrous CH.sub.2Cl.sub.2 (5 mL) was added HCl-dioxane (5 mL) andstirred at 16-34.degree. C. for 1 h. The mixture was concentratedto afford 2,7-diazaspiro[4.4]nonan-3-one (HCl salt, crude) as whitesolid, which was used in next step directly. Yield: 900 mg (HClsalt).
Step 2:7-(5-(2-bromo-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]n-onan-3-one
##STR00159##
To solution of 2,7-diazaspiro[4.4]nonan-3-one (900 mg, 4.1 mmol,HCl salt, crude) in CH.sub.3CN (20 mL) was added5-(2-bromo-4-fluorophenoxy)-4-chloropyrimidine (Intermediate 1, 1.3g, 4.05 mmol) and K.sub.2CO.sub.3 (1.1 g, 8.1 mmol). The mixturewas stirred at 85.degree. C. for 24 h. The mixture was filtered andthe filtrate was concentrated to purify by ISCO columnchromatography on silica gel (from 100% DCM to 5% MeOH in DCM) togive7-(5-(2-bromo-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-3--one as colorless oil. Yield: 1.2 g (73%); LCMS Method C:R.sub.t=0.659 min. (M+H).sup.+=407.0, 409.0 (bromo isotopes).
Step 3:7-(5-(4-fluoro-2-(1-isopropyl-1H-pyrazol-5-yl)phenoxy)pyrimidin-4--yl)-2,7-diaza spiro[4.4]nonan-3-one
##STR00160##
To solution of7-(5-(2-bromo-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-3--one (850 mg, 2.09 mmmol) in dioxane:H.sub.2O (15 mL, 1:1) was added(1-isopropyl-1H-pyrazol-5-yl)boronic acid (385 mg, 2.51 mmol),Sphos Pallacycle-gen 2 (75 mg, 0.105 mmol) and K.sub.3PO.sub.4(1.34 g, 6.27 mmol). The mixture was heated at 115.degree. C. for30 min in a microwave. The mixture was then concentrated anddiluted with EtOAc (30 mL) and washed with brine (50 mL.times.2).The organic layers were concentrated and the residue was purifiedby ISCO column chromatography on silica gel (from 100% DCM to 10%MeOH in DCM) to afford a brown solid. This solid was purified bybasic preparative RP-HPLC method D to afford7-(5-(4-fluoro-2-(1-isopropyl-1H-pyrazol-5-yl)phenoxy)pyrimidin-4-yl)-2,7--diazaspiro[4.4]nonan-3-one as a white solid. Yield: 350 mg. LCMSMethod C: R.sub.t=0.629 min; (M+H).sup.+=437.2. .sup.1H NMR(CDCl.sub.3): .delta. 8.40 (s, 1H), 7.82 (s, 1H), 7.57 (s, 1H),7.05-7.15 (m, 2H), 6.81 (dd, J=9.2 4.4 Hz, 1H), 6.17 (d, J=2.0 Hz,1H), 5.74 (s, 1H), 4.30-4.41 (m, 1H), 3.80-3.85 (m, 1H), 3.71 (d,J=11.2 Hz, 1H), 3.50-3.65 (m, 2H), 3.30-3.43 (m, 2H), 2.15-2.25 (m,1H), 2.00-2.10 (m, 2H), 1.75-1.85 (m, 1H), 143 (d, J=6.8 Hz, 3H),1.47 (d, J=6.8 Hz, 3H). .sup.19F NMR (CDCl.sub.3): .delta.-119.08.
Step 4: 7-(5-(4-fluoro-2-(1-isopropyl-1H-pyrazol-5-yl)phenoxy)pyrimidin-4-yl)-2-(4-fluoro-3-nitrobenzyl)-2,7-diazaspiro[4.4]non-an-3-one
##STR00161##
To a solution of7-(5-(4-fluoro-2-(1-isopropyl-1H-pyrazol-5-yl)phenoxy)pyrimidin-4-yl)-2,7--diazaspiro[4.4]nonan-3-one (50 mg, 0.11 mmmol) in anhydrous THF (3mL) was added NaH (7 mg, 0.17 mmol) and n-Bu.sub.4I (4 mg, 0.01mmol). Then 4-(bromomethyl)-1-fluoro-2-nitrobenzene (33 mg, 0.14mmol, dissolved in 1 mL THF) was added dropwise into the mixtureand the mixture was stirred at 0.degree. C. for 30 min. Then themixture was stirred at 16-25.degree. C. for 2 h. The mixture wasquenched with saturated NH.sub.4Cl (5 mL, aq.) and extracted withEtOAc (5 mL.times.2). The combined organic layers were dried overNa.sub.2SO.sub.4 and concentrated. The resulting residue waspurified by acidic preparative RP-HPLC method A to give7-(5-(4-fluoro-2-(1-isopropyl-1H-pyrazol-5-yl)phenoxy)pyrimidin-4-yl)-2-(-4-fluoro-3-nitrobenzyl)-2,7-diazaspiro[4.4]nonan-3-one as the TFAsalt as a white solid. Yield: 21 mg (32%); LCMS Method C:R.sub.t=0.740 min; (M+H).sup.+=589.9. .sup.1H NMR (MeOD): .delta.8.54 (s, 1H), 8.03 (d, J=6.8 Hz, 1H), 7.94 (s, 1H), 7.60-7.70 (m,1H), 7.56 (s, 1H), 7.46 (t, J=9.2 Hz, 1H), 7.35-7.40 (m, 2H), 7.31(d, J=8.8 Hz, 1H), 6.30 (s, 1H), 4.57 (s, 2H), 4.35-4.45 (m, 1H),4.05-4.15 (m, 1H), 4.00-4.05 (m, 1H), 3.85-3.95 (m, 1H), 3.65-3.80(m, 1H), 3.35-3.50 (m, 2H), 2.00-2.25 (m, 4H), 1.30-1.45 (m, 6H)..sup.19F NMR (MeOD): .delta. -77.21, -117.66, -122.07.
Step 5:2-(4-amino-3-nitrobenzyl)-7-(5-(4-fluoro-2-(1-isopropyl-1H-pyrazol--5-yl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-3-one
##STR00162##
To solution of7-(5-(4-fluoro-2-(1-isopropyl-1H-pyrazol-5-yl)phenoxy)pyrimidin-4-yl)-2-(-4-fluoro-3-nitrobenzyl)-2,7-diazaspiro[4.4]nonan-3-one (80 mg, 0.14mmmol) in NH.sub.3-MeOH (5 mL) was heated to 70.degree. C. for 36 hin an autocalve. The mixture was then concentrated and purified bypreparative TLC on silica gel (DCM:MeOH=10:1) to give2-(4-amino-3-nitrobenzyl)-7-(5-(4-fluoro-2-(1-isopropyl-1H-pyrazol-5-yl)p-henoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-3-one as yellowsolid. Yield: 65 mg (80%); LCMS method C: R.sub.t=0.713 min;(M+H).sup.+=587.2. .sup.1H NMR (MeOD): .delta. 8.29 (s, 1H), 7.96(s, 1H), 7.83 (s, 1H), 7.51 (s, 1H), 7.22-7.30 (m, 2H), 7.19 (dd,J=8.0 2.8 Hz, 1H), 6.96-6.99 (m, 2H), 6.19 (s, 1H), 4.38-4.43 (m,3H), 3.65-3.73 (m, 1H), 3.59-3.71 (m, 2H), 3.51 (d, J=12.0 Hz, 1H),3.35 (s, 1H), 3.27-3.29 (m, 1H), 2.11-2.16 (m, 1H), 1.84-2.06 (m,3H), 1.33-1.44 (m, 6H). .sup.19F NMR (MeOD): .delta. -120.79.
Step 6:2-(3,4-diaminobenzyl)-7-(5-(4-fluoro-2-(1-isopropyl-1H-pyrazol-5-y-l)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-3-one
##STR00163##
To a solution of2-(4-amino-3-nitrobenzyl)-7-(5-(4-fluoro-2-(1-isopropyl-1H-pyrazol-5-yl)p-henoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-3-one (50 mg, 0.85mmol) in anhydrous EtOH (10 mL) was added Raney Ni (10 mg, wet) andstirred at 17-26.degree. C. for 18 h under H.sub.2 (15 psi). Themixture was filtered and the filtrate was concentrated. The residuewas purified by preparative TLC on silica gel (DCM:MeOH=10:1) togive2-(3,4-diaminobenzyl)-7-(5-(4-fluoro-2-(1-isopropyl-1H-pyrazol-5-yl)pheno-xy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-3-one as a white solid.Yield: 20 mg (42%); LCMS method C: R.sub.t=0.624 min.(M+H).sup.+=557.3.
Step 7:5-((7-(5-(4-fluoro-2-(1-isopropyl-1H-pyrazol-5-yl)phenoxy)pyrimidi-n-4-yl)-3-oxo-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol-2(-3H)-one
To solution of2-(3,4-diaminobenzyl)-7-(5-(4-fluoro-2-(1-isopropyl-1H-pyrazol-5-yl)pheno-xy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-3-one (13 mg, 0.023mmol) in anhydrous THF (5 mL) was added Et.sub.3N (10 .mu.L) andbis(trichlormethyl)carbonate (7 mg, 0.023 mmol) and the resultingmixture was stirred at 18-26.degree. C. for 16 h. TLC(DCM:MeOH==10:1, R.sub.f=0.7) showed a new spot and2-(3,4-diaminobenzyl)-7-(5-(4-fluoro-2-(1-isopropyl-1H-pyrazol-5-yl)pheno-xy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-3-one was not consumedcompletely. The mixture was poured into water (5 mL) and extractedwith EA (10 mL.times.2). The combined organic layers were washedwith brine (30 mL.times.2), dried over Na.sub.2SO.sub.4 andconcentrated to purify by basic preparative RP-HPLC method D togive5-((7-(5-(4-fluoro-2-(1-isopropyl-1H-pyrazol-5-yl)phenoxy)pyrimidin-4-yl)--3-oxo-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-oneas a white solid. Yield: 2.9 mg (22%); LCMS method C: R.sub.t=:1.596 min, (M+H).sup.+=583.2. .sup.1H NMR (MeOD): .delta. 8.30 (s,1H), 7.83 (s, 1H), 7.48 (s, 1H), 7.25-7.35 (m, 1H), 7.21 (d, J=8.4Hz, 1H), 7.00-7.05 (m, 1H), 6.95-7.00 (m, 3H), 6.16 (s, 1H),4.35-4.55 (m, 3H), 3.80-3.90 (m, 1H), 3.55-3.70 (m, 2H), 3.45-3.55(m, 1H), 3.20-3.30 (m, 2H), 1.85-2.20 (m, 4H), 1.35-1.45 (m, 6H)..sup.19F NMR (MeOD): .delta. -120.78.
Examples 14A-14B
N-(4-fluoro-2-(5-isopropyl-3-methylisoxazol-4-yl)phenyl)-4-(6-((tetrahydro--2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-amine(Example 14A) &4-(5-fluoro-2-((4-(6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.-3]heptan-2-yl)pyrimidin-5-yl)oxy)phenyl)-5-isopropyl-3-methylisoxazole(Example 14B)
##STR00164##
Step 1. 5-isopropyl-3-methylisoxazole and3-isopropyl-5-methylisoxazole
##STR00165##
A suspension of 5-methylhexane-2,4-dione (300 mg, 2.34 mmol) andhydroxylamine HCl (194 mg, 2.82 mmol) in EtOH was heated for 3 minin a microwave at 130.degree. C. The EtOH was evaporated and crudeproduct was partitioned between Et.sub.2O (5 mL) and water (3 mL).The Et.sub.2O layer was dried using MgSO.sub.4 and subsequentlyevaporated to give the crude product as a 4:1 mixture of isoxazoleregioisomers. The major isomer was assigned as5-isopropyl-3-methylisoxazole and the minor as3-isopropyl-5-methylisoxazole. This crude mixture was used directlyfor the next step without further purification. LCMS method A:t.sub.R=1.485; [M+H].sup.+=126.28.
Step 2. 4-bromo-5-isopropyl-3-methylisoxazole and4-bromo-3-isopropyl-5-methylisoxazole
##STR00166##
To a solution of crude 5-isopropyl-3-methylisoxazole (4:1 crudemixture from Step 1, 2.34 mmol) in DMF (3 mL) was addedN-bromosuccinimide (625 mg, 3.51 mmol) at RT and the reactionmixture was stirred for 15 h at RT. EtOAc (10 mL) and H-.sub.2O (10mL) were then added for the workup. The EtOAc layer was separatedand washed with a saturated Na.sub.2S.sub.2O.sub.5 aqueous solutionfollowed by brine. The EtOAc layer was then dried usingNa.sub.2SO.sub.4 and evaporated. The crude product was purified byISCO flash column chromatography (eluting with 20% EtOAc inhexanes) to afford 200 mg (42% over 2 steps) of product as a 4:1mixture of regioisomers. The major isomer was assigned as4-bromo-5-isopropyl-3-methylisoxazole and the minor isomer as4-bromo-3-isopropyl-5-methylisoxazole. LCMS method A:t.sub.R=1.787; [M].sup.+=204.25 and 206.26. .sup.1H NMR(CDCl.sub.3): major isoxazole regioisomer(4-bromo-5-isopropyl-3-methylisoxazole) .delta. 3.21-3.14 (m, 1H),2.26 (s, 3H), 1.32 (d, J=7.2 Hz, 6H).
Step 3.5-isopropyl-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y-l)isoxazole and3-isopropyl-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxa-zole
##STR00167##
A mixture of 4-bromo-5-isopropyl-3-methylisoxazole (4:1 mixture ofregioisomers from Step 2, 100 mg, 0.49 mmol), pinacol borane (0.11mL, 0.78 mmol), PdCl.sub.2(MeCN).sub.2 (3 mg, 2 mol %), SPhosligand (10 mg, 5 mol %) and Et.sub.3N (0.24 mL, 1.72 mmol) indioxane (2 mL) was heated at 100.degree. C. in a sealed vial undera blanket of N.sub.2 for 1 h. The reaction mixture was cooled toRT, filtered through a plug of celite and evaporated. The cruderesidue was purified using ISCO flash column chromatography(eluting with 20% EtOAc in hexanes) to afford 100 mg of5-isopropyl-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxa-zole and3-isopropyl-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2--yl)isoxazole as a 4:1 mixture of regioisomers and used in the nextstep without further purification.
Step 4. tert-butyl6-(5-bromopyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate
##STR00168##
A suspension of 5-bromo-4-chloropyrimidine (1.67 g, 8.65 mmol),tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate hemioxalatesalt (2 g, 4.12 mmol) and iPr.sub.2NEt (1.80 mL, 10.3 mmol) in.sup.iPrOH (10 mL) was heated at reflux for 15 h. SaturatedNH.sub.4Cl aqueous solution (10 mL) and EtOAc (20 mL) were added tothe reaction for the workup. The EtOAc layer was separated and theaqueous layer was extracted again with EtOAc. The EtOAc layers werecombined, washed with water, then brine, and dried usingNa.sub.2SO.sub.4. Evaporation of the EtOAc gave tert-butyl6-(5-bromopyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylateas an off-white foamy solid (2 grams, 70%) that was nearly pure byLCMS analysis and used directly for the next step without furtherpurification. LCMS method A: t.sub.R=1.330 min; [M+H].sup.30=355.41and 357.
Step 5. tert-butyl6-(5-((2-chloro-4-fluorophenyl)amino)pyrimidin-4-yl)-2,6-diazaspiro[3.3]h-eptane-2-carboxylate
##STR00169##
A mixture of tert-butyl6-(5-bromopyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate(100 mg, 0.28 mmol), 2-chloro-4-fluoroaniline (39 mg, 0.27 mmol),Pd.sub.2(dba).sub.3 (5 mg, 0.005 mmol), Xphos (11 mg, 0.023 mmol)and NaOtBu (60 mg, 0.63 mmol) in toluene (2 mL) was heated in a CEMmicrowave at 160.degree. C. for 30 min. Upon cooling, the reactionwas diluted with 5 mL of EtOAc and filtered through a plug ofcelite. Evaporation of the solvents gave a crude solid which wastriturated overnight using hexanes. Filtration of the solidmaterial afforded 92 mg (79%) of tert-butyl6-(5-((2-chloro-4-fluorophenyl)amino)pyrimidin-4-yl)-2,6-diazaspiro[3.3]h-eptane-2-carboxylate which was nearly pure by LCMS analysis andused directly in the next step without further purification. LCMSmethod A: t.sub.R=1.411; [M+H].sup.+=420.54 and 422.55.
Step 6. tert-butyl6-(5-((4-fluoro-2-(5-isopropyl-3-methylisoxazol-4-yl)phenyl)amino)pyrimid-in-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate and tert-butyl6-(5-((4-fluoro-2-(3-isopropyl-5-methylisoxazol-4-yl)phenyl)amino)pyrimid-in-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate
##STR00170##
A mixture of tert-butyl6-(5-((2-chloro-4-fluorophenyl)amino)pyrimidin-4-yl)-2,6-diazaspiro[3.3]h-eptane-2-carboxylate (35 mg, 0.083 mmol) and5-isopropyl-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxa-zole and3-isopropyl-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2--yl)isoxazole as a 4:1 mixture of isomers (Step 3, 21 mg, 0.083mmol), K.sub.3PO.sub.4 (53 mg, 0.25 mmol) and SPhos-palladacycle(CAS#:1375325-64-6, 3 mg, 0.004 mmol) in dioxane/H.sub.2O (1mL/0.40 mL) was heated to 120.degree. C. for 15 min in a CEMmicrowave. Upon cooling, the reaction mixture was filtered throughcelite and evaporated. Purification by ISCO flash columnchromatography (eluting with 100% EtOAc) gave tert-butyl6-(5-((4-fluoro-2-(5-isopropyl-3-methylisoxazol-4-yl)phenyl)amino)pyrimid-in-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate as the majorisoxazole isomer (4:1 mixture) from the isomeric mixture ofstarting materials. This isomeric mixture of products was useddirectly for the next step without further purification. LCMSmethod A: t.sub.R=1.367; [M+H].sup.+==509.70.
Step 7.N-(4-fluoro-2-(5-isopropyl-3-methylisoxazol-4-yl)phenyl)-4-(2,6-di-azaspiro[3.3]heptan-2-yl)pyrimidin-5-amine andN-(4-fluoro-2-(3-isopropyl-5-methylisoxazol-4-yl)phenyl)-4-(2,6-diazaspir-o[3.3]heptan-2-yl)pyrimidin-5-amine
##STR00171##
To a solution of tert-butyl6-(5-((4-fluoro-2-(5-isopropyl-3-methylisoxazol-4-yl)phenyl)amino)pyrimid-in-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate and tert-butyl6-(5-((4-fluoro-2-(3-isopropyl-5-methylisoxazol-4-yl)phenyl)amino)pyrimid-in-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (4:1 mixture ofisoxazole regioisomers from Step 6, 40 mg, 0.079 mmol) in DCM (3mL) was added TFA (1 mL) at RT. The reaction stirred for 1 h at RTand the solvents were then removed. DCM (2 mL) and Et.sub.3N (0.05mL) were added to form the free base amine from the TFA salt.Evaporation of the solvents and drying under high vacuum gaveN-(4-fluoro-2-(5-isopropyl-3-methylisoxazol-4-yl)phenyl)-4-(2,6-diazaspir-o[3.3]heptan-2-yl)pyrimidin-5-amine andN-(4-fluoro-2-(3-isopropyl-5-methylisoxazol-4-yl)phenyl)-4-(2,6-diazaspir-o[3.3]heptan-2-yl)pyrimidin-5-amine as the free base (4:1 mixtureof isoxazole regioisomers). This material was used directly for thenext step without further purification.
Step 8.N-(4-fluoro-2-(5-isopropyl-3-methylisoxazol-4-yl)phenyl)-4-(6-((te-trahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5--amine andN-(4-fluoro-2-(3-isopropyl-5-methylisoxazol-4-yl)phenyl)-4-(6-((-tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin--5-amine
To a solution of crudeN-(4-fluoro-2-(5-isopropyl-3-methylisoxazol-4-yl)phenyl)-4-(2,6-diazaspir-o[3.3]heptan-2-yl)pyrimidin-5-amine andN-(4-fluoro-2-(3-isopropyl-5-methylisoxazol-4-yl)phenyl)-4-(6-((tetrahydr-o-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-amine(4:1 mixture of isoxazole regioisomers from Step 7, 0.079 mmol) andtetrahydro-2H-pyran-4-carbaldehyde (27 mg, 0.24 mmol) indichloroethane (2 mL, containing 1% AcOH) was added NaBH(OAc).sub.3(50 mg, 0.24 mmol) at RT. The reaction mixture was stirred for 30min and was complete by LCMS analysis. Evaporation of the solventfollowed by purification using HPLC method A affordedN-(4-fluoro-2-(5-isopropyl-3-methylisoxazol-4-yl)phenyl)-4-(6-((tetrahydr-o-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-amineTFA salt andN-(4-fluoro-2-(3-isopropyl-5-methylisoxazol-4-yl)phenyl)-4-(6-((tetrahydr-o-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-amineTFA salt as a 4:1 mixture of isoxazole regioisomers (15 mg). LCMSmethod B: t.sub.R=1.124; [M+H].sup.+=507.70.
Example 14A: Major Isoxazole Regioisomer
LCMS method B: t.sub.R=1.013; [M+H].sup.+=507.70 .sup.1H NMR(CD.sub.3OD). .delta. 8.55 (bs, 1H), 7.79 (bs, 1H), 7.17-7.12 (m,1H), 7.00 (dd, J=3.2, 8.8 Hz, 1H), 6.83 (dd, J=5.2, 9.2 Hz, 1H),4.60-4.35 (m, 8H), 3.93 (dd, J=4.0, 11.6 Hz, 2H), 3.40 (t, J=11.6Hz, 2H), 3.11 (d, J=7.2 Hz, 2H), 3.07-3.00 (m, 1H), 2.17 (s, 3H),1.93-1.87 (m, 1H), 1.60 (d, J=11.6 Hz, 2H), 1.37-1.20 (m, 1H), 1.27(d, J=6.4 Hz, 3H), 1.26 (d, J=6.4 Hz, 3H), 1.21-1.16 (1H, m).
Example 14B: Minor Isoxazole Regioisomer
LCMS method B t.sub.R=1.124; [M+H].sup.+=507.70.
Example 15
N-(5-fluoro-2'-isopropyl-[1,1'-biphenyl]-2-yl)-4-(6-((tetrahydro-2H-pyran--4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-amine
##STR00172##
The title product was synthesized by the method described inExamples 14A-14B. In Step 3, 2-isopropyl phenyl boronic acid wasused. LCMS Method G: R.sub.t=4.88 min; M+H.sup.+=502.85. .sup.1HNMR (d4-MeOH) 8.45 (s, 1H), 7.72, (s, 1H), 7.47 (d, 1H), 7.42 (m,1H), 7.28 (m, 1H), 7.20 (d, 1H), 7.07 (m, 1H), 6.92 (m, 1H), 6.81(m, 1H), 4.32-4.56 (m, 8H), 3.94 (m, 2H), 3.39 (m, 2H), 3.11 (d,2H), 2.82 (m, 2H), 1.86 (m, 1H), 1.59 (d, 2H), 1.33 (m, 2H), 1.20(d, 3H), 1.13 (d, 3H) ppm.
Example 16
5-fluoro-2-((4-(2-(2-hydroxy-2-methylpropyl)-2,7-diazaspiro[3.5]nonan-7-yl-)pyrimidin-5-yl)amino)-N,N-diisopropylbenzamide
##STR00173##
Step 1.2-((4-(2-(tert-butoxycarbonyl)-2,7-diazaspiro[3.5]nonan-7-yl)pyrim-idin-5-yl)amino)-5-fluorobenzoic Acid
##STR00174##
To a round bottom flask was added tert-butyl7-(5-iodopyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate(Example 71, Step 1, 500 mg, 1 eq.), 2-amino-5-fluorobenzoic acid(216 mg, 1.2 eq), Pd.sub.2(dba).sub.3 (21 mg, 0.02 eq.), Xantphos(54 mg, 0.08 eq.) and Cs.sub.2CO.sub.3 (1.33 g, 3.5 eq.). To thissolid mixture was added dioxane (8 mL, 0.15 M with respect totert-butyl7-(5-iodopyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate).The heterogenous solution was purged with a nitrogen stream for 1min The flask was capped and the reaction was heated overnight at100.degree. C. The Cs.sub.2CO.sub.3 was then filtered off and thefiltrate was diluted with EtOAc and 0.5 M HCl was added. Theresulting while solid was filtered and dried over vacuum. Yield:400 mg.
Step 2. tert-butyl7-(5-((2-(diisopropylcarbamoyl)-4-fluorophenyl)amino)pyrimidin-4-yl)-2,7--diazaspiro[3.5]nonane-2-carboxylate
##STR00175##
To a round bottom flask were added2-((4-(2-(tert-butoxycarbonyl)-2,7-diazaspiro[3.5]nonan-7-yl)pyrimidin-5--yl)amino)-5-fluorobenzoic acid (500 mg) and HOBt (184 mg). To thissolid mixture was added DMF (3.65 mL), diisopropylamine (1 mL) anddiisopropylethylamine (209 .mu.L), followed by BOP reagent (532 mg,1.1 eq.) and the mixture was stirred overnight. The mixture wasthen partitioned between EtOAc and water. The phases were separatedand the aqueous phase was back-extracted with EtOAc twice. Thecombined organic phases were dried over magnesium sulfate andconcentrated. The crude material was purified by flashchromatography (40 g SiO.sub.2, MeOH/DCM as the eluents) yieldingtert-butyl7-(5-((2-(diisopropylcarbamoyl)-4-fluorophenyl)amino)pyrimidin-4-yl)-2,7--diazaspiro[3.5]nonane-2-carboxylate (300 mg).
Step 3.5-fluoro-2-((4-(2-(2-hydroxy-2-methylpropyl)-2,7-diazaspiro[3.5]no-nan-7-yl)pyrimidin-5-yl)amino)-N,N-diisopropylbenzamide
To a round bottom flask was added tert-butyl7-(5-((2-(diisopropylcarbamoyl)-4-fluorophenyl)amino)pyrimidin-4-yl)-2,7--diazaspiro[3.5]nonane-2-carboxylate (300 mg), DCM (5 mL), and TFA(5 mL) and the reaction mixture was stirred for 30 min at RT. Thevolatiles were then removed under vacuum. The crude residue wasco-evaporated with DCM twice yielding2-((4-(2,7-diazaspiro[3.5]nonan-7-yl)pyrimidin-5-yl)amino)-5-fluoro-N,N-d-iisopropylbenzamide bis-TFA salt. To a round bottom flask was addedthe bis-TFA salt (20 mg), 2,2-dimethyloxirane (11 mg),triethylamine (21 .mu.L) and THF: ethanol (2 mL, 1:1 ratio). Theflask was capped and the mixture was heated at 65.degree. C.overnight. When the reaction was complete, the volatiles wereremoved under vacuum. The crude material was purified by RP-HPLCmethod A yielding5-fluoro-2-((4-(2-(2-hydroxy-2-methylpropyl)-2,7-diazaspiro[3.5]nonan-7-y-l)pyrimidin-5-yl)amino)-N,N-diisopropylbenzamide (3.7 mg). LCMSmethod G R.sub.t=3.65 min; (M+H).sup.+=513.61. .sup.1H NMR(d4-MeOH) 8.52 (s, 1H), 7.87 (s, 1H), 7.07-7.15 (m, 2H), 6.93 (m,1H), 4.23 (d, 2H), 4.04 (d, 2H), 3.82-3.89 (m, 6H), 1.93-1.99 (m,4H), 1.26-1.34 (m, 18H).
Example 17
5-((7-(5-(2-(dimethylphosphoryl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diaza-spiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one
##STR00176##
Step 1. tert-Butyl7-(5-(2-(dimethylphosphoryl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspi-ro[4.4]nonane-2-carboxylate
##STR00177##
To a mixture of tert-butyl7-(5-(2-bromo-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2--carboxylate (Intermediate 11, 200 mg, 0.41 mmol),(CH.sub.3).sub.2PO (35 mg, 0.45 mmol), K.sub.3PO.sub.4 (104 mg,0.49 mmol) in anhydrous DMF (3 mL) was added Pd(OAc).sub.2 (1.0 mg,0.004 mmol) and Xantphos (4.0 mg, 0.006 mmol) and the reaction wasstirred at 150.degree. C. under a microwave for 30 min. Thereaction was filtered through a Celite pad and concentrated underreduced pressure to afford the residue which was purified by columnchromatography on silica gel (eluting withdichloromethane:methanol=1:0.about.10:1) to afford tert-butyl7-(5-(2-(dimethylphosphoryl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspi-ro[4.4]nonane-2-carboxylate as light yellow oil. Yield: 120 mg.LCMS method E: R.sub.t=0.836 min. (M+H).sup.+=491.2.
Steps 2-3.5-((7-(5-(2-(dimethylphosphoryl)-4-fluorophenoxy)pyrimidin-4-yl-)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one
Steps 2-3 were performed according to the procedures of Steps 4-5of Example 1. LCMS method E: R.sub.t=1.344 min; (M+H).sup.+=537.2..sup.1H NMR (CD.sub.3OD): .delta. 8.34 (s, 1H), 7.89 (s, 1H), 7.61(m, 1H), 7.22-7.60 (m, 1H), 6.96-7.00 (m, 3H), 6.73-6.77 (m, 1H),3.59 (s, 6H), 2.43-2.67 (m, 4H), 1.90 (d, J=14 Hz, 8H), 1.78 (t,J=6.4 Hz, 2H). .sup.19F NMR (CD.sub.3OD): .delta. -120.92.
Example 18
2-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-N-(4-f-luorobenzyl)-5-oxa-2-azaspiro[3.4]octan-7-amine
##STR00178##
Step 1. 5-oxa-2-azaspiro[3.4]octan-7-one trifluoroacetate
##STR00179##
To a solution of tert-butyl7-oxo-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (300 mg, 1.32 mmol)in DCM (3 mL) was added TFA (1 mL) at RT and the reaction mixturewas stirred for 1 h at RT. The solvents were removed to afford5-oxa-2-azaspiro[3.4]octan-7-one TFA salt which was used directlyfor the next step without further purification. LCMS Method A:t.sub.R=0.269 min; [M+H].sup.+=128.28.
Step 2.2-(5-(2-bromo-4-fluorophenoxy)pyrimidin-4-yl)-5-oxa-2-azaspiro[3.4-]octan-7-one
##STR00180##
A mixture of 5-oxa-2-azaspiro[3.4]octan-7-one TFA salt (168 mg,1.32 mmol), 5-(2-bromo-4-fluorophenoxy)-4-chloropyrimidine(Intermediate 1, 481 mg, 1.58 mmol) and iPr.sub.2NEt (0.92 mL, 5.28mmol) in .sup.iPrOH (3 mL) was heated at 100.degree. C. for 12 h.Purification using ISCO flash column chromatography (eluting with10% MeOH in DCM) gave 406 mg of2-(5-(2-bromo-4-fluorophenoxy)pyrimidin-4-yl)-5-oxa-2-azaspiro[3.4]octan--7-one. LCMS Method A: t.sub.R=0.961 min; [M+H].sup.+=394.35 and396.37.
Step 3.2-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl-)-5-oxa-2-azaspiro[3.4]octan-7-one
##STR00181##
A mixture of2-(5-(2-bromo-4-fluorophenoxy)pyrimidin-4-yl)-5-oxa-2-azaspiro[3.4]octan--7-one (147 mg, 0.37 mmol), (4-isopropylpyrimidin-5-yl)boronic acid(93 mg, 0.56 mmol), PdCl.sub.2(PPh.sub.3).sub.2 (26 mg, 0.037 mmol)and K.sub.3PO.sub.4 (237 mg, 1.12 mmol) in dioxane (2.5 mL) andwater (0.25 mL) was heated at 120.degree. C. in a CEM microwave for2 h. The mixture was filtered through celite and evaporated.Purification using ISCO flash column chromatography (eluting with10% MeOH in DCM) gave 151 mg of2-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-5-oxa--2-azaspiro[3.4]octan-7-one. LCMS Method A: t.sub.R=0.926 min;[M+H].sup.+=436.48.
Step 4.2-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl-)-N-(4-fluorobenzyl)-5-oxa-2-azaspiro[3.4]octan-7-amine
To a solution of2-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-5-oxa--2-azaspiro[3.4]octan-7-one (14 mg, 0.03 mmol) and(4-fluorophenyl)methanamine (0.006 mL, 0.047 mmol) in MeOH (2 mL)was added NaBH.sub.3CN (8 mg, 0.12 mmol) and the reaction mixturewas stirred at 50.degree. C. for 6 h. Evaporation of the solventand purification using a Gilson HPLC afforded 4.6 mg of2-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-N-(4--fluorobenzyl)-5-oxa-2-azaspiro[3.4]octan-7-amine TFA salt. LCMSMethod A: t.sub.R=0.572 min; [M+H].sup.+=545.60. .sup.1H NMR(CD.sub.3OD): .delta. 9.10 (s, 1H), 8.57 (s, 1H), 8.21 (s, 1H),7.69 (s, 1H), 7.38-7.34 (m, 2H), 7.30-7.22 (m, 2H), 7.10-7.03 (m,3H), 4.19 (bs, 1H), 4.14-4.03 (m, 3H), 3.91 (dd, J=6.0, 9.0 Hz,1H), 3.75 (d, J=6.4 Hz, 2H), 3.71-3.66 (m, 1H), 3.46-3.41 (m, 1H),3.08-3.01 (m, 1H), 2.35-2.30 (m, 1H), 2.08-2.02 (m, 1H), 1.19 (d,J=6.8 Hz, 6H).
Example 19
4-(((2-(5-((5-fluoro-2'-isopropyl-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)--5-oxa-2-azaspiro[3.4]octan-7-yl)amino)methyl)benzonitrile
##STR00182##
The title compound was synthesized according to the methoddescribed for Example 18. In Step 3, 2-isopropylphenyl boronic acidwas used. In Step 4, 4-cyanobenzaldehyde was used. LCMS method A:R.sub.t=1.125 min; (M+H).sup.+=550.68. .sup.1H NMR (CD.sub.3OD):.delta. 8.12 (s, 1H), 7.70 (d, J=7.6 Hz, 2H), 7.55 (d, J=7.6 Hz,2H), 7.38-7.32 (m, 2H), 7.21-7.05 (m, 5H), 4.19-4.09 (m, 2H),4.03-3.97 (m, 2H), 3.92-3.87 (m, 1H), 3.87-3.82 (m, 2H), 3.67 (dd,J=4.8, 9.0 Hz, 1H), 3.40 (bs, 1H), 2.84-2.78 (m, 1H), 2.29-2.22 (m,1H), 2.05-2.01 (m, 2H), 1.11-1.08 (m, 6H).
Example 20
7-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-N-(4-f-luorobenzyl)-1-oxa-7-azaspiro[4.4]nonan-3-amine
##STR00183##
The title compound was synthesized starting with tert-butyl3-oxo-1-oxa-7-azaspiro[4.4]nonane-7-carboxylate according to themethod described for Example 18. LCMS Method A: t.sub.R=0.585;[M+H].sup.+=559.61. .sup.1H NMR (CD.sub.3OD): .delta. 9.10 (s, 1H),8.57 (s, 1H), 8.21 (s, 1H), 7.78 (s, 1H), 7.41-7.35 (m, 2H),7.28-7.20 (m, 2H), 7.09-6.95 (m, 3H), 4.42 (bs, 1H), 3.97-3.47 (m,8H), 3.12-3.05 (m, 1H), 2.27-2.23 (m, 1H), 2.18-2.10 (m, 1H),1.99-1.81 (m, 2H), 1.24-1.19 (m, 6H).
Example 21
5-fluoro-N-isopropyl-N-methyl-2-((4-(7-(((1r,4r)-4-(methylcarbamoyl)cycloh-exyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide
##STR00184##
Step 1. methyl(1r,4r)-4-((2-(5-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenoxy)pyrimidi-n-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)cyclohexane-1-carboxylate
##STR00185##
The title compound was synthesized by reductive amination between2-((4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopr-opyl-N-methylbenzamide (0.18 mmol) and methyl(1r,4r)-4-formylcyclohexane-1-carboxylate (100 .mu.L) by the methoddescribed for Example 18, Step 4. LCMS method B: R.sub.t=0.73 min,(M+H).sup.+=568.5.
Step 2.(1r,4r)-4-((2-(5-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenoxy)p-yrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)cyclohexane-1-carboxyl-ic acid
##STR00186##
To a solution of methyl(1r,4r)-4-((2-(5-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)cyclohexane--1-carboxylate (30 mg, 0.053 mmol) in MeOH (1 mL), there was added 2N LiOH solution (0.2 mL). The solution was stirred at RT overnight,the solvent was removed to dryness, and the residue was used fornext step without purification; LCMS method B: R.sub.t=0.63 min,(M+H).sup.+=554.6.
Step 3.5-fluoro-N-isopropyl-N-methyl-2-((4-(7-(((1r,4r)-4-(methylcarbamoy-l)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benz-amide
To a solution of the crude product from Step 2 in DMF (0.5 mL) wasadded MeNH.sub.2HCl (15 mg) and Et.sub.3N (200 .mu.L), followed byHATU (20 mg) and the resulting solution was stirred at RT for 30min. The product was purified by preparative RP-HPLC Method A togive5-fluoro-N-isopropyl-N-methyl-2-((4-(7-(((1r,4r)-4-(methylcarbamoyl)cyclo-hexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamideas a TFA salt (7 mg); LCMS method B: R.sub.t=0.60 min,(M+H).sup.+=567.6; .sup.1H NMR (MeOH-d4): .delta. 8.38, 8.37 (s,1H), 7.73, 7.61 (br.s, 1H), 7.24-7.12 (m, 3H), 4.65 (m, 1H),4.52-3.96 (m, 4H), 3.45 (m, 2H), 2.88 (m, 4H), 2.82, 2.68 (two s,3H), 2.58 (s, 3H), 2.16 (m, 2H), 2.08-1.88 (m, 3H), 1.74 (m, 5H),1.41 (m, 2H), 1.12-0.92 (m, 8H).
Examples 22A and 22B
2-((4-(7-amino-7-(4-cyanobenzyl)-2-azaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)-oxy)-5-fluoro-N,N-diisopropylbenzamide (Isomers 1-2)
##STR00187##
Step 1. tert-butyl7-(4-bromobenzyl)-7-((tert-butylsulfinyl)amino)-2-azaspiro[4.4]nonane-2-c-arboxylate
##STR00188##
To a solution oftert-butyl-7-((tert-butylsulfinyl)imino)-2-azaspiro[4.4]nonane-2-carboxyl-ate (Examples 250A-250B, Step 1, 0.73 g, 2.13 mmol) in THF (15 mL)at 0.degree. C., 4-bromo-benzylmagnesium bromide (0.25M inEt.sub.2O, 20 mL) was added, the solution was to warmed to RT.After 2 h, another 20 mL Grignard reagent was added and the mixturewas stirred for another 2 h. The reaction was quenched reactionwith sat. NH.sub.4Cl and organic layer was separated. The aqueouslayer was extracted with EtOAc (2.times.5 mL), the combined organiclayers were dried over Na.sub.2SO.sub.4, and concentrated undervacuum. The residue was purified by silica gel column to givetert-butyl7-(4-bromobenzyl)-7-((tert-butylsulfinyl)amino)-2-azaspiro[4.4]nonane-2-c-arboxylate (174.4 mg, 16%). LCMS method B: R.sub.t=2.22 min;(M+H).sup.+=513.6.
Step 2. tert-butyl7-((tert-butylsulfinyl)amino)-7-(4-cyanobenzyl)-2-azaspiro[4.4]nonane-2-c-arboxylate
##STR00189##
To a solution of tert-butyl7-(4-bromobenzyl)-7-((tert-butylsulfinyl)amino)-2-azaspiro[4.4]nonane-2-c-arboxylate (88.4 mg, 0.17 mmol) in anhydrous DMF (0.5 mL), therewas added Zn(CN).sub.2 (20 mg, 0.17 mmol) and Pd(PPh.sub.3).sub.4(20 mg, 0.02 mmol). The resulting solution was degassed, and heatedat 110.degree. C. under N.sub.2 in an oil bath overnight. Thereaction was cooled, diluted with EtOAc, washed with 1N HCl (5 mL),brine, and dried over Na.sub.2SO.sub.4. After removing the solvent,the residue was purified by silica gel column (0-9% MeOH/DCM) togive tert-butyl7-((tert-butylsulfinyl)amino)-7-(4-cyanobenzyl)-2-azaspiro[4.4]nonane-2-c-arboxylate (56 mg, 72%). LCMS method B: R.sub.t=1.67 min;(M+H).sup.+=460.6.
Step 3.4-((7-amino-2-azaspiro[4.4]nonan-7-yl)methyl)benzonitrile
##STR00190##
To a solution of tert-butyl7-((tert-butylsulfinyl)amino)-7-(4-cyanobenzyl)-2-azaspiro[4.4]nonane-2-c-arboxylate (56 mg, 0.12 mmol) in DCM (2 mL) was added TFA (50.mu.L), and the resulting solution was stirred at RT overnight togive 4-((7-amino-2-azaspiro[4.4]nonan-7-yl)methyl)benzonitrile. Thesolvent was removed and the resulting residue was used in the nextstep without purification. LCMS method B: R.sub.t=0.32 min;(M+H).sup.+=256.6.
Step 4.2-((4-(7-amino-7-(4-cyanobenzyl)-2-azaspiro[4.4]nonan-2-yl)pyrimid-in-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide (Isomers 1-2)
To a solution of the crude product from Step 3 in isopropanol (0.5mL), was added2-((4-chloropyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzami- de(Intermediate 41, 30 mg) and Et.sub.3N (200 .mu.L), the resultingsolution was heated in a CEM microwave reactor at 110.degree. C.for 1 hr. The reaction was cooled down to RT, and purified bypreparative RP-HPLC method A to give:
Isomer 1 as TFA salt (1.22 mg); LCMS method B: R.sub.t=0.83 min;(M+H).sup.+=571.4. .sup.1H NMR (MeOH-d4): .delta. 8.49 (s, 1H),7.92 (s, 1H), 7.70 (m, 2H), 7.47 (d, J=6.8 Hz, 2H), 7.19 (m, 2H),7.07 (br, 1H), 4.04-3.66 (m, 4H), 3.61 (m, 2H), 3.26 (m, 1H), 3.08(s, 2H), 2.28-1.76 (m, 8H), 1.49 (m, 3H), 1.40 (m, 3H), 1.17 (d,J=7.6 Hz, 3H), 1.10 (m, 3H); and
Isomer 2 as TFA salt (1.36 mg); LCMS method B: R.sub.t=0.89 min;(M+H).sup.+=571.4. .sup.1H NMR (MeOH-d4): .delta. 8.36 (s, 1H),7.86 (br, 1H), 7.57 (d, J=8 Hz, 2H), 7.32 (d, J=7.6 Hz, 2H), 7.04(d, J=7.6 Hz, 2H), 6.96 (br, 1H), 3.80-3.48 (m, 5H), 3.18 (m, 1H),2.94 (s, 2H), 2.05 (m, 2H), 1.86-1.58 (m, 4H), 1.49 (m, 2H), 1.34(d, J=6.8 Hz, 3H), 1.24 (d, J=6. 4 Hz, 3H), 1.02 (d, J=6.8 Hz, 3H),0.94 (d, J=6.8 Hz, 3H).
Examples 23A-23C
5-fluoro-2-((4-(7-hydroxy-8-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)m-ethyl)-2-azaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-N,N-diisopropylbenzam-ide (Isomers 1-3)
##STR00191##
Step 1.tert-butyl-7-oxo-8-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)me-thylene)-2-azaspiro[4.4]nonane-2-carboxylate
##STR00192##
To a solution of tert-butyl7-oxo-2-azaspiro[4.4]nonane-2-carboxylate (0.28 g, 1.17 mmol) and2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbaldehyde (Intermediate40, 0.23 g, 1.29 mmol) in DMSO (3 mL), there was added L-proline(40 mg), 3-ethyl-1-methyl-1H-imidazol-3-ium 2,2,2-trifluoroacetate([EMIm][CF.sub.3COO]) (79 mg, 0.35 mmol) and H.sub.2O (0.32 g). Theresulting mixture was heated at 80.degree. C. for 4 days, cooled toRT, diluted with H.sub.2O (5 mL), and extracted with EtOAc(4.times.5 mL). The combined organic layers were concentrated, andthe residue was purified by silica gel column (0-4% MeOH/DCM) togivetert-butyl-7-oxo-8-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methylene-)-2-azaspiro [4.4]nonane-2-carboxylate (.about.190 mg, .about.42%,with the aldehyde starting material still present); LCMS method B:R.sub.t=1.16 min; (M-55).sup.+=328.3; .sup.1H NMR (MeOH-d4):.delta. 9.62 (br 1H), 9.46 (br, 1H), 7.40 (s, 1H), 7.18 (d, J=6.8Hz, 1H), 7.03 (d, J=6.8 Hz, 1H), 5.24 (s, 1H), 3.40 (m, 2H), 3.28,3.20 (two s, 2H), 2.88 (s, 2H), 2.40 (s, 2H), 1.80 (m, 2H), 1.4,1.40 (two s, 9H).
Step 2. tert-butyl7-hydroxy-8-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2-azaspi-ro[4.4]nonane-2-carboxylate and tert-butyl7-oxo-8-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2-azaspiro[4-.4]nonane-2-carboxylate
##STR00193##
To a solution oftert-butyl-7-oxo-8-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methylene-)-2-azaspiro [4.4]nonane-2-carboxylate (130 mg) in MeOH (10 mL),was added Pd--C (10 mg), and the solution was stirred at RT with aH.sub.2 balloon overnight. LC-MS showed a mixture of tert-butyl7-hydroxy-8-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2-azaspi-ro[4.4]nonane-2-carboxylate and tert-butyl7-oxo-8-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2-azaspiro[4-.4]nonane-2-carboxylate. The reaction mixture was filtered througha Celite pad, and solvent was removed under vacuum. The residue waspurified by a silica gel column (3-7% MeOH/DCM) to give tert-butyl7-oxo-8-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2-azaspiro[4-.4]nonane-2-carboxylate (.about.50 mg); LCMS method B: R.sub.t=1.17min; (M-55).sup.+=330.3; and tert-butyl7-hydroxy-8-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2-azaspi-ro[4.4]nonane-2-carboxylate (.about.80 mg); LCMS method B:R.sub.t=1.17 min; (M-55).sup.+=332.3.
Step 3.5-((8-hydroxy-2-azaspiro[4.4]nonan-7-yl)methyl)-1,3-dihydro-2H-ben-zo[d]imidazol-2-one
##STR00194##
To a solution of tert-butyl7-hydroxy-8-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2-azaspi-ro[4.4]nonane-2-carboxylate (20 mg, 0.052 mmol) in DCM (0.5 mL),was added TFA (0.2 mL) and the solution was stirred at RT for halfan h. The solvent was then removed to dryness to give a TFA salt of5-((8-hydroxy-2-azaspiro[4.4]nonan-7-yl)methyl)-1,3-dihydro-2H-benzo[d]im-idazol-2-one, which was used for the next step withoutpurification; LCMS method B: R.sub.t=0.47 min;(M+H).sup.+=288.3.
Step 4.5-fluoro-2-((4-(7-hydroxy-8-((2-oxo-2,3-dihydro-1H-benzo[d]imidazo-l-5-yl)methyl)-2-azaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-N,N-diisoprop-ylbenzamide (Isomers 1-3)
To a solution of the crude product from Step 3 in isopropanol (0.3mL), there was added2-((4-chloropyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide(Intermediate 41, 20 mg) and Et.sub.3N (150 .mu.L), and theresulting solution was heated in a CEM microwave reactor at110.degree. C. for 1 h. LC-MS showed three products att.sub.R=0.88, 0.90 and 0.95 min with a ratio of 1:1:5. The productswere isolated by preparative RP-HPLC method A to give:
Isomer 1 as a TFA salt (1.4 mg), LCMS method B: R.sub.t=0.88 min;(M+H).sup.+=603.5. .sup.1H NMR (MeOH-d4): .delta. 8.37 (s, 1H),7.68, 7.54 (two br, 1H), 7.10 (m, 3H), 6.84-6.72 (m, 3H), 4.08-3.94(m, 2H), 3.94-3.50 (m, 5H), 3.00-2.74 (m, 1H), 2.52-2.26 (m, 1H),2.14-1.78 (m, 5H), 1.68-1.30 (m, 6H), 1.24-1.02 (m, 6H), 1.02-0.82(m, 2H);
Isomer 2 as a TFA salt (0.82 mg), LCMS method B: R.sub.t=0.90 min;(M+H).sup.+=603.5. .sup.1H NMR (MeOH-d4): .delta. 8.33 (s, 1H),7.62, 7.50 (two br, 1H), 7.10 (m, 3H), 6.84-6.70 (m, 3H), 3.98-3.54(m, 6H), 3.52-3.34 (m, 1H), 3.02-2.92 (m, 1H), 2.78, 2.48 (two br,1H), 2.28 (m, 1H), 2.08-1.92 (m, 2H), 1.90-1.72 (m, 2H), 1.68-1.46(m, 2H), 1.34 (m, 3H), 1.28-0.84 (m, 7H); and
Isomer 3 as a TFA salt (5 mg), LCMS method B: R.sub.t=0.95 min;(M+H).sup.+=603.5. .sup.1H NMR (MeOH-d4): .delta. 8.35 (s, 1H),7.68-7.50 (m, 1H), 7.22-7.04 (m, 3H), 6.77 (m, 3H), 4.08-3.90 (m,2H), 3.90-3.56 (m, 4H), 3.56-3.32 (m, 1H), 2.76 (m, 1H), 2.45 (m,1H), 2.11 (m, 1H), 1.88-1.58 (m, 4H), 1.55-1.24 (m, 6H), 1.22-0.98(m, 6H), 0.92 (br, 1H), 0.84 (br, 1H).
Examples 24A-24B
2-((4-(7-amino-8-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2-az-aspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamid-e (Isomers 1-2)
##STR00195##
Step 1.tert-butyl-7-((tert-butylsulfinyl)imino)-8-((2-oxo-2,3-dihydro-1H--benzo[d]imidazol-5-yl)methyl)-2-azaspiro[4.4]nonane-2-carboxylate
##STR00196##
The title product was synthesized as a mixture of multiplediasteoroisomers according the procedure described in Examples23A-23C, Step 1, followed by Step 1 of Examples 250A-250B, startingwith tert-butyl7-oxo-8-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2-azaspiro[4-.4]nonane-2-carboxylate (see Examples 23A-23C, Step 2). The titleproduct was used for the next step without purification. LCMSmethod B: R.sub.t=1.29-1.32 min, multiple peaks;(M+H).sup.+=489.4.
Step 2. tert-butyl7-((tert-butylsulfinyl)amino)-8-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5--yl)methyl)-2-azaspiro[4.4]nonane-2-carboxylate
##STR00197##
To a solution of the residue from Step 1 in THF (5 mL), was addedNaBH.sub.4 (10 mg, 0.26 mmol), and 1 drop of water. The resultingsolution was stirred at RT for two h. The reaction was quenchedwith ice water and extracted with EtOAc. The combined organiclayers was concentrated under vacuum and the residue was purifiedby preparative-RF HPLC method A to give two fractions ofdiasteoroiosmers: Fraction 1 (5.8 mg, TFA salt): LC-MS method B:R.sub.t=1.26 min, (M+H).sup.+=491.4; Fraction 2 (18.8 mg, TFAsalt): LC-MS method B: R.sub.t=1.32 min, (M+H).sup.+=491.4.
Step 3.2-methyl-N-(8-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)--2-azaspiro[4.4]nonan-7-yl)propane-2-sulfinamide
##STR00198##
To a solution of tert-butyl7-((tert-butylsulfinyl)amino)-8-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5--yl)methyl)-2-azaspiro[4.4]nonane-2-carboxylate (18.8 mg, 0.038mmol, Fraction 2, Step 2) in DCM (3 mL), was added TFA (50 .mu.L)and the resulting solution was stirred at RT overnight. Et.sub.3Nwas then added to the solution to neutralize the acid. Uponremoving solvent, the residue was used for the next step withoutpurification.
Step 4.2-((4-(7-((tert-butylsulfinyl)amino)-8-((2-oxo-2,3-dihydro-1H-benz-o[d]imidazol-5-yl)methyl)-2-azaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5--fluoro-N,N-diisopropylbenzamide
##STR00199##
To a solution of the crude product from Step 3 in isopropanol (0.3mL) was added2-((4-chloropyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzami- de(Intermediate 41, 20 mg) and Et.sub.3N (100 .mu.L), and theresulting solution was heated in a CEM microwave reactor at110.degree. C. for 1 h. The solvent was removed to give the crudeproduct, which was used for the next step without purification;LCMS method B: R.sub.t=1.06 min, (M+H).sup.+=706.6.
Step 5.2-((4-(7-amino-8-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)meth-yl)-2-azaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropyl-benzamide (Isomers 1-2)
To the crude product from Step 4 in MeOH (2 mL) was added 6N HCl (2mL) and the resulting solution was stirred at RT overnight. LC-MSshowed two product at t.sub.r=0.65, 0.69 min with a ratio of 1:6;The products were isolated by preparative RP-HPLC method A to givetwo isomers.
Isomer 1 as a TFA salt (0.67 mg); LCMS method B: R.sub.t=0.65 min,(M+H).sup.+=602.5; .sup.1H NMR (MeOH-d4): .delta. 8.33, 8.31 (twos, 1H), 7.78, 7.71 (two br, 1H), 7.06 (m, 2H), 6.96 (m, 1H), 6.82(m, 1H), 6.76 (m, 2H), 3.78-3.62 (m, 3H), 3.56-3.40 (m, 2H),3.38-3.28 (m, 1H), 3.08-2.82 (m, 1H), 2.58-2.12 (m, 2H), 1.92-1.54(m, 4H), 1.36 (m, 6H), 1.22 (m, 1H), 1.06 (m, 6H), 1.02-0.88 (m,2H).
Isomer 2 as a TFA salt (4.24 mg); LCMS method B: R.sub.t=0.69 min,(M+H).sup.+=602.5. .sup.1H NMR (MeOH-d4): .delta. 8.34 (s, 1H),7.80 (br, 1H), 7.09 (m, 2H), 6.99 (m, 1H), 6.82 (m, 1H), 6.76 (m,2H), 3.84-3.62 (m, 3H), 3.58-3.42 (m, 2H), 3.36-3.26 (m, 1H),3.08-2.98 (m, 1H), 2.45-2.12 (m, 2H), 1.88-1.54 (m, 4H), 1.37 (m,6H), 1.22 (m, 1H), 1.05 (m, 6H), 0.95 (m, 2H).
Example 25
2-((4-(7-amino-8-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2-az-aspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamid-e (Isomer 3)
##STR00200##
The title compound was synthesized according to the procedure ofExamples 24A-24B, using Fraction 1 (5.8 mg) prepared at Step 2 ofExamples 24A-24B. LCMS method B: R.sub.t=0.69 min,(M+H).sup.+=602.5.
Examples 26A-26B
5-fluoro-2-((4-(8-(4-fluorobenzyl)-7-(2-hydroxyethyl)-2,7-diazaspiro[4.4]n-onan-2-yl)pyrimidin-5-yl)oxy)-N,N-diisopropylbenzamide (Isomers1-2)
##STR00201##
Step 1. Tert-butyl7-benzyl-3-oxo-2,7-diazaspiro[4.4]nonane-2-carboxylate
##STR00202##
To a solution of 7-benzyl-2,7-diazaspiro[4.4]nonan-3-one (500 mg,2.17 mmol) in DCM (15 mL) was added Boc.sub.2O (1.04 g, 4.8 mmol)followed by portionwise addition of DMAP (662 mg, 5.4 mmol) at RTand the mixture was stirred at RT for 2 days. The reaction wasquenched by addition of H.sub.2O (20 mL) and the aqueous phase wasextracted with EtOAc (30 mL). The organic layers were combined,dried over Na.sub.2SO.sub.4 and evaporated to afford crude product,which was purified by flash chromatography over silica gel elutingwith 70% EtOAc/Hexanes to afford 400 mg tert-Butyl7-benzyl-3-oxo-2,7-diazaspiro[4.4]nonane-2-carboxylate as acolorless oil (56% yield). LCMS Method A: t.sub.R=0.73 min,[M+H].sup.+=331.4.
Step 2. Tert-butyl((1-benzyl-3-(3-(4-fluorophenyl)-2-oxopropyl)pyrrolidin-3-yl)methyl)carba-mate
##STR00203##
At 0.degree. C., to a solution of tert-butyl7-benzyl-3-oxo-2,7-diazaspiro[4.4]nonane-2-carboxylate (280 mg,0.85 mmol) in dry THF (2 mL) was added 0.25 M(4-fluorobenzyl)magnesium chloride in Et.sub.2O (5.0 mL, 1.25 mmol)slowly under N.sub.2. The mixture was stirred for 1 h at 0.degree.C. then quenched by addition of H.sub.2O (10 mL). The mixture wasthen extracted with EtOAc (2.times.30 mL). The organic layers werewashed with brine, dried over Na.sub.2SO.sub.4 and evaporated toafford crude product, which was purified by flash chromatographyover silica gel eluting with 30% EtOAc/Hexanes to afford 240 mgtert-Butyl((1-benzyl-3-(3-(4-fluorophenyl)-2-oxopropyl)pyrrolidin-3-yl)methyl)carba-mate as a colorless oil (65% yield). LCMS Method A: t.sub.R=1.10min, [M+H].sup.+=441.4.
Step 3. tert-butyl7-benzyl-3-(4-fluorobenzyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate
##STR00204##
To a solution of tert-butyl((1-benzyl-3-(3-(4-fluorophenyl)-2-oxopropyl)pyrrolidin-3-yl)methyl)carbamate (240 mg, 0.55 mmol) in DCM (3 mL) was added TFA (0.5 mL)at RT and the reaction mixture was stirred for 1 h at RT and thenconcentrated under reduced pressure.
The resulting crude product was dissolved into DCM (3 mL) andneutralized with TEA, followed by addition of NaCNBH.sub.3 (39 mg,0.6 mmol) and the mixture was stirred at RT for 1 h. Boc.sub.2O(135 mg, 0.65 mmol) was added to the reaction mixture and stirredat RT for 4 h. The mixture was diluted with H.sub.2O (20 mL) andextracted with EtOAc (2.times.20 mL). The organic layers werecombined, washed with brine, dried over Na.sub.2SO.sub.4, filteredand concentrated under reduced pressure. The crude product waspurified by flash chromatography over silica gel eluting with 20%EtOAc/hexanes to afford 184 mg tert-butyl7-benzyl-3-(4-fluorobenzyl)-2,7-diazaspiro[4.4]nonane-2-carboxylateas a colorless oil (80% yield). LCMS Method A: t.sub.R=1.17 min,[M+H].sup.+=425.5.
Step 4. Tert-butyl3-(4-fluorobenzyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate
##STR00205##
To a solution of tert-butyl7-benzyl-3-(4-fluorobenzyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate(184 mg, 0.43 mmol) in MeOH (5 mL) was added Pd(OH).sub.2 on Carbon(5% dry basis, 123 mg, 43 .mu.mol). The mixture was stirred at RTunder a hydrogen balloon for 40 h and filtered through a celitepad. The residue was concentrated under reduced pressure. The crudeproduct was used directly for the next step reaction withoutfurther purification. LCMS Method A: t.sub.R=1.01 min,[M+H].sup.+=335.5.
Step 5. Tert-butyl7-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-3-(4-fluor-obenzyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate
##STR00206##
A solution of tert-butyl3-(4-fluorobenzyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (94 mg,0.28 mmol) and2-((4-chloropyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzami- de(Intermediate 41, 100 mg, 0.31 mmol) in .sup.iPrOH (2 mL) washeated in a microwave reactor at 120.degree. C. for 2 h. Aftercooling to RT, the mixture was diluted with H.sub.2O (10 mL) andextracted with EtOAc (3.times.15 mL). The organic layer was washedwith brine, dried over Na.sub.2SO.sub.4, and concentrated. Thecrude product was purified by flash chromatography over silica geleluting with 70% EtOAc/Hexanes to afford 127 mg tert-butyl7-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-3-(4-fluor-obenzyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate as a colorless oil(70% yield). LCMS Method A: t.sub.R=1.48 min,[M+H].sup.+=650.4.
Step 6.5-fluoro-2-((4-(8-(4-fluorobenzyl)-2,7-diazaspiro[4.4]nonan-2-yl)p-yrimidin-5-yl)oxy)-N,N-diisopropylbenzamide
##STR00207##
To a solution of tert-butyl7-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-3-(4-fluor-obenzyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (100 mg, 0.15mmol) in DCM (2 mL) was added TFA (0.4 mL) at RT. The reactionmixture was stirred for 1 h and neutralized with aqueousNaHCO.sub.3 solution. The mixture was then extracted with DCM(4.times.15 mL). The organic layers were combined, dried overNa.sub.2SO.sub.4, filtered and concentrated under reduced pressure.The crude product was purified by flash chromatography over silicagel eluting with 10% MeOH/DCM to afford 65 mg5-fluoro-2-((4-(8-(4-fluorobenzyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidi-n-5-yl)oxy)-N,N-diisopropylbenzamide as a colorless oil (80%yield). LCMS Method A: t.sub.R=0.92 min, [M+H].sup.+=550.5.
Step 6.2-((4-(7-(2-((tert-butyldimethylsilyl)oxy)ethyl)-8-(4-fluorobenzyl-)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisoprop-ylbenzamide
##STR00208##
To a solution of5-fluoro-2-((4-(8-(4-fluorobenzyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidi-n-5-yl)oxy)-N,N-diisopropylbenzamide (10 mg, 18 .mu.mol) and(2-bromoethoxy)(tert-butyl) dimethylsilane (7 mg, 27 .mu.mol) inDMF (0.5 mL) was added K.sub.2CO.sub.3 (7 mg, 45 .mu.mol) at RT.The reaction mixture was stirred at 50.degree. C. for 4 h andextracted with EtOAc (4.times.5 mL). The organic layers werecombined, dried over Na.sub.2SO.sub.4, filtered and concentratedunder reduced pressure. The crude product was used directly for thenext step reaction without further purification. LCMS Method A:t.sub.R=1.34 min, [M+H].sup.+=708.5.
Step 7.5-fluoro-2-((4-(8-(4-fluorobenzyl)-7-(2-hydroxyethyl)-2,7-diazaspi-ro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-N,N-diisopropylbenzamide(Isomers 1-2)
To a solution of crude2-((4-(7-(2-((tert-butyldimethylsilyl)oxy)ethyl)-8-(4-fluorobenzyl)-2,7-d-iazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenza-mide in THF (0.5 mL) was added TBAF in THF solution (1 M, 0.1 mL,0.1 .mu.mol) at RT. The reaction mixture was stirred at RT for 2 hand concentrated under reduced pressure. The crude product waspurified on a Gilson-HPLC to yield the title product as a mixtureof two racemates.
Isomer 1:
LCMS Method A: t.sub.R=0.93 min, [M+H].sup.+=594.3. .sup.1H NMR(CD.sub.3OD): .delta. 8.58 (s, 1H), 8.00 (s, 1H), 7.33-7.25 (m,5H), 7.27-7.09 (m, 2H), 3.97-3.88 (m, 8H), 3.68-3.61 (m, 2H),3.48-3.41 (m, 2H), 3.26-3.21 (m, 1H), 3.15-3.05 (m, 1H), 2.90-2.85(m, 1H), 2.15-2.04 (m, 4H), 1.55-1.52 (m, 3H), 1.39-1.37 (m, 3H),1.23-1.21 (m, 3H), 1.11-1.07 (m, 3H). .sup.19F NMR (CD.sub.3OD):.delta. -76.90, -77.38, -117.20.
Isomer 2:
LCMS Method A: t.sub.R=0.92 min, [M+H].sup.+=594.3. .sup.1H NMR(CD.sub.3OD): .delta. 8.56 (s, 1H), 8.00 (s, 1H), 7.33-7.31 (m,2H), 7.28-7.25 (m, 1H), 7.24-7.20 (m, 2H), 7.10-7.08 (m, 2H),3.90-3.81 (m, 8H), 3.62-3.53 (m, 2H), 3.48-3.41 (m, 2H), 3.24-3.13(m, 2H), 2.90-2.81 (m, 1H), 2.16-2.10 (m, 2H), 1.94-1.91 (m, 2H),1.53-1.51 (m, 3H), 1.29-1.27 (m, 3H), 1.21-1.19 (m, 3H), 1.11-1.07(m, 3H).
Example 27
6-((7-(5-(2-chloro-4-fluorophenoxy)pyrimidin-4-yl)-2-azaspiro[4.4]nonan-2--yl)methyl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one
##STR00209##
Step 1. tert-butyl7-(((trifluoromethyl)sulfonyl)oxy)-2-azaspiro[4.4]non-7-ene-2-carboxylate
##STR00210##
To a solution of LiHMDS (4 mL, 4 mmol, 1M in THF) in THF (10 mL,anhydrous) was added tert-butyl7-oxo-2-azaspiro[4.4]nonane-2-carboxylate (500 mg, 2 mmol) in THF(4 mL, anhydrous) dropwise at -78.degree. C. and the mixture wasstirred at -78.degree. C. for 1 h under N.sub.2. PhNTf.sub.2 (1.1g, 3 mmol) in THF (6 mL, anhydrous) was added and the reaction waswarmed to 12-21.degree. C. and stirred for 16 h under N.sub.2. Theresulting mixture was quenched by sat. aq. NH.sub.4Cl (30 mL) andextracted with EtOAc (3.times.30 mL). The organic layers werewashed with brine (30 mL), dried over Na.sub.2SO.sub.4, filteredand concentrated to give the crude residue. The residue waspurification by flash chromatography (SiO.sub.2, 1%.about.50%EtOAc/Petroleum ether) to give tert-butyl7-(((trifluoromethyl)sulfonyl)oxy)-2-azaspiro[4.4]non-7-ene-2-carboxylate(impure) as a colorless oil. Yield: 950 mg. .sup.1H NMR (MeOD-d4):.delta. 5.69 (s, 1H), 3.38-3.50 (m, 2H), 3.20-3.30 (m, 2H),2.65-2.80 (m, 2H), 1.90-2.10 (m, 3H), 1.77-1.85 (m, 1H), 1.46 (s,9H).
Step 2. tert-butyl7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-azaspiro[4.4]non-7-ene--2-carboxylate
##STR00211##
To a solution of tert-butyl7-(((trifluoromethyl)sulfonyl)oxy)-2-azaspiro[4.4]non-7-ene-2-carboxylate(950 mg, 2 mmol, 55% purity), and4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (760mg, 3 mmol) in dioxane (10 mL, anhydrous) was added toPd(dppf)Cl.sub.2 (73 mg, 0.11 mmol) and KOAc (390 mg, 4 mmol) underN.sub.2. The resulting mixture was stirred at 80.degree. C. for 16h under N.sub.2. The resulting mixture was concentrated to give thecrude residue. The residue was purified by flash chromatography(SiO.sub.2, 1%.about.100% EtOAc in petroleum ether) to givetert-butyl7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-azaspiro[4.4]non-7-ene--2-carboxylate (impure crude) as a colorless oil. Yield: 800 mg..sup.1H NMR (MeOD-d4): .delta. 6.27 (s, 1H), 3.38-3.50 (m, 2H),3.15-3.30 (m, 2H), 2.40-2.60 (m, 2H), 1.65-1.90 (m, 2H), 1.40-1.50(m, 9H), 1.26 (s, 12H), 0.80-0.95 (m, 2H).
Step 3. tert-butyl7-(5-(2-chloro-4-fluorophenoxy)pyrimidin-4-yl)-2-azaspiro[4.4]non-7-ene-2--carboxylate
##STR00212##
To a solution of 4-chloro-5-(2-chloro-4-fluorophenoxy)pyrimidine(Intermediate 10A, 50 mg, 0.2 mmol), tert-butyl7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-azaspiro[4.4]non-7-ene--2-carboxylate (140 mg, 0.4 mmol, 50% purity) in dioxane (2.5 mL)and H.sub.2O (0.5 mL) was added to Pd(dppf)Cl.sub.2 (15 mg, 0.02mmol) and Na.sub.2CO.sub.3 (42 mg, 0.4 mmol) under N.sub.2. Theresulting mixture was stirred at 80.degree. C. for 16 h underN.sub.2. The resulting mixture was diluted with water (10 mL) andextracted with EtOAc (3.times.20 mL). The organic layers werewashed with brine (30 mL), dried over Na.sub.2SO.sub.4, filteredand concentrated to give the residue. The residue was purified byprep-TLC (EtOAc:petroleum ether=2:1) to give tert-butyl7-(5-(2-chloro-4-fluorophenoxy)pyrimidin-4-yl)-2-azaspiro[4.4]non-7-ene-2--carboxylate as a yellow oil. Yield: 50 mg. LCMS method C:R.sub.t=0.914 min; (M+H).sup.+=446.0, 448.0 (chlorineisotopes).
Step 4. tert-butyl7-(5-(2-chloro-4-fluorophenoxy)pyrimidin-4-yl)-2-azaspiro[4.4]nonane-2-ca-rboxylate
##STR00213##
To a solution of tert-butyl7-(5-(2-chloro-4-fluorophenoxy)pyrimidin-4-yl)-2-azaspiro[4.4]non-7-ene-2--carboxylate (50 mg, 0.11 mmol) in MeOH (5 mL, anhydrous) and THF(5 mL, anhydrous) was added PtO.sub.2 (5 mg, 10%). The resultingmixture was stirred at 25.degree. C. for about 16 h under H.sub.2(20 psi). The mixture was filtered and the filtrate wasconcentrated and purified by preparative TLC on silica gel(EtOAc:petroleum ether=1:5) to give tert-butyl7-(5-(2-chloro-4-fluorophenoxy)pyrimidin-4-yl)-2-azaspiro[4.4]nonane-2-ca-rboxylate as a yellow oil. Yield: 30 mg (61%). LCMS method C:R.sub.t=0.923 min, (M+H).sup.+=448.0, 450.0 (chlorineisotopes).
Step 5.7-(5-(2-chloro-4-fluorophenoxy)pyrimidin-4-yl)-2-azaspiro[4.4]nona-ne
##STR00214##
A solution of tert-butyl7-(5-(2-chloro-4-fluorophenoxy)pyrimidin-4-yl)-2-azaspiro[4.4]nonane-2-ca-rboxylate (30 mg, 0.07 mmol) in TFA-CH.sub.2Cl.sub.2 (3 mL,V:V=1:4) was stirred at 10-21.degree. C. for about 3 h. The mixturewas then concentrated. The resulting mixture was adjusted to pH 8with sat. aq. NaHCO.sub.3 and extracted with CH.sub.2Cl.sub.2(2.times.20 mL). The combined organic layers were washed with brine(10 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated togive7-(5-(2-chloro-4-fluorophenoxy)pyrimidin-4-yl)-2-azaspiro[4.4]nonaneas a yellow oil, which was used for next step directly withoutfurther purification. Yield: 30 mg. LCMS method C: R.sub.t=0.642min; (M+H).sup.+=348.0, 350.0 (chlorine isotopes).
Step 6.6-((7-(5-(2-chloro-4-fluorophenoxy)pyrimidin-4-yl)-2-azaspiro[4.4]-nonan-2-yl)methyl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one
To a solution of7-(5-(2-chloro-4-fluorophenoxy)pyrimidin-4-yl)-2-azaspiro[4.4]nonane(30 mg, 0.07 mmol, crude) and1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbaldehyde (12mg, 0.07 mmol,) in MeOH (3 mL, anhydrous) was added NaBH.sub.3CN(22 mg, 0.35 mmol). The resulting mixture was stirred at10-21.degree. C. for about 16 h. The mixture was concentrated andpurified by acidic preparative RP-HPLC method A to give6-((7-(5-(2-chloro-4-fluorophenoxy)pyrimidin-4-yl)-2-azaspiro[4.4]nonan-2--yl)methyl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one (TFA salt) as awhite solid. Yield: 15 mg. LCMS method E: R.sub.t=0.902 min;(M+H).sup.+=508.3, 510.3 (chlorine isotopes). .sup.1H NMR(MeOD-d4): .delta. 8.70-8.85 (m, 1H), 7.99 (d, J=5.2 Hz, 1H),7.35-7.50 (m, 1H), 7.10-7.35 (m, 5H), 4.35-4.50 (m, 2H), 3.80-3.95(m, 1H), 3.35-3.70 (m, 6H), 3.20-3.30 (m, 1H), 1.75-2.40 (m, 8H)..sup.19F NMR (MeOD-d4): .delta. -77.02, -116.39.
Example 28
5-((7-(3-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyridin-4-yl)-2,7--diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one
##STR00215##
Step 1. 4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenol
##STR00216##
To a solution of 2-bromo-4-fluorophenol (650 mg, 3.40 mmol) indioxane (15 mL) and H.sub.2O (3 mL) was added(4-isopropylpyrimidin-5-yl)boronic acid (622 mg, 3.74 mmol),Pd(dppf)Cl.sub.2 (125 mg, 0.17 mmol) and Na.sub.2CO.sub.3 (720 mg,6.55 mmol). The resulting mixture was degassed with N.sub.2 andstirred at 90.degree. C. in an oil bath under N.sub.2 for about 20h. The reaction mixture was concentrated under reduced pressure toremove dioxane and the resulting residue was diluted with EtOAc (20mL). The suspension was filtered through a short pad of silica gel.The filtrate was diluted with EtOAc (20 mL) and water (20 mL). Theorganic layer was separated, washed with brine (2.times.30 mL) andconcentrated under reduced pressure. The residue was purified bycolumn chromatography on silica gel (petroleum ether:EtOAc=10:1 to1:1) to give 4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenol as ayellow solid. Yield: 300 mg. LCMS method C: R.sub.t=0.705 min;(M+H).sup.+=233.1.
Step 2. tert-butyl 7-(3-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy) pyridin-4-yl)-2, 7-diazaspiro [4.4]nonane-2-carboxylate
##STR00217##
To a solution of 4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenol (250mg, 1.08 mmol) in DMSO (25 mL) was added tert-butyl7-(3-bromopyridin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate(412 mg, 1.08 mmol), CuI (206 mg, 1.08 mmol), 2-picolinic acid (266mg, 2.16 mmol) and K.sub.3PO.sub.4 (916 mg, 4.32 mmol). Theresulting mixture was purged with N.sub.2 for 10 min and stirred at110.degree. C. in an oil bath under N.sub.2 for about 24 h. Thereaction mixture was diluted with water (30 mL) and extracted withEtOAc (2.times.30 mL). The organic layers were washed with brine(3.times.40 mL), dried over anhydrous Na.sub.2SO.sub.4, filteredand concentrated under reduced pressure. The residue was purifiedby preparative TLC (EtOAc) to give tert-butyl7-(3-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyridin-4-yl)-2,7-dia-zaspiro[4.4]nonane-2-carboxylate as a yellow solid. Yield: 25 mg.LCMS method C: R.sub.t=0.747 min; (M+H).sup.+=534.1.
Steps 3-4. 5-((7-(3-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyridin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol-2-(3H)-one
Steps 3 and 4 were performed as described in Example 1, Steps 4-5.LCMS method C: R.sub.t=1.190 min; (M+H).sup.+=580.3. .sup.1H NMR(MeOD-d4): .delta. 9.12 (s, 1H), 8.67 (s, 1H), 7.91-8.10 (m, 2H),7.10-7.38 (m, 6H), 6.89 (s, 1H), 4.40-4.48 (m, 2H), 3.37-3.87 (m,8H), 3.00-3.14 (m, 1H), 1.99-2.25 (m, 4H), 1.11-1.29 (m, 6H)..sup.19F NMR (MeOD-d4): .delta. -118.50, -76.93.
Example 29
5-((7-(5-(2-(3-cyclopropyl-1-methyl-6-oxo-1,6-dihydropyridin-2-yl)-4-fluor-ophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro--2H-benzo[d]imidazol-2-one (Racemic Mixture)
##STR00218##
Step 1. 2-chloro-3-cyclopropyl-6-methoxypyridine
##STR00219##
To a round bottom flask was added3-bromo-2-chloro-6-methoxypyridine (10.57 g), cyclopropyl boronicacid (4.28 g), palladium acetate (533 mg), tricyclohexylphosphine(1.33 g) and potassium phosphate (35.2 g). To this solid mixturewas added toluene:H.sub.2O (158 mL; 9:1 ratio). The heterogeneousmixture was purged with a nitrogen stream for 1 min and then washeated at reflux overnight. The reaction mixture was diluted withEtOAc (100 mL) and water (100 mL). The phases were separated andthe aqueous phase was back extracted twice with ethyl acetate (100mL each). The combined organic phases were dried over magnesiumsulfate and the crude residue was purified by flash chromatography(ethyl acetate/hexanes as the eluents) yielding 8.6 grams of2-chloro-3-cyclopropyl-6-methoxypyridine as a colorless oil. LCMSmethod A: R.sub.t=0.61 min; (M+H).sup.+=222.2, 224.2. .sup.1H NMR(CD.sub.3OD): .delta. 8.45 (s, 1H), 8.33 (s, 1H), 3.90-4.00 (m,2H), 3.70-3.80 (m, 2H), 3.20-3.55 (m, 4H), 1.80-2.0 (m, 4H), 1.27(s, 9H).
Step 2. 6-chloro-5-cyclopropylpyridin-2(1H)-one
##STR00220##
To a round bottom flask was added2-chloro-3-cyclopropyl-6-methoxypyridine (15.6 g) and acetonitrile(170 mL). To this solution was added chlorotrimethylsilane (21.6mL) followed by sodium iodide (25.6 g,). The heterogenous solutionwas heated at 50.degree. C. for 3 h. Methanol (40 mL) was thenadded to quench the reaction and the volatiles were removed undervacuum. Dichloromethane was added (250 mL) and the solution wasstirred for 30 min. The solids were precipitated, filtered out, andthe filtrate was concentrated. The crude residue was purified byflash chromatography (120 g SiO.sub.2, MeOH/CH.sub.2Cl.sub.2 as theeluents yielding a light brown oil (14 g). LCMS method A:R.sub.t=0.0.54 min; (M+H).sup.+=222.2, 224.2 .sup.1H NMR(CDCl.sub.3): .delta. 7.19 (d, J=8.4 Hz, 1H), 6.59 (d, J=8.0 Hz,1H), 3.93 (s, 3H), 1.95-2.10 (m, 1H), 0.90-1.05 (m, 2H), 0.55-0.65(m, 4H).
Step 3. 6-chloro-5-cyclopropyl-1-methylpyridin-2(1H)-one
##STR00221##
To a round bottom flask was added6-chloro-5-cyclopropylpyridin-2(1H)-one (7.9 g), potassiumcarbonate (12.9 g), lithium bromide (8.12 g) and tetrabutylammonium bromide (1.5 g). To this solid mixture was addedtoluene:H.sub.2O (156 mL, 100:1 ratio) followed by methyl iodide(14.6 mL) and the heterogenous mixture was heated at 50.degree. C.The reaction mixture was diluted with EtOAc and washed with 1M HCl.The organic phase was dried over MgSO.sub.4 and concentrated. Thecrude material was purified by flash chromatography (120 gSiO.sub.2, MeOH/CH.sub.2Cl.sub.2 as the eluents) yielding 4.5 g of6-chloro-5-cyclopropyl-1-methylpyridin-2(1H)-one as a light yellowoil. LCMS method A: R.sub.t=0.0.63 min; (M+H).sup.+=222.2,224.2
Step 4.5-cyclopropyl-6-(5-fluoro-2-hydroxyphenyl)-1-methylpyridin-2(1H)-o-ne
##STR00222##
To a 100 mL round bottom flask was added(5-fluoro-2-hydroxyphenyl)boronic acid (852 mg), Sphos palladacyleGen 2 (39 mg), potassium fluoride (951 mg), and6-chloro-5-cyclopropyl-1-methylpyridin-2(1H)-one (500 mg). To thissolid mixture was added dioxane (8 mL) and water (2 mL). Thesolution was purged with N.sub.2 for 1 min and then heated atreflux for 2 h. Toluene:EtOAc (30 mL, 1:1 ratio) was added,followed by water (30 mL). The solid were filtered out and rinsedwith 15 mL of toluene:EtOAc (1:1), Yielding 581 mg of the desiredproduct. LC/MS (16 min method)--R.sub.t=5.40 min.; M+H=260.56 1HNMR (d4-MeOH)--7.27 (d, 1H), 7.11 (dd, 1H), 6.99-6.3 (m, 2H), 6.55(d, 1H), 3.32 (s, 3H), 1.40 (m, 1H), 0.71-0.66 (m, 1H), 0.49-0.60(m, 3H) ppm.
Steps 5-7.5-((7-(5-(2-(3-cyclopropyl-1-methyl-6-oxo-1,6-dihydropyridin-2--yl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)--1,3-dihydro-2H-benzo[d]imidazol-2-one
The title product was prepared as described in Steps 2-4 of Example28. LC/MS method G R.sub.t=3.15 min.; M+H=608.64. .sup.1H NMR(d4-MeOH) 8.21 (s, 1H), 7.75 (s, 1H), 7.30-7.34 (m, 2H), 7.15 (m,1H), 6.97-7.06 (m, 4H), 6.54 (d, 1H), 3.57-3.69 (m, 4H), 3.42-3.52(m, 2H), 3.31 (d, 3H), 2.72 (bm, 2H), 2.55 (bm, 2H), 1.89 (m, 2H),1.79 (m, 2H), 1.28 (m, 1H), 0.75 (m, 1H), 0.66 (m, 1H), 0.55 (m,1H), 0.48 (m, 1H) ppm.
Examples 29A-29B
5-((7-(5-(2-(3-cyclopropyl-1-methyl-6-oxo-1,6-dihydropyridin-2-yl)-4-fluor-ophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro--2H-benzo[d]imidazol-2-one (Isomers 1-2)
##STR00223##
The compound of Example 29 was separated by SFC method A to affordtwo isomers.
Example 29A (Isomer 1)
.sup.1H NMR (CD.sub.3OD): .delta. 8.24 (d, J=5.2 Hz, 1H), 7.77 (s,1H), 7.30-7.40 (m, 2H), 7.10-7.20 (m, 1H), 6.95-7.07 (m, 4H),6.50-6.60 (m, 1H), 3.40-3.70 (m, 6H), 3.30-3.40 (m, 3H), 2.60-2.70(m, 2H), 2.40-2.50 (m, 2H), 1.75-1.95 (m, 4H), 1.20-1.35 (m, 1H),0.40-0.85 (m, 4H). .sup.19F NMR: (CD.sub.3OD 400 MHz): .delta.-119.20.about.-119.12. SFC: t.sub.R=17.556 min, EE=98.93%.ROTATION: OR .degree.Arc=0.389.
Example 29B (Isomer 2)
.sup.1H NMR (CD.sub.3OD): .delta. 8.24 (d, J=5.2 Hz, 1H), 7.77 (s,1H), 7.30-7.40 (m, 2H), 7.10-7.20 (m, 1H), 7.00-7.07 (m, 4H),6.50-6.60 (m, 1H), 3.50-3.70 (m, 6H), 3.30-3.40 (m, 3H), 2.60-2.75(m, 2H), 2.40-2.50 (m, 2H), 1.75-1.95 (m, 4H), 1.20-1.35 (m, 1H),0.45-0.85 (m, 4H). .sup.19F NMR: (CD.sub.3OD): .delta.-119.21.about.-119.13. SFC: t.sub.R=14.363 min, EE=98.46%.
Example 30
N-(5-fluoro-2'-isopropyl-[1,1'-biphenyl]-2-yl)-4-(6-((tetrahydro-2H-pyran--4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-amine
##STR00224##
The title product was synthesized by the method described forExample 28. In Step 1, 2-bromo-4-fluoroaniline and 2-isopropylphenyl boronic acid were utilized. In Step 2, tert-butyl2,6-diazaspiro[3.3]heptane-2-carboxylate was utilized. In Step 5,tetrahydro-2H-pyran-4-carbaldehyde was utilized. LCMS method A:R.sub.t=0.96 min; (M+H).sup.+=500. .sup.1H NMR (CD.sub.3OD).delta.: 8.00 (d, J=6.4 Hz, 1H), 7.77 (s, 1H), 7.49-7.43 (m, 2H),7.31-7.23 (m, 2H), 7.02 (s, 1H), 6.88 (d, J=7.2 Hz, 1H), 6.64-6.57(m, 2H).
Example 31
2-(5-((4',5-difluoro-2'-(2-fluoropropan-2-yl)-[1,1'-biphenyl]-2-yl)oxy)pyr-imidin-4-yl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]hepta-ne
##STR00225##
Step 1. methyl 2-bromo-5-fluorobenzoate
##STR00226##
To a solution of 2-bromo-5-fluorobenzoic acid (4.00 g, 18.26 mmol)in MeOH (120 mL, anhydrous) was added SOCl.sub.2 (3.26 g, 27.40mmol) dropwise at 0.degree. C. and the mixture was heated at68.degree. C. for 18 h. TLC (petroleum ether:EtOAc=5:1) confirmedthe desired product. The mixture was concentrated and the residuewas mixed with EtOAc (200 mL), washed by NaHCO.sub.3 (150 mL),brine (150 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered andconcentrated to give methyl 2-bromo-5-fluorobenzoate as a colorlessoil. Yield: 2.7 g LCMS method C: R.sub.t=0.77 min.
Step 2: 2-(2-bromo-5-fluorophenyl)propan-2-ol
##STR00227##
To a solution of 2-bromo-5-fluorobenzoate (2.70 g, 11.59 mmol) inTHF (85 mL, anhydrous) at 0.degree. C. under N.sub.2 was addedMeMgBr (9.66 mL, 28.97 mmol, 3.0 M in Et.sub.2O) dropwise, and themixture was stirred at 23-28.degree. C. for 4 h. The mixture wasquenched by aq. sat. NH.sub.4Cl (80 mL) and extracted by EtOAc (60mL). The organic layer was washed with brine (40 mL), dried overanhydrous Na.sub.2SO.sub.4, filtered and concentrated. The residuewas purified by ISCO column chromatography on silica gel (13% EtOAcin petroleum ether) to give 2-(2-bromo-5-fluorophenyl)propan-2-olas a colorless oil. Yield: 2.5 g (94%). .sup.1H NMR (CDCl.sub.3):.delta. 7.42-7.57 (m, 2H), 6.77-6.88 (m, 1H), 1.75 (s, 6H).
Step 3. 1-bromo-4-fluoro-2-(2-fluoropropan-2-yl)benzene
##STR00228##
To a solution of 2-(2-bromo-5-fluorophenyl)propan-2-ol (2.54 g,10.90 mmol) at -78.degree. C. was added DAST (2.28 g, 14.17 mmol)dropwise. The resulting mixture was stirred at 21-27.degree. C. for18 h. The mixture was quenched by aq. sat. NH.sub.4Cl (50 mL),extracted by EtOAc (50 mL), washed by brine (50 mL), dried overanhydrous Na.sub.2SO.sub.4, filtered and concentrated. Theresulting residue was purified by ISCO column chromatography (5%EtOAc in petroleum ether) to give1-bromo-4-fluoro-2-(2-fluoropropan-2-yl)benzene as a colorless oil.Yield: 2.2 g. .sup.1H NMR (CDCl.sub.3): .delta. 7.49-7.56 (m, 1H),7.40 (dd, J=10.5, 3.0 Hz, 1H), 6.81-6.90 (m, 1H), 1.88 (s, 3H),1.82 (s, 3H).
Step 4.4',5-difluoro-2'-(2-fluoropropan-2-yl)-[1,1'-biphenyl]-2-ol
##STR00229##
A solution of 1-bromo-4-fluoro-2-(2-fluoropropan-2-yl)benzene (400mg, 1.70 mmol), (5-fluoro-2-hydroxyphenyl)boronic acid (316 mg,2.04 mmol) and K.sub.3PO.sub.4 (720 mg, 3.40 mmol) in dioxane (9mL) and H.sub.2O (3 mL) was bubbled with N.sub.2 for 1 min andSPhos Palladacycle (62 mg, 0.086 mmol) was then added. Theresulting mixture was heated under a microwave at 115.degree. C.for 0.5 h. The mixture was diluted by EtOAc (30 mL) and H.sub.2O(30 mL). The organic layer was washed with brine (30 mL), driedover anhydrous Na.sub.2SO.sub.4, filtered and concentrated. Theresidue was purified by preparative TLC on silica gel (petroleumether:EtOAc=5:1) to give4',5-difluoro-2'-(2-fluoropropan-2-yl)-[1,1'-biphenyl]-2-ol as alight yellow gel. Yield: 380 mg. LCMS method A: R.sub.t=1.070 min;(M+H).sup.+=247.1.
Step 5. tert-butyl6-(5-((4',5-difluoro-2'-(2-fluoropropan-2-yl)-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate
##STR00230##
To a solution of tert-butyl6-(5-iodopyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate(231 mg, 0.58 mmol) in DMSO (6 mL) was bubbled N.sub.2 for 1 minand a solution of4',5-difluoro-2'-(2-fluoropropan-2-yl)-[1,1'-biphenyl]-2-ol (183mg, 0.69 mmol) in DMSO (2 mL) was then added. The resulting mixturewas heated at 110.degree. C. for 22 h. The mixture was then dilutedby EtOAc (25 mL) and H.sub.2O (25 mL). The organic layer was washedby brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filteredand concentrated. The residue was purified by basic prep-HPLC togive tert-butyl6-(5-((4',5-difluoro-2'-(2-fluoropropan-2-yl)-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate as acolorless gel. Yield: 90 mg. LCMS method C: R.sub.t=0.808 min;(M+H).sup.+=541.2.
Step 6.2-(5-((4',5-difluoro-2'-(2-fluoropropan-2-yl)-[1,1'-biphenyl]-2-yl-)oxy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane
##STR00231##
To a solution of tert-butyl6-(5-((4',5-difluoro-2'-(2-fluoropropan-2-yl)-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (40 mg,0.09 mmol) in DCM (2 mL, anhydrous) cooled to 0.degree. C. wasadded TFA (0.25 mmol). The mixture was stirred at 0.degree. C. for4 h. The mixture was quenched by aq. sat. NaHCO.sub.3 (5 mL). ThenDCM (20 mL) was added, the organic layer was separated, dried overanhydrous Na.sub.2SO.sub.4, filtered and concentrated to give thecrude product of2-(5-((4',5-difluoro-2'-(2-fluoropropan-2-yl)-[1,1'-biphenyl]-2-yl)oxy)py-rimidin-4-yl)-2,6-diazaspiro[3.3]heptane as a light yellow gel,which was directly used in the next step. Yield: 44 mg
Step 7.2-(5-((4',5-difluoro-2'-(2-fluoropropan-2-yl)-[1,1'-biphenyl]-2-yl-)oxy)pyrimidin-4-yl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[-3.3]heptanes
To a solution of2-(5-((4',5-difluoro-2'-(2-fluoropropan-2-yl)-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane (44 mg, 0.10 mmol,crude) and tetrahydro-2H-pyran-4-carbaldehyde (15 mg, 0.13 mmol) inMeOH (2 mL, anhydrous) was added NaBH.sub.3CN (12 mg, 0.20 mmol)and the mixture was stirred at 20-25.degree. C. for 17 h. LCMSshowed the desired product was produced in .about.30% yield, and abyproduct was also produced in .about.32% yield. The mixture wasconcentrated, and the residue was purified by basic RP-HPLC methodD to give2-(5-((4',5-difluoro-2'-(2-fluoropropan-2-yl)-[1,1'-biphenyl]-2-yl)oxy)py-rimidin-4-yl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]hept-anes as a colorless gel. Yield: 6.7 mg. LCMS method C: R.sub.t=0.88min; (M+H).sup.+=539.2. .sup.1H NMR (CD.sub.3OD): .delta. 8.15 (s,1H), 7.61 (s, 1H), 7.25 (dd, J=10.8, 2.4 Hz, 1H), 7.04-7.20 (m,4H), 7.00 (dd, J=9.2, 4.8 Hz, 1H), 4.14-4.22 (m, 4H), 3.93 (dd,J=11.2, 4.0 Hz, 2H), 3.35-3.45 (m, 6H), 2.38 (d, J=6.4 Hz, 2H),1.57-1.66 (m, 8H), 1.19-1.33 (m, 2H). .sup.19F NMR (CD.sub.3OD):.delta. -115.50, -121.33, -132.73.
Example 32
5-fluoro-N-isopropyl-2-((4-(6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diaza-spiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)benzenesulfonamide
##STR00232##
Step 1. tert-butyl6-(5-(2-(benzylthio)-4-fluorophenoxy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]h-eptane-2-carboxylate
##STR00233##
A mixture of tert-butyl6-(5-(2-bromo-4-fluorophenoxy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane--2-carboxylate (Intermediate 20, 200 mg, 0.43 mmol), benzylmercaptan (0.06 mL, 0.52 mmol), Pd.sub.2(dba).sub.3 (39 mg, 10 mol%), Xantphos (50 mg, 20 mol %) and iPrNEt (0.15 mL, 0.86 mmol) indioxane was heated to 110.degree. C. in a CEM microwave for 2.5 h.The reaction mixture was then filtered through celite and thesolvents evaporated. The crude residue was purified using ISCOflash column chromatography (eluting with 100% EtOAc) to afford 210mg of tert-butyl6-(5-(2-(benzylthio)-4-fluorophenoxy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]h-eptane-2-carboxylate as a yellow solid (96%). LCMS method B:R.sub.t=1.544 min; (M+H).sup.+=509.6.
Step 2. tert-butyl6-(5-(2-(chlorosulfonyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,6-diazaspiro[3-.3]heptane-2-carboxylate
##STR00234##
To a solution of tert-butyl6-(5-(2-(benzylthio)-4-fluorophenoxy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]h-eptane-2-carboxylate (50 mg, 0.10 mmol) in MeCN (2 mL), H.sub.2O(0.10 mL) and AcOH (0.10 mL) was added1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (39 mg, 0.20 mmol)at 0.degree. C. The reaction was warmed to RT and stirred for 2 h.EtOAc (5 mL) and H.sub.2O (5 mL) were then added for the workup.The EtOAc layer was separated, dried using Na.sub.2SO.sub.4, andevaporated. The crude residue was purified using ISCO flash columnchromatography (eluting with 10% MeOH in DCM) to afford 21 mg oftert-butyl6-(5-(2-(chlorosulfonyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,6-diazaspiro[3-.3]heptane-2-carboxylate. LCMS method B: R.sub.t=1.492 min;(M+H).sup.+=485.47 and 487.50
Step 3. tert-butyl6-(5-(4-fluoro-2-(N-isopropylsulfamoyl)phenoxy)pyrimidin-4-yl)-2,6-diazas-piro[3.3]heptane-2-carboxylate
##STR00235##
To a solution of tert-butyl6-(5-(2-(chlorosulfonyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,6-diazaspiro[3-.3]heptane-2-carboxylate (21 mg, 0.04 mmol) in DCM (2 mL) was addedpropan-2-amine (0.20 mL) at RT. After 1 h, the solvents wereremoved and the crude product was triturated with 50% EtOAc inhexanes to afford 15 mg of tert-butyl6-(5-(4-fluoro-2-(N-isopropylsulfamoyl)phenoxy)pyrimidin-4-yl)-2,6-diazas-piro[3.3]heptane-2-carboxylate (75%). LCMS method B: R.sub.t=1.374min; (M+H).sup.+=508.64
Step 4.2-((4-(2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro--N-isopropylbenzenesulfonamide
##STR00236##
To a solution of tert-butyl6-(5-(4-fluoro-2-(N-isopropylsulfamoyl)phenoxy)pyrimidin-4-yl)-2,6-diazas-piro[3.3]heptane-2-carboxylate (15 mg) in DCM (3 mL) was added TFA(1 mL) at RT. The reaction stirred for 30 min at RT and thesolvents were then removed to afford2-((4-(2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isop-ropylbenzenesulfonamide TFA salt. The material was mixed with DCMand Et.sub.3N (0.10 mL) was added. Upon complete dissolution of thematerial, the solvents were removed to afford the product as thefree base. This crude material was used directly for the next stepwithout further purification.
Step 5.5-fluoro-N-isopropyl-2-((4-(6-((tetrahydro-2H-pyran-4-yl)methyl)-2-,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)benzenesulfonamide
To solution of crude2-((4-(2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isop-ropylbenzenesulfonamide and tetrahydro-2H-pyran-4-carbaldehyde (14mg, 0.12 mmol) in dichloroethane (2 mL, containing 1% AcOH) wasadded NaBH(OAc).sub.3 (25 mg, 0.12 mmol) at RT. The reactionmixture was stirred for 30 min and the reaction was confirmedcomplete by LCMS analysis. Evaporation of the solvent followed bypurification using a Gilson HPLC afforded5-fluoro-N-isopropyl-2-((4-(6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diaz-aspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)benzenesulfonamide TFAsalt. LCMS method B: R.sub.t=1.293 min; (M+H).sup.+=506.57. .sup.1HNMR (CD.sub.3OD): .delta. 8.55 (d, J=4.8 Hz, 1H), 7.77-7.75 (m,2H), 7.53-7.49 (m, 1H), 7.40-7.37 (m, 1H), 4.60-4.40 (m, 8H), 3.96(d, J=11.6 Hz, 2H), 3.57-3.54 (m, 1H), 3.44 (t, J=11.6 Hz, 2H),3.17 (d, J=6.8 Hz, 2H), 2.00-1.84 (m, 1H), 1.63 (d, J=11.6 Hz, 2H),1.40-1.32 (m, 2H), 1.17 (d, J=6.0 Hz, 6H).
Example 33
5-((7-(5-(4-fluoro-2-(2-methoxybutan-2-yl)phenoxy)pyrimidin-4-yl)-2,7-diaz-aspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one
##STR00237##
Step 1. tert-butyl7-(5-(4-fluoro-2-(2-hydroxybutan-2-yl)phenoxy)pyrimidin-4-yl)-2,7-diazasp-iro[4.4]nonane-2-carboxylate
##STR00238##
To a solution of tert-butyl7-(5-(2-bromo-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2--carboxylate (Intermediate 11, 53 mg, 0.11 mmol) and butan-2-one (5equiv.) in THF (2 mL) was added a 1.6 M solution of n-BuLi inhexanes (0.08 mL) at -78.degree. C. The reaction mixture was warmedto RT over 1 h and upon reaching RT, a saturated NH.sub.4Cl aqueoussolution (1 mL) was added in addition to EtOAc (5 mL) for theworkup. Purification of the crude residue using ISCO flash columnchromatography (eluting with 5% MeOH in DCM) gave 20 mg oftert-butyl7-(5-(4-fluoro-2-(2-hydroxybutan-2-yl)phenoxy)pyrimidin-4-yl)-2,7-diazasp-iro[4.4]nonane-2-carboxylate (38%). LCMS method B: R.sub.t=1.589min; (M+H).sup.+=487.62. .sup.1H NMR (CDCl.sub.3): .delta. 8.42 (s,1H), 7.76 (s, 1H), 7.36 (d, J=9.2 Hz, 1H), 6.90-6.86 (m, 1H),6.58-6.50 (m, 1H), 3.80-3.25 (m, 8H), 2.53-2.42 (m, 1H), 2.15-2.05(m, 1H), 1.95-1.82 (m, 5H), 1.65 (s, 3H), 1.45 (s, 9H), 0.84 (t,J=7.6 Hz, 3H).
Step 2.2-(2-((4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluo-rophenyl)butan-2-ol
##STR00239##
A 4 N solution of HCl in dioxane (2 mL) was added totert-butyl-7-(5-(4-fluoro-2-(2-hydroxybutan-2-yl)phenoxy)pyrimidin-4-yl)--2,7-diazaspiro[4.4]nonane-2-carboxylate (10 mg) at RT and thereaction mixture was stirred for 2 h. The solvents were removed toafford the product as the HCl salt. DCM (2 mL) and Et.sub.3N (0.10mL) were added to the product and the solvents were removed toafford crude2-(2-((4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoropheny-l)butan-2-ol as the free base which was used for the next stepwithout further purification.
Step 3.5-((7-(5-(4-fluoro-2-(2-methoxybutan-2-yl)phenoxy)pyrimidin-4-yl)--2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-on-e
To a solution of crude2-(2-((4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoropheny-l)butan-2-ol and2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbaldehyde (Intermediate40, 7 mg, 0.04 mmol) in MeOH (3 mL) was added NaBH.sub.3CN (8 mg,0.13 mmol) at RT and the reaction mixture was stirred for 15 h.Evaporation of the solvent followed by purification by RP-HPLCmethod A afforded5-((7-(5-(4-fluoro-2-(2-methoxybutan-2-yl)phenoxy)pyrimidin-4-yl-)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2--one TFA salt. LCMS method G: R.sub.t=4.01 min; (M+H).sup.+=547.62..sup.1H NMR (CD.sub.3OD): .delta. 8.52 (bs, 1H), 7.65 (m, 1H), 7.34(d, J=9.6 Hz, 1H), 7.21-7.18 (m, 2H), 7.13-7.10 (m, 3H), 4.43 (s,2H), 4.20-3.95 (m, 4H), 3.70-3.50 (m, 2H), 3.47-3.36 (m, 2H), 3.15(s, 3H), 2.34-2.05 (m, 4H), 1.96-1.87 (m, 2H), 1.58 (s, 3H), 0.76(t, J=7.6 Hz, 3H).
Example 34
5-((7-(5-(4-fluoro-2-(3-hydroxypentan-3-yl)phenoxy)pyrimidin-4-yl)-2,7-dia-zaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one
##STR00240##
Step 1. tert-butyl7-(5-(4-fluoro-2-(3-hydroxypentan-3-yl)phenoxy)pyrimidin-4-yl)-2,7-diazas-piro[4.4]nonane-2-carboxylate
##STR00241##
To a solution of tert-butyl7-(5-(2-bromo-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2--carboxylate (Intermediate 11, 106 mg, 0.22 mmol) and pentan-3-one(0.10 mL, 1.07 mmol) in THF (3 mL) was added a 1.6 M solution ofn-BuLi in hexanes (0.66 mL) at -78.degree. C. The reaction waswarmed to RT over 1 h. Upon reaching RT, a saturated NH.sub.4Claqueous solution (2 mL) was added in addition to EtOAc (8 mL) forthe workup. Purification of the crude residue using flash columnchromatography (eluting with 5% MeOH in DCM) gave 32 mg oftert-butyl-7-(5-(4-fluoro-2-(3-hydroxypentan-3-yl)phenoxy)pyrimidin-4-yl)--2,7-diazaspiro[4.4]nonane-2-carboxylate.
Step 2.3-(2-((4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluo-rophenyl)pentan-3-ol
##STR00242##
A 4 N solution of HCl in dioxane (2 mL) was added to tert-butyl7-(5-(4-fluoro-2-(3-hydroxypentan-3-yl)phenoxy)pyrimidin-4-yl)-2,7-diazas-piro[4.4]nonane-2-carboxylate (32 mg) at RT and the reactionmixture was stirred for 2 h. The solvents were then removed toafford the product as the HCl salt. DCM (2 mL) and Et.sub.3N (0.10mL) were added to the product and the solvents were removed toafford crude3-(2-((4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoropheny-l)pentan-3-ol as the free base which was used for the next stepwithout further purification.
Step 3.5-((7-(5-(4-fluoro-2-(3-hydroxypentan-3-yl)phenoxy)pyrimidin-4-yl)--2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-o-ne
To a solution of crude3-(2-((4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoropheny-l)pentan-3-ol from above and2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbaldehyde (Intermediate40, 20 mg, 0.12 mmol) in MeOH (3 mL) was added NaBH.sub.3CN (10 mg,0.16 mmol) at RT and the reaction mixture stirred for 4 h.Evaporation of the solvent followed by RP-HPLC method A afforded5-((7-(5-(4-fluoro-2-(3-hydroxypentan-3-yl)phenoxy)pyrimidin-4-yl)-2,7-di-azaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one.LCMS method G: R.sub.t=3.197 min; (M+H).sup.+=547.61. .sup.1H NMR(CD.sub.3OD): .delta. 8.52 (bs, 1H), 7.60 (m, 1H), 7.45 (dd, J=2.8,10.6 Hz, 1H), 7.21-7.18 (m, 2H), 7.11 (d, J=8.4 Hz, 2H), 7.05-6.96(m, 1H), 4.43 (s, 2H), 4.20-3.90 (m, 4H), 3.70-3.50 (m, 2H),3.48-3.33 (m, 2H), 2.34-1.90 (m, 6H), 1.89-1.80 (m, 2H), 0.78 (t,J=7.2 Hz, 6H).
Examples 35-36
2-(5-fluoro-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)--2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)phenyl)-N-methylcycloprop-ane carboxamide (Example 35) &5-((7-(5-(4-fluoro-2-(3-hydroxy-3-methylbutyl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol--2(3H)-one (Example 36)
##STR00243##
Step 1. tert-butyl7-(5-(4-fluoro-2-(3-methoxy-3-oxopropyl)phenoxy)pyrimidin-4-yl)-2,7-diaza-spiro[4.4]nonane-2-carboxylate
##STR00244##
To solution of (E)-tert-butyl7-(5-(4-fluoro-2-(3-methoxy-3-oxoprop-1-en-1-yl)phenoxy)pyrimidin-4-yl)-2-,7-diazaspiro[4.4]nonane-2-carboxylate (Example 37, Step 1, 450 mg,0.9 mmmol) in anhydrous MeOH (25 mL) was added Pd/C (45 mg). Themixture was stirred under H.sub.2 (30 psi) at 14-25.degree. C. for18 h. LCMS showed the reaction was complete. The mixture wasfiltered and concentrated to give tert-butyl7-(5-(4-fluoro-2-(3-methoxy-3-oxopropyl)phenoxy)pyrimidin-4-yl)-2,7-diaza-spiro[4.4]nonane-2-carboxylate as light yellow gel. Yield: 402 mg.LCMS method C: R.sub.t=0.749 min; (M+H).sup.+=501.2.
Step 2. tert-butyl7-(5-(4-fluoro-2-(3-hydroxy-3-methylbutyl)phenoxy)pyrimidin-4-yl)-2,7-dia-zaspiro[4.4]nonane-2-carboxylate
##STR00245##
To solution of tert-butyl7-(5-(4-fluoro-2-(3-methoxy-3-oxopropyl)phenoxy)pyrimidin-4-yl)-2,7-diaza-spiro[4.4]nonane-2-carboxylate (200 mg, 0.4 mmol) in anhydrous THF(5 mL) was added dropwise methylmagnesium bromide (0.53 mL, 1.6mmol) at 0.degree. C. for 10 min. The mixture was quenched withsaturation NH.sub.4Cl (aq.) (10 mL) and extracted with ethylacetate (20 mL.times.2). The combined organic layers were washedwith brine (30 mL.times.3), dry over Na.sub.2SO.sub.4 andconcentrated to purify by ISCO column on silica gel (100% DCM to 2%MeOH in DCM) to give tert-butyl7-(5-(4-fluoro-2-(3-hydroxy-3-methylbutyl)phenoxy)pyrimidin-4-yl)-2,7-dia-zaspiro[4.4]nonane-2-carboxylate as colorless oil. Yield: 180 mg.LCMS method C: R.sub.t=0.744 min; (M+H).sup.+=501.3.
Step 3. tert-butyl7-(5-(4-fluoro-2-(3-fluoro-3-methylbutyl)phenoxy)pyrimidin-4-yl)-2,7-diaz-aspiro[4.4]nonane-2-carboxylate
##STR00246##
To solution of tert-butyl7-(5-(4-fluoro-2-(3-hydroxy-3-methylbutyl)phenoxy)pyrimidin-4-yl)-2,7-dia-zaspiro[4.4]nonane-2-carboxylate (180 mg, 0.16 mmmol) in anhydrousCH.sub.2Cl.sub.2 (3 mL) was added DAST (70 mg, 0.43 mmol) at0.degree. C., dropwise over 5 min and the mixture was then stirredat 17-25.degree. C. for 2 h. LCMS showed desired compound and thatthe tert-butyl 7-(5-(4-fluoro-2-(3-hydroxy-3-methylbutyl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate wasconsumed completely. The mixture was poured into saturatedNH.sub.4Cl (aq) (5 mL) and extracted with DCM (10 mL.times.3). Thecombined organic layers were dried over Na.sub.2SO.sub.4,concentrated, and purified by acidic preparative HPLC to givetert-butyl7-(5-(4-fluoro-2-(3-fluoro-3-methylbutyl)phenoxy)pyrimidin-4-yl)-2,7-diaz-aspiro[4.4]nonane-2-carboxylate as colorless oil. Yield: 84 mg.LCMS method C: R.sub.t=0.790 min; (M+H).sup.+=503.3.
Step 4.2-(5-(4-fluoro-2-(3-fluoro-3-methylbutyl)phenoxy)pyrimidin-4-yl)-2-,7-diazaspiro[4.4]nonane
##STR00247##
To a solution of tert-butyl7-(5-(4-fluoro-2-(3-fluoro-3-methylbutyl)phenoxy)pyrimidin-4-yl)-2,7-diaz-aspiro[4.4]nonane-2-carboxylate (80 mg, 0.16 mmmol) in anhydrousCH.sub.2Cl.sub.2 (4 mL) was added TFA (0.5 mL) and the resultingmixture was stirred at 16-25.degree. C. for 2 h. The mixture wasthen poured into saturated NaHCO.sub.3 (aq) (10 mL) and extractedwith DCM (10 mL.times.2). The combined organic layers were driedover Na.sub.2SO.sub.4 and concentrated to give2-(5-(4-fluoro-2-(3-fluoro-3-methylbutyl)phenoxy)pyrimidin-4-yl)-2,7-diaz-aspiro[4.4]nonane as a colorless oil, which was used in the nextstep without further purification. Yield: 50 mg.
Step 5:5-((7-(5-(4-fluoro-2-(3-fluoro-3-methylbutyl)phenoxy)pyrimidin-4-y-l)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]200midazole-2(3H)-oneand5-((7-(5-(4-fluoro-2-(3-hydroxy-3-methylbutyl)phenoxy)pyrimidin-4-yl)--2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one
To a solution of2-(5-(4-fluoro-2-(3-fluoro-3-methylbutyl)phenoxy)pyrimidin-4-yl)-2,7-diaz-aspiro[4.4]nonane (50 mg, 0.12 mmmol) in anhydrous MeOH (2 mL) wasadded 2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbaldehyde(Intermediate 40, 22 mg, 0.14 mmol) and NaBH.sub.3CN (23 mg, 0.37mmol) and the solution was stirred at 50.degree. C. for 16 h. LCMSshowed the desired compound and that the2-(5-(4-fluoro-2-(3-fluoro-3-methylbutyl)phenoxy)pyrimidin-4-yl)-2,7-diaz-aspiro[4.4]nonane was consumed. The mixture was purified by basicpreparative RP-HPLC method D to give5-((7-(5-(4-fluoro-2-(3-fluoro-3-methylbutyl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol--2(3H)-one and5-((7-(5-(4-fluoro-2-(3-hydroxy-3-methylbutyl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol--2(3H)-one, both products as a white solid.
Example 35
LCMS method E: R.sub.t=0.618 min; (M+H).sup.+=610.3. .sup.1H NMR(CD.sub.3OD): .delta. 8.23 (d, J=5.6 Hz, 1H), 7.55 (s, 1H),7.05-7.12 (m, 1H), 7.03 (s, 1H), 6.95-7.01 (m, 2H), 6.85-6.95 (m,1H), 6.70-6.75 (m, 1H), 3.63-3.83 (m, 4H), 3.61 (s, 2H), 2.72-2.78(m, 2H), 2.60-2.70 (m, 2H), 2.48-2.59 (m, 2H), 1.78-1.98 (m, 6H),1.33 (d, J=21.6 Hz, 6H). .sup.19F NMR (CD.sub.3OD): .delta.-120.97, -140.72.
Example 36
LCMS method C: R.sub.t=0.586 min; (M+H).sup.+=547.3. .sup.1H NMR(CD.sub.3OD): .delta. 8.23 (s, 1H), 7.56 (s, 1H), 7.09 (dd, J=9.22.8 Hz, 1H), 7.05 (s, 1H), 6.95-7.00 (m, 2H), 6.85-6.95 (m, 1H),6.72 (dd, J=8.8 4.8 Hz, 1H), 3.69-3.83 (m, 4H), 3.65 (s, 2H),2.49-2.75 (m, 6H), 1.90-2.00 (m, 2H), 1.84 (t, J=6.8 Hz, 2H),1.67-1.76 (m, 2H), 1.20 (s, 6H). .sup.19F NMR (MeOD): .delta.-121.18.
Example 37
Methyl2-(5-fluoro-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)m-ethyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)phenyl)cyclopropan-ecarboxylate
##STR00248##
Step 1. (E)-tert-butyl7-(5-(4-fluoro-2-(3-methoxy-3-oxoprop-1-en-1-yl)phenoxy)pyrimidin-4-yl)-2-,7-diazaspiro[4.4]nonane-2-carboxylate
##STR00249##
To a solution of tert-butyl7-(5-(2-bromo-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2--carboxylate (Intermediate 11, 1.20 g, 2.44 mmol), methyl acrylate(838 mg, 9.74 mmol) and Et.sub.3N (246 mg, 2.44 mmol) in THF (24mL, anhydrous) was added P(o-Tol).sub.3 (292 mg, 0.96 mmol)followed by Pd.sub.2(dba).sub.3 (448 mg, 0.48 mmol) under N.sub.2.The mixture was heated in a sealed tube at 80.degree. C. for 17 h.The mixture was then diluted by EtOAc (300 mL) and H.sub.2O (30mL). The organic layer was filtered and dried over anhydrousNa.sub.2SO.sub.4, filtered and concentrated. The residue waspurified by RP-HPLC method D to give (E)-tert-butyl7-(5-(4-fluoro-2-(3-methoxy-3-oxoprop-1-en-1-yl)phenoxy)pyrimidin-4-yl)-2-,7-diazaspiro[4.4]nonane-2-carboxylate as a colorless gel. Yield:482 mg. LCMS method E: R.sub.t=1.005 min; (M+H).sup.+=499.3.
Step 2. tert-butyl7-(5-(4-fluoro-2-(2-(methoxycarbonyl)cyclopropyl)phenoxy)pyrimidin-4-yl)--2,7-diazaspiro[4.4]nonane-2-carboxylate
##STR00250##
To a suspension of NaH (43 mg, 1.07 mmol, 60% in mineral oil) inDMSO (3 mL) was added Me.sub.3SOI (383 mg, 1.74 mmol) underN.sub.2. Then a solution of (E)-tert-butyl7-(5-(4-fluoro-2-(3-methoxy-3-oxoprop-1-en-1-yl)phenoxy)pyrimidin-4-yl)-2-,7-diazaspiro[4.4]nonane-2-carboxylate (383 mg, 1.74 mmol) in DMSO(3 mL) and THF (3 mL) was added and the mixture was stirred at18-23.degree. C. for 4 h. The mixture was then quenched by 1N HCl(20 mL) and extracted with EtOAc (20 mL). The organic layer waswashed by H.sub.2O, dried over anhydrous Na.sub.2SO.sub.4, filteredand concentrated. The residue was purified by ISCO columnchromatography (EtOAc) to give tert-butyl7-(5-(4-fluoro-2-(2-(methoxycarbonyl)cyclopropyl)phenoxy)pyrimidin-4-yl)--2,7-diazaspiro [4.4]nonane-2-carboxylate as a colorless gel. Yield:300 mg. LCMS method E: R.sub.t=1.014 min; (M+H).sup.+=513.3.
Step 3: methyl 2-(2-((4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluorophenyl)cyclopropanecarboxylate
##STR00251##
To a solution of tert-butyl7-(5-(4-fluoro-2-(2-(methoxycarbonyl)cyclopropyl)phenoxy)pyrimidin-4-yl)--2,7-diazaspiro[4.4]nonane-2-carboxylate (300 mg, 0.58 mmol) in DCM(8 mL) was added HCl-dioxane (1.6 mL, 4 N). The mixture was stirredat 11-16.degree. C. for 4 h, at which time TLC (DCM:Methanol=10:1)showed the reaction was complete. The mixture was concentrated,mixed with DCM (20 mL), washed by sat. aq. NaHCO.sub.3 (20 mL),brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered andconcentrated to give methyl2-(2-((4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoropheny-l)cyclopropanecarboxylate as a colorless gel. Yield: 220 mg. LCMSmethod E: R.sub.t=0.846 min; (M+H).sup.+=413.3.
Step 4. methyl2-(5-fluoro-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)phenyl)cycloprop-anecarboxylate
To a solution of methyl2-(2-((4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoropheny-l)cyclopropanecarboxylate (110 mg, 0.27 mmol) and2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbaldehyde (Intermediate40, 53 mg, 0.33 mmol) in MeOH (2 mL) was added NaBH.sub.3CN (34 mg,0.54 mmol). The mixture was stirred at 11-16.degree. C. for 16 h.The mixture was concentrated, and purified by silica chromatography(DCM:MeOH=10:1) to give methyl2-(5-fluoro-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)--2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)phenyl)cyclopropanecarbo-xylate as a white solid. Yield: 80 mg. LCMS method E: R.sub.t=0.898min; (M+H).sup.+=599.3. .sup.1H NMR (CDCl.sub.3): .delta.9.95-10.20 (s, 2H), 8.32-8.39 (m, 1H), 7.68 (d, J=8.8 Hz, 1H), 7.10(d, J=6.0 Hz, 1H), 6.88-6.97 (m, 2H), 6.77-6.86 (m, 1H), 6.58-6.72(m, 2H), 3.51-3.79 (m, 9H), 2.41-2.81 (m, 5H), 1.75-1.98 (m, 5H),1.55-1.60 (m, 1H), 1.25-1.38 (m, 1H). .sup.19F NMR (CDCl.sub.3):.delta. -119.00.
Example 38
2-(5-fluoro-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)--2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)phenyl)-N-methylcycloprop-ane carboxamide
##STR00252##
To a solution of methyl2-(5-fluoro-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)--2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)phenyl)cyclopropanecarbo-xylate (Example 37, 36 mg, 0.064 mmol) in THF (0.5 mL) was addedMeNH.sub.2 (1 mL, water solution) and the mixture was stirred at14-18.degree. C. for 72 h. The mixture was then concentrated andthe residue was purified by RP-HPLC method A to give2-(5-fluoro-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)--2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)phenyl)-N-methylcyclopro-panecarboxamide (TFA salt) as a white solid. Yield: 22 mg. LCMSmethod E: R.sub.t=0.892 min; (M+H).sup.+=558.1. .sup.1H NMR(CD.sub.3OD): .delta. 8.49 (s, 1H), 7.46 (s, 1H), 7.17-7.28 (m,3H), 7.05-7.15 (m, 2H), 6.98 (d, J=7.2 Hz, 1H), 4.46 (s, 2H),4.05-4.20 (m, 4H), 3.35-3.78 (m, 4H), 2.66 (s, 3H), 2.45-2.50 (m,1H), 2.02-2.40 (m, 4H), 1.65 (s, 1H), 1.27-1.47 (m, 2H). .sup.19FNMR (CD.sub.3OD): .delta. -77.03, -116.71.
Example 39
6-((2-(5-(2-chloro-4-fluorophenoxy)pyrimidin-4-yl)-2,6-diazaspiro[3.4]octa-n-6-yl)methyl)-3,3-dimethylindolin-2-one
##STR00253##
A mixture of2-(5-(2-chloro-4-fluorophenoxy)pyrimidin-4-yl)-2,6-diazaspiro[3.4]octanesynthesized from Intermediate 24A by acid deprotection (80 mg, 0.19mmol, 81% purity), Intermediate 45 (54 mg, 0.29 mmol) andNaBH.sub.3CN (60 mg, 0.95 mmol) in MeOH (5 mL) was stirred at70.degree. C. (oil bath) for 18 h. The mixture was concentratedunder reduced pressure and the residue was purified by basicpreparative RP-HPLC method D to give6-((2-(5-(2-chloro-4-fluorophenoxy)pyrimidin-4-yl)-2,6-diazaspiro[3.4]octan-6-yl)methyl)-3,3-dimethylindolin-2-one as a white solid.Yield: 17 mg. LCMS method E: R.sub.t=0.584 min; (M+H).sup.+=508.0,510.0 (chlorine isotopes). .sup.1H NMR (CD.sub.3OD): .delta. 8.24(s, 1H), 7.57 (s, 1H), 7.41-7.42 (m, 1H), 7.20 (m, J=7.6 Hz, 1H),6.99-7.08 (m, 3H), 6.95 (s, 1H), 4.21-4.26 (m, 4H), 3.62 (s, 2H),2.81 (s, 2H), 2.66 (t, J=6.8 Hz, 2H), 2.16 (t, J=7.2 Hz, 2H), 1.34(s, 6H). .sup.19F NMR (CD.sub.3OD): .delta.-118.54.about.-117.89.
Example 40
2-(6-(5-(2-chloro-4-fluorophenoxy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]hepta-ne-2-carbonyl)-2,3-dihydro-1H-indene-5-sulfonamide
##STR00254##
Step 1. methyl 2,3-dihydro-1H-indene-2-carboxylate
##STR00255##
To a solution of 2,3-dihydro-1H-indene-2-carboxylic acid (8.40 g,51.85 mmol) in MeOH (220 mL, anhydrous) was added H.sub.2SO.sub.4(4.4 mL) at 0.degree. C. and the mixture was heated at 70.degree.C. for 17 h. The mixture was concentrated, diluted by EtOAc (80mL), washed by H.sub.2O (80 mL), dried over anhydrousNa.sub.2SO.sub.4, filtered and concentrated to give methyl2,3-dihydro-1H-indene-2-carboxylate (8.70 g, 95%) as a light yellowoil. Yield: 8.7 g. LCMS method E: R.sub.t=1.045 min;(M+H).sup.+=177.2.
Step 2. methyl5-(chlorosulfonyl)-2,3-dihydro-1H-indene-2-carboxylate
##STR00256##
Methyl 2,3-dihydro-1H-indene-2-carboxylate (1.00 g, 5.68 mmol) wasadded over 20 min to a pre-cooled solution of ClSO.sub.3H (5 mL)and the resulting mixture was stirred at 13-21.degree. C. for 3 h,after which time, it was poured into ice-cooled water followed byEtOAc (30 mL). The organic layer was separated, and dried overanhydrous Na.sub.2SO.sub.4, filtered and concentrated to givemethyl 5-(chlorosulfonyl)-2,3-dihydro-1H-indene-2-carboxylate as acolorless oil. Yield: 1.4 g. .sup.1H NMR (CDCl.sub.3): .delta.7.82-7.89 (m, 2H), 7.43 (d, J=8.4 Hz, 1H), 3.74-3.77 (m, 3H),3.28-3.50 (m, 5H).
Step 3. methyl 5-sulfamoyl-2,3-dihydro-1H-indene-2-carboxylate
##STR00257##
To a solution of methyl5-(chlorosulfonyl)-2,3-dihydro-1H-indene-2-carboxylate (100 mg,0.36 mmol) in THF (2 mL) was added NH.sub.3.H.sub.2O (100 .mu.L)under 0.degree. C. and the mixture was stirred at 0.degree. C. for1 h. The mixture was then concentrated, diluted by EtOAc (15 mL),washed by sat. aq. NH.sub.4Cl (10 mL) and brine (10 mL), dried overanhydrous Na.sub.2SO.sub.4, filtered and concentrated to givemethyl 5-sulfamoyl-2,3-dihydro-1H-indene-2-carboxylate as acolorless gel. Yield: 80 mg. .sup.1H NMR (CDCl.sub.3): .delta.7.65-7.75 (m, 2H), 7.34 (d, J=8.0 Hz, 1H), 3.70 (s, 3H), 3.37-3.46(m, 1H), 3.21-3.27 (m, 4H).
Step 4. 5-sulfamoyl-2,3-dihydro-1H-indene-2-carboxylic Acid
##STR00258##
To a solution of 5-sulfamoyl-2,3-dihydro-1H-indene-2-carboxylate(80 mg, 0.31 mmol), in MeOH (1 mL) was added H.sub.2O (1 mL)followed by LiOH (96 mg, 4.0 mmol). The mixture was stirred at18-23.degree. C. for 4 h. The pH was adjusted to 2-3 with aq. HCl,and the mixture was concentrated to give crude5-sulfamoyl-2,3-dihydro-1H-indene-2-carboxylic acid as a whitesolid. Yield: 131 mg.
Step 5.2-(6-(5-(2-chloro-4-fluorophenoxy)pyrimidin-4-yl)-2,6-diazaspiro[3-.3]heptanes-2-carbonyl)-2,3-dihydro-1H-indene-5-sulfonamide
To a solution of 5-sulfamoyl-2,3-dihydro-1H-indene-2-carboxylicacid (131 mg, 0.31 mmol) and2-(5-(2-chloro-4-fluorophenoxy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptanesynthesized from Intermediate 20A by acid deprotection (100 mg,0.31 mmol) in DMF (4 mL, anhydrous) was added HATU (177 mg, 0.47mmol) and DIEA (120 mg, 154 .mu.L). The mixture was stirred at13-20.degree. C. for 17 h at which time LCMS showed the desiredproduct was produced in about 17% yield. The mixture was diluted byEtOAc (20 mL), washed by H.sub.2O (20 mL), brine (20 mL), driedover anhydrous Na.sub.2SO.sub.4, filtered and concentrated. Theresidue was purified by acidic preparative RP-HPLC method A to give2-(6-(5-(2-chloro-4-fluorophenoxy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]hept-ane-2-carbonyl)-2,3-dihydro-1H-indene-5-sulfonamide (TFA salt) as awhite solid. Yield: 9 mg. LCMS method E: R.sub.t=0.843 min;(M+H).sup.+=544.2. .sup.1H NMR (CD.sub.3OD): .delta. 8.48 (s, 1H),7.67-7.76 (m, 2H), 7.59 (s, 1H), 7.50 (dd, J=8.4, 3.2 Hz, 1H),7.33-7.43 (m, 2H), 7.21-7.29 (m, 1H), 4.71-4.86 (m, 4H), 4.57 (s,2H), 4.27 (s, 2H), 3.36-3.45 (m, 1H), 3.17-3.24 (m, 4H). .sup.19FNMR (CD.sub.3OD): .delta. -77.02, -115.29.
Example 41
5-((7-(5-((5-fluoro-2'-isopropyl-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol--2(3H)-one
##STR00259##
Step 1. tert-butyl7-(5-(2-bromo-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2--carboxylate
##STR00260##
A mixture of 5-(2-bromo-4-fluorophenoxy)-4-chloropyrimidine(Intermediate 1, 15 g, 49.4 mmol), tert-butyl2,7-diazaspiro[4.4]nonane-2-carboxylate (14.7 g, 54.3 mmol) andNa.sub.2CO.sub.3 (20.9 g, 197.6 mmol) in CH.sub.3CN (300 mL) wasstirred at reflux for 3 h. The mixture was then filtered and thefiltrate was concentrated under reduced pressure. The residue waspurified by column chromatography on silica gel (eluting with ethylacetate) to give tert-butyl7-(5-(2-bromo-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2--carboxylate (i.e., Intermediate 11), as a yellow solid. Yield: 23g. LCMS method A: R.sub.t=0.759 min; (M+H).sup.+=492.8, 494.9(bromo isotopes). .sup.1H NMR (CDCl.sub.3): .delta. 8.35 (s, 1H),7.71 (s, 1H), 7.31-7.33 (d, J=6.8 Hz, 1H), 6.90-6.95 (m, 1H),6.68-6.70 (m, 1H), 3.50-3.85 (m, 4H), 3.10-3.45 (m, 4H), 1.80-1.95(m, 4H), 1.39 (s, 9H).
Step 2. tert-butyl7-(5-((5-fluoro-2'-isopropyl-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,7--diazaspiro[4.4]nonane-2-carboxylate
##STR00261##
To a degassed mixture of Intermediate 11 (15 g, 30.4 mmol),(2-isopropylphenyl)boronic acid (7.8 g, 45.6 mmol) andK.sub.3PO.sub.4 (19.4 g, 91.2 mmol) in dioxane (360 mL) andH.sub.2O (90 mL) was added Sphos Palladacycle (2.2 g, 3.04 mmol)under N.sub.2 and the mixture was stirred at 90.degree. C. for 18h. The mixture was then filtered and the filtrate was concentratedunder reduced pressure to remove dioxane. The resulting residue wasextracted with ethyl acetate (3.times.100 mL). The combined organiclayers were washed with H.sub.2O (100 mL) and brine (100 mL), driedover anhydrous sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by column chromatographon silica gel (eluting with petroleum ether:ethyl acetate=1:2 to1:3) to give tert-butyl7-(5-((5-fluoro-2'-isopropyl-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,7--diazaspiro[4.4]nonane-2-carboxylate as a yellow solid. Yield: 8.6g. LCMS method A: R.sub.t=0.785 min; (M+H).sup.+=533.1. .sup.1H NMR(CDCl.sub.3): .delta. 8.33 (s, 1H), 7.76 (s, 1H), 7.3-7.38 (m, 2H),7.10-7.20 (m, 1H), 6.90-7.05 (m, 3H), 6.70-6.80 (m, 1H), 3.30-3.70(m, 6H), 3.10-3.30 (m, 2H), 2.80-2.90 (m, 1H), 1.70-1.85 (m, 4H),1.46 (s, 9H), 1.11-1.16 (m, 6H).
Step 3.2-(5-((5-fluoro-2'-isopropyl-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4--yl)-2,7-diazaspiro[4.4]nonane
##STR00262##
To a mixture of tert-butyl7-(5-((5-fluoro-2'-isopropyl-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,7--diazaspiro[4.4]nonane-2-carboxylate (8.6 g, 16.1 mmol) inCH.sub.2Cl.sub.2 (150 mL) was added HCl-dioxane (30 mL, 4 N) underice-cold water and the mixture was stirred at 14-18.degree. C. for2 h. The mixture was then concentrated under reduced pressure andthe residue was basified to pH 12-13 with 10% NaOH aqueoussolution, extracted with EtOAc (3.times.100 mL). The combinedorganic layers were dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure to give2-(5-((5-fluoro-2'-isopropyl-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,7--diazaspiro[4.4]nonane as a yellow solid, which was used in thenext step without further purification. Yield: 6.8 g. LCMS methodC: R.sub.t=0.649 min; (M+H).sup.+=433.1.
Step 4.5-((7-(5-((5-fluoro-2'-isopropyl-[1,1'-biphenyl]-2-yl)oxy)pyrimidi-n-4-yl)-2,7-diazaspiro[4. 4]nonan-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one
A mixture of2-(5-((5-fluoro-2'-isopropyl-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,7--diazaspiro[4.4]nonane (6.8 g, 15.7 mmol),2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbaldehyde (Intermediate40, 3.05 g, 18.8 mmol), NaBH.sub.3CN (3.9 g, 62.8 mmol) and HOAc(3.4 mL) in MeOH (130 mL) was stirred at 70.degree. C. for 18 h.The mixture was then concentrated under reduced pressure and theresidue adjusted to pH=8 with saturated NaHCO.sub.3 solution andextracted with ethyl acetate (3.times.150 mL). The combined organiclayers were dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified bybasic preparative RP-HPLC method D to give5-((7-(5-((5-fluoro-2'-isopropyl-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)--2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-oneas a slight yellow solid. Yield: 7.2 g. LCMS method C:R.sub.t=0.663 min; (M+H).sup.+=579.1. .sup.1H NMR (CD.sub.3OD):.delta. 8.13 (s, 1H), 7.58 (d, J=6.8 Hz, 1H), 6.95-7.35 (m, 10H),3.62 (s, 2H), 3.40-3.55 (m, 3H), 2.55-2.85 (m, 4H), 2.30-2.45 (m,2H), 1.65-1.85 (m, 4H), 1.00-1.10 (m, 6H).
Examples 41A-41B
5-((7-(5-((5-fluoro-2'-isopropyl-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)--2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one(Isomers 1-2)
##STR00263##
5-((7-(5-((5-fluoro-2'-isopropyl-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)--2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one(Example 40, 1 g, 1.7 mmol) was purified by SFC separation method Ato give two isomers as a white solids which were isolated as HClsalts.
Isomer 1:
LCMS method C: R.sub.t=0.660 min; (M+H).sup.+=579.1. .sup.1H NMR(CD.sub.3OD): .delta. 8.28 (s, 1H), 7.66 (s, 1H), 7.10-7.37 (m,10H), 4.45 (s, 2H), 3.71-3.34 (m, 8H), 2.77-2.85 (m, 1H), 2.03-2.11(m, 4H), 1.06-1.14 (m, 6H). .sup.19F NMR (CD.sub.3OD): .delta.-119.18. SFC Anal. Method D: 8.122 min, ee=91.32%
Isomer 2:
LCMS method C: R.sub.t=0.659 min; (M+H).sup.+=579.1.
.sup.1H NMR (CD.sub.3OD 400 MHz): .delta. 8.27 (s, 1H), 7.66 (s,1H), 7.10-7.37 (m, 10H), 4.44 (s, 2H), 3.33-3.70 (m, 8H), 2.77-2.83(m, 1H), 2.03-2.11 (m, 4H), 1.06-1.14 (m, 6H). .sup.19F NMR(CD.sub.3OD 400 MHz): .delta. -119.30. SFC Anal. Method D: 8.122min, ee=93.84%
Example 42
2-cyclopropyl-5'-fluoro-2'-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol--5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-[1,1'-biphe-nyl]-4-carbonitrile (Racemic Mixture)
##STR00264##
The title product was synthesized according to the method describedfor Example 41. In Step 2, 4-cyano-2-cyclopropyl phenyl boronicacid was used. LCMS method A: R.sub.t=1.42 min, 602 (M+H).sup.+..sup.1H NMR CD.sub.3OD) .delta.: 8.15 (s, 1H), 7.64 (s, 1H), 7.42(m, 1H), 7.29 (m, 1H), 7.23-7.14 (m, 3H), 7.07-7.01 (m, 4H), 3.65(s, 2H), 3.58-3.41 (m, 4H), 2.68 (m, 2H), 2.47 (m, 2H), 1.85 (m,2H), 1.72 (m, 3H), 0.87 (m, 2H), 0.65 (m, 2H).
Examples 42A-42B
2-cyclopropyl-5'-fluoro-2'-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol--5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-[1,1'-biphe-nyl]-4-carbonitrile (Isomers 1-2)
##STR00265##
The compound of Example 42 was separated by SFC method A to affordtwo isomers.
Isomer 1:
LCMS method D: R.sub.t value: 1.435 min, M+H).sup.+=602.2; .sup.1HNMR (CD.sub.3OD): .delta. 8.15 (s, 1H), 7.64 (s, 1H), 7.43 (d,J=9.6 Hz, 1H), 7.29 (d, J=5.6 Hz, 1H), 7.10-7.20 (m, 3H), 7.05-7.10(m, 2H), 7.01 (s, 2H), 3.63 (s, 2H), 3.35-3.60 (m, 4H), 2.60-2.75(m, 2H), 2.35-2.50 (m, 2H), 1.80-1.90 (m, 2H), 1.60-1.75 (m, 3H),0.87 (s, 2H), 0.66 (s, 2H). .sup.19F NMR (CD.sub.3OD): .delta.-120.38. SFC Anal. Method D: t.sub.R=5.306 min, ee=99.70%.
Isomer 2:
LCMS method D: R.sub.t value: 1.435 min, M+H).sup.+=602.2; .sup.1HNMR (CD.sub.3OD 400 MHz): .delta. 8.15 (s, 1H), 7.64 (s, 1H), 7.42(s, 1H), 7.29 (d, J=4.8 Hz, 1H), 7.10-7.25 (m, 3H), 6.95-7.10 (m,4H), 3.60-3.70 (m, 2H), 3.35-3.60 (m, 4H), 2.55-2.75 (m, 2H),2.35-2.50 (m, 2H), 1.80-1.90 (m, 2H), 1.60-1.75 (m, 3H), 0.87 (s,2H), 0.65 (s, 2H). .sup.19F NMR (CD.sub.3OD 400 MHz): .delta.-120.383. SFC Anal. Method D: t.sub.R=7.188 min, ee=99.32%.
Examples 43-44
2-cyclopropyl-5'-fluoro-2'-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol--5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-[1,1'-biphe-nyl]-4-carboxamide (Example 43) and2-cyclopropyl-5'-fluoro-2'-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol--5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-[1,1'-biph-enyl]-4-carboxylic Acid (Example 44)
##STR00266##
A mixture of2-cyclopropyl-5'-fluoro-2'-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol--5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-[1,1'-biph-enyl]-4-carbonitrile bis-HCl salt (Example 42, 41 mg, 0.06 mmol),THF (3 mL) and 2 M LiOH (1 mL) was charged in a 10 mL CEM microwavetest tube and heated to 120.degree. C. for 4.5 h in a CEM microwavereactor. LC/MS showed two products in a ratio of about 1:1. Thereaction mixture was neutralized with 1 M HCl solution, andevaporated to dryness and the resulting residue was purified byRP-HPLC method A to afford2-cyclopropyl-5'-fluoro-2'-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol--5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-[1,1'-biph-enyl]-4-carboxamide TFA salt and2-cyclopropyl-5'-fluoro-2'-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol--5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-[1,1'-biph-enyl]-4-carboxylic acid as a TFA salt.
Example 43
LCMS method A: R.sub.t=0.68 min, (M+H).sup.+=620.3. .sup.1H NMR(CD.sub.3OD) .delta.: 8.38 (s, 1H), 7.71 (s, 1H), 7.63 (m, 1H),7.45 (dd, J=8.4, 4.4 Hz, 1H), 7.34-7.30 (m, 2H), 7.25-7.20 (m, 4H),7.12 (d, J=8.0 Hz, 1H), 4.43 (s, 2H), 3.91-3.34 (m, 8H), 2.05 (m,4H), 1.62 (s, 1H), 0.91-0.70 (m, 4H).
Example 44
LCMS method A: R.sub.t=0.75 min, (M+H).sup.+=621.3. .sup.1H NMR(CD.sub.3OD) .delta.: 8.38 (s, 1H), 7.78 (d, J=7.2 Hz, 1H), 7.71(s, 1H), 7.45-7.42 (m, 2H), 7.33 (td, J=8.4, 4.4 Hz, 1H), 7.28-7.23(m, 3H), 7.20 (d, J=8.0 Hz, 1H), 7.12 (d, J=8.0 Hz, 1H), 4.42 (s,2H), 3.82-3.46 (m, 8H), 2.07 (m, 4H), 1.63 (s, 1H), 0.92 (m, 2H),0.65 (m, 2H).
Example 45
2-cyclopropyl-5'-fluoro-N,N-dimethyl-2'-((4-(7-((2-oxo-2,3-dihydro-1H-benz-o[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy-)-[1,1'-biphenyl]-4-carboxamide
##STR00267##
To a solution of2-cyclopropyl-5'-fluoro-2'-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol--5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-[1,1'-biph-enyl]-4-carboxylic acid (Example 44, 10 mg, 0.012 mmol) in DCM (1mL) was added TEA (0.05 mL), HATU (5 mg, 0.013 mmol) and 2.0 MMe.sub.2NH in THF (0.2 mL). The resulting mixture was stirredovernight and then the solvents were removed under reducedpressure. The residue was then purified by RP-HPLC method A toafford2-cyclopropyl-5'-fluoro-N,N-dimethyl-2'-((4-(7-((2-oxo-2,3-dihydro-1H-ben-zo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)ox-y)-[1,1'-biphenyl]-4-carboxamide as a TFA salt. Yield: 8.5 mg. LCMSmethod A: R.sub.t=0.74 min, (M+H).sup.+=648.3. .sup.1H NMR(CD.sub.3OD) .delta.: 8.40 (s, 1H), 7.34 (m, 1H), 7.45 (m, 1H),7.33 (m, 1H), 7.26-7.22 (m, 5H), 7.12 (d, J=7.6 Hz, 1H), 6.84 (s,1H), 4.45 (s, 2H), 3.85-3.42 (m, 8H), 3.06 (s, 3H), 2.95 (s, 3H),2.09 (m, 4H), 1.62 (s, 1H), 0.91 (m, 2H), 0.62 (m, 2H).
Example 46
5-((7-(2-chloro-5-(4-fluoro-2-(1-isopropyl-1H-pyrazol-5-yl)phenoxy)pyrimid-in-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imid-azol-2-one
##STR00268##
The title compound was synthesized as described in Example 41starting from 2,4-dichloro-5-bromo pyrimidine. LCMS method B:R.sub.t=1.45 min, (M+H).sup.+=603.6; .sup.1H NMR (MeOH-d4): .delta.7.90 (s, 1H), 7.45 (d, J=6.4 Hz, 1H), 7.30 (d, J=5.6 Hz, 2H), 7.21(s, 1H), 7.18 (d, J=8 Hz, 1H), 7.16 (d, J=8 Hz, 1H), 7.12 (d, J=8Hz, 1H), 6.14 (s, 1H), 4.41 (s, 2H), 4.37 (m, 1H), 3.90-3.65 (m,3H), 3.64-3.34 (m, 4H), 3.26 (m, 1H), 2.18 (m, 1H), 2.32-1.92 (m,3H), 1.36 (m, 6H).
Examples 47-52
Examples 47-52 were prepared according to the procedure provided inExample 41.
TABLE-US-00023 TABLE 7 Examples 47-52 Example No. Structure Yield47. 5-((7-(5-((4,5-difluoro-2'- isopropyl-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,7- diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol- 2(3H)-one ##STR00269## 17% 48.5'-fluoro-2-methyl-2'-((4-(7- ((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)- 2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-[1,1'- biphenyl]-4-carbonitrile ##STR00270##22% 49. 5-((7-(5-((2'-cyclopropyl-5- fluoro-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,7- diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one ##STR00271## 46% 50.5-((7-(5-((5-fluoro-2'- (trifluoromethyl)-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,7- diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one (TFA salt) ##STR00272## 62% 51.5'-fluoro-2,6-dimethyl-2'-((4- (7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)- 2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-[1,1'- biphenyl]-4-carbonitrile ##STR00273##14% 52. 2-cyclopropyl-3',5'-difluoro-2'-((4-(7-((2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2- yl)pyrimidin-5-yl)oxy)-[1,1'-biphenyl]-4-carbonitrile ##STR00274## 3%
TABLE-US-00024 TABLE 8 Characterization Data for Examples 47-52.Mass peak(s) Example No. NMR Data (M + H)+ R.sub.f or R.sub.t 47.5-((7-(5-((4,5- .sup.1H NMR (CD.sub.3OD) .delta. 597.3 1.620 mindifluoro-2'-isopropyl- 8.45 (s, 1 H), 7.88 (s, 1 LCMS method E[1,1'-biphenyl]-2- H), 7.00-7.45 (m, 9 H), yl)oxy)pyrimidin-4- 4.44(s, 2 H), 3.33-3.83 yl)-2,7-diazaspiro (m, 8 H), 2.75-2.81 (m,[4.4]nonan-2- 1 H), 1.96-2.09 (m, 4 yl)methyl)-1H- H), 1.07-1.15(m, 6 H). benzo[d]imidazol- .sup.19F NMR (CD.sub.3OD): 2(3H)-one.delta. -137.27~-135.21, -142.54. 48. 5'-fluoro-2- .sup.1H NMR(CD.sub.3OD): .delta. 576.1 1.520 min in methyl-2'-((4-(7-((2- 8.16(s, 1H), 7.47-7.64 LCMS method E oxo-2,3-dihydro-1H- (m, 3H),7.31-7.33 (m, benzo[d]imidazol-5- 1H), 7.18-7.22 (m, 1H),yl)methyl)-2,7- 7.01-7.12 (m, 5H), 3.43- diazaspiro[4.4]nonan- 3.66(m, 6H), 2.64-2.69 2-yl)pyrimidin-5- (m, 2H), 2.46 (s, 2H),yl)oxy)-[1,1'- 2.21 (s, 3H), 1.73-1.90 biphenyl]-4- (m, 4H)..sup.19F NMR carbonitrile (CD.sub.3OD): .delta. -120.33. 49.5-((7-(5-((2'- .sup.1H NMR (CD.sub.3OD): .delta. 577.2 0.647 min incyclopropyl-5-fluoro- 8.35 (s, 1H), 7.66 (s, 1.520 min in[1,1'-biphenyl]-2- 1H), 7.35-7.45 (m, 1H), LCMS method Ayl)oxy)pyrimidin-4- 7.25-7.35 (m, 2H), 7.10- yl)-2,7- 7.25 (m, 3H),7.10-7.15 diazaspiro[4.4]nonan- (m, 1H), 6.95-7.10 (m,2-yl)methyl)-1H- 2H), 6.65-6.80 (m, 1H), benzo[d]imidazol- 4.45 (s,2H), 3.75-3.90 2(3H)-one (m, 4H), 3.35-3.75 (m, 4H), 2.00-2.30 (m,4H), 1.50-1.65 (m, 1H), 0.70- 1.00 (m, 2H), 0.50-0.70 (m, 2H)..sup.19F NMR (CD.sub.3OD): .delta. -76.96, -117.69.sub.o 50.5-((7-(5-((5- .sup.1H NMR (CD.sub.3OD): .delta. 605.1 0.645 min influoro-2'- 8.42 (s, 1H), 7.65-7.80 LCMS method A (trifluoromethyl)-(m, 2H), 7.50-7.65 (m, [1,1'-biphenyl]-2- 2H), 7.42 (d, J = 6.8 Hz,yl)oxy)pyrimidin-4- 1H), 7.29 (d, J = 6.4 Hz, yl)-2,7- 2H),7.10-7.20 (m, 3H), diazaspiro[4.4]nonan- 7.05-7.10 (m, 1H), 4.392-yl)methyl)-1H- (s, 2H), 3.46-3.80 (m, benzo[d]imidazol- 8H),1.90-2.20 (m, 2(3H)-one (TFA salt) 4H). .sup.19F NMR (CD.sub.3OD):.delta. -59.35, -118.69. 51. 5'-fluoro-2,6- .sup.1H NMR(CD.sub.3OD): .delta. 592.0 0.644 min in dimethyl-2'-((4-(7- 8.17(s, 1H), 7.66 (s, LCMS method A ((2-oxo-2,3-dihydro- 1H), 7.46 (s,1H), 7.39 1H-benzo[d]imidazol- (s, 1H), 7.20-7.25 (m,5-yl)methyl)-2,7- 1H), 7.10-7.15 (m, 1H), diazaspiro[4.4]nonan-7.00-7.10 (m, 4H), 3.67 2-yl)pyrimidin-5- (s, 2H), 3.37-3.57 (m,yl)oxy)-[1,1'- 4H), 2.65-2.70 (m, 2H), biphenyl]-4- 2.40-2.50 (m,2H), 2.08 carbonitrile (d, J = 1.2 Hz, 6H), 1.60-1.95 (m, 4H)..sup.19F NMR (CD.sub.3OD): .delta. -76.93, -119.73. 52.2-cyclopropyl- .sup.1H NMR (CD.sub.3OD): .delta. 620.2 0.660 min in3',5'-difluoro-2'-((4- 8.05 (s, 1H), 7.36-7.47 LCMS method A(7-((2-oxo-2,3- (m, 2H), 7.30-7.33 (m, dihydro-1H- 1H), 7.25 (s,1H), 7.13 benzo[d]imidazol-5- (s, 1H), 6.95-7.10 (m,yl)methyl)-2,7- 4H), 3.35-3.75 (m, 6H), diazaspiro[4.4]nonan-2.64-2.77 (m, 2H), 2.40- 2-yl)pyrimidin-5- 2.54 (m, 2H), 1.70-1.96yl)oxy)-[1,1'- (m, 4H), 1.52-1.66 (m, biphenyl]-4- 1H), 0.65-0.95(m, 2H), carbonitrile 0.50-0.60 (m, 2H). .sup.19F NMR (CD.sub.3OD):.delta. -113.73 (s, 2F).
Example 53
5-((7-(5-(4-fluoro-2-(2-isopropyl-1H-imidazol-1-yl)phenoxy)pyrimidin-4-yl)--2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one
##STR00275##
Step 1. 1-(5-fluoro-2-methoxyphenyl)-2-isopropyl-1H-imidazole
##STR00276##
To a solution of (5-fluoro-2-methoxyphenyl)boronic acid (12.0 g,70.59 mmol), 2-isopropyl-1H-imidazole (7.0 g, 64.17 mmol) inanhydrous DCM (150 mL) was added Cu(OAc).sub.2 (1.73 g, 9.62 mmol)and pyridine (15 mL, 192.51 mmol) under O.sub.2 (30 psi) and theresulting mixture was stirred at 20.degree. C. for 16 h. Themixture was filtered and the filtrate was washed with water(2.times.100 mL), dried over anhydrous Na.sub.2SO.sub.4, filteredthrough celite, and concentrated under reduced pressure to givecrude 1-(5-fluoro-2-methoxyphenyl)-2-isopropyl-1H-imidazole as ablack oil, which was used for next step. Yield: 15.0 g. LCMS methodE: R.sub.t=0.948 min, (M+H).sup.+=253.3.
Step 2. 4-fluoro-2-(2-isopropyl-1H-imidazol-1-yl)phenol
##STR00277##
A solution of 1-(5-fluoro-2-methoxyphenyl)-2-isopropyl-1H-imidazole(15.0 g, 64.17 mmol) in HCl-Py (150 g) was stirred at 195.degree.C. for 2 h under N.sub.2. LCMS showed the starting material wasconsumed. The reaction was added water (500 mL), and adjusted topH.about.10 by 1N NaOH solution. The mixture was extracted withEtOAc (3.times.200 mL), dried over anhydrous Na.sub.2SO.sub.4,filtered through a celite, concentrated under reduced pressure. Theresidue was purified by column chromatograph on silica gel (elutingwith DCM/MeOH=10:1) to give4-fluoro-2-(2-isopropyl-1H-imidazol-1-yl)phenol as a white solid.About 760 mg of 4-fluoro-2-(2-isopropyl-1H-imidazol-1-yl)phenol wasfurther purified by column chromatograph on silica gel (elutingwith dichloromethane:methanol=10:1) to give compound4-fluoro-2-(2-isopropyl-1H-imidazol-1-yl)phenol (541.40 mg) as awhite solid. Yield: 1.41 g. LCMS method E: R.sub.t=0.980 min,(M+H).sup.+=221.2. .sup.1H NMR (CD.sub.3OD): .delta. 10.06 (s, 1H),7.15-7.20 (m, 2H), 7.00-7.03 (m, 2H), 6.88 (s, 1H), 2.73-2.76 (m,1H), 1.10 (d, J=6.8 Hz, 2H). .sup.19F NMR (CD.sub.3OD): .delta.-124.63.
Step 3. ethyl2-(4-fluoro-2-(2-isopropyl-1H-imidazol-1-yl)phenoxy)acetate
##STR00278##
To a solution of 4-fluoro-2-(2-isopropyl-1H-imidazol-1-yl)phenol(0.65 g, 2.95 mmol) and ethyl 2-bromoacetate (492 mg, 2.95 mmol) inCH.sub.3CN (15 mL) was added K.sub.2CO.sub.3 (610 mg, 4.42 mmol),then the reaction was stirred at 80.degree. C. for 16 h underN.sub.2. The reaction mixture was then filtered through Celite andthe filtrate was concentrated under reduced pressure. The residuewas purified by column chromatography on silica gel (eluting withpetroleum ether:EtOAc=1:1.about.1:2) to afford ethyl2-(4-fluoro-2-(2-isopropyl-1H-imidazol-1-yl)phenoxy)acetate as ayellow oil. Yield: 720 mg. LCMS method E: R.sub.t=0.619 min,(M+H).sup.+=307.0
Step 4.5-(4-fluoro-2-(2-isopropyl-1H-imidazol-1-yl)phenoxy)-2-thioxo-2,3--dihydropyrimidin-4(1H)-one
##STR00279##
To a solution of ethyl2-(4-fluoro-2-(2-isopropyl-1H-imidazol-1-yl)phenoxy)acetate (720mg, 2.35 mmol) and ethyl formate (782 mg, 10.58 mmol) in anhydrousTHF (15 mL) was added NaH (141 mg, 3.52 mmol, 60% in mineral oil)under N.sub.2 and the reaction mixture was stirred at 35.degree. C.for 2 h. The solvent was removed under reduced pressure to affordethyl(Z)-2-(4-fluoro-2-(2-isopropyl-1H-imidazol-1-yl)phenoxy)-3-hydroxyacrylat-e as light brown oil, which was used for the next step withoutfurther purification. The intermediate was dissolved in anhydrousEtOH (15 mL), and thiourea (179 mg, 2.35 mmol) was added underN.sub.2. The reaction mixture was then stirred at 90.degree. C. forabout 16 h. The solvent was removed under reduced pressure toafford the residue which was purified by column chromatograph onsilica gel (eluting with dichloromethane:methanol=20:1 to 10:1) togive5-(4-fluoro-2-(2-isopropyl-1H-imidazol-1-yl)phenoxy)-2-thioxo-2,3-dihydro-pyrimidin-4(1H)-one as a yellow oil, and about 300 mg of ethyl2-(4-fluoro-2-(2-isopropyl-1H-imidazol-1-yl)phenoxy)acetate wasrecycled. Yield: 280 mg. LCMS method E: R.sub.t=0.945 min,(M+H).sup.+=347.1
Step 5.5-(4-fluoro-2-(2-isopropyl-1H-imidazol-1-yl)phenoxy)pyrimidin-4-ol
##STR00280##
To a solution of5-(4-fluoro-2-(2-isopropyl-1H-imidazol-1-yl)phenoxy)-2-thioxo-2,3-dihydro-pyrimidin-4(1H)-one (280 mg, 0.813 mmol) in EtOH (10 mL) was addedwet Raney nickel (1 g), and the reaction mixture was stirred at90.degree. C. for 16 h under N.sub.2. The mixture was filtered andthe filtrate was concentrated under reduced pressure to afford the5-(4-fluoro-2-(2-isopropyl-1H-imidazol-1-yl)phenoxy)pyrimidin-4-ol(256 mg, 98% purity, crude 100%) as a yellow oil, which was used inthe next step without further purification. Yield: 256 mg. LCMSmethod E: R.sub.t=0.958 min, (M+H).sup.+=315.1
Step 6.4-chloro-5-(4-fluoro-2-(2-isopropyl-1H-imidazol-1-yl)phenoxy)pyrim-idine
##STR00281##
To a solution of5-(4-fluoro-2-(2-isopropyl-1H-imidazol-1-yl)phenoxy)pyrimidin-4-ol(256 mg, 0.813 mmol) in anhydrous SOCl.sub.2 (5 mL) was addedanhydrous DMF (0.5 mL) under N.sub.2 and the reaction mixture wasstirred at 80.degree. C. for 2 h. The solvent was removed underreduced pressure to afford the residue which was mixed withCH.sub.2Cl.sub.2 (100 mL) and washed with sat. aq. NaHCO.sub.3 (30mL), brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filteredand concentrated under reduced pressure to afford4-chloro-5-(4-fluoro-2-(2-isopropyl-1H-imidazol-1-yl)phenoxy)pyrim-idine as a yellow oil. Yield: 210 mg. LCMS method E: R.sub.t=0.958min, (M+H).sup.+=333.1.
Step 7. tert-butyl7-(5-(4-fluoro-2-(2-isopropyl-1H-imidazol-1-yl)phenoxy)pyrimidin-4-yl)-2,-7-diazaspiro[4.4]nonane-2-carboxylate
##STR00282##
A solution of4-chloro-5-(4-fluoro-2-(2-isopropyl-1H-imidazol-1-yl)phenoxy)pyrimidine(100 mg, 0.301 mmol), tert-butyl2,7-diazaspiro[4.4]nonane-2-carboxylate (82 mg, 0.301 mmol) andDIEA (116 mg, 0.903 mmol) in propan-2-ol (3 mL) was stirred at90.degree. C. for 2 h. The mixture was concentrated under reducedpressure to give crude tert-butyl7-(5-(4-fluoro-2-(2-isopropyl-1H-imidazol-1-yl)phenoxy)pyrimidin-4-yl)-2,-7-diazaspiro[4.4]nonane-2-carboxylate as a yellow oil, which wasused in the next step. Yield: 157 mg. LCMS method E: R.sub.t=0.675min, (M+H).sup.+=523.1.
Step 8.2-(5-(4-fluoro-2-(2-isopropyl-1H-imidazol-1-yl)phenoxy)pyrimidin-4--yl)-2,7-diazaspiro[4.4]nonane
##STR00283##
To a solution of tert-butyl7-(5-(4-fluoro-2-(2-isopropyl-1H-imidazol-1-yl)phenoxy)pyrimidin-4-yl)-2,-7-diazaspiro[4.4]nonane-2-carboxylate (157 mg, 0.301 mmol) inanhydrous DCM (5 mL) was added TFA (1 mL) slowly at 0.degree. C.under N.sub.2 and the reaction mixture was stirred at 4-10.degree.C. for 2 h. The reaction mixture was then concentrated underreduced pressure. The resulting residue was dissolved in water (30mL) and adjusted to pH 10 with NaOH (10% in water) to pH 10. Theaqueous layer was extracted with CH.sub.2Cl.sub.2/PrOH (10:1,3.times.20 mL). The organic layer was dried over anhydrousNa.sub.2SO.sub.4, filtered and concentrated under reduced pressureto give2-(5-(4-fluoro-2-(2-isopropyl-1H-imidazol-1-yl)phenoxy)pyrimidin-4-yl)-2,-7-diazaspiro[4.4]nonane as a yellow solid, which was used in thenext step.
Step 9.5-((7-(5-(4-fluoro-2-(2-isopropyl-1H-imidazol-1-yl)phenoxy)pyrimid-in-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-o-ne
To a solution of2-(5-(4-fluoro-2-(2-isopropyl-1H-imidazol-1-yl)phenoxy)pyrimidin-4-yl)-2,-7-diazaspiro[4.4]nonane (10 mg, 0.024 mmol) in anhydrous MeOH (2mL) was added 2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbaldehyde(Intermediate 40, 6 mg, 0.036 mmol), and the mixture was stirredfor 5 min under N.sub.2. Then NaBH.sub.3CN (70 mg, 0.118 mmol) wasadded and the resulting mixture was stirred at 65.degree. C. for 16h. The reaction mixture was then concentrated under reducedpressure to afford the residue which was purified by preparativeRP-HPLC method G to give5-((7-(5-(4-fluoro-2-(2-isopropyl-1H-imidazol-1-yl)phenoxy)pyrimidin-4-yl-)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-oneas a white solid. Yield: 2.7 mg (20%) LCMS method D: R.sub.t=1.675min, (M+H).sup.+=569.1. .sup.1H NMR (CD.sub.3OD): .delta. 8.27 (s,1H), 7.78 (s, 1H), 7.30-7.40 (m, 2H), 6.98-7.11 (m, 6H), 3.41-3.65(m, 6H), 2.81-2.96 (m, 1H), 2.62-2.70 (m, 2H), 2.42-2.55 (m, 2H),1.71-1.96 (m, 4H), 1.22 (d, J=5.2 Hz, 6H). .sup.19F NMR(CD.sub.3OD): .delta. -119.023.
Example 54
5-((7-(5-(2-(cyclopropylmethoxy)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diaza-spiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one
##STR00284##
Step 1. tert-butyl7-(5-(2-(cyclopropylmethoxy)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspi-ro[4.4]nonane-2-carboxylate
##STR00285##
To a solution of Intermediate 43b (40 mg, 90 .mu.mol) in DMF (0.5mL) was added (bromomethyl)cyclopropane (11 .mu.L, 110 .mu.mol)followed by K.sub.2CO.sub.3 (20 mg, 135 .mu.mol) and the resultingmixture was stirred at 50.degree. C. for 15 h. After cooling to RT,the mixture was diluted with H.sub.2O (10 mL) and extracted withEtOAc (2.times.10 mL). The organic layer was washed with brine,dried over Na.sub.2SO.sub.4, and concentrated under vacuum. Thecrude product was purified by flash chromatography over silica geleluting with 50% EtOAc/hexanes to afford 42 mg tert-butyl7-(5-(2-(cyclopropylmethoxy)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspi-ro[4.4]nonane-2-carboxylate as a yellow oil (90% yield). LCMSmethod B: R.sub.t=1.69 min; (M+H).sup.+=485.6. .sup.1H NMR(CD.sub.3OD): .delta. 8.50 (s, 1H), 7.58 (s, 1H), 7.33-7.29 (m,1H), 7.00-6.97 (m, 1H), 6.80-6.75 (m, 1H), 3.84-3.82 (m, 3H),3.48-3.35 (m, 4H), 2.12-2.02 (m, 5H), 1.46 (s, 11H), 1.10-1.09 (m,1H), 0.54-0.52 (m, 2H), 0.20-0.19 (m, 2H).
Step 2.5-((7-(5-(2-(cyclopropylmethoxy)-4-fluorophenoxy)pyrimidin-4-yl)-2-,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one
To a solution of tert-butyl7-(5-(2-(cyclopropylmethoxy)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspi-ro[4.4]nonane-2-carboxylate (42 mg, 87 mol) in DCM (2 mL) was addedTFA (0.4 mL) at RT. The reaction mixture was stirred for 1 h andthen neutralized with aqueous NaHCO.sub.3 solution. The mixture wasextracted with DCM (5.times.15 mL). The organic layers werecombined, dried over Na.sub.2SO.sub.4, filtered and concentratedunder reduced pressure. The crude product was used without furtherpurification.
To a solution of the crude product, (12 mg, 30 .mu.mol),2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbaldehyde (Intermediate40, 5 mg, 30 .mu.mol) in MeOH (1 mL) was added NaCNBH.sub.3 (10 mg,45 .mu.mol). The resulting mixture was stirred at RT for 15 h andpurified by HPLC method A to afford5-((7-(5-(2-(cyclopropylmethoxy)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diaz-aspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-oneTFA salt as a colorless oil. LCMS method G: R.sub.t=3.83 min;(M+H).sup.+=531.7. .sup.1H NMR (CD.sub.3OD): .delta. 8.51 (s, 1H),7.59 (s, 1H), 7.30-7.28 (m, 1H), 7.22-7.18 (m, 2H), 7.12-7.10 (m,1H), 6.98 (s, 1H), 6.77 (s, 1H), 4.43-4.41 (m, 2H), 4.12-4.09 (m,2H), 3.80-3.78 (m, 2H), 2.30-2.15 (m, 5H), 1.29-1.20 (m, 5H),0.90-0.88 (m, 1H), 0.51-0.48 (m, 2H), 0.15-0.13 (m, 2H).
Example 55
Ethyl2-(7-(5-((4'-cyano-2'-cyclopropyl-5-fluoro-[1,1'-biphenyl]-2-yl)oxy)-pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)thiazole-4-carboxylate
##STR00286##
To a solution of2'-((4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-2-cyclopropyl-5-'-fluoro-[1,1'-biphenyl]-4-carbonitrile (220 mg, 0.48 mmol) in DMF(5 mL) was added ethyl 2-chlorothiazole-4-carboxylate (111 mg, 0.58mmol), CuI (9.2 mg, 0.048 mmol) and K.sub.2CO.sub.3 (132 mg, 0.96mmol) and the reaction mixture was heated in a microwave at100.degree. C. for 16 h. The mixture was then filtered throughcelite and the filter cake was washed twice with EtOAc (30 mL). Thefiltrate was combined and diluted with H.sub.2O (100 mL), extractedwith EtOAc (50 mL.times.2). The combined organic layer was driedover Na.sub.2SO.sub.4, filtered and concentrated to give the crudeproduct which was purified by preparative TLC (petroleumether:ethyl acetate=1:2) to afford ethyl2-(7-(5-((4'-cyano-2'-cyclopropyl-5-fluoro-[1,1'-biphenyl]-2-yl)oxy)pyrim-idin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)thiazole-4-carboxylate asa brown oil. Yield: 100 mg. LCMS method C: R.sub.t=0.783 min,(M+H).sup.+=610.9. .sup.1H NMR (CDCl.sub.3): .delta. 8.35 (s, 1H),7.77 (s, 1H), 7.35-7.50 (m, 2H), 7.15-7.25 (m, 2H), 6.95-7.10 (m,2H), 6.83 (s, 1H), 4.30-4.45 (m, 2H), 3.60-3.75 (m, 2H), 3.40-3.60(m, 6H), 1.85-2.05 (m, 4H), 1.55-1.80 (m, 1H), 1.20-1.50 (m, 3H),0.85-0.95 (m, 2H), 0.60-0.75 (s, 2H). .sup.19F NMR (CDCl): .delta.-118.94.
Example 56
2-(7-(5-((4'-cyano-2'-cyclopropyl-5-fluoro-[1,1'-biphenyl]-2-yl)oxy)pyrimi-din-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)thiazole-4-carboxylicacid
##STR00287##
To a solution of ethyl2-(7-(5-((4'-cyano-2'-cyclopropyl-5-fluoro-[1,1'-biphenyl]-2-yl)oxy)pyrim-idin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)thiazole-4-carboxylate (20mg, 0.033 mmol) in THF (2 mL) was added aq. LiOH (1 mL, 4 N) andthe reaction mixture was stirred at 18-26.degree. C. for 16 h. Themixture was concentrated and purified by RP-HPLC method A to give2-(7-(5-((4'-cyano-2'-cyclopropyl-5-fluoro-[1,1'-biphenyl]-2-yl)oxy)pyrim-idin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)thiazole-4-carboxylic acidas a solid. Yield: 6 mg. LCMS method C: R.sub.t=0.726 min,(M+H).sup.+=582.9. .sup.1H NMR (CD.sub.3OD): .delta. 8.46 (s, 1H),7.80 (s, 1H), 7.50-7.55 (m, 2H), 7.20-7.45 (m, 5H), 3.70-4.05 (m,4H), 3.45-3.65 (m, 4H), 2.00-2.20 (m, 4H), 1.70-1.75 (m, 1H),0.60-1.00 (m, 4H). .sup.19F NMR (CD.sub.3OD): .delta. -117.77.
Example 57
2-(7-(5-((4'-cyano-2'-cyclopropyl-5-fluoro-[1,1'-biphenyl]-2-yl)oxy)pyrimi-din-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)-N-methylthiazole-4-carboxamide
##STR00288##
To a solution of(2'-((4-(7-(4-amino-3-fluorobenzyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimid-in-5-yl)oxy)-2-cyclopropyl-5'-fluoro-[1,1'-biphenyl]-4-carbonitrile(25 mg, 0.03 mmol) in DMF (2 mL) were added DIEA (12 mg, 0.06mmol), HATU (17 mg, 0.045 mmol) and methanamine solution of THF (30.mu.L, 0.06 mmol, 2 N). Then the reaction was stirred at16-25.degree. C. for 16 h. The mixture was purified by RP-HPLCmethod A to afford2-(7-(5-((4'-cyano-2'-cyclopropyl-5-fluoro-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)-N-methylthiazole-4-carboxa-mide (TFA salt) as a white solid. Yield: 2.7 mg. LCMS method C:R.sub.t=0.744 min, (M+H).sup.+=596.1. .sup.1H NMR (CD.sub.3OD):.delta. 8.47 (s, 1H), 7.81 (s, 1H), 7.25-7.48 (m, 7H), 3.49-3.92(m, 8H), 2.92 (s, 3H), 1.95-2.20 (m, 4H), 1.70 (s, 1H), 0.89-0.90(m, 2H), 0.67 (s, 2H). .sup.19F NMR: (CD.sub.3OD 400 MHz): .delta.-117.725 (s 1F).
Example 58
2-(7-(5-((4'-cyano-2'-cyclopropyl-5-fluoro-[biphenyl]-2-yl)oxy)-[1,1'-biph-enyl]-2-yl)oxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)-N,N-dimethyl-thiazole-4-carboxamide
##STR00289##
The title compound was synthesized according to the methodsdescribed for Example 57, substituting dimethyl amine for methylamine. LCMS method D: R.sub.t=1.191 min, (M+H).sup.+=610.3. .sup.1HNMR (CD.sub.3OD): .delta. 8.45 (s, 1H), 7.80 (s, 1H), 7.51 (s, 1H),7.30-7.40 (m, 3H), 7.20-7.30 (m, 2H), 7.06 (s, 1H), 3.70-4.10 (m,4H), 3.35-3.65 (m, 4H), 3.21 (s, 3H), 3.07 (s, 3H), 2.00-2.20 (m,4H), 1.65-1.75 (m, 1H), 0.60-0.95 (m, 4H). .sup.19F NMR(CD.sub.3OD): .delta. -119.19.
Example 59
7-benzyl-2-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-y-l)-2-azaspiro[4.4]nonane
##STR00290##
Step 1. (E)-tert-butyl7-benzylidene-2-azaspiro[4.4]nonane-2-carboxylate
##STR00291##
To a stirred suspension of NaH (160 mg, 4 mmol, 60% in mineral oil)in THF (8 mL, anhydrous) was added diethyl benzylphosphonate (920mg, 4 mmol) in THF (6 mL, anhydrous) dropwise at 0.degree. C. underN.sub.2 and the mixture was stirred for 20 min at 0.degree. C. Amixture of tert-butyl 7-oxo-2-azaspiro[4.4]nonane-2-carboxylate(200 mg, 0.8 mmol) and 15-crown-5 (880 mg, 4 mmol) in THF (6 mL,anhydrous) was added dropwise to the reaction mixture at 0.degree.C. and the mixture was then warmed to 14-17.degree. C. stirred for16 h under N.sub.2. The resulting mixture was quenched with sat.aq. NH.sub.4Cl (20 mL) and extracted with EtOAc (3.times.30 mL).The organic layers were washed with brine (20 mL), dried overNa.sub.2SO.sub.4, filtered and concentrated to give a residue whichwas purified by flash chromatography (SiO.sub.2, 10%.about.100%EtOAc/Petroleum ether) to give (E)-tert-butyl7-benzylidene-2-azaspiro[4.4]nonane-2-carboxylate as a colorlessoil. Yield: 230 mg. LCMS method C: R.sub.t=0.911 min,(M+H).sup.+=258.0.
Step 2. tert-butyl 7-benzyl-2-azaspiro[4.4]nonane-2-carboxylate
##STR00292##
To a solution of (E)-tert-butyl7-benzylidene-2-azaspiro[4.4]nonane-2-carboxylate (230 mg, 0.73mmol) in MeOH (20 mL, anhydrous) was added Pd--C (100 mg, 10% oncarbon, dry) and the resulting mixture was stirred at 30.degree. C.for about 16 h under H.sub.2 (40 psi). The suspension was filteredthrough fritted funnel and the filtrate was concentrated andpurified by flash chromatography (EtOAc in petroleum ether from10%.about.100%) to give tert-butyl7-benzyl-2-azaspiro[4.4]nonane-2-carboxylate as a colorless oil.Yield: 120 mg. LCMS method C: R.sub.t=0.965 min,(M+H).sup.+=338.0.
Step 3. 7-benzyl-2-azaspiro[4.4]nonane
##STR00293##
A solution of tert-butyl7-benzyl-2-azaspiro[4.4]nonane-2-carboxylate (120 mg, 0.38 mmol) inTFA-CH.sub.2Cl.sub.2 (5 mL, v:v=1:4) was stirred at 12-18.degree.C. for about 2 h at which time LCMS showed the reaction wascomplete. The resulting mixture was adjusted to pH=8 by sat. aq.NaHCO.sub.3 and extracted with CH.sub.2Cl.sub.2 (3.times.10 mL).The combined organic layers were washed with brine (10 mL), driedover Na.sub.2SO.sub.4, filtered and concentrated to give crude7-benzyl-2-azaspiro[4.4]nonane as a colorless oil, which was usedfor next step directly without further purification. Yield: 120 mg.LCMS method C: R.sub.t=0.627 min, (M+H).sup.+=216.1.
Step 4.7-benzyl-2-(5-(2-chloro-4-fluorophenoxy)pyrimidin-4-yl)-2-azaspiro-[4.4]nonane
##STR00294##
A solution of 7-benzyl-2-azaspiro[4.4]nonane (120 mg, 0.38 mmol,crude) and 4-chloro-5-(2-chloro-4-fluorophenoxy)pyrimidine (98 mg,0.38 mmol) in MeCN (10 mL) was added K.sub.2CO.sub.3 (158 mg, 1.14mmol). The resulting mixture was stirred at 90.degree. C. for about4 h. The mixture was filtered and filter cake washed with EtOAc(2.times.30 mL). The filtrate was concentrated and purified byRP-HPLC method A to give7-benzyl-2-(5-(2-chloro-4-fluorophenoxy)pyrimidin-4-yl)-2-azaspiro[4.4]no-nane (TFA salt) as a white solid. Yield: 80 mg. LCMS method D:R.sub.t=1.144 min, (M+H).sup.+=483.8.
.sup.1H NMR (CD.sub.3OD): .delta. 8.43-8.59 (m, 1H), 7.60-7.79 (m,1H), 7.40-7.55 (m, 1H), 7.30-7.40 (m, 1H), 7.10-7.30 (m, 6H),3.65-4.30 (m, 4H), 2.60-2.75 (m, 2H), 2.20-2.45 (m, 1H), 1.55-2.10(m, 6H), 1.25-1.50 (m, 2H). .sup.19F NMR (MeOD): .delta. -77.26,-115.69.
Step 5.7-benzyl-2-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrim-idin-4-yl)-2-azaspiro[4.4]nonane
To a solution of7-benzyl-2-(5-(2-chloro-4-fluorophenoxy)pyrimidin-4-yl)-2-azaspiro[4.4]no-nane (70 mg, 0.16 mmol), (4-isopropylpyrimidin-5-yl)boronic acid(40 mg, 0.24 mmol) in dioxane (2 mL) and H.sub.2O (1 mL) was addedto Sphos Pallodacyle (6 mg, 0.008 mmol) and K.sub.3PO.sub.4 (85 mg,0.4 mmol) under N.sub.2 and the resulting mixture was stirred at115.degree. C. for 45 min under microwave. The resulting mixturewas diluted with water (20 mL) and extracted with EtOAc (3.times.20mL). The organic layers were washed with brine (20 mL), dried overNa.sub.2SO.sub.4, filtered and concentrated to give a residue whichwas purified by RP-HPLC method A to give7-benzyl-2-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimid-in-4-yl)-2-azaspiro[4.4]nonane (TFA salt) as a white solid. Yield:45 mg. LCMS method D: R.sub.t=1.135 min, (M+H).sup.+=524.4. .sup.1HNMR (CD3OD): .delta. 9.03-9.20 (m, 1H), 8.55-8.67 (m, 1H), 8.48 (s,1H), 7.93 (s, 1H), 7.21-7.40 (m, 5H), 7.10-7.20 (m, 3H), 3.35-3.93(m, 4H), 2.95-3.12 (m, 1H), 2.55-2.70 (m, 2H), 2.20-2.40 (m, 1H),1.49-1.96 (m, 6H), 1.10-1.30 (m, 8H).sup.19F NMR (MeOD): .delta.-77.23, -117.91.
Example 60
5-((7-(5-((5-fluoro-2'-(1-hydroxyethyl)-[1,1'-biphenyl]-2-yl)oxy)pyrimidin--4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one(Mixture)
##STR00295##
Step 1. tert-butyl7-(5-((2'-acetyl-5-fluoro-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,7-di-azaspiro[4.4]nonane-2-carboxylate
##STR00296##
To a solution of tert-butyl7-(5-(2-bromo-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2--carboxylate (Intermediate 11, 600 mg, 1.2 mmol),(2-acetylphenyl)boronic acid (390 mg, 2.4 mmol) in dioxane (10 mL)and H.sub.2O (2 mL) was added to Pd(dppf)Cl.sub.2 (87 mg, 0.12mmol) and Na.sub.2CO.sub.3 (320 mg, 3 mmol) under N.sub.2 and theresulting mixture was stirred at 80.degree. C. for 16 h underN.sub.2. The resulting mixture was diluted with water (50 mL) andextracted with EtOAc (3.times.30 mL). The organic layers werewashed with brine (20 mL), dried over Na.sub.2SO.sub.4, filteredand concentrated in vacuo to give a residue Which was purified byflash chromatography (SiO.sub.2, 10%.about.100% EtOAc/Petroleumether) to give tert-butyl7-(5-((2'-acetyl-5-fluoro-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,7-di-azaspiro[4.4]nonane-2-carboxylate as a yellow solid. Yield: 400 mg.LCMS method C: R.sub.t=0.761 min, (M+H).sup.+=533.2.
Step 2. tert-butyl7-(5-((5-fluoro-2'-(1-hydroxyethyl)-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4--yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate
##STR00297##
To a solution of tert-butyl7-(5-((2'-acetyl-5-fluoro-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,7-di-azaspiro[4.4]nonane-2-carboxylate (350 mg, 0.66 mmol) in MeOH (20mL, anhydrous) and THF (10 mL, anhydrous) was added NaBH.sub.4 (98mg, 2.65 mmol) and the resulting mixture was stirred at 50.degree.C. for about 2 h under N.sub.2. The resulting mixture was thenquenched with sat. aq.NH.sub.4Cl (20 mL) and extracted with EtOAc(3.times.20 mL). The organic layers were washed with brine (20 mL),dried over Na.sub.2SO.sub.4, filtered and concentrated to givetert-butyl7-(5-((5-fluoro-2'-(1-hydroxyethyl)-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4--yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate as a black solid, whichwas used for next step directly without further purification.Yield: 380 mg.
Step 3.1-(2'-((4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5'-fl-uoro-[1,1'-biphenyl]-2-yl)ethanol
##STR00298##
A solution of tert-butyl7-(5-((5-fluoro-2'-(1-hydroxyethyl)-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4--yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (380 mg, 0.66 mmol,crude) in TFA-CH.sub.2Cl.sub.2 (9 mL, v:v=1:8) was stirred at17-24.degree. C. for about 2 h. The mixture was concentrated andadjusted to pH=8 with sat. aq. NaHCO.sub.3 and extracted with EtOAc(3.times.20 mL). The combined organic layers were washed with brine(20 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated togive1-(2'-((4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5'-fluoro-[1-,1'-biphenyl]-2-yl)ethanol as a yellow solid, which was used fornext step directly without further purification. Yield: 330 mg.LCMS method C: R.sub.t=0.581 min, (M+H).sup.+=435.2.
Step 4.5-((7-(5-((5-fluoro-2'-(1-hydroxyethyl)-[1,1'-biphenyl]-2-yl)oxy)p-yrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol-2-(3H)-one
To a solution of1-(2'-((4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5'-fluoro-[1-,1'-biphenyl]-2-yl)ethanol (330 mg, 0.66 mmol, crude) and2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbaldehyde (Intermediate40, 106 mg, 0.66 mmol,) in MeOH (10 mL, anhydrous) was added AcOH(0.2 mL). The mixture was stirred at 17-25.degree. C. for about 30min, then NaBH.sub.3CN (82 mg, 1.32 mmol) was added and theresulting mixture was stirred at 17-25.degree. C. for about 16 h.The mixture was quenched by sat. aq. NaHCO.sub.3 (10 mL) andextracted with CH.sub.2Cl.sub.2 (3.times.20 mL). The combinedorganic layers were washed with brine (20 mL), dried overNa.sub.2SO.sub.4, filtered and concentrated to give a residue whichwas purified by RP-HPLC method A to give5-((7-(5-((5-fluoro-2'-(1-hydroxyethyl)-[1,1'-biphenyl]-2-yl)oxy)pyrimidi-n-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-on-e (TFA salt) as a white solid. Yield: 290 mg. LCMS method C:R.sub.t=0.593 min, (M+H).sup.+=581.2 .sup.1H NMR (CD.sub.3OD):.delta. 8.00-8.15 (m, 1H), 7.50-7.70 (m, 2H), 6.90-7.40 (m, 9H),4.67 (s, 1H), 4.43 (s, 2H), 3.35-3.95 (m, 8H), 1.90-2.25 (m, 4H),1.20-1.35 (m, 3H). .sup.19F NMR (CD.sub.3OD): .delta. -76.92,-117.29.about.-118.17.
Examples 60A-60D
5-((7-(5-((5-fluoro-2'-(1-hydroxyethyl)-[1,1'-biphenyl]-2-yl)oxy)pyrimidin--4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one(Isomers 1-4)
##STR00299##
The title compound of Example 60 was separated as diastereomers bySFC method A and each diastereomer was further separated asenantiomers by SFC method 2.
Isomer 1:
LCMS method C: R.sub.t=0.606 min, (M+H).sup.+=581.2. .sup.1H NMR(CD.sub.3OD): .delta. 8.30-8.45 (m, 1H), 7.52-7.79 (m, 2H),7.10-7.40 (m, 8H), 6.95-7.10 (m, 1H), 4.66 (s, 1H), 4.35-4.50 (m,2H), 3.55-3.95 (m, 5H), 3.35-3.50 (m, 3H), 1.82-2.26 (m, 4H),1.20-1.35 (m, 3H). .sup.19F NMR (CD.sub.3OD): .delta. -76.99,-117.37.about.-118.33. SFC: t.sub.R=3.036 min (ee=100%).
Isomer 2:
LCMS method C: R.sub.t=0.608 min, (M+H).sup.+=581.2. .sup.1H NMR(CD.sub.3OD): .delta. 8.30-8.45 (m, 1H), 7.50-7.75 (m, 2H),7.25-7.40 (m, 3H), 7.10-7.25 (m, 5H), 6.95-7.10 (m, 1H), 4.66 (s,1H), 4.35-4.45 (m, 2H), 3.55-4.00 (m, 8H), 1.95-2.30 (m, 4H),1.20-1.35 (m, 3H). .sup.19F NMR (CD.sub.3OD): .delta. -76.98 8,-117.39.about.-118.17. SFC: t.sub.R=3.353 min (ee=100%).
Isomer 3:
LCMS method C: R.sub.t=0.606 min, (M+H).sup.+=581.2. .sup.1H NMR(CD.sub.3OD): .delta. 8.15 (s, 1H), 7.57-7.66 (m, 2H), 7.31-7.40(m, 1H), 7.10-7.25 (m, 3H), 6.83-7.10 (m, 5H), 4.72-4.82 (m, 1H),3.63 (s, 2H), 3.35-3.60 (m, 4H), 2.55-2.75 (m, 2H), 2.35-2.50 (m,2H), 1.65-1.90 (m, 4H), 1.20-1.30 (m, 3H). .sup.19F NMR(CD.sub.3OD): .delta. -120.89.about.-121.17. SFC: t.sub.R=7.926 min(ee=100%).
Isomer 4:
LCMS method C: R.sub.t=0.609 min, (M+H).sup.+=581.2. .sup.1H NMR(CD.sub.3OD): .delta. 8.15 (s, 1H), 7.55-7.68 (m, 2H), 7.30-7.40(m, 1H), 6.81-7.27 (m, 8H), 4.71-4.82 (m, 1H), 3.40-3.72 (m, 6H),2.60-2.70 (m, 2H), 2.40-2.50 (m, 2H), 1.65-1.90 (m, 4H), 1.28 (dd,J=13.6, 6.4 Hz, 3H). .sup.19F NMR (CD.sub.3OD): .delta.-120.79.about.-121.27 (m, 1F). SFC: t.sub.R=9.407 min(ee=100%).
Example 61
5-fluoro-N-isopropyl-N-methyl-2-((4-(7-(3-(2-oxooxazolidin-3-yl)benzyl)-2,-7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide
##STR00300##
Step 1. 3-(2-oxooxazolidin-3-yl)benzonitrile
##STR00301##
To a solution of oxazolidin-2-one (240 mg, 2.75 mmol),K.sub.2CO.sub.3 (760 mg, 5.5 mmol), CuI (16 mg, 0.083 mmol) andtrans-cyclohexanediamine (32 mg, 0.275 mmol) in anhydrous dioxane(15 mL) was added 3-bromobenzonitrile (500 mg, 2.75 mmol) under anitrogen atmosphere and the mixture was stirred at 110.degree. C.for 16 h. Then the reaction mixture was added into EtOAc (30 mL)and filtered with diatomite. The filtrate was concentrated under areduced pressure to give the crude product which was purified bycolumn chromatography on silica gel (petroleum ether:ethylacetate=1:1) to give 3-(2-oxooxazolidin-3-yl)benzonitrile as awhite solid. Yield: 75 mg. .sup.1H NMR (CDCl.sub.3): .delta.7.80-7.90 (m, 2H), 7.45-7.55 (m, 1H), 7.35-7.45 (m, 1H), 4.45-4.55(m, 2H), 4.00-4.10 (m, 2H).
Step 2. 3-(2-oxooxazolidin-3-yl)benzaldehyde
##STR00302##
To a solution of 3-(2-oxooxazolidin-3-yl)benzonitrile (75 mg, 0.4mmol) in HCO.sub.2H (11 mL) and H.sub.2O (4 mL) was added Ni--Alalloy (86 mg, 1 mmol) at 20-24.degree. C., then the mixture wasstirred at 90.degree. C. for 16 h. The reaction mixture was stirredfor an additional 6 h and was then filtered. The filtrate wasconcentrated under a reduced pressure and the resulting residue wasadded into water (50 mL) and extracted with CH.sub.2Cl.sub.2(3.times.50 mL). The organic layers were dried over anhydrousNa.sub.2SO.sub.4, filtered and concentrated under a reducedpressure to give crude product 3-(2-oxooxazolidin-3-yl)benzaldehydeas a white solid. Yield: 60 mg. LCMS method D: R.sub.t=0.911 min,(M+H).sup.+=192.2.
Step 3.5-fluoro-N-isopropyl-N-methyl-2-((4-(7-(3-(2-oxooxazolidin-3-yl)be-nzyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide
The title product was prepared according to the procedure describedin Step 4 of Example 41. The crude product was purified by RP-HPLCmethod D to give5-fluoro-N-isopropyl-N-methyl-2-((4-(7-(3-(2-oxooxazolidin-3-yl)b-enzyl)-2,7-diazaspiro [4.4]nonan-2-yl)pyrimidin-5-yl)oxy)benzamideas a white solid. LCMS method E: R.sub.t=1.230 min,(M+H).sup.+=589.2. .sup.1H NMR (CD.sub.3OD): .delta. 8.20-8.30 (m,1H), 7.70-7.85 (m, 1H), 7.56 (s, 1H), 7.40-7.50 (m, 1H), 7.25-7.35(m, 1H), 7.05-7.20 (m, 3H), 6.75-6.95 (m, 1H), 4.40-4.55 (m, 2H),4.00-4.15 (m, 2H), 3.55-3.80 (m, 6H), 2.94 (d, J=4.0 Hz, 2H), 2.77(s, 2H), 2.60-2.75 (m, 2H), 2.40-2.60 (m, 2H), 1.85-2.00 (m, 2H),1.70-1.85 (m, 2H), 1.05-1.25 (m, 6H). .sup.19F NMR (MeOD): .delta.-120.09.about.-120.54.
Example 62
5-fluoro-N-isopropyl-N-methyl-2-((4-(7-(4-(2-oxooxazolidin-3-yl)benzyl)-2,-7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide
##STR00303##
The title product was synthesized according to a method similar tothe procedure described for Example 61 starting from 4-bromocyanobenzene. LCMS method C: R.sub.t=0.607 min, (M+H).sup.+=589.2..sup.1H NMR (CD.sub.3OD): .delta. 8.29-8.33 (m, 1H), 7.80-7.88 (m,1H), 7.60-7.62 (m, 2H), 7.43-7.45 (m, 2H), 7.18-7.20 (m, 2H),6.83-6.97 (m, 1H), 4.50-4.52 (m, 2H), 4.11-4.15 (m, 2H), 3.93-3.96(m, 3H), 3.55-3.76 (m, 4H), 2.95-3.05 (m, 2H), 2.75-2.90 (m, 3H),1.93-2.05 (m, 5H), 1.18-1.35 (m, 7H). .sup.19F NMR (CD.sub.3OD):.delta. -120.17.about.-120.58
Example 63
5-((7-(5-((5-fluoro-2'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-2-yl)oxy)pyr-imidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol-2(3-H)-one
##STR00304##
Step 1.1-(2'-((4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5'-fl-uoro-[1,1'-biphenyl]-2-yl)ethanone
##STR00305##
A solution of tert-butyl7-(5-((2'-acetyl-5-fluoro-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,7-di-azaspiro[4.4]nonane-2-carboxylate (200 mg, 0.37 mmol) inTFA-CH.sub.2Cl.sub.2 (5 mL, V:V=1:5) was stirred at 16-24.degree.C. for about 2 h. The resulting mixture was concentrated andadjusted to pH=8 with sat. aq. Na.sub.2CO.sub.3. The mixture wasthen extracted with CH.sub.2Cl.sub.2 (3.times.20 mL) and thecombined organic layers were washed with brine (10 mL), dried overNa.sub.2SO.sub.4, filtered and concentrated to give crude1-(2'-((4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5'-fluoro-[1-,1'-biphenyl]-2-yl)ethanone as a yellow oil, which was used fornext step directly without further purification.
Step 2. 5-((7-(5-((2'-acetyl-5-fluoro-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,7-diazaspiro[4. 4] nonan-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one
##STR00306##
To a solution of1-(2'-((4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5'-fluoro-[1-,1'-biphenyl]-2-yl)ethanone (200 mg, 0.37 mmol, crude) and2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbaldehyde (Intermediate40, 60 mg, 0.37 mmol,) in MeOH (5 mL, anhydrous) was added AcOH(0.2 mL). The resulting mixture was stirred at 50.degree. C. forabout 2 h under N.sub.2, then NaBH.sub.3CN (156 mg, 0.74 mmol) wasadded and the resulting mixture was stirred at 50.degree. C. forabout 16 h. The mixture was quenched by sat. aq. NaHCO.sub.3 (50mL) and extracted with CH.sub.2Cl.sub.2 (5.times.20 mL). Thecombined organic layers were washed with brine (30 mL), dried overNa.sub.2SO.sub.4, filtered and concentrated to give a residue whichwas purified by flash chromatography on silica gel (MeOH inCH.sub.2Cl.sub.2 from 10%.about.100%) to give5-((7-(5-((2'-acetyl-5-fluoro-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,-7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-oneas a yellow solid. Yield: 100 mg. LCMS method C: R.sub.t=0.606 min,(M+H).sup.+=579.2.
Step 3.5-((7-(5-((5-fluoro-2'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-2-yl-)oxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imid-azol-2(3H)-one
To a solution of5-((7-(5-((2'-acetyl-5-fluoro-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,-7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one(100 mg, 0.17 mmol) in THF (5 mL, anhydrous) was added MeMgBr (0.6mL, 1.7 mmol, 3 M in ether) dropwise at -78.degree. C. underN.sub.2 and the resulting mixture was stirred at -78.degree. C. forabout 4 h under N.sub.2. The mixture was then quenched with sat.aq. NH.sub.4Cl (10 mL) and extracted with EtOAc (3.times.20 mL).The combined organic layers were washed with brine (20 mL), driedover Na.sub.2SO.sub.4, filtered and concentrated to give a residuewhich was purified by basic preparative RP-HPLC method D to give5-((7-(5-((5-fluoro-2'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-2-y-l)oxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one as a white solid. Yield: 6mg. LCMS method C: R.sub.t=0.614 min, (M+H).sup.+=595.2. .sup.1HNMR (CD.sub.3OD): .delta. 8.10-8.31 (m, 1H), 7.58-7.86 (m, 2H),7.24-7.40 (m, 1H), 6.81-7.22 (m, 8H), 4.04 (s, 2H), 3.45-3.63 (m,4H), 2.69-3.20 (m, 4H), 1.80-2.03 (m, 4H), 1.23-1.55 (m, 6H)..sup.19F NMR (CD.sub.3OD): .delta. -76.92, -121.82.
Example 64
2-(1,4-dioxaspiro[4.5]decan-8-ylmethyl)-6-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane
##STR00307##
The title compound was prepared from Intermediate 27 (200 mg, 0.49mmol) and 1,4-dioxaspiro[4.5]decane-8-carbaldehyde (101 mg, 0.59mmol), by reductive amination as described in Step 4 of Example 11.The product was purified by RP-HPLC method D to give2-(1,4-dioxaspiro[4.5]decan-8-ylmethyl)-6-(5-(4-fluoro-2-(4-isopropylpyri-midin-5-yl)phenoxy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane aslight-yellow oil. Yield: 50 mg. LCMS method D: R.sub.t=0.803 min,(M+H).sup.+=561.4 .sup.1H NMR (CD.sub.3OD): .delta. 9.09 (s, 1H),8.63 (s, 1H), 8.18 (s, 1H), 7.61-7.68 (m, 1H), 7.20-7.30 (m, 2H),7.03-7.10 (m, 1H), 4.17 (s, 4H), 3.90 (s, 4H), 3.36 (s, 4H),3.01-3.11 (m, 1H), 2.30-2.35 (m, 2H), 1.68-1.78 (m, 4H), 1.43-1.51(m, 2H), 1.32-1.39 (m, 1H), 1.15-1.26 (m, 8H). .sup.19F NMR(CD.sub.3OD): .delta. -119.88.
Example 65
4-((6-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-2,-6-diazaspiro[3.3]heptan-2-yl) methyl)cyclohexanol
##STR00308##
(2-(1,4-dioxaspiro[4.5]decan-8-ylmethyl)-6-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane(1.0 mmol) was treated with 4 N aq. HCl (10 ml) at RT for 6 h. Thesolvent was removed via rotary evaporation, the crude product wasmixed with MeOH (5 mL), NaBH.sub.4 (3.0 mmol) was added and theresulting mixture was stirred for 30 min. The solvent was removedvia rotary evaporation and the resulting residue was purified byRP-HPLC method A to give4-((6-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-2-,6-diazaspiro[3.3]heptan-2-yl) methyl)cyclohexanol (TFA salt) as acolorless oil. Yield: 6.3 mg. LCMS method C: R.sub.t=0.854 min,(M+H).sup.+=519.4 .sup.1H NMR (CD.sub.3OD): .delta. 9.12 (s, 1H),8.63 (s, 1H), 8.39 (s, 1H), 7.80 (s, 1H), 7.25-7.41 (m, 3H),4.22-4.65 (m, 8H), 3.43-3.53 (m, 1H), 3.00-3.14 (m, 3H), 1.94-1.99(m, 2H), 1.72-1.79 (m, 2H), 1.50-1.59 (m, 1H), 1.03-1.33 (m, 10H)..sup.19F NMR (CD.sub.3OD): .delta. -117.71, -77.02.
Example 66
2-cyclopropyl-5'-fluoro-2'-((4-(6-((4-hydroxycyclohexyl)methyl)-2,6-diazas-piro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)-[1,1'-biphenyl]-4-carbonitrile
##STR00309##
The title product was synthesized according to the method describedfor Example 65 starting from2'-((4-(2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)-2-cyclopropyl--5'-fluoro-[1,1'-biphenyl]-4-carbonitrile (Intermediate 32). LCMSmethod D: R.sub.t=1.154 min, (M+H).sup.+=540.4.
Example 67
2-(5-((5-fluoro-2'-(1-methoxyethyl)-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-y-l)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane
##STR00310##
Step 1. tert-butyl6-(5-((2'-acetyl-5-fluoro-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,6-di-azaspiro[3.3]heptane-2-carboxylate
##STR00311##
To a solution of tert-butyl6-(5-(2-bromo-4-fluorophenoxy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane--2-carboxylate (Intermediate 20, 150 mg, 0.322 mmol),(2-acetylphenyl)boronic acid (63 mg, 0.387 mmol) andK.sub.3PO.sub.4 (205 mg, 0.97 mmol) in dioxane/H.sub.2O (2 mL/0.5mL) was added Sphos palladcycle (23 mg, 0.032 mmol) under N.sub.2.The reaction mixture was sealed and heated in a microwave at115.degree. C. for 0.5 h. The mixture was then diluted withH.sub.2O (20 mL), filtered and extracted with ethyl acetate (20mL.times.3). The combined organic layers were dried over anhydrousNa.sub.2SO.sub.4, filtered, and the filtrate was concentrated underreduced pressure. The crude residue were combined and purified bycolumn chromatography on silica gel (eluting with petroleumether:ethyl acetate=10:1 to 2:3) to afford tert-butyl6-(5-((2'-acetyl-5-fluoro-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,6-di-azaspiro[3.3]heptane-2-carboxylate as a yellow oil. Yield: 180 mg.LCMS method C: R.sub.t=0.755 min, (M+H).sup.+=505.2
Step 2.6-(5-((5-fluoro-2'-(1-hydroxyethyl)-[1,1'-biphenyl]-2-yl)oxy)pyrim-idin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate
##STR00312##
To a solution of tert-butyl6-(5-((2'-acetyl-5-fluoro-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,6-di-azaspiro[3.3]heptane-2-carboxylate (180 mg, 0.36 mmol) in anhydrousTHF (10 mL) was added NaBH.sub.4 (40 mg, 1.07 mmol) at -30.degree.C. under N.sub.2 and the reaction mixture was stirred at RT for 2h. The mixture was quenched with H.sub.2O (20 mL) and concentratedunder reduced pressure to remove THF and MeOH. The residue wasextracted with EtOAc (20 mL.times.3) and the combined organiclayers were dried over anhydrous Na.sub.2SO.sub.4, filtered and thefiltrate was concentrated under reduced pressure to affordtert-butyl6-(5-((5-fluoro-2'-(1-hydroxyethyl)-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4--yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate as a yellow solid,which was used in the next step without further purification.Yield: 181 mg. LCMS method C: R.sub.t=0.745 min,(M+H).sup.+=507.2
Step 3. tert-butyl6-(5-((5-fluoro-2'-(1-methoxyethyl)-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate
##STR00313##
To a solution of tert-butyl6-(5-((5-fluoro-2'-(1-hydroxyethyl)-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4--yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (100 mg, 0.20 mmol) inanhydrous THF (5 mL) was added NaH (40 mg, 1.00 mmol, 60% inmineral oil) at 0.degree. C. under N.sub.2 and the reaction mixturewas stirred at 0.degree. C. for 0.5 h. MeI (2.19 g, 15.43 mmol) wasthen added and the reaction mixture was stirred at RT for 18 h. Themixture was quenched with H.sub.2O (0.1 mL) and concentrated underreduced pressure and purified by column chromatography on silicagel (eluting with petroleum ether:ethyl acetate=10:1 to 2:3) toafford tert-butyl6-(5-((5-fluoro-2'-(1-methoxyethyl)-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4--yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate as a yellow oil.Yield: 43 mg. LCMS method C: R.sub.t=0.748 min,(M+H).sup.+=521.2
Step 4.2-(5-((5-fluoro-2'-(1-methoxyethyl)-[1,1'-biphenyl]-2-yl)oxy)pyrim-idin-4-yl)-2,6-diazaspiro[3.3]heptane
##STR00314##
To a solution of tert-butyl6-(5-((5-fluoro-2'-(1-methoxyethyl)-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4--yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (43 mg, 0.082 mmol) inanhydrous DCM (10 mL) was added TFA (2 mL) at 0.degree. C. and thereaction mixture was stirred at 19-26.degree. C. for 2 h. Themixture was diluted with 1N NaOH (20 mL) and extracted with ethylacetate (20 mL.times.3). The combined organic layers were driedover anhydrous Na.sub.2SO.sub.4, filtered and the filtrate wasconcentrated under reduced pressure to afford2-(5-((5-fluoro-2'-(1-methoxyethyl)-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4--yl)-2,6-diazaspiro[3.3]heptane as a yellow oil, which was used inthe next step without further purification.
Step 5.2-(5-((5-fluoro-2'-(1-methoxyethyl)-[1,1'-biphenyl]-2-yl)oxy)pyrim-idin-4-yl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane
A solution of2-(5-((5-fluoro-2'-(1-methoxyethyl)-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4--yl)-2,6-diazaspiro[3.3]heptane (35 mg, 0.083 mmol, crude),tetrahydro-2H-pyran-4-carbaldehyde (19 mg, 0.17 mmol), and HOAc (20.mu.L) in anhydrous MeOH (10 mL) was stirred at 19-25.degree. C.for 0.5 h. NaBH.sub.3CN (21 mg, 0.33 mmol) was then added and thereaction mixture was stirred at 60.degree. C. for 4 h, at whichtime LCMS showed the desired product was produced. The mixture wasthen concentrated under reduced pressure and the resulting residuepurified by HPLC method A to afford2-(5-((5-fluoro-2'-(1-methoxyethyl)-[1,1'-biphenyl]-2-yl)oxy)pyrim-idin-4-yl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane(TFA salt) as a white solid. Yield: 22 mg. LCMS method C:R.sub.t=0.735 min, (M+H).sup.+=519.2 .sup.1H NMR (CD.sub.3OD):.delta. 8.38 (d, J=1.6 Hz, 1H), 7.72 (s, 1H), 7.55-7.60 (m, 1H),7.40-7.50 (m, 1H), 7.30-7.34 (m, 3H), 7.13-7.28 (m, 2H),4.4.25-4.60 (m, 9H), 3.94 (d, J=11.6 Hz, 2H), 3.35-3.45 (m, 2H),3.05-3.15 (m, 5H), 1.80-1.95 (m, 1H), 1.62 (d, J=12.4 Hz, 2H),1.27-1.37 (m, 5H). .sup.19F NMR (MeOD): .delta. -76.83, 117.75.
Example 68
5-(5-fluoro-2-((4-(6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3-]heptan-2-yl)pyrimidin-5-yl)oxy)phenyl)-2,3-dihydro-1H-inden-2-amine
##STR00315##
Step 1.2-(5-(2-bromo-4-fluorophenoxy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]-heptane
##STR00316##
To a mixture of Intermediate 20 (120 mg, 0.3 mmol) inCH.sub.2Cl.sub.2 (3 mL) was added TFA (1 mL) under ice-cold waterand the resulting mixture was stirred at RT for 2 h. The mixturewas then concentrated under reduced pressure and the residue wasadjusted to pH 10-12 with 10% NaOH solution and extracted withCH.sub.2Cl.sub.2 (3.times.30 mL). The combined organic layers weredried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure to give2-(5-(2-bromo-4-fluorophenoxy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptaneas a yellow solid, which was used in the next step without furtherpurification.
Step 2.2-(5-(2-bromo-4-fluorophenoxy)pyrimidin-4-yl)-6-((tetrahydro-2H-py-ran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane
##STR00317##
A mixture of2-(5-(2-bromo-4-fluorophenoxy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane(90 mg, 0.24 mmol), tetrahydro-2H-pyran-4-carbaldehyde (41 mg, 0.36mmol), NaBH.sub.3CN (60 mg, 0.96 mmol) and HOAc (0.05 mL) in MeOH(5 mL) was stirred at 70.degree. C. for 5 h. Sat. solution ofNaHCO.sub.3 was then added to adjust the pH to 8. The mixture wasconcentrated under reduced pressure. Water (20 mL) was added to theresidue and subsequently extracted with EtOAc (2.times.30 mL). Thecombined organic layers were dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The residue waspurified by column chromatography on silica gel (eluting withdichloromethane:methanol=10:1) to give2-(5-(2-bromo-4-fluorophenoxy)pyrimidin-4-yl)-6-((tetrahydro-2H-pyran-4-y-l)methyl)-2,6-diazaspiro[3.3]heptane as a white solid. Yield: 90mg. LCMS method C: R.sub.t=0.539 min, (M+H).sup.+=463.0, 465.0(bromine isotopes).
Step 3. tert-butyl(5-(5-fluoro-2-((4-(6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3-.3]heptan-2-yl)pyrimidin-5-yl)oxy)phenyl)-2,3-dihydro-1H-inden-2-yl)carbamate
##STR00318##
To a mixture of2-(5-(2-bromo-4-fluorophenoxy)pyrimidin-4-yl)-6-((tetrahydro-2H-pyran-4-y-l)methyl)-2,6-diazaspiro[3.3]heptane (50 mg, 0.13 mmol), tert-butyl(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-y-l)carbamate (59 mg, 0.17 mmol) and K.sub.3PO.sub.4 (70 mg, 0.33mmol) in dioxane (2 mL) and H.sub.2O (0.5 mL) was added SphosPalladacycle (8 mg, 0.011 mmol) under N.sub.2 and the mixture wasstirred at 115.degree. C. for 30 min in a microwave. The mixturewas then concentrated under reduced pressure. The resulting residuewas added to H.sub.2O (20 mL) and extracted with EtOAc (2.times.30mL). The combined organic layers were dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. Theresidue was purified by preparative TLC on silica gel (eluting withdichloromethane:methanol=10:1) to give tert-butyl(5-(5-fluoro-2-((4-(6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3-.3]heptan-2-yl)pyrimidin-5-yl)oxy)phenyl)-2,3-dihydro-1H-inden-2-yl)carbam-ate as a yellow oil. Yield: 35 mg.
Step 4.5-(5-fluoro-2-((4-(6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazas-piro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)phenyl)-2,3-dihydro-1H-inden-2-ami-ne
To a mixture of tert-butyl(5-(5-fluoro-2-((4-(6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3-.3]heptan-2-yl)pyrimidin-5-yl)oxy)phenyl)-2,3-dihydro-1H-inden-2-yl)carbam-ate (35 mg, 0.06 mmol) in CH.sub.2Cl.sub.2 (3 mL) was added TFA (1mL) under ice-cold water and the mixture was stirred at RT for 2 h.The mixture was concentrated under reduced pressure and the residuewas purified by RP-HPLC method D to give5-(5-fluoro-2-((4-(6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.-3]heptan-2-yl)pyrimidin-5-yl)oxy)phenyl)-2,3-dihydro-1H-inden-2-amineas a white solid. Yield: 1.2 mg. LCMS method C: R.sub.t=0.516 min,(M+H).sup.+=516.2 .sup.1H NMR (CD.sub.3OD): .delta. 8.10 (s, 1H),7.30-7.40 (m, 4H), 7.10-7.23 (m, 3H), 4.31 (s 4H), 3.90-4.05 (m,3H), 3.35-3.40 (m, 8H), 2.85-2.95 (m, 2H), 2.37-2.39 (d, J=6.0 Hz,2H), 1.62-1.64 (d, J=10.0 Hz, 3H), 1.20-1.35 (m, 2H). .sup.19F NMR(CD.sub.3OD): .delta. -76.93, -119.56.
Example 69
5-((7-(5-((5-fluoro-2'-(1-hydroxypropan-2-yl)-[1,1'-biphenyl]-2-yl)oxy)pyr-imidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol-2(3-H)-one
##STR00319##
Step 1. tert-butyl7-(5-((2'-bromo-5-fluoro-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4] nonane-2-carboxylate
##STR00320##
A 100 mL round flask equipped with a nitrogen balloon and acondenser were charged with tert-butyl7-(5-(2-bromo-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2--carboxylate (Intermediate 11, 1.0 g, 2.0 mmol), EtOH (20 mL),toluene (8 mL) and H.sub.2O (8 mL) respectively. To the resultingmixture was added (2-bromophenyl)boronic acid (0.41 g, 2.0 mmol),Pd(OAc).sub.2 (9 mg, 0.04 mmol), PPh.sub.3 (26 mg, 0.1 mmol) andNa.sub.2CO.sub.3 (636 mg, 6.0 mmol) respectively, under N.sub.2with stirring. After addition, the final mixture was degassed andpurged with N.sub.2 3 times, then heated at 75-80.degree. C. underN.sub.2 for 16 h. The mixture was then concentrated under reducedpressure to remove organic solvents and H.sub.2O (30 mL) and brine(30 mL) were added to the residue, then extracted with EtOAc (20mL.times.3). The combined organic layers were washed with brine (20mL.times.2), dried over Na.sub.2SO.sub.4, filtered and concentratedunder reduced pressure, and the resulting residue was purified byRP-HPLC method D to give tert-butyl7-(5-((2'-bromo-5-fluoro-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,7-dia-zaspiro[4.4]nonane-2-carboxylate as a white solid. Yield: 0.26 g.LCMS method D: R.sub.t=1.074 min, (M+H).sup.+=569.2.
Step 2. tert-butyl7-(5-((5-fluoro-2'-(prop-1-en-2-yl)-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate
##STR00321##
To a suspension of tert-butyl7-(5-((2'-bromo-5-fluoro-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,7-dia-zaspiro[4.4]nonane-2-carboxylate (0.26 g, 0.37 mmol) in dioxane (15mL) and H.sub.2O (3 mL) was added4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (0.12 g,0.74 mmol) and K.sub.3PO.sub.4 (0.16 g, 0.74 mmol), Sphospalladacycle (13 mg, 0.019 mmol) under a nitrogen atmosphere. Theresulting mixture was degassed and purged with N.sub.2 3 times, andsubsequently heated at 70-75.degree. C. under N.sub.2 for 24 h. Anadditional batch of4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (70 mg,0.42 mmol) and Sphos palladacycle (7 mg, 0.0097 mmol) were addedunder N.sub.2, and the resulting mixture was heated at70-75.degree. C. under N.sub.2 for another 18 h, at which time LCMSshowed the reaction was complete. After cooling, H.sub.2O (30 mL)and brine (30 mL) were added to the mixture, which was thenextracted with EtOAc (20 mL.times.3). The combined organic layerswere washed with brine (20 mL.times.2), dried overNa.sub.2SO.sub.4, filtered and concentrated under reduced pressure,and the resulting residue was purified by column chromatography onsilica gel (petroleum ether:EtOAc=1:1 to 1:2) to give tert-butyl7-(5-((5-fluoro-2'-(prop-1-en-2-yl)-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate as a whitesolid. Yield: 0.20 g. LCMS method D: R.sub.t=1.108 min,(M+H).sup.+=531.2. .sup.1H NMR (CDCl.sub.3): .delta. 8.35 (s, 1H),7.83 (s, 1H), 7.20-7.35 (m, 3H), 7.10-7.15 (m, 1H), 6.90-7.10 (m,2H), 6.65-6.75 (m 1H), 5.03 (s, 1H), 4.80 (s, 1H), 3.50-3.65 (m2H), 3.35-3.50 (m, 3H), 3.20-3.35 (m, 1H), 3.10-3.20 (m, 2H), 1.82(s, 3H), 1.70-1.80 (m, 4H), 1.47 (s, 9H). .sup.19F NMR(CDCl.sub.3): .delta. -120.31.
Step 3. tert-butyl7-(5-((5-fluoro-2'-(1-hydroxypropan-2-yl)-[1,1'-biphenyl]-2-yl)oxy)pyrimi-din-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate
##STR00322##
A 500 mL round flask equipped with a nitrogen balloon charged withtert-butyl7-(5-((5-fluoro-2'-(prop-1-en-2-yl)-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4--yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (140 mg, 0.23 mmol) andTHF (5 mL, dry) under nitrogen atmosphere, and the resultingmixture was cooled to 0-3.degree. C. under N.sub.2. BH.sub.3-THF (1mL, 1.0 mmol, 1.0 M in THF) was then added dropwise at 0-3.degree.C. under N.sub.2 with stirring, and the reaction mixture wasstirred at 0-3.degree. C. under N.sub.2 for 1 h, then warmed to RTovernight. H.sub.2O (0.5 mL) and NaBO.sub.3.4H.sub.2O (50 mg, 0.32mmol) were added sequentially and the resulting mixture was stirredat RT for 3 h. The reaction was quenched by addition of H.sub.2O(30 mL). Brine (30 mL) was added to the residue and the mixture wasextracted with EtOAc (15 mL.times.3). The combined organic layerswere washed with brine (15 mL.times.2), dried overNa.sub.2SO.sub.4, filtered and concentrated under reduced pressure,and the resulting residue was purified using preparative TLC onsilica gel (petroleum ether:EtOAc=1:4) to give tert-butyl7-(5-((5-fluoro-2'-(1-hydroxypropan-2-yl)-[1,1'-biphenyl]-2-yl)oxy)pyrimi-din-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate as a white solid.Yield: 71 mg. LCMS method D: R.sub.t=1.019 min,(M+H).sup.+=549.2.
Step 4. 2-(2'-((4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5'-fluoro-[1,1'-biphenyl]-2-yl)propan-1-ol
##STR00323##
To a solution of tert-butyl7-(5-((5-fluoro-2'-(1-hydroxypropan-2-yl)-[1,1'-biphenyl]-2-yl)oxy)pyrimi-din-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (35 mg, 0.064mmol) in CH.sub.2Cl.sub.2 (3 mL) was added HCl-MeOH (0.5 mL, 2mmol, 4 M in MeOH) at 0-3.degree. C. with stirring and the reactionmixture was stirred for 1 h. The reaction was quenched by additionof H.sub.2O (5 mL), and adjusted to pH=12 with 10% aq. NaOH. Brine(10 mL) was added and the mixture was extracted withCH.sub.2Cl.sub.2 (10 mL.times.2). The combined organic layers werewashed with brine (10 mL.times.2), dried over Na.sub.2SO.sub.4,filtered and concentrated under reduced pressure to give crude2-(2'-((4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5'-fluoro-[1-,1'-biphenyl]-2-yl)propan-1-ol as a yellow sticky solid.
Step 5.5-((7-(5-((5-fluoro-2'-(1-hydroxypropan-2-yl)-[1,1'-biphenyl]-2-yl-)oxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imi-dazol-2(3H)-one
##STR00324##
To a suspension of2-(2'-((4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5'-fluoro-[1-,1'-biphenyl]-2-yl)propan-1-ol (20 mg, 0.45 mmol) and2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbaldehyde (Intermediate40, 7.3 mg, 0.045 mmol) in anhydrous MeOH (3 mL) was addedNaBH.sub.3CN (5.8 mg, 0.09 mmol) under a nitrogen atmosphere andthe mixture was stirred at 60-65.degree. C. for 16 h. An additionalbatch of 2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbaldehyde (10mg, 0.062 mmol) and NaBH.sub.3CN (7 mg, 0.11 mmol) were added, thereaction mixture was stirred at 60-65.degree. C. for an additional18 h. The reaction mixture was concentrated under reduced pressureand purified by RP-HPLC-method A to give5-((7-(5-((5-fluoro-2'-(1-hydroxypropan-2-yl)-[1,1'-biphenyl]-2-y-l)oxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imi-dazol-2(3H)-one (TFA salt) as a white solid. Yield: 13 mg. LCMSmethod E: R.sub.t=1.752 min, (M+H).sup.+=595.2 .sup.1H NMR(CD.sub.3OD): .delta. 8.45 (s, 1H), 7.74 (s, 1H), 7.07-7.44 (m,10H), 4.35-4.50 (m, 2H), 3.40-3.95 (m, 9H), 3.10-3.25 (m, 1H),2.75-2.85 (m, 1H), 1.95-2.20 (m, 4H), 1.00-1.25 (m, 3H). .sup.19FNMR (C MeOD): .delta. -117.47, -76.69.about.-77.90.
Example 70
5-((7-(5-(4-fluoro-2-(morpholinomethyl)phenoxy)pyrimidin-4-yl)-2,7-diazasp-iro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one
##STR00325##
Step 1. tert-butyl7-(5-(4-fluoro-2-(morpholine-4-carbonyl)phenoxy)pyrimidin-4-yl)-2,7-diaza-spiro[4.4]nonane-2-carboxylate
##STR00326##
To a solution of2-((4-(7-(tert-butoxycarbonyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5--yl)oxy)-5-fluorobenzoic acid (Intermediate 33, Step 2, 60 mg, 0.13mmol) in anhydrous CH.sub.2Cl.sub.2 (5 mL) was added HATU (61 mg,0.16 mmol), DIEA (168 mg, 1.3 mmol) and morpholine (113 mg, 1.3mmol) and the mixture was stirred at 7.degree. C. for 16 h. Thereaction mixture was concentrated under reduced pressure andpurified by silica gel chromatography (CH.sub.2Cl.sub.2:MeOH=20:1)to afford crude tert-butyl7-(5-(4-fluoro-2-(morpholine-4-carbonyl)phenoxy)pyrimidin-4-yl)-2,7-diaza-spiro[4.4]nonane-2-carboxylate as a brown oil. Yield: 60 mg. LCMSmethod C: R.sub.t=0.700 min, (M+H).sup.+=528.2.
Step 2. tert-butyl7-(5-(4-fluoro-2-(morpholinomethyl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro-[4.4]nonane-2-carboxylate
##STR00327##
To a solution of tert-butyl7-(5-(4-fluoro-2-(morpholine-4-carbonyl)phenoxy)pyrimidin-4-yl)-2,7-diaza-spiro[4.4]nonane-2-carboxylate (50 mg, 0.09 mmol) in anhydrous THF(5 mL) was added BH.sub.3-Me.sub.2S (0.2 mL, 10.0 M in Me.sub.2S)at 0.degree. C. and the mixture was stirred at 60.degree. C. for 4h under N.sub.2. The reaction mixture was quenched with MeOH (5 mL)at 0.degree. C. and stirred at 60.degree. C. for 0.5 h. Theresulting mixture was concentrated under reduced pressure to afforda residue which was purified by silica gel chromatography(CH.sub.2Cl.sub.2:MeOH=20:1) to give tert-butyl7-(5-(4-fluoro-2-(morpholinomethyl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro-[4.4]nonane-2-carboxylate as a white solid. Yield: 35 mg. LCMSmethod C: R.sub.t=0.642 min, (M+H).sup.+=514.2.
Step 3.4-(2-((4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluo-robenzyl)morpholine
##STR00328##
To a solution of tert-butyl7-(5-(4-fluoro-2-(morpholinomethyl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro-[4.4]nonane-2-carboxylate (35 mg, 0.05 mmol) in anhydrousCH.sub.2Cl.sub.2 (3 mL) was added TFA (1 mL) and the mixture wasstirred at 10.degree. C. for 0.5 h under N.sub.2. The reactionmixture was concentrated under reduced pressure to afford a residuewhich was adjusted to pH 9-10 with 10% NaOH solution and extractedwith EtOAc (5 mL). The organic layer was dried over anhydrousNa.sub.2SO.sub.4, filtered and concentrated under reduced pressureto give4-(2-((4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluorobenzy-l)morpholine as a brown oil which was used in the next step.
Step 4.5-((7-(5-(4-fluoro-2-(morpholinomethyl)phenoxy)pyrimidin-4-yl)-2,7--diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one
To a solution of4-(2-((4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluorobenzy-l)morpholine (20 mg, crude, 0.05 mmol) and2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbaldehyde (Intermediate40, 16 mg, 0.10 mmol) in anhydrous MeOH (3 mL) was addedNaBH.sub.3CN (17 mg, 0.25 mmol) under N.sub.2 and the reactionmixture was stirred at 55.degree. C. for 16 h. The reaction mixturewas concentrated under reduced pressure to afford a residue whichwas purified by RP-HPLC method F to give the compound5-((7-(5-(4-fluoro-2-(morpholinomethyl)phenoxy)pyrimidin-4-yl)-2,7-diazas-piro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one as awhite solid. Yield: 7.10 mg. LCMS method E: R.sub.t=1.635 min,(M+H).sup.+=560.2. .sup.1H NMR (CD.sub.3OD): .delta. 8.23 (s, 1H),7.57 (s, 1H), 7.27 (dd, J=9.2, 3.2 Hz, 1H), 7.00-7.05 (dd, J=8.8,4.4 Hz, 4H), 3.74-3.81 (m, 3H), 3.57-3.68 (m, 9H), 2.59-2.74 (m,3H), 2.45-2.51 (m, 5H), 1.93-1.99 (s, 2H), 1.84 (t, J=6.8 Hz, 2H)..sup.19F NMR (CD.sub.3OD): .delta. -121.05.
Example 71
1-(7-(5-((2'-ethyl-5-fluoro-[1,1'-biphenyl]-2-yl)amino)pyrimidin-4-yl)-2,7--diazaspiro[3.5]nonan-2-yl)-2-methylpropan-2-ol
##STR00329##
Step 1. tert-butyl7-(5-iodopyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate
##STR00330##
To a solution of 4-chloro-5-iodopyrimidine (2 g, 8.3 mmol) in MeCN(30 mL) was added tert-butyl2,7-diazaspiro[3.5]nonane-2-carboxylate (1.9 g, 8.3 mmol) andK.sub.2CO.sub.3 (2.3 g, 16.6 mmol) and the resulting suspension wasstirred at 90.degree. C. for 16 h. The mixture was filtered and thefiltrate was concentrated and then purified by ISCO column onsilica gel (petroleum ether:EtOAc=10:1 to 3:1) to afford tert-butyl7-(5-iodopyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate asa yellow solid. Yield: 3.4 g. LCMS method C: R.sub.t=0.718 min,(M+H).sup.+=431.1.
Step 2. tert-butyl7-(5-((2-bromo-4-fluorophenyl)amino)pyrimidin-4-yl)-2,7-diazaspiro[3.5]no-nane-2-carboxylate
##STR00331##
To a solution of tert-butyl7-(5-iodopyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate(350 mg, 0.813 mmol) and 2-bromo-4-fluoroaniline (186 mg, 0.976mmol) and NaO.sup.tBu (234 mg, 2.44 mmol) in anhydrous toluene (5mL) was added Pd.sub.2(dba).sub.3 (37 mg, 0.041 mmol) under N.sub.2and the reaction mixture was sealed and heated in a microwave at120.degree. C. for 1 h. The mixture was then diluted with H.sub.2O(20 mL), filtered and extracted with ethyl acetate (50 mL.times.3).The combined organic layers were dried over anhydrousNa.sub.2SO.sub.4, filtered, and the filtrate was concentrated underreduced pressure and purified by column chromatography on silicagel eluting with petroleum ether:EtOAc (100:0 to 1:1) to affordtert-butyl7-(5-((2-bromo-4-fluorophenyl)amino)pyrimidin-4-yl)-2,7-diazaspiro[3.5]no-nane-2-carboxylate as a brown solid. Yield: 485 mg. LCMS method E:R.sub.t=2.229 min, (M+H).sup.+=492.1, 494.1 (bromine isotopes).
Step 3. tert-butyl7-(5-((2'-ethyl-5-fluoro-[1,1'-biphenyl]-2-yl)amino)pyrimidin-4-yl)-2,7-d-iazaspiro[3.5]nonane-2-carboxylate
##STR00332##
To a mixture of tert-butyl7-(5-((2-bromo-4-fluorophenyl)amino)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (350 mg, 0.711 mmol), (2-ethylphenyl) boronicacid (128 mg, 0.853 mmol) and Na.sub.2CO.sub.3 (226 mg, 2.133 mmol)in dioxane/H.sub.2O (20 mL/5 mL) was added Pd(dppf)Cl.sub.2 (52 mg,0.071 mmol) under N.sub.2 and the reaction mixture was stirred at100.degree. C. for 18 h. The mixture was then diluted with H.sub.2O(20 mL), filtered and extracted with EtOAc (20 mL.times.3). Thecombined organic layers were dried over anhydrous Na.sub.2SO.sub.4,filtered, and the filtrate was concentrated under reduced pressureand purified by column chromatography on silica gel eluting withpetroleum ether:EtOAc (10:1 to 3:2) to afford tert-butyl7-(5-((2'-ethyl-5-fluoro-[1,1'-biphenyl]-2-yl)amino)pyrimidin-4-yl)-2,7-d-iazaspiro[3.5]nonane-2-carboxylate as a red oil. Yield: 300 mg.LCMS method C: R.sub.t=0.803 min, (M+H).sup.+=518.3.
Step 4.N-(2'-ethyl-5-fluoro-[1,1'-biphenyl]-2-yl)-4-(2,7-diazaspiro[3.5]n-onan-7-yl)pyrimidin-5-amine
##STR00333##
To a solution of tert-butyl7-(5-((2'-ethyl-5-fluoro-[1,1'-biphenyl]-2-yl)amino)pyrimidin-4-yl)-2,7-d-iazaspiro[3.5]nonane-2-carboxylate (250 mg, 0.483 mmol) inanhydrous DCM (20 mL) was added HCl-dioxane (5 mL, 4 M in dioxane)at 0.degree. C. and the mixture was stirred at 20-24.degree. C. for2 h. The resulting residue was concentrated under reduced pressureand high vacuum to affordN-(2'-ethyl-5-fluoro-[1,1'-biphenyl]-2-yl)-4-(2,7-diazaspiro[3.5]nonan-7--yl)pyrimidin-5-amine HCl salt as a grey oil, which was used in thenext step without further purification.
Step 5.1-(7-(5-((2'-ethyl-5-fluoro-[1,1'-biphenyl]-2-yl)amino)pyrimidin-4--yl)-2,7-diazaspiro[3.5]nonan-2-yl)-2-methylpropan-2-ol
A solution ofN-(2'-ethyl-5-fluoro-[1,1'-biphenyl]-2-yl)-4-(2-(3,3,3-trifluoropropyl)-2-,7-diazaspiro[3.5]nonan-7-yl)pyrimidin-5-amine (20 mg, 0.05 mmol),2,2-dimethyloxirane (5 mg, 0.07 mmol) and Et.sub.3N (24 mg, 0.4 mL,0.24 mmol) in anhydrous EtOH (3 mL) was stirred at 60.degree. C.for 18 h. The mixture was concentrated under reduced pressure andpurified by RP-HPLC method A to afford1-(7-(5-((2'-ethyl-5-fluoro-[1,1'-biphenyl]-2-yl)amino)pyrimidin-4-yl)-2,-7-diazaspiro[3.5]nonan-2-yl)-2-methylpropan-2-ol (TFA salt) as acolorless oil. Yield: 15.8 mg. LCMS method C: R.sub.t=0.616 min,(M+H).sup.+=490.1. .sup.1H NMR (CD.sub.3OD): .delta. 8.39 (s, 1H),7.68 (s, 1H), 7.30-7.40 (m, 2H), 7.15-7.25 (m, 1H), 7.05-7.15 (m,2H), 6.98 (d, J=8.4 Hz, 1H), 6.85-6.95 (m, 1H), 4.15-4.25 (m, 2H),3.95-4.05 (m, 2H), 3.65-3.85 (m, 4H), 3.25-3.35 (m, 2H), 2.40-2.55(m, 2H), 1.70-2.00 (m, 4H), 1.27 (s, 1H), 1.08 (t, J=7.6 Hz, 3H)..sup.19F NMR (CD.sub.3OD): .delta. -76.88, -122.09.
Example 72
1-((6-(5-(4-fluoro-2-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)phen-oxy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)cyclohexan-1-ol
##STR00334##
Step 1. tert-butyl6-(5-(4-fluoro-2-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenoxy-)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate
##STR00335##
To a round bottom flask was added tert-butyl6-(5-(2-bromo-4-fluorophenoxy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane--2-carboxylate (Intermediate 20, 1 g, 1 eq.),(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)boronic acid (598mg, 1.25 eq.), Sphos palladacycle 2.sup.nd generation (47 mg, 0.03eq.; CAS #1375325-64-6) and potassium phosphate tribasic (1.37 g, 3eq.). To this solid mixture was added dioxane (5.6 mL) and water(1.4 mL). The resulting solution was purged with a nitrogen streamfor 1 min and heated at reflux overnight. The reaction mixture wasthen diluted with EtOAc and water. The phases were separated andthe aqueous phase was back-extracted with EtOAc twice. The combinedorganic phases were dried over MgSO.sub.4 and the filtrate wasconcentrated. The crude residue was purified by flashchromatography (80 g SiO.sub.2, ethyl acetate/hexanes as theeluents) yielding tert-butyl6-(5-(4-fluoro-2-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenoxy-)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (1.0 g)as a white solid.
Step 2.2-(5-(4-fluoro-2-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-phenoxy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane (Intermediate101)
##STR00336##
To a round bottom flask was added tert-butyl6-(5-(4-fluoro-2-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenoxy-)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (200 mg,1 eq.), DCM (2 mL) and TFA (2 mL) and the reaction mixture wasstirred for 30 min at RT. The volatiles were then removed undervacuum and the crude residue was co-evaporated with dichloromethanetwice yielding2-(5-(4-fluoro-2-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenoxy-)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane bis-TFA salt (i.e.,Intermediate 101).
Step 3.1-((6-(5-(4-fluoro-2-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5--yl)phenoxy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)cyclohex-an-1-ol
To a round bottom flask was added2-(5-(4-fluoro-2-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenoxy-)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane bis-TFA salt (20 mg, 1eq.), 1-oxaspiro[2.5]octane (16 mg, 5 eq.), triethylamine (21.mu.L, 5 eq.) and isopropanol (2 mL). The flask was capped and themixture was heated at 70.degree. C. overnight. The volatiles werethen removed under vacuum and the resulting crude material waspurified by RP-HPLC Method A yielding1-((6-(5-(4-fluoro-2-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)phe-noxy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)cyclohexan-1-ol(2.42 mg) as a colorless oil. LCMS Method G: R.sub.t=5.58 min.;M+H=575.68. .sup.1H NMR (d4-MeOH) 8.41 (s, 1H), 7.84 (s, 1H),7.25-7.38 (m, 3H), 6.67 (s, 1H), 4.58 (bs, 2H), 4.20-4.49 (m, 6H),3.12-3.32 (m, 7H), 1.39 (m, 5H), 1.24-1.30 (m, 6H).
Example 73
N-(2-amino-2-oxoethyl)-N-(5-fluoro-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d-]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)ph-enyl)isobutyramide
##STR00337##
Step 1. tert-butyl7-(5-(2-(N-(cyanomethyl)isobutyramido)-4-fluorophenoxy)pyrimidin-4-yl)-2,-7-diazaspiro[4.4]nonane-2-carboxylate
##STR00338##
To a solution of tert-butyl7-(5-(4-fluoro-2-isobutyramidophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]-nonane-2-carboxylate (100 mg, 0.2 mmol) in anhydrous THF (4 mL) wasadded NaH (24 mg, 1.0 mmol) under N.sub.2, then the reactionmixture was stirred at RT for 30 min. 2-bromoacetonitrile (48 mg,0.4 mmol) was added and the reaction mixture was stirred at RT for12 h. The solvent was removed under reduced pressure and theresidue was partitioned with EtOAc (10 mL) and H.sub.2O (5 mL). Theorganic layer was washed with brine (20 mL), dried over anhydrousNa.sub.2SO.sub.4, filtered and concentrated under reduced pressureto afford tert-butyl7-(5-(2-(N-(cyanomethyl)isobutyramido)-4-fluorophenoxy)pyrimidin-4-yl)-2,-7-diazaspiro[4.4]nonane-2-carboxylate as a brown oil. Yield: 100mg. LCMS method E: R.sub.t=1.190 min, (M+H).sup.+=539.3.
Step 2.N-(2-((4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluo-rophenyl)-N-(2-amino-2-oxoethyl)isobutyramide
##STR00339##
To a solution of tert-butyl7-(5-(2-(N-(cyanomethyl)isobutyramido)-4-fluorophenoxy)pyrimidin-4-yl)-2,-7-diazaspiro[4.4]nonane-2-carboxylate (100 mg, 0.185 mmol) inanhydrous CH.sub.2Cl.sub.2 (10 mL) was added TFA (2 mL) underN.sub.2 and the reaction mixture was stirred at RT for 2 h. Thesolvent was removed under reduced pressure to afford a residue andthe pH was adjusted to 9-10 with 10% NaOH. Then the mixture wasextracted with CH.sub.2Cl.sub.2 (10 mL.times.3). The organic layerswere concentrated under reduced pressure to affordN-(2-((4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-f-luorophenyl)-N-(2-amino-2-oxoethyl)isobutyramide as a brown oilwhich was used for the next step without further purification.Yield: 80 mg. LCMS method E: R.sub.t=1.714 min,(M+H).sup.+=457.2.
Step 3.N-(2-amino-2-oxoethyl)-N-(5-fluoro-2-((4-(7-((2-oxo-2,3-dihydro-1H--benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-y-l)oxy)phenyl)isobutyramide
To a solution ofN-(2-((4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoropheny-l)-N-(2-amino-2-oxoethyl)isobutyramide (40 mg, crude) and2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbaldehyde (Intermediate40, 29 mg, 0.18 mmol) in anhydrous MeOH (4 mL) was added 4.ANG.-molecular sieves (50 mg), then the reaction was stirred at50.degree. C. for 2 h under N.sub.2. After 2 h, NaBH.sub.3CN (28mg, 0.45 mmol) was added into the solution and the reaction mixturewas stirred at 50.degree. C. for 12 h. The reaction mixture wasthen filtered, concentrated under reduced pressure, and purified byRP-HPLC method G to affordN-(2-amino-2-oxoethyl)-N-(5-fluoro-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[-d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)p-henyl)isobutyramide as a white solid. Yield: 7.00 mg. LCMS methodE: R.sub.t=1.498 min, (M+H).sup.+=603.3. .sup.1H NMR (CD.sub.3OD):.delta. 8.30 (s, 1H), 7.76 (d, J=2.4 Hz, 1H), 7.52 (d, J=8.8 Hz,1H), 7.15 (t, J=8.0 Hz, 1H), 6.87-7.03 (m, 4H), 4.73 (dd, J=16.4,3.6 Hz, 1H), 3.82 (dd, J=16.0, 4.8 Hz, 1H), 3.56-3.85 (m, 5H),2.45-2.69 (m, 5H), 1.81-1.94 (m, 5H), 1.05 (dd, J=36.8, 6.8 Hz,6H). .sup.19F NMR (CD.sub.3OD): .delta. -119.24.
Example 74
N-(5-fluoro-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohexyl)methyl)-2,7--diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)phenyl)propane-2-sulfonamide
##STR00340##
Step 1. tert-butyl2-(5-(4-fluoro-2-(1-methylethylsulfonamido)phenoxy)pyrimidin-4-yl)-2,7-di-azaspiro[3.5]nonane-7-carboxylate
##STR00341##
A flask was charged with tert-butyl7-(5-bromopyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate(1.264 g, 3.3 mmol),N-(5-fluoro-2-hydroxyphenyl)propane-2-sulfonamide (0.727 g, 3.16mmol), CuI (30 mg, 0.16 mmol), K.sub.3PO.sub.4 (1.34 g, 6.3 mmol)and picolinic acid (20 mg, 0.16 mmol) and was degassed and refilledwith N.sub.2 three times. Anhydrous DMSO (10 mL) was added and themixture was degassed refilled with N.sub.2, and the reactionmixture was heated at 80.degree. C. for 16 h. The reaction mixturewas diluted with EtOAc, washed with H.sub.2O, brine, dried overanhydrous Na.sub.2SO.sub.4 and filtered. The filtrate wasconcentrated to dryness and the resulting residue was purified byflash chromatography using DCM/MeOH as an eluent to afford 1.33 gof tert-butyl 2-(5-(4-fluoro-2-(1-methylethylsulfonamido)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxyla-te. LCMS method B: R.sub.t=1.35 min, (M+H).sup.+=536.3.
Step 2.N-(2-((4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluo-rophenyl)propane-2-sulfonamide
A mixture of tert-butyl2-(5-(4-fluoro-2-(1-methylethylsulfonamido)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (526 mg,0.98 mmol) in MeOH (10 mL) containing 4 M HCl/dioxane (4 mL) wasstirred at RT for 30 min. The reaction mixture was concentratedunder reduced pressure to yieldN-(2-((4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fl-uorophenyl)propane-2-sulfonamide as the HCl salt. LCMS method B:R.sub.t=0.56 min, (M+H).sup.+=436.1.
Steps 3-5.N-(5-fluoro-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohexyl)-methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)phenyl)propane-2--sulfonamide
Steps 3-5 were performed as described for Steps 3-5 of Example 6A.LCMS method A: R.sub.t=0.68 min, (M+H).sup.+=625.1. .sup.1H NMR(CD.sub.3OD) .delta.: 8.50 (s, 1H), 7.62 (brs, 1H), 7.35 (dd,J=8.8, 1.6 Hz, 1H), 7.24 (dd, J=8.8, 1.6 Hz, 1H), 7.03 (m, 1H),4.64 (m, 2H), 4.22 (m, 2H), 3.58 (d, J=12.4 Hz, 2H), 3.47 (m, 1H),3.17 (m, 1H), 3.03-2.94 (m, 7H), 2.28 (d, J=13.6 Hz, 2H), 2.13 (d,J=12.8 Hz, 2H), 2.06 (d, J=10.8 Hz, 2H), 1.87 (d, J=12.8 Hz, 2H),1.81 (m, 1H), 1.41 (d, J=6.8 Hz, 6H), 1.36 (m, 2H), 1.17 (m,2H).
Example 75
tert-butyl7-(5-(4-fluoro-2-(N-methylisobutyramido)phenoxy)pyrimidin-4-yl)--2,7-diazaspiro[4.4]nonane-2-carboxylate
##STR00342##
Step 1: tert-butyl7-(5-(2-amino-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2--carboxylate (Intermediate 102)
##STR00343##
To a mixture of tert-butyl7-(5-(2-bromo-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2--carboxylate (Intermediate 11, 2.0 g, 4.0 mmol) and NaN.sub.3 (1.63g, 25 mmol) in EtOH (20 mL) and H.sub.2O (10 mL) was added CuI (1.0g, 5.0 mmol) and -sodium ascorbate (0.5 g, 2.5 mmol) under N.sub.2and the reaction mixture was stirred at 100.degree. C. for 24 h.The reaction mixture was filtered through Celite and concentratedunder reduced pressure to afford a residue which was purified bycolumn chromatography on silica gel (eluting withDCM:MeOH=1:0-10:1) to afford tert-butyl7-(5-(2-amino-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2--carboxylate as a light brown solid. Yield: 1.4 g. LCMS method C:R.sub.t=0.724 min, (M+H).sup.+=430.1.
Step 2. tert-butyl7-(5-(4-fluoro-2-isobutyramidophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]-nonane-2-carboxylate (Intermediate 103)
##STR00344##
To a mixture of tert-butyl7-(5-(2-amino-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2--carboxylate (700 mg, 1.63 mmol) in pyridine (20 mL) was addedisobutyryl chloride (1.73 g, 16.3 mmol) under N.sub.2 and thereaction mixture was stirred at 19-21.degree. C. for 12 h. Thesolvent was removed under reduced pressure to afford a residuewhich was extracted with EtOAc (20 mL) and H.sub.2O (10 mL). Theorganic layer was washed with brine (20 mL), dried over anhydrousNa.sub.2SO.sub.4, filtered and concentrated under reduced pressureto afford tert-butyl7-(5-(4-fluoro-2-isobutyramidophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]-nonane-2-carboxylate as brown oil. Yield: 700 mg. LCMS method C:R.sub.t=0.732 min, (M+H).sup.+=500.1.
Step 3. tert-butyl7-(5-(4-fluoro-2-(N-methylisobutyramido)phenoxy)pyrimidin-4-yl)-2,7-diaza-spiro[4.4]nonane-2-carboxylate
To a mixture of tert-butyl7-(5-(4-fluoro-2-isobutyramidophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]-nonane-2-carboxylate (400 mg, 0.80 mmol) and CH.sub.3I (500 mg, 3.5mmol) in anhydrous THF (10 mL) was added NaH (96 mg, 4.00 mmol)under N.sub.2 and the reaction mixture was stirred at 12-21.degree.C. for 2 h. The solvent was removed under reduced pressure toafford a residue which was extracted with EtOAc (10 mL) andH.sub.2O (5 mL). The organic layer was washed with brine (20 mL),dried over anhydrous Na.sub.2SO.sub.4, filtered and concentratedunder reduced pressure to afford a residue which was purified bycolumn chromatography on silica gel (eluting withDCM:MeOH=1:0.about.10:1) to afford the tert-butyl7-(5-(4-fluoro-2-(N-methylisobutyramido)phenoxy)pyrimidin-4-yl)-2,7-diaza-spiro[4.4]nonane-2-carboxylate as a white solid. Yield: 201 mg.LCMS method D: R.sub.t=0.995 min, (M+H).sup.+=514.1. .sup.1H NMR(CD.sub.3OD): .delta. 8.29-8.34 (m, 1H), 7.78 (s, 1H), 7.33 (d,J=8.0 Hz, 1H), 7.17-7.21 (m, 1H), 6.85-7.05 (m, 1H), 3.35-3.81 (m,8H), 2.57-2.62 (m, 1H), 1.88-1.97 (m, 5H), 1.45 (s, 11H), 1.05 (dd,J=18.8, 6.8 Hz, 6H). .sup.19F NMR (CD.sub.3OD): .delta.-119.09.
Example 76
N-(5-fluoro-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)--2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)phenyl)-N-methylisobutyra-mide
##STR00345##
Step 1.N-(2-((4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluo-rophenyl)-N-methylisobutyramide
##STR00346##
To a solution of tert-butyl7-(5-(4-fluoro-2-(N-methylisobutyramido)phenoxy)pyrimidin-4-yl)-2,7-diaza-spiro[4.4]nonane-2-carboxylate (Example 75, 70 mg, 0.14 mmol) inanhydrous CH.sub.2Cl.sub.2 (10 mL) was added TFA (2 mL) underN.sub.2 and the reaction mixture was stirred at 19-25.degree. C.for 5 h. The solvent was removed under reduced pressure and theresulting residue was adjusted to pH 9-10 using 10% NaOH solution.The crude residue was then extracted with CH.sub.2Cl.sub.2(3.times.15 mL). The organic layer was concentrated under reducedpressure to affordN-(2-((4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoropheny-l)-N-methylisobutyramide as a brown oil which was used in the nextstep without further purification.
Step 2.N-(5-fluoro-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)phenyl)-N-methyli-sobutyramide
To a mixture ofN-(2-((4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoropheny-l)-N-methylisobutyramide (55 mg, 0.15 mmol) and2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbaldehyde (Intermediate40, 45 mg, 0.28 mmol) in anhydrous MeOH (2 mL) and HOAc (0.1 mL)was added NaBH.sub.3CN (43.4 mg, 0.7 mmol) under N.sub.2 and thereaction mixture was stirred at 65.degree. C. for 2 h, at whichtime LCMS showed that the starting material was consumed. Thereaction mixture was filtered and concentrated under reducedpressure and the resulting residue was diluted with MeOH (5 mL)purified by preparative HPLC Method G to affordN-(5-fluoro-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)--2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)phenyl)-N-methylisobutyr-amide as a white solid. Yield: 7.8 mg. LCMS method E: R.sub.t=0.936min, (M+H).sup.+=560.1. .sup.1H NMR (CD.sub.3OD): .delta. 8.29 (s,1H), 7.74 (s, 1H), 7.32 (d, J=8.4 Hz, 1H), 7.14 (brs, 1H),6.87-6.91 (m, 4H), 3.60-3.73 (m, 2H), 3.61 (d, J=4.4 Hz, 2H), 3.21(s, 3H), 2.45-2.67 (m, 6H), 1.79-1.95 (m, 5H), 1.06 (d, J=6.8 Hz,6H). .sup.19F NMR (CD.sub.3OD): .delta. -119.16.
Example 77
5-((7-(5-(4-fluoro-2-isobutylphenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]no-nan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one
##STR00347##
Step 1. tert-butyl7-(5-(2-benzyl-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane--2-carboxylate
##STR00348##
To a round bottom flask was added tert-butyl7-(5-(2-bromo-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2--carboxylate (Intermediate 11, 50 mg, 1 eq.) and THF (1 mL) and thesolution was purged with a nitrogen stream for 1 min. Benzylzincbromide (610 .mu.L, 0.5 M in THF, 3 eq.) was added and the solutionwas purged with a nitrogen stream. Pd(PtBu.sub.3).sub.2 (3 mg, 0.05eq.) was added and the solution was purged with a nitrogen streamfor 1 min and the solution was heated to 60.degree. C. The reactionmixture was then cooled to RT. Celite was added to the solution andconcentrated under vacuum. The crude residue was purified by flashchromatography (12 g SiO.sub.2, ethyl acetate/hexanes) using a dryloading technique. The corresponding fractions were combined andconcentrated, yielding tert-butyl7-(5-(2-benzyl-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane--2-carboxylate (70 mg).
Steps 2-4.5-((7-(5-(2-benzyl-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspi-ro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one
The title product was synthesized from tert-butyl7-(5-(2-benzyl-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane--2-carboxylate according to the methods described in Steps 3-4 ofExample 41. LCMS method G: R.sub.t=4.07 min.; M+H=551.59.
Example 78
2-(3-((2'-ethyl-5-fluoro-[1,1'-biphenyl]-2-yl)methyl)pyridin-4-yl)-6-((tet-rahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane
##STR00349##
Step 1. tert-butyl6-(3-(2-chloro-4-fluorobenzyl)pyridin-4-yl)-2,6-diazaspiro[3.3]heptane-2--carboxylate
##STR00350##
To a solution of tert-butyl6-(3-bromopyridin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate(63 mg, 0.178 mmol) in anhydrous THF (4 mL) under N.sub.2atmosphere was added (2-chloro-4-fluorophenyl)zinc(II) bromidesolution in THF (0.7 mL, 0.35 mmol, 0.5 M), followed byPd(PBu.sub.3).sub.2 (6 mg, 7 mol %) and the mixture was heated at70.degree. C. for 1.5 h. The reaction mixture was diluted withEtOAc, washed with aqueous NH.sub.4Cl, brine, dried over anhydrousNa.sub.2SO.sub.4, filtered and the filtrate was concentrated todryness. The residue was purified by flash chromatography, followedby preparative HPLC method A to afford 29 mg of tert-butyl6-(3-(2-chloro-4-fluorobenzyl)pyridin-4-yl)-2,6-diazaspiro[3.3]heptane-2--carboxylate as a TFA salt. LCMS method B: R.sub.t=1.17 min.;M+H=418.1.
Step 2. tert-butyl6-(3-((2'-ethyl-5-fluoro-[1,1'-biphenyl]-2-yl)methyl)pyridin-4-yl)-2,6-di-azaspiro[3.3]heptane-2-carboxylate
##STR00351##
tert-Butyl6-(3-(2-chloro-4-fluorobenzyl)pyridin-4-yl)-2,6-diazaspiro[3.3]heptane-2--carboxylate TFA salt (29 mg, 0.055 mmol), (2-ethylphenyl)boronicacid (9.8 mg, 0.065 mmol), K.sub.3PO.sub.4 (80 mg, 0.38 mmol),SPhos-Pd-G2 (8 mg), and dioxane (2 mL) and H.sub.2O (1 mL) weremixed under N.sub.2 atmosphere and heated at 110.degree. C. for 15min in a microwave. The reaction mixture was diluted with EtOAc,washed with H.sub.2O, brine, dried over anhydrous Na.sub.2SO.sub.4,filtered, and the filtrate was concentrated to dryness. The residuewas purified by flash chromatography to afford 16 mg of tert-butyl6-(3-((2'-ethyl-5-fluoro-[1,1'-biphenyl]-2-yl)methyl)pyridin-4-yl)-2,6-di-azaspiro[3.3]heptane-2-carboxylate. LCMS method B: R.sub.t=1.34min.; M+H=488.1.
Step 3:2-(3-((2'-ethyl-5-fluoro-[1,1'-biphenyl]-2-yl)methyl)pyridin-4-yl)--2,6-diazaspiro[3.3]heptane
##STR00352##
tert-Butyl6-(3-((2'-ethyl-5-fluoro-[1,1'-biphenyl]-2-yl)methyl)pyridin-4-yl)-2,6-di-azaspiro[3.3]heptane-2-carboxylate was dissolved in 20% TFA/DCM (1mL) and stirred and RT for 30 min. The solvents were removed togive2-(3-((2'-ethyl-5-fluoro-[1,1'-biphenyl]-2-yl)methyl)pyridin-4-yl)-2,6-di-azaspiro[3.3]heptane as the TFA salt which was used for next stepwithout further purification.
Step 4.2-(3-((2'-ethyl-5-fluoro-[1,1'-biphenyl]-2-yl)methyl)pyridin-4-yl)--6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane
2-(3-((2'-Ethyl-5-fluoro-[1,1'-biphenyl]-2-yl)methyl)pyridin-4-yl)-2,6-di-azaspiro[3.3]heptane was dissolved in MeOH (2 mL), K.sub.2CO.sub.3(40 mg) was added and the resulting mixture was stirred for 10 minand filtered through an HPLC micro filter. The filtrate wasconcentrated to dryness to afford free amine. One third of theamine was dissolved in DCM (1 mL), and to this solution was added 1drop of HOAc and tetrahydro-2H-pyran-4-carbaldehyde (1 drop),followed by NaBH(OAc).sub.3 (18 mg, 0.085 mmol). The mixture wasstirred at RT for 30 min and concentrated to remove the solvent.The resulting residue was purified by preparative HPLC method A togive 1.93 mg of2-(3-((2'-ethyl-5-fluoro-[1,1'-biphenyl]-2-yl)methyl)pyridin-4-yl)-6-((te-trahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane as a TFAsalt. LCMS method B: R.sub.t=0.89 min.; M+H=496.1. .sup.1H NMR(CD.sub.3OD) .delta.: 7.99 (d, J=7.2 Hz, 1H), 7.46 (s, 1H), 7.35(s, 1H), 7.26 (m, 1H), 7.21-7.18 (m, 2H), 6.99 (m, 2H), 6.44 (d,J=7.2 Hz, 2H), 4.43 (m, 4H), 3.95 (m, 2H), 3.84 (d, J=16.4 Hz,2H),), 3.71 (d, J=16.4 Hz, 2H), 3.41 (m, 2H), 3.12 (d, J=7.2 Hz,2H), 2.31 (m, 2H), 1.90 (m, 1H), 1.61 (m, 2H), 1.34 (m, 2H), 1.06(t, J=7.6 Hz, 3H).
Examples 79-240
Examples 79-240 were prepared according to the procedure describedin Table 9 using the appropriate starting materials.Characterization data for Examples 79-240 is shown in Table 10.
TABLE-US-00025 TABLE 9 Examples 79-240 Example Name StructureProcedure 79 N-((1r,4r)-4-((2-(5- (2-(3-cyclopropyl-1-methyl-6-oxo- 1,6-dihydropyridin- 2-yl)-4- fluorophenoxy)pyri-midin-4-yl)-2,7- diazaspiro[3.5]nonan- 7- yl)methyl)cyclohex-yl)-2,2,2- trifluoroacetamide ##STR00353## Synthesized by a methodsimilar to Example 74. In final step trifluoroaceticanhy- dride wasused. 80 N-(4-((2-(5-(2-(3- cyclopropyl-1- methyl-6-oxo-1,6-dihydropyridin-2- yl)-4- fluorophenoxy)pyri- midin-4-yl)-2,7-diazaspiro[3.5]nonan- 7- yl)methyl)cyclohex- yl)methane-sulfonamide ##STR00354## Synthesized by a method similar to Example74 starting from 5- cyclopropyl-6-(5- fluoro-2- hydroxyphenyl)-1-methylpyridin- 2(1H)-one 81A Isomer 1: 5-((7-(5-(2-(3-cyclopropyl- 1-methyl-6-oxo- 1,6-dihydropyridin- 2-yl)-4-fluorophenoxy)pyri- midin-4-yl)-2,7- diazaspiro[4.4]nonan-2-yl)methyl)-1- (2-hydroxyethyl)- 1H- benzo[d]imidazol- 2(3H)-one##STR00355## Synthesized by a method similar to Examples 29A- 29B81B Isomer 2: 5-((7-(5- (2-(3-cyclopropyl- 1-methyl-6-oxo-1,6-dihydropyridin- 2-yl)-4- fluorophenoxy)pyri- midin-4-yl)-2,7-diazaspiro[4.4]nonan- 2-yl)methyl)-1- (2-hydroxyethyl)- 1H-benzo[d]imidazol- 2(3H)-one ##STR00356## Synthesized by a methodsimilar to Examples 29A- 29B 82 (1r,4r)-4-(2-(6-(5- (2-(2-cyclopropylpyridin- 3-yl)-4- fluorophenoxy) pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptan- 2- yl)ethyl)cyclohexan- 1-amine ##STR00357##Synthesized from Example 88 by deprotection with TFA 83 tert-butyl((1r,4r)-4- (((2-(5-(4-fluoro-2- (isopropyl(methyl)car-bamoyl)phenoxy) pyrimidin-4-yl)-2- azaspiro[3.3]heptan- 6-yl)amino)methyl)cyclo- hexyl)carbamate ##STR00358## Synthesizedfrom Intermediate 38 and tert-butyl ((1r,4r)-4- formylcyclohexyl)carbamate by reductive amination as described in step 5 of Example1 84 tert-butyl ((1r,4r)-4- ((2-(5-(2-(N- ethylisobutyramido)- 4-fluorophenoxy)pyri- midin-4-yl)-2,7- diazaspiro[3.5]nonan- 7-yl)methyl)cyclohex- yl)carbamate ##STR00359## Synthesized fromIntermediate 23 by method descibed in synthesis of Example 75. Infinal step, it was condensed with tert-butyl ((1r,4r)-4-formylcyclohexyl) carbamate. 85 methyl ((1r,4r)-4- ((2-(5-(2-(N-ethylisobutyramido)- 4- fluorophenoxy)pyri- midin-4-yl)-2,7-diazaspiro[3.5]nonan- 7- yl)methyl)cyclohex- yl)carbamate##STR00360## Synthesized from Example 84, by acid deprotectionfollowed by reaction with methyl chloroformate 86 N-ethyl-N-(5-fluoro-2-((4-(7- (((1r,4r)-4- (methylsulfonamido)cyclohexyl)methyl)- 2,7-diazaspiro [3.5]nonan-2- yl)pyrimidin-5-yl)oxy)phenyl)iso- butyramide ##STR00361## Synthesized fromIntermediate 23 by method described in synthesis of Example 75. Infinal step, it was condensed with N-((1r,4r)-4- formylcyclohexyl)methane- sulfonamide. 87 2-((4-(6-(2-((1r,4r)- 4-(3,3-dimethyl-butanamido)cyclo- hexyl)ethyl)-2,6- diazaspiro[3.3]heptan-2-yl)pyrimidin- 5-yl)oxy)-5-fluoro- N,N-diisopropyl- benzamide##STR00362## Synthesized from Intermediate 41 by reductiveamination with tert-butyl ((1r,4r)-4-(2- oxoethyl) cyclohexyl)carbamateas described in step 5 of Example 1. The BOC deprotectionwas followed by reaction with 3,3- dimethylbutanoyl chloride. 88tert-butyl ((1r,4r)-4- (2-(6-(5-(2-(2- cyclopropylpyridin- 3-yl)-4-fluorophenoxy)pyri- midin-4-yl)-2,6- diazaspiro[3.3]heptan- 2-yl)ethyl)cyclohexyl) carbamate ##STR00363## Synthesized fromIntermediate 31C and tert-butyl ((1r,4r)-4-(2- oxoethyl)cyclohex-yl)carbamate by method described in step 4 of Example 41 895-fluoro-2-((4-(7- (2-hydroxy-2- methylpropyl)-2,7-diazaspiro[3.5]nonan- 2-yl)pyrimidin-5- yl)oxy)-N,N-diisopropylbenzamide ##STR00364## Synthesized from the intermediateprepared in step 2 of Example 6A and reacting with epoxide bymethod shown in step 5 of Example 71 90 2-((4-(7-((3-cyano-3-methyl-2- oxoindolin-6- yl)methyl)-2,7- diazaspiro[4.4]nonan-2-yl)pyrimidin-5- yl)oxy)-5-fluoro- N,N- diisopropylbenzamide##STR00365## Synthesized from Example 99A and intermediate 46 bythe method described in step 5 of Example 1 91 methyl ethyl(5-fluoro-2-((4-(7-((2- oxo-2,3-dihydro- 1H- benzo[d]imidazol-5-yl)methyl)-2,7- diazaspiro [4.4]nonan-2- yl)pyrimidin-5-yl)oxy)phenyl)carba- mate ##STR00366## Synthesized by methodsimilar to Example 75, starting from Intermediate 2, followed byacylation with methyl- chloroformate and alkylation with ethyliodide 91a 5-fluoro-2-((4-(7- ((1-(2- hydroxyethyl)-2-oxo-2,3-dihydro- 1H- benzo[d]imidazol- 5-yl)methyl)-2,7-diazaspiro[4.4]nonan- 2-yl)pyrimidin-5- yl)oxy)-N- isopropyl-N-methylbenzamide ##STR00367## Synthesized by a method similar toExample 3 from intermediate 33 92 5-fluoro-N- isopropyl-N-methyl-2-((4-(6- ((tetrahydro-2H- pyran-4-yl)amino)- 2-azaspiro[3.3]heptan- 2-yl)pyrimidin-5- yl)oxy)benzamide##STR00368## Synthesized from Intermediate 38 and 4-pyrancarboxyaldehyde by reductive amination as described in step 5 ofExample 1 93 5-fluoro-N- isopropyl-N- methyl-2-((4-(7- (((1r,4r)-4-(methylsulfonamido) cyclohexyl) methyl)-2,7- diazaspiro[3.5]nonan-2- yl)pyrimidin-5- yl)oxy)benzamide ##STR00369##Synthesized from Intermediate 36 and N-((1r,4r)-4-formylcyclohexyl) methanesulfonamide by reductive amination asdescribed in step 5 of Example 1. 94 tert-butyl ((1r,4r)-4-((2-(5-(4-fluoro-2- (isopropyl(methyl)carba- moyl)phenoxy)pyrimidin-4-yl)-2,7- diazaspiro[3.5]nonan- 7- yl)methyl)cyclohex-yl)carbamate ##STR00370## Synthesized from Intermediate 36 andtert-butyl ((1r,4r)-4- formylcyclohexyl) carbamate by reductiveamination as described in step 5 of Example 1 95 methyl ((1r,4r)-4-(92-(5-(4-fluoro-2- (isopropyl(methyl)carba- moyl)phenoxy)pyrimdin-4-yl)-2,7- diazaspiro[3.5]nonan- 7- yl)methyl)cyclohex-yl)carbamate ##STR00371## Synthesized from Intermediate 36 andmethyl ((1r,4r)-4- formylcyclohexyl) carbamate by reductiveamination as described in step 5 of Example 1 96N-(tert-butyl)-2-(5- (4-fluoro-2-(4- isopropylpyrimidin- 5-yl)phenoxy)pyrimid- in-4-yl)-2- azaspiro[3.4]octan- 6-amine##STR00372## Synthesized by the method described in Example 18. Instep 1, tert-butyl 6-oxo-2- azaspiro[3.4]octane- 2-carboxylate wasused. In step 3, tert-butyl amine was utilized. 972-((4-(7-(((1r,4r)-4- (3,3- dimethylureido)cyclo- hexyl)methyl)-2,7-diazaspiro [3.5]nonan-2- yl)pyrimidin-5- yl)oxy)-5-fluoro-N,N-diisopropyl benzamide ##STR00373## Synthesized from theintermediate prepared in step 4 of Example 6A by reaction withdimethylcarbamic chloride 98 5-fluoro-2-((4-(7- ((4-hydroxycyclohexyl) methyl)-2,7- diazaspiro[3.5]nonan-2-yl)pyrimidin-5- yl)oxy)-N,N- diisopropylbenzamide ##STR00374##Synthesized from Example 100 by treatment with acid followed byreduction with NaBH4 99 5-fluoro-2-((4-(6- ((4- hydroxycyclohexyl)methyl)-2,6- diazaspiro[3.4]octan- 2-yl)pyrimidin-5- yl)oxy)-N,N-diisopropylbenzamide ##STR00375## Synthesized by method similar toExample 98 starting from Intermediate 41b 100 2-((4-(7-((1,4-dioxaspiro[4.5]decan- 8-yl)methyl)-2,7- diazaspiro[3.5]nonan-2-yl)pyrimidin-5- yl)oxy)-5-fluoro- N,N- diisopropylbenzamide##STR00376## Synthesized from intermediate prepared in step 2 ofExample 6A by reductive amination with 1,4- dioxaspiro[4.5]de-cane-8- carbaldehyde as described in step 5 of Example 1 1015-fluoro-N,N- diisopropyl-2-((4- (7-((tetrahydro-2H-pyran-4-yl)methyl)- 2,7- diazaspiro[3.5]nonan- 2-yl)pyrimidin-5-yl)oxy)benzamide ##STR00377## Synthesized from intermediate made instep 2 of Example 6A by reductive amination with tetrahydro-2H-pyran-4- carbaldehyde as described in step 5 of Example 1 1025-fluoro-N,N- diisopropyl-2-((4- (6-neopentyl-2,6-diazaspiro[3.4]octan- 2-yl)pyrimidin-5- yl)oxy)benzamide##STR00378## Synthesized from Intermediate 41b by reductiveamination with pivalaldehyde as described in step 5 of Example 1103 2-((4-(6- (cyclopropylmethyl)- 2,6-diazaspiro [3.4]octan-2-yl)pyrimidin-5- yl)oxy)-5-fluoro- N,N- diisopropylbenzamide##STR00379## Synthesized from Intermediate 41b by reductiveamination with cyclopropanecarb- aldehyde as described in step 5 ofExample 1 104 2-((4-(6-(6-cyano- 1,2,3,4-tetrahydro-naphthalen-2-yl)- 2,6- diazaspiro[3.4]octan- 2-yl)pyrimidin-5-yl)oxy)-5-fluoro- N,N-diisopropyl- benzamide ##STR00380##Synthesized from Intermediate 41b by reductive amination with 6-oxo-5,6,7,8- tetrahydronaph- thalene-2- carbonitrile as describedin step 5 of Example 1 105 5-fluoro-N,N- diisopropyl-2-((4-(6-(2-((1r,4r)-4- pivalamidocyclohex- yl)ethyl)-2,6-diazaspiro[3.3]heptan- 2-yl)pyrimidin- 5-yl)oxy)benzamide##STR00381## Synthesized from Intermediate 41 by reductiveamination with N-((1r,4r)-4-(2- oxoethyl) cyclohexyl) pivalamide asdescribed in step 5 of Example 1 106 N-(2-((4-(6-(cyclohexylmethyl)- 2,6-diaza- spiro[3.3]heptan- 2-yl)pyrimidin-5-yl)oxy)-5-fluoro- phenyl)-N- ethylisobutyramide ##STR00382##Synthesized by a method similar to Example 75 starting fromIntermediate 20 107 N-ethyl-5-fluoro-N- isopropyl-2-((4-(7-((1-methyl-2-oxo- 2,3-dihydro-1H- benzo[d]imdazol-5-yl)methyl)-2,7- diazaspiro[4.4]nonan- 2-yl)pyrimidin-5-yl)oxy)benzamide ##STR00383## Synthesized by a method similar toExample 1. In step 3, N- isoprpyl-N-ethyl amine was utilized. 1082-(5-(2- (cyclopentyloxy)-4- fluorophenoxy)pyri- midin-4-yl)-7-((tetrahydro-2H- pyran-4-yl) methyl)-2,7-di- azaspiro[4.4]nonane##STR00384## Synthesized by the method described in Example 54 1092-(5-(2- cyclopropoxy-4- fluoro- phenoxy)pyrimidin- 4-yl)-7-((tetrahydro-2H- pyran-4-yl) methyl)-2,7- diazaspiro[4.4]nonane##STR00385## Synthesized by the method described in Example 54 110N-ethyl-N-(5- fluoro-2-((4-(7- ((tetrahydro-2H- pyran-4-yl)methyl)-2,7- diazaspiro[3.5]nonan- 2-yl)pyrimidin-5- yl)oxy)phenyl)iso-butyramide ##STR00386## Starting from Intermediate 23, it wassynthesized by the method described in Example 75 111 5-fluoro-N,N-diisopropyl-2-((4- (6-((tetrahydro-2H- pyran-4-yl)methyl)- 2,6-diazaspiro[3.4]octan- 2-yl)pyrimidin-5- yl)oxy)benzamide##STR00387## Synthesized from Intermediate 41b by reductiveamination with tetrahydro-2H- pyran-4- carbaldehyde, as describedin step 5 of Example 1 112 5-fluoro-N,N- diisopropyl-2-((4-(6-((tetrahydro-2H- pyran-4-yl)methyl)- 2,6-di-azaspiro[3.3]heptan- 2-yl)pyrimidin- 5-yl)oxy)benzamide##STR00388## Synthesized from Intermediate 41a by reductiveamination with tetrahydro-2H- pyran-4- carbaldehyde, as describedin step 5 of Example 1 113 2-((4-((6-(2-(4- cyanophenyl)acetyl)-2,6- diazaspiro[3.4]octan- 2-yl)pyrimidin-5- yl)oxy)-5-fluoro- N,N-diisopropylbenzamide ##STR00389## Synthesized from Intermediate 41bby amide formation with with 2-(4- cyanophenyl)acetic acid, asdescribed in step 5 of Example 12 114 5-fluoro-2-((4-(6-(6-fluoro-1,2,3,4- tetrahydronaphthalen- 2-yl)-2,6-diazaspiro[3.4]octan- 2-yl)pyrimidin-5- yl)oxy)-N,N-diisopropylbenzamide ##STR00390## Synthesized from Intermediate 41bby reductive amination with 2- fluoro 6-oxo- 5,6,7,8-tetrahydronaph- thalene, as described in step 5 of Example 1 115tert-butyl ((1r,4r)-4- (2-(6-(5-(2-(diiso- propylcarbamoyl)- 4-fluorophenoxy)pyri- midin-4-yl)-2,6- diazaspiro[3.3]heptan- 2-yl)ethyl)cyclohexyl) carbamate ##STR00391## Synthesized fromIntermediate 41a by reductive amination with tert-butyl((1r,4r)-4-(2- oxoethyl)cyclohex- yl)carbamate, as described instep 5 of Example 1. 116 2-((4-(6-(2-(4- cyanophenyl)acetyl)-2,6-di- azaspiro[3.3]heptan- 2-yl)pyrimidin- 5-yl)oxy)-5-fluoro-N,N- diisopropylbenzamide ##STR00392## Synthesized fromIntermediate 41a by amide formation with with 2-(4-cyanophenyl)acetic acid, as described in step 5 of Example 12 117N-ethyl-N-(5- fluoro-2-((4-(6-(5- (methylsulfonyl)- 2,3-dihydro-1H-indene-2-carbonyl)- 2,6diazaspiro[3.3]heptan- 2- yl)pyrimidin-5-yl)oxy)phenyl)iso- butyramide ##STR00393## Synthesized startingwith Example 120 by conversion of bromo to methyl sulfone 1183-(((2-(5-(4-fluoro- 2-(4- isopropylpyrimidin- 5-yl)phenoxy)pyrimidin- 4-yl)-2- azaspiro[3.3]heptan- 6-yl)amino)methyl)bi- cyclo[1.1.1]pentane- 1-carbonitrile##STR00394## Synthesized by method similar to the proceduresdescribed in Example 41. In first step, tert- butyl (2-aza-spiro[3.3]heptan- 6- yl)carbamate was used, in 2.sup.nd step4-isopropyl-4- pyrimidnyl boronic acid was used, and in 4.sup.thstep: 3- formylbicyclo [1.1.1]pentane-1- carbonitrile was used.
119 N-ethyl-N-(5- fluoro-2-((4-(6-(2- (4- (methylsulfonyl)phen-yl)acetyl)-2,6- diazaspiro[3.3]heptan- 2-yl)pyrimidin- 5-yl)oxy)phenyl)isobutyramide ##STR00395## Starting from Intermediate 22 andsynthesized by the method described in Example 12. In final step,2-(4- (methylsulfonyl) phenyl)acetic acid was utilized. 120N-(2-((4-(6-(5- bromo-2,3-dihydro- 1H-indene-2- carbonyl)-2,6-diazaspiro [3.3]heptan-2- yl)pyrimidin-5- yl)oxy)-5-fluorophenyl)-N- ethylisobutyramide ##STR00396## Starting fromIntermediate 22, and synthesized by method described in Example 12.In final step, 5- bromo-2,3- dihydro-1H- indene-2- carboxylic acidwas utilized. 121 N-ethyl-N-(5- fluoro-2-((4-(6- ((tetrahydro-2H-pyran-4-yl)methyl)- 2,6- diazaspiro[3.3]heptan- 2-yl)pyrimidin-5-yl)oxy) phenyl)isobutyramide ##STR00397## Synthesized by a methodsimilar to Example 75, starting from Intermediate 20, and in finalstep, it was condensed with tetrahydro- 2H-pyran-4- carbaldehyde122 N-cyclopropyl-5- fluoro-N-isopropyl- 2-((4-(7-((2-oxo-2,3-dihydro-1H- benzo[d]imidazol- 5-yl)methyl)-2,7-diazaspiro[4.4]nonan- 2-yl)pyrimidin-5- yl)oxy)benzamide##STR00398## Synthesized by a method similar to Example 1. In step4, N- isopropyl-N- cyclopropyl amine was utilized. 1232-((4-(7-((1-(2- acetamidoethyl)-2- oxo-2,3-dihydro- 1H-benzo[d]imidazol- 5-yl)methyl)-2,7- diazaspiro[4.4]nonan-2-yl)pyrimidin-5- yl)oxy)-5-fluoro-N- isopropyl-N- methylbenzamide##STR00399## Synthesized by a method similar to Example 1, startingfrom Intermediate 33. In the final step, Intermediate 46 wasutilized. 124 2-((4-(7-((1-(2- (dimethylamino)eth- yl)-2-oxo-2,3-dihydro-1H- benzo[d]imidazol- 5-yl)methyl)-2,7-diazaspiro[4.4]nonan- 2-yl)pyrimidin-5- yl)oxy)-5-fluoro-N-isopropyl-N- methylbenzamide ##STR00400## Synthesized by a methodsimilar to Example 1, starting from Intermediate 33. In the finalstep, Intermediate 44a was utilized. 125 2-((4-(7-((3-cyano-3-methyl-2- oxoindolin-6- yl)methyl)-2,7- diazaspiro [4.4]nonan-2-yl)pyrimidin-5- yl)oxy)-5-fluoro-N- isopropyl-N- methylbenzamide##STR00401## Synthesized by a method similar to Example 1, startingfrom Intermediate 33. In the final step, Intermediate 46 wasutilized. 126 5-((7-(5-(4-fluoro- 2-(1-isopropyl-1H- pyrazol-5-yl)phenoxy)-2- methylpyrimidin-4- yl)-2,7- diazaspiro[4.4]nonan-2-yl)methyl)-1,3- dihydro-2H- benzo[d]imidazol- 2-one ##STR00402##Synthesized by a method similar to Example 41, starting with 5-bromo-4-chloro- 2-methyl pyrimidine. In 2.sup.nd step, 2-isopropyl-3-pyrazole boronic acid was used. 127 2-((4-(2-(2-(4-cyanophenyl)acetyl)- 2,6- diazaspiro[3.4]octan- 6-yl)pyrimidin-5-yl)oxy)-5-fluoro-N- isopropyl-N- methylbenzamide ##STR00403##Synthesized from Intermediate 37 by coupling with (4-cyano-benzene)acetic acid, as described in Example 12 1282-((4-(7-((1-ethyl-2- oxo-2,3-dihydro- 1H- benzo[d]imidazol-5-yl)methyl)-2,7- diazaspiro[4.4]nonan- 2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N- isopropyl-N- methylbenzamide ##STR00404##Synthesized by a method similar to Example 1, starting fromIntermediate 33. In the final step, 1-ethyl-2-oxo- 2,3-dihydro-1H-benzo[d]imidazole- 5-carbaldehyde was utilized. 129 5-fluoro-N-isopropyl-2-((4-(7- ((1-(2- methoxyethyl)-2- oxo-2,3-dihydro- 1H-benzo[d]imidazol- 5-yl)methyl)-2,7- diazaspiro[4.4]nonan-2-yl)pyrimidin-5- yl)oxy)-N-methyl benzamide ##STR00405##Synthesized by a method similar to Example 1, starting fromIntermediate 33. In the final step, Intermediate 42A was utilized130 4-(2-(6-(5-(4- fluoro-2-(4- isopropylpyrimidin- 5-yl)phenoxy)pyrimidin- 4-yl)-2,6- diazaspiro[3.4]octan- 2-yl)-2-oxoethyl)benzonitrile ##STR00406## Intermediate 28 was coupled with4-cyanobenzene- acetyl chloride, as described in Example 12 1315-((7-(5-(4-fluoro- 2-(4- isopropylpyrimidin- 5-yl)phenoxy)pyrimidin- 4-yl)-2,7- diazaspiro[4.4]nonan-2-yl)methyl)-1- (2-methoxyethyl)- 1,3-dihydro-2H- benzo[d]imidazol-2-one ##STR00407## Synthesized by a method similar to Example 41.In step 2, 4- isopropyl 5- pyrimadine- boronic acid was used and instep 4, Intermediate 42 was utilized. 132 1-(6-(5-(4-fluoro-2- (4-isopropylpyrimidin- 5- yl)phenoxy)pyrimidin- 4-yl)-2,6-diazaspiro[3.3]heptan- 2-yl)-2-(6- methoxypyridin-3- yl)ethan-1-one##STR00408## Intermediate 27 was coupled with (2-methoxypyridyl)acetic acid, as described in step 5 of Example 12133 6-(2-(6-(5-(4- fluoro-2-(4- isopropylpyrimidin- 5-yl)phenoxy)pyrimidin- 4-yl)-2,6- diazaspiro[3.3]heptan- 2-yl)-2-oxoethyl)-3,3- dimethylindole-2- one ##STR00409## Intermediate 27was coupled with 2-(3,3-dimethyl- 2-oxoindolin-6- yl)acetic acid,as described in step 5 of Example 12 134 tert-butyl ((1r,4r)-4-(2-(6-(5-(4-fluoro- 2-(isopropyl(meth- yl)carbamoyl)phen- oxy)pyri-midin-4-yl)-2,6- diazaspiro[3.3]heptan- 2- yl)ethyl)cyclohexyl)carbamate ##STR00410## Synthesized from Intermediate 39 byreductive amination with tert-butyl ((1r,4r)-4-(2-oxoethyl)cyclohex- yl)carbamate, as described in the final step ofExample 1 135 5-((7-(5-(4-fluoro- 2- ((isopropyl(methyl)amino)methyl)phen- oxy)pyrimidin-4- yl)-2,7- diazaspiro[4.4]nonan-2-yl)methyl)-1,3- dihydro-2H- benzo[d]imidazol- 2-one ##STR00411##Synthesized by a method similar to Example 70 136 N-ethyl-N-(5-fluoro-2-((4-(6- isobutyl-2,6- diazaspiro[3.4]octan-2-yl)pyrimidin-5- yl)oxy)phenyl)iso- butyramide ##STR00412##Synthesized by a method similar to Example 75, starting fromIntermediate 24 137 N-(2-((4-(6-((4,4- difluorocyclohexyl)methyl)-2,6- diazaspiro[3.4]octan- 2-yl)pyrimidin-5- yl)oxy)-5-fluorophenyl)-N- ethylisobutyramide ##STR00413## Synthesized bymethod similar to Example 75, starting from Intermediate 24, Infinal step 4, 4- difluorocyclohex- ane-1- carbaldehyde was used 138tert-butyl ((1r,4r)-4- (2-(6-(5-(4-fluoro- 2-(N-methyl-isobutyramido)phen- oxy)pyrimidin-4- yl)-2,6-diazaspiro[3.3]heptan-2- yl)ethyl) cyclohexyl)carbamate ##STR00414##Synthesized by method similar to Example 75, starting fromIntermediate 24. In final step, tert- butyl ((1r,4r)-4- (2-oxoethyl)cyclohex- yl)carbamate was used. 139 2-(5-(4-fluoro-2-(4-isopropylpyrimidin- 5- yl)phenoxy)pyrimidin- 4-yl)-7-(6-fluoro-3,4- dihydroisoquinolin- 2(1H)-yl)-5-oxa-2- azaspiro[3.4]octane##STR00415## Synthesized by a method similar to Example 18. In step4, 6-fluoro- 1,2,3,4- tetrahydroiso- quinoline was utilized. 1404-(((2-(5-(4-fluoro- 2-(4- isopropylpyrimidin- 5-yl)phenoxy)pyrimidin- 4-yl)-2- azaspiro[3.3]heptan- 6-yl)amino)methyl)- 1- methylcyclohexane- 1-carbonitrile ##STR00416##Intermediate 29 was condensed with 4-formyl-1- methylcyclohexane-1-carbonitrile, as described in step 4 of Example 41 1414-(1-((2-(5-(4- fluoro-2-(4- isopropylpyrimidin- 5-yl)phenoxy)pyrimidin- 4-yl)-2- azaspiro[3.3]heptan- 6-yl)amino)eth-yl)benzonitrile ##STR00417## Intermediate 29 was condensed with 4-acetylbenzonitrile as described in step 4 of Example 41 1425-fluoro-N- isopropyl-N- methyl-2-((4-(7-(4- (2-oxooxazolidin-3-yl)benzyl)-2,7- diazaspiro[4.4]nonan- 2-yl)pyrimidin-5-yl)oxy)benzamide ##STR00418## Synthesized from Intermediate 33 byreductive amination with 4- (2- oxooxazolidin-3- yl)benzaldehyde,as described in final step of Example 1 143 N-((1r,4r)-4-(2-(6-(5-((4'-cyano-2'- cyclopropyl-5- fluoro-[1,1'- biphenyl]-2-yl)oxy)pyrimidin-4- yl)-2,6- diazaspiro[3.3]heptan- 2-yl)ethyl)cyclohexyl) acetamide ##STR00419## Synthesized fromIntermediate 32 by reductive amination with N-((1r,4r)-4-(2-oxoethyl)cyclohex- yl)acetamide, as described for step 4 of Example41 144 methyl (5-fluoro-2- ((4-(7-((2-oxo-2,3- dihydro-1H-benzo[d]imidazol- 5-yl)methyl)-2,7- diazaspiro[4.4]nonan-2-yl)pyrimidin-5- yl)oxy)phenyl)(iso- propyl)carbamate ##STR00420##Synthesized by method similar to Example 75, starting fromIntermediate 102 145 2-((4-(7-((1H- indazol-6- yl)methyl)-2,7-diazaspiro[4.4]nonan- 2-yl)pyrimidin-5- yl)oxy)-5-fluoro-N-isopropyl-N- methylbenzamide ##STR00421## Synthesized by a methodsimilar to Example 1. In the last step, 1H- indazole-6-carbaldehyde was utilized. 146 2-((4-(7-((3-cyano- 1H-indazol-6-yl)methyl)-2,7- diazaspiro[4.4]nonan- 2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N- isopropyl-N- methylbenzamide ##STR00422##Synthesized from Intermediate 33 and 6-formyl-1H- indazole-3-carbonitrile, by method described in step 4 of Example 6A 147tert-butyl ((1r,4r)-4- ((7-(5-(2- (cyclopentyloxy)-4-fluorophenoxy)pyri- midin-4-yl)-2,7- diazaspiro[4.4]nonan- 2-yl)methyl)cyclohex- yl)carbamate ##STR00423## Synthesized by themethod described in Example 54 148A Isomer 1: 4-((2-(5-(4-fluoro-2-(4- isopropylpyrimidin- 5- yl)phenoxy)pyrimidin-4-yl)-2- azaspiro[3.3]heptan- 6-yl)amino)-1- methylcyclohexanecarbonitrile ##STR00424## Intermediate 29 was condensed with1-methyl-4- oxocyclohexane- 1-carbonitrile, as described in step 4of Example 41 148B Isomer 2: 4-((2-(5- (4-fluoro-2-(4-isopropylpyrimidin- 5- yl)phenoxy)pyrimidin- 4-yl)-2-azaspiro[3.3]heptan- 6-yl)amino)-1- methylcyclohexane carbonitrile##STR00425## Minor isomer separated from the synthesis of Example148A by SFC method A 149 4-(2-(2-(5-(4- fluoro-2-(4-isopropylpyrimidin- 5- yl)phenoxy)pyrimidin- 4-yl)-2,6-diazaspiro[3.4]octan- 6-yl)-2- oxoethyl)benzonitrile ##STR00426##Intermediate 28 was reacted with (4- cynophenyl)acetic acid, asdescribed in Example 12 150 5-((7-(5-(4-fluoro- 2-(4-isopropylpyrimidin- 5- yl)phenoxy)pyrimidin- 4-yl)-2,7-diazaspiro[4.4]nonan- 2-yl)methyl)-1- methyl-1,3-dihydro- 2H-benzo[d]imidazol- 2-one ##STR00427## Intermediate 26 was condensedwith 1-methyl-2- oxo-2,3-dihydro- 1H- benzo[d]imidazole-5-carbaldehyde, as described in step 4 of Example 41. 1512-cyclopropyl-5'- fluoro-2'-((4-(6-((4- hydroxycyclohexyl)methyl)-2,6- diazaspiro[3.3]heptan- 2-yl)pyrimidin-5-yl)oxy)-[1,1'- biphenyl]-4- carbonitrile ##STR00428## Synthesizedby a method similar to Example 65, starting with Intermediate 32.152 4-(((2-(5-(4-fluoro- 2-(4- isopropylpyrimidin- 5-yl)phenoxy)pyrimidin- 4-yl)-2- azaspiro[3.3]heptan- 6-yl)amino)methyl)benzo- nitrile ##STR00429## Intermediate 29 wascondensed with 4- cyanobenzaldehyde. 153 5-((7-(5-(2-(2,5-dimethylpyrrolidine- 1-carbonyl)-4- fluorophenoxy)pyri-midin-4-yl)-2,7- diazaspiro[4.4]nonan- 2-yl)methyl)-1,3-dihydro-2H- benzo[d]imidazol- 2-one ##STR00430## Synthesized by amethod similar to Example 1. In step 4, 2,5- dimethypyrrolidine wasutilized. 154 5-((7-(5-(4-fluoro- 2-(pyrrolidine-1-carbonyl)phenoxy)py- rimidin-4-yl)-2,7- diazaspiro [4.4]nonan-2-yl)methyl)-1,3- dihydro-2H- benzo[d]imidazol- 2-one ##STR00431##Synthesized by a method similar to Example 1. In step 4,pyrrolidine was utilized. 155 5-((7-(5-(4-fluoro- 2-(morpholine-4-carbonyl) phenoxy)pyrimidin- 4-yl)-2,7-diaza- spiro[4.4]nonan-2-yl)methyl)-1,3- dihydro-2H- benzo[d]imidazol- 2-one ##STR00432##Synthesized by a method similar to Example 1. In step 4, morpholinewas utilized. 156 N-ethyl-N-(5- fluoro-2-((4-(6- ((tetrahydro-2H-pyran-4-yl)methyl)- 2,6- diazaspiro[3.4]octan- 2-yl)pyrimidin-5-yl)oxy)phenyl)iso- butyramide ##STR00433## Synthesized by a methodsimilar to Example 75, starting from Intermediate 24 1577-(5-(4-fluoro-2-(4- isopropylpyrimidin- 5- yl)phenoxy)pyrimidin-4-yl)-3-(6-fluoro- 3,4- dihydroisoquinolin- 2(1H)-yl)-1-oxa-7-azaspiro[4.4]nonane ##STR00434## Synthesized from 1-oxa-7-azaspiro[4.4]nonan- 3-one, as described in synthesis of Example 18158 N-(2-((4-(6- (cyclohexylmethyl)- 2,6- diazaspiro[3.4]octan-2-yl)pyrimidin-5- yl)oxy)-5- fluorophenyl)-N- ethylisobutyramide##STR00435## Starting from Intermediate 24 and synthesized bymethod similar to Example 75 159 N-benzyl-2-(5-(4- fluoro-2-(4-isopropylpyrimidin- 5- yl)phenoxy)pyrimidin- 4-yl)-5-oxa-2-azaspiro[3.4]octan- 7-amine ##STR00436## 2-(5-(4-fluoro-2- (4-isopropylpyrimidin- 5-yl)phenoxy) pyrimidin-4-yl)- 5-oxa-2-azaspiro[3,4]octan-7-one was condensed with benzaldehyde, as described insynthesis of Example 18 160 5-((7-(5-(4-fluoro- 2-(4-isopropylpyrimidin- 5- yl)phenoxy)pyrimidin- 4-yl)-2,7-diazaspiro[4.4]nonan- 2-yl)methyl)-1,3- dihydro-2H-benzo[d]imidazol- 2-one ##STR00437## Synthesized by a methodsimilar to Example 41, starting from Intermediate 26. 160A Isomer1: 5-((7-(5- (4-fluoro-2-(4- isopropylpyrimidin- 5-yl)phenoxy)pyrimidin- 4-yl)-2,7- diazaspiro[4.4]nonan-2-yl)methyl)-1,3- dihydro-2H- benzo[d]imidazol- 2-one ##STR00438##Single isomer of Example 160, separated by SFC method A 160B Isomer2: 5-((7-(5- (4-fluoro-2-(4- isopropylpyrimidin- 5-yl)phenoxy)pyrimidin- 4-yl)-2,7- diazaspiro[4.4]nonan-2-yl)methyl)-1,3- dihydro-2H- benzo[d]imidazol- 2-one ##STR00439##Single isomer of
Example 160, separated by SFC method A 161 5-((7-(5-((5-fluoro-2'-(prop-1-en-2-yl)- [1,1'-biphenyl]-2- yl)oxy)pyrimidin-4-yl)-2,7- diazaspiro[4.4]nonan- 2-yl)methyl)-1,3- dihydro-2H-benzo[d]imidazol- 2-one ##STR00440## Synthesized by treatingExample 63 with TFA 162 2-(5-(4-fluoro-2-(2- isopropoxypyridin- 3-yl)phenoxy)pyrimidin- 4-yl)-6- ((tetrahydro-2H- pyran-4-yl)methyl)-2,6- diazaspiro[3.3]heptane ##STR00441## Intermediate 20, wascoupled with 2-isoprpoxy-3- pyridyl boronic acid. In step 4 ofExample 41, tetrahydro-2H- pyran-4- carbaldehyde was utilized. 1635-fluoro-N- isopropyl-N- methyl-2-((4-(7-((1- methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol- 5-yl)methyl)-2,7-diazaspiro[4.4]nonan- 2-yl)pyrimidin-5- yl)oxy)benzamide##STR00442## Synthesized by method similar to Example 1. In thelast step, 1- methyl-2-oxo- 2,3-dihydro-1H- benzo[d]imidazole-5-carbaldehyde was utilized. 164 ethyl (5-fluoro-2-((4-(7-((2-oxo-2,3- dihydro-1H- benzo[d]imidazol- 5-yl)methyl)-2,7-diazaspiro[4.4]nonan- 2-yl)pyrimidin-5- yl)oxy)phenyl)(meth-yl)carbamate ##STR00443## Starting from Intermediate 102, thiscompound was synthesized by a method similar to Example 75 165N-cyclopropyl-5- fluoro-N-methyl-2- ((4-(7-((2-oxo-2,3- dihydro-1H-benzo[d]imidazol- 5-yl)methyl)-2,7- diazaspiro[4.4]nonan-2-yl)pyrimidin-5- yl)oxy)benzamide ##STR00444## Synthesized by amethod similar to Example 1. In step 4, N-methyl- cyclopropyl aminewas utilized. 166 5-fluoro-N-methyl- 2-((4-(7-((2-oxo-2,3-dihydro-1H- benzo[d]imidazol- 5-yl)methyl)-2,7-diazaspiro[4.4]nonan- 2-yl)pyrimidin-5- yl)oxy)-N- phenylbenzamide##STR00445## Synthesized by a method similar to Example 1. In step4, N-methyl- aniline was utilized. 167 2-((4-(6-(cyclohexylmethyl)- 2,6- diazaspiro[3.3]heptan- 2-yl)pyrimidin-5-yl)oxy)-5-fluoro- N-isopropyl-N- methylbenzamide ##STR00446##Synthesized from Intermediate 39 and cyclohexane carbaldehyde byreductive amination, as described in final step of Example 1 1682-(5-(2- (cyclopentyloxy)-4- fluorophenoxy) pyrimidin-4-yl)-6-((tetrahydro-2H- pyran-4-yl)methyl)- 2,6- diazaspiro[3.3]heptane##STR00447## Synthesized by method described in Example 54 fromIntermediate 43a 169 2-cyclopropyl-5'- fluoro-2'-((4-(7-((2-oxo-2,3- dihydrobenzo[d]oxa- zol-5-yl)methyl)- 2,7-diazaspiro[4.4]nonan- 2-yl)pyrimidin-5- yl)oxy)-[1,1'- biphenyl]-4-carbonitrile ##STR00448## Synthesized from Intermediate 31 bycondenstation with 2-oxo-2,3- dihydrobenzo[d]oxa- zole-5-carbaldehyde, as described in step 4 of Example 41 170 methyl(3-((7-(5- ((4'-cyano-2'- cyclopropyl-5- fluoro-[1,1'- biphenyl]-2-yl)oxy)pyrimidin-4- yl)-2,7- diazaspiro[4.4]nonan- 2-yl)methyl)phenyl)carba- mate ##STR00449## Synthesized fromIntermediate 31 by condenstation with methyl (3- formylphenyl)car-bamate, as described in step 4 of Example 41 171 2'-((4-(7-((1H-benzo[d][1,2,3]triazol- 6-yl)methyl)-2,7- diazaspiro[4.4]nonan-2-yl)pyrimidin-5- yl)oxy)-2- cyclopropyl-5'- fluoro-[1,1'-biphenyl]-4- carbonitrile ##STR00450## Synthesized fromIntermediate 31 by condenstation with 1H- benzo[d][1,2,3]tri-azole-6- carbaldehyde, as described in step 4 of Example 41 172N-(2-chloro-4-((7- (5-((4'-cyano-2'- cyclopropyl-5- fluoro-[1,1'-biphenyl]-2- yl)oxy)pyrimidin-4- yl)-2,7- diazaspiro[4.4]nonan- 2-yl)methyl)phenyl)acet- amide ##STR00451## Synthesized fromIntermediate 31 by condenstation with N-(2-chloro- 4-formylphenyl)ace- tamide, as described in step 4 of Example 41 173N,N-diethyl-5- fluoro-2-((4-(7-((2- oxo-2,3-dihydro- 1H-benzo[d]imidazol- 5-yl)methyl)-2,7- diazaspiro[4.4]nonan-2-yl)pyrimidin- yl)oxy)benzamide ##STR00452## Synthesized by amethod similar to Example 1. In step 4, N-N- diethylamine wasutilized. 174 5-fluoro-N- isopropyl-N- methyl-2-((4-(7-((2-oxo-2,3- dihydrobenzo[d]oxa- zol-5-yl)methyl)- 2,7-diazaspiro[4.4]nonan- 2-yl)pyrimidin-5- yl)oxy)benzamide##STR00453## Synthesized from intermediate 33 and 2-oxo-2,3-dihydrobenzo[d]oxa- zole-5- carbaldehyde by reductive amnination,as described in final step of Example 1 175 N-(tert-butyl)-5-fluoro-N-methyl-2- ((4-(7-((2-oxo-2,3- dihdyro-1H-benzo[d]imidazol- 5-yl)methyl)-2,7- diazaspiro[4.4]nonan-2-yl)pyrimidin-5- yl)oxy)benzamide ##STR00454## Synthesized by amethod similar to Example 1. In step 4, tert-butyl methyl amine wasutilized. 176 1-(7-(5-(4-fluoro-2- (4- isopropylpyrimidin- 5-yl)phenoxy)pyrimidin- 4-yl)-2,7- diazaspiro[4.4]nonan- 2-yl)-2-methylpropan-2-ol ##STR00455## Synthesized from Intermediate 26 and2,2- dimethyloxirane, by method described in Example 72 1772-(5-(2-(2- cyclopropylpyridin- 3-yl)-4- fluorophenoxy)pyri-midin-4-yl)-6- ((tetrahydro-2H- pyran-4-yl)methyl)- 2,6-diazaspiro[3.3]heptane ##STR00456## Synthesized from Intermediate31c and tetrahydro- 2H-pyran-4- carbaldehyde, by method describedin step 4 of Example 41 178 6-((7-(5-(4-fluoro- 2-(4-isopropylpyrimidin- 5- yl)phenoxy)pyrimidin- 4-yl)-2,7-diazaspiro[4.4]nonan- 2-yl)methyl)-3,3- dimethylindolin-2- one##STR00457## Synthesized from Intermediate 26 by condenstation withIntermediate 45, as described in step 4 of Example 41 1796-((7-(5-(2-(2- cyclopropylpyridin- 3-yl)-4- fluorophenoxy)pyri-midin-4-yl)-2,7- diazaspiro[4.4]nonan- 2-yl)methyl)-3,3-dimethylindolin-2- one ##STR00458## Synthesized from Intermediate31b by condenstation with Intermediate 45, as described in step 4of Example 41 180 5-((7-(5-(2-(2- cyclopropylpyridin- 3-yl)-4-fluorophenoxy)pyri- midin-4-yl)-2,7- diazaspiro[4.4]nonan-2-yl)methyl)-1,3- dihydro-2H- benzo[d]imidazol- 2-one ##STR00459##Synthesized by method similar to Example 41, starting fromIntermediate 31b 181 4-(((2-(5-(4-fluoro- 2-(4- isopropylpyrimidin-5- yl)phenoxy)pyrimidin- 4-yl)-5-oxa-2- azaspiro[3.4]octan- 7-yl)(methyl)amino)meth- yl)benzonitrile ##STR00460## Synthesized bythe method described for Example 157, starting from 5- oxa-2-azaspiro[3.4]octan- 7-one 182 6-((7-(5-(4-fluoro- 2-(2,2,2-trifluoroethoxy) phenoxy)pyrimidin- 4-yl)-2,7-diazaspiro[4.4]nonan- 2-yl)methyl)-3,3- dimethylindolin-2- one##STR00461## Synthesized by the method described in Example 54 fromIntermediate 43a 183 5-fluoro-N- isopropyl-N- methyl-2-((4-(7-((2-oxo-2,3-dihydro- 1H- benzo[d]imidazol- 5-yl)methyl)-2,7-diazaspiro[4.4]nonan- 2-yl)pyrimidin-5- yl)oxy)benzamide (mixture)##STR00462## Synthesized from Intermediate 33 and 2-oxo-2,3-dihydro-1H- benzo[d]imidazole- 5-carbaldehyde, as described inExample 1 183A Isomer 1: 5-fluoro- N-isopropyl-N-methyl-2-((4-(7-((2- oxo-2,3-dihydro- 1H- benzo[d]imidazol-5-yl)methyl)-2,7- diazaspiro[4.4]nonan- 2-yl)pyrimidin-5-yl)oxy)benzamide ##STR00463## Single enantiomer of Example 183separrated by SFC method A 183B Isomer 2: 5-fluoro- N-isopropyl-N-methyl-2-((4-(7-((2- oxo-2,3-dihydro- 1H-benzo[d]imidazol-5-yl)methyl)-2,7- diazaspiro[4.4]nonan- 2-yl)pyrimidin-5-yl)oxy)benzamide ##STR00464## Single enantiomer of Example 183separated by SFC method A 184 N- (cyclohexylmethyl)-2-(5-(4-fluoro-2-(4- isopropylpyrimidin- 5- yl)phenoxy)pyrimidin-4-yl)-5-oxa-2- azaspiro[3.4]octan- 7-amine ##STR00465## Synthesizedby a method similar to Example 19. In step 3,4- isoprpyl-5-pyrmidine boronic acid was used. In step 4, cyclohexylemthyl aminewas utilized. 185 N-(5-fluoro-2-((4- (7-((2-oxo-2,3- dihydro-1H-benzo[d]imidazol- 5-yl)methyl)-2,7- diazaspiro[4.4]nonan-2-yl)pyrimidin-5- yl)oxy)phenyl)-N- (2- hydroxyethyl)iso-butyramide ##STR00466## Synthesized by a method similar to Example75, starting from Intermediate 103, and alkylated with (2-bromoethoxy)tri- methylsilane 186 N-ethyl-N-(5-fluoro-2-((4-(7-((2- oxo-2,3-dihydro- 1H- benzo[d]imidazol-5-yl)methyl)-2,7- diazaspiro[4.4]nonan- 2-yl)pyrimidin-5-yl)oxy)phenyl) isobutyramide ##STR00467## Synthesized by a methodsimilar to Example 75 187 N-(5-fluoro-2-((4- (7-((2-oxo-2,3-dihydro-1H- benzo[d]imidazol- 5-yl)methyl)-2,7-diazaspiro[4.4]nonan- 2-yl)pyrimidin-5- yl)oxy)phenyl)-N- (2,2,2-trifluoroethyl)iso- butyramide ##STR00468## Synthesized by a methodsimilar to Example 75, starting from Intermediate 103, andalkylated with 2,2,2- trifluoroethyl 4- methylbenzene- sulfonate188 N-((1r,4r)-4-((7-(5- ((4'-cyano-2'- cyclopropyl-5-fluoro-[1,1'- biphenyl]-2- yl)oxy)pyrimidin-4- yl)-2,7-diazaspiro[4.4]nonan- 2- yl)methyl)cyclo- hexyl)acetamide##STR00469## Synthesized from Intermediate 31 and N-((1r,4r)-4-formylcyclohexyl) acetamide, as described in step 4 of Example 41189 tert-butyl ((1r,4r)-4- (2-(6-(5-((4'-cyano- 2'-cyclopropyl-5-fluoro-[1,1'- biphenyl]-2- yl)oxy)pyrimidin-4- yl)-2,6-diazaspiro[3.3]heptan- 2- yl)ethyl)cyclohexyl) carbamate##STR00470## Synthesized from Intermediate 32 and tert-butyl((1r,4r)-4-(2- oxoethyl)cyclo- hexyl)carbamate, by method describedin step 4 of Example 41 190 5-((7-(5-(4-fluoro- 2-(5-isopropylthiazol-4- yl)phenoxy)pyrimidin- 4-yl)-2,7-diazaspiro[4.4]nonan- 2-yl)methyl)-1,3- dihydro-2H-benzo[d]imidazol- 2-one ##STR00471## Synthesized by a methodsimilar to Example 41. In step 1, 5- isopropyl-4- thiazole boronicacid was utilized. 190A N-((1s,4s)-4-((7-(5- ((4'-cyano-2'-cyclopropyl-5- fluoro-[1,1'- biphenyl]-2- yl)oxy)pyrimidin-4-yl)-2,7- diazaspiro[4.4]nonan- 2- yl)methyl)cyclohex- yl)acetamide##STR00472## Minor isomer isolated from the synthesis of Example188 using SFC method A 191 2-cyclopropyl-2'- ((4-(7-((1-ethyl-2-oxo-2,3-dihydro- 1H- benzo[d]imidazol- 5-yl)methyl)-2,7-diazaspiro[4.4]nonan- 2-yl)pyrimidin-5- yl)oxy)-5'-fluoro-[1,1'-biphenyl]-4- carbonitrile ##STR00473## Synthesized fromIntermediate 31 and Intermediate 42b, as described in step 4 ofExample 41 192 3-((7-(5-(2- (cyclopentyloxy)-4- fluorophenoxy)pyri-midin-4-yl)-2,7- diazaspiro[4.4]nonan- 2-yl)methyl)-1H- indole-6-carbonitrile ##STR00474## Synthesized by the method described inExample 54 from Intermediate 43a 193 6-((7-(5-(2-(cyclopentyloxy)-4- fluorophenoxy)pyri- midin-4-yl)-2,7-diazaspiro[4.4]nonan- 2-yl)methyl)-3,3- dimethylindolin-2- one##STR00475## Synthesized by the method described in Example 54 fromIntermediate 43a 194 2-((4-(7-((6-cyano- 1H-indol-3-yl)methyl)-2,7- diazaspiro[4.4]nonan- 2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N- isopropyl-N- methylbenzamide ##STR00476##Synthesized from Intermediate 33 and 3-formyl-1H- indole-6-carbonitrile, as described in last step of Example 1 1952-cyclopropyl-5'- fluoro-2'-((4-(7-(4- (2-oxopyrrolidin-1-yl)benzyl)-2,7- diazaspiro [4.4]nonan-2- yl)pyrimidin-5-yl)oxy)-[1,1'- biphenyl]-4- carbonitrile ##STR00477## Synthesizedfrom Intermediate 31 and 4-(2- oxopyrrolidin-1- yl)benzaldehyde, asdescribed in step 4 of Example 41 196 2-cyclopropyl-5'-fluoro-2'-((4-(7-((2- oxoindolin-6- yl)methyl)-2,7-diazaspiro[4.4]nonan- 2-yl)pyrimidin-5- yl)oxy)-[1,1'- biphenyl]-4-carbonitrile ##STR00478## Synthesized from Intermediate 31 and 2-oxoindoline-6- carbaldehyde, as described in step 4 of Example 41197A Isomer 1: 5-((7-(5- (4-fluoro-2-(1- isopropyl-1H- pyrazol-5-yl)phenoxy)pyrimidin- 4-yl)-2,7- diazaspiro[4.4]nonan-2-yl)methyl)-1,3- dihydro-2H- benzo[d]imidazol- 2-one ##STR00479##Single isomer of Example 237, separated by SFC method A 197B Isomer2: 5-((7-(5- (4-fluoro-2-(1- isopropyl-1H- pyrazol-5-yl)phenoxy)pyrimidin- 4-yl)-2,7- diazaspiro[4.4]nonan-2-yl)methyl)-1,3- dihydro-2H- benzo[d]imidazol- 2-one ##STR00480##Single isomer of Example 237, separated by SFC method A 1986-((7-(5-(4-fluoro- 2-(1-isopropyl-1H- pyrazol-5-yl)phenoxy)pyrimidin- 4-yl)-2,7- diazaspiro[4.4]nonan-2-yl)methyl)-1H- benzo[d][1,2,3]tri- azole ##STR00481## Synthesizedby a method similar to Example 41, starting from Intermediate 31a.1H- benzo[d][1,2,3]tri- azole-6- carbaldehyde was used in step 4.199 2-cyclopropyl-3',5'- difluoro-2'-((4-(7- ((2-oxo-2,3-dihydro-1H- benzo[d]imidazol- 5-yl)methyl)-2,7-diazaspiro[4.4]nonan- 2-yl)pyrimidin-5- yl)oxy)-[1,1'- biphenyl]-4-carbonitrile ##STR00482## Synthesized from Intermediate 17 bymethod described for Example 42 200 3-((7-(5-(2- (cyclopropylmeth-oxy)-4- fluorophenoxy)pyri- midin-4-yl)-2,7- diazaspiro[4.4]nonan-2-yl)methyl)-1H- indole-6- carboxamide ##STR00483## Synthesized bythe method described in Example 54 from Intermediate 43a 2013-((7-(5-(2- (cyclopropylmethoxy)- 4- fluorophenoxy)pyri-midin-4-yl)-2,7- diazaspiro[4.4]nonan- 2-yl)methyl)-1H- indole-6-carbonitrile ##STR00484## Synthesized by the method described inExample 54 from Intermediate 43a
202 2-((4-(7-((3,3- dimethyl-2- oxoindolin-6- yl)methyl)-2,7-diazaspiro[4.4]nonan- 2-yl)pyrimidin-5- yl)oxy)-5-fluoro-N-isopropyl-N- methylbenzamide ##STR00485## Synthesized fromIntermediate 33 and 3,3- dimethyl-2- oxoindoline-6- carbaldehyde,as described in final step of Example 1 203 2'-((4-(6-(4-cyanophenethyl)- 2,6- diazaspiro[3.3]heptan- 2-yl)pyrimidin-5-yl)oxy)-2- cyclopropyl-5'- fluoro-[1,1'- biphenyl]-4-carbonitrile ##STR00486## Synthesized from Intermediate 32 and4-(2- oxoethyl) benzonitrile by the method described for Example 41204 2-cyclopropyl-5'- fluoro-2'-((4-(7-((2- oxoindolin-5-yl)methyl)-2,7- diazaspiro[4.4]nonan- 2-yl)pyrimidin-5-yl)oxy)-[1,1'- biphenyl]-4- carbonitrile ##STR00487## Synthesizedfrom Intermediate 31 and 2- oxoindoline-5- carbaldehyde, asdescribed in step 4 of Example 41 205 2-cyclopropyl-2'-((4-(7-((3,3- dimethyl-2- oxoindolin-6- yl)methyl)-2,7-diazaspiro[4.4]nonan- 2-yl)pyrimidin-5- yl)oxy)-5'-fluoro-[1,1'-biphenyl]-4- carbonitrile ##STR00488## Synthesized fromIntermediate 31 and Intermediate 42, as described in step 4 ofExample 41 206A Isomer 1: 2-amino- 2-cyclohexyl-1-(7-(5-(4-fluoro-2-(1- isopropyl-1H- pyrazol-5- yl)phenoxy)pyrimidin-4-yl)-2,7- diazaspiro[4.4]nonan- 2-yl)ethanone ##STR00489##Synthesized from Intermediate 31a and (R)-2-((tert- butoxy-carbonyl)amino)-2- cyclohexylacetic acid, by the method describedin Example 12, followed by deprotection of Boc group and separationof isomers by SFC method A 206B Isomer 2: 2-amino-2-cyclohexyl-1-(7- (5-(4-fluoro-2-(1- isopropyl-1H- pyrazol-5-yl)phenoxy)pyrimidin- 4-yl)-2,7- diazaspiro[4.4]nonan-2-yl)ethanone ##STR00490## Synthesized from Intermediate 31a and(R)-2-((tert- butoxy- carbonyl)amino)-2- cyclohexylacetic acid, bythe method described in Example 12, followed by deprotection of Bocgroup and separation of isomer by SFC method A 206C Isomer 3:2-amino- 2-cyclohexyl-1-(7- (5-(4-fluoro-2-(1- isopropyl-1H-pyrazol-5- yl)phenoxy)pyrimidin- 4-yl)-2,7- diazaspiro[4.4]nonan-2-yl)ethanone ##STR00491## Synthesized from Intermediate 31a and(R)-2-((tert- butoxy- carbonyl)amino)-2- cyclohexylacetic acid, bymethod described in Example 12, followed by deprotection of Bocgroup and separation of isomers by SFC method A 207 methyl(5-fluoro-2- ((4-(7-((2-oxo-2,3- dihydro-1H- benzo[d]imidazol-5-yl)methyl)-2,7- diazaspiro[4.4]nonan- 2-yl)pyrimidin-5-yl)oxy)phenyl)(meth- yl)carbamate ##STR00492## Synthesized by amethod similar to Example 75. Intermediate 102 was reacted withmethylchloro- formate. 208 5-((7-(5-(2- (benzyloxy)-4-fluorophenoxy) pyrimidin-4-yl)-2,7- diazaspiro [4.4]nonan-2-yl)methyl)-1,3- dihydro-2H- benzo[d]imidazol- 2-one ##STR00493##Synthesized by the method described in Example 54 from Intermediate43a 209 5-((7-(5-(4-fluoro- 2 - methoxyphenoxy)pyri-midin-4-yl)-2,7- diazaspiro[4.4]nonan- 2-yl)methyl)-1,3-dihydro-2H- benzo[d]imidazol- 2-one ##STR00494## Synthesized by themethod described in Example 54 from Intermediate 43a 2105-fluoro-N- isopropyl-N- methyl-2-((4-(7-((3- oxo-3,4-dihydro- 2H-benzo[b][1,4]oxazin- 6-yl)methyl)-2,7- diazaspiro[4.4]nonan-2-yl)pyrimidin-5- yl)oxy)benzamide ##STR00495## Synthesized fromIntermediate 33 and 3-oxo-3,4- dihydro-2H- benzo[b][1,4]oxa-zine-6- carbaldehyde, by method described in last step of Example 1211 5-((7-(5-(4-fluoro- 2-(2- methylpyrrolidine- 1-carbonyl)phenoxy)pyri- midin-4-yl)-2,7- diazaspiro[4.4]nonan-2-yl)methyl)-1,3- dihydro-2H-benzo [d]imidazol-2-one ##STR00496##Synthesized by the method described in Example 1. In step 4,2-methyl pyrrolidine was utilized. 212 5-((7-(5-(2-((1s,4s)- 7-aza-bicyclo[2.2.1]heptane- 7-carbonyl)- 4-fluorophenoxy)pyrimidin-4-yl)-2,7- diazaspiro [4.4]nonan-2- yl)methyl)-1,3-dihydro-2H- benzo[d]imidazol- 2-one ##STR00497## Synthesized by themethod described in Example 1. In step 4, (1s,4s)-7-azabicyclo[2.2.1] heptane was utilized. 213 5-((7-(5-((2'-(1,1-difluoroethyl)-5- fluoro-[1,1'- biphenyl]-2- yl)oxy)pyrimidin-4-yl)-2,7- diazaspiro[4.4]nonan- 2-yl)methyl)-1,3- dihydro-2H-benzo[d]imidazol- 2-one ##STR00498## Synthesized by method similarto Example 41. In step 1, (2-(1,1- difluoroethyl)phen- yl)boronicacid was utilized. 214 2-cyclopropyl-5'- fluoro-2'-((4-(6-((4-hydroxytetrahydro- 2H-pyran-4- yl)methyl)-2,6-diazaspiro[3.3]heptan- 2-yl)pyrimidin- 5-yl)oxy)-[1,1'-biphenyl]-4- carbonitrile ##STR00499## Synthesized fromIntermediate 32 and 4-(oxiran-2- yl)tetrahydro-2H- pyran, by methoddescribed in Example 72 215 2-cyclopropyl-5'- fluoro-2'-((4-(6-((tetrahydro-2H- pyran-4-yl)methyl)- 2,6- diazaspiro[3.3]heptan-2-yl)pyrimidin- 5-yl)oxy)-[1,1'- biphenyl]-4- carbonitrile##STR00500## Synthesized from Intermediate 32 and tetrahydro-2H-pyran-4- carbaldehyde, by method described in step 4 of Example41 216 5-fluoro-N- isopropyl-N- methyl-2-((4-(7-((2-oxo-2,3-dihydro- 1H- benzo[d]imidazol- 5-yl)methyl)-2,7-diazaspiro[4.4]nonan- 2-yl)pyrimidin-5- yl)oxy)benzamide##STR00501## Synthesized by a method to similar to Example 41,starting with 1- isopropyl-5- (tributylstannyl)- 3-(trifluoromethyl)- 1H-pyrazole 217 5-((7-(5-(4-fluoro-2-(1-isopropyl-3- (trifluoromethyl)- 1H-pyrazol-5-yl)phenoxy)pyrimidin- 4-yl)-2,7- diazaspiro[4.4]nonan-2-yl)methyl)-1,3- dihydro-2H- benzo[d]imidazol- 2-one ##STR00502##Synthesized by a method similar to Example 41. In step 1,1-isopropyl-5- (tributylstannyl)- 3- (trifluoromethyl)- 1H-pyrazolewas utilized. 218 5-((7-(5-(4-fluoro- 2-(2-isopropyl-5-oxopyrrolidin-1- yl)phenoxy)pyrimidin- 4-yl)-2,7-diazaspiro[4.4]nonan- 2-yl)methyl)-1,3- dihydro-2H-benzo[d]imidazol- 2-one ##STR00503## Synthesized from Intermediate11 by copper coupling with 5- isopropylpyrrolidin- 2-one, asdescribed in steps 3 and 4 of Example 41 219 (1r,4r)-4-((7-(5-((5-fluoro-2'-isopropyl- [1,1'-biphenyl]-2- yl)oxy)pyrimidin-4-yl)-2,7- diazaspiro[4.4]nonan- 2- yl)methyl)cyclohex- an-1-amine##STR00504## Synthesized from Example 220 by acid deprotection 220tert-butyl ((1r,4r)-4- ((7-(5-((5-fluoro-2'- isopropyl-[1,1'-biphenyl]-2- yl)oxy)pyrimidin-4- yl)-2,7- diazaspiro[4.4]nonan- 2-yl)methyl)cyclohex- yl)carbamate ##STR00505## Synthesized by themethod described in Example 41. In step 4, tert-butyl ((1r,4r)-4-formylcyclohexyl) carbamate was utilized. 221 N-(4-((7-(5-((5-fluoro-2'-isopropyl- [1,1'-biphenyl]-2- yl)oxy)pyrimidin-4-yl)-2,7- diazaspiro[4.4]nonan- 2- yl)methyl)phenyl)ace- tamide##STR00506## Synthesized by a method similar to Example 41. In thefinal step, 4- acetamidobenzal- dehyde was utilized. 2225-fluoro-N- isopropyl-N- methyl-2-((4-(7-((2- oxo-2,3-dihydro- 1H-benzo[d]imidazol- 5-yl)methyl)-2,7- diazaspiro[4.4]nonan-2-yl)pyrimidin-5- yl)oxy)benzene- sulfonamide ##STR00507##Synthesized by method similar to Example 74, starting from tert-butyl 7-(5- bromopyrimidin- 4-yl)-2,7- diazaspiro[4.4]nonane- 2-carboxylate 223 ethyl 5'-fluoro-2'- ((4-(7-((2-oxo-2,3- dihydro-1H-benzo[d]imidazol- 5-yl)methyl)-2,7- diazaspiro[4.4]nonan-2-yl)pyrimidin-5- yl)oxy)-[1,1'- biphenyl]-2- carboxylate##STR00508## Synthesized by a method similar to Example 41,starting from 2- ethoxycarbonyl- phenyl boronic acid 2245-((7-(5-(4-fluoro- 2-(4- isopropylthiazol-5- yl)phenoxy)pyrimidin-4-yl)-2,7- diazaspiro[4.4]nonan- 2-yl)methyl)-1,3- dihydro-2H-benzo[d]imidazol- 2-one ##STR00509## Synthesized by a methodsimilar to Example 41, starting from 4- isoprpyl-5-thiazole-boronic acid 225 5-fluoro-N- isopropyl-N- methyl-2-((4-(6-((tetrahydro-2H- pyran-4-yl)methyl)- 2,6- diazaspiro[3.3]heptan-2-yl)pyrimidin- 5-yl)oxy)benzamide ##STR00510## Synthesized fromIntermediate 39 and 4- pyrancarbaldehyde, by the method describedin Example 1 226 5'-fluoro-2-methyl- 2'-((4-(7-((2-oxo-2,3-dihydro-1H- benzo[d]imidazol- 5-yl)methyl)-2,7-diazaspiro[4.4]nonan- 2-yl)pyrimidin-5- yl)oxy)-[1,1'- biphenyl]-4-carbonitrile ##STR00511## Synthesized from Example 41, startingfrom 4- cyano-2-methyl phenyl boronic acid 227 4-(2-(6-(5-(4-fluoro-2-(4- isopropylpyrimidin- 5- yl)phenoxy)pyrimidin-4-yl)-2,6- diazaspiro[3.3]heptan- 2-yl)-2- oxoethyl)benzonitrile##STR00512## Synthesized from Intermediate 27 and and 4-cyanophenyl acetyl chloride, by method described in Example 12 2284-(2-(6-(5-((5- fluoro-2'-isopropyl- [1,1'-biphenyl]-2-yl)oxy)pyrimidin-4- yl)-2,6- diazaspiro[3.3]heptan- 2-yl)-2-oxoethyl)benzonitrile ##STR00513## Synthesized from Intermediate 30and 4- cyanophenyl acetyl chloride, by method described in Example12 229 1-(6-(5-((5-fluoro- 2'-isopropyl-[1,1'- biphenyl]-2-yl)oxy)pyrimidin-4- yl)-2,6- diazaspiro[3.3]heptan- 2-yl)-2-(4-(methylsulfonyl)phen- yl)ethan-1-one ##STR00514## Synthesized fromIntermediate 30 and 2-(4- (methylsulfonyl) phenyl)acetyl chloride,by method described in Example 12 230 5'-fluoro-2-methyl-2'-((4-(7-((2-oxo- 2,3-dihydro-1H- benzo[d]imidazol-5-yl)methyl)-2,7- diazaspiro[4.4]nonan- 2-yl)pyrimidin-5-yl)oxy)-[1,1'- biphenyl]-3- carbonitrile ##STR00515## Synthesizedby a method similar to Example 41, starting from 3- cyano-2-methylphenyl boronic acid 231 2-((3,3- difluorocyclohexyl)methyl)-6-(5-(4- fluoro-2-(1- isopropyl-1H- pyrazol-5-yl)phenoxy)pyrimidin- 4-yl)-2,6- diazaspiro[3.3]heptane##STR00516## Synthesized from Intermediate 101 and 3,3-difluorocyclohex- ane-1- carbaldehyde by reductive amination, asdescribed in step 4 of Example 41 232 2-((3,3- difluorocyclohexyl)methyl)-6-(5-(4- fluoro-2-(4- isopropylpyrimidin- 5-yl)phenoxy)pyrimidin- 4-yl)-2,6- diazaspiro[3.3]heptane##STR00517## Synthesized from Intermediate 27 and 3,3-difluorocyclohex- ane-1- carbaldehyde, by method described in step4 of Example 41 233 4-(((2-(5-(4-fluoro- 2-(1-isopropyl-1H-pyrazol-5- yl)phenoxy)pyrimidin- 4-yl)-5-oxa-2- azaspiro[3.4]octan-7- yl)amino)methyl)benzo- nitrile ##STR00518## Synthesized bymethod similar to Example 19. In step 3, 2- isoprpyl-3-pyrazole-boronic acid was utilized. 234 5-((7-(5-(2-(2-ethylpyridin-3-yl)- 4-fluorophenoxy) pyrimidin-4-yl)-2,7-diazaspiro [4.4]nonan-2- yl)methyl)-1,3- dihydro-2H-benzo[d]imidazol- 2-one ##STR00519## Synthesized by a methodsimilar to Example 41, starting with 2- ethyl-3-pyridyl boronicacid 235 5-((7-(5-(4-fluoro- 2- isopentylphenoxy)pyri-midin-4-yl)-2,7- diazaspiro[4.4]nonan- 2-yl)methyl)-1,3-dihydro-2H- benzo[d]imidazol- 2-one ##STR00520## By methoddescribed for Example 77, starting with isopentyl zinc chloride 2365-((7-(5-(4-fluoro- 2- isobutylphenoxy)pyri- midin-4-yl)-2,7-diazaspiro[4.4]nonan- 2-yl)methyl)-1,3- dihydro-2H-benzo[d]imidazol- 2-one ##STR00521## By method described froExample 77, starting with isobutyl zinc chloride 2375-((7-(5-(4-fluoro- 2-(1-isopropyl-1H- pyrazol-5-yl)phenoxy)pyrimidin- 4-yl)-2,7- diazaspiro[4.4]nonan-2-yl)methyl)-1,3- dihydro-2H- benzo[d]imidazol- 2-one ##STR00522##Synthesized from Intermediate 31a by the method described inExample 41 237A 2-(5-((5-fluoro-2'- isopropyl-[1,1'- biphenyl]-2-yl)oxy)pyrimidin-4- yl)-6-((tetrahydro- 2H-pyran-4- yl)methyl)-2,6-diazaspiro[3.3]heptane ##STR00523## Synthesized from Intermediate30 by reductive amination with 4- pyran- carboxyladehyde 238N-ethyl-5-fluoro-N- isopropyl-2-((4-(7- (((1r,4r)-4-(methylsulfonamido) cyclohexyl)methyl)- 2,7- diazaspiro[3.5]nonan-2-yl)pyrimidin-5- yl)oxy)benzamide ##STR00524## Synthesized bymethod similar to Example 6A from Intermediate 41F 2395-fluoro-N,N- diisopropyl-2-((4- (6-((tetrahydro-2H-pyran-4-yl)amino)- 2- azaspiro[3.3]heptan- 2-yl)pyrimidin-5-yl)oxy)benzamide ##STR00525## Synthesized from Intermediate 38 and4- pyrancarbaldehyde, by method described in last step of Example 1240 5-fluoro-N,N- diisopropyl-2-((4- (6- (methyl(tetrahydro-2H-pyran-4- yl)amino)-2- azaspiro[3.3]heptan- 2-yl)pyrimidin-5-yl)oxy)benzamide ##STR00526## Synthesized from Example 239 byreductive amination with formaldehyde.
TABLE-US-00026 TABLE 10 Characterization Data for Examples 79-240.Example 1H NMR MS 79 1H NMR (d4-MeOH) 8.44 (s, LCMS method G: 1H),7.83 (s, 1H), 7.57 (m, 1H), R.sub.t = 4.25 min, 7.46-7.51 (m, 2H),7.06 (d, (M + H).sup.+ = 669.6 1H), 6.60 (d, 1H), 3.93-4.40 (m,4H), 3.72 (m, 1H), 3.55 (d, 2H), 3.32 (d, 3H), 2.94-3.04 (m, 4H),2.20 (m, 2H), 1.90- 2.06 (m, 7H), 1.45 (dd, 2H), 1.16- 1.31 (m,3H), 0.84 (m, 1H), 0.65 (m, 2H), 0.37 (m, 1H) ppm. 80 1H NMR(d4-MeOH)-8.42 (s, LCMS method G: 1H), 7.82 (s, 1H), 7.47-7.55 (m,R.sub.t = 3.48 min, 3H), 7.04 (d, 1H), 6.61 (d, 1H), (M + H).sup.+= 651.6 3.71-4.40 (m, 4H), 3.54 (d, 2H), 3.31 (d, 3H), 3.19 (m,1H), 3.00 (m, 4H), 2.94 (s, 3H), 1.75- 2.20 (m, 9H), 1.20-1.36 (m,5H), 0.82 (m, 2H), 0.63 (m, 2H), 0.36 (m, 1H) ppm. 81A .sup.1H NMR(MeOD): .delta. 8.24 (s, LCMS method D: 1H), 7.77 (s, 1H),7.30-7.40 (m, R.sub.t = 2.045 min, 2H), 7.10-7.20 (m, 2H), 7.00- (M+ H).sup.+ = 652.3 7.10 (m, 3H), 6.50-6.65 (m, 1H), 3.95-4.05 (m,2H), 3.80-3.90 (m, 2H), 3.55-3.70 (m, 4H), 3.40- 3.55 (m, 2H),3.35-3.40 (m, 3H), 2.60-2.80 (m, 2H), 2.40-2.55 (m, 2H), 1.75-1.95(m, 4H), 1.25- 1.35 (m, 1H), 0.50-0.85 (m, 4H). .sup.19F NMR(MeOD): .delta. -119.21~-119.14. 81B .sup.1H NMR (MeOD): .delta.8.24 (s, LCMS method D: 1H), 7.77 (s, 1H), 7.30-7.40 (m, R.sub.t =2.048 min, 2H), 7.10-7.20 (m, 2H), 7.00- (M + H).sup.+ = 652.3 7.10(m, 3H), 6.56-6.59 (m, 1H), 3.95-4.05 (m, 2H), 3.80-3.87 (m, 2H),3.55-3.70 (m, 4H), 3.40- 3.55 (m, 2H), 3.35-3.40 (m, 3H), 2.40-2.80(m, 4H), 1.75-1.96 (m, 4H), 1.20-1.35 (m, 1H), 0.40- 0.85 (m, 4H)..sup.19F NMR (MeOD): .delta. -119.15. 82 LCMS method G: R.sub.t =4.21 min, (M + H).sup.+ = 529.8 83 .sup.1H NMR (CD.sub.3OD):.delta. 8.21-8.30 LCMS method G: (m, 1H), 7.70-7.79 (m, 1H), 6.89-R.sub.t = 0.936 min, 7.21 (m, 3H), 4.76-4.79 (m, 1H), (M + H).sup.+= 611.4 3.84-4.27 (m, 5H), 3.19-3.27 (m, 3H), 2.78-2.96 (m, 3H),2.37- 2.50 (m, 4H), 1.79-2.06 (m, 7H), 1.42 (s, 9H), 1.17-1.19 (m,6H), 0.99-1.13 (m, 2H) .sup.19F NMR (CD.sub.3OD): .delta.-120.92~-118.61. 84 LCMS method G: R.sub.t = 5.11 min, (M +H).sup.+ = 639.8 85 LCMS method G: R.sub.t = 3.21 min, (M +H).sup.+ = 597.2 86 LCMS method G: R.sub.t = 3.41 min, (M +H).sup.+ = 616.2 87 LCMS method G: R.sub.t = 5.21 min, (M +H).sup.+ = 637.8 88 LCMS method G: R.sub.t = 6.31 min, (M +H).sup.+ = 629.8 89 LCMS method G: R.sub.t = 2.21 min, (M +H).sup.+ = 514.6 90 .sup.1H NMR (CD.sub.3OD) .delta.: 8.58 (s, LCMSmethod A: 1H), 8.00 (m, 1H), 7.59 (d, J = R.sub.t = 0.84 min, 7.6Hz, 1H), 7.29 (d, J = 8.4 Hz, (M + H).sup.+ = 626 1H), 7.24 (m,3H), 7.17 (s, 1H), 4.47 (m, 2H), 4.01-3.48 (m, 8H), 2.15 (m, 4H),1.78 (s, 3H), 1.52 (s, 3H), 1.39 (s, 3H), 1.21 (d, J = 6.4 Hz, 3H).1.21 (d, J = 6.4 Hz, 3H), 1.10 (d, J = 6.4 Hz, 3H). 91 LCMS methodD: R.sub.t = 0.946 min, (M + H)+ = 562.1 91A .sup.1HNMR(CD.sub.3OD): .delta. 8.26 (d, J = LCMS method E: 16.0 Hz, 1 H),8.07 (d, J = 7.6 R.sub.t = 0.840 min, Hz, 1 H), 7.69-7.82 (m, 2 H),(M + H).sup.+ = 567.1 7.33-7.38 (m, 1 H), 7.15 (d, J = 8.0 Hz, 2H), 6.83-6.93 (m, 1 H), 3.93 (s, 1 H), 3.68 (brs, 6 H), 2.94 (s, 3H), 2.77 (s, 3 H), 1.82- 1.94 (m, 5 H), 1.18 (d, J = 6.8 Hz, 6H)..sup.19F NMR (CD.sub.3OD): .delta. -120.66, -123.26. 92 LCMSmethod D: R.sub.t = 0.826 min (M + H)+ = 484.1 93 .sup.1H NMR(CD.sub.3OD): .delta. 8.20-8.24 LCMS method E: (m, 1H), 7.68-7.77(m, 1H), 6.92- R.sub.t = 1.740 min, 7.20 (m, 3H), 4.76-4.78 (m,1H), (M + H).sup.+ = 603.3 3.86-3.95 (m, 5H), 3.10-3.13 (m, 1H),2.76-2.95 (m, 6H), 2.37- 2.39 (m, 4H), 2.16-2.17 (m, 2H), 1.99-2.03(m, 2H), 1.81-1.86 (m, 5H), 0.99-1.48 (m, 11H). .sup.19F NMR(CD.sub.3OD): .delta. -121.47~-118.42. 94 .sup.1H NMR (CD.sup.3OD):.delta. 8.20-8.24 LCMS method (m, 1H), 7.67-7.76 (m, 1H), 7.15- E:= 2.141 min; 7.20 (m, 2H), 6.93-7.04 (m, 1H), (M + H).sup.+ = 625.44.76-4.78 (m, 1H), 3.85-3.95 (m, 5H), 3.23-3.24 (m, 4H), 2.76- 2.94(m, 3H), 2.12-2.35 (m, 6H), 1.80-1.90 (m, 7H), 1.41 (s, 9H),1.14-1.17 (m, 6H), 0.92-1.01 (m, 2H). .sup.19F NMR (CD.sub.3OD):.delta. -120.43~-118.81. 95 .sup.1H NMR (CD.sub.3OD): .delta.8.20-8.24 LCMS method D: (m, 1H), 7.67-7.76 (m, 1H), 7.15- R.sub.t= 1.829 min; 7.20 (m, 2H), 6.93-7.04 (m, 1H), (M + H).sup.+ = 583.34.76-4.77 (m, 1H), 3.85-3.95 (m, 5H), 3.59 (s, 3H), 2.76-2.94 (m,3H), 1.80-2.35 (m, 14H), 1.45- 1.47 (m, 2H), 1.14-1.23 (m, 7H),0.93-1.02 (m, 2H). .sup.19F NMR (CD.sub.3OD): .delta.-120.03~-119.55. 96 LCMS method G: R.sub.t = 2.21 min; (M +H).sup.+ = 491.2 97 LCMS method G: R.sub.t = 4.21 min; (M +H).sup.+ = 624.69 98 LCMS method G: R.sub.t = 3.66 min; (M +H).sup.+ = 554.63 99 LCMS method G: R.sub.t = 3.68 min; (M +H).sup.+ = 540.63 100 LCMS method B: R.sub.t = 0.784 min; (M +H).sup.+ = 596.77 101 LCMS method G: R.sub.t = 3.79 min; (M +H).sup.+ = 540.7 102 LCMS method G: R.sub.t = 4.57 min; (M +H).sup.+ = 498.61 103 LCMS method G: R.sub.t = 4.12 min; (M +H).sup.+ = 482.54 104 LCMS method G: R.sub.t = 5.36 min; (M +H).sup.+ = 583.63 105 LCMS method G: R.sub.t = 5.40 min; (M +H).sup.+ = 623.70 106 LCMS method D: R.sub.t = 0.897 min; (M +H).sup.+ = 496.2 107 .sup.1H NMR (CD.sub.3OD): .delta. 8.56-8.65LCMS method D: (s, 1H), 7.81-8.15 (m, 1H), 7.27- R.sub.t = 1.73min; 7.39 (m, 5H), 7.20-7.22 (m, 1H), (M + H).sup.+ = 588.34.32-4.51 (m, 3H), 3.90-4.06 (m, 3H), 3.41-3.58 (m, 9H), 3.32- 3.33(s, 1H), 2.11-2.28 (m, 4H), 1.11-1.37 (m, 9H). .sup.19F NMR(CD.sub.3OD): .delta. -117.18. 108 LCMS method D: R.sub.t = 1.73min; (M + H).sup.+ = 468.6 109 LCMS method D: R.sub.t = 1.65 min;(M + H).sup.+ = 497.6 110 LCMS method G: R.sub.t = 3.40 min; (M +H).sup.+ = 526.2 111 LCMS method G: R.sub.t = 3.88 min; (M +H).sup.+ = 526.69 112 LCMS method G: R.sub.t = 3.88 min; (M +H).sup.+ = 5120.63 113 LCMS method G: R.sub.t = 5.93 min; (M +H).sup.+ = 571.63 114 LCMS method G: R.sub.t = 5.93 min; (M +H).sup.+ = 576.69 115 LCMS method G: R.sub.t = 6.14 min; (M +H).sup.+ = 639.79 116 LCMS method G: R.sub.t = 5.84 min; (M +H).sup.+ = 557.62 117 LCMS method G: R.sub.t = 5.12 min; (M +H).sup.+ = 622.5 118 LCMS method G: R.sub.t = 3.99 min; (M +H).sup.+ = 526.62 119 LCMS method G: R.sub.t = 4.75 min; (M +H).sup.+ = 596.49 120 LCMS method G: R.sub.t = 7.22 min; (M +H).sup.+ = 622.49 & 624.44 121 LCMS method D: R.sub.t = 1.71min; (M + H).sup.+ = 498.3 122 LCMS method E: R.sub.t 1.710 min; (M+ H).sup.+ = 586.3 123 .sup.1H NMR (CD.sub.3OD): .delta. 8.24-8.29LCMS method D: (m, 1 H), 7.74-7.83 (m, 1 H), R.sub.t = 0.900 min;6.83-7.16 (m, 6 H), 3.92-3.99 (m, (M + H).sup.+ = 645.4 3 H),3.46-3.64 (m, 8 H), 2.94- 2.95 (m, 2 H), 2.37-2.79 (m, 6 H), 1.92(brs, 3 H), 1.80 (s, 3 H), 1.17-1.24 (m, 6H). .sup.19F NMR(CD.sub.3OD): .delta. -120.40 124 LCMS method E: R.sub.t + 1.711min; (M + H).sup.+ = 631.3 125 LCMS method G: R.sub.t 3.710 min; (M+ H).sup.+ = 598.3 126 .sup.1H NMR (MeOH-d4): .delta. 7.71 (s, LCMSmethod B: 1 H), 7.40 (s, 1 H), 7.28-6.90 (m, R.sub.t = 0.62 min, 6H), 6.17 (s, 1 H), 4.29 (s, 2 H), (M + H).sup.+ = 583.6 4.24 (m, 1H), 3.71 (m, 4 H), 3.58-3.32 (m, 4 H), 2.39 (s, 3 H), 1.97 (m, 4H), 1.23 (m, 6 H). 127 .sup.1H NMR (CD.sub.3OD) .delta. 8.32 (d,LCMS method D: J = 14.8 Hz, 1 H), 7.81-7.89 (m, 1 R.sub.t = 0.92;H), 7.70 (d, J = 8.4 Hz, 2 H), (M + H).sup.+ = 543.2 7.47-7.50 (m,2 H), 7.17-7.21 (m, 2 H), 6.88-7.00 (m, 1 H), 4.19- 4.25 (m, 2 H),3.63-3.98 (m, 9 H), 2.80-2.97 (m, 3 H), 2.05-2.15 (m, 2 H),1.18-1.30 (m, 6 H). .sup.19F NMR (CD.sub.3OD): .delta.-120.11~-120.62. 128 .sup.1H NMR (CD.sub.3OD): .delta. 8.25-8.30LCMS method E: (m, 1 H), 7.76-7.83 (m, 1 H), R.sub.t = 1.764 min;7.08-7.18 (m, 5 H), 6.84-6.95 (m, (M + H).sup.+ = 588.3
1 H), 3.50-3.94 (m, 9 H), 2.77- 2.98 (m, 3 H), 2.54-2.77 (m, 4 H),1.83-1.95 (m, 4 H), 1.31 (t, J = 7.2 Hz, 3 H), 1.15-1.20 (m, 6 H)..sup.19F NMR (CD.sub.3OD): .delta. -120.12~-120.58. 129 .sup.1H NMR(CD.sub.3OD): .delta. 8.20-8.30 LCMS method E: (m, 1 H), 7.70-7.85(m, 1 H), R.sub.t = 1.734 min; 7.00-7.16 (m, 5 H), 6.80-6.93 (m, (M+ H).sup.+ = 618.3 1 H), 4.02 (t, J = 5.2 Hz, 2 H), 3.52-3.92 (m,12 H), 2.75-2.93 (m, 3 H), 2.48-2.68 (m, 4 H), 1.81-1.93 (m, 4 H),1.12-1.18 (m, 6 H). .sup.19F NMR (CD.sub.3OD): .delta.-120.12~-120.56. 130 .sup.1H NMR (CD.sub.3OD): .delta. 9.11 (s, 1LCMS method E: H), 8.63 (s, 1 H), 8.27 (s, 1 H), R.sub.t = 0.835min 7.79 (s, 1 H), 7.71 (d, J = 8.0 Hz, (M + H).sup.+ = 564.2 2 H),7.48 (d, J = 8.0 Hz, 2 H), 7.25-7.31 (m, 2 H), 7.04-7.06 (m, 1 H),4.17 (s, 2 H), 3.90 (s, 2 H), 3.64-3.77 (m, 6 H), 3.06-3.13 (m, 1H), 2.05-2.15 (m, 2 H), 1.22 (d, J = 5.6 Hz, 6H). .sup.19F NMR(CD.sub.3OD): .delta. -120.26~-120.34. 131 .sup.1H NMR(CD.sub.3OD): .delta. 9.10 (s, 1 LCMS method E: H), 8.61 (s, 1 H),8.25 (s, 1 H), R.sub.t = 1.834 min; 7.76 (s, 1 H), 7.20-7.25 (m, 2H), (M + H).sup.+ = 693.3 6.90-7.15 (m, 4 H), 4.06 (t, J = 5.2 Hz,2 H), 3.35-3.70 (m, 11 H), 3.05-3.11 (m, 1 H), 2.40-2.67 (m, 4 H),1.70-1.95 (m, 4 H), 1.15-1.25 (m, 6 H). .sup.19F NMR (CD.sub.3OD):.delta. -120.63 (s, 1 F). 132 .sup.1H NMR (CD.sub.3OD): .delta.9.09 LCMS method E: (s, 1H), 8.62 (s, 1H), 8.20 (s, 1H), R.sub.t =31.370 min; 7.98 (m, 1H), 7.67 (s, 1H), 7.50- M + H).sup.+ = 556.37.60 (m, 1H), 7.20-7.30 (m, 2H), 7.05-7.10 (m, 1H), 6.75-6.77 (d, J= 8.8 Hz, 1H), 4.38 (s, 2H), 4.26 (s, 4H), 4.09 (s, 2H), 3.88 (s,3H), 3.42 (s, 2H), 3.00-3.10 (m, 1H), 1.15-1.25 (m, 6H). .sup.19FNMR (CD.sub.3OD): .delta. -119.69~-119.72. 133 .sup.1H NMR(CD.sub.3OD): .delta. 9.09 (s, LCMS method D: 1H), 8.62 (s, 1H),8.19 (s, 1H), R.sub.t = 0.910 min; 7.67 (s, 1H), 7.22-7.27 (m, 3H),(M + H).sup.+ = 608.4 7.17-7.19 (m, 1H), 6.90-7.10 (m, 1H), 6.84(s, 1H), 4.35 (s, 2H), 4.24 (s, 4H), 4.09 (s, 2H), 3.46 (s, 2H),3.03-3.07 (m, 1H), 1.32 (s, 6H), 1.18-1.19 (m, 6H). .sup.19F NMR(CD.sub.3OD): .delta. -119.72~-119.69. 134 LCMS method D: R.sub.t =0.910 min; (M + H).sup.+ = 611.6 135 LCMS method E: R.sub.t =1.894; (M + H) = 546.3 136 LCMS method G: R.sub.t = 3.12 min; (M +H).sup.+ = 470.6 137 LCMS method G: R.sub.t = 4.12 min; (M +H).sup.+ = 546.2 138 LCMS method G: R.sub.t = 5.32 min; (M +H).sup.+ = 611.7 139 LCMS method G: R.sub.t = 6.32 min; (M +H).sup.+ = 571.2 140 .sup.1H NMR (CD.sub.3OD): .delta. 9.12 (s,LCMS method C: 1H), 8.61 (s, 1H), 8.19 (s, 1H), R.sub.t = 1.13 min;7.67 (s, 1H), 7.25-7.30 (m, 2H), (M + H).sup.+ = 556.4 7.08-7.12(m, 1H), 4.12 (s, 2H), 4.02 (s, 2H), 3.00-3.15 (m, 2H), 2.35-2.50(m, 4H), 1.70-2.05 (m, 8H), 1.30-1.45 (m, 5H), 1.15- 1.30 (m, 7H)..sup.19F NMR (CD.sub.3OD): .delta. -119.82. 141 .sup.1H NMR (MeOD):.delta. 9.07 (s, LCMS method C: 1H), 8.55 (s, 1H), 8.14 (s, 1H),R.sub.t = 0.639 min; 7.67-7.69 (m, 2H), 7.62 (s, 1H), (M + H).sup.+= 550.1 7.48-7.50 (m, 2H), 7.20-7.25 (m, 2H), 7.03-7.06 (m, 1H),3.94- 3.97 (m, 4H), 3.76-3.79 (m, 1H), 3.00-3.03 (m, 1H), 2.88-2.92(m, 1H), 2.25-2.35 (m, 1H), 2.12- 2.14 (m, 1H), 1.91-1.97 (m, 1H),1.78-1.83 (m, 1H), 1.32 (d, J = 6.8 Hz, 3H), 1.18-1.18 (m, 6H)..sup.19F NMR (CD.sub.3OD): .delta. -119.85 142 .sup.1H NMR(CD.sub.3OD 400 MHz): .delta. LCMS method C: 8.29-8.33 (m, 1H),7.80-7.88 (m, R.sub.t = 0.607 min; 1H), 7.60-7.62 (m, 2H),7.43-7.45 (M + H).sup.+ = 589.0; (m, 2H), 7.18-7.20 (m, 2H), 6.83-6.97 (m, 1H), 4.50-4.52 (m, 2H), 4.11-4.15 (m, 2H), 3.93-3.96 (m,3H), 3.55-3.76 (m, 4H), 2.95- 3.05 (m, 2H), 2.75-2.90 (m, 3H),1.93-2.05 (m, 5H), 1.18-1.35 (m, 7H). .sup.19F NMR (CD.sub.3OD):.delta. -120.17~-120.58 143 .sup.1H NMR (CD.sub.3OD): .delta. 8.15(s, LCMS method D: 1H), 7.55-7.57 (m, 3H), 7.37- R.sub.t = 0.843min; 7.39 (m, 1H), 7.15-7.27 (m, 3H), (M + H).sup.+ = 595.4 4.26(d, J = 8.4 Hz, 2H), 3.97- 3.98 (m, 3H), 3.55-3.57 (m, 2H),2.69-3.05 (m, 4H), 1.56-1.95 (m, 9H), 0.92-1.33 (m, 8H), 0.71- 0.73(m, 2H). .sup.19F NMR (CD.sub.3OD): .delta. -119.61~-119.49. 144LCMS method E: R.sub.t = 0.780 min (M + H).sup.+ = 576.1 145 LCMSmethod E: R.sub.t = 0.68 min; (M + H).sup.+ = 544.1 146 LCMS methodD: R.sub.t = 0.75 min; (M + H).sup.+ = 569.1 147 LCMS method B:R.sub.t = 1.34 min; (M + H).sup.+ = 610.2 148A .sup.1H NMR(CD.sub.3OD): .delta. 9.10 (s, LCMS method D: 1H), 8.59 (s, 1H),8.17 (s, 1H), R.sub.t = 0.621 min; 7.64 (s, 1H), 7.22-7.28 (m, 2H),(M + H).sup.+ = 542.1 7.06-7.10 (m, 1H), 4.10 (s, 2H), 3.98 (s,2H), 3.16-3.20 (m, 1H), 3.05-3.08 (m, 1H), 2.65-2.75 (m, 1H),2.44-2.46 (m, 2H), 1.92- 1.97 (m, 2H), 1.70-1.80 (m, 6H), 1.45-1.60(m, 2H), 1.35 (s, 3H), 1.20-1.21 (d, J = 6.8 Hz, 6H). .sup.19F NMR(MeOD): .delta. -119.85~-119.86. 148B .sup.1H NMR (CD.sub.3OD):.delta. 9.10 (s, LCMS method C: 1H), 8.59 (s, 1H), 8.17 (s, 1H),R.sub.t = 0.713 min; 7.64 (s, 1H), 7.22-7.28 (m, 2H), (M + H).sup.+= 542.1 7.06-7.09 (m, 1H), 4.10 (s, 2H), 3.98 (s, 2H), 3.23-3.25(m, 1H), 3.05-3.08 (m, 1H), 2.40-2.50 (m, 3H), 1.91-1.96 (m, 6H),1.38-1.43 (m, 4H), 1.34 (s, 3H), 1.20-1.22 (d, J = 7.2 Hz, 6H)..sup.19F NMR (CD.sub.3OD): .delta. -119.85~-119.86. 149 LCMS methodD: R.sub.t = 0.816 min; (M + H).sup.+ = 573.2 150 .sup.1H NMR(CD.sub.3OD): .delta. 9.09 (s, 1 LCMS method D: H), 8.63 (s, 1 H),8.45 (s, 1 H), R.sub.t = 0.616 min; 7.88 (s, 1 H), 7.18-7.37 (m, 6H), (M + H).sup.+ = 595.0 4.45 (s, 2 H), 3.75-3.90 (m, 4 H),3.35-3.64 (m, 7 H), 2.95-3.15 (m, 1 H), 1.95-2.15 (s, 4 H), 1.05-1.25 (m, 6 H). 151 LCMS method C: R.sub.t = 0.421 min; (M +H).sup.+ = 540.2 152 .sup.1H NMR (CD.sub.3OD): .delta. 9.12 (s,LCMS method D: 1H), 8.60 (s, 1H), 8.19 (s, 1H), R.sub.t = 0.626min; 7.67-7.70 (m, 2H), 7.67 (s, 1H), (M + H).sup.+ = 536.17.50-7.55 (m, 2H), 7.25-7.30 (m, 2H), 7.05-7.10 (m, 1H), 4.09 (s,2H), 4.02 (s, 2H), 3.75 (s, 2H), 3.14-3.18 (m, 1H), 3.06-3.09 (m,1H), 2.39-2.42 (m, 2H), 1.95- 2.00 (m, 2H), 1.21-1.22 (d, J =6.0Hz, 6H). .sup.19F NMR (CD.sub.3OD): .delta. -119.81. 153 LCMSmethod D: R.sub.t = 0.959 min; (M + H).sup.+ = 586.1 154 LCMSmethod C: R.sub.t = 0.541 min; (M + H).sup.+ = 558.0 155 LCMSmethod D: R.sub.t = 0.875 min (M + H)+ = 574.1 156 LCMS method G:R.sub.t = 3.12 min; (M + H).sup.+ = 512.2 157 LCMS method G:R.sub.t = 5.813 min; (M + H).sup.+ = 585.7 158 LCMS method G:R.sub.t = 7.22 min; (M + H).sup.+ = 510.2 159 LCMS method G:R.sub.t = 6.38 min; (M + H).sup.+ = 527.2 160A .sup.1H NMR(CD.sub.3OD): .delta. 9.10 (s, LCMS method E: 1H), 8.61 (s, 1H),8.25 (s, 1H), R.sub.t = 1.060: 7.76 (s, 1H), 7.20-7.30 (m, 2H), (M+ H).sup.+ = 581.2 6.80-7.15 (m, 4H), 3.80 (s, 2H), 3.40-3.65 (m,4H), 3.00-3.15 (m, 1H), 2.50-3.00 (m, 4H), 1.75- 2.00 (m, 4H), 1.22(d, J = 6.4 Hz, 6H). .sup.19F NMR (CD.sub.3OD): .delta. -120.46.160B .sup.1H NMR (CD.sub.3OD): .delta. 9.08 (s, LCMS method E: 1H),8.59 (s, 1H), 8.23 (s, 1H), R.sub.t = 1.112 min; 7.74 (s, 1H),7.15-7.25 (m, 2H), (M + H).sup.+ = 581.2 6.90-7.15 (m, 4H),3.85-4.00 (m, 2H), 3.45-3.65 (m, 5H), 2.55- 3.15 (m, 4H), 1.75-2.05(m, 4H), 1.15-1.25 (m, 6H). .sup.19F NMR (CD.sub.3OD): .delta.-120.31. 161 LCMS method C: R.sub.t = 0.702 min; (M + H).sup.+ =771 162 .sup.1H NMR (CD.sub.3OD): .delta. 8.13-8.16 LCMS method C:(m, 2H), 7.59-7.64 (m, 2H), 7.13- R.sub.t = 0.612 min; 7.20 (m,3H), 6.99-7.02 (m, 1H), (M + H).sup.+ = 520.1 5.23-5.31 (m, 1H),4.19 (s, 4H), 3.91-3.94 (m, 2H), 3.32-3.37 (m, 6H), 2.34-2.36 (d, J= 6.4 Hz, 2H), 1.61-1.64 (m, 2H), 1.23- 1.30 (m, 2H), 1.18-1.20 (d,J = 6.0 Hz, 6H). .sup.19F NMR (CD.sub.3OD): .delta. -120.36 163.sup.1H NMR (CD.sub.3OD): .delta. 8.56 (d, J = LCMS method C: 8.8Hz, 1 H), 7.82-8.10 (m, 1 H), R.sub.t = 0.598 min; 7.05-7.40 (m, 6H), 4.60-4.65 (m, (M + H).sup.+ = 574.0 1 H), 4.47 (s, 2 H),3.75-4.15 (m, 4 H), 3.33-3.72 (m, 7 H), 2.65- 3.00 (m, 3 H),1.91-2.36 (m, 4 H), 0.93-1.33 (m, 6 H). .sup.19F NMR (CD.sub.3OD):.delta. -76.96, -117.20~-117.40. 164 LCMS method D: R.sub.t = 0.951min; (M + H).sup.+ = 562.1 165 LCMS method E: R.sub.t = 0.911 min;(M + H).sup.+ = 558.1 166 LCMS method E: R.sub.t = 0.962 min; (M +H)+ = 594.1 167 LCMS method E: R.sub.t = 1.024 min; (M + H).sup.+ =482.2 168 LCMS method G: R.sub.t = 3.12 min; (M + H).sup.+ = 469.2169 .sup.1H NMR (MeOH-d4): .delta. 8.25 (s, LCMS method B: 1 H),7.59 (s, 1 H), 7.34 (d, J = R.sub.t = 1.63 min; 7.2 Hz, 1 H),7.28-7.04 (m, 8 H), (M + H).sup.+ = 603.7 4.29 (s, 2 H), 3.72 (m, 4H), 3.32 (m, 4 H), 1.97 (m, 4 H), 1.52 (m, 1 H), 0.77 (m, 2 H),0.56 (m, 2 H). 170 .sup.19F NMR (MeOD): .delta. -76.962 (s, LCMSmethod C:
7 F), -117.586 (s, 1 F). .sup.1H NMR R.sub.t = 0.703 min; (MeOD):.delta. 8.40 (s, 1 H), 7.77 (d, (M + H).sup.+ = 619.0 J = 18.0 Hz,2 H), 7.45-7.59 (m, 1 H), 7.29-7.44 (m, 5 H), 7.13- 7.28 (m, 3 H),4.40 (s, 2 H). 3.78- 3.94 (m, 4 H), 3.75 (s, 3 H), 3.34- 3.72 (m, 4H) 1.98-2.37 (m, 4 H), 1.69 (s, 1 H), 0.93 (s, 2 H), 0.71 (s, 2 H)171 .sup.1H NMR (CD.sub.3OD): .delta. 8.41 (s, LCMS method C: 1H),8.15 (s, 1H), 7.98 (d, J = 8.4 R.sub.t = 0.845 min; Hz, 1H), 7.75(s, 1H), 7.65 (d, (M + H).sup.+ = 587.3 J = 8.8 Hz, 1H), 7.50 (d, J= 8.0 Hz, 1H), 7.30-7.45 (m, 3H), 7.10-7.30 (m, 2H), 4.64 (s, 2H),3.86 (s, 4H), 3.48 (s, 4H), 2.13 (s, 4H), 1.68 (s, 1H), 0.92 (s,2H), 0.71 (s, 2H). .sup.19F NMR (CD.sub.3OD): .delta. -77.106. 172.sup.1H NMR (CD.sub.3OD): .delta. 8.16 (s, LCMS method C: 1H),7.68-7.73 (m, 1H), 7.67 (s, R.sub.t = 0.683 min; 1H), 7.48 (d, J =8.0 Hz, 1H), (M + H).sup.+ = 637.0 7.41 (s, 1H), 7.32 (d, J = 8.0Hz, 1H), 7.13-7.26 (m, 4H), 7.03 (dd, J = 9.2 4.4 Hz, 1H),3.44-3.64 (m, 5H), 3.30-3.40 (m, 1H), 2.54- 2.72 (m, 2H), 2.34-2.46(m, 2H), 2.18 (s, 3H), 1.65-1.95 (m, 5H), 0.85-0.95 (m, 2H),0.60-0.75 (m, 2H). .sup.19F NMR (CD.sub.3OD): .delta. -120.48 (s,1F). 173 LCMS method C: R.sub.t = 0.56 min; (M + H).sup.+ = 560.0174 LCMS method G: R.sub.t = 2.36 min; (M + H).sup.+ = 561.2 175LCMS method G: R.sub.t = 3.36 min; (M + H).sup.+ = 574.2 176 LCMSmethod A: R.sub.t = 0.66 min; (M + H).sup.+ = 507.1 177 LCMS methodA: R.sub.t = 0.66 min; (M + H).sup.+ = 502.1 178 LCMS method B:R.sub.t = 1.51 min; (M + H).sup.+ = 608.1 179 LCMS method B:R.sub.t = 1.48 min; (M + H).sup.+ = 605.1 180 .sup.1H NMR(CD.sub.3OD) .delta.: 8.48 (s, LCMS method B: 1H), 8.03 (m, 1H),7.88 (m, R.sub.t = 1.45 min; 1H), 7.49 (m, 1H), 7.39-7.36 (m, (M +H).sup.+ = 578.1 3H), 7.23 (s, 1H), 7.19 (d, J = 8.4 Hz, 1H), 7.11(d, J = 8.4 Hz, 1H), 4.43 (s, 1H), 3.91 (m, 4H), 3.64- 3.42 (m,3H), 2.22-2.03 (m, 5H), 1.11 (m, 4H). 181 LCMS method B: R.sub.t =1.45 min; (M + H).sup.+ = 566.2 182 LCMS method G: R.sub.t = 3.36min; (M + H)+ = 586.2 183 LCMS method G: R.sub.t = 3.07 min; (M +H).sup.+ = 560.49 183A .sup.1H NMR (CD.sub.3OD): .delta. 8.28 (s,LCMS method E: 1H), 7.79 (s, 1H), 6.86-7.19 (m, R.sub.t = 1.595min; 6H), 4.74-4.76 (m, 0.5 H), 3.55- (M + H).sup.+ = 560.3 3.96(m, 6.5H), 2.95-2.96 (m, 2.0 H), 2.56-2.76 (m, 5 H), 1.84-1.96 (m,4H), 1.14-1.20 (m, 6H). .sup.19F NMR (CD.sub.3OD): .delta. -120.340SFC analytical method A: t.sub.R = 2.254 min, ee = 100%. 183B.sup.1H NMR (CD.sub.3OD): .delta. 8.28 (s, LCMS method D: 1H), 7.79(s, 1H), 6.86-7.19 (m, R.sub.t = 1.596 min; 6H), 4.74-4.76 (m, 0.5H), 3.55- (M + H).sup.+ = 560.3 3.96 (m, 6.5H), 2.95-2.96 (m, 2.0H), 2.56-2.76 (m, 5 H), 1.84-1.98 (m, 4H), 1.15-1.20 (m, 6H)..sup.19F NMR (CD.sub.3OD): .delta. -120.340 SFC analytical methodA: t.sub.R = 0.879 min, ee = 100%. 184 LCMS method B: R.sub.t =1.36 min; (M + H).sup.+ = 533.2 185 .sup.1H NMR (CD.sub.3OD):.delta. 8.44-8.53 LCMS method D: (m, 1 H), 7.68-7.95 (m, 1 H),R.sub.t = 0.898 min; 7.02-7.37 (m, 6 H), 4.37-4.41 (m, (M +H).sup.+ = 590.2 2 H), 3.88-4.11 (m, 5 H), 3.30- 3.67 (m, 6 H),2.07-2.45 (m, 6 H), 0.75-1.07 (m, 6 H). .sup.19F NMR (CD.sub.3OD):.delta. -116.59. 186 LCMS method D: R.sub.t = 0.878 min; (M +H).sup.+ = 574.4 187 .sup.1H NMR (CD.sub.3OD): .delta. 8.30 (s, 1LCMS method D: H), 7.78 (d, J = 1.2 Hz, 1 H), R.sub.t = 0.813 min;7.32-7.35 (m, 1 H), 7.19-7.20 (m, (M + H).sup.+ = 628.1 1 H),6.90-7.02 (m, 4 H), 4.04- 4.08 (m, 1 H), 3.56-3.68 (m, 7 H),2.48-2.64 (m, 5 H), 1.78-1.93 (m, 4 H), 1.09 (d, J = 6.8 Hz, 3 H),0.99-1.01 (m, 3 H). .sup.19F NMR (CD.sub.3OD): .delta. -70.50,-119.30. 188 .sup.1H NMR (MeOH-d4): .delta. 8.42 (s, LCMS method B:1 H), 7.76 (s, 1 H), 7.44 (m, 1 H), R.sub.t = 1.49 min; 7.38 (m, 5H), 7.22 (m, 2 H), (M + H).sup.+ = 601.5 6.98 (d, J = 7.6 Hz, 1 H),4.38 (s, 2 H), 4.02-3.72 (m, 4 H), 3.62 (m, 2 H), 3.58 (s, 2 H),3.40 (m, 2 H), 2.24-1.98 (m, 4 H), 1.64 (m, 1 H), 0.92 (m, 2 H),0.70 (m, 2 H). 189 .sup.1H NMR (CD.sub.3OD): .delta. 8.14 (s, LCMSmethod C: 1H), 7.61 (s, 1H), 7.50-7.58 (m, R.sub.t = 0.750 min;1H), 7.38 (d, J = 7.6 Hz, 1H), (M + H).sup.+ = 653.1 7.10-7.30 (m,4H), 4.17 (s, 4H), 3.35-3.40 (m, 5H), 2.45-2.50 (m, 2H), 1.85-1.95(m, 2H), 1.65- 1.75 (m, 3H), 1.44-1.74 (m, 10H), 1.15-1.35 (m, 5H),0.90- 1.10 (m, 4H), 0.70-0.80 (m, 1H). .sup.19F NMR (MeOD): .delta.-119.75. 190 LCMS method E: R.sub.t = 1.314 min; (M + H).sup.+ =586.2 190A LCMS method E: R.sub.t = 1.724 min; (M + H).sup.+ =608.2 191 .sup.1H NMR (CD3OD): .delta. 8.16 (s, LCMS method E: 1H),7.66 (s, 1H), 7.42 (s, 1H), R.sub.t = 1.614 min; 7.31 (s, 1H),7.06-7.23 (m, 7H), (M + H).sup.+ = 630.3 3.94 (q, J = 7.2 Hz, 2H),3.75 (s, 2H), 3.41-3.63 (m, 4H), 2.78 (s, 2H), 2.56 (s, 2H),1.69-1.92 (m, 5H), 1.31 (t, J = 7.2 Hz, 3H), 0.89 (s, 2H), 0.67 (s,2H). .sup.19F NMR (CD.sub.3OD): .delta. -76.916 (s, 0.3F), -120.337(s, 1F). 192 .sup.1H NMR (CD.sub.3OD): .delta. 11.77 (s, LCMSmethod B: 1H), 8.51 (s, 1H), 7.92 (d, J = 8.4 R.sub.t = 1.32 min;Hz, 1H), 7.87-7.84 (m, 2H), (M + H).sup.+ = 553.6 7.55 (s, 1H),7.43 (d, J = 8.4 Hz, 1H), 7.28 (m, 1H), 7.00 (m, 1H), 6.76 (m, 1H),4.80-4.70 (m, 1H), 4.68 (s, 2H), 4.45-4.30 (m, 2H), 4.05-3.95 (m,2H), 3.80- 3.60 (m, 2H), 3.50-3.30 (m, 2H), 2.35-2.10 (m, 5H), 1.85(m, 2H), 1.57 (m, 4H), 1.30 (m, 2H). 193 .sup.1H NMR (CD.sub.3OD):.delta. 8.52 (s, LCMS method B: 1H), 7.57 (s, 1H), 7.36 (d, J = 7.2R.sub.t = 1.43 min; Hz, 1H), 7.32-7.30 (m, 1H), (M + H).sup.+ =532.7 7.19 (d, J = 7.2 Hz, 1H), 7.10 (s, 1H), 7.01-6.98 (m, 1H),6.79- 6.75 (m, 1H), 4.80-4.70 (m, 1H), 4.42 (s, 2H), 4.40-3.95 (m,4H), 3.80-3.60 (m, 2H), 3.50- 3.30 (m, 2H), 2.35-2.10 (m, 5H), 1.85(m, 2H), 1.58 (m, 4H), 1.34 (s, 6H), 1.30 (m, 2H). 194 LCMS methodG: R.sub.t = 4.29 min; (M + H).sup.+ = 568.54 195 .sup.1H NMR(MeOH-d4): .delta. 8.27 (s, LCMS method B: 1 H), 7.63 (m, 1 H),7.60 (d, J = 8 R.sub.t = 1.43 min; Hz, 2 H), 7.42 (d, J = 8 Hz, 2H), (M + H).sup.+ = 629.8 7.39-7.14 (m, 4 H), 7.08 (m, 2 H), 4.27(s, 2 H), 3.78 (t, J = 6.8 Hz, 2 H), 3.86-3.58 (m, 4 H), 3.58-3.22(m, 4 H), 2.45 (t, J = 7.6 Hz, 2 H), 2.24-1.86 (m, 6 H), 1.54 (m, 1H), 0.78 (m, 2 H), 0.56 (m, 2 H). 196 .sup.1H NMR (MeOH-d4):.delta. 8.36 (s, LCMS method B: 1 H), 7.74 (s, 1 H), 7.49 (d, J =R.sub.t = 1.37 min; 7.3 Hz, 1 H), 7.38-7.30 (m, 4 H), (M + H).sup.+= 601.5 7.24 (m, 2 H), 7.15 (d, J = 7.6 Hz, 1 H), 7.06 (s, 1 H),4.29 (s, 2 H), 3.84-3.64 (m, 4 H), 3.60-3.48 (m, 1 H), 3.44 (m, 2H), 3.40- 3.26 (m, 2 H), 2.16-1.80 (m, 4 H), 1.57 (m, 1 H), 0.82(m, 2 H), 0.60 (m, 2 H). 197A LCMS method E: R.sub.t = 1.814 min;(M + H).sup.+ = 568.6 197B LCMS method E: R.sub.t = 1.834 min; (M +H).sup.+ = 568.6 198 .sup.1H NMR (CD.sub.3OD): .delta. 8.49 (s,LCMS method D: 1H), 8.14 (s, 1H), 7.96 (d, J = 8.4 R.sub.t = 0.602min; Hz, 1H), 7.84 (s, 1H), 7.65 (dd, J = (M + H)+ = 554.2 8.4,1H), 7.45-7.6 (m, 1H), 7.37 (d, J = 5.2 Hz, 2H), 7.29 (d, J = 7.2Hz, 1H), 6.30 (s, 1H), 4.64 (s, 2H), 4.38 (m, 1H), 3.90 (d, J = 2.8Hz, 4H), 3.40-3.75 (m, 4H), 2.15 (brs, 4H), 1.36 (d, J = 6.4 Hz,6H). .sup.19F NMR (CD.sub.3OD): .delta. -77.146, -117.398. 199.sup.1H NMR (CD.sub.3OD): .delta. 8.05 (s, LCMS method D: 1H),7.36-7.47 (m, 2H), 7.30- R.sub.t = 0.660 min; 7.33 (m, 1H), 7.25(s, 1H), 7.13 (M + H).sup.+ = 620.2 (s, 1H), 6.95-7.10 (m, 4H),3.35- 3.75 (m, 6H), 2.64-2.77 (m, 2H), 2.40-2.54 (m, 2H), 1.70-1.96(m, 4H), 1.52-1.66 (m, 1H), 0.65- 0.95 (m, 2H), 0.50-0.60 (m, 2H)..sup.19F NMR(CD.sub.3OD): .delta. -113.73 (s, 2F). 200 LCMS methodB: R.sub.t = 1.48 min; (M + H).sup.+ = 557.7 201 .sup.1H NMR(CD.sub.3OD): .delta. 11.77 (s, LCMS method B: 1H), 8.51 (s, 1H),7.93-7.87 (m, R.sub.t = 1.48 min; 2H), 7.84 (s, 1H), 7.59 (s, 1H),(M + H).sup.+ = 539.7 7.42 (d, J = 8.0 Hz, 1H), 7.30 (m, 1H), 6.96(m, 1H), 6.77 (m, 1H), 4.68 (s, 2H), 4.40-4.35 (m, 2H), 4.05-3.95(m, 2H), 3.80-3.60 (m, 4H), 3.50-3.30 (m, 2H), 2.28-2.11 (m, 5H),1.01 (m, 1H), 0.47 (m, 2H), 0.15 (m, 2H). 202 LCMS method B:R.sub.t = 1.53 min; (M + H).sup.+ = 587.6 203 LCMS methodG: R.sub.t= 4.53 min; (M + H).sup.+ = 557.3 204 LCMS methodG: R.sub.t = 2.53min; (M + H).sup.+ = 601.7 205 LCMS method D: R.sub.t = 1.48 min;(M + H)+ = 629.1 206A LCMS method C: R.sub.t = 1.38 min; (M + H)+ =562.7 206B LCMS method D: R.sub.t = 0.723 min; (M + H).sup.+ =562.1 206C LCMS method D: R.sub.t = 0.713 min; (M + H).sup.+ =562.1 207 .sup.1H NMR (CD.sub.3OD): .delta. 8.25 (s, 1 LCMS methodD:
H), 7.66 (brs, 1 H), 7.20 (dd, J = R.sub.t = 0.903 min; 8.8, 3.2Hz, 1 H), 7.04 (s, 2 H), (M + H).sup.+ = 548.1 6.98 (m, 2 H),6.87-6.88 (m, 1 H), 3.58-3.69 (m, 9 H), 3.19 (s, 3 H), 2.64-2.67(m, 4 H), 1.80-1.94 (m, 4 H). .sup.19F NMR (CD.sub.3OD): .delta.-119.65. 208 .sup.1H NMR (CD.sub.3OD): .delta. 8.48 (s, LCMS methodB: 1H), 7.64 (s, 1H), 7.35-7.33 (m, R.sub.t = 1.43 min; 4H),7.20-7.10 (m, 6H), 6.85- (M + H).sup.+ = 567.6 6.81 (m, 1H),5.01-4.95 (m, 2H), 4.40-4.35 (m, 2H), 4.30- 4.05 (m, 2H), 3.80-3.53(m, 2H), 3.48-3.30 (m, 3H), 2.06- 1.90 (m, 5H). 209 LCMS method G:R.sub.t = 3.81 min; (M + H).sup.+ = 491.6 210 LCMS method G:R.sub.t = 3.59 min; (M + H).sup.+ = 575.54 211 LCMS method G:R.sub.t = 2.52 min; (M + H).sup.+ = 572.70 212 LCMS method G:R.sub.t = 2.99 min; (M + H).sup.+ = 584.72 213 LCMS method D:R.sub.t = 0.13 min; (M + H).sup.+ = 601.3 214 LCMS method A:R.sub.t = 1.40 min (M + H)+ = 542.1 215 LCMS method E: R.sub.t =1.42 min; (M + H)+ = 526.1 216 LCMS method G: R.sub.t = 3.19 min;(M + H).sup.+ = 621.7 217 LCMS method D: R.sub.t = 0.39 min; (M +H).sup.+ = 637.3 218 LCMS method G: R.sub.t = 3.62 min; (M +H).sup.+ = 586.80 219 LCMS method A: R.sub.t = 0.1 min; (M +H).sup.+ = 544.1 220 LCMS method E: R.sub.t = 1.44 min; (M +H).sup.+ = 644.1 221 LCMS method E: R.sub.t = 3.83 min; (M +H).sup.+ = 596.76 222 LCMS method G: R.sub.t = 4.75 min; (M +H).sup.+ = 596.49 223 LCMS method D: R.sub.t = 0.13 min; (M +H).sup.+ = 609.1 224 LCMS method D: R.sub.t = 0.12 min; (M +H).sup.+ = 586.1 225 LCMS method C: R.sub.t = 0.539 min; (M +H).sup.+ = 484.2 226 .sup.1H NMR (CD.sub.3OD): .delta. 8.16 (s,LCMS method C: 1H), 7.47-7.64 (m, 3H), 7.31- R.sub.t = 0.361 min;7.33 (m, 1H), 7.18-7.22 (m, 1H), (M + H).sup.+ = 576.1 7.01-7.12(m, 5H), 3.43-3.66 (m, 6H), 2.64-2.69 (m, 2H), 2.46 (s, 2H), 2.21(s, 3H), 1.73-1.90 (m, 4H). .sup.19F NMR (CD.sub.3OD): .delta.-120.33. 227 .sup.1H NMR (CD.sub.3OD): .delta. 9.12 (s, LCMS methodC: 1H), 8.65 (s, 1H), 8.22 (s, 1H), R.sub.t = 0.670 min; 7.67-7.71(m, 3H), 7.46 (d, J = (M + H).sup.+ = 550.1 8.8 Hz, 2H), 7.25-7.33(m, 2H), 7.10-7.14 (m, 1H), 4.41 (s, 2H), 4.28 (s, 4H), 4.13 (s,2H), 3.60 (s, 2H), 3.05-3.13 (m, 1H), 1.16- 1.22 (m, 6H). .sup.19FNMR (CD.sub.3OD): .delta. -119.62. 228 .sup.1H NMR (CD.sub.3OD).delta. 8.13 (s, LCMS method C: 1H), 7.70 (d, J = 8.4 Hz, 2H),R.sub.t = 0.735 min; 7.56 (s, 1H), 7.47 (d, J = 8.4 Hz, (M +H).sup.+ = 548.1 2H), 7.34-7.40 (m, 2H), 7.11- 7.24 (m, 5H), 4.36(s, 2H), 4.21 (s, 4H), 4.09 (s, 2H), 3.61 (s, 2H), 2.78-2.89 (m,1H), 1.13 (d, J = 6.8 Hz, 3H), 1.10 (d, J = 7.2 Hz, 3H). .sup.19FNMR (CD.sub.3OD): .delta. -119.81. 229 .sup.1H NMR(CD.sub.3OD):.delta. 8.13 (s, LCMS method C: 1H), 7.93 (d, J = 8.4 Hz, 2H),R.sub.t = 0.712 min; 7.53-7.57 (m, 3H), 7.35-7.40 (m, (M + H).sup.+= 601.1 2H), 7.10-7.22 (m, 5H), 4.38 (s, 2H), 4.22 (s, 4H), 4.10(s, 2H), 3.64 (s, 2H), 3.13 (s, 3H), 2.79- 2.88 (m, 1H), 1.13 (d, J= 6.8 Hz, 3H), 1.10 (d, J = 6.8 Hz, 3H). .sup.19F NMR (CD.sub.3OD):.delta. -119.81. 230 .sup.1H NMR (CD.sub.3OD): .delta. 8.15 (s,LCMS method C: 1H), 7.62-7.66 (m, 2H), 7.41- R.sub.t = 0.616 min;7.47 (m, 1H), 7.18-7.32 (m, 2H), (M + H).sup.+ = 576.1 7.13 (dd, J= 8.4, 2.8 Hz, 1H), 6.95-7.08 (m, 4H), 3.43-3.66 (m, 6H), 2.65-2.71(m, 2H), 2.45- 2.50 (m, 2H), 2.36 (s, 3H), 1.75- 1.90 (m, 4H)..sup.19F NMR (CD.sub.3OD): .delta. -120.15~--120.21. 231 LCMSmethod D: R.sub.t = 0.682 min; (M + H).sup.+ = 526.6 232 .sup.1HNMR (CD.sub.3OD): .delta. 9.14 (s, 1 LCMS method C: H), 8.65 (s, 1H), 8.40 (s, 1 H), R.sub.t = 0.652 min; 7.81 (s, 1H), 7.25-7.45 (m,3 H), (M + H).sup.+ = 539.2 4.30-4.50 (m, 8 H), 3.15-3.20 (m, 2 H),3.05-3.15 (m, 1 H), 1.80- 2.09 (m, 4 H), 1.70-1.79 (m, 2 H),1.45-1.65 (m, 3 H), 1.10-1.25 (m, 6 H). .sup.19F NMR (CD.sub.3OD):.delta. -77.06, -117.77, -101.11~-101.76, -90.19~-90.83. 233 LCMSmethod B: R.sub.t = 1.152 min; (M + H).sup.+ = 540.2 234 .sup.1HNMR (CD.sub.3OD) .delta.: 8.68 (s, LCMS method D: 1H), 8.47 (m,1H), 8.18 (d, J = 7.2 R.sub.t = 0.812 min; Hz, 1H), 7.90 (m, 1H),7.68 (m, (M + H).sup.+ = 566.1 1H), 7.36-7.33 (m, 3H), 7.22 (s,1H), 7.19 (d, J = 8.0 Hz, 1H), 7.11 (d, J = 8.0 Hz, 1H), 4.42 (s,1H), 3.85 (m, 4H), 3.66-3.48 (m, 3H), 2.87 (q, J = 7.6 Hz, 2H),2.11 (m, 4H), 2.87 (d, J = 7.6 Hz, 6H). 235 LCMS method B: R.sub.t= 1.252 min; (M + H).sup.+ = 531.2 236 LCMS method B: R.sub.t =1.112 min; (M + H).sup.+ = 517.2 237 LCMS method E: R.sub.t = 0.07min; (M + H).sup.+ = 569.5 237A .sup.1H NMR (d4-MeOH) 8.38 (s,LC/MS (16 min method) - 1H), 7.62 (s, 1H), 7.16-7.42 (m, Rt = 5.07min; 5H), 7.14 (m, 2H), 4.25-4.62 (M + H).sup.+ = 503.8 (m, 8H),3.94 (m, 2H), 3.41 (m, 2H), 3.12 (d, 2H), 2.81 (m, 1H), 1.88 (m,1H), 1.61 (d, 2H), 1.33 (m, 2H), 1.14 (d, 3H), 1.10 (d, 3H) ppm.238 .sup.1H NMR (CD.sub.3OD): .delta. 8.50-8.60 LCMS method D: (m,1H), 7.65-7.95 (m, 1H), 7.20- R.sub.t = 0.709 min; 7.45 (m, 3H),4.20-4.75 (m, 5H), (M + H).sup.+ = 617.3 3.85-3.95 (m, 1H),3.35-3.65 (m, 3H), 2.90-3.25 (m, 9H), 1.75- 2.40 (m, 9H), 1.05-1.45(m, 12H). .sup.19F NMR (CD.sub.3OD): .delta. -117.14~-116.42,-83.63. 239 .sup.1H NMR (MeOD): .delta. 8.52 (s, LCMS method D:1H), 7.84 (s, 1H), 7.20-7.35 (m, R.sub.t = 1.055 min; 3H),4.30-4.60 (m, 4H), 3.85- (M + H).sup.+ = 512.3 4.05 (m, 3H),3.75-3.85 (m, 1H), 3.60-3.70 (m, 1H), 3.40-3.50 (m, 2H), 3.25-3.30(m, 1H), 2.65- 2.80 (m, 2H), 2.45-2.60 (m, 2H), 1.90-2.05 (m, 2H),1.55-1.70 (m, 2H), 1.40-1.55 (m, 6H), 1.05- 1.25 (m, 6H). .sup.19FNMR (MeOD): .delta. -116.90~117.18, -76.95. 240 LCMS method D:R.sub.t = 1.155 min; (M + H).sup.+ = 526.3
Examples 241-249
Examples 241-249 were prepared according to the procedure describedin Table 11 using the appropriate starting materials.Characterization data for Examples 241-249 is shown in Table12.
TABLE-US-00027 TABLE 11 Examples 241-249 Example Name StructureSynthetic method 241 tert-butyl ((1r,4r)- 4-((7-(5-((2-(diisopropylcar- bamoyl)-4- fluorophenyl)amino) pyrimidin-4-yl)-2,7-diazaspiro [3.5]nonan-2- yl)methyl) cyclohexyl) carbamate##STR00527## Synthesized by method described in Example 16. Infinal step, tert- butyl ((1r,4r)-4- formylcyclohexyl) carbamate wasused under reductive amination conditions. 242 1-((6-(5-((5-fluoro-2'-isopropyl-[1,1'- biphenyl]-2- yl)amino) pyrimidin-4-yl)-2,6-diaza spiro[3.3]heptan-2- yl)methyl)cyclo- hexan-1-ol##STR00528## Synthesized by a method similar to Example 71utilizing 1- oxaspiro[2.5] octane in final step 2435-((7-(5-((5-fluoro- 2'-isopropyl-[1,1'- biphenyl]-2- yl)amino)pyrimidin-4-yl)- 2,7-diazaspiro [4.4]nonan-2- yl)methyl)-1,3-dihydro-2H- benzo[d]imidazol- 2-one ##STR00529## Synthesized by amethod similar to Example 71. In the final step, i 2-oxo-2,3-dihydro- 1H- benzo[d]imidazole 5-carbaldehyde was usedunder reductive amination conditions. 244 N-(4-fluoro-2-(4-isopropylpyrimidin- 5-yl)phenyl)-4-(6- ((tetrahydro-2H- pyran-4-yl)methyl)-2,6- diazaspiro[3.3]heptan- 2-yl)pyrimidin- 5-amine##STR00530## Synthesized by method similar to Example 71. In thefinal step, tetrahydro-2H- pyran-4- carbaldehyde was used underreductive amination conditions. 245 N-(5-fluoro-2'-isopropoxy-[1,1'- biphenyl]-2-yl)-4- (2-isobutyl-2,7-diazaspiro[3.5]nonan- 7-yl)pyrimidin- 5-amine ##STR00531##Synthesized by a method similar to Example 71. In the final step,isobutyraldehyde was used under reductive amination conditions. 246N-(5-fluoro-2'- isopropyl-[1,1'- biphenyl]-2-yl)-4-(2-isobutyl-2,7- diazaspiro[3.5] nonan-7-yl)pyrimidin- 5-amine##STR00532## Synthesized by a method similar to Example 71. In thefinal step, isobutyraldehyde was used under reductive aminationconditions. 247 N-(2'-ethyl-5- fluoro-[1,1'- biphenyl]-2-yl)-4-(2-isobutyl-2,7- diazaspiro[3.5] nonan-7-yl)pyrimidin- 5-amine##STR00533## Synthesized by a method similar to Example 71. In thefinal step, isobutraldehyde was used under reductive aminationconditions. 248A Isomer 1: 5- fluoro-N,N- diisopropyl-2-((4- (2-(4-(methylsulfonamido) cyclohexyl)-2,7- diazaspiro[3.5]nonan-7-yl)pyrimidin- 5-yl)amino) benzamide ##STR00534## Synthesized bymethod described in Example 16. In final step, N-(4- oxocyclohexyl)methane sulfonamide was used under reductive amination conditions.248B Isomer 2: 5- fluoro-N,N- diisopropyl-2-((4- (2-(4-(methylsulfonamido) cyclohexyl)-2,7- diazaspiro[3.5]nonan-7-yl)pyrimidin- 5-yl)amino)benzamide ##STR00535## Minor isomerisolated from the preparation of Example 248A by SFC method A 2495-((7-(3-((5-fluoro- 2'-isopropyl-[1,1'- biphenyl]-2-yl)oxy)pyridin-4- yl)-2,7- diazaspiro[4.4]nonan- 2-yl)methyl)-1,3-dihydro-2H- benzo[d]imidazol- 2-one ##STR00536## Synthesized bya method similar to Example 41, starting with 3- bromo-4-chloropyridine
TABLE-US-00028 TABLE 12 Characterization Data for Examples 241-249Example .sup.1H NMR MS 241 LCMS method D: R.sub.t = 1.15 min; (M +H).sup.+ = 652.1 242 LCMS method D: R.sub.t = 1.055 min; (M +H).sup.+ = 516.1 243 LCMS method D: R.sub.t =: 0.8 min; (M +H).sup.+ = 578.1 244 LCMS method B: R.sub.t = 0.54 min; (M +H).sup.+ = 504.7 245 .sup.1H NMR (CD.sub.3OD): .delta. 8.21 LCMSmethod D: (s, 1H), 7.94 (s, 1H), 7.34 (t, R.sub.t = 0.890 min; J =7.2 Hz, 1H), 7.22 (d, J = (M + H).sup.+ = 504.3 7.6 Hz, 1H),7.02-7.11 (m, 4H), 6.95-7.00 (m, 1H), 4.44-4.50 (m, 1H), 3.15-3.25(m, 4H), 3.13 (s, 4H), 2.40 (d, J = 6.8 Hz, 2H), 1.60- 1.70 (m,1H), 1.50-1.60 (m, 4H), 1.11 (d, J = 5.6 Hz, 6H), 0.89 (d, J = 3.2Hz, 6H). .sup.19F NMR (MeOD): .delta. -123.08; 246 LCMS method D:R.sub.t = 0.72 min; (M + H).sup.+ = 488.2 247 LCMS method B:R.sub.t = 0.68 min; (M + H).sup.+ = 474.7 248A LCMS method D:R.sub.t = 0.921 min; (M + H).sup.+ = 616.6. 248B LCMS method D:R.sub.t = 0.932 min; (M + H).sup.+ = 616.6. 249 .sup.1H NMR(CD.sub.3OD): .delta. 7.95 LCMS method A: (d, J = 8.0 Hz, 1H), 7.74(s, R.sub.t = 0.81 min; 1H), 7.40-7.10 (m, 10 H), (M + H).sup.+ =578.1 6.77 (m, 1H), 4.41 (s, 2H), 3.63-3.26 (m, 8H), 2.78 (m, 1H),2.15 (m, 4H), 1.12 (d, J = 6.8 Hz, 3H), 1.03 (d, J = 6.8 Hz,3H).
Examples 250A-250B
2'-((4-(7-amino-7-benzyl-2-azaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-2-c-yclopropyl-5'-fluoro-[1,1'-biphenyl]-4-carbonitrile (Isomers1-2)
##STR00537##
Step 1.tert-butyl-7-((tert-butylsulfinyl)imino)-2-azaspiro[4.4]nonane-2-c-arboxylate
##STR00538##
To a solution of tert-butyl7-oxo-2-azaspiro[4.4]nonane-2-carboxylate (175 mg, 0.73 mmol) and2-methylpropane-2-sulfinamide (106.2 mg, 1.2 eq) in THF (6 mL), wasadded tetraethoxytitanium (283 mg, 260 .mu.L, 1.7 eq) and theresulting solution was heated at reflux under N.sub.2 for 5 h. Thereaction mixture was cooled to RT and brine (10 drops) was added tothe solution, and stirred for 1 h at RT. The mixture was filteredthrough a pad of Celite and washed with EtOAc. The combined organiclayers were removed to givetert-butyl-7-((tert-butylsulfinyl)imino)-2-azaspiro[4.4]nonane-2-carboxyl-ate (0.16 g, 64%). LCMS method B: R.sub.t=1.48 min;(M+H).sup.+=343.1.
Step 2. tert-butyl7-benzyl-7-((tert-butylsulfinyl)amino)-2-azaspiro[4.4]nonane-2-carboxylat-e
##STR00539##
To the solution oftert-butyl-7-((tert-butylsulfinyl)imino)-2-azaspiro[4.4]nonane-2-carboxyl-ate (0.16 g, 0.47 mmol) in THF (0.5 mL) at 0.degree. C., was addedbenzylmagnesium bromide (1 N in THF, 1 mL). The resulting solutionwas warmed to RT stirred overnight, and then quenched withsaturated NH.sub.4Cl aqueous solution. Extraction with EtOAc gavetert-butyl7-benzyl-7-((tert-butylsulfinyl)amino)-2-azaspiro[4.4]nonane-2-carboxylat-e (112 mg), which was used for the next step withoutpurification.
Step 3.N-(7-benzyl-2-azaspiro[4.4]nonan-7-yl)-2-methylpropane-2-sulfinami-de
##STR00540##
To a solution of tert-butyl7-benzyl-7-((tert-butylsulfinyl)amino)-2-azaspiro[4.4]nonane-2-carboxylat-e (112 mg) in DCM (2 mL) was added TFA (200 .mu.L), and theresulting solution was stirred at RT overnight. The solvent wasremoved under vacuum, and crude product was used for next stepwithout purification. LCMS method B: R.sub.t=1.27 min;(M+H).sup.+=335.2.
Step 4.N-(7-benzyl-2-(5-(2-chloro-4-fluorophenoxy)pyrimidin-4-yl)-2-azasp-iro[4.4]nonan-7-yl)-2-methylpropane-2-sulfinamide
##STR00541##
To a TFA salt ofN-(7-benzyl-2-azaspiro[4.4]nonan-7-yl)-2-methylpropane-2-sulfinamide(0.18 mmol) in .sup.iPrOH (1 mL) was added trimethylamine (100.mu.L) and 4-chloro-5-(2-chloro-4-fluorophenoxy)pyrimidine(Intermediate 10a) (40 mg, 0.15 mmol). The resulting solution washeated in a CEM microwave at 110.degree. C. for 1 hr. Aftercooling, the solution was diluted with EtOAc, filtered, and thefiltrate was concentrated to dryness. The residue was purified withISCO silica column with 100% EtOAc to giveN-(7-benzyl-2-(5-(2-chloro-4-fluorophenoxy)pyrimidin-4-yl)-2-azaspiro[4.4-]nonan-7-yl)-2-methylpropane-2-sulfinamide (31 mg, 31%). LCMSmethod B: R.sub.t=1.72 min; (M+H).sup.+=558.1.
Step 5.N-(7-benzyl-2-(5-((4'-cyano-2'-cyclopropyl-5-fluoro-[1,1'-biphenyl-]-2-yl)oxy)pyrimidin-4-yl)-2-azaspiro[4.4]nonan-7-yl)-2-methylpropane-2-su-lfinamide
##STR00542##
To a solution ofN-(7-benzyl-2-(5-(2-chloro-4-fluorophenoxy)pyrimidin-4-yl)-2-azaspiro[4.4-]nonan-7-yl)-2-methylpropane-2-sulfinamide (31 mg, 0.056 mmol),3-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile(18 mg, 0.067 mmol), K.sub.3PO.sub.4 (24 mg, 0.112 mmol) in1,4-dioxane (0.6 mL) and water (0.3 mL), was addedchloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2'-amino--1,1'-biphenyl)]palladium(II) (2 mg, 5 mol %). The resultingsolution was degassed, flushed with N.sub.2, and heated in a CEMmicrowave reactor at 110.degree. C. for 1 h. After cooling, thereaction mixture was extracted with EtOAc and washed with brine.The combined organic layers were dried over Na.sub.2SO.sub.4,concentrated to dryness to give crude product, which was used fornext step. LCMS method B: R.sub.t=1.79 min; (M+H).sup.+=664.7.
Step 5.2'-((4-(7-amino-7-benzyl-2-azaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)-oxy)-2-cyclopropyl-5'-fluoro-[1,1'-biphenyl]-4-carbonitrile(Isomers 1-2)
ToN-(7-benzyl-2-(5-((4'-cyano-2'-cyclopropyl-5-fluoro-[1,1'-biphenyl]-2--yl)oxy)pyrimidin-4-yl)-2-azaspiro[4.4]nonan-7-yl)-2-methylpropane-2-sulfin-amide in MeOH (1 mL) was added 6 N HCl aq. solution (1 mL) and theresulting solution was stirred at room temperature until nostarting material remained. The solvent was removed under vacuumand the residue was purified by preparative RP-HPLC method E togive the desired product as two isomers.
Isomer 1 as TFA salt (1.81 mg): LCMS method B: R.sub.t=1.41 min;(M+H).sup.+=560.6. .sup.1H NMR (MeOH-d4): .delta. 8.34 (s, 1H),7.71 (s, 1H), 7.45-7.21 (m, 11H), 3.72 (m, 2H), 3.44 (m, 1H), 3.32(m, 1H), 2.96 (s, 2H), 2.14 (m, 2H), 1.88 (m, 8H), 1.84 (m, 1H),0.78 (m, 2H), 0.60 (m, 2H).
Isomer 2 as TFA salt (1.76 mg): LCMS method B: R.sub.t=1.45 min;(M+H).sup.+=560.6. .sup.1H NMR (MeOH-d4): .delta. 8.24 (s, 1H),7.58 (s, 1H), 7.38 (d, J=8 Hz, 1H), 7.35-7.18 (m, 8H), 7.13 (m,2H), 3.70-3.40 (m, 3H), 3.28 (m, 1H), 2.92 (s, 2H), 2.08 (m, 2H),1.86-1.50 (m, 6H), 1.49 (m, 1H), 0.78 (m, 2H), 0.60 (m, 4H).
Example 251
2-((4-(3-(4-acetamidobenzyl)-2-amino-4-oxo-1,3,7-triazaspiro[4.4]non-1-en--7-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropyl-N-methylbenzamide
##STR00543##
Step 1: tert-butyl 4-acetamidobenzylcarbamate
##STR00544##
A cooled solution of tert-butyl 4-aminobenzylcarbamate (510 mg,2.29 mmol) at 0.degree. C. in pyridine (5 mL) was treated with theacetyl chloride (216 mg, 2.75 mmol) and stirred for 18 h at RT. Thesolvent was concentrated under reduced pressure and the residue waspurified by flash column chromatography (ISCO) on silica gel(eluting with petroleum ether:EtOAc=10:1 to 1:1) to affordtert-butyl 4-acetamidobenzylcarbamate as a white solid. LCMS MethodC: R.sub.t=0.894 min; (M+Na).sup.+=287.2.
Step 2: N-(4-(aminomethyl)phenyl)acetamide
##STR00545##
To a solution of tert-butyl 4-acetamidobenzylcarbamate (550 mg,2.08 mmol) in anhydrous DCM (12 mL) was added TFA (3 mL) slowly at0.degree. C. under N.sub.2 and the reaction mixture was stirred at0.degree. C. for 1.5 h. The mixture was concentrated under reducedpressure to afford N-(4-(aminomethyl)phenyl)acetamide, which wasused for the next step without further purification as a whitesolid as TFA salt. Yield: 342 mg (100% crude). LCMS Method D:R.sub.t=0.1.338 min; (2M+H).sup.+=329.1.
Step 3:N-(4-((3-tert-butoxycarbonylthioureido)methyl)phenyl)acetamide
##STR00546##
To a mixture of N,N'-bis-tert-butoxycarbonylthiourea (500 mg, 1.81mmol) and anhydrous THF (20 mL) was added 60% NaH (87 mg, 2.17mmol) at 0.degree. C. The reaction mixture was stirred at14-17.degree. C. for 1 h, then TFAA (193 mg/0.129 mL, 1.99 mmol)was added and the stirring continued for an additional 1 h. Then,N-(4-(aminomethyl)phenyl)acetamide (249 mg, 1.99 mmol) andEt.sub.3N (1 mL) in anhydrous THF (10 mL) was added and theresulting reaction was stirred at 14-17.degree. C. for 18 h.H.sub.2O (50 mL) was added to quench the reaction and the mixturewas extracted with EtOAc (3.times.50 mL). The combined organiclayers were washed with brine (2.times.40 mL), dried over withanhydrous Na.sub.2SO.sub.4, filtered, and the filtrate wasconcentrated under reduced pressure. The residue was purified byflash column chromatography (ISCO) on silica gel (eluting withpetroleum ether:EtOAc=1:0 to 10:1) to affordN-(4-((3-tert-butoxycarbonyl thioureido)methyl)phenyl)acetamide asa white solid. LCMS Method C: R.sub.t=0.998 min;(M+Na).sup.+=346.2.
Step 4: tert-butyl3-(4-acetamidobenzyl)-2-((tert-butoxycarbonyl)amino)-4-oxo-1,3,7-triazasp-iro[4.4]non-1-ene-7-carboxylate
##STR00547##
To a solution of 1-tert-butyl 3-methyl3-aminopyrrolidine-1,3-dicarboxylate (100 mg, 0.409 mmol) in 5 mLof DMF was addedN-(4-((3-tert-butoxycarbonylthioureido)methyl)phenyl)acetamide (159mg, 0.491 mmol), EDCI (127 mg, 0.819 mmol) and DIEA (106 mg, 0.819mmol). The mixture was stirred at RT for 48 h. The solvent wasconcentrated under reduced pressure. The residue was purified byflash column chromatography (ISCO) on silica gel (eluting withpetroleum ether:EtOAc=10:1 to 1:1) to afford tert-butyl3-(4-acetamidobenzyl)-2-((tert-butoxycarbonyl)amino)-4-oxo-1,3,7-triazasp-iro[4.4]non-1-ene-7-carboxylate as a white solid. Yield: 114 mg(55% two steps). LCMS Method D: R.sub.t=1.090 min;(M+H).sup.+=502.4.
Step 5:N-(4-((2-amino-4-oxo-1,3,7-triazaspiro[4.4]non-1-en-3-yl)methyl)ph-enyl)acetamide
##STR00548##
To a solution of tert-butyl3-(4-acetamidobenzyl)-2-((tert-butoxycarbonyl)amino)-4-oxo-1,3,7-triazasp-iro[4.4]non-1-ene-7-carboxylate (114 mg, 0.227 mmol) in anhydrousDCM (3 mL) was added TFA (1 mL) slowly at 0.degree. C. underN.sub.2 and the reaction mixture was stirred at RT for 30 min. Thereaction mixture was concentrated under reduced pressure to affordcrudeN-(4-((2-amino-4-oxo-1,3,7-triazaspiro[4.4]non-1-en-3-yl)methyl)phenyl)ac-etamide which was used for the next step without furtherpurification as a colorless oil. Yield: 68 mg (100% crude).
Step 6:2-((4-(3-(4-acetamidobenzyl)-2-amino-4-oxo-1,3,7-triazaspiro[4.4]n-on-1-en-7-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropyl-N-methylbenzamide
To a solution ofN-(4-((2-amino-4-oxo-1,3,7-triazaspiro[4.4]non-1-en-3-yl)methyl)phenyl)ac-etamide (25 mg, 0.077 mmol) and Intermediate 43 (30 mg, 0.1 mmol)in i-PrOH (5 mL) was added DIEA (60 mg, 0.462 mmol) and thereaction mixture was heated to 110.degree. C. at reflux for 18 h.The reaction mixture was concentrated under reduced pressure toafford the residue which was purified by prep HPLC method A to givethe title product as a white solid. Yield: 10.20 mg (22%). LCMSMethod D: R.sub.t=0.995 min; (M+H).sup.+=589.1. .sup.1H NMR(CD.sub.3OD): .delta. 8.55-8.79 (m, 1H), 7.99 (s, 1H), 7.61 (d,J=8.4 Hz, 2H), 7.25-7.46 (m, 5H), 4.16-4.88 (m, 6H), 3.91 (brs,1H), 2.72-3.03 (m, 3H), 2.43-2.70 (m, 2H), 2.14 (s, 3H), 1.02-1.30(m, 6H). .sup.19F NMR (CD.sub.3OD): .delta. -116.87, 117.22.
Example 252
N-Ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)-2,7-diaz-aspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide
##STR00549##
Step 1: tert-butyl2-(5-(4-fluoro-2-(methoxycarbonyl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[-3.5]nonane-7-carboxylate
##STR00550##
A mixture of methyl2-((4-chloropyrimidin-5-yl)oxy)-5-fluorobenzoate (Intermediate 48,0.30 g, 0.11 mmol), tert-butyl2,7-diazaspiro[3.5]nonane-7-carboxylate hydrochloride (CAS#:1023301-84-9) (0.28 g, 1.06 mmol) and TEA (0.32 g, 3.18 mmol) in.sup.iPrOH (3 mL) was heated with a CEM microwave reactor at110.degree. C. for 1 h. After cooling, the mixture was diluted withEtOAc (15 mL) and stirred until white solid formed, then filteredthrough a Celite.TM. pad, and subsequently washed with EtOAc(.about.10 mL). The combined filtrate was concentrated under vacuumto give the crude product tert-butyl2-(5-(4-fluoro-2-(methoxycarbonyl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[-3.5]nonane-7-carboxylate as a dark solid (0.59 g, 100% conversion),which was used for the next step without purification; LCMS methodB: R.sub.t=1.13 min; (M+H).sup.+15=473.5.
Step 2:2-((4-(7-(tert-butoxycarbonyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrim-idin-5-yl)oxy)-5-fluorobenzoic acid
##STR00551##
To a solution of tert-butyl2-(5-(4-fluoro-2-(methoxycarbonyl)phenoxy)-pyrimidin-4-yl)-2,7-diazaspiro-[3.5]nonane-7-carboxylate (0.59 g, .about.1.06 mmol) in MeOH (3mL), was added 2N LiOH aqueous solution (1.1 mL, 2.2 mmol). Theresulting solution was stirred at RT for 4 h, the solvent wasremoved, and the residue was washed with EtOAc (10 mL), acidifiedto pH=3, and dried to give2-((4-(7-(tert-butoxycarbonyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5--yl)oxy)-5-fluorobenzoic acid as a solid (0.47 g, 97%), which wasused for the next step without purification; LCMS method B:R.sub.t=1.02 min; (M+H).sup.+=458.6.
Step 3. tert-butyl2-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-d-iazaspiro[3.5]nonane-7-carboxylate
##STR00552##
To a mixture of2-((4-(7-(tert-butoxycarbonyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5--yl)oxy)-5-fluorobenzoic acid (0.2 g, 0.44 mmol),N-ethylpropan-2-amine (114 mg, 1.32 mmol), and TEA (200 .mu.L) inDMF (1 mL) at 0.degree. C., was added BOP reagent (233 mg, 0.53mmol). The resulting solution was warmed slowly to RT, and stirredfor 4 h. Water was added, the mixture was extracted with DCM(4.times., 5 mL), and the combined organic layers were washed withbrine, concentrated to dryness, and purified by ISCO flash column(10% MeOH/DCM) to give tert-butyl2-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-d-iazaspiro[3.5]nonane-7-carboxylate (160 mg, 70%) as a foam; LCMSmethod B: R.sub.t=1.16 min; (M+H).sup.+=528.6.
Step 4:2-((4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5--fluoro-N-isopropylbenzamide
##STR00553##
To a solution of tert-butyl2-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-pyrimidin-4-yl)-2,7--diazaspiro[3.5]nonane-7-carboxylate (160 mg, 0.30 mmol) inanhydrous DCM (3 mL), was added TFA (0.6 mL). The resultingsolution was stirred at RT for 30 min. The mixture was concentratedunder reduced pressure to dryness and used for the next step as acrude TFA salt; LCMS method B: R.sub.t=0.57 min,(M+H).sup.+=427.6.
Step 5: tert-butyl((1r,4r)-4-((2-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidi-n-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)cyclohexyl)carbamate
##STR00554##
To a solution of2-((4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro--N-isopropylbenzamide (0.30 mmol) in anhydrous MeOH (5 mL) wasadded NaOAc (140 mg) to adjust the pH to 6-7. Then tert-butyl((1r,4r)-4-formylcyclohexyl)carbamate (CAS#: 181308-57-6) (105 mg,0.45 mmol) was added. After being stirred at RT for 10 min,NaBH.sub.3CN (28 mg, 0.45 mmol) was added and the resulting mixturewas stirred at RT overnight. The mixture was concentrated and theresidue was purified on an ISCO flash column (8% MeOH/DCM) to givetert-butyl((1r,4r)-4-((2-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidi-n-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)cyclohexyl)carbamateas a white solid (156.5 mg, 82% in two steps); LCMS method B:R.sub.t=0.87 min; (M+H).sup.+=639.5.
Step 6:2-((4-(7-(((1r,4r)-4-aminocyclohexyl)methyl)-2,7-diazaspiro[3.5]no-nan-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide
##STR00555##
A solution of tert-butyl((1r,4r)-4-((2-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidi-n-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)cyclohexyl)carbamate(156.5 mg, 0.25 mmol) in 1.25 N HCl/MeOH (3 mL) was stirred at RTovernight. The solvent was then removed to give2-((4-(7-(((1r,4r)-4-aminocyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-y-l)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide as aHCl salt with 100% conversion, which was used for next step withoutfurther purification. LCMS method B: R.sub.t=0.52 min;(M+H).sup.+=539.6.
Step 7:N-Ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)--2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenz-amide
To a solution of2-((4-(7-(((1r,4r)-4-aminocyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-y-l)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamidehydrochloride (0.25 mmol) and Et.sub.3N (75 mg, 0.75 mmol) inanhydrous DCM (2 mL) at 0.degree. C., was added ethanesulfonylchloride (33 mg, 0.26 mmol) dropwise and the mixture was stirred at0.degree. C. for 2 h. The reaction mixture was quenched withH.sub.2O (5 mL), extracted with DCM (3.times.5 mL), and thecombined organic layers were washed with brine (5 mL), dried overanhydrous Na.sub.2SO.sub.4, filtered, and concentrated underreduced pressure. The residue was purified by ISCO flash columneluting with 8-10% MeOH/DCM to affordN-ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)-cyclohexyl)methyl)-2,7-di-azaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropyl-benzamideas a white solid (41 mg, 26%); LCMS method B: R.sub.t=0.73 min;(M+H).sup.+=631.6; .sup.1H NMR (MeOD-d4): .delta. 8.23, 8.22 (twos, 1H), 7.74, 7.70 (two s, 1H), 7.22-7.15 (m, 2H), 7.03-6.96 (m,1H), 4.45, 3.51 (two m, 1H), 4.08-3.82 (m, 4H), 3.36 (m, 1H), 3.24(m, 1H), 3.12-2.94 (m, 3H), 2.32 (m, 4H), 2.10 (d, J=6.8 Hz, 2H),1.96 (m, 2H), 1.88-1.76 (m, 6H), 1.48 (m, 1H), 1.20-1.04 (m, 14H),1.02 (m, 2H); .sup.19F NMR (MeOD-d4): .delta. -119.7.
Example 253
Scale-Up Synthesis ofN-ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)-2,7-dia-zaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide
##STR00556##
Step 1:N-ethyl-5-fluoro-N-isopropyl-2-(pyrimidin-5-yloxy)benzamide
##STR00557##
To a solution of 5-fluoro-2-(pyrimidin-5-yloxy)benzoic acid(Intermediate 49, 5 g, 21.4 mmol) in anhydrous DCM (60 mL) at0.degree. C., was added oxalyl chloride (2.2 mL, 25.6 mmol) slowly.The mixture was stirred at 0.degree. C. for 30 min and the solutionturned cloudy. Triethylamine (3.6 mL, 25.6 mmol) was then addedinto the reactor portionwise every 30 min. After the addition wascomplete, the water bath was warmed to ambient temperature and thereaction mixture was stirred for about 3 h. Then a solution ofisopropyl ethylamine (6.5 mL, 53.5 mmol) was added to the reactionmixture slowly and the mixture was stirred at RT for 10 h. Thereactor contents were washed sequentially with 1 N HCl aqueoussolution and 1 N sodium hydroxide. The organic layer wasconcentrated and dried under high vacuum to afford the crudeproduct N-ethyl-5-fluoro-N-isopropyl-2-(pyrimidin-5-yloxy)benzamideas a brown oil (6.2 g); LCMS Method B: t.sub.R=1.18 min;[M+H].sup.+=304.2
Step 2: 5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidine1-oxide
##STR00558##
At RT, a round bottom flask was charged with crudeN-ethyl-5-fluoro-N-isopropyl-2-(pyrimidin-5-yloxy)benzamide fromStep 1 and urea hydrogen peroxide powder (15-17% active oxygenbasis, 14.1 g, 150 mmol) in THF (60 mL). Trifluoroacetic anhydride(6 mL, 42.8 mmol) was then added slowly into the reaction mixture.After the addition was complete, the mixture was stirred at RT for45 min. The reaction was quenched by slow addition of saturatedNaHCO.sub.3 solution. The product was extracted withdichloromethane. The organic layer was treated with 1 MNa.sub.2S.sub.2O.sub.3. The biphasic mixture was tested byKI-starch test paper and showed negative result. Then the phaseswere then separated, the organic layer was dried overNa.sub.2SO.sub.4 and concentrated under reduced pressure. The crudeproduct5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-pyrimidine1-oxide was then dried in a high vacuum to furnish an orange oil(5.8 g); LC-MS Method B: t.sub.R=1.03 min; [M+H].sup.+=320.3.
Step 3:2-((4-Chloropyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzam-ide
##STR00559##
To a suspension of crude5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidine 1-oxidefrom Step 2 (5.8 g, .about.90% purity) and DIEA (16.2 mL, 90.9mmol) in EtOAc (70 mL) was added POCl.sub.3 (2.0 mL, 21.8 mmol)slowly at 0.degree. C. After addition, the resulting reactionmixture was warmed to RT and stirred at RT for 1 h. The reactionmixture was cooled to 0.degree. C. and quenched by slow addition ofH.sub.2O (30 mL). The organic layer was separated and the aqueouslayer was extracted twice with EtOAc (2.times.50 mL). The combinedorganic layers were dried over brine, Na.sub.2SO.sub.4, filtered,and then concentrated under reduced pressure and dried under vacuumto afford the crude product2-((4-chloropyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamideas a dark solid, which was used directly for the next step withoutfurther purifications; LC-MS Method B: t.sub.R=1.40 min;[M+H].sup.+=338.2
Step 4: tert-butyl2-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-d-iazaspiro[3.5]nonane-7-carboxylate
##STR00560##
A mixture of crude2-((4-chloropyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamidefrom Step 3, tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylatehydrochloride (CAS#: 1023301-84-9) (5.0 g, 19.1 mmol) and DIEA (9.8mL, 54.6 mmol) in .sup.iPrOH (35 mL) was stirred at 80.degree. C.for 5 h. The reaction mixture was cooled to RT and diluted withEtOAc (60 mL). The mixture was then washed with H.sub.2O (60 mL);the organic layer was separated and the aqueous layer was extractedwith EtOAc (60 mL). The combined organic layers were dried overbrine, Na.sub.2SO.sub.4, filtered, and then concentrated underreduced pressure and dried under vacuum. The crude product waspurified by ISCO flash column (3% MeOH/DCM) to provide tert-butyl2-(5-(2-(ethyl(isopropyl)-carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7--diazaspiro-[3.5]nonane-7-carboxylate as a brown solid (4.95 g, 44%over 4 steps); LC-MS Method B: t.sub.R=1.17 min; [M+H].sup.+=528.4;.sup.1H NMR (CD.sub.3OD, 400 MHz): .delta. 8.24 (s, 1H), 7.76 (s,1H), 7.21-7.15 (m, 2H), 7.00-6.96 (m, 1H), 4.05-3.95 (m, 2H),3.95-3.90 (m, 3H), 3.31-3.27 (m, 2H), 1.75-1.70 (m, 5H), 1.45 (s,9H), 1.31-1.10 (m, 12H).
Step 5:2-((4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5--fluoro-N-isopropylbenzamide
##STR00561##
To a solution of tert-butyl2-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)-pyrimidin-4-yl)-2,7--diazaspiro[3.5]nonane-7-carboxylate from Step 4 (69 g, 130.9 mmol)in anhydrous DCM (300 mL) was added HCl-dioxane (110 mL, 4M indioxane). The reaction mixture was stirred at 5-9.degree. C. for 4h. The mixture was diluted with water (500 mL) and extracted withDCM (3.times.400 m). The aqueous layer was adjusted to pH=12-14with 10% NaOH solution and extracted with DCM (3.times.800 mL). Thecombined organic layers were dried over anhydrous Na.sub.2SO.sub.4,filtered, and concentrated under reduced pressure to give2-((4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro--N-isopropyl-benzamide (46 g, 100%) as yellow solid, which was usedfor the next step directly without further purification; LC-MSMethod C: R.sub.t=0.416 min; [M+H].sup.+=428.2.
Step 6:N-ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)--2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenz-amide
To a mixture of2-((4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro--N-isopropylbenzamide from Step 5 (39.0 g, 91.3 mmol) inN-methyl-2-pyrrolidone (400 mL) was added((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl4-methylbenzenesulfonate (Intermediate 50, 41 g, 109.56 mmol), KI(16 g, 95.9 mmol) and K.sub.2CO.sub.3 (63 g, 456.5 mmol). Thereaction mixture was then stirred at 70-75.degree. C. for 6 h underN.sub.2 atmosphere. The reaction was cooled to RT and additional((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl4-methylbenzenesulfonate (Intermediate 50, 4.0 g, 10.9 mmol) wasadded and the reaction mixture was stirred at 70-75.degree. C. foranother 12 h under N.sub.2 atmosphere. The mixture was cooled toRT, diluted with water (500 mL), and extracted with DCM(3.times.800 mL). The combined organic layers were washed withwater (3.times.1.5 L), dried over anhydrous Na.sub.2SO.sub.4,filtered, and concentrated under reduced pressure. The residue waspurified by neutral prep-HPLC Method A to affordN-ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)-2,7-dia-zaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide(20.9 g, 36.8%) as white solid; LCMS Method A: R.sub.t=1.82 min;[M+H].sup.+=631.3; .sup.1H NMR (CDCl.sub.3 400 MHz): .delta. ppm8.36-8.37 (m, 1H), 7.76 (s, 1H), 6.99-7.04 (m, 2H), 6.74-6.80 (m,1H), 4.59-4.66 (m, 0.2H), 4.04-4.06 (m, 1H), 3.83-3.93 (m, 4H),3.48-3.53 (m, 0.8H), 3.30-3.39 (m, 1H), 3.17-3.21 (m, 1H),3.02-3.06 (m, 2H), 2.25 (s, 4H), 2.03-2.05 (s, 4H), 1.73-1.84 (m,7H), 1.12-1.36 (m, 14H), 0.89-0.98 (m, 2H); .sup.19F NMR(CDCl.sub.3 400 MHz): .delta. ppm -118.57; SFC Method A:t.sub.R=1.357 min; HPLC Method A: t.sub.R=6.84 min.
Example 254
N-Ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)-2,7-diaz-aspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamideFree Amine Crystallization
Free amine ofN-ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)-2,7-dia-zaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide(0.50 g) was dissolved in a mixture of EtOAc (6 mL) and hexane (9mL) to give a clear solution, which was seeded with <1 mg of5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidefree amine crystal (Example 6A). The resulting solution was stirredat 25.degree. C. for 2 days, the white solid was collected byfiltration, and dried over high vacuum overnight (0.39 g, 76%);.sup.1H NMR (MeOD-d4): .delta. 8.23, 8.22 (two s, 1H), 7.74, 7.70(two s, 1H), 7.22-7.15 (m, 2H), 7.03-6.96 (m, 1H), 4.45, 3.51 (twom, 1H), 4.08-3.82 (m, 4H), 3.36 (m, 1H), 3.24 (m, 1H), 3.12-2.94(m, 3H), 2.32 (m, 4H), 2.10 (d, J=6.8 Hz, 2H), 1.96 (m, 2H),1.88-1.76 (m, 6H), 1.48 (m, 1H), 1.20-1.04 (m, 14H), 1.02 (m, 2H);.sup.19F NMR (MeOD-d4): .delta. -119.7; meltingpoint=156.6-157.6.degree. C. Concentration in water to achievepH=7: 7.6 mg/mL.
The X-ray powder diffraction (XRPD) pattern was determined for thefree amine crystalline compound (XRPD Method A) and is shown inFIG. 1. A list of 2-theta peaks is provided in Table 13 below.
TABLE-US-00029 TABLE 13 2-theta (.degree.) Relative Height (%) 5.53.38 7.4 4.45 8.7 4.46 9.7 10.26 10.7 1.11 11.6 12.68 12.6 15.7714.8 2.8 15.3 7.52 15.6 6.68 15.8 8.92 16.6 100 17.5 12.82 17.95.84 18.8 32.29 19.2 28.69 19.8 22.32 21.0 18.85 21.4 7.86 22.03.31 22.8 6.98 23.4 3.78 24.6 2.77 25.3 7.45 26.1 2.04 26.64.55
Example 255
N-Ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)-2,7-diaz-aspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamideSesquifumaric Acid Salt (Sesquifumarate) Crystallization
N-Ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)-2,7-dia-zaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamidefree amine (497.2 mg, 0.79 mmol) and fumaric acid (137.2 mg, 1.5eq) were dissolved in EtOH (5 mL) to give a clear solution; EtOHwas removed under vacuum, and the salt was dried over high vacuumovernight.
The salt (0.54 g) was dissolved in EtOH/MeCN (21.8 mL, .about.4%EtOH) and the resulting solution was stirred at 25.degree. C.overnight, during which a white solid precipitated slowly. Thewhite solid was collected by filtration and dried over high vacuumfor 24 h (0.41 g, 76%). .sup.1H-NMR (DMSO-d6, 25 s relax delay):.delta. 8.26, 8.25 (two s, 1H), 7.72, 7.66 (two s, 1H), 7.32-7.22(m, 2H), 7.06 (m, 1H), 7.00 (d, J=7.6 Hz, 1H), 6.59 (s, 3H), 4.39,3.72 (two m, 1H), 3.98-3.76 (m, 4H), 3.38 (m, 1H), 3.22 (m, 1H),2.98 (m, 3H), 2.42 (m, 4H), 2.20 (d, J=6.4 Hz, 2H), 1.84 (m, 2H),1.74 (m, 6H), 1.43 (m, 1H), 1.28-0.82 (m, 16H); .sup.19F NMR(DMSO-d6): .delta. -118.43; melting point=176.1-177.8.degree. C.Concentration in water to achieve pH=7: 224.7 mg/mL.
The X-ray powder diffraction (XRPD) pattern was determined for thesesquifumaric acid crystalline salt (XRPD Method B) and is shown inFIG. 2. A list of 2-theta peaks is provided in Table 14 below.Ratio ofN-ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)-2,7-dia-zaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide:f-umaric acid=1:1.5).
TABLE-US-00030 TABLE 14 Peak No. 2-theta (deg) Rel. Int. I 1 2.92.29 2 5.8 100 3 8.7 30.83 4 10.7 2 5 11.3 6.2 6 12.6 7.44 7 13.232.95 8 14.5 11.48 9 15.3 10.8 10 16.0 82.33 11 17.1 9.59 12 17.433.3 13 17.6 29.24 14 18.0 6.2 15 18.9 9.23 16 19.1 56.98 17 20.341.59 18 20.7 15.72 19 21.2 4.29 20 21.8 39.15 21 23.0 39.41 2223.3 89.63 23 23.8 11.88 24 24.1 4.11 25 24.9 23.75 26 26.0 27.3727 26.9 7.73 28 27.8 4.3 29 28.3 6.99 30 28.8 16.43 31 29.0 1.46 3231.7 13.12 33 34.0 1.49 34 34.6 8.69 35 34.9 2.8 36 35.2 1 37 37.22.42 38 37.5 1.24 39 38.4 1.05 40 40.1 6.27 41 42.5 4.29 42 45.61.49
Example 256
N-Ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)-2,7-diaz-aspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamideBis-Methanesulfonic Acid Salt (Bis-Mesylate) Crystallization
To a clear solution ofN-ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)-2,7-dia-zaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamidefree amine (419.7 mg) in .sup.iPrOH (2.5 mL) and EtOAc (3 mL), wasadded MeSO.sub.3H (>99.5%, Sigma-Aldrich) (0.13 g, 88.6 .mu.L,2.05 eq) dropwise. An additional 3 mL of EtOAc was added to theresultant solution, and the mixture was stirred at RT overnight.White solid was then collected by filtration, all solid wastransferred with the mother liquor twice, and dried over highvacuum for 2 days (535.1 g, 97%); .sup.1H-NMR (MeOD-d4): .delta.8.53, 8.52 (two s, 1H), 7.92, 7.82, 7.71 (three s, 1H), 7.38-7.22(m, 3H), 4.69-4.16 (br, m, 4H), 3.90 (m, 1H), 3.57 (m, 2H), 3.45(m, 1H), 3.26 (m, 1H), 3.16 (m, 1H), 3.03 (q, J=7.6 Hz, 2H), 2.98(m, 4H), 2.68 (s, 6H), 2.22-2.02 (m, 6H), 1.92-1.74 (m, 3H),1.44-1.06 (m, 16H); .sup.19F NMR (MeOD-d4): .delta. -116.53,-116.79, -117.27; melting point=207.6-209.7.degree. C.Concentration in water to achieve pH=7: 261 mg/mL.
The X-ray powder diffraction (XRPD) pattern was determined for thebis-methanesulfonic acid crystalline salt (XRPD Method A) and isshown in FIG. 3. A list of 2-theta peaks is provided in Table 15below. Ratio ofN-ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)-2,7-dia-zaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide:m-ethanesulfonic acid=1:2).
TABLE-US-00031 TABLE 15 2-theta (.degree.) Relative Height (%) 5.658.6 11.0 4.48 13.3 6.67 16.7 100 17.5 2.81 18.1 2.75 20.1 13.4320.6 7.78 20.9 15.37 22.1 4.08 23.6 4.44 24.4 0.88 24.9 4.33 25.82.33 27.0 3.5 28.0 1.91 29.6 6.5 30.4 0.82 31.8 1.61 33.7 1.18
Example 257
N-Ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)-2,7-diaz-aspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamideBis-Hydrochloric Acid Salt (Bis-Hydrochloride) Crystallization
To a clear solution ofN-ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)-2,7-dia-zaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamidefree amine (0.71 g) in EtOH (3 mL) was added 1 N HCl aqueoussolution (2.25 mL, 2 eq) dropwise. The resulting solution was mixedand evaporated to dryness under high vacuum.
The resultant salt (0.71 g) was dissolved in .sup.iPrOH (4 mL) andEtOAc (7 mL) to give a clear solution. A seed crystal was generatedby dissolving Example 252 (.about.5 mg) in EtOH (100 .mu.L),followed by slow evaporation in a chamber containing iPrOH(.about.5 mL). The bis-hydrochloric acid salt solution was seededwith the seed crystal and the solution was stirred at 25.degree. C.overnight. White solid was collected by filtration and dried overhigh vacuum for 2 days (0.54 g, 76%); .sup.1H NMR (MeOD-d4):.delta. 8.54, 8.52 (two s, 1H), 7.92, 7.82, 7.71 (three s, 1H),7.38-7.24 (m, 3H), 4.68-4.12 (br, m, 4H), 3.88 (m, 1H), 3.57 (m,2H), 3.45 (m, 1H), 3.26 (m, 1H), 3.16 (m, 1H), 3.03 (q, J=7.6 Hz,2H), 2.99 (m, 4H), 2.34-2.02 (m, 6H), 1.94-1.76 (m, 3H), 1.44-1.06(m, 16H); .sup.19F NMR (MeOD-d4): .delta. -116.48, -116.77,-117.26; melting point=219-220.degree. C. Concentration in water toachieve pH=7: 317.6 mg/mL.
The X-ray powder diffraction (XRPD) pattern was determined for thebis-hydrochloric acid crystalline salt (XRPD Method A) and is shownin FIG. 4. A list of 2-theta peaks is provided in Table 16 below.Ratio ofN-ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)-2,7-dia-zaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide:h-ydrochloric acid=1:2).
TABLE-US-00032 TABLE 16 2-theta (.degree.) Relative Height (%) 4.787.32 9.3 8.17 10.7 15.59 11.4 11.99 11.9 9.62 13.4 16.46 14.0 6.7615.1 7.1 15.9 33.04 17.0 100 18.6 14.63 19.5 39.53 20.1 16.47 21.412.15 23.8 34.71 24.4 8.37 25.1 4.31 25.8 22.42 26.6 4.53 28.116.14 28.7 8.75
Example 258
5-Fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohexy-l)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamideFree Amine Crystallization
Free amine of5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide(Example 6A, 0.79 g) was dissolved in a mixture of EtOAc and hexane(28 mL, .about.38% volume of EtOAc). Once all the material wentinto the solution, the clear solution gradually turned cloudy. Theresulting solution was stirred at 25.degree. C. overnight. Thewhite solid was then collected by filtration and dried over highvacuum overnight (0.58 g, 73%); .sup.1H-NMR showed pure compoundwith trace of EtOAc; melting point=177-178.degree. C.
The X-ray powder diffraction (XRPD) pattern was determined for thefree amine crystalline compound (XRPD Method B) and is shown inFIG. 5. A list of 2-theta peaks is provided in Table 17 below.
TABLE-US-00033 TABLE 17 Peak 2-theta No. (deg) Rel. Int. I 1 6.215.16 2 8.3 6.31 3 12.3 4.1 4 12.7 5.92 5 13.4 7.82 6 14.5 1.41 715.0 2.65 8 15.7 5.05 9 16.1 28.24 10 16.6 100 11 17.3 12.06 1217.7 8.6 13 18.6 3.34 14 19.0 46.74 15 19.3 2.78 16 20.2 0.91 1720.7 3.76 18 21.5 2.37 19 22.1 4.99 20 22.4 5.43 21 22.7 0.83 2223.5 12.82 23 23.8 1.66 24 24.7 3.75 25 25.0 1.25 26 25.3 13.75 2725.7 1.48 28 26.9 13.48 29 27.6 2.21 30 28.7 1.41 31 28.8 0.78 3229.1 2.46 33 29.8 1.61 34 30.3 5.42 35 30.8 1.37 36 31.6 2.1 3732.3 0.73 38 32.5 0.42 39 32.9 1.72 40 33.5 5.09 41 34.0 0.91 4234.6 0.93 43 35.7 0.65 44 36.1 0.99 45 36.9 0.46 46 37.6 0.53 4737.9 1.78 48 38.8 0.44 49 39.2 0.24 50 39.5 0.32 51 39.8 0.48 5241.2 1.47 53 41.9 0.49 54 42.1 1.43 55 42.6 1.06 56 42.9 0.74 5744.0 0.55 58 44.3 1.39 59 45.0 0.15 60 45.8 2.16
Example 259
5-Fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohexy-l)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamideBis-Methanesulfonic Acid Salt (Bis-Mesylate) Crystallization
5-Fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide(Example 6A) free amine (1.02 g) was dissolved in .sup.iPrOH (25mL) and MeSO.sub.3H (>99.5%, Sigma-Aldrich) (0.31 g, 207.5.mu.L, 2.05 eq) was added to the solution slowly. The resultingsolution was seeded with a single crystal of5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidebis-methanesulfonic acid salt (Example 264) and stirred at roomtemperature overnight. White solid was collected by filtration, anddried over high vacuum for 4 days (0.94 g, 73%); 1HNMR confirmedbis-mesylate without solvent peaks; meltingpoint=217.6-219.6.degree. C.
The X-ray powder diffraction (XRPD) pattern was determined for thebis-methanesulfonic acid crystalline salt (XRPD Method B),confirming it to be crystalline, and is shown in FIG. 6. A list of2-theta peaks is provided in Table 18 below.
TABLE-US-00034 TABLE 18 Peak 2-theta No. (deg) Rel. Int. I 1 5.612.05 2 8.8 7.15 3 10.2 14.78 4 11.0 9.26 5 12.0 3.86 6 12.6 18.257 12.9 3.26 8 13.8 16.04 9 14.1 14.7 10 15.3 61.65 11 16.2 20.21 1216.3 4.22 13 16.8 38.78 14 17.6 100 15 18.6 33.5 16 20.3 57.51 1720.7 12.84 18 20.9 19.21 19 21.2 18.21 20 21.5 15.41 21 21.8 9.0622 22.1 2.08 23 22.4 14.23 24 22.7 17.02 25 23.6 3.46 26 24.6 17.4527 24.9 4.88 28 25.3 11.87 29 25.7 5.37 30 26.0 9.41 31 26.3 10.6532 26.7 7.5 33 27.2 11.08 34 27.8 1.58 35 28.6 4.7 36 29.5 3.58 3730.0 1.54 38 30.4 12.64 39 31.7 4.4 40 32.7 5.31 41 36.2 1.99 4237.9 1.86 43 39.6 2.29 44 40.2 2.82 45 42.1 3.32 46 42.7 1.03 4745.4 2.2 48 46.0 0.99 49 47.0 0.71 50 49.3 1.14
Example 260
5-Fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohexy-l)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamideSesquifumaric Acid Salt (Sesquifumarate) Crystallization
5-Fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide(Example 6A) free amine (0.34 g) was dissolved in MeCN (2 mL).Fumaric acid (82.3 mg, 1.3 eq) was dissolved in EtOH (1.5 mL,warmed until dissolved). The fumaric acid solution was thentransferred to the amine solution, mixed well, then solvent wasremoved under vacuum to dryness. The resulting residue wasredissolved in a mixture of MeCN (10 mL) and EtOH (0.2 mL) to givea clear solution. After seeding with a single crystal of thesesquifumaric acid salt (Example 265), the solution was stirred at30.degree. C. overnight. White solid was collected by filtration,and dried under high vacuum for 24 hr (0.35 g, 83%). Meltingpoint=176-178.degree. C.
The X-ray powder diffraction (XRPD) pattern was determined for thesesquifumaric acid crystalline salt (XRPD Method B) and is shown inFIG. 7. A list of 2-theta peaks is provided in Table 19 below.
TABLE-US-00035 TABLE 19 Peak 2-theta No. (deg) Rel. Int. I 1 2.956.27 2 5.8 73.54 3 7.6 1.21 4 8.7 33.16 5 10.7 2.9 6 11.3 5.23 712.6 5.55 8 13.2 35.83 9 14.3 6.7 10 14.5 6.96 11 15.1 8.22 12 15.34.32 13 16.0 100 14 17.1 11.22 15 17.4 22.99 16 17.6 46.84 17 18.110.97 18 18.9 12.77 19 19.1 70.8 20 20.3 21.58 21 20.4 21.2 22 20.818.63 23 21.2 3.5 24 21.8 45.24 25 22.2 2.33 26 22.9 12.63 27 23.046.11 28 23.3 83.24 29 23.8 13.36 30 24.2 4.36 31 24.9 29.15 3225.9 8.57 33 26.0 25.8 34 26.9 10.93 35 27.6 2.42 36 27.8 2.71 3728.3 5.33 38 28.5 3.73 39 28.8 7.98 40 29.0 6.07 41 29.4 8.58 4230.1 0.81 43 30.4 1.3 44 30.9 2.63 45 31.2 0.88 46 31.7 13.42 4732.1 1.94 48 32.3 1.12 49 32.8 1.86 50 34.0 1.79 51 34.4 3.03 5234.6 7.16 53 34.9 4.56 54 35.2 1.64 55 36.0 2.93 56 37.2 2.95 5737.5 1.55 58 38.4 1.44 59 39.1 1.82 60 39.7 2.22
Example 261
5-Fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohexy-l)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamideBis-Hydrochloric Acid Salt (Bis-Hydrochloride)
To the crude free base of5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide(.about.86 grams, .about.92% purity), was added EtOH (13 volumes)at RT. To this solution was added 3 equivalents of a 1-2 M solutionof HCl in EtOH at RT. The solution was stirred for about 15 minutesand diisopropyl ether (iPr.sub.2O, 7 volumes) was then slowly addedto the stirring EtOH solution at RT. The mixture was stirred at RTand a white precipitate formed over about 1 day. The whiteprecipitate was filtered and washed with a 1:1 mixture of EtOH andiPr.sub.2O to afford 67 grams of the bis-HCl salt with a purity of.about.96% by HPLC analysis. The resulting material appeared to bea mixture of amorphous and crystalline forms. Residual EtOH(.about.4.5 wt %) was removed by lyophilization with .about.8volumes of water. The material after lyophilization had a meltingpoint of .about.210-215.degree. C. and appeared to decompose atthese temperatures during melting point analysis.
The X-ray powder diffraction (XRPD) pattern was determined for thebis-hydrochloric acid salt (XRPD Method B) and is shown in FIG. 8.The powder pattern shown in FIG. 8 exhibited an essentially smoothand continuous profile characteristic of a non-crystallinematerial.
Example 262. Crystalline Response Analysis
Digital Filter Method
A percent crystalline response was determined for Examples 258-261.In X-ray powder diffraction data, the presence of crystallinematerial is indicated by the presence of sharp well defineddiffraction peaks. The percent crystalline response is essentiallythe total diffraction signal contained in all the crystalline peaksexpressed as a percentage with respect to the total diffractionsignal from the sample. To determine the diffraction response fromthe sample, the measured data were first pre-processed by removingthe instrumental background and then normalized to a common area.The pre-processed data were then passed through two digitalfilters, one to remove the Compton and thermal diffuse scatteringand the other to remove the non-crystalline sample response fromthe pattern. The percentage of the total normalized intensityremaining after passing the data through the digital filtersindicates the percentage of perfect crystalline material in thesample. The percent crystalline response values determined usingthe digital filter are summarized in Table 20. These numbers do notinclude defected crystalline material and, as a result, are not theabsolute percent crystallinity value for the sample. The percentcrystallinity values as provided in Table 20, allow for relativecomparison of percent crystallinity between samples containing thesame crystalline polymorph.
TABLE-US-00036 TABLE 20 Example No. Percent Crystalline (%) 25891.4 259 76.7 260 84.0 261 1.5
Bayesian Model
Taking the essentially non crystalline response observed forExample 261 as being a representative non-crystalline pattern forall samples, allows the definition of a Bayesian model which can beused to estimate the maximum non-crystalline component allowed bythe observed data. The combined percent crystalline results usingthe Bayesian model are shown in Table 21. The Bayesian modelprovided a good approximation for the diffuse X-ray scatteringobserved for data set Example 259, which suggested that the percentcrystalline values of between 71% to 75% are reasonable. TheBayesian model did not provide a good fit for Examples 258 and 260.Both data sets appear to be essentially crystalline in nature.
TABLE-US-00037 TABLE 21 Minimum Crystallinity Example No. (%) 25894 259 71 260 88
Example 263. Crystalline Form Screen of5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamideSesquifumaric Acid Salt
Preparation of5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamideSesquifumaric Acid Salt
The fumaric acid salt used in the solid form screen assays wasprepared from5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyc-lohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidefree amine base according to the following procedure:
The free amine base was purified by adding to water and stirringovernight. The resulting solids were then dried under nitrogen.Then 1.6 molar equivalents of fumaric acid was added to 4.4 g ofthe5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidefree base in EtOH (35 mL) and the reaction mixture was stirred. Anadditional portion of EtOH (5 mL) was added and the reactionmixture was dried over MgSO.sub.4. The mixture was then filteredand diethyl ether (150 mL) was added and the slurry was stirredovernight. A sample of the slurry solid was identified as Form B(see below). The resulting solids were then collected via vacuumfiltration. A sample of the resulting wet cake was also identifiedas Form B. The wet cake was then dried under vacuum at 45.degree.C. for 1 day and the resulting dry sample was identified as Form D(see below).
Identification of Solid Forms
Seven different solid forms of5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidesesquifumaric acid salt were observed and are described below.X-ray powder diffraction (XRPD) patterns (XRPD Method C) for theidentified sesquifumaric acid salt forms are shown in FIG. 9.
Amorphous:
Formed from EtOH via fast evaporation.
Form A:
Sesquifumaric Acid Monohydrate; Ratio: 2:3:25-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide:fuma-ric acid:water. XRPD: Consistent with sesquifumaric acid hydrate(XRPD Method C), as shown in FIG. 10. A list of 2-theta peaks isprovided in Table 22 below. DSC/TG: broad endotherm occurringconcurrently with weight loss in the TG between 70 and 130.degree.C. Final endothermic event with onset at 179.degree. C., as shownin FIG. 11. A 1.7% weight loss observed up to 90.degree. C. asshown in FIG. 12. DVS: 0.92% weight gain from 5 to 95% RH. Weightlost upon desorption is shown FIG. 13. Variable temperature(VT)-XRPD: No form change observed. Peak shifting consistent withthermal expansion upon heating, as shown in FIG. 14. XRPD patternat 165.degree. C. consistent with Form A. No changes upon vacuumdrying or heating. Form B and Form D convert to Form A in wateractivity slurries at 0.22 a.sub.w and up.
TABLE-US-00038 TABLE 22 2- Peak theta Intensity Number (deg) (%) 12.9 15 2 5.8 34 3 7.5 5 4 8.7 12 5 10.4 3 6 10.7 6 7 11.3 9 8 11.73 9 12.6 7 10 13.2 30 11 14.3 5 12 14.5 4 13 15.1 7 14 15.3 12 1515.9 100 16 16.7 4 17 17.1 9 18 17.4 8 19 17.6 13 20 17.9 5 21 18.010 22 18.6 4 23 18.9 11 24 19.2 45 25 20.3 17 26 20.4 15 27 20.8 1128 21.2 4 29 21.4 4 30 21.8 28 31 22.2 4 32 22.8 9 33 23.0 17 3423.3 19 35 23.8 10 36 24.2 7 37 24.4 5 38 24.9 14 39 25.3 4 40 26.014 41 26.9 6
Form B--
Isostructural solvate with MeOH or EtOH. Form B observed from MeOHand EtOH experiments. XRPD pattern (XRPD Method C) indexed andconsistent with solvate, as shown in FIG. 15. A list of 2-thetapeaks is provided in Table 23 below. .sup.1H-NMR indicated limitedamounts of MeOH in the sample analyzed. During a scale-upexperiment, two sub samples were isolated (slurry and wet cake) andobserved to be Form B. Drying of the bulk material in a 45.degree.C. vacuum oven converted to Form D, as shown in FIG. 16 (XRPDMethod C). Stability: Converted to Form A in water activity slurry,0.22 a.sub.w.
TABLE-US-00039 TABLE 23 Peak 2-theta Intensity Number (deg) (%) 16.2 24 2 6.9 7 3 7.8 57 4 8.5 29 5 9.6 8 6 9.8 13 7 10.4 8 8 10.924 9 11.4 12 10 11.9 17 11 12.4 6 12 12.6 20 13 13.0 9 14 13.2 2115 13.5 33 16 13.7 6 17 14.0 13 18 14.2 14 19 15.4 9 20 15.7 10 2116.1 100 22 16.9 15 23 17.0 8 24 17.2 12 25 18.6 16 26 19.0 24 2719.3 23 28 19.7 12 29 19.9 9 30 20.2 9 31 20.4 12 32 20.6 15 3320.8 12 34 21.0 11 35 21.2 28 36 21.4 27 37 21.6 36 38 22.0 10 3922.4 7 40 22.4 8 41 22.7 6 42 22.9 13 43 23.2 7 44 24.0 8 45 24.1 846 24.4 8 47 24.7 8 48 25.0 9
Form C:
Observed as a mixture with Form A EtOH generated. Form C onlyobserved from ethanol.
Form D:
Formed from scale-up using "dry" conditions and from MeOH/heptaneslow evaporation XRPD: lower crystallinity, as shown in FIGS. 16and 23 (XRPD Method C). A list of 2-theta peaks is provided inTable 24 below. .sup.1H NMR consistent with sesquifumarate salt, noorganic solvent observed. DSC/TG: broad endothermic event withonset at 157.degree. C. observed in the DSC (FIG. 17) and 0.4%weight loss upon heating up to 90.degree. C., as shown in FIG. 18.Stability: Converted to Form A in water activity slurry, 0.22a.sub.w.
TABLE-US-00040 TABLE 24 Peak 2-theta Intensity Number (deg) (%) 10.6 14 2 7.2 35 3 8.5 60 4 9.5 20 5 10.6 24 6 10.9 16 7 11.8 28 813.5 19 9 14.1 29 10 14.5 35 11 15.0 13 12 16.0 100 13 17.4 28 1418.1 12 15 19.3 26 16 19.7 27 17 20.4 26 18 21.8 35 19 22.7 23 2023.8 20 21 24.4 22 22 25.7 18
Form E: THF Solvate No changes observed in XRPD after 45.degree. C.vacuum oven for 1 day (XRPD Method C). .sup.1H-NMR indicates THFsolvate. After vacuum drying, 0.6 moles of THF still evident. FormF: DSC: Broad low temperature endotherm with maximum near65.degree. C. leading into an apparent exothermic event withmaximum near 109.degree. C. Final endotherm with an onset near143.degree. C., as shown in FIG. 19. Conversion to Form A wasobserved when slurried in ACN/water mixture. Water ActivityAnalysis
Table 25 shows results of a water activity analysis of5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidesesquifumaric acid salt in various aqueous and organic solventsystems.
TABLE-US-00041 TABLE 25 Water Activity Solvent (vol % H.sub.2O)Condition Observation Result H.sub.2O/IPA 0.96 (50%) ambient, 7white solids, Form A days yellow solution H.sub.2O/acetone 0.91(50%) ambient, 7 white solids, Form A days yellow solutionH.sub.2O/acetone 0.80 (18%) ambient, 7 white solids, Form A daysyellow solution H.sub.2O/IPA 0.70 (11%) ambient, 7 yellow solidsForm A days H.sub.2O/ACN 0.60 (4%) ambient, 7 white solids Form Adays H.sub.2O/IPA 0.50 (6%) ambient, 7 yellow solids Form A daysH.sub.2O/acetone 0.44 (3%) ambient, 7 white solids Form A daysH.sub.2O/ACN 0.38 (2%) ambient, 7 white solids Form A daysH.sub.2O/acetone 0.22 (1%) ambient, 7 white solids Form A days
Physical Stability Analysis
Table 26 shows results of a physical stability analysis of5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidesesquifumaric acid salt.
TABLE-US-00042 TABLE 26 Source Method Observation Result Form B +Form A 75% RH, 2 white, free Form A days flowing Form B + Form A75% RH, 3 -- Form A days Form D 75% RH, 2 -- Form D days Form A105.degree. C. 3 days 20% LOD Form A Form A 70.degree. C. vacuum noweight Form A + peaks 3 days change Form A ambient no weight Form Avacuum 3 days change Form A 95.degree. C., under free-flowing FormA N.sub.2, 2 days white solids Form A + B 1. 45.degree. C. -- FormD + Form A vacuum, 4 days 2. ambient storage, 15 days Form A +peaks ambient -- Form A vacuum, 2 days Form E 45.degree. C. vacuum,free flowing Form E 1 day white solids Form A + B 45.degree. C.vacuum, white solids Form A + Form B 4 days RH = relativehumidity
Example 264. Preparation of Single Crystal5-Fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamideBis-Methanesulfonic Acid Salt (Bis-Mesylate)
Single crystals of5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidebis-methanesulfonic acid salt were obtained by slow diffusion ofEtOAc to an iPrOH solution and confirmed by X-ray structureanalysis. A summary of the single crystal X-ray structure analysisis shown below in Table 27. ORTEP representations of thebis-methanesulfonic acid salt with 50% probability thermalellipsoids displayed are shown in FIGS. 20-21.
TABLE-US-00043 TABLE 27 Instrument Bruker APEXII CCD area detectorwith graphite-monochromated Mo-K.alpha. radiation (.lamda. =0.71073 .ANG.) Temperature/K 100 Crystal system triclinic Spacegroup P1 a 16.9767(4) .ANG. b 17.1695(4) .ANG. c 21.5658(5) .ANG..alpha. 72.8540(10).degree. .beta. 81.8960(10).degree. .gamma.61.5280(10).degree. Volume .sup. 5280.2(2) .ANG..sup.3 Z 4d.sub.calc 1.166 g/cm.sup.3 .mu. 0.200 mm.sup.-1 F(000) 1984.0Crystal size, mm 0.48 .times. 0.3 .times. 0.08 2.theta. range fordata collection 2.73-50.938.degree. Index ranges -20 .ltoreq. h.ltoreq. 20, -20 .ltoreq. k .ltoreq. 18, -26 .ltoreq. l .ltoreq. 26Reflections collected 159085 Independent reflections 19412[R(int) =0.0273] Data/restraints/parameters 19412/162/1155 Goodness-of-fiton F.sup.2 1.115 Final R indexes [I >= 2.sigma. (I)] R.sub.1 =0.0495, wR.sub.2 = 0.1387 Final R indexes [all data] R.sub.1 =0.0609, wR.sub.2 = 0.1497 Largest diff peak/hole 0.93/-0.75e.ANG..sup.-3
Example 265. Preparation of Single Crystal5-Fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamideSesquifumaric Acid Salt (Sesquifumarate)
Single crystals of the5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidesesquifumaric acid salt were obtained by slow evaporation in MeCNsolution. X-ray analysis of the single crystal showed a ratio of1:1.5 between5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)-cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzam-ide and fumaric acid. A summary of the single crystal X-raystructure analysis is shown below in Table 28. An ORTEPrepresentation of the5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidesesquifumaric acid salt with 50% thermal ellipsoids is shown inFIG. 22.
TABLE-US-00044 TABLE 28 Instrument Bruker D8QUEST CMOS areadetector with graphite-monochromated Mo-K.alpha. radiation (.lamda.= 0.71073 .ANG.) Temperature/K 100 Crystal system monoclinic Spacegroup C2/c a 60.682(3) .ANG. b 11.7644(5) .ANG. c 11.5570(6) .ANG..beta. 93.854(2).degree. Volume .sup. 8231.8(7) .ANG..sup.3 Z 8d.sub.calc 1.328 g/cm.sup.3 .mu. 0.149 mm.sup.-1 F(000) 3504.0Crystal size, mm 0.25 .times. 0.10 .times. 0.01 2.theta. range fordata collection 5.846-50.928.degree. Index ranges -73 .ltoreq. h.ltoreq. 73, -13 .ltoreq. k .ltoreq. 14, -13 .ltoreq. l .ltoreq. 13Reflections collected 164974 Independent reflections 7568[R(int) =0.1031] Data/restraints/parameters 7568/451/583 Goodness-of-fit onF.sup.2 2.231 Final R indexes [I >= 2.sigma.(I)] R.sub.1 =0.1568, wR.sub.2 = 0.4560 Final R indexes [all data] R.sub.1 =0.1874, wR.sub.2 = 0.4951 Largest diff. peak/hole 2.84/-3.16e.ANG..sup.-3
Example 266. Preparation of Single Crystal5-Fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamideBis-Hydrochloric Acid Salt
A 5N HCl solution in .sup.iPrOH (2 mL) was added to5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidefree base (140 mg) at room temp. After being stirred at room tempfor 30 min, the solvent was removed to afford the bis-hydrochloricacid salt of5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide.A portion of this white amorphous material (.about.25 mg) was takenand MeCN (0.5 mL) was added at room temp. The resulting suspensionwas gently heated for 2 minutes until complete dissolution of thematerial. The solution was then slowly cooled to RT overnight uponstanding to afford crystalline5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidebis-hydrochloric acid salt. Melting point: .about.210-215.degree.C.
Example 267. Crystalline Salt Screen of5-Fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide
Pharmaceutically acceptable counterions were selected based onknown pKa values and salt crystallization experiments wereperformed according to a general procedure of direct addition ofapproximately one or two molar equivalents of the counterion to5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohex-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamidefree base (Example 6A) in solution or suspension. Solid materialswere harvested when precipitation of sufficient quantity occurred.Additional steps such as cooling, anti-solvent addition, and/orslurrying were performed to induce crystallization or increaseyields if needed. The products were qualitatively evaluated forcrystallinity by polarized light microscopy (PLM) and/or XRPD.Vacuum drying was used to identify unsolvated crystal forms of thepotential salts. Solution 1H-NMR spectroscopy was used to confirmcomposition and stoichiometry, that chemical degradation did notoccur, and to evaluate the amount of solvent present. Forhydrochloric acid salts, energy-dispersive X-ray (EDX) spectroscopywas used to confirm stoichiometry. Table 29 shows a list ofpharmaceutically acceptable salts identified in the salt screeningexperiments. "n/a" refers to data not available (e.g., the salt wasunable to be isolated in crystalline form; the salt deliquesced at75% relative humidity; the salt converted to another form; or adisordered XRPD pattern was observed).
TABLE-US-00045 TABLE 29 Stoichiometry Salt Form (Example 6A:acid)Acetate n/a Besylate Material A 1:1 Fumarate Material A 2:1Fumarate Material B n/a Fumarate Material C n/a Fumarate Material Dn/a Fumarate Material E n/a Sesquifumarate Form A 2:3Sesquifumarate Material B 2:3 HCl Material A n/a HCl Material B 1:2HCl Material C 1:2 Malate Material A n/a Malate Material B 1:1Mesylate Material A 1:1 Mesylate Material B n/a Mesylate Material Cn/a Napsylate (amorphous) n/a Napadisylate Material A n/aNapadisylate Material B n/a Phosphate (amorphous) n/a SuccinateMaterial A 2:1 Succinate (amorphous) n/a Sulfate n/a Tartrate n/aTosylate Material A 1:1 Tosylate Material B 1:1 Tosylate Material Cn/a Tosylate Material D 1:1
Biological Assays Assay 1 (Binding Assay)
Potencies of inhibitor compounds against menin/MLL binding wereassessed by AlphaLISA assay using biotinylated (1) wild-type meninor (2) mutated menin (described in Huang et al, 2012, Nature, 482,542-546) and MLL-AF9 fusion protein bearing a FLAG epitope at itsC-terminus. Menin proteins were expressed in E. coli and covalentlymodified with biotin using EZ-Link.TM. Sulfo-NHS-Biotin(ThermoFisher Cat. No. 21217) according to manufacturer's protocol.MLL1-1,396 fused to AF91-92 and the C-terminal FLAG peptide wasexpressed in HEK293 cells and used as a lysate cleared at21,000.times.g for 10 min.
Compounds (2 .mu.L of solutions in DMSO) were dispensed in white96-well half-area plates (Corning Cat. No. 3693) and incubated for30 min at RT with 5 nM biotinylated menin and appropriate amount ofMLL-AF9-FLAG lysate in 40 .mu.L of 50 mM Tris-HCl buffer pH 7.4containing 5% (v/v) DMSO, 50 mM NaCl, 0.01% (w/v) bovine serumalbumin (BSA) and 1 mM DTT. To this incubation mixture, 40 .mu.L ofAlphaLISA anti-FLAG acceptor (PerkinElmer Cat. No. AL112C) andstreptavidin donor (PerkinElmer Cat. No. 6760002) beads (10.mu.g/mL each) was added and incubation continued at RT for 60 min.Alpha (amplified luminescent proximity hom*ogeneous assay) signalwas measured on an Envision multi-label plate reader at the end ofthe incubation. All steps were conducted under dim fluorescentlight.
Percent inhibition values were calculated based on uninhibited(DMSO) and fully inhibited (10 .mu.M MI-2-2, EMD Millipore Cat. No.444825) controls. These percent inhibition values were regressedagainst compound concentrations in the assay using four parameterlogit non-linear curve fitting (XLFit, IDBS). The IC.sub.50 valueswere derived from the curve fitting as inflection points on thedose-response curves and are set out in Table 30 below.
Assay 2: (Cell Proliferation Assay)
Potencies of inhibitor compounds against cell proliferation wasassessed against the human acute monocytic leukemia cell lineMV-4-11 (ATCC.RTM. CRL-9591.TM.) based on ATP quantitation. MV-4-11cells or toxicity control HL-60 cells (ATCC.RTM. CCL-240.TM.) wereincubated in 96-well tissue culture plates (1.67.times.10.sup.4cells in 200 .mu.L culture media containing 10% FBS per well) withor without test compound for 72 h at 37.degree. C., 5% CO.sub.2.After incubation, each well was mixed by pipetting and 95 .mu.Lfrom each well was transferred to a well in 96-well blackOptiPlate.RTM. plates (PerkinElmer). An equal volume ofCellTiter-Glo.RTM. Luminescent Cell Viability Assay reagent(Promega) was added to each well, followed by mixing for 5 min onan orbital plate shaker. Luminescence was measured on a WallacEnVision 2104 Multilabel Reader (PerkinElmer) to quantitate ATP.Percent inhibition of cell proliferation by test compounds wascalculated based on uninhibited cell growth (DMSO) versus cellstreated with a potent menin inhibitor at a concentration yieldingat least 100.times.LD.sub.50. EC.sub.50 values were calculatedbased on dose response curves of percent inhibition versus compoundconcentration and are set out in Table 30 below.
Data for Assays 1 and 2 are provided below in Table 27 ("n/a"refers to data not available; "+++" means <100 nM; "++" means.gtoreq.100 nM and <1000 nM; and "+" means .gtoreq.1000 nM).
TABLE-US-00046 TABLE 30 Biological Data Example Assay 1 Assay 2 1+++ +++ 1A +++ +++ 1B +++ +++ 2 +++ +++ 2A +++ +++ 2B +++ +++ 3A+++ +++ 3B +++ +++ 4 +++ +++ 4A +++ +++ 4B +++ +++ 5 +++ +++ 6A ++++++ 6B +++ +++ 7 +++ ++ 8 +++ +++ 9 +++ + 10 +++ + 11 +++ +++ 12+++ ++ 13 +++ n/a 14A +++ n/a 15 +++ ++ 16 +++ ++ 17 ++ n/a 18 +++++ 19 +++ ++ 20 ++ n/a 21 ++ n/a 22A +++ + 22B +++ n/a 23A +++ ++23B ++ n/a 23C +++ + 24A +++ + 24B +++ + 25 +++ + 26A +++ ++ 26B+++ + 27 +++ + 28 +++ +++ 29 +++ +++ 29A +++ +++ 29B +++ ++ 30 +++n/a 31 +++ n/a 32 +++ n/a 33 +++ ++ 34 +++ + 35 +++ ++ 36 +++ ++ 37+++ ++ 38 +++ + 39 ++ n/a 40 ++ + 41 +++ +++ 41A +++ +++ 41B ++++++ 42 +++ +++ 42A +++ +++ 42B +++ +++ 43 +++ +++ 44 +++ ++ 45 ++++++ 46 ++ n/a 47 +++ ++ 48 +++ ++ 49 +++ n/a 50 +++ n/a 51 +++ +++52 +++ +++ 53 +++ +++ 54 +++ ++ 55 + n/a 56 + n/a 57 +++ n/a 58 ++n/a 59 + n/a 60 +++ ++ 60A +++ +++ 60B +++ +++ 60C +++ +++ 60D ++++++ 61 ++ n/a 62 +++ ++ 63 +++ +++ 64 +++ ++ 65 +++ ++ 66 +++ + 67+++ ++ 68 +++ + 69 +++ +++ 70 +++ +++ 71 +++ n/a 72 +++ ++ 73 +++++ 74 +++ n/a 76 +++ +++ 77 +++ + 78 ++ n/a 79 +++ +++ 80 +++ +++81A +++ ++ 81B +++ +++ 82 +++ ++ 83 +++ ++ 84 +++ +++ 85 +++ ++ 86+++ +++ 87 +++ ++ 88 +++ +++ 89 +++ ++ 90 +++ +++ 91 +++ +++ 91A+++ +++ 92 +++ ++ 93 +++ ++ 94 +++ ++ 95 +++ ++ 96 +++ ++ 97 +++ ++98 +++ ++ 99 +++ ++ 99A +++ +++ 100 +++ ++ 101 +++ ++ 102 +++ +++103 +++ ++ 104 +++ +++ 105 +++ +++ 106 +++ +++ 107 +++ +++ 108 ++++ 109 +++ + 110 +++ ++ 111 +++ +++ 112 +++ +++ 113 +++ +++ 114 +++++ 115 +++ +++ 116 +++ ++ 117 +++ ++ 118 +++ ++ 119 +++ ++ 120 ++++++ 121 +++ ++ 122 +++ +++ 123 +++ + 124 +++ ++ 125 +++ +++ 126 +++++ 127 +++ ++ 128 +++ ++ 129 +++ ++ 130 +++ ++ 131 +++ +++ 132 +++++ 133 +++ ++ 134 +++ ++ 135 +++ + 136 +++ ++ 137 +++ ++ 138 ++++++ 139 +++ ++ 140 +++ ++ 141 +++ ++ 142 +++ + 143 +++ + 144 ++++++ 145 +++ ++ 146 +++ ++ 147 +++ + 148A +++ ++ 148B +++ ++ 149 ++++++ 150 +++ +++ 151 +++ + 152 +++ +++ 153 +++ ++ 154 +++ ++ 155 +++++ 156 +++ ++ 157 +++ n/a 158 +++ ++ 159 +++ ++ 160 +++ +++ 160A+++ +++ 160B +++ +++ 161 +++ +++ 162 +++ ++ 163 +++ ++ 164 +++ ++165 +++ + 166 +++ ++ 167 +++ ++ 168 +++ + 169 +++ +++ 170 +++ ++171 +++ +++ 172 +++ ++ 173 +++ ++ 174 +++ +++ 175 +++ + 176 +++ +177 +++ +++ 178 +++ +++ 179 +++ +++ 180 +++ +++ 181 +++ ++ 182 +++++ 183 +++ +++ 183A +++ +++ 183B +++ +++ 184 +++ ++ 185 +++ ++ 186+++ +++ 187 +++ +++ 188 +++ ++ 189 +++ ++ 190 +++ +++ 190A +++ ++191 +++ +++ 192 +++ ++ 193 +++ +++ 194 +++ ++ 195 +++ ++ 196 ++++++ 197A +++ +++ 197B +++ +++ 198 +++ +++ 199 +++ + 200 +++ ++ 201+++ + 202 +++ ++ 203 +++ + 204 +++ ++ 205 +++ +++ 206A +++ ++ 206B++ n/a 206C ++ n/a 207 +++ ++ 208 +++ + 209 +++ ++ 210 +++ ++ 211+++ ++
212 +++ ++ 213 +++ +++ 214 +++ ++ 215 +++ ++ 216 +++ ++ 217 +++ +++218 +++ + 219 +++ ++ 220 +++ ++ 221 +++ ++ 222 +++ + 223 +++ ++ 224+++ +++ 225 +++ ++ 226 +++ + 227 +++ +++ 228 +++ ++ 229 +++ ++ 230+++ ++ 231 +++ ++ 232 +++ +++ 233 +++ ++ 234 +++ +++ 235 +++ ++ 236+++ ++ 237 +++ +++ 237A +++ +++ 238 +++ +++ 239 +++ +++ 240 +++ +++241 +++ ++ 242 +++ ++ 243 +++ n/a 244 +++ n/a 245 +++ n/a 246 +++n/a 247 +++ n/a 248A +++ ++ 248B +++ ++ 249 +++ ++ 250A ++ n/a 250B+++ + 251 +++ + 252 +++ +++
While we have described a number of embodiments of this invention,it is apparent that our basic examples may be altered to provideother embodiments that utilize the compounds and methods of thisinvention. Therefore, it will be appreciated that the scope of thisinvention is to be defined by the appended claims rather than bythe specific embodiments that have been represented by way ofexample.
The contents of all references (including literature references,issued patents, published patent applications, and co-pendingpatent applications) cited throughout this application are herebyexpressly incorporated herein in their entireties by reference.Unless otherwise defined, all technical and scientific terms usedherein are accorded the meaning commonly known to one with ordinaryskill in the art.
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