Indazole compounds as kinase inhibitors

Abstract

Disclosed herein are compounds and methods for treating diseases and / or conditions associated with FGFR inhibition.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 132,031, filed December 30, 2020, and U.S. Provisional Patent Application No. 63 / 216,879, filed June 30, 2021, each of which is incorporated herein by reference in its entirety.

[0002] The present disclosure relates to indazole compounds useful for treating cancer, pharmaceutical compositions comprising one or more such indazole compounds, and methods of using such indazole compounds in the treatment of cancer. [Background technology]

[0003] Kinase inhibitors have been used to block the activity of kinases, thereby treating cancer (e.g., by inhibiting the mitotic process). These kinase inhibitors are often small molecules that target kinases to block the development, growth, or spread of cancer.

[0004] However, despite the fact that various inhibitors of kinases are known, there remains a need for selective inhibitors for use in the treatment of diseases, e.g., hyperproliferative diseases, that offer one or more advantages over current compounds. These advantages include improved activity and / or efficacy; a kinase selectivity profile beneficial to the respective therapeutic needs; an improved side effect profile, e.g., fewer undesirable side effects, less intense side effects, or reduced (cyto)toxicity; improved targeting of mutant receptors in affected cells; improved physicochemical properties, e.g., improved solubility / stability in water, body fluids, and / or pharmaceutical formulations; improved pharmacokinetic properties, e.g., allowing for reduced doses or simplified dosing schemes; and simplified drug substance production, e.g., shorter synthetic routes or simplified purification. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] U.S. Patent No. 5,023,252 [Patent Document 2] U.S. Patent No. 4,992,445 [Patent Document 3] U.S. Patent No. 5,001,139 [Patent Document 4] U.S. Patent No. 5,451,233 [Patent Document 5] U.S. Patent No. 5,040,548 [Patent Document 6] U.S. Patent No. 5,061,273 [Patent Document 7] U.S. Patent No. 5,496,346 [Patent Document 8] U.S. Patent No. 5,292,331 [Patent Document 9] U.S. Patent No. 5,674,278 [Patent Document 10] U.S. Patent No. 3,657,744 [Patent Document 11] U.S. Patent No. 4,739,762 [Patent Document 12] U.S. Patent No. 5,195,984 [Patent Document 13] U.S. Patent No. 5,879,382 [Patent Document 14] U.S. Patent No. 6,344,053 [Patent Document 15] PCT Patent Application Publication No. WO2014 / 071419A2 [Patent Document 16] U.S. Patent Application Publication No. 2015 / 0366866Al [Patent Document 17] PCT Patent Application Publication No. WO2016 / 084883Al [Patent Document 18] PCT Patent Application Publication No. WO2016 / 030509Al [Patent Document 19] PCT Patent Application Publication No. WO2015 / 150900A2 [Patent Document 20] PCT Patent Application Publication No. WO2015 / 120094A2 [Patent Document 21] U.S. Patent Application Publication No. 2013 / 009621 [Patent Document 22] U.S. Patent Application Publication No. 2011 / 0008347 [Patent Document 23] U.S. Patent Application Publication No. US2016 / 0235744Al [Patent Document 24] U.S. Patent No. 9,254,288 B2 [Patent Document 25] U.S. Patent No. 9267176B2 [Patent Document 26] U.S. Patent Application Publication No. S2016 / 0215350Al [Patent Document 27] European Patent Application Publication No. EP3023101Al [Patent Document 28] PCT Patent Application Publication Number WO2016105503Al [Patent Document 29] European Patent No. EP2203449B1 [Patent Document 30] European Patent Application Publication No. 3023101A1 [Patent Document 31] PCT Application Publication No. WO2015 / 099127Al [Patent Document 32] European Patent No. EP2203449Bl [Patent Document 33] Japanese Patent No. 05868992 [Patent Document 34] U.S. Patent No. 9447098B2 [Patent Document 35] PCT Patent Application Publication Number WO2016139227Al [Patent Document 36] Australian Patent Application Publication No. AU2014362227Al [Patent Document 37] Chinese license number CN102741256B [Non-licensed literature]

[0006] [Non-licensed Document 1] Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002 [Non-licensed Document 2] Pratt and Taylor, eds., Principles of Drug Action, 3rd Edition, Churchill Livingston, New York, 1990 [Non-licensed Document 3] Edited by Katzung, Basic and Clinical Pharmacology, 9th Edition, McGraw Hill, 2003 (7ybg) [Non-licensed Document 4] Goodman and Gilman (eds.), The Pharmacological Basis of Therapeutics, 10th Edition, McGraw Hill, 2001 [Non-licensed Document 5] Remingtons Pharmaceutical Sciences, 20th Edition, Lippincott Williams & Wilkins., 2000 [Non-licensed Document 6] Martindale, The Extra Pharmacopoeia, 32nd Edition (The Pharmaceutical Press, London, 1999) [Non-licensed Document 7] Johnson, Adv. Cancer Res. 60:1~40 pages, 1993 [Non-licensed Document 8] Wilkie, Curr. Biol. 5:500~page 507, 1995 [Non-licensed Document 9] Johnson, Mol. Cell. Biol. 11:4627~4634, 1995 [Non-licensed Document 10] Chellaiah, J. Biol. Chem. 269:11620~11627 pages, 1994 [Non-licensed Document 11] Zimmer, J. Biol. Chem. 268:7899~7903 pages, 1993 [Non-licensed Document 12] Cheonら, Proc. Natl. Acad. Sci. USA 91:989~993 pages, 1994 [Non-licensed Document 13] Miki, Proc. Natl. Acad. Sci. USA 89:246~250 pages, 1992 [Non-licensed Document 14] Baroy, PloS One; 11(9):e0163859. doi: 10.1371 / journal.pone.0163859, 2016 [Non-licensed Document 15] Renら, Int. J. Cancer, 139(4):836~40 pages, 2016 [Non-licensed Document 16] Marchwicka, Cell Biosci., 6:7. doi: 10.1186 / s13578-016-0075-9, 2016 [Non-licensed Document 17] Kasaianら, BMC Cancer., 15:984 pages, 2015 [Non-licensed Document 18] Vakil, Neuro-Oncology, 18: Appendix 3, pp. iii, 93. Abstract Number: LG-64, 17th International Symposium on Pediatric Neuro-Oncology, Liverpool, United Kingdom, 2016 [Non-licensed Document 19] Astsaturov et al., Journal of Clinical Oncology, 34:Appendix 15, Abstract Number: 11504, 2016 Annual Meeting of the American Society of Clinical Oncology, Chicago, IL. [Non-Patent Document 20] Heinrich et al., Journal of Clinical Oncology, 34:Appendix 15, Abstract Number: 11012, 2016 Annual Meeting of the American Society of Clinical Oncology, Chicago, IL. [Non-Patent Document 21] Hall et al., Molecular Cancer Therapeutics, Volume 14, Issue 12, Supplement 2, Abstract Number: B151, AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics, 2015 [Non-Patent Document 22] Reuther et al., Journal of Molecular Diagnostics, Volume 17, Issue 6, Page 813, Abstract Number: ST02, 2015 Annual Meeting of the Association for Molecular Pathology, Austin, TX [Non-Patent Document 23] Moeini et al., Clin. Cancer. Res., 22(2):291-300, 2016 [Non-Patent Document 24] Schrock et al., J Thorac. Oneal. pii S1556-0864(18)30674-9, 2018. doi: 10.1016 / j.jtho.2018.05.027 [Non-Patent Document 25] Pekmezciら, Acta Nurotapho / . Commun. 6(1):47. doi: 10.1186 / s40478-018-0551-z [Non-licensed Document 26] LoweryらClin Cancer Res. pii: clincanres.0078.2018. doi: 10.1158 / 1078-0432.CCR-18-0078 [Non-licensed Document 27] RylandらJ Clin Patho / pii: jclinpath-2018-205195, 2018. doi: 10.1136 / jclinpath-2018-205195 [Non-licensed Document 28] Ferguson, J Neuropatho / Exp Neural 77(6):437-442, 2018. doi: 10.1093 / jnen / nly022 [Non-licensed Document 29] Wuら, BMC Cancer 18(1):343, 2018. doi: 10.1186 / s12885-018-4236-6 [Non-licensed Document 30] Shibata, Cancer Sci 109(5):1282~1291, 2018. doi: 10.1111 / cas.13582 [Non-licensed Document 31] Papdopoulos, Br J Cancer, 1117(11):1592~1599, 2017. doi: 10.1038 / bjc.2017.330 [Non-licensed Document 32] Hallら, PLoS One, 11(9):e1062594, 2016. doi: 10.1371 / journal.pone.0162594 [Non-licensed Document 33] Johnson, Oncologist, 22(12):1478~1490, 2017. doi: 10.1634 / theoncologist.2017-0242 [Non-licensed Document 34] Yang, Am J Hum Genet, 98(5):843~856, 2016. doi: 10.1016 / j.ajhg.2016.03.017 [Non-licensed Document 35] Babina and Turner, Nat Rev Cancer 17(5):318~332 pages, 2017. doi: 10.1038 / nrc.2017.8 [Non-licensed Document 36] Rylandら, J Clin Patho / ., May 14, 2018. pii: jclinpath-2018-205195. doi: 10.1136 / jclinpath-2018-205195 [Non-licensed Document 37] Kumarら、Am J Clin Patho / . 143(5):738~748 pages、2015. doi: 10.1309 / AJCPUD6W1JLQQMNA [Non-licensed Document 38] Grandら, Genes Chromosomes Cancer40(1): pages 78~83, 2004. doi: 10.1002 / gcc.20023 [Non-licensed Document 39] Reeser, J Mo / Diagn, 19(5):682~696, 2017. doi: 10.1016 / j.jmoldx.2017.05.006 [Non-licensed Document 40] Basturk, Mod Patho / , 30(12):1760~1772, 2017. doi: 10.1038 / modpathol.2017.60 [Non-licensed Document 41] Wangら, Cancer 123(20): pages 3916~3924, 2017. doi: 10.1002 / cncr.30837 [Non-licensed Document 42] Kim, Oncotarget, 8(9): 15014-15022, 2017. doi: 10.18632 / oncotarget.14788 [Non-licensed Document 43] Busse, Genes Chromosomes Cancer, 56(10): pages 730~749, 2017. doi: 10.1002 / gcc.22477 [Non-licensed Document 44] Shiら, J Transl Med., 14(1):339, 2016. doi: 10.1186 / s12967-016-1075-6 [Non-licensed Document 45] Angら、Diagn. Mo / . Patho / .2014, February 24 [Non-licensed Document 46] Gallo, Cytokine Growth Factor Rev. 26:425~449 pages, 2015 [Non-licensed Document 47] Davies, J. Cancer Res. 65:7591, 2005 [Non-licensed Document 48] Kelleher, Carcinogenesis 34:2198, 2013 [Non-licensed Document 49] Cazierら, Nat. Commun. 5:3756, 2014 [Non-licensed Document 50] Liu, Genet. Mo / . Res. 13:1109, 2014 [Non-licensed Document 51] Trudel, Blood 107:4039, 2006 [Non-licensed Document 52] Gallo, Cytokine Growth Factor Rev. 26:425, 2015 [Non-licensed Document 53] Liaoら, Cancer Res. 73:5195~5205 pages, 2013 [Non-licensed Document 54] Martincorenaら, Science 348:880 (2015) [Non-licensed Document 55] Rivera, Acta. Neuropatho / ., 131(6):847~63, 2016 [Non-licensed Document 56] Lo Iacono et al., Oncotarget., 7(12):14394~404, 2016 [Non-Patent Document 57] Deeken et al., Journal of Clinical Oncology, 34: Appendix 15, page iii93. Abstract Number: el 7520, 2016 Annual Meeting of the American Society of Clinical Oncology, Chicago, IL. [Non-Patent Document 58] Sullivan et al., Journal of Clinical Oncology, 34: Appendix 15, page iii93. Abstract Number: 11596, 2016 Annual Meeting of the American Society of Clinical Oncology, Chicago, IL. [Non-Patent Document 59] Nguyen et al., Molecular Cancer Therapeutics, Volume 14, Issue 12, Supplement 2, Abstract Number: C199, AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics, 2015 [Non-Patent Document 60] Li et al., Hum. Patho / ., 55:143-50, 2016 [Non-Patent Document 61] Yoza et al., Genes Cells., (10):1049-1058, 2016 [Non-Patent Document 62] Bunney et al., BioMedicine, 2(3):194-204, 2015 [Non-Patent Document 63] Byron et al., Neop / asia, 15(8):975-88, 2013 [Non-Patent Document 64] Thussbas et al., J. Clin. Oncol., 24(23):3747-55, 2006 [Non-licensed Document 65] Chellら, Oncogene, 32(25):3059~70 pages, 2013 [Non-licensed Document 66] Tanizaki, Cancer Res. 75(15):3149~3146 pages doi: 10.1158 / 0008-5472.CAN-14-3771 [Non-licensed Document 67] Yangら, EBioMedicine pii S2352~3964 pages (18)30218-4. doi: 10.1016 / j.ebiom.2018.06.011 [Non-licensed Document 68] Jakobsen, Oncotarget 9(40):26195~26208 pages, 2018. doi: 10.18632 / oncotarget.25490 [Non-licensed Document 69] Stoneら、Acta Neuropatho / 135(1):115~129, 2017. doi: 10.1007 / s00401-017-1773-z [Non-licensed Document 70] Pekmezciら, Acta Nurotaphol. Commun. 6(1):47. doi: 10.1186 / s40478-018-0551-z [Non-licensed Document 71] De Mattos-Arruda, Oncotarget 9(29):20617~20630 pages, 2018. doi:10.18632 / oncotarget.25041 [Non-licensed Document 72] Oliveira, J Exp Clin Cancer Res 37(1):84, 2018. doi: 10.1186 / s13046-018-0746-y [Non-licensed Document 73] Chaら, Mo / Oneal 12(7): pages 993~1003, 2018. doi: 10.1002 / 1878-0261.12194 [Non-licensed Document 74] Ikeda, Oncologist, 23(5): 586-593, 2018. doi: 10.1634 / theoncologist.2017-0479 [Non-licensed Document 75] Pelaez-Garda, PLoS One, 8(5):e63695, 2013. doi: 10.1371 / journal.pone.0063695 [Non-licensed Document 76] Shimada, Oncotarget, 8(55):93567~93579, 2017. doi: 10.18632 / oncotarget.20510 [Non-licensed Document 77] Welander, World J Surg, 42(2):482~489 pages, 2018. doi: 10.1007 / s00268-0l 7-4320-0 [Non-licensed Document 78] Chandrani, Ann Oneal, 28(3): pages 597~603, 2017. doi: 10.1093 / annonc / mdw636 [Non-licensed Document 79] Dalinら, Nat Commun, 8(1):1197, 2017. doi: 10.1038 / s41467-017-01178-z [Non-licensed Document 80] Taurin, Intl Gyneco / Cancer, 28(1):152~160 pages, 2018. doi: 10.1097 / IGC.0000000000001129 [Non-licensed Document 81] Haugh, J Invest Dermatol 138(2):384~393, 2018. doi: 10.1016 / j.jid.2017.08.022 [Non-licensed Document 82] Greenman, Nature 446(7132):153~158 pages, 2007. doi: 10.1038 / nature05610 [Non-licensed Document 83] Helsten, Clin Cancer Res, 22(1):259~267 pages, 2016. doi: 10.1158 / 1078-0432.CCR-14-3212 [Non-licensed Document 84] Kimら, BMC Urol, 18:68, 2018. doi: 10.1186 / s12894-018-0380-1 [Non-licensed Document 85] Goyalら、Cancer Discov、7(3):252~263 pages、2017. doi: 10.1158 / 2159-8290.CD-16-1000 [Non-licensed Document 86] Premov, Oncogene, 36(22): 3168~3177, 2017. doi: 10.1038 / onc.2016.464 [Non-licensed Document 87] Geelvinkら, Int J Mo / Sci. 19(9): pii:E2548, 2018. doi: 10.3390 / ijms19092548 [Non-licensed Document 88] Leeら、Exp Ther Med. 16(2):1343~1349、2018. doi: 10.3892 / etm.2018.6323 [Non-licensed Document 89] Kasら, Cancer Res, 78(19): pages 5668~5679, 2018. doi: 10.1158 / 0008-5472.CAN-18-0757 [Non-licensed Document 90] Chesi, Blood, 97(3):729~736, 2001. PMID: 11157491 [Non-licensed Document 91] Geら、Am J Cancer Res. 7(7):1540~1553 pages, 2017. PMID: 28744403 [Non-licensed Document 92] Jiaoら, Nat Genet, 45(12):1470~1473 pages, 2013. doi: 10.1038 / ng.2813 [Non-licensed Document 93] Jusakulら, Cancer Discov. 7(10):1116~1135 pages, 2017. doi: 10.1158 / 2159-8290.CD-17-0368 [Non-licensed Document 94] Guyard, Respir Res., 18(1):120, 2018. doi: 10.1186 / s12931-017-0605-y [Non-licensed Document 95] Paik, Clin Cancer Res., 23(18): 5366~5373, 2017. doi: 10.1158 / 1078-0432.CCR-17-0645 [Non-licensed Document 96] Roy, Mod Patho / ., 30(8):1133~1143 pages, 2017. doi: 10.1038 / modpathol.2017.33 [Non-licensed Document 97] Chakrabarty, Br J Cancer, 117(1):136~143, 2017. doi: 10.1038 / bjc.2017.148 [Non-licensed Document 98] Hoangら, Sci Transl Med., 5(197):197ra102. doi: 10.1126 / scitranslmed.3006200 [Non-licensed Document 99] Kim, Ann Oneal., 28(6): 1250-1259. doi: 10.1093 / annonc / mdx098 [100 Non-Licensed Documents] Yong-Xing, Hum. Mol. Genet. 9(13): 2001~2008, 2000 [Non-licensed Document 101] Eeva-Maria Laitinenら, PLoS One7(6):e39450, 2012 [Non-licensed Document 102] Hart, Oncogene 19(29):3309~3320 pages, 2000 [Non-licensed Document 103] Shiang et al., Cell 76:335-342, 1994 [Non-Patent Document 104] Rosseau et al., Nature 371:252-254, 1994 [Non-Patent Document 105] Tavormina et al., Nature Genet. 9:321-328, 1995 [Non-Patent Document 106] Bellus et al., Nature Genet. 10:357-359, 1995 [Non-Patent Document 107] Muenke et al., Nature Genet. 8:269-274, 1994 [Non-Patent Document 108] Rutland et al., Nature Genet. 9:173-176, 1995 [Non-Patent Document 109] Reardon et al., Nature Genet. 8:98-103, 1994 [Non-Patent Document 110] Wilkie et al., Nature Genet. 9:165-172, 1995 [Non-Patent Document 111] Jabs et al., Nature Genet. 8:275-279, 1994 [Non-Patent Document 112] Ye et al., Plast. Reconstr. Surg., 137(3):952-61, 2016 [Non-Patent Document 113] Bellus et al., Am. J. Med. Genet. 85(1):53-65, 1999 [Non-Patent Document 114] Ohishi et al., Am. J. Med. Genet. A., doi: 10.1002 / ajmg.a.37992, 2016 [Non-Patent Document 115] Nagahara et al., Clin. Pediatr. Endocrinol., 25(3): pp. 103-106, 2016 [Non-Patent Document 116] Hibberd, Am. J. Med. Genet. A., doi: 10.1002 / ajmg.a.37862, 2016 [Non-licensed Document 117] Diasら, Exp. Mol. Pathol., 101(1):116~23 pages, 2016 [Non-licensed Document 118] Lin ら, Mol. Med. Rep., 14(3):1941~6 pages, 2016 [Non-licensed Document 119] Barnett, Hum. Mutat., 37(9):955~63 pages, 2016 [Non-licensed Document 120] Krstevska-Konstantinova., Med. Arch., 70(2):148~50 pages, 2016 [Non-licensed Document 121] Kuentzら, Br. J. Dermatol., doi: 10.1111 / bjd.14681, 2016 [Non-licensed Document 122] Ronra, Am. J. Case Rep., 15;17:254~8, 2016 [Non-licensed Document 123] Fernandes, Am. J. Med. Genet. A., 170(6):1532~7 pages, 2016 [Non-licensed Document 124] Lindy, Am. J. Med. Genet. A., 170(6):1573~9 pages, 2016 [Non-licensed Document 125] Bennett, Am. J. Hum. Genet., 98(3): pages 579~87, 2016 [Non-licensed Document 126] lchiyamaら, J. Eur. Acad. Dermatol. Venereal., 30(3):442~5 pages, 2016 [Non-licensed Document 127] Zhao ら, Int. J. Clin. Exp. Med., 8(10):19241~9 pages, 2015 [Non-licensed Document 128] Hasegawa, Am. J. Med. Genet. A., 170A(5):1370~2 pages, 2016 [Non-licensed Document 129] Legeai-Mallet, Endocr. Dev., 30:98-105, 2016 [Non-licensed Document 130] Takagi, Am. J. Med. Genet. A., 167A(ll): 2851-4, 2015 [Non-licensed Document 131] Goncalves, Fertil. Steril., 104(5):1261~7 pages. el, 2015 [Non-licensed Document 132] Miller, Journal of Clinical Oncology, 34: Supp. Supplement 15, page iii93. AbstractNumber: e22500, 2016 Annual Meeting of the American Society of Clinical Oncology, Chicago, IL [Non-licensed Document 133] Sarabipour, J. Mol. Biol., 428(20):3903~3910, 2016 [Non-licensed Document 134] Escobar, Am. J. Med. Genet. A., 170(7):1908~11 pages, 2016 [Non-licensed Document 135] Mazenら、Sex Dev., 10(1):16~22 pages, 2016 [Non-licensed Document 136] Taylanら, J Allergy Clin Immunol, 136(2):507~9 pages, 2015. doi: 10.1016 / j.jaci.2015.02.010 [Non-licensed Document 137] Kant, EuroJourn Endocrinol, 172(6): pages 763~770, 2015. doi: 10.1530 / EJE-14-0945 [Non-Patent Document 138] Gonzalez-Del Angel et al., Am J med Genet A, 176(1):161–166, 2018. doi: 10.1002 / ajmg.a.38526 [Non-Patent Document 139] Lei and Deng, Int J Biol Sci 13(9):1163:1171, 2017. doi: 10.7150 / ijbs.20792 [Non-Patent Document 140] Lajeunie et al., Eur J Hum Genet, 14(3):289-298, 2006. doi: 10.1038 / sj.ejhg.5201558 [Non-Patent Document 141] Karadimas et al., Prenat Diagn, 26(3):258-261, 2006. doi: 10.1002 / pd.1392 [Non-Patent Document 142] lbrahimi et al., Hum Mo / Genet 13(19):2313–2324, 2004. doi: 10.1093 / hmg / ddh235 [Non-Patent Document 143] Trarbach et al., J Clin Endocrinol Metab., 91(10):4006–4012, 2006. doi: 10.1210 / jc.2005-2793 [Non-Patent Document 144] Dode et al., Nat Genet, 33(4):463-465, 2003. doi: 10.1038 / ng1122 [Non-Patent Document 145] Turner and Grose, Nat. Rev. Cancer, 10(2): pp. 116-129, 2010 Summary of the Invention [Problem to be solved by the invention]

[0007] The compounds disclosed herein provide small molecule kinase inhibitors that are both effective and selective. [Means for solving the problem]

[0008] In some aspects, the present disclosure provides a compound of formula (I)

[0009] [ka]

[0010] or a pharmaceutically acceptable salt thereof wherein n=1, 2, or 3; m=0, 1, 2, or 3; Each R 1 are independently H, CN, or optionally substituted C1-C6 alkyl; Each R 2 are independently H, CN, or optionally substituted C1-C6 alkyl; or two R attached to the same carbon atom 1 groups, taken together with the carbon atoms to which they are both attached, form an optionally substituted 3- to 7-membered spirocycloalkyl ring or an optionally substituted 3- to 7-membered spiroheterocycloalkyl ring, or or two R attached to the same carbon atom 1 The group together with its carbon atom represents a carbonyl group (C=O), or or two R attached to the same carbon atom 2 groups, taken together with the carbon atoms to which they are both attached, form an optionally substituted 3- to 7-membered spirocycloalkyl ring or an optionally substituted 3- to 7-membered spiroheterocycloalkyl ring, or or two R attached to the same carbon atom 2 The group together with its carbon atom represents a carbonyl group (C=O), or or two R attached to different carbon atoms 1groups taken together with the carbon atom to which they are attached form a 3- to 7-membered cycloalkyl ring, or or two R attached to different carbon atoms 2 groups taken together with the carbon atom to which they are attached form a 3- to 7-membered cycloalkyl ring, or or R 1 Groups and R 2 the groups are joined to form a 6- to 9-membered bridged bicyclic ring; A=N or CH; Z = S(O)2; S(O); O, NR 3 or CR 4 R 4' and R 3 is H; optionally substituted C1-C6 alkyl, 3- to 5-membered cycloalkyl, 3- to 5-membered heterocycloalkyl, —C(O)NR a R b ;-C(O)OR c ;-C(O)R c ;-S(O)2R c ; or -S(O)2NR a R b Or or R 3 is R 1 or R 2 together with R a is H or C1-C6 alkyl, R b is H or C1-C6 alkyl, or R a and R b together with the N atom to which they are both attached form an optionally substituted 3- to 7-membered heterocycloalkyl ring; R c is optionally substituted C1-C6 alkyl or cycloalkyl; R 4 is H, —F, or optionally substituted C1-C6 alkyl; R 4'is H, -F, -OH, -CN, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, -N(C1-C3 alkyl)-SO2(C1-C3 alkyl), -C1-C6 haloalkyl, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 alkoxyl; or R 4 and R 4' together with the C atom to which they are both attached form an optionally substituted 3- to 7-membered heterocycloalkyl ring or an optionally substituted 3- to 7-membered cycloalkyl ring, or or R 4 and R 4' together with the carbon atom to which they are both attached to form an oxo group, or or R 4' is R 1 or R 2 together with Y is a 5- or 6-membered heteroaryl ring or a 6-membered aryl ring; Q 5 , Q 6 , Q 7 , Q 8 , and Q 9 are each independently N or CR 5 and Q 5 , Q 6 , Q 7 , Q 8 , and Q 9 One or two of these are N and the rest are CR 5 and R 5 is H, halogen, C1-C3 alkyl; C1-C3 alkoxyl, or cycloalkyl, X=O, S, or NR, where R is H or C1-C3 alkyl; R 6 is a C1-C6 alkyl; R 7is H, halogen, -C1-C6 alkyl; -C1-C6 alkoxyl, or -cycloalkyl; R 8 is H, halogen, -C1-C6 alkyl; -C1-C6 alkoxyl, or -cycloalkyl.

[0011] In some embodiments, the compound of formula (I) (In the formula, n=1, 2, or 3; m=1, 2, or 3; Each R 1 are independently H; or optionally substituted C1-C6 alkyl; Each R 2 are independently H; or optionally substituted C1-C6 alkyl; or two R attached to the same carbon atom 1 groups, taken together with the carbon atoms to which they are both attached, form an optionally substituted 3- to 7-membered spirocycloalkyl ring or an optionally substituted 3- to 7-membered spiroheterocycloalkyl ring, or or two R attached to the same carbon atom 1 The group together with its carbon atom represents a carbonyl group (C=O), or or two R attached to the same carbon atom 2 groups, taken together with the carbon atoms to which they are both attached, form an optionally substituted 3- to 7-membered spirocycloalkyl ring or an optionally substituted 3- to 7-membered spiroheterocycloalkyl ring, or or two R attached to the same carbon atom 2 The group together with its carbon atom represents a carbonyl group (C=O), or or two R attached to different carbon atoms 1 groups taken together with the carbon atom to which they are attached form a 3- to 7-membered cycloalkyl ring, or or two R attached to different carbon atoms 2groups taken together with the carbon atom to which they are attached form a 3- to 7-membered cycloalkyl ring, or or R 1 Groups and R 2 the groups are joined to form a 6- to 9-membered bridged bicyclic ring; A=N or CH; Z = S(O)2; S(O); O, NR 3 or CR 4 R 4' and R 3 is H; optionally substituted C1-C6 alkyl, 3- to 5-membered cycloalkyl, 3- to 5-membered heterocycloalkyl, —C(O)NR a R b ;-C(O)OR c ;-C(O)R c ;-S(O)2R c or -S(O)NR a R b and R a is H or C1-C6 alkyl, R b is H or C1-C6 alkyl, or R a and R b together with the N atom to which they are both attached form an optionally substituted 3- to 7-membered heterocycloalkyl ring; R c is an optionally substituted C1-C6 alkyl or cycloalkyl; R 4 is H or optionally substituted C1-C6 alkyl; R 4' is H, —OH, or optionally substituted C1-C6 alkyl; or R 4 and R 4' together with the C atom to which they are both attached form an optionally substituted 3- to 7-membered heterocycloalkyl ring, Y is a 5- or 6-membered heteroaryl ring; Q 5 , Q 6 , Q7 , Q 8 , and Q 9 are each independently N or CR 5 and Q 5 , Q 6 , Q 7 , Q 8 , and Q 9 One or two of these are N and the rest are CR 5 and R 5 is H, halogen, C1-C3 alkyl; C1-C3 alkoxyl, or cycloalkyl; X=O, S, or NR, where R is H or C1-C3 alkyl; R 6 is a C1-C6 alkyl; R 7 is H, halogen, -C1-C6 alkyl; -C1-C6 alkoxyl, or -cycloalkyl; R 8 is H, halogen, -C1-C6 alkyl; -C1-C6 alkoxyl, or -cycloalkyl).

[0012] Stereoisomers of the compounds of formula (I), as well as pharmaceutical salts and solvates thereof, are also described. Methods of using the compounds of formula (I), and pharmaceutical compositions containing the compounds of formula (I) are also described. DETAILED DESCRIPTION OF THE INVENTION

[0013] The present disclosure may be more fully appreciated by reference to the following description, including the following definitions and examples. Certain features of the disclosed compositions and methods that are described herein in the context of separate embodiments may also be provided in combination in a single embodiment. Alternatively, various features of the disclosed compositions and methods that are, for brevity, described in the context of a single embodiment may also be provided separately or in any subcombination.

[0014] The terms "optionally substituted" or "substituted," as used herein, describe a substituent as defined herein, including any of the following: halo (i.e., -F, -Cl, -Br, -I), cyano, -OH, -C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, -C3-C6 spirocycloalkyl, 3- to 7-membered spiroheterocycloalkyl, bridged cycloalkyl, bridged heterocycloalkyl, C2 ~C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl (e.g., -CF3; -CHF2, -CH2CF3, etc.), -C1-C6 alkoxy, -C1-C6 haloalkoxy (e.g., -OCF3; -OCHF2, -OCH2CF3, etc.), C1-C6 alkylthio (e.g., -SCH3; -SCH2CH3, etc.), C1-C6 alkylamino (e.g., -CH2NH2; -CH2CH2NH2, etc.), -NH2, -NH(C1-C6 alkyl), -N(C1-C -6 alkyl)2, -NH(C1-C6 alkoxy), -C(O)NHC1-C6 alkyl, -C(O)N(C1-C6 alkyl)2, -COOH, -C1-C6 alkylCOOH 、- C3-C6 cycloalkyl COOH, -C(O)NH2, -C1-C6 alkyl CONH 2、This means that it may be substituted with one or more of -C3-C6 cycloalkylCONH2, -C1-C6 alkylCONHC1-C6 alkyl, -C1-C6 alkylCON(C1-C6 alkyl)2, -C(O)C1-C6 alkyl, -C(O)OC1-C6 alkyl, -NHCO(C1-C6 alkyl), -N(C1-C6 alkyl)C(O)(C1-C6 alkyl), -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, oxo (i.e., ═O), 6- to 12-membered aryl, or 5- to 12-membered heteroaryl groups, but does not necessarily have to be substituted. In other embodiments, "optionally substituted" or "substituted" means that a substituent may, but need not, be substituted with one or more of: -C(O)(C-C haloalkyl), -NHSO(C-C alkyl), -N(C-C alkyl)SO(C-C alkyl), or -P(O)(C-C alkyl) (e.g., -P(O)(CH)). In some embodiments, each of the optional substituents is itself optionally substituted with one or two of these groups.

[0015] When a range of carbon atoms is used herein, such as C1 to C6, all ranges as well as individual numbers of carbon atoms are included. For example, "C1 to C3" means C 1~ C3, C 1~ C2, C 2~ C3, C1, C2, and C3 are included. Thus, for example, a "C1-C4 alkyl" group refers to all alkyl groups having one to four carbons (e.g., one, two, three, or four), i.e., CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, and (CH3)3C-. A "C1-C6 alkyl" group refers to all alkyl groups having one to six carbons (e.g., one, two, three, four, five, or six).

[0016] As used herein, the term "alkyl" refers to a fully saturated aliphatic hydrocarbon group. The alkyl moiety may be branched or straight-chain. Examples of branched alkyl groups include, but are not limited to, iso-propyl, sec-butyl, t-butyl, etc. Examples of straight-chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, etc. An alkyl group may have 1 to 30 carbon atoms (whenever it appears herein, a numerical range, e.g., "1 to 30," refers to each integer within the given range. For example, "1 to 30 carbon atoms" means that the alkyl group may consist of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 carbon atoms; however, the present definition also covers appearances of the term "alkyl" where no numerical range is specified). An "alkyl" group may also be a medium-sized alkyl having 1 to 12 carbon atoms. An "alkyl" group may also be a lower alkyl having 1 to 6 carbon atoms. An alkyl group may be substituted or unsubstituted. By way of example only, "C1-C5 alkyl" indicates that there are 1 to 5 carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight chain), and the like. Exemplary alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, and hexyl. In some embodiments, "Me" is methyl (e.g., CH3).

[0017] As used herein, "alkenyl" refers to an alkyl group that contains one or more double bonds in the straight or branched hydrocarbon chain. An alkenyl group can be unsubstituted or substituted.

[0018] As used herein, "alkynyl" refers to an alkyl group that contains one or more triple bonds in the straight or branched hydrocarbon chain. An alkynyl group can be unsubstituted or substituted.

[0019] As used herein, "cycloalkyl" refers to a monocyclic or polycyclic hydrocarbon ring system that is fully saturated (no double or triple bonds). When composed of two or more rings, the rings may be linked together in a fused form. A cycloalkyl group can contain between 3 and 12 carbon atoms. For example, a C3-C6 cycloalkyl group indicates that there are 3 to 6 carbon atoms in the ring, and the ring is a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group. A cycloalkyl group can be unsubstituted or substituted.

[0020] As used herein, the term "spirocycloalkyl ring" refers to a cycloalkyl ring that shares one carbon atom with another cyclic ring. For example, a 3- to 7-membered spirocycloalkyl ring indicates that there are 3, 4, 5, 6, or 7 carbon atoms in the cycloalkyl ring that shares a single carbon atom with another cyclic ring. Illustratively, shown below are exemplary 3- to 7-membered spirocycloalkyl groups attached to a piperidine ring:

[0021] [ka]

[0022] As used herein, "aryl" refers to a carbocyclic (all-carbon) monocyclic or polycyclic aromatic ring system (including fused ring systems in which two carbon rings share a chemical bond) having a completely delocalized pi-electron system throughout all rings. The number of carbon atoms in an aryl group can vary. For example, an aryl group can be C6 to C8. 14 Aryl groups, C6-C 10It can be an aryl group or a C6 aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene, and azulene. The aryl group can be substituted or unsubstituted.

[0023] As used herein, "heteroaryl" refers to a monocyclic or polycyclic aromatic ring system (a ring system having a fully delocalized pi-electron system) containing one or more heteroatoms, i.e., elements other than carbon, including, but not limited to, nitrogen, oxygen, and sulfur. The number of atoms in the rings of a heteroaryl group can vary. For example, a heteroaryl group can contain 4 to 14 atoms in the rings, 5 to 10 atoms in the rings, or 5 to 6 atoms in the rings. Furthermore, the term "heteroaryl" includes fused ring systems in which two rings, e.g., at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings, share at least one chemical bond. Examples of heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, and triazine. Heteroaryl rings can also contain bridgehead nitrogen atoms. For example, but not limited to, pyrazolo[1,5-a]pyridine, imidazo[1,2-a]pyridine, and pyrazolo[1,5-a]pyrimidine. The heteroaryl group can be substituted or unsubstituted.

[0024] As used herein, "heterocycloalkyl" refers to monocyclic, bicyclic, and tricyclic ring systems of up to 3, 4, 5, 6, 7, 8, 9, 10, or 18 members, in which carbon atoms, together with 1 to 5 heteroatoms, comprise said ring system. Heterocycloalkyls may optionally contain one or more unsaturated bonds positioned in such a manner, however, a completely delocalized pi-electron system does not occur throughout all rings. Heteroatoms are elements other than carbon, including, but not limited to, oxygen, sulfur, and nitrogen. Heterocycloalkyls may further contain one or more carbonyl or thiocarbonyl functional groups, thereby including oxo and thio systems within the definition, such as lactams, lactones, cyclic imides, cyclic thioimides, and cyclic carbamates. When composed of more than one ring, the rings may be joined together in a fused fashion. Furthermore, any nitrogen in a heterocycloalkyl may be quaternized. Heterocycloalkyl groups may be unsubstituted or substituted.Examples of such "heterocycloalkyl" groups include, but are not limited to, 1,3-dioxine, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1,4-oxathiin, 1,3-oxathiolane, 1,3-dithiol, 1,3-dithiolane, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-1,3,5-triazine, imidazoline, and the like. thiazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, oxirane, piperidine N-oxide, piperidine, piperazine, pyrrolidine, pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone, and benzo-fused analogs thereof (e.g., benzimidazolidinone, tetrahydroquinoline, 3,4-methylenedioxyphenyl).

[0025] As used herein, the term "spiroheterocycloalkyl ring" refers to a heterocycloalkyl ring that shares one carbon atom with another cyclic ring. For example, a 3- to 7-membered spiroheterocycloalkyl ring indicates that there are 3, 4, 5, 6, or 7 atoms in the heterocycloalkyl ring, and only one of the carbon atoms in the heterocycloalkyl ring is also a member of another cyclic ring. Exemplary 3- to 7-membered spiroheterocycloalkyl groups attached to a piperidine ring are shown below as examples:

[0026] [ka]

[0027] As used herein, the term "bridged bicyclic ring" refers to a ring system comprising two linked cycloalkyl or heterocycloalkyl rings that share at least three atoms, e.g., a 6-9 membered bridged bicyclic ring indicates that there are 6, 7, 8, or 9 atoms in the bridged bicyclic ring. Exemplary 6-9 membered bridged bicyclic rings are shown by way of example below:

[0028] [ka]

[0029] As used herein, the term "amino" refers to the group --NH.sub.2.

[0030] As used herein, the term "hydroxy" refers to an --OH group.

[0031] As used herein, the term "halogen atom" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0032] The term "pharmaceutically acceptable salt" refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abolish the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting a compound with an inorganic acid, such as a hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid. Pharmaceutical salts can also be obtained by reacting a compound with an organic acid, such as an aliphatic or aromatic carboxylic or sulfonic acid, for example, formic acid, acetic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt, for example, an ammonium salt, an alkali metal salt, for example, a sodium or potassium salt, an alkaline earth metal salt, for example, a calcium or magnesium salt, a salt of an organic base, for example, dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamine, cyclohexylamine, triethanolamine, ethylenediamine, and a salt with an amino acid, for example, arginine and lysine, etc.

[0033] Other pharmaceutically acceptable salts include trifluoroacetate salts.

[0034] In any compound described herein having one or more chiral centers, where the absolute stereochemistry is not explicitly indicated, it is understood that each center may independently be in the R- or S-configuration, or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture. Additionally, in any compound described herein having one or more double bonds that produce geometric isomers that can be defined as E or Z, it is understood that each double bond may independently be E or Z, or a mixture thereof. It is understood that in any compound described herein having one or more chiral centers, all possible diastereomers are also contemplated. It is understood that in any compound described herein, all tautomers are contemplated. It is also understood that in any compound described herein, all isotopes of the atoms contained are contemplated. For example, any instance of hydrogen may include hydrogen-1 (protium), hydrogen-2 (deuterium), hydrogen-3 (tritium), or other isotopes. Any instance of carbon may include carbon-12, carbon-13, carbon-14, or other isotopes. Any instance of oxygen may include oxygen-16, oxygen-17, oxygen-18, or other isotopes. Any instance of fluorine may include one or more of fluorine-18, fluorine-19, or other isotopes. Any instance of sulfur may include one or more of sulfur-32, sulfur-34, sulfur-35, sulfur-36, or other isotopes.

[0035] As used herein, the term "kinase inhibitor" refers to any compound, molecule, or composition that inhibits or reduces the activity of a kinase. Inhibition can be achieved, for example, by blocking phosphorylation of the kinase (e.g., by competing with adenosine triphosphate (ATP), a phosphorylating entity), by binding to a site outside the active site, by affecting its activity through conformational changes, or by denying kinases access to molecular chaperone systems on which they depend for their cellular stability, leading to their ubiquitination and degradation.

[0036] As used herein, the terms "subject," "host," "patient," and "individual" are used interchangeably and are given their ordinary meaning, and also refer to organisms that possess FGFR proteins. This includes mammals, such as humans, non-human primates, ungulates, dogs, cats, horses, mice, rats, etc. The term "mammal" includes both human and non-human mammals.

[0037] The terms "sample" or "biological sample" shall be given their ordinary meaning and encompass a variety of sample types obtained from an organism and may be used in imaging, diagnostic, prognostic, or monitoring assays. The term encompasses blood and other liquid samples of biological origin, solid tissue samples, e.g., biopsy specimens or tissue cultures, or cells derived therefrom, and their progeny. The term encompasses samples that have been manipulated in any way after their procurement, such as by treatment with reagents, solubilization, or enrichment for certain components. The term encompasses clinical samples, and also includes cells in cell cultures, cell supernatants, cell lysates, serum, plasma, biological fluids, and tissue samples.

[0038] The terms "treatment," "treating," "treating," and the like are to be given their ordinary meaning and are intended to be included herein to generally refer to obtaining a desired pharmacological and / or physiological effect. The effect may be prophylactic, in that it completely or partially prevents a disease or its symptoms, and / or therapeutic, in that it partially or completely stabilizes or cures the disease and / or adverse effects caused by the disease. "Treatment," as used herein, is to be given its ordinary meaning and is intended to encompass any treatment of disease in a mammal, particularly a human, including: (a) preventing a disease or condition from occurring in a subject who may be susceptible to the disease or condition but has not yet been diagnosed as having the disease or condition; (b) inhibiting a symptom of the disease, e.g., arresting its development; and / or (c) alleviating a disease symptom, e.g., causing regression of the disease or condition.

[0039] The terms "cancer," "neoplasm," and "tumor" are used interchangeably herein and are given their ordinary meanings, and refer to cells that exhibit relatively autonomous growth, and thus, an abnormal growth phenotype characterized by a significant loss of control of cell proliferation. Generally, cells of interest for detection or treatment in this application include precursor, pre-cancerous (e.g., benign), malignant, pre-metastatic, metastatic, and non-metastatic cells. As used herein, "FGFR-associated cancer" refers to those cancers in which increased activity in mutant FGFR kinases, e.g., continued activation of FGFR, is implicated.

[0040] The term "control" is given its ordinary meaning and also includes a sample or standard used for comparison with a sample being tested, treated, characterized, analyzed, etc. In some embodiments, a control is a sample obtained from a healthy patient or a non-tumor tissue sample obtained from a patient diagnosed with a tumor. In some embodiments, a control is a historical control or standard reference value or range of values. In some embodiments, a control is a comparison with a wild-type FGFR configuration or scenario.

[0041] With respect to the use of virtually all plural and / or singular terms herein, those skilled in the art can translate from plural to singular and / or from singular to plural as appropriate to the context and / or application. Various singular / plural permutations may be expressly set forth herein for the sake of clarity. The indefinite article "a" or "an" does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that these measures cannot be used to advantage in combination. Any reference signs in the claims shall not be construed as limiting the scope.

[0042] In some aspects, the present disclosure provides a compound of formula (I)

[0043] [ka]

[0044] or a pharmaceutically acceptable salt thereof.

[0045] In some embodiments, n is 1, 2, or 3 in the compound of formula (I).

[0046] In some embodiments, n is 1. In other embodiments, n is 2. In other embodiments, n is 3.

[0047] In other embodiments, m of a compound of Formula (I) is 0, 1, 2, or 3. In some embodiments, m of a compound of Formula (I) is 0 or 1. In some embodiments, m of a compound of Formula (I) is 0, 1, or 2. In some embodiments, m of a compound of Formula (I) is 1 or 2. In some embodiments, m of a compound of Formula (I) is 2 or 3.

[0048] In other embodiments, m in the compound of formula (I) is 1, 2, or 3.

[0049] In some embodiments, m is 1. In other embodiments, m is 2. In other embodiments, m is 3.

[0050] In some embodiments, m is 0.

[0051] In some embodiments, each R of the compound of formula (I) 1 are independently H, CN, or optionally substituted C1-C6 alkyl.

[0052] In some embodiments, each R of the compound of formula (I) 1 is independently H or optionally substituted C1-C6 alkyl.

[0053] In some embodiments, at least one R of the compound of Formula (I) 1 is H. In another embodiment, each R of the compound of Formula (I) 1 is H.

[0054] In some embodiments, R of the compound of formula (I) 1 is optionally substituted C1-C6 alkyl, for example, optionally substituted C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentanyl, hexanyl, and the like.

[0055] In some embodiments, R of the compound of formula (I) 1 is unsubstituted C1 to C6 alkyl, for example, C1 to C6 alkyl, C1 to C5 alkyl, C1 to C4 alkyl, C1 to C3 alkyl, C1 to C2 alkyl, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentanyl, hexanyl, etc.

[0056] In some embodiments, R of the compound of formula (I) 1 is -CH3.

[0057] In some embodiments of the compounds of Formula (I), one or more R 1 is H, and one or more R 1 is an optionally substituted C1-C6 alkyl.

[0058] In some embodiments of the compounds of Formula (I), one or more R 1 is a substituted C1-C6 alkyl. In some embodiments of the compound of Formula (I), one or more R 1 is a substituted C1-C6 alkyl, for example, —CH2OH, —CH2N(CH3)2, or —CH2—CN, —CH2SO2CH3, or —CH2N(CH3)SO2CH3.

[0059] In some embodiments, each R of the compound of formula (I) 2 are independently H, CN, or optionally substituted C1-C6 alkyl.

[0060] In some embodiments, each R of the compound of formula (I) 2 is independently H or optionally substituted C1-C6 alkyl.

[0061] In some embodiments, at least one R of the compound of Formula (I) 2 is H. In another embodiment, each R of the compound of Formula (I) 2 is H.

[0062] In some embodiments, R of the compound of formula (I) 2 is optionally substituted C1-C6 alkyl, for example, optionally substituted C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentanyl, hexanyl, and the like.

[0063] In some embodiments, R of the compound of formula (I) 2 is unsubstituted C1-C6 alkyl, for example, optionally substituted C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentanyl, hexanyl, etc.

[0064] In some embodiments, R of the compound of formula (I) 2 is -CH3.

[0065] In some embodiments of the compounds of Formula (I), one or more R 2 is H, and one or more R 2 is an optionally substituted C1-C6 alkyl.

[0066] In some embodiments of the compounds of Formula (I), one or more R 2 is a substituted C1-C6 alkyl. In some embodiments of the compound of Formula (I), one or more R 1 is a substituted C1-C6 alkyl, for example, —CH2OH, —CH2N(CH3)2, or —CH2—CN, —CH2SO2CH3, or —CH2N(CH3)SO2CH3.

[0067] In some embodiments of compounds of Formula (I), two R 1 The groups, together with the carbon atoms to which they are both attached, form an optionally substituted 3- to 7-membered spirocycloalkyl ring or an optionally substituted 3- to 7-membered spiroheterocycloalkyl ring.

[0068] In some embodiments of compounds of Formula (I), two R 1The groups, taken together with the carbon atoms to which they are both attached, form an optionally substituted 3- to 7-membered spirocycloalkyl ring. 1 The 3- to 7-membered spirocycloalkyl ring formed by the group is an optionally substituted 3-membered spirocycloalkyl ring, an optionally substituted 4-membered spirocycloalkyl ring, an optionally substituted 5-membered spirocycloalkyl ring, an optionally substituted 6-membered spirocycloalkyl ring, an optionally substituted 7-membered spirocycloalkyl ring, an optionally substituted spirocyclopropyl ring, an optionally substituted spirocyclobutyl ring, an optionally substituted spirocyclopentyl ring, an optionally substituted spirocyclohexyl ring, or an optionally substituted spirocycloheptyl ring.

[0069] In some embodiments, two R 1 The ring formed by the group is a spirocyclopropyl ring.

[0070] In some embodiments, two R 1 The three rings formed by the group are spirocyclobutyl rings.

[0071] In some embodiments, two R 1 The ring formed by the group is a spirocyclopentyl ring.

[0072] In some embodiments, two R 1 The ring formed by the group is a spirocyclohexyl ring.

[0073] In some embodiments, two R 1 The ring formed by the group is a spirocycloheptyl ring.

[0074] In another embodiment of the compounds of formula (I), two R 1 The R groups, taken together with the carbon atoms to which they are both attached, form an optionally substituted 3- to 7-membered spiroheterocycloalkyl ring.1 The 3- to 7-membered spiroheterocycloalkyl ring formed by the group is an optionally substituted 3-membered spiroheterocycloalkyl ring, an optionally substituted 4-membered spiroheterocycloalkyl ring, an optionally substituted 5-membered spiroheterocycloalkyl ring, an optionally substituted 6-membered spiroheterocycloalkyl ring, an optionally substituted 7-membered spiroheterocycloalkyl ring, an optionally substituted spiroaziridinyl ring, an optionally substituted spiroazetidinyl ring, an optionally substituted spiropyrrolidinyl ring, an optionally substituted spiropiperidinyl ring, an optionally substituted spiroazepanyl ring, an optionally substituted spirooxiranyl ring, an optionally substituted spirooxetanyl ring, an optionally substituted spirotetrahydrofuranyl ring, an optionally substituted spirotetrahydropyranyl ring, an optionally substituted spirooxepanyl ring, or the like.

[0075] In some embodiments of compounds of Formula (I), two R 1 The group together with its carbon atom represents a carbonyl group (C=O).

[0076] In some embodiments of compounds of Formula (I), two R 2 The groups, together with the carbon atoms to which they are both attached, form an optionally substituted 3- to 7-membered spirocycloalkyl ring or an optionally substituted 3- to 7-membered spiroheterocycloalkyl ring.

[0077] In some embodiments of compounds of Formula (I), two R 2 The groups, taken together with the carbon atoms to which they are both attached, form an optionally substituted 3- to 7-membered spirocycloalkyl ring. 2The 3- to 7-membered spirocycloalkyl ring formed by the group is an optionally substituted 3-membered spirocycloalkyl ring, an optionally substituted 4-membered spirocycloalkyl ring, an optionally substituted 5-membered spirocycloalkyl ring, an optionally substituted 6-membered spirocycloalkyl ring, an optionally substituted 7-membered spirocycloalkyl ring, an optionally substituted spirocyclopropyl ring, an optionally substituted spirocyclobutyl ring, an optionally substituted spirocyclopentyl ring, an optionally substituted spirocyclohexyl ring, or an optionally substituted spirocycloheptyl ring.

[0078] In some embodiments, two R 2 The ring formed by the group is a spirocyclopropyl ring.

[0079] In some embodiments, two R 2 The ring formed by the group is a spirocyclobutyl ring.

[0080] In some embodiments, two R 2 The ring formed by the group is a spirocyclopentyl ring.

[0081] In some embodiments, two R 2 The ring formed by the group is a spirocyclohexyl ring.

[0082] In some embodiments, two R 2 The spirocycloalkyl ring formed by the group is a spirocycloheptyl ring.

[0083] In another embodiment of the compounds of formula (I), two R 2 The R groups, taken together with the carbon atoms to which they are both attached, form an optionally substituted 3- to 7-membered spiroheterocycloalkyl ring. 2The 3- to 7-membered spiroheterocycloalkyl ring formed by the group is an optionally substituted 3-membered spiroheterocycloalkyl ring, an optionally substituted 4-membered spiroheterocycloalkyl ring, an optionally substituted 5-membered spiroheterocycloalkyl ring, an optionally substituted 6-membered spiroheterocycloalkyl ring, an optionally substituted 7-membered spiroheterocycloalkyl ring, an optionally substituted spiroaziridinyl ring, an optionally substituted spiroazetidinyl ring, an optionally substituted spiropyrrolidinyl ring, an optionally substituted spiropiperidinyl ring, an optionally substituted spiroazepanyl ring, an optionally substituted spirooxiranyl ring, an optionally substituted spirooxetanyl ring, an optionally substituted spirotetrahydrofuranyl ring, an optionally substituted spirotetrahydropyranyl ring, an optionally substituted spirooxepanyl ring, or the like.

[0084] In some embodiments of compounds of Formula (I), two R 2 The group together with its carbon atom represents a carbonyl group (C=O).

[0085] In some embodiments of compounds of Formula (I), two R 1The groups, together with the carbon atoms to which they are attached, form an optionally substituted 3- to 7-membered cycloalkyl ring, for example, an optionally substituted 3- to 7-membered cycloalkyl ring, an optionally substituted 3- to 6-membered cycloalkyl ring, an optionally substituted 3- to 5-membered cycloalkyl ring, an optionally substituted 3- to 4-membered cycloalkyl ring, an optionally substituted 3-membered cycloalkyl ring, an optionally substituted 4-membered cycloalkyl ring, an optionally substituted 5-membered cycloalkyl ring, an optionally substituted 6-membered cycloalkyl ring, an optionally substituted 7-membered cycloalkyl ring, an optionally substituted cyclopropyl ring, an optionally substituted cyclobutyl ring, an optionally substituted cyclopentyl ring, an optionally substituted cyclohexyl ring, or an optionally substituted cycloheptyl ring.

[0086] In some embodiments of compounds of Formula (I), two R 2 The groups, together with the carbon atoms to which they are attached, form an optionally substituted 3- to 7-membered cycloalkyl ring, for example, an optionally substituted 3- to 7-membered cycloalkyl ring, an optionally substituted 3- to 6-membered cycloalkyl ring, an optionally substituted 3- to 5-membered cycloalkyl ring, an optionally substituted 3- to 4-membered cycloalkyl ring, an optionally substituted 3-membered cycloalkyl ring, an optionally substituted 4-membered cycloalkyl ring, an optionally substituted 5-membered cycloalkyl ring, an optionally substituted 6-membered cycloalkyl ring, an optionally substituted 7-membered cycloalkyl ring, an optionally substituted cyclopropyl ring, an optionally substituted cyclobutyl ring, an optionally substituted cyclopentyl ring, an optionally substituted cyclohexyl ring, or an optionally substituted cycloheptyl ring.

[0087] In some embodiments of compounds of Formula (I), R 1 Groups and R 2The groups are linked to form a 6- to 9-membered bridged bicyclic ring, for example, a 6- to 9-membered bridged bicyclic ring, a 6- to 8-membered bridged bicyclic ring, a 6- to 7-membered bridged bicyclic ring, a 6-membered bridged bicyclic ring, a 7-membered bridged bicyclic ring, an 8-membered bridged bicyclic ring, a 9-membered bridged bicyclic ring.

[0088] In some embodiments, A in the compounds of formula (I) is N or CH.

[0089] In some embodiments of the compounds of Formula (I), A is N.

[0090] In some embodiments of the compounds of Formula (I), A is CH.

[0091] In some embodiments of the present disclosure, Z in the compound of formula (I) is S(O); S(O); O, NR 3 or CR 4 R 4' is.

[0092] In some embodiments of the compounds of Formula (I), Z is S(O)2.

[0093] In some embodiments of the compounds of Formula (I), Z is S(O).

[0094] In some embodiments of the compounds of Formula (I), Z is O.

[0095] In some embodiments of the compounds of Formula (I), Z is NR 3 is.

[0096] In some embodiments of the compounds of Formula (I), Z is CR 4 R 4' is.

[0097] In some embodiments of the present disclosure, R of the compound of formula (I) 3 is H; optionally substituted C1-C6 alkyl, 3- to 5-membered cycloalkyl, 3- to 5-membered heterocycloalkyl, -C(O)NR a R b ;-C(O)OR c ;-C(O)R c;-S(O)2R c ; or -S(O)2NR a R b or R 3 is R 1 or R 2 together form an optionally substituted 3- to 7-membered heterocycloalkyl ring.

[0098] In some embodiments of the present disclosure, R of the compound of formula (I) 3 is H; optionally substituted C1-C6 alkyl, 3- to 5-membered cycloalkyl, 3- to 5-membered heterocycloalkyl, —C(O)NR a R b ;-C(O)OR c ;-C(O)R c ;-S(O)2R c or -S(O)NR a R b is.

[0099] In some embodiments of the compound of Formula (I), R of the compound of Formula (I) 3 is H.

[0100] In some embodiments of the compound of Formula (I), R of the compound of Formula (I) 3 is optionally substituted C1-C6 alkyl, for example, optionally substituted C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentanyl, hexanyl, and the like.

[0101] In some embodiments of the compound of Formula (I), R of the compound of Formula (I) 3 is a 3- to 5-membered cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, etc. In some embodiments of the compound of Formula (I), R 3is a 3- to 5-membered substituted cycloalkyl, for example, substituted cyclopropyl, cyclobutyl, cyclopentyl, etc.

[0102] In some embodiments, R 3 is cyclobutyl. In some embodiments, R 3 is a substituted cyclobutyl.

[0103] In some embodiments of the compound of Formula (I), R of the compound of Formula (I) 3 is a 3- to 5-membered heterocycloalkyl. In some embodiments of the compound of Formula (I), R 3 is a 3- to 5-membered substituted heterocycloalkyl.

[0104] In some embodiments of the compound of Formula (I), R of the compound of Formula (I) 3 is -C(O)NR a R b is.

[0105] In some embodiments of the compound of Formula (I), R of the compound of Formula (I) 3 -C(O)OR c is.

[0106] In some embodiments of the compound of Formula (I), R of the compound of Formula (I) 3 -C(O)R c is.

[0107] In some embodiments of the compound of Formula (I), R of the compound of Formula (I) 3 -S(O)2R c is.

[0108] In some embodiments of the compound of Formula (I), R of the compound of Formula (I) 3 is -S(O)2NR a R b is.

[0109] In some embodiments of the present disclosure, R of the compound of formula (I) a is H or C1-C6 alkyl.

[0110] In some embodiments of the compound of Formula (I), R of the compound of Formula (I) a is H.

[0111] In some embodiments of the compound of Formula (I), R of the compound of Formula (I) a is C1 to C6 alkyl, for example, C1 to C6 alkyl, C1 to C5 alkyl, C1 to C4 alkyl, C1 to C3 alkyl, C1 to C2 alkyl, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentanyl, hexanyl, etc.

[0112] In some embodiments of the present disclosure, R of the compound of formula (I) b is H or C1-C6 alkyl.

[0113] In some embodiments of the compound of Formula (I), R of the compound of Formula (I) b is H.

[0114] In some embodiments of the compound of Formula (I), R of the compound of Formula (I) b is C1 to C6 alkyl, for example, C1 to C6 alkyl, C1 to C5 alkyl, C1 to C4 alkyl, C1 to C3 alkyl, C1 to C2 alkyl, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentanyl, hexanyl, etc.

[0115] In some aspects of the present disclosure, R a and R bare taken together with the N atom to which they are both attached to form an optionally substituted 3- to 7-membered heterocycloalkyl ring, e.g., an optionally substituted 3- to 7-membered heterocycloalkyl ring, an optionally substituted 3- to 6-membered heterocycloalkyl ring, an optionally substituted 3- to 5-membered heterocycloalkyl ring, an optionally substituted 3- to 4-membered heterocycloalkyl ring, an optionally substituted 3-membered heterocycloalkyl ring, an optionally substituted 4-membered heterocycloalkyl ring, an optionally substituted 5-membered heterocycloalkyl ring, an optionally substituted 6-membered heterocycloalkyl ring, an optionally substituted 7-membered heterocycloalkyl ring, an optionally substituted aziridinyl ring, an optionally substituted azetidinyl ring, an optionally substituted pyrrolidinyl ring, an optionally substituted piperidinyl ring, or an optionally substituted azepanyl ring.

[0116] In some embodiments of the present disclosure, R of the compound of formula (I) c is an optionally substituted C1-C6 alkyl or cycloalkyl.

[0117] In some embodiments of the compounds of Formula (I), R c is optionally substituted C1-C6 alkyl, for example, optionally substituted C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentanyl, hexanyl, and the like.

[0118] In some embodiments, R c is methyl.

[0119] In some embodiments, R c is (dimethylamino)methyl, i.e., —CHN(CH)

[0120] In some embodiments, R c is ethyl.

[0121] In some embodiments, R c is (dimethylamino)ethyl, i.e., —CH2CH2N(CH3)2.

[0122] In other embodiments of the compounds of Formula (I), R c is cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

[0123] In some embodiments of the compound of Formula (I), R of the compound of Formula (I) 3 is R 1 or R 2 together to form an optionally substituted 3- to 7-membered heterocycloalkyl ring, such as aziridine, azetidine, pyrrolidine, pyrazine, imidazoline, etc. Thus, in some embodiments of compounds of formula (I), the substructure

[0124] [ka]

[0125] For example,

[0126] [ka]

[0127] is

[0128] In some embodiments of the present disclosure, R of the compound of formula (I) 4 is H, —F, or optionally substituted C1-C6 alkyl.

[0129] In some embodiments of the present disclosure, R of the compound of formula (I) 4 is H or optionally substituted C1-C6 alkyl.

[0130] In some embodiments of the compounds of Formula (I), R 4 is H.

[0131] In some embodiments of the compounds of Formula (I), R 4 is optionally substituted C1-C6 alkyl, for example, optionally substituted C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentanyl, hexanyl, etc.

[0132] In some embodiments of the compounds of Formula (I), R 4 is unsubstituted C1-C6 alkyl, for example, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentanyl, hexanyl, etc. In some embodiments of compounds of Formula (I), R 4 is methyl (i.e., -CH3).

[0133] In some embodiments of the compounds of Formula (I), R 4 is a substituted C1-C6 alkyl. In some embodiments of the compounds of Formula (I), R 4 is -CH2OH.

[0134] In some embodiments of the compounds of Formula (I), R 4 is -F.

[0135] In some embodiments of the present disclosure, R of the compound of formula (I) 4'is H, -F, -OH, -CN, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, -N(C1-C3 alkyl)-SO2(C1-C3 alkyl), -C1-C6 haloalkyl, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxyl, or R 4 and R 4' together with the C atom to which they are both attached form an optionally substituted 3- to 7-membered heterocycloalkyl ring or an optionally substituted 3- to 7-membered cycloalkyl ring, or R 4 and R 4' together with the carbon atom to which they are both attached form an oxo group, or R 4' is R 1 or R 2 together with the group consisting of an optionally substituted 3- to 7-membered heterocycloalkyl ring or an optionally substituted 3- to 7-membered cycloalkyl ring.

[0136] In some embodiments of the present disclosure, R of the compound of formula (I) 4' is H, —OH, or optionally substituted C1-C6 alkyl.

[0137] In some embodiments of the compounds of Formula (I), R 4' is H.

[0138] In some embodiments of the compounds of Formula (I), R 4' is -F.

[0139] In some embodiments of the compounds of Formula (I), R 4' is -OH.

[0140] In some embodiments of the compounds of Formula (I), R 4' is -CN.

[0141] In some embodiments of the compounds of Formula (I), R 4' is -NH2.

[0142] In some embodiments of the compounds of Formula (I), R 4' is —NH(C1-C3 alkyl), e.g., —NH(C1 alkyl), —NH(C2 alkyl), —NH(C3 alkyl), —NH(CH3), —NH—CH(CH3)2, etc. In some embodiments of compounds of Formula (I), R 4' is —NH(CH). In some embodiments of the compounds of Formula (I), R 4' is -NH-CH(CH3)2.

[0143] In some embodiments of the compounds of Formula (I), R 4' is —N(C1-C3 alkyl)2, e.g., —N(C1 alkyl)2, —N(C2 alkyl)2, —N(C3 alkyl)2, —N(C1 alkyl)(C2 alkyl), —N(CH3)2, etc. In some embodiments of compounds of Formula (I), R 4' is -N(CH3)2.

[0144] In some embodiments of the compounds of Formula (I), R 4' is —N(C1-C3 alkyl)-SO2(C1-C3 alkyl), for example, —N(C1 alkyl)-SO2(C1-C3 alkyl), —N(C2 alkyl)-SO2(C1-C3 alkyl), —N(C3 alkyl)-SO2(C1-C3 alkyl), —N(C1-C3 alkyl)-SO2(C1 alkyl), —N(C1-C3 alkyl)-SO2(C2 alkyl), —N(C1-C3 alkyl)-SO2(C3 alkyl), —NH—SO2(CH3), —N(CH3)—SO2(CH3), etc. In some embodiments of compounds of Formula (I), R 4' is -N(CH3)-SO2(CH3).

[0145] In some embodiments of the compounds of Formula (I), R 4' is —C1 to C6 haloalkyl, for example, —C1 haloalkyl, —C2 haloalkyl, —C3 haloalkyl, —C4 haloalkyl, —C5 haloalkyl, —C6 haloalkyl, —CF3, —CH2CF3, —CHF2, —CH2CHF2 and the like.

[0146] In some embodiments of the compounds of Formula (I), R 4' is optionally substituted C1-C6 alkyl, for example, optionally substituted C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentanyl, hexanyl, and the like.

[0147] In some embodiments of the compounds of Formula (I), R 4' is unsubstituted C1-C6 alkyl, for example, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentanyl, hexanyl, etc. In some embodiments of compounds of Formula (I), R 4' is methyl (i.e., -CH3).

[0148] In some embodiments of the compounds of Formula (I), R 4' is a substituted C1-C6 alkyl, for example, —CH2OH, —CH2N(CH3)2, —C(CH3)2—OH, —CH2—CN, —CH2SO2CH3, or —CH2N(CH3)SO2CH3.

[0149] In some embodiments of the compounds of Formula (I), R 4' is an optionally substituted C1-C6 alkoxyl, for example, optionally substituted C1-C6 alkoxyl, C1-C5 alkoxyl, C1-C4 alkoxyl, C1-C3 alkoxyl, C1-C2 alkoxyl, C1 alkoxyl, C2 alkoxyl, C3 alkoxyl, C4 alkoxyl, C5 alkoxyl, C6 alkoxyl, methoxyl, ethoxyl, n-propoxyl, isopropoxyl, n-butoxyl, isobutoxyl, sec-butoxyl, and the like.

[0150] In some embodiments of the compounds of Formula (I), R 4' is unsubstituted C1-C6 alkoxyl, such as C1-C6 alkoxyl, C1-C5 alkoxyl, C1-C4 alkoxyl, C1-C3 alkoxyl, C1-C2 alkoxyl, C1 alkoxyl, C2 alkoxyl, C3 alkoxyl, C4 alkoxyl, C5 alkoxyl, C6 alkoxyl, methoxyl, ethoxyl, n-propoxyl, isopropoxyl, n-butoxyl, isobutoxyl, sec-butoxyl, etc. In some embodiments of compounds of Formula (I), R 4' is -OCH3.

[0151] In some embodiments of the present disclosure, R of the compound of formula (I) 4 and R 4'together with the carbon atoms to which they are both attached form an optionally substituted 3- to 7-membered heterocycloalkyl ring or an optionally substituted 3- to 7-membered cycloalkyl ring, for example, an optionally substituted 3- to 7-membered heterocycloalkyl ring, an optionally substituted 3- to 6-membered heterocycloalkyl ring, an optionally substituted 3- to 5-membered heterocycloalkyl ring, an optionally substituted 3- to 4-membered heterocycloalkyl ring, an optionally substituted 3-membered heterocycloalkyl ring, an optionally substituted 4-membered heterocycloalkyl ring, an optionally substituted 5-membered heterocycloalkyl ring, an optionally substituted 6-membered heterocycloalkyl ring, an optionally substituted 7-membered heterocycloalkyl ring, an optionally substituted aziridinyl ring, an optionally substituted azetidinyl ring, an optionally substituted pyrrolidinyl ring, an optionally substituted piperidinyl ring, an optionally substituted azepanyl ring, an optionally substituted forms an oxetanyl ring, an optionally substituted tetrahydrofuranyl ring, an optionally substituted tetrahydrothiophene 1,1-dioxide, or an optionally substituted tetrahydro-2H-thiopyran 1,1-dioxide, or an optionally substituted 3- to 7-membered cycloalkyl ring, an optionally substituted 3- to 6-membered cycloalkyl ring, an optionally substituted 3- to 5-membered cycloalkyl ring, an optionally substituted 3- to 4-membered cycloalkyl ring, an optionally substituted 3-membered cycloalkyl ring, an optionally substituted 4-membered cycloalkyl ring, an optionally substituted 5-membered cycloalkyl ring, an optionally substituted 6-membered cycloalkyl ring, an optionally substituted 7-membered cycloalkyl ring, an optionally substituted cyclopropanyl ring, an optionally substituted cyclobutanyl ring, an optionally substituted cyclopentanyl ring, an optionally substituted cyclohexanyl ring, or an optionally substituted cycloheptanyl ring.

[0152] In some embodiments of the present disclosure, R of the compound of formula (I) 4 and R 4'taken together with the carbon atoms to which they are both attached, form an optionally substituted 3- to 7-membered heterocycloalkyl ring, e.g., an optionally substituted 3- to 7-membered heterocycloalkyl ring, an optionally substituted 3- to 6-membered heterocycloalkyl ring, an optionally substituted 3- to 5-membered heterocycloalkyl ring, an optionally substituted 3- to 4-membered heterocycloalkyl ring, an optionally substituted 3-membered heterocycloalkyl ring, an optionally substituted 4-membered heterocycloalkyl ring, an optionally substituted 5-membered heterocycloalkyl ring, an optionally substituted 6-membered heterocycloalkyl ring, an optionally substituted 7-membered heterocycloalkyl ring, an optionally substituted aziridinyl ring, an optionally substituted azetidinyl ring, an optionally substituted pyrrolidinyl ring, an optionally substituted piperidinyl ring, or an optionally substituted azepanyl ring.

[0153] In an embodiment of the present disclosure, R of the compound of formula (I) 4 and R 4' taken together with the carbon atoms to which they are both attached, form an optionally substituted 3- to 7-membered cycloalkyl ring, e.g., an optionally substituted 3- to 7-membered cycloalkyl ring, an optionally substituted 3- to 6-membered cycloalkyl ring, an optionally substituted 3- to 5-membered cycloalkyl ring, an optionally substituted 3- to 4-membered cycloalkyl ring, an optionally substituted 3-membered cycloalkyl ring, an optionally substituted 4-membered cycloalkyl ring, an optionally substituted 5-membered cycloalkyl ring, an optionally substituted 6-membered cycloalkyl ring, an optionally substituted 7-membered cycloalkyl ring, an optionally substituted cyclopropanyl ring, an optionally substituted cyclobutanyl ring, an optionally substituted cyclopentanyl ring, an optionally substituted cyclohexanyl ring, or an optionally substituted cycloheptanyl ring.

[0154] In some embodiments, R of the compound of formula (I) 4 and R 4'together with the carbon atoms to which they are both attached form an optionally substituted 4-membered cycloalkyl ring or an optionally substituted 5-membered cycloalkyl ring.

[0155] In some embodiments, R of the compound of formula (I) 4 and R 4' taken together with the carbon atoms to which they are both attached form an optionally substituted cyclobutanyl ring or an optionally substituted cyclopentanyl ring.

[0156] In some embodiments, R of the compound of formula (I) 4 and R 4' together with the carbon atom to which they are both attached form a hydroxy-substituted cyclopentanyl ring, e.g.,

[0157] [ka]

[0158] Form.

[0159] In another embodiment, R of the compound of formula (I) 4 and R 4' together with the carbon atom to which they are both attached form a methoxy-substituted cyclobutanyl ring, e.g.,

[0160] [ka]

[0161] Form.

[0162] In some embodiments of Formula (I), R 4' is R 1 or R 2 together with the group consisting of an optionally substituted 3- to 7-membered heterocycloalkyl ring or an optionally substituted 3- to 7-membered cycloalkyl ring.

[0163] In some embodiments of Formula (I), R 4' is R 1 or R 2 together with - to form an optionally substituted 3- to 7-membered heterocycloalkyl ring.

[0164] In other embodiments of Formula (I), R 4' is R 1 or R 2 together to form an optionally substituted 3- to 7-membered cycloalkyl ring, for example, an optionally substituted 3-membered cycloalkyl ring, an optionally substituted 4-membered cycloalkyl ring, an optionally substituted 5-membered cycloalkyl ring, an optionally substituted 6-membered cycloalkyl ring, an optionally substituted fused 7-membered cycloalkyl ring, a cyclopropyl ring, etc.

[0165] In some embodiments, R 4' is R 1 or R 2 and together form an optionally substituted cyclopropyl ring. Thus, in some embodiments of compounds of formula (I), the substructure

[0166] [ka]

[0167] For example,

[0168] [ka]

[0169] is.

[0170] In some embodiments of the present disclosure, R of the compound of formula (I) 4 and R 4' together with the carbon atom to which they are both attached form an oxo group, i.e.,

[0171] [ka]

[0172] Form.

[0173] In some embodiments of the present disclosure, Y in the compounds of formula (I) is a 5- or 6-membered heteroaryl ring or a 6-membered aryl ring.

[0174] In some embodiments of the present disclosure, Y in the compound of formula (I) is a 5- or 6-membered heteroaryl ring. In some embodiments of the present disclosure, Y in the compound of formula (I) is a substituted 5- or 6-membered heteroaryl ring.

[0175] In some embodiments, Y in the compound of Formula (I) is a 5-membered heteroaryl ring, such as furan, pyrrole, thiophene, isoxazole, oxazole, pyrazole, imidazole, isothiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3,5-thiatriazole, 1,3,4-oxadiazole, 1,2,4-oxadiazole, 1,2,3-oxadiazole, 1,2,5-oxadiazole, 1,2,3,5-oxatriazole, 2H-1,2,3-triazole, 1H-1,2,4-triazole, 1H-1,2,3-triazole, 4H-1,2,4-triazole, 2H-tetrazole, 1H-tetrazole, etc.

[0176] In some embodiments, Y in compounds of Formula (I) is a substituted 5-membered heteroaryl ring, such as a substituted furan, pyrrole, thiophene, isoxazole, oxazole, pyrazole, imidazole, isothiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3,5-thiatriazole, 1,3,4-oxadiazole, 1,2,4-oxadiazole, 1,2,3-oxadiazole, 1,2,5-oxadiazole, 1,2,3,5-oxatriazole, 2H-1,2,3-triazole, 1H-1,2,4-triazole, 1H-1,2,3-triazole, 4H-1,2,4-triazole, 2H-tetrazole, 1H-tetrazole, etc.

[0177] In some embodiments, Y in the compound of Formula (I) is a 6-membered heteroaryl ring, e.g., pyridine, pyridazine, pyrimidine, pyrazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3,4-tetrazine, 1,2,3,5-tetrazine, 1,2,4,5-tetrazine, etc. In some embodiments, Y in the compound of Formula (I) is a substituted 6-membered heteroaryl ring, e.g., substituted pyridine, pyridazine, pyrimidine, pyrazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3,4-tetrazine, 1,2,3,5-tetrazine, 1,2,4,5-tetrazine, etc.

[0178] In some embodiments of the compounds of Formula (I), Y is a 6-membered aryl ring. In some embodiments, Y is a substituted 6-membered aryl ring. In some embodiments, Y is a phenyl ring. In some embodiments, Y is a substituted phenyl ring.

[0179] In some embodiments, Y is

[0180] [ka]

[0181] is.

[0182] In some embodiments of the present disclosure, Q of the compound of formula (I) 5 , Q 6 , Q 7 , Q 8 , and Q 9 are each independently N or CR 5 and Q 5 , Q 6 , Q 7 , Q 8 , and Q 9 one or two of which are N, and the rest are each independently CR 5 is.

[0183] In some embodiments, Q 5 , Q 6 , Q 7 , Q 8 , or Q 9 One of them is N, and the rest are each independently CR 5 is.

[0184] In some embodiments, Q 5 is N and Q 6 , Q 7 , Q 8 , and Q 9 are each independently CR 5 is.

[0185] In some embodiments, Q 6 is N and Q 5 , Q 7 , Q 8 , and Q 9 are each independently CR 5 is.

[0186] In some embodiments, Q 7 is N and Q 5 , Q 6 , Q 8 , and Q 9 are each independently CR 5 is.

[0187] In some embodiments, Q8 is N and Q 5 , Q 6 , Q 7 , and Q 9 are each independently CR 5 is.

[0188] In some embodiments, Q 9 is N and Q 5 , Q 6 , Q 7 , and Q 8 are each independently CR 5 is.

[0189] In other embodiments, Q 5 , Q 6 , Q 7 , Q 8 , or Q 9 Two of them are N, and the rest are independently CR 5 is.

[0190] In some embodiments, Q 5 and Q 6 is N and Q 7 , Q 8 , and Q 9 are each independently CR 5 is.

[0191] In some embodiments, Q 5 and Q 7 is N and Q 6 , Q 8 , and Q 9 are each independently CR 5 is.

[0192] In some embodiments, Q 5 and Q 8 is N and Q 6 , Q 7 , and Q 9 are each independently CR 5 is.

[0193] In some embodiments, Q 5 and Q 9 is N and Q6 , Q 7 , and Q 8 are each independently CR 5 is.

[0194] In some embodiments, Q 6 and Q 7 is N and Q 5 , Q 8 , and Q 9 are each independently CR 5 is.

[0195] In some embodiments, Q 6 and Q 8 is N and Q 5 , Q 7 , and Q 9 are each independently CR 5 is.

[0196] In some embodiments, Q 6 and Q 9 is N and Q 5 , Q 7 , and Q 8 are each independently CR 5 is.

[0197] In some embodiments, Q 7 and Q 8 N and Q 5 , Q 6 , and Q 9 are each independently CR 5 is.

[0198] In some embodiments, Q 7 and Q 9 is N and Q 5 , Q 6 , and Q 8 are each independently CR 5 is.

[0199] In some embodiments, Q 8 and Q 9 is N and Q 5 , Q 6 , and Q 7are each independently CR 5 is.

[0200] In some embodiments of the present disclosure, each R of the compound of formula (I) 5 is independently H, halogen, C1-C3 alkyl, C1-C3 alkoxyl, or cycloalkyl. In some embodiments of the present disclosure, each R 5 are independently H, halogen, substituted C1-C3 alkyl, substituted C1-C3 alkoxyl, or substituted cycloalkyl.

[0201] In some embodiments of the compounds of Formula (I), R 5 is H.

[0202] In some embodiments of the compounds of Formula (I), R 5 is a halogen, for example, —F, —Cl, —Br, or —I.

[0203] In some embodiments, at least one R 5 is -Cl.

[0204] In some embodiments of the compounds of Formula (I), R 5 is C1-C3 alkyl, e.g., C1-C3 alkyl, C1-C2 alkyl, C1 alkyl, C2 alkyl, C3 alkyl, -CH3, -CH2CH3, -propyl, etc. In some embodiments, R 5 is -CH3.

[0205] In some embodiments of the compounds of Formula (I), R 5 is C1-C3 alkoxyl, for example, C1-C3 alkoxyl, C1-C2 alkoxyl, C1 alkoxyl, C2 alkoxyl, C3 alkoxyl, -OCH3, -OCH2CH3, -propoxyl, etc. In some embodiments, R 5 is -OCH3.

[0206] In some embodiments of the compounds of Formula (I), R 5is cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

[0207] In some embodiments of the compounds of Formula (I), two R 5 are halogens, and the remaining R 5 is H.

[0208] In other embodiments of the compounds of Formula (I), two R 5 is -Cl, and the remaining R 5 is H.

[0209] In some embodiments of the compounds of Formula (I), Q 5 and Q 9 are each independently CR 5 and each R 5 is a halogen and Q 6 and Q 8 are each independently CR 5 and R 5 is H and Q 7 is N.

[0210] In some embodiments of the compounds of Formula (I), Q 5 , Q 8 , and Q 9 are each independently CR 5 and each R 5 is a halogen and Q 6 is CR 5 and R 5 is H and Q 7 is N.

[0211] In some embodiments of the compounds of Formula (I), Q 5 and Q 9 are each independently CR 5 and each R 5 is -Cl, and Q 6 and Q 8 are each independently CR 5 and R 5 is H and Q 7 is N.

[0212] In some embodiments of the compounds of Formula (I), Q 5 and Q 9 are each independently CR 5 and each R 5 is -Cl, and Q 6 is CR 5 and R 5 is H and Q 8 is CR 5 and R 5 is -F and Q 7 is N.

[0213] In some embodiments of the compounds of Formula (I), Q 5 and Q 9 are each independently CR 5 and each R 5 is a halogen and Q 6 is CR 5 and R 5 is H and Q 8 is CR 5 and R 5 is C1-C3 alkyl, and Q 7 is N.

[0214] In some embodiments of the compounds of Formula (I), Q 5 and Q 9 are each independently CR 5 and each R 5 is -Cl, and Q 6 is CR 5 and R 5 is H and Q 8 is CR 5 and R 5 is -CH3 and Q 7 is N.

[0215] In some embodiments of the compounds of Formula (I), Q 5 and Q 9 are each independently CR 5 and each R 5 is a halogen and Q 6 is CR 5 and R 5 is H and Q 8 is N and Q7 is CR 5 and R 5 is H.

[0216] In some embodiments of the compounds of Formula (I), Q 5 and Q 9 are each independently CR 5 and each R 5 is -Cl, and Q 6 is CR 5 and R 5 is H and Q 8 is N and Q 7 is CR 5 and R 5 is H.

[0217] In some embodiments of the compounds of Formula (I), Q 5 and Q 9 are each independently CR 5 and each R 5 is a halogen and Q 6 is CR 5 and R 5 is H and Q 8 is N and Q 7 is N.

[0218] In some embodiments of the compounds of Formula (I), Q 5 and Q 9 are each independently CR 5 and each R 5 is -Cl, and Q 6 is CR 5 and R 5 is H and Q 8 is N and Q 7 is N.

[0219] In some embodiments of the compounds of Formula (I), Q 5 and Q 9 are each independently CR 5 and each R 5 is C1-C3 alkyl, and Q 6 is CR 5 and R 5 is H and Q 8is N and Q 7 is N.

[0220] In some embodiments of the compounds of Formula (I), Q 5 and Q 9 are each independently CR 5 and each R 5 is -CH3 and Q 6 is CR 5 and R 5 is H and Q 8 is N and Q 7 is N.

[0221] In some embodiments of the present disclosure, X in the compound of formula (I) is O, S, or NR, and R is H or C1-C3 alkyl.

[0222] In some embodiments of the compounds of Formula (I), X is O.

[0223] In some embodiments of the compounds of Formula (I), X is S.

[0224] In some embodiments of the compounds of Formula (I), X is NR and R is H or C1-C3 alkyl.

[0225] In some embodiments of the compounds of Formula (I), X is NR and R is H, i.e., X is NH.

[0226] In some embodiments of a compound of Formula (I), X is NR and R is C1-C3 alkyl, i.e., —N(C1-C3 alkyl)-, such as —N(C1-C3 alkyl)-, —N(C1-C2 alkyl)-, —N(C1 alkyl)-, —N(C2 alkyl)-, —N(C3 alkyl)-, —N(CH3)-, —N(CH2CH3)-, —N(CH2CH2CH3)-, etc.

[0227] In some embodiments of the present disclosure, R of the compound of formula (I) 6is C1 to C6 alkyl, for example, C1 to C6 alkyl, C1 to C5 alkyl, C1 to C4 alkyl, C1 to C3 alkyl, C1 to C2 alkyl, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentanyl, hexanyl, etc.

[0228] In some embodiments of the compounds of the present disclosure, R 6 is -CH3.

[0229] In some embodiments, R of the compound of formula (I) 7 is H, halogen, -C1-C6 alkyl, -C1-C6 alkoxyl, or -cycloalkyl.

[0230] In some embodiments, R of the compound of formula (I) 7 is H.

[0231] In some embodiments, R of the compound of formula (I) 7 is a halogen, for example, —F, —Cl, —Br, or —I.

[0232] In some embodiments, R of the compound of formula (I) 7 is -F.

[0233] In another embodiment, R of the compound of formula (I) 7 is -Cl.

[0234] In some embodiments, R of the compound of formula (I) 7 is -C1-C6 alkyl, for example, substituted or unsubstituted C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentanyl, hexanyl, etc. In some embodiments, R 7 is -CH3.

[0235] In some embodiments, R of the compound of formula (I) 7 is -C1-C6 alkoxyl, for example, -C1-C6 alkoxyl, -C1-C5 alkoxyl, -C1-C4 alkoxyl, -C1-C3 alkoxyl, -C1-C2 alkoxyl, -C1 alkoxyl, -C2 alkoxyl, -C3 alkoxyl, -C4 alkoxyl, -C5 alkoxyl, -C6 alkoxyl, -OCH3, -OCH2CH3, -propoxyl, etc. In some embodiments, R 7 is -OCH3.

[0236] In some embodiments, R of the compound of formula (I) 7 is cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

[0237] In some embodiments, R 8 is H, halogen, -C1-C6 alkyl, -C1-C6 alkoxyl, or -cycloalkyl.

[0238] In some embodiments, R of the compound of formula (I) 8 is H.

[0239] In some embodiments, R of the compound of formula (I) 8 is a halogen, for example, —F, —Cl, —Br, or —I.

[0240] In some embodiments, R of the compound of formula (I) 8 is -C1-C6 alkyl, for example, substituted or unsubstituted: C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentanyl, hexanyl, etc. In some embodiments, R 8 is -CH3.

[0241] In some embodiments, R of the compound of formula (I) 8 is -C1-C6 alkoxyl, for example, -C1-C6 alkoxyl, -C1-C5 alkoxyl, -C1-C4 alkoxyl, -C1-C3 alkoxyl, -C1-C2 alkoxyl, -C1 alkoxyl, -C2 alkoxyl, -C3 alkoxyl, -C4 alkoxyl, -C5 alkoxyl, -C6 alkoxyl, -OCH3, -OCH2CH3, -propoxyl, etc. In some embodiments, R 8 is -OCH3.

[0242] In some embodiments, R of the compound of formula (I) 8 is -cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

[0243] In some embodiments of the compounds of Formula (I), R 7 is -F and R 8 is H.

[0244] In some embodiments of the compounds of Formula (I), R 7 is -Cl, and R 8 is H.

[0245] In some embodiments of the compounds of Formula (I), R 7 is -CH3 and R 8 is H.

[0246] In some embodiments of the compounds of Formula (I), R 7 is -OCH3 and R 8 is H.

[0247] In some embodiments of the compounds of Formula (I), R 7 is -H and R 8 is -F.

[0248] In some embodiments of the compounds of Formula (I), R 7 is -H and R 8 is -Cl.

[0249] In some embodiments of the compounds of Formula (I), R 7 is -H and R 8 is -CH3.

[0250] In some embodiments of the compounds of Formula (I), R 7 is -H and R 8 is OCH3.

[0251] In some embodiments of the present disclosure, the compound of formula (I) is a compound of formula (IA):

[0252] [ka]

[0253] [In the formula, Q 1 , Q 2 , Q 3 , Q 4 one or two of which are N, and the remaining are each independently CR 5a and each R 5a are independently H, halogen, —CN, —C1-C3 alkyl, —C1-C3 haloalkyl, —C1-C3 alkoxyl, —SO2C1-C3 alkyl, —CH2—OH, —CH2—N(C1-C3 alkyl)2, or —CH2—NH(C1-C3 alkyl), and other variables are as described for formula (I).

[0254] In some embodiments of the present disclosure, the compound of formula (I) is a compound of formula (IA), 5a is —P(O)(C1-C6 alkyl)2, for example, may be —P(O)(CH3)2).

[0255] In some aspects of the present disclosure, the compound of formula (I) is a compound of formula (IA) 5a are independently H, halogen, —CN, or C1-C3 alkyl).

[0256] In some embodiments, Q 1 , Q 2 , Q3 , Q 4 One of them is N, and the rest are each independently CR 5a is.

[0257] In some embodiments, Q 1 is N and Q 2 , Q 3 , and Q 4 are each independently CR 5a is.

[0258] In some embodiments, Q 2 is N and Q 1 , Q 3 , and Q 4 are each independently CR 5a is.

[0259] In some embodiments, Q 3 is N and Q 1 , Q 2 , and Q 4 are each independently CR 5a is.

[0260] In some embodiments, Q 4 is N and Q 1 , Q 2 , and Q 3 are each independently CR 5a is.

[0261] In other embodiments, Q 1 , Q 2 , Q 3 , Q 4 Two of them are N, and the rest are independently CR 5a is.

[0262] In some embodiments, Q 1 and Q 2 is N and Q 3 , and Q 4 are each independently CR 5a is.

[0263] In some embodiments, Q 1 and Q3 is N and Q 2 and Q 4 are each independently CR 5a is.

[0264] In some embodiments, Q 1 and Q 4 is N and Q 2 and Q 3 are each independently CR 5a is.

[0265] In some embodiments, Q 2 and Q 3 is N and Q 1 and Q 4 are each independently CR 5a is.

[0266] In some embodiments, Q 2 and Q 4 is N and Q 1 and Q 3 are each independently CR 5a is.

[0267] In some embodiments, Q 3 and Q 4 is N and Q 1 and Q 2 are each independently CR 5a is.

[0268] In some embodiments of compounds of Formula (IA), each R 5a are independently H, halogen, —CN, or C1-C3 alkyl.

[0269] In another embodiment of the compound of formula (IA), each R 5a is H, halogen, —CN, C1-C3 alkyl, —C1-C3 haloalkyl, —C1-C3 alkoxyl, —SO2C1-C3 alkyl, —CH2—N(C1-C3 alkyl)2, or —CH2—NH(C1-C3 alkyl).

[0270] In some embodiments of the compounds of Formula (IA), R 5ais H.

[0271] In some embodiments of the compounds of Formula (IA), R 5a is a halogen, i.e., —F, —Cl, —Br, or —I.

[0272] In some embodiments of the compound of Formula (IA), at least one R 5a is -F.

[0273] In some embodiments of the compounds of Formula (IA), R 5a is -CN.

[0274] In some embodiments of the compounds of Formula (IA), R 5a is C1-C3 alkyl, for example, C1-C3 alkyl, C1-C2 alkyl, C1 alkyl, C2 alkyl, C3 alkyl, -CH3, -CH2CH3, -propyl, etc. In some embodiments, R 5a is -CH3.

[0275] In some embodiments of the compounds of Formula (IA), R 5a is C1-C3 haloalkyl, for example, C1-C3 haloalkyl, C1-C2 haloalkyl, C1 haloalkyl, C2 haloalkyl, C3 haloalkyl, -CF3, -CH2CF3, etc. In some embodiments, R 5a is -CF3.

[0276] In some embodiments of the compounds of Formula (IA), R 5a is -C1-C3 alkoxyl, for example, -C3 alkoxyl, -C2 alkoxyl, or -C1 alkoxyl, -OCH2CH3, -OCH3, etc. In some embodiments, R 5a is -OCH3.

[0277] In some embodiments of the compounds of Formula (IA), R 5a is -SO2C1-C3 alkyl, e.g., -SO2C1 alkyl, -SO2C2 alkyl, -SO2C3 alkyl, -SO2CH2CH3, -SO2CH3, etc. In some embodiments, R 5ais -SO2CH3.

[0278] In some embodiments of the compounds of Formula (IA), R 5a is -CH2-N(C1-C3 alkyl)2, e.g., -CH2-N(C3 alkyl)2, -CH2-N(C2 alkyl)2, -CH2-N(C1 alkyl)2, -CH2-N(C3 alkyl)(C1 alkyl), -CH2-N(C2 alkyl)(C1 alkyl), -CH2-N(C3 alkyl)(C2 alkyl), -CH2-N(CH3)2, etc. In some embodiments, R 5a is -CH2-N(CH3)2.

[0279] In some embodiments of the compounds of Formula (IA), R 5a is —CH—NH(C1-C3 alkyl), for example, —CH—NH(C3 alkyl), —CH—NH(C2 alkyl), —CH—NH(C1 alkyl), —CH—NH(CH3), etc. In some embodiments, R 5a is -CH2-NH(CH3).

[0280] In some embodiments of the compound of Formula (IA), X is O.

[0281] In some embodiments of the present disclosure, the compound of formula (IA) is a compound of formula (IA-1):

[0282] [ka]

[0283] wherein the variables have the values ​​described above for formulas (I) and (IA).

[0284] In some embodiments of the compound of Formula (IA-1), R 6 is -CH3.

[0285] In some embodiments of the compound of formula (IA-1), Q 3 is CR 5a is.

[0286] In some embodiments of the compound of Formula (IA-1), at least one R 5a is a halogen.

[0287] In some embodiments of the compound of Formula (IA-1), at least one R 5a is -F.

[0288] In some embodiments of the present disclosure, the compound of formula (IA) is a compound of formula (IA-2):

[0289] [ka]

[0290] wherein the variables have the values ​​described above for formulas (I) and (IA).

[0291] In some embodiments of compounds of formula (IA-2), n is 2 and m is 2.

[0292] In some embodiments of compounds of formula (IA-2), n is 1 and m is 1.

[0293] In some embodiments of compounds of formula (IA-2), n is 1 and m is 2.

[0294] In some embodiments of compounds of formula (IA-2), n is 3 and m is 2.

[0295] In some embodiments of the present disclosure, the compound of formula (IA-2) is a compound of formula (IA-3):

[0296] [ka]

[0297] wherein the variables have the values ​​described above for formula (IA-2).

[0298] In some embodiments of compounds of Formula (IA-3), each R 1 and each R 2 is independently H or optionally substituted C1-C6 alkyl.

[0299] In some embodiments of compounds of Formula (IA-3), each R 1 and each R 2 is H.

[0300] In some embodiments of compounds of Formula (IA-3), each R 1 and each R 2 are independently optionally substituted C1-C6 alkyl, for example, optionally substituted C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentanyl, hexanyl, and the like.

[0301] In some embodiments of the compound of Formula (IA-3), at least one R 1 is H and at least one R 2 is an optionally substituted C1-C6 alkyl.

[0302] In some embodiments of the compound of Formula (IA-3), at least one R 1 is an optionally substituted C1-C6 alkyl, and at least one R 2 is H.

[0303] In some embodiments of compounds of Formula (IA-3), each R 1 is H and one R 2 is an optionally substituted C1-C6 alkyl.

[0304] In some embodiments of compounds of Formula (IA-3), one R 1 is an optionally substituted C1-C6 alkyl, and each R 2is H.

[0305] In some embodiments of compounds of Formula (IA-3), each R 1 is H, and two R bonded to the same carbon atom 2 The groups, together with the carbon atoms to which they are both attached, form a 3- to 7-membered spirocycloalkyl ring, for example, a 3-membered spirocycloalkyl ring, a 4-membered spirocycloalkyl ring, a 5-membered spirocycloalkyl ring, a 6-membered spirocycloalkyl ring, a 7-membered spirocycloalkyl ring, a spirocyclopropyl ring, a spirocyclobutyl ring, a spirocyclopentyl ring, a spirocyclohexyl ring, or a spirocycloheptyl ring.

[0306] In some embodiments of compounds of Formula (IA-3), each R 1 is H, and two R bonded to the same carbon atom 2 The groups, together with the carbon atoms to which they are both attached, form a 3-membered spirocycloalkyl ring, for example a spirocyclopropyl ring.

[0307] In some embodiments of compounds of formula (IA-3), one R 1 group and one of R 2 The groups are joined to form a 6- to 9-membered bridged bicyclic ring, and the other R 1 is H, and the other R 2 is H. In such embodiments, the 6-9 membered bridged bicyclic ring is a 6 membered bridged bicyclic ring, a 7 membered bridged bicyclic ring, an 8 membered bridged bicyclic ring, or a 9 membered bridged bicyclic ring. In some embodiments, the 6-9 membered bridged bicyclic ring is a 7 membered bridged bicyclic ring.

[0308] In some embodiments of compounds of Formula (IA-3), each R 1 is H, and two R bonded to the same carbon atom 2 The group together with its carbon atom represents a carbonyl group (C=O).

[0309] In some embodiments of the present disclosure, the compound of formula (IA-2) is a compound of formula (IA-4):

[0310] [ka]

[0311] wherein the variables have the values ​​described above for formula (IA-2).

[0312] In some embodiments of the compound of formula (IA-4), two R 2 The group together with its carbon atom represents a carbonyl group (C=O).

[0313] In some embodiments of the present disclosure, the compound of formula (IA-2) is a compound of formula (IA-5):

[0314] [ka]

[0315] wherein the variables have the values ​​described above for formula (IA-2).

[0316] In some embodiments of compounds of Formula (IA-5), each R 1 and each R 2 are independently H or optionally substituted C1-C6 alkyl, for example, optionally substituted C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentanyl, hexanyl, and the like.

[0317] In some embodiments of compounds of Formula (IA-5), each R 1 and each R 2 is H.

[0318] In some embodiments of compounds of Formula (IA-5), each R 1 is H, and two R bonded to the same carbon atom2 The groups, together with the carbon atoms to which they are both attached, form a 3- to 7-membered spirocycloalkyl ring, for example, a 3-membered spirocycloalkyl ring, a 4-membered spirocycloalkyl ring, a 5-membered spirocycloalkyl ring, a 6-membered spirocycloalkyl ring, a 7-membered spirocycloalkyl ring, a spirocyclopropyl ring, a spirocyclobutyl ring, a spirocyclopentyl ring, a spirocyclohexyl ring, or a spirocycloheptyl ring.

[0319] In some embodiments of compounds of Formula (IA-5), the 3-7 membered spirocycloalkyl ring is a 3 membered spirocycloalkyl ring.

[0320] In some embodiments of compounds of Formula (IA-5), one R 1 group and one of R 2 groups are linked to form a 6- to 9-membered bridged bicyclic ring, and the other R 1 is H, and the other R 2 is H. In such embodiments, the 6-9 membered bridged bicyclic ring is a 6 membered bridged bicyclic ring, a 7 membered bridged bicyclic ring, an 8 membered bridged bicyclic ring, or a 9 membered bridged bicyclic ring. In some embodiments, the 6-9 membered bridged bicyclic ring is a 7 membered bridged bicyclic ring.

[0321] In some embodiments of the present disclosure, the compound of formula (I) is a compound of formula (IA-8):

[0322] [ka]

[0323] [In the formula, R 9 is —C1-C6 alkyl, —C1-C6 haloalkyl, —C(O)C1-C6 haloalkyl, —C(O)OC1-C6 alkyl, —C(O)C1-C6 alkyl, —C(O)N(C1-C6 alkyl)2, or —SO2-C1-C6 alkyl, and the other variables have the values ​​described above for formula (I).

[0324] In some embodiments of compounds of formula (IA-8), R 9is -CH2CF3, -CH2CHF2, -C(O)CF3, -C(O)OCH3, -C(O)OCH2CH3, -SO2CH2CH3, -SO2CH(CH3)2, -CH3, -CH(CH3)2, -C(O)N(CH3)2, or -SO2CH3.

[0325] In some embodiments of compounds of formula (IA-8), R 7 and R 8 are H respectively.

[0326] In some embodiments of compounds of Formula (IA-8), each R 1 and each R 2 is H.

[0327] In some embodiments of the compound of formula (IA-8), Q 1 , Q 2 , Q 3 , Q 4 One of them is N, and the rest are each independently CR 5a is.

[0328] In some embodiments of the compound of formula (IA-8), Q 4 is N and Q 1 , Q 2 , Q 3 are each independently CR 5a is.

[0329] In other embodiments of the compound of formula (IA-8), Q 1 , Q 2 , Q 3 , Q 4 Two of them are N, and the rest are independently CR 5a is.

[0330] In other embodiments of the compound of formula (IA-8), Q 2 and Q 4 is N and Q 1 and Q 3 are each independently CR 5a is.

[0331] In some embodiments of the compound of formula (IA-8), Q 5 , Q 6 , Q 7 , Q 8 , or Q 9 One of them is N, and the rest are each independently CR 5 is.

[0332] In some embodiments of the compound of formula (IA-8), Q 7 is N and Q 5 , Q 6 , Q 8 , and Q 9 are each independently CR 5 is.

[0333] In some embodiments of the compound of formula (IA-8), Q 5 , Q 6 , Q 7 , Q 8 , or Q 9 Two of them are N, and the rest are independently CR 5 is.

[0334] In some embodiments, Q 6 and Q 7 is N and Q 5 , Q 8 , and Q 9 are each independently CR 5 is.

[0335] In some embodiments of the present disclosure, the compound of formula (IA-2) is a compound of formula (IA-6):

[0336] [ka]

[0337] wherein the variables have the values ​​described above for formula (IA-2).

[0338] In some embodiments of the compound of formula (IA-6), two R 1The group together with its carbon atom represents a carbonyl group (C=O).

[0339] In some embodiments of the compound of formula (IA-6), two R 2 The groups, together with the carbon atoms to which they are both attached, form an optionally substituted 3- to 7-membered spirocycloalkyl ring or an optionally substituted 3- to 7-membered spiroheterocycloalkyl ring.

[0340] In some embodiments of the compound of formula (IA-6), two R 2 The groups, together with the carbon atoms to which they are both attached, form an optionally substituted 3- to 7-membered spiroheterocycloalkyl ring, such as an optionally substituted 3-membered spiroheterocycloalkyl ring, an optionally substituted 4-membered spiroheterocycloalkyl ring, an optionally substituted 5-membered spiroheterocycloalkyl ring, an optionally substituted 6-membered spiroheterocycloalkyl ring, an optionally substituted 7-membered spiroheterocycloalkyl ring, an optionally substituted spiroaziridinyl ring, an optionally substituted spiroazetidinyl ring, an optionally substituted spiropyrrolidinyl ring, an optionally substituted spiropiperidinyl ring, an optionally substituted spiroazepanyl ring, an optionally substituted spirooxiranyl ring, an optionally substituted spirooxetanyl ring, an optionally substituted spirotetrahydrofuranyl ring, an optionally substituted spirotetrahydropyranyl ring, an optionally substituted spirooxepanyl ring, etc.

[0341] In some embodiments of compounds of Formula (IA-6), the optionally substituted 3- to 7-membered spiroheterocycloalkyl ring is an optionally substituted spiroazetinyl ring, an optionally substituted spiropyrrolidinyl ring, or an optionally substituted spiropiperidinyl ring.

[0342] In some embodiments of compounds of Formula (IA-6), the optionally substituted 3- to 7-membered spiroheterocycloalkyl ring is a spiroazetinyl ring, a spiropyrrolidinyl ring, a spiropiperidinyl ring, an N-methylspiropiperidinyl ring, or an N-(methylsulfonyl)spiropiperidinyl ring.

[0343] In some embodiments of the present disclosure, the compound of formula (IA-2) is a compound of formula (IA-7):

[0344] [ka]

[0345] wherein the variables have the values ​​described above for formula (IA-2).

[0346] In some embodiments of compounds of Formula (IA-7), each R 1 is H.

[0347] In some embodiments of the compound of formula (IA-7), two R 1 The group together with its carbon atom represents a carbonyl group (C=O).

[0348] In some embodiments of compounds of Formula (IA-7), each R 2 is H.

[0349] In some embodiments of the compound of formula (IA-7), two R 2 The group together with its carbon atom represents a carbonyl group (C=O).

[0350] In some aspects of the present disclosure, compounds of formula (IA) (and subgenera IA-1, IA-2, IA-3, IA-4, IA-5, IA-6, IA-7) are 2 In another aspect of the disclosure, compounds of formula (IA) (and subgenus IA-8) are compounds where Q 2 is a compound in which N

[0351] In some aspects of the present disclosure, compounds of formula (IA) (and subgenera IA-1, IA-2, IA-3, IA-4, IA-5, IA-6, IA-7) are 4 In another aspect of the disclosure, compounds of formula (IA) (and subgenus IA-8) are compounds where Q 4 is a compound in which N

[0352] In some aspects of the present disclosure, the compound of formula (IA) is 2 and Q 4 are compounds in which both are N.

[0353] In some aspects of the present disclosure, the compound of formula (IA) is 4 is CR 5a It is a compound in which

[0354] Q 4 is CR 5a In some embodiments, R 5a is H.

[0355] Q 4 is CR 5a In some embodiments, R 5a is a halogen.

[0356] Q 4 is CR 5a In some embodiments, R 5a is -F.

[0357] In some embodiments of the compound of Formula (IA), Q 2 is N and Q 4 is CR 5a and R 5a is -F.

[0358] In some aspects of the disclosure, the compound of formula (I) is a compound of formula (IB):

[0359] [ka]

[0360] wherein the variables have the values ​​described above for formula (I).

[0361] In some embodiments of the present disclosure, the compound of formula (IB) is a compound of formula (IB-1):

[0362] [ka]

[0363] wherein the variables have the values ​​described above for formula (I).

[0364] In some embodiments of the present disclosure, the compound of formula (IB-1) is a compound of formula (IB-2):

[0365] [ka]

[0366] wherein the variables have the values ​​described above for formula (I).

[0367] In some embodiments of compounds of Formula (IB), (IB-1), and (IB-2), n=2 and m=2.

[0368] In other embodiments of compounds of formula (IB), (IB-1), and (IB-2), n=1 and m=1.

[0369] In some embodiments of compounds of Formula (IB), (IB-1), and (IB-2), n=1 and m=2.

[0370] In other embodiments of compounds of formula (IB), (IB-1), and (IB-2), n=3 and m=2.

[0371] In some embodiments of compounds of Formula (IB), (IB-1), and (IB-2), each R 1 is H, and each R 2is H.

[0372] In some embodiments, A in the compounds of formula (I) is N or CH.

[0373] In some embodiments of the compounds of Formula (I), A is N.

[0374] In some embodiments of the compounds of Formula (I), A is CH.

[0375] In some embodiments, Z in the compound of formula (I) is S(O)2;S(O);O;NR 3 ; or CR 4 R 4' is.

[0376] In some embodiments of the compounds of Formula (I), Z is S(O)2.

[0377] In some embodiments of the compounds of Formula (I), Z is S(O).

[0378] In some embodiments of the compounds of Formula (I), Z is O.

[0379] In some embodiments of the compounds of Formula (I), Z is NR 3 is.

[0380] Z is NR 3 In some embodiments of compounds of Formula (I), R 3 is H.

[0381] Z is NR 3 In other embodiments of compounds of Formula (I), R 3 is -C(O)NR a R b is.

[0382] Z is NR 3 In other embodiments of compounds of Formula (I), R 3 is -S(O)2NR a R b is.

[0383] R 3 -C(O)NR a R b or -S(O)NR a R b In some embodiments of compounds of Formula (I), R a is H and R b is H.

[0384] In some embodiments of the compounds of Formula (I), R 3 is -C(O)NH2.

[0385] R 3 -C(O)NR a R b or -S(O)NR a R b In some embodiments of compounds of Formula (I), R a is H and R b is C1 to C6 alkyl, for example, C1 to C6 alkyl, C1 to C5 alkyl, C1 to C4 alkyl, C1 to C3 alkyl, C1 to C2 alkyl, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentanyl, hexanyl, etc.

[0386] R 3 -C(O)NR a R b or -S(O)NR a R b In some embodiments of compounds of Formula (I), R a is C1 to C6 alkyl, for example, C1 to C6 alkyl, C1 to C5 alkyl, C1 to C4 alkyl, C1 to C3 alkyl, C1 to C2 alkyl, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentanyl, hexanyl, etc., and R bis C1 to C6 alkyl, for example, C1 to C6 alkyl, C1 to C5 alkyl, C1 to C4 alkyl, C1 to C3 alkyl, C1 to C2 alkyl, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentanyl, hexanyl, etc.

[0387] In some embodiments of the compounds of Formula (I), R 3 is -C(O)N(CH3)2.

[0388] R 3 -C(O)NR a R b or -S(O)NR a R b In some embodiments of compounds of Formula (I), R a and R b taken together with the N atom to which they are both attached form an optionally substituted 3- to 7-membered heterocycloalkyl ring, e.g., an optionally substituted 3-membered heterocycloalkyl, an optionally substituted 4-membered heterocycloalkyl, an optionally substituted 5-membered heterocycloalkyl, an optionally substituted 6-membered heterocycloalkyl, or an optionally substituted 7-membered heterocycloalkyl.

[0389] In some embodiments of compounds of Formula (I), the optionally substituted 3- to 7-membered heterocycloalkyl ring is an optionally substituted piperidinyl, an optionally substituted piperazinyl, or an optionally substituted morpholinyl ring.

[0390] In some embodiments of compounds of Formula (I), the optionally substituted 3- to 7-membered heterocycloalkyl ring is a 4-methylpiperazin-1-yl, or morpholinyl ring.

[0391] R 3 -C(O)NR a R bIn some embodiments of compounds of Formula (I), R 3 teeth

[0392] [ka]

[0393] is.

[0394] R 3 -S(O)NR a R b In some embodiments of compounds of Formula (I), R 3 teeth,

[0395] [ka]

[0396] is.

[0397] Z is NR 3 In some embodiments of compounds of Formula (I), R 3 -C(O)OR c is.

[0398] Z is NR 3 In some embodiments of compounds of Formula (I), R 3 -C(O)R c is.

[0399] Z is NR 3 In some embodiments of compounds of Formula (I), R 3 -S(O)2R c is.

[0400] Z is NR 3 and R 3 -C(O)OR c , -C(O)R c , or -S(O)R c In some embodiments of compounds of Formula (I), R cis optionally substituted C1-C6 alkyl or 3- to 7-membered cycloalkyl.

[0401] In some embodiments of the compounds of Formula (I), R c is optionally substituted C1-C6 alkyl, for example, optionally substituted C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentanyl, hexanyl, and the like.

[0402] In some embodiments of the compounds of Formula (I), R c is methyl, i.e., -CH3.

[0403] In some embodiments of the compounds of Formula (I), R c is (C1-C6 alkyl)2N-methyl, i.e., —CH2N(C1-C6 alkyl)2.

[0404] In some embodiments of the compounds of Formula (I), R c is (dimethylamino)methyl, i.e., —CHN(CH)

[0405] In some embodiments of the compounds of Formula (I), R c is ethyl.

[0406] In some embodiments of the compounds of Formula (I), R c is (C1-C6 alkyl)2N-ethyl, i.e., —CH2CH2N(C1-C6 alkyl)2.

[0407] In some embodiments of the compounds of Formula (I), R c is (dimethylamino)ethyl, i.e., —CH2CH2N(CH3)2.

[0408] Z is NR 3In some embodiments of compounds of Formula (I), R 3 is —C(O)OCH3, —C(O)CH3, or —S(O)2CH3.

[0409] Z is NR 3 In some embodiments of compounds of Formula (I), R 3 is -C(O)OCH3.

[0410] Z is NR 3 In some embodiments of compounds of Formula (I), R 3 is -C(O)CH3.

[0411] Z is NR 3 In some embodiments of compounds of Formula (I), R 3 is -C(O)CH2N(CH3)2.

[0412] Z is NR 3 In some embodiments of compounds of Formula (I), R 3 is -C(O)CH2CH2N(CH3)2.

[0413] Z is NR 3 In some embodiments of compounds of Formula (I), R 3 is -S(O)2CH3.

[0414] In other embodiments of the compounds of Formula (I), R c is -CH2CH3.

[0415] Z is NR 3 In some embodiments of compounds of Formula (I), R 3 is —C(O)OCH2CH3, —C(O)CH2CH3, or —S(O)2CH2CH3.

[0416] Z is NR 3 In some embodiments of compounds of Formula (I), R 3 is -C(O)OCH2CH3.

[0417] Z is NR 3In some embodiments of compounds of Formula (I), R 3 is -C(O)CH2CH3.

[0418] Z is NR 3 In some embodiments of compounds of Formula (I), R 3 is -S(O)2CH2CH3.

[0419] In some embodiments of the compounds of Formula (I), R c is a 3- to 7-membered cycloalkyl, for example, a 3-membered cycloalkyl, a 4-membered cycloalkyl, a 5-membered cycloalkyl, a 6-membered cycloalkyl, or a 7-membered cycloalkyl.

[0420] Z is NR 3 In some embodiments of compounds of Formula (I), R 3 is optionally substituted C1-C6 alkyl, for example, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentanyl, hexanyl, etc.

[0421] Z is NR 3 and R 3 In some embodiments of compounds of Formula (I) where is optionally substituted C1-C6 alkyl, C1-C6 alkyl is -CH3.

[0422] Z is NR 3 and R 3 In some embodiments of compounds of Formula (I) where is optionally substituted C1-C6 alkyl, C1-C6 alkyl is -CH2CH3.

[0423] Z is NR 3 and R 3 In other embodiments of compounds of Formula (I) where is optionally substituted C1-C6 alkyl, C1-C6 alkyl is -CH(CH3)2.

[0424] Z is NR 3 and R 3 In other embodiments of compounds of Formula (I) where is optionally substituted C1-C6 alkyl, the optionally substituted C1-C6 alkyl is 2-hydroxyethyl, ie, -CH2CH2OH.

[0425] Z is NR 3 and R 3 In other embodiments of compounds of Formula (I) where is optionally substituted C1-C6 alkyl, the optionally substituted C1-C6 alkyl is -CH2C(CH3)2OH.

[0426] Z is NR 3 In some embodiments of compounds of Formula (I), R 3 is a 3- to 5-membered cycloalkyl, for example, a 3-membered cycloalkyl, a 4-membered cycloalkyl, or a 5-membered cycloalkyl.

[0427] Z is NR 3 and R 3 In some embodiments of compounds of Formula (I) where is a 3- to 5-membered cycloalkyl, the 3- to 5-membered cycloalkyl is cyclobutyl.

[0428] Z is NR 3 In some embodiments of compounds of Formula (I), R 3 is a 3- to 5-membered heterocycloalkyl, for example, a 3-membered heterocycloalkyl, a 4-membered heterocycloalkyl, or a 5-membered heterocycloalkyl.

[0429] Z is NR 3 and R 3 In some embodiments of compounds of Formula (I) where is a 3-5 membered heterocycloalkyl, the 3-5 membered heterocycloalkyl is oxetanyl,

[0430] [ka]

[0431] is.

[0432] In some embodiments of the compounds of Formula (I), Z is CR 4 R 4' is.

[0433] Z is CR 4 R 4' In some embodiments of compounds of Formula (I), R 4 and R 4' are H respectively.

[0434] Z is CR 4 R 4' In some embodiments of compounds of Formula (I), R 4 and R 4' are each optionally substituted C1-C6 alkyl, for example, optionally substituted C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentanyl, hexanyl, etc.

[0435] Z is CR 4 R 4' In some embodiments of compounds of Formula (I), R 4 is H and R 4' is OH.

[0436] Z is CR 4 R 4' In some embodiments of compounds of Formula (I), R 4 and R 4'together with the carbon atoms to which they are both attached form an optionally substituted 3- to 7-membered heterocycloalkyl ring, e.g., an optionally substituted 3-membered heterocycloalkyl ring, an optionally substituted 4-membered heterocycloalkyl ring, an optionally substituted 5-membered heterocycloalkyl ring, an optionally substituted 6-membered heterocycloalkyl ring, or an optionally substituted 7-membered heterocycloalkyl ring.

[0437] In some embodiments of compounds of Formula (I), the optionally substituted 3- to 7-membered heterocycloalkyl ring is an optionally substituted 4-membered heterocycloalkyl ring.

[0438] In some embodiments of the compounds of Formula (I), the optionally substituted 4-membered heterocycloalkyl ring is an azetidinyl ring.

[0439] Z is CR 4 R 4' and R 4 and R 4' are taken together with the carbon atoms to which they are attached to form an optionally substituted azetidinyl ring, the azetidinyl ring is unsubstituted, i.e.,

[0440] [ka]

[0441] is.

[0442] Z is CR 4 R 4' and R 4 and R 4' are taken together with the carbon atom to which they are attached to form an optionally substituted azetidinyl ring, the azetidinyl ring is

[0443] [ka]

[0444] is.

[0445] Z is CR 4 R 4' and R 4 and R 4' In other embodiments of compounds of formula (I) where both, together with the carbon atoms to which they are attached, form an optionally substituted azetidinyl ring, the azetidinyl ring may be N-substituted.

[0446] Z is CR 4 R 4' and R 4 and R 4' In some embodiments of compounds of Formula (I) where both of these, together with the carbon atoms to which they are attached, form an N-substituted azetidinyl ring, the N substituent is -C1-C6 alkyl, -C1-C6 haloalkyl, -C(O)C1-C6 haloalkyl, -C(O)OC1-C6 alkyl, -C(O)C1-C6 alkyl, -C(O)N(C1-C6 alkyl)2, or -SO2-C1-C6 alkyl.

[0447] Z is CR 4 R 4' and R 4 and R 4' In some embodiments of compounds of Formula (I) where both of these, together with the carbon atoms to which they are attached, form an N-substituted azetidinyl ring, the N substituent is -C1-C6 alkyl, -C(O)OC1-C6 alkyl, -C(O)C1-C6 alkyl, -C(O)N(C1-C6 alkyl)2, or -SO2-C1-C6 alkyl.

[0448] In some embodiments of compounds of Formula (I), the N substituent is —CH 3 , —CH(CH 3 ) 2 , —C(O)N(CH 3 ) 2 , or —SO 2 CH 3 , i.e.,

[0449] [ka]

[0450] is.

[0451] In other embodiments of compounds of Formula (I), the N substituent is —CH 2 CF 3 , —CH 2 CHF 2 , —C(O)CF 3 , —C(O)OCH 3 , —C(O)OCH 2 CH 3 , or —SO 2 CH 2 CH 3 , e.g.,

[0452] [ka]

[0453] is.

[0454] Z is CR 4 R 4' and R 4 and R 4' but taken together with the carbon atom to which they are attached to form an N-substituted azetidinyl ring, in some embodiments of compounds of Formula (I), the N-substituted azetidinyl ring is

[0455] [ka]

[0456] is.

[0457] Z is CR 4 R 4' and R 4 and R 4' In some embodiments of compounds of Formula (I) where both of these, together with the carbon atom to which they are attached, form an N-substituted azetidinyl ring, the N-substituent is —C(O)OCH2CH3, —SO2CH(CH3)2, or —SO2CH2CH3.

[0458] Z is CR 4 R 4' and R 4 and R 4' but taken together with the carbon atom to which they are attached to form an N-substituted azetidinyl ring, in some embodiments of compounds of Formula (I), the N-substituted azetidinyl ring is

[0459] [ka]

[0460] is.

[0461] Z is CR 4 R 4' In some embodiments of compounds of Formula (I), R 4 and R 4' taken together with the carbon atoms to which they are both attached form an optionally substituted thietane 1,1-dioxide ring.

[0462] In some embodiments of compounds of Formula (I), Z is:

[0463] [ka]

[0464] is.

[0465] Z is CR 4 R 4' and R 4 and R 4' are both taken together with the carbon atom to which they are attached to form an optionally substituted 4-membered heterocycloalkyl ring, the optionally substituted 4-membered heterocycloalkyl ring is preferably an optionally substituted oxetane ring, e.g.,

[0466] [ka]

[0467] is.

[0468] Z is CR 4 R 4' and R 4 and R 4'are taken together with the carbon atom to which they are attached to form an optionally substituted 3- to 7-membered heterocycloalkyl ring, the optionally substituted 3- to 7-membered heterocycloalkyl ring is an optionally substituted 5-membered heterocycloalkyl ring.

[0469] Z is CR 4 R 4' and R 4 and R 4' are taken together with the carbon atoms to which they are attached to form an optionally substituted 5-membered heterocycloalkyl ring, the optionally substituted 5-membered heterocycloalkyl ring is an unsubstituted pyrrolidinyl ring, an N-substituted pyrrolidinyl ring, an unsubstituted pyrrolidinyl-2-one ring, an N-substituted pyrrolidinyl-2-one ring, an unsubstituted pyrrolo-2,5-dione ring, an N-substituted pyrrolo-2,5-dione ring, an unsubstituted imidazolidinyl-2-one ring, an N-substituted imidazolidinyl-2-one ring, a tetrahydrofuranyl ring, or a tetrahydrothiophene-1,1-dioxide ring.

[0470] In some embodiments of the compounds of Formula (I), the N substituent is -C1-C6 alkyl, for example, -CH3.

[0471] In some embodiments, the N substituent is —C1-C6 alkyl, —C(O)OC1-C6 alkyl, —C(O)C1-C6 alkyl, —C(O)N(C1-C6 alkyl)2, or —SO2—C1-C6 alkyl.

[0472] In some embodiments, the N substituent is -C(O)OCi-C6 alkyl, such as -C(O)OCH3, -C(O)OCH2CH3, -C(O)OCH(CH3)2, or -SO2Ci-C6 alkyl, such as -SO2CH3.

[0473] In some embodiments of the compounds of Formula (I), Z is

[0474] [ka]

[0475] is.

[0476] In other embodiments of the compounds of Formula (I), Z is

[0477] [ka]

[0478] is.

[0479] Z is CR 4 R 4' and R 4 and R 4' are both taken together with the carbon atom to which they are attached to form an optionally substituted 3- to 7-membered heterocycloalkyl ring, the optionally substituted 3- to 7-membered heterocycloalkyl ring is an optionally substituted 6-membered heterocycloalkyl ring.

[0480] In some embodiments of compounds of Formula (I), the optionally substituted 6-membered heterocycloalkyl ring is an unsubstituted piperidin-2-one ring or an N-substituted piperidin-2-one ring.

[0481] In some embodiments of the compounds of Formula (I), the N-substituent is —CH 3 .

[0482] In some embodiments of the compounds of Formula (I), Z is

[0483] [ka]

[0484] is.

[0485] In other embodiments of compounds of Formula (I), the optionally substituted 6-membered heterocycloalkyl ring is a substituted or unsubstituted piperidine ring, or a tetrahydro-2H-thiopyran 1,1-dioxide ring.

[0486] In some embodiments of compounds of Formula (I), the piperidine ring is N-substituted with -C(O)OCi-C6 alkyl, e.g., -C(O)OCH3, -C(O)OCH2CH3, -C(O)OCH(CH3)2, -Ci-C6 alkyl, -C(O)Ci-C6 alkyl, or -SO2Ci-C6 alkyl, e.g., -SO2CH3, -SO2CH2CH3.

[0487] In some embodiments of compounds of Formula (I), the piperidine ring is N-substituted with -C(O)OCi-C6 alkyl, e.g., -C(O)OCH3, -C(O)OCH2CH3, -C(O)OCH(CH3)2, -Ci-C6 alkyl, -C(O)Ci-C6 alkyl, or -SO2Ci-C6 alkyl, e.g., -SO2CH3.

[0488] In some embodiments of the compounds of Formula (I), Z is

[0489] [ka]

[0490] is.

[0491] In some embodiments of other compounds of Formula (I), Z is

[0492] [ka]

[0493] is.

[0494] Compound of formula (II) In some aspects, the present disclosure provides a compound of formula (II)

[0495] [ka]

[0496] or a pharmaceutically acceptable salt thereof wherein n=1, 2, or 3; m=1, 2, or 3; Each R 1 are independently H; or optionally substituted C1-C6 alkyl; Each R 2 are independently H; or optionally substituted C1-C6 alkyl; or two R attached to the same carbon atom 1 groups, taken together with the carbon atoms to which they are both attached, form an optionally substituted 3- to 7-membered spirocycloalkyl ring or an optionally substituted 3- to 7-membered spiroheterocycloalkyl ring, or or two R attached to the same carbon atom 1 The group together with its carbon atom represents a carbonyl group (C=O), or or two R attached to the same carbon atom 2 groups, taken together with the carbon atoms to which they are both attached, form an optionally substituted 3- to 7-membered spirocycloalkyl ring or an optionally substituted 3- to 7-membered spiroheterocycloalkyl ring, or or two R attached to the same carbon atom 2 The group together with its carbon atom represents a carbonyl group (C=O), or or two R attached to different carbon atoms 1 groups taken together with the carbon atom to which they are attached form a 3- to 7-membered cycloalkyl ring, or or two R attached to different carbon atoms 2 groups taken together with the carbon atom to which they are attached form a 3- to 7-membered cycloalkyl ring, or or R 1 Groups and R 2 the groups are joined to form a 6- to 9-membered bridged bicyclic ring; A=N or CH; Z = S(O)2; S(O); O, NR 3 or CR 4 R 4' and R 3 is H; optionally substituted -C1-C6 alkyl, 3- to 5-membered cycloalkyl, 3- to 5-membered heterocycloalkyl, -C(O)NR a R b ;-C(O)OR c ;-C(O)R c ;-S(O)2R c or -S(O)NR a R b and R a is H or C1-C6 alkyl, R b is H or C1-C6 alkyl, or R a and R b together with the N atom to which they are both attached form an optionally substituted 3- to 7-membered heterocycloalkyl ring; R c is an optionally substituted C1-C6 alkyl or cycloalkyl; R 4 is H or optionally substituted C1-C6 alkyl, R 4' is H, —OH, or optionally substituted C1-C6 alkyl; or R 4 and R 4' together with the C atom to which they are both attached form an optionally substituted 3- to 7-membered heterocycloalkyl ring, Y is a 5- or 6-membered heteroaryl ring; Q 5 , Q 6 , Q 7 , Q 8 , and Q 9 are each independently CR 5 and R 5is H, halogen, C1-C3 alkyl; C1-C3 alkoxyl, or cycloalkyl, X=O, S, or NR, where R is H or C1-C3 alkyl; R 6 is C1-C6 alkyl.

[0497] In some embodiments of the present disclosure, the compound of formula (II) is a compound of formula (IIA):

[0498] [ka]

[0499] [In the formula, Q 1 , Q 2 , Q 3 , Q 4 One or two of these are N and the rest are CR 5a and each R 5a are independently H, halogen, or C1-C3 alkyl, and other variables are as described for formula (II).

[0500] In some embodiments, the compound of formula (II) is a compound of formula (IIB):

[0501] [ka]

[0502] wherein the variables have the values ​​described above for formula (II).

[0503] In some embodiments of the compound of Formula (II), Q 6 and Q 8 are each independently 5 and each R 5 is a halogen and Q 5 , Q 7 , and Q 9 are each independently CR 5 and each R 5 is H.

[0504] In some embodiments of the compound of Formula (II), Q 6 and Q 8 are each independently CR 5 and each R 5 is -F and Q 5 , Q 7 , and Q 9 are each independently CR 5 and each R 5 is H.

[0505] In some embodiments of the compound of Formula (II), Q 5 and Q 9 are each independently CR 5 and each R 5 is a halogen and Q 6 , Q 7 , and Q 8 are each independently CR 5 and R 5 is H.

[0506] In some embodiments of the compound of Formula (II), Q 5 and Q 9 are each independently CR 5 and each R 5 is -Cl, and Q 6 , Q 7 , and Q 8 are each independently CR 5 and each R 5 is H.

[0507] In some aspects, the present disclosure is directed to the following compounds, or pharmaceutically acceptable salts thereof:

[0508] [ka]

[0509] In other aspects, the present disclosure is directed to the following compounds, or pharmaceutically acceptable salts thereof:

[0510] [Table 1A]

[0511] [Table 1B]

[0512] [Table 1C]

[0513] [Table 1D]

[0514] [Table 1E]

[0515] [Table 1F]

[0516] [Table 1G]

[0517] [Table 1H]

[0518] [Table 1I]

[0519] In other aspects, the present disclosure is directed to the following compounds, or pharmaceutically acceptable salts thereof:

[0520] [ka]

[0521] In some aspects, the present disclosure is directed to the compounds set forth in the examples below, or pharmaceutically acceptable salts thereof.

[0522] Reference herein to Formula (I) or Formula (II) or any subgenus thereof is intended to encompass the specified formula and all subgenuses of those formulas disclosed herein. For example, reference to Formula (I) also encompasses the subgenus Formulas IA, IA-1, IA-2, IA-3, IA-4, IA-5, IA-6, IA-7, IB, IB-1, and IB-2. Reference to Formula (I) also encompasses the subgenus Formula IA-8.

[0523] Stereoisomers of the compounds of Formula (I) or Formula (II) are also contemplated by the present disclosure. Thus, the present disclosure encompasses all stereoisomers and structural isomers of any compound disclosed or claimed herein, including all enantiomers and diastereomers, or mixtures thereof.

[0524] Pharmaceutically acceptable salts and solvates of the compounds of Formula (I) or Formula (II) are also within the scope of this disclosure.

[0525] It should be recognized that, for the sake of clarity, certain features of the invention that are described herein in the context of separate embodiments may also be provided in combination in a single embodiment. That is, unless clearly incompatible or specifically excluded, each individual embodiment is considered combinable with any other embodiment, and such combinations are considered to be separate embodiments. Conversely, various features of the invention that are described for the sake of brevity in the context of a single embodiment may also be provided separately or in any subcombination. While embodiments are described as part of a series of steps or as part of a more general structure, each such step may also be considered to be an independent embodiment in itself and combinable with other embodiments.

[0526] Pharmaceutical Compositions and Methods of Administration The subject pharmaceutical compositions are typically formulated to provide a therapeutically effective amount of a compound of the present disclosure as the active ingredient, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof. In some embodiments, the pharmaceutical compositions contain a compound of the present disclosure or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, carriers including inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers, and adjuvants.

[0527] The subject pharmaceutical compositions can be administered alone or in combination with one or more other drugs, which are also usually administered in the form of pharmaceutical compositions. If desired, one or more compounds of the present invention and the other drugs can be mixed together in a preparation, or both components can be formulated into separate preparations for use separately or in combination at the same time.

[0528] In some embodiments, the concentration of one or more compounds provided in the pharmaceutical compositions of the present invention is 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.1%. or less than 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% (or a number in a range defined by and including any two of the foregoing numbers) w / w, w / v, or v / v.

[0529] In some embodiments, the concentration of one or more compounds of the present invention is 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25%, 18%, 17.75%, 17.50%, 17.25%, 17%, 16.75%, 16.50%, 16.25%, 16%, 15.75%, 15.50%, 15.25%, 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%, 12.25%, 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25%, 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25%, 7%, 6.75%, 6.50%, 6.25%, 6%, 5.75%, 5.50%, 5.25%, 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 1.25%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0. 0.0001%, 0.0005%, 0.004%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% (or a number in a range defined by and including any two of the foregoing numbers) w / w, w / v, or v / v.

[0530] In some embodiments, the concentration of one or more compounds of the present invention is from about 0.0001% to about 50%, from about 0.001% to about 40%, from about 0.01% to about 30%, from about 0.02% to about 29%, from about 0.03% to about 28%, from about 0.04% to about 27%, from about 0.05% to about 26%, from about 0.06% to about 25%, from about 0.07% to about 24%, from about 0.08% to about The range is approximately 23%, approximately 0.09% to approximately 22%, approximately 0.1% to approximately 21%, approximately 0.2% to approximately 20%, approximately 0.3% to approximately 19%, approximately 0.4% to approximately 18%, approximately 0.5% to approximately 17%, approximately 0.6% to approximately 16%, approximately 0.7% to approximately 15%, approximately 0.8% to approximately 14%, approximately 0.9% to approximately 12%, approximately 1% to approximately 10% w / w, w / v or v / v.

[0531] In some embodiments, the concentration of one or more compounds of the invention is in the range of about 0.001% to about 10%, about 0.01% to about 5%, about 0.02% to about 4.5%, about 0.03% to about 4%, about 0.04% to about 3.5%, about 0.05% to about 3%, about 0.06% to about 2.5%, about 0.07% to about 2%, about 0.08% to about 1.5%, about 0.09% to about 1%, about 0.1% to about 0.9% w / w, w / v or v / v.

[0532] In some embodiments, the amount of one or more compounds of the present invention is 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.0 and is equal to or less than 8g, 0.07g, 0.06g, 0.05g, 0.04g, 0.03g, 0.02g, 0.01g, 0.009g, 0.008g, 0.007g, 0.006g, 0.005g, 0.004g, 0.003g, 0.002g, 0.001g, 0.0009g, 0.0008g, 0.0007g, 0.0006g, 0.0005g, 0.0004g, 0.0003g, 0.0002g, or 0.0001g (or a number in a range defined by and inclusive of any two of the foregoing numbers).

[0533] In some embodiments, the amount of one or more compounds of the present invention is 0.0001g, 0.0002g, 0.0003g, 0.0004g, 0.0005g, 0.0006g, 0.0007g, 0.0008g, 0.0009g, 0.001g, 0.0015g, 0.002g, 0.0025g, 0.003g, 0.003 5g, 0.004g, 0.0045g, 0.005g, 0.0055g, 0.006g, 0.0065g, 0.007g, 0.0075g, 0.008g, 0 .0085g, 0.009g, 0.0095g, 0.01g, 0.015g, 0.02g, 0.025g, 0.03g, 0.035g, 0.04g, 0.04 5g, 0.05g, 0.055g, 0.06g, 0.065g, 0.07g, 0.075g, 0.08g, 0.085g, 0.09g, 0.095g, 0.1 g, 0.15g, 0.2g, 0.25g, 0.3g, 0.35g, 0.4g, 0.45g, 0.5g, 0.55g, 0.6g, 0.65g, 0.7g, 0.7 More than 5g, 0.8g, 0.85g, 0.9g, 0.95g, 1g, 1.5g, 2g, 2.5g, 3g, 3.5g, 4g, 4.5g, 5g, 5.5g, 6g, 6.5g, 7g, 7.5g, 8g, 8.5g, 9g, 9.5g, or 10g (or a number in a range defined by and including any two of the above numbers).

[0534] In some embodiments, the amount of one or more compounds of the invention ranges from 0.0001 to 10 g, 0.0005 to 9 g, 0.001 to 8 g, 0.005 to 7 g, 0.01 to 6 g, 0.05 to 5 g, 0.1 to 4 g, 0.5 to 4 g, or 1 to 3 g.

[0535] In some embodiments, the compounds according to the invention are effective over a wide dosage range. For example, in treating adult humans, doses of 0.01-1000 mg per day, 0.5-100 mg per day, 1-50 mg per day, and 5-40 mg per day are examples of dosages that can be used. An exemplary dosage is 10-30 mg per day. The exact dosage will depend on the route of administration, the form in which the compound is administered, the subject being treated, the subject's weight, and the preference and experience of the attending physician.

[0536] Unless otherwise specified, amounts of compounds described herein are described on a free base basis, i.e., the amount refers to that amount of compound administered, excluding, for example, solvent (e.g., in a solvate) or counterion (e.g., in a pharmaceutically acceptable salt).

[0537] Non-limiting exemplary pharmaceutical compositions and methods for preparing the same are described below.

[0538] Pharmaceutical Composition for Oral Administration In some embodiments, the present invention provides pharmaceutical compositions for oral administration comprising a compound of the present invention and a pharmaceutical excipient suitable for oral administration.

[0539] In some embodiments, the present invention provides a solid pharmaceutical composition for oral administration, comprising (i) an effective amount of a compound of the present invention, optionally (ii) an effective amount of a second pharmaceutical agent, and (iii) a pharmaceutical excipient suitable for oral administration. In some embodiments, the composition further comprises (iv) an effective amount of a third pharmaceutical agent.

[0540] In some embodiments, the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral consumption. Pharmaceutical compositions of the present invention suitable for oral administration can also be presented in separate dosage forms, such as capsules, cachets, or tablets, or liquids or aerosol sprays, each containing a predetermined amount of the active ingredient as a powder, granules, liquid, or suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. Such dosage forms can be prepared by any method of pharmacy, but all methods include the step of bringing the active ingredient into association with a carrier, which constitutes one or more necessary ingredients. Generally, the composition is prepared by uniformly and intimately mixing the active ingredient with a liquid carrier or a finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired appearance. For example, tablets can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form, for example, as a powder or granules, optionally mixed with excipients such as, but not limited to, binders, lubricants, inert diluents, and / or surfactants or dispersing agents. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0541] The present invention further encompasses anhydrous pharmaceutical compositions and dosage forms containing active ingredients, as water can accelerate the degradation of some compounds. For example, water may be added (e.g., 5%) as a means of simulating long-term pharmaceutical storage to determine characteristics such as shelf life and formulation stability over time. Anhydrous pharmaceutical compositions and dosage forms of the present invention can be prepared using anhydrous or low-moisture containing ingredients and low-moisture or low-humidity conditions. Pharmaceutical compositions and dosage forms of the present invention containing lactose can be made anhydrous if substantial contact with moisture and / or humidity is expected during manufacturing, packaging, and / or storage. Anhydrous pharmaceutical compositions can be prepared and stored such that their anhydrous nature is maintained. Thus, anhydrous compositions may be packaged using materials known to prevent exposure to water, allowing them to be included in suitable formulation kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit-dose containers, blister packs, and strip packs.

[0542] The active ingredient can be combined in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a variety of forms depending on the form of preparation desired for administration. In preparing compositions for oral administration, for oral liquid preparations (e.g., suspensions, solutions, and elixirs) or aerosols, any of the usual pharmaceutical media can be used as a carrier, such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, etc. Alternatively, for oral solid preparations, carriers such as starch, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrants can be used without the use of lactose in some embodiments. For example, suitable carriers include powders, capsules, and tablets, as well as solid oral preparations. If desired, tablets can be coated by standard aqueous or non-aqueous techniques.

[0543] Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose), polyvinylpyrrolidone, methylcellulose, pregelatinized starch, hydroxypropyl methylcellulose, microcrystalline cellulose, and mixtures thereof.

[0544] Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.

[0545] Disintegrants can be used in the compositions of the present invention to provide tablets that disintegrate when exposed to an aqueous environment. Using too much disintegrant can result in tablets that may disintegrate in the bottle. Using too little can result in insufficient disintegration, which may alter the rate and extent of release of the active ingredient from the dosage form. Thus, dosage forms of the compounds disclosed herein can be formed using a sufficient amount of disintegrant that is neither too little nor too much, which would adversely alter the release of the active ingredient. The amount of disintegrant used can vary based on the type of formulation and mode of administration, as can be readily discerned by those skilled in the art. About 0.5 to about 15 weight percent of disintegrant, or about 1 to about 5 weight percent of disintegrant, can be used in the pharmaceutical compositions. Disintegrants that can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pregelatinized starch, other starches, clays, other algins, other celluloses, gums, or mixtures thereof.

[0546] Lubricants that can be used to form the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, or mixtures thereof. Additional lubricants include, for example, syloid silica gel, a coagulated aerosol of synthetic silica, or mixtures thereof. Lubricants can optionally be added in an amount of less than about 1 weight percent of the pharmaceutical composition.

[0547] When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredient therein can be combined with various sweetening or flavoring agents, coloring substances or dyes and, if so desired, emulsifying and / or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin, and various combinations thereof.

[0548] Tablets may be uncoated, or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, time-delay materials such as glyceryl monostearate or glyceryl distearate may be used. Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil.

[0549] Surfactants that can be used to form the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof, i.e., a mixture of hydrophilic surfactants can be used, a mixture of lipophilic surfactants can be used, or at least one hydrophilic surfactant and at least one lipophilic surfactant can be used.

[0550] Suitable hydrophilic surfactants may generally have an HLB value of at least 10, while suitable lipophilic surfactants may generally have an HLB value of about 10 or less. An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of nonionic amphiphilic compounds is the hydrophilic-lipophilic balance ("HLB" value). Surfactants with lower HLB values ​​are more lipophilic or hydrophobic and have greater solubility in oil, while surfactants with higher HLB values ​​are more hydrophilic and have greater solubility in aqueous solutions.

[0551] Hydrophilic surfactants are generally considered to be compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable. Similarly, lipophilic (i.e., hydrophobic) surfactants are compounds having an HLB value less than or equal to about 10. However, the HLB value of a surfactant is merely a rough guide that is commonly used to enable the formulation of industrial, pharmaceutical, and cosmetic emulsions.

[0552] The hydrophilic surfactant may be either ionic or nonionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts, fusidate salts, fatty acid derivatives of amino acids, oligopeptides, and polypeptides, glyceride derivatives of amino acids, oligopeptides, and polypeptides, lecithin and hydrogenated lecithin, lysolecithin and hydrogenated lysolecithin, phospholipids and derivatives thereof, lysophospholipids and derivatives thereof, carnitine fatty acid ester salts, alkyl sulfate salts, fatty acid salts, docusate sodium, acyl lactylates, mono- and di-acetylated tartaric acid esters of mono- and di-glycerides, succinylated mono- and di-glycerides, citrate esters of mono- and di-glycerides, and mixtures thereof.

[0553] Within the above group, examples of ionic surfactants include: lecithin, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkyl sulfates; fatty acid salts; docusate sodium; acyl lactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citrate esters of mono- and di-glycerides; and mixtures thereof.

[0554] Ionic surfactants include lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, stearic acid ... The ionic forms and salts of thiamin, succinylated monoglycerides, mono / diacetylated tartaric acid esters of mono / diglycerides, citrate esters of mono / diglycerides, cholylsarcosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, teraceyl sulfate, docusate, lauroylcarnitine, palmitoylcarnitine, myristoylcarnitine, and their mixtures.

[0555] Hydrophilic nonionic surfactants may include, but are not limited to, alkyl glucosides; alkyl maltosides; alkyl thioglucosides; lauryl macrogol glycerides; polyoxyalkylene alkyl ethers, such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols, such as polyethylene glycol alkylphenols; polyoxyalkylene alkylphenol fatty acid esters, such as polyethylene glycol fatty acid monoesters and polyethylene glycol fatty acid diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters, such as polyethylene glycol sorbitan fatty acid esters; hydrophilic interesterification products of polyols and at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene sterols, derivatives, and analogs thereof; polyoxyethylated vitamins and derivatives thereof; polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; polyethylene glycol sorbitan fatty acid esters, and hydrophilic interesterification products of polyols and at least one member of the group consisting of triglycerides, vegetable oils, and hydrogenated vegetable oils. The polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a sugar.

[0556] Other hydrophilic nonionic surfactants include, without limitation, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG-1 stearate 00, PEG-20 Dilaurate, PEG-25 Glyceryl Trioleate, PEG-32 Dioleate, PEG-20 Glyceryl Laurate, PEG-30 Glyceryl Laurate, PEG-20 Glyceryl Stearate, Glyceryl PEG-20 Oleate, Glyceryl PEG-30 Oleate, PEG-30 Glyceryl Laurate, PEG-40 Glyceryl Laurate, PEG-40 Palm Kernel Oil, PEG-50 Hydrogenated Castor Oil, PEG-40 Castor Oil, PEG-35 Castor Oil, PEG-60 Castor Oil, PEG-40 Hydrogenated Castor Oil, PEG-60 Hydrogenated Castor Oil, PEG-60 Corn Oil, PEG-6 Capric / Caprylic Glycerides, PEG-8 Capric / Caprylic Glycerides, Polyglyceryl-10 Laurate, PEG-30 Cholesterol, PEG-25 Phytosterols, PEG-30 Soybean Sterols, PEG-20 Trioleate, PEG-40 Sorbitan Oleate, PEG-80 Sorbitan Laurate, Polysorbate 20, Polysorbate 80, POE-9 Lauryl Ether, PO Examples of suitable sucrose monoesters include E-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, polyglyceryl-10 oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonylphenol series, PEG 15-100 octylphenol series, and poloxamer.

[0557] Suitable lipophilic surfactants include, by way of example only, fatty alcohols, glycerol fatty acid esters, acetylated glycerol fatty acid esters, lower alcohol fatty acid esters, propylene glycol fatty acid esters, sorbitan fatty acid esters, polyethylene glycol sorbitan fatty acid esters, sterols and sterol derivatives, polyoxyethylated sterols and sterol derivatives, polyethylene glycol alkyl ethers, sugar esters, sugar ethers, lactic acid derivatives of mono- and diglycerides, hydrophobic transesterification products of polyols with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols, oil-soluble vitamins / vitamin derivatives, and mixtures thereof. Within this group, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or preferred lipophilic surfactants are hydrophobic transesterification products of polyols with at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides.

[0558] In one embodiment, the composition may include a solubilizing agent to ensure good solubilization and / or dissolution of the compound of the present invention and minimize precipitation of the compound of the present invention. This may be particularly important for compositions for parenteral use, such as injectable compositions. Solubilizing agents may also be added to increase the solubility of hydrophilic drugs and / or other components, such as surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion.

[0559] Examples of suitable solubilizing agents include, but are not limited to, alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediol and its isomers, glycerol, pentaerythritol, sorbitol, mannitol, transquitol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrin and cyclodextrin derivatives; ethers of polyethylene glycol having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG; amides and other nitrogen-containing compounds, such as 2-pyrrolidone, ... -piperidone, ε-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esters such as ethyl propionate, tributyl citrate, triethyl acetylcitrate, tributyl acetylcitrate, triethyl citrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and its isomers, δ-valerolactone and its isomers, β-butyrolactone and its isomers; and other solubilizing agents known in the art, such as dimethylacetamide, dimethyl isosorbide, N-methylpyrrolidone, monooctanoin, diethylene glycol monoethyl ether, and water.

[0560] Mixtures of solubilizers may also be used. Examples include, but are not limited to, triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcyclodextrin, ethanol, polyethylene glycol 200-100, glycofurol, transquitol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol, and propylene glycol.

[0561] The amount of solubilizer that can be included is not particularly limited. The amount of a given solubilizer may be limited to a biotolerable amount, which can be easily determined by one skilled in the art. In some situations, it may be advantageous to include an amount of solubilizer that far exceeds the biotolerable amount, for example, to maximize drug concentration, but the excess solubilizer is removed using conventional techniques, such as distillation or evaporation, before providing the composition to a subject. Thus, when present, the solubilizer can be present in a weight ratio of 10%, 25%, 50%, 100%, or up to about 200% by weight, based on the combined weight of the drug and other excipients. If desired, very small amounts of solubilizer, for example, 5%, 2%, 1%, or even less, can be used. Typically, the solubilizer may be present in an amount of about 1% to about 100% by weight, more typically about 5% to about 25% by weight.

[0562] The composition may further comprise one or more pharmaceutically acceptable additives and excipients, including, without limitation, detackifying agents, antifoaming agents, buffering agents, polymers, antioxidants, preservatives, chelating agents, viscosity adjusting agents, tonicity adjusting agents, flavoring agents, coloring agents, odorants, opacifying agents, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

[0563] Additionally, acids or bases may be incorporated into the compositions to facilitate processing, enhance stability, or for other reasons. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium bicarbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS), and the like. Also suitable are bases that are salts of pharmaceutically acceptable acids, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinonesulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, and the like. Salts of polybasic acids, such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate, can also be used. When the base is a salt, the cation can be any convenient, pharmaceutically acceptable cation, such as ammonium, an alkali metal, an alkaline earth metal, or the like. Examples include, but are not limited to, sodium, potassium, lithium, magnesium, calcium, and ammonium.

[0564] Suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, etc. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinonesulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, etc.

[0565] Injectable pharmaceutical composition

[0566] In some embodiments, the present invention provides an injectable pharmaceutical composition comprising a compound of the present invention and a pharmaceutical excipient suitable for injection, wherein the components and amounts of the drugs in the composition are as described herein.

[0567] Forms into which the novel compositions of the present invention can be incorporated for administration by injection include aqueous or oily suspensions or emulsions using sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles.

[0568] Aqueous solutions in physiological saline are also commonly used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils can also be used. Proper fluidity can be maintained, for example, in the case of dispersions, by using a coating such as lecithin to maintain the required particle size, and by using surfactants. Prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[0569] Injectable sterile solution is prepared by incorporating the required amount of the compound of the present invention into suitable solvent with various other components as listed above, and then optionally sterilizing by filtration.Generally, dispersion is prepared by incorporating various sterilized active ingredients into a sterile vehicle that contains basic dispersion medium and the other components as listed above that are required.For the sterile powder used to prepare injectable sterile solution, a particular preferred preparation method is vacuum drying and freeze-drying technology, which produces a powder of active ingredient and any additional desired components from the solution that has been previously sterilized and filtered.

[0570] Pharmaceutical compositions for topical (eg, transdermal) delivery.

[0571] In some embodiments, the present invention provides a pharmaceutical composition for transdermal delivery comprising a compound of the present invention and a pharmaceutical excipient suitable for transdermal delivery.

[0572] The compositions of the present invention can be formulated into solid, semi-solid or liquid form preparations suitable for local or topical administration, such as gel, water-soluble jelly, cream, lotion, suspension, foam, powder, slurry, ointment, solution, oil, paste, suppository, spray, emulsion, saline, dimethyl sulfoxide (DMSO)-based solution.Generally, the carrier with higher density can provide the active ingredient with longer exposure to the area.In contrast, solution formulation can provide the active ingredient with more immediate exposure to the selected area.

[0573] The pharmaceutical compositions may also include suitable solid or gel phase carriers or excipients, which are compounds that enable increased penetration of or assist in the delivery of therapeutic molecules through the permeability barrier of the stratum corneum of the skin. There are many such penetration-enhancing molecules known to those skilled in the art of topical formulations.

[0574] Examples of such carriers and excipients include, but are not limited to, humectants (e.g., urea), glycols (e.g., propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleic acid), surfactants (e.g., isopropyl myristate and sodium lauryl sulfate), pyrrolidone, glycerol monolaurate, sulfoxides, terpenes (e.g., menthol), amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycol.

[0575] Another exemplary formulation for use in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches can be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts, with or without other agents.

[0576] The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent Nos. 5,023,252, 4,992,445, and 5,001,139. ​​Such patches may be constructed for continuous, pulsatile, or on-demand delivery of pharmaceutical agents.

[0577] Inhaled pharmaceutical composition Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. Preferably, the compositions are administered by the oral or nasal respiratory route for localized or systemic effect. Compositions, preferably in pharmaceutically acceptable solvents, can be nebulized using inert gases. Nebulized solutions can be inhaled directly from the nebulizing device, or the nebulizing device can be attached to a face mask tent or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from a device that delivers the formulation in an appropriate manner.

[0578] Other pharmaceutical compositions Pharmaceutical compositions can also be prepared from the compositions described herein and one or more pharmaceutically acceptable excipients suitable for sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration. Formulations for such pharmaceutical compositions are well known in the art. See, for example, Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, eds., Basic and Clinical Pharmacology, Ninth Edition, McGraw-Hill, 20037ybg; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw-Hill, 2001; Remington's Pharmaceutical Sciences, 20th Edition Ed., Lippincott Williams & Wilkins, 2000; Martindale, The Extra Pharmacopoeia, 32nd Edition (The Pharmaceutical Press, London, 1999), all of which are incorporated herein by reference in their entireties.

[0579] Administration of the compounds or pharmaceutical compositions of the present invention can be carried out by any method that allows delivery of the compound to the site of action. These methods include oral route, intraduodenal route, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion), topical (e.g., transdermal application), rectal administration, administration via localized delivery by catheter or stent, or administration via inhalation. The compounds can also be administered intraadiposely or intrathecally.

[0580] The amount of compound administered will depend on the subject being treated, the severity of the disorder or condition, the rate of administration, the pharmacokinetics of the compound, and the discretion of the prescribing physician. However, effective dosages range from about 0.001 to about 100 mg per kg of body weight per day, preferably about 1 to about 35 mg / kg / day, in single or divided doses. For a 70 kg human, this amounts to about 0.05 to 7 g / day, preferably about 0.05 to about 2.5 g / day. In some cases, dosage levels below the lower end of the aforementioned range may be more than sufficient, while in other cases, even larger doses may be used without causing any adverse side effects, e.g., by dividing such larger doses into several smaller doses for administration throughout the day.

[0581] In some embodiments, the compounds of the invention are administered in a single dose.

[0582] Typically, such administration is by injection, for example, intravenous injection, to rapidly introduce the drug. However, other routes can be used if necessary. A single dose of the compound of the present invention can also be used to treat acute conditions.

[0583] In some embodiments, the compound of the present invention is administered in multiple doses. Dosing may be about once, twice, three times, four times, five times, six times, or more than six times per day. Dosing may be about once per month, once every two weeks, once every week, or once every two days. In another embodiment, the compound of the present invention and another agent are administered together about once per day to about six times per day. In another embodiment, administration of the compound of the present invention and another agent continues for less than about seven days. In yet another embodiment, administration continues for more than about 6, 10, 14, 28 days, 2 months, 6 months, or 1 year. In some cases, continuous dosing is achieved and maintained for as long as necessary.

[0584] Administration of the compounds of the invention can continue for as long as necessary. In some embodiments, the compounds of the invention are administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, the compounds of the invention are administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, the compounds of the invention are administered on an ongoing basis, e.g., chronically, for the treatment of chronic effects.

[0585] An effective amount of the compounds of this invention can be administered in either single or multiple doses by any of the generally accepted modes of administration for drugs having similar utilities, including rectal, oral buccal, intranasal and transdermal routes, intraarterial injection, intravenous, intraperitoneal, parenterally, intramuscular, subcutaneous, oral, topical, or as an inhalant.

[0586] The compositions of the present invention can also be delivered via an impregnated or coated device, such as a stent, or via a cylindrical polymer inserted into an artery. Such administration methods are useful for preventing or ameliorating restenosis, for example, following procedures such as balloon angioplasty. Without being bound by theory, the compounds of the present invention can slow down or inhibit the migration and proliferation of smooth muscle cells in the arterial wall, which contribute to restenosis. The compounds of the present invention may be administered by localized delivery, for example, from the struts of a stent, from a stent graft, from a graft, or from the cover or sheath of a stent. In some embodiments, the compounds of the present invention are mixed with a matrix. Such a matrix may be a polymer matrix and can function to bind the compound to the stent. Suitable polymeric matrices for such uses include, for example, lactone-based polyesters or copolyesters, such as polylactic acid, polycaprolactone glycolide, polyorthoesters, polyanhydrides, polyamino acids, polysaccharides, polyphosphazenes, poly(ether-ester) copolymers (e.g., PEO-PLLA); polydimethylsiloxane, poly(ethylene-vinyl acetate), acrylate-based polymers or copolymers (e.g., polyhydroxyethylmethylmethacrylate, polyvinylpyrrolidinone), fluorinated polymers, such as polytetrafluoroethylene, and cellulose esters. Suitable matrices may be non-degradable or may degrade over time to release the compound(s). The compounds of the present invention can be applied to the surface of a stent by various methods, such as dip / spin coating, spray coating, dip coating, and / or brush coating. The compound may be applied in a solvent, and the solvent may be evaporated to form a layer of the compound on the stent. Alternatively, the compound may be located within the body of the stent or graft, for example, within microchannels or micropores. When implanted, the compound diffuses from the stent body and contacts the arterial wall.Such stents can be prepared by dipping a stent fabricated to contain such micropores or microchannels into a solution of the compound of the present invention in an appropriate solvent, followed by evaporation of the solvent. Excess drug on the surface of the stent can be removed by washing with additional solvent. In yet other embodiments, the compound of the present invention may be covalently attached to the stent or graft. A covalent linker that degrades in vivo can be used to effect release of the compound of the present invention. Any biolabile linkage, such as an ester, amide, or anhydride linkage, can be used for this purpose. The compound of the present invention may also be administered intravascularly from a balloon used during angioplasty. Extravascular administration of the compound via pericardial or epicardial application of the formulation of the present invention can also be performed to reduce restenosis.

[0587] Various stent devices that can be used as described are disclosed, for example, in the following references, all of which are incorporated herein by reference: U.S. Patent No. 5,451,233; U.S. Patent No. 5,040,548; U.S. Patent No. 5,061,273; U.S. Patent No. 5,496,346; U.S. Patent No. 5,292,331; U.S. Patent No. 5,674,278; U.S. Patent No. 3,657,744; U.S. Patent No. 4,739,762; U.S. Patent No. 5,195,984; U.S. Patent No. 5,292,331; U.S. Patent No. 5,674,278; U.S. Patent No. 5,879,382; U.S. Patent No. 6,344,053.

[0588] The compound of the present invention is administered in dosage.It is known in the art that due to the variability of the pharmacokinetics of the compound between subjects, individualized administration regimen is necessary for optimal therapy.Dosage for the compound of the present invention can be found by routine experimentation in light of the present disclosure.

[0589] When a compound of the invention is administered in a composition containing one or more drugs that have a shorter half-life than the compound of the invention, the unit dosage forms of the drugs and the compound of the invention can be adjusted accordingly.

[0590] The subject pharmaceutical compositions may be in a form suitable for oral administration as, for example, tablets, capsules, pills, powders, sustained-release formulations, solutions, or suspensions; for parenteral injection as a sterile solution, suspension, or emulsion; for topical administration as an ointment or cream; or for rectal administration as a suppository. The pharmaceutical composition may be in a unit dosage form suitable for single administration of a precise dosage. The pharmaceutical composition comprises a conventional pharmaceutical carrier or excipient and a compound according to the present invention as an active ingredient. In addition, the pharmaceutical composition may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.

[0591] Exemplary parenteral dosage forms include solutions or suspensions of active compounds in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired.

[0592] How to use The FGFR receptors (FGFRl, FGFR2, FGFR3, and FGFR4) share several common structural features, including three extracellular immunoglobulin-like (Ig) domains, a hydrophobic transmembrane domain, and an intracellular tyrosine kinase domain separated by a kinase insert domain, followed by a cytoplasmic C-terminal tail (Johnson et al., Adv. Cancer Res. 60:1-40, 1993; and Wilkie et al., Curr. Biol. 5:500-507, 1995). In FGFRl, the kinase insert domain spans positions 582-595 of the alpha-Al isoform of FGFRl. In FGFR2, the kinase insert domain spans positions 585-598 of the FGFR2 Ile isoform. In FGFR3, the kinase insert domain spans positions 576-589 of the FGFR3 Ile isoform. In FGFR4, the kinase insert domain spans positions 571-584 of FGFR4 isoform 1. The C-terminal tail of the FGFR begins at the end of the tyrosine kinase domain and extends to the C-terminus of the protein. Several isoforms of each FGFR have been identified, which are the result of alternative splicing of their mRNAs (Johnson et al., Mol. Cell. Biol. 11:4627-4634, 1995; and Chellaiah et al., J. Biol. Chem. 269:11620-11627, 1994).

[0593] Some of the receptor variants resulting from this alternative splicing have different ligand-binding specificities and affinities (Zimmer et al., J. Biol. Chem. 268:7899-7903, 1993; Cheon et al., Proc. Natl. Acad. Sci. USA 91:989-993, 1994; and Miki et al., Proc. Natl. Acad. Sci. USA 89:246-250, 1992). Protein sequences for FGFR proteins and nucleic acids encoding FGFR proteins are known in the art. Signaling by FGFRs regulates major biological processes, including cell proliferation, survival, migration, and differentiation. Dysregulation of FGFR genes, FGFR proteins, or their expression, activity, or levels is associated with many types of cancer. For example, dysregulation of FGFRs can occur through a number of mechanisms, including overexpression of FGFR genes, gene amplification of FGFRs, activating mutations (e.g., point mutations or truncations), and chromosomal rearrangements resulting in FGFR fusion proteins. Dysregulation of FGFR genes, FGFR proteins, or their expression or activity or levels can result in (or partially cause) the development of a variety of different FGFR-associated cancers.

[0594] FGFR fusion proteins are known in the art, for example, see Baroy et al., PloS One; 11(9):e0163859. doi: 10.1371 / journal.pone.0163859, 2016; Ren et al., Int. J. Cancer, 139(4):836-40, 2016; Marchwicka et al., Cell Biosci., 6:7. doi: 10.1186 / s13578-016-0075-9, each of which is incorporated herein by reference. 2016; PCT Patent Application Publication No. WO2014 / 071419A2; U.S. Patent Application Publication No. 2015 / 0366866A1; PCT Patent Application Publication No. WO2016 / 084883A1; PCT Patent Application Publication No. WO2016 / 030509A1; PCT Patent Application Publication No. WO2015 / 150900A2; PCT Patent Application Publication No. WO2015 / 120094A2; Kasaian et al., BMC Cancer., 15:984, 2015; Vakil et al., Neuro-Oncology, 18: Suppl. 3, iii93. Abstract Number: LG-64, 17 thInternational Symposium on Pediatric Neuro-Oncology, Liverpool, UK, 2016; Astsaturov et al., Journal of Clinical Oncology, 34: Appendix 15, Abstract Number: 11504, 2016 Annual Meeting of the American Society of Clinical Oncology, Chicago, IL; Heinrich et al., Journal of Clinical Oncology, 34: Appendix 15, Abstract Number: 11012, 2016 Annual Meeting of the American Society of Clinical Oncology, Chicago, IL; Hall et al., Molecular Cancer Therapeutics, Volume 14, Issue 12, Appendix 2, Abstract Number: B151, AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics, 2015; Reuther et al., Journal of Molecular Diagnostics, Volume 17, Issue 6, Page 813, Abstract Number: ST02, 2015 Annual Meeting of the Association for Molecular Pathology, Austin, TX; Moeini et al., Clin. Cancer. Res., 22(2):291 - 300, 2016; Schrock et al., J Thorac. Oneal. pii S1556-0864(18)30674-9, 2018. doi: 10.1016 / j.jtho.2018.05.027; Pekmezci et al., Acta Nurotapho / . Commun. 6(1):47. doi: 10.118CCR-18-0078; RylandらJ Clin Patho / more: jclinpath-2018-205195、2018. doi: 10.1136 / jclinpath-2018-205195; FergusonらJ Neuropatho / Neural Exp 77(6):437–442 2018. doi:10.1093 / jnen / nly022; Wu. BMC Cancer 18(1):343,2018. doi: 10.1186 / s12885-018-4236-6; Shibata.Cancer Sci 109(5):1282~1291. doi: 10.1111 / cas.13582; Papdopoulos. Br J Cancer.1117(11):1592~1599. doi: 10.1038 / bjc.2017.330; Hall, PLoS One, 11(9):e1062594,2016. doi: 10.1371 / journal.pone.0162594; Johnson, Oncologist, 22(12):1478~1490,2017. doi: 10.1634 / theoncologist.2017-0242; Yang, Am J Hum Genet, 98(5):843~856,2016. doi: 10.1016 / j.ajhg.2016.03.017;Organization of Internal Medicine 2013 / 009621; Babina and Turner, Nat Rev Cancer 17(5):318~332,2017. doi: 10.1038 / nrc.2017.8; Ryland, J Clin Patho / ., May 5, 2018. pii: jclinpath-2018-2 doi: 10.1136 / jclinpath-2018-205195; Am J Clin Patho / . 2015. 143(5):738~748. doi: 10.1309 / AJCPUD6W1JLQQMNA; Grand, Genes Chromosomes Cancer40(1):78~83,2004. doi: 10.1002 / gcc.20023; Reeser et al., J Mo / Diagn, 19(5):682–696, 2017. doi: 10.1016 / j.jmoldx.2017.05.006; Basturk et al., Mod Patho / , 30(12):1760–1772, 2017. doi: 10.1038 / modpathol.2017.60; Wang et al., Cancer 123(20):3916~3924, 2017. doi: 10.1002 / cncr.30837; Kim et al., Oncotarget, 8(9):15014~15022, 2017. doi: 10.18632 / oncotarget.14788; Busse et al. Genes Chromosomes Cancer, 56(10):730-749, 2017. doi: 10.1002 / gcc.22477; Shi et al., J Transl Med., 14(1):339, 2016. doi: 10.1186 / s12967-016-1075-6.

[0595] FGFR point mutations are known in the art. See, for example, UniParc entry UPI00000534B8; UniParc entry UPI000000lCOF; UniParc entry UPI000002A99A; UniParc entry UPI000012A72A; UniParc entry UPI000059D1C2; UniParc entry UPI000002A9AC; Uniparc entry UPI000012A72C; Uniparc entry UPI000012A72D; Uniparc entry UPI000013EOB8; Uniparc entry UPI0001CE06A3; Genbank entry BAD92868.l; Ang et al., Diagn. Mo / . Patho / . 2014, February 24; U.S. Patent Application Publication No. 2011 / 0008347; Gallo et al., Cytokine Growth Factor Rev. 26:425-449, 2015; Davies et al., J. Cancer Res. 65:7591, 2005; Kelleher et al., Carcinogenesis 34:2198, 2013; Cazier et al., Nat. Commun. 5:3756, 2014; Liu et al., Genet. Mo / . Res. 13:1109, 2014; Trudel et al., Blood 107:4039, 2006; Gallo et al., Cytokine Growth Factor Rev. 26:425, 2015; Liao et al., Cancer Res. 73:5195-5205, 2013; Martincorena et al., Science 348:880 (2015); U.S. Patent Application Publication No. US2016 / 0235744Al; U.S. Patent No. 9254288B2; U.S. Patent No. 9267176B2; U.S. Patent Application Publication No. S2016 / 0215350Al; European Patent Application Publication No. EP3023101Al; PCT Patent Publication No. WO2016105503Al; Rivera et al., Acta. Neuropatho / ., 131(6):847-63, 2016; Lo Iacono et al., Oncotarget., 7(12):14394~404, 2016; Deeken et al., Journal of Clinical Oncology, 34:Suppl 15, p. iii93. Abstract Number: el 7520, 2016 Annual Meeting of the American Society of Clinical Oncology, Chicago, IL; Sullivan et al., Journal of Clinical Oncology, 34: Supplement 15, p. iii93. Abstract Number: 11596, 2016 Annual Meeting of the American Society of Clinical Oncology, Chicago, IL; Nguyen et al., Molecular Cancer Therapeutics, Vol. 14, No. 12, Supplement 2, Abstract Number: C199, AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics, 2015; Li et al., Hum. Patho / ., 55: 143-50, 2016; European Patent No. EP2203449B1; Yoza et al., Genes Cells., (10):1049-1058, 2016; U.S. Patent No. 9,254,288 B2; European Patent Application Publication No. 3023101 A1; PCT Application Publication No. WO2015 / 099127 A1; European Patent No. EP2203449 B1; Yoza et al., Genes Cells., (10):1049-1058, 2016; Bunney et al., EbioMedicine, 2(3):194-204, 2015; Byron et al., Neop / asia, 15(8):975-88, 2013; European Patent Application Publication No. EP3023101 A1; PCT Application Publication No. WO2015 / 099127 A1; Thussbas et al., J. Clin. Oncol., 24(23):3747-55, 2006; Chell et al., Oncogene, 32(25):3059-70, 2013; Tanizaki et al., Cancer Res., 75(15):3149-3146, doi: 10.1158 / 0008-5472.CAN-14-3771; Yang et al., EBioMedicine pii S2352 - 3964 (18)30218-4. doi: 10.1016 / j.ebiom.2018.06.011; Jakobsen et al., Oncotarget 9(40):26195 - 26208, 2018. doi: 10.18632 / oncotarget.25490; Stone et al., Acta Neuropathol 135(1):115 - 129, 2017. doi: 10.1007 / s00401-017-1773-z; Pekmezci et al., Acta Nurotaphol. Commun. 6(1):47. doi: 10.1186 / s40478-018-0551-z; De Mattos-Arruda et al., Oncotarget 9(29):20617 - 20630, 2018. doi:10.18632 / oncotarget.25041; Oliveira et al., J Exp Clin Cancer Res 37(1):84, 2018. doi: 10.1186 / s13046-018-0746-y; Cha et al., Mol Oncol 12(7):993 - 1003, 2018. doi: 10.1002 / 1878-0261.12194; Ikeda et al., Oncologist, 23(5):586 - 593, 2018. doi: 10.1634 / theoncologist.2017-0479; Pelaez-Garda et al., PLoS One, 8(5):e63695, 2013. doi: 10.1371 / journal.pone.0063695; Shimada et al., Oncotarget, 8(55):93567 - 93579, 2017. doi: 10.18632 / oncotarget.20510; Welander et al., World J Surg, 42(2):482 - 489, 2018. doi: 10.1007 / s00268-017-4320-0; Chandrani et al., Ann Oncol, 28(3):597 - 603, 2017. doi: 10.1093 / annonc / mdw636; Dalin et al., Nat Commun, 8(1):1197, 2017. doi: 10.1038 / s41467-017-01178-z; Taurin, Intl Gyneco / Cancer, 28(1): 152~160 pages, 2018. doi: 10.1097 / IGC.0000000000001129; Haugh, J Invest Dermatol 138(2): 384~393 pages, 2018. doi: 10.1016 / j.jid.2017.08.022; Babina and Turner, Nat Rev Cancer 17(5): 318~332 pages, 2017. doi: 10.1038 / nrc.2017.8; Greenman, Nature 446(7132): 153~158 pages, 2007. doi: 10.1038 / nature05610; Helsten, Clin Cancer Res, 22(1):259~267, 2016. doi: 10.1158 / 1078-0432.CCR-14-3212; Kim, BMC Urol, 18:68, 2018. doi: 10.1186 / s12894-018-0380-1; Goyal, Cancer Discov, 7(3):252~263, 2017. doi: 10.1158 / 2159-8290.CD-16-1000; Premov, Oncogene, 36(22):3168~3177, 2017. doi: 10.1038 / onc.2016.464; Geelvink, Int J Mo / Sci. 19(9): pii:E2548, 2018. doi: 10.3390 / ijms19092548; Lee, Exp Ther Med. 16(2):1343~1349, 2018. doi: 10.3892 / etm.2018.6323; Kas, Cancer Res, 78(19):5668~5679, 2018. doi: 10.1158 / 0008-5472.CAN-18-0757; Chesi, Blood, 97(3):729~736, 2001.See PMID: 11157491. Note that deletion of residues 795-808 of the FGFR3 isoform also eliminates the stop codon and extends the protein by 99 amino acids (ATGPQQCEGSLAAHPAAGAQPLPGMRLSADGETATQSFGLCVCVCVCVCVCTSACACVRAHLASRCRGTLGVPAAVQRSPDWCCSTEGPLFWGDPVQNVSGPTRWDPVGQGAGPDMARPLPLHHGTSQGALGPSHTQS); Ge et al., Am J Cancer Res. 7(7):1540-1553, 2017. PMID: 28744403; Jiao et al., Nat Genet, 45(12):1470-1473, 2013. doi: 10.1038 / ng.2813; Jusakul et al., Cancer Discov. 7(10):1116-1135, 2017. doi: 10.1158 / 2159-8290.CD-17-0368; Guyard et al., Respir Res., 18(1):120, 2018. doi: 10.1186 / s12931-017-0605-y; Paik et al., Clin Cancer Res., 23(18):5366~5373, 2017. doi: 10.1158 / 1078-0432.CCR-17-0645; Roy et al., Mod Patho / ., 30(8):1133~1143, 2017. doi: 10.1038 / modpathol.2017.33; Chakrabarty et al., Br J Cancer, 117(1):136–143, 2017. doi: 10.1038 / bjc.2017.148; Hoang et al., Sci Transl Med., 5(197):197ra102. doi: 10.1126 / scitranslmed.3006200; Kim et al., Ann Oneal., 28(6):1250-1259. doi: 10.1093 / annonc / mdx098, each of which is incorporated herein by reference.

[0596] The compounds of the present disclosure have been found to inhibit FGFRl, FGFR2, FGFR3, and / or FGFR4 and are therefore believed to be useful for treating diseases and disorders that can be treated with inhibitors of FGFRl, FGFR2, FGFR3, and / or FGFR4. For example, the compounds of the present disclosure may be useful for treating FGFR-related diseases and disorders, such as proliferative disorders, including cancers, including hematological cancers and solid tumors, and angiogenesis-related disorders. The compounds of the present disclosure may also be useful for treating disorders resulting from autosomal dominant mutations in FGFRs, such as FGFR3, including developmental disorders. Developmental disorders that may be treated with the compounds of the present disclosure include achondroplasia (Ach) and related chondrodysplastic syndromes, including hypochondroplasia (Hch), severe achondroplasia with growth retardation and acanthosis nigricans (SADDAN), and thanatophoric dysplasia (TD).

[0597] Non-limiting examples of diseases and disorders associated with FGFR include acanthosis nigricans, achondroplasia, Apert syndrome, Beare-Stevenson syndrome (BSS), Camptodactyly-Tall-Hardness-Deafness (CATSHL) syndrome, cleft lip and palate, congenital heart disease (e.g., associated with ambiguous genitalia), craniosynostosis, Crouzon syndrome, cleft hand and foot, cerebrocranial dermatolipomatosis, Hartsfield syndrome, hypochondroplasia, hypogonadotropic hypogonadism (e.g., associated with anosmia or These include hypogonadotropic hypogonadism without steroids, Kallmann syndrome, ichthyosis vulgaris and / or atopic dermatitis, Jackson-Weiss syndrome, lethal pulmonary acinar dysplasia, microphthalmia, Muenke coronal synostosis, cavitary dysplasia, Pfeiffer syndrome, seborrheic keratoepitheliosis, syndactyly, thanatophoric dysplasia (e.g., type I or type II), trigonocephaly (also called frontal craniosynostosis), and tumor-induced osteomalacia.

[0598] Non-limiting examples of diseases and disorders associated with FGFRl include congenital heart disease (e.g., with ambiguous genitalia), craniosynostosis, cerebrocranial lipomatosis, Hartsfield's syndrome, hypogonadotropic hypogonadism (e.g., hypogonadotropic hypogonadism with or without anosmia, Kallmann syndrome), ichthyosis vulgaris and / or atopic dermatitis, Jackson-Weiss syndrome, cavitary dysplasia, Pfeiffer syndrome, trigonocephaly (also called frontal craniosynostosis), and tumor-induced osteomalacia.

[0599] Non-limiting examples of diseases and disorders associated with FGFR2 include Apert syndrome, Beare-Stevenson syndrome (BSS), Crouzon syndrome, split hand / foot, Jackson-Weiss syndrome, lethal pulmonary acinar dysplasia, Pfeiffer syndrome, and syndactyly. Non-limiting examples of diseases and disorders associated with FGFR3 include acanthosis nigricans, achondroplasia, camptodactyly-tall-deafness syndrome (feline SHL) syndrome, cleft lip and palate, craniosynostosis, hypochondroplasia, microphthalmia, Muenke coronal synostosis, seborrheic keratoepitheliosis, and thanatophoric dysplasia (e.g., type I or type II). UniParc entry UPI00000534B8; UniParc entry UPI000000lCOF; UniParc entry UPI000002A99A; UniParc entry UPI000012A72A; Yong-Xing et al., Hum. Mol. Genet. 9(13):2001-2008, 2000; Eeva-Maria Laitinen et al., PLoS One7(6):e39450, 2012; Hart et al., Oncogene 19(29):3309-3320, 2000; Shiang et al., Cell 76:335-342, 1994; Rosseau et al., Nature 371:252-254, 1994; Tavormina et al., Nature Genet. 9:321-328, 1995; Bellus et al., Nature Genet. 10:357-359, 1995; Muenke et al., Nature Genet. 8:269-274, 1994; Rutland et al., Nature Genet. 9:173-176, 1995; Reardon et al., Nature Genet. 8:98-103, 1994; Wilkie et al., Nature Genet. 9:165-172, 1995; Jabs et al., Nature Genet. 8:275-279, 1994; Japanese Patent No. JP05868992; Ye et al., Plast. Reconstr. Surg., 137(3):952-61, 2016; U.S. Patent No. 9447098B2; Bellus et al., Am. J. Med. Genet.85(1):53-65, 1999; PCT Patent Application Publication No. WO2016139227Al; Australian Patent Application Publication No. AU2014362227Al; Chinese Patent No. CN102741256B; Ohishi et al., Am. J. Med. Genet. A., doi: 10.1002 / ajmg.a.37992, 2016; Nagahara et al., Clin. Pediatr. Endocrinol., 25(3):103-106, 2016; Hibberd et al., Am. J. Med. Genet. A., doi: 10.1002 / ajmg.a.37862, 2016; Dias et al., Exp. Mol. Pathol., 101(1):116-23, 2016; Lin et al., Mol. Med. Rep., 14(3):1941–1946, 2016; Barnett et al., Hum. Mutat., 37(9):955–1956, 2016; Krstevska-Konstantinova et al., Med. Arch., 70(2):148–1950, 2016; Kuentz et al., Br. J. Dermatol., doi: 10.1111 / bjd.14681, 2016; Ron et al., Am. J. Case Rep., 15;17:254–1958, 2016; Fernandes et al., Am. J. Med. Genet. A., 170(6):1532–1957, 2016; Lindy et al., Am. J. Med. Genet. A., 170(6):1573–1959, 2016; Bennett et al., Am. J. Hum. Genet., 98(3):579~87, 2016; lchiyama et al., J. Eur. Acad. Dermatol. Venereal., 30(3):442~5, 2016; Zhao et al., Int. J. Clin. Exp. Med., 8(10):19241~9, 2015; Hasegawa et al., Am. J. Med. Genet. A., 170A(5):1370~2, 2016; Legeai-Mallet, Endocr. Dev., 30:98~105, 2016; Takagi, Am. J. Med. Genet. A., 167A(ll):2851~4, 2015; Goncalves, Fertil. Steril., 104(5): 1261 - 1267 pages. el, 2015; Miller et al., Journal of Clinical Oncology, 34: Supp. Supplement 15, iii93 pages. AbstractNumber: e22500, 2016 Annual Meeting of the American Society of Clinical Oncology, Chicago, IL; Sarabipour et al., J. Mol. Biol., 428(20): 3903 - 3910 pages, 2016; Escobar et al., Am. J. Med. Genet. A., 170(7): 1908 - 1911 pages, 2016; Mazen et al., Sex Dev., 10(1): 16 - 22 pages, 2016; Taylan et al., J Allergy Clin Immunol, 136(2): 507 - 509 pages, 2015. doi: 10.1016 / j.jaci.2015.02.010; Kant et al., EuroJourn Endocrinol, 172(6): 763 - 770 pages, 2015. doi: 10.1530 / EJE - 14 - 0945; Gonzalez - Del Angel et al., Am J med Genet A, 176(1): 161 - 166 pages, 2018. doi: 10.1002 / ajmg.a.38526; Lei and Deng, Int J Biol Sci 13(9): 1163 - 1171, 2017. doi: 10.7150 / ijbs.20792; Lajeunie et al., Eur J Hum Genet, 14(3): 289 - 298 pages, 2006. doi: 10.1038 / sj.ejhg.5201558; Karadimas et al., Prenat Diagn, 26(3): 258 - 261 pages,See also doi: 10.1038 / ng1122, each of which is incorporated herein by reference.

[0600] The term "angiogenesis-associated disorder" refers to a disease characterized in part by an increased number or size of blood vessels in tissue in a subject or patient compared to a similar tissue from a subject without the disease. Non-limiting examples of angiogenesis-associated disorders include cancer (e.g., any of the exemplary cancers described herein, e.g., prostate cancer, lung cancer, breast cancer, bladder cancer, kidney cancer, colon cancer, stomach cancer, pancreatic cancer, ovarian cancer, melanoma, liver cancer, sarcoma, and lymphoma), exudative macular degeneration, proliferative diabetic retinopathy, ischemic retinopathy, retinopathy of prematurity, neovascular glaucoma, rubeosis iridis, corneal neovascularization, cyclitis, sickle cell retinopathy, and pterygium.

[0601] Compounds of the present disclosure inhibit wild-type FGFR1, FGFR2, FGFR3, and / or FGFR4. In other embodiments, compounds of the present disclosure inhibit mutated FGFR1, FGFR2, FGFR3, and / or FGFR4. In other embodiments, compounds of the present disclosure inhibit FGFR1, FGFR2, FGFR3, and / or FGFR4 containing FGFR kinase inhibitor mutations.

[0602] In some embodiments of any of the methods or uses described herein, the cancer (e.g., an FGFR-associated cancer) is a hematological cancer. In some embodiments of any of the methods or uses described herein, the cancer (e.g., an FGFR-associated cancer) is a solid tumor.

[0603] In some embodiments of any of the methods or uses described herein, the cancer (e.g., an FGFR-associated cancer) is lung cancer (e.g., small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma, lung adenocarcinoma, large cell carcinoma, mesothelioma, lung neuroendocrine carcinoma, smoking-related lung cancer), prostate cancer, colorectal cancer (e.g., rectal adenocarcinoma), endometrial cancer (e.g., endometrioid endometrial carcinoma, endometrial adenocarcinoma), breast cancer (e.g., hormone-receptor-positive breast cancer, triple-negative breast cancer, breast neuroendocrine carcinoma), skin cancer (e.g., For example, melanoma, cutaneous squamous cell carcinoma, basal cell carcinoma, giant squamous cell carcinoma), gallbladder cancer, liposarcoma (e.g., dedifferentiated liposarcoma, myxoid liposarcoma), pheochromocytoma, myoepithelial carcinoma, urothelial carcinoma, spermatocytic seminoma, gastric cancer, head and neck cancer (e.g., head and neck (squamous) carcinoma, head and neck adenoid cystic carcinoma), brain cancer (e.g., glial cell tumor, glioma, neuroblastoma, glioblastoma, pilocytic astrocytoma, rosette-forming glioneuronal tumor, dysembryoplastic neuroepithelial tumor, anaplastic astrocytoma, medulloblastoma, ganglioglioma, oligodendroglioma), malignant tumors peripheral nerve sheath tumor, sarcoma (e.g., soft tissue sarcoma (e.g., leiomyosarcoma), osteosarcoma), esophageal cancer (e.g., esophageal adenocarcinoma), lymphoma, bladder cancer (e.g., bladder urothelial (metastatic cell) carcinoma), cervical cancer (e.g., cervical squamous cell carcinoma, cervical adenocarcinoma), fallopian tube cancer (e.g., fallopian tube carcinoma), ovarian cancer (e.g., ovarian serous carcinoma, ovarian mucinous carcinoma), bile duct carcinoma, adenoid cystic carcinoma, pancreatic cancer (e.g., exocrine pancreatic carcinoma, pancreatic tubular adenocarcinoma, pancreatic intraepithelial neoplasia), salivary gland cancer (e.g., pleomorphic salivary gland carcinoma, salivary adenoid cystic carcinoma), oral cancer Cancer (e.g., oral squamous cell carcinoma), uterine cancer, stomach cancer or gastric cancer (e.g., gastric adenocarcinoma), gastrointestinal stromal tumor, myeloma (e.g., multiple myeloma), lymphoepithelioma, anal cancer (e.g., anal squamous cell carcinoma), prostate cancer (e.g., prostate adenocarcinoma), renal alveolar carcinoma, thymic carcinoma, gastroesophageal junction adenocarcinoma, testicular cancer, rhabdomyosarcoma (e.g., alveolar rhabdomyosarcoma, embryonal rhabdomyosarcoma), papillary renal carcinoma, liver cancer (e.g., hepatocellular carcinoma, intrahepatic cholangiocarcinoma), carcinoid, myeloproliferative disorder (also called myeloproliferative neoplasm (MPN));For example, myeloproliferative syndrome (EMS, also called stem cell leukemia / lymphoma), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), lymphoma (e.g., T-cell lymphoma, T-lymphoblastic lymphoma, acute lymphoblastic leukemia (ALL), B-cell lymphoma), myeloid and lymphoid neoplasms, chronic neutrophilic leukemia, phosphaturic mesenchymal tumor, thyroid cancer (e.g., anaplastic thyroid carcinoma), or ductal carcinoma of the bile duct;

[0604] In some embodiments of any of the methods or uses described herein, the cancer (e.g., an FGFR-associated cancer) is selected from the group consisting of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adolescent cancer, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytoma, atypical teratoid / rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, carcinoma Id tumors, cancer of unknown primary origin, cardiac tumors, cervical cancer, childhood cancer, chordoma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative neoplasms, neoplasms by site, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, cutaneous angiosarcoma, bile duct carcinoma, ductal carcinoma in situ, embryonal tumors, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing's sarcoma, extracranial germ cell tumors, extragonadal germ cell tumors, Extrahepatic bile duct cancer, eye cancer, fallopian tube cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic disease, glioma, hairy cell tumor, hairy cell leukemia, head and neck cancer, breast neoplasm, head and neck neoplasm, CNS tumor, primary CNS tumor, cardiac cancer, hepatocellular carcinoma, histiocytosis, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor, pancreatic neuroendocrine tumor, Kaposi's sarcoma , kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, lip and oral cavity cancer, liver cancer, lung cancer, lymphoma, macroglobulinemia, malignant fibrous histiocytoma of bone, bone cancer, melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous neck cancer, midline carcinoma, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, neoplasm by site, myeloid leukemia, myeloid leukemialeukemia), multiple myeloma, myeloproliferative neoplasms, nasal and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, lung neoplasm, cancer of the lung, lung neoplasm, respiratory neoplasm, bronchogenic lung carcinoma, bronchial neoplasm, oral cavity cancer, oral cavity cancer, lip cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary cancer, plasma cell neoplasm, pleuropulmonary blastoma, pregnancy-associated breast cancer, primary The cancer is selected from the group consisting of: advanced central nervous system lymphoma, primary peritoneal cancer, prostate cancer, rectal cancer, colon cancer, neoplasms of the colon, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Sezary syndrome, skin cancer, Spitz tumor, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, squamous neck cancer, gastric cancer, T-cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, carcinoma of unknown primary, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilms' tumor.

[0605] In some embodiments, the hematological cancer (e.g., a hematological cancer that is an FGFR-associated cancer) is a leukemia, lymphoma (non-Hodgkin's lymphoma), Hodgkin's disease (also called Hodgkin's lymphoma), and myeloma, e.g., acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML). , chronic neutrophilic leukemia (CNL), acute anaplastic leukemia (AUL), anaplastic large cell lymphoma (ALCL), prolymphocytic leukemia (PML), juvenile myelomonocytic leukemia (JMML), AML with trilineage myelodysplasia (AML / TMDS), adult T-cell ALL, mixed plasma leukemia (MLL), myelodysplastic syndrome (MDS), myeloproliferative disorder (MPD), and multiple myeloma (MM).

[0606] Additional examples of hematological cancers include myeloproliferative disorders (MPDs), such as polycythemia vera (PV), essential thrombocytopenia (ET), and idiopathic primary myelofibrosis (IMF / IPF / PMF). In some embodiments, the hematological cancer (e.g., a hematological cancer that is an FGFR-associated cancer) is AML or CMML. In some embodiments, the cancer (e.g., an FGFR-associated cancer) is a solid tumor. Examples of solid tumors (e.g., solid tumors that are FGFR-associated cancers) include, for example, lung cancer (e.g., lung adenocarcinoma, non-small cell lung cancer, squamous cell lung cancer), bladder cancer, colorectal cancer, brain cancer, testicular cancer, cholangiocarcinoma, cervical cancer, prostate cancer, and spermatocytic seminoma. See, e.g., Turner and Grose, Nat. Rev. Cancer, 10(2): 116-129, 2010.

[0607] In some embodiments, the cancer is selected from the group consisting of bladder cancer, brain cancer, breast cancer, cholangiocarcinoma, head and neck cancer, lung cancer, multiple myeloma, rhabdomyosarcoma, urethral cancer, and uterine cancer. In some embodiments, the cancer is selected from the group consisting of lung cancer, breast cancer, and brain cancer.

[0608] In some embodiments, the FGFRl-associated cancer is selected from the group consisting of lung cancer, breast cancer, and brain cancer.

[0609] In some embodiments, the cancer is selected from the group consisting of breast cancer, uterine cancer, cholangiocarcinoma, and lung cancer.

[0610] In some embodiments, the FGFR2-associated cancer is selected from the group consisting of breast cancer, uterine cancer, cholangiocarcinoma, and lung cancer. In some embodiments, the cancer is selected from the group consisting of lung cancer, bladder cancer, urethral cancer, multiple myeloma, and head and neck cancer.

[0611] In some embodiments, the FGFR3-associated cancer is selected from the group consisting of lung cancer, bladder cancer, urethral cancer, multiple myeloma, and head and neck cancer.

[0612] In some embodiments, the cancer is selected from lung cancer, rhabdomyosarcoma, and breast cancer.

[0613] In some embodiments, the FGFR4-associated cancer is selected from lung cancer, rhabdomyosarcoma, and breast cancer.

[0614] In some aspects, the compounds of the present disclosure are useful in treating cancers associated with amplification or overexpression of FGFR1, such as breast cancer or carcinoma (e.g., hormone receptor-positive breast cancer, ductal carcinoma in situ (breast)), tubular adenocarcinoma of the pancreas, exocrine pancreatic cancer, smoking-related lung cancer, small cell lung cancer, lung adenocarcinoma, non-small cell lung cancer, squamous cell lung cancer or carcinoma, prostate cancer or carcinoma, ovarian cancer, fallopian tube cancer, bladder cancer, rhabdomyosarcoma, head and neck cancer (e.g., head and neck squamous cell carcinoma), esophageal cancer, and the like. It is useful for treating cancer (e.g., esophageal squamous cell carcinoma), sarcoma (e.g., osteosarcoma), hepatocellular carcinoma, renal alveolar carcinoma, colorectal cancer (e.g., colorectal adenocarcinoma), prostate cancer, salivary gland tumors, glioblastoma multiforme, bladder cancer, urothelial carcinoma, carcinoma of unknown primary site, squamous non-lung tumors, gastric cancer, gastroesophageal junction cancer, adenoid cystic carcinoma, anal squamous cell carcinoma, oral squamous cell carcinoma, cholangiocarcinoma, hemangioendothelioma, leiomyosarcoma, melanoma, neuroendocrine carcinoma, squamous cell carcinoma, and uterine carcinosarcoma.

[0615] In some embodiments, the compounds of the present disclosure are useful for treating cancers associated with FGFR2 amplification, such as gastric cancer, gastroesophageal junction adenocarcinoma, breast cancer (e.g., triple-negative breast cancer), colon cancer, colorectal cancer (e.g., colorectal adenocarcinoma), urothelial cancer, bladder adenocarcinoma, carcinoma of unknown primary, bile duct carcinoma, endometrial adenocarcinoma, adenocarcinoma of the esophagus, gallbladder cancer, ovarian cancer, fallopian tube cancer, exocrine pancreatic carcinoma, sarcoma, and squamous cell carcinoma.

[0616] In some embodiments, the compounds of the present disclosure are useful for treating cancers associated with overexpression of FGFR2, such as mucinous lipocarcinoma, rectal cancer, renal alveolar carcinoma, and breast cancer.

[0617] In some embodiments, the compounds of the present disclosure are useful for treating cancers associated with upregulated FGFR3 activity, such as colorectal cancer, hepatocellular carcinoma, and exocrine pancreatic cancer. In some embodiments, the compounds of the present disclosure are useful for treating cancers associated with overexpression of FGFR3 activity, such as multiple myeloma and thyroid cancer. In some embodiments, the compounds of the present disclosure are useful for treating cancers associated with amplification of FGFR3 activity, such as bladder cancer and salivary adenoid cystic carcinoma, urothelial carcinoma, breast cancer, carcinoid, cancer of unknown primary site, colorectal cancer (e.g., colorectal adenocarcinoma), gallbladder cancer, gastric cancer, gastroesophageal junction adenocarcinoma, glioma, mesothelioma, non-small cell lung cancer, small cell lung cancer, ovarian cancer, fallopian tube cancer, and exocrine pancreatic cancer.

[0618] In some embodiments, the compounds of the present disclosure are useful for treating cancers associated with FGFR4 amplification, such as rhabdomyosarcoma, prostate cancer or carcinoma, breast cancer, urothelial cancer, carcinoid, carcinoma of unknown primary origin, adenocarcinoma of the esophagus, head and neck cancer, hepatocellular carcinoma, non-small cell lung cancer, ovarian cancer, fallopian tube cancer, peritoneal cancer, and renal alveolar carcinoma.

[0619] In some embodiments, the compounds of the present disclosure are useful for treating cancers associated with upregulated activity of FGFR4, such as colorectal cancer, hepatocellular carcinoma, adrenal cancer, and breast cancer.

[0620] In some embodiments, compounds of the present disclosure are useful for treating cancers associated with overexpression of FGFR4 activity, such as pancreatic intraepithelial neoplasia and pancreatic ductal adenocarcinoma.

[0621] In some aspects, compounds of the present disclosure are more selective for one FGFR than for another FGFR. As used herein, the "selectivity" of a compound for a first target over a second target means that the compound has more potent activity on the first target than on the second target. The selectivity factor can be calculated by any method known in the art. For example, the selectivity factor can be calculated by dividing the IC50 value (or Kd value) of a compound for a second target (e.g., FGFR1) by the IC50 value of the same compound for a first target (e.g., FGFR2 or FGFR3). IC50 values ​​can be determined by any method known in the art. In some embodiments, a compound is initially determined to have activity of less than 500 nM against a first target. In some embodiments, a compound is initially determined to have activity of less than 500 nM against a second target.

[0622] For example, in some embodiments, compounds of the present disclosure are more selective for FGFR3 than for FGFR1. In some embodiments, compounds are at least 3 times more selective for FGFR3 than for FGFR1. In some embodiments, compounds are 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 75, 100, 200, 500, or 1000 times more selective for FGFR3 than for FGFR1.

[0623] In some embodiments, the compounds of the present disclosure are more selective for FGFR2 than for FGFR1. In some embodiments, the compounds are at least 3 times more selective for FGFR2 than for FGFR1. In some embodiments, the compounds are 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 75, 100, 200, 500, or 1000 times more selective for FGFR2 than for FGFR1.

[0624] In some aspects, the compounds of the present disclosure are more selective for a first FGFR family member (e.g., FGFR2 or FGFR3) compared to a second FGFR family member (e.g., FGFR1 or FGFR4). In some aspects, the compounds of the present disclosure are at least 3-fold more selective for a first FGFR family member compared to a second FGFR family member. In some aspects, the compounds are at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 200, 300, 400, 500, 600, 700, 800, 900, or at least 1000-fold more selective for a first FGFR family member compared to a second FGFR family member.

[0625] In some embodiments, the compounds of the present disclosure are more selective for FGFR kinases than other kinases that are not FGFR kinases. For example, the compounds of the present disclosure are at least 3 times more selective for FGFR kinases than other kinases that are not FGFR kinases. In some embodiments, the compounds of the present disclosure are at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 200, 300, 400, 500, 600, 700, 800, 900, or at least 1000 times more selective for FGFR kinases than other kinases that are not FGFR kinases. Kinases that are not FGFR kinases include, for example, KDR kinase and Aurora B kinase.

[0626] In some embodiments, compounds of the present disclosure exhibit brain and / or central nervous system (CNS) penetrability. Such compounds are capable of crossing the blood-brain barrier and inhibiting FGFR kinases in the brain and / or other CNS structures. In some embodiments, compounds provided herein are capable of crossing the blood-brain barrier in therapeutically effective amounts. For example, treating a subject with cancer (e.g., an FGFR-associated cancer, e.g., an FGFR-associated brain or CNS cancer) can include administering (e.g., orally administering) a compound to the subject. In some such embodiments, compounds provided herein are useful for treating primary or metastatic brain tumors, e.g., FGFR-associated primary or metastatic brain tumors.

[0627] In some embodiments, compounds of the present disclosure exhibit one or more of high GI absorption, low clearance, and low potential for drug-drug interactions.

[0628] In some aspects, compounds of the present disclosure can be used to treat a subject diagnosed with (or identified as having) an FGFR-associated disease or disorder (e.g., an FGFR-associated cancer), comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure. Also provided herein are methods for treating a subject identified or diagnosed with an FGFR-associated disease or disorder (e.g., an FGFR-associated cancer), comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure. In some embodiments, a subject is identified or diagnosed as having an FGFR-associated disease or disorder (e.g., an FGFR-associated cancer) through the use of a regulatory agency-approved, e.g., FDA-approved, test or assay to identify dysregulation of expression or activity or levels of an FGFR gene, an FGFR kinase, or any of these, in the subject or in a biopsy sample obtained from the subject, or by performing any of the non-limiting examples of assays described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the FGFR-associated disease or disorder is an FGFR-associated cancer. For example, an FGFR-associated cancer can be a cancer containing one or more FGFR inhibitor-resistant mutations.

[0629] Also provided are methods for treating a disease or disorder in a subject in need thereof, comprising: (a) detecting an FGFR-associated disease or disorder in the subject; and (b) administering to the subject a therapeutically effective amount of a compound of the present disclosure. Some embodiments of these methods further comprise administering an additional therapy or therapeutic agent to the subject (e.g., a second FGFR inhibitor, a second compound of the present disclosure, or immunotherapy). In some embodiments, the subject has been previously treated with a first FGFR inhibitor or has been previously treated with another treatment. In some embodiments, the subject is determined to have an FGFR-associated disease or disorder through the use of a regulatory agency-approved test or assay, such as an FDA-approved test or assay to identify dysregulation of expression, activity, or levels of an FGFR gene, an FGFR kinase, or any of these, in the subject or in a biopsy sample obtained from the subject, or by performing any of the non-limiting examples of assays described herein. In some embodiments, the test or assay is provided as a kit.

[0630] Also provided are methods for treating cancer in a subject in need thereof, comprising: (a) detecting an FGFR-associated cancer in the subject; and (b) administering to the subject a therapeutically effective amount of a compound of the present disclosure. Some embodiments of these methods further comprise administering an additional therapy or therapeutic agent to the subject (e.g., a second FGFR inhibitor, a second compound of the present disclosure, or immunotherapy). In some embodiments, the subject has been previously treated with a first FGFR inhibitor or has been previously treated with another anti-cancer treatment, e.g., at least partial tumor resection or radiation therapy. In some embodiments, the subject is determined to have an FGFR-associated cancer through the use of a regulatory agency-approved test or assay, such as an FDA-approved test or assay to identify dysregulation of expression, activity, or levels of an FGFR gene, an FGFR kinase, or any of these, in the subject or in a biopsy sample obtained from the subject, or by performing any of the non-limiting examples of assays described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the cancer is an FGFR-associated cancer. For example, the FGFR-related cancer can be a cancer that contains one or more FGFR inhibitor-resistant mutations. In some embodiments, the cancer is a FGFR-related cancer. For example, the FGFR-related cancer can be a cancer that contains one or more FGFR-activating mutations.

[0631] Also provided are methods of treating a subject, the methods comprising: performing an assay on a sample obtained from the subject to determine whether the subject has abnormal regulation of expression, activity, or level of an FGFR gene, an FGFR kinase, or any of these; and administering (e.g., specifically or selectively administering) a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof, to the subject determined to have abnormal regulation of expression, activity, or level of an FGFR gene, an FGFR kinase, or any of these. Some embodiments of these methods further comprise administering to the subject an additional therapy or therapeutic agent (e.g., a second FGFR inhibitor, a second compound of the present disclosure, or an immunotherapy). In some embodiments of these methods, the subject has been previously treated with a first FGFR inhibitor, or has been previously treated with another anti-cancer treatment, e.g., at least partial tumor resection or radiation therapy. In some embodiments, the subject is suspected of having an FGFR-associated disease or disorder (e.g., an FGFR-associated cancer), is a subject who exhibits one or more symptoms of an FGFR-associated disease or disorder (e.g., an FGFR-associated cancer), or is a subject who is at elevated risk for developing an FGFR-associated disease or disorder (e.g., an FGFR-associated cancer). In some embodiments, the assay utilizes next-generation sequencing, pyrosequencing, immunohistochemistry, or break apart FISH analysis. In some embodiments, the assay is an agency-approved assay, e.g., an FDA-approved kit. In some embodiments, the assay is a liquid biopsy. Additional, non-limiting assays that can be used in these methods are described herein. Additional assays are also known in the art. In some embodiments, the dysregulation of expression or activity or levels of an FGFR gene, an FGFR kinase, or any of these comprises one or more FGFR inhibitor-resistant mutations.

[0632] Also provided herein are methods for selecting a treatment for a subject, the methods comprising: performing an assay on a sample obtained from the subject to determine whether the subject has dysregulated expression, activity, or levels of an FGFR gene, an FGFR kinase, or any of these (e.g., one or more FGFR inhibitor-resistant mutations); and identifying or diagnosing the subject determined to have an FGFR-associated cancer having dysregulated expression, activity, or levels of an FGFR gene, an FGFR kinase, or any of these. Some embodiments further comprise administering the selected treatment to the subject identified or diagnosed with an FGFR-associated cancer. For example, in some embodiments, the selected treatment can comprise administering a therapeutically effective amount of a compound of the present disclosure to the subject identified or diagnosed with an FGFR-associated cancer. In some embodiments, the assay is an in vitro assay, e.g., an assay utilizing next-generation sequencing, immunohistochemistry, or break-apart FISH analysis. In some embodiments, the assay is a regulatory agency-approved, e.g., FDA-approved, kit. In some embodiments, the assay is a liquid biopsy.

[0633] Also provided herein are methods of treating an FGFR-associated cancer in a subject, the methods comprising: (a) administering one or more (e.g., two or more, three or more, four or more, five or more, or ten or more) doses of a first FGFR kinase inhibitor to a subject (e.g., identified or diagnosed as having an FGFR-associated cancer using any of the exemplary methods described herein or known in the art) identified or diagnosed as having an FGFR-associated cancer (e.g., any type of FGFR-associated cancer described herein); (b) after step (a), determining the level of circulating tumor DNA in a biological sample obtained from the subject (e.g., a biological sample comprising blood, serum, or plasma); and (c) administering a therapeutically effective amount of a second FGFR inhibitor or a compound of the present disclosure, as a monotherapy or in combination with an additional therapy or therapeutic agent, to a subject identified as having approximately the same or elevated levels of circulating tumor DNA compared to a baseline level of circulating tumor DNA (e.g., any of the baseline levels of circulating tumor DNA described herein). In some examples of these methods, the reference level of circulating tumor DNA is the level of circulating tumor DNA in a biological sample obtained from the subject prior to step (a). Some embodiments of these methods further include determining the level of circulating tumor DNA in the biological sample obtained from the subject prior to step (a). In some examples of these methods, the reference level of circulating tumor DNA is a threshold level of circulating tumor DNA (e.g., the average level of circulating tumor DNA in a population of subjects with a similar FGFR-associated cancer and a similar stage of the FGFR-associated cancer but who have received an ineffective treatment or placebo, or have not yet received a therapeutic treatment, or the level of circulating tumor DNA in subjects with a similar FGFR-associated cancer and a similar stage of the FGFR-associated cancer but who have received an ineffective treatment or placebo, or have not yet received a therapeutic treatment).In some examples of these methods, the first FGFR inhibitor is ARQ-087, ASP5878, AZD4547, B-701, BAY1179470, BAY1187982, BGJ398, brivanib, Debio 1347, dovitinib, E7090, erdafitinib, FPA144, HMPL-453, INCB054828, lenvatinib, lucitanib, LY3076226, MAX-40279, nintedanib, orantinib, pemigatinib, ponatinib, PRN1371, rogaratinib, surufatinib, TAS-120, or RLY-4008.

[0634] The compounds of the present disclosure can also be administered with additional therapies or therapeutic agents. In some aspects, the additional therapies or therapeutic agents include one or more of radiation therapy, a chemotherapeutic agent (e.g., any of the exemplary chemotherapeutic agents described herein or known in the art), a checkpoint inhibitor (e.g., any of the exemplary checkpoint inhibitors described herein or known in the art), surgery (e.g., at least partial removal of the tumor), and one or more other kinase inhibitors (e.g., any of the kinase inhibitors described herein or known in the art).

[0635] The compounds of the present disclosure can also be useful as adjuvants for the treatment of cancer, i.e., the compounds of the present disclosure can be used in combination with one or more additional therapies or therapeutic agents, for example, chemotherapeutic agents that work by the same or different mechanisms of action. In some embodiments, the compounds of the present disclosure can be used before the administration of the additional therapeutic agent or therapy. For example, a subject in need thereof can be administered one or more doses of a compound of the present disclosure for a period of time and then undergo at least partial tumor removal. In some embodiments, treatment with one or more doses of a compound of the present disclosure reduces tumor size (e.g., tumor burden) before at least partial tumor removal. In some embodiments, the subject has cancer (e.g., locally advanced or metastatic tumors) that is resistant to or cannot tolerate standard therapy (e.g., administration of a chemotherapeutic agent, e.g., a first FGFR inhibitor or multikinase inhibitor, immunotherapy, radiation, or a platinum-based agent (e.g., cisplatin)). In some embodiments, the subject has cancer (e.g., locally advanced or metastatic tumors) that is refractory to or intolerant of previous therapy (e.g., administration of a chemotherapeutic agent, e.g., a first FGFR inhibitor or multikinase inhibitor, immunotherapy, radiation, or a platinum-based agent (e.g., cisplatin)).

[0636] In some embodiments of any of the methods described herein, a compound of the present disclosure is administered in combination with a therapeutically effective amount of at least one additional therapeutic agent selected from one or more additional therapeutic or therapeutic (e.g., chemotherapy) agents. Non-limiting examples of additional therapeutic agents include other FGFR-targeting therapeutic agents (i.e., first or second FGFR kinase inhibitors), other kinase inhibitors (e.g., receptor tyrosine kinase-targeting therapeutic agents (e.g., Trk inhibitors or EGFR inhibitors)), signal transduction pathway inhibitors, checkpoint inhibitors, apoptosis pathway modulators (e.g., obataclax); cytotoxic chemotherapy agents, angiogenesis-targeting therapies, immune-targeting agents, including immunotherapy, and radiation therapy.

[0637] Also provided herein are methods for treating a disease or disorder, comprising administering to a subject in need thereof a pharmaceutical combination for treating the disease or disorder, the pharmaceutical combination comprising (a) a compound of the present disclosure, (b) an additional therapeutic agent, and (c) optionally at least one pharmaceutically acceptable carrier, for simultaneous, separate, or sequential use for treating the disease or disorder, wherein the amounts of the compound of the present disclosure and the additional therapeutic agent together are effective to treat the disease or disorder. In some embodiments, the compound of the present disclosure and the additional therapeutic agent are administered simultaneously as separate dosages. In some embodiments, the compound of the present disclosure and the additional therapeutic agent are administered sequentially as separate dosages in any order, in jointly therapeutically effective amounts, for example, daily or intermittent dosages. In some embodiments, the compound of the present disclosure and the additional therapeutic agent are administered simultaneously as a combined dosage. In some embodiments, the disease or disorder is an FGFR-related disease or disorder. In some embodiments, the subject is administered one or more doses of a compound of the present disclosure prior to administration of the pharmaceutical composition.

[0638] In some embodiments, the treatment period is at least 7 days (e.g., at least or about 8 days, at least or about 9 days, at least or about 10 days, at least or about 11 days, at least or about 12 days, at least or about 13 days, at least or about 14 days, at least or about 15 days, at least or about 16 days, at least or about 17 days, at least or about 18 days, at least or about 19 days, at least or about 20 days, at least or about 21 days, at least or about 22 days, at least or about 23 days, at least or about 24 days, at least or about 25 days, at least or about 26 days, at least or about 27 days, at least or about 28 days, at least or about 29 days, or at least or about 30 days).

[0639] In some embodiments, the treatment period is at least 21 days (e.g., at least or about 22 days, at least or about 23 days, at least or about 24 days, at least or about 25 days, at least or about 26 days, at least or about 27 days, at least or about 28 days, at least or about 29 days, at least or about 30 days, at least or about 31 days, at least or about 32 days, at least or about 33 days, at least or about 34 days, at least or about 35 days, at least or about 36 days, at least or about 37 days, at least or about 38 days, at least or about 39 days, or at least or about 40 days).

[0640] Also provided herein are pharmaceutical compositions containing the compounds of the present disclosure as an active ingredient in combination with one or more pharmaceutically acceptable carriers (excipients). In some embodiments, the compositions are suitable for topical administration. In preparing the compositions provided herein, the active ingredient is typically mixed with an excipient, diluted by an excipient, or enclosed in such a carrier, for example, in the form of a capsule, sachet, paper, or other container. When an excipient serves as a diluent, it can be a solid, semi-solid, or liquid material and acts as a vehicle, carrier, or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments containing up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders. In some embodiments, the composition is formulated for oral administration, hi some embodiments, the composition is formulated as a tablet or capsule.

[0641] Compositions containing compounds of the present disclosure can be formulated in unit dosage form, each dosage containing from about 5 to about 1,000 mg (1 g), more usually about 100 mg to about 500 mg, of the active ingredient. The term "unit dosage form" refers to physically discrete units for human and other subjects, each unit containing a predetermined amount of the active agent (i.e., a compound of the present disclosure) that produces a desired therapeutic effect, together with a suitable pharmaceutical excipient.

[0642] In some embodiments, the compositions provided herein contain about 5 mg to about 50 mg of the active ingredient, i.e., a compound of the present disclosure. One of skill in the art will recognize that this embodies a compound or composition containing about 5 mg to about 10 mg, about 10 mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, or about 45 mg to about 50 mg of the active ingredient. In some embodiments, the compositions provided herein contain about 50 mg to about 500 mg of the active ingredient. One of ordinary skill in the art will recognize that this embodies compounds or compositions containing about 50 mg to about 100 mg, about 100 mg to about 150 mg, about 150 mg to about 200 mg, about 200 mg to about 250 mg, about 250 mg to about 300 mg, about 350 mg to about 400 mg, or about 450 mg to about 500 mg of the active ingredient. In some embodiments, the compositions provided herein contain about 500 mg to about 1,000 mg of the active ingredient. One of ordinary skill in the art will recognize that this embodies a compound or composition containing about 500 mg to about 550 mg, about 550 mg to about 600 mg, about 600 mg to about 650 mg, about 650 mg to about 700 mg, about 700 mg to about 750 mg, about 750 mg to about 800 mg, about 800 mg to about 850 mg, about 850 mg to about 900 mg, about 900 mg to about 950 mg, or about 950 mg to about 1,000 mg of the active ingredient.

[0643] The active compounds can be effective over a wide dosage range and are generally administered in a pharmaceutically effective amount, however, it will be understood that the amount of compound actually administered will normally be determined by a physician according to the relevant circumstances, including the condition to be treated, the selected route of administration, the actual compound administered, the age, weight, and response of the individual subject, the severity of the subject's symptoms, etc.

[0644] In some embodiments, the compounds provided herein can be administered in an amount ranging from about 1 mg / kg to about 100 mg / kg. In some embodiments, the compounds provided herein can be administered in an amount of about 1 mg / kg to about 20 mg / kg, about 5 mg / kg to about 50 mg / kg, about 10 mg / kg to about 40 mg / kg, about 15 mg / kg to about 45 mg / kg, about 20 mg / kg to about 60 mg / kg, or about 40 mg / kg to about 70 mg / kg. For example, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 55 mg / kg, about 60 mg / kg, about 65 mg / kg, about 70 mg / kg, about 75 mg / kg, about 80 mg / kg, about 85 mg / kg, about 90 mg / kg, about 95 mg / kg, or about 100 mg / kg. In some embodiments, such administration can be once daily or twice daily (BID) administration. [Example]

[0645] The examples and preparations provided below further illustrate and illustrate the compounds of the present invention and methods of preparing such compounds. It is understood that the scope of the present invention is in no way limited by the scope of the following examples and preparations.

[0646] In some embodiments where a single enantiomer is provided, the enantiomers can be separated by conventional means (chiral chromatography, diastereomeric salt preparation, chiral derivatization, crystallization, enzymatic reaction, etc.). In some embodiments, chiral intermediate compounds are purified to prepare enantiomerically pure (or substantially enantiomerically pure, enantiomerically enriched, etc.) intermediates.

[0647] [ka]

[0648] Example 1 4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-1,4-thiazinane 1,1-dioxide

[0649] [ka]

[0650] Step 1. 5-((R)-1-(3,5-Dichloropyridin-4-yl)ethoxy)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole. A mixture of 3-iodo-1-tetrahydropyran-2-yl-indazol-5-ol (1.0 g, 2.90 mmol, 1.0 equiv), [(1S)-1-(3,5-dichloro-4-pyridyl)ethyl]methanesulfonate (780 mg, 2.90 mmol, 1.0 equiv), and cesium carbonate (1.41 g, 14.45 mmol, 1.5 equiv) in N,N-dimethylformamide (20 mL) was heated at 130° C. for 16 hours. The volatiles were removed under reduced pressure, and the residue was suspended in saturated ammonium chloride (50 mL). The solution was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified on a Buchi automated chromatography system (Sorbtech 40 g silica gel column) eluting with a gradient of 0 to 30% ethyl acetate in heptane to give a white solid (1.01 g, 88% yield). Analysis: LCMS: m / z = 517.2 (M+H).

[0651] Step 2. 3-(6-chloro-3-pyridyl)-5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1-tetrahydropyran-2-yl-indazole. A solution of 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1.32 g, 2.55 mmol, 1.0 equiv), 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (790 mg, 3.31 mmol, 1.3 equiv), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (190 mg, 0.255 mmol, 0.1 equiv) and potassium carbonate (700 mg, 5.1 mmol, 2.0 equiv) in 1,4-dioxane (20 mL) and water (1 mL) was sparged with nitrogen for 15 minutes. After heating at 90°C for 16 hours, the reaction was cooled to room temperature and filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was suspended in saturated sodium bicarbonate (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on a Buchi automated chromatography system (Sorbtech 25 g silica gel column) eluting with a gradient of 0-50% ethyl acetate in heptane to give a white solid (870 mg, 68% yield). Analytical: LCMS: m / z = 503.1 (M+H).

[0652] Step 3. 4-(5-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyridin-2-yl)thiomorpholine 1,1-dioxide. A solution of the product from Step 2 (280 mg, 0.56 mmol, 1.0 equiv), (150 mg, 1.12 mmol, 2.0 equiv), Xantphos (64 mg, 0.11 mmol, 0.2 equiv), tris(dibenzylideneacetone)dipalladium(0) (51 mg, 0.06 mmol, 0.1 equiv) and cesium carbonate (364 mg, 1.1 mmol, 2.0 equiv) in N,N-dimethylformamide (10 mL) was sparged with nitrogen for 15 minutes. After heating at 95°C for 16 hours, the reaction was cooled to room temperature and filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was purified on a Buchi automated chromatography system (Sorbtech 40 g column) eluting with a gradient of 0 to 100% ethyl acetate in heptane to give a brown solid (290 mg, 89% yield). Analytical: LCMS: m / z = 601.2 (M+H).

[0653] Step 4. 4-[5-[5-[(1R)-1-(3,5-Dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-1,4-thiazinane 1,1-dioxide. A solution of the product of Step 3 (290 mg, 0.47 mmol, 1.0 equiv) in 1,4-dioxane (2.0 mL) and water (0.5 mL) was treated with 4 M HCl in 1,4-dioxane (0.95 mL, 3.79 mmol, 8.0 equiv) and heated at 100 °C for 1 h in a CEM microwave reactor. Volatiles were removed under reduced pressure. The residue was dissolved in 20% methanol in dichloromethane (10 mL), followed by the addition of MP-carbonate (1.0 g). After stirring at room temperature for 1 h, the suspension was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified on a Buchi automated chromatography system (RediSep Rf Gold HP C18, 50 g column) eluting with a gradient of 0-80% acetonitrile in water to give a white solid (29 mg, 12% yield). Analysis: LCMS: m / z = 518.1 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 13.04 (s, 1H), 8.60 (s, 2H), 8.59 (d, J = 2.1 Hz, 1H), 7.93 (dd, J = 2.4, 8.9 Hz, 1H), 7.47 (d, J = 9.0 Hz, 1H), 7.20 - 7.15 (m, 2H), 7.10 (dd, J = 2.3, 9.0 Hz, 1H), 6.10 (q, J = 6.7 Hz, 1H), 4.18 - 4.11 (m, 4H), 3.20 - 3.15 (m, 4H), 1.76 (d, J = 6.6Hz, 3H).

[0654] [ka]

[0655] Example 2 (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(6-(piperazin-1-yl)pyridin-3-yl)-1H-indazole dihydrochloride

[0656] [ka]

[0657] Step 1. tert-Butyl 4-(5-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyridin-2-yl)piperazine-1-carboxylate. A solution of 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (3.1 g, 5.99 mmol, 1 equiv.) and tert-butyl 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]piperazine-1-carboxylate (3.03 g, 7.78 mmol, 1.3 equiv.) in a 20 to 1 mixture of 1,4-dioxane and water (50 mL) was sparged with nitrogen for 10 minutes. Potassium carbonate (1.65 g, 11.98 mmol, 2.0 equiv.) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.44 g, 0.6 mmol, 0.1 equiv.) were added, and the reaction mixture was sparged with nitrogen for an additional 5 minutes. The reaction was heated at 90 °C for 16 hours. After cooling to room temperature, the reaction was concentrated under reduced pressure. The residue was diluted with water (100 mL) and dichloromethane (100 mL). The organic layer was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was preabsorbed onto silica gel (5 g) and purified on an Interchim automated chromatography system (Sorbtech 120 g silica gel cartridge) eluting with a gradient of 0-30% ethyl acetate in heptane to give a white solid (2.19 g, 56% yield). Analysis: LCMS: m / z = 653 (M+H).

[0658] Step 2. (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(6-(piperazin-1-yl)pyridin-3-yl)-1H-indazole dihydrochloride. A solution of the product of Step 1 (70.0 mg, 0.11 mmol, 1.0 equiv) in 1,4-dioxane (1.0 mL) was treated with 4 M HCl in dioxane (0.27 mL, 1.1 mmol, 10.0 equiv) at room temperature overnight. The volatiles were removed under reduced pressure. The residue was triturated with a 1:3 mixture of dichloromethane and methanol (2.8 mL) to give a white solid (23.0 mg, 40% yield). Analysis: LCMS: m / z = 469.2 (free base M+H). 1 H NMR (400 MHz, DMSO-d6) δ 9.47 (br s, 2H), 8.59 (s, 2H), 8.50 (d, J = 2.1 Hz, 1H), 8.13 (dd, J = 2.0, 9.0 Hz, 1H), 7.50 (d, J = 9.0 Hz, 1H), 7.29 (d, J = 9.2 Hz, 1H), 7.18 (d, J = 1.8 Hz, 1H), 7.11 (dd, J = 2.2, 9.0 Hz, 1H), 6.12 (q, J = 6.6 Hz, 1H), 3.97 - 3.93 (m, 4H), 3.27 (br s, 4H), 1.76 (d, J = 6.6 Hz, 3H).

[0659] Example 3 [4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]piperazin-1-yl]-morpholino-methanone

[0660] [ka]

[0661] Step 1. (4-(5-(5-((R)-1-(3,5-Dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyridin-2-yl)piperazin-1-yl)(morpholino)methanone. Triethylamine (28.0 uL, 0.204 mmol, 1.1 equiv) and morpholine-4-carbonyl chloride (30.5 mg, 0.204 mmol, 1.1 equiv) were added to a solution of Example 2 (102.6 mg, 0.185 mmol, 1 equiv) in anhydrous THF (3 mL) at room temperature. After stirring for 1 hour, the reaction was diluted with saturated brine (20 mL) and dichloromethane (20 mL). The organic layer was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow solid (90 mg, 73% yield). Analytical: LCMS: m / z=666 (M+H).

[0662] Step 2. (R)-(4-(5-(5-(1-(3,5-Dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)pyridin-2-yl)piperazin-1-yl)(morpholino)methanone. Example 3, Step 1 (90 mg, 0.135 mmol, 1 equiv) in 1,4-dioxane (4.0 mL) and water (1 mL) was treated with 4 M HCl in 1,4-dioxane (0.27 mL, 1.08 mmol, 8.0 equiv) and heated in a CEM microwave reactor at 60° C. for 20 minutes. Additional 4 M HCl in 1,4-dioxane (0.27 mL, 1.08 mmol, 8.0 equiv) was added and the reaction heated in a CEM microwave reactor at 60° C. for an additional 20 minutes. After cooling to room temperature, the volatiles were removed under reduced pressure. The residue was dissolved in methanol (20 mL), treated with MP-carbonate resin (3.2 mmol / g, 1 g), stirred for 30 minutes, filtered, and concentrated under reduced pressure. The residue was preabsorbed onto Celite (1 g) and purified on an Interchim automated chromatography system (RediSep Rf Gold HP C18, 15.5 g cartridge) eluting with a gradient of 0 to 100% acetonitrile in water. The product-containing fractions were collected and lyophilized to give a white solid (36.9 mg, 47% yield). Analysis: LCMS: m / z = 582.2 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 13.01 (br s, 1H), 8.60 (s, 2H), 8.56 (d, J = 2.2 Hz, 1H), 7.89 (dd, J = 2.4, 8.9 Hz, 1H), 7.47 (d, J = 9.0 Hz, 1H), 7.16 (d, J = 2.1 Hz, 1H), 7.09 (dd, J = 2.3, 9.0 Hz, 1H), 6.98 (d, J = 8.8 Hz, 1H), 6.10 (q, J = 6.6 Hz, 1H), 3.63 - 3.57 (m, 8H), 3.33 - 3.30 (m, 4H), 3.22 - 3.18 (m, 4H), 1.76 (d, J = 6.6 Hz, 3H).

[0663] Examples 4-9 were synthesized using the procedure for Example 3.

[0664] [Table 2A]

[0665] [Table 2B]

[0666] Example 10 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-(5-fluoro-6-piperazin-1-yl-3-pyridyl)-1H-indazole

[0667] [ka]

[0668] This example was synthesized using the procedure for Example 1 using 2-chloro-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine and BOC-piperazine to give a white solid. Analysis: LCMS: m / z = 487.0 (M+H);1 H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 8.44 (s, 2H), 7.66 (dd, J = 1.7, 14.1 Hz, 1H), 7.38 (d, J = 8.9 Hz, 1H), 7.19 (d, J = 2.0 Hz, 1H), 7.15 (dd, J = 2.2, 9.0 Hz, 1H), 6.06 (q, J = 6.6 Hz, 1H), 3.61 - 3.53 (m, 4H), 3.12 - 3.01 (m, 4H), 1.83 (d, J = 6.7 Hz, 3H).

[0669] Example 11 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-(2-piperazin-1-ylpyrimidin-5-yl)-1H-indazole

[0670] [ka]

[0671] Example 11 was synthesized using tert-butyl 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]piperazine-1-carboxylate and the procedure for Example 2 to give an off-white solid (150 mg, 64% yield). Analysis: LCMS: m / z = 470.1 (M+H); 1 H NMR (400 MHz, DMSO-d6) δ 13.11 (br s, 1H), 8.75 (s, 2H), 8.57 (s, 2H), 7.47 (d, J = 8.9 Hz, 1H), 7.24 (d, J = 2.0 Hz, 1H), 7.09 (dd, J = 2.2, 9.0 Hz, 1H), 6.14 (q, J = 6.6 Hz, 1H), 3.82 - 3.67 (m, 4H), 2.87 - 2.68 (m, 4H), 1.75 (d, J = 6.7 Hz, 3H).

[0672] Example 12 4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]piperazine-1-carboxamide

[0673] [ka]

[0674] (R)-4-(5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)pyridin-2-yl)piperazine-1-carboxamide. (Trimethylsilyl)isocyanate (66 μL, 0.49 mmol, 1.1 equiv) and triethylamine (68 μL, 0.49 mmol, 1.1 equiv) were added sequentially to a solution of Example 2 (208 mg, 0.45 mmol, 1 equiv) in anhydrous THF (5 mL) at room temperature. After stirring for 20 h, volatiles were removed under reduced pressure, and the crude product was preabsorbed onto Celite (0.5 g) and then purified on an Interchim automated chromatography system (RediSep Rf Gold HP C18, 15.5 g cartridge) eluting with a gradient of 0 to 100% acetonitrile in water. The fractions containing the product were collected and lyophilized to give a white solid (36.0 mg, 16% yield). Analysis: LCMS: m / z = 512.2 (M+H); 1 H NMR (400 MHz, DMSO-d6) δ 13.02 (br s, 1H), 8.60 (s, 2H), 8.56 (d, J = 2.0 Hz, 1H), 7.87 (dd, J = 2.4, 8.8 Hz, 1H), 7.46 (d, J = 8.9 Hz, 1H), 7.16 (d, J = 2.1 Hz, 1H), 7.09 (dd, J = 2.3, 9.0 Hz, 1H), 7.01 (d, J = 8.9 Hz, 1H), 6.14 - 6.02 (m, 3H), 3.62 - 3.50 (m, 5H), 3.50 - 3.39 (m, 4H), 1.76 (d, J = 6.6 Hz, 3H).

[0675] Example 13 [4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-3-fluoro-2-pyridyl]piperazin-1-yl]-(4-methylpiperazin-1-yl)methanone

[0676] [ka]

[0677] (R)-(4-(5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-3-fluoropyridin-2-yl)piperazin-1-yl)(4-methylpiperazin-1-yl)methanone. Triethylamine (21.6 μL, 0.156 mmol, 2.0 equiv) and 4-methylpiperazine-1-carbonyl chloride hydrochloride (17.6 mg, 0.089 mmol, 1.0 equiv) were added sequentially to a solution of Example 10 (43 mg, 0.089 mmol, 1 equiv) in anhydrous THF (5 mL) at room temperature. After stirring for 1 hour, additional triethylamine (21.6 μL, 0.156 mmol, 2.0 equiv.) and 4-methylpiperazine-1-carbonyl chloride hydrochloride (17.6 mg, 0.089 mmol, 1.0 equiv.) were added, and the reaction was stirred at room temperature for 20 hours. Volatiles were removed under reduced pressure. The crude product was preabsorbed onto Celite (0.5 g) and purified on an Interchim automated chromatography system (RediSep Rf Gold HP C18, 15.5 g cartridge) eluting with a gradient of 0-100% acetonitrile in water. Further purification on an Interchim automated chromatography system (Sorbtech 25 g silica gel cartridge) eluting with a gradient of 0-15% methanol in dichloromethane gave a white solid (12.0 mg, 22% yield). Analysis: LCMS: m / z = 613.2 (M+H); 1H NMR (400 MHz, CDCl3) δ 10.51 (br s, 1H), 8.50 (t, J = 1.5 Hz, 1H), 8.43 (s, 2H), 7.69 (dd, J = 1.8, 13.9 Hz, 1H), 7.37 (dd, J = 0.4, 8.9 Hz, 1H), 7.17 (d, J = 1.8 Hz, 1H), 7.14 (d, J = 9.3 Hz, 1H), 6.05 (q, J = 6.7 Hz, 1H), 3.62 - 3.57 (m, 4H), 3.47 - 3.42 (m, 4H), 3.40 - 3.34 (m, 4H), 2.44 (br t, J = 4.8 Hz, 4H), 2.33 (s, 3H), 1.82 (d, J = 6.7 Hz, 3H).

[0678] Example 14 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[2-(4-methylsulfonylpiperazin-1-yl)pyrimidin-5-yl]-1H-indazole

[0679] [ka]

[0680] (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(2-(4-(methylsulfonyl)piperazin-1-yl)pyrimidin-5-yl)-1H-indazole. Methanesulfonyl chloride (25 mg, 0.22 mmol, 1 equiv) in acetonitrile (1 mL) was added dropwise to a solution of Example 11 (104 mg, 0.22 mmol, 1 equiv) in pyridine (10 mL) at 0° C. After stirring at room temperature for 16 hours, additional methanesulfonyl chloride (13 mg, 0.11 mmol, 0.5 equiv) in acetonitrile (0.5 mL) was added. After stirring for 70 hours, the reaction was concentrated under reduced pressure. The residue was dissolved in DMSO (6 mL) and purified on an InterChim automated chromatography system (RediSep Rf GOLD 100 g HP C18 column) eluting with a gradient of 0 to 100% acetonitrile in water to give an off-white solid (20 mg, 17% yield). Analysis: LCMS: m / z = 548.1 (M+H); 1 H NMR (400 MHz, DMSO-d6) δ = 13.12 (br s, 1H), 8.82 (s, 2H), 8.57 (s, 2H), 7.48 (d, J = 9.0 Hz, 1H), 7.26 (d, J = 2.1 Hz, 1H), 7.11 (dd, J = 2.3, 9.0 Hz, 1H), 6.15 (q, J = 6.7 Hz, 1H), 4.00 - 3.91 (m, 4H), 3.27 - 3.22 (m, 4H), 2.92 (s, 3H), 1.76 (d, J = 6.6 Hz, 3H).

[0681] Example 15 [4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]pyrimidin-2-yl]piperazin-1-yl]-(4-methylpiperazin-1-yl)methanone

[0682] [ka]

[0683] 4-Methylpiperazine-1-carbonyl chloride (44 mg, 0.22 mmol, 1 equiv.) was added to a solution of Example 11 (104 mg, 0.22 mmol, 1 equiv.) in pyridine (10 mL) at room temperature. After stirring for 16 h, the mixture was concentrated under reduced pressure. The residue was dissolved in DMSO (6 mL) and purified on an InterChim automated chromatography system (RediSep Rf GOLD 100 g HP C18 column) eluting with a gradient of 0-100% acetonitrile in water to give an off-white solid (30 mg, 23% yield). Analysis: LCMS: m / z = 596.2 (M+H); 1 H NMR (400 MHz, DMSO-d6) δ 13.05 (br s, 1H), 8.79 (s, 2H), 8.57 (s, 2H), 7.48 (d, J = 9.2 Hz, 1H), 7.25 (d, J = 2.1 Hz, 1H), 7.10 (dd, J = 2.3, 9.0 Hz, 1H), 6.14 (q, J = 6.7 Hz, 1H), 3.88 - 3.79 (m, 4H), 3.29 - 3.25 (m, 4H), 3.24 - 3.17 (m, 4H), 2.31 (br t, J = 4.6 Hz, 4H), 2.19 (s, 3H), 1.76 (d, J = 6.6 Hz, 3H).

[0684] [ka]

[0685] Example 16 3-[6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-3-pyridyl]-5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole

[0686] [ka]

[0687] Step 1. tert-Butyl 3-(5-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate. 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-iodo-1-tetrahydropyran-2-yl-indazole (170 mg, 0.33 mmol, 1.0 equiv.), tert-butyl 3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]-3,6-di A solution of azabicyclo[3.1.1]heptane-6-carboxylate (128 mg, 0.40 mmol, 1.2 equiv.), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (24 mg, 0.04 mmol, 0.1 equiv.), and potassium carbonate (91 mg, 0.66 mmol, 2.0 equiv.) was sparged with nitrogen for 15 minutes and then heated at 90 °C for 16 hours. After cooling to room temperature, the reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified on a Buchi automated chromatography system (Sorbtech 25 g silica gel column) eluting with a gradient of 0 to 70% ethyl acetate in heptane to give a white solid (80 mg, 36% yield). Analysis: LCMS: m / z = 665.1 (M+H).

[0688] Step 2. 3-(5-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane. A solution of the product from Step 1 (80 mg, 0.13 mmol, 1.0 equiv.) in 1,4-dioxane (2.0 mL) and water (0.5 mL) was treated with 4 M HCl in 1,4-dioxane (0.65 mL, 2.65 mmol, 20.0 equiv.) and heated in a CEM microwave reactor at 100° C. for 1 hour. After cooling to room temperature, the volatiles were removed under reduced pressure. The residue was dissolved in 20% methanol in dichloromethane (10 mL) followed by the addition of MP-carbonate resin (1.0 g). After stirring at room temperature for 1 hour, the suspension was filtered and the filtrate was concentrated under reduced pressure. The residue was purified on a Buchi automated chromatography system (RediSep Rf Gold HP C18, 50 g column) eluting with a gradient of 0-100% acetonitrile in water. The product-containing fractions were lyophilized to give an off-white solid (8 mg, 14% yield). Analysis: LCMS: m / z = 481.1 (M+H); 1 H NMR (400 MHz, METHANOL-d4) δ 8.55 (dd, J = 0.5, 2.3 Hz, 1H), 8.46 (s, 2H), 7.97 (ddd, J = 2.0, 4.5, 8.6 Hz, 2H), 7.48 - 7.35 (m, 2H), 7.17 (dd, J = 2.3, 9.0 Hz, 1H), 7.11 (d, J = 2.1 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 6.12 (q, J = 6.6 Hz, 1H), 4.52 (br d, J = 6.1 Hz, 2H), 4.12 - 3.99 (m, 4H), 3.18 - 3.06 (m, 1H), 1.97 (d, J = 10.3 Hz, 1H), 1.82 (d, J = 6.7 Hz, 3H).

[0689] Example 17 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[5-fluoro-6-(4-methylsulfonyl-piperazin-1-yl)-3-pyridyl]-1H-indazole

[0690] [ka]

[0691] Step 1. 3-(6-chloro-4-fluoropyridin-3-yl)-5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole. A solution of 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-iodo-1-tetrahydropyran-2-yl-indazole (0.4 g, 0.77 mmol, 1 equivalent) and 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.258 g, 1.0 mmol, 1.3 equivalents) in a 20:1 mixture of 1,4-dioxane and water (10 mL) was sparged with nitrogen for 15 minutes. Potassium carbonate (0.28 g, 2.0 mmol, 2.6 equiv.) and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (56 mg, 0.077 mmol, 0.01 equiv.) were added, and the reaction mixture was sparged with nitrogen for an additional 5 minutes. The reaction was heated at 90 °C for 16 hours. After cooling to room temperature, the reaction was concentrated under reduced pressure and diluted with saturated brine (20 mL) and dichloromethane (20 mL). The layers were separated, and the organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was preabsorbed onto silica gel (1 g) and purified on an Interchim automated chromatography system (Sorbtech 40 g silica gel cartridge) eluting with a gradient of 5-50% ethyl acetate in heptane to give a white solid (360 mg, 89% yield). Analysis: LCMS: m / z = 521.8 (M+H).

[0692] Step 2. tert-Butyl 4-(5-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyridin-2-yl)piperazine-1-carboxylate. A solution of the product of Step 1 (360 mg, 0.69 mmol, 1 equiv), BOC-piperazine (193 mg, 1.04 mmol, 1.5 equiv), Xantphos (80 mg, 0.14 mmol, 0.2 equiv), tris(dibenzylideneacetone)dipalladium(0) (63 mg, 0.07 mmol, 0.1 equiv) and cesium carbonate (450 mg, 1.4 mmol, 2.0 equiv) in N,N-dimethylformamide (10 mL) was sparged with nitrogen for 10 minutes. After heating at 95°C for 16 hours, the reaction was cooled to room temperature and filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was purified on a Buchi automated chromatography system (Sorbtech 25g silica gel column) eluting with a gradient of 0-15% methanol in dichloromethane to give a brown solid (107 mg, 23% yield). Analytical: LCMS: m / z = 653.1 (M+H).

[0693] Step 3. (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(4-fluoro-6-(piperazin-1-yl)pyridin-3-yl)-1H-indazole. A solution of the product of Step 2 (90 mg, 0.14 mmol, 1 equiv) in 1,4-dioxane (2.0 mL) and water (0.2 mL) was treated with 4 M HCl in 1,4-dioxane (0.7 mL, 2.68 mmol, 20 equiv) and heated in a CEM microwave reactor at 100° C. for 1 h. The volatiles were removed under reduced pressure. The residue was dissolved in 20% methanol in dichloromethane (10 mL), followed by the addition of MP-carbonate (1.0 g). After stirring at room temperature for 1 h, the suspension was filtered and the filtrate was concentrated under reduced pressure. The residue was purified on a Buchi automated chromatography system (RediSep Rf Gold HP C18, 25 g column) eluting with a gradient of 0 to 80% acetonitrile in water to give an off-white solid (15 mg, 20% yield). Analytical: LCMS: m / z = 487.1 (M+H).

[0694] Step 4. (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(4-fluoro-6-(4-(methylsulfonyl)piperazin-1-yl)pyridin-3-yl)-1H-indazole. Methanesulfonyl chloride (3 μL, 0.04 mmol, 1.5 equiv) was added to a solution of the product of Step 3 (15 mg, 0.03 mmol, 1.0 equiv) in pyridine (2.0 mL) at room temperature. After stirring for 16 hours, the volatiles were removed under reduced pressure. The residue was first purified on a Buchi automated chromatography system (RediSep Rf Gold HP C18, 50 g column) eluting with a gradient of 0-80% acetonitrile in water, then repurified on a Teledyne ACCQPrep automated chromatography system (Waters Atlantis T3 Prep OBD column, 5 μm, 19 × 250 mm) eluting with a gradient of 0-80% acetonitrile in water containing 0.1% formic acid. The product-containing fractions were lyophilized to give a white solid (R)-ADE-163 (12 mg, 70% yield). Analysis: LCMS: m / z = 565.1 (M+H); 1 H NMR (400 MHz, CD3OD) δ 8.47 (s, 2H), 8.36 (d, J = 10.8 Hz, 1H), 7.45 (d, J = 9.0 Hz, 1H), 7.17 (dd, J = 2.4, 9.0 Hz, 1H), 6.86 (t, J = 2.4 Hz, 1H), 6.78 (d, J = 13.7 Hz, 1H), 6.05 (q, J = 6.7 Hz, 1H), 3.81 - 3.76 (m, 4H), 3.38 - 3.34 (m, 4H), 2.89 (s, 3H), 1.80 (d, J = 6.6 Hz, 3H).

[0695] Example 18 3-(6-chloro-3-pyridyl)-5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole

[0696] [ka]

[0697] 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-chloro-1-tetrahydropyran-2-yl-indazole was deprotected using the conditions for Example 1, step 4. Analysis: LCMS: m / z = 421.1 (M+H); 1 H NMR (400 MHz, DMSO) δ 13.42 (br s, 1H), 8.84 )dd, J = 0.6, 2.4 Hz, 1H), 8.59 (s, 2H), 8.21 (dd, J = 2.6, 8.3 Hz, 1H), 7.67 (dd, J = 0.6, 8.3 Hz, 1H), 7.54 (d, J - 9.2 Hz, 1H), 7.24 d, J = 2.2 Hz, 1H), 7.13 (dd, J = 2.2, 9 Hz, 1H), 6.14 (q, J = 6.6 Hz, 1H), 1.77 (d, J = 6.6 Hz, 3H).

[0698] Example 19 4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]pyrimidin-2-yl]-N,N-dimethyl-piperazine-1-carboxamide

[0699] [ka]

[0700] 4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]pyrimidin-2-yl]-N,N-dimethyl-piperazine-1-carboxamide. Triethylamine (65 mg, 0.638 mmol, 3 equiv.) and N,N-dimethylcarbamoyl chloride (23 mg, 0.213 mmol, 1 equiv.) in acetonitrile (1 mL) were added dropwise to a solution of Example 11 (100 mg, 0.213 mmol, 1 equiv.) in THF (10 mL) at room temperature. After stirring for 16 hours, the mixture was concentrated under reduced pressure. The residue was dissolved in DMSO (6 mL) and purified on an InterChim automated chromatography system (RediSep Rf GOLD 100 g HP C18 column) eluting with a gradient of 0 to 100% acetonitrile in water to give an off-white solid (40 mg, 35% yield). Analysis: LCMS: m / z = 541.2 (M+H); 1 H NMR (400 MHz, DMSO-d6) δ 13.13 (br s, 1H), 8.79 (s, 2H), 8.57 (s, 2H), 7.47 (d, J = 9.0 Hz, 1H), 7.25 (d, J = 2.1 Hz, 1H), 7.10 (dd, J = 2.2, 9.0 Hz, 1H), 6.14 (q, J = 6.7 Hz, 1H), 3.87 - 3.80 (m, 4H), 3.26 - 3.21 (m, 4H), 2.80 (s, 6H), 1.76 (d, J = 6.6 Hz, 3H).

[0701] Example 20 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[6-(6-methylsulfonyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)-3-pyridyl]-1H-indazole

[0702] [ka]

[0703] 5-[(1R)-1-(3,5-Dichloro-4-pyridyl)ethoxy]-3-[6-(6-methylsulfonyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)-3-pyridyl]-1H-indazole. Triethylamine (24.8 μL, 0.178 mmol, 1.2 equiv.) and methanesulfonyl chloride (11.5 μL, 0.149 mmol, 1 equiv.) were added sequentially to a solution of Example 16 (71 mg, 0.149 mmol, 1 equiv.) in anhydrous THF (2 mL) at room temperature. After stirring for 16 hours, additional methanesulfonyl chloride (2 × 11.5 μL, 0.149 mmol, 2 equiv.) and triethylamine (24.8 μL, 0.178 mmol, 1.2 equiv.) were added at 24-hour intervals for a total stirring time of 72 hours. Volatiles were removed under reduced pressure, and the crude product was preabsorbed onto Celite (0.5 g) and then purified on an Interchim automated chromatography system (RediSep Rf Gold HP C18, 15.5 g cartridge) eluting with a gradient of 0 to 100% acetonitrile in water. Product-containing fractions were collected and lyophilized to give a white solid. Analysis: LCMS: m / z = 559.1 (M+H); 1 H NMR (400 MHz, CDCl3) δ 8.71 (d, J = 2.3 Hz, 1H), 8.43 (s, 2H), 7.97 (dd, J = 2.1, 8.7 Hz, 1H), 7.35 (d, J = 9.0 Hz, 1H), 7.26 (s, 1H), 7.24 (d, J = 2.1 Hz, 1H), 7.13 (dd, J = 1.9, 9.0 Hz, 1H), 6.64 (d, J = 8.8 Hz, 1H), 6.05 (q, J = 6.7 Hz, 1H), 4.57 (br d, J = 6.2 Hz, 2H), 4.10 (br d, J = 11.7 Hz, 2H), 3.88 (br d, J = 11.7 Hz, 2H), 3.14 - 3.08 (m, 1H), 2.95 (s, 3H), 1.82 (d, J = 6.6 Hz, 3H).

[0704] [ka]

[0705] Example 21 3-[6-(4,7-diazaspiro[2.5]octan-7-yl)-3-pyridyl]-5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole

[0706] [ka]

[0707] Step 1. (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(6-fluoropyridin-3-yl)-1H-indazole. A solution of 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-iodo-1-tetrahydropyran-2-yl-indazole (3.0 g, 5.80 mmol, 1.0 equiv), 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.6 g, 6.96 mmol, 1.2 equiv), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (430 mg, 0.58 mmol, 0.1 equiv) and potassium carbonate (1.6 g, 11.66 mmol, 2.0 equiv) in 1,4-dioxane (30 mL) and water (3 mL) was sparged with nitrogen for 15 minutes and then heated at 100° C. for 16 hours. After cooling to room temperature, the reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified on a Buchi automated chromatography system (Sorbtech 40 g silica gel column) eluting with a gradient of 0 to 60% ethyl acetate in heptane to give a white solid (2.5 g, 88% yield). Analysis: LCMS: m / z = 487.1 (M+H).

[0708] Step 2. tert-Butyl 7-(5-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyridin-2-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate. A suspension of the product Step 1 (350 mg, 0.72 mmol, 1.0 equiv.), tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate (310 mg, 1.44 mmol, 2.0 equiv.) and potassium carbonate (400 mg, 2.88 mmol, 4.0 equiv.) in DMSO (5.0 mL) was heated in a sealed tube at 120 °C for 20 hours. After cooling to room temperature, the reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified on a Buchi automated chromatography system (RediSep Rf Gold HP C18, 50 g column) eluting with a gradient of 0 to 100% acetonitrile in water to give an off-white solid (417 mg, 87% yield). Analytical: LCMS: m / z = 679.1 (M+H).

[0709] Step 3. 3-[6-(4,7-diazaspiro[2.5]octan-7-yl)-3-pyridyl]-5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole. A solution of the product of Step 2 (25 mg, 0.04 mmol, 1.0 equiv) in 1,4-dioxane (1.0 mL) and water (0.4 mL) was treated with 4 M HCl in 1,4-dioxane (0.2 mL, 0.75 mmol, 20.0 equiv) and heated in a microwave at 100° C. for 1 h. After cooling to room temperature, the volatiles were removed under reduced pressure. The residue was dissolved in 20% methanol in dichloromethane (10 mL), followed by the addition of MP-carbonate (1.0 g). After stirring at room temperature for 1 h, the suspension was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified on a Buchi automated chromatography system (RediSep Rf Gold HP C18, 50 g column) eluting with a gradient of 0-80% acetonitrile. The product fractions were lyophilized to give an off-white solid (7.5 mg, 20% yield). Analysis: LCMS: m / z = 495.1 (M+H); 1H NMR (400 MHz, CD3OD) δ 8.50 - 8.44 (m, 3H), 7.88 (dd, J = 2.4, 8.8 Hz, 1H), 7.43 (d, J = 9.0 Hz, 1H), 7.16 (dd, J = 2.3, 9.0 Hz, 1H), 7.11 (d, J = 2.0 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.13 (q, J = 6.6 Hz, 1H), 3.66 - 3.62 (m, 2H), 3.51 (s, 2H), 3.08 - 3.02 (m, 2H), 1.82 (d, J = 6.6 Hz, 3H), 0.72 - 0.65 (m, 4H).

[0710] Example 22 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[6-(4-methylsulfonyl-4,7-diazaspiro[2.5]octan-7-yl)-3-pyridyl]-1H-indazole

[0711] [ka]

[0712] Methanesulfonyl chloride (21 μL, 0.26 mmol, 1.5 equiv) was added to a solution of Example 21 (100 mg, 0.17 mmol, 1.0 equiv) in pyridine (5.0 mL) at room temperature. After stirring for 16 h, additional methanesulfonyl chloride (21 μL, 0.26 mmol, 1.5 equiv) was added at room temperature along with N,N-diisopropylethylamine (0.1 mL). After stirring for an additional 2 h, the volatiles were removed under reduced pressure. The residue was first purified on a Buchi automated chromatography system (RediSep Rf Gold HP C18, 50 g column) eluting with a gradient of 0–80% acetonitrile in water, then repurified on a Buchi automated chromatography system (RediSep Rf Gold HP C18, 4 g column) eluting with a gradient of 0–80% acetonitrile in water. The fractions containing the product were lyophilized to give an off-white solid (16.0 mg, 16% yield). Analysis: LCMS: m / z = 573.2 (M+H); 1 H NMR (400 MHz, CD3OD) δ 8.48 (s, 3H), 7.90 (dd, J = 2.4, 8.9 Hz, 1H), 7.44 (d, J = 8.9 Hz, 1H), 7.17 (dd, J = 2.3, 9.0 Hz, 1H), 7.11 (d, J = 1.7 Hz, 1H), 6.93 (dd, J = 0.5, 8.9 Hz, 1H), 6.13 (q, J = 6.6 Hz, 1H), 3.80 - 3.74 (m, 4H), 3.04 (s, 3H), 1.82 (d, J = 6.7 Hz, 3H), 1.29 (s, 3H), 1.23 - 1.20 (m, 2H), 1.00 - 0.96 (m, 2H).

[0713] Example 23 (R)-7-(5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)pyridin-2-yl)-N,N-dimethyl-4,7-diazaspiro[2.5]octane-4-carboxamide

[0714] [ka]

[0715] Dimethylcarbamic acid chloride (23 μL, 0.26 mmol, 1.5 equiv.) was added to a solution of Example 21 (100 mg, 0.17 mmol, 1.0 equiv.) in pyridine (5.0 mL) at room temperature. After stirring for 16 h, additional dimethylcarbamic acid chloride (23 μL, 0.26 mmol, 1.5 equiv.) was added at room temperature along with N,N-diisopropylethylamine (0.1 mL). After stirring for an additional 2 h, the volatiles were removed under reduced pressure. The residue was first purified on a Buchi automated chromatography system (RediSep Rf Gold HP C18, 50 g column) eluting with a gradient of 0–80% acetonitrile in water, and then repurified on a Buchi automated chromatography system (RediSep Rf Gold HP C18, 4 g column) eluting with a gradient of 0–80% acetonitrile in water to give an off-white solid (5 mg, 5% yield). Analysis: LCMS: m / z = 566.3 (M+H); 1 H NMR (400 MHz, CD3OD) δ 8.52 (dd, J = 0.6, 2.4 Hz, 1H), 8.47 (s, 2H), 7.93 (dd, J = 2.4, 8.9 Hz, 1H), 7.88 (dd, J = 0.4, 9.2 Hz, 1H), 7.24 (dd, J = 2.4, 9.1 Hz, 1H), 7.16 (d, J = 2.3 Hz, 1H), 6.92 (dd, J = 0.5, 8.9 Hz, 1H), 6.16 (q, J = 6.6 Hz, 1H), 3.70 - 3.65 (m, 2H), 3.55 (s, 2H), 3.24 (s, 6H), 3.08 - 3.01 (m, 2H), 1.83 (d, J = 6.7 Hz, 3H), 0.76 - 0.61 (m, 4H).

[0716] Example 24 7-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-4,7-diazaspiro[2.5]octane-4-carboxamide

[0717] [ka]

[0718] Step 1. 4-Nitrophenyl (R)-7-(5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)pyridin-2-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate. p-Nitrophenyl chloroformate (48.8 mg, 0.242 mmol, 1.1 equiv) and triethylamine (150 μL, 1.1 mmol, 5 equiv) were added sequentially to a solution of Example 21 (119 mg, 0.22 mmol, 1 equiv) in anhydrous THF (3 mL) at room temperature. After stirring overnight, the brown solution was diluted with water (10 mL) and ethyl acetate (10 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (3 × 5 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified on an Interchim automated chromatography system (RediSep Rf Gold HP C18, 4 g column) eluting with a gradient of 0 to 100% acetonitrile in water to give a white solid (40 mg, 28% yield). Analytical: LCMS: m / z = 660.1 (M+H).

[0719] Step 2. 7-[5-[5-[(1R)-1-(3,5-Dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-4,7-diazaspiro[2.5]octane-4-carboxamide. Concentrated ammonium hydroxide (71 μL, 0.515 mmol, 10 equiv.) was added to a solution of the product from Step 1 (34 mg, 0.0515 mmol, 1 equiv.) in DMSO (2 mL). The yellow solution was heated at 90° C. overnight, cooled to room temperature, and diluted with water (5 mL) and ethyl acetate (5 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (3×5 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified on an Interchim automated chromatography system (RediSep Rf Gold HP C18, 4 g column) eluting with a gradient of 0-100% acetonitrile in water to give a white solid (40 mg, 28% yield). Analysis: LCMS: m / z = 538.2 (M+H). 1 H NMR (400 MHz, CDCl3) δ 10.12 (br s, 1H), 8.64 (d, J = 1.8 Hz, 1H), 8.42 (s, 2H), 7.93 (dd, J = 2.3, 8.8 Hz, 1H), 7.36 (d, J = 9.0 Hz, 1H), 7.21 (d, J = 2.2 Hz, 1H), 7.13 (dd, J = 2.3, 9.0 Hz, 1H), 6.72 (d, J = 8.4 Hz, 1H), 6.05 (q, J = 6.6 Hz, 1H), 5.08 (s, 2H), 3.85 (br s, 2H), 3.61 (s, 4H), 1.81 (d, J = 6.7 Hz, 3H), 1.14 - 1.05 (m, 4H).

[0720] Example 25 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-(6-fluoro-3-pyridyl)-1H-indazole

[0721] [ka]

[0722] Step 1. (R)-5-(1-(3,5-Dichloropyridin-4-yl)ethoxy)-3-iodo-1H-indazole. A mixture of 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-iodo-1-tetrahydropyran-2-yl-indazole (1.0 g, 1.93 mmol, 1 equiv.) in dichloromethane (10 mL) was treated with trifluoroacetic acid (3 mL, 39.2 mmol, 20 equiv.) at room temperature for 24 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane (100 mL), washed with saturated sodium bicarbonate (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The product was dried under vacuum at room temperature overnight to give an orange solid (1.05 g), which was used subsequently. Analysis: LCMS (ESI) m / z = 434 (M+H); 1 H NMR (400 MHz, DMSO-d6) δ 13.37 (br s, 1H), 8.60 (s, 2H), 7.46 (d, J = 8.9 Hz, 1H), 7.13 (dd, J = 2.4, 9.0 Hz, 1H), 6.59 (d, J = 2.3 Hz, 1H), 6.07 (q, J = 6.6 Hz, 1H), 1.75 (d, J = 6.6 Hz, 3H).

[0723] Step 2. (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(6-fluoropyridin-3-yl)-1H-indazole. A solution of the product from Step 1 (1.0 g, 2.3 mmol, 1 equivalent) and 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.67 g, 2.995 mmol, 1.3 equivalents) in a 20:1 mixture of 1,4-dioxane and water (21 mL) was sparged with nitrogen for 15 minutes. Potassium carbonate (0.825 g, 5.98 mmol, 2.6 equivalents) and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (168 mg, 0.23 mmol, 0.01 equivalents) were added, and the reaction mixture was sparged with nitrogen for an additional 5 minutes. The reaction was heated at 90°C for 2 hours. After cooling to room temperature, the reaction was concentrated under reduced pressure and diluted with saturated brine (30 mL) and dichloromethane (30 mL). The layers were separated, and the organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was absorbed onto silica gel (2 g) and purified on an Interchim automated chromatography system (Sorbtech 40 g silica gel cartridge) eluting with a gradient of 20-80% ethyl acetate in heptane to give a yellow solid (0.42 g, 45% yield). Analysis: LCMS (ESI) m / z = 403.1 (M+H); 1 H NMR (400 MHz, CDCl3) δ 10.55 (br s, 1H), 8.68 (d, J = 2.1 Hz, 1H), 8.43 (s, 2H), 8.24 (dt, J = 2.4, 8.1 Hz, 1H), 7.39 (dd, J = 0.8, 8.7 Hz, 1H), 7.20 - 7.14 (m, 2H), 7.06 (dd, J = 2.8, 8.4 Hz, 1H), 6.06 (q, J = 6.7 Hz, 1H), 1.82 (d, J = 6.6 Hz, 3H).

[0724] Example 26 8-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-1-oxa-8-azaspiro[4.5]decane

[0725] [ka]

[0726] Step 1. 8-(5-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyridin-2-yl)-1-oxa-8-azaspiro[4.5]decane. A suspension of 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-(6-fluoro-3-pyridyl)-1-tetrahydropyran-2-yl-indazole (100 mg, 0.21 mmol, 1.0 equiv.), 1-oxa-8-azaspiro[4.5]decane (110 mg, 0.42 mmol, 3.0 equiv.), and potassium carbonate (145 mg, 1.05 mmol, 5.0 equiv.) in 1-methyl-2-pyrrolidone (5 mL) was heated at 120 °C for 16 h in a sealed tube. The reaction mixture was cooled to room temperature and absorbed onto Celite under reduced pressure. The residue was purified on a Buchi automated chromatography system (RediSep Rf Gold HP C18, 50 g column) eluting with a gradient of 0 to 100% acetonitrile in water to give a white solid (105 mg, 84% yield). Analysis: LCMS (ESI) m / z=608.1 (M+H).

[0727] Step 2. (R)-8-(5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)pyridin-2-yl)-1-oxa-8-azaspiro[4.5]decane. A solution of the product of Step 1 (105 mg, 0.18 mmol, 1.0 equiv) in 1,4-dioxane (2.0 mL) and water (0.1 mL) was treated with 4 M HCl in 1,4-dioxane (0.86 mL, 3.45 mmol, 20.0 equiv) and heated in a microwave at 100° C. for 1 h. After cooling to room temperature, the volatiles were removed under reduced pressure. The residue was dissolved in 20% methanol in dichloromethane (10 mL), followed by the addition of MP-carbonate resin (1.0 g). After stirring at room temperature for 1 h, the suspension was filtered and the filtrate was concentrated under reduced pressure. The residue was purified on a Buchi automated chromatography system (RediSep Rf Gold HP C18, 50 g column) eluting with a gradient of 0-80% acetonitrile in water. The product-containing fractions were lyophilized to give a white solid (40.1 mg, 44% yield). Analysis: LCMS (ESI) m / z = 524.2 (M+H); 1 H NMR (400 MHz, DMSO-d6) δ 13.01 (br s, 1H), 8.60 (s, 2H), 8.53 (d, J = 2.1 Hz, 1H), 7.83 (dd, J = 2.4, 8.9 Hz, 1H), 7.46 (d, J = 9.0 Hz, 1H), 7.16 (d, J = 2.1Hz, 1H), 7.08 (dd, J = 2.3, 8.9 Hz, 1H), 6.98 (d, J = 8.8 Hz, 1H), 6.10 (q, J = 6.7 Hz, 1H), 3.80 - 3.73 (m, 4H), 3.58 - 3.51 (m, 2H), 1.94 - 1.86 (m, 2H), 1.76 (d, J = 6.6 Hz, 3H), 1.74 - 1.68 (m, 2H), 1.61 (t, J = 5.6 Hz, 4H).

[0728] Examples 27-34 were synthesized using the procedure for Example 26.

[0729] [Table 3A]

[0730] [Table 3B]

[0731] [Table 3C]

[0732] [Table 3D]

[0733] Example 41 8-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-3-fluoro-2-pyridyl]-1,8-diazaspiro[4.5]decan-2-one

[0734] [ka]

[0735] This example was synthesized by the method for Example 17 using 3-(6-chloro-4-fluoropyridin-3-yl)-5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole to give a white solid (49 mg, 35% yield). Analysis: LCMS: m / z = 555.2 (M+H); 1H NMR (400 MHz, CDCL3) δ 10.57 (br s, 1H), 8.47 (t, J = 1.6 Hz, 1H), 8.44 (s, 2H), 7.64 (dd, J = 2.0, 14.1 Hz, 1H), 7.37 (d, J = 9.0 Hz, 1H), 7.17 (d, J = 2.0 Hz, 1H), 7.13 (dd, J = 2.3, 9.0 Hz, 1H), 6.09 - 5.97 (m, 2H), 4.16 (td, J = 3.8, 13.4 Hz, 2H), 3.40 (t, J = 6.8 Hz, 2H), 3.21 (br t, J = 11.7 Hz, 2H), 2.22 - 2.10 (m, 4H), 1.82 (d, J = 6.7 Hz, 3H), 1.66 - 1.52 (m, 2H).

[0736] Example 42 8-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-3-fluoro-2-pyridyl]-1,8-diazaspiro[4.5]decan-2-one

[0737] [ka]

[0738] This example was synthesized by the method for Example 17 using 3-(6-chloro-4-fluoropyridin-3-yl)-5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole to give a white solid (45 mg, 58% yield). Analysis: LCMS: m / z = 555.2 (M+H); 1H NMR (400 MHz, CDCl3) δ 11.91 (br s, 1H), 8.42 (s, 2H), 8.39 (t, J = 1.6 Hz, 1H), 7.80 (s, 1H), 7.57 (dd, J = 1.9, 14.0 Hz, 1H), 7.42 (d, J = 8.9 Hz, 1H), 7.14 (dd, J = 2.2, 8.9 Hz, 1H), 7.11 (d, J = 2.0 Hz, 1H), 6.03 (q, J = 6.7 Hz, 1H), 3.84 - 3.71 (m, 2H), 3.36 - 3.24 (m, 2H), 2.51 (t, J = 8.1 Hz, 2H), 2.05 (t, J = 8.1 Hz, 2H), 1.90 - 1.78 (m, 7H).

[0739] Example 43 8-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-3-fluoro-2-pyridyl]-1-methyl-1,8-diazaspiro[4.5]decan-2-one

[0740] [ka]

[0741] This example was synthesized by the method for Example 17 using 3-(6-chloro-4-fluoropyridin-3-yl)-5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole. Analysis: LCMS: m / z = 569.2 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 13.17 (s, 1H), 8.57 (s, 2H), 8.46 (t, J = 1.7 Hz, 1H), 7.78 (dd, J = 2.0, 14.4 Hz, 1H), 7.49 (d, J = 8.9 Hz, 1H), 7.21 (d, J = 2.1 Hz, 1H), 7.11 (dd, J = 2.3, 9.0 Hz, 1H), 6.13 (q, J = 6.6 Hz, 1H), 4.11 (br d, J = 13.4 Hz, 2H), 3.12 - 3.03 (m, 2H), 2.64 (s, 3H), 2.32 - 2.26 (m, 2H), 2.06 - 1.97 (m, 4H), 1.76 (d, J = 6.6 Hz, 3H), 1.49 (br d, J = 12.5 Hz, 2H).

[0742] Example 44 9-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-3-fluoro-2-pyridyl]-1-methyl-1,4,9-triazaspiro[5.5]undecan-5-one

[0743] [ka]

[0744] This example was synthesized by the method for Example 17 using 3-(6-chloro-4-fluoropyridin-3-yl)-5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole. Analysis: LCMS: m / z = 584.2 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 13.16 (br s, 1H), 8.57 (s, 2H), 8.44 (t, J = 1.7 Hz, 1H), 7.74 (dd, J = 2.0, 14.5 Hz, 1H), 7.48 (d, J = 9.2 Hz, 1H), 7.45 (s, 1H), 7.20 (d, J = 2.2 Hz, 1H), 7.10 (dd, J = 2.3, 9.0 Hz, 1H), 6.14 (q, J = 6.6 Hz, 1H), 3.85 (br d, J = 12.8 Hz, 2H), 3.38 - 3.32 (m, 2H), 3.06 (t, J = 5.9 Hz, 2H), 2.41 (s, 3H), 2.05 - 1.91 (m, 4H), 1.76 (d, J = 6.7 Hz, 3H).

[0745] Example 45 3-[6-(2,6-diazaspiro[3.3]heptan-2-yl)-3-pyridyl]-5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole

[0746] [ka]

[0747] Step 1. tert-Butyl (R)-6-(5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)pyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate. A mixture of Example 25 (0.295 g, 0.732 mmol, 1 equiv.), tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (0.29 g, 1.464 mmol, 2 equiv.), and potassium carbonate (0.4 g, 2.93 mmol, 4 equiv.) in anhydrous N-methylpyrrolidone was heated at 120° C. for 16 hours. The reaction mixture was filtered through a syringe filter, and the filtrate was pre-absorbed onto Celite (5 g). The material was purified on an Interchim automated chromatography system (RediSep Rf Gold HP C18, 15.5 g cartridge) eluting with a gradient of 0-100% acetonitrile in water. The product-containing fractions were collected and lyophilized to give a yellowish solid (0.3 g, 71% yield). Analysis: LCMS (ESI) m / z = 581 (M+H).

[0748] Step 2. 3-[6-(2,6-diazaspiro[3.3]heptan-2-yl)-3-pyridyl]-5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole. A solution of the product of Step 1 (50 mg, 0.086 mmol, 1 equiv) in anhydrous dichloromethane (2 mL) was treated with trifluoroacetic acid (0.53 mL, 6.88 mmol, 80 equiv) at room temperature for 16 hours. Additional trifluoroacetic acid (0.23 mL, 3.01 mmol, 35 equiv) was added and stirred for 1 hour. The reaction mixture was concentrated to dryness under reduced pressure. The residue was dissolved in methanol (10 mL), treated with MP-carbonate resin (3.2 mmol / g, 1 g), stirred for 30 minutes, filtered, and concentrated under reduced pressure. The residue was absorbed onto Celite (1 g) and purified on an Interchim automated chromatography system (RediSep Rf Gold HP C18, 15.5 g cartridge) eluting with a gradient of 0 to 100% acetonitrile in water. The product-containing fractions were collected and lyophilized to give a white solid (30 mg, 73% yield). Analysis: LCMS: m / z = 481.1 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 13.00 (br s, 1H), 8.59 (s, 2H), 8.50 (d, J = 1.8 Hz, 1H), 7.84 (dd, J = 2.3, 8.7 Hz, 1H), 7.45 (d, J = 9.0 Hz, 1H), 7.16 (d, J = 2.1 Hz, 1H), 7.08 (dd, J = 2.3, 9.0 Hz, 1H), 6.51 (d, J = 8.4 Hz, 1H), 6.10 (q, J = 6.6 Hz, 1H), 4.20 - 3.82 (m, 5H), 3.66 (br s, 4H), 1.76 (d, J = 6.6 Hz, 3H).

[0749] Example 46 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[6-(2-methylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)-3-pyridyl]-1H-indazole

[0750] [ka]

[0751] (5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[6-(2-methylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)-3-pyridyl]-1H-indazole. Triethylamine (20.5 uL, 0.148 mmol, 1.2 equiv.) and methylsulfonyl chloride (9.5 uL, 0.123 mmol, 1.0 equiv.) were dissolved in anhydrous THF (3 mL) to prepare Example 45 (59.0 mg, The resulting mixture was added sequentially to a solution of 0.123 mmol, 1 equiv. (C1H 0.123 mmol, 1 equiv.) at room temperature. After stirring for 2 h, the reaction mixture was concentrated under reduced pressure and diluted with saturated brine (30 mL) and dichloromethane (30 mL). The layers were separated. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure onto Celite (1 g). The product was purified by chromatography on an Interchim automated chromatography system (RediSep 1000) eluting with a gradient of 0-100% acetonitrile in water. Purification was performed on a Rf Gold HP C18 (15.5 g cartridge). Fractions containing the product were collected and lyophilized to give a white solid (45.0 mg, 65% yield). Analysis: LCMS: m / z = 559.2 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 13.02 (br s, 1H), 8.59 (s, 2H), 8.52 (dd, J = 0.6, 2.2 Hz, 1H), 7.87 (dd, J = 2.4, 8.6 Hz, 1H), 7.46 (d, J = 8.9 Hz, 1H), 7.16 (d, J = 2.1 Hz, 1H), 7.09 (dd, J = 2.3, 9.0 Hz, 1H), 6.54 (dd, J = 0.4, 8.6 Hz, 1H), 6.10 (q, J = 6.6 Hz, 1H), 4.17 (s, 4H), 4.12 (s, 4H), 3.03 (s, 3H), 1.76 (d, J = 6.6 Hz, 3H).

[0752] Example 47 6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-N,N-dimethyl-2,6-diazaspiro[3.3]heptane-2-carboxamide

[0753] [ka]

[0754] 6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-N,N-dimethyl-2,6-diazaspiro[3.3]heptane-2-carboxamide. Triethylamine (24.4 μL, 0.175 mmol, 1.2 equiv.) and dimethylcarbamic chloride (14.8 μL, 0.161 mmol, 1.1 equiv.) were added sequentially to a solution of Example 45 (70.0 mg, 0.146 mmol, 1 equiv.) in anhydrous THF (3 mL) at room temperature. After stirring for 2 hours, additional dimethylcarbamic chloride (4 μL, 0.044 mmol, 0.3 equiv.) and triethylamine (8.1 μL, 0.058 mmol, 0.4 equiv.) were added, and the reaction was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and diluted with saturated brine (30 mL) and dichloromethane (30 mL). The layers were separated. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was absorbed onto Celite (1 g) and purified on an Interchim automated chromatography system (RediSep Rf Gold HP C18, 15.5 g cartridge) eluting with a gradient of 0 to 100% acetonitrile in water. The product-containing fractions were collected and lyophilized to give a white solid (33.0 mg, 41% yield). Analysis: LCMS: m / z = 552.2 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 2H), 8.51 (dd, J = 0.7, 2.3 Hz, 1H), 7.86 (dd, J = 2.3, 8.6 Hz, 1H), 7.46 (d, J = 8.9 Hz, 1H), 7.16 (d, J = 2.1 Hz, 1H), 7.09 (dd, J = 2.3, 9.0 Hz, 1H), 6.53 (dd, J = 0.6, 8.7 Hz, 1H), 6.11 (q, J = 6.6 Hz, 1H), 4.14 (s, 4H), 4.10 (s, 4H), 2.77 (s, 6H), 1.76 (d, J = 6.6 Hz, 3H), 1.36 (s, 1H).

[0755] [ka]

[0756] Example 48 8-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]pyrimidin-2-yl]-1,8-diazaspiro[4.5]decan-2-one

[0757] [ka]

[0758] Step 1. 3-(2-chloropyrimidin-5-yl)-5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole. A mixture of 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-iodo-1-tetrahydropyran-2-yl-indazole (1.5 g, 2.89 mmol, 1 equiv.), 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (904 mg, 3.76 mmol, 1.3 equiv.), [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (211 mg, 0.289 mmol, 0.1 equiv.), potassium carbonate (798 mg, 5.79 mmol, 2 equiv.), and water (2 mL) in 1,4-dioxane (24 mL) was sparged with nitrogen for 10 minutes. The mixture was vigorously stirred at 90 °C under a nitrogen atmosphere overnight. The brown reaction mixture was cooled to room temperature and diluted with water (20 mL) and ethyl acetate (20 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was absorbed onto Celite (10 g) and purified on an Interchim automated chromatography system (Sorbtech 80 g silica gel cartridge) eluting with a gradient of 0-50% ethyl acetate in heptane to give a white solid (1.17 g, 80% yield). Analytical: LCMS: m / z = 504.1 (M+H).

[0759] Step 2. 8-(5-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrimidin-2-yl)-1,8-diazaspiro[4.5]decan-2-one. A mixture of the product from Step 1 (185 mg, 0.366 mmol, 1 equiv.), 1,8-diazaspiro[4.5]decan-2-one (62 mg, 0.403 mmol, 1.1 equiv.), and potassium carbonate (76 mg, 0.549 mmol, 1.5 equiv.) in anhydrous NMP (3 mL) was heated at 120° C. overnight. The reaction mixture was cooled to room temperature and diluted with water (10 mL) and ethyl acetate (10 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (3×5 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give a white solid (290 mg) which was used subsequently. Analysis: LCMS m / z=622.1 (M+H).

[0760] Step 3. 8-[5-[5-[(1R)-1-(3,5-Dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]pyrimidin-2-yl]-1,8-diazaspiro[4.5]decan-2-one. The product from Step 2 (290 mg) was dissolved in a 1:1 mixture of trifluoroacetic acid and dichloromethane (2 mL) at room temperature, and the red solution was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with saturated sodium bicarbonate (5 mL) and ethyl acetate (5 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (3 × 5 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The brown residue was adsorbed onto Celite (1 g) and purified on an Interchim automated chromatography system (RediSep Rf GOLD HP C18, 15 g column) eluting with a gradient of 0-100% methanol in water to give a white solid after lyophilization (100 mg, 40% yield over two steps). Analysis: LCMS: m / z = 538.2 (M+H); 1H NMR (400 MHz, CDCl3) δ 12.24 (br s, 1H), 8.61 (s, 2H), 8.55 (s, 1H), 8.41 (s, 2H), 7.43 (dd, J = 0.5, 9.0 Hz, 1H), 7.14 (dd, J = 2.3, 9.0 Hz, 1H), 7.10 (d, J = 2.1 Hz, 1H), 6.03 (q, J = 6.7 Hz, 1H), 4.44 - 4.34 (m, 2H), 3.36 - 3.21 (m, 2H), 2.51 (t, J = 8.1 Hz, 2H), 2.02 (t, J = 8.1 Hz, 2H), 1.80 (d, J = 6.7 Hz, 3H), 1.74 - 1.69 (m, 4H).

[0761] Examples 49-58 were synthesized using the procedure for Example 26.

[0762] [Table 4A]

[0763] [Table 4B]

[0764] [Table 4C]

[0765] Example 59 3-(2-chloropyrimidin-5-yl)-5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole

[0766] [ka]

[0767] The product of Step 1 from Example 48 (60 mg, 0.12 mmol, 1 equiv.) in dichloromethane (0.6 mL) was treated with trifluoroacetic acid (0.6 mL, 7.84 mmol, 65 equiv.) at room temperature overnight. Volatiles were removed under reduced pressure. The residue was dissolved in a 3:1 mixture of dichloromethane and methanol (2.4 mL) and treated with MP-Carbonate® (2.42 g) for 2 hours. The resin was filtered, and the filtrate was concentrated directly onto Celite. The residue was purified on a Biotage automated chromatography system (RediSep HP Gold C18 50 g column) eluting with a gradient of 0-100% acetonitrile in water to give an off-white solid (17.6 mg, 36% yield). Analysis: LCMS: m / z = 422.0 (M+H); 1 H NMR (400 MHz, CDCl3) δ 10.41 (br s, 1H), 9.11 (s, 2H), 8.45 (s, 2H), 7.45 (dd, J = 0.5, 9.0 Hz, 1H), 7.21 (dd, J = 2.3, 9.0 Hz, 1H), 7.15 (d, J = 2.1 Hz, 1H), 6.08 (q, J = 6.6 Hz, 1H), 1.84 (d, J = 6.6 Hz, 3H).

[0768] Example 60 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[2-[4-(oxetan-3-yl)-1,4-diazepan-1-yl]pyrimidin-5-yl]-1H-indazole

[0769] [ka]

[0770] 5-[(1R)-1-(3,5-Dichloro-4-pyridyl)ethoxy]-3-[2-[4-(oxetan-3-yl)-1,4-diazepan-1-yl]pyrimidin-5-yl]-1H-indazole. A mixture of Example 59 (135 mg, 0.321 mmol, 1.0 equiv.), 1-(oxetan-3-yl)-1,4-diazepane (136 mg, 0.354 mmol, 1.1 equiv.), and potassium carbonate (444 mg, 3.22 mmol, 10 equiv.) in N-methylpyrrolidinone was heated at 120° C. overnight. The brown reaction mixture was cooled to room temperature and diluted with water (5 mL) and ethyl acetate (5 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (3×5 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The brown oil was adsorbed onto Celite (1 g) and purified on an Interchim automated chromatography system (RediSep Rf Gold HP C18 15 g column) eluting with a gradient of 0-100% methanol and water to give a white solid (100 mg, 57% yield). Analysis: LCMS: m / z = 541.2 (M+H); 1 H NMR (400 MHz, CDCl3) δ 10.11 (br s, 1H), 8.75 (s, 2H), 8.42 (s, 2H), 7.36 (dd, J = 0.6, 9.0 Hz, 1H), 7.19 (d, J = 2.1 Hz, 1H), 7.13 (dd, J = 2.3, 9.0 Hz, 1H), 6.05 (q, J = 6.7 Hz, 1H), 4.69 - 4.63 (m, 2H), 4.63 - 4.56 (m, 2H), 4.03 - 3.98 (m, 2H), 3.95 (t, J = 6.4 Hz, 2H), 3.71 (quintet, J = 6.5 Hz, 1H), 2.65 - 2.58 (m, 2H), 2.49 - 2.42 (m, 2H), 2.07 - 2.00 (m, 2H), 1.82 (d, J = 6.6 Hz, 3H).

[0771] Example 61 3-[2-(1,4-diazepan-1-yl)pyrimidin-5-yl]-5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole

[0772] [ka]

[0773] Step 1. tert-Butyl 4-(5-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrimidin-2-yl)-1,4-diazepane-1-carboxylate. Potassium carbonate (164.1 mg, 1.2 mmol, 4 equiv.) and 1-Boc-hexahydro-1,4-diazepine (117 μL, 0.6 mmol, 2 equiv.) were added sequentially to a nitrogen-purged solution of 3-(2-chloropyrimidin-5-yl)-5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1-tetrahydropyran-2-yl-indazole (149.8 mg, 0.30 mmol, 1 equiv.) in N-methyl-2-pyrrolidone (3.0 mL) at room temperature. The resulting mixture was heated at 120° C. overnight. After cooling to room temperature, the reaction was concentrated under reduced pressure. The residue was purified on a Biotage automated chromatography system (Biotage Sfar 60 μm 15.5 g silica gel cartridge) eluting with a gradient of 0 to 100% ethyl acetate in heptane to give a yellow solid (179 mg, 90% yield). Analytical: LCMS: m / z = 668.2 (M+H).

[0774] Step 2. 3-[2-(1,4-diazepan-1-yl)pyrimidin-5-yl]-5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole trifluoroacetate. The product from Step 1 (178.6 mg, 0.27 mmol, 1 equiv.) in dichloromethane (2.0 mL) was treated with trifluoroacetic acid (2.0 mL, 26.1 mmol, 96 equiv.) at room temperature for 2 hours. The reaction mixture was concentrated directly onto Celite and purified on a Biotage automated chromatography system (RediSep Gold HP C18 column, 50 g) eluting with a gradient of 0-100% acetonitrile in water to give an off-white solid (103 mg, 72% yield). Analysis: LCMS: m / z = 484.2 (M+H), 1 H NMR (400 MHz, CD3OD) δ 8.76 (s, 2H), 8.47 (s, 2H), 7.47 (dd, J = 0.4, 9.1 Hz, 1H), 7.19 (dd, J = 2.3, 9.0 Hz, 1H), 7.09 (d, J = 2.1 Hz, 1H), 6.14 (q, J = 6.6 Hz, 1H), 4.56 (br s, 1H), 4.22 - 4.17 (m, 2H), 4.06 (t, J = 6.2 Hz, 2H), 3.49 - 3.46 (m, 2H), 3.38 - 3.35 (m, 2H), 2.21 (td, J = 5.9, 11.5 Hz, 2H), 1.83 (d, J = 6.6 Hz, 3H).

[0775] Example 62 4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]pyrimidin-2-yl]-1,4-diazepane-1-carboxamide

[0776] [ka]

[0777] Step 1. 3-(2-(1,4-diazepan-1-yl)pyrimidin-5-yl)-5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole: A suspension of 3-(2-chloropyrimidin-5-yl)-5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1-tetrahydropyran-2-yl-indazole (145 mg, 0.28 mmol, 1 equiv.) and potassium carbonate (160 mg, 1.12 mmol, 4 equiv.) in 1-methyl-2-pyrrolidone (2 mL) was treated with 1,4-diazepane dihydrochloride (97 mg, 0.57 mmol, 2 equiv.). After heating at 120° C. for 16 hours, the reaction mixture was cooled to room temperature and diluted with water (10 mL). The resulting solid was stirred at room temperature for 30 minutes and filtered to give a light brown solid (86 mg, 53% yield) which was used further. Analysis: LCMS (ESI) m / z=568.1 (M+H).

[0778] Step 2. 4-(5-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrimidin-2-yl)-1,4-diazepane-1-carboxamide (209-4): (Trimethylsilyl)isocyanate (23 μL, 0.17 mmol, 1.1 equiv.) was added to a solution of the product from Step 1 (86 mg, 0.15 mmol, 1 equiv.) and triethylamine (24 μL, 0.17 mmol, 1.1 equiv.) in THF (2 mL) at room temperature. After 4 hours, the volatiles were removed under reduced pressure. The residue was purified on a Buchi automated chromatography system (Sorbtech 24 g silica gel column) eluting with a gradient of 0 to 80% ethyl acetate in heptane to give a light brown solid (25 mg, 27% yield). Analysis: LCMS (ESI) m / z = 611.1 (M+H).

[0779] Step 3. (4-[5-[5-[(1R)-1-(3,5-Dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]pyrimidin-2-yl]-1,4-diazepane-1-carboxamide. The product from step 2 (25 mg, 0.04 mmol, 1 equiv) was treated with a 1:1 mixture of dichloromethane and trifluoroacetic acid (0.5 mL) at room temperature for 2 hours. The volatiles were removed under reduced pressure. The residue was diluted with saturated sodium bicarbonate (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on a Buchi automated chromatography system (RediSep Rf Gold HP C18, 50 g column) eluting with a gradient of 0-80% acetonitrile in water. The product-containing fractions were lyophilized to give a white solid (11 mg, 53% yield). Analysis: LCMS (ESI) m / z = 527.2 (M+H); 1 H NMR (400 MHz, CD3OD) δ 8.70 - 8.67 (m, 2H), 8.48 (s, 2H), 7.45 (d, J = 9.0 Hz, 1H), 7.17 (dd, J = 2.3, 9.0 Hz, 1H), 7.09 (d, J = 2.2 Hz, 1H), 6.14 (q, J = 6.6 Hz, 1H), 4.55 (br s, 2H), 4.02 (t, J = 5.5 Hz, 2H), 3.91 (t, J = 6.1 Hz, 2H), 3.69 - 3.64 (m, 2H), 3.49 - 3.45 (m, 2H), 2.05 - 1.99 (m, 2H), 1.82 (d, J = 6.6 Hz, 3H).

[0780] Example 63 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[2-(4-methylsulfonyl-1,4-diazepan-1-yl)pyrimidin-5-yl]-1H-indazole

[0781] [ka]

[0782] Example 61 (76.5 mg, 0.16 mmol, 1 equiv) in THF (1.6 mL) was treated with triethylamine (22.0 μL, 0.63 mmol, 4 equiv) and methanesulfonyl chloride (12.2 μL, 0.63 mmol, 4 equiv) at 40° C. for 4 days. The reaction mixture was concentrated directly onto Celite and then purified on a Biotage automated chromatography system (RediSep Gold HP C18 50 g column) eluting with a gradient of 0 to 100% acetonitrile in water to give a white solid (14.8 mg, 17% yield). Analysis: LCMS: m / z = 562.2 (M+H); 1 H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.77 (s, 2H), 8.56 (s, 2H), 7.47 (d, J = 8.9 Hz, 1H), 7.23 (d, J = 1.7 Hz, 1H), 7.09 (dd, J = 2.3, 9.0 Hz, 1H), 6.14 (q, J = 6.7 Hz, 1H), 3.97 (t, J = 5.6 Hz, 2H), 3.91 (t, J = 6.0 Hz, 2H), 3.50 (t, J = 5.5 Hz, 2H), 3.34 - 3.31 (m, 2H), 2.84 (s, 3H), 1.90 (quintet, J = 5.7 Hz, 2H), 1.76 (d, J = 6.7 Hz, 3H).

[0783] Examples 64-68 were synthesized using the procedures and methods for Examples 3-9, using tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate or 1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine.

[0784] [Table 5A]

[0785] [Table 5B]

[0786] Examples 69-72 were synthesized using the procedures and methods for Examples 3-9, using tert-butyl 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]piperidine-1-carboxylate.

[0787] [Table 6]

[0788] Examples 73-76 were synthesized using the procedures and methods for Examples 3-9, using tert-butyl 6-oxo-5-oxa-2,7-diazaspiro[3.4]octane-2-carboxylate and tert-butyl 2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylate.

[0789] [Table 7]

[0790] Example 77 8-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-3-fluoro-2-pyridyl]-2λ 6 -Thia-8-azaspiro[4.5]decane 2,2-dioxide

[0791] [ka]

[0792] This example illustrates the synthesis of 3-(6-chloro-4-fluoropyridin-3-yl)-5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole and 2λ6 -thia-8-azaspiro[4.5]decane 2,2-dioxide and synthesized using the methods for Examples 17 and 42. LCMS: m / z= 590.2 (M+H); 1 H NMR (400 MHz, DMSO-d6) δ = 13.18 (br s, 1H), 8.57 (s, 2H), 8.44 (t, J = 1.7 Hz, 1H), 7.76 (dd, J = 1.9, 14.5 Hz, 1H), 7.49 (d, J = 9.0 Hz, 1H), 7.20 (d, J = 2.1 Hz, 1H), 7.10 (dd, J = 2.3, 9.0 Hz, 1H), 6.13 (q, J = 6.6 Hz, 1H), 3.77 - 3.69 (m, 2H), 3.35 - 3.28 (m, 4H), 3.24 (t, J = 7.6 Hz, 2H), 2.10 (t, J = 7.6 Hz, 2H), 1.88 - 1.81 (m, 2H), 1.78 - 1.70 (m, 5H).

[0793] Example 78 8-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2λ 6 -Thia-8-azaspiro[4.5]decane 2,2-dioxide

[0794] [ka]

[0795] This example illustrates the synthesis of 3-(6-chloro-pyridin-3-yl)-5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole and 2λ 6 Synthesized using the methods for Examples 17 and 42 using -thia-8-azaspiro[4.5]decane 2,2-dioxide. LCMS: m / z= 572.2 (M+H). 1H NMR (400 MHz, DMSO-d6) δ = 12.97 (s, 1H), 8.60 (s, 2H), 8.54 (d, J = 2.2 Hz, 1H), 7.84 (dd, J = 2.4, 8.9 Hz, 1H), 7.45 (d, J = 8.9 Hz, 1H), 7.16 (d, J = 1.6 Hz, 1H), 7.09 (dd, J = 2.3, 9.0 Hz, 1H), 7.00 (d, J = 8.9 Hz, 1H), 6.10 (q, J = 6.7 Hz, 1H), 3.96 - 3.87 (m, 2H), 3.40 - 3.32 (m, 2H), 3.24 (t, J = 7.5 Hz, 2H), 3.18 (s, 2H), 2.09 (t, J = 7.6 Hz, 2H), 1.81 (br d, J = 4.9 Hz, 2H), 1.76 (d, J = 6.6 Hz, 3H), 1.65 (ddd, J = 3.9, 9.6, 13.4 Hz, 2H).

[0796] (R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethanol and (S)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethanol

[0797] [ka]

[0798] Step 1. (Trichloro-4-pyridyl)ethanol. A 500 mL three-necked round-bottom flask was charged with 2,3,5-trichloropyridine-4-carbaldehyde (40 g, 0.19 mol) and THF (200 mL). MeMgBr (70 mL, 0.21 mol) was added portionwise, and the mixture was stirred at −70° C. for 1 h. The reaction was quenched with aqueous ammonium chloride solution, extracted with ethyl acetate (200 mL × 3), dried over NaSO, and concentrated. The residue was purified using a silica gel column (PE / EA = 30 / 1) to give (33 g) a yellow liquid (33 g, 77%). Analysis: LCMS: m / z = 227 (M+H).

[0799] Step 2. 1-(3,5-Dichloro-2-methyl-4-pyridyl)ethanol. A mixture of the product from Step 1 (33 g, 0.147 mmol), methylboronic acid (26.3 g, 0.429 mmol), K2CO3 (40 g, 0.290 mmol), and Pd(PPh3)2Cl2 (3 g) in dioxane (300 mL) was stirred at 110 °C overnight. The resulting mixture was filtered, and the filtrate was concentrated in vacuo to give the crude product, which was further purified by silica gel column chromatography to give a yellow liquid (15 g, 50%). LCMS: m / z = 206.1 (M+H). The products were separated by preparative HPLC (Chiralpak ID 5 x 25 cm, hexane / ethanol (80 / 20), 60 mL / min, 38 °C) to give (S)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethanol (5 g) and (R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethanol R (5 g) as a yellow liquid. Peak 1 5.5 min; (S)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethanol. Analysis: LCMS: m / z = 206.1 (M+H). 1 H NMR (400 MHz, CDCl) δ 8.36 (s, 1H), 5.57 (m, 1H), 2.93 (b, 1H), 2.64 (s, 3H), 1.65 (d, 3H). Peak 2 at 6.9 min; (R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethanol. Analytical: LCMS: m / z = 206.1 (M+H). 1 H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 5.57 (m, 1H), 2.93 (b, 1H), 2.64 (s, 3H), 1.65 (d, 3H).

[0800] Examples 79-95 use the procedure and methods for Example 64 to produce tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate, tert-butyl (3S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]pyrrolidine-1-carboxylate, tert-butyl (3R)-3-[4-(4,4,5 The synthesis was carried out using tert-butyl 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]pyrrolidine-1-carboxylate or tert-butyl 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]azetidine-1-carboxylate and (1R)-1-(3,5-dichloro-4-pyridyl)ethanol or (1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethanol.

[0801] [Table 8A]

[0802] [Table 8B]

[0803] [Table 8C]

[0804] [Table 8D]

[0805] [Table 8E]

[0806] Examples 96-140 were synthesized using the procedures described above.

[0807] Table 9A

[0808] Table 9B

[0809] Table 9C

[0810] Table 9D

[0811]

Table 9E

[0812] Table 9F

[0813]

Table 9G

[0814] Table 9H

[0815] Table 9I

[0816]

Table 9J

[0817]

Table 9K

[0818] [ka]

[0819] Example 144 2-[5-[5-[(1R)-1-(3,5-dimethylpyridazin-4-yl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-6λ 6 -Thia-2-azaspiro[3.4]octane 6,6-dioxide

[0820] [ka]

[0821] Step 1. 1-(3,5-Dichloropyridazin-4-yl)ethanone. To a solution of 3,5-dichloropyridazine (50.0 g, 0.336 mol) in CHCN (500 mL) and water (500 mL) was added 2-oxopropanoic acid (37.0 g, 0.403 mol), KSO (136.0 g, 0.504 mol), and AgNO (11.4 g, 0.067 mol). The reaction mixture was stirred at 70 °C for 6 h. Upon completion, the reaction was cooled to room temperature and the ACN was removed. The aqueous solution was extracted with EtOAc (3 × 500 mL). The combined organic layers were washed with brine (2 × 300 mL), dried over NaSO, and concentrated. The residue was purified by silica gel flash column chromatography (petroleum ether / EtOAc=4 / 1) to give 1-(3,5-dichloropyridazin-4-yl)ethanone as a pale yellow solid (35.0 g, 56%). LCMS m / z=191 (M+1).

[0822] Step 2. 1-(3,5-Dimethylpyridazin-4-yl)ethanone. To a solution of 1-(3,5-dichloropyridazin-4-yl)ethanone (35.0 g, 0.184 mol) in dioxane (700 mL) and water (35 mL) was added 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (157 mL, 3.5 mol / L in THF, 0.552 mol), KCO (63.5 g, 0.460 mol), and Pd(dppf)Cl (5.3 g, 0.0074 mol). The mixture was stirred at 110 °C under a N atmosphere for 36 h. Upon completion, the reaction was cooled to room temperature and concentrated. The crude product was purified by silica gel flash column chromatography (DCM / MeOH=60 / 1) to give a brown oil (17.5 g, 63.2%). LCMS m / z - 151 (M+1).

[0823] Step 3. 1-(3,5-Dimethylpyridazin-4-yl)ethanol. To a solution of 1-(3,5-dimethylpyridazin-4-yl)ethanone (17.5 g, 0.12 mol) in THF (180 mL) was added NaBH (5.06 g, 0.132 mol) at 0 °C, followed by dropwise addition of MeOH (18 mL) at the same...

Claims

1. Compounds of formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, wherein n=1, 2, or 3; m=0, 1, 2, or 3; Each R 1 are independently H, CN, or optionally substituted C 1 ~C 6 is alkyl, Each R 2 are independently H, CN, or optionally substituted C 1 ~C 6 Is it alkyl? or two R attached to the same carbon atom 1 groups, taken together with the carbon atoms to which they are both attached, form an optionally substituted 3- to 7-membered spirocycloalkyl ring or an optionally substituted 3- to 7-membered spiroheterocycloalkyl ring, or or two R attached to the same carbon atom 1 The group together with its carbon atom represents a carbonyl group (C=O), or or two R attached to the same carbon atom 2 groups, taken together with the carbon atoms to which they are both attached, form an optionally substituted 3- to 7-membered spirocycloalkyl ring or an optionally substituted 3- to 7-membered spiroheterocycloalkyl ring, or or two R attached to the same carbon atom 2 The group together with its carbon atom represents a carbonyl group (C=O), or or two R attached to different carbon atoms 1 groups taken together with the carbon atom to which they are attached form a 3- to 7-membered cycloalkyl ring, or or two R attached to different carbon atoms 2 groups taken together with the carbon atom to which they are attached form a 3- to 7-membered cycloalkyl ring, or or R 1 Groups and R 2 the groups are joined to form a 6- to 9-membered bridged bicyclic ring; A=N or CH; Z=S(O) 2 ;S(O);O,NR 3 or CR 4 R 4' and R 3 is H; optionally substituted C 1 ~C 6 Alkyl, 3- to 5-membered cycloalkyl, 3- to 5-membered heterocycloalkyl, -C(O)NR a R b ;-C(O)OR c ;-C(O)R c ;-S(O) 2 R c ; or -S(O) 2 NR a R b Or or R 3 is R 1 or R 2 together with R a is H or C 1 ~C 6 Is it alkyl? R b is H or C 1 ~C 6 Is it alkyl? or R a and R b together with the N atom to which they are both attached form an optionally substituted 3- to 7-membered heterocycloalkyl ring; R c is optionally substituted with C 1 ~C 6 alkyl or cycloalkyl; R 4 is H, -F, or optionally substituted C 1 ~C 6 Is it alkyl? R 4' -H, -F, -OH, -CN, -NH 2 , -NH(C 1 ~C 3 alkyl), -N(C 1 ~C 3 alkyl) 2 , -N(C 1 ~C 3 (Alkyl)-SO 2 (C 1 ~C 3 alkyl), -C 1 ~C 6 Haloalkyl, optionally substituted C 1 ~C 6 Alkyl or optionally substituted C 1 ~C 6 Is it alkoxyl? or R 4 and R 4' together with the C atom to which they are both attached form an optionally substituted 3- to 7-membered heterocycloalkyl ring or an optionally substituted 3- to 7-membered cycloalkyl ring, or or R 4 and R 4' together with the carbon atom to which they are both attached to form an oxo group, or or R 4' is R 1 or R 2 together with Y is a 5- or 6-membered heteroaryl ring or a 6-membered aryl ring; Q 5 , Q 6 , Q 7 , Q 8 , and Q 9 are each independently N or CR 5 and Q 5 , Q 6 , Q 7 , Q 8 , and Q 9 One or two of these are N and the rest are CR 5 and R 5 H, halogen, C 1 ~C 3 Alkyl; C 1 ~C 3 alkoxyl or cycloalkyl; X=O, S, or NR, and R is H or C 1 ~C 3 is alkyl, R 6 is C 1 ~C 6 is alkyl, R 7 is H, halogen, -C 1 ~C 6 Alkyl;-C 1 ~C 6 alkoxyl, or -cycloalkyl; R 8 is H, halogen, -C 1 ~C 6 Alkyl;-C 1 ~C 6 -alkoxyl, or -cycloalkyl].

2. The compound of claim 1 wherein n=1, 2, or 3; m=1, 2, or 3; Each R 1 are independently H or optionally substituted C 1 ~C 6 is alkyl, Each R 2 are independently H or optionally substituted C 1 ~C 6 Is it alkyl? or two R attached to the same carbon atom 1 groups, taken together with the carbon atoms to which they are both attached, form an optionally substituted 3- to 7-membered spirocycloalkyl ring or an optionally substituted 3- to 7-membered spiroheterocycloalkyl ring, or or two R attached to the same carbon atom 1 The group together with its carbon atom represents a carbonyl group (C=O), or or two R attached to the same carbon atom 2 groups, taken together with the carbon atoms to which they are both attached, form an optionally substituted 3- to 7-membered spirocycloalkyl ring or an optionally substituted 3- to 7-membered spiroheterocycloalkyl ring, or or two R attached to the same carbon atom 2 The group together with its carbon atom represents a carbonyl group (C=O), or or two R attached to different carbon atoms 1 groups taken together with the carbon atom to which they are attached form a 3- to 7-membered cycloalkyl ring, or or two R attached to different carbon atoms 2 groups taken together with the carbon atom to which they are attached form a 3- to 7-membered cycloalkyl ring, or or R 1 Groups and R 2 the groups are joined to form a 6- to 9-membered bridged bicyclic ring; A=N or CH; Z=S(O) 2 ;S(O);O,NR 3 or CR 4 R 4' and R 3 is H; optionally substituted C 1 ~C 6 Alkyl, 3- to 5-membered cycloalkyl, 3- to 5-membered heterocycloalkyl, -C(O)NR a R b ;-C(O)OR c ;-C(O)R c ;-S(O) 2 R c ; or -S(O) 2 NR a R b and R a is H or C 1 ~C 6 is alkyl, R b is H or C 1 ~C 6 Is it alkyl? or R a and R b together with the N atom to which they are both attached form an optionally substituted 3- to 7-membered heterocycloalkyl ring; R c is optionally substituted C 1 ~C 6 alkyl, or cycloalkyl; R 4 is H or optionally substituted C 1 ~C 6 is alkyl, R 4' is H, -OH, or optionally substituted C 1 ~C 6 Is it alkyl? or R 4 and R 4' together with the C atom to which they are both attached form an optionally substituted 3- to 7-membered heterocycloalkyl ring, Y is a 5- or 6-membered heteroaryl ring; Q 5 , Q 6 , Q 7 , Q 8 , and Q 9 are each independently N or CR 5 and Q 5 , Q 6 , Q 7 , Q 8 , and Q 9 One or two of these are N and the rest are CR 5 and R 5 H, halogen, C 1 ~C 3 Alkyl; C 1 ~C 3 alkoxyl or cycloalkyl; X=O, S, or NR, and R is H or C 1 ~C 3 is alkyl, R 6 is C 1 ~C 6 is alkyl, R 7 is H, halogen, -C 1 ~C 6 Alkyl;-C 1 ~C 6 alkoxyl, or -cycloalkyl; R 8 is H, halogen, -C 1 ~C 6 Alkyl;-C 1 ~C 6 -alkoxyl, or -cycloalkyl].

3. 3. The compound of claim 1 or claim 2, wherein Y is a 6-membered heteroaryl ring.

4. The compound of formula (I) may be a compound of formula (IA): 【Chemistry 2】 [In the formula, Q 1 , Q 2 , Q 3 , Q 4 one or two of which are N, and the others are each independently CR 5a and R 5a is H, halogen, -CN, or C 1 ~C 3 The compound of claim 3, wherein:

5. 5. The compound of claim 1, wherein X is O.

6. (a)Q 5 and Q 9 are CR 5 and each R 5 is a halogen and Q 6 and Q 8 are CR 5 and each R 5 is H and Q 7 is N; or (b) Q 5 and Q 9 are each CR 5 , each R 5 is halogen, Q 6 is CR 5 , R 5 is H, Q 8 is CR 5 , R 5 is C 1 -C 3 alkyl, and Q 7 is N; or (c) Q 5 and Q 9 are each CR 5 , each R 5 is —Cl, Q 6 is CR 5 , R 5 is H, Q 8 is CR 5 , R 5 is —CH 3 , and Q 7 is N; or (d) Q 5 and Q 9 are each CR 5 , each R 5 is halogen, Q 6 is CR 5 , R 5 is H, Q 8 is N, Q 7 is CR 5 , and R 5 is H; or (e) Q 5 and Q 9 are each CR 5 , each R 5 is —Cl, Q 6 is CR 5 , R 5 is H, Q 8 is N, Q 7 is CR 5 , and R 5 is H; or (f) Q 5 and Q 9 are each CR 5 , each R 5 is halogen, Q 6 is CR 5 , R 5 is H, Q 8 is N, and Q 7 is N; or (g) Q 5 and Q 9 are each CR 5 , each R 5 is —Cl, Q 6 is CR 5 , R 5 is H, Q 8 is N, and Q 7 is N; or (h) Q 5 and Q 9 are each CR 5 , each R 5 is C 1 -C 3 alkyl, Q 6 is CR 5 , R 5 is H, Q 8 is N, and Q 7 is N; or (i) Q 5 and Q 9 are each CR 5 , each R 5 is —CH 3 , Q 6 is CR 5 , R 5 is H, Q 8 is N, and Q 7 is N; or (j) Q 5 , Q 8 , and Q 9 are each independently CR 5 , each R 5 is halogen, Q 6 is CR 5 , R 5 is H, and Q 7 is N; or (k) A compound according to any one of claims 1 to 5, wherein Q5 and Q9 are each independently CR5, each R5 is -Cl, Q6 is CR5, R5 is H, Q8 is CR5, R5 is -F, and Q7 is N.

7. The compound of formula (IA) is a compound of formula (IA-1): 【Transformation 3】 7. The compound according to any one of claims 4 to 6, wherein

8. R 6 Ha-CH 3 8. The compound of any one of claims 1 to 7, wherein

9. Q 3 is CR 5a and optionally R 5a is halogen, optionally the halogen is -F.

10. The compound of formula (IA-1) can be prepared by reacting with a compound of formula (IA-2): 【Chemistry 4】 8. The compound of claim 7, wherein:

11. 11. A compound according to any one of claims 1 to 10, wherein n=2 and m=2; or n=1 and m=1; or n=1 and m=2; or n=3 and m=2.

12. The compound of formula (IA-2) is (a) A compound of formula (IA-3): 【Transformation 5】 and optionally wherein (i) each R 1 and each R 2 is independently H or optionally substituted C 1 -C 6 alkyl; or (ii) each R 1 and each R 2 is H; or (iii) each R 1 is H, and two R 2 groups bonded to the same carbon atom together with the carbon atom to which they are both bonded form a 3- to 7-membered spirocycloalkyl ring, optionally said 3- to 7-membered spirocycloalkyl ring being a 3-membered spirocycloalkyl ring; or (iv) one R 1 group and one R 2 group are joined to form a 6- to 9-membered bridged bicyclic ring, the other R 1 is H and the other R 2 is H, and optionally the 6- to 9-membered bridged bicyclic ring is a 7-membered bridged bicyclic ring; or (v) each R 1 is H and two R 2 groups attached to the same carbon atom represent a carbonyl group (C═O); or (b) Compound of formula (IA-4): 【Transformation 6】 wherein optionally, two R 2 groups attached to the same carbon atom represent a carbonyl group (C═O); or (c) Compound of formula (IA-5): 【Transformation 7】 and optionally wherein (i) each R 1 and each R 2 is independently H or optionally substituted C 1 -C 6 alkyl; or (ii) each R 1 and each R 2 is H; or (iii) each R 1 is H, and two R 2 groups bonded to the same carbon atom together with the carbon atom to which they are both bonded form a 3- to 7-membered spirocycloalkyl ring, optionally said 3- to 7-membered spirocycloalkyl ring being a 3-membered spirocycloalkyl ring; or (iv) one R 1 group and one R 2 group are joined to form a 6- to 9-membered bridged bicyclic ring, the other R 1 is H and the other R 2 is H, and optionally the 6- to 9-membered bridged bicyclic ring is a 7-membered bridged bicyclic ring; or (d) Compound of formula (IA-6): 【Transformation 8】 and optionally wherein (i) two R 1 groups attached to the same carbon atom represent a carbonyl group (C═O); and / or (ii) two R 2 groups attached to the same carbon atom together with the carbon atom to which they are both attached form an optionally substituted 3- to 7-membered spirocycloalkyl ring or an optionally substituted 3- to 7-membered spiroheterocycloalkyl ring; optionally, two R 2 groups attached to the same carbon atom, together with the carbon atom to which they are both attached, form an optionally substituted 3- to 7-membered spiroheterocycloalkyl ring; optionally, the optionally substituted 3- to 7-membered spiroheterocycloalkyl ring is an optionally substituted azetinyl ring, an optionally substituted pyrrolidinyl ring, or an optionally substituted piperidinyl ring; optionally, the optionally substituted 3- to 7-membered spiroheterocycloalkyl ring is an azetinyl ring, a pyrrolidinyl ring, a piperidinyl ring, an N-methylpiperidinyl ring, or an N-(methylsulfonyl)piperidinyl ring; or (e) Compound of formula (IA-7): 【Chemistry 9】 and optionally, in the formula (i) each R 1 is H; or two R 1 groups attached to the same carbon atom represent a carbonyl group (C═O); and / or (ii) The compound of claim 10, wherein each R2 is H; or two R2 groups attached to the same carbon atom represent a carbonyl group (C=O).

13. The compound of formula (I) may be a compound of formula (IA-8): 【Chemistry 10】 [In the formula, R 9 -C 1 ~C 6 Alkyl, -C 1 ~C 6 Haloalkyl, -C(O)C 1 ~C 6 Haloalkyl, -C(O)OC 1 ~C 6 Alkyl, -C(O)C 1 ~C 6 Alkyl, -C(O)N(C 1 ~C 6 alkyl) 2 , or -SO 2 -C 1 ~C 6 alkyl]; 3. The compound of claim 1 or claim 2, wherein optionally R9 is -CH2CF3, -CH2CHF2, -C(O)CF3, -C(O)OCH3, -C(O)OCH2CH3, -SO2CH2CH3, or -SO2CH(CH3)2.

14. (a)Q 2 is N; or (b) Q 4 is N; or (c) Q 4 is CR 5a and in some cases (i) R 5a is H; or (ii) A compound according to any one of claims 7 to 13, wherein R 5a is halogen, optionally wherein the halogen is -F.

15. 2. The compound of claim 1, wherein Y is a 5-membered heteroaryl ring.

16. (a) The compound of formula (I) is a compound of formula IB: 【Chemistry 11】 and / or (b) X is O; and / or (c) Q 5 and Q 9 are each independently CR 5 , each R 5 is halogen, Q 6 and Q 8 are CR 5 , R 5 is H, and Q 7 is N; or (d) Q 5 and Q 9 are each independently CR 5 , each R 5 is halogen, Q 6 is CR 5 , R 5 is H, Q 8 is CR 5 , R 5 is C 1 -C 3 alkyl, and Q 7 is N; or (e) Q 5 and Q 9 are each independently CR 5 , each R 5 is —Cl, Q 6 is CR 5 , R 5 is H, Q 8 is CR 5 , R 5 is —CH 3 , and Q 7 is N; or (f) Q 5 and Q 9 are each independently CR 5 , each R 5 is halogen, Q 6 is CR 5 , R 5 is H, Q 8 is N, Q 7 is CR 5 , and R 5 is H; or (g) Q 5 and Q 9 are each independently CR 5 , each R 5 is —Cl, Q 6 is CR 5 , R 5 is H, Q 8 is N, Q 7 is CR 5 , and R 5 is H; or (h) Q 5 and Q 9 are each independently CR 5 , each R 5 is halogen, Q 6 is CR 5 , R 5 is H, Q 8 is N, and Q 7 is N; or (i) Q 5 and Q 9 are each independently CR 5 , each R 5 is —Cl, Q 6 is CR 5 , R 5 is H, Q 8 is N, and Q 7 is N; or (j) Q 5 and Q 9 are each independently CR 5 , each R 5 is C 1 -C 3 alkyl, Q 6 is CR 5 , R 5 is H, Q 8 is N, and Q 7 is N; or (k) Q 5 and Q 9 are each independently CR 5 , each R 5 is —CH 3 , Q 6 is CR 5 , R 5 is H, Q 8 is N, and Q 7 is N; or (l) Q 5 , Q 8 , and Q 9 are each independently CR 5 , each R 5 is halogen, Q 6 is CR 5 , R 5 is H, and Q 7 is N; or (m) The compound of claim 15, wherein Q5 and Q9 are each independently CR5, each R5 is -Cl, Q6 is CR5, R5 is H, Q8 is CR5, R5 is -F, and Q7 is N.

17. The compound of formula (IB) can be prepared by reacting a compound of formula IB-1: 【Chemistry 12】 and optionally the compound of formula (IB-1) is a compound of formula IB-2: 【Chemistry 13】 and optionally wherein n=2 and m=2; or n=1 and m=1; or n=1 and m=2; or n=3 and m=2; or 17. The compound of claim 16, wherein each R<1> is H and each R<2> is H.

18. 18. The compound of any one of claims 1 to 17, wherein A is N; or A is CH.

19. (a) Z is S(O) 2 is; or (b) Z is S(O); or (c) Z is O; or (d) Z is NR 3 and optionally (i) R 3 is H; or (ii) R 3 is —C(O)NR a R b ; or (iii) R 3 is —S(O) 2 NR a R b 1, where optionally R a is H and R b is H; or R a is H and R b is C 1 -C 6 alkyl; or R a is C 1 -C 6 alkyl and R b is C 1 -C 6 alkyl; R a and R b together with the N atom to which they are both attached form an optionally substituted 3- to 7-membered heterocycloalkyl ring; optionally, said optionally substituted 3- to 7-membered heterocycloalkyl ring is an optionally substituted piperidinyl, an optionally substituted piperazinyl, or an optionally substituted morpholinyl ring; optionally, said optionally substituted 3- to 7-membered heterocycloalkyl ring is a 4-methylpiperazin-1-yl, or morpholinyl ring; or (iv) R 3 is —C(O)OR c , optionally R c is —CH 3 or —CH 2 CH 3 ; or (v) R 3 is —C(O)R c , optionally R c is —CH 3 or —CH 2 CH 3 ; or (vi) R 3 is —S(O) 2 R c , optionally R c is —CH 3 or —CH 2 CH 3 ; or (vii) R 3 is C 1 -C 6 alkyl, optionally wherein said C 1 -C 6 alkyl is —CH 3 ; or (viii) The compound of any one of claims 1 to 18, wherein R 3 is a 3- to 5-membered heterocycloalkyl, optionally wherein said 3- to 5-membered heterocycloalkyl is oxetanyl.

20. Z is CR 4 R 4' and in some cases: (a) R 4 and R 4′ are each H; or (b) R 4 and R 4′ are each optionally substituted C 1 -C 6 alkyl; or (c) R 4 is H and R 4′ is —OH; or (d) R 4 and R 4′ together with the C atom to which they are both attached form an optionally substituted 3- to 7-membered heterocycloalkyl ring; optionally, said optionally substituted 3- to 7-membered heterocycloalkyl ring is an optionally substituted 4-membered heterocycloalkyl ring; optionally, said optionally substituted 4-membered heterocycloalkyl ring is an azetidinyl ring; optionally, the azetidinyl ring is unsubstituted; or Optionally, the azetidinyl ring is N-substituted, and optionally: (i) the N substituent is -C1-C6 alkyl, -C1-C6 haloalkyl, -C(O)C1-C6 haloalkyl, -C(O)OC1-C6 alkyl, -C(O)C1-C6 alkyl, -C(O)N(C1-C6 alkyl)2, or -SO2-C1-C6 alkyl; or (ii) the N substituent is -CH2CF3, -CH2CHF2, -C(O)CF3, -C(O)OCH3, -C(O)OCH2CH3, -SO2CH2CH3, -SO2CH(CH3)2, -CH3, -CH(CH3)2, -C(O)N(CH3)2, or -SO2CH3; or (iii) the N substituent is -CH3, -CH(CH3)2, -C(O)OCH2CH3, -C(O)N(CH3)2, -SO2CH3, -SO2CH(CH3)2, or -SO2CH2CH3, and optionally said optionally substituted 4-membered heterocycloalkyl ring is an optionally substituted thietane 1,1-dioxide ring; or optionally, said optionally substituted 3- to 7-membered heterocycloalkyl ring is an optionally substituted 5-membered heterocycloalkyl ring; optionally, the optionally substituted 5-membered heterocycloalkyl ring is an unsubstituted pyrrolidinyl ring, an N-substituted pyrrolidinyl ring, an unsubstituted pyrrolidinyl-2-one ring, an N-substituted pyrrolidinyl-2-one ring, an unsubstituted pyrrolo-2,5-dione ring, an N-substituted pyrrolo-2,5-dione ring, an unsubstituted imidazolidinyl-2-one ring, an N-substituted imidazolidinyl-2-one ring, a tetrahydrofuranyl ring, or a tetrahydrothiophene-1,1-dioxide ring; optionally said N substituent is -C 1 -C 6 alkyl, -C(O)OC 1 -C 6 alkyl, -C(O)C 1 -C 6 alkyl, or -SO 2 C 1 -C 6 alkyl; optionally said N substituent is -CH3, -C(O)OCH3, -C(O)OCH2CH3, -C(O)OCH(CH3)2, or -SO2CH3; or optionally, said optionally substituted 3- to 7-membered heterocycloalkyl ring is an optionally substituted 6-membered heterocycloalkyl ring; optionally, said optionally substituted 6-membered heterocycloalkyl ring is an unsubstituted piperidinyl-2-one ring, an N-substituted piperidinyl-2-one ring, an N-substituted or unsubstituted piperidine ring, or a tetrahydro-2H-thiopyran 1,1-dioxide ring; Optionally the N-substituent is -C 1 -C 6 alkyl, -C(O)OC 1 -C 6 alkyl, -C(O)C 1 -C 6 alkyl, or -SO 2 C 1 -C 6 alkyl; optionally the N-substituent is -CH3, -C(O)OCH3, -C(O)OCH2CH3, -C(O)OCH(CH3)2, -SO2CH2CH3, or -SO2CH3; or 19. The compound of any one of claims 1 to 18, wherein the optional N-substituent is -SO2CH2CH3.

21. 4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-1,4-thiazinane 1,1-dioxide; (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(6-(piperazin-1-yl)pyridin-3-yl)-1H-indazole dihydrochloride; [4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]piperazin-1-yl]-morpholino-methanone; [4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]piperazin-1-yl]-(4-methylpiperazin-1-yl)methanone; 4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-N,N-dimethyl-piperazine-1-carboxamide; 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[6-(4-methylsulfonylpiperazin-1-yl)-3-pyridyl]-1H-indazole; Methyl 4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]piperazine-1-carboxylate; 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[6-[4-(4-methylpiperazin-1-yl)sulfonylpiperazin-1-yl]-3-pyridyl]-1H-indazole; 1-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]piperazin-1-yl]propan-1-one; 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-(5-fluoro-6-piperazin-1-yl-3-pyridyl)-1H-indazole; 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-(2-piperazin-1-ylpyrimidin-5-yl)-1H-indazole; 4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]piperazine-1-carboxamide; [4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-3-fluoro-2-pyridyl]piperazin-1-yl]-(4-methylpiperazin-1-yl)methanone; 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[2-(4-methylsulfonylpiperazin-1-yl)pyrimidin-5-yl]-1H-indazole; [4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]pyrimidin-2-yl]piperazin-1-yl]-(4-methylpiperazin-1-yl)methanone; 3-[6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-3-pyridyl]-5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole; 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[5-fluoro-6-(4-methylsulfonyl-piperazin-1-yl)-3-pyridyl]-1H-indazole; 3-(6-chloro-3-pyridyl)-5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole; 4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]pyrimidin-2-yl]-N,N-dimethyl-piperazine-1-carboxamide; 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[6-(6-methylsulfonyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)-3-pyridyl]-1H-indazole; 3-[6-(4,7-diazaspiro[2.5]octan-7-yl)-3-pyridyl]-5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole; 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[6-(4-methylsulfonyl-4,7-diazaspiro[2.5]octan-7-yl)-3-pyridyl]-1H-indazole; (R)-7-(5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)pyridin-2-yl)-N,N-dimethyl-4,7-diazaspiro[2.5]octane-4-carboxamide; 7-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-4,7-diazaspiro[2.5]octane-4-carboxamide; 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-(6-fluoro-3-pyridyl)-1H-indazole; 8-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-1-oxa-8-azaspiro[4.5]decane; 8-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2,8-diazaspiro[4.5]decan-1-one; 8-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2-oxa-8-azaspiro[4.5]decane; 8-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-1,8-diazaspiro[4.5]decan-2-one; 1-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-1,4-diazepan-5-one; 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[6-(2-isopropyl-2,6-diazaspiro[3.3]heptan-6-yl)-3-pyridyl]-1H-indazole; 8-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2-methyl-2,8-diazaspiro[4.5]decane; 8-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-1-methyl-1,8-diazaspiro[4.5]decane; 9-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-1-methyl-1,4,9-triazaspiro[5.5]undecan-5-one; 4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-1,4-diazepan-2-one; 4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]piperazin-2-one; 1-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]piperazin-2-one; 1-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-4-methyl-piperazin-2-one; 1-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-4-methylsulfonyl-piperazin-2-one; 8-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-1-methyl-1,8-diazaspiro[4.5]decan-2-one; 8-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-3-fluoro-2-pyridyl]-1,8-diazaspiro[4.5]decan-2-one; 8-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-3-fluoro-2-pyridyl]-1,8-diazaspiro[4.5]decan-2-one; 8-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-3-fluoro-2-pyridyl]-1-methyl-1,8-diazaspiro[4.5]decan-2-one; 9-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-3-fluoro-2-pyridyl]-1-methyl-1,4,9-triazaspiro[5.5]undecan-5-one; 3-[6-(2,6-diazaspiro[3.3]heptan-2-yl)-3-pyridyl]-5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole; 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[6-(2-methylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)-3-pyridyl]-1H-indazole; 6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-N,N-dimethyl-2,6-diazaspiro[3.3]heptane-2-carboxamide; 8-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]pyrimidin-2-yl]-1,8-diazaspiro[4.5]decan-2-one; 8-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]pyrimidin-2-yl]-2,8-diazaspiro[4.5]decan-3-one; 8-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]pyrimidin-2-yl]-2,8-diazaspiro-[4.5]decane-1,3-dione; 8-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]pyrimidin-2-yl]-2-methyl-2,8-diazaspiro[4.5]decan-1-one; 8-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]pyrimidin-2-yl]-1-methyl-1,8-diazaspiro[4.5]decane; 8-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]pyrimidin-2-yl]-1,3,8-triazaspiro-[4.5]decan-2-one; 8-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]pyrimidin-2-yl]-1-methyl-1,8-diazaspiro[4.5]decan-2-one; 8-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]pyrimidin-2-yl]-2,8-diazaspiro-[4.5]decan-1-one; 8-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]pyrimidin-2-yl]-1,8-diazaspiro[4.5]decane; 8-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]pyrimidin-2-yl]-2λ 6 -thia-8-azaspiro[4.5]decane 2,2-dioxide; 9-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]pyrimidin-2-yl]-1-methyl-1,4,9-triazaspiro[5.5]undecan-5-one; 3-(2-chloropyrimidin-5-yl)-5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole; 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[2-[4-(oxetan-3-yl)-1,4-diazepan-1-yl]pyrimidin-5-yl]-1H-indazole; 3-[2-(1,4-diazepan-1-yl)pyrimidin-5-yl]-5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole; 4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]pyrimidin-2-yl]-1,4-diazepane-1-carboxamide; 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[2-(4-methylsulfonyl-1,4-diazepan-1-yl)pyrimidin-5-yl]-1H-indazole; 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[1-(4-piperidyl)pyrazol-4-yl]-1H-indazole; 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[1-(1-methyl-4-piperidyl)pyrazol-4-yl]-1H-indazole; 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[1-(1-methylsulfonyl-4-piperidyl)pyrazol-4-yl]-1H-indazole; 4-[4-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]pyrazol-1-yl]-N,N-dimethyl-piperidine-1-carboxamide; 4-[4-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]pyrazol-1-yl]piperidine-1-carboxamide; 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[6-(4-piperidyl)-3-pyridyl]-1H-indazole; 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[6-(1-methylsulfonyl-4-piperidyl)-3-pyridyl]-1H-indazole; 4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-N,N-dimethyl-piperidine-1-carboxamide; 4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]piperidine-1-carboxamide; 7-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-5-oxa-2,7-diazaspiro[3.4]octan-6-one; 3-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-1-oxa-3,8-diazaspiro[4.5]decan-2-one; 3-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-8-methyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one; 3-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-8-methylsulfonyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one; 8-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-3-fluoro-2-pyridyl]-2λ 6 -thia-8-azaspiro[4.5]decane 2,2-dioxide; 8-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]--2-pyridyl]-2λ 6 -thia-8-azaspiro[4.5]decane 2,2-dioxide; 2-[4-[4-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]pyrazol-1-yl]-1-piperidyl]ethanol; 5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-3-[1-(1-methyl-4-piperidyl)pyrazol-4-yl]-1H-indazole; 1-[4-[4-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]pyrazol-1-yl]-1-piperidyl]-2-(dimethylamino)ethanone; 1-[4-[4-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]pyrazol-1-yl]-1-piperidyl]-3-(dimethylamino)propan-1-one; 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[1-(1-isopropyl-4-piperidyl)pyrazol-4-yl]-1H-indazole; 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[(1R)-1-(1-isopropylpyrrolidin-3-yl)pyrazol-4-yl]-1H-indazole; 3-[1-(azetidin-3-yl)pyrazol-4-yl]-5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole; 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[1-(1-isopropylazetidin-3-yl)pyrazol-4-yl]-1H-indazole; 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[1-[1-(oxetan-3-yl)-4-piperidyl]pyrazol-4-yl]-1H-indazole; 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[1-[(3S)-pyrrolidin-3-yl]pyrazol-4-yl]-1H-indazole; 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[1-[(3S)-1-ethylpyrrolidin-3-yl]pyrazol-4-yl]-1H-indazole; 3-[1-(1-cyclobutyl-4-piperidyl)pyrazol-4-yl]-5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole; 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[1-[(3R)-1-ethylpyrrolidin-3-yl]pyrazol-4-yl]-1H-indazole; 5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-3-[1-(4-piperidyl)pyrazol-4-yl]-1H-indazole; 5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-3-[1-(1-isopropyl-4-piperidyl)pyrazol-4-yl]-1H-indazole; 5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-3-[1-[1-(oxetan-3-yl)-4-piperidyl]pyrazol-4-yl]-1H-indazole; 3-[1-(1-cyclobutyl-4-piperidyl)pyrazol-4-yl]-5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-1H-indazole; 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[6-(1-methyl-1,6-diazaspiro[3.3]heptan-6-yl)-3-pyridyl]-1H-indazole; 9-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-4-methyl-1,4,9-triazaspiro[5.5]undecan-2-one; 9-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-1,4-dimethyl-1,4,9-triazaspiro[5.5]undecan-2-one; 3-[6-(1,6-diazaspiro[3.3]heptan-6-yl)-3-pyridyl]-5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole; 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[6-(1-methylsulfonyl-1,6-diazaspiro[3.3]heptan-6-yl)-3-pyridyl]-1H-indazole; 4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-3-methyl-2-pyridyl]morpholine; 5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-morpholino-pyridine-3-carbonitrile; 4-[6-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-3-pyridyl]morpholine; 5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-3-(1-tetrahydropyran-4-ylpyrazol-4-yl)-1H-indazole; 4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-3-methoxy-2-pyridyl]morpholine; 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-(1-tetrahydropyran-4-ylpyrazol-4-yl)-1H-indazole; 5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-3-[6-(2-methylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)-3-pyridyl]-1H-indazole; 5-[1-(2,4-dichloro-3-pyridyl)ethoxy]-3-[1-[1-(oxetan-3-yl)-4-piperidyl]pyrazol-4-yl]-1H-indazole; 5-[1-(2,4-dichloro-3-pyridyl)ethoxy]-3-[6-(2-methylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)-3-pyridyl]-1H-indazole; 3-[6-(2,7-diazaspiro[3.5]nonan-2-yl)-3-pyridyl]-5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole; 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[6-(7-methylsulfonyl-2,7-diazaspiro[3.5]nonan-2-yl)-3-pyridyl]-1H-indazole; 6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2λ 6 -thia-6-azaspiro[3.3]heptane 2,2-dioxide; 2-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-7λ 6 -thia-2-azaspiro[3.5]nonane 7,7-dioxide; 4-[4-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]pyrazol-1-yl]thiane 1,1-dioxide; 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[6-(7-methylsulfonyl-2,7-diazaspiro[3.4]octan-2-yl)-3-pyridyl]-1H-indazole; 4-[4-[5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-1H-indazol-3-yl]pyrazol-1-yl]thiane 1,1-dioxide; 2-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-6λ 6 -thia-2-azaspiro[3.4]octane 6,6-dioxide; 3-[2-(2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl]-5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole; 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[2-(2-methylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)pyrimidin-5-yl]-1H-indazole; 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[2-(2-isopropylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)pyrimidin-5-yl]-1H-indazole; Ethyl 6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate; 2-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]pyrimidin-2-yl]-6λ 6 -thia-2-azaspiro[3.4]octane 6,6-dioxide; Methyl 6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate; 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[6-(2-ethylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)-3-pyridyl]-1H-indazole; Methyl 2-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2,7-diazaspiro[3.5]nonane-7-carboxylate; Ethyl 2-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]pyrimidin-2-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate; 7-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]pyrimidin-2-yl]-2λ 6 -thia-7-azaspiro[4.4]nonane 2,2-dioxide; 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[2-(2-ethylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)pyrimidin-5-yl]-1H-indazole; 2-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]pyrimidin-2-yl]-6λ 6 -thia-2-azaspiro[3.5]nonane 6,6-dioxide; Ethyl 2-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2,7-diazaspiro[3.5]nonane-7-carboxylate; Ethyl 2-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]pyrimidin-2-yl]-2,8-diazaspiro[3.5]nonane-8-carboxylate; 3-[2-(2,8-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl]-5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole; 3-[2-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl]-5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole; 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[2-(8-methylsulfonyl-2,8-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl]-1H-indazole; Isopropyl 2-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]pyrimidin-2-yl]-2,8-diazaspiro[3.5]nonane-8-carboxylate; Methyl 2-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]pyrimidin-2-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate; 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[2-(7-methylsulfonyl-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl]-1H-indazole; Methyl 2-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]pyrimidin-2-yl]-2,8-diazaspiro[3.5]nonane-8-carboxylate; 5-[(1R)-1-(3,5-dimethyl-4-pyridyl)ethoxy]-3-[6-(2-methylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)-3-pyridyl]-1H-indazole; 5-[(1S)-1-(3,5-dimethyl-4-pyridyl)ethoxy]-3-[6-(2-methylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)-3-pyridyl]-1H-indazole; 2-[5-[5-[(1R)-1-(3,5-dimethylpyridazin-4-yl)ethoxy]-1H-indazol-3-yl]pyrimidin-2-yl]-6λ 6 -thia-2-azaspiro[3.4]octane 6,6-dioxide; Ethyl 6-[5-[5-[(1R)-1-(3,5-dimethylpyridazin-4-yl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate; Methyl 6-[5-[5-[(1R)-1-(3,5-dimethylpyridazin-4-yl)ethoxy]-1H-indazol-3-yl]pyrimidin-2-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate; 2-[5-[5-[(1R)-1-(3,5-dimethylpyridazin-4-yl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-6λ 6 -thia-2-azaspiro[3.4]octane 6,6-dioxide; 2-[5-[5-[(1S)-1-(3,5-dimethylpyridazin-4-yl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-6λ 6 -thia-2-azaspiro[3.4]octane 6,6-dioxide; Ethyl 6-[5-[5-[(1R)-1-(3,5-dimethylpyridazin-4-yl)ethoxy]-1H-indazol-3-yl]pyrimidin-2-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate; 2-[5-[5-[(1S)-1-(3,5-dimethylpyridazin-4-yl)ethoxy]-1H-indazol-3-yl]pyrimidin-2-yl]-6λ 6 -thia-2-azaspiro[3.4]octane 6,6-dioxide; 5-[(1R)-1-(3,5-dimethylpyridazin-4-yl)ethoxy]-3-[6-(2-methylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)-3-pyridyl]-1H-indazole; 5-[(1S)-1-(3,5-dimethylpyridazin-4-yl)ethoxy]-3-[6-(2-methylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)-3-pyridyl]-1H-indazole; Methyl 6-[5-[5-[(1R)-1-(3,5-dimethylpyridazin-4-yl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate; Ethyl 6-[5-[5-[(1S)-1-(3,5-dimethylpyridazin-4-yl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate; 8-[5-[5-[(1R)-1-(3,5-dimethylpyridazin-4-yl)ethoxy]-1H-indazol-3-yl]pyrimidin-2-yl]-2λ 6 -thia-8-azaspiro[4.5]decane 2,2-dioxide; Methyl 6-[5-[5-[(1S)-1-(3,5-dimethylpyridazin-4-yl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate; 8-[5-[5-[(1S)-1-(3,5-dimethylpyridazin-4-yl)ethoxy]-1H-indazol-3-yl]pyrimidin-2-yl]-2λ 6 -thia-8-azaspiro[4.5]decane 2,2-dioxide; 5-[(1S)-1-(3,5-dimethylpyridazin-4-yl)ethoxy]-3-[2-(2-methylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)pyrimidin-5-yl]-1H-indazole; 5-[(1R)-1-(3,5-dimethylpyridazin-4-yl)ethoxy]-3-[2-(2-methylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)pyrimidin-5-yl]-1H-indazole; 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[2-(7-methylsulfonyl-2,7-diazaspiro[3.4]octan-2-yl)pyrimidin-5-yl]-1H-indazole; 3-[2-(2,7-diazaspiro[3.4]octan-2-yl)pyrimidin-5-yl]-5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole; 2-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-6λ 6 -thia-2-azaspiro[3.5]nonane 6,6-dioxide; 5-[(1S)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[6-(2-methylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)-3-pyridyl]-1H-indazole; 3-[6-(2,8-diazaspiro[3.5]nonan-2-yl)-3-pyridyl]-5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole; 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[6-(8-methylsulfonyl-2,8-diazaspiro[3.5]nonan-2-yl)-3-pyridyl]-1H-indazole; 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[6-(7-methylsulfonyl-2,7-diazaspiro[3.4]octan-2-yl)-3-pyridyl]-1H-indazole; 3-[6-(2,7-diazaspiro[3.4]octan-2-yl)-3-pyridyl]-5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole; Methyl 2-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2,8-diazaspiro[3.5]nonane-8-carboxylate; 5-[(1R)-1-(3,5-difluorophenyl)ethoxy]-3-[1-(4-piperidyl)pyrazol-4-yl]-1H-indazole; 3-[1-(1-cyclobutyl-4-piperidyl)pyrazol-4-yl]-5-[(1R)-1-(3,5-difluorophenyl)ethoxy]-1H-indazole; 5-[(1R)-1-(3,5-difluorophenyl)ethoxy]-3-[1-[1-(oxetan-3-yl)-4-piperidyl]pyrazol-4-yl]-1H-indazole; 3-[6-(2,6-diazaspiro[3.3]heptan-2-yl)-3-pyridyl]-5-[(1R)-1-(3,5-difluorophenyl)ethoxy]-1H-indazole; 5-[(1R)-1-(2,6-dichlorophenyl)ethoxy]-3-[6-(2-methylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)-3-pyridyl]-1H-indazole; 4-[4-[5-[(1R)-1-(3,5-difluorophenyl)ethoxy]-1H-indazol-3-yl]pyrazol-1-yl]thiane 1,1-dioxide; 5-[(1R)-1-(3,5-difluorophenyl)ethoxy]-3-[6-(2-methylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)-3-pyridyl]-1H-indazole; 5-[5-[(1R)-1-(3,5-dimethylpyridazin-4-yl)ethoxy]-1H-indazol-3-yl]-2-pyrrolidin-1-yl-pyridine-3-carbonitrile; 3-[6-[(8aS)-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]-3-pyridyl]-5-[(1R)-1-(3,5-dimethylpyridazin-4-yl)ethoxy]-1H-indazole; 3-[6-[(8aR)-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]-3-pyridyl]-5-[(1R)-1-(3,5-dimethylpyridazin-4-yl)ethoxy]-1H-indazole; (7R,8aS)-2-[5-[5-[(1R)-1-(3,5-dimethylpyridazin-4-yl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-7-ol; 3-[6-(2,6-diazaspiro[3.3]heptan-2-yl)-3-pyridyl]-5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-1H-indazole; (7R,8aS)-2-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-7-ol; 3-[2-(2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl]-5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-1H-indazole; 5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-3-[6-(2-ethylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)-3-pyridyl]-1H-indazole; 5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-3-[2-(2-ethylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)pyrimidin-5-yl]-1H-indazole; Ethyl 2-[5-[5-[(1R)-1-(3,5-dimethylpyridazin-4-yl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2,8-diazaspiro[3.5]nonane-8-carboxylate; 3-[6-[(8aS)-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]-3-pyridyl]-5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole; 3-[6-[(8aR)-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]-3-pyridyl]-5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole; Ethyl 6-[5-[5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-1H-indazol-3-yl]pyrimidin-2-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate; 5-[(1R)-1-(3,5-dimethylpyridazin-4-yl)ethoxy]-3-[6-(8-ethylsulfonyl-2,8-diazaspiro[3.5]nonan-2-yl)-3-pyridyl]-1H-indazole; Methyl 2-[5-[5-[(1R)-1-(3,5-dimethylpyridazin-4-yl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2,8-diazaspiro[3.5]nonane-8-carboxylate; 5-[(1R)-1-(3,5-dimethylpyridazin-4-yl)ethoxy]-3-[6-(8-methylsulfonyl-2,8-diazaspiro[3.5]nonan-2-yl)-3-pyridyl]-1H-indazole; Isopropyl 2-[5-[5-[(1R)-1-(3,5-dimethylpyridazin-4-yl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2,8-diazaspiro[3.5]nonane-8-carboxylate; Ethyl 6-[5-[5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate; 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-3-[6-(2-methylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)-3-pyridyl]-1H-indazole; 5-[(1S)-1-(3,5-dimethylpyridazin-4-yl)ethoxy]-6-methoxy-3-[6-(2-methylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)-3-pyridyl]-1H-indazole; Ethyl 6-[5-[5-[(1S)-1-(3,5-dichloro-2-fluoro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate; 5-[(1R)-1-(3,5-dimethylpyridazin-4-yl)ethoxy]-6-methoxy-3-[6-(2-methylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)-3-pyridyl]-1H-indazole; Methyl 6-[5-[5-[(1R)-1-(3,5-dichloro-2-fluoro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate; Ethyl 6-[5-[5-[(1R)-1-(3,5-dichloro-2-fluoro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate; 5-[(1R)-1-(3,5-dichloro-2-fluoro-4-pyridyl)ethoxy]-3-[6-(2-methylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)-3-pyridyl]-1H-indazole; Methyl 6-[5-[5-[(1S)-1-(3,5-dichloro-2-fluoro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate; 5-[(1S)-1-(3,5-dichloro-2-fluoro-4-pyridyl)ethoxy]-3-[6-(2-methylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)-3-pyridyl]-1H-indazole; 5-[(1R)-1-(3,5-dimethylpyridazin-4-yl)ethoxy]-4-methoxy-3-[6-(2-methylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)-3-pyridyl]-1H-indazole; 6-[5-[5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2-oxa-6-azaspiro[3.3]heptane; 6-[5-[5-[(1R)-1-(3,5-dimethylpyridazin-4-yl)ethoxy]-6-methoxy-1H-indazol-3-yl]-2-pyridyl]-2-oxa-6-azaspiro[3.3]heptane; 6-[5-[5-[(1R)-1-(3,5-dichloro-2-fluoro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2-oxa-6-azaspiro[3.3]heptane; (R)-2-(5-(5-(1-(3,5-dichloro-2-fluoropyridin-4-yl)ethoxy)-1H-indazol-3-yl)pyridin-2-yl)-6-oxa-2-azaspiro[3.4]octane; 6-[5-[5-[(1R)-1-(3,5-dimethylpyridazin-4-yl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2-oxa-6-azaspiro[3.3]heptane; (R)-2-(5-(5-(1-(3,5-dimethylpyridazin-4-yl)ethoxy)-1H-indazol-3-yl)pyridin-2-yl)-6-oxa-2-azaspiro[3.4]octane; 5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-6-methoxy-3-[6-(2-methylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)-3-pyridyl]-1H-indazole; 1-[5-[5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-6-methoxy-1H-indazol-3-yl]-2-pyridyl]azetidin-3-ol; (3R)-1-[5-[5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-6-methoxy-1H-indazol-3-yl]-2-pyridyl]pyrrolidin-3-ol; 5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-3-[6-(3-methoxy-3-methyl-azetidin-1-yl)-3-pyridyl]-1H-indazole; 6-[5-[5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-6-methoxy-1H-indazol-3-yl]-2-pyridyl]-2-oxa-6-azaspiro[3.3]heptane; 3-[6-(2-azaspiro[3.3]-heptan-2-yl)-3-pyridyl]-5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-1H-indazole; 3-(5-(5-((R)-1-(3,5-dimethylpyridazin-4-yl)ethoxy)-6-methoxy-1H-indazol-3-yl)pyridin-2-yl)-6-ethyl-3,6-diazabicyclo[3.1.1]heptane; 1-(3-(5-(5-((R)-1-(3,5-dimethylpyridazin-4-yl)ethoxy)-6-methoxy-1H-indazol-3-yl)-3-methylpyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)-2-methylpropan-2-ol; 2-[5-[5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-6-methoxy-1H-indazol-3-yl]-2-pyridyl]-1,3,4,7,8,8a-hexahydropyrrolo[1,2-a]pyrazin-6-one; 2-[5-[5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-6-oxa-2-azaspiro[3.4]octane; 2-[5-[5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-1H-indazol-3-yl]-3-methyl-2-pyridyl]-6-oxa-2-azaspiro[3.4]octane; (R)-5-(5-(1-(3,5-dimethylpyridazin-4-yl)ethoxy)-6-methoxy-1H-indazol-3-yl)-2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)nicotinonitrile; (R)-6-(5-(5-(1-(3,5-dimethylpyridazin-4-yl)ethoxy)-6-methoxy-1H-indazol-3-yl)-3-methylpyridin-2-yl)-2-oxa-6-azaspiro[3.3]heptane; 5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-6-methoxy-3-(6-pyrrolidin-1-yl-3-pyridyl)-1H-indazole; (3S)-1-[5-[5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-6-methoxy-1H-indazol-3-yl]-2-pyridyl]pyrrolidin-3-ol; 1-[5-[5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-3-methyl-azetidin-3-ol; (R)-2-(5-(5-(1-(3,5-dichloropyridazin-4-yl)ethoxy)-1H-indazol-3-yl)pyridin-2-yl)-6-oxa-2-azaspiro[3.4]octane; (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(6-(6-(2,2,2-trifluoroethyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-1H-indazole; 2-[5-[5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-1,3,4,7,8,8a-hexahydropyrrolo[1,2-a]pyrazin-6-one; 2-[5-[5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-5-oxa-2-azaspiro[3.4]octane; 2-[5-[5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2-azaspiro[3.3]heptan-6-ol; 7-(5-(5-((R)-1-(3,5-dimethylpyridazin-4-yl)ethoxy)-6-methoxy-1H-indazol-3-yl)pyridin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one; (R)-6-(5-(5-(1-(3,5-dichloropyridazin-4-yl)ethoxy)-1H-indazol-3-yl)pyridin-2-yl)-2-oxa-6-azaspiro[3.3]heptane; (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(6-(6-(2,2-difluoroethyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-1H-indazole; 7-(5-(5-((R)-1-(3,5-dimethylpyridazin-4-yl)ethoxy)-1H-indazol-3-yl)-3-methylpyridin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one; [(2R)-1-[5-[5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]pyrrolidin-2-yl]methanol; (R)-5-(1-(3,5-dichloropyridazin-4-yl)ethoxy)-3-(6-(6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-1H-indazole; [1-[5-[5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-1H-indazol-3-yl]-3-methyl-2-pyridyl]-3-(hydroxymethyl)azetidin-3-yl]methanol; 5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-3-[5-methyl-6-(2-methylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)-3-pyridyl]-1H-indazole; ((R)-1-(5-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)pyridin-2-yl)pyrrolidin-2-yl)methanol; ((S)-1-(5-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)pyridin-2-yl)pyrrolidin-2-yl)methanol; 5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-3-[6-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)-3-pyridyl]-1H-indazole; 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-3-[2-(2-methylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)pyrimidin-5-yl]-1H-indazole; 5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-6-methoxy-3-[2-(2-methylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)pyrimidin-5-yl]-1H-indazole; [(2S)-1-[5-[5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]pyrrolidin-2-yl]methanol; 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[5-fluoro-6-(2-methylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)-3-pyridyl]-6-methoxy-1H-indazole; 5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-3-[5-fluoro-6-(2-methylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)-3-pyridyl]-6-methoxy-1H-indazole; 5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-3-[5-fluoro-6-(2-methylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)-3-pyridyl]-1H-indazole; 1-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2,6-diazaspiro[3.3]heptan-2-yl]-2,2,2-trifluoro-ethanone; (R)-5-(1-(3,5-dichloropyridazin-4-yl)ethoxy)-3-(6-(6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-1H-indazole; 2-[5-[5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2-azaspiro[3.4]octan-6-ol; 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[5-methyl-6-(2-methylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)-3-pyridyl]-1H-indazole; (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(6-(3-(trifluoromethyl)azetidin-1-yl)pyridin-3-yl)-1H-indazole; 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-3-[5-methyl-6-(2-methylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)-3-pyridyl]-1H-indazole; (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methyl-3-(6-(6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-1H-indazole; (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(6-(3-(difluoromethyl)azetidin-1-yl)pyridin-3-yl)-1H-indazole; (R)-1-(5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)pyridin-2-yl)azetidine-3-carbonitrile; (S)-5-(1-(3,5-dichloropyridazin-4-yl)ethoxy)-3-(5-fluoro-6-(6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-6-methyl-1H-indazole; (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-6-fluoro-3-(6-(6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-1H-indazole; 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-fluoro-3-[5-fluoro-6-(2-methylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)-3-pyridyl]-1H-indazole; (R)-1-(5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)pyridin-2-yl)-3-methylazetidin-3-amine; (R)-5-(1-(3,5-dichloropyridazin-4-yl)ethoxy)-6-fluoro-3-(5-fluoro-6-(6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-1H-indazole; (R)-5-(1-(3,5-dichloropyridazin-4-yl)ethoxy)-3-(5-fluoro-6-(6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-6-methyl-1H-indazole; (R)-6-chloro-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(6-(6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-1H-indazole; (R)-5-(1-(3,5-dichloropyridazin-4-yl)ethoxy)-6-methoxy-3-(6-(6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-1H-indazole; (R)-5-(1-(3,5-dichloropyridazin-4-yl)ethoxy)-6-fluoro-3-(6-(6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-1H-indazole; (R)-6-chloro-5-(1-(3,5-dichloropyridazin-4-yl)ethoxy)-3-(6-(6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-1H-indazole; (R)-6-chloro-5-(1-(3,5-dichloropyridazin-4-yl)ethoxy)-3-(5-fluoro-6-(6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-1H-indazole; (R)-1-(5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-3-fluoropyridin-2-yl)-3-methylazetidin-3-amine; 5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-6-fluoro-3-[6-(2-methylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)-3-pyridyl]-1H-indazole; 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(5-fluoro-6-((R)-2-methylazetidin-1-yl)pyridin-3-yl)-6-methoxy-1H-indazole; (R)-3-(6-(azetidin-1-yl)-5-fluoropyridin-3-yl)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methoxy-1H-indazole; 5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-6-fluoro-3-[5-fluoro-6-(2-methylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)-3-pyridyl]-1H-indazole; 6-chloro-5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-3-[5-fluoro-6-(2-methylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)-3-pyridyl]-1H-indazole; 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(5-fluoro-6-((S)-2-methylazetidin-1-yl)pyridin-3-yl)-6-methoxy-1H-indazole; 6-chloro-5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(5-fluoro-6-((R)-2-methylazetidin-1-yl)pyridin-3-yl)-1H-indazole; 5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-3-[5-fluoro-6-(2-methylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)-3-pyridyl]-6-methyl-1H-indazole; 3-[6-(azetidin-1-yl)-5-fluoro-3-pyridyl]-6-chloro-5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-1H-indazole; 1-[5-[6-chloro-5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-1H-indazol-3-yl]-3-fluoro-2-pyridyl]-N,3-dimethyl-azetidin-3-amine; (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(6-(3,3-dimethylazetidin-1-yl)-5-fluoropyridin-3-yl)-6-methoxy-1H-indazole; 6-chloro-5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(5-fluoro-6-((S)-2-methylazetidin-1-yl)pyridin-3-yl)-1H-indazole; (R)-3-(6-(azetidin-1-yl)-5-fluoropyridin-3-yl)-6-chloro-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazole; (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(3,5-difluoro-4-(6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-6-methoxy-1H-indazole; (R)-3-(4-(azetidin-1-yl)-3,5-difluorophenyl)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methoxy-1H-indazole; (R)-1-(5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methoxy-1H-indazol-3-yl)-3-fluoropyridin-2-yl)-N,N,3-trimethylazetidin-3-amine; (R)—N-(1-(5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methoxy-1H-indazol-3-yl)-3-fluoropyridin-2-yl)-3-methylazetidin-3-yl)-N-methylmethanesulfonamide; (S)-2-(azetidin-1-yl)-5-(5-(1-(3,5-dichloro-2-fluoropyridin-4-yl)ethoxy)-1H-indazol-3-yl)nicotinonitrile; 5-(5-((R)-1-(3,5-dichloro-2-fluoropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-2-((R)-3-hydroxypyrrolidin-1-yl)nicotinonitrile; 5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyrrolidin-1-yl-pyridine-3-carbonitrile; (R)-2-(azetidin-1-yl)-5-(5-(1-(3,5-dichloro-2-fluoropyridin-4-yl)ethoxy)-1H-indazol-3-yl)nicotinonitrile; (R)-5-(5-(1-(3,5-dichloro-2-fluoropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-2-(3-hydroxyazetidin-1-yl)nicotinonitrile; 5-(5-((R)-1-(3,5-dichloro-2-fluoropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-2-((S)-3-hydroxypyrrolidin-1-yl)nicotinonitrile; 2-(Azetidin-1-yl)-5-[5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-1H-indazol-3-yl]pyridine-3-carbonitrile; 5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-[(3S)-3-(1-hydroxy-1-methyl-ethyl)pyrrolidin-1-yl]pyridine-3-carbonitrile; (S)-5-(5-(1-(3,5-dichloro-2-fluoropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-2-(3-hydroxyazetidin-1-yl)nicotinonitrile; (R)-5-(5-(1-(3,5-dichloro-2-fluoropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-2-(pyrrolidin-1-yl)nicotinonitrile; 5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-[(3S)-3-hydroxypyrrolidin-1-yl]pyridine-3-carbonitrile; 5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-[(3R)-3-(1-hydroxy-1-methyl-ethyl)pyrrolidin-1-yl]pyridine-3-carbonitrile; 5-[5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-[3-(2,2,2-trifluoroethyl)azetidin-1-yl]pyridine-3-carbonitrile; 5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-[3-(2,2,2-trifluoroethyl)azetidin-1-yl]pyridine-3-carbonitrile; 5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-[(3R)-3-hydroxypyrrolidin-1-yl]pyridine-3-carbonitrile; 5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-(4-hydroxy-1-piperidyl)pyridine-3-carbonitrile; 2-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-5-(5-((R)-1-(3,5-dimethylpyridazin-4-yl)ethoxy)-1H-indazol-3-yl)nicotinonitrile; 3-(5-(5-((R)-1-(3,5-dimethylpyridazin-4-yl)ethoxy)-1H-indazol-3-yl)-3-methoxypyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane; 5-(5-((R)-1-(3,5-dimethylpyridazin-4-yl)ethoxy)-1H-indazol-3-yl)-2-((S)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)nicotinonitrile; 5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-(3-hydroxyazetidin-1-yl)pyridine-3-carbonitrile; 5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-[4-(1-hydroxy-1-methyl-ethyl)-1-piperidyl]pyridine-3-carbonitrile; (R)-3-(6-(azetidin-1-yl)-5-methoxypyridin-3-yl)-5-(1-(3,5-dimethylpyridazin-4-yl)ethoxy)-1H-indazole; (R)-5-(1-(3,5-dimethylpyridazin-4-yl)ethoxy)-3-(5-methoxy-6-(pyrrolidin-1-yl)pyridin-3-yl)-1H-indazole; 5-(5-((R)-1-(3,5-dimethylpyridazin-4-yl)ethoxy)-1H-indazol-3-yl)-2-((S)-3-hydroxypyrrolidin-1-yl)nicotinonitrile; 5-(5-((R)-1-(3,5-dimethylpyridazin-4-yl)ethoxy)-1H-indazol-3-yl)-2-((R)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)nicotinonitrile; 5-[5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-(3-hydroxyazetidin-1-yl)pyridine-3-carbonitrile; 2-(Azetidin-1-yl)-5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]pyridine-3-carbonitrile; (R)-3-(6-(azetidin-1-yl)pyridin-3-yl)-5-(1-(3,5-dimethylpyridazin-4-yl)ethoxy)-6-methoxy-1H-indazole; 5-(5-((R)-1-(3,5-dimethylpyridazin-4-yl)ethoxy)-6-methoxy-1H-indazol-3-yl)-2-((S)-3-hydroxypyrrolidin-1-yl)nicotinonitrile; 5-(5-((R)-1-(3,5-dimethylpyridazin-4-yl)ethoxy)-1H-indazol-3-yl)-2-(6-(2-hydroxy-2-methylpropyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)nicotinonitrile; 5-(5-((R)-1-(3,5-dimethylpyridazin-4-yl)ethoxy)-1H-indazol-3-yl)-2-((R)-3-hydroxypyrrolidin-1-yl)nicotinonitrile; 3-(5-(5-((R)-1-(3,5-dimethylpyridazin-4-yl)ethoxy)-6-methoxy-1H-indazol-3-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane; (R)-5-(1-(3,5-dimethylpyridazin-4-yl)ethoxy)-6-methoxy-3-(6-(pyrrolidin-1-yl)pyridin-3-yl)-1H-indazole; 5-(5-((R)-1-(3,5-dimethylpyridazin-4-yl)ethoxy)-6-methoxy-1H-indazol-3-yl)-2-((S)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)nicotinonitrile; 3-(5-(5-((R)-1-(3,5-dimethylpyridazin-4-yl)ethoxy)-6-methoxy-1H-indazol-3-yl)-3-methylpyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane; (R)-5-(5-(1-(3,5-dimethylpyridazin-4-yl)ethoxy)-1H-indazol-3-yl)-2-(3-hydroxyazetidin-1-yl)nicotinonitrile; 5-(5-((R)-1-(3,5-dimethylpyridazin-4-yl)ethoxy)-6-methoxy-1H-indazol-3-yl)-2-((R)-3-hydroxypyrrolidin-1-yl)nicotinonitrile; (R)-5-(5-(1-(3,5-dimethylpyridazin-4-yl)ethoxy)-6-methoxy-1H-indazol-3-yl)-2-(3-hydroxyazetidin-1-yl)nicotinonitrile; 5-(5-((R)-1-(3,5-dimethylpyridazin-4-yl)ethoxy)-6-methoxy-1H-indazol-3-yl)-2-((R)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)nicotinonitrile; (R)-2-(azetidin-1-yl)-5-(5-(1-(3,5-dimethylpyridazin-4-yl)ethoxy)-6-methoxy-1H-indazol-3-yl)nicotinonitrile; 1-(3-(5-(5-((R)-1-(3,5-dimethylpyridazin-4-yl)ethoxy)-1H-indazol-3-yl)-3-methoxypyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)-2-methylpropan-2-ol; (R)-5-(5-(1-(3,5-dimethylpyridazin-4-yl)ethoxy)-6-methoxy-1H-indazol-3-yl)-2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)nicotinonitrile; 5-(5-((R)-1-(3,5-dimethylpyridazin-4-yl)ethoxy)-1H-indazol-3-yl)-2-(3-oxohexahydroimidazo[1,5-a]pyrazin-7(1H)-yl)nicotinonitrile; 5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-1H-indazol-3-yl]-2-(3-hydroxyazetidin-1-yl)pyridine-3-carbonitrile; 5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-1H-indazol-3-yl]-2-[(3S)-3-hydroxypyrrolidin-1-yl]pyridine-3-carbonitrile; 7-(5-(5-((R)-1-(3,5-dimethylpyridazin-4-yl)ethoxy)-1H-indazol-3-yl)-3-methoxypyridin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one; (R)-5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-2-(6-(2,2,2-trifluoroethyl)-2,6-diazaspiro[3.3]heptan-2-yl)nicotinonitrile; (R)-5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-2-(6-(2,2-difluoroethyl)-2,6-diazaspiro[3.3]heptan-2-yl)nicotinonitrile; 5-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-2-(6-hydroxy-3-azabicyclo[3.1.0]hexan-3-yl)nicotinonitrile; 5-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-2-((R)-2-(hydroxymethyl)pyrrolidin-1-yl)nicotinonitrile; 5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-1H-indazol-3-yl]-2-pyrrolidin-1-yl-pyridine-3-carbonitrile; 5-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-2-((S)-2-(hydroxymethyl)pyrrolidin-1-yl)nicotinonitrile; 5-(5-((R)-1-(3,5-dimethylpyridazin-4-yl)ethoxy)-1H-indazol-3-yl)-2-((R)-2-(hydroxymethyl)pyrrolidin-1-yl)nicotinonitrile; 5-(5-((R)-1-(3,5-dimethylpyridazin-4-yl)ethoxy)-1H-indazol-3-yl)-2-((S)-2-(hydroxymethyl)pyrrolidin-1-yl)nicotinonitrile; (R)-5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-2-(6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)nicotinonitrile; (R)-5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-2-(6-(methylsulfonyl)-2,6-diazaspiro[3.5]nonan-2-yl)nicotinonitrile; (R)-5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methoxy-1H-indazol-3-yl)-2-(6,6-dioxide-6-thia-2-azaspiro[3.4]octan-2-yl)nicotinonitrile; (R)-5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-2-(6,6-dioxide-6-thia-2-azaspiro[3.5]nonan-2-yl)nicotinonitrile; 5-[5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-6-methoxy-1H-indazol-3-yl]-2-(2-methylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)pyridine-3-carbonitrile; 5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-1H-indazol-3-yl]-2-(2-methylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)pyridine-3-carbonitrile; (R)-5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-2-(6,6-dioxide-6-thia-2-azaspiro[3.4]octan-2-yl)nicotinonitrile; (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(5-methoxy-6-(6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-1H-indazole; (R)-5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-2-(3-(difluoromethyl)azetidin-1-yl)nicotinonitrile; (R)-5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methoxy-1H-indazol-3-yl)-2-(6,6-dioxide-6-thia-2-azaspiro[3.5]nonan-2-yl)nicotinonitrile; (R)-5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-2-(3-(trifluoromethyl)azetidin-1-yl)nicotinonitrile; (R)-2-(3-cyanoazetidin-1-yl)-5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)nicotinonitrile; 5-[5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-(6,6-dioxo-6λ 6 -thia-2-azaspiro[3.5]nonan-2-yl)pyridine-3-carbonitrile; 5-[5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-(8-methylsulfonyl-2,8-diazaspiro[3.5]nonan-2-yl)pyridine-3-carbonitrile; 5-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-2-((R)-2-(hydroxymethyl)azetidin-1-yl)nicotinonitrile; (R)-5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methyl-1H-indazol-3-yl)-2-(6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)nicotinonitrile; (R)-5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-2-(3,3-difluoroazetidin-1-yl)nicotinonitrile; 5-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-2-((S)-2-(hydroxymethyl)azetidin-1-yl)nicotinonitrile; (R)-5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-6-fluoro-1H-indazol-3-yl)-2-(6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)nicotinonitrile; (R)-1-(5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-2-(6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-N,N-dimethylmethanamine; (R)-1-(5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methoxy-1H-indazol-3-yl)-2-(6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-N,N-dimethylmethanamine; (R)-2-(3-amino-3-methylazetidin-1-yl)-5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)nicotinonitrile; (R)-5-(6-chloro-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-2-(6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)nicotinonitrile; (R)-2-(azetidin-1-yl)-5-(5-(1-(3,5-dichloropyridazin-4-yl)ethoxy)-6-methoxy-1H-indazol-3-yl)nicotinonitrile; (R)-2-(azetidin-1-yl)-5-(5-(1-(3,5-dichloropyridazin-4-yl)ethoxy)-1H-indazol-3-yl)nicotinonitrile; 5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-fluoro-1H-indazol-3-yl]-2-(6,6-dioxo-6λ 6 -thia-2-azaspiro[3.5]nonan-2-yl)pyridine-3-carbonitrile; 5-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-2-(2-((dimethylamino)methyl)azetidin-1-yl)nicotinonitrile; (R)-5-(6-chloro-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-2-(3,3-dimethylazetidin-1-yl)nicotinonitrile; 5-(6-chloro-5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-2-((S)-2-methylazetidin-1-yl)nicotinonitrile; (R)-1-(2-(azetidin-1-yl)-5-(6-chloro-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)pyridin-3-yl)-N,N-dimethylmethanamine; (R)-3-(6-(azetidin-1-yl)-5-(methylsulfonyl)pyridin-3-yl)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methoxy-1H-indazole; (R)-1-(5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-2-(6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-N-methylmethanamine; (R)-1-(5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methoxy-1H-indazol-3-yl)-2-(6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-N-methylmethanamine; (R)-3-(6-(azetidin-1-yl)-5-(methylsulfonyl)pyridin-3-yl)-6-chloro-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazole; (R)-1-(5-(6-chloro-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-2-(3,3-dimethylazetidin-1-yl)pyridin-3-yl)-N,N-dimethylmethanamine; 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methoxy-3-(6-((R)-2-methylazetidin-1-yl)-5-(methylsulfonyl)pyridin-3-yl)-1H-indazole; 5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-fluoro-1H-indazol-3-yl]-2-(2-methylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)pyridine-3-carbonitrile; 5-(6-chloro-5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-2-((R)-2-methylazetidin-1-yl)nicotinonitrile; 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methoxy-3-(6-((S)-2-methylazetidin-1-yl)-5-(methylsulfonyl)pyridin-3-yl)-1H-indazole; (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(6-(3,3-dimethylazetidin-1-yl)-5-(methylsulfonyl)pyridin-3-yl)-6-methoxy-1H-indazole; 2-(Azetidin-1-yl)-5-[6-chloro-5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]pyridine-3-carbonitrile; 5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-fluoro-1H-indazol-3-yl]-2-(6,6-dioxo-6λ 6 -thia-2-azaspiro[3.4]octan-2-yl)pyridine-3-carbonitrile; 5-[5-[(1R)-1-(3,5-dichloro-2-methyl-4-pyridyl)ethoxy]-6-fluoro-1H-indazol-3-yl]-2-(2-methylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)pyridine-3-carbonitrile; 5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-fluoro-1H-indazol-3-yl]-2-(8-methylsulfonyl-2,8-diazaspiro[3.5]nonan-2-yl)pyridine-3-carbonitrile; (R)-6-chloro-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(6-(3,3-dimethylazetidin-1-yl)-5-(methylsulfonyl)pyridin-3-yl)-1H-indazole; (R)-1-(2-(azetidin-1-yl)-5-(6-chloro-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)pyridin-3-yl)-N-methylmethanamine; (R)-3-(6-(azetidin-1-yl)-5-(trifluoromethyl)pyridin-3-yl)-6-chloro-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazole; 6-chloro-5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(6-((S)-2-methylazetidin-1-yl)-5-(trifluoromethyl)pyridin-3-yl)-1H-indazole; (R)-1-(5-(6-chloro-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-3-(trifluoromethyl)pyridin-2-yl)-N,N,3-trimethylazetidin-3-amine; 6-chloro-5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(6-((R)-2-methylazetidin-1-yl)-5-(trifluoromethyl)pyridin-3-yl)-1H-indazole; or 1. A compound, or a pharmaceutically acceptable salt thereof, which is (R)-1-(5-(6-chloro-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-3-(methylsulfonyl)pyridin-2-yl)-N,N,3-trimethylazetidin-3-amine.

22. The compound of claim 21, which is 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[6-(2-methylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)-3-pyridyl]-1H-indazole, or a pharmaceutically acceptable salt thereof.

23. 23. A pharmaceutical composition comprising a compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

24. 24. The pharmaceutical composition of claim 23 for use in treating cancer in a subject in need thereof, optionally comprising the cancer is urothelial carcinoma, breast cancer, endometrial adenocarcinoma, ovarian cancer, primary glioma, cholangiocarcinoma, gastric adenocarcinoma, non-small cell lung cancer, exocrine pancreatic carcinoma, oral, prostate, bladder, colorectal cancer, renal alveolar carcinoma, neuroendocrine carcinoma, myeloproliferative neoplasm, head and neck (squamous), melanoma, leiomyosarcoma, and / or sarcoma; or the cancer is intrahepatic cholangiocarcinoma; or The pharmaceutical composition, wherein the cancer is an FGFR-mutant cancer.

25. A pharmaceutical composition according to claim 23 for use in treating achondroplasia, chondrodysplastic syndrome, hypochondroplasia (Hch), severe achondroplasia with growth retardation and acanthosis nigricans (SADDAN), or thanatophoric dysplasia (TD) in a subject in need thereof.

Images