Bicyclic amines as CDK2 inhibitors

Abstract

The present application provides bicyclic amine inhibitors of cyclin-dependent kinase 2 (CDK2), as well as pharmaceutical compositions thereof and methods for treating cancer using same.

Description

Technical Field

[0001] This application claims the benefit of priority of U.S. Provisional Application No. 62 / 914,114, filed on October 11, 2019, the entire disclosure of which is incorporated herein by reference.

[0002] Sequence Listing This application includes a Sequence Listing that has been electronically submitted in ASCII format, which is hereby incorporated by reference in its entirety. A copy of the ASCII created on October 2, 2020, is named 20443-0634WO1_SL.txt and is 15.3 kilobytes in size.

[0003] Technical Field This application relates to bicyclic amines that inhibit cyclin-dependent kinase 2 (CDK2) and are useful for the treatment of cancer.

Background Art

[0004] Cyclin-dependent kinases (CDKs) are a family of serine / threonine kinases. When forming a heterodimer with a regulatory subunit known as cyclin, CDKs become fully activated and regulate major cellular processes including cell cycle progression and cell division (Morgan, D.O., Annu Rev Cell Dev Biol, 1997.13:261-91). Uncontrolled proliferation is a prominent feature of cancer cells. Dysregulation of CDK activity is associated with abnormal regulation of the cell cycle, which is detected in virtually all forms of human cancer (Sherr, C.J., Science, 1996.274(5293):1672-7).

[0005] CDK2 is of particular interest because deregulation of CDK2 activity frequently occurs in various human cancers. CDK2 plays an essential role in promoting G1 / S transition and S-phase progression. When forming a complex with cyclin E (CCNE), CDK2 phosphorylates retinoblastoma pocket protein family members (p107, p130, pRb), leading to the derepression of E2F transcription factors, the expression of G1 / S transition-related genes, and the transition from G1 phase to S phase (Henley, S.A. and F.A. Dick, Cell Div, 2012, 7(1): p. 10). This in turn enables the activation of CDK2 / cyclin A, and CDK2 / cyclin A phosphorylates endogenous substrates, allowing DNA synthesis, replication, and centrosome replication (Ekholm, S.V. and S.I. Reed, Curr Opin Cell Biol, 2000. 12(6): 676 - 84). The CDK2 pathway has been reported to affect tumorigenesis mainly through amplification and / or overexpression of CCNE1 and / or mutations that inactivate CDK2 endogenous inhibitors (e.g., p27) (Xu, X., et al., Biochemistry, 1999. 38(27): 8713 - 22).

[0006] Increases in CCNE1 copy number and overexpression have been identified in ovarian, gastric, endometrial, breast, and other cancers and are associated with poor outcomes in these tumors (Keyomarsi, K., et al., N Engl J Med, 2002. 347(20):1566 - 75, Nakayama, N., et al., Cancer, 2010. 116(11):2621 - 34, Au - Yeung, G., et al., Clin Cancer Res, 2017. 23(7):1862 - 1874, Rosen, D.G., et al., Cancer, 2006. 106(9):1925 - 32). CCNE1 amplification and / or overexpression has also been reported to contribute to trastuzumab resistance in HER2+ breast cancer and resistance to CDK4 / 6 inhibitors in estrogen receptor - positive breast cancer (Scaltriti, M., et al., Proc Natl Acad Sci U S A, 2011. 108(9):3761 - 6, Herrera - Abreu, M.T., et al., Cancer Res, 2016. 76(8):2301 - 13). Various approaches targeting CDK2 have been shown to induce cell - cycle arrest and inhibit tumor growth (Chen, Y.N., et al., Proc Natl Acad Sci U S A, 1999. 96(8):4325 - 9, Mendoza, N., et al., Cancer Res, 2003. 63(5):1020 - 4). Inhibition of CDK2 has also been reported to restore sensitivity to trastuzumab treatment in resistant HER2+ breast tumors in pre - clinical models (Scaltriti (supra)).

[0007] These data provide a basis for considering CDK2 as a potential target for new drug development in cancers associated with deregulated CDK2 activity. Over the past decade, there has been increasing interest in the development of CDK-selective inhibitors. Despite significant efforts, to date, no approved agents that target CDK2 exist (Cicenas, J., et al., Cancers (Basel), 2014.6(4): p. 2224-42). Therefore, there remains a need to discover CDK inhibitors with novel activity profiles, particularly those that target CDK2. This application relates to this need and other needs.

SUMMARY OF THE INVENTION

[0008] The present invention relates, inter alia, to a compound of formula (I),

CHEMICAL

[0009] The present invention further provides a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0010] The present invention further provides a method for inhibiting CDK2, comprising contacting CDK2 with a compound described herein, or a pharmaceutically acceptable salt thereof.

[0011] The present invention further provides a method for inhibiting CDK2 in a patient, comprising administering to the patient a compound described herein, or a pharmaceutically acceptable salt thereof.

[0012] The present invention further provides a method for treating a disease or disorder associated with CDK2 in a patient, comprising administering to the patient a compound described herein, or a pharmaceutically acceptable salt thereof.

[0013] The present invention further provides a compound described herein, or a pharmaceutically acceptable salt thereof, for use in any of the methods described herein.

[0014] The present invention further provides the use of a compound described herein, or a pharmaceutically acceptable salt thereof, for preparing a medicament for use in any of the methods described herein.

Embodiments for Carrying Out the Invention

[0015] This application relates, inter alia, to a compound of formula (I),

Chemical Formula

Chemical Formula

Chemical Formula

Chemical Formula

Chemical Formula

Chemical Formula

[0016] In some embodiments, R 1 is independently H, halo, CN, NO2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 alkyl, 5- to 6-membered heteroaryl-C 1-4 alkyl, OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , NR c1 S(O)2R b1 , NR c1 S(O)2NR c1 R d1 , S(O)2R b1 , and S(O)2NR c1 R d1 selected from, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and 5- to 6-membered heteroaryl-C 1-4 Alkyl is each optionally, independently, substituted with 1, 2, 3, or 4 independently selected R 1A substituents.

[0017] In some embodiments, R 1 is independently H, halo, CN, NO2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 alkyl, 5- to 6-membered heteroaryl-C 1-4 alkyl, OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , NR c1 S(O)2R b1 , NR c1 , NR c1 R d1 , S(O)2R b1 , and S(O)2NR c1 Rd1 selected from, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 alkyl, and 5- to 6-membered heteroaryl-C 1-4 alkyl is each optionally, independently selected from 1, 2, 3, or 4 R 1A substituents.

[0018] In some embodiments, R 1 is independently H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-3 alkyl, phenyl-C 1-3 alkyl, 4- to 7-membered heterocycloalkyl-C 1-3 alkyl, 5- to 6-membered heteroaryl-C 1-3 alkyl, OR a1 , SR a1 , and NR c1 R d1 selected from, the C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-3 alkyl, phenyl-C 1-3 alkyl, 4- to 7-membered heterocycloalkyl-C 1-3 alkyl, and 5- to 6-membered heteroaryl-C 1-3 alkyl is each optionally, independently selected from 1 or 2 R 1A substituents.

[0019] In some embodiments, R 1 is independently selected from H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-3 alkyl, phenyl-C 1-3 alkyl, 4- to 7-membered heterocycloalkyl-C 1-3 alkyl, 5- to 6-membered heteroaryl-C 1-3 alkyl, OR a1 , and NR c1 R d1 and is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-3 alkyl, phenyl-C 1-3 alkyl, 4- to 7-membered heterocycloalkyl-C 1-3 alkyl, and 5- to 6-membered heteroaryl-C 1-3 alkyl may each independently be optionally substituted with one or two R 1A substituents.

[0020] In some embodiments, R 1 is independently selected from H, halo, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-4 cycloalkyl, and OR a1 and is selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, and C 3-4 cycloalkyl may each independently be optionally substituted with 1, 2, 3, or 4 R 1A substituents.

[0021] In some embodiments, R 1 is independently selected from H, halo, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-4 cycloalkyl, and OR a1 and the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, and C 3-4 cycloalkyl are each optionally substituted with one or two independently selected R 1A substituents.

[0022] In some embodiments, R 1 is independently selected from H, C 1-6 alkyl, phenyl, 5- to 7-membered heterocycloalkyl, OR a1 , SR a1 , and NR c1 R d1 and the C 1-6 alkyl, phenyl, and 5- to 7-membered heterocycloalkyl are each optionally substituted with one or two independently selected R 1A substituents.

[0023] In some embodiments, R 1 is independently selected from H and OR a1 .

[0024] In some embodiments, each R a1 , R c1 , and R d1 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and 5- to 6-membered heteroaryl-C 1-4 Selected from alkyl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and 5- to 6-membered heteroaryl-C 1-4 Alkyl is each optionally, 1, 2, 3, or 4 independently selected R 1A Substituted with substituents, Each R b1 Is independently, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and 5- to 6-membered heteroaryl-C 1-4 Selected from alkyl, these are each optionally, 1, 2, 3, or 4 independently selected R 1A Substituted with substituents, Each R 1A Is independently, H, halo, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C1-4 alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 alkyl, 5- to 6-membered heteroaryl-C 1-4 alkyl, OR a11 , C(O)R b11 , C(O)NR c11 R d11 , C(O)OR a11 , OC(O)R b11 , OC(O)NR c11 R d11 , NR c11 R d11 , NR c11 C(O)R b11 , NR c11 C(O)OR a11 , NR c11 C(O)NR c11 R d11 , NR c11 , S(O)2R b11 , NR c11 , S(O)2NR c11 R d11 , S(O)2R b11 , and S(O)2NR c11 R d11 selected from, and the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 alkyl, and 5- to 6-membered heteroaryl-C 1-4 alkyl is, optionally, each independently substituted with 1, 2, 3, or 4 selected R 1B substituents, each R a11 , R c11 , and R d11 is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and 5- to 6-membered heteroaryl-C 1-4 Selected from alkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and 5- to 6-membered heteroaryl-C 1-4 Alkyl is each optionally, 1, 2, 3, or 4 independently selected R 1B Substituted with substituents, Each R b11 Is independently, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and 5- to 6-membered heteroaryl-C 1-4 Selected from alkyl, and these are each optionally, 1, 2, 3, or 4 independently selected R 1B Substituted with substituents, Each R 1B Is independently, H, halo, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-4 Cycloalkyl, OR a12 , C(O)R b12 , C(O)NR c12 R d12, C(O)OR a12 , OC(O)R b12 , NR c12 R d12 , NR c12 C(O)R b12 , NR c12 S(O)2R b12 , S(O)2R b12 , and S(O)2NR c12 R d12 selected from each R a12 , R c12 , and R d12 is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl, each R b12 is independently selected from C 1-6 alkyl and C 1-6 haloalkyl.

[0025] In some embodiments, each R a1 , R c1 , and R d1 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 alkyl, and 5- to 6-membered heteroaryl-C 1-4 alkyl, where the C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 alkyl, and 5- to 6-membered heteroaryl-C 1-4 alkyl may each optionally be substituted with 1, 2, 3, or 4 independently selected R1A substituted with a substituent, each R b1 is independently C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 alkyl, and 5- to 6-membered heteroaryl-C 1-4 alkyl, selected from these, and each of these is optionally substituted with 1, 2, 3, or 4 independently selected R 1A substituents, each R 1A is independently H, D, halo, CN, NO2, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 alkyl, 5- to 6-membered heteroaryl-C 1-4 alkyl, OR a11 、C(O)R b11 、C(O)NR c11 R d11 、C(O)OR a11 、OC(O)R b11 、OC(O)NR c11 R d11 、NR c11 R d11 、NR c11 C(O)R b11 、NR c11 C(O)OR a11 、NR c11 C(O)NR c11 R d11 、NR c11 S(O)2R b11 、NR c11 S(O)2NR c11 R d11 、S(O)2Rb11 and S(O)2NR c11 R d11 selected from, the C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 alkyl, and 5- to 6-membered heteroaryl-C 1-4 alkyl is each optionally, 1, 2, 3, or 4 independently selected R 1B substituted with substituents, each R a11 , R c11 , and R d11 is independently, H, C 1-6 alkyl, and C 1-6 haloalkyl selected from, each R b11 is independently, C 1-6 alkyl and C 1-6 haloalkyl selected from, each R 1B is independently, H, D, and OR a12 selected from, each R a12 is independently, H and C 1-6 alkyl selected from.

[0026] In some embodiments, each R a1 , R c1 , and R d1 is independently, H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 alkyl, and 5- to 6-membered heteroaryl-C 1-4 alkyl selected from, the C1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4 - to 7 - membered heterocycloalkyl, 5 - to 6 - membered heteroaryl, C 3-7 Cycloalkyl - C 1-4 Alkyl, phenyl - C 1-4 Alkyl, 4 - to 7 - membered heterocycloalkyl - C 1-4 Alkyl, and 5 - to 6 - membered heteroaryl - C 1-4 Alkyl is, each optionally, substituted with 1, 2, 3, or 4 independently selected R 1A substituents, each R b1 is independently, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4 - to 7 - membered heterocycloalkyl, 5 - to 6 - membered heteroaryl, C 3-7 Cycloalkyl - C 1-4 Alkyl, phenyl - C 1-4 Alkyl, 4 - to 7 - membered heterocycloalkyl - C 1-4 Alkyl, and 5 - to 6 - membered heteroaryl - C 1-4 Alkyl selected from, and these are, each optionally, substituted with 1, 2, 3, or 4 independently selected R 1A substituents, each R 1A is independently, H, halo, CN, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4 - to 7 - membered heterocycloalkyl, 5 - to 6 - membered heteroaryl, C 3-7 Cycloalkyl - C 1-4 Alkyl, phenyl - C 1-4 Alkyl, 4 - to 7 - membered heterocycloalkyl - C 1-4 Alkyl, 5 - to 6 - membered heteroaryl - C 1-4 Alkyl, OR a11 , C(O)R b11 , C(O)NR c11 R d11 , C(O)OR a11 , OC(O)R b11 , OC(O)NR c11 Rd11 , NR c11 R d11 , NR c11 C(O)R b11 , NR c11 C(O)OR a11 , NR c11 C(O)NR c11 R d11 , NR c11 S(O)2R b11 , NR c11 S(O)2NR c11 R d11 , S(O)2R b11 , and S(O)2NR c11 R d11 is selected from each R a11 , R c11 , and R d11 is independently H, C 1-6 alkyl, and C 1-6 haloalkyl, and is selected from each R b11 is independently C 1-6 alkyl and C 1-6 haloalkyl.

[0027] In some embodiments, each R a1 , R c1 , and R d1 is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl, and the C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and 5- to 6-membered heteroaryl-C 1-4 The alkyls are each optionally substituted with 1, 2, 3, or 4 independently selected R 1A substituents, each R b1 is independently C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 alkyl, and 5- to 6-membered heteroaryl-C 1-4 selected from alkyls, which are each optionally substituted with 1, 2, 3, or 4 independently selected R 1A substituents, each R 1A is independently H, halo, CN, C 1-4 alkyl, C 1-4 haloalkyl, OH, C 1-3 alkoxy, C 1-3 haloalkoxy, amino, C 1-3 alkylamino, di(C 1-3 alkyl)amino, cyano-C 1-4 alkyl, HO-C 1-4 alkyl, C 1-3 alkoxy-C 1-4 alkyl, and C 3-4 selected from cycloalkyl.

[0028] In some embodiments, each R a1 , R c1 , and R d1 is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, phenyl, 4- to 6-membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkyl, and 4- to 6-membered heterocycloalkyl-C 1-3Selected from alkyl, the C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, phenyl, 4- to 6-membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkyl, and 4- to 6-membered heterocycloalkyl-C 1-3 alkyls are each optionally substituted with 1, 2, or 3 independently selected R 1A substituents, each R b1 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-2 alkyl, and 4- to 6-membered heterocycloalkyl-C 1-2 alkyls, which are each optionally substituted with 1 or 2 independently selected R 1A substituents, each R 1A is independently selected from H, D, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, OR a11 , and C(O)OR a11 and the C 1-6 alkyl and C 1-6 haloalkyl are each optionally substituted with 1, 2, or 3 independently selected R 1B substituents, each R a11 is independently selected from H and C 1-4 alkyl, and the C 1-4 alkyl is optionally substituted with 1, 2, or 3 independently selected R 1B substituents, each R 1B is independently selected from H, D, and O-C 1-4 alkyl.

[0029] In some embodiments, each R a1 , R c1 , and R d1 is independently selected from H, C1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkyl, and 4- to 6-membered heterocycloalkyl-C 1-3 Selected from alkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkyl, and 4- to 6-membered heterocycloalkyl-C 1-3 The alkyls are each optionally substituted with one or two independently selected R 1A Substituents, Each R b1 Is independently C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-2 Alkyl, and 4- to 6-membered heterocycloalkyl-C 1-2 Selected from alkyl, these being each optionally substituted with one or two independently selected R 1A Substituents, Each R 1A Is independently H, halo, OH, C 1-3 Alkoxy, and C 1-3 Selected from haloalkoxy.

[0030] In some embodiments, R 1 Is H, C 1-6 Alkyl, phenyl, 5- to 7-membered heterocycloalkyl, OR a1 , SR a1 , or NR c1 R d1 And the C 1-6 Alkyl, phenyl, and 5- to 7-membered heterocycloalkyl are each optionally substituted with one or two independently selected R 1A Substituents, Each Ra1 , R c1 , and R d1 are independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, phenyl, 4- to 6-membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkyl, and 4- to 6-membered heterocycloalkyl-C 1-3 alkyl, selected from 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, phenyl, 4- to 6-membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkyl, and 4- to 6-membered heterocycloalkyl-C 1-3 alkyl are each optionally substituted with one, two, or three independently selected R 1A substituents, each R 1A is independently D, halo, CN, C 1-4 alkyl, C 1-4 haloalkyl, OR a11 , and C(O)OR a11 selected from, the C 1-4 alkyl and C 1-4 haloalkyl are each optionally substituted with one, two, or three independently selected R 1B substituents, each R a11 is independently H and C 1-4 alkyl selected from each R 1B is independently H, D, and O-C 1-4 alkyl selected from.

[0031] In some embodiments, R 1 is H or OR a1 and, each R a1 is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, C3-6 Cycloalkyl-C 1-3 alkyl, and 4- to 6-membered heterocycloalkyl-C 1-3 selected from alkyl, the C 1-6 alkyl, C 1-6 haloalkyl C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkyl, and 4- to 6-membered heterocycloalkyl-C 1-3 alkyls are each optionally substituted with one or two independently selected R 1A substituents, each R 1A is independently selected from OH, C 1-3 alkoxy, and C 1-3 haloalkoxy.

[0032] In some embodiments, R 1 is independently selected from H and OR a1 wherein R a1 is C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-3 alkyl, phenyl-C 1-3 alkyl, 4- to 7-membered heterocycloalkyl-C 1-3 alkyl, and 5- to 6-membered heteroaryl-C 1-3 alkyl.

[0033] In some embodiments, R 1 is independently selected from H, C 1-6 alkyl, phenyl, 5- to 7-membered heterocycloalkyl, OR a1 , SR a1 and NR c1 R d1 selected from, the C 1-6 alkyl, phenyl, and 5- to 7-membered heterocycloalkyls are each optionally substituted with one or two independently selected R 1A substituents, Ra1 is selected from ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, CF3CH2-, CHF2CH2-, CF3CH2CH2-, CHF2CF2CH2-, CH3OCH2CH2-, CD3CD2-, (CH3)2-CD-, (CD3)2-CH-, (CD3)2-CD-, cyclopropyl, cyclobutyl, 3-methylcyclobutyl, 3-difluoromethylcyclobutyl, 3,3-difluorocyclobutyl, cyclopentyl, 3,3-difluorocyclopentyl, 4,4-difluorocyclohexyl, tetrahydro-1H-pyran-4-yl, tetrahydro-2H-pyran-4-yl, 2-methyltetrahydro-2H-pyran-4-yl, 3-methyltetrahydro-2H-pyran-4-yl, 2-(trifluoromethyl)tetrahydro-2H-pyran-4-yl, tetrahydrofuran-3-yl, MeO-C(O)-piperidin-4-yl, cyclopropyl-CH2-, cyclobutyl-CH2-, 1-trifluoromethylcyclobutyl-CH2-, cyclopentyl-CH2-, and (tetrahydrofuran-3-yl)-CH2-; R c1 is H; R d1 is phenyl; each R 1A is independently selected from halo, CN, C 1-3 alkyl, and C 1-3 haloalkyl.

[0034] In some embodiments, R 1 is independently selected from H and OR a1 wherein R a1is selected from ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, CF3CH2-, CHF2CH2-, CF3CH2CH2-, CHF2CF2CH2-, CH3OCH2CH2-, CD3CD2-, (CH3)2-CD-, (CD3)2-CH-, (CD3)2-CD-, cyclopropyl, cyclobutyl, 3-methylcyclobutyl, 3-difluoromethylcyclobutyl, 3,3-difluorocyclobutyl, cyclopentyl, 3,3-difluorocyclopentyl, 4,4-difluorocyclohexyl, tetrahydro-1H-pyran-4-yl, tetrahydro-2H-pyran-4-yl, 2-methyltetrahydro-2H-pyran-4-yl, 3-methyltetrahydro-2H-pyran-4-yl, 2-(trifluoromethyl)tetrahydro-2H-pyran-4-yl, tetrahydrofuran-3-yl, MeO-C(O)-piperidin-4-yl, cyclopropyl-CH2-, cyclobutyl-CH2-, 1-trifluoromethylcyclobutyl-CH2-, cyclopentyl-CH2-, and (tetrahydrofuran-3-yl)-CH2-.

[0035] In some embodiments, R 1 is independently selected from H and OR a1 wherein R a1 is ethyl, isopropyl, isobutyl, tetrahydro-1H-pyran-4-yl, cyclopropyl-CH2-, (tetrahydrofuran-3-yl)-CH2-, CH3OCH2CH2-, CF3CH2-, and CHF2CH2-.

[0036] In some embodiments, R 1 is selected from C 1-3 alkyl.

[0037] In some embodiments, R 1 is selected from propyl and isopropyl.

[0038] In some embodiments, R 1 is phenyl optionally substituted with one or two independently selected R 1A substituents, wherein each R1A is independently selected from halo, CN, and C 1-3 haloalkyl.

[0039] In some embodiments, R 1 is selected from phenyl, 4-fluorophenyl, 3-trifluoromethylphenyl, and 2-fluoro-3-cyano-phenyl.

[0040] In some embodiments, R 1 is selected from 5- to 7-membered heterocycloalkyl optionally substituted with one or two independently selected R 1A substituents, wherein each R 1A is independently selected from halo, C 1-3 alkyl, and C 1-3 haloalkyl.

[0041] In some embodiments, R 1 is selected from pyrrolidin-1-yl, 3,3-difluoropyrrolidin-1-yl, piperidin-1-yl, 3-fluoropiperidin-1-yl, 4-fluoropiperidin-1-yl, 4-methylpiperidin-1-yl, (4-trifluoromethyl)piperidin-1-yl, 3,3-difluoropiperidin-1-yl, 3-(difluoromethyl)pyrrolidinyl, 2-methylpyrrolidinyl, 2-methylpiperidinyl, 3-(trifluoromethyl)piperidinyl, azabicyclo[2.2.1]heptan-7-yl, azabicyclo[2.2.1]heptan-2-yl, and (2-methoxyethyl)piperazin-1-yl.

[0042] In some embodiments, R 1 is selected from SR a1 wherein R a1 is selected from C 1-3 alkyl.

[0043] In some embodiments, R 1 is selected from SR a1 wherein R a1 is selected from ethyl, propyl, and isopropyl.

[0044] In some embodiments, R 1 is NR c1 R d1 selected from, where R c1 and R d1 are each independently selected from H and phenyl.

[0045] In some embodiments, R 1 is NR c1 R d1 selected from, where R c1 is H and R d1 is phenyl.

[0046] In some embodiments, R 1 is OR a1 .

[0047] In some embodiments, R 1 is OR a1 and R a1 is C 1-3 alkyl.

[0048] In some embodiments, R 2 is H, halo, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, OH, C 1-3 alkoxy, C 1-3 haloalkoxy, amino, C 1-3 alkylamino, di(C 1-3 alkyl)amino, cyano-C 1-4 alkyl, HO-C 1-4 alkyl, C 1-3 alkoxy-C 1-4 alkyl, and C 3-4 cycloalkyl.

[0049] In some embodiments, R 2 is H, halo, CN, C 1-3 alkyl, and C 1-3 haloalkyl.

[0050] In some embodiments, R 2 is H or halo.

[0051] In some embodiments, R 2 is H or F.

[0052] In some embodiments, R 2 is H.

[0053] In some embodiments, ring moiety B is a monocyclic 4- to 7-membered heterocycloalkyl.

[0054] In some embodiments, ring moiety B is azetidinyl, pyrrolidinyl, or piperidinyl.

[0055] In some embodiments, ring moiety B is piperidinyl.

[0056] In some embodiments, n is 0, 1, or 2.

[0057] In some embodiments, n is 0 or 1.

[0058] In some embodiments, n is 0.

[0059] In some embodiments, n is 1.

[0060] In some embodiments, each R 3 is independently selected from H, halo, C 1-3 alkyl, and cyclopropyl.

[0061] In some embodiments, each R 3 is independently selected from H, F, and methyl.

[0062] In some embodiments, each R 3 is independently selected from H and methyl.

[0063] In some embodiments, R4 is C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 alkyl, and 5- to 6-membered heteroaryl-C 1-4 selected from alkyl, the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 alkyl, and 5- to 6-membered heteroaryl-C 1-4 alkyl is each optionally, independently selected from 1, 2, 3, or 4 R 4A substituents.

[0064] In some embodiments, R 4 is C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl-C 1-4 selected from alkyl, the C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each optionally, independently selected from 1, 2, 3, or 4 R 4A substituents.

[0065] In some embodiments, R 4 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, and the C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 independently selected R 4A substituents.

[0066] In some embodiments, R 4 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl-C 1-4 alkyl, and the C 1-6 alkyl, C 3-6 cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl-C 1-4 alkyl are each optionally substituted with 1 or 2 independently selected R 4A substituents.

[0067] In some embodiments, R 4 is optionally substituted with 1 or 2 independently selected R 4A substituents and is selected from C 1-6 alkyl.

[0068] In some embodiments, R 4 is C 1-6 alkyl and C 3-6 cycloalkyl.

[0069] In some embodiments, R 4 is selected from methyl, ethyl, propyl, butyl, and cyclopropyl.

[0070] In some embodiments, R 4is selected from methyl and cyclopropyl.

[0071] In some embodiments, R 4 is selected from 5- to 6-membered heteroaryl optionally substituted with one or two independently selected R 4A substituents.

[0072] In some embodiments, R 4 is selected from 4- to 7-membered heterocycloalkyl-C 4A alkyl optionally substituted with one or two independently selected R 1-4 substituents.

[0073] In some embodiments, each R 4A is independently H, halo, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 alkyl, 5- to 6-membered heteroaryl-C 1-4 alkyl, OR a41 , SR a41 , NHOR a41 , C(O)R b41 , C(O)NR c41 R d41 , C(O)OR a41 , OC(O)R b41 , OC(O)NR c41 R d41 , NR c41 R d41 , NR c41 C(O)R b41 , NR c41 C(O)OR a41 , NR c41 C(O)NR c41 R d41 , NRc41 S(O)2R b41 , N.R. c41 S(O)2NR c41 R d41 , S(O)2R b41 , and S(O)NR c41 R d41 C is selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl is optionally selected from 1, 2, 3, or 4 independently selected R 4B is substituted with a substituent, Each R a41 , R c41 , and R d41 are independent, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and 5- to 6-membered heteroaryl-C 1-4 The alkyls are each optionally substituted with 1, 2, 3, or 4 independently selected R 4B substituents, each R b41 is independently C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 alkyl, and 5- to 6-membered heteroaryl-C 1-4 selected from alkyls, which are each optionally substituted with 1, 2, 3, or 4 independently selected R 4B substituents, each R 4B is independently H, halo, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 alkyl, 5- to 6-membered heteroaryl-C 1-4 alkyl, OR a42 , C(O)R b42 , C(O)NR c42 R d42 , C(O)OR a42 , OC(O)R b42 , OC(O)NR c42 R d42 , NR c42 R d42 , NR c42 , C(O)R b42, NR c42 C(O)OR a42 , NR c42 C(O)NR c42 R d42 , NR c42 S(O)2R b42 , NR c42 S(O)2NR c42 R d42 , S(O)2R b42 , and S(O)2NR c42 R d42 selected from, said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl, each optionally, independently selected from 1, 2, 3, or 4 R 4C substituents, each R a42 , R c42 , and R d42 independently, H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl selected from, said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and 5- to 6-membered heteroaryl-C 1-4 Alkyl is each optionally substituted with 1, 2, 3, or 4 independently selected R 4C substituents, each R b42 is independently C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and 5- to 6-membered heteroaryl-C 1-4 alkyl selected from, and these are each optionally substituted with 1, 2, 3, or 4 independently selected R 4C substituents, each R 4C is independently H, halo, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-4 cycloalkyl, OR a43 , C(O)R b43 , C(O)NR c43 R d43 , C(O)OR a43 , OC(O)R b43 , NR c43 R d43 , NR c43 C(O)R b43 , NR c43 S(O)2R b43 , S(O)2R b43 , and S(O)2NR c43 R d43selected from each R a43 , R c43 and R d43 is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl, each R b43 is independently selected from C 1-6 alkyl and C 1-6 haloalkyl.

[0074] In some embodiments, each R 4A is independently selected from H, halo, CN, NO2, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 alkyl, 5- to 6-membered heteroaryl-C 1-4 alkyl, OR a41 SR a41 NHOR a41 C(O)R b41 C(O)NR c41 R d41 C(O)OR a41 OC(O)R b41 OC(O)NR c41 R d41 NR c41 R d41 NR c41 C(O)R b41 NR c41 C(O)OR a41 NR c41 C(O)NR c41 R d41 NR c41 S(O)2R b41 NR c41 S(O)2NR c41 R d41 S(O)2R b41 and S(O)2NR c41 R d41 selected from, the C1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and 5- to 6-membered heteroaryl-C 1-4 The alkyls are each optionally substituted with 1, 2, or 3 independently selected R 4B substituents, Each R a41 , R c41 , and R d41 is independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and 5- to 6-membered heteroaryl-C 1-4 is selected from alkyl, and the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and 5- to 6-membered heteroaryl-C 1-4 The alkyls are each optionally substituted with 1, 2, or 3 independently selected R 4B substituents, Each R b41 is independently C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and 5- to 6-membered heteroaryl-C 1-4 Selected from alkyl, where each of these is optionally, independently, one, two, or three independently selected R 4B Substituted with substituents, Each R 4B Is independently H, halo, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-4 Cycloalkyl, OR a42 , C(O)R b42 , C(O)NR c42 R d42 , C(O)OR a42 , NR c42 R d42 , NR c42 C(O)R b42 , NR c42 C(O)OR a42 , NR c42 C(O)NR c42 R d42 , NR c42 S(O)2R b42 , NR c42 , NR c42 S(O)2NR d42 R b42 , and S(O)2NR c42 R d42 Selected from, Each R a42 , R c42 , and R d42 Is independently H, C 1-6 Alkyl, and C 1-6 Selected from haloalkyl, Each R b42 Is independently C 1-6 Selected from alkyl and C 1-6 Selected from haloalkyl.

[0075] In some embodiments, Each R 4A Is independently H, halo, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C3-4 cycloalkyl, OR a41 , C(O)R b41 , C(O)NR c41 R d41 , C(O)OR a41 , OC(O)R b41 , OC(O)NR c41 R d41 , NR c41 R d41 , NR c41 C(O)R b41 , NR c41 C(O)OR a41 , NR c41 C(O)NR c41 R d41 , NR c41 , S(O)2R b41 , NR c41 , S(O)2NR c41 R d41 , S(O)2R b41 , and S(O)2NR c41 R d41 selected from, said C 1-6 alkyl, C 1-6 haloalkyl, and C 3-4 cycloalkyl is each optionally, independently selected from 1, 2, or 3 R 4B substituents, each R a41 , R c41 , and R d41 is independently H, C 1-6 alkyl, C 1-6 haloalkyl, and C 3-4 cycloalkyl selected from, said C 1-6 alkyl, C 1-6 haloalkyl, and C 3-4 cycloalkyl is each optionally, independently selected from 1 or 2 R 4B substituents, each R b41 is independently C 1-6 alkyl, C 1-6 haloalkyl, and C 3-4 cycloalkyl selected from, these are each optionally, independently selected from 1 or 2 R 4B substituents, each R4B independently, H, halo, CN, C 1-3 alkyl, C 1-3 haloalkyl, OR a42 and NR c42 R d42 selected from, each R a42 , R c42 and R d42 independently, H, C 1-3 alkyl, and C 1-3 haloalkyl selected from, each R b42 independently, C 1-3 alkyl and C 1-3 haloalkyl selected from.

[0076] In some embodiments, each R 4A independently, H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-4 cycloalkyl, OR a41 , C(O)R b41 , C(O)NR c41 R d41 , C(O)OR a41 , OC(O)R b41 , OC(O)NR c41 R d41 , NR c41 R d41 , NR c41 C(O)R b41 , NR c41 C(O)OR a41 , NR c41 C(O)NR c41 R d41 , NR c41 S(O)2R b41 , NR c41 S(O)2NR c41 R d41 , S(O)2R b41 and S(O)2NR c41 R d41 selected from, each R a41 , R c41 and R d41 independently, H, C 1-3 alkyl, and C1-3 selected from haloalkyl, each R b41 is independently C 1-3 alkyl and C 1-3 selected from haloalkyl.

[0077] In some embodiments, each R 4A is independently H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, OR a41 , and NR c41 R d41 selected from each R a41 , R c41 , and R d41 is independently H and C 1-3 alkyl, and C 1-3 selected from haloalkyl. each R b41 is independently C 1-3 alkyl.

[0078] In some embodiments, R 4 is C 4A alkyl optionally substituted by R 1-6 , where R 4A is NR c41 R d41 , and R c41 and R d41 are each independently selected from H, C 1-3 alkyl, and C 1-3 selected from haloalkyl.

[0079] In some embodiments, R 4 is selected from dimethylaminopropyl, diethylaminopropyl, ethyl(methyl)aminopropyl, isopropyl(methyl)aminopropyl, 4-dimethylaminobutyl, 4-ethyl(methyl)aminobutyl, and 2,2-difluoroethylaminobutyl.

[0080] In some embodiments, R 4 is one or two independently selected R 4ASelected from 5- to 6-membered heteroaryl, optionally substituted by substituents, wherein each R 4A is independently selected from C 1-3 alkyl.

[0081] In some embodiments, R 4 is selected from 1-methyl-1H-pyrazol-4-yl, 1-methyl-1H-imidazol-4-yl, and 2-methyl-2H-1,2,3-triazol-4-yl.

[0082] In some embodiments, R 4 is 4- to 7-membered heterocycloalkyl-C 4A alkyl, optionally substituted by one or two independently selected R 1-4 substituents, wherein each R 4A is independently selected from C 1-3 alkyl and OH.

[0083] In some embodiments, R 4 is selected from methyl, ethyl, propyl, butyl, cyclopropyl, pyrazol-4-yl, imidazol-4-yl, 1,2,3-triazol-4-yl, morpholin-4-yl-C 1-4 alkyl, piperidnyl-C 1-4 alkyl, piperazinyl-C 1-4 alkyl, pyrrolidinyl-C 1-4 alkyl, each of which is optionally substituted by one or two independently selected R 4A substituents.

[0084] In some embodiments, R 4is selected from (pyrrolidin-1-yl)CH2CH2, -(pyrrolidin-3-yl)CH2CH2-, (pyrrolidin-1-yl)CH2CH2CH2-, (3-difluoromethylpyrrolidin-1-yl)CH2CH2CH2CH2-, (piperidin-1-yl)CH2CH2CH2-, (4-methylpiperazin-1-yl)CH2CH2CH2-, (4-ethylpiperazin-1-yl)CH2CH2CH2-, and 4-morpholinobutyl.

[0085] In some embodiments, R 4 is methyl, ethyl, propyl, butyl, cyclopropyl, dimethylaminopropyl, diethylaminopropyl, ethyl(methyl)aminopropyl, isopropyl(methyl)aminopropyl, 4-dimethylaminobutyl, 4-ethyl(methyl)aminobutyl, 2,2-difluoroethylaminobutyl, 1-methyl-1H-pyrazol-4-yl, 1-methyl-1H-imidazol-4-yl, 2-methyl-2H-1,2,3-triazol-4-yl, (pyrrolidin-1-yl)CH2CH2, -(pyrrolidin-3-yl)CH2CH2-, (pyrrolidin-1-yl)CH2CH2CH2-, (3-difluoromethylpyrrolidin-1-yl)CH2CH2CH2CH2-, (piperidin-1-yl)CH2CH2CH2-, (4-methylpiperazin-1-yl)CH2CH2CH2-, (4-ethylpiperazin-1-yl)CH2CH2CH2-, and 4-morpholinobutyl.

[0086] In some embodiments, ring moiety A is a 5- to 10-membered heteroaryl.

[0087] In some embodiments, ring moiety A is a 5- to 6-membered heteroaryl.

[0088] In some embodiments, ring moiety A is 1H-pyrrolo[2,3-b]pyridinyl, pyridinyl, or pyrazolyl.

[0089] In some embodiments, ring moiety A is 1H-pyrrolo[2,3-b]pyridin-4-yl, pyridin-4-yl, or 1H-pyrazol-4-yl.

[0090] In some embodiments, ring moiety A is 1H-pyrazol-4-yl.

[0091] In some embodiments, ring moiety A is 1H-pyrazol-4-yl and ring moiety B is selected from the following.

Chemical formula

[0092] In some embodiments, p is 0, 1, or 2.

[0093] In some embodiments, p is 0 or 1.

[0094] In some embodiments, p is 0.

[0095] In some embodiments, p is 1.

[0096] In some embodiments, each R 5 is independently H, halo, NO2, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, 5-6 membered heteroaryl-C 1-4 alkyl, OR a5 , SR a5 , NHOR a5 , C(O)R b5, C(O)NR c5 R d5 , C(O)OR a5 , OC(O)R b5 , OC(O)NR c5 R d5 , NR c5 R d5 , NR c5 C(O)R b5 , NR c5 C(O)OR a5 , NR c5 C(O)NR c5 R d5 , NR c5 S(O)2R b5 , NR c5 S(O)2NR c5 R d5 , S(O)2R b5 , and S(O)2NR c5 R d5 selected from, said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 alkyl, and 5- to 6-membered heteroaryl-C 1-4 alkyl is each optionally, independently, substituted with 1, 2, 3, or 4 independently selected R 5A substituents.

[0097] In some embodiments, each R 5 is independently H, halo, NO2, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, OR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , NRc5 R d5 、 NR c5 C(O)R b5 、 NR c5 S(O)2R b5 、 S(O)2R b5 、 and S(O)2NR c5 R d5 selected from, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each optionally, independently, substituted with 1, 2, 3, or 4 R 5A substituents selected therefrom.

[0098] In some embodiments, each R 5 is independently selected from H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-4 cycloalkyl, OR a5 、 and NR c5 R d5 selected from, wherein the C 1-6 alkyl, C 1-6 haloalkyl, and C 3-4 cycloalkyl are each optionally, independently, substituted with 1, 2, 3, or 4 R 5A substituents selected therefrom.

[0099] In some embodiments, each R 5 is independently selected from H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-4 cycloalkyl, OR a5 、 and NR c5 R d5 selected from, and each R a5 、 R c5 、 and R d5 is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl selected therefrom.

[0100] In some embodiments, each R 5 is independently H, C1-3 Selected from alkyl and amino.

[0101] In some embodiments, each R 5 is independently selected from CH3 or NH2.

[0102] In some embodiments, each R 5 is independently selected from H and amino.

[0103] In some embodiments, each R 5 is independently selected from H and C 1-3 alkyl.

[0104] In some embodiments, each R a5 , R c5 and R d5 are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl, and the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl are each optionally, 1, 2, 3, or 4 independently selected R 5Asubstituted with a substituent, each R b5 is independently C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 alkyl, and 5- to 6-membered heteroaryl-C 1-4 alkyl, selected from these, and each of these is optionally substituted with 1, 2, 3, or 4 independently selected R 5A substituents, each R 5A is independently H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 alkyl, 5- to 6-membered heteroaryl-C 1-4 alkyl, OR a51 , SR a51 , NHOR a51 , C(O)R b51 , C(O)NR c51 R d51 , C(O)OR a51 , OC(O)R b51 , OC(O)NR c51 R d51 , NR c51 R d51 , NR c51 C(O)R b51 , NR c51 C(O)OR a51 , NR c51 C(O)NR c51 R d51 , NR c51 S(O)2R b51 , NRc51 S(O)2NR c51 R d51 、S(O)2R b51 、and S(O)2NR c51 R d51 selected from, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 alkyl, and 5- to 6-membered heteroaryl-C 1-4 alkyl is each optionally, independently, substituted with 1, 2, 3, or 4 R 5B substituents, each R a51 , R c51 , and R d51 is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 alkyl, and 5- to 6-membered heteroaryl-C 1-4 alkyl is each optionally, independently, substituted with 1, 2, 3, or 4 R 1-6 substituents, 1-6 each R 3-7 , R 3-7 , and R 1-4 is independently H, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 5B cycloalkyl-C alkyl, phenyl-C b51independently, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 alkyl, and 5- to 6-membered heteroaryl-C 1-4 alkyl, selected from, each of which is optionally, 1, 2, 3, or 4 independently selected R 5B substituted with substituents, each R 5B independently is H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-4 cycloalkyl, OR a52 , SR a52 , NHOR a52 , C(O)R b52 , C(O)NR c52 R d52 , C(O)OR a52 , OC(O)R b52 , OC(O)NR c52 R d52 , NR c52 R d52 , NR c52 C(O)R b52 , NR c52 C(O)OR a52 , NR c52 C(O)NR c52 R d52 , NR c52 S(O)2R b52 , NR c52 S(O)2NR c52 R d52 , S(O)2R b52 , and S(O)2NR c52 R d52 selected from, each R a52 , R c52 , and R d52 independently is H, C 1-6 alkyl, and C 1-6 haloalkyl selected from, Each R b52 is independently selected from C 1-6 alkyl and C 1-6 haloalkyl.

[0105] In some embodiments, each R a5 , R c5 , and R d5 are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 alkyl, and 5- to 6-membered heteroaryl-C 1-4 alkyl, and the C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 alkyl, and 5- to 6-membered heteroaryl-C 1-4 alkyl may each optionally be substituted with 1, 2, 3, or 4 independently selected R 5A substituents, each R b5 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 alkyl, and 5- to 6-membered heteroaryl-C 1-4 alkyl, and these may each optionally be substituted with 1, 2, 3, or 4 independently selected R5A substituted with a substituent, each R 5A is independently H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-4 cycloalkyl, OR a51 , SR a51 , NHOR a51 , C(O)R b51 , C(O)NR c51 R d51 , C(O)OR a51 , OC(O)R b51 , OC(O)NR c51 R d51 , NR c51 R d51 , NR c51 C(O)R b51 , NR c51 C(O)OR a51 , NR c51 C(O)NR c51 R d51 , NR c51 S(O)2R b51 , NR c51 S(O)2NR c51 R d51 , S(O)2R b51 , and S(O)2NR c51 R d51 is selected from, each R a51 , R c51 and R d51 is independently H, C 1-6 alkyl, and C 1-6 haloalkyl is selected from, each R b51 is independently C 1-6 alkyl and C 1-6 haloalkyl is selected from.

[0106] In some embodiments, each R a5 , R c5 and R d5 is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7Selected from cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, the C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each optionally, independently selected from 1, 2, 3, or 4 R 5A substituents, each R b5 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, which are each optionally, independently selected from 1, 2, 3, or 4 R 5A substituents, each R 5A is independently selected from H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-4 cycloalkyl, OR a51 and NR c51 R d51 selected from each R a51 R c51 and R d51 is independently selected from H and C 1-3 alkyl, each R b51 is independently C 1-3 alkyl.

[0107] In some embodiments, each R a5 R c5 and R d5 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and C 3-4 cycloalkyl, each R b5 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, and C 3-4 cycloalkyl.

[0108] In some embodiments, n is 0, 1, or 2, p is 0, 1, or 2, ring moiety A is selected from C 3-10 cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, ring moiety B is monocyclic 4- to 7-membered heterocycloalkyl, R 1 is independently H, halo, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 alkyl, 5- to 6-membered heteroaryl-C 1-4 alkyl, OR a1 , SR a1 and NR c1 R d1 is selected from, and the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 alkyl, and 5- to 6-membered heteroaryl-C 1-4 alkyl is each optionally substituted with 1, 2, 3, or 4 independently selected R 1A substituents, each R a1 , R c1 and R d1 is independently H, C1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and 5- to 6-membered heteroaryl-C 1-4 Selected from alkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and 5- to 6-membered heteroaryl-C 1-4 Alkyl is each optionally, 1, 2, 3, or 4 independently selected R 1A Substituted with substituents, Each R b1 Is independently, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and 5- to 6-membered heteroaryl-C 1-4 Selected from alkyl, and these are each optionally, 1, 2, 3, or 4 independently selected R 1A Substituted with substituents, Each R 1A Is independently, H, D, halo, CN, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C1-4 Alkyl, phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, 5- to 6-membered heteroaryl-C 1-4 Alkyl, OR a11 , C(O)R b11 , C(O)NR c11 R d11 , C(O)OR a11 , OC(O)R b11 , OC(O)NR c11 R d11 , NR c11 R d11 , NR c11 C(O)R b11 , NR c11 C(O)OR a11 , NR c11 C(O)NR c11 R d11 , NR c11 S(O)2R b11 , NR c11 S(O)2NR c11 R d11 , S(O)2R b11 , and S(O)2NR c11 R d11 selected from, said C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 alkyl, and 5- to 6-membered heteroaryl-C 1-4 alkyl is, each optionally, substituted with 1, 2, 3, or 4 independently selected R 1B substituents, each R a11 , R c11 , and R d11 is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl, each R b11 is independently C 1-6 alkyl and C1-6 selected from haloalkyl, each R 1B is independently selected from H, D, and OR a12 and each R a12 is independently selected from H and C 1-6 alkyl, R 2 is selected from H, halo, CN, C 1-3 alkyl, and C 1-3 haloalkyl, each R 3 is independently selected from H, halo, C 1-3 alkyl, and cyclopropyl, R 4 is C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl, where the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyls are each optionally substituted with 1, 2, 3, or 4 independently selected R 4A substituents, each R 4A is independently selected from H, halo, CN, NO2, C 1-6 alkyl, C1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 alkyl, 5- to 6-membered heteroaryl-C 1-4 alkyl, OR a41 , SR a41 , NHOR a41 , C(O)R b41 , C(O)NR c41 R d41 , C(O)OR a41 , OC(O)R b41 , OC(O)NR c41 R d41 , NR c41 R d41 , NR c41 C(O)R b41 , NR c41 C(O)OR a41 , NR c41 C(O)NR c41 R d41 , NR c41 , S(O)2R b41 , NR c41 , S(O)2NR c41 R d41 , S(O)2R b41 , and S(O)2NR c41 R d41 selected from, said C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 alkyl, and 5- to 6-membered heteroaryl-C 1-4 alkyl is, each optionally, substituted with 1, 2, or 3 independently selected R 4B substituents, each R a41 , R c41 , and Rd41 independently, H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 alkyl, and 5- to 6-membered heteroaryl-C 1-4 selected from alkyl, the C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 alkyl, and 5- to 6-membered heteroaryl-C 1-4 alkyls are each optionally, independently, 1, 2, or 3 R 4B substituents, each R b41 is independently, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 alkyl, and 5- to 6-membered heteroaryl-C 1-4 selected from alkyls, which are each optionally, independently, 1, 2, or 3 R 4B substituents, each R 4B is independently, H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-4 cycloalkyl, OR a42 , C(O)R b42 , C(O)NRc42 R d42 , C(O)OR a42 , N.R. c42 R d42 , N.R. c42 C(O)R b42 , N.R. c42 C(O)OR a42 , N.R. c42 C(O)NR c42 R d42 , N.R. c42 S(O)2R b42 , N.R. c42 S(O)2NR c42 R d42 , S(O)2R b42 , and S(O)NR c42 R d42 is selected from Each R a42 , R c42 , and R d42 are independent, H, C 1-6 Alkyl, and C 1-6 haloalkyl; Each R b42 became independent, C 1-6 Alkyl and C 1-6 haloalkyl; Each R 5 are independent, H, halo, NO2, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a5 , S.R. a5 , N.H.O.R. a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , O.C.(O)R b5 , O-C(O)NRc5 R d5 、 NR c5 R d5 、 NR c5 C(O)R b5 、 NR c5 C(O)OR a5 、 NR c5 C(O)NR c5 R d5 、 NR c5 S(O)2R b5 、 NR c5 S(O)2NR c5 R d5 、 S(O)2R b5 、 and S(O)2NR c5 R d5 selected from, said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl, each optionally, independently selected from 1, 2, 3, or 4 R 5A substituents, each R a5 、 R c5 、 and R d5 are independently, H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl selected from, said C 1-6Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl, and 5-6 membered heteroaryl-C 1-4 The alkyls are each optionally substituted with 1, 2, 3, or 4 independently selected R 5A substituents, Each R b5 is independently C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl, and 5-6 membered heteroaryl-C 1-4 selected from alkyls, which are each optionally substituted with 1, 2, 3, or 4 independently selected R 5A substituents, Each R 5A is independently H, halo, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a51 , SR a51 , NHOR a51 , C(O)R b51, C(O)NR c51 R d51 , C(O)OR a51 , OC(O)R b51 , OC(O)NR c51 R d51 , NR c51 R d51 , NR c51 C(O)R b51 , NR c51 C(O)OR a51 , NR c51 C(O)NR c51 R d51 , NR c51 S(O)2R b51 , NR c51 S(O)2NR c51 R d51 , S(O)2R b51 , and S(O)2NR c51 R d51 is selected from, the C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl, each optionally, is substituted with 1, 2, 3, or 4 independently selected R 5B substituents, each R a51 , R c51 , and R d51 is independently, H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl, the C 1-6Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4 - to 7 - membered heterocycloalkyl, 5 - to 6 - membered heteroaryl, C 3-7 Cycloalkyl - C 1-4 Alkyl, phenyl - C 1-4 Alkyl, 4 - to 7 - membered heterocycloalkyl - C 1-4 Alkyl, and 5 - to 6 - membered heteroaryl - C 1-4 The alkyls are each optionally substituted with 1, 2, 3, or 4 independently selected R 5B substituents, each R b51 is independently C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4 - to 7 - membered heterocycloalkyl, 5 - to 6 - membered heteroaryl, C 3-7 Cycloalkyl - C 1-4 Alkyl, phenyl - C 1-4 Alkyl, 4 - to 7 - membered heterocycloalkyl - C 1-4 Alkyl, and 5 - to 6 - membered heteroaryl - C 1-4 selected from alkyls, and these are each optionally substituted with 1, 2, 3, or 4 independently selected R 5B substituents, each R 5B is independently H, halo, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-4 Cycloalkyl, OR a52 , SR a52 , NHOR a52 , C(O)R b52 , C(O)NR c52 R d52 , C(O)OR a52 , OC(O)R b52 , OC(O)NR c52 R d52 , NR c52 R d52 , NR c52 C(O)R b52 , NR c52 C(O)OR a52 , NR c52 C(O)NR c52R d52 , NR c52 S(O)2R b52 , NR c52 S(O)2NR c52 R d52 , S(O)2R b52 , and S(O)2NR c52 R d52 is selected from each R a52 , R c52 , and R d52 is independently H, C 1-6 alkyl, and C 1-6 haloalkyl, each R b52 is independently C 1-6 alkyl and C 1-6 haloalkyl.

[0109] In some embodiments, n is 0, 1, or 2, p is 0, 1, or 2, ring moiety A is selected from C 3-10 cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, ring moiety B is monocyclic 4- to 7-membered heterocycloalkyl, R 1 is independently H, halo, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 alkyl, 5- to 6-membered heteroaryl-C 1-4 alkyl, OR a1 , and NR c1 R d1 is selected from, the C 1-6 alkyl, C 2-6 alkenyl, C2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 alkyl, and 5- to 6-membered heteroaryl-C 1-4 alkyl is each optionally substituted with 1, 2, 3, or 4 independently selected R 1A substituents, each R a1 、R c1 、and R d1 is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 alkyl, and 5- to 6-membered heteroaryl-C 1-4 alkyl, and the C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 alkyl, and 5- to 6-membered heteroaryl-C 1-4 alkyl is each optionally substituted with 1, 2, 3, or 4 independently selected R 1A substituents, each R b1 is independently C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and 5- to 6-membered heteroaryl-C 1-4 Selected from alkyl, where each of these is optionally, independently, substituted with 1, 2, 3, or 4 independently selected R 1A Substituents, Each R 1A Is independently H, halo, CN, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, 5- to 6-membered heteroaryl-C 1-4 Alkyl, OR a11 , C(O)R b11 , C(O)NR c11 R d11 , C(O)OR a11 , OC(O)R b11 , OC(O)NR c11 R d11 , NR c11 R d11 , NR c11 C(O)R b11 , NR c11 C(O)OR a11 , NR c11 C(O)NR c11 R d11 , NR c11 S(O)2R b11 , NR c11 S(O)2NR c11 R d11 , S(O)2R b11 , and S(O)2NR c11 R d11 Selected from, Each R a11 , R c11 , and R d11 Is independently H, C 1-6 Alkyl, and C 1-6Selected from haloalkyl, each R b11 is independently selected from C 1-6 alkyl and C 1-6 haloalkyl, R 2 is selected from H, halo, CN, C 1-3 alkyl, and C 1-3 haloalkyl, each R 3 is independently selected from H, halo, C 1-3 alkyl, and cyclopropyl, R 4 is C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 alkyl, and 5- to 6-membered heteroaryl-C 1-4 alkyl, where the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 alkyl, and 5- to 6-membered heteroaryl-C 1-4 alkyl is each optionally substituted with 1, 2, 3, or 4 independently selected R 4A substituents, each R 4A is independently selected from H, halo, CN, NO2, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, 5- to 6-membered heteroaryl-C 1-4 Alkyl, OR a41 , SR a41 , NHOR a41 , C(O)R b41 , C(O)NR c41 R d41 , C(O)OR a41 , OC(O)R b41 , OC(O)NR c41 R d41 , NR c41 R d41 , NR c41 C(O)R b41 , NR c41 C(O)OR a41 , NR c41 C(O)NR c41 R d41 , NR c41 S(O)2R b41 , NR c41 S(O)2NR c41 R d41 , S(O)2R b41 , and S(O)2NR c41 R d41 selected from, said C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 alkyl, and 5- to 6-membered heteroaryl-C 1-4 alkyl is, each optionally, substituted with 1, 2, or 3 independently selected R 4B substituents, each R a41 , R c41 , and R d41 is independently, H, C1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and 5- to 6-membered heteroaryl-C 1-4 Selected from alkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and 5- to 6-membered heteroaryl-C 1-4 Alkyl is each optionally, independently selected from one, two, or three R 4B Substituted with substituents, Each R b41 Is independently C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and 5- to 6-membered heteroaryl-C 1-4 Selected from alkyl, and these are each optionally, independently selected from one, two, or three R 4B Substituted with substituents, Each R 4B Is independently H, halo, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-4 Cycloalkyl, OR a42 、C(O)R b42 、C(O)NR c42 R d42, C(O)OR a42 , NR c42 R d42 , NR c42 C(O)R b42 , NR c42 C(O)OR a42 , NR c42 C(O)NR c42 R d42 , NR c42 S(O)2R b42 , NR c42 S(O)2NR c42 R d42 , S(O)2R b42 , and S(O)2NR c42 R d42 selected from each R a42 , R c42 , and R d42 is independently H, C 1-6 alkyl, and C 1-6 haloalkyl, each R b42 is independently C 1-6 alkyl and C 1-6 haloalkyl, each R 5 is independently H, halo, NO2, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, 5-6 membered heteroaryl-C 1-4 alkyl, OR a5 , SR a5 , NHOR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , OC(O)R b5 , OC(O)NR c5 R d5, NR c5 R d5 , NR c5 C(O)R b5 , NR c5 C(O)OR a5 , NR c5 C(O)NR c5 R d5 , NR c5 S(O)2R b5 , NR c5 S(O)2NR c5 R d5 , S(O)2R b5 , and S(O)2NR c5 R d5 selected from, said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl, each optionally, 1, 2, 3, or 4 independently selected R 5A substituted by substituents, each R a5 , R c5 , and R d5 independently, H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl selected from, said C 1-6 alkyl, C 2-6 alkenyl, C2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and 5- to 6-membered heteroaryl-C 1-4 The alkyls are each optionally substituted with 1, 2, 3, or 4 independently selected R 5A substituents, Each R b5 is independently C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and 5- to 6-membered heteroaryl-C 1-4 selected from alkyls, and these are each optionally substituted with 1, 2, 3, or 4 independently selected R 5A substituents, Each R 5A is independently H, halo, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, 5- to 6-membered heteroaryl-C 1-4 Alkyl, OR a51 、SR a51 、NHOR a51 、C(O)R b51 、C(O)NR c51 Rd51 , C(O)OR a51 , OC(O)R b51 , OC(O)NR c51 R d51 , NR c51 R d51 , NR c51 C(O)R b51 , NR c51 C(O)OR a51 , NR c51 C(O)NR c51 R d51 , NR c51 S(O)2R b51 , NR c51 S(O)2NR c51 R d51 , S(O)2R b51 , and S(O)2NR c51 R d51 selected from, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 alkyl, and 5- to 6-membered heteroaryl-C 1-4 alkyl is each optionally substituted with 1, 2, 3, or 4 independently selected R 5B substituents, each R a51 , R c51 , and R d51 is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 alkyl, and 5- to 6-membered heteroaryl-C 1-4 alkyl selected from, wherein the C 1-6 alkyl, C 1-6Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and 5- to 6-membered heteroaryl-C 1-4 Alkyl is each optionally substituted with 1, 2, 3, or 4 independently selected R 5B substituents, each R b51 is independently C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and 5- to 6-membered heteroaryl-C 1-4 Alkyl selected from, and these are each optionally substituted with 1, 2, 3, or 4 independently selected R 5B substituents, each R 5B is independently H, halo, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-4 Cycloalkyl, OR a52 , SR a52 , NHOR a52 , C(O)R b52 , C(O)NR c52 R d52 , C(O)OR a52 , OC(O)R b52 , OC(O)NR c52 R d52 , NR c52 R d52 , NR c52 C(O)R b52 , NR c52 C(O)OR a52 , NR c52 C(O)NR c52 R d52 , NRc52 S(O)2R b52 , N.R. c52 S(O)2NR c52 R d52 , S(O)2R b52 , and S(O)NR c52 R d52 is selected from Each R a52 , R c52 , and R d52 are independent, H, C 1-6 Alkyl, and C 1-6 haloalkyl; Each R b52 became independent, C 1-6 Alkyl and C 1-6 haloalkyl.

[0110] In some embodiments, n is 0, 1, or 2; p is 0, 1, or 2; The ring portion A is C 3-10 selected from cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl; Ring moiety B is azetidinyl, pyrrolidinyl, or piperidinyl; R 1 But, H, halo, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, phenyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl-C 1-3 Alkyl, Phenyl-C 1-3 Alkyl, 4-7 membered heterocycloalkyl-C 1-3 Alkyl, 5-6 membered heteroaryl-C 1-3 Alkyl, OR a1 , S.R. a1 , and N.R. c1 R d1 and the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C3-6 Cycloalkyl, phenyl, 4- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-6 Cycloalkyl-C 1-3 Alkyl, phenyl-C 1-3 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-3 Alkyl, and 5- to 6-membered heteroaryl-C 1-3 Alkyl is each optionally substituted with 1, 2, or 3 independently selected R 1A substituents, each R a1 , R c1 and R d1 is independently H, D, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, and C 3-7 cycloalkyl-C 1-4 alkyl selected from, the C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, and C 3-7 cycloalkyl-C 1-4 alkyl is each optionally substituted with 1, 2, or 3 independently selected R 1A substituents, each R 1A is independently H, D, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-4 cycloalkyl, OR a11 , C(O)R b11 , C(O)NR c11 R d11 , C(O)OR a11 , OC(O)R b11 , OC(O)NR c11 R d11 , NR c11 R d11 , NR c11 C(O)R b11 , NR c11 , C(O)OR a11 , NR c11 , C(O)NR c11 Rd11 、 NR c11 S(O)2R b11 、 NR c11 S(O)2NR c11 R d11 、 S(O)2R b11 、 and S(O)2NR c11 R d11 selected from, said C 1-6 alkyl, C 1-6 haloalkyl, and C 3-4 cycloalkyl is each optionally, independently selected from 1, 2, or 3 R 1B substituents, each R a11 、 R c11 、 and R d11 is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl, each R b11 is independently selected from C 1-6 alkyl and C 1-6 haloalkyl, each R 1B is independently selected from H, D, and OR a12 、 each R a12 is independently selected from H and C 1-6 alkyl, R 2 is selected from H, halo, CN, C 1-3 alkyl, and C 1-3 haloalkyl, each R 3 is independently selected from H, halo, C 1-3 alkyl, and cyclopropyl, R 4 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl-C 1-4 alkyl, said C 1-6 alkyl, C 1-6 haloalkyl, C 3-7Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl-C 1-4 alkyl is each optionally, independently, selected from one or two R 4A substituents, each R 4A is independently H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-4 cycloalkyl, OR a41 , C(O)R b41 , C(O)NR c41 R d41 , C(O)OR a41 , OC(O)R b41 , OC(O)NR c41 R d41 , NR c41 R d41 , NR c41 C(O)R b41 , NR c41 C(O)OR a41 , NR c41 C(O)NR c41 R d41 , NR c41 S(O)2R b41 , NR c41 , NR c41 R d41 , S(O)2R b41 , and S(O)2NR c41 R d41 selected from, the C 1-6 alkyl, C 1-6 haloalkyl, and C 3-4 cycloalkyl is each optionally, independently, selected from one, two, or three R 4B substituents, each R a41 , R c41 , and R d41 is independently H, C 1-6 alkyl, C 1-6 haloalkyl, and C 3-4 cycloalkyl selected from, the C 1-6 alkyl, C 1-6 haloalkyl, and C 3-4The cycloalkyl is each optionally substituted with one or two independently selected R 4B substituents, each R b41 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, and C 3-4 cycloalkyl, and these are each optionally substituted with one or two independently selected R 4B substituents, each R 4B is independently selected from H, halo, CN, C 1-3 alkyl, C 1-3 haloalkyl, OR a42 and NR c42 R d42 and is selected from each R a42 R c42 and R d42 is independently selected from H, C 1-3 alkyl, and C 1-3 haloalkyl, each R b42 is independently selected from C 1-3 alkyl and C 1-3 haloalkyl, each R 5 is independently selected from H, halo, NO2, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, 5-6 membered heteroaryl-C 1-4 alkyl, OR a5 SR a5 NHOR a5 C(O)R b5 C(O)NR c5 R d5 C(O)OR a5 OC(O)R b5 OC(O)NR c5 R d5 NRc5 R d5 、 NR c5 C(O)R b5 、 NR c5 C(O)OR a5 、 NR c5 C(O)NR c5 R d5 、 NR c5 S(O)2R b5 、 NR c5 S(O)2NR c5 R d5 、 S(O)2R b5 、 and S(O)2NR c5 R d5 selected from, said C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 alkyl, and 5- to 6-membered heteroaryl-C 1-4 alkyl, each optionally, independently selected from 1, 2, 3, or 4 R 5A substituents, each R a5 、 R c5 、 and R d5 independently are, H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 alkyl, and 5- to 6-membered heteroaryl-C 1-4 alkyl, said C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C1-4 Alkyl, phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and 5- to 6-membered heteroaryl-C 1-4 The alkyls are each optionally substituted with 1, 2, 3, or 4 independently selected R 5A substituents, each R b5 is independently C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 alkyl, and 5- to 6-membered heteroaryl-C 1-4 selected from alkyls, which are each optionally substituted with 1, 2, 3, or 4 independently selected R 5A substituents, each R 5A is independently H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-4 cycloalkyl, OR a51 , SR a51 , NHOR a51 , C(O)R b51 , C(O)NR c51 R d51 , C(O)OR a51 , OC(O)R b51 , OC(O)NR c51 R d51 , NR c51 R d51 , NR c51 , C(O)R b51 , NR c51 , C(O)OR a51 , NR c51 , C(O)NR c51 R d51 , NR c51 , S(O)2R b51 , NR c51 , S(O)2NR c51 R d51, S(O)2R b51 , and S(O)2NR c51 R d51 is selected from each R a51 , R c51 , and R d51 is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl. each R b51 is independently selected from C 1-6 alkyl and C 1-6 haloalkyl.

[0111] In some embodiments, n is 0, 1, or 2, p is 0, 1, or 2, the ring moiety A is selected from C 3-10 cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, the ring moiety B is azetidinyl, pyrrolidinyl, or piperidinyl, R 1 is H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, phenyl, 4- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-6 cycloalkyl-C 1-3 alkyl, phenyl-C 1-3 alkyl, 4- to 7-membered heterocycloalkyl-C 1-3 alkyl, 5- to 6-membered heteroaryl-C 1-3 alkyl, OR a1 and NR c1 R d1 wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, phenyl, 4- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-6 cycloalkyl-C 1-3 alkyl, phenyl-C1-3 alkyl, 4- to 7-membered heterocycloalkyl-C 1-3 alkyl, and 5- to 6-membered heteroaryl-C 1-3 each alkyl is optionally substituted with one or two independently selected R 1A substituents, each R 1A is independently H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-4 cycloalkyl, OR a11 , C(O)R b11 , C(O)NR c11 R d11 , C(O)OR a11 , OC(O)R b11 , OC(O)NR c11 R d11 , NR c11 R d11 , NR c11 C(O)R b11 , NR c11 C(O)OR a11 , NR c11 C(O)NR c11 R d11 , NR c11 S(O)2R b11 , NR c11 S(O)2NR c11 R d11 , S(O)2R b11 , and S(O)2NR c11 R d11 selected from each R a11 , R c11 , and R d11 is independently H, C 1-6 alkyl, and C 1-6 haloalkyl selected from each R b11 is independently C 1-6 alkyl and C 1-6 haloalkyl selected from R 2 is H, halo, CN, C 1-3 alkyl, and C 1-3 haloalkyl selected from each R 3 is independently H, halo, C1-3 selected from alkyl and cyclopropyl, R 4 wherein R 1-6 is selected from alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, and the C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 independently selected R 4A substituents, each R 4A is independently H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-4 cycloalkyl, OR a41 , C(O)R b41 , C(O)NR c41 R d41 , C(O)OR a41 , OC(O)R b41 , OC(O)NR c41 R d41 , NR c41 R d41 , NR c41 C(O)R b41 , NR c41 C(O)OR a41 , NR c41 C(O)NR c41 R d41 , NR c41 S(O)2R b41 , NR c41 S(O)2NR c41 R d41 , S(O)2R b41 , and S(O)2NR c41 R d41 and the C 1-6 alkyl, C 1-6 haloalkyl, and C 3-4 cycloalkyl are each optionally substituted with 1, 2, or 3 independently selected R 4B substituents, each R a41, R c41 , and R d41 are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and C 3-4 cycloalkyl, and the C 1-6 alkyl, C 1-6 haloalkyl, and C 3-4 cycloalkyl are each optionally substituted with one or two independently selected R 4B substituents, each R b41 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, and C 3-4 cycloalkyl, and these are each optionally substituted with one or two independently selected R 4B substituents, each R 4B is independently selected from H, halo, CN, C 1-3 alkyl, C 1-3 haloalkyl, OR a42 , and NR c42 R d42 selected from, each R a42 , R c42 , and R d42 are independently selected from H, C 1-3 alkyl, and C 1-3 haloalkyl selected from, each R b42 is independently selected from C 1-3 alkyl and C 1-3 haloalkyl selected from, each R 5 is independently selected from H, halo, NO2, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4 - 7 membered heterocycloalkyl, 5 - 6 membered heteroaryl, C 3-7 cycloalkyl - C 1-4 alkyl, phenyl - C 1-4 alkyl, 4 - 7 membered heterocycloalkyl - C 1-4 alkyl, 5 - 6 membered heteroaryl - C 1-4 alkyl, OR a5, SR a5 , NHOR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , OC(O)R b5 , OC(O)NR c5 R d5 , NR c5 R d5 , NR c5 , C(O)R b5 , NR c5 , C(O)OR a5 , NR c5 , C(O)NR c5 R d5 , NR c5 , S(O)2R b5 , NR c5 , S(O)2NR c5 R d5 , S(O)2R b5 , and S(O)2NR c5 R d5 selected from, said C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl is each optionally substituted with 1, 2, 3, or 4 independently selected R 5A substituents, each R a5 , R c5 , and R d5 are independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4Alkyl, and 5- to 6-membered heteroaryl-C 1-4 selected from alkyl, the C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 alkyl, and 5- to 6-membered heteroaryl-C 1-4 alkyl, each optionally, 1, 2, 3, or 4 independently selected R 5A substituted with substituents, each R b5 is independently, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 alkyl, and 5- to 6-membered heteroaryl-C 1-4 selected from alkyl, which are each optionally, 1, 2, 3, or 4 independently selected R 5A substituted with substituents, each R 5A is independently, H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-4 cycloalkyl, OR a51 、SR a51 、NHOR a51 、C(O)R b51 、C(O)NR c51 R d51 、C(O)OR a51 、OC(O)R b51 、OC(O)NR c51 R d51 、NR c51 R d51 、NR c51 C(O)R b51 、NRc51 C(O)OR a51 , N.R. c51 C(O)NR c51 R d51 , N.R. c51 S(O)2R b51 , N.R. c51 S(O)2NR c51 R d51 , S(O)2R b51 , and S(O)NR c51 R d51 is selected from Each R a51 , R c51 , and R d51 are independent, H, C 1-6 Alkyl, and C 1-6 haloalkyl; Each R b51 became independent, C 1-6 Alkyl and C 1-6 haloalkyl.

[0112] In some embodiments, n is 0 or 1; p is 0 or 1; Ring moiety A is a 5-10 membered heteroaryl; Ring moiety B is piperidinyl; R 1 But, H, C 1-6 Alkyl, phenyl, 5-7 membered heterocycloalkyl, OR a1 , S.R. a1 , or N.R. c1 R d1 and the C 1-6 Alkyl, phenyl, and 5- to 7-membered heterocycloalkyl are each optionally represented by one or two independently selected R 1A is substituted with a substituent, Each R a1 , R c1 , and R d1 are independent, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, phenyl, 4-6 membered heterocycloalkyl, C 3-6 Cycloalkyl-C1-3 alkyl, and 4- to 6-membered heterocycloalkyl-C 1-3 selected from alkyl, the C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, phenyl, 4- to 6-membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkyl, and 4- to 6-membered heterocycloalkyl-C 1-3 alkyl is each optionally substituted with 1, 2, or 3 independently selected R 1A substituents, each R 1A is independently H, D, halo, CN, C 1-4 alkyl, C 1-4 haloalkyl, OH, C 1-3 alkoxy, C 1-3 haloalkoxy, amino, C 1-3 alkylamino, di(C 1-3 alkyl)amino, cyano-C 1-4 alkyl, HO-C 1-4 alkyl, C 1-3 alkoxy-C 1-4 alkyl, C 3-4 cycloalkyl, and C(O)O-C 1-4 selected from alkyl, the C 1-4 alkyl, C 1-4 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, amino, C 1-3 alkylamino, di(C 1-3 alkyl)amino, C 1-3 alkoxy-C 1-4 alkyl, C 3-4 cycloalkyl, and C(O)O-C 1-4 alkyl is each optionally substituted with 1, 2, or 3 independently selected R 1B substituents, each R 1B is independently H, D, and O-C 1-4 selected from alkyl, R 2 is H or halo, each R 3is independently selected from H, F, or methyl, R 4 is C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl-C 1-4 alkyl, where the C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, and 4- to 10-membered heterocycloalkyl-C 1-4 alkyl are each optionally substituted with one or two independently selected R 4A substituents, each R 4A is independently selected from H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-4 cycloalkyl, OR a41 , C(O)R b41 , C(O)NR c41 R d41 , C(O)OR a41 , OC(O)R b41 , OC(O)NR c41 R d41 , NR c41 R d41 , NR c41 C(O)R b41 , NR c41 C(O)OR a41 , NR c41 C(O)NR c41 R d41 , NR c41 S(O)2R b41 , NR c41 S(O)2NR c41 R d41 , S(O)2R b41 , and S(O)2NR c41 R d41 selected from, where the C 1-6 alkyl, C 1-6 haloalkyl, and C 3-4The cycloalkyl is each optionally substituted with one, two, or three independently selected R 4B substituents, each R a41 R c41 and R d41 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and C 3-4 cycloalkyl, where the C 1-6 alkyl, C 1-6 haloalkyl, and C 3-4 cycloalkyl is each optionally substituted with one or two independently selected R 4B substituents, each R b41 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, and C 3-4 cycloalkyl, and these are each optionally substituted with one or two independently selected R 4B substituents, each R 4B is independently selected from H, halo, CN, C 1-3 alkyl, C 1-3 haloalkyl, OR a42 and NR c42 R d42 and is selected from, each R a42 R c42 and R d42 is independently selected from H, C 1-3 alkyl, and C 1-3 haloalkyl and is selected from, each R b42 is independently selected from C 1-3 alkyl and C 1-3 haloalkyl and is selected from, each R 5 is independently selected from H, halo, NO2, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, OR a5 C(O)R b5 C(O)NR c5 Rd5 、 C(O)OR a5 、 NR c5 R d5 、 NR c5 C(O)R b5 、 NR c5 S(O)2R b5 、 S(O)2R b5 、 and S(O)2NR c5 R d5 selected from, said C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl, each optionally, independently selected 1, 2, 3, or 4 R 5A substituted with substituents, each R a5 、 R c5 、 and R d5 are independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl selected from, said C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl, each optionally, independently selected 1, 2, 3, or 4 R 5A substituted with substituents, each R b5 is independently C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl selected from, these being, each optionally, independently selected 1, 2, 3, or 4 R 5A substituted with substituents, each R 5A is independently H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-4 cycloalkyl, OR a51 、 and NR c51 Rd51 selected from each R a51 , R c51 , and R d51 is independently selected from H and C 1-3 alkyl, each R b51 is independently C 1-3 alkyl.

[0113] In some embodiments, n is 0 or 1, p is 0 or 1, ring moiety A is 5- to 10-membered heteroaryl, ring moiety B is piperidinyl, R 1 is H or OR a1 . Each R a1 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkyl, and 4- to 6-membered heterocycloalkyl-C 1-3 alkyl, and the C 1-6 alkyl, C 1-6 haloalkyl C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkyl, and 4- to 6-membered heterocycloalkyl-C 1-3 alkyl are each optionally substituted with one or two independently selected R 1A substituents, each R 1A is independently selected from H, halo, CN, C 1-4 alkyl, C 1-4 haloalkyl, OH, C 1-3 alkoxy, C 1-3 haloalkoxy, amino, C 1-3 alkylamino, di(C 1-3 alkyl)amino, cyano-C 1-4 alkyl, HO-C 1-4Alkyl, C 1-3 Alkoxy-C 1-4 Alkyl, and C 3-4 Selected from cycloalkyl, R 2 is H or halo, Each R 3 is independently selected from H, F, or methyl, R 4 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, and the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each optionally, independently selected 1, 2, 3, or 4 R 4A Substituted by substituents, Each R 4A is independently selected from H, halo, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-4 Cycloalkyl, OR a41 , C(O)R b41 , C(O)NR c41 R d41 , C(O)OR a41 , OC(O)R b41 , OC(O)NR c41 R d41 , NR c41 R d41 , NR c41 C(O)R b41 , NR c41 C(O)OR a41 , NR c41 C(O)NR c41 R d41 , NR c41 S(O)2R b41 , NR c41 S(O)2NR c41 R d41 , S(O)2R b41 , and S(O)2NR c41 R d41 Selected from, and the C1-6 Alkyl, C 1-6 Haloalkyl, and C 3-4 Cycloalkyl is each optionally substituted with 1, 2, or 3 independently selected R 4B substituents, each R a41 , R c41 , and R d41 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and C 3-4 cycloalkyl, and the C 1-6 alkyl, C 1-6 haloalkyl, and C 3-4 cycloalkyl is each optionally substituted with 1 or 2 independently selected R 4B substituents, each R b41 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, and C 3-4 cycloalkyl, and these are each optionally substituted with 1 or 2 independently selected R 4B substituents, each R 4B is independently selected from H, halo, CN, C 1-3 alkyl, C 1-3 haloalkyl, OR a42 , and NR c42 R d42 selected from each R a42 , R c42 , and R d42 is independently selected from H, C 1-3 alkyl, and C 1-3 haloalkyl selected from each R b42 is independently selected from C 1-3 alkyl and C 1-3 haloalkyl selected from each R 5 is independently selected from H, halo, NO2, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4 - 7 membered heterocycloalkyl, 5 - 6 membered heteroaryl, ORa5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , NR c5 R d5 , NR c5 , C(O)R b5 , NR c5 , S(O)2R b5 , S(O)2R b5 , and S(O)2NR c5 R d5 selected from, said C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each optionally, independently, 1, 2, 3, or 4 R 5A substituents, each R a5 , R c5 , and R d5 are independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, said C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each optionally, independently, 1, 2, 3, or 4 R 5A substituents, each R b5 is independently C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, these are each optionally, independently, 1, 2, 3, or 4 R 5A substituents, each R 5A is independently H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C3-4 Cycloalkyl, OR a51 , and NR c51 R d51 selected from, each R a51 , R c51 , and R d51 is independently selected from H and C 1-3 alkyl, each R b51 is independently C 1-3 alkyl.

[0114] In some embodiments, n is 0 or 1, p is 0 or 1, ring moiety A is 5- to 10-membered heteroaryl, ring moiety B is piperidinyl, R 1 is H or OR a1 . each R a1 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkyl, and 4- to 6-membered heterocycloalkyl-C 1-3 alkyl, and the C 1-6 alkyl, C 1-6 haloalkyl C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkyl, and 4- to 6-membered heterocycloalkyl-C 1-3 alkyl are each optionally substituted with 1, 2, or 3 independently selected R 1A substituents, each R 1A is independently selected from H, D, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, OR a11 , and C(O)OR a11 , and the C 1-6 alkyl and C 1-6The haloalkyls are each independently optionally substituted with one, two, or three independently selected Rs 1B and are each R a11 is independently selected from H and C 1-4 alkyl, and the C 1-4 alkyl is optionally substituted with one, two, or three independently selected Rs 1B and is each R b11 is independently selected from C 1-6 alkyl and C 1-6 haloalkyl, each R 1B is independently selected from H, D, and OR a12 and is each R a12 is independently selected from H and C 1-6 alkyl, R 2 is H or halo, each R 3 is independently selected from H, F, or methyl, R 4 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, and the C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each optionally substituted with one, two, three, or four independently selected Rs 4A and are each R 4A is independently selected from H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-4 cycloalkyl, OR a41 C(O)R b41 C(O)NR c41 R d41 C(O)OR a41 OC(O)R b41 OC(O)NR c41R d41 、 NR c41 R d41 、 NR c41 C(O)R b41 、 NR c41 C(O)OR a41 、 NR c41 C(O)NR c41 R d41 、 NR c41 S(O)2R b41 、 NR c41 S(O)2NR c41 R d41 、 S(O)2R b41 、 and S(O)2NR c41 R d41 selected from, said C 1-6 alkyl, C 1-6 haloalkyl, and C 3-4 cycloalkyl is each optionally substituted with 1, 2, or 3 independently selected R 4B substituents, each R a41 、 R c41 、 and R d41 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and C 3-4 cycloalkyl, said C 1-6 alkyl, C 1-6 haloalkyl, and C 3-4 cycloalkyl is each optionally substituted with 1 or 2 independently selected R 4B substituents, each R b41 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, and C 3-4 cycloalkyl, and these are each optionally substituted with 1 or 2 independently selected R 4B substituents, each R 4B is independently selected from H, halo, CN, C 1-3 alkyl, C 1-3 haloalkyl, OR a42 、 and NR c42 R d42 selected from, each R a42, R c42 , and R d42 is independently selected from H, C 1-3 alkyl, and C 1-3 haloalkyl, each R b42 is independently selected from C 1-3 alkyl and C 1-3 haloalkyl, each R 5 is independently selected from H, halo, NO2, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, OR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , NR c5 R d5 , NR c5 C(O)R b5 , NR c5 S(O)2R b5 , S(O)2R b5 , and S(O)2NR c5 R d5 selected from, the C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each optionally, independently selected from 1, 2, 3, or 4 R 5A substituents, each R a5 , R c5 , and R d5 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, the C 1-6 alkyl, C 1-6 haloalkyl, C 3-7Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 independently selected R 5A substituents, each R b5 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, and these are each optionally substituted with 1, 2, 3, or 4 independently selected R 5A substituents, each R 5A is independently selected from H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-4 cycloalkyl, OR a51 and NR c51 R d51 and is selected from each R a51 R c51 and R d51 is independently selected from H and C 1-3 alkyl, each R b51 is independently C 1-3 alkyl.

[0115] In some embodiments, n is 0 or 1, p is 0 or 1, ring moiety A is 5- to 10-membered heteroaryl having 1 or 2 N ring-forming atoms, ring moiety B is piperidinyl, R 1 is independently selected from H, C 1-6 alkyl, phenyl, 5- to 7-membered heterocycloalkyl, OR a1 SR a1 and NR c1 R d1 and the C 1-6 alkyl, phenyl, and 5- to 7-membered heterocycloalkyl are each optionally substituted with 1 or 2 independently selected R 1Asubstituted with a substituent, each R a1 、R c1 、and R d1 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, phenyl, 4- to 6-membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkyl, and 4- to 6-membered heterocycloalkyl-C 1-3 alkyl, and the C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, phenyl, 4- to 6-membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkyl, and 4- to 6-membered heterocycloalkyl-C 1-3 alkyl is each optionally substituted with 1, 2, or 3 independently selected R 1A substituents, each R 1A is independently selected from D, halo, CN, C 1-3 alkyl, C 1-3 haloalkyl, C 3-4 cycloalkyl, OR a11 、and C(O)OR a11 and the C 1-6 alkyl, and C 1-6 haloalkyl are each optionally substituted with 1, 2, or 3 independently selected R 1B substituents, each R a11 is independently selected from H and C 1-4 alkyl, and the C 1-4 alkyl is optionally substituted with 1, 2, or 3 independently selected R 1B substituents, each R 1B is independently selected from H, D, and O-C 1-4 alkyl, R 2 is H or F, each R 3 is independently selected from H or methyl, R4 is C 1-6 alkyl, C 3-6 cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl-C 1-4 alkyl, selected from, the C 1-6 alkyl, C 3-6 cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl-C 1-4 alkyl is each optionally, 1, 2, 3, or 4 independently selected R 4A substituted with substituents, each R 4A is independently, H, C 1-6 alkyl, OH, and NR c41 R d41 selected from, each R c41 and R d41 is independently, H, C 1-6 alkyl, and C 1-6 haloalkyl, selected from, each R 5 is independently, H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-4 cycloalkyl, OR a5 and NR c5 R d5 selected from, each R a5 , R c5 , and R d5 is independently, H, C 1-6 alkyl, and C 1-6 haloalkyl, selected from.

[0116] In some embodiments, n is 0 or 1, p is 0 or 1, ring moiety A is 5- to 10-membered heteroaryl having 1 or 2 N ring-forming atoms, ring moiety B is piperidinyl, R 1 is independently selected from H and OR a1 , each R a1 is independently, H, C1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkyl, and 4- to 6-membered heterocycloalkyl-C 1-3 Selected from alkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkyl, and 4- to 6-membered heterocycloalkyl-C 1-3 The alkyls are each optionally, one or two independently selected R 1A Substituted with substituents, Each R 1A Is independently, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-4 Cycloalkyl, OH, C 1-3 Alkoxy, and C 1-3 Selected from haloalkoxy, R 2 Is H or F, Each R 3 Is independently selected from H or methyl, R 4 Is, C 1-6 Alkyl and C 3-6 Selected from cycloalkyl, the C 1-6 Alkyl and C 3-6 Cycloalkyl are each optionally, 1, 2, 3, or 4 independently selected R 4A Substituted by substituents, Each R 4A Is independently selected from H and C 1-6 Alkyl, Each R 5 Is independently selected from H, halo, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-4 Cycloalkyl, OR a5 And NR c5 R d5 Selected from, Each R a5 、R c5 、and R d5 is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl.

[0117] In some embodiments, the compound is a compound of formula (II),

Chemical formula

[0118] In some embodiments, the compound is a compound of formula (IIa),

Chemical formula

[0119] In some embodiments, the compound is a compound of formula (IIb),

Chemical formula

[0120] In some embodiments, the compound is a compound of formula (III),

Chemical formula

[0121] In some embodiments, the compound is a compound of formula (IIIa),

Chemical formula

[0122] In some embodiments, the compound is a compound of formula (IIIb),

Chemical formula

[0123] In some embodiments, the compound is a compound of formula (IV),

Chemical formula

[0124] In some embodiments, the compound is a compound of formula (V),

Chemical formula

[0125] In some embodiments, the compound is a compound of formula (Va),

Chemical formula

[0126] In some embodiments, the compound is a compound of formula (Vb),

Chemical formula

[0127] In some embodiments, the compound is a compound of formula (Vc),

Chemical formula

[0128] In some embodiments, the compound is a compound of formula (Vd),

Chemical formula

[0129] In some embodiments, the compound is a compound of formula (VI),

Chem.

[0130] In some embodiments, the compound is a compound of formula (VIa),

Chem.

[0131] In some embodiments, the compound is a compound of formula (VIb),

Chem.

[0132] In some embodiments, the compound is a compound of formula (VIc),

Chem.

[0133] In some embodiments, the compound is a compound of formula (VIIa),

Chem.

[0134] In some embodiments, the compound is a compound of formula (VIIIa),

Chem.

[0135] In some embodiments, the compound is a compound of formula (VIIIb), [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0136] In some embodiments, the compound is a compound of formula (VIIIc), [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0137] In some embodiments, the compound is a compound of formula (IXa), [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0138] In some embodiments, the compound is a compound of formula (IXb), [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0139] In some embodiments, the compound is a compound of formula (IXc), [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0140] In some embodiments, Z is CR 2 is.

[0141] In some embodiments, Z is N.

[0142] In some embodiments, X is N and Y is C.

[0143] In some embodiments, X is C and Y is N.

[0144] In some embodiments, Z is N, X is N, and Y is C.

[0145] In some embodiments, Z is N, X is C, and Y is N.

[0146] In some embodiments, Z is CR 2 and X is N and Y is C.

[0147] In some embodiments, Z is CR 2 and X is C and Y is N.

[0148] In some embodiments, one, two, three, four, five, six, seven, or eight hydrogen atoms bonded to the carbon atoms of an “alkyl,” “alkenyl,” “alkynyl,” “aryl,” “phenyl,” “cycloalkyl,” “heterocycloalkyl,” or “heteroaryl” substituent, or a “-C 1-4 alkyl-” and “alkylene” linking group, as described herein, are optionally replaced with deuterium atoms.

[0149] It is further understood that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention that are, for brevity, described in the context of a single embodiment may also be provided separately or in any suitable sub-combination.

[0150] Divalent linking substituents are described at various places in this specification. Unless otherwise specified, each divalent linking substituent is specifically intended to include both the forward and reverse forms of the linking substituent. For example, -NR(CR’R’’) n - includes both -NR(CR’R’’) n - and -(CR’R’’) n NR-. When the structure specifically requires a linking group, the Markush variables recited for that group are understood to be linking groups.

[0151] The term "n-membered" (where n is an integer) typically describes the number of ring-forming atoms in a moiety, where the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.

[0152] As used herein, the phrase "optionally substituted" means unsubstituted or substituted. Substituents are selected independently, and substitution may be at any chemically accessible position. As used herein, the term "substituted" means that a hydrogen atom has been removed and replaced with a substituent. A single divalent substituent, such as oxo, can replace two hydrogen atoms. It should be understood that substitution at a given atom is limited by valence, does not exceed the normal valence of the specified atom, and results in a stable compound.

[0153] As used herein, the term "selected independently from" means that each occurrence of a variable or substituent is independently selected, for each occurrence, from the corresponding list.

[0154] As used herein, the phrase "each 'variable' is independently selected from" means substantially the same thing as "in each occurrence, the 'variable' is selected from".

[0155] In any component or formula for a compound, if any variable (e.g., R G ) appears more than once, its definition in each occurrence is independent of its definition in any other occurrence. Thus, for example, if a group is shown to be substituted with 1, 2, 3, or 4 independently selected R G substituents, the group may optionally have up to 4 R Gmay be substituted with a radical, and R in each occurrence G is selected independently from the definition of R G .

[0156] In some embodiments, optionally when a plurality of substituents are specified in the following form

Chemical formula

[0157] Throughout the definitions, the term "C n-m " indicates a range including the endpoints, where n and m are integers and indicate the number of carbons. Examples include C 1-3 , C 1-4 , C 1-6 , etc.

[0158] As used herein, the term "C n-mThe term "alkyl" refers to a saturated hydrocarbon group that can be linear or branched and has n to m carbon atoms. Examples of alkyl moieties include chemical groups such as methyl (Me), ethyl (Et), n-propyl (n-Pr), isopropyl (i-Pr), n-butyl, tert-butyl, isobutyl, sec-butyl, etc., and higher homologues such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, etc., but are not limited thereto. In some embodiments, the alkyl group contains 1 to 6 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms.

[0159] As used herein, "C" n-m "Alkenyl" refers to an alkyl group having one or more carbon-carbon double bonds and having n to m carbon atoms. Exemplary alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, etc. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

[0160] As used herein, "C" n-m "Alkynyl" refers to an alkyl group having one or more carbon-carbon triple bonds and having n to m carbon atoms. Exemplary alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, etc. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. As used herein, "C" used alone or in combination with other terms n-m The term "alkoxy" refers to a group of the formula -O-alkyl, wherein the alkyl group has n to m carbon atoms. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), butoxy (e.g., n-butoxy and tert-butoxy), etc. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0161] As used herein, the term "amino" refers to a group of the formula -NH2.

[0162] As used herein, the term "aryl", used alone or in combination with other terms, refers to an aromatic hydrocarbon group which can be monocyclic or polycyclic (e.g., having two fused rings). The term "C n-m aryl" refers to an aryl group having n to m ring carbon atoms. In some embodiments, the aryl group has 6 to 10 carbon atoms. In some embodiments, the aryl group is phenyl or naphthyl. In some embodiments, aryl is phenyl.

[0163] As used herein, "halo" refers to F, Cl, Br, or I. In some embodiments, halo is F, Cl, or Br. In some embodiments, halo is F or Cl. In some embodiments, halo is F. In some embodiments, halo is Cl.

[0164] As used herein, "C n-m haloalkoxy" refers to a group of the formula -O-haloalkyl having n to m carbon atoms. Exemplary haloalkoxy groups include OCF3 and OCHF2. In some embodiments, the haloalkoxy group is fluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0165] As used herein, the term "C n-mThe term "haloalkyl" refers to an alkyl group having from 1 halogen atom to 2s + 1 halogen atoms (which may be the same or different), where "s" is the number of carbon atoms in the alkyl group, and the alkyl group has from n to m carbon atoms. In some embodiments, the haloalkyl group is fluorinated only. In some embodiments, the alkyl group of the haloalkyl has from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms. Exemplary haloalkyl groups include CF3, C2F5, CHF2, CH2F, CCl3, CHCl2, C2Cl5, and the like.

[0166] As used herein, "C" n-m The term "fluoroalkyl" refers to an alkyl group having from 1 fluorine atom to 2s + 1 fluorine atoms, where "s" is the number of carbon atoms in the alkyl group, and the alkyl group has from n to m carbon atoms. In some embodiments, the alkyl group of the fluoroalkyl has from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms. Exemplary fluoroalkyl groups include CF3, C2F5, CHF2, CH2F, and the like.

[0167] As used herein, the term "thio" refers to a group of the formula -SH.

[0168] As used herein, "C" n-m The term "alkylamino" refers to a group of the formula -NH(alkyl), wherein the alkyl group has from n to m carbon atoms. In some embodiments, the alkyl group of the alkylamino has from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

[0169] As used herein, "C" n-m The term "alkoxycarbonyl" refers to a group of the formula -C(O)O-alkyl, wherein the alkyl group has from n to m carbon atoms. In some embodiments, the alkyl group of the alkoxycarbonyl has from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

[0170] As used herein, "C"n-m The term "alkylcarbonyl" refers to a group of the formula -C(O)-alkyl, wherein the alkyl group has from n to m carbon atoms. In some embodiments, the alkyl group of the alkylcarbonyl has from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

[0171] As used herein, "C" n-m The term "alkylcarbonylamino" refers to a group of the formula -NHC(O)-alkyl, wherein the alkyl group has from n to m carbon atoms. In some embodiments, the alkyl group of the alkylcarbonylamino has from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

[0172] As used herein, "C" n-m The term "alkoxycarbonylamino" refers to a group of the formula -NHC(O)O(C n-m alkyl), wherein the alkyl group has from n to m carbon atoms. In some embodiments, the alkyl group of the alkoxycarbonylamino has from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

[0173] As used herein, "C" n-m The term "alkylsulfonylamino" refers to a group of the formula -NHS(O)2-alkyl, wherein the alkyl group has from n to m carbon atoms. In some embodiments, the alkyl group of the alkylsulfonylamino has from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

[0174] As used herein, the term "aminosulfonyl" refers to a group of the formula -S(O)2NH2.

[0175] As used herein, "C" n-m The term "alkylaminosulfonyl" refers to a group of the formula -S(O)2NH(alkyl), wherein the alkyl group has from n to m carbon atoms. In some embodiments, the alkyl group of the alkylaminosulfonyl has from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

[0176] As used herein, the term "di(C n-m alkyl)aminosulfonyl" refers to a group of the formula -S(O)2N(alkyl)2, wherein each alkyl group independently has from n to m carbon atoms. In some embodiments, each alkyl group of the dialkylaminosulfonyl independently has from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

[0177] As used herein, the term "aminosulfonylamino" refers to a group of the formula -NHS(O)2NH2.

[0178] As used herein, "C n-m alkylaminosulfonylamino" refers to a group of the formula -NHS(O)2NH(alkyl), wherein the alkyl group has from n to m carbon atoms. In some embodiments, the alkyl group of the alkylaminosulfonylamino has from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

[0179] As used herein, the term "di(C n-m alkyl)aminosulfonylamino" refers to a group of the formula -NHS(O)2N(alkyl)2, wherein each alkyl group independently has from n to m carbon atoms. In some embodiments, each alkyl group of the dialkylaminosulfonylamino independently has from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

[0180] As used herein, the term "aminocarbonylamino", used alone or in combination with other terms, refers to a group of the formula -NHC(O)NH2.

[0181] As used herein, "C n-m alkylaminocarbonylamino" refers to a group of the formula -NHC(O)NH(alkyl), wherein the alkyl group has from n to m carbon atoms. In some embodiments, the alkyl group of the alkylaminocarbonylamino has from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

[0182] As used herein, the term "di(C n-m alkyl)aminocarbonylamino" refers to a group of the formula -NHC(O)N(alkyl)2, wherein each alkyl group independently has from n to m carbon atoms. In some embodiments, each alkyl group of the dialkylaminocarbonylamino has from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

[0183] As used herein, the term "C n-m alkylcarbamoyl" refers to a group of the formula -C(O)-NH(alkyl), wherein the alkyl group has from n to m carbon atoms. In some embodiments, the alkyl group of the alkylcarbamoyl has from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

[0184] As used herein, the term "C n-m alkylthio" refers to a group of the formula -S-alkyl, wherein the alkyl group has from n to m carbon atoms. In some embodiments, the alkyl group of the alkylthio has from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

[0185] As used herein, the term "C n-m alkylsulfinyl" refers to a group of the formula -S(O)-alkyl, wherein the alkyl group has from n to m carbon atoms. In some embodiments, the alkyl group of the alkylsulfinyl has from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

[0186] As used herein, the term "C n-m alkylsulfonyl" refers to a group of the formula -S(O)2-alkyl, wherein the alkyl group has from n to m carbon atoms. In some embodiments, the alkyl group of the alkylsulfonyl has from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

[0187] As used herein, the term "cyano-C n-m alkyl" refers to a group of the formula -(Cn-m refers to the group of -(C 1-6 alkylene)-CN, wherein the alkylene group has n to m carbon atoms. As used herein, "cyano-C 1-6 alkyl" refers to the group of -(C 1-3 alkylene)-CN. As used herein, "cyano-C 1-3 alkyl" refers to the group of -(C

[0188] As used herein, "HO-C n-m alkyl" refers to the group of -(C n-m alkylene)-OH, wherein the alkylene group has n to m carbon atoms. As used herein, "HO-C 1-3 alkyl" refers to the group of -(C 1-3 alkylene)-OH.

[0189] As used herein, "C n-m alkoxy-C o-p alkyl" refers to the group of -(C n-m alkylene)-O(C o-p alkyl), wherein the alkylene group has n to m carbon atoms and the alkyl group has o to p carbon atoms. As used herein, "C 1-6 alkoxy-C 1-6 alkyl" refers to the group of -(C 1-6 alkylene)-O(C 1-6 alkyl). As used herein, "C 1-3 alkoxy-C 1-3 alkyl" refers to the group of -(C 1-3 alkylene)-O(C 1-3 alkyl).

[0190] As used herein, the term "carboxy" refers to the group of -C(O)OH.

[0191] As used herein, "di(C n-mThe term “di(C - alkyl)amino” refers to a group of the formula -N(alkyl)2, where each of the two alkyl groups independently has from n to m carbon atoms. In some embodiments, each alkyl group of the dialkylamino independently has from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

[0192] As used herein, “di(C n-m - alkyl)carbamyl” refers to a group of the formula -C(O)N(alkyl)2, where each of the two alkyl groups independently has from n to m carbon atoms. In some embodiments, each alkyl group of the dialkylcarbamyl independently has from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

[0193] As used herein, “C n-m alkylcarbonyloxy” is a group of the formula -OC(O)-alkyl, where the alkyl group has from n to m carbon atoms. In some embodiments, the alkyl group of the alkylcarbonyloxy has from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

[0194] As used herein, “aminocarbonyloxy” is a group of the formula -OC(O)-NH2.

[0195] As used herein, “C n-m alkylaminocarbonyloxy” is a group of the formula -OC(O)-NH-alkyl, where the alkyl group has from n to m carbon atoms. In some embodiments, the alkyl group of the alkylaminocarbonyloxy has from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

[0196] As used herein, “di(C n-m alkyl)aminocarbonyloxy” is a group of the formula -OC(O)-N(alkyl)2, where each alkyl group independently has from n to m carbon atoms. In some embodiments, each alkyl group of the dialkylaminocarbonyloxy independently has from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

[0197] As used herein, "C n-m alkoxycarbonylamino" refers to a group of the formula -NHC(O)-O-alkyl, wherein the alkyl group has from n to m carbon atoms.

[0198] As used herein, the term "carbamyl" refers to a group of the formula -C(O)NH2.

[0199] As used herein, the term "carbonyl", used alone or in combination with other terms, refers to a -C(O)- group.

[0200] As used herein, "cycloalkyl" refers to a non-aromatic cyclic hydrocarbon containing a cyclized alkyl and alkenyl group. Cycloalkyl groups can include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) groups, spiro rings, and bridged rings (e.g., bridged bicycloalkyl groups). The ring-forming carbon atoms of the cycloalkyl group can optionally be substituted with oxo or sulfide (e.g., C(O) or C(S)). The definition of cycloalkyl also includes moieties having one or more aromatic rings fused to the cycloalkyl ring (i.e., having a common bond therewith), such as, for example, benzo or thienyl derivatives of cyclopentane, cyclohexane, etc. A cycloalkyl group containing a fused aromatic ring can be attached via any ring-forming atom including the ring-forming atoms of the fused aromatic ring. A cycloalkyl group can have 3, 4, 5, 6, 7, 8, 9, or 10 ring-forming carbons (i.e., C 3-10 ). In some embodiments, cycloalkyl is C 3-10 monocyclic or bicyclic cycloalkyl. In some embodiments, cycloalkyl is C 3-7 monocyclic cycloalkyl. In some embodiments, cycloalkyl is C 4-7 monocyclic cycloalkyl. In some embodiments, cycloalkyl is C 4-10It is a spiro ring or a bridged cycloalkyl (for example, a bridged bicycloalkyl group). Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, cubane, adamantane, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[2.2.2]octanyl, spiro[3.3]heptanyl, and the like. In some embodiments, the cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0201] As used herein, "heteroaryl" refers to a monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) aromatic heterocycle having at least 1 heteroatom ring member selected from N, O, or S. In some embodiments, any ring-forming N in the heteroaryl moiety can be an N-oxide. In some embodiments, heteroaryl is a 5- to 10-membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, and S. In some embodiments, heteroaryl is a 5- to 6-membered monocyclic heteroaryl having 1 or 2 heteroatom ring members independently selected from N, O, and S. In some embodiments, the heteroaryl group contains 5 to 10 or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to 4 ring-forming heteroatoms, 1 to 3 ring-forming heteroatoms, 1 to 2 ring-forming heteroatoms, or 1 ring-forming heteroatom. When the heteroaryl group contains more than 1 heteroatom ring member, those heteroatoms can be the same or different. Exemplary heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, azolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, furyl, thienyl, triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl), tetrazolyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl), quinolinyl, isoquinolinyl, indolyl, benzothienyl, benzofuranyl, benzoisoxazolyl, imidazo[1,2-b]thiazolyl, purinyl, triazinyl, thieno[3,2-b]pyridinyl, imidazo[1,2-a]pyridinyl, 1,5-naphthyridinyl, 1H-pyrazolo[4,3-b]pyridinyl, oxadiazolyl (e.g., 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl), 1,2-dihydro-1,2-azaborinyl, and the like.

[0202] As used herein, "heterocycloalkyl" refers to a monocyclic or polycyclic heterocycle having at least one non-aromatic ring (saturated or partially unsaturated ring), wherein one or more of the ring-forming carbon atoms of the heterocycloalkyl are replaced by a heteroatom selected from N, O, or S, and the ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group may optionally be substituted with one or more oxo or sulfide groups (e.g., C(O), S(O), C(S), or S(O)2, etc.). Heterocycloalkyl groups include monocyclic and polycyclic (e.g., having two fused rings) systems. Heterocycloalkyl includes monocyclic and polycyclic 4- to 10-membered, 4- to 7-membered, and 5- to 6-membered heterocycloalkyl groups. Heterocycloalkyl groups may also include spiro and bridged rings. The heterocycloalkyl group may be attached via a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds.

[0203] Also included in the definition of heterocycloalkyl are moieties having one or more aromatic rings fused to (i.e., having a common bond with) a non-aromatic heterocyclic ring, such as, for example, benzoyl or thienyl derivatives of piperidine, morpholine, azepine, etc. A heterocycloalkyl group containing a fused aromatic ring may be attached via any ring-forming atom including the ring-forming atoms of the fused aromatic ring. In some embodiments, the heterocycloalkyl group contains 4 to 10 ring-forming atoms, 4 to 7 ring-forming atoms, 4 to 6 ring-forming atoms, or 5 to 6 ring-forming atoms. In some embodiments, the heterocycloalkyl group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0204] In some embodiments, the heterocycloalkyl is a 4- to 10-membered monocyclic, bicyclic, or tricyclic heterocycloalkyl having 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, wherein the 1, 2, 3, or 4 ring-forming carbon or heteroatoms may optionally be substituted by one or more oxo or sulfide groups. In some embodiments, the heterocycloalkyl is a 4- to 10-membered bicyclic heterocycloalkyl having 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, wherein the 1, 2, 3, or 4 ring-forming carbon or heteroatoms may optionally be substituted by one or more oxo or sulfide groups. In some embodiments, the heterocycloalkyl is a 4- to 7-membered monocyclic heterocycloalkyl having 1 or 2 ring-forming heteroatoms independently selected from N, O, and S, wherein the 1, 2, or 3 ring-forming carbon or heteroatoms may optionally be substituted by one or more oxo or sulfide groups. In some embodiments, the heterocycloalkyl is a monocyclic 4- to 6-membered heterocycloalkyl having 1 or 2 heteroatoms independently selected from N, O, S, and B and having one or more oxidized ring members.

[0205] Examples of the heterocycloalkyl group include pyrrolidin-2-one, 1,3-isoxazolidin-2-one, pyranyl, tetrahydropyran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, benzazepane, 1,2,3,4-tetrahydroisoquinoline, azabicyclo[3.1.0]hexanyl, diazabicyclo[3.1.0]hexanyl, oxabicyclo[2.1.1]hexanyl, azabicyclo[2.2.1]heptanyl, azabicyclo[2.2.1]heptan-7-yl, azabicyclo[2.2.1]heptan-2-yl, diazabicyclo[2.2.1]heptanyl, azabicyclo[3.1.1]heptanyl, diazabicyclo[3.1.1]heptanyl, azabicyclo[3.2.1]octanyl, diazabicyclo[3.2.1]octanyl, oxabicyclo[2.2.2]octanyl, azabicyclo[2.2.2]octanyl, azadamantanyl, diazadamantanyl, oxa-adamantanyl, azaspiro[3.3]heptanyl, diazaspiro[3.3]heptanyl, oxa-azaspiro[3.3]heptanyl, azaspiro[3.4]octanyl, diazaspiro[3.4]octanyl, oxa-azaspiro[3.4]octanyl, azaspiro[2.5]octanyl, diazaspiro[2.5]octanyl, azaspiro[4.4]nonanyl, diazaspiro[4.4]nonanyl, oxa-azaspiro[4.4]nonanyl, azaspiro[4.5]decanyl, diazaspiro[4.5]decanyl, diazaspiro[4.4]nonanyl, oxa-diazaspiro[4.4]nonanyl, etc.

[0206] As used herein, "C o-p cycloalkyl-C n-m alkyl-" refers to a group of the formula cycloalkyl-alkylene-, wherein cycloalkyl has o to p carbon atoms and the alkylene linking group has n to m carbon atoms.

[0207] As used herein, "C o-p aryl-C n-m alkyl-" refers to a group of the formula aryl-alkylene-, wherein aryl has o to p carbocyclic members and the alkylene linking group has n to m carbon atoms.

[0208] As used herein, "heteroaryl-C n-m alkyl-" refers to a group of the formula heteroaryl-alkylene-, wherein the alkylene linking group has n to m carbon atoms.

[0209] As used herein, "heterocycloalkyl-C n-m alkyl-" refers to a group of the formula heterocycloalkyl-alkylene-, wherein the alkylene linking group has n to m carbon atoms.

[0210] As used herein, the term "alkylene" refers to a divalent straight-chain or branched alkyl linking group. Examples of an "alkylene group" include methylene, ethane-1,1-diyl, ethane-1,2-diyl, propane-1,3-diyl, propane-1,2-diyl, propane-1,1-diyl, and the like.

[0211] As used herein, the term "alkenylene" refers to a divalent straight-chain or branched alkenyl linking group. Examples of an "alkenylene group" include ethene-1,1-diyl, ethene-1,2-diyl, propene-1,3-diyl, 2-butene-1,4-diyl, 3-pentene-1,5-diyl, 3-hexene-1,6-diyl, 3-hexene-1,5-diyl, and the like.

[0212] As used herein, the term "alkynylene" refers to a divalent straight-chain or branched alkynyl linking group. Examples of an "alkynylene group" include propyne-1,3-diyl, 2-butyne-1,4-diyl, 3-pentyne-1,5-diyl, 3-hexyne-1,6-diyl, 3-hexyne-1,5-diyl, and the like.

[0213] As used herein, an "alkyl linking group" is a divalent straight-chain or branched alkyl linking group ("alkylene group"). For example, " o-p cycloalkyl-C n-m alkyl-", " o-p aryl-C n-m alkyl-", " n-m phenyl-C n-m alkyl-", " n-m heteroaryl-C

[0214] alkyl-", and "

[0215] heterocycloalkyl-C

[0216] alkyl-" contain an alkyl linking group. Examples of an "alkyl linking group" or "alkylene group" include methylene, ethane-1,1-diyl, ethane-1,2-diyl, propane-1,3-diyl, propane-1,2-diyl, propane-1,1-diyl, and the like.

[0217] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). Unless otherwise indicated, all stereoisomers such as enantiomers and diastereomers are contemplated. Compounds of the disclosure containing an asymmetrically substituted carbon atom can be isolated in optically active form or racemic form. Methods for preparing optically active forms from optically inactive starting materials are known in the art and include, for example, resolution of a racemic mixture or stereoselective synthesis. Many geometric isomers such as olefins, C=N double bonds, etc. can also be present in the compounds described herein, and all such stable isomers are contemplated by the present invention. The cis and trans geometric isomers of the compounds of the disclosure are described and can be isolated as mixtures of isomers or as separated isomeric forms. In some embodiments, the compound has the (R) configuration. In some embodiments, the compound has the (S) configuration. The formulas provided herein (e.g., formula (I), (II), etc.) include the stereoisomers of the compound.

[0218] Resolution of a racemic mixture of a compound can be carried out by any of a number of methods known in the art. Exemplary methods include fractional recrystallization using a chiral resolving acid which is an optically active salt-forming organic acid. Suitable resolving agents for the fractional recrystallization method are, for example, optically active acids such as tartaric acid, diacetyl tartaric acid, dibenzoyl tartaric acid, mandelic acid, malic acid, D- and L-forms of lactic acid, or various optically active camphorsulfonic acids such as β-camphorsulfonic acid. Other resolving agents suitable for the fractional crystallization method include stereoisomerically pure forms such as α-methylbenzylamine (e.g., S- and R-forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc.

[0219] Resolution of a racemic mixture can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). The composition of a suitable elution solvent can be determined by one skilled in the art.

[0220] The compounds provided herein also include tautomeric forms. Tautomeric forms result from the exchange of a single bond with an adjacent double bond and the accompanying movement of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonated states having the same empirical formula and total charge. Exemplary prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which a proton can occupy two or more positions of a heterocyclic system, such as 1H- and 3H-imidazole, 1H-, 2H-, and 4H-1,2,4-triazole, 1H- and 2H-isoindole, 2-hydroxypyridine and 2-pyridone, and 1H- and 2H-pyrazole. Tautomeric forms can be in an equilibrium state or can be stereochemically fixed in one form by appropriate substitution.

[0221] All compounds, and their pharmaceutically acceptable salts, can be found together with, or isolated from, other substances such as water and solvents (e.g., hydrates and solvates).

[0222] In some embodiments, the preparation of the compounds can involve, for example, the addition of an acid or a base to affect the catalysis of a desired reaction or the formation of a salt form such as an acid addition salt.

[0223] In some embodiments, the compounds provided herein, or salts thereof, are substantially isolated. "Substantially isolated" means that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, the enrichment of the composition in the compounds provided herein. Substantial separation can include compositions containing the compounds provided herein, or salts thereof, at least about 50 wt%, at least about 60 wt%, at least about 70 wt%, at least about 80 wt%, at least about 90 wt%, at least about 95 wt%, at least about 97 wt%, or at least about 99 wt%. Methods for isolating the compounds and their salts are conventional in the art.

[0224] As used herein, the term "compound" is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. A compound identified by name or structure as a particular tautomeric form herein is intended to include other tautomeric forms thereof unless otherwise specified.

[0225] The phrase "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions, and / or dosage forms that, within the scope of sound medical judgment, in view of a reasonable benefit / risk ratio, are suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications.

[0226] This application also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the compounds of the present disclosure in which the parent compound is modified by converting an existing acidic or basic moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, and alkali or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts of the present disclosure include, for example, conventional non-toxic salts of the parent compound formed from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts of the present disclosure can be synthesized from parent compounds containing basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water, an organic solvent, or a mixture of the two (generally, non-aqueous media such as ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol), or acetonitrile (ACN) are preferred). A list of suitable salts can be found in Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

[0227] Synthesis As will be appreciated by those skilled in the art, the compounds provided herein can be prepared using known organic synthetic techniques, including their salts and stereoisomers, and can be synthesized according to any of a number of possible synthetic routes, such as the synthetic routes provided in the following schemes.

[0228] The reactions for preparing the compounds described herein can be carried out in a suitable solvent that can be readily selected by one of ordinary skill in organic synthesis. A suitable solvent can be substantially non-reactive with the starting materials (reactants), intermediates, or products at the temperature at which the reaction is carried out (e.g., a temperature that can range from the freezing temperature of the solvent to the boiling temperature of the solvent). A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, a solvent suitable for the particular reaction step can be selected by one of ordinary skill in the art.

[0229] As used herein, the expressions “ambient temperature” or “room temperature” or “r.t.” are understood in the art and generally refer to a temperature, e.g., a reaction temperature, i.e., approximately the temperature of the room in which the reaction is carried out, e.g., a temperature of about 20 °C to about 30 °C.

[0230] The preparation of the compounds of the present invention can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, as well as the selection of appropriate protecting groups, can be readily determined by one of ordinary skill in the art. For the chemical nature of protecting groups, see, for example, Kocienski, Protecting Groups, (Thieme, 2007), Robertson, Protecting Group Chemistry, (Oxford University Press, 2000), Smith et al., March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6 th Ed. (Wiley, 2007), Peturssion et al., “Protecting Groups in Carbohydrate Chemistry,” J. Chem. Educ., 1997, 74(11), 1297, and Wuts et al., Protective Groups in Organic Synthesis, 4th Ed., (Wiley, 2006).

[0231] The reaction can be monitored according to any suitable method known in the art. For example, the formation of the product can be monitored by spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., ultraviolet-visible), mass spectrometry, etc., or by chromatographic methods such as high performance liquid chromatography (HPLC), liquid chromatography-mass spectroscopy (LCMS), or thin layer chromatography (TLC). The compounds can be purified by those skilled in the art by various methods including high performance liquid chromatography (HPLC) and normal phase silica chromatography.

[0232] The following scheme provides general guidelines related to the preparation of the compounds of the present invention. Those skilled in the art will understand that the preparations shown in the scheme can be modified or optimized using general knowledge of organic chemistry to prepare various compounds of the present invention.

[0233] The compounds of Formula 1-5 can be synthesized using the process shown in Scheme 1. The compound of Formula 1-3 was obtained by a palladium-catalyzed cross-coupling reaction of a suitable aryl halide 1-1 and boronic acid / ester 1-2. The compound of Formula 1-5 was provided by a transition metal (including but not limited to Pd and Cu) catalyzed C-N bond formation reaction. Scheme 1.

Chemical formula

[0234] The compounds of formula 2-10 can also be synthesized using the process shown in Scheme 2. Nucleophilic substitution of compound 2-1 with O-ethyl carbonisothiocyanatidate 2-2 gave intermediate compound 2-3. Cyclization of 2-3 with hydroxylamine hydrochloride / DIPEA can provide the amino bicyclic core 2-4. The palladium-catalyzed cross-coupling reaction of compound 2-4 and boronic acid / ester 2-5 gave the compound of formula 2-6. Sandmeyer bromination of compound 2-6 generated aryl bromide 2-7, which can be reacted with amino compound 2-8 to provide compound 2-10 under transition-metal-catalyzed C-N bond formation reaction conditions. Alternatively, the compounds of formula 2-10 can be generated directly from amino compound 2-6 using a reductive amination protocol. Scheme 2.

Chemical Structure

[0235] The compounds of formula 3-10 can be synthesized using the process shown in Scheme 3. Nucleophilic substitution of compound 3-1 with O-ethyl carbonisothiocyanatidate 3-2 gave intermediate compound 3-3. Cyclization of 3-3 with hydroxylamine hydrochloride / DIPEA can provide the amino bicyclic core 3-4. The palladium-catalyzed cross-coupling reaction of compound 3-4 and boronic acid / ester 3-5 gave the compound of formula 3-6. Sandmeyer bromination of compound 3-6 generated aryl bromide 3-7, which can be reacted with amino compound 3-8 to provide compound 3-10 under transition-metal-catalyzed C-N bond formation reaction conditions. Alternatively, the compounds of formula 3-10 can be generated directly from amino compound 3-6 using a reductive amination protocol. Scheme 3.

Chemical Structure

[0236] Method of Use The compounds of the present disclosure can inhibit CDK2 and are thus useful for treating diseases in which the underlying pathology is mediated in whole or in part by CDK2. Such diseases include cancer and other diseases associated with proliferative disorders. In some embodiments, the present disclosure provides for the in vivo treatment of an individual or patient with a compound of formula (I) or a salt thereof such that the growth of a cancerous tumor is inhibited. The compound of formula (I) or any of the compounds of the formulas described herein, or a compound recited in any of the claims and described herein, or a salt thereof can be used to inhibit the growth of a cancerous tumor associated with an abnormality that activates CDK2 kinase activity. These include, but are not limited to, diseases (e.g., cancers) characterized by amplification or overexpression of CCNE1 such as ovarian cancer, uterine carcinosarcoma, and breast cancer, and diseases characterized by p27 inactivation such as breast cancer and melanoma. Thus, in some embodiments of the method, the patient has previously been determined to have an amplification of the cyclin E1 (CCNE1) gene and / or an expression level of CCNE1 that is higher than the control expression level of CCNE1 in a biological sample obtained from a human subject. Alternatively, the compound of formula (I) or any of the compounds of the formulas described herein, or a compound recited in any of the claims and described herein, or a salt thereof can be used in combination with other agents or standard cancer treatments as described below. In one embodiment, the present disclosure provides a method for inhibiting the growth of tumor cells in vitro. The method includes contacting tumor cells in vitro with a compound of formula (I) or any of the compounds of the formulas described herein, or a compound recited in any of the claims and described herein, or a salt thereof. In another embodiment, the present disclosure provides a method for inhibiting the growth of tumor cells associated with CCNE1 amplification and overexpression in an individual or patient. The method includes administering to an individual or patient in need thereof a therapeutically effective amount of a compound of formula (I) or any of the compounds of the formulas described herein, or a compound recited in any of the claims and described herein, or a salt or stereoisomer thereof.

[0237] In some embodiments, a method of inhibiting CDK2 is provided herein, the method comprising contacting CDK2 with a compound of formula (I) or of a formula as described herein, a compound recited in any of the claims and as described herein, or a salt thereof. In some embodiments, a method of inhibiting CDK2 in a patient is provided herein, the method comprising administering to the patient a compound of formula (I) or of a formula as described herein, a compound recited in any of the claims and as described herein, or a salt thereof.

[0238] In some embodiments, a method of treating cancer is provided herein. The method comprises administering to a patient (in need thereof) a therapeutically effective amount of a compound of formula (I) or of a formula as described herein, a compound recited in any of the claims and as described herein, or a salt thereof. In another embodiment, the cancer is characterized by amplification or overexpression of CCNE1. In some embodiments, the cancer is ovarian cancer or breast cancer characterized by amplification or overexpression of CCNE1.

[0239] In some embodiments, a method of treating a disease or disorder associated with CDK2 in a patient is provided herein, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (I) or of a formula as described herein, a compound recited in any of the claims and as described herein, or a salt thereof. In some embodiments, the disease or disorder associated with CDK2 is related to amplification of the cyclin E1 (CCNE1) gene and / or overexpression of CCNE1.

[0240] In some embodiments, the diseases or disorders associated with CDK2 are N-myc amplified neuroblastoma cells (see Molenaar, et al., Proc Natl Acad Sci USA 106(31):12968-12973), K-Ras mutant lung cancer (see Hu, S., et al., Mol Cancer Ther, 2015.14(11):2576-85), and cancers with FBW7 mutation and CCNE1 overexpression (see Takada, et al., Cancer Res, 2017.77(18):4881-4893).

[0241] In some embodiments, the diseases or disorders associated with CDK2 are squamous cell lung cancer, adenocarcinoma of the lung, pancreatic adenocarcinoma, invasive breast cancer, uterine carcinosarcoma, serous cystadenocarcinoma of the ovary, gastric adenocarcinoma, esophageal cancer, urothelial carcinoma of the bladder, mesothelioma, or sarcoma.

[0242] In some embodiments, the diseases or disorders associated with CDK2 are adenocarcinoma of the lung, invasive breast cancer, uterine carcinosarcoma, serous cystadenocarcinoma of the ovary, or gastric adenocarcinoma.

[0243] In some embodiments, the diseases or disorders associated with CDK2 are adenocarcinoma, carcinoma, or cystadenocarcinoma.

[0244] In some embodiments, the diseases or disorders associated with CDK2 are uterine cancer, ovarian cancer, gastric cancer, esophageal cancer, lung cancer, bladder cancer, pancreatic cancer, or breast cancer.

[0245] In some embodiments, the diseases or disorders associated with CDK2 are cancer.

[0246] In some embodiments, the cancer is characterized by amplification or overexpression of CCNE1. In some embodiments, the cancer is ovarian cancer or breast cancer characterized by amplification or overexpression of CCNE1.

[0247] In some embodiments, the breast cancer is chemotherapy- or radiotherapy-resistant breast cancer, endocrine therapy-resistant breast cancer, trastuzumab-resistant breast cancer, or breast cancer showing primary or acquired resistance to CDK4 / 6 inhibition. In some embodiments, the breast cancer is advanced or metastatic breast cancer.

[0248] Examples of cancers treatable using the compounds of the present disclosure include bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, gastric cancer, testicular cancer, uterine cancer, fallopian tube cancer, carcinoma of the endometrium, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic or acute leukemia including chronic lymphocytic leukemia, pediatric solid tumors, lymphocytic lymphoma, bladder cancer, kidney or urethral cancer, renal pelvis cancer, central nervous system (CNS) neoplasms, primary CNS lymphoma, tumor angiogenesis, spinal axis tumors, brainstem gliomas, pituitary adenomas, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T cell lymphoma, environmentally induced cancers including cancers induced by asbestos, and combinations of these cancers, but are not limited thereto. The compounds of the present disclosure are also useful for the treatment of metastatic cancers.

[0249] In some embodiments, cancers treatable with the compounds of the present disclosure include melanoma (e.g., metastatic malignant melanoma, BRAF- and HSP90-inhibition resistant melanoma), renal cancer (e.g., clear cell carcinoma), prostate cancer (e.g., hormone-refractory prostate cancer), breast cancer, colon cancer, lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), head and neck squamous cell carcinoma, urothelial cancer (e.g., bladder), and cancers having high-frequency microsatellite instability (MSI 高 ). Additionally, the present disclosure includes refractory or recurrent malignant tumors whose growth can be inhibited using the compounds of the present disclosure.

[0250] In some embodiments, cancers that can be treated using the compounds of the present disclosure include solid tumors (e.g., prostate cancer, colon cancer, esophageal cancer, endometrial cancer, ovarian cancer, uterine cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, sarcoma, bladder cancer, etc.), blood cancers (e.g., leukemia such as lymphoma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), etc., DLBCL, mantle cell lymphoma, non-Hodgkin lymphoma (including follicular lymphoma including recurrent or refractory NHL and recurrent follicular), Hodgkin lymphoma, or multiple myeloma), and combinations of these cancers, but are not limited thereto.

[0251] In some embodiments, cancers that can be treated using the compounds of the present disclosure include cholangiocarcinoma, bile duct cancer, triple-negative breast cancer, rhabdomyosarcoma, small cell lung cancer, leiomyosarcoma, hepatocellular carcinoma, Ewing sarcoma, brain cancer, brain tumor, astrocytoma, neuroblastoma, neurofibroma, basal cell carcinoma, chondrosarcoma, epitheloid sarcoma, eye cancer, fallopian tube cancer, gastrointestinal cancer, gastrointestinal stromal tumor, hairy cell leukemia, intestinal cancer, pancreatic islet cell cancer, oral cancer, mouth cancer, throat cancer, laryngeal cancer, lip cancer, mesothelioma, cervical cancer, nasal cavity cancer, ocular cancer, uveal melanoma, pelvic cancer, rectal cancer, renal cell cancer, salivary gland cancer, paranasal sinus cancer, spinal cancer, tongue cancer, tubular carcinoma, urethral cancer, and ureteral cancer, but are not limited thereto.

[0252] In some embodiments, the compounds of the present disclosure can be used to treat sickle cell disease and sickle cell anemia.

[0253] In some embodiments, diseases and indications that can be treated using the compounds of the present disclosure include blood cancers, sarcomas, lung cancers, gastrointestinal cancers, urogenital cancers, liver cancers, bone cancers, cancers of the nervous system, gynecological cancers, and skin cancers, but are not limited thereto.

[0254] Exemplary blood cancers include acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, non-Hodgkin lymphoma (including relapsed or refractory NHL and relapsed follicular), Hodgkin lymphoma, and other lymphomas and leukemias, myeloproliferative disorders (e.g., primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocythemia (ET)), myelodysplastic syndromes (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), and multiple myeloma (MM).

[0255] Exemplary sarcomas include chondrosarcoma, Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxosarcoma, rhabdomyoma, rhabdomyosarcoma, fibroma, lipoma, myoma, and teratoma.

[0256] Exemplary lung cancers include non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), bronchiogenic carcinoma, squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma, alveolar (bronchiolar) carcinoma, bronchial adenoma, chondromyxoid fibroma, and mesothelioma.

[0257] Exemplary gastrointestinal cancers include esophageal cancer (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (carcinoma, lymphoma, leiomyosarcoma), pancreatic cancer (pancreatic ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, VIPoma), small intestine cancer (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi sarcoma, leiomyosarcoma, hemangioma, lipoma, neurofibroma, fibroma), colorectal cancer (adenocarcinoma, tubular adenoma, villous adenoma, fibroma, leiomyosarcoma), and colorectal cancer.

[0258] Exemplary urogenital cancers include kidney cancer (adenocarcinoma, Wilms tumor [nephroblastoma]), bladder and urethral cancer (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate cancer (adenocarcinoma, sarcoma), and testicular cancer (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma).

[0259] Exemplary liver cancers include hepatocellular carcinoma (HCC), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.

[0260] Exemplary bone cancers include, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulosarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteochondromatosis), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor.

[0261] Exemplary cancers of the nervous system include skull cancer (osteoma, hemangioma, granuloma, xanthoma, Paget's disease), meningeal cancer (meningioma, meningiosarcoma, gliomatosis), brain cancer (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pinealoma), glioblastoma, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), and spinal cord cancer (neurofibroma, meningioma, glioma, sarcoma), as well as neuroblastoma and Lhermitte - Duclos disease.

[0262] Exemplary gynecological cancers include uterine cancer (endometrial cancer), cervical cancer (cervical cancer, pre - cancerous cervical dysplasia), ovarian cancer (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified cancer), granulosa - theca cell tumor, Sertoli - Leydig cell tumor, undifferentiated germ cell tumor, malignant teratoma), vulvar cancer (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vaginal cancer (clear cell carcinoma, squamous cell carcinoma, sarcoma botryoides (fetal rhabdomyosarcoma), and fallopian tube cancer (carcinoma).

[0263] Exemplary skin cancers include melanoma, basal cell carcinoma, Merkel cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, and keloid. In some embodiments, diseases and conditions treatable using the compounds of the present disclosure include, but are not limited to, sickle cell disease (e.g., sickle cell anemia), triple - negative breast cancer (TNBC), myelodysplastic syndrome, testicular cancer, cholangiocarcinoma, esophageal cancer, and urothelial cancer.

[0264] The compound of formula (I), or any of its embodiments, is considered to have the potential to have satisfactory pharmacological profiles and promising biopharmaceutical properties, such as toxicological profiles, metabolism and pharmacokinetic properties, solubility, and permeability. It will be understood that the determination of appropriate biopharmaceutical properties, for example, cytotoxicity in cells, or the inhibition of certain targets or channels to determine potential toxicity, is within the knowledge of those skilled in the art.

[0265] The terms "individual", "patient", and "subject", which are used interchangeably, refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, most preferably humans.

[0266] The phrase "therapeutically effective amount" refers to the amount of an active compound or pharmaceutical agent that elicits a biological or pharmaceutical response in a tissue, system, animal, individual, or human that is sought by a researcher, veterinarian, physician, or other clinician.

[0267] As used herein, the terms "treating" or "treatment" refer to one or more of (1) inhibiting a disease, e.g., inhibiting a disease, condition, or disorder in an individual who is experiencing or presenting the symptoms or general manifestations of the disease, condition, or disorder (i.e., stopping further progression of the symptoms and / or general manifestations), and (2) ameliorating a disease, e.g., ameliorating a disease, condition, or disorder in an individual who is experiencing or presenting the symptoms or general manifestations of the disease, condition, or disorder (i.e., improving the symptoms and / or general manifestations), such as reducing the severity of the disease.

[0268] In some embodiments, the compounds of the invention prevent or reduce the risk of developing any of the diseases referred to herein, e.g., are useful in preventing or reducing the risk of developing a disease, condition, or disorder in an individual who may be predisposed to the disease, condition, or disorder, but has not yet experienced or manifested the symptoms or overall condition of the disease.

[0269] Combination therapy I. Cancer treatment The growth and survival of cancer cells can be affected by dysfunctions in multiple signaling pathways. Thus, it is useful to combine different enzyme / protein / receptor inhibitors that exhibit different preferences for targets to modulate activity to treat such conditions. By targeting more than one signaling pathway (or more than one biomolecule involved in a given signaling pathway), the potential for drug resistance that occurs in a cell population can be reduced and / or the toxicity of the treatment can be reduced.

[0270] For example, one or more additional pharmaceuticals such as chemotherapeutic agents, anti-inflammatory agents, steroids, immunosuppressive agents, cancer immunotherapeutic agents, metabolic enzyme inhibitors, chemokine receptor inhibitors, and phosphatase inhibitors, and targeted therapies such as Bcr-Abl, Flt-3, EGFR, HER2, JAK, c-MET, VEGFR, PDGFR, c-Kit, IGF-1R, RAF, FAK, and CDK4 / 6 kinase inhibitors, such as those described in WO2006 / 056399, can be used in combination with the compounds of the present disclosure for the treatment of CDK2-related diseases, disorders, or conditions. Other agents such as therapeutic antibodies can be used in combination with the compounds of the present disclosure for the treatment of CDK2-related diseases, disorders, or conditions. The one or more additional pharmaceuticals can be administered to the patient simultaneously or sequentially.

[0271] In some embodiments, the CDK2 inhibitor is administered or used in combination with a BCL2 inhibitor or a CDK4 / 6 inhibitor.

[0272] Compounds as disclosed herein can be used in combination with therapy with one or more other enzyme / protein / receptor inhibitors for the treatment of diseases such as cancer and other diseases or disorders described herein. Examples of diseases and indications treatable by combination therapy include diseases and indications as described herein. Examples of cancer include solid tumors, as well as non-solid tumors such as liquid tumors and blood cancers. Examples of infectious diseases include viral infections, bacterial infections, fungal infections, or parasitic infections. For example, the compounds of the present disclosure can be combined with one or more inhibitors of the following kinases for the treatment of cancer: Akt1, Akt2, Akt3, BCL2, CDK4 / 6, TGF-βR, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IDH2, IGF-1R, IR-R, PDGFαR, PDGFβR, PI3K (alpha, beta, gamma, delta, and multiple or selective), CSF1R, KIT, FLK-II, KDR / FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, PARP, Ron, Sea, TRKA, TRKB, TRKC, TAM kinase (Axl, Mer, Tyro3), FLT3, VEGFR / Flt2, Flt4, EphA1, EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL, ALK, and B-Raf. In some embodiments, the compounds of the present disclosure can be combined with one or more of the following inhibitors for the treatment of cancer or infectious diseases. Non-limiting examples of inhibitors that can be combined with the compounds of the present disclosure for the treatment of cancer and infectious diseases include FGFR inhibitors (FGFR1, FGFR2, FGFR3, or FGFR4, e.g., pemigatinib (INCB54828), INCB62079), EGFR inhibitors (also known as ErB-1 or HER-1, e.g., erlotinib, gefitinib, vandetanib, osimertinib, cetuximab, necitumumab, or panitumumab), VEGFR inhibitors or pathway blockers (e.g., bevacizumab, pazopanib,Sunitinib, sorafenib, axitinib, regorafenib, ponatinib, cabozantinib, vandetanib, ramucirumab, lenvatinib, ziv-aflibercept), PARP inhibitors (e.g., olaparib, rucaparib, veliparib, or niraparib), JAK inhibitors (JAK1 and / or JAK2, e.g., ruxolitinib or baricitinib; JAK1, e.g., itacitinib (INCB39110), INCB052793, or INCB054707), IDO inhibitors (e.g., epacadostat, NLG919, or BMS-986205, MK7162), LSD1 inhibitors (e.g., GSK2979552, INCB59872, and INCB60003), TDO inhibitors, PI3K-delta inhibitors (e.g., parsaclisib (INCB50465) or INCB50797), PI3K-gamma inhibitors, e.g., PI3K-gamma selective inhibitors, Pim inhibitors (e.g., INCB53914), CSF1R inhibitors, TAM receptor tyrosine kinases (Tyro-3, Axl, and Mer, e.g., INCB081776), adenosine receptor antagonists (e.g., A2a / A2b receptor antagonists), HPK1 inhibitors, chemokine receptor inhibitors (e.g., CCR2 or CCR5 inhibitors), SHP1 / 2 phosphatase inhibitors, histone deacetylase inhibitors (HDAC), e.g., HDAC8 inhibitors, angiogenesis inhibitors, interleukin receptor inhibitors, bromo and extra terminal family member inhibitors (e.g., bromodomain inhibitors or BET inhibitors, e.g., INCB54329 and INCB57643), c-MET inhibitors (e.g., capmatinib), anti-CD19 antibodies (e.g., tafasitamab), ALK2 inhibitors (e.g., INCB00928), or combinations thereof.

[0273] In some embodiments, the compounds or salts described herein are administered with a PI3Kδ inhibitor. In some embodiments, the compounds or salts described herein are administered with a JAK inhibitor. In some embodiments, the compounds or salts described herein are administered with a JAK1 or JAK2 inhibitor (e.g., baricitinib or ruxolitinib). In some embodiments, the compounds or salts described herein are administered with a JAK1 inhibitor. In some embodiments, the compounds or salts described herein are administered with a JAK1 inhibitor that is more selective for JAK1 than for JAK2.

[0274] Examples of antibodies for use in combination therapies include, but are not limited to, trastuzumab (e.g., anti-HER2), ranibizumab (e.g., anti-VEGF-A), bevacizumab (AVASTIN™, e.g., anti-VEGF), panitumumab (e.g., anti-EGFR), cetuximab (e.g., anti-EGFR), rituxan (e.g., anti-CD20), and antibodies directed to c-MET.

[0275] One or more of the following agents may be used in combination with the compounds of the present disclosure and are presented as a non-limiting list: cell division inhibitors, cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, epothilone, tamoxifen, 5-fluorouracil, methotrexate, temozolomide, cyclophosphamide, SCH 66336, R115777, L778,123, BMS 214662, IRESSA™ (gefitinib), TARCEVA™ (erlotinib), antibodies against EGFR, interferon, Ara-C, adriamycin, cytoxan, gemcitabine, uracil mustard, chlorambucil, ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, oxaliplatin, leucovorin, ELOXATIN™ (oxaliplatin), pentostatin, vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, mitomycin, deoxycoformycin, mitomycin C, L-asparaginase, teniposide 17. alpha.- Ethinyl estradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, drostanolone propionate, testolactone, megestrol acetate, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide, flutamide, tamoxifen, goserelin, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, navelbine, anastrozole, letrozole, capecitabine, raloxifene, droloxifene, hexamethylmelamine, abaxin, HERCEPTIN (trademark) (trastuzumab), BEXXAR (trademark) (tositumomab), VELCADE (trademark) (bortezomib), ZEVALIN (trademark) (ibritumomab tiuxetan), TRISENOX (trademark) (arsenic trioxide), XELODA (trademark) (capecitabine), vinorelbine, porfimer, ERBITUX (trademark) (cetuximab), thiotepa, altretamine, melphalan, trastuzumab, letrozole, fulvestrant, exemestane, ifosfamide, rituximab, C225 (cetuximab), Campath (alemtuzumab), clofarabine, cladribine, aphidicolin, Rituxan, sunitinib, dasatinib, tiazofurin, Sml1, fludarabine, pentostatin, triapine, didox, trimidox, amidox, 3-AP, and MDL-101,731.

[0276] The compounds of the present disclosure can further be used in combination with other methods of treating cancer, such as chemotherapy, radiation therapy, tumor-targeted therapy, adjuvant therapy, immunotherapy, or surgery. Examples of immunotherapy include cytokine therapy (e.g., interferon, GM-CSF, G-CSF, IL-2), CRS-207 immunotherapy, cancer vaccines, monoclonal antibodies, bispecific or multispecific antibodies, antibody-drug conjugates, adoptive T cell transfer, toll-like receptor agonists, RIG-I agonists, oncolytic virus therapy, and immunomodulatory small molecules including thalidomide or JAK1 / 2 inhibitors, PI3Kδ inhibitors, etc. The compounds can be administered in combination with one or more anticancer drugs such as chemotherapeutic agents. Examples of chemotherapeutic drugs include abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bevacizumab, bexarotene, baricitinib, bleomycin, bortezomib, intravenous busulfan, oral busulfan, calusterone, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, drostanolone propionate, eculizumab, epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib mesylate, interferon alpha 2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, mechlorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen,Any of mitomycin C, mitotane, mitoxantrone, nandrolone phenylpropionate, nelarabine, nofetumomab, oxaliplatin, paclitaxel, pamidronate, panitumumab, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin, procarbazine, quinacrine, rasburicase, rituximab, lestaurtinib, sorafenib, streptozocin, sunitinib, sunitinib maleate, tamoxifen, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, vorinostat, and zoledronic acid is included.

[0277] Additional examples of chemotherapeutic agents include proteasome inhibitors (e.g., bortezomib), thalidomide, lenalidomide, and DNA damaging agents such as melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide, carmustine, and the like.

[0278] Exemplary steroids include corticosteroids such as dexamethasone or prednisone.

[0279] Exemplary Bcr-Abl inhibitors include imatinib mesylate (GLEEVAC (trademark)), nilotinib, dasatinib, bosutinib, and ponatinib, as well as pharmaceutically acceptable salts. Other exemplary suitable Bcr-Abl inhibitors include the compounds of the genera and species disclosed in U.S. Patent No. 5,521,184, WO04 / 005281, and U.S. 60 / 578,491, and pharmaceutically acceptable salts thereof.

[0280] Exemplary suitable Flt-3 inhibitors include midostaurin, lestaurtinib, lenvatinib, sunitinib, sunitinib maleate, sorafenib, quizartinib, crenolanib, pacritinib, tandutinib, PLX3397 and ASP2215, and pharmaceutically acceptable salts thereof. Other exemplary suitable Flt-3 inhibitors include compounds as disclosed in WO03 / 037347, WO03 / 099771, and WO04 / 046120, and pharmaceutically acceptable salts thereof.

[0281] Exemplary suitable RAF inhibitors include dabrafenib, sorafenib, and vemurafenib, and pharmaceutically acceptable salts thereof. Other exemplary suitable RAF inhibitors include compounds as disclosed in WO00 / 09495 and WO05 / 028444, and pharmaceutically acceptable salts thereof.

[0282] Exemplary suitable FAK inhibitors include VS-4718, VS-5095, VS-6062, VS-6063, BI853520, and GSK2256098, and pharmaceutically acceptable salts thereof. Other exemplary suitable FAK inhibitors include compounds as disclosed in WO04 / 080980, WO04 / 056786, WO03 / 024967, WO01 / 064655, WO00 / 053595, and WO01 / 014402, and pharmaceutically acceptable salts thereof.

[0283] Exemplary suitable CDK4 / 6 inhibitors include palbociclib, ribociclib, trilaciclib, ribociclib, and abemaciclib, and pharmaceutically acceptable salts thereof. Other exemplary suitable CDK4 / 6 inhibitors include compounds as disclosed in WO09 / 085185, WO12 / 129344, WO11 / 101409, WO03 / 062236, WO10 / 075074, and WO12 / 061156, and pharmaceutically acceptable salts thereof.

[0284] In some embodiments, the compounds of the present disclosure can be used in combination with one or more other kinase inhibitors, including imatinib, to treat patients who are particularly resistant to imatinib or other kinase inhibitors.

[0285] In some embodiments, the compounds of the present disclosure can be used in combination with chemotherapeutic agents in the treatment of cancer, and can improve the treatment response compared to the response to the chemotherapeutic agent alone without worsening its toxic effects. In some embodiments, the compounds of the present disclosure can be used in combination with the chemotherapeutic agents provided herein. For example, additional pharmaceuticals used in the treatment of multiple myeloma may include, but are not limited to, melphalan, melphalan and prednisone [MP], doxorubicin, dexamethasone, and Velcade (bortezomib). Further additional agents used in the treatment of multiple myeloma include Bcr-Abl, Flt-3, RAF, and FAK kinase inhibitors. In some embodiments, this agent is an alkylating agent, a proteasome inhibitor, a corticosteroid, or an immunomodulatory agent. Examples of alkylating agents include cyclophosphamide (CY), melphalan (MEL), and bendamustine. In some embodiments, the proteasome inhibitor is carfilzomib. In some embodiments, the corticosteroid is dexamethasone (DEX). In some embodiments, the immunomodulatory agent is lenalidomide (LEN) or pomalidomide (POM). An additive or synergistic effect is a desirable result of combining the CDK2 inhibitor of the present disclosure with an additional agent.

[0286] The agent can be combined with the present compound in a single or continuous dosage form, or the agent can be administered simultaneously or sequentially as a separate dosage form.

[0287] The compounds of the present disclosure can be used in combination with one or more other inhibitors or one or more therapies for the treatment of infectious diseases. Examples of infectious diseases include viral infections, bacterial infections, fungal infections, or parasitic infections.

[0288] In some embodiments, a corticosteroid such as dexamethasone is administered to a patient in combination with a compound of the present disclosure, wherein dexamethasone is administered intermittently rather than continuously.

[0289] A compound of formula (I) or any of the formulas as described herein, a compound listed in any of the claims and as described herein, or a salt thereof, can be combined with another immunogenic substance such as cancerous cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells transfected with a gene encoding an immunostimulatory cytokine. Non-limiting examples of tumor vaccines that can be used include peptides of gp100, MAGE antigens, Trp-2, MART1, and / or peptides of melanoma antigens such as tyrosinase, or tumor cells transfected to express the cytokine GM-CSF.

[0290] A compound of formula (I) or any of the formulas as described herein, a compound listed in any of the claims and as described herein, or a salt thereof, can be used in combination with a vaccination protocol for the treatment of cancer. In some embodiments, the tumor cells are transduced to express GM-CSF. In some embodiments, the tumor vaccine comprises proteins from viruses such as human papillomavirus (HPV), hepatitis viruses (HBV and HCV), and Kaposi's sarcoma herpesvirus (KHSV) that are associated with human cancers. In some embodiments, the compounds of the present disclosure can be used in combination with tumor-specific antigens such as heat shock proteins isolated from the tumor tissue itself. In some embodiments, a compound of formula (I) or any of the formulas as described herein, a compound listed in any of the claims and as described herein, or a salt thereof, can be combined with immunization of dendritic cells to activate a strong anti-tumor response.

[0291] The compounds of the present disclosure can be used in combination with a bispecific macrocyclic peptide that targets Fe alpha or Fe gamma receptor-expressing effector cells to tumor cells. The compounds of the present disclosure can also be combined with a macrocyclic peptide that activates the host's immune responsiveness.

[0292] In some further embodiments, the combination of the compounds of the present disclosure with other therapeutic agents can be administered to a patient before, during, and / or after bone marrow transplantation or stem cell transplantation. The compounds of the present disclosure can be used in combination with bone marrow transplantation for the treatment of various tumors of hematopoietic origin.

[0293] A compound of formula (I) or of any of the formulas described herein, a compound listed in any of the claims and described herein, or a salt thereof can be used in combination with a vaccine to stimulate an immune response against pathogens, toxins, and autoantigens. Examples of pathogens for which this therapeutic approach may be particularly useful include pathogens for which there is currently no effective vaccine, or pathogens for which the effectiveness of conventional vaccines is not fully satisfactory. These include, but are not limited to, HIV, hepatitis (type A, B, and C), influenza, herpes, giardia, malaria, leishmania, Staphylococcus aureus, Pseudomonas Aeruginosa.

[0294] Viruses that cause infectious diseases treatable by the methods of the present disclosure include, but are not limited to, human papillomavirus, influenza, hepatitis A, B, C, or D virus, adenovirus, poxvirus, herpes simplex virus, human cytomegalovirus, severe acute respiratory syndrome virus, Ebola virus, measles virus, herpes virus (e.g., VZV, HSV-1, HAV-6, HSV-II, and CMV, Epstein-Barr virus), flavivirus, echovirus, rhinovirus, coxsackievirus, coronavirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum contagiosum virus, poliovirus, rabies virus, JC virus, and arbovirus encephalitis virus.

[0295] Pathogenic bacteria that cause infectious diseases treatable by the methods of the present disclosure include, but are not limited to, Chlamydia, Rickettsia bacteria, Mycobacteria, staphylococci, streptococci, pneumococci, meningococci, and conococci, Klebsiella, Proteus, Serratia, Pseudomonas, Legionella, diphtheria, Salmonella, Bacillus, cholera, tetanus, botulism, anthrax, plague, leptospirosis, and Lyme disease bacteria.

[0296] Pathogenic fungi that cause infectious diseases treatable by the methods of the present disclosure include, but are not limited to, Candida (albicans, krusei, glabrata, tropicalis, etc.), Cryptococcus neoformans, Aspergillus (fumigatus, niger, etc.), Mucorales genus (mucor, absidia, rhizophus), Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis, and Histoplasma capsulatum.

[0297] Pathogenic parasites that cause infectious diseases treatable by the methods of the present disclosure include, but are not limited to, Entamoeba histolytica, Balantidium coli, Naegleriafowleri, Acanthamoeba species, Giardia lambia, Cryptosporidium species, Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondi, and Nippostrongylus brasiliensis.

[0298] When more than one pharmaceutical is administered to a patient, they can be administered simultaneously, separately, sequentially, or in combination (e.g., in the case of more than two agents).

[0299] Methods for administering most of these chemotherapeutic agents safely and effectively are known to those skilled in the art. In addition, their administration is described in standard literature. For example, for the administration of many of the chemotherapeutic agents, it is described in the "Physicians’ Desk Reference" (PDR, e.g., 1996 edition, Medical Economics Company, Montvale, NJ), and the disclosure of this document is incorporated herein by reference as if the whole were set forth herein.

[0300] II. Immune Checkpoint Therapy The compounds of the present disclosure can be used in combination with one or more immune checkpoint inhibitors for the treatment of diseases such as cancer or infectious diseases. Exemplary immune checkpoint inhibitors include inhibitors against immune checkpoint molecules such as CBL-B, CD20, CD28, CD40, CD70, CD122, CD96, CD73, CD47, CDK2, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, HPK1, CD137 (also known as 4-1BB), ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, TLR (TLR7 / 8), TIGIT, CD112R, VISTA, PD-1, PD-L1, and PD-L2. In some embodiments, the immune checkpoint molecule is a stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS, OX40, GITR, and CD137. In some embodiments, the immune checkpoint molecule is an inhibitory checkpoint molecule selected from A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, TIGIT, and VISTA. In some embodiments, the compounds provided herein can be used in combination with one or more agents selected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors, and TGFR beta inhibitors.

[0301] In some embodiments, the compounds provided herein can be used in combination with one or more agonists of immune checkpoint molecules, such as OX40, CD27, GITR, and CD137 (also known as 4-1BB).

[0302] In some embodiments, the inhibitor of the immune checkpoint molecule is an anti-PD1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

[0303] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of PD-1 or PD-L1, such as an anti-PD-1 or anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-1 or anti-PD-L1 antibody is nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, semaprimab, atezolizumab, avelumab, tislelizumab, spartalizumab (PDR001), cetrelimab (JNJ-63723283), toripalimab (JS001), camrelizumab (SHR-1210), sintilimab (IBI308), AB122 (GLS-010), AMP-224, AMP-514 / MEDI-0680, BMS936559, JTX-4014, BGB-108, SHR-1210, MEDI4736, FAZ053, BCD-100, KN035, CS1001, BAT1306, LZM009, AK105, HLX10, SHR-1316, CBT-502 (TQB2450), A167 (KL-A167), STI-A101 (ZKAB001), CK-301, BGB-A333, MSB-2311, HLX20, TSR-042, or LY3300054. In some embodiments, the inhibitor of PD-1 or PD-L1 is disclosed in U.S. Patent Nos. 7,488,802, 7,943,743, 8,008,449, 8,168,757, 8,217,149, WO03042402, WO2008156712, WO2010089411, WO2010036959, WO2011066342, WO2011159877, WO2011082400, or WO2011161699, each of which is incorporated herein by reference in its entirety.

[0304] In some embodiments, the antibody is an anti-PD-1 antibody, e.g., an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 antibody is nivolumab, pembrolizumab, semiprilimab, spartalizumab, camrelizumab, cetrelimab, tripalimab, sintilimab, AB122, AMP-224, JTX-4014, BGB-108, BCD-100, BAT1306, LZM009, AK105, HLX10, or TSR-042. In some embodiments, the anti-PD-1 antibody is nivolumab, pembrolizumab, semiprilimab, spartalizumab, camrelizumab, cetrelimab, tripalimab, or sintilimab. In some embodiments, the anti-PD-1 antibody is pembrolizumab. In some embodiments, the anti-PD-1 antibody is nivolumab. In some embodiments, the anti-PD-1 antibody is semiprilimab. In some embodiments, the anti-PD-1 antibody is spartalizumab. In some embodiments, the anti-PD-1 antibody is camrelizumab. In some embodiments, the anti-PD-1 antibody is cetrelimab. In some embodiments, the anti-PD-1 antibody is tripalimab. In some embodiments, the anti-PD-1 antibody is sintilimab. In some embodiments, the anti-PD-1 antibody is AB122. In some embodiments, the anti-PD-1 antibody is AMP-224. In some embodiments, the anti-PD-1 antibody is JTX-4014. In some embodiments, the anti-PD-1 antibody is BGB-108. In some embodiments, the anti-PD-1 antibody is BCD-100. In some embodiments, the anti-PD-1 antibody is BAT1306. In some embodiments, the anti-PD-1 antibody is LZM009. In some embodiments, the anti-PD-1 antibody is AK105. In some embodiments, the anti-PD-1 antibody is HLX10. In some embodiments, the anti-PD-1 antibody is TSR-042. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab or pembrolizumab. In some embodiments, the anti-PD-1 monoclonal antibody is MGA012. In some embodiments, the anti-PD1 antibody is SHR-1210.Other anti-cancer agent(s) include antibody therapeutics such as 4-1BB, for example, urelumab, utomilumab. In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of PD-L1, for example, an anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is atezolizumab, avelumab, durvalumab, tislelizumab, BMS-935559, MEDI4736, atezolizumab (MPDL3280A (also known as RG7446)), avelumab (MSB0010718C), FAZ053, KN035, CS1001, SHR-1316, CBT-502, A167, STI-A101, CK-301, BGB-A333, MSB-2311, HLX20, or LY3300054. In some embodiments, the anti-PD-L1 antibody is atezolizumab, avelumab, durvalumab, or tislelizumab. In some embodiments, the anti-PD-L1 antibody is atezolizumab. In some embodiments, the anti-PD-L1 antibody is avelumab. In some embodiments, the anti-PD-L1 antibody is durvalumab. In some embodiments, the anti-PD-L1 antibody is tislelizumab. In some embodiments, the anti-PD-L1 antibody is BMS-935559. In some embodiments, the anti-PD-L1 antibody is MEDI4736. In some embodiments, the anti-PD-L1 antibody is FAZ053. In some embodiments, the anti-PD-L1 antibody is KN035. In some embodiments, the anti-PD-L1 antibody is CS1001. In some embodiments, the anti-PD-L1 antibody is SHR-1316. In some embodiments, the anti-PD-L1 antibody is CBT-502. In some embodiments, the anti-PD-L1 antibody is A167. In some embodiments, the anti-PD-L1 antibody is STI-A101. In some embodiments, the anti-PD-L1 antibody is CK-301. In some embodiments, the anti-PD-L1 antibody is BGB-A333. In some embodiments, the anti-PD-L1 antibody is MSB-2311. In some embodiments, the anti-PD-L1 antibody is HLX20. In some embodiments, the anti-PD-L1 antibody is LY3300054.

[0305] In some embodiments, the inhibitor of the immune checkpoint molecule is a small molecule that binds to PD-L1, or a pharmaceutically acceptable salt thereof. In some embodiments, the inhibitor of the immune checkpoint molecule is a small molecule that binds to PD-L1 and internalizes it, or a pharmaceutically acceptable salt thereof. In some embodiments, the inhibitor of the immune checkpoint molecule is a compound selected from those in US2018 / 0179201, US2018 / 0179197, US2018 / 0179179, US2018 / 0179202, US2018 / 0177784, US2018 / 0177870, US Patent Application No. 16 / 369,654 (filed on March 29, 2019), and US Patent Application No. 62 / 688,164, each of which is incorporated herein by reference in its entirety.

[0306] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of KIR, TIGIT, LAIR1, CD160, 2B4, and TGFR beta.

[0307] In some embodiments, the inhibitor is MCLA-145.

[0308] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of CTLA-4, such as an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab, tremelimumab, AGEN1884, or CP-675,206.

[0309] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of LAG3, such as an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody is BMS-986016, LAG525, INCAGN2385, or eftilagimod alpha (IMP321).

[0310] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of CD73. In some embodiments, the inhibitor of CD73 is oleclumab.

[0311] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of TIGIT. In some embodiments, the inhibitor of TIGIT is OMP-31M32.

[0312] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of VISTA. In some embodiments, the inhibitor of VISTA is JNJ-61610588 or CA-170.

[0313] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of B7-H3. In some embodiments, the inhibitor of B7-H3 is enoblituzumab, MGD009, or 8H9.

[0314] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of KIR. In some embodiments, the inhibitor of KIR is lirilumab or IPH4102.

[0315] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of A2aR. In some embodiments, the inhibitor of A2aR is CPI-444.

[0316] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of TGF-beta. In some embodiments, the inhibitor of TGF-beta is trabedersen, galusertinib, or M7824.

[0317] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of PI3K-gamma. In some embodiments, the inhibitor of PI3K-gamma is IPI-549.

[0318] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of CD47. In some embodiments, the inhibitor of CD47 is Hu5F9-G4 or TTI-621.

[0319] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of CD73. In some embodiments, the inhibitor of CD73 is MEDI9447.

[0320] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of CD70. In some embodiments, the inhibitor of CD70 is cosatuzumab or BMS-936561.

[0321] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of TIM3, such as an anti-TIM3 antibody. In some embodiments, the anti-TIM3 antibody is INCAGN2390, MBG453, or TSR-022.

[0322] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of CD20, such as an anti-CD20 antibody. In some embodiments, the anti-CD20 antibody is obinutuzumab or rituximab.

[0323] In some embodiments, the agonist of the immune checkpoint molecule is an agonist of OX40, CD27, CD28, GITR, ICOS, CD40, TLR7 / 8, and CD137 (also known as 4-1BB).

[0324] In some embodiments, the agonist of CD137 is urelumab. In some embodiments, the agonist of CD137 is utomilumab.

[0325] In some embodiments, the agonist of the immune checkpoint molecule is an inhibitor of GITR. In some embodiments, the agonist of GITR is TRX518, MK-4166, INCAGN1876, MK-1248, AMG228, BMS-986156, GWN323, MEDI1873, or MEDI6469. In some embodiments, the agonist of the immune checkpoint molecule is an agonist of OX40, for example, an OX40 agonist antibody or an OX40L fusion protein. In some embodiments, the anti-OX40 antibody is INCAGN01949, MEDI0562 (tavolimab), MOXR-0916, PF-04518600, GSK3174998, BMS-986178, or 9B12. In some embodiments, the OX40L fusion protein is MEDI6383.

[0326] In some embodiments, the agonist of the immune checkpoint molecule is an agonist of CD40. In some embodiments, the agonist of CD40 is CP-870893, ADC-1013, CDX-1140, SEA-CD40, RO7009789, JNJ-64457107, APX-005M, or Chi Lob 7 / 4.

[0327] In some embodiments, the agonist of the immune checkpoint molecule is an agonist of ICOS. In some embodiments, the agonist of ICOS is GSK-3359609, JTX-2011, or MEDI-570.

[0328] In some embodiments, the agonist of the immune checkpoint molecule is an agonist of CD28. In some embodiments, the agonist of CD28 is seralizumab.

[0329] In some embodiments, the agonist of the immune checkpoint molecule is an agonist of CD27. In some embodiments, the agonist of CD27 is balstilimab.

[0330] In some embodiments, the agonist of the immune checkpoint molecule is an agonist of TLR7 / 8. In some embodiments, the agonist of TLR7 / 8 is MEDI9197.

[0331] The compounds of the present disclosure can be used in combination with bispecific antibodies. In some embodiments, one of the domains of the bispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3, CD137, ICOS, CD3, or the TGFβ receptor. In some embodiments, the bispecific antibody binds to PD-1 and PD-L1. In some embodiments, the bispecific antibody that binds to PD-1 and PD-L1 is MCLA-136. In some embodiments, the bispecific antibody binds to PD-L1 and CTLA-4. In some embodiments, the bispecific antibody that binds to PD-L1 and CTLA-4 is AK104.

[0332] In some embodiments, the compounds of the present disclosure can be used in combination with one or more metabolic enzyme inhibitors. In some embodiments, the metabolic enzyme inhibitor is an inhibitor of IDO1, TDO, or arginase. Examples of IDO1 inhibitors include epacadostat, NLG919, BMS-986205, PF-06840003, IOM2983, RG-70099, and LY338196.

[0333] As provided throughout, additional compounds, inhibitors, agents, etc. can be combined with the present compounds in a single or continuous dosage form, or they can be administered simultaneously or sequentially as separate dosage forms.

[0334] Pharmaceutical formulations and dosage forms When used as a pharmaceutical, the compounds of the present disclosure can be administered in the form of a pharmaceutical composition. These compositions can be prepared in a manner well known in the pharmaceutical art and can be administered by various routes depending on whether local treatment is desired or systemic treatment is desired and on the area to be treated. Administration can be local (including transdermal, epithelial, ocular, and to mucous membranes including intranasal, intravaginal, and rectal delivery), pulmonary (e.g., by inhalation or insufflation of a powder or aerosol including by nebulizer; intratracheal or intranasal), oral, or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or injection or infusion; or intracranial, e.g., intrathecal or intraventricular administration. Parenteral administration can be in the form of a single bolus dose or, for example, by continuous perfusion pump. Pharmaceutical compositions and formulations for local administration can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, solutions, and powders. Conventional pharmaceutical carriers, aqueous, powder, or oily bases, thickeners, etc. may be required or desirable.

[0335] The present disclosure also includes pharmaceutical compositions containing a compound of the present disclosure or a pharmaceutically acceptable salt thereof as an active ingredient in combination with one or more pharmaceutically acceptable carriers (excipients). In some embodiments, the composition is suitable for local administration. In preparing the compositions of the present disclosure, the active ingredient is typically admixed with, diluted by, or enclosed within such a carrier in the form of, for example, capsules, sachets, paper, or other containers. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, troches, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), e.g., ointments containing up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0336] When preparing the formulation, the active compound can be milled to provide an appropriate particle size before being combined with other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water-soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, for example, about 40 mesh.

[0337] The compounds of the present disclosure may be milled using known milling procedures such as wet milling to obtain an appropriate particle size for tablet formation and other formulation types. Fine divided (nanoparticle) preparations of the compounds of the present disclosure can be prepared by processes known in the art, see, for example, International Application No. WO2002 / 000196.

[0338] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. The formulation can additionally include lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl benzoate and propyl hydroxybenzoate; sweetening agents; and flavoring agents. The compositions of the present disclosure can be formulated to provide rapid, sustained, or delayed release of the active ingredient after administration to a patient by using procedures known in the art.

[0339] The composition can be formulated in unit dosage form, with each dosage containing about 5 to about 1000 mg (1 g), or more, of the active ingredient, for example, about 100 to about 500 mg. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of the active material calculated to produce the desired therapeutic effect in association with a suitable pharmaceutical excipient.

[0340] In some embodiments, the compositions of the present disclosure contain from about 5 to about 50 mg of the active ingredient. One of ordinary skill in the art will understand that this encompasses compositions containing from about 5 to about 10, about 10 to about 15, about 15 to about 20, about 20 to about 25, about 25 to about 30, about 30 to about 35, about 35 to about 40, about 40 to about 45, or about 45 to about 50 mg of the active ingredient.

[0341] In some embodiments, the compositions of the present disclosure contain from about 50 to about 500 mg of the active ingredient. One of ordinary skill in the art will understand that this encompasses compositions containing from about 50 to about 100, about 100 to about 150, about 150 to about 200, about 200 to about 250, about 250 to about 300, about 350 to about 400, or about 450 to about 500 mg of the active ingredient.

[0342] In some embodiments, the compositions of the present disclosure contain from about 500 to about 1000 mg of the active ingredient. One of ordinary skill in the art will understand that this encompasses compositions containing from about 500 to about 550, about 550 to about 600, about 600 to about 650, about 650 to about 700, about 700 to about 750, about 750 to about 800, about 800 to about 850, about 850 to about 900, about 900 to about 950, or about 950 to about 1000 mg of the active ingredient.

[0343] In the methods and uses of the present disclosure, similar dosages of the compounds described herein may be used.

[0344] The active compounds can be effective over a wide dosage range and are generally administered in a pharmaceutically effective amount. However, the amount of the compound actually administered will typically be determined by the physician according to relevant circumstances including the condition to be treated, the selected route of administration, the actual compound being administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms.

[0345] When preparing solid compositions such as tablets, the main active ingredient is mixed with pharmaceutical excipients to form a solid preformulation composition containing a uniform mixture of the compounds of the present disclosure. When these preformulation compositions are referred to as uniform, the active ingredient is typically uniformly dispersed throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above containing, for example, from about 0.1 to about 1000 mg of the active ingredient of the present disclosure.

[0346] The tablets or pills of the present disclosure can be coated or otherwise formulated to provide dosage forms that afford the advantages of a long-term action. For example, a tablet or pill can include inner dosage and outer dosage components, the latter being in the form of a coating that covers the former. These two components can be separated by an enteric layer that resists disintegration in the stomach and functions to allow the inner component to pass intact into the duodenum or to delay its release. A variety of materials can be used for such enteric layers or coatings, including some polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0347] Liquid forms in which the compounds and compositions of the present disclosure can be incorporated for oral or injectable administration include aqueous solutions, preferably flavored syrups, aqueous or oily suspensions, and emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0348] Compositions for inhalation or insufflation include solutions and suspensions, and powders, in a pharmaceutically acceptable aqueous or organic solvent, or mixtures thereof. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the compositions are administered via the oral or nasal respiratory route for local or systemic effects. The compositions can be nebulized by use of an inert gas. The nebulized solution may be inhaled directly from the nebulizing device, or the nebulizing device can be attached to a face mask, tent, or intermittent positive pressure breathing apparatus. Solutions, suspensions, or powder compositions can be administered orally or nasally from a device that delivers the formulation in a suitable manner.

[0349] Topical formulations can contain one or more conventional carriers. In some embodiments, an ointment can contain water and one or more hydrophobic carriers selected, for example, from liquid paraffin, polyoxyethylene alkyl ethers, propylene glycol, white petrolatum, and the like. The carrier composition of a cream can be based on water combined with glycerol and one or more other constituents, such as glycerol monostearate, PEG-glycerol monostearate, and cetylstearyl alcohol. A gel can be formulated using isopropyl alcohol and water, suitably combined with other constituents such as glycerol, hydroxyethylcellulose, and the like. In some embodiments, the topical formulation contains at least about 0.1, at least about 0.25, at least about 0.5, at least about 1, at least about 2, or at least about 5 weight % of the compounds of the present disclosure. The topical formulation can be suitably packaged, for example, in a 100 g tube, which is optionally associated with instructions regarding the indication selected, for example, the treatment of psoriasis or other skin pathologies.

[0350] The amount of the compound or composition administered to a patient will vary depending on what is being administered, the purpose of administration such as prophylaxis or treatment, the condition of the patient, the mode of administration, etc. For therapeutic use, the composition can be administered in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications in a patient already suffering from the disease. The effective dose will depend on the clinical judgment of the attending physician according to factors such as the condition being treated, as well as the severity of the disease, the age, weight, and general condition of the patient, etc.

[0351] The composition administered to a patient can be in the form of the pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques or can be sterile filtered. Aqueous solutions can be packaged for use as is or can be lyophilized, and the lyophilized preparation is combined with a sterile aqueous carrier prior to administration. The pH of the preparation of the compound will typically be from 3 to 11, more preferably from 5 to 9, and most preferably from 7 to 8. It will be understood that the use of certain of the excipients, carriers, or stabilizers described above can result in the formation of pharmaceutical salts.

[0352] The therapeutic dosage of the compounds of the present disclosure can vary, for example, depending on the particular use for which the treatment is being carried out, the mode of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of the compounds of the present disclosure in the pharmaceutical composition can vary depending on several factors including the dosage, chemical nature (e.g., hydrophobicity), and route of administration. For example, the compounds of the present disclosure can be provided in a physiologically buffered aqueous solution containing from about 0.1 to about 10 w / v% of the compound for parenteral administration. Some typical dosage ranges are from about 1 μg / kg body weight to about 1 g / kg body weight per day. In some embodiments, the dosage range is from about 0.01 mg / kg body weight to about 100 mg / kg body weight per day. The dosage can be influenced by variable factors such as the type and degree of progression of the disease or disorder, the overall health of the particular patient, the biological effect ratio of the selected compound, the formulation form of the excipient, and its route of administration. The effective dose can be extrapolated from a dose-response curve derived from in vitro or animal model test systems.

[0353] The compositions of the present disclosure can further include one or more additional pharmaceuticals such as chemotherapeutic agents, steroids, anti-inflammatory compounds, or immunosuppressive agents, examples of which are listed herein.

[0354] Labeled Compounds and Assay Methods Another aspect of the present disclosure relates to labeled compounds (radiolabels, fluorescent labels, etc.) of the present disclosure that are useful not only in imaging techniques but also in in vitro and in vivo assays to identify and quantify the location of CDK2 in tissue samples, including human, by the inhibitory binding of the labeled compound, and to identify CDK2 activators. Substitution of one or more of the atoms of the compounds of the present disclosure may also be useful in creating differentiated ADME (absorption, distribution, metabolism, and excretion). Accordingly, the present disclosure includes CDK2 assays containing such labeled or substituted compounds.

[0355] The present disclosure further includes isotopically labeled compounds of the present disclosure. An "isotopic" or "radiolabeled" compound is one in which one or more atoms in the compounds of the present disclosure have been replaced or substituted with atoms having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring). Suitable radionuclides that can be incorporated into the compounds of the present disclosure include 2 H (also described as D representing deuterium), 3 H (also described as T representing tritium), 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 18 F, 35 S, 36 Cl, 82 Br, 75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I, and 131I is included, but not limited thereto. For example, one or more hydrogen atoms in the compounds of the present disclosure may be replaced with deuterium atoms (e.g., replacing CH3 with -CD3, etc., C of formula (I)) 1-6 One or more hydrogen atoms of the alkyl group may optionally be replaced with deuterium atoms). In some embodiments, the alkyl groups of the disclosed formula (e.g., formula (I)) may be fully perdeuterated.

[0356] One or more constituent atoms of the compounds presented herein may be replaced or substituted with isotopes of natural or non-natural abundant atoms. In some embodiments, the compound contains at least one deuterium atom. For example, one or more hydrogen atoms in the compounds presented herein may be replaced or substituted with deuterium atoms (e.g., replacing -CH3 with -CD3, etc., C) 1-6 One or more hydrogen atoms of the alkyl group may be replaced with deuterium atoms). In some embodiments, the compound contains two or more deuterium atoms. In some embodiments, the compound contains 1 - 2, 1 - 3, 1 - 4, 1 - 5, or 1 - 6 deuterium atoms. In some embodiments, all of the hydrogen atoms in the compound may be replaced or substituted with deuterium atoms.

[0357] In some embodiments, such as described herein, alkyl, alkenyl, alkynyl, aryl, phenyl, cycloalkyl, heterocycloalkyl, or heteroaryl substituents, or -C 1-4 One, two, three, four, five, six, seven, or eight hydrogen atoms bonded to the carbon atoms of the alkyl-, alkylene-, alkenylene-, and alkynylene linking groups may optionally be replaced with deuterium atoms.

[0358] Synthetic methods for incorporating isotopes into organic compounds are known in the art (Deuterium Labeling in Organic Chemistry by Alan F. Thomas, New York, N.Y., Appleton-Century-Crofts, 1971; The Renaissance of H / D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistry of Isotopic Labelling by James R. Hanson, Royal Society of Chemistry, 2011). Isotopically labeled compounds can be used in various studies such as NMR spectroscopy, metabolic experiments, and / or assays.

[0359] Substitution with heavier isotopes such as deuterium can result in certain therapeutic advantages arising from greater metabolic stability, such as increased in vivo half-life or reduced required dosage, and may therefore be preferred in some situations. (See, for example, A. Kerekes et al. J. Med. Chem. 2011, 54, 201-210; R. Xu et al. J. Label Compd. Radiopharm. 2015, 58, 308-312). In particular, substitution at one or more metabolic sites can result in one or more of the therapeutic advantages.

[0360] The radionuclide incorporated into the radiolabeled compound will depend on the specific use of the radiolabeled compound. For example, in the case of in vitro CDK2 labeling and competitive assays, 3 H, 14 C, 82 Br, 125 I, 131 I, or 35 S-incorporating compounds may be useful. For imaging applications using radiation, 11 C, 18 F, 125 I,123 I、 124 I、 131 I、 75 Br、 76 Br, or 77 Br may be useful.

[0361] It is understood that a "radiolabel" or "labeled compound" is a compound incorporating at least one radionuclide. In some embodiments, the radionuclide is 3 H, 14 C, 125 I, 35 S, and 82 selected from the group consisting of Br.

[0362] The present disclosure can further include synthetic methods for incorporating radioisotopes into the compounds of the present disclosure. Synthetic methods for incorporating radioisotopes into organic compounds are well known in the art, and one of ordinary skill in the art will readily recognize methods applicable to the compounds of the present disclosure.

[0363] The labeled compounds of the present disclosure can be used in screening assays to identify / evaluate compounds. For example, a labeled, newly synthesized or identified compound (i.e., a test compound) can be evaluated for its ability to bind to and activate CDK2 by monitoring its concentration fluctuations when contacted with CDK2 through tracking of the label. For example, a test compound (labeled) can be evaluated for its ability to reduce the binding of another compound known to inhibit CDK2 (i.e., a standard compound). Thus, the ability of a test compound to compete with a standard compound for binding to CDK2 is directly correlated with its binding affinity. Conversely, in some other screening assays, the standard compound is labeled and the test compound is unlabeled. Thus, to evaluate the competition between the standard compound and the test compound, the concentration of the labeled standard compound is monitored and the relative binding affinity of the test compound is thereby confirmed.

[0364] Kit The present disclosure also includes a pharmaceutical kit useful in the treatment or prevention of CDK2-related diseases or disorders (e.g., cancer, inflammatory diseases, cardiovascular diseases, or neurodegenerative diseases, etc.), which comprises one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present disclosure. As will be readily apparent to those skilled in the art, such a kit can further comprise one or more of the components of various conventional pharmaceutical kits, such as, if desired, containers containing one or more pharmaceutically acceptable carriers, additional containers, etc. Instructions in the form of either a package insert or a label indicating the amounts of the components to be administered, guidelines for administration, and / or guidelines for mixing the components can also be included in the kit.

[0365] Biomarkers and pharmacodynamic markers The present disclosure further provides predictive markers (e.g., biomarkers and pharmacodynamic markers, such as gene copy number, gene sequence, expression level, or phosphorylation level) for identifying a human subject having, suspected of having, or at risk of developing a CDK2-related disease or disorder in which administration of a CDK2 inhibitor (as used herein, "CDK2 inhibitor" refers to a compound of the present disclosure, or a pharmaceutically acceptable salt thereof) is likely to be effective. The present disclosure also provides pharmacodynamic markers (e.g., phosphorylation level) for identifying a human subject having, suspected of having, or at risk of developing a CDK2-related disease or disorder who is responsive to a CDK2 inhibitor. The use of CCNE1, p16, and Rb S780 is further described in WO2020 / 168178 (and U.S. Application No. 16 / 791,561), the figures and disclosure of which are incorporated herein by reference in their entirety.

[0366] The method is based, at least in part, on the discovery that the functional status of cyclin-dependent kinase inhibitor 2A (“CDKN2A” (also referred to as “p16”)) is a biomarker for predicting sensitivity to CDK2-targeted therapy in G1 / S-specific cyclin-E1- (“CCNE1-”) amplified cells, which is suitable for use in patient stratification. In addition, the present invention is based, at least in part, on the discovery that in CCNE1-amplified cell lines, the level of phosphorylation of human retinoblastoma-associated protein (“Rb”) at serine corresponding to amino acid position 780 of SEQ ID NO: 3 is a pharmacodynamic marker for CDK2 activity and is suitable for use, for example, in cell assays or in the measurement of CDK2 enzyme activity in preclinical and clinical applications, such as monitoring the progression or responsiveness to treatment with a CDK2 inhibitor.

[0367] CCNE1 and p16 CCNE1 and p16 were identified in examples as genes useful in predicting responsiveness (e.g., improvement of a disease as evidenced by disease remission / dissipation) to a CDK2 inhibitor in a subject having a disease or disorder associated with CDK2 when combined.

[0368] p16 (also known as cyclin-dependent kinase inhibitor 2A, cyclin-dependent kinase 4 inhibitor A, multiple tumor suppressor 1, and p16-INK4a) acts as a negative regulator of normal cell proliferation by interacting with CDK4 and CDK6. p16 is encoded by the cyclin-dependent kinase inhibitor 2A (「CDKN2A」) gene (GenBank accession number NM_000077). The cytogenic location of the CDKN2A gene is 9p21.3, which is the short (p) arm of chromosome 9, position 21.3. The molecular location of the CDKN2A gene is base pairs 21,967,752 to 21,995,043 on chromosome 9 (Homo sapiens Annotation Release 109, GRCh38.p12). Genetic and epigenetic abnormalities in the gene encoding p16 are thought to lead to escape from senescence and carcinogenesis (Okamoto et al., 1994, PNAS 91(23):11045-9). Non-limiting examples of genetic abnormalities in the gene encoding p16 are described in Table A below. The amino acid sequence of human p16 is provided below (GenBank accession number NP_000068 / UniProtKB accession number P42771). [Chemical formula]

[0369] CCNE1 is a cell cycle factor essential for the control of the cell cycle at the G1 / S transition (Ohtsubo et al., 1995, Mol. Cell. Biol. 15:2612-2624). CCNE1 acts as a regulatory subunit of CDK2, which interacts with CDK2 to form a serine / threonine kinase holoenzyme complex. The CCNE1 subunit of this holoenzyme complex provides the substrate specificity of the complex (Honda et al., 2005, EMBO 24:452-463). CCNE1 is encoded by the cyclin E1 (「CCNE1」) gene (GenBank accession number NM_001238). The amino acid sequence of human CCNE1 is provided below (GenBank accession number NP_001229 / UniProtKB accession number P24864).

Chemical formula

[0370] The examples demonstrate that CDK2 knockdown inhibits the growth of CCNE1-amplified cell lines but not the growth of CCNE1 non-amplified cell lines. Conversely, the examples show that CDK4 / 6 inhibition inhibits the growth of CCNE1 non-amplified cell lines but not the growth of CCNE1-amplified cell lines. The examples further demonstrate that the presence of a normal (e.g., non-mutated or non-deleted) p16 gene is required for the observed inhibition of cell growth in CCNE1-amplified cells treated with a CDK2 inhibitor. Thus, CCNE1 and p16 together are a combination biomarker. That is, cells that respond to treatment with a CDK2 inhibitor exhibit amplification of the CCNE1 gene and / or an expression level of CCNE1 that is higher than the control expression level of CCNE1, and have a nucleotide sequence (e.g., a gene or mRNA) encoding the p16 protein (e.g., the p16 protein comprising the amino acid sequence of SEQ ID NO: 1) and / or the presence of the p16 protein, while control cells that do not respond to treatment with a CDK2 inhibitor do not have amplification of the CCNE1 gene and / or an expression level of CCNE1 that is higher than the control expression level of CCNE1, and have a mutation or deletion of the gene encoding the p16 protein and / or tend to lack expression of the p16 protein.

[0371] Accordingly, the present disclosure provides a method of treating a human subject having, suspected of having, or at risk of developing a CDK2-related disease or disorder, the method comprising administering a CDK2 inhibitor to the human subject, wherein the human subject has (i) (a) a nucleotide sequence encoding a p16 protein comprising the amino acid sequence of SEQ ID NO: 1, (b) a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions, and / or (c) expresses a p16 protein, and (ii) (a) has an amplification of the CCNE1 gene, and / or (b) has been previously determined to have a CCNE1 expression level in a biological sample obtained from the human subject that is higher than the control expression level of CCNE1. In certain embodiments, the prediction method described herein predicts that a subject will respond to treatment with a CDK2 inhibitor with at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or 100% accuracy. For example, in some embodiments, the prediction method described herein is applied to 10 subjects having, suspected of having, or at risk of developing a CDK2-related disease or disorder, and based on the prediction method described herein, 8 of those 10 subjects are predicted to respond to treatment with a CDK2 inhibitor, and if 7 of those 8 subjects actually respond to treatment with a CDK2 inhibitor, this prediction method has an accuracy of 87.5% (7 divided by 8). A subject is considered to respond to a CDK2 inhibitor if the subject exhibits some improvement in the disease state as evidenced, for example, by reduction or alleviation of symptoms, disease remission / dissipation, etc.

[0372] In some embodiments, the subject has a disease or disorder associated with CDK2. In some embodiments, the human subject has (i) (a) a nucleotide sequence encoding a p16 protein comprising the amino acid sequence of SEQ ID NO: 1, and / or (b) a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions, and (ii) has previously been determined to have amplification of the CCNE1 gene in a biological sample obtained from the human subject. In some embodiments, the CDKN2A gene encodes a protein comprising the amino acid sequence of SEQ ID NO: 1. In a specific embodiment, the CDKN2A gene encodes a protein comprising the amino acid sequence of SEQ ID NO: 1.

[0373] In a specific embodiment, one or more inactivating nucleic acid substitutions and / or deletions in the CDKN2A gene are as described in Table A. In a specific embodiment, one or more inactivating nucleic acid substitutions and / or deletions in the CDKN2A gene are as described in Yarbrough et al., Journal of the National Cancer Institute, 91(18):1569-1574, 1999, Liggett and Sidransky, Biology of Neoplasia, Journal of Oncology, 16(3):1197-1206, 1998, and Cairns et al., Nature Genetics, 11:210-212, 1995, each of which is incorporated herein by reference in its entirety.

Table 1-1

Table 1-2

Table 1-3

[0374] The present disclosure also addresses methods of treating a human subject having, suspected of having, or at risk of developing a disease or disorder associated with CDK2, the method comprising: (i) in a biological sample obtained from the human subject, identifying (a) a nucleotide sequence encoding a p16 protein comprising the amino acid sequence of SEQ ID NO: 1, (b) a CDKN2A gene lacking one or more inactivating nucleic acid substitutions, and / or (c) the presence of the p16 protein; (ii) in a biological sample obtained from the human subject, identifying (a) amplification of the CCNE1 gene and / or (b) an expression level of CCNE1 that is higher than a control expression level of CCNE1; and (iii) administering a CDK2 inhibitor to the human subject. In some embodiments, the subject has a disease or disorder associated with CDK2. In some embodiments, the subject is suspected of having or at risk of developing a disease or disorder associated with CDK2. In some embodiments, the method comprises: (i) in a biological sample obtained from the human subject, identifying (a) a nucleotide sequence encoding a p16 protein comprising the amino acid sequence of SEQ ID NO: 1, (b) a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions, and / or (c) the presence of the p16 protein; (ii) in a biological sample obtained from the human subject, identifying amplification of the CCNE1 gene; and (iii) administering a CDK2 inhibitor to the human subject.

[0375] The present disclosure also addresses a method for predicting the response of a human subject having, suspected of having, or at risk of developing a disease or disorder associated with CDK2 to a CDK2 inhibitor, the method comprising: (i) determining from a biological sample obtained from the human subject, (a) the nucleotide sequence of the CDKN2A gene, (b) the presence of the CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions, and / or (c) the presence of the p16 protein; and (ii) determining from a biological sample obtained from the human subject, (a) the copy number of the CCNE1 gene and / or (b) the expression level of CCNE1, wherein (1) (a) the presence of the CDKN2A gene encoding the p16 protein comprising the amino acid sequence of SEQ ID NO: 1, (b) the presence of the CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions, and / or (c) the presence of the p16 protein, and (2) (a) amplification of the CCNE1 gene and / or (b) an expression level of CCNE1 that is higher than the control expression level of CCNE1 predict that the human subject will respond to a CDK2 inhibitor. In some embodiments, the subject has a disease or disorder associated with CDK2. In some embodiments, the subject is suspected of having, or at risk of developing, a disease or disorder associated with CDK2. In some embodiments, the method comprises: (i) determining from a biological sample obtained from the human subject, (a) the nucleotide sequence of the CDKN2A gene and / or (b) the presence of the CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions; and (ii) determining from a biological sample obtained from the human subject, (a) the copy number of the CCNE1 gene, wherein (1) (a) the presence of the CDKN2A gene encoding the p16 protein comprising the amino acid sequence of SEQ ID NO: 1 and / or (b) the presence of the CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions, and (2) (a) amplification of the CCNE1 gene predict that the human subject will respond to a CDK2 inhibitor.

[0376] In a specific embodiment, the determination of (i) (a) the nucleotide sequence of the CDKN2A gene, (b) the presence of the CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions, and / or (c) the presence of the p16 protein is carried out before administering a CDK2 inhibitor to a human subject (e.g., at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 2 weeks, at least 3 weeks, or at least 4 weeks, or 6 hours to 16 hours, 6 hours to 20 hours, or 6 hours to 24 hours, 2 days to 3 days, 2 days to 4 days, 2 days to 5 days, 2 days to 6 days, 2 days to 7 days, 1 week to 2 weeks, 1 week to 3 weeks, or 1 week to 4 weeks before). In a specific embodiment, the determination of (ii) (a) the copy number of the CCNE1 gene and / or (b) the expression level of CCNE1 in a biological sample obtained from a human subject is carried out before administering a CDK2 inhibitor to a human subject (e.g., at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 2 weeks, at least 3 weeks, or at least 4 weeks, or 6 hours to 16 hours, 6 hours to 20 hours, or 6 hours to 24 hours, 2 days to 3 days, 2 days to 4 days, 2 days to 5 days, 2 days to 6 days, 2 days to 7 days, 1 week to 2 weeks, 1 week to 3 weeks, or 1 week to 4 weeks before).

[0377] The amplification of the CCNE1 gene and / or the expression level of CCNE1 that is higher than the control expression level of CCNE1, in combination with the presence of the CDKN2A gene encoding the p16 protein containing the amino acid sequence of SEQ ID NO: 1, the presence of the CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions, and / or the presence of the p16 protein (e.g., the p16 protein containing the amino acid sequence of SEQ ID NO: 1) indicates / predicts that a human subject having, suspected of having, or at risk of developing a disease or disorder related to CDK2 will respond to a CDK2 inhibitor.

[0378] In some embodiments, the CCNE1 gene is amplified to a gene copy number of 3 to 25. In a specific embodiment, the CCNE1 gene is amplified to a gene copy number of at least 3. In a specific embodiment, the CCNE1 gene is amplified to a gene copy number of at least 5. In a specific embodiment, the CCNE1 gene is amplified to a gene copy number of at least 7. In a specific embodiment, the CCNE1 gene is amplified to a gene copy number of at least 10. In a specific embodiment, the CCNE1 gene is amplified to a gene copy number of at least 12. In a specific embodiment, the CCNE1 gene is amplified to a gene copy number of at least 14. In a specific embodiment, the CCNE1 gene is amplified to a gene copy number of at least 21.

[0379] In a specific embodiment, the expression level of CCNE1 is at the level of CCNE1 mRNA. In a specific embodiment, the expression level of CCNE1 is at the level of CCNE1 protein.

[0380] In some embodiments of the above method, the expression level of control CCNE1 is a pre-set cut-off value. In some embodiments of the above method, the expression level of control CCNE1 is the expression level of CCNE1 in a sample(s) obtained from one or more subjects who did not respond to treatment with a CDK2 inhibitor.

[0381] In some embodiments of the above method, the expression level of CCNE1 is the expression level of CCNE1 mRNA. In some embodiments of the above method, the expression level of CCNE1 is the expression level of CCNE1 protein. In some embodiments where the expression level of CCNE1 is the expression level of CCNE1 mRNA, the expression level of CCNE1 is measured by RNA sequencing, quantitative polymerase chain reaction (PCR), in situ hybridization, nucleic acid array, or RNA sequencing. In some embodiments where the expression level of CCNE1 is the expression level of CCNE1 protein, the expression level of CCNE1 is measured by Western blot, enzyme-linked immunosorbent assay, or immunohistochemical staining.

[0382] Rb S780 The present disclosure also addresses a method for assessing the CDKN2A gene and the CCNE1 gene, the method comprising determining, from a biological sample(s) obtained from a human subject having a disease or disorder associated with CDK2, (i) (a) the nucleotide sequence of the CDKN2A gene, or (b) the presence of the CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions, and (ii) the copy number of the CCNE1 gene.

[0383] The present disclosure also addresses a method for evaluating the response of a human subject having, suspected of having, or at risk of developing a disease or disorder associated with CDK2 to a CDK2 inhibitor, the method comprising: (a) administering a CDK2 inhibitor to the human subject (wherein the human subject has previously been determined to have an amplification of the CCNE1 gene and / or an expression level of CCNE1 that is higher than the control expression level of CCNE1), and (b) measuring, in a biological sample obtained from the subject following the administration of step (a), the level of phosphorylation of the retinoblastoma (Rb) protein at serine corresponding to position 780 of amino acid of SEQ ID NO: 3, wherein a reduced level of Rb phosphorylation at serine corresponding to position 780 of amino acid of SEQ ID NO: 3 as compared to the control level of Rb phosphorylation at serine corresponding to position 780 of amino acid of SEQ ID NO: 3 indicates that the human subject responds to the CDK2 inhibitor. In some embodiments, the subject has a disease or disorder associated with CDK2. In some embodiments, the subject is suspected of having or at risk of developing a disease or disorder associated with CDK2. In some embodiments, the biological sample comprises a blood sample or a tumor biopsy sample.

[0384] Phosphorylation of Rb at serine corresponding to position 780 of amino acid of SEQ ID NO: 3 (referred to herein as "Ser780" or "S780") was identified in an example as a pharmacodynamic marker useful in assessing the responsiveness (e.g., inhibition by CDK2) of a human subject having a disease or disorder with CCNE1 amplification to a CDK2 inhibitor.

[0385] Rb is a cell cycle regulator and acts as a tumor suppressor. Rb is activated when phosphorylated by cyclin D-CDK4 / 6 at Ser780 and Ser795 and by cyclin E / CDK2 at Ser807 and Ser811. Rb is encoded by the RB transcriptional corepressor 1 (「RB1」) gene (GenBank accession number NM_000321). The amino acid sequence of human Rb is provided below (GenBank accession number NP_000312 / UniProtKB accession number P06400) (S780 is in bold and underlined).

Chemical formula

[0386] As described above, the examples demonstrate that CDK2 knockdown inhibits proliferation in CCNE1-amplified cell lines but not in CCNE1-nonamplified cell lines. The examples further demonstrate that CDK2 knockdown or inhibition blocks Rb phosphorylation at S780 in CCNE1-amplified cell lines but not in CCNE1-nonamplified cell lines. Thus, Rb phosphorylation at the serine corresponding to amino acid position 780 of SEQ ID NO: 3 is a pharmacodynamic marker for assessing the response to CDK2 inhibition in CCNE1-amplified cancer cells or in patients with a disease or disorder having amplification of CCNE1. Accordingly, provided herein is a method for using the level of Rb phosphorylation at the serine corresponding to amino acid position 780 of SEQ ID NO: 3 as a marker for indicating the response of a human subject having, suspected of having, or at risk of developing a disease or disorder associated with CDK2 to a CDK2 inhibitor in the human subject, wherein the human subject has an increased expression level of CCNE1.

[0387] Accordingly, the present disclosure is concerned with a method for measuring the amount of protein in a sample, the method comprising: (a) providing a biological sample obtained from a human subject having a disease or disorder associated with CDK2; and (b) measuring the level of phosphorylation of the Rb protein at serine corresponding to position 780 of SEQ ID NO: 3 in the biological sample. In some embodiments, the biological sample comprises a blood sample or a tumor biopsy sample. In a specific embodiment, there is provided herein a method for evaluating the response of a human subject having, suspected of having, or at risk of developing a disease or disorder associated with CDK2 to a CDK2 inhibitor, the method comprising: (a) administering a CDK2 inhibitor to the human subject (wherein the human subject has previously been determined to have an amplification of the CCNE1 gene and / or an expression level of CCNE1 that is higher than the control expression level of CCNE1); and (b) measuring, in a biological sample obtained from the human subject following the administration of step (a), the level of Rb phosphorylation at serine corresponding to position 780 of SEQ ID NO: 3, wherein a reduced level of Rb phosphorylation at serine corresponding to position 780 of SEQ ID NO: 3 as compared to the control level of Rb phosphorylation at serine corresponding to position 780 of SEQ ID NO: 3 indicates that the human subject responds to the CDK2 inhibitor. In a specific embodiment, the human subject has a disease or disorder associated with CDK2.

[0388] Reduced levels of Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO: 3, compared to control levels of Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO: 3, in combination with amplification of the CCNE1 gene and / or an expression level of CCNE1 that is higher than the control expression level of CCNE1, indicates that a human subject having, suspected of having, or at risk of developing a CDK2-related disease or disorder responds to a CDK2 inhibitor. For example, in a subject having amplification of the CCNE1 gene and / or an expression level of CCNE1 that is higher than the control expression level of CCNE1, the presence of low (e.g., reduced compared to control) or undetectable levels of Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO: 3 in a biological sample obtained from the subject after treatment with a CDK2 inhibitor indicates that the subject responds to the CDK2 inhibitor.

[0389] (i) Amplification of the CCNE1 gene and / or an expression level of CCNE1 that is higher than the control expression level of CCNE1, and (ii) the presence of the CDKN2A gene encoding a p16 protein comprising the amino acid sequence of SEQ ID NO: 1, the presence of the CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions, and / or the presence of the p16 protein (e.g., a p16 protein comprising the amino acid sequence of SEQ ID NO: 1), in combination with a biological sample obtained from a subject after administration of a CDK2 inhibitor to the subject having a reduced level of Rb phosphorylation at serine corresponding to position 780 of the amino acid sequence of SEQ ID NO: 3 as compared to the control level of Rb phosphorylation at serine corresponding to position 780 of the amino acid sequence of SEQ ID NO: 3 indicates that a human subject having, suspected of having, or at risk of developing a disease or disorder associated with CDK2 responds to the CDK2 inhibitor. For example, in a human subject having (i) amplification of the CCNE1 gene and / or an expression level of CCNE1 that is higher than the control expression level of CCNE1, and (ii) the presence of the CDKN2A gene encoding a p16 protein comprising the amino acid sequence of SEQ ID NO: 1, the presence of the CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions, and / or the presence of the p16 protein (e.g., a p16 protein comprising the amino acid sequence of SEQ ID NO: 1), a biological sample obtained from the human subject after administration of a CDK2 inhibitor to the subject having a low (e.g., reduced compared to the control) or undetectable level of Rb phosphorylation at serine corresponding to position 780 of the amino acid sequence of SEQ ID NO: 3 indicates that the human subject responds to the CDK2 inhibitor.

[0390] In some embodiments, the CCNE1 gene is amplified to a gene copy number of 3 to 25. In a specific embodiment, the CCNE1 gene is amplified to a gene copy number of at least 3. In a specific embodiment, the CCNE1 gene is amplified to a gene copy number of at least 5. In a specific embodiment, the CCNE1 gene is amplified to a gene copy number of at least 7. In a specific embodiment, the CCNE1 gene is amplified to a gene copy number of at least 10. In a specific embodiment, the CCNE1 gene is amplified to a gene copy number of at least 12. In a specific embodiment, the CCNE1 gene is amplified to a gene copy number of at least 14. In a specific embodiment, the CCNE1 gene is amplified to a gene copy number of at least 21. In a specific embodiment, the expression level of CCNE1 is at the level of CCNE1 mRNA. In a specific embodiment, the expression level of CCNE1 is at the level of CCNE1 protein.

[0391] Control As described above, methods related to biomarkers and pharmacodynamic markers may involve measuring one or more markers (e.g., a biomarker or a pharmacodynamic marker, such as amplification of the CCNE1 gene, the expression level of CCNE1, the presence of the CDKN2A gene encoding the p16 protein comprising the amino acid sequence of SEQ ID NO: 1, the presence of the CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions, the presence of the p16 protein (e.g., the p16 protein comprising the amino acid sequence of SEQ ID NO: 1), and Rb phosphorylation at serine corresponding to position 780 of SEQ ID NO: 3) in a biological sample from a human subject having, suspected of having, or at risk of developing a disease or disorder associated with CDK2. In a specific embodiment, the human subject has a disease or disorder associated with CDK2. In a specific embodiment, the human subject is suspected of having or is at risk of developing a disease or disorder associated with CDK2. In certain aspects, the level of one or more biomarkers (e.g., amplification (e.g., for the CCNE1 gene), expression level (e.g., for CCNE1 or the p16 protein), or phosphorylation level (e.g., for Rb)) compared to the control level of the one or more biomarkers predicts / indicates the response of the human subject to treatment with a CDK2 inhibitor. In certain specific embodiments, the human subject is identified as likely to respond to a CDK2 inhibitor if (i) the CCNE1 gene is amplified and / or the expression level of CCNE1 is higher than the control expression level of CCNE1, and (ii) the CDKN2A gene encoding the p16 protein comprising the amino acid sequence of SEQ ID NO: 1 is present, the CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions is present, and / or the p16 protein (e.g., the p16 protein comprising the amino acid sequence of SEQ ID NO: 1) is present.In another embodiment, a human subject is identified as responsive to a CDK2 inhibitor if (i) the CCNE1 gene is amplified and / or the expression level of CCNE1 is higher than the control expression level of CCNE1, and (ii) the level of Rb phosphorylation at serine corresponding to position 780 of amino acid of SEQ ID NO: 3 in a biological sample from the human subject after administration of the CDK2 inhibitor is less than the control level of Rb phosphorylation at serine corresponding to position 780 of amino acid of SEQ ID NO: 3. In yet another embodiment, a human subject is identified as responsive to a CDK2 inhibitor if (i) the CCNE1 gene is amplified and / or the expression level of CCNE1 is higher than the control expression level of CCNE1, (ii) the CDKN2A gene encoding a p16 protein comprising the amino acid sequence of SEQ ID NO: 1 is present, the CDKN2A gene is absent of one or more inactivating nucleic acid substitutions and / or deletions, and / or the p16 protein (e.g., the p16 protein comprising the amino acid sequence of SEQ ID NO: 1) is present, and (iii) the level of Rb phosphorylation at serine corresponding to position 780 of amino acid of SEQ ID NO: 3 in a biological sample from the human subject after administration of the CDK2 inhibitor is less than the control level of Rb phosphorylation at serine corresponding to position 780 of amino acid of SEQ ID NO: 3. In this context, the term "control" includes samples (from the same tissue type) obtained from human subjects known not to respond to the CDK2 inhibitor. The term "control" also includes samples (from the same tissue type) that are used as a reference for future comparison to test samples obtained from human subjects that were obtained in the past from human subjects known not to respond to the CDK2 inhibitor and for which therapeutic responsiveness is to be predicted. The "control" level (e.g., gene copy number, expression level, or phosphorylation level) for a particular biomarker (e.g., CCNE1, p16, or Rb phosphorylation) in a particular cell type or tissue may be pre-set by analysis of biomarker levels (e.g., expression level or phosphorylation level) in one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, or 40, or more) human subjects who did not respond to treatment with the CDK2 inhibitor.Next, this pre-set reference value (which can be the average or median of levels (e.g., gene copy number, expression level, or phosphorylation level) obtained from multiple human subjects who did not respond to treatment) may be used as the "control" level of a biomarker (e.g., CCNE1, p16, or Rb phosphorylation) in comparison with a test sample. In such a comparison, a human subject is predicted to respond to a CDK2 inhibitor if (i) the CCNE1 gene is amplified and / or the expression level of CCNE is higher than the pre-set reference, and (ii) there is a CDKN2A gene encoding a p16 protein containing the amino acid sequence of SEQ ID NO: 1, without one or more inactivating nucleic acid substitutions and / or deletions, and / or there is a p16 protein (e.g., a p16 protein containing the amino acid sequence of SEQ ID NO: 1). In another such comparison, a human subject is predicted to respond to a CDK2 inhibitor if (i) the CCNE1 gene is amplified and / or the expression level of CCNE is higher than the pre-set reference, and (ii) after administration of a CDK2 inhibitor to the human subject, the level of Rb phosphorylation at serine corresponding to position 780 of SEQ ID NO: 3 is lower than the pre-set reference. In yet another such comparison, a human subject is shown to respond to a CDK2 inhibitor if (i) the CCNE1 gene is amplified and / or the expression level of CCNE is higher than the pre-set reference, (ii) there is a CDKN2A gene encoding a p16 protein containing the amino acid sequence of SEQ ID NO: 1, without one or more inactivating nucleic acid substitutions and / or deletions, and / or there is a p16 protein (e.g., a p16 protein containing the amino acid sequence of SEQ ID NO: 1), and (iii) after administration of a CDK2 inhibitor to the human subject, the level of Rb phosphorylation at serine corresponding to position 780 of SEQ ID NO: 3 is lower than the pre-set reference.

[0392] The "control" level for a particular biomarker in a particular cell type or tissue may alternatively be pre-set by analysis of biomarker levels in one or more human subjects treated with a CDK2 inhibitor. This pre-set reference value, which may be an average or median of levels (e.g., expression levels or phosphorylation levels) obtained from multiple human subjects responsive to treatment, may then be used as the "control" level (e.g., expression level or phosphorylation level) in comparison with a test sample. In such a comparison, a human subject is shown to respond to a CDK2 inhibitor if the level of the biomarker being analyzed (e.g., copy number of the CCNE1 gene, expression level of CCNE1, expression level of p16, or phosphorylation level of Rb at serine corresponding to amino acid position 780 of SEQ ID NO: 3) is equal to or equivalent to (e.g., at least 85% but less than 115% of) the pre-set reference.

[0393] In certain embodiments, the "control" is a pre-set cut-off value. The cut-off value is typically a level of a biomarker (e.g., copy number, expression level, or phosphorylation level) above or below which is considered to be predictive of responsiveness of a human subject to a treatment of interest. Thus, according to the methods and compositions described herein, the reference level (e.g., CCNE1 gene copy number, CCNE1 expression, p16 expression, or Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO: 3) is identified as a cut-off value above or below which is predictive of responsiveness to a CDK2 inhibitor. The cut-off value determined for use in the methods described herein may be compared, for example, to published concentration ranges, but may be individualized according to the techniques used and the patient population.

[0394] In some embodiments, the expression level of CCNE1 is increased compared to the expression level of CCNE1 in the control. For example, the expression level of CCNE1 being analyzed may be at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 20-fold, at least 25-fold, at least 50-fold, at least 75-fold, or at least 100-fold higher than the expression level of CCNE1 in the control, or at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 200%, at least 300%, at least 400%, at least 500%, a...

Claims

1. Formula (I): 【Chemical Formula 1】 A compound of or a pharmaceutically acceptable salt thereof, wherein In the formula, n is 0, 1, 2, 3, or 4, p is 0, 1, 2, 3, or 4, 【Chemical Formula 2】 is a single bond or a double bond, X is N, Y is C, and the ring 【Chemical Formula 3】 is 【Chemical Formula 4】 or X is C, Y is N, and the ring 【Chemical Formula 5】 is 【Chemical Formula 6】 and Z is CR ２ or N, Ring moiety A is a 5- to 10-membered heteroaryl, Ring moiety B is a monocyclic 4- to 7-membered heterocycloalkyl, where ring moiety B is attached to the -NH- group of formula (I) at a ring member of the saturated or partially saturated ring of said monocyclic 4- to 7-membered heterocycloalkyl, R １is selected from H, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4- to 7-membered heterocycloalkyl-C₁₋₄ alkyl, 5- to 6-membered heteroaryl-C₁₋₄ alkyl, ORₐ₁, SRₐ₁, C(O)Rb₁, C(O)NRc₁Rd₁, C(O)ORₐ₁, OC(O)Rb₁, OC(O)NRc₁Rd₁, NRc₁Rd₁, NRc₁C(O)Rb₁, NRc₁C(O)ORₐ₁, NRc₁C(O)NRc₁Rd₁, NRc₁S(O)₂Rb₁, NRc₁S(O)₂NRc₁Rd₁, S(O)₂Rb₁, and S(O)₂NRc₁Rd₁, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4- to 7-membered heterocycloalkyl-C₁₋₄ alkyl, and 5- to 6-membered heteroaryl-C₁₋₄ alkyl may each be substituted with 1, 2, 3, or 4 independently selected R₁A substituents, Each of Ra1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl, and the C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl may each be substituted with 1, 2, 3, or 4 independently selected R1A substituents. Each of Rb1 is independently selected from C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl, and these may each be substituted with 1, 2, 3, or 4 independently selected R1A substituents. Each R1A is independently selected from H, D, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, 5-6 membered heteroaryl-C1-4 alkyl, ORa11, C(O)Rb11, C(O)NRc11Rd11, C(O)ORa11, OC(O)Rb11, OC(O)NRc11Rd11, NRc11Rd11, NRc11C(O)Rb11, NRc11C(O)ORa11, NRc11C(O)NRc11Rd11, NRc11S(O)2Rb11, NRc11S(O)2NRc11Rd11, S(O)2Rb11, and S(O)2NRc11Rd11, and the C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl may each be substituted with 1, 2, 3, or 4 independently selected R1B substituents. Each Ra11, Rc11, and Rd11 is independently selected from H, C1-6 alkyl, and C1-6 haloalkyl. Each Rb11 is independently selected from C1-6 alkyl and C1-6 haloalkyl. Each R1B is independently selected from H, D, and ORa12. Each Ra12 is independently selected from H and C1-6 alkyl. R ２is selected from H, halo, CN, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, OH, C1-3 alkoxy, C1-3 haloalkoxy, amino, C1-3 alkylamino, di(C1-3 alkyl)amino, cyano-C1-4 alkyl, HO-C1-4 alkyl, C1-3 alkoxy-C1-4 alkyl, and C3-4 cycloalkyl, each R ３ is independently selected from H, F, and methyl, R ４ is C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C ３－１０ cycloalkyl-C １－４ alkyl, 6-10 membered aryl-C １－４ alkyl, 4-10 membered heterocycloalkyl-C １－４ alkyl, and 5-10 membered heteroaryl-C １－４ alkyl, wherein the C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C ３－１０ cycloalkyl-C １－４ alkyl, 6-10 membered aryl-C １－４ alkyl, 4-10 membered heterocycloalkyl-C １－４ alkyl, and 5-10 membered heteroaryl-C １－４ alkyl may each be substituted with 1, 2, 3, or 4 independently selected R ４Ａ substituents, Each R4A is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, C3-4 cycloalkyl, ORa41, C(O)Rb41, C(O)NRc41Rd41, C(O)ORa41, OC(O)Rb41, OC(O)NRc41Rd41, NRc41Rd41, NRc41C(O)Rb41, NRc41C(O)ORa41, NRc41C(O)NRc41Rd41, NRc41S(O)2Rb41, NRc41S(O)2NRc41Rd41, S(O)2Rb41, and S(O)2NRc41Rd41, and the C1-6 alkyl, C1-6 haloalkyl, and C3-4 cycloalkyl may each be substituted with one, two, or three independently selected R4B substituents. Each Ra41, Rc41, and Rd41 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, and C3-4 cycloalkyl, and the C1-6 alkyl, C1-6 haloalkyl, and C3-4 cycloalkyl may each be substituted with one or two independently selected R4B substituents. Each Rb41 is independently selected from C1-6 alkyl, C1-6 haloalkyl, and C3-4 cycloalkyl, and these may each be substituted with one or two independently selected R4B substituents. Each R4B is independently selected from H, halo, CN, C1-3 alkyl, C1-3 haloalkyl, ORa42, and NRc42Rd42. Each Ra42, Rc42, and Rd42 is independently selected from H, C1-3 alkyl, and C1-3 haloalkyl. Each R ５ is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, C3-4 cycloalkyl, ORa5, and NRc5Rd5, and Each of Ra5, Rc5, and Rd5 is independently selected from H, C1-6 alkyl, and C1-6 haloalkyl. The compound, or a pharmaceutically acceptable salt thereof.

2. R １ is independently selected from H, halo, CN, C １－６ alkyl, C １－６ haloalkyl, C ３－７ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C ３－７ cycloalkyl-C １－３ alkyl, phenyl-C １－３ alkyl, 4-7 membered heterocycloalkyl-C １－３ alkyl, 5-6 membered heteroaryl-C １－３ alkyl, OR ａ１ SR ａ１ and NR ｃ１ R ｄ１ and is selected from the group consisting of, said C １－６ alkyl, C １－６ haloalkyl, C ３－７ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C ３－７ cycloalkyl-C １－３ alkyl, phenyl-C １－３ alkyl, 4-7 membered heterocycloalkyl-C １－３ alkyl, and 5-6 membered heteroaryl-C １－３ alkyl may each be substituted with one or two independently selected R １Ａ substituents, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

3. R １ is independently selected from H, C １－６ alkyl, phenyl, 5-7 membered heterocycloalkyl, OR ａ１ SR ａ１ and NR ｃ１ R ｄ１ and is selected from the group consisting of, said C １－６ alkyl, phenyl, and 5-7 membered heterocycloalkyl may each be substituted with one or two independently selected R １Ａ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which may be substituted with a substituent.

4. R １ is independently selected from H and OR ａ１ The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

5. Each R ａ１ 、R ｃ１ 、and R ｄ１ is independently selected from H, C １－６ alkyl, C １－６ haloalkyl, C ３－６ cycloalkyl, phenyl, 4- to 6-membered heterocycloalkyl, C ３－６ cycloalkyl-C １－３ alkyl, and 4- to 6-membered heterocycloalkyl-C １－３ alkyl, and the C １－６ alkyl, C １－６ haloalkyl, C ３－６ cycloalkyl, phenyl, 4- to 6-membered heterocycloalkyl, C ３－６ cycloalkyl-C １－３ alkyl, and 4- to 6-membered heterocycloalkyl-C １－３ alkyl may each be substituted with one, two, or three independently selected R １Ａ substituents, Each R ｂ１ is independently selected from C １－６ alkyl, C １－６ haloalkyl, C ３－６ cycloalkyl, 4- to 6-membered heterocycloalkyl, C ３－６ cycloalkyl-C １－２ alkyl, and 4- to 6-membered heterocycloalkyl-C １－２ alkyl, and these may each be substituted with one or two independently selected R １Ａ substituents, Each R １Ａ is independently selected from H, D, halo, CN, C １－６ alkyl, C １－６ haloalkyl, OR ａ１１ 、and C(O)OR ａ１１selected from, said C １－６ alkyl, and C １－６ haloalkyl may each be substituted with one, two, or three independently selected R １Ｂ substituents, each R ａ１１ is independently selected from H and C １－４ alkyl, said C １－４ alkyl may be substituted with one, two, or three independently selected R １Ｂ substituents, each R １Ｂ is independently selected from H, D, and O-C １－４ alkyl, The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

6. R １ is OR ａ１ and R ａ１ is C １－３ alkyl, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

7. R ２ is H or halo, the compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof.

8. R ２ is H or F, the compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof.

9. The ring moiety B is piperidinyl, the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.

10. n is 0 or 1, the compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof.

11. each R ３ is independently selected from H and methyl, the compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof.

12. R ４ is C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－７ cycloalkyl-C １－４ alkyl, phenyl-C １－４ alkyl, 4- to 7-membered heterocycloalkyl-C １－４ alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, selected from, said C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－７ cycloalkyl-C １－４ alkyl, phenyl-C １－４ alkyl, 4- to 7-membered heterocycloalkyl-C １－４ alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, each, 1, 2, 3, or 4 independently selected R ４Ａ substituted optionally by substituents, the compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof.

13. R ４ is C １－６ alkyl, C ３－６ cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl-C １－４ alkyl, selected from, said C １－６ alkyl, C ３－６ cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl-C １－４ alkyl, each, 1 or 2 independently selected R ４Ａ substituted optionally by substituents, the compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof.

14. R ４ is C １－６ alkyl and C ３－６ cycloalkyl, the compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof.

15. Each R ４Ａ is independently H, halo, CN, C １－６ alkyl, C １－６ haloalkyl, C ３－４ cycloalkyl, OR ａ４１ , C(O)R ｂ４１ , C(O)NR ｃ４１ R ｄ４１ , C(O)OR ａ４１ , OC(O)R ｂ４１ , OC(O)NR ｃ４１ R ｄ４１ , NR ｃ４１ R ｄ４１ , NR ｃ４１ C(O)R ｂ４１ , NR ｃ４１ C(O)OR ａ４１ , NR ｃ４１ C(O)NR ｃ４１ R ｄ４１ , NR ｃ４１ S(O) ２ R ｂ４１ , NR ｃ４１ S(O) ２ , NR ｃ４１ R ｄ４１ , S(O) ２ R ｂ４１ , and S(O) ２ , NR ｃ４１ R ｄ４１ selected from, Each R ａ４１ , R ｃ４１ , and R ｄ４１ is independently H, C １－３ alkyl, and C １－３ haloalkyl selected from, Each R ｂ４１ is independently C １－３ alkyl and C １－３ haloalkyl selected from, The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof.

16. Each R ４Ａ is independently selected from H, halo, CN, C １－６ alkyl, C １－６ haloalkyl, OR ａ４１ , and NR ｃ４１ R ｄ４１ and is selected from Each R ａ４１ , R ｃ４１ , and R ｄ４１ is independently selected from H, C １－３ alkyl, and C １－３ haloalkyl and is selected from Each R ｂ４１ is independently C １－３ alkyl The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof.

17. The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein the ring moiety A is a 5- to 6-membered heteroaryl.

18. The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein the ring moiety A is 1H-pyrrolo[2,3-b]pyridinyl, pyridinyl, or pyrazolyl.

19. The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein the ring moiety A is pyrazolyl.

20. The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein p is 0 or 1.

21. Each R ５ is independently selected from CH ３ or NH ２ and is selected from

22. n is 0, 1, or 2, p is 0, 1, or 2, the ring moiety A is a 5- to 10-membered heteroaryl, The ring moiety B is azetidinyl, pyrrolidinyl, or piperidinyl, R １ is H, halo, CN, C １－６ alkyl, C １－６ haloalkyl, C ３－６ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－６ cycloalkyl-C １－３ alkyl, phenyl-C １－３ alkyl, 4- to 7-membered heterocycloalkyl-C １－３ alkyl, 5- to 6-membered heteroaryl-C １－３ alkyl, OR ａ１ , SR ａ１ , and NR ｃ１ R ｄ１ and the C １－６ alkyl, C １－６ haloalkyl, C ３－６ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－６ cycloalkyl-C １－３ alkyl, phenyl-C １－３ alkyl, 4- to 7-membered heterocycloalkyl-C １－３ alkyl, and 5- to 6-membered heteroaryl-C １－３ alkyl may each be substituted with one, two, or three independently selected R １Ａ substituents, each R ａ１ , R ｃ１ , and R ｄ１ is independently selected from H, C １－６ alkyl, C １－６ haloalkyl, C ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, and C ３－７ cycloalkyl-C １－４ alkyl, and the C １－６ alkyl, C １－６ haloalkyl, C ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, and C ３－７ cycloalkyl-C １－４Each alkyl is independently selected from one, two, or three Rs １Ａ and may be substituted with substituents, each R １Ａ is independently H, halo, CN, C １－６ alkyl, C １－６ haloalkyl, C ３－４ cycloalkyl, OR ａ１１ , C(O)R ｂ１１ , C(O)NR ｃ１１ R ｄ１１ , C(O)OR ａ１１ , OC(O)R ｂ１１ , OC(O)NR ｃ１１ R ｄ１１ , NR ｃ１１ R ｄ１１ , NR ｃ１１ C(O)R ｂ１１ , NR ｃ１１ C(O)OR ａ１１ , NR ｃ１１ C(O)NR ｃ１１ R ｄ１１ , NR ｃ１１ , S(O) ２ R ｂ１１ , NR ｃ１１ , S(O) ２ , NR ｃ１１ R ｄ１１ , S(O) ２ R ｂ１１ , and S(O) ２ , NR ｃ１１ R ｄ１１ and is selected from, the C １－６ alkyl, C １－６ haloalkyl, and C ３－４ cycloalkyl may each be substituted with one, two, or three independently selected Rs １Ｂ and may be substituted with substituents, each R ａ１１ , R ｃ１１ , and R ｄ１１ is independently selected from H, C １－６ alkyl, and C １－６ haloalkyl, each R ｂ１１ is independently selected from C １－６ alkyl and C １－６ haloalkyl, each R １Ｂare independently H, D, and OR ａ１２ selected from each R ａ１２ is independently H and C １－６ selected from alkyl R ２ is H, halo, CN, C １－３ alkyl, and C １－３ selected from haloalkyl each R ３ is independently H, halo, C １－３ selected from alkyl and cyclopropyl R ４ is C １－６ alkyl, C １－６ haloalkyl, C ３－７ selected from cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl-C １－４ alkyl, wherein the C １－６ alkyl, C １－６ haloalkyl, C ３－７ selected from cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl-C １－４ alkyl may each be substituted with one or two independently selected R ４Ａ substituents each R ４Ａ is independently H, halo, CN, C １－６ alkyl, C １－６ haloalkyl, C ３－４ selected from cycloalkyl, OR ａ４１ , C(O)R ｂ４１ , C(O)NR ｃ４１ R ｄ４１ , C(O)OR ａ４１ , OC(O)R ｂ４１ , OC(O)NR ｃ４１ R ｄ４１ , NR ｃ４１ R ｄ４１ , NR ｃ４１ , C(O)R ｂ４１ , NR ｃ４１ , C(O)OR ａ４１ , NR ｃ４１ , C(O)NR ｃ４１ R ｄ４１ 、 NR ｃ４１ S(O) ２ R ｂ４１ 、 NR ｃ４１ S(O) ２ NR ｃ４１ R ｄ４１ 、 S(O) ２ R ｂ４１ 、 and S(O) ２ NR ｃ４１ R ｄ４１ selected from, said C １－６ alkyl, C １－６ haloalkyl, and C ３－４ cycloalkyl may each be substituted with one, two, or three independently selected R ４Ｂ substituents, each R ａ４１ 、 R ｃ４１ 、 and R ｄ４１ is independently selected from H, C １－６ alkyl, C １－６ haloalkyl, and C ３－４ cycloalkyl, said C １－６ alkyl, C １－６ haloalkyl, and C ３－４ cycloalkyl may each be substituted with one or two independently selected R ４Ｂ substituents, each R ｂ４１ is independently selected from C １－６ alkyl, C １－６ haloalkyl, and C ３－４ cycloalkyl, and these may each be substituted with one or two independently selected R ４Ｂ substituents, each R ４Ｂ is independently selected from H, halo, CN, C １－３ alkyl, C １－３ haloalkyl, OR ａ４２ 、 and NR ｃ４２ R ｄ４２ selected from, each R ａ４２ 、 R ｃ４２ 、 and R ｄ４２ is independently selected from H, C １－３ alkyl, and C １－３ haloalkyl selected from, Each R5 is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, C3-4 cycloalkyl, ORa5, and NRc5Rd5, and each Ra5, Rc5, and Rd5 is independently selected from H, C1-6 alkyl, and C1-6 haloalkyl, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

23. n is 0 or 1, p is 0 or 1, Ring moiety A is a 5- to 10-membered heteroaryl having one or two N ring-forming atoms, Ring moiety B is piperidinyl, R １ is independently selected from H, C １－６ alkyl, phenyl, 5- to 7-membered heterocycloalkyl, OR ａ１ , SR ａ１ , and NR ｃ１ R ｄ１ is selected from, the C １－６ alkyl, phenyl, and 5- to 7-membered heterocycloalkyl may each be substituted with one or two independently selected R １Ａ substituents, Each R ａ１ , R ｃ１ , and R ｄ１ is independently selected from H, C １－６ alkyl, C １－６ haloalkyl, C ３－６ cycloalkyl, phenyl, 4- to 6-membered heterocycloalkyl, C ３－６ cycloalkyl-C １－３ alkyl, and 4- to 6-membered heterocycloalkyl-C １－３ alkyl, the C １－６ alkyl, C １－６ haloalkyl, C ３－６ cycloalkyl, phenyl, 4- to 6-membered heterocycloalkyl, C ３－６ cycloalkyl-C １－３ alkyl, and 4- to 6-membered heterocycloalkyl-C １－３Each alkyl is independently selected from 1, 2, or 3 Rs １Ａ and may be substituted with each R １Ａ independently selected from D, halo, CN, C １－３ alkyl, C １－３ haloalkyl, C ３－４ cycloalkyl, OR ａ１１ , and C(O)OR ａ１１ wherein said C １－６ alkyl and C １－６ haloalkyl may each be independently substituted with 1, 2, or 3 Rs １Ｂ and may be substituted with each R ａ１１ independently selected from H and C １－４ alkyl, and said C １－４ alkyl may be independently substituted with 1, 2, or 3 Rs １Ｂ and may be substituted with each R １Ｂ independently selected from H, D, and O-C １－４ alkyl, R ２ is H or F, each R ３ is independently selected from H or methyl, R ４ is C １－６ alkyl, C ３－６ cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl-C １－４ alkyl, and said C １－６ alkyl, C ３－６ cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl-C １－４ alkyl may each be independently substituted with 1, 2, 3, or 4 Rs ４Ａ and may be substituted with each R ４Ａ is independently selected from H, C １－６ alkyl, OH, and NR ｃ４１ R ｄ４１ and is selected from each R ｃ４１ and R ｄ４１ is independently H, C １－６ alkyl, and C １－６ haloalkyl selected from each R ５ is independently H, halo, CN, C １－６ alkyl, C １－６ haloalkyl, C ３－４ cycloalkyl, OR ａ５ , and NR ｃ５ R ｄ５ selected from each R ａ５ , R ｃ５ , and R ｄ５ is independently H, C １－６ alkyl, and C １－６ haloalkyl selected from The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

24. n is 0 or 1, p is 0 or 1, the ring moiety A is a 5- to 10-membered heteroaryl having one or two N ring-forming atoms, the ring moiety B is piperidinyl, R １ is independently H and OR ａ１ selected from each R ａ１ is independently H, C １－６ alkyl, C １－６ haloalkyl, C ３－６ cycloalkyl, 4- to 6-membered heterocycloalkyl, C ３－６ cycloalkyl-C １－３ alkyl, and 4- to 6-membered heterocycloalkyl-C １－３ alkyl selected from, said C １－６ alkyl, C １－６ haloalkyl C ３－６ cycloalkyl, 4- to 6-membered heterocycloalkyl, C ３－６ cycloalkyl-C １－３ alkyl, and 4- to 6-membered heterocycloalkyl-C １－３ alkyl are each one or two independently selected R １Ａmay be substituted with a substituent, each R １Ａ is independently selected from C １－３ alkyl, C １－３ haloalkyl, C ３－４ cycloalkyl, OH, C １－３ alkoxy, and C １－３ haloalkoxy, R ２ is H or F, each R ３ is independently selected from H or methyl, R ４ is selected from C １－６ alkyl and C ３－６ cycloalkyl, wherein said C １－６ alkyl and C ３－６ cycloalkyl may each be substituted with one, two, three, or four independently selected R ４Ａ substituents, each R ４Ａ is independently selected from H and C １－６ alkyl, each R ５ is independently selected from H, halo, CN, C １－６ alkyl, C １－６ haloalkyl, C ３－４ cycloalkyl, OR ａ５ and NR ｃ５ R ｄ５ and each R ａ５ R ｃ５ and R ｄ５ is independently selected from H, C １－６ alkyl, and C １－６ haloalkyl, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

25. Formula (Va), or (Vb), or (Vc), or (Vd), 【Chemical Formula 7】 or a compound according to any one of claims 1 to 24 having any of the above pharmaceutically acceptable salts.

26. Formula (VIa), or (VIIa), or (VIIIa), or (IXa), [Chemical Formula 8] or a compound according to any one of claims 1 to 24 having any of the above pharmaceutically acceptable salts.

27. Formula (VIb), or (VIIIb), or (IXb), [Chemical Formula 9] or a compound according to any one of claims 1 to 24 having any of the above pharmaceutically acceptable salts.

28. Formula (VIc), or (VIIIc), or (IXc), [Chemical Formula 10] or a compound according to any one of claims 1 to 24 having any of the above pharmaceutically acceptable salts.

29. N-(1-(Methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, 8-Ethoxy-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, 8-Isobutoxy-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, 8-(Cyclopropylmethoxy)-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, N-(1-(Methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-8-((tetrahydro-2H-pyran-4-yl)oxy)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, 8-(2-Methoxyethoxy)-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, 6-Fluoro-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, N-(1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine, 8-(2,2-Difluoroethoxy)-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-8-(2,2,2-trifluoroethoxy)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-8-((tetrahydrofuran-3-yl)methoxy)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, 8-Ethoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, N-((3R,4S)-1-(cyclopropylsulfonyl)-3-methylpiperidin-4-yl)-8-ethoxy-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, 8-Isopropoxy-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine, 8-Isobutoxy-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrrolo[2,3-b]pyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, and 7-(2-Aminopyridin-4-yl)-8-isobutoxy-N-(1-(methylsulfonyl)piperidin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, a compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof.

30. 8-Ethoxy-7-(3-methyl-1H-pyrazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, Methyl 4-((2-(((1-(methylsulfonyl)piperidin-4-yl)amino)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)oxy)piperidine-1-carboxylate, (R)-1-(2-((((3R,4S)-4-((8-Ethoxy-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-3-methylpiperidin-1-yl)sulfonyl)ethyl)pyrrolidin-3-ol, 8-Ethoxy-N-((3R,4S)-3-methyl-1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, 8-Ethoxy-N-((3R,4S)-3-methyl-1-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, N-(1-(methylsulfonyl)piperidin-4-yl)-8-phenyl-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, 8-(4-Fluoropiperidin-1-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, N ２ -(1-(methylsulfonyl)piperidin-4-yl)-N ８ -phenyl-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine, 8-(4-Fluorophenyl)-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-8-(3-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, 8-Ethoxy-N-((3R,4S)-3-methyl-1-((3-(piperidin-1-yl)propyl)sulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, N-((3R,4S)-1-((3-(dimethylamino)propyl)sulfonyl)-3-methylpiperidin-4-yl)-8-ethoxy-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, 8-Ethoxy-N-((3R,4S)-3-methyl-1-((3-(pyrrolidin-1-yl)propyl)sulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-8-(4-(trifluoromethyl)piperidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, 8-(3-Fluoropiperidin-1-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, 8-Ethoxy-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine, 8-Isopropoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine, 8-(4-Methylpiperidin-1-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine, N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-8-(3-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine, 2-Fluoro-4-(2-(((1-(methylsulfonyl)piperidin-4-yl)amino)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl)benzonitrile, N-(1-(methylsulfonyl)piperidin-4-yl)-8-propyl-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, 8-Isopropoxy-N-((3R,4S)-3-methyl-1-((2-(pyrrolidin-1-yl)ethyl)sulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine, 8-((4,4-Difluorocyclohexyl)oxy)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, N-((3R,4S)-3-Methyl-1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-8-((tetrahydrofuran-3-yl)oxy)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, 8-(Ethoxy-d5)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, N-((3R,4S)-3-Methyl-1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-8-((tetrahydro-2H-pyran-4-yl)oxy)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, 8-Isopropoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, 8-Isobutoxy-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine, 8-(2,2-Difluoroethoxy)-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine, N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-8-(3,3,3-trifluoropropoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine, 8-Butoxy-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine, N-(1-(methylsulfonyl)piperidin-4-yl)-8-propoxy-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine, N-(1-(Methylsulfonyl)piperidin-4-yl)-8-(piperidin-1-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine, N-(3-Methyl-1-(methylsulfonyl)piperidin-4-yl)-8-(piperidin-1-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine, 8-(4-(2-Methoxyethyl)piperazin-1-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine, N-(1-(Methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-8-(pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine, N-((3R,4S)-1-(Cyclopropylsulfonyl)-3-methylpiperidin-4-yl)-8-isopropoxy-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine, N-((3R,4S)-1-(Ethylsulfonyl)-3-methylpiperidin-4-yl)-8-isopropoxy-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine, N-((3R,4S)-1-((3-(Ethyl(methyl)amino)propyl)sulfonyl)-3-methylpiperidin-4-yl)-8-isopropoxy-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine, N-((3R,4S)-1-((3-(Dimethylamino)propyl)sulfonyl)-3-methylpiperidin-4-yl)-8-isopropoxy-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine, 8-Isopropoxy-N-((3R,4S)-1-((3-(isopropyl(methyl)amino)propyl)sulfonyl)-3-methylpiperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine, 8-Isopropoxy-N-((3R,4S)-3-methyl-1-((3-(piperidin-1-yl)propyl)sulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine, 8-Isopropoxy-N-((3R,4S)-3-methyl-1-((3-(pyrrolidin-1-yl)propyl)sulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine, N-((3R,4S)-1-((3-(diethylamino)propyl)sulfonyl)-3-methylpiperidin-4-yl)-8-isopropoxy-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine, 8-Isopropoxy-N-((3R,4S)-3-methyl-1-((3-(4-methylpiperazin-1-yl)propyl)sulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine, N-((3R,4S)-1-((3-(4-ethylpiperazin-1-yl)propyl)sulfonyl)-3-methylpiperidin-4-yl)-8-isopropoxy-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine, 8-Isopropoxy-N-((3R,4S)-3-methyl-1-((4-morpholinobutyl)sulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine, N-((3R,4S)-1-((4-((2,2-difluoroethyl)amino)butyl)sulfonyl)-3-methylpiperidin-4-yl)-8-isopropoxy-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine, N-((3R,4S)-1-((4-(ethyl(methyl)amino)butyl)sulfonyl)-3-methylpiperidin-4-yl)-8-isopropoxy-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine, N-((3R,4S)-1-((4-(dimethylamino)butyl)sulfonyl)-3-methylpiperidin-4-yl)-8-isopropoxy-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine, N-((3R,4S)-1-((4-((R)-3-(difluoromethyl)pyrrolidin-1-yl)butyl)sulfonyl)-3-methylpiperidin-4-yl)-8-isopropoxy-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine, 5-isopropoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, 5-cyclobutoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, 5-isobutoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-5-propoxy-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, 5-(2,2-Difluoroethoxy)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-5-(2,2,3,3-tetrafluoropropoxy)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, 5-Cyclopropoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, 5-((3,3-Difluorocyclopentyl)oxy)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, 5-(Cyclobutylmethoxy)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, 5-(Cyclopentylmethoxy)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, N-(1-(Methylsulfonyl)piperidin-4-yl)-5-propoxy-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, 5-Isobutoxy-N-(1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, 5-(2,2-Difluoroethoxy)-N-(1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, N-(1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-5-(2,2,3,3-tetrafluoropropoxy)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, 5-(Cyclopropylmethoxy)-N-(1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-5-(piperidin-1-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, N-((3R,4S)-1-(ethylsulfonyl)-3-methylpiperidin-4-yl)-5-(piperidin-1-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, N-((3R,4S)-1-(cyclopropylsulfonyl)-3-methylpiperidin-4-yl)-5-(piperidin-1-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, N-((3R,4S)-3-methyl-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(piperidin-1-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, 5-Isopropoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolopyrazin-2-amine, N-((3R,4S)-1-(ethylsulfonyl)-3-methylpiperidin-4-yl)-5-isopropoxy-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine, N-((3R,4S)-1-(cyclopropylsulfonyl)-3-methylpiperidin-4-yl)-5-isopropoxy-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine, N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-5-((tetrahydro-2H-pyran-4-yl)oxy)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine, N-((3R,4S)-1-(ethylsulfonyl)-3-methylpiperidin-4-yl)-6-(1H-pyrazol-4-yl)-5-((tetrahydro-2H-pyran-4-yl)oxy)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine, N-((3R,4S)-1-(cyclopropylsulfonyl)-3-methylpiperidin-4-yl)-6-(1H-pyrazol-4-yl)-5-((tetrahydro-2H-pyran-4-yl)oxy)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine, 5-cyclobutoxy-N-((3R,4S)-1-(ethylsulfonyl)-3-methylpiperidin-4-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine, 5-cyclobutoxy-N-((3R,4S)-3-methyl-1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine, 5-cyclobutoxy-N-((3R,4S)-3-methyl-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine, N-((3R,4S)-1-(ethylsulfonyl)-3-methylpiperidin-4-yl)-5-isopropoxy-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, N-((3R,4S)-1-(cyclopropylsulfonyl)-3-methylpiperidin-4-yl)-5-isopropoxy-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-5-((tetrahydro-2H-pyran-4-yl)oxy)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, N-((3R,4S)-3-methyl-1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-5-((tetrahydro-2H-pyran-4-yl)oxy)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, 5-cyclobutoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolopyrazin-2-amine, 5-isobutoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolopyrazin-2-amine, N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-5-propoxy-6-(1H-pyrazol-4-yl)-[1,2,4]triazolopyrazin-2-amine, 5-butoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolopyrazin-2-amine, 5-Isobutoxy-N-(1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine, N-(1-(methylsulfonyl)piperidin-4-yl)-5-propoxy-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine, 5-Butoxy-N-(1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine, N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-5-(3-methylcyclobutoxy)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine, 5-(3-(Difluoromethyl)cyclobutoxy)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine, 5-Cyclopropoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine, 5-((4,4-Difluorocyclohexyl)oxy)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine, N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-5-((3-methyltetrahydro-2H-pyran-4-yl)oxy)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine, N-((3R,4S)-3-Methyl-1-(methylsulfonyl)piperidin-4-yl)-5-((2-methyltetrahydro-2H-pyran-4-yl)oxy)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine, N-((3R,4S)-3-Methyl-1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-5-((2-(trifluoromethyl)tetrahydro-2H-pyran-4-yl)oxy)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine, N-((3R,4S)-3-Methyl-1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-5-((1-(trifluoromethyl)cyclobutyl)methoxy)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine, 5-(Cyclopropylmethoxy)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine, 5-(Isopentyloxy)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine, 5-Cyclobutoxy-N-(1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine, 5-(3,3-Difluorocyclobutoxy)-N-(1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine, N-(1-(Methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-5-((2-(trifluoromethyl)tetrahydro-2H-pyran-4-yl)oxy)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine, N-(1-(Methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-5-((1-(trifluoromethyl)cyclobutyl)methoxy)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine, 5-(Isopentyloxy)-N-(1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine, 5-Ethoxy-N-(1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine, 5-(Ethylthio)-N-(1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine, 5-(Isopropylthio)-N-(1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine, N-((3R,4S)-3-Methyl-1-(methylsulfonyl)piperidin-4-yl)-5-(piperidin-1-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine, N-(1-(Methylsulfonyl)piperidin-4-yl)-5-(piperidin-1-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine, 5-(3,3-Difluoropiperidin-1-yl)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine, (R)-5-(3-Fluoropiperidin-1-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine, (S)-5-(3-Fluoropiperidin-1-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine, 5-(3,3-Difluoropyrrolidin-1-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine, 5-(2-Azabicyclo[2.2.1]heptan-2-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine, (S)-5-(2-Methylpiperidin-1-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine, (S)-5-(2-Methylpyrrolidin-1-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine, (S)-5-(3-(Difluoromethyl)pyrrolidin-1-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine, 5-(7-Azabicyclo[2.2.1]heptan-7-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine, N-(1-(Methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-5-(3-(trifluoromethyl)piperidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine, N-((3R,4S)-3-Methyl-1-(methylsulfonyl)piperidin-4-yl)-5-((propan-2-yl-2-d)oxy)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine, N-((3R,4S)-3-Methyl-1-(methylsulfonyl)piperidin-4-yl)-5-((propan-2-yl-1,1,1,3,3,3-d ６ )oxy)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine, N-((3R,4S)-3-Methyl-1-(methylsulfonyl)piperidin-4-yl)-5-((propan-2-yl-d ７ )oxy)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine, 5-(Cyclopentyloxy)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine, 5-Isopropoxy-N-(1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine, and N-(1-(methylsulfonyl)piperidin-4-yl)-5-((propan-2-yl-2-d)oxy)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine, A compound selected from the above, or a pharmaceutically acceptable salt thereof.

31. A compound which is 8-ethoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, or a pharmaceutically acceptable salt thereof.

32. A compound which is N-((3R,4S)-1-(cyclopropylsulfonyl)-3-methylpiperidin-4-yl)-8-ethoxy-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, or a pharmaceutically acceptable salt thereof.

33. A compound which is 8-isopropoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine, or a pharmaceutically acceptable salt thereof.

34. A compound which is 8-(ethoxy-d5)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, or a pharmaceutically acceptable salt thereof.

35. A compound which is 8-isopropoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine, or a pharmaceutically acceptable salt thereof.

36. A pharmaceutical composition comprising a compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

37. A pharmaceutical composition for inhibiting CDK2, comprising a compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof.

38. A pharmaceutical composition for use in the treatment of a disease or disorder associated with CDK2, comprising a compound according to any one of claims 1 to 35 or a pharmaceutically acceptable salt thereof, wherein the disease or disorder is related to amplification of the cyclin E1 (CCNE1) gene and / or overexpression of CCNE1, The disease or disorder is cancer. The pharmaceutical composition.

39. A pharmaceutical composition for use in treating a disease or disorder associated with cyclin-dependent kinase 2 (CDK2) in a human subject, comprising the compound according to any one of claims 1 to 35 or a pharmaceutically acceptable salt thereof, wherein the human subject (i) (a) has a nucleotide sequence encoding a p16 protein comprising the amino acid sequence of SEQ ID NO: 1 and / or (b) has a cyclin-dependent kinase inhibitor 2A (CDKN2A) gene lacking one or more inactivating nucleic acid substitutions and / or deletions, (ii) (a) has an amplification of the cyclin E1 (CCNE1) gene and / or (b) has an expression level of CCNE1 in a biological sample obtained from the human subject that is higher than the control expression level of CCNE1, as previously determined, The disease or disorder is cancer. The pharmaceutical composition.

40. A pharmaceutical composition for use in treating a disease or disorder associated with cyclin-dependent kinase 2 (CDK2) in a human subject, comprising the compound according to any one of claims 1 to 35 or a pharmaceutically acceptable salt thereof, wherein the treatment (i) in a biological sample obtained from the human subject, (a) identifying a nucleotide sequence encoding a p16 protein comprising the amino acid sequence of SEQ ID NO: 1 and / or (b) a cyclin-dependent kinase inhibitor 2A (CDKN2A) gene lacking one or more inactivating nucleic acid substitutions, (ii) in a biological sample obtained from the human subject, (a) an amplification of the cyclin E1 (CCNE1) gene and / or (b) identifying an expression level of CCNE1 that is higher than a control expression level of CCNE1; (iii) administering to the human subject a compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof; comprising wherein the disease or disorder is cancer; the pharmaceutical composition.

41. wherein the treatment is (i) in a biological sample obtained from the human subject, (a) a nucleotide sequence encoding a p16 protein comprising the amino acid sequence of SEQ ID NO: 1, and / or (b) a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions; identifying; (ii) in a biological sample obtained from the human subject, (a) identifying an amplification of the CCNE1 gene; (iii) administering the compound or the salt to the human subject; comprising the pharmaceutical composition according to claim 40.

42. A pharmaceutical composition for use in evaluating the response of a human subject having a disease or disorder associated with cyclin-dependent kinase 2 (CDK2), comprising a compound according to any one of claims 1 to 35 or a pharmaceutically acceptable salt thereof, wherein the evaluation is (a) administering the compound or the salt to the human subject, wherein the human subject has previously been determined to have an amplification of the cyclin E1 (CCNE1) gene and / or an expression level of CCNE1 that is higher than a control expression level of CCNE1; (b) measuring, in a biological sample obtained from the subject following the administration of step (a), the level of phosphorylation of the retinoblastoma (Rb) protein at serine corresponding to position 780 of amino acid of SEQ ID NO: 3; A reduced level of Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO: 3, as compared to the control level of Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO: 3, indicates that the human subject responds to the compound or the salt, wherein the disease or the disorder is cancer, the pharmaceutical composition.

43. The pharmaceutical composition according to any one of claims 38 to 42, wherein the cancer is selected from blood cancer, sarcoma, adenocarcinoma, urogenital cancer, liver cancer, nervous system cancer, gynecological cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, metastatic cancer, kidney cancer, prostate cancer, breast cancer, colon cancer, lung cancer, urothelial cancer, and gastrointestinal cancer.

44. Cancer is selected from melanoma, cutaneous malignant melanoma, intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, gastric cancer, testicular cancer, fallopian tube cancer, carcinoma of the endometrium, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, chronic leukemia, acute leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, pediatric solid tumors, lymphocytic lymphoma, bladder cancer, kidney cancer, renal pelvis cancer, central nervous system (CNS) neoplasms, primary CNS lymphoma, tumor angiogenesis, spinal axis tumors, brainstem gliomas, pituitary adenomas, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T cell lymphoma, environmentally induced cancer, cancer induced by asbestos, head and neck squamous cell carcinoma, cholangiocarcinoma, bile duct cancer, triple negative breast cancer, rhabdomyosarcoma, small cell lung cancer, leiomyosarcoma, hepatocellular carcinoma, Ewing's sarcoma, brain cancer, brain tumor, astrocytoma, neuroblastoma, neurofibroma, basal cell carcinoma, lung squamous cell carcinoma, lung adenocarcinoma, pancreatic adenocarcinoma, invasive breast cancer, uterine carcinosarcoma, ovarian serous cystadenocarcinoma, gastric adenocarcinoma, esophageal cancer, bladder urothelial carcinoma, chondrosarcoma, epitheloid sarcoma, eye cancer, fallopian tube cancer, gastrointestinal stromal tumor, hairy cell leukemia, intestinal cancer, pancreatic islet cell cancer, oral cancer, mouth cancer, throat cancer, laryngeal cancer, lip cancer, mesothelioma, cervical cancer, nasal cancer, ocular cancer, ocular melanoma, pelvic cancer, rectal cancer, renal cell carcinoma, salivary gland cancer, paranasal sinus cancer, spinal cancer, tongue cancer, tubular carcinoma, urethral cancer, ureteral cancer, and high frequency microsatellite instability (MSI 高 ) The pharmaceutical composition according to any one of claims 38 to 42, which is selected from the group consisting of

45. The pharmaceutical composition according to any one of claims 38 to 42, wherein the cancer is characterized by amplification or overexpression of CCNE1.

46. The pharmaceutical composition according to any one of claims 38 to 42, wherein the cancer is ovarian cancer.

47. The pharmaceutical composition according to claim 46, wherein the ovarian cancer is serous cystadenocarcinoma, mucinous cystadenocarcinoma, or an unclassifiable cancer.

48. The pharmaceutical composition according to any one of claims 38 to 42, wherein the cancer is breast cancer.

49. The pharmaceutical composition according to any one of claims 38 to 42, wherein the cancer is lung cancer.

50. The pharmaceutical composition according to claim 49, wherein the lung cancer is non-small cell lung cancer or small cell lung cancer.

51. The pharmaceutical composition according to any one of claims 38 to 42, wherein the cancer is fallopian tube cancer.

52. The pharmaceutical composition according to any one of claims 38 to 42, wherein the cancer is endometrial cancer.

53. The pharmaceutical composition according to any one of claims 38 to 42, wherein the cancer is gastrointestinal cancer.

54. The pharmaceutical composition according to any one of claims 38 to 42, wherein the cancer is uterine cancer.

55. The pharmaceutical composition according to any one of claims 38 to 42, wherein the cancer is urothelial cancer.

56. The pharmaceutical composition according to any one of claims 38 to 42, wherein the cancer is anal cancer.

57. The pharmaceutical composition according to any one of claims 38 to 42, wherein the cancer is cholangiocarcinoma.

58. The pharmaceutical composition according to any one of claims 38 to 42, wherein the cancer is small intestine cancer.

59. The pharmaceutical composition according to claim 58, wherein the small intestine cancer is adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, or fibroma.

60. The pharmaceutical composition according to any one of claims 38 to 42, wherein the cancer is colorectal cancer.

61. The pharmaceutical composition according to claim 60, wherein the colorectal cancer is adenocarcinoma, tubular adenoma, villous adenoma, hyperplastic polyp, or leiomyoma.

62. The pharmaceutical composition according to any one of claims 38 to 42, wherein the cancer is colon cancer. The pharmaceutical composition according to any one of claims 38 to 42, wherein the cancer is colorectal cancer. The pharmaceutical composition according to any one of claims 38 to 42, wherein the cancer is rectal cancer. The pharmaceutical composition according to any one of claims 38 to 42, wherein the cancer is small intestine cancer. The pharmaceutical composition according to any one of claims 38 to 42, wherein the cancer is esophageal cancer. The pharmaceutical composition according to any one of claims 38 to 42, wherein the cancer is pancreatic cell cancer. The pharmaceutical composition according to any one of claims 38 to 42, wherein the cancer is liver cancer. The pharmaceutical composition according to any one of claims 38 to 42, wherein the cancer is hepatocellular carcinoma. The pharmaceutical composition according to any one of claims 38 to 42, wherein the cancer is pancreatic cancer. The pharmaceutical composition according to any one of claims 38 to 42, wherein the cancer is gastric cancer.

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