Bicyclic amine as CDK2 inhibitor

Abstract

To provide a compound that is an inhibitor of cyclin-dependent kinase 2 (CDK2).SOLUTION: A bicyclic amine represented by formula (I), or a pharmaceutically acceptable salt thereof, is provided.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 62 / 914,114, filed October 11, 2019, which is incorporated by reference in its entirety.

[0002] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in ASCII format, which is incorporated by reference in its entirety. The ASCII copy, 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 in the treatment of cancer. [Background technology]

[0004] Cyclin-dependent kinases (CDKs) are a family of serine / threonine kinases. Upon heterodimerization with regulatory subunits known as cyclins, CDKs become fully activated and regulate key cellular processes, including cell cycle progression and cell division (Morgan, DO, Annu Rev Cell Dev Biol, 1997.13:261-91). Uncontrolled proliferation is a hallmark of cancer cells. Deregulation of CDK activity is associated with dysregulation of the cell cycle, which has been detected in virtually all forms of human cancer (Sherr, CJ, 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 the G1 / S transition and S-phase progression. When complexed with cyclin E (CCNE), CDK2 phosphorylates retinoblastoma pocket protein family members (p107, p130, and pRb), leading to the derepression of E2F transcription factors, the expression of G1 / S transition-related genes, and the transition from G1 to S phase (Henley, SA and FA Dick, Cell Div, 2012, 7(1):p.10). This, in turn, enables the activation of CDK2 / cyclin A, which phosphorylates endogenous substrates, thereby enabling DNA synthesis, replication, and centrosome duplication (Ekholm, SV and SI Reed, Curr Opin Cell Biol, 2000, 12(6):676-84). The CDK2 pathway has been reported to affect tumorigenesis primarily through amplification and / or overexpression of CCNE1 and mutations that inactivate CDK2 endogenous inhibitors (e.g., p27), respectively (Xu, X., et al., Biochemistry, 1999.38(27):8713-22).

[0006] CCNE1 copy number gain and overexpression have been identified in ovarian, gastric, endometrial, breast, and other cancers and are associated with poor outcome 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, DG, et al., Cancer, 2006. 106(9): 1925-32). Amplification and / or overexpression of CCNE1 also reportedly contributes 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 USA, 2011. 108(9):3761-6; Herrera-Abreu, MT, et al., Cancer Res, 2016. 76(8):2301-13). Various approaches targeting CDK2 have been shown to induce cell cycle arrest and tumor growth inhibition (Chen, YN, et al., Proc Natl Acad Sci USA, 1999. 96(8):4325-9; Mendoza, N., et al., Cancer Res, 2003. 63(5):1020-4). Inhibition of CDK2 also reportedly restores sensitivity to trastuzumab treatment in resistant HER2+ breast tumors in preclinical models (Scaltriti, see above).

[0007] These data provide evidence 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 growing interest in developing CDK-selective inhibitors. Despite significant efforts, to date, there are no approved drugs that target CDK2 (Cicenas, J., et al., Cancers (Basel), 2014.6(4):p.2224-42). Thus, there remains a need to discover CDK inhibitors with novel activity profiles, particularly CDK inhibitors that target CDK2. The present application addresses this and other needs. Summary of the Invention

[0008] The present invention relates in particular to compounds of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein the constituent members are defined herein.

[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 invention further provides the use of a compound described herein, or a pharmaceutically acceptable salt thereof, to prepare a medicament for use in any of the methods described herein. DETAILED DESCRIPTION OF THE INVENTION

[0015] The present application relates inter alia to compounds of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; [ka] is a single bond or a double bond, X is N, Y is C, and the ring [ka] but, [ka] or X is C, Y is N, and the ring [ka] but, [ka] and Z is CR 2 or N, 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 a 4-10 membered heterocycloalkyl, wherein ring moiety B is attached to the -NH- group of formula (I) at a ring member of a saturated or partially saturated ring of the 4-10 membered heterocycloalkyl; R 1 are independently H, D, halo, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 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, 5-10 membered heteroaryl-C 1-4 Alkyl, OR a1 , S.R. a1 , NHOR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)NR c1 (OR a1 ), C(O)OR a1 ,OC(O)R b1 , OC(O)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 NR c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , C(=NR e1 )R b1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NRe1 )R b1 , N.R. c1 S(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)(=NR e1 )R b1 , N.R. c1 S(O)NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 , S(O)NR c1 R d1 , OS(O)(=NR e1 )R b1 , OS(O)2R b1 , S(O)(=NR e1 )R b1 , SF5, P(O)R f1 R g1 , OP(O)(OR h1 )(OR i1 ), P(O)(OR h1 )(OR i1 ), and BR j1 R k1 wherein C is selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 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 is each optionally selected from 1, 2, 3, or 4 independently selected R 1A is substituted with a substituent, Each R a1 , R c1 , and R d1are independent, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 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, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 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 is each optionally selected from 1, 2, 3, or 4 independently selected R 1A be substituted with a substituent, Alternatively, any R bonded to the same N atom c1 and R d1 together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl group, and the 4- to 10-membered heterocycloalkyl group optionally contains 1, 2, 3, or 4 independently selected R 1A is substituted with a substituent, Each R b1 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl-C1-4 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, each of which is optionally selected from 1, 2, 3, or 4 independently selected R 1A is substituted with a substituent, Each R e1 are independently H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 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, Each R f1 and R g1 are independent, H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 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, Each R h1 and R i1 are independent, H, C 1-6 Alkyl, C1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 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, Each R j1 and R k1 are independent, OH, C 1-6 Alkoxy, and C 1-6 haloalkoxy; Alternatively, any R bonded to the same B atom j1 and R k1 together with the B atoms to which they are bonded, C 1-6 Alkyl and C 1-6 forming a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from haloalkyl; Each R 1A are independently H, D, 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, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a11 , S.R. a11 , NHOR a11 , C(O)R b11 , C(O)NR c11 R d11 , C(O)NR c11 (ORa11 )、C(O)OR a11 、OC(O)R b11 、OC(O)NR c11 R d11 、NR c11 R d11 、NR c11 NR c11 R d11 、NR c11 C(O)R b11 、NR c11 C(O)OR a11 、NR c11 C(O)NR c11 R d11 、C(=NR e11 )R b11 、C(=NR e11 )NR c11 R d11 、NR c11 C(=NR e11 )NR c11 R d11 、NR c11 C(=NR e11 )R b11 、NR c11 S(O)NR c11 R d11 、NR c11 S(O)R b11 、NR c11 S(O)2R b11 、NR c11 S(O)(=NR e11 )R b11 、NR c11 S(O)2NR c11 R d11 、S(O)R b11 、S(O)NR c11 R d11 、S(O)2R b11 、S(O)2NR c11 R d11 、OS(O)(=NR e11 )R b11 、OS(O)2R b11 、S(O)(=NR e11 )R b11 、SF5、P(O)R f11 R g11 、OP(O)(OR h11 )(OR i11 )、P(O)(OR h11)(OR i11 ), and BR j11 R k11 wherein 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- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl is each optionally selected from 1, 2, 3, or 4 independently selected R 1B is substituted with a substituent, Each R a11 , R c11 , and R d11 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- to 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 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4alkyl is each optionally selected from 1, 2, 3, or 4 independently selected R 1B be substituted with a substituent, Alternatively, any R bonded to the same N atom c11 and R d11 together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl group, and the 4- to 7-membered heterocycloalkyl group optionally contains 1, 2, 3, or 4 independently selected R 1B is substituted with a substituent, Each R b11 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 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally selected from 1, 2, 3, or 4 independently selected R 1B is substituted with a substituent, Each R e11 are independently H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, 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 5-6 membered heteroaryl-C 1-4 alkyl, Each R f11 and R g11are independent, H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, 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 5-6 membered heteroaryl-C 1-4 alkyl, Each R h11 and R i11 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- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, Each R j11 and R k11 are independent, OH, C 1-6 Alkoxy, and C 1-6 haloalkoxy; Alternatively, any R bonded to the same B atom j11 and R k11 together with the B atoms to which they are bonded, C 1-6 Alkyl and C 1-6 forming a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from haloalkyl; Each R 1B are independently H, D, halo, CN, NO2, C 1-6Alkyl, 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, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a12 , S.R. a12 , NHOR a12 , C(O)R b12 , C(O)NR c12 R d12 , C(O)NR c12 (OR a12 ), C(O)OR a12 ,OC(O)R b12 , OC(O)NR c12 R d12 , N.R. c12 R d12 , N.R. c12 NR c12 R d12 , N.R. c12 C(O)R b12 , N.R. c12 C(O)OR a12 , N.R. c12 C(O)NR c12 R d12 , C(=NR e12 )R b12 , C(=NR e12 )NR c12 R d12 , N.R. c12 C(=NR e12 )NR c12 R d12 , N.R. c12 C(=NR e12 )R b12 , N.R. c12 S(O)NR c12 R d12 , N.R. c12 S(O)R b12 , N.R. c12 S(O)2R b12 , N.R. c12 S(O)(=NRe12 )R b12 , N.R. c12 S(O)NR c12 R d12 , S(O)R b12 , S(O)NR c12 R d12 , S(O)2R b12 , S(O)NR c12 R d12 , OS(O)(=NR e12 )R b12 , OS(O)2R b12 , S(O)(=NR e12 )R b12 , SF5, P(O)R f12 R g12 , OP(O)(OR h12 )(OR i12 ), P(O)(OR h12 )(OR i12 ), and BR j12 R k12 wherein 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- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl is each optionally selected from 1, 2, 3, or 4 independently selected R G is substituted with a substituent, Each R a12 , R c12 , and R d12 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 1-4Alkyl, Phenyl-C 1-4 Alkyl, 4- to 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 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl is each optionally selected from 1, 2, 3, or 4 independently selected R G be substituted with a substituent, Alternatively, any R bonded to the same N atom c12 and R d12 together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl group, and the 4- to 7-membered heterocycloalkyl group optionally contains 1, 2, 3, or 4 independently selected R G is substituted with a substituent, Each R b12 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 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally selected from 1, 2, 3, or 4 independently selected R G is substituted with a substituent, Each R e12 are independently H, OH, CN, C1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, 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 5-6 membered heteroaryl-C 1-4 alkyl, Each R f12 and R g12 are independent, H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, 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 5-6 membered heteroaryl-C 1-4 alkyl, Each R h12 and R i12 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- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, Each R j12 and R k12 are independent, OH, C 1-6 Alkoxy, and C 1-6 haloalkoxy; Alternatively, any R bonded to the same B atom j12 and R k12 together with the B atoms to which they are bonded, C 1-6 Alkyl and C 1-6 forming a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from haloalkyl; R 2 are independently H, D, halo, CN, OH, NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, Amino, C 1-4 Alkylamino, di(C 1-4 Alkyl)amino, cyano-C 1-4 Alkyl, HO-C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 3-4 Cycloalkyl, thio, C 1-4 Alkylthio, C 1-4 Alkylsulfinyl, C 1-4 Alkyl sulfonyl, carbamyl, C 1-4 Alkylcarbamyl, di(C 1-4 Alkyl) carbamyl, carboxy, C 1-4 Alkyl carbonyl, C 1-4 Alkoxycarbonyl, C 1-4 Alkylcarbonyloxy, C 1-4 Alkylcarbonylamino, C 1-4 Alkoxycarbonylamino, C 1-4 Alkylaminocarbonyloxy, C 1-4 Alkyl sulfonyl amino, amino sulfonyl, C 1-4 Alkylaminosulfonyl, di(C 1-4Alkyl)aminosulfonyl, aminosulfonylamino, C 1-4 Alkylaminosulfonylamino, di(C 1-4 Alkyl)aminosulfonylamino, aminocarbonylamino, C 1-4 Alkylaminocarbonylamino, and di(C 1-4 alkyl)aminocarbonylamino; Each R 3 Independently, H, D, 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; R 4 But C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 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, 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl-C 1-4Alkyl, 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 is each optionally selected from 1, 2, 3, or 4 independently selected R 4A is substituted by a substituent, Each R 4A are independently H, D, halo, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 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, 5-10 membered heteroaryl-C 1-4 Alkyl, OR a41 , S.R. a41 , NHOR a41 , C(O)R b41 , C(O)NR c41 R d41 , C(O)NR c41 (OR a41 ), C(O)OR a41 ,OC(O)R b41 , OC(O)NR c41 R d41 , N.R. c41 R d41 , N.R. c41 NR c41 R d41 , N.R. c41 C(O)R b41 , N.R. c41 C(O)OR a41 , N.R. c41 C(O)NR c41 R d41 , C(=NR e41 )R b41 , C(=NR e41 )NR c41 R d41 , N.R. c41 C(=NRe41 )NR c41 R d41 , N.R. c41 C(=NR e41 )R b41 , N.R. c41 S(O)NR c41 R d41 , N.R. c41 S(O)R b41 , N.R. c41 S(O)2R b41 , N.R. c41 S(O)(=NR e41 )R b41 , N.R. c41 S(O)NR c41 R d41 , S(O)R b41 , S(O)NR c41 R d41 , S(O)2R b41 , S(O)NR c41 R d41 , OS(O)(=NR e41 )R b41 , OS(O)2R b41 , S(O)(=NR e41 )R b41 , SF5, P(O)R f41 R g41 , OP(O)(OR h41 )(OR i41 ), P(O)(OR h41 )(OR i41 ), and BR j41 R k41 wherein C is selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 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 is each optionally selected from 1, 2, 3, or 4 independently selected R 4Bis 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 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 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, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 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 is each optionally selected from 1, 2, 3, or 4 independently selected R 4B be substituted with a substituent, Alternatively, any R bonded to the same N atom c41 and R d41 together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl group, and the 4- to 10-membered heterocycloalkyl group optionally contains 1, 2, 3, or 4 independently selected R 4B is substituted with a substituent, Each R b41 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 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, each of which is optionally selected from 1, 2, 3, or 4 independently selected R 4B is substituted with a substituent, Each R e41 are independently H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 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, Each R f41 and R g41 are independent, H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 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-C1-4 alkyl, Each R h41 and R i41 are independent, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 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, Each R j41 and R k41 are independent, OH, C 1-6 Alkoxy, and C 1-6 haloalkoxy; Alternatively, any R bonded to the same B atom j41 and R k41 together with the B atoms to which they are bonded, C 1-6 Alkyl and C 1-6 forming a 5- or 10-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from haloalkyl; Each R 4B are independently H, D, 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, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a42 , S.R. a42 , NHORa42 、C(O)R b42 、C(O)NR c42 R d42 、C(O)NR c42 (OR a42 )、C(O)OR a42 、OC(O)R b42 、OC(O)NR c42 R d42 、NR c42 R d42 、NR c42 NR c42 R d42 、NR c42 C(O)R b42 、NR c42 C(O)OR a42 、NR c42 C(O)NR c42 R d42 、C(=NR e42 )R b42 、C(=NR e42 )NR c42 R d42 、NR c42 C(=NR e42 )NR c42 R d42 、NR c42 C(=NR e42 )R b42 、NR c42 S(O)NR c42 R d42 、NR c42 S(O)R b42 、NR c42 S(O)2R b42 、NR c42 S(O)(=NR e42 )R b42 、NR c42 S(O)2NR c42 R d42 、S(O)R b42 、S(O)NR c42 R d42 、S(O)2R b42 、S(O)2NR c42 R d42 、OS(O)(=NR e42 )R b42 、OS(O)2R b42 、S(O)(=NR e42 )R b42 、SF5、P(O)Rf42 R g42 , OP(O)(OR h42 )(OR i42 ), P(O)(OR h42 )(OR i42 ), and BR j42 R k42 wherein 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- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl is each optionally selected from 1, 2, 3, or 4 independently selected R 4C is substituted with a substituent, Each R a42 , R c42 , and R d42 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- to 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 5-6 membered heteroaryl-C 1-4 alkyl is each optionally selected from 1, 2, 3, or 4 independently selected R 4C be substituted with a substituent, Alternatively, any R bonded to the same N atom c42 and R d42 together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl group, and the 4- to 7-membered heterocycloalkyl group optionally contains 1, 2, 3, or 4 independently selected R 4C is substituted with a substituent, Each R b42 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 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally selected from 1, 2, 3, or 4 independently selected R 4C is substituted with a substituent, Each R e42 are independently H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, 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 5-6 membered heteroaryl-C1-4 alkyl, Each R f42 and R g42 are independent, H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, 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 5-6 membered heteroaryl-C 1-4 alkyl, Each R h42 and R i42 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- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, Each R j42 and R k42 are independent, OH, C 1-6 Alkoxy, and C 1-6 haloalkoxy; Alternatively, any R bonded to the same B atom j42 and R k42 together with the B atoms to which they are bonded, C 1-6 Alkyl and C 1-6forming a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from haloalkyl; Each R 4C are independently H, D, 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, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a43 , S.R. a43 , NHOR a43 , C(O)R b43 , C(O)NR c43 R d43 , C(O)NR c43 (OR a43 ), C(O)OR a43 ,OC(O)R b43 , OC(O)NR c43 R d43 , N.R. c43 R d43 , N.R. c43 NR c43 R d43 , N.R. c43 C(O)R b43 , N.R. c43 C(O)OR a43 , N.R. c43 C(O)NR c43 R d43 , C(=NR e43 )R b43 , C(=NR e43 )NR c43 R d43 , N.R. c43 C(=NR e43 )NR c43 R d43 , N.R. c43 C(=NR e43 )R b43 , N.R. c43S(O)NR c43 R d43 , N.R. c43 S(O)R b43 , N.R. c43 S(O)2R b43 , N.R. c43 S(O)(=NR e43 )R b43 , N.R. c43 S(O)NR c43 R d43 , S(O)R b43 , S(O)NR c43 R d43 , S(O)2R b43 , S(O)NR c43 R d43 , OS(O)(=NR e43 )R b43 , OS(O)2R b43 , S(O)(=NR e43 )R b43 , SF5, P(O)R f43 R g43 , OP(O)(OR h43 )(OR i43 ), P(O)(OR h43 )(OR i43 ), and BR j43 R k43 wherein 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- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl is each optionally selected from 1, 2, 3, or 4 independently selected R G is substituted with a substituent, Each R a43 , R c43 , and R d43 are independent, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C2-6 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 5-6 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 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl is each optionally selected from 1, 2, 3, or 4 independently selected R G be substituted with a substituent, Alternatively, any R bonded to the same N atom c43 and R d43 together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl group, and the 4- to 7-membered heterocycloalkyl group optionally contains 1, 2, 3, or 4 independently selected R G is substituted with a substituent, Each R b43 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 1-4Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally selected from 1, 2, 3, or 4 independently selected R G is substituted with a substituent, Each R e43 are independently H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, 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 5-6 membered heteroaryl-C 1-4 alkyl, Each R f43 and R g43 are independent, H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, 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 5-6 membered heteroaryl-C 1-4 alkyl, Each R h43 and R i43 are independent, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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 5-6 membered heteroaryl-C 1-4 alkyl, Each R j43 and R k43 are independent, OH, C 1-6 Alkoxy, and C 1-6 haloalkoxy; Alternatively, any R bonded to the same B atom j43 and R k43 together with the B atoms to which they are bonded, C 1-6 Alkyl and C 1-6 forming a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from haloalkyl; Each R 5 are independent, H, D, halo, NO2, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 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, 5-10 membered heteroaryl-C 1-4 Alkyl, OR a5 , S.R. a5 , NHOR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)NR c5 (OR a5 ), C(O)OR a5 ,OC(O)R b5 , OC(O)NR c5 Rd5 , N.R. c5 R d5 , N.R. c5 NR c5 R d5 , N.R. c5 C(O)R b5 , N.R. c5 C(O)OR a5 , N.R. c5 C(O)NR c5 R d5 , C(=NR e5 )R b5 , C(=NR e5 )NR c5 R d5 , N.R. c5 C(=NR e5 )NR c5 R d5 , N.R. c5 C(=NR e5 )R b5 , N.R. c5 S(O)NR c5 R d5 , N.R. c5 S(O)R b5 , N.R. c5 S(O)2R b5 , N.R. c5 S(O)(=NR e5 )R b5 , N.R. c5 S(O)NR c5 R d5 , S(O)R b5 , S(O)NR c5 R d5 , S(O)2R b5 , S(O)NR c5 R d5 , OS(O)(=NR e5 )R b5 , OS(O)2R b5 , S(O)(=NR e5 )R b5 , SF5, P(O)R f5 R g5 , OP(O)(OR h5 )(OR i5 ), P(O)(OR h5 )(OR i5 ), and BR j5 R k5 wherein C is selected from 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 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 is each optionally selected from 1, 2, 3, or 4 independently selected R 5A is substituted by a substituent, Each R a5 , R c5 , and R d5 are independent, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 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, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 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 is each optionally selected from 1, 2, 3, or 4 independently selected R 5Abe substituted with a substituent, Alternatively, any R bonded to the same N atom c5 and R d5 together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl group, which optionally are joined by 1, 2, 3, or 4 independently selected R 5A is substituted with a substituent, Each R b5 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 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, each of which is optionally selected from 1, 2, 3, or 4 independently selected R 5A is substituted with a substituent, Each R e5 are independently H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 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, Each R f5 and R g5 are independent, H, C 1-6 Alkyl, C 1-6Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 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, Each R h5 and R i5 are independent, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 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, Each R j5 and R k5 are independent, OH, C 1-6 Alkoxy, and C 1-6 haloalkoxy; Alternatively, any R bonded to the same B atom j5 and R k5 together with the B atoms to which they are bonded, C 1-6 Alkyl and C 1-6 forming a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from haloalkyl; Each R 5A are independently H, D, halo, CN, NO2, C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 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, 5-10 membered heteroaryl-C 1-4 Alkyl, OR a51 , S.R. a51 , NHOR a51 , C(O)R b51 , C(O)NR c51 R d51 , C(O)NR c51 (OR a51 ), C(O)OR a51 ,OC(O)R b51 , OC(O)NR c51 R d51 , N.R. c51 R d51 , N.R. c51 NR c51 R d51 , N.R. c51 C(O)R b51 , N.R. c51 C(O)OR a51 , N.R. c51 C(O)NR c51 R d51 , C(=NR e51 )R b51 , C(=NR e51 )NR c51 R d51 , N.R. c51 C(=NR e51 )NR c51 R d51 , N.R. c51 C(=NR e51 )R b51 , N.R. c51 S(O)NR c51 R d51 , N.R. c51 S(O)R b51 , N.R. c51 S(O)2R b51 , N.R. c51 S(O)(=NRe51 )R b51 , N.R. c51 S(O)NR c51 R d51 , S(O)R b51 , S(O)NR c51 R d51 , S(O)2R b51 , S(O)NR c51 R d51 , OS(O)(=NR e51 )R b51 , OS(O)2R b51 , S(O)(=NR e51 )R b51 , SF5, P(O)R f51 R g51 , OP(O)(OR h51 )(OR i51 ), P(O)(OR h51 )(OR i51 ), and BR j51 R k51 wherein C is selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 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 is each optionally selected from 1, 2, 3, or 4 independently selected R 5B is substituted with a substituent, Each R a51 , R c51 , and R d51 are independent, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl-C1-4 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, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 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 is each optionally selected from 1, 2, 3, or 4 independently selected R 5B be substituted with a substituent, Alternatively, any R bonded to the same N atom c51 and R d51 together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl group, which optionally is joined to one, two, three, or four independently selected R 5B is substituted with a substituent, Each R b51 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 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, each of which is optionally selected from 1, 2, 3, or 4 independently selected R 5B is substituted with a substituent, Each R e51 are independently H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 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, Each R f51 and R g51 are independent, H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 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, Each R h51 and R i51 are independent, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl, Each R j51 and R k51 are independent, OH, C 1-6 Alkoxy, and C 1-6 haloalkoxy; Alternatively, any R bonded to the same B atom j51 and R k51 together with the B atoms to which they are bonded, C 1-6 Alkyl and C 1-6 forming a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from haloalkyl; Each R 5B are independently H, D, 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, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a52 , S.R. a52 , NHOR a52 , C(O)R b52 , C(O)NR c52 R d52 , C(O)NR c52 (OR a52 ), C(O)OR a52 ,OC(O)R b52 , OC(O)NR c52 R d52 , N.R. c52 R d52 , N.R. c52 NR c52 R d52 , N.R. c52 C(O)Rb52 , N.R. c52 C(O)OR a52 , N.R. c52 C(O)NR c52 R d52 , C(=NR e52 )R b52 , C(=NR e52 )NR c52 R d52 , N.R. c52 C(=NR e52 )NR c52 R d52 , N.R. c52 C(=NR e52 )R b52 , N.R. c52 S(O)NR c52 R d52 , N.R. c52 S(O)R b52 , N.R. c52 S(O)2R b52 , N.R. c52 S(O)(=NR e52 )R b52 , N.R. c52 S(O)NR c52 R d52 , S(O)R b52 , S(O)NR c52 R d52 , S(O)2R b52 , S(O)NR c52 R d52 , OS(O)(=NR e52 )R b52 , OS(O)2R b52 , S(O)(=NR e52 )R b52 , SF5, P(O)R f52 R g52 , OP(O)(OR h52 )(OR i52 ), P(O)(OR h52 )(OR i52 ), and BR j52 R k52 wherein C is selected from 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 5-6 membered heteroaryl-C 1-4 alkyl is each optionally selected from 1, 2, 3, or 4 independently selected R 5C is substituted with a substituent, Each R a52 , R c52 , and R d52 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- to 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 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl is each optionally selected from 1, 2, 3, or 4 independently selected R 5C be substituted with a substituent, Alternatively, any R bonded to the same N atom c52 and R d52together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl group, which optionally is joined to one, two, three, or four independently selected R 5C is substituted with a substituent, Each R b52 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 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally selected from 1, 2, 3, or 4 independently selected R 5C is substituted with a substituent, Each R e52 are independently H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, 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 5-6 membered heteroaryl-C 1-4 alkyl, Each R f52 and R g52 are independent, H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, 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 5-6 membered heteroaryl-C 1-4 alkyl, Each R h52 and R i52 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- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, Each R j52 and R k52 are independent, OH, C 1-6 Alkoxy, and C 1-6 haloalkoxy; Alternatively, any R bonded to the same B atom j52 and R k52 together with the B atoms to which they are bonded, C 1-6 Alkyl and C 1-6 forming a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from haloalkyl; Each R 5C are independently H, D, 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-C1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a53 , S.R. a53 , NHOR a53 , C(O)R b53 , C(O)NR c53 R d53 , C(O)NR c53 (OR a53 ), C(O)OR a53 ,OC(O)R b53 , OC(O)NR c53 R d53 , N.R. c53 R d53 , N.R. c53 NR c53 R d53 , N.R. c53 C(O)R b53 , N.R. c53 C(O)OR a53 , N.R. c53 C(O)NR c53 R d53 , C(=NR e53 )R b53 , C(=NR e53 )NR c53 R d53 , N.R. c53 C(=NR e53 )NR c53 R d53 , N.R. c53 C(=NR e53 )R b53 , N.R. c53 S(O)NR c53 R d53 , N.R. c53 S(O)R b53 , N.R. c53 S(O)2R b53 , N.R. c53 S(O)(=NR e53 )R b53 , N.R. c53 S(O)NR c53 R d53 , S(O)R b53 , S(O)NR c53 R d53 , S(O)2R b53, S(O)NR c53 R d53 , OS(O)(=NR e53 )R b53 , OS(O)2R b53 , S(O)(=NR e53 )R b53 , SF5, P(O)R f53 R g53 , OP(O)(OR h53 )(OR i53 ), P(O)(OR h53 )(OR i53 ), and BR j53 R k53 wherein 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- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl is each optionally selected from 1, 2, 3, or 4 independently selected R G is substituted with a substituent, Each R a53 , R c53 , and R d53 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- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, 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 5-6 membered heteroaryl-C 1-4 alkyl is each optionally selected from 1, 2, 3, or 4 independently selected R G be substituted with a substituent, Alternatively, any R bonded to the same N atom c53 and R d53 together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl group, which optionally are joined by 1, 2, 3, or 4 independently selected R G is substituted with a substituent, Each R b53 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 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally selected from 1, 2, 3, or 4 independently selected R G is substituted with a substituent, Each R e53 are independently H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, 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 5-6 membered heteroaryl-C 1-4 alkyl, Each R f53 and R g53 are independent, H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, 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 5-6 membered heteroaryl-C 1-4 alkyl, Each R h53 and R i53 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- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, Each R j53 and R k53 are independent, OH, C 1-6 Alkoxy, and C 1-6 haloalkoxy; Alternatively, any R bonded to the same B atom j53 and R k53 together with the B atoms to which they are bonded, C 1-6 Alkyl and C 1-6 forming a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from haloalkyl; Each R G are independently OH, NO2, CN, halo, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Haloalkyl, Cyano-C 1-3 Alkyl, HO-C 1-3 Alkyl, C 1-3 Alkoxy-C 1-3 Alkyl, C 3-7 Cycloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, Amino, C 1-3 Alkylamino, di(C 1-3 Alkyl)amino, thio, C 1-3 Alkylthio, C 1-3 Alkylsulfinyl, C 1-3 Alkyl sulfonyl, carbamyl, C 1-3 Alkylcarbamyl, di(C 1-3 Alkyl) carbamyl, carboxy, C 1-3 Alkyl carbonyl, C 1-3 Alkoxycarbonyl, C 1-3 Alkylcarbonyloxy, C 1-3 Alkylcarbonylamino, C 1-3 Alkoxycarbonylamino, C 1-3 Alkylaminocarbonyloxy, C 1-3 Alkyl sulfonyl amino, amino sulfonyl, C 1-3 Alkylaminosulfonyl, di(C 1-3 Alkyl)aminosulfonyl, aminosulfonylamino, C 1-3 Alkylaminosulfonylamino, di(C 1-3 Alkyl)aminosulfonylamino, aminocarbonylamino, C 1-3Alkylaminocarbonylamino, and di(C 1-3 alkyl)aminocarbonylamino; The compound, or a pharmaceutically acceptable salt thereof, is provided.

[0016] In some embodiments, R 1 are 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, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a1 , S.R. 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 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)NR c1 R d1 , S(O)2R b1 , and S(O)NR c1 R d1 wherein C is selected from 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 5-6 membered heteroaryl-C 1-4 The alkyl is optionally selected from 1, 2, 3, or 4 independently selected R 1A It is substituted with a substituent.

[0017] In some embodiments, R 1 are 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, 5-6 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 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)NR c1 R d1 , S(O)2R b1 , and S(O)NR c1 Rd1 wherein 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- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 The alkyl is optionally selected from 1, 2, 3, or 4 independently selected R 1A It is substituted with a substituent.

[0018] In some embodiments, R 1 are independently H, halo, CN, and 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, 5-6 membered heteroaryl-C 1-3 Alkyl, OR a1 , S.R. a1 , and NR c1 R d1 wherein C is selected from 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 5-6 membered heteroaryl-C 1-3 The alkyl is optionally selected from one or two independently selected R 1A It is substituted with a substituent.

[0019] In some embodiments, R 1 are independently H, halo, CN, and 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, 5-6 membered heteroaryl-C 1-3 Alkyl, OR a1 , and NR c1 R d1 wherein C is selected from 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 5-6 membered heteroaryl-C 1-3 The alkyl is optionally selected from one or two independently selected R 1A It is substituted with a substituent.

[0020] In some embodiments, R 1 are independently H, halo, CN, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-4 Cycloalkyl and OR a1 wherein C is selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, and C 3-4 Cycloalkyl is optionally selected from 1, 2, 3, or 4 independently selected R 1A It is substituted with a substituent.

[0021] In some embodiments, R 1 are independently H, halo, CN, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-4 Cycloalkyl and OR a1 wherein C is selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, and C 3-4 Cycloalkyl is optionally substituted with one or two independently selected R 1A It is substituted with a substituent.

[0022] In some embodiments, R 1 are independently H, C 1-6 Alkyl, phenyl, 5- to 7-membered heterocycloalkyl, OR a1 , S.R. a1 , and NR c1 R d1 wherein C is selected from 1-6 Alkyl, phenyl, and 5- to 7-membered heterocycloalkyl are each optionally joined by one or two independently selected R 1A It is substituted with a substituent.

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

[0024] In some embodiments, each R a1 , R c1 , and R d1 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-C1-4 Alkyl, 4- to 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 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl is each optionally selected from 1, 2, 3, or 4 independently selected R 1A is substituted with a substituent, Each R b1 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 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally selected from 1, 2, 3, or 4 independently selected R 1A is substituted with a substituent, Each R 1A are 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, 5-6 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 , N.R. c11 R d11 , N.R. c11 C(O)R b11 , N.R. c11 C(O)OR a11 , N.R. c11 C(O)NR c11 R d11 , N.R. c11 S(O)2R b11 , N.R. c11 S(O)NR c11 R d11 , S(O)2R b11 , and S(O)NR c11 R d11 wherein 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- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl is each optionally selected from 1, 2, 3, or 4 independently selected R 1B is substituted with a substituent, Each R a11 , R c11 , and R d11 are independent, 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 5-6 membered heteroaryl-C 1-4 alkyl, 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 5-6 membered heteroaryl-C 1-4 alkyl is each optionally selected from 1, 2, 3, or 4 independently selected R 1B is substituted with a substituent, Each R b11 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 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally selected from 1, 2, 3, or 4 independently selected R 1B is substituted with a substituent, Each R 1B are 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 , N.R. c12 R d12 , N.R. c12 C(O)R b12 , N.R. c12 S(O)2R b12 , S(O)2R b12 , and S(O)NR c12 R d12 is selected from Each R a12 , R c12 , and R d12 are independent, H, C 1-6 Alkyl, and C 1-6 haloalkyl; Each R b12 independently, C 1-6 Alkyl and C 1-6 haloalkyl.

[0025] In some embodiments, each R a1 , R c1 , and R d1 are independent, 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 5-6 membered heteroaryl-C 1-4 alkyl, 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 5-6 membered heteroaryl-C 1-4 alkyl is each optionally selected from 1, 2, 3, or 4 independently selected R1A is substituted with a substituent, Each R b1 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 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally selected from 1, 2, 3, or 4 independently selected R 1A is substituted with a substituent, Each R 1A are 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, 5-6 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 , N.R. c11 R d11 , N.R. c11 C(O)R b11 , N.R. c11 C(O)OR a11 , N.R. c11 C(O)NR c11 R d11 , N.R. c11 S(O)2R b11 , N.R. c11 S(O)NR c11 R d11 , S(O)2Rb11 , and S(O)NR c11 R d11 wherein C is selected from 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 5-6 membered heteroaryl-C 1-4 alkyl is each optionally selected from 1, 2, 3, or 4 independently selected R 1B is substituted with a substituent, Each R a11 , R c11 , and R d11 are independent, H, C 1-6 Alkyl, and C 1-6 haloalkyl; Each R b11 independently, C 1-6 Alkyl and C 1-6 haloalkyl; Each R 1B independently H, D, and OR a12 is selected from Each R a12 are independently H and C 1-6 alkyl.

[0026] In some embodiments, each R a1 , R c1 , and R d1 are independent, 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 5-6 membered heteroaryl-C 1-4 alkyl,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 5-6 membered heteroaryl-C 1-4 alkyl is each optionally selected from 1, 2, 3, or 4 independently selected R 1A is substituted with a substituent, Each R b1 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 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally selected from 1, 2, 3, or 4 independently selected R 1A is substituted with a substituent, Each R 1A are 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, 5-6 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 , N.R. c11 R d11 , N.R. c11 C(O)R b11 , N.R. c11 C(O)OR a11 , N.R. c11 C(O)NR c11 R d11 , N.R. c11 S(O)2R b11 , N.R. c11 S(O)NR c11 R d11 , S(O)2R b11 , and S(O)NR c11 R d11 is selected from Each R a11 , R c11 , and R d11 are independent, H, C 1-6 Alkyl, and C 1-6 haloalkyl; Each R b11 independently, C 1-6 Alkyl and C 1-6 haloalkyl.

[0027] In some embodiments, each R a1 , R c1 , and R d1 are independent, 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 5-6 membered heteroaryl-C 1-4 alkyl, 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 1-4Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl is each optionally selected from 1, 2, 3, or 4 independently selected R 1A is substituted with a substituent, Each R b1 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 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally selected from 1, 2, 3, or 4 independently selected R 1A is substituted with a substituent, Each R 1A are 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 cycloalkyl.

[0028] In some embodiments, 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-C 1-3 Alkyl and 4-6 membered heterocycloalkyl-C 1-3alkyl, 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, phenyl, 4-6 membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkyl and 4-6 membered heterocycloalkyl-C 1-3 alkyl is optionally selected from 1, 2, or 3 independently selected R 1A is substituted with a substituent, Each R b1 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-2 Alkyl and 4-6 membered heterocycloalkyl-C 1-2 alkyl, each of which is optionally selected from one or two independently selected R 1A is substituted with a substituent, Each R 1A Independently, H, D, halo, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, OR a11 , and C(O)OR a11 wherein C is selected from 1-6 Alkyl and C 1-6 haloalkyl, each optionally selected from 1, 2, or 3 independently selected R 1B is substituted with a substituent, Each R a11 are independently H and C 1-4 alkyl, 1-4 The alkyl is optionally selected from one, two, or three independently selected R 1B is substituted by a substituent, Each R 1B independently, H, D, and OC 1-4 alkyl.

[0029] In some embodiments, each R a1 , R c1 , and R d1 are independent, H, C1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkyl and 4-6 membered heterocycloalkyl-C 1-3 alkyl, 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkyl and 4-6 membered heterocycloalkyl-C 1-3 alkyl is optionally selected from one or two independently selected R 1A is substituted with a substituent, Each R b1 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-2 Alkyl and 4-6 membered heterocycloalkyl-C 1-2 alkyl, each of which is optionally selected from one or two independently selected R 1A is substituted with a substituent, Each R 1A are independently H, halo, OH, C 1-3 Alkoxy, and C 1-3 haloalkoxy.

[0030] In some embodiments, R 1 But H, C 1-6 Alkyl, phenyl, 5- to 7-membered heterocycloalkyl, OR a1 , S.R. 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 is substituted with a substituent, Each Ra1 , 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-C 1-3 Alkyl and 4- to 6-membered heterocycloalkyl-C 1-3 alkyl, 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, phenyl, 4-6 membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkyl and 4- to 6-membered heterocycloalkyl-C 1-3 alkyl is optionally selected from 1, 2, or 3 independently selected R 1A is substituted with a substituent, Each R 1A Independently, D, halo, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, OR a11 , and C(O)OR a11 wherein C is selected from 1-4 Alkyl and C 1-4 haloalkyl, each optionally selected from 1, 2, or 3 independently selected R 1B is substituted with a substituent, Each R a11 are independently H and C 1-4 alkyl, Each R 1B independently, H, D, and OC 1-4 alkyl.

[0031] In some embodiments, R 1 But H or OR a1 and Each R a1 are independent, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C3-6 Cycloalkyl-C 1-3 Alkyl and 4- to 6-membered heterocycloalkyl-C 1-3 alkyl, 1-6 Alkyl, C 1-6 Haloalkyl C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkyl and 4- to 6-membered heterocycloalkyl-C 1-3 alkyl is optionally selected from one or two independently selected R 1A is substituted with a substituent, Each R 1A are independent, OH, C 1-3 Alkoxy, and C 1-3 haloalkoxy.

[0032] In some embodiments, R 1 are independently 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 5-6 membered heteroaryl-C 1-3 It is alkyl.

[0033] In some embodiments, R 1 are independent, H, C 1-6 Alkyl, phenyl, 5- to 7-membered heterocycloalkyl, OR a1 , S.R. a1 , and NR c1 R d1 wherein C is selected from 1-6 alkyl, phenyl, and 5- to 7-membered heterocycloalkyl are each optionally substituted with one or two independently selected R 1A is substituted with a substituent, Ra1 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-1 2H-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-CH—, cyclobutyl-CH—, 1-trifluoromethylcyclobutyl-CH—, cyclopentyl-CH—, and (tetrahydrofuran-3-yl)-CH—; R c1 is H, R d1 is phenyl, Each R 1A Independently, halo, CN, C 1-3 Alkyl, and C 1-3 haloalkyl.

[0034] In some embodiments, R 1 are independently H and OR a1 wherein R a1is 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-1 2H-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-CH—, cyclobutyl-CH—, 1-trifluoromethylcyclobutyl-CH—, cyclopentyl-CH—, and (tetrahydrofuran-3-yl)-CH—.

[0035] In some embodiments, R 1 are independently H and OR a1 wherein R a1 are 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 C 1-3 alkyl.

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

[0038] In some embodiments, R 1 is one or two independently selected R 1A phenyl optionally substituted by substituents, wherein each R1A are independently 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 one or two independently selected R 1A 5-7 membered heterocycloalkyl optionally substituted by substituents, wherein each R 1A independently, 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 SR a1 wherein R a1 is C 1-3 alkyl.

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

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

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

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

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

[0048] In some embodiments, R 2 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 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 4-7 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 are independently H, halo, and 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 5-6 membered heteroaryl-C 1-4 alkyl, 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 5-6 membered heteroaryl-C 1-4 The alkyl is optionally selected from 1, 2, 3, or 4 independently selected R 4A It is substituted by a substituent.

[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 alkyl, 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 joined to one, two, three, or four independently selected R 4A It is substituted by a substituent.

[0065] In some embodiments, 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, 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 joined to one, two, three, or four independently selected R 4A It is substituted by a substituent.

[0066] In some embodiments, 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, 1-6 Alkyl, C 3-6 Cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl-C 1-4 The alkyl is optionally selected from one or two independently selected R 4A It is substituted by a substituent.

[0067] In some embodiments, R 4 is one or two independently selected R 4A C optionally substituted by substituents 1-6 alkyl.

[0068] In some embodiments, R 4 is C 1-6 Alkyl and C 3-6 It is 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 one or two independently selected R 4A is selected from 5-6 membered heteroaryl optionally substituted by substituents.

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

[0073] In some embodiments, Each R 4A are 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, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a41 , S.R. 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 , N.R. c41 R d41 , N.R. c41 C(O)R b41 , N.R. c41 C(O)OR a41 , N.R. c41 C(O)NR c41 R d41 , N.R.c41 S(O)2R b41 , N.R. c41 S(O)NR c41 R d41 , S(O)2R b41 , and S(O)NR c41 R d41 wherein 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- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl is each 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- to 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 5-6 membered heteroaryl-C 1-4 alkyl is each optionally selected from 1, 2, 3, or 4 independently selected R 4B is substituted with a substituent, Each R b41 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 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally selected from 1, 2, 3, or 4 independently selected R 4B is substituted with a substituent, Each R 4B are 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, 5-6 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 , 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)NR c42 R d42 , S(O)2R b42 , and S(O)NR c42 R d42 wherein 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- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl is each optionally selected from 1, 2, 3, or 4 independently selected R 4C is substituted with a substituent, Each R a42 , R c42 , and R d42 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- to 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 3-7Cycloalkyl, 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 5-6 membered heteroaryl-C 1-4 alkyl is each optionally selected from 1, 2, 3, or 4 independently selected R 4C is substituted with a substituent, Each R b42 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 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally selected from 1, 2, 3, or 4 independently selected R 4C is substituted with a substituent, Each R 4C are 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 , N.R. c43 R d43 , N.R. c43 C(O)R b43 , N.R. c43 S(O)2R b43 , S(O)2R b43 , and S(O)NR c43 R d43is selected from Each R a43 , R c43 , and R d43 are independent, H, C 1-6 Alkyl, and C 1-6 haloalkyl; Each R b43 independently, C 1-6 Alkyl and C 1-6 haloalkyl.

[0074] In some embodiments, Each R 4A are 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, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a41 , S.R. 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 , N.R. c41 R d41 , N.R. c41 C(O)R b41 , N.R. c41 C(O)OR a41 , N.R. c41 C(O)NR c41 R d41 , N.R. c41 S(O)2R b41 , N.R. c41 S(O)NR c41 R d41 , S(O)2R b41 , and S(O)NR c41 R d41 wherein C is selected from1-6 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 5-6 membered heteroaryl-C 1-4 alkyl is optionally selected from 1, 2, or 3 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 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 5-6 membered heteroaryl-C 1-4 alkyl, 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 5-6 membered heteroaryl-C 1-4 alkyl is optionally selected from 1, 2, or 3 independently selected R 4B is substituted with a substituent, Each R b41 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 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally followed by 1, 2, or 3 independently selected R 4B is substituted with a substituent, Each R 4B are 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 , 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)NR 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 independently, C 1-6 Alkyl and C 1-6 haloalkyl.

[0075] In some embodiments, Each R 4A are 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 , N.R. c41 R d41 , N.R. c41 C(O)R b41 , N.R. c41 C(O)OR a41 , N.R. c41 C(O)NR c41 R d41 , N.R. c41 S(O)2R b41 , N.R. c41 S(O)NR c41 R d41 , S(O)2R b41 , and S(O)NR c41 R d41 wherein C is selected from 1-6 Alkyl, C 1-6 Haloalkyl, and C 3-4 cycloalkyl is optionally selected from 1, 2, or 3 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, and C 3-4 cycloalkyl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, and C 3-4 cycloalkyl is optionally selected from one or two independently selected R 4B is substituted with a substituent, Each R b41 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 3-4 cycloalkyl, each of which is optionally selected from one or two independently selected R 4B is substituted with a substituent, Each R4B are independently H, halo, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, OR a42 , and NR c42 R d42 is selected from Each R a42 , R c42 , and R d42 are independent, H, C 1-3 Alkyl, and C 1-3 haloalkyl; Each R b42 independently, C 1-3 Alkyl and C 1-3 haloalkyl.

[0076] In some embodiments, Each R 4A are 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 , N.R. c41 R d41 , N.R. c41 C(O)R b41 , N.R. c41 C(O)OR a41 , N.R. c41 C(O)NR c41 R d41 , N.R. c41 S(O)2R b41 , N.R. c41 S(O)NR c41 R d41 , S(O)2R b41 , and S(O)NR c41 R d41 is selected from Each R a41 , R c41 , and R d41 are independent, H, C 1-3 Alkyl, and C1-3 haloalkyl; Each R b41 independently, C 1-3 Alkyl and C 1-3 haloalkyl.

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

[0078] In some embodiments, R 4 is R 4A C optionally replaced by 1-6 alkyl, where R 4A is NR c41 R d41 and R c41 and R d41 are each independently H, C 1-3 Alkyl, and C 1-3 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 4A5-6 membered heteroaryl optionally substituted by substituents, wherein each R 4A independently, 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 one or two independently selected R 4A 4-7 membered heterocycloalkyl-C optionally substituted by substituents 1-4 alkyl, wherein each R 4A independently, C 1-3 It is selected from alkyl and OH.

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

[0084] In some embodiments, R 4is selected from (pyrrolidin-1-yl)CH2CH2, -(pyrrolidin-3-ol)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 aryl, (pyrrolidin-1-yl)CH2CH2, -(pyrrolidin-3-ol)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, the ring moiety A is a 5-10 membered heteroaryl.

[0087] In some embodiments, the ring moiety A is a 5-6 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: [ka] In some embodiments, ring moiety A is 1H-pyrazol-4-yl and ring moiety B is piperidinyl.

[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 are 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- 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, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a5 , S.R. 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 , N.R. c5 R d5 , N.R. c5 C(O)R b5 , N.R. c5 C(O)OR a5 , N.R. c5 C(O)NR c5 R d5 , N.R. c5 S(O)2R b5 , N.R. c5 S(O)NR c5 R d5 , S(O)2R b5 , and S(O)NR c5 R d5 wherein 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- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 The alkyl is optionally selected from 1, 2, 3, or 4 independently selected R 5A It is substituted by a substituent.

[0097] In some embodiments, each R 5 are 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 , N.R.c5 R d5 , N.R. c5 C(O)R b5 , N.R. c5 S(O)2R b5 , S(O)2R b5 , and S(O)NR c5 R d5 wherein C is selected from 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 joined to one, two, three, or four independently selected R 5A It is substituted by a substituent.

[0098] In some embodiments, each R 5 are independently H, halo, CN, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-4 Cycloalkyl, OR a5 , and NR c5 R d5 wherein C is selected from 1-6 Alkyl, C 1-6 Haloalkyl, and C 3-4 Cycloalkyl is optionally selected from 1, 2, 3, or 4 independently selected R 5A It is substituted by a substituent.

[0099] In some embodiments, each R 5 are independently H, halo, CN, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-4 Cycloalkyl, OR a5 , and NR c5 R d5 Each R a5 , R c5 , and R d5 are independently H, C 1-6 Alkyl, and C 1-6 haloalkyl.

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

[0101] In some embodiments, each R 5 are 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 are independently H and C 1-3 alkyl.

[0104] In some embodiments, Each R a5 , R c5 , and R d5 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- to 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 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl is each optionally selected from 1, 2, 3, or 4 independently selected R 5Ais substituted with a substituent, Each R b5 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 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally selected from 1, 2, 3, or 4 independently selected R 5A is substituted with a substituent, Each R 5A are 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, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a51 , S.R. 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 , N.R. c51 R d51 , N.R. c51 C(O)R b51 , N.R. c51 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)NR c51 R d51 , S(O)2R b51 , and S(O)NR c51 R d51 wherein C is selected from 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 5-6 membered heteroaryl-C 1-4 alkyl is each optionally selected from 1, 2, 3, or 4 independently selected R 5B is substituted with a substituent, Each R a51 , R c51 , and R d51 are independent, 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 5-6 membered heteroaryl-C 1-4 alkyl, 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 5-6 membered heteroaryl-C 1-4 alkyl is each optionally selected from 1, 2, 3, or 4 independently selected R 5B is substituted with a substituent, Each R 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 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally selected from 1, 2, 3, or 4 independently selected R 5B is substituted with a substituent, Each R 5B are independently H, halo, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-4 Cycloalkyl, OR a52 , S.R. 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 , N.R. c52 R d52 , N.R. c52 C(O)R b52 , N.R. c52 C(O)OR a52 , N.R. c52 C(O)NR c52 R d52 , N.R. c52 S(O)2R b52 , N.R. c52 S(O)NR 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 independently, C 1-6 Alkyl and C 1-6 haloalkyl.

[0105] In some embodiments, Each R a5 , R c5 , and R d5 are independent, 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 5-6 membered heteroaryl-C 1-4 alkyl, 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 5-6 membered heteroaryl-C 1-4 alkyl is each optionally selected from 1, 2, 3, or 4 independently selected R 5A is substituted with a substituent, Each R b5 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 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally selected from 1, 2, 3, or 4 independently selected R5A is substituted with a substituent, Each R 5A are independently H, halo, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-4 Cycloalkyl, OR a51 , S.R. 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 , N.R. c51 R d51 , N.R. c51 C(O)R b51 , N.R. c51 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)NR 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 independently, C 1-6 Alkyl and C 1-6 haloalkyl.

[0106] In some embodiments, Each R a5 , R c5 , and R d5 are independent, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, 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 joined to one, two, three, or four independently selected R 5A is substituted with a substituent, Each R b5 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, each of which is optionally followed by 1, 2, 3, or 4 independently selected R 5A is substituted with a substituent, Each R 5A are independently H, halo, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-4 Cycloalkyl, OR a51 , and NR c51 R d51 is selected from Each R a51 , R c51 , and R d51 are independently H and C 1-3 alkyl, Each R b51 independently, C 1-3 It is alkyl.

[0107] In some embodiments, Each R a5 , R c5 , and R d5 are independent, H, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 3-4 cycloalkyl; Each R b5 independently, 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; 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 a monocyclic 4- to 7-membered heterocycloalkyl; R 1 are 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, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a1 , S.R. a1 , and NR c1 R d1 wherein 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- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl is each optionally selected from 1, 2, 3, or 4 independently selected R 1A is substituted with a substituent, Each R a1 , R c1 , and R d1 are independent, 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 5-6 membered heteroaryl-C 1-4 alkyl, 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 5-6 membered heteroaryl-C 1-4 alkyl is each optionally selected from 1, 2, 3, or 4 independently selected R 1A is substituted with a substituent, Each R b1 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 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally selected from 1, 2, 3, or 4 independently selected R 1A is substituted with a substituent, Each R 1A are 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, 5-6 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 , N.R. c11 R d11 , N.R. c11 C(O)R b11 , N.R. c11 C(O)OR a11 , N.R. c11 C(O)NR c11 R d11 , N.R. c11 S(O)2R b11 , N.R. c11 S(O)NR c11 R d11 , S(O)2R b11 , and S(O)NR c11 R d11 wherein C is selected from 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 5-6 membered heteroaryl-C 1-4 alkyl is each optionally selected from 1, 2, 3, or 4 independently selected R 1B is substituted by a substituent, Each R a11 , R c11 , and R d11 are independent, H, C 1-6 Alkyl, and C 1-6 haloalkyl; Each R b11 independently, C 1-6 Alkyl and C1-6 haloalkyl; Each R 1B independently H, D, and OR a12 is selected from Each R a12 are independently H and C 1-6 alkyl, R 2 But, H, halo, CN, C 1-3 Alkyl, and C 1-3 haloalkyl; Each R 3 are independent, H, halo, C 1-3 alkyl, and cyclopropyl; R 4 But 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 5-6 membered heteroaryl-C 1-4 alkyl, 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 5-6 membered heteroaryl-C 1-4 alkyl is each optionally selected from 1, 2, 3, or 4 independently selected R 4A is substituted by a substituent, Each R 4A are independently 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, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a41 , S.R. 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 , N.R. c41 R d41 , N.R. c41 C(O)R b41 , N.R. c41 C(O)OR a41 , N.R. c41 C(O)NR c41 R d41 , N.R. c41 S(O)2R b41 , N.R. c41 S(O)NR c41 R d41 , S(O)2R b41 , and S(O)NR c41 R d41 wherein C is selected from 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 5-6 membered heteroaryl-C 1-4 alkyl is optionally selected from 1, 2, or 3 independently selected R 4B is substituted with a substituent, Each R a41 , R c41 , and Rd41 are independent, 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 5-6 membered heteroaryl-C 1-4 alkyl, 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 5-6 membered heteroaryl-C 1-4 alkyl is optionally selected from 1, 2, or 3 independently selected R 4B is substituted with a substituent, Each R b41 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 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally followed by 1, 2, or 3 independently selected R 4B is substituted with a substituent, Each R 4B are 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)NR 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 independently, C 1-6 Alkyl and C 1-6 haloalkyl; Each R 5 are 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- 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, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a5 , S.R. a5 , NHOR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 ,OC(O)R b5 , OC(O)NRc5 R d5 , N.R. c5 R d5 , N.R. c5 C(O)R b5 , N.R. c5 C(O)OR a5 , N.R. c5 C(O)NR c5 R d5 , N.R. c5 S(O)2R b5 , N.R. c5 S(O)NR c5 R d5 , S(O)2R b5 , and S(O)NR c5 R d5 wherein 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- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl is each optionally selected from 1, 2, 3, or 4 independently selected R 5A is substituted by a substituent, Each R a5 , R c5 , and R d5 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- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, 1-6Alkyl, 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 5-6 membered heteroaryl-C 1-4 alkyl is each optionally selected from 1, 2, 3, or 4 independently selected R 5A is substituted with a substituent, Each R b5 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 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally selected from 1, 2, 3, or 4 independently selected R 5A is substituted with a substituent, Each R 5A are 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, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a51 , S.R. 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 , N.R. c51 R d51 , N.R. c51 C(O)R b51 , N.R. c51 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)NR c51 R d51 , S(O)2R b51 , and S(O)NR c51 R d51 wherein C is selected from 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 5-6 membered heteroaryl-C 1-4 alkyl is each optionally selected from 1, 2, 3, or 4 independently selected R 5B is substituted with a substituent, Each R a51 , R c51 , and R d51 are independent, 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 5-6 membered heteroaryl-C 1-4 alkyl, 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 5-6 membered heteroaryl-C 1-4 alkyl is each optionally selected from 1, 2, 3, or 4 independently selected R 5B is substituted with a substituent, Each R b51 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 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally selected from 1, 2, 3, or 4 independently selected R 5B is substituted with a substituent, Each R 5B are independently H, halo, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-4 Cycloalkyl, OR a52 , S.R. 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 , N.R. c52 R d52 , N.R. c52 C(O)R b52 , N.R. c52 C(O)OR a52 , N.R. c52 C(O)NR c52R d52 , N.R. c52 S(O)2R b52 , N.R. c52 S(O)NR 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 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; 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 a monocyclic 4- to 7-membered heterocycloalkyl; R 1 are 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, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a1 , and NR c1 R d1 wherein C is selected from 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 5-6 membered heteroaryl-C 1-4 alkyl is each optionally selected from 1, 2, 3, or 4 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 3-7 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 5-6 membered heteroaryl-C 1-4 alkyl, 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 5-6 membered heteroaryl-C 1-4 alkyl is each optionally selected from 1, 2, 3, or 4 independently selected R 1A is substituted with a substituent, Each R b1 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 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally selected from 1, 2, 3, or 4 independently selected R 1A is substituted with a substituent, Each R 1A are 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, 5-6 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 , N.R. c11 R d11 , N.R. c11 C(O)R b11 , N.R. c11 C(O)OR a11 , N.R. c11 C(O)NR c11 R d11 , N.R. c11 S(O)2R b11 , N.R. c11 S(O)NR c11 R d11 , S(O)2R b11 , and S(O)NR c11 R d11 is selected from Each R a11 , R c11 , and R d11 are independent, H, C 1-6 Alkyl, and C 1-6haloalkyl; Each R b11 independently, C 1-6 Alkyl and C 1-6 haloalkyl; R 2 But, H, halo, CN, C 1-3 Alkyl, and C 1-3 haloalkyl; Each R 3 are independent, H, halo, C 1-3 alkyl, and cyclopropyl; R 4 But 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 5-6 membered heteroaryl-C 1-4 alkyl, 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 5-6 membered heteroaryl-C 1-4 alkyl is each optionally selected from 1, 2, 3, or 4 independently selected R 4A is substituted by a substituent, Each R 4A are independently 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, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a41 , S.R. 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 , N.R. c41 R d41 , N.R. c41 C(O)R b41 , N.R. c41 C(O)OR a41 , N.R. c41 C(O)NR c41 R d41 , N.R. c41 S(O)2R b41 , N.R. c41 S(O)NR c41 R d41 , S(O)2R b41 , and S(O)NR c41 R d41 wherein C is selected from 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 5-6 membered heteroaryl-C 1-4 alkyl is optionally selected from 1, 2, or 3 independently selected R 4B is substituted with a substituent, Each R a41 , R c41 , and R d41 are independent, 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 5-6 membered heteroaryl-C 1-4 alkyl, 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 5-6 membered heteroaryl-C 1-4 alkyl is optionally selected from 1, 2, or 3 independently selected R 4B is substituted with a substituent, Each R b41 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 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally followed by 1, 2, or 3 independently selected R 4B is substituted with a substituent, Each R 4B are 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 , 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)NR 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 independently, C 1-6 Alkyl and C 1-6 haloalkyl; Each R 5 are 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- 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, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a5 , S.R. 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, N.R. c5 R d5 , N.R. c5 C(O)R b5 , N.R. c5 C(O)OR a5 , N.R. c5 C(O)NR c5 R d5 , N.R. c5 S(O)2R b5 , N.R. c5 S(O)NR c5 R d5 , S(O)2R b5 , and S(O)NR c5 R d5 wherein 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- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl is each optionally selected from 1, 2, 3, or 4 independently selected R 5A is substituted by a substituent, Each R a5 , R c5 , and R d5 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- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, 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 5-6 membered heteroaryl-C 1-4 alkyl is each optionally selected from 1, 2, 3, or 4 independently selected R 5A is substituted with a substituent, Each R b5 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 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally selected from 1, 2, 3, or 4 independently selected R 5A is substituted with a substituent, Each R 5A are 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, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a51 , S.R. 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 , N.R. c51 R d51 , N.R. c51 C(O)R b51 , N.R. c51 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)NR c51 R d51 , S(O)2R b51 , and S(O)NR c51 R d51 wherein C is selected from 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 5-6 membered heteroaryl-C 1-4 alkyl is each optionally selected from 1, 2, 3, or 4 independently selected R 5B is substituted with a substituent, Each R a51 , R c51 , and R d51 are independent, 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 5-6 membered heteroaryl-C 1-4 alkyl, 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 5-6 membered heteroaryl-C 1-4 alkyl is each optionally selected from 1, 2, 3, or 4 independently selected R 5B is substituted with a substituent, Each R b51 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 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally selected from 1, 2, 3, or 4 independently selected R 5B is substituted with a substituent, Each R 5B are independently H, halo, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-4 Cycloalkyl, OR a52 , S.R. 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 , N.R. c52 R d52 , N.R. c52 C(O)R b52 , N.R. c52 C(O)OR a52 , N.R. c52 C(O)NR c52 R d52 , N.R.c52 S(O)2R b52 , N.R. c52 S(O)NR 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 independently, 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- 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, 5-6 membered heteroaryl-C 1-3 Alkyl, OR a1 , S.R. a1 , and NR 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 5-6 membered heteroaryl-C 1-3 alkyl is optionally selected from 1, 2, or 3 independently selected R 1A is substituted with a substituent, Each R a1 , R c1 , and R d1 are independent, 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, 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 optionally selected from 1, 2, or 3 independently selected R 1A is substituted with a substituent, Each R 1A 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 , N.R. c11 R d11 , N.R. c11 C(O)R b11 , N.R. c11 C(O)OR a11 , N.R. c11 C(O)NR c11 Rd11 , N.R. c11 S(O)2R b11 , N.R. c11 S(O)NR c11 R d11 , S(O)2R b11 , and S(O)NR c11 R d11 wherein C is selected from 1-6 Alkyl, C 1-6 Haloalkyl, and C 3-4 cycloalkyl is optionally selected from 1, 2, or 3 independently selected R 1B is substituted by a substituent, Each R a11 , R c11 , and R d11 are independent, H, C 1-6 Alkyl, and C 1-6 haloalkyl; Each R b11 independently, C 1-6 Alkyl and C 1-6 haloalkyl; Each R 1B independently H, D, and OR a12 is selected from Each R a12 are independently H and C 1-6 alkyl, R 2 But, H, halo, CN, C 1-3 Alkyl, and C 1-3 haloalkyl; Each R 3 are independent, H, halo, C 1-3 alkyl, and cyclopropyl; R 4 But 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, 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 optionally selected from one or two independently selected R 4A is substituted by a substituent, Each R 4A are 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 , N.R. c41 R d41 , N.R. c41 C(O)R b41 , N.R. c41 C(O)OR a41 , N.R. c41 C(O)NR c41 R d41 , N.R. c41 S(O)2R b41 , N.R. c41 S(O)NR c41 R d41 , S(O)2R b41 , and S(O)NR c41 R d41 wherein C is selected from 1-6 Alkyl, C 1-6 Haloalkyl, and C 3-4 cycloalkyl is optionally selected from 1, 2, or 3 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, and C 3-4 cycloalkyl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, and C 3-4cycloalkyl is optionally selected from one or two independently selected R 4B is substituted with a substituent, Each R b41 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 3-4 cycloalkyl, each of which is optionally selected from one or two independently selected R 4B is substituted with a substituent, Each R 4B are independently H, halo, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, OR a42 , and NR c42 R d42 is selected from Each R a42 , R c42 , and R d42 are independent, H, C 1-3 Alkyl, and C 1-3 haloalkyl; Each R b42 independently, C 1-3 Alkyl and C 1-3 haloalkyl; Each R 5 are 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, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a5 , S.R. 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 , N.R.c5 R d5 , N.R. c5 C(O)R b5 , N.R. c5 C(O)OR a5 , N.R. c5 C(O)NR c5 R d5 , N.R. c5 S(O)2R b5 , N.R. c5 S(O)NR c5 R d5 , S(O)2R b5 , and S(O)NR c5 R d5 wherein C is selected from 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 5-6 membered heteroaryl-C 1-4 alkyl is each optionally selected from 1, 2, 3, or 4 independently selected R 5A is substituted by a substituent, Each R a5 , R c5 , and R d5 are independent, 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 5-6 membered heteroaryl-C 1-4 alkyl, 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 5-6 membered heteroaryl-C 1-4 alkyl is each optionally selected from 1, 2, 3, or 4 independently selected R 5A is substituted with a substituent, Each R b5 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 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally selected from 1, 2, 3, or 4 independently selected R 5A is substituted with a substituent, Each R 5A are independently H, halo, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-4 Cycloalkyl, OR a51 , S.R. 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 , N.R. c51 R d51 , N.R. c51 C(O)R b51 , N.R. c51 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)NR 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 independently, 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 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- 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, 5-6 membered heteroaryl-C 1-3 Alkyl, OR a1 and NR c1 R d1 and 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 5-6 membered heteroaryl-C 1-3 alkyl is optionally selected from one or two independently selected R 1A is substituted with a substituent, Each R 1A are 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 , N.R. c11 R d11 , N.R. c11 C(O)R b11 , N.R. c11 C(O)OR a11 , N.R. c11 C(O)NR c11 R d11 , N.R. c11 S(O)2R b11 , N.R. c11 S(O)NR c11 R d11 , S(O)2R b11 , and S(O)NR c11 R d11 is selected from Each R a11 , R c11 , and R d11 are independent, H, C 1-6 Alkyl, and C 1-6 haloalkyl; Each R b11 independently, C 1-6 Alkyl and C 1-6 haloalkyl; R 2 But, H, halo, CN, C 1-3 Alkyl, and C 1-3 haloalkyl; Each R 3 are independent, H, halo, C1-3 alkyl, and cyclopropyl; R 4 But C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, 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 joined to one, two, three, or four independently selected R 4A is substituted by a substituent, Each R 4A are 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 , N.R. c41 R d41 , N.R. c41 C(O)R b41 , N.R. c41 C(O)OR a41 , N.R. c41 C(O)NR c41 R d41 , N.R. c41 S(O)2R b41 , N.R. c41 S(O)NR c41 R d41 , S(O)2R b41 , and S(O)NR c41 R d41 wherein C is selected from 1-6 Alkyl, C 1-6 Haloalkyl, and C 3-4 cycloalkyl is optionally selected from 1, 2, or 3 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, and C 3-4 cycloalkyl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, and C 3-4 cycloalkyl is optionally selected from one or two independently selected R 4B is substituted with a substituent, Each R b41 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 3-4 cycloalkyl, each of which is optionally selected from one or two independently selected R 4B is substituted with a substituent, Each R 4B are independently H, halo, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, OR a42 , and NR c42 R d42 is selected from Each R a42 , R c42 , and R d42 are independent, H, C 1-3 Alkyl, and C 1-3 haloalkyl; Each R b42 independently, C 1-3 Alkyl and C 1-3 haloalkyl; Each R 5 are 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, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a5, S.R. 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 , N.R. c5 R d5 , N.R. c5 C(O)R b5 , N.R. c5 C(O)OR a5 , N.R. c5 C(O)NR c5 R d5 , N.R. c5 S(O)2R b5 , N.R. c5 S(O)NR c5 R d5 , S(O)2R b5 , and S(O)NR c5 R d5 wherein C is selected from 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 5-6 membered heteroaryl-C 1-4 alkyl is each optionally selected from 1, 2, 3, or 4 independently selected R 5A is substituted by a substituent, Each R a5 , R c5 , and R d5 are independent, 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 1-4Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, 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 5-6 membered heteroaryl-C 1-4 alkyl is each optionally selected from 1, 2, 3, or 4 independently selected R 5A is substituted with a substituent, Each R b5 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 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally selected from 1, 2, 3, or 4 independently selected R 5A is substituted with a substituent, Each R 5A are independently H, halo, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-4 Cycloalkyl, OR a51 , S.R. 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 , N.R. c51 R d51 , N.R. c51 C(O)R b51 , N.R.c51 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)NR 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 independently, 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- to 10-membered heteroaryl; Ring moiety B is piperidinyl; R 1 But H, C 1-6 Alkyl, phenyl, 5- to 7-membered heterocycloalkyl, OR a1 , S.R. 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 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 alkyl, 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, phenyl, 4-6 membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkyl and 4- to 6-membered heterocycloalkyl-C 1-3 alkyl is optionally selected from 1, 2, or 3 independently selected R 1A is substituted with a substituent, Each R 1A 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)OC 1-4 alkyl, 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)OC 1-4 alkyl is optionally selected from 1, 2, or 3 independently selected R 1B is substituted with a substituent, Each R 1B independently, H, D, and OC 1-4 alkyl, R 2 is H or halo, Each R 3are independently selected from H, F, or methyl; R 4 But 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, 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 is optionally selected from one or two independently selected R 4A is substituted by a substituent, Each R 4A are 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 , N.R. c41 R d41 , N.R. c41 C(O)R b41 , N.R. c41 C(O)OR a41 , N.R. c41 C(O)NR c41 R d41 , N.R. c41 S(O)2R b41 , N.R. c41 S(O)NR c41 R d41 , S(O)2R b41 , and S(O)NR c41 R d41 wherein C is selected from 1-6 Alkyl, C 1-6 Haloalkyl, and C 3-4cycloalkyl is optionally selected from 1, 2, or 3 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, and C 3-4 cycloalkyl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, and C 3-4 cycloalkyl is optionally selected from one or two independently selected R 4B is substituted with a substituent, Each R b41 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 3-4 cycloalkyl, each of which is optionally selected from one or two independently selected R 4B is substituted with a substituent, Each R 4B are independently H, halo, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, OR a42 , and NR c42 R d42 is selected from Each R a42 , R c42 , and R d42 are independent, H, C 1-3 Alkyl, and C 1-3 haloalkyl; Each R b42 independently, C 1-3 Alkyl and C 1-3 haloalkyl; Each R 5 are 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 Rd5 , C(O)OR a5 , N.R. c5 R d5 , N.R. c5 C(O)R b5 , N.R. c5 S(O)2R b5 , S(O)2R b5 , and S(O)NR c5 R d5 wherein C is selected from 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 joined to one, two, three, or four independently selected R 5A is substituted by a substituent, Each R a5 , R c5 , and R d5 are independent, 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, 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 joined to one, two, three, or four independently selected R 5A is substituted with a substituent, Each R b5 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, each of which is optionally followed by 1, 2, 3, or 4 independently selected R 5A is substituted with a substituent, Each R 5A are independently H, halo, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-4 Cycloalkyl, OR a51 , and NR c51 Rd51 is selected from Each R a51 , R c51 , and R d51 are independently H and C 1-3 alkyl, Each R b51 independently, C 1-3 It is alkyl.

[0113] In some embodiments, n is 0 or 1, p is 0 or 1, Ring moiety A is a 5- to 10-membered heteroaryl; Ring moiety B is piperidinyl; R 1 But H or OR a1 and Each R a1 are independent, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkyl and 4-6 membered heterocycloalkyl-C 1-3 alkyl, 1-6 Alkyl, C 1-6 Haloalkyl C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkyl and 4-6 membered heterocycloalkyl-C 1-3 alkyl is optionally selected from one or two independently selected R 1A is substituted with a substituent, Each R 1A are 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 1-4Alkyl, C 1-3 Alkoxy-C 1-4 Alkyl, and C 3-4 cycloalkyl; R 2 is H or halo, Each R 3 are independently selected from H, F, or methyl; R 4 But C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, 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 joined to one, two, three, or four independently selected R 4A is substituted by a substituent, Each R 4A are 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 , N.R. c41 R d41 , N.R. c41 C(O)R b41 , N.R. c41 C(O)OR a41 , N.R. c41 C(O)NR c41 R d41 , N.R. c41 S(O)2R b41 , N.R. c41 S(O)NR c41 R d41 , S(O)2R b41 , and S(O)NR c41 R d41 wherein C is selected from1-6 Alkyl, C 1-6 Haloalkyl, and C 3-4 cycloalkyl is optionally selected from 1, 2, or 3 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, and C 3-4 cycloalkyl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, and C 3-4 cycloalkyl is optionally selected from one or two independently selected R 4B is substituted with a substituent, Each R b41 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 3-4 cycloalkyl, each of which is optionally selected from one or two independently selected R 4B is substituted with a substituent, Each R 4B are independently H, halo, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, OR a42 , and NR c42 R d42 is selected from Each R a42 , R c42 , and R d42 are independent, H, C 1-3 Alkyl, and C 1-3 haloalkyl; Each R b42 independently, C 1-3 Alkyl and C 1-3 haloalkyl; Each R 5 are 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, ORa5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , N.R. c5 R d5 , N.R. c5 C(O)R b5 , N.R. c5 S(O)2R b5 , S(O)2R b5 , and S(O)NR c5 R d5 wherein C is selected from 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 joined to one, two, three, or four independently selected R 5A is substituted by a substituent, Each R a5 , R c5 , and R d5 are independent, 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, 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 joined to one, two, three, or four independently selected R 5A is substituted with a substituent, Each R b5 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, each of which is optionally followed by 1, 2, 3, or 4 independently selected R 5A is substituted with a substituent, Each R 5A are independently H, halo, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C3-4 Cycloalkyl, OR a51 , and NR c51 R d51 is selected from Each R a51 , R c51 , and R d51 are independently H and C 1-3 alkyl, Each R b51 independently, C 1-3 It is alkyl.

[0114] In some embodiments, n is 0 or 1, p is 0 or 1, Ring moiety A is a 5- to 10-membered heteroaryl; Ring moiety B is piperidinyl; R 1 But H or OR a1 and Each R a1 are independent, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkyl and 4-6 membered heterocycloalkyl-C 1-3 alkyl, 1-6 Alkyl, C 1-6 Haloalkyl C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkyl and 4-6 membered heterocycloalkyl-C 1-3 alkyl is optionally selected from 1, 2, or 3 independently selected R 1A is substituted with a substituent, Each R 1A Independently, H, D, halo, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, OR a11 , and C(O)OR a11 wherein C is selected from 1-6 Alkyl and C 1-6haloalkyl, each optionally selected from 1, 2, or 3 independently selected R 1B is substituted with a substituent, Each R a11 are independently H and C 1-4 alkyl, 1-4 The alkyl is optionally selected from one, two, or three independently selected R 1B is substituted by a substituent, Each R b11 independently, C 1-6 Alkyl and C 1-6 haloalkyl; Each R 1B independently H, D, and OR a12 is selected from Each R a12 are independently H and C 1-6 alkyl, R 2 is H or halo, Each R 3 are independently selected from H, F, or methyl; R 4 But C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, 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 joined to one, two, three, or four independently selected R 4A is substituted by a substituent, Each R 4A are 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 c41R d41 , N.R. c41 R d41 , N.R. c41 C(O)R b41 , N.R. c41 C(O)OR a41 , N.R. c41 C(O)NR c41 R d41 , N.R. c41 S(O)2R b41 , N.R. c41 S(O)NR c41 R d41 , S(O)2R b41 , and S(O)NR c41 R d41 wherein C is selected from 1-6 Alkyl, C 1-6 Haloalkyl, and C 3-4 cycloalkyl is optionally selected from 1, 2, or 3 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, and C 3-4 cycloalkyl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, and C 3-4 cycloalkyl is optionally selected from one or two independently selected R 4B is substituted with a substituent, Each R b41 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 3-4 cycloalkyl, each of which is optionally selected from one or two independently selected R 4B is substituted with a substituent, Each R 4B are independently H, halo, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, OR a42 , and NR c42 R d42 is selected from Each R a42, R c42 , and R d42 are independent, H, C 1-3 Alkyl, and C 1-3 haloalkyl; Each R b42 independently, C 1-3 Alkyl and C 1-3 haloalkyl; Each R 5 are 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 , N.R. c5 R d5 , N.R. c5 C(O)R b5 , N.R. c5 S(O)2R b5 , S(O)2R b5 , and S(O)NR c5 R d5 wherein C is selected from 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 joined to one, two, three, or four independently selected R 5A is substituted by a substituent, Each R a5 , R c5 , and R d5 are independent, 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, 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 joined to one, two, three, or four independently selected R 5A is substituted with a substituent, Each R b5 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, each of which is optionally followed by 1, 2, 3, or 4 independently selected R 5A is substituted with a substituent, Each R 5A are independently H, halo, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-4 Cycloalkyl, OR a51 , and NR c51 R d51 is selected from Each R a51 , R c51 , and R d51 are independently H and C 1-3 alkyl, Each R b51 independently, C 1-3 It is alkyl.

[0115] In some embodiments, n is 0 or 1, p is 0 or 1, ring moiety A is a 5-10 membered heteroaryl having 1 or 2 N ring-forming atoms; Ring moiety B is piperidinyl; R 1 are independent, H, C 1-6 Alkyl, phenyl, 5- to 7-membered heterocycloalkyl, OR a1 , S.R. a1 , and NR c1 R d1 wherein C is selected from 1-6 alkyl, phenyl, and 5- to 7-membered heterocycloalkyl are each optionally substituted with one or two independently selected R 1Ais 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-C 1-3 Alkyl and 4- to 6-membered heterocycloalkyl-C 1-3 alkyl, 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, phenyl, 4-6 membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkyl and 4- to 6-membered heterocycloalkyl-C 1-3 alkyl is optionally selected from 1, 2, or 3 independently selected R 1A is substituted with a substituent, Each R 1A Independently, D, halo, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-4 Cycloalkyl, OR a11 , and C(O)OR a11 wherein C is selected from 1-6 Alkyl, and C 1-6 haloalkyl, each optionally selected from 1, 2, or 3 independently selected R 1B is substituted with a substituent, Each R a11 are independently H and C 1-4 alkyl, 1-4 The alkyl is optionally selected from one, two, or three independently selected R 1B is substituted by a substituent, Each R 1B independently, H, D, and OC 1-4 alkyl, R 2 is H or F, Each R 3 is independently selected from H or methyl; R4 But C 1-6 Alkyl, C 3-6 Cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl-C 1-4 alkyl, 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 selected from 1, 2, 3, or 4 independently selected R 4A is substituted by a substituent, Each R 4A are independent, H, C 1-6 Alkyl, OH, and NR c41 R d41 is selected from Each R c41 and R d41 are independent, H, C 1-6 Alkyl, and C 1-6 haloalkyl; Each R 5 are independently H, halo, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-4 Cycloalkyl, OR a5 , and NR c5 R d5 is selected from Each R a5 , R c5 , and R d5 are independent, H, C 1-6 Alkyl, and C 1-6 haloalkyl.

[0116] In some embodiments, n is 0 or 1, p is 0 or 1, ring moiety A is a 5-10 membered heteroaryl having 1 or 2 N ring-forming atoms; Ring moiety B is piperidinyl; R 1 independently, H and OR a1 is selected from Each R a1 are independent, H, C1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkyl and 4- to 6-membered heterocycloalkyl-C 1-3 alkyl, 1-6 Alkyl, C 1-6 Haloalkyl C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkyl and 4- to 6-membered heterocycloalkyl-C 1-3 alkyl is optionally selected from one or two independently selected R 1A is substituted with a substituent, Each R 1A independently, 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 But C 1-6 Alkyl and C 3-6 cycloalkyl, wherein C 1-6 Alkyl and C 3-6 cycloalkyl is optionally selected from 1, 2, 3, or 4 independently selected R 4A is substituted by a substituent, Each R 4A are independently H and C 1-6 alkyl, Each R 5 are independently H, halo, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-4 Cycloalkyl, OR a5 , and NR c5 R d5 is selected from Each R a5 , R c5 , and R d5 are independent, H, C 1-6 Alkyl, and C 1-6 haloalkyl.

[0117] In some embodiments, the compound is a compound of formula (II): [ka] or a pharmaceutically acceptable salt thereof.

[0118] In some embodiments, the compound is a compound of formula (IIa): [ka] or a pharmaceutically acceptable salt thereof.

[0119] In some embodiments, the compound is a compound of formula (IIb): [ka] or a pharmaceutically acceptable salt thereof.

[0120] In some embodiments, the compound is a compound of formula (III): [ka] or a pharmaceutically acceptable salt thereof.

[0121] In some embodiments, the compound is a compound of formula (IIIa): [ka] or a pharmaceutically acceptable salt thereof.

[0122] In some embodiments, the compound is a compound of formula (IIIb): [ka] or a pharmaceutically acceptable salt thereof.

[0123] In some embodiments, the compound is a compound of formula (IV): [ka] or a pharmaceutically acceptable salt thereof, wherein: X 1 is a bond, CH2, or CH2CH2, X 2 is a bond or CH2.

[0124] In some embodiments, the compound is a compound of formula (V): [ka] or a pharmaceutically acceptable salt thereof.

[0125] In some embodiments, the compound is a compound of formula (Va): [ka] or a pharmaceutically acceptable salt thereof.

[0126] In some embodiments, the compound is a compound of formula (Vb): [ka] or a pharmaceutically acceptable salt thereof.

[0127] In some embodiments, the compound is a compound of formula (Vc): [ka] or a pharmaceutically acceptable salt thereof.

[0128] In some embodiments, the compound is a compound of formula (Vd): [ka] or a pharmaceutically acceptable salt thereof.

[0129] In some embodiments, the compound is a compound of formula (VI): [ka] or a pharmaceutically acceptable salt thereof.

[0130] In some embodiments, the compound is a compound of formula (VIa): [ka] or a pharmaceutically acceptable salt thereof.

[0131] In some embodiments, the compound is a compound of formula (VIb): [ka] or a pharmaceutically acceptable salt thereof.

[0132] In some embodiments, the compound is a compound of formula (VIc): [ka] or a pharmaceutically acceptable salt thereof.

[0133] In some embodiments, the compound is a compound of formula (VIIa): [ka] or a pharmaceutically acceptable salt thereof.

[0134] In some embodiments, the compound is a compound of formula (VIIIa): [ka] or a pharmaceutically acceptable salt thereof.

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

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

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

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

[0139] In some embodiments, the compound is a compound of formula (IXc): [ka] 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 where 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, an “alkyl,” “alkenyl,” “alkynyl,” “aryl,” “phenyl,” “cycloalkyl,” “heterocycloalkyl,” or “heteroaryl” substituent, as described herein, or “—C 1-4 One, two, three, four, five, six, seven, or eight hydrogen atoms bonded to carbon atoms of the "alkyl-" and "alkylene" linking group are optionally replaced with deuterium atoms.

[0149] It will be 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, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0150] At various points in this specification, divalent linking substituents are described. 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 -NR(CR'R'') n -and-(CR'R'') n It includes both NR- When a structure explicitly requires a linking group, the Markush variable recited for that group is understood to be the linking group.

[0151] The term "n-membered" (where n is an integer) typically describes the number of ring-forming atoms in a moiety, where n is the number of ring-forming atoms. 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 independently selected, and substitution may occur 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, for example, oxo, can replace two hydrogen atoms. It is understood that substitution at a given atom is limited by valence, not to exceed the normal valence of the designated atom, and that the substitution results in a stable compound.

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

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

[0155] In any component or formula for a compound, any variable (e.g., R G ) occurs more than one time, its definition on each occurrence is independent of its definition at every other occurrence. Thus, for example, a group may be selected from 1, 2, 3 or 4 independently selected R G When indicated to be substituted with a substituent, the group may optionally be substituted with up to four R GIn each occurrence, R G is R G is selected independently from the definition of

[0156] In some embodiments, when multiple optional substituents are specified in the form: [ka] It is understood that the substituent R can occur p times on the ring and that R can be a different moiety at each occurrence. Each R group can be (CH) n It is understood that any hydrogen atom bonded to a ring atom may be replaced, including one or both of the hydrogen atoms in the ring. Furthermore, when the variable Q is defined to include hydrogen, such as when Q is stated to be CH, NH, etc. in the above example, any floating substituent, such as R in the above example, can replace a hydrogen in the Q variable as well as a hydrogen in any other non-variable component of the ring.

[0157] Throughout the definition, "C n-m The term "" denotes a range inclusive of 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, "C" when used alone or in combination with other terms n-mThe term "alkyl" refers to a saturated hydrocarbon group having n to m carbons, which may be straight-chained or branched. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl (Me), ethyl (Et), n-propyl (n-Pr), isopropyl (i-Pr), n-butyl, tert-butyl, isobutyl, sec-butyl, and higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, and the like. In some embodiments, alkyl groups contain 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 carbons. Exemplary alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like. 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 carbons. Exemplary alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, and the like. 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 refers to an alkyl group having n to m carbons. n-m The term "alkoxy" refers to a group of formula -O-alkyl, where the alkyl group has n to m carbons. 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), and the like. 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 formula -NH2.

[0162] As used herein, the term "aryl," used alone or in combination with other terms, refers to an aromatic hydrocarbon group, which may be monocyclic or polycyclic (e.g., having two fused rings). n-m The term "aryl" refers to an aryl group having n to m ring carbon atoms. In some embodiments, an aryl group has 6 to 10 carbon atoms. In some embodiments, an aryl group is phenyl or naphthyl. In some embodiments, an 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 exclusively fluorinated. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0165] As used herein, "C" when used alone or in combination with other terms n-mThe term "haloalkyl" refers to an alkyl group having 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 n to m carbon atoms. In some embodiments, the haloalkyl group is exclusively fluorinated. In some embodiments, the alkyl group of the haloalkyl has 1 to 6, 1 to 4, or 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 1 fluoro atom to 2s+1 fluoro atoms, where "s" is the number of carbon atoms in the alkyl group, and the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group of the fluoroalkyl has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Exemplary fluoroalkyl groups include CF, C2F5, CHF2, CH2F, and the like.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0189] As used herein, "C n-m Alkoxy-C o-p The term "alkyl" refers to a group of the formula -(C n-m alkylene)-O(C o-p As used herein, "C" refers to a group of alkylene groups having n to m carbon atoms and alkyl groups having o to p carbon atoms. 1-6 Alkoxy-C 1-6 The term "alkyl" refers to a group of the formula -(C 1-6 alkylene)-O(C 1-6 As used herein, "C" refers to a group of alkyl groups. 1-3 Alkoxy-C 1-3 The term "alkyl" refers to a group of the formula -(C 1-3 alkylene)-O(C 1-3 It refers to a group of (alkyl).

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

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

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

[0193] As used herein, "C n-m The term "alkylcarbonyloxy" refers to a group of formula -OC(O)-alkyl, where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group of the alkylcarbonyloxy has 1 to 6, 1 to 4, or 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 formula -OC(O)-NH-alkyl, where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group of the alkylaminocarbonyloxy has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

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

[0197] As used herein, "C n-m "Alkoxycarbonylamino" refers to a radical of the formula -NHC(O)-O-alkyl, where the alkyl radical has n to m carbon atoms.

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

[0199] As used herein, the term "carbonyl," employed 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, including cyclized alkyl and alkenyl groups. Cycloalkyl groups can include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings), spirocyclic, and bridged rings (e.g., bridged bicycloalkyl groups). Ring-forming carbon atoms of a cycloalkyl group can be optionally substituted with oxo or sulfido (e.g., C(O) or C(S)). The definition of cycloalkyl also includes moieties having one or more aromatic rings fused to (i.e., having a common bond with) a cycloalkyl ring, such as, for example, benzo or thienyl derivatives of cyclopentane, cyclohexane, etc. Cycloalkyl groups containing fused aromatic rings can be bonded through any ring-forming atom, including the ring-forming atoms of the fused aromatic ring. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, or 10 ring-forming carbon atoms (i.e., C 3-10 In some embodiments, the cycloalkyl can have a C 3-10 In some embodiments, the cycloalkyl is a monocyclic or bicyclic cycloalkyl. 3-7 In some embodiments, the cycloalkyl is a C 4-7 In some embodiments, the cycloalkyl is a C 4-10and spirocyclic or bridged cycloalkyl (e.g., bridged bicycloalkyl). 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 one 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, a heteroaryl is a 5-10-membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, and S. In some embodiments, a heteroaryl is a 5-6 monocyclic heteroaryl having 1 or 2 heteroatom ring members independently selected from N, O, and S. In some embodiments, a heteroaryl group contains 5 to 10 or 5 to 6 ring-forming atoms. In some embodiments, a 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 a heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different. Exemplary heteroaryl groups include 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, and the like. Examples of aryl include, but are not limited to, benzoyl, indolyl, benzothienyl, benzofuranyl, benzisoxazolyl, 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-azoborinyl, 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), wherein one or more of the ring-forming carbon atoms of the heterocycloalkyl are replaced with a heteroatom selected from N, O, or S, and the ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group can be optionally substituted with one or more oxo or sulfido (e.g., C(O), S(O), C(S), or S(O)). Heterocycloalkyl groups include monocyclic and polycyclic (e.g., having two fused rings) systems. Heterocycloalkyl groups include monocyclic and polycyclic 4- to 10-membered, 4- to 7-membered, and 5- to 6-membered heterocycloalkyl groups. Heterocycloalkyl groups can also include spirocyclic and bridged rings. A heterocycloalkyl group can be bonded through a ring-forming carbon atom or ring-forming heteroatom. In some embodiments, a heterocycloalkyl group contains zero to three double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds.

[0203] Also included within the definition of heterocycloalkyl are moieties having one or more aromatic rings fused to (i.e., sharing a bond with) a non-aromatic heterocyclic ring, such as, for example, benzo or thienyl derivatives of piperidine, morpholine, and azepine. Heterocycloalkyl groups containing fused aromatic rings can be bonded through any ring-forming atom, including those of the fused aromatic ring. In some embodiments, heterocycloalkyl groups contain 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, heterocycloalkyl groups have 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0204] In some embodiments, heterocycloalkyl is a 4-10 membered monocyclic, bicyclic, or tricyclic heterocycloalkyl having 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, where 1, 2, 3, or 4 ring-forming carbon or heteroatoms can be optionally substituted with one or more oxo or sulfido. In some embodiments, heterocycloalkyl is a 4-10 membered bicyclic heterocycloalkyl having 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, where 1, 2, 3, or 4 ring-forming carbon or heteroatoms can be optionally substituted with one or more oxo or sulfido. In some embodiments, heterocycloalkyl is a 4- to 7-membered monocyclic heterocycloalkyl having 1 or 2 ring-forming heteroatoms independently selected from N, O, and S, where 1, 2, or 3 ring-forming carbon or heteroatoms can be optionally replaced by one or more oxo or sulfido. In some embodiments, 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 heterocycloalkyl groups 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, Benzazapene, 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, diaza Bicyclo[3.1.1]heptanyl, azabicyclo[3.2.1]octanyl, diazabicyclo[3.2.1]octanyl, oxabicyclo[2.2.2]octanyl, azabicyclo[2.2.2]octanyl, azaadamantanyl, diazaadamantanyl, oxa-adamantanyl, azaspiro[3.3]heptanyl, diazaspiro[3.3]heptanyl, oxa-azaspiro[3.3]heptanyl, azaspiro[3.4]octanyl azaspiro[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, and the like.

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

[0207] As used herein, "C o-p Aryl-C n-m "Alkyl-" refers to a group of formula aryl-alkylene- where the aryl has from o to p carbon ring members and the alkylene linking group has from n to m carbon atoms.

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

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

[0210] As used herein, the term "alkylene" refers to a divalent straight or branched alkyl linking group. Examples of "alkylene groups" 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 "alkenylene groups" 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 "alkynylene groups" 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 or branched alkyl linking group (an "alkylene group"). For example, "C o-p Cycloalkyl-C n-m Alkyl-, C o-p Aryl-C n-m Alkyl-, Phenyl-C n-m alkyl-, heteroaryl-C n-m alkyl-, and heterocycloalkyl-C n-m "Alkyl-" contains an alkyl linking group. Examples of "alkyl linking groups" or "alkylene groups" 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.

[0214] As used herein, the term "oxo" refers to an oxygen atom (i.e., =0) as a divalent substituent which, when attached to carbon, forms a carbonyl group (e.g., C=O or C(O)), or to a nitrogen or sulfur heteroatom to form a nitroso, sulfinyl, or sulfonyl group.

[0215] As used herein, the term "independently selected from" means that each occurrence of a variable or substituent is independently selected at each occurrence from the corresponding list.

[0216] In certain places, definitions or embodiments refer to specific rings (e.g., azetidine rings, pyridine rings, etc.). Unless otherwise indicated, these rings can be bonded to any ring member as long as the valence of that atom is not exceeded. For example, an azetidine ring can be bonded at any position on the ring, while a pyridin-3-yl ring is bonded at the 3-position.

[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 intended. Compounds of the present disclosure containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically inactive starting materials are known in the art, for example, by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated herein. Cis and trans geometric isomers of the compounds of the present disclosure are described and can be isolated as a mixture of isomers or as separated isomeric forms. In some embodiments, the compounds have the (R) configuration. In some embodiments, the compounds have the (S) configuration. The formulas provided herein (e.g., Formulas (I), (II), etc.) include stereoisomers of the compounds.

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

[0219] Resolution of racemic mixtures 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 swapping of a single bond with an adjacent double bond and the accompanying migration of a proton. Tautomeric forms include prototropic tautomers, which are isomeric protonation states with 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 protons can occupy more than one position on a heterocyclic ring 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 may be in equilibrium or sterically locked into one form by appropriate substitution.

[0221] All compounds, and pharmaceutically acceptable salts thereof, may be found together with other substances such as water and solvents (eg, hydrates and solvates) or may be isolated.

[0222] In some embodiments, preparation of compounds may involve the addition of acids or bases, for example to affect catalysis of a desired reaction or the formation of salt forms, such as acid addition salts.

[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, a composition enriched in the compounds provided herein. Substantial separation can include a composition containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compounds provided herein, or salts thereof. Methods for isolating compounds and their salts are routine 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 herein by name or structure as one particular tautomeric form is intended to include other tautomeric forms unless otherwise specified.

[0225] The phrase "pharmaceutically acceptable" is used herein to refer to compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, within the scope of sound medical judgment, commensurate with a reasonable benefit / risk ratio.

[0226] The present 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 acid or base moiety into 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, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutically acceptable salts of the present disclosure include conventional non-toxic salts of the parent compound, formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound containing a basic or acidic moiety 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 or an organic solvent, or in a mixture of the two (generally, non-aqueous media such as ether, ethyl acetate, alcohol (e.g., methanol, ethanol, isopropanol, or butanol), or acetonitrile (ACN) are preferred). Lists 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, including their salts and stereoisomers, can be prepared using known organic synthesis techniques, or can be synthesized according to any of a number of possible synthetic routes, such as those provided in the schemes below.

[0228] The reactions for preparing the compounds described herein can be carried out in a suitable solvent that can be easily selected by those skilled in the art of organic synthesis. A suitable solvent can be substantially non-reactive with the starting material (reactant), intermediate, or product at the temperature at which the reaction is carried out (for example, 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 specific reaction step, a suitable solvent for a particular reaction step can be selected by those skilled in the art.

[0229] As used herein, the expressions "ambient temperature" or "room temperature" or "rt" are art-recognized and generally refer to a temperature, e.g., a reaction temperature, i.e., about the temperature of the room at 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 may involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be easily determined by one skilled in the art. The chemistry of protecting groups is described, for example, in 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., "Protective 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, product formation can be monitored by nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., ultraviolet-visible), mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC), liquid chromatography-mass spectroscopy (LCMS), or thin layer chromatography (TLC). Compounds can be purified by one skilled in the art by a variety of methods, including high performance liquid chromatography (HPLC) and normal phase silica chromatography.

[0232] The following schemes provide general guidance related to the preparation of compounds of the present invention. Those skilled in the art will appreciate that the preparations shown in the schemes may be modified or optimized using general knowledge of organic chemistry to prepare various compounds of the present invention.

[0233] Compounds of formula 1-5 can be synthesized using the process shown in Scheme 1. Palladium-catalyzed cross-coupling reaction of the appropriate aryl halide 1-1 and boronic acid / ester 1-2 gave compounds of formula 1-3. Transition metal (including but not limited to Pd and Cu)-catalyzed C-N bond formation reaction provided compounds of formula 1-5. Scheme 1. [ka]

[0234] 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 aminobicyclic core 2-4. Palladium-catalyzed cross-coupling of compound 2-4 and boronic acid / ester 2-5 gave compounds of formula 2-6. Sandmeyer bromination of compound 2-6 produced aryl bromide 2-7, which can be reacted with amino compound 2-8 under transition metal-catalyzed C-N bond-forming reaction conditions to provide compound 2-10. Alternatively, compounds of formula 2-10 can be generated directly from amino compound 2-6 using a reductive amination protocol. Scheme 2. [ka]

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

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

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

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

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

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

[0241] In some embodiments, the disease or disorder associated with CDK2 is lung squamous cell carcinoma, lung adenocarcinoma, pancreatic adenocarcinoma, invasive breast cancer, uterine carcinosarcoma, ovarian serous cystadenocarcinoma, gastric adenocarcinoma, esophageal carcinoma, bladder urothelial carcinoma, mesothelioma, or sarcoma.

[0242] In some embodiments, the disease or disorder associated with CDK2 is lung adenocarcinoma, invasive breast cancer, uterine carcinosarcoma, ovarian serous cystadenocarcinoma, or gastric adenocarcinoma.

[0243] In some embodiments, the CDK2-related disease or disorder is adenocarcinoma, carcinoma, or cystadenocarcinoma.

[0244] In some embodiments, the disease or disorder associated with CDK2 is uterine cancer, ovarian cancer, gastric cancer, esophageal cancer, lung cancer, bladder cancer, pancreatic cancer, or breast cancer.

[0245] In some embodiments, the CDK2-related disease or disorder is 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 that exhibits primary or acquired resistance to CDK4 / 6 inhibition. In some embodiments, the breast cancer is advanced or metastatic breast cancer.

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

[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 carcinoma (e.g., bladder), and microsatellite instability-high (MSI) cancer. 高 Additionally, the present disclosure includes refractory or recurrent malignancies whose growth can be inhibited using the compounds of the present disclosure.

[0250] In some embodiments, cancers treatable using compounds of the present disclosure include, but are not limited to, solid tumors (e.g., prostate cancer, colon cancer, esophageal cancer, endometrial cancer, ovarian cancer, uterine cancer, renal cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, sarcoma, bladder cancer, etc.), hematological cancers (e.g., leukemias such as lymphoma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), DLBCL, mantle cell lymphoma, non-Hodgkin's lymphoma (including relapsed or refractory NHL and follicular lymphoma, including relapsed follicular), Hodgkin's lymphoma, or multiple myeloma), and combinations of said cancers.

[0251] In some embodiments, cancers treatable using the compounds of the present disclosure include, but are not limited to, 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, chondrosarcoma, epithelioid sarcoma, eye cancer, fallopian tube cancer, gastrointestinal cancer, gastrointestinal stromal tumor, hairy cell leukemia, intestinal cancer, pancreatic islet cell carcinoma, oral cancer, mouth cancer, throat cancer, laryngeal cancer, lip cancer, mesothelioma, neck cancer, nasal cavity cancer, ocular cancer, ocular melanoma, pelvic cancer, rectal cancer, renal cell carcinoma, salivary gland cancer, paranasal sinus cancer, spinal cancer, tongue cancer, tubular cancer, urethral cancer, and ureteral cancer.

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

[0253] In some embodiments, diseases and indications treatable using compounds of the present disclosure include, but are not limited to, hematological cancers, sarcomas, lung cancers, gastrointestinal cancers, genitourinary tract cancers, liver cancer, bone cancers, cancers of the nervous system, gynecological cancers, and skin cancers.

[0254] Exemplary hematological 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's lymphoma (including relapsed or refractory NHL and relapsed follicular), lymphomas and leukemias such as Hodgkin's lymphoma, myeloproliferative disorders (e.g., primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocytosis (ET)), myelodysplastic syndromes (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), and multiple myeloma (MM).

[0255] Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, rhabdomyosarcoma, fibroma, lipoma, hamartoma, and teratoma.

[0256] Exemplary lung cancers include non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), bronchogenic carcinoma, squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma, alveolar (bronchial) carcinoma, bronchial adenoma, chondroitin hamartoma, 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's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colon cancer (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), and colorectal cancer.

[0258] Exemplary genitourinary tract 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, choriomas, sarcomas, stromal cell carcinoma, fibroma, fibroadenoma, adenoid tumor, lipoma).

[0259] Exemplary liver cancers include hepatocellular carcinoma (hepatocellular carcinoma), 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 (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteochondroid exostosis), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor.

[0261] Exemplary cancers of the nervous system include skull cancers (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meningeal cancers (meningiomas, meningeal sarcomas, gliomatosis), brain cancers (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumors (pinealoma), glioblastoma, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), and spinal cancers (neurofibromas, meningiomas, gliomas, sarcomas), as well as neuroblastoma and Lhermitte-Dacros disease.

[0262] Exemplary gynecological cancers include uterine cancer (endometrial cancer), cervical cancer (cervical carcinoma, precancerous cervical dysplasia), ovarian cancer (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulvar cancer (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vaginal cancer (clear cell carcinoma, squamous cell carcinoma, sarcoma botryoides (embryonal 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 nevi, lipoma, hemangioma, dermatofibroma, and keloids. In some embodiments, diseases and indications 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, bile duct cancer, esophageal cancer, and urothelial cancer.

[0264] It is believed that the compounds of formula (I), or any of its embodiments, may have satisfactory pharmacological profiles and promising biopharmaceutical properties, such as toxicological profile, metabolic and pharmacokinetic properties, solubility, and permeability. It will be understood that determining appropriate biopharmaceutical properties, such as cytotoxicity in cells or inhibition of certain targets or channels to determine potential toxicity, is within the knowledge of one of ordinary skill in the art.

[0265] The terms "individual," "patient," and "subject," used interchangeably, refer to any animal, including a mammal, preferably a mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse, or primate, most preferably a human.

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

[0267] As used herein, the term "treating" or "treatment" refers to one or more of: (1) inhibiting a disease, e.g., inhibiting a disease, condition, or disorder (i.e., halting further progression of the symptoms and / or symptomology) in an individual experiencing or exhibiting the symptoms or symptomology of the disease, condition, or disorder; and (2) ameliorating a disease, e.g., improving a disease, condition, or disorder (i.e., reversing the symptoms and / or symptomology) in an individual experiencing or exhibiting the symptoms or symptomology of the disease, condition, or disorder, such as reducing the severity of the disease.

[0268] In some embodiments, the compounds of the invention are useful in preventing or reducing the risk of developing any of the diseases mentioned herein, for example, 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 who has not yet experienced or exhibited the symptoms or symptomology of the disease.

[0269] Combination therapy I. Cancer Treatment The proliferation and survival of cancer cells can be affected by the dysfunction of multiple signal transduction pathways.Therefore, it is useful to treat such pathologies by combining different enzyme / protein / receptor inhibitors that have different preferences for the targets that regulate their activity.Targeting more than one signal transduction pathway (or more than one biomolecule involved in a given signal transduction pathway) can reduce the possibility of drug resistance occurring in cell populations and / or reduce the toxicity of treatment.

[0270] For example, one or more additional pharmaceutical agents, such as chemotherapeutic agents, anti-inflammatory agents, steroids, immunosuppressants, cancer immunotherapeutic agents, metabolic enzyme inhibitors, chemokine receptor inhibitors, and phosphatase inhibitors, as well as 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 WO 2006 / 056399, can be used in combination with the compounds of the present disclosure to treat CDK2-related diseases, disorders, or conditions. Other agents, such as therapeutic antibodies, can be used in combination with the compounds of the present disclosure to treat CDK2-related diseases, disorders, or conditions. The one or more additional pharmaceutical agents can be administered to a 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 one or more other enzyme / protein / receptor inhibitor therapy for the treatment of diseases such as cancer and other diseases or disorders described herein. Examples of diseases and indications treatable with combination therapy include those described herein. Examples of cancer include solid tumors and non-solid tumors, such as liquid tumors and hematological cancers. Examples of infectious diseases include viral infections, bacterial infections, fungal infections, or parasitic infections. For example, 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 selected kinases). 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: CSF1R, KIT, FLK-II, KDR / FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, PARP, Ron, Sea, TRKA, TRKB, TRKC, TAM kinases (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. 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 inhibitors (e.g., palsaclisib (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 extraterminal (bromo and extraterminal) 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 together with a PI3Kδ inhibitor. In some embodiments, the compounds or salts described herein are administered together with a JAK inhibitor. In some embodiments, the compounds or salts described herein are administered together with a JAK1 or JAK2 inhibitor (e.g., baricitinib or ruxolitinib). In some embodiments, the compounds or salts described herein are administered together with a JAK1 inhibitor. In some embodiments, the compounds or salts described herein are administered together with a JAK1 inhibitor that is more selective than JAK2.

[0274] Exemplary antibodies for use in combination therapy 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 against 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: cytostatic agents, cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, epothilones, tamoxifen, 5-fluorouracil, methotrexate, temozolomide, cyclophosphamide, SCH 66336, R115777, L778,123, BMS 214662, IRESSA™ (gefitinib), TARCEVA™ (erlotinib), antibodies to EGFR, Intron, Ara-C, adriamycin, cytoxan, gemcitabine, uracil mustard, chlormethine, ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, da Carbazine, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, oxaliplatin, leucovorin, ELOXATIN™ (oxaliplatin), pentostatin, vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, mithramycin, deoxycoformycin, mitomycin C, L-asparaginase, teniposide 17.alpha.ethinyl estradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, dromostanolone propionate, testolactone, megestrol acetate, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide, flutamide, toremifene, goserelin, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, navelbine, anastrozole, letrozole, capecitabine, raloxifene, droloxifene, hexamethylmelamine, Avastin, HERCEPTIN™ (trastuzumab), BEXXAR™ (tositumomab), VELCADE™ (bortezomib), ZEVALIN™ (ibritumomab tiuxetan), TRISENOX™ (arsenic trioxide), XELODA™ (capecitabine), vinorelbine, porfimer, ERBITUX™ (cetuximab), thiotepa, altretamine, melphalan, trastuzumab, retrozole fluprexa, fulvestrant, exemestane, ifosfamide, rituximab, C225 (cetuximab), campath (alemtuzumab), clofarabine, cladribine, aphidicolin, rituximab, sunitinib, dasatinib, tezacitabine, Sml1, fludarabine, pentostatin, triapine, didox, trimidox, amidox, 3-AP, and MDL-101,731.

[0276] The compounds of the present disclosure can also 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 receptor agonists, RIG-I agonists, oncolytic virotherapy, and immunomodulatory small molecules, including thalidomide or JAK1 / 2 inhibitors, PI3Kδ inhibitors, etc. The compounds can be administered in combination with one or more anti-cancer drugs, such as chemotherapeutic agents. Examples of chemotherapy drugs include abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bevacizumab, bexarotene, baricitinib, bleomycin, bortezomib, intravenous busulfan, oral busulfan, calcitonin, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, and doxorubicin propionate. Lomostanolone, 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 alfa-2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, mechlorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen,Mitomycin C, mitotane, mitoxantrone, nandrolone phenylpropionate, nelarabine, nofetumomab, oxaliplatin, paclitaxel, pamidronate, panitumumab, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin, procarbazine, quinacrine, rasburicase, rituximab, ruxoli Examples of the anti-cancer drug include sunitinib, 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 zoledronate.

[0277] Additional examples of chemotherapeutic agents include proteasome inhibitors (e.g., bortezomib), thalidomide, revlimid, 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™), nilotinib, dasatinib, bosutinib, and ponatinib, and pharmaceutically acceptable salts. Other exemplary suitable Bcr-Abl inhibitors include compounds of the genera and species disclosed in U.S. Pat. No. 5,521,184, WO 04 / 005281, and U.S. Ser. No. 60 / 578,491, and pharmaceutically acceptable salts thereof.

[0280] Exemplary suitable Flt-3 inhibitors include midostaurin, lestaurtinib, linifanib, sunitinib, sunitinib maleate, sorafenib, quizartinib, crenolanib, pacritinib, tandutinib, PLX3397, and ASP2215, and pharmaceutically acceptable salts thereof. Other exemplary suitable Flt-3 inhibitors include compounds such as those 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 such as those 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 those compounds 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 such as those disclosed in WO09 / 085185, WO12 / 129344, WO11 / 101409, WO03 / 062236, WO10 / 075074, and WO12 / 061156, and pharmaceutically acceptable salts thereof.

[0284] In some embodiments, compounds of the present disclosure can be used in combination with one or more other kinase inhibitors, including imatinib, particularly to treat patients who are 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 exacerbating 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 pharmaceutical agents used in the treatment of multiple myeloma can 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, the 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). Additive or synergistic effects are desirable results of combining a CDK2 inhibitor of the present disclosure with an additional agent.

[0286] The agents can be combined with the compound in a single or sequential dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms.

[0287] The compounds of the present disclosure can be used in combination with one or more other inhibitors or one or more therapies to treat infectious diseases. Examples of infectious diseases include viral, bacterial, fungal, 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 the dexamethasone is administered intermittently rather than continuously.

[0289] A compound of Formula (I) or any of the formulae as described herein, a compound as recited in any of the claims and 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 genes encoding immunostimulatory cytokines. Non-limiting examples of tumor vaccines that can be used include peptides of gp100, MAGE antigens, melanoma antigens such as Trp-2, MARTI, and / or tyrosinase, or tumor cells transfected to express the cytokine GM-CSF.

[0290] A compound of Formula (I) or any of the formulae as described herein, a compound as recited in any of the claims and described herein, or a salt thereof, can be used in combination with vaccination protocols for the treatment of cancer. In some embodiments, tumor cells are transduced to express GM-CSF. In some embodiments, tumor vaccines include proteins from viruses implicated in human cancers, such as human papillomavirus (HPV), hepatitis viruses (HBV and HCV), and Kaposi's herpes sarcoma virus (KHSV). In some embodiments, 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 formulae as described herein, a compound as recited in any of the claims and described herein, or a salt thereof can be combined with dendritic cell immunization to activate a potent anti-tumor response.

[0291] The compounds of the present disclosure can be used in combination with bispecific macrocyclic peptides that target Fe alpha or Fe gamma receptor-expressing effector cells to tumor cells. The compounds of the present disclosure can also be combined with macrocyclic peptides that activate host immune responsiveness.

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

[0293] Compounds of formula (I) or any of the formulae described herein, compounds as recited in any of the claims and described herein, or salts thereof, can be used in combination with vaccines to stimulate immune responses to pathogens, toxins, and autoantigens. Examples of pathogens for which this therapeutic approach may be particularly useful include those for which no effective vaccine currently exists or for which conventional vaccines are less than completely effective. These include, but are not limited to, HIV, hepatitis (types A, B, and C), influenza, herpes, giardia, malaria, leishmaniasis, Staphylococcus aureus, and Pseudomonas aeruginosa.

[0294] Viruses causing 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, herpesvirus (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 arboviral encephalitis virus.

[0295] Pathogenic bacteria that cause infections treatable by the methods of the present disclosure include, but are not limited to, chlamydia, rickettsia, 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 infections treatable by the methods of the present disclosure include, but are not limited to, Candida (e.g., albicans, krusei, glabrata, tropicalis), Cryptococcus neoformans, Aspergillus (e.g., fumigatus, niger), Mucorales (e.g., mucor, absidia, rhizophus), Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis, and Histoplasma capsulatum.

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

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

[0299] Methods for safely and effectively administering most of these chemotherapeutic agents are known to those skilled in the art. In addition, their administration is described in standard references. For example, the administration of many of these chemotherapeutic agents is described in the Physicians' Desk Reference (PDR, e.g., 1996 ed., Medical Economics Company, Montvale, NJ), the disclosure of which is incorporated herein by reference as if set forth in its entirety.

[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 of 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 a KIR inhibitor, a TIGIT inhibitor, a LAIR1 inhibitor, a CD160 inhibitor, a 2B4 inhibitor, and a TGFRbeta inhibitor.

[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 an 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 an immune checkpoint molecule is an inhibitor of PD-1 or PD-L1, e.g., an anti-PD-1 or anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-1 or anti-PD-L1 antibody is selected from the group consisting of nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, cemiplimab, atezolizumab, avelumab, tislelizumab, spartalizumab (PDR001), cetrelimab (JNJ-63723283), toripalimab (JS001), camrelizumab (SHR-1210), sintilimab (IBI308), AB122 (GLS-010), AMP-224, AMP-514 / MEDI-0 680, 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 PD-1 or PD-L1 inhibitor is one disclosed in U.S. Pat. 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 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, cemiplimab, spartalizumab, camrelizumab, cetrelimab, toripalimab, 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, cemiplimab, spartalizumab, camrelizumab, cetrelimab, toripalimab, 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 cemiplimab. 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 toripalimab. 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 (e.g., urelumab, utomilumab). In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1, e.g., 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 an immune checkpoint molecule is a small molecule that binds to PD-L1, or a pharmaceutically acceptable salt thereof. In some embodiments, the inhibitor of an immune checkpoint molecule is a small molecule that binds to and internalizes PD-L1, or a pharmaceutically acceptable salt thereof. In some embodiments, the inhibitor of an immune checkpoint molecule is a compound selected from those in US2018 / 0179201, US2018 / 0179197, US2018 / 0179179, US2018 / 0179202, US2018 / 0177784, US2018 / 0177870, US Ser. No. 16 / 369,654 (filed March 29, 2019), and US Ser. No. 62 / 688,164, each of which is incorporated by reference in its entirety.

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

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

[0308] In some embodiments, the inhibitor of an 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 an 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 an immune checkpoint molecule is an inhibitor of CD73. In some embodiments, the inhibitor of CD73 is oleclumab.

[0311] In some embodiments, the inhibitor of an 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 an immune checkpoint molecule is an inhibitor of VISTA, hi some embodiments, the inhibitor of VISTA is JNJ-61610588 or CA-170.

[0313] In some embodiments, the inhibitor of an 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 an immune checkpoint molecule is an inhibitor of a KIR. In some embodiments, the inhibitor of a KIR is lirilumab or IPH4102.

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

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

[0317] In some embodiments, the inhibitor of an 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 an 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 an immune checkpoint molecule is an inhibitor of CD73. In some embodiments, the inhibitor of CD73 is MEDI9447.

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

[0321] In some embodiments, the inhibitor of an 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 an immune checkpoint molecule is an inhibitor of CD20, e.g., an anti-CD20 antibody. In some embodiments, the anti-CD20 antibody is obinutuzumab or rituximab.

[0323] In some embodiments, the agonist of an 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, such as 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 immune checkpoint molecule agonist is a CD40 agonist, hi some embodiments, the CD40 agonist 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, hi 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, hi some embodiments, the agonist of CD28 is celalizumab.

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

[0330] In some embodiments, the agonist of the immune checkpoint molecule is an agonist of TLR7 / 8, hi 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 a 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, the additional compounds, inhibitors, drugs, etc. can be combined with the present compounds in a single or sequential dosage form, or they can be administered simultaneously or sequentially as separate dosage forms.

[0334] Pharmaceutical Preparations and Dosage Forms When used as a pharmaceutical, the compounds of the present disclosure can be administered in the form of pharmaceutical compositions. These compositions can be prepared in a manner well known in the pharmaceutical arts and can be administered by various routes, depending on whether local or systemic treatment is desired and the area to be treated. Administration can be topical (including transdermal, epithelial, ophthalmic, and mucosal, including intranasal, intravaginal, and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, 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 a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.

[0335] The present disclosure also includes pharmaceutical compositions containing the compounds of the present disclosure or pharmaceutically acceptable salts thereof as an active ingredient in combination with one or more pharmaceutically acceptable carriers (excipients). In some embodiments, the compositions are suitable for topical administration. When preparing the compositions of the present disclosure, the active ingredient is typically mixed with an excipient, diluted by an excipient, or enclosed within such a carrier, for example, in the form of a capsule, sachet, paper, or other container. 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, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), for example, ointments containing up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injection solutions, and sterile packaged powders.

[0336] When preparing formulation, active compound can be milled to obtain suitable particle size before being combined with other components.If active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh.If active compound is substantially water-soluble, particle size can be adjusted by milling to obtain substantially uniform distribution in 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 a particle size suitable for tablet formation and other formulation types. Finely divided (nanoparticulate) 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.Preparation can additionally contain lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl benzoate and propyl hydroxybenzoate; sweeteners; and flavoring agents.The composition of the present disclosure can be formulated to provide rapid, sustained, or delayed release of active ingredients after administration to patients by using procedures known in the art.

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

[0340] In some embodiments, compositions of the present disclosure contain about 5 to about 50 mg of the active ingredient. One of skill in the art will appreciate that this embodies compositions containing 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, compositions of the present disclosure contain about 50 to about 500 mg of the active ingredient. One of skill in the art will appreciate that this embodies compositions containing 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, compositions of the present disclosure contain about 500 to about 1000 mg of the active ingredient. One of skill in the art will appreciate that this represents compositions containing 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] Similar dosages of the compounds described herein may be used in the methods and uses of the present disclosure.

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

[0345] When preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of the compounds of the present disclosure. When these preformulation compositions are referred to as homogeneous, the active ingredient is typically evenly 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 compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter in the form of an envelope over the former. These two components can be separated by an enteric layer, which serves to resist disintegration in the stomach and allow the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, including several polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0347] Liquid forms into which the compounds and compositions of the present disclosure may be incorporated for oral or injectable administration include aqueous solutions, suitably 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 in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions may be nebulized by the use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a face mask, tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0349] Topical formulations may contain one or more conventional carriers. In some embodiments, ointments may contain water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white petrolatum, etc. Cream carrier compositions may be based on water in combination with glycerol and one or more other components, such as glyceryl monostearate, PEG-glyceryl monostearate, and cetylstearyl alcohol. Gels may be formulated using isopropyl alcohol and water, suitably combined with other components, such as glycerol, hydroxyethylcellulose, etc. In some embodiments, topical formulations contain 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% by weight of a compound of the present disclosure. Topical formulations may be suitably packaged, for example, in a 100 g tube, optionally associated with instructions for treating a selected indication, such as psoriasis or other skin conditions.

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

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

[0352] Therapeutic dosages of compounds of the present disclosure can vary depending, for example, on the particular application for which the treatment is given, 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 a compound of the present disclosure in a pharmaceutical composition can vary depending on several factors, including dosage, chemical properties (e.g., hydrophobicity), and the route of administration. For example, compounds of the present disclosure can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10 wt.% compound for parenteral administration. Some typical dose ranges are about 1 μg / kg to about 1 g / kg body weight per day. In some embodiments, the dose range is about 0.01 mg / kg to about 100 mg / kg body weight per day. The dosage can depend on such variables as the type and extent of progression of the disease or disorder, the overall health of the particular patient, the relative biological effectiveness of the selected compound, the formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0353] The compositions of the present disclosure may further comprise one or more additional pharmaceutical agents, such as chemotherapeutic agents, steroids, anti-inflammatory compounds, or immunosuppressants, examples of which are listed herein.

[0354] Labeled Compounds and Assay Methods Another aspect of the present disclosure relates to labeled compounds (radiolabeled, fluorescently labeled, etc.) of the present disclosure that may be useful in both in vitro and in vivo assays, as well as imaging techniques, for localizing and quantifying CDK2 in tissue samples, including humans, and for identifying CDK2 activators through inhibitory binding of the labeled compounds. Substitution of one or more atoms of the compounds of the present disclosure may also be useful in generating differentiated ADME (adsorption, distribution, metabolism, and excretion). Thus, 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 "isotopically" or "radiolabeled" compound is one in which one or more atoms in the compounds of the present disclosure are replaced or substituted with an atom having an atomic mass or mass number different from that 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 written as D for deuterium), 3 H (also written as T for 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 131For example, one or more hydrogen atoms in the compounds of the present disclosure can be replaced with a deuterium atom (e.g., C of formula (I), such as replacing CH with -CD). 1-6 (One or more hydrogen atoms of an alkyl group can be optionally replaced with a deuterium atom.) In some embodiments, the alkyl groups of the disclosed formulas (e.g., Formula (I)) can be fully perdeuterated.

[0356] One or more constituent atoms of the compounds provided herein can be replaced or substituted with naturally or non-naturally abundant atom isotopes.In some embodiments, the compound comprises at least one deuterium atom.For example, one or more hydrogen atoms in the compounds provided herein can be replaced or substituted with deuterium atoms (for example, -CD3 can be replaced with -CH3), and the like. 1-6 (One or more hydrogen atoms of the alkyl group may be replaced with a deuterium atom.) In some embodiments, the compound contains two or more deuterium atoms. In some embodiments, the compound contains 1 to 2, 1 to 3, 1 to 4, 1 to 5, or 1 to 6 deuterium atoms. In some embodiments, all of the hydrogen atoms in the compound may be replaced or substituted with a deuterium atom.

[0357] In some embodiments, an alkyl, alkenyl, alkynyl, aryl, phenyl, cycloalkyl, heterocycloalkyl, or heteroaryl substituent, as described herein, or —C 1-4 1, 2, 3, 4, 5, 6, 7, or 8 hydrogen atoms bonded to carbon atoms of the alkyl-, alkylene, alkenylene, and alkynylene linking group are optionally 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, NY, 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 a variety of studies, such as NMR spectroscopy, metabolic studies, and / or assays.

[0359] Substitution with heavier isotopes, such as deuterium, can provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and may therefore be preferable 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 provide one or more therapeutic advantages.

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

[0361] A "radiolabel" or "labeled compound" is understood to be a compound that incorporates at least one radionuclide. In some embodiments, the radionuclide is: 3 H, 14 C. 125 I, 35 S, and 82 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 change when contacted with CDK2 through tracking the label. For example, a test compound (labeled) can be evaluated for its ability to reduce the binding of another compound (i.e., a standard compound) known to inhibit CDK2. 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. Therefore, 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 thus determined.

[0364] kit The present disclosure also includes pharmaceutical kits useful in the treatment or prevention of CDK2-related diseases or disorders (e.g., cancer, inflammatory disease, cardiovascular disease, or neurodegenerative disease, etc.), which include one or more containers housing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present disclosure. As will be readily apparent to one of skill in the art, such kits can further include one or more of a variety of conventional pharmaceutical kit components, if desired, such as, for example, a container containing one or more pharmaceutically acceptable carriers, additional containers, etc. Instructions, either as a package insert or label, indicating the amounts of the components to be administered, guidelines for administration, and / or guidelines for mixing the components, may 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 human subjects having, suspected of having, or at risk of developing a CDK2-related disease or disorder who are likely to benefit from the administration of a CDK2 inhibitor (as used herein, "CDK2 inhibitor" refers to a compound of the present disclosure, or a pharmaceutically acceptable salt thereof). The present disclosure also provides pharmacodynamic markers (e.g., phosphorylation levels) for identifying human subjects having, suspected of having, or at risk of developing a CDK2-related disease or disorder who are 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 disclosures of which are incorporated herein by reference in their entireties.

[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, suitable for use in patient stratification. In addition, the present invention is based, at least in part, on the discovery that the level of phosphorylation of human retinoblastoma-associated protein ("Rb") at serine corresponding to amino acid position 780 of SEQ ID NO: 3 in CCNE1-amplified cell lines is a pharmacodynamic marker for CDK2 activity, suitable for use in measuring CDK2 enzyme activity in cellular assays or preclinical and clinical applications, e.g., to monitor progress of or responsiveness to treatment with CDK2 inhibitors.

[0367] CCNE1 and p16 CCNE1 and p16, in combination, are identified in the Examples as genes useful in predicting the responsiveness (e.g., improvement of disease as evidenced by disease remission / resolution) of a subject with a CDK2-related disease or disorder to a CDK2 inhibitor.

[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 growth 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 aging and cancer formation (Okamoto et al., 1994, PNAS 91(23):11045-9). Non-limiting examples of genetic abnormalities in the gene encoding p16 are listed in Table A below. The amino acid sequence of human p16 is provided below (GenBank Accession No. NP_000068 / UniProtKB Accession No. P42771). [ka]

[0369] CCNE1 is a cell cycle factor essential for cell cycle regulation at the G1 / S transition (Ohtsubo et al., 1995, Mol. Cell. Biol. 15:2612-2624). CCNE1 acts as a regulatory subunit of CDK2, interacting with CDK2 to form a serine / threonine kinase holoenzyme complex. The CCNE1 subunit of this holoenzyme complex provides substrate specificity for 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). [ka]

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

[0371] Thus, the present disclosure provides methods of treating a human subject having, suspected of having, or at risk of developing a disease or disorder associated with CDK2, the methods comprising administering a CDK2 inhibitor to the human subject, wherein the human subject has previously been determined to (i) (a) have a nucleotide sequence encoding a p16 protein comprising the amino acid sequence of SEQ ID NO: 1, (b) have a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions, and / or (c) express a p16 protein, and (ii) (a) have an amplification of the CCNE1 gene, and / or (b) have an expression level of CCNE1 in a biological sample obtained from the human subject that is higher than a control expression level of CCNE1. In certain embodiments, the prediction methods described herein predict 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 that the subject will respond to treatment with a CDK2 inhibitor. For example, in some embodiments, if the prediction methods described herein are applied to 10 subjects having, suspected of having, or at risk of developing a disease or disorder associated with CDK2, and 8 of those 10 subjects are predicted to respond to treatment with a CDK2 inhibitor based on the prediction methods described herein, and 7 of those 8 subjects actually respond to treatment with the CDK2 inhibitor, then the prediction method has an accuracy of 87.5% (7 divided by 8). A subject is considered to be responsive to a CDK2 inhibitor if the subject shows any improvement in disease status as evidenced, for example, by a reduction or alleviation of symptoms, disease remission / resolution, etc.

[0372] In some embodiments, the subject has a disease or disorder associated with CDK2. In some embodiments, the human subject (i) has (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 specific embodiments, the one or more inactivating nucleic acid substitutions and / or deletions in the CDKN2A gene are as described in Table A. In specific embodiments, the 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 features methods for treating a human subject having, suspected of having, or at risk of developing a disease or disorder associated with CDK2, the methods comprising: (i) identifying, in a biological sample obtained from the human subject, the presence of (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) a p16 protein; (ii) identifying, in a biological sample obtained from the human subject, (a) amplification of the CCNE1 gene and / or (b) an expression level of CCNE1 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 includes: (i) identifying, in a biological sample obtained from the human subject, the presence of (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) a p16 protein; (ii) identifying, in the biological sample obtained from the human subject, (a) amplification of the CCNE1 gene; and (iii) administering a CDK2 inhibitor to the human subject.

[0375] The present disclosure also features 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 a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions; and / or (c) the presence of p16 protein; and (ii) determining from the biological sample obtained from the human subject: (a) the copy number and and / or (b) determining an expression level of CCNE1, wherein (1) (a) the presence of a CDKN2A gene encoding a p16 protein comprising the amino acid sequence of SEQ ID NO: 1, (b) the presence of a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions, and / or (c) the presence of a p16 protein, and (2) (a) amplification of the CCNE1 gene, and / or (b) an expression level of CCNE1 higher than a control expression level of CCNE1, is predictive 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 is 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 the presence of (a) the nucleotide sequence of the CDKN2A gene, and / or (b) the CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions; and (ii) determining from the biological sample obtained from the human subject the copy number of (a) the CCNE1 gene, wherein (1) the presence of (a) the CDKN2A gene encoding a 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) amplification of (a) the CCNE1 gene, is predictive that the human subject will respond to a CDK2 inhibitor.

[0376] In specific embodiments, (i) the determination of (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 performed prior to administering a CDK2 inhibitor to the 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). In a specific embodiment, (ii) the determination of (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 performed prior to administering a CDK2 inhibitor to the 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).

[0377] The presence of a CDKN2A gene encoding a p16 protein comprising the amino acid sequence of SEQ ID NO: 1, the presence of a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions, and / or the presence of a p16 protein (e.g., a p16 protein comprising the amino acid sequence of SEQ ID NO: 1), combined with amplification of the CCNE1 gene and / or an expression level of CCNE1 higher than a control expression level of CCNE1, is indicative / predictive that a human subject having, suspected of having, or at risk of developing a CDK2-related disease or disorder 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 specific embodiments, the CCNE1 gene is amplified to a gene copy number of at least 3. In specific embodiments, the CCNE1 gene is amplified to a gene copy number of at least 5. In specific embodiments, the CCNE1 gene is amplified to a gene copy number of at least 7. In specific embodiments, the CCNE1 gene is amplified to a gene copy number of at least 10. In specific embodiments, the CCNE1 gene is amplified to a gene copy number of at least 12. In specific embodiments, the CCNE1 gene is amplified to a gene copy number of at least 14. In specific embodiments, 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 the level of CCNE1 mRNA. In a specific embodiment, the expression level of CCNE1 is the level of CCNE1 protein.

[0380] In some embodiments of the above-mentioned method, the control CCNE1 expression level is a predetermined cutoff value. In some embodiments of the above-mentioned method, the control CCNE1 expression level is the CCNE1 expression level in a sample(s) obtained from one or more subjects who have not responded to treatment with a CDK2 inhibitor.

[0381] In some embodiments of the above-mentioned methods, the expression level of CCNE1 is the expression level of CCNE1 mRNA. In some embodiments of the above-mentioned methods, 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 features methods for assessing the CDKN2A gene and the CCNE1 gene, the methods comprising determining (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, from a biological sample(s) obtained from a human subject having a disease or disorder associated with CDK2.

[0383] The present disclosure also features a method for assessing the response of a human subject having, suspected of having, or at risk of developing a CDK2-related disease or disorder 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 CCNE1 gene amplification and / or a CCNE1 expression level higher than a control expression level of CCNE1; and (b) measuring the level of retinoblastoma (Rb) protein phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO:3 in a biological sample obtained from the subject following administration of step (a), wherein a reduced level of Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO:3 compared to a control level of Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO:3 indicates that the human subject will respond to the CDK2 inhibitor. In some embodiments, the subject has a CDK2-related disease or disorder. In some embodiments, the subject is suspected of having or at risk of developing a CDK2-related disease or disorder. In some embodiments, the biological sample comprises a blood sample or a tumor biopsy sample.

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

[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 cyclin E / CDK2 at Ser807 and Ser811. Rb is encoded by the RB-coupled transcriptional repressor 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 bold and underlined): [ka]

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

[0387] Thus, the present disclosure features a method for measuring the amount of a 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, in the biological sample, the level of phosphorylation of Rb protein at serine corresponding to amino acid position 780 of SEQ ID NO: 3. In some embodiments, the biological sample comprises a blood sample or a tumor biopsy sample. In a specific embodiment, provided herein is a method for assessing 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 CCNE1 gene amplification and / or a CCNE1 expression level higher than a control expression level of CCNE1; and (b) measuring the level of Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO:3 in a biological sample obtained from the human subject following administration of step (a), wherein a reduced level of Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO:3, 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 will respond to the CDK2 inhibitor. In a specific embodiment, the human subject has a disease or disorder associated with CDK2.

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

[0389] In combination with (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 a CDKN2A gene encoding a p16 protein comprising the amino acid sequence of SEQ ID NO: 1, the presence of a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions, and / or the presence of a p16 protein (e.g., a p16 protein comprising the amino acid sequence of SEQ ID NO: 1), a biological sample obtained from the subject after administration of a CDK2 inhibitor to the subject has a reduced level of Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO: 3 compared to a control level of Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO: 3, indicates that a human subject who has, is suspected of having, or is at risk of developing a disease or disorder associated with CDK2 will respond to a 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 a CDKN2A gene encoding a p16 protein comprising the amino acid sequence of SEQ ID NO: 1, the presence of a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions, and / or the presence of a 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 has a low (e.g., reduced compared to a control) or undetectable level of Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO: 3, indicating that the human subject will respond to the CDK2 inhibitor.

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

[0391] Control As described above, methods related to biomarkers and pharmacodynamic markers can involve measuring one or more markers (e.g., biomarkers or pharmacodynamic markers, e.g., amplification of the CCNE1 gene, expression levels of CCNE1, the presence of a CDKN2A gene encoding a p16 protein comprising the amino acid sequence of SEQ ID NO: 1, the presence of a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions, the presence of a p16 protein (e.g., a p16 protein comprising the amino acid sequence of SEQ ID NO: 1), and Rb phosphorylation at serine corresponding to amino acid 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 CDK2-associated disease or disorder. In a specific embodiment, the human subject has a CDK2-associated disease or disorder. In a specific embodiment, the human subject is suspected of having, or at risk of developing a CDK2-associated disease or disorder. 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 p16 protein), or phosphorylation level (e.g., for Rb)) relative to a control level of the one or more biomarkers is predictive / indicative of a human subject's response to treatment comprising a CDK2 inhibitor. In certain embodiments, a 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) a CDKN2A gene encoding a p16 protein comprising the amino acid sequence of SEQ ID NO: 1 is present, a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions is present, and / or a p16 protein (e.g., a p16 protein comprising the amino acid sequence of SEQ ID NO: 1) is present.In other embodiments, 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 amino acid position 780 of SEQ ID NO: 3 in a biological sample from the human subject after the human subject has been administered a CDK2 inhibitor is less than the control level of Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO: 3. In yet another embodiment, a human subject is identified as responding to a CDK2 inhibitor if: (i) the CCNE1 gene is amplified and / or the expression level of CCNE1 is higher than a control expression level of CCNE1, (ii) a CDKN2A gene encoding a p16 protein comprising the amino acid sequence of SEQ ID NO: 1 is present, a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions is present, and / or a p16 protein (e.g., a 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 amino acid position 780 of SEQ ID NO: 3 in a biological sample from the human subject after the human subject has been administered a CDK2 inhibitor is less than the control level of Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO: 3. In this context, the term "control" includes a sample (from the same tissue type) obtained from a human subject known not to respond to CDK2 inhibitors. The term "control" also includes a sample (from the same tissue type) previously obtained from a human subject known not to respond to CDK2 inhibitors and used as a reference for future comparison to test samples obtained from human subjects whose therapeutic response is predicted. A "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 previously established by analyzing the biomarker level (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 a CDK2 inhibitor.This predetermined reference value (which may 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 then be used for the "control" level of the biomarker (e.g., CCNE1, p16, or Rb phosphorylation) in comparison with the test sample. In such a comparison, a human subject is predicted to respond to a CDK2 inhibitor if the CCNE1 gene is amplified and / or the expression level of CCNE is higher than the predetermined reference, and if a CDKN2A gene encoding a p16 protein comprising the amino acid sequence of SEQ ID NO: 1 is present, if a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions is present, and / or if a p16 protein (e.g., a p16 protein comprising the amino acid sequence of SEQ ID NO: 1) is present. In another such comparison, a human subject is predicted to be responsive to a CDK2 inhibitor if (i) the CCNE1 gene is amplified and / or the expression level of CCNE is higher than a predetermined reference, and (ii) after administration of a CDK2 inhibitor to the human subject, the level of Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO: 3 is lower than a predetermined reference. In yet another such comparison, a human subject is shown to be responsive to a CDK2 inhibitor if (i) the CCNE1 gene is amplified and / or the expression level of CCNE is higher than a predetermined reference, (ii) a CDKN2A gene encoding a p16 protein comprising the amino acid sequence of SEQ ID NO: 1 is present, a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions is present, and / or a p16 protein (e.g., a p16 protein comprising the amino acid sequence of SEQ ID NO: 1) is present,...

Claims

1. A compound of formula (I), 【Chemical 1】 or a pharmaceutically acceptable salt thereof, wherein: n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; 【Chemistry 2】 is a single bond or a double bond, X is N, Y is C, and the ring 【Chemistry 3】 but, 【Chemistry 4】 or X is C, Y is N, and the ring 【Chemistry 5】 but, 【Chemistry 6】 and Z is CR ２ or N, 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 a 4- to 10-membered heterocycloalkyl, wherein ring moiety B is attached to the —NH— group of formula (I) at a ring member of a saturated or partially unsaturated ring of said 4- to 10-membered heterocycloalkyl; R １ are independently H, D, halo, CN, NO ２ , C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl, OR ａ１ , S.R. ａ１ , NHOR ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)NR ｃ１ (OR ａ１ ), C(O)OR ａ１ , O.C.(O.)R ｂ１ , OC(O)NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ NR ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , N.R. ｃ１ C(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ ) R ｂ１ , C(=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ ) R ｂ１ , N.R. ｃ１ S(O)NR ｃ１ R ｄ１ , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S (O) ２ R ｂ１ , N.R. ｃ１ S(O) (=NR ｅ１ ) R ｂ１ , N.R. ｃ１ S (O) ２ NR ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ , S(O) ２ NR ｃ１ R ｄ１ , OS(O)(=NR ｅ１ ) R ｂ１ , OS(O) ２ R ｂ１ , S(O)(=NR ｅ１ ) R ｂ１ , S.F. ５ , P(O)R ｆ１ R ｇ１ , OP(O)(OR ｈ１ ) (OR ｉ１ ), P(O)(OR ｈ１ ) (OR ｉ１ ), and B.R. ｊ１ R ｋ１ and C is selected from １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 10-membered heteroaryl-C １－４ alkyl is optionally selected from 1, 2, 3, or 4 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 ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 10-membered heteroaryl-C １－４ alkyl, wherein C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 10-membered heteroaryl-C １－４ alkyl is optionally selected from 1, 2, 3, or 4 independently selected R １Ａ be substituted with a substituent, Alternatively, any R bonded to the same N atom ｃ１ and R ｄ１ together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl group, and the 4- to 10-membered heterocycloalkyl group optionally contains 1, 2, 3, or 4 independently selected R １Ａ is substituted with a substituent, Each R ｂ１ became independent and C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl and 5- to 10-membered heteroaryl-C １－４ alkyl, each of which is optionally followed by 1, 2, 3, or 4 independently selected R １Ａ is substituted with a substituent, Each R ｅ１ are independently H, OH, CN, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl, C １－６ Haloalkoxy, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 10-membered heteroaryl-C １－４ alkyl, Each R ｆ１ and R ｇ１ are independent, H, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl, C １－６ Haloalkoxy, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 10-membered heteroaryl-C １－４ alkyl, Each R ｈ１ and R ｉ１ are independent, H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl and 5- to 10-membered heteroaryl-C １－４ alkyl, Each R ｊ１ and R ｋ１ are independent, OH, C １－６ Alkoxy, and C １－６ haloalkoxy; Alternatively, any R bonded to the same B atom ｊ１ and R ｋ１ together with the B atoms to which they are attached, C １－６ Alkyl and C １－６ forming a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from haloalkyl; Each R １Ａ are independently H, D, halo, CN, NO ２ , 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 ａ１１ , S.R. ａ１１ , NHOR ａ１１ , C(O)R ｂ１１ , C(O)NR ｃ１１ R ｄ１１ , C(O)NR ｃ１１ (OR ａ１１ ), C(O)OR ａ１１ , O.C.(O.)R ｂ１１ , OC(O)NR ｃ１１ R ｄ１１ , N.R. ｃ１１ R ｄ１１ , N.R. ｃ１１ NR ｃ１１ R ｄ１１ , N.R. ｃ１１ C(O)R ｂ１１ , N.R. ｃ１１ C(O)OR ａ１１ , N.R. ｃ１１ C(O)NR ｃ１１ R ｄ１１ , C(=NR ｅ１１ ) R ｂ１１ , C(=NR ｅ１１ ) NR ｃ１１ R ｄ１１ , N.R. ｃ１１ C (=NR ｅ１１ ) NR ｃ１１ R ｄ１１ , N.R. ｃ１１ C (=NR ｅ１１ ) R ｂ１１ , N.R. ｃ１１ S(O)NR ｃ１１ R ｄ１１ , N.R. ｃ１１ S(O)R ｂ１１ , N.R. ｃ１１ S (O) ２ R ｂ１１ , N.R. ｃ１１ S(O) (=NR ｅ１１ ) R ｂ１１ , N.R. ｃ１１ S (O) ２ NR ｃ１１ R ｄ１１ , S(O)R ｂ１１ , S(O)NR ｃ１１ R ｄ１１ , S(O) ２ R ｂ１１ , S(O) ２ NR ｃ１１ R ｄ１１ , OS(O)(=NR ｅ１１ ) R ｂ１１ , OS(O) ２ R ｂ１１ , S(O)(=NR ｅ１１ ) R ｂ１１ , S.F. ５ , P(O)R ｆ１１ R ｇ１１ , OP(O)(OR ｈ１１ ) (OR ｉ１１ ), P(O)(OR ｈ１１ ) (OR ｉ１１ ), and B.R. ｊ１１ R ｋ１１ and 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- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl is optionally selected from 1, 2, 3, or 4 independently selected R １Ｂ is substituted with a substituent, Each R ａ１１ , R ｃ１１ , and R ｄ１１ 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- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, wherein 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 selected from 1, 2, 3, or 4 independently selected R １Ｂ be substituted with a substituent, Alternatively, any R bonded to the same N atom ｃ１１ and R ｄ１１ together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl group, and the 4- to 7-membered heterocycloalkyl group optionally contains 1, 2, 3, or 4 independently selected R １Ｂ is substituted with a substituent, Each R ｂ１１ became independent and 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 of which is optionally followed by 1, 2, 3, or 4 independently selected R １Ｂ is substituted with a substituent, Each R ｅ１１ are independently H, OH, CN, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl, C １－６ Haloalkoxy, 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 R ｆ１１ and R ｇ１１ are independent, H, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl, C １－６ Haloalkoxy, 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 R ｈ１１ and R ｉ１１ 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- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, Each R ｊ１１ and R ｋ１１ are independent, OH, C １－６ Alkoxy, and C １－６ haloalkoxy; Alternatively, any R bonded to the same B atom ｊ１１ and R ｋ１１ together with the B atoms to which they are attached, C １－６ Alkyl and C １－６ forming a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from haloalkyl; Each R １Ｂ are independently H, D, halo, CN, NO ２ , 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 ａ１２ , S.R. ａ１２ , NHOR ａ１２ , C(O)R ｂ１２ , C(O)NR ｃ１２ R ｄ１２ , C(O)NR ｃ１２ (OR ａ１２ ), C(O)OR ａ１２ , O.C.(O.)R ｂ１２ , OC(O)NR ｃ１２ R ｄ１２ , N.R. ｃ１２ R ｄ１２ , N.R. ｃ１２ NR ｃ１２ R ｄ１２ , N.R. ｃ１２ C(O)R ｂ１２ , N.R. ｃ１２ C(O)OR ａ１２ , N.R. ｃ１２ C(O)NR ｃ１２ R ｄ１２ , C(=NR ｅ１２ ) R ｂ１２ , C(=NR ｅ１２ ) NR ｃ１２ R ｄ１２ , N.R. ｃ１２ C (=NR ｅ１２ ) NR ｃ１２ R ｄ１２ , N.R. ｃ１２ C (=NR ｅ１２ ) R ｂ１２ , N.R. ｃ１２ S(O)NR ｃ１２ R ｄ１２ , N.R. ｃ１２ S(O)R ｂ１２ , N.R. ｃ１２ S (O) ２ R ｂ１２ , N.R. ｃ１２ S(O) (=NR ｅ１２ ) R ｂ１２ , N.R. ｃ１２ S (O) ２ NR ｃ１２ R ｄ１２ , S(O)R ｂ１２ , S(O)NR ｃ１２ R ｄ１２ , S(O) ２ R ｂ１２ , S(O) ２ NR ｃ１２ R ｄ１２ , OS(O)(=NR ｅ１２ ) R ｂ１２ , OS(O) ２ R ｂ１２ , S(O)(=NR ｅ１２ ) R ｂ１２ , S.F. ５ , P(O)R ｆ１２ R ｇ１２ , OP(O)(OR ｈ１２ ) (OR ｉ１２ ), P(O)(OR ｈ１２ ) (OR ｉ１２ ), and B.R. ｊ１２ R ｋ１２ and 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- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl is optionally selected from 1, 2, 3, or 4 independently selected R Ｇ is substituted with a substituent, Each R ａ１２ , R ｃ１２ , and R ｄ１２ 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- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, wherein 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 selected from 1, 2, 3, or 4 independently selected R Ｇ be substituted with a substituent, Alternatively, any R bonded to the same N atom ｃ１２ and R ｄ１２ together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl group, and the 4- to 7-membered heterocycloalkyl group optionally contains 1, 2, 3, or 4 independently selected R Ｇ is substituted with a substituent, Each R ｂ１２ became independent and 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 of which is optionally followed by 1, 2, 3, or 4 independently selected R Ｇ is substituted with a substituent, Each R ｅ１２ are independently H, OH, CN, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl, C １－６ Haloalkoxy, 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 R ｆ１２ and R ｇ１２ are independent, H, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl, C １－６ Haloalkoxy, 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 R ｈ１２ and R ｉ１２ 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- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, Each R ｊ１２ and R ｋ１２ are independent, OH, C １－６ Alkoxy, and C １－６ haloalkoxy; Alternatively, any R bonded to the same B atom ｊ１２ and R ｋ１２ together with the B atoms to which they are attached, C １－６ Alkyl and C １－６ forming a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from haloalkyl; R ２ are independently H, D, halo, CN, OH, NO ２ , C １－４ Alkyl, C １－４ Haloalkyl, C ２－４ Alkenyl, C ２－４ Alkynyl, C １－４ Alkoxy, C １－４ Haloalkoxy, Amino, C １－４ Alkylamino, di(C １－４ alkyl)amino, cyano-C １－４ Alkyl, HO-C １－４ Alkyl, C １－４ Alkoxy-C １－４ Alkyl, C ３－４ Cycloalkyl, thio, C １－４ Alkylthio, C １－４ Alkylsulfinyl, C １－４ Alkyl sulfonyl, carbamyl, C １－４ Alkylcarbamyl, di(C １－４ alkyl) carbamyl, carboxy, C １－４ Alkylcarbonyl, C １－４ Alkoxycarbonyl, C １－４ Alkylcarbonyloxy, C １－４ Alkylcarbonylamino, C １－４ Alkoxycarbonylamino, C １－４ Alkylaminocarbonyloxy, C １－４ Alkyl sulfonyl amino, amino sulfonyl, C １－４ Alkylaminosulfonyl, di(C １－４ alkyl)aminosulfonyl, aminosulfonylamino, C １－４ Alkylaminosulfonylamino, di(C １－４ alkyl)aminosulfonylamino, aminocarbonylamino, C １－４ Alkylaminocarbonylamino, and di(C １－４ alkyl)aminocarbonylamino; Each R ３ are independent, H, D, 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; R ４ But C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 10-membered heteroaryl-C １－４ alkyl, wherein C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 10-membered heteroaryl-C １－４ alkyl is optionally selected from 1, 2, 3, or 4 independently selected R ４Ａ is substituted by a substituent, Each R ４Ａ are independently H, D, halo, CN, NO ２ , C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl, OR ａ４１ , S.R. ａ４１ , NHOR ａ４１ , C(O)R ｂ４１ , C(O)NR ｃ４１ R ｄ４１ , C(O)NR ｃ４１ (OR ａ４１ ), C(O)OR ａ４１ , O.C.(O.)R ｂ４１ , OC(O)NR ｃ４１ R ｄ４１ , N.R. ｃ４１ R ｄ４１ , N.R. ｃ４１ NR ｃ４１ R ｄ４１ , N.R. ｃ４１ C(O)R ｂ４１ , N.R. ｃ４１ C(O)OR ａ４１ , N.R. ｃ４１ C(O)NR ｃ４１ R ｄ４１ , C(=NR ｅ４１ ) R ｂ４１ , C(=NR ｅ４１ ) NR ｃ４１ R ｄ４１ , N.R. ｃ４１ C (=NR ｅ４１ ) NR ｃ４１ R ｄ４１ , N.R. ｃ４１ C (=NR ｅ４１ ) R ｂ４１ , N.R. ｃ４１ S(O)NR ｃ４１ R ｄ４１ , N.R. ｃ４１ S(O)R ｂ４１ , N.R. ｃ４１ S (O) ２ R ｂ４１ , N.R. ｃ４１ S(O) (=NR ｅ４１ ) R ｂ４１ , N.R. ｃ４１ S (O) ２ NR ｃ４１ R ｄ４１ , S(O)R ｂ４１ , S(O)NR ｃ４１ R ｄ４１ , S(O) ２ R ｂ４１ , S(O) ２ NR ｃ４１ R ｄ４１ , OS(O)(=NR ｅ４１ ) R ｂ４１ , OS(O) ２ R ｂ４１ , S(O)(=NR ｅ４１ ) R ｂ４１ , SF ５ , P(O)R ｆ４１ R ｇ４１ , OP(O)(OR ｈ４１ ) (OR ｉ４１ ), P(O)(OR ｈ４１ ) (OR ｉ４１ ), and B.R. ｊ４１ R ｋ４１ and C is selected from １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl and 5- to 10-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 ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 10-membered heteroaryl-C １－４ alkyl, wherein C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 10-membered heteroaryl-C １－４ alkyl is optionally selected from 1, 2, 3, or 4 independently selected R ４Ｂ be substituted with a substituent, Alternatively, any R bonded to the same N atom ｃ４１ and R ｄ４１ together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl group, and the 4- to 10-membered heterocycloalkyl group optionally contains 1, 2, 3, or 4 independently selected R ４Ｂ is substituted with a substituent, Each R ｂ４１ became independent and C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 10-membered heteroaryl-C １－４ alkyl, each of which is optionally followed by 1, 2, 3, or 4 independently selected R ４Ｂ is substituted with a substituent, Each R ｅ４１ are independently H, OH, CN, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl, C １－６ Haloalkoxy, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－７ Cycloalkyl, C ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 10-membered heteroaryl-C １－４ alkyl, Each R ｆ４１ and R ｇ４１ are independent, H, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl, C １－６ Haloalkoxy, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 10-membered heteroaryl-C １－４ alkyl, Each R ｈ４１ and R ｉ４１ are independent, H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl and 5- to 10-membered heteroaryl-C １－４ alkyl, Each R ｊ４１ and R ｋ４１ are independent, OH, C １－６ Alkoxy, and C １－６ haloalkoxy; Alternatively, any R bonded to the same B atom ｊ４１ and R ｋ４１ together with the B atoms to which they are attached, C １－６ Alkyl and C １－６ forming a 5- or 10-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from haloalkyl; Each R ４Ｂ are independently H, D, halo, CN, NO ２ , 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 , S.R. ａ４２ , NHOR ａ４２ , C(O)R ｂ４２ , C(O)NR ｃ４２ R ｄ４２ , C(O)NR ｃ４２ (OR ａ４２ ), C(O)OR ａ４２ , O.C.(O.)R ｂ４２ , OC(O)NR ｃ４２ R ｄ４２ , N.R. ｃ４２ R ｄ４２ , N.R. ｃ４２ NR 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 , C(=NR ｅ４２ ) R ｂ４２ , C(=NR ｅ４２ ) NR ｃ４２ R ｄ４２ , N.R. ｃ４２ C (=NR ｅ４２ ) NR ｃ４２ R ｄ４２ , N.R. ｃ４２ C (=NR ｅ４２ ) R ｂ４２ , N.R. ｃ４２ S(O)NR ｃ４２ R ｄ４２ , N.R. ｃ４２ S(O)R ｂ４２ , N.R. ｃ４２ S (O) ２ R ｂ４２ , N.R. ｃ４２ S(O) (=NR ｅ４２ ) R ｂ４２ , N.R. ｃ４２ S (O) ２ NR ｃ４２ R ｄ４２ , S(O)R ｂ４２ , S(O)NR ｃ４２ R ｄ４２ , S(O) ２ R ｂ４２ , S(O) ２ NR ｃ４２ R ｄ４２ , OS(O)(=NR ｅ４２ ) R ｂ４２ , OS(O) ２ R ｂ４２ , S(O)(=NR ｅ４２ ) R ｂ４２ , SF ５ , P(O)R ｆ４２ R ｇ４２ , OP(O)(OR ｈ４２ ) (OR ｉ４２ ), P(O)(OR ｈ４２ ) (OR ｉ４２ ), and B.R. ｊ４２ R ｋ４２ and 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- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl is optionally selected from 1, 2, 3, or 4 independently selected R ４Ｃ is substituted with a substituent, Each R ａ４２ , R ｃ４２ , and R ｄ４２ 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- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, wherein 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 selected from 1, 2, 3, or 4 independently selected R ４Ｃ be substituted with a substituent, Alternatively, any R bonded to the same N atom ｃ４２ and R ｄ４２ together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl group, and the 4- to 7-membered heterocycloalkyl group optionally contains 1, 2, 3, or 4 independently selected R ４Ｃ is substituted with a substituent, Each R ｂ４２ became independent and 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 of which is optionally followed by 1, 2, 3, or 4 independently selected R ４Ｃ is substituted with a substituent, Each R ｅ４２ are independently H, OH, CN, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl, C １－６ Haloalkoxy, 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 R ｆ４２ and R ｇ４２ are independent, H, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl, C １－６ Haloalkoxy, 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 R ｈ４２ and R ｉ４２ 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- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, Each R ｊ４２ and R ｋ４２ are independent, OH, C １－６ Alkoxy, and C １－６ haloalkoxy; Alternatively, any R bonded to the same B atom ｊ４２ and R ｋ４２ together with the B atoms to which they are attached, C １－６ Alkyl and C １－６ forming a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from haloalkyl; Each R ４Ｃ are independently H, D, halo, CN, NO ２ , 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 ａ４３ , S.R. ａ４３ , NHOR ａ４３ , C(O)R ｂ４３ , C(O)NR ｃ４３ R ｄ４３ , C(O)NR ｃ４３ (OR ａ４３ ), C(O)OR ａ４３ , O.C.(O.)R ｂ４３ , OC(O)NR ｃ４３ R ｄ４３ , N.R. ｃ４３ R ｄ４３ , N.R. ｃ４３ NR ｃ４３ R ｄ４３ , N.R. ｃ４３ C(O)R ｂ４３ , N.R. ｃ４３ C(O)OR ａ４３ , N.R. ｃ４３ C(O)NR ｃ４３ R ｄ４３ , C(=NR ｅ４３ ) R ｂ４３ , C(=NR ｅ４３ ) NR ｃ４３ R ｄ４３ , N.R. ｃ４３ C (=NR ｅ４３ ) NR ｃ４３ R ｄ４３ , N.R. ｃ４３ C (=NR ｅ４３ ) R ｂ４３ , N.R. ｃ４３ S(O)NR ｃ４３ R ｄ４３ , N.R. ｃ４３ S(O)R ｂ４３ , N.R. ｃ４３ S (O) ２ R ｂ４３ , N.R. ｃ４３ S(O) (=NR ｅ４３ ) R ｂ４３ , N.R. ｃ４３ S (O) ２ NR ｃ４３ R ｄ４３ , S(O)R ｂ４３ , S(O)NR ｃ４３ R ｄ４３ , S(O) ２ R ｂ４３ , S(O) ２ NR ｃ４３ R ｄ４３ , OS(O)(=NR ｅ４３ ) R ｂ４３ , OS(O) ２ R ｂ４３ , S(O)(=NR ｅ４３ ) R ｂ４３ , SF ５ , P(O)R ｆ４３ R ｇ４３ , OP(O)(OR ｈ４３ ) (OR ｉ４３ ), P(O)(OR ｈ４３ ) (OR ｉ４３ ), and B.R. ｊ４３ R ｋ４３ and 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- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl is optionally selected from 1, 2, 3, or 4 independently selected R Ｇ is substituted with a substituent, Each R ａ４３ , R ｃ４３ , and R ｄ４３ 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- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, wherein 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 selected from 1, 2, 3, or 4 independently selected R Ｇ be substituted with a substituent, Alternatively, any R bonded to the same N atom ｃ４３ and R ｄ４３ together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl group, and the 4- to 7-membered heterocycloalkyl group optionally contains 1, 2, 3, or 4 independently selected R Ｇ is substituted with a substituent, Each R ｂ４３ became independent and 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 of which is optionally followed by 1, 2, 3, or 4 independently selected R Ｇ is substituted with a substituent, Each R ｅ４３ are independently H, OH, CN, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl, C １－６ Haloalkoxy, 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 R ｆ４３ and R ｇ４３ are independent, H, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl, C １－６ Haloalkoxy, 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 R ｈ４３ and R ｉ４３ 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- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, Each R ｊ４３ and R ｋ４３ are independent, OH, C １－６ Alkoxy, and C １－６ haloalkoxy; Alternatively, any R bonded to the same B atom ｊ４３ and R ｋ４３ together with the B atoms to which they are attached, C １－６ Alkyl and C １－６ forming a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from haloalkyl; Each R ５ are independent, H, D, halo, NO ２ , C.N., C. １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl, OR ａ５ , S.R. ａ５ , NHOR ａ５ , C(O)R ｂ５ , C(O)NR ｃ５ R ｄ５ , C(O)NR ｃ５ (OR ａ５ ), C(O)OR ａ５ , O.C.(O.)R ｂ５ , OC(O)NR ｃ５ R ｄ５ , N.R. ｃ５ R ｄ５ , N.R. ｃ５ NR ｃ５ R ｄ５ , N.R. ｃ５ C(O)R ｂ５ , N.R. ｃ５ C(O)OR ａ５ , N.R. ｃ５ C(O)NR ｃ５ R ｄ５ , C(=NR ｅ５ ) R ｂ５ , C(=NR ｅ５ ) NR ｃ５ R ｄ５ , N.R. ｃ５ C (=NR ｅ５ ) NR ｃ５ R ｄ５ , N.R. ｃ５ C (=NR ｅ５ ) R ｂ５ , N.R. ｃ５ S(O)NR ｃ５ R ｄ５ , N.R. ｃ５ S(O)R ｂ５ , N.R. ｃ５ S (O) ２ R ｂ５ , N.R. ｃ５ S(O) (=NR ｅ５ ) R ｂ５ , N.R. ｃ５ S (O) ２ NR ｃ５ R ｄ５ , S(O)R ｂ５ , S(O)NR ｃ５ R ｄ５ , S(O) ２ R ｂ５ , S(O) ２ NR ｃ５ R ｄ５ , OS(O)(=NR ｅ５ ) R ｂ５ , OS(O) ２ R ｂ５ , S(O)(=NR ｅ５ ) R ｂ５ , S.F. ５ , P(O)R ｆ５ R ｇ５ , OP(O)(OR ｈ５ ) (OR ｉ５ ), P(O)(OR ｈ５ ) (OR ｉ５ ), and B.R. ｊ５ R ｋ５ and C is selected from １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 10-membered heteroaryl-C １－４ alkyl is optionally selected from 1, 2, 3, or 4 independently selected R ５Ａ is substituted by a substituent, Each R ａ５ , R ｃ５ , and R ｄ５ are independent, H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 10-membered heteroaryl-C １－４ alkyl, wherein C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 10-membered heteroaryl-C １－４ alkyl is optionally selected from 1, 2, 3, or 4 independently selected R ５Ａ be substituted with a substituent, Alternatively, any R bonded to the same N atom ｃ５ and R ｄ５ together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl group, which optionally is joined to one, two, three, or four independently selected R ５Ａ is substituted with a substituent, Each R ｂ５ became independent and C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl and 5- to 10-membered heteroaryl-C １－４ alkyl, each of which is optionally followed by 1, 2, 3, or 4 independently selected R ５Ａ is substituted with a substituent, Each R ｅ５ are independently H, OH, CN, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl, C １－６ Haloalkoxy, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl and 5- to 10-membered heteroaryl-C １－４ alkyl, Each R ｆ５ and R ｇ５ are independent, H, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl, C １－６ Haloalkoxy, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 10-membered heteroaryl-C １－４ alkyl, Each R ｈ５ and R ｉ５ are independent, H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl and 5- to 10-membered heteroaryl-C １－４ alkyl, Each R ｊ５ and R ｋ５ are independent, OH, C １－６ Alkoxy, and C １－６ haloalkoxy; Alternatively, any R bonded to the same B atom ｊ５ and R ｋ５ together with the B atoms to which they are attached, C １－６ Alkyl and C １－６ forming a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from haloalkyl; Each R ５Ａ are independently H, D, halo, CN, NO ２ , C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl, OR ａ５１ , S.R. ａ５１ , NHOR ａ５１ , C(O)R ｂ５１ , C(O)NR ｃ５１ R ｄ５１ , C(O)NR ｃ５１ (OR ａ５１ ), C(O)OR ａ５１ , O.C.(O.)R ｂ５１ , OC(O)NR ｃ５１ R ｄ５１ , N.R. ｃ５１ R ｄ５１ , N.R. ｃ５１ NR ｃ５１ R ｄ５１ , N.R. ｃ５１ C(O)R ｂ５１ , N.R. ｃ５１ C(O)OR ａ５１ , N.R. ｃ５１ C(O)NR ｃ５１ R ｄ５１ , C(=NR ｅ５１ ) R ｂ５１ , C(=NR ｅ５１ ) NR ｃ５１ R ｄ５１ , N.R. ｃ５１ C (=NR ｅ５１ ) NR ｃ５１ R ｄ５１ , N.R. ｃ５１ C (=NR ｅ５１ ) R ｂ５１ , N.R. ｃ５１ S(O)NR ｃ５１ R ｄ５１ , N.R. ｃ５１ S(O)R ｂ５１ , N.R. ｃ５１ S (O) ２ R ｂ５１ , N.R. ｃ５１ S(O) (=NR ｅ５１ ) R ｂ５１ , N.R. ｃ５１ S (O) ２ NR ｃ５１ R ｄ５１ , S(O)R ｂ５１ , S(O)NR ｃ５１ R ｄ５１ , S(O) ２ R ｂ５１ , S(O) ２ NR ｃ５１ R ｄ５１ , OS(O)(=NR ｅ５１ ) R ｂ５１ , OS(O) ２ R ｂ５１ , S(O)(=NR ｅ５１ ) R ｂ５１ , SF ５ , P(O)R ｆ５１ R ｇ５１ , OP(O)(OR ｈ５１ ) (OR ｉ５１ ), P(O)(OR ｈ５１ ) (OR ｉ５１ ), and B.R. ｊ５１ R ｋ５１ and C is selected from １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl and 5- to 10-membered heteroaryl-C １－４ alkyl is optionally selected from 1, 2, 3, or 4 independently selected R ５Ｂ is substituted with a substituent, Each R ａ５１ , R ｃ５１ , and R ｄ５１ are independent, H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 10-membered heteroaryl-C １－４ alkyl, wherein C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 10-membered heteroaryl-C １－４ alkyl is optionally selected from 1, 2, 3, or 4 independently selected R ５Ｂ be substituted with a substituent, Alternatively, any R bonded to the same N atom ｃ５１ and R ｄ５１ together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl group, which optionally is joined to one, two, three, or four independently selected R ５Ｂ is substituted with a substituent, Each R ｂ５１ became independent and C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 10-membered heteroaryl-C １－４ alkyl, each of which is optionally followed by 1, 2, 3, or 4 independently selected R ５Ｂ is substituted with a substituent, Each R ｅ５１ are independently H, OH, CN, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl, C １－６ Haloalkoxy, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 10-membered heteroaryl-C １－４ alkyl, Each R ｆ５１ and R ｇ５１ are independent, H, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl, C １－６ Haloalkoxy, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl and 5- to 10-membered heteroaryl-C １－４ alkyl, Each R ｈ５１ and R ｉ５１ are independent, H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 10-membered heteroaryl-C １－４ alkyl, Each R ｊ５１ and R ｋ５１ are independent, OH, C １－６ Alkoxy, and C １－６ haloalkoxy; Alternatively, any R bonded to the same B atom ｊ５１ and R ｋ５１ together with the B atoms to which they are attached, C １－６ Alkyl and C １－６ forming a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from haloalkyl; Each R ５Ｂ are independently H, D, halo, CN, NO ２ , 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 ａ５２ , S.R. ａ５２ , NHOR ａ５２ , C(O)R ｂ５２ , C(O)NR ｃ５２ R ｄ５２ , C(O)NR ｃ５２ (OR ａ５２ ), C(O)OR ａ５２ , O.C.(O.)R ｂ５２ , OC(O)NR ｃ５２ R ｄ５２ , N.R. ｃ５２ R ｄ５２ , N.R. ｃ５２ NR ｃ５２ R ｄ５２ , N.R. ｃ５２ C(O)R ｂ５２ , N.R. ｃ５２ C(O)OR ａ５２ , N.R. ｃ５２ C(O)NR ｃ５２ R ｄ５２ , C(=NR ｅ５２ ) R ｂ５２ , C(=NR ｅ５２ ) NR ｃ５２ R ｄ５２ , N.R. ｃ５２ C (=NR ｅ５２ ) NR ｃ５２ R ｄ５２ , N.R. ｃ５２ C (=NR ｅ５２ ) R ｂ５２ , N.R. ｃ５２ S(O)NR ｃ５２ R ｄ５２ , N.R. ｃ５２ S(O)R ｂ５２ , N.R. ｃ５２ S (O) ２ R ｂ５２ , N.R. ｃ５２ S(O) (=NR ｅ５２ ) R ｂ５２ , N.R. ｃ５２ S (O) ２ NR ｃ５２ R ｄ５２ , S(O)R ｂ５２ , S(O)NR ｃ５２ R ｄ５２ , S(O) ２ R ｂ５２ , S(O) ２ NR ｃ５２ R ｄ５２ , OS(O)(=NR ｅ５２ ) R ｂ５２ , OS(O) ２ R ｂ５２ , S(O)(=NR ｅ５２ ) R ｂ５２ , S.F. ５ , P(O)R ｆ５２ R ｇ５２ , OP(O)(OR ｈ５２ ) (OR ｉ５２ ), P(O)(OR ｈ５２ ) (OR ｉ５２ ), and B.R. ｊ５２ R ｋ５２ and 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- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl is optionally selected from 1, 2, 3, or 4 independently selected R ５Ｃ is substituted with a substituent, Each R ａ５２ , R ｃ５２ , and R ｄ５２ 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- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, wherein 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 selected from 1, 2, 3, or 4 independently selected R ５Ｃ be substituted with a substituent, Alternatively, any R bonded to the same N atom ｃ５２ and R ｄ５２ together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl group, which optionally is joined to one, two, three, or four independently selected R ５Ｃ is substituted with a substituent, Each R ｂ５２ became independent and 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 of which is optionally followed by 1, 2, 3, or 4 independently selected R ５Ｃ is substituted with a substituent, Each R ｅ５２ are independently H, OH, CN, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl, C １－６ Haloalkoxy, 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 R ｆ５２ and R ｇ５２ are independent, H, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl, C １－６ Haloalkoxy, 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 R ｈ５２ and R ｉ５２ 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- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, Each R ｊ５２ and R ｋ５２ are independent, OH, C １－６ Alkoxy, and C １－６ haloalkoxy; Alternatively, any R bonded to the same B atom ｊ５２ and R ｋ５２ together with the B atoms to which they are attached, C １－６ Alkyl and C １－６ forming a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from haloalkyl; Each R ５Ｃ are independently H, D, halo, CN, NO ２ , 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 ａ５３ , S.R. ａ５３ , NHOR ａ５３ , C(O)R ｂ５３ , C(O)NR ｃ５３ R ｄ５３ , C(O)NR ｃ５３ (OR ａ５３ ), C(O)OR ａ５３ , O.C.(O.)R ｂ５３ , OC(O)NR ｃ５３ R ｄ５３ , N.R. ｃ５３ R ｄ５３ , N.R. ｃ５３ NR ｃ５３ R ｄ５３ , N.R. ｃ５３ C(O)R ｂ５３ , N.R. ｃ５３ C(O)OR ａ５３ , N.R. ｃ５３ C(O)NR ｃ５３ R ｄ５３ , C(=NR ｅ５３ ) R ｂ５３ , C(=NR ｅ５３ ) NR ｃ５３ R ｄ５３ , N.R. ｃ５３ C (=NR ｅ５３ ) NR ｃ５３ R ｄ５３ , N.R. ｃ５３ C (=NR ｅ５３ ) R ｂ５３ , N.R. ｃ５３ S(O)NR ｃ５３ R ｄ５３ , N.R. ｃ５３ S(O)R ｂ５３ , N.R. ｃ５３ S (O) ２ R ｂ５３ , N.R. ｃ５３ S(O) (=NR ｅ５３ ) R ｂ５３ , N.R. ｃ５３ S (O) ２ NR ｃ５３ R ｄ５３ , S(O)R ｂ５３ , S(O)NR ｃ５３ R ｄ５３ , S(O) ２ R ｂ５３ , S(O) ２ NR ｃ５３ R ｄ５３ , OS(O)(=NR ｅ５３ ) R ｂ５３ , OS(O) ２ R ｂ５３ , S(O)(=NR ｅ５３ ) R ｂ５３ , S.F. ５ , P(O)R ｆ５３ R ｇ５３ , OP(O)(OR ｈ５３ ) (OR ｉ５３ ), P(O)(OR ｈ５３ ) (OR ｉ５３ ), and B.R. ｊ５３ R ｋ５３ and 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- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl is optionally selected from 1, 2, 3, or 4 independently selected R Ｇ is substituted with a substituent, Each R ａ５３ , R ｃ５３ , and R ｄ５３ 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- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, wherein 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 selected from 1, 2, 3, or 4 independently selected R Ｇ be substituted with a substituent, Alternatively, any R bonded to the same N atom ｃ５３ and R ｄ５３ together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl group, which optionally is joined to one, two, three, or four independently selected R Ｇ is substituted with a substituent, Each R ｂ５３ became independent and 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 of which is optionally followed by 1, 2, 3, or 4 independently selected R Ｇ is substituted with a substituent, Each R ｅ５３ are independently H, OH, CN, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl, C １－６ Haloalkoxy, 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 R ｆ５３ and R ｇ５３ are independent, H, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl, C １－６ Haloalkoxy, 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 R ｈ５３ and R ｉ５３ 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- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, Each R ｊ５３ and R ｋ５３ are independent, OH, C １－６ Alkoxy, and C １－６ haloalkoxy; Alternatively, any R bonded to the same B atom ｊ５３ and R ｋ５３ together with the B atoms to which they are attached, C １－６ Alkyl and C １－６ forming a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from haloalkyl; Each R Ｇ are independent, OH, NO ２ , CN, Halo, C １－３ Alkyl, C ２－３ Alkenyl, C ２－３ Alkynyl, C １－３ Haloalkyl, cyano-C １－３ Alkyl, HO-C １－３ Alkyl, C １－３ Alkoxy-C １－３ Alkyl, C ３－７ Cycloalkyl, C １－３ Alkoxy, C １－３ Haloalkoxy, Amino, C １－３ Alkylamino, di(C １－３ alkyl) amino, thio, C １－３ Alkylthio, C １－３ Alkylsulfinyl, C １－３ Alkyl sulfonyl, carbamyl, C １－３ Alkylcarbamyl, di(C １－３ alkyl) carbamyl, carboxy, C １－３ Alkylcarbonyl, C １－３ Alkoxycarbonyl, C １－３ Alkylcarbonyloxy, C １－３ Alkylcarbonylamino, C １－３ Alkoxycarbonylamino, C １－３ Alkylaminocarbonyloxy, C １－３ Alkyl sulfonyl amino, amino sulfonyl, C １－３ Alkylaminosulfonyl, di(C １－３ alkyl)aminosulfonyl, aminosulfonylamino, C １－３ Alkylaminosulfonylamino, di(C １－３ alkyl)aminosulfonylamino, aminocarbonylamino, C １－３ Alkylaminocarbonylamino, and di(C １－３ alkyl)aminocarbonylamino; The compound or a pharmaceutically acceptable salt thereof.

2. R １ are independently H, halo, CN, NO ２ , 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 , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O.)R ｂ１ , OC(O)NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , N.R. ｃ１ C(O)NR ｃ１ R ｄ１ , N.R. ｃ１ S (O) ２ R ｂ１ , N.R. ｃ１ S (O) ２ NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ , and S(O) ２ NR ｃ１ R ｄ１ and 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- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl is optionally selected from 1, 2, 3, or 4 independently selected R １Ａ 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is substituted with a substituent.

3. R １ are 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 , S.R. ａ１ , and N.R. ｃ１ R ｄ１ and C is selected from 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 optionally selected from one or two independently selected R １Ａ 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is substituted with a substituent.

4. R １ are independent, H, C １－６ alkyl, phenyl, 5- to 7-membered heterocycloalkyl, OR ａ１ , S.R. ａ１ , and N.R. ｃ１ R ｄ１ and C is selected from １－６ alkyl, phenyl, and 5- to 7-membered heterocycloalkyl are each optionally joined to one or two independently selected R １Ａ 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is substituted with a substituent.

5. R １ are independently H and OR ａ１ 2. The compound of claim 1, selected from:

6. Each R ａ１ , R ｃ１ , and R ｄ１ are independent, 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, wherein 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 optionally selected from 1, 2, 3, or 4 independently selected R １Ａ is substituted with a substituent, Each R ｂ１ became independent and 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 of which is optionally followed by 1, 2, 3, or 4 independently selected R １Ａ is substituted with a substituent, Each R １Ａ are independently H, D, halo, CN, NO ２ , 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 , O.C.(O.)R ｂ１１ , OC(O)NR ｃ１１ R ｄ１１ , N.R. ｃ１１ R ｄ１１ , N.R. ｃ１１ C(O)R ｂ１１ , N.R. ｃ１１ C(O)OR ａ１１ , N.R. ｃ１１ C(O)NR ｃ１１ R ｄ１１ , N.R. ｃ１１ S (O) ２ R ｂ１１ , N.R. ｃ１１ S (O) ２ NR ｃ１１ R ｄ１１ , S(O) ２ R ｂ１１ , and S(O) ２ NR ｃ１１ R ｄ１１ and C is selected from 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 optionally selected from 1, 2, 3, or 4 independently selected R １Ｂ is substituted with a substituent, Each R ａ１１ , R ｃ１１ , and R ｄ１１ are independent, H, C １－６ Alkyl, and C １－６ haloalkyl; Each R ｂ１１ became independent and C １－６ Alkyl and C １－６ haloalkyl; Each R １Ｂ are independently H, D, and OR ａ１２ is selected from Each R ａ１２ are independently H and C １－６ selected from alkyl, 6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof.

7. 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- to 6-membered heterocycloalkyl, C ３－６ Cycloalkyl-C １－３ Alkyl, and 4- to 6-membered heterocycloalkyl-C １－３ alkyl, wherein 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 optionally selected from one, two, or three independently selected R １Ａ is substituted with a substituent, Each R ｂ１ became independent and 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, each of which is optionally selected from one or two independently selected R １Ａ is substituted with a substituent, Each R １Ａ are independent, H, D, halo, CN, C １－６ Alkyl, C １－６ Haloalkyl, OR ａ１１ , and C(O)OR ａ１１ and C is selected from １－６ Alkyl, and C １－６ haloalkyl, each optionally selected from 1, 2, or 3 independently selected R １Ｂ is substituted with a substituent, Each R ａ１１ are independently H and C １－４ alkyl, wherein C １－４ The alkyl is optionally selected from one, two, or three independently selected R １Ｂ is substituted by a substituent, Each R １Ｂ are independently H, D, and O-C １－４ selected from alkyl, 6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof.

8. R １ But OR ａ１ and R ａ１ But C １－３ 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R is alkyl.

9. R ２ But, 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 9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, selected from cycloalkyl.

10. R ２ The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein is H or halo.

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

12. 12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein ring moiety B is a monocyclic 4- to 7-membered heterocycloalkyl.

13. 12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein ring moiety B is piperidinyl.

14. The compound according to any one of claims 1 to 13, wherein n is 0 or 1, or a pharmaceutically acceptable salt thereof.

15. Each R ３ 15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein is independently selected from H, F, and methyl.

16. Each R ３ 15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein: is independently selected from H and methyl.

17. R ４ But 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, wherein 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 optionally selected from 1, 2, 3, or 4 independently selected R ４Ａ 17. The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, which is substituted by a substituent.

18. R ４ But C １－６ Alkyl, C ３－６ Cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl-C １－４ alkyl, wherein C １－６ Alkyl, C ３－６ Cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl-C １－４ alkyl is optionally selected from one or two independently selected R ４Ａ 17. The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, which is substituted by a substituent.

19. R ４ But C １－６ Alkyl, C ３－６ Cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl-C １－４ alkyl, wherein C １－６ Alkyl, C ３－６ The cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each optionally joined to one or two independently selected R ４Ａ 17. The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, which is substituted by a substituent.

20. R ４ But C １－６ Alkyl and C ３－６ 17. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, which is cycloalkyl.

21. Each R ４Ａ are 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 , O.C.(O.)R ｂ４１ , OC(O)NR ｃ４１ R ｄ４１ , N.R. ｃ４１ R ｄ４１ , N.R. ｃ４１ C(O)R ｂ４１ , N.R. ｃ４１ C(O)OR ａ４１ , N.R. ｃ４１ C(O)NR ｃ４１ R ｄ４１ , N.R. ｃ４１ S (O) ２ R ｂ４１ , N.R. ｃ４１ S (O) ２ NR ｃ４１ R ｄ４１ , S(O) ２ R ｂ４１ , and S(O) ２ NR ｃ４１ R ｄ４１ and C is selected from １－６ Alkyl, C １－６ Haloalkyl, and C ３－４ cycloalkyl is optionally selected from one, two, or three 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, and C ３－４ cycloalkyl, wherein C １－６ Alkyl, C １－６ Haloalkyl, and C ３－４ cycloalkyl is optionally selected from one or two independently selected R ４Ｂ is substituted with a substituent, Each R ｂ４１ became independent and C １－６ Alkyl, C １－６ Haloalkyl, and C ３－４ cycloalkyl, each of which is optionally selected from one or two independently selected R ４Ｂ is substituted with a substituent, Each R ４Ｂ are independently H, halo, CN, C １－３ Alkyl, C １－３ Haloalkyl, OR ａ４２ , and N.R. ｃ４２ R ｄ４２ is selected from Each R ａ４２ , R ｃ４２ , and R ｄ４２ are independent, H, C １－３ Alkyl, and C １－３ haloalkyl; Each R ｂ４２ became independent and C １－３ Alkyl and C １－３ haloalkyl, 21. The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof.

22. Each R ４Ａ are 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 , O.C.(O.)R ｂ４１ , OC(O)NR ｃ４１ R ｄ４１ , N.R. ｃ４１ R ｄ４１ , N.R. ｃ４１ C(O)R ｂ４１ , N.R. ｃ４１ C(O)OR ａ４１ , N.R. ｃ４１ C(O)NR ｃ４１ R ｄ４１ , N.R. ｃ４１ S (O) ２ R ｂ４１ , N.R. ｃ４１ S (O) ２ NR ｃ４１ R ｄ４１ , S(O) ２ R ｂ４１ , and S(O) ２ NR ｃ４１ R ｄ４１ is selected from Each R ａ４１ , R ｃ４１ , and R ｄ４１ are independent, H, C １－３ Alkyl, and C １－３ haloalkyl; Each R ｂ４１ became independent and C １－３ Alkyl and C １－３ haloalkyl, 21. The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof.

23. Each R ４Ａ are independently H, halo, CN, C １－６ Alkyl, C １－６ Haloalkyl, OR ａ４１ , and N.R. ｃ４１ R ｄ４１ is selected from Each R ａ４１ , R ｃ４１ , and R ｄ４１ are independently H and C １－３ Alkyl, and C １－３ haloalkyl; Each R ｂ４１ However, independently C １－３ is alkyl, 21. The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof.

24. 24. The compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein ring moiety A is a 5- to 10-membered heteroaryl.

25. 24. The compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein ring moiety A is a 5- to 6-membered heteroaryl.

26. 24. The compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein ring moiety A is 1H-pyrrolo[2,3-b]pyridinyl, pyridinyl, or pyrazolyl.

27. 24. The compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein ring moiety A is pyrazolyl.

28. 28. The compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein p is 0 or 1.

29. Each R ５ are independently H, halo, CN, C １－６ Alkyl, C １－６ Haloalkyl, C ３－４ Cycloalkyl, OR ａ５ , and N.R. ｃ５ R ｄ５ and each R ａ５ , R ｃ５ , and R ｄ５ are independent, H, C １－６ Alkyl, and C １－６ 29. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, selected from haloalkyl.

30. Each R ５ became independent and CH ３ or NH ２ 29. The compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, selected from:

31. 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- 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 , S.R. ａ１ , and N.R. ｃ１ R ｄ１ and said C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 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 is optionally selected from one, two, or three independently selected R １Ａ is substituted with a substituent, Each R ａ１ , R ｃ１ , and R ｄ１ are independent, 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, wherein 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 optionally selected from one, two, or three independently selected R １Ａ is substituted with a substituent, Each R １Ａ are independent, 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 , O.C.(O.)R ｂ１１ , OC(O)NR ｃ１１ R ｄ１１ , N.R. ｃ１１ R ｄ１１ , N.R. ｃ１１ C(O)R ｂ１１ , N.R. ｃ１１ C(O)OR ａ１１ , N.R. ｃ１１ C(O)NR ｃ１１ R ｄ１１ , N.R. ｃ１１ S (O) ２ R ｂ１１ , N.R. ｃ１１ S (O) ２ NR ｃ１１ R ｄ１１ , S(O) ２ R ｂ１１ , and S(O) ２ NR ｃ１１ R ｄ１１ and C is selected from １－６ Alkyl, C １－６ Haloalkyl, and C ３－４ cycloalkyl is optionally selected from one, two, or three independently selected R １Ｂ is substituted by a substituent, Each R ａ１１ , R ｃ１１ , and R ｄ１１ are independent, H, C １－６ Alkyl, and C １－６ haloalkyl; Each R ｂ１１ became independent and C １－６ Alkyl and C １－６ haloalkyl; Each R １Ｂ are independently H, D, and OR ａ１２ is selected from Each R ａ１２ are independently H and C １－６ alkyl, R ２ But, H, halo, CN, C １－３ Alkyl, and C １－３ haloalkyl; Each R ３ are independent, H, halo, C １－３ alkyl, and cyclopropyl; R ４ But 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, wherein 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 is optionally selected from one or two independently selected R ４Ａ is substituted by a substituent, Each R ４Ａ are 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 , O.C.(O.)R ｂ４１ , OC(O)NR ｃ４１ R ｄ４１ , N.R. ｃ４１ R ｄ４１ , N.R. ｃ４１ C(O)R ｂ４１ , N.R. ｃ４１ C(O)OR ａ４１ , N.R. ｃ４１ C(O)NR ｃ４１ R ｄ４１ , N.R. ｃ４１ S (O) ２ R ｂ４１ , N.R. ｃ４１ S (O) ２ NR ｃ４１ R ｄ４１ , S(O) ２ R ｂ４１ , and S(O) ２ NR ｃ４１ R ｄ４１ and C is selected from １－６ Alkyl, C １－６ Haloalkyl, and C ３－４ cycloalkyl is optionally selected from one, two, or three 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, and C ３－４ cycloalkyl, wherein C １－６ Alkyl, C １－６ Haloalkyl, and C ３－４ cycloalkyl is optionally selected from one or two independently selected R ４Ｂ is substituted with a substituent, Each R ｂ４１ became independent and C １－６ Alkyl, C １－６ Haloalkyl, and C ３－４ cycloalkyl, each of which is optionally selected from one or two independently selected R ４Ｂ is substituted with a substituent, Each R ４Ｂ are independently H, halo, CN, C １－３ Alkyl, C １－３ Haloalkyl, OR ａ４２ , and N.R. ｃ４２ R ｄ４２ is selected from Each R ａ４２ , R ｃ４２ , and R ｄ４２ are independent, H, C １－３ Alkyl, and C １－３ haloalkyl; Each R ｂ４２ became independent and C １－３ Alkyl and C １－３ haloalkyl; Each R ５ are independent, H, halo, NO ２ , C.N., 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 ａ５ , S.R. ａ５ , NHOR ａ５ , C(O)R ｂ５ , C(O)NR ｃ５ R ｄ５ , C(O)OR ａ５ , O.C.(O.)R ｂ５ , OC(O)NR ｃ５ R ｄ５ , N.R. ｃ５ R ｄ５ , N.R. ｃ５ C(O)R ｂ５ , N.R. ｃ５ C(O)OR ａ５ , N.R. ｃ５ C(O)NR ｃ５ R ｄ５ , N.R. ｃ５ S (O) ２ R ｂ５ , N.R. ｃ５ S (O) ２ NR ｃ５ R ｄ５ , S(O) ２ R ｂ５ , and S(O) ２ NR ｃ５ R ｄ５ and C is selected from 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 optionally selected from 1, 2, 3, or 4 independently selected R ５Ａ is substituted by a substituent, Each R ａ５ , R ｃ５ , and R ｄ５ are independent, 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, wherein 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 optionally selected from 1, 2, 3, or 4 independently selected R ５Ａ is substituted with a substituent, Each R ｂ５ became independent and 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 of which is optionally followed by 1, 2, 3, or 4 independently selected R ５Ａ is substituted with a substituent, Each R ５Ａ are independently H, halo, CN, C １－６ Alkyl, C １－６ Haloalkyl, C ３－４ Cycloalkyl, OR ａ５１ , S.R. ａ５１ , NHOR ａ５１ , C(O)R ｂ５１ , C(O)NR ｃ５１ R ｄ５１ , C(O)OR ａ５１ , O.C.(O.)R ｂ５１ , OC(O)NR ｃ５１ R ｄ５１ , N.R. ｃ５１ R ｄ５１ , N.R. ｃ５１ C(O)R ｂ５１ , N.R. ｃ５１ C(O)OR ａ５１ , N.R. ｃ５１ C(O)NR ｃ５１ R ｄ５１ , N.R. ｃ５１ S (O) ２ R ｂ５１ , N.R. ｃ５１ S (O) ２ NR ｃ５１ R ｄ５１ , S(O) ２ R ｂ５１ , and S(O) ２ 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 and C １－６ Alkyl and C １－６ haloalkyl, 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

32. n is 0 or 1; p is 0 or 1; ring moiety A is a 5-10 membered heteroaryl having 1 or 2 N ring-forming atoms; Ring moiety B is piperidinyl; R １ are independent, H, C １－６ alkyl, phenyl, 5- to 7-membered heterocycloalkyl, OR ａ１ , S.R. ａ１ , and N.R. ｃ１ R ｄ１ and C is selected from １－６ alkyl, phenyl, and 5- to 7-membered heterocycloalkyl are each optionally joined to 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- to 6-membered heterocycloalkyl, C ３－６ Cycloalkyl-C １－３ Alkyl, and 4- to 6-membered heterocycloalkyl-C １－３ alkyl, wherein 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 optionally selected from one, two, or three independently selected R １Ａ is substituted with a substituent, Each R １Ａ are independent, D, halo, CN, C １－３ Alkyl, C １－３ Haloalkyl, C ３－４ Cycloalkyl, OR ａ１１ , and C(O)OR ａ１１ and C is selected from １－６ Alkyl, and C １－６ haloalkyl, each optionally selected from 1, 2, or 3 independently selected R １Ｂ is substituted with a substituent, Each R ａ１１ are independently H and C １－４ alkyl, wherein C １－４ The alkyl is optionally selected from one, two, or three independently selected R １Ｂ is substituted by a substituent, Each R １Ｂ are independently 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 But C １－６ Alkyl, C ３－６ Cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl-C １－４ alkyl, wherein C １－６ Alkyl, C ３－６ Cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl-C １－４ alkyl is optionally selected from 1, 2, 3, or 4 independently selected R ４Ａ is substituted by a substituent, Each R ４Ａ are independent, H, C １－６ Alkyl, OH, and NR ｃ４１ R ｄ４１ is selected from Each R ｃ４１ and R ｄ４１ are independent, H, C １－６ Alkyl, and C １－６ haloalkyl; Each R ５ are independently H, halo, CN, C １－６ Alkyl, C １－６ Haloalkyl, C ３－４ Cycloalkyl, OR ａ５ , and N.R. ｃ５ R ｄ５ is selected from Each R ａ５ , R ｃ５ , and R ｄ５ are independent, H, C １－６ Alkyl, and C １－６ haloalkyl, 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

33. n is 0 or 1; p is 0 or 1; ring moiety A is a 5-10 membered heteroaryl having 1 or 2 N ring-forming atoms; Ring moiety B is piperidinyl; R １ are independently H and OR ａ１ is selected from Each R ａ１ are independent, 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, wherein 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 is optionally selected from one or two independently selected R １Ａ is substituted with a substituent, Each R １Ａ became independent and 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 But C １－６ Alkyl and C ３－６ cycloalkyl, wherein C １－６ Alkyl and C ３－６ cycloalkyl is optionally selected from 1, 2, 3, or 4 independently selected R ４Ａ is substituted by a substituent, Each R ４Ａ are independently H and C １－６ alkyl, Each R ５ are independently H, halo, CN, C １－６ Alkyl, C １－６ Haloalkyl, C ３－４ Cycloalkyl, OR ａ５ , and N.R. ｃ５ R ｄ５ is selected from Each R ａ５ , R ｃ５ , and R ｄ５ are independent, H, C １－６ Alkyl, and C １－６ haloalkyl, 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

34. Formula (Va), or (Vb), or (Vc), or (Vd), 【Chemistry 7】 or a pharmaceutically acceptable salt thereof.

34. The compound of any one of claims 1 to 33,

35. Formula (VIa), or (VIIa), or (VIIIa), or (IXa), 【Chemistry 8】 or a pharmaceutically acceptable salt of any of the above.

36. Formula (VIb), or (VIIIb), or (IXb), 【Chemistry 9】 or a pharmaceutically acceptable salt thereof.

34. The compound of any one of claims 1 to 33,

37. Formula (VIc), or (VIIIc), or (IXc), 【Chemistry 10】 or a pharmaceutically acceptable salt thereof.

34. The compound of any one of claims 1 to 33,

38. 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, 2. The compound of claim 1, selected from:

39. 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]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]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]triazolo[1,5-a]pyrazin-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]pyrazin-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]pyrazin-2-amine, 5-butoxy-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-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, 2. The compound of claim 1, selected from:

40. A pharmaceutical composition comprising a compound according to any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

41. 40. A method of inhibiting CDK2, comprising contacting said CDK2 with a compound according to any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof.

42. 40. A method of inhibiting CDK2 in a patient, comprising administering to said patient a compound of any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof.

43. 40. A method of treating a disease or disorder associated with CDK2 in a patient, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof.

44. 44. The method of claim 43, wherein the disease or disorder is associated with amplification of the cyclin E1 (CCNE1) gene and / or overexpression of CCNE1.

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

46. 1. A method of treating a human subject having a disease or disorder associated with cyclin-dependent kinase 2 (CDK2), comprising: (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) identifying a cyclin-dependent kinase inhibitor 2A (CDKN2A) gene lacking one or more inactivating nucleic acid substitutions; and (ii) in a biological sample obtained from the human subject, (a) 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 39, or a pharmaceutically acceptable salt thereof; The method comprising:

47. (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) identifying a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions; (ii) in a biological sample obtained from the human subject, (a) identifying the amplification of the CCNE1 gene; (iii) administering said compound or said salt to said human subject; and 47. The method of claim 46, comprising:

48. 40. A method for assessing the response of a human subject having a disease or disorder associated with cyclin-dependent kinase 2 (CDK2) to a compound of any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, comprising: (a) administering said compound or said salt to said human subject, wherein said human subject has previously been determined to have 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) following said administering of step (a), measuring in a biological sample obtained from said subject the level of phosphorylation of retinoblastoma (Rb) protein at serine corresponding to amino acid position 780 of SEQ ID NO: 3; The method, wherein a reduced level of Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO: 3 compared to a control level of Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO: 3 indicates that the human subject is responsive to the compound or salt.

49. The method of any one of claims 43 to 48, wherein the disease or disorder is cancer.

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