Bicyclic amines as CDK2 inhibitors

Abstract

Provided herein are bicyclic amines that are inhibitors of cyclin dependent kinase 2 (CDK2), as well as pharmaceutical compositions thereof, and methods of using the bicyclic amines and pharmaceutical compositions in the treatment of cancer.

Description

[0001] This application is a divisional application of the Chinese patent application No. 202080085261.1 (application date: October 9, 2020, invention name: Dicyclomine as a CDK2 inhibitor).

[0002] This application claims the benefit of priority to U.S. Provisional Application No. 62 / 914,114, filed October 11, 2019, which is incorporated herein by reference in its entirety.

[0003] Sequence Listing

[0004] This application contains a sequence listing, which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. The ASCII copy was created on October 2, 2020, is named 20443-0634WO1_SL.txt, and is 15.3 kilobytes in size. Technical Field

[0005] The present application relates to bicyclic amines that inhibit cyclin-dependent kinase 2 (CDK2) and are useful in treating cancer. Background Art

[0006] Cyclin-dependent kinases (CDKs) are a family of serine / threonine kinases. CDKs that dimerize with regulatory subunits called cyclins 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. CDK activity dysregulation is associated with abnormal regulation of the cell cycle and has been detected in almost all forms of human cancer (Sherr, CJ, Science, 1996.274(5293):1672-7).

[0007] CDK2 has received particular attention because dysregulation of CDK2 activity frequently occurs in a variety of human cancers. CDK2 plays a crucial role in promoting the G1 / S transition and S phase progression. In a complex with cyclin E (CCNE), CDK2 phosphorylates members of the retinoblastoma pocket protein family (p107, p130, pRb), leading to derepression of E2F transcription factors, expression of G1 / S transition-related genes, and transition from G1 phase to S phase (Henley, SA and FADick, Cell Div, 2012, 7(1): p.10). This in turn can activate CDK2 / cyclin A, allowing phosphorylation of endogenous substrates that allow DNA synthesis, replication, and centrosome duplication (Ekholm, SV and SI Reed, Curr Opin Cell Biol, 2000. 12(6): 676-84). It has been reported that the CDK2 pathway affects tumor formation mainly through amplification and / or overexpression of CCNE1 and mutations that inactivate endogenous inhibitors of CDK2 (e.g., p27), respectively (Xu, X. et al., Biochemistry, 1999. 38(27):8713-22).

[0008] 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 has also been reported to contribute to trastuzumab resistance in HER2+ breast cancer and resistance to CDK4 / 6 inhibitors in estrogen receptor-positive breast cancer (Scaltriti, M. et al., Proc Natl Acad Sci 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 has been reported to restore sensitivity of resistant HER2+ breast tumors to trastuzumab treatment in preclinical models (Scaltriti, supra).

[0009] These data provide a rationale for considering CDK2 as a potential target for new drug development in cancers associated with dysregulated CDK2 activity. In recent decades, interest in developing CDK selective inhibitors has gradually increased. Despite extensive efforts, there are still no approved agents targeting CDK2 (Cicenas, J. et al., Cancers (Basel), 2014.6(4): p.2224-42). Therefore, there is still a need to find CDK inhibitors with novel activity profiles, particularly those targeting CDK2. This application relates to this need and other needs. Summary of the Invention

[0010] The present invention particularly relates to compounds of formula (I):

[0011]

[0012] or a pharmaceutically acceptable salt thereof, wherein the constituent members are defined herein.

[0013] The present invention further provides a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0014] The present invention further provides a method of inhibiting CDK2, comprising contacting the CDK2 with a compound described herein or a pharmaceutically acceptable salt thereof.

[0015] The present invention further provides a method of inhibiting CDK2 in a patient comprising administering to the patient a compound described herein or a pharmaceutically acceptable salt thereof.

[0016] The present invention further provides a method of treating a disease or condition associated with CDK2 in a patient, comprising administering to the patient a compound described herein or a pharmaceutically acceptable salt thereof.

[0017] The present invention further provides a compound as described herein, or a pharmaceutically acceptable salt thereof, for use in any of the methods described herein.

[0018] The present invention further provides the use of a compound described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for use in any of the methods described herein. DETAILED DESCRIPTION

[0019] The present application particularly provides a compound of formula (I):

[0020]

[0021] or a pharmaceutically acceptable salt thereof, wherein:

[0022] n is 0, 1, 2, 3 or 4;

[0023] p is 0, 1, 2, 3, or 4;

[0024] ---- is a single bond or a double bond;

[0025] X is N, Y is C, and the ring for or

[0026] X is C, Y is N, and the ring for

[0027] Z is CR 2 or N;

[0028] The ring portion A is selected from C 3-10 cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl;

[0029] The ring portion B is a 4-10 membered heterocycloalkyl, wherein the ring portion B is attached to a -NH- group of formula (I) at a ring member of the saturated or partially saturated ring of the 4-10 membered heterocycloalkyl;

[0030] R 1 Independently selected from H, D, halogen, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, OR a1 SR 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 NR c1 R d1 NR c1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 、C(=NR e1 )R b1 、C(=NR e1 )NR c1 R d1 NR c1 C(=NR e1 )NR c1 R d1 NR c1 C(=NR e1 )R b1 NR c1 S(O)NR c1 R d1NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)(=NR e1 )R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 、S(O)2NR 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 the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R 1A Substituent substitution;

[0031] Each R a1 、R c1 and R d1 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 Alkyl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3, or 4 independently selected R 1A Substituent substitution;

[0032] Alternatively, any R attached to the same N atom c1 and R d1 Together with the N atom to which it is attached, it forms a 4-10 membered heterocycloalkyl, wherein the 4-10 membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 independently selected R 1A Substituent substitution;

[0033] Each R b1 Independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl, each of which is optionally substituted with 1, 2, 3 or 4 independently selected R 1A Substituent substitution;

[0034] Each R e1 Independently selected from H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl;

[0035] Each R f1 and R g1 Independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl;

[0036] Each R h1 and R i1 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl;

[0037] Each R j1 and R k1 Independently selected from OH, C 1-6 Alkoxy and C 1-6 haloalkoxy;

[0038] Alternatively, any R attached to the same B atom j1 and R k1 Together with the B atom to which it is attached, it forms a 5-membered or 6-membered heterocycloalkyl group, which is optionally substituted by 1, 2, 3 or 4 independently selected C 1-6 Alkyl and C1-6 Substitution of haloalkyl groups;

[0039] Each R 1A Independently selected from H, D, halogen, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a11 SR a11 NHOR a11 、C(O)R b11 、C(O)NR c11 R d11 、C(O)NR c11 (OR a11 )、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 c11S(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 the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R 1B Substituent substitution;

[0040] Each R a11 、R c11 and R d11 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4Alkyl and 5-6 membered heteroaryl-C 1-4 Alkyl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R 1B Substituent substitution;

[0041] Alternatively, any R attached to the same N atom c11 and R d11 Together with the N atom to which it is attached, it forms a 4-7 membered heterocycloalkyl, wherein the 4-7 membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 independently selected R 1B Substituent substitution;

[0042] Each R b11 Independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally substituted with 1, 2, 3 or 4 independently selected R 1B Substituent substitution;

[0043] Each R e11 Independently selected from H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl;

[0044] Each R f11 and R g11 Independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl;

[0045] Each R h11 and R i11 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl;

[0046] Each R j11 and R k11 Independently selected from OH, C 1-6 Alkoxy and C 1-6 haloalkoxy;

[0047] Alternatively, any R attached to the same B atom j11 and R k11 Together with the B atom to which it is attached, it forms a 5-membered or 6-membered heterocycloalkyl group, which is optionally substituted by 1, 2, 3 or 4 independently selected C 1-6 Alkyl and C 1-6 Substitution of haloalkyl groups;

[0048] Each R 1B Independently selected from H, D, halogen, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a12 SR 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 NR c12 R d12 NR c12 NR c12 R d12 NR c12 C(O)R b12 NR c12 C(O)OR a12 NR c12 C(O)NR c12 R d12 、C(=NR e12 )R b12 、C(=NR e12 )NR c12 R d12 NR c12 C(=NR e12 )NR c12 R d12 NR c12 C(=NR e12 )R b12 NR c12 S(O)NR c12 R d12 NR c12 S(O)R b12 NR c12 S(O)2R b12 NR c12 S(O)(=NR e12 )R b12 NR c12 S(O)2NR c12 R d12 、S(O)R b12 、S(O)NRc12 R d12 、S(O)2R b12 、S(O)2NR 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 the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R G Substituent substitution;

[0049] Each R a12 、R c12 and R d12 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Alkyl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R G Substituent substitution;

[0050] Alternatively, any R attached to the same N atom c12 and R d12 Together with the N atom to which it is attached, it forms a 4-7 membered heterocycloalkyl, wherein the 4-7 membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 independently selected R G Substituent substitution;

[0051] Each R b12 Independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally substituted with 1, 2, 3 or 4 independently selected R G Substituent substitution;

[0052] Each R e12 Independently selected from H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl;

[0053] Each R f12 and R g12 Independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl;

[0054] Each R h12 and R i12 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl;

[0055] Each R j12 and R k12 Independently selected from OH, C 1-6 Alkoxy and C 1-6 haloalkoxy;

[0056] Alternatively, any R attached to the same B atom j12 and R k12 Together with the B atom to which it is attached, it forms a 5-membered or 6-membered heterocycloalkyl group, which is optionally substituted by 1, 2, 3 or 4 independently selected C 1-6 Alkyl and C 1-6 Substitution of haloalkyl groups;

[0057] R 2 Independently selected from H, D, halogen, CN, OH, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, 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-C1-4 Alkyl, C 3-4 Cycloalkyl, thio, C 1-4 Alkylthio, C 1-4 Alkylsulfinyl, C 1-4 Alkylsulfonyl, carbamoyl, C 1-4 Alkylcarbamoyl, di(C 1-4 Alkyl)carbamoyl, carboxyl, 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 Alkylsulfonylamino, aminosulfonyl, 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;

[0058] Each R 3 Independently selected from H, D, halogen, CN, C 1-4 Alkyl, C 1-4 Halogenated alkyl, 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;

[0059] R 4 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 Alkyl; wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R 4A Substituent substitution;

[0060] Each R 4A Independently selected from H, D, halogen, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, OR a41 SR 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 NR c41 R d41 NR c41 NR c41 R d41 NR c41 C(O)R b41 NR c41 C(O)OR a41 NR c41 C(O)NR c41 Rd41 、C(=NR e41 )R b41 、C(=NR e41 )NR c41 R d41 NR c41 C(=NR e41 )NR c41 R d41 NR c41 C(=NR e41 )R b41 NR c41 S(O)NR c41 R d41 NR c41 S(O)R b41 NR c41 S(O)2R b41 NR c41 S(O)(=NR e41 )R b41 NR c41 S(O)2NR c41 R d41 、S(O)R b41 、S(O)NR c41 R d41 、S(O)2R b41 、S(O)2NR 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 the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R 4B Substituent substitution;

[0061] Each R a41 、R c41 and R d41 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 Alkyl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R 4B Substituent substitution;

[0062] Alternatively, any R attached to the same N atom c41 and R d41 Together with the N atom to which it is attached, it forms a 4-10 membered heterocycloalkyl, wherein the 4-10 membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 independently selected R 4B Substituent substitution;

[0063] Each R b41 Independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl, each of which is optionally substituted with 1, 2, 3 or 4 independently selected R 4B Substituent substitution;

[0064] Each R e41 Independently selected from H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl;

[0065] Each R f41 and R g41 Independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl;

[0066] Each R h41 and R i41 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl;

[0067] Each R j41 and R k41 Independently selected from OH, C 1-6 Alkoxy and C 1-6 haloalkoxy;

[0068] Alternatively, any R attached to the same B atom j41 and R k41 Together with the B atom to which it is attached, it forms a 5-membered or 10-membered heterocycloalkyl group, which is optionally substituted by 1, 2, 3 or 4 independently selected C 1-6 Alkyl and C 1-6 Substitution of haloalkyl groups;

[0069] Each R 4B Independently selected from H, D, halogen, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a42 SR a42 NHOR a42 、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(=NRe42 )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)R f42 R g42 、OP(O)(OR h42 )(OR i42 )、P(O)(OR h42 )(OR i42 ) and BR j42 R k42 , wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R4C Substituent substitution;

[0070] Each R a42 、R c42 and R d42 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Alkyl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R 4C Substituent substitution;

[0071] Alternatively, any R attached to the same N atom c42 and R d42 Together with the N atom to which it is attached, it forms a 4-7 membered heterocycloalkyl, wherein the 4-7 membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 independently selected R 4C Substituent substitution;

[0072] Each R b42 Independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally substituted with 1, 2, 3 or 4 independently selected R 4CSubstituent substitution;

[0073] Each R e42 Independently selected from H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl;

[0074] Each R f42 and R g42 Independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl;

[0075] Each R h42 and R i42 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl;

[0076] Each R j42 and R k42 Independently selected from OH, C 1-6 Alkoxy and C1-6 haloalkoxy;

[0077] Alternatively, any R attached to the same B atom j42 and R k42 Together with the B atom to which it is attached, it forms a 5-membered or 6-membered heterocycloalkyl group, which is optionally substituted by 1, 2, 3 or 4 independently selected C 1-6 Alkyl and C 1-6 Substitution of haloalkyl groups;

[0078] Each R 4C Independently selected from H, D, halogen, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a43 SR 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 NR c43 R d43 NR c43 NR c43 R d43 NR c43 C(O)R b43 NR c43 C(O)OR a43 NR c43 C(O)NR c43 R d43 、C(=NR e43 )R b43 、C(=NR e43 )NR c43 R d43 NR c43 C(=NR e43 )NR c43 R d43 NRc43 C(=NR e43 )R b43 NR c43 S(O)NR c43 R d43 NR c43 S(O)R b43 NR c43 S(O)2R b43 NR c43 S(O)(=NR e43 )R b43 NR c43 S(O)2NR c43 R d43 、S(O)R b43 、S(O)NR c43 R d43 、S(O)2R b43 、S(O)2NR 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 the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R G Substituent substitution;

[0079] Each R a43 、R c43 and R d43 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Alkyl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R G Substituent substitution;

[0080] Alternatively, any R attached to the same N atom c43 and R d43 Together with the N atom to which it is attached, it forms a 4-7 membered heterocycloalkyl, wherein the 4-7 membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 independently selected R G Substituent substitution;

[0081] Each R b43 Independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally substituted with 1, 2, 3 or 4 independently selected R G Substituent substitution;

[0082] Each R e43 Independently selected from H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 2-6Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl;

[0083] Each R f43 and R g43 Independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl;

[0084] Each R h43 and R i43 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl;

[0085] Each R j43 and R k43 Independently selected from OH, C 1-6 Alkoxy and C 1-6 haloalkoxy;

[0086] Alternatively, any R attached to the same B atom j43 and R k43 Together with the B atom to which it is attached, it forms a 5-membered or 6-membered heterocycloalkyl group, which is optionally substituted by 1, 2, 3 or 4 independently selected C 1-6 Alkyl and C 1-6Substitution of haloalkyl groups;

[0087] Each R 5 Independently selected from H, D, halogen, NO2, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, OR a5 SR 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 R d5 NR c5 R d5 NR c5 NR c5 R d5 NR c5 C(O)R b5 NR c5 C(O)OR a5 NR c5 C(O)NR c5 R d5 、C(=NR e5 )R b5 、C(=NR e5 )NR c5 R d5 NR c5 C(=NR e5 )NR c5 R d5 NR c5 C(=NR e5 )R b5 NR c5 S(O)NR c5 R d5 NR c5 S(O)R b5 NR c5S(O)2R b5 NR c5 S(O)(=NR e5 )R b5 NR c5 S(O)2NR c5 R d5 、S(O)R b5 、S(O)NR c5 R d5 、S(O)2R b5 、S(O)2NR 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 said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R 5A Substituent substitution;

[0088] Each R a5 、R c5 and R d5 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 Alkyl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R 5A Substituent substitution;

[0089] Alternatively, any R attached to the same N atom c5 and R d5 Together with the N atom to which it is attached, it forms a 4-10 membered heterocycloalkyl group, which is optionally substituted by 1, 2, 3 or 4 independently selected R 5A Substituent substitution;

[0090] Each R b5 Independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl, each of which is optionally replaced by 1, 2, 3 or 4 independently selected R 5A Substituent substitution;

[0091] Each R e5 Independently selected from H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-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;

[0092] Each R f5 and R g5 Independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl;

[0093] Each R h5 and R i5 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl;

[0094] Each R j5 and R k5 Independently selected from OH, C 1-6 Alkoxy and C 1-6 haloalkoxy;

[0095] Alternatively, any R attached to the same B atom j5 and R k5 Together with the B atom to which it is attached, it forms a 5-membered or 6-membered heterocycloalkyl group, which is optionally substituted by 1, 2, 3 or 4 independently selected C 1-6 Alkyl and C 1-6 Substitution of haloalkyl groups;

[0096] Each R5A Independently selected from H, D, halogen, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, OR a51 SR 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 NR c51 R d51 NR c51 NR c51 R d51 NR c51 C(O)R b51 NR c51 C(O)OR a51 NR c51 C(O)NR c51 R d51 、C(=NR e51 )R b51 、C(=NR e51 )NR c51 R d51 NR c51 C(=NR e51 )NR c51 R d51 NR c51 C(=NR e51 )R b51 NR c51 S(O)NR c51 R d51 NR c51 S(O)R b51 NR c51 S(O)2R b51 NR c51S(O)(=NR e51 )R b51 NR c51 S(O)2NR c51 R d51 、S(O)R b51 、S(O)NR c51 R d51 、S(O)2R b51 、S(O)2NR 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 the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R 5B Substituent substitution;

[0097] Each R a51 、R c51 and R d51 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C1-4 Alkyl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R 5B Substituent substitution;

[0098] Alternatively, any R attached to the same N atom c51 and R d51 Together with the N atom to which it is attached, it forms a 4-7 membered heterocycloalkyl group, which is optionally substituted by 1, 2, 3 or 4 independently selected R 5B Substituent substitution;

[0099] Each R b51 Independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl, each of which is optionally substituted with 1, 2, 3 or 4 independently selected R 5B Substituent substitution;

[0100] Each R e51 Independently selected from H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl;

[0101] Each R f51 and R g51 Independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl;

[0102] Each R h51 and R i51 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl;

[0103] Each R j51 and R k51 Independently selected from OH, C 1-6 Alkoxy and C 1-6 haloalkoxy;

[0104] Alternatively, any R attached to the same B atom j51 and R k51 Together with the B atom to which it is attached, it forms a 5-membered or 6-membered heterocycloalkyl group, which is optionally substituted by 1, 2, 3 or 4 independently selected C 1-6 Alkyl and C 1-6 Substitution of haloalkyl groups;

[0105] Each R 5B Independently selected from H, D, halogen, CN, NO2, C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a52 SR 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 NR c52 R d52 NR c52 NR c52 R d52 NR c52 C(O)R b52 NR c52 C(O)OR a52 NR c52 C(O)NR c52 R d52 、C(=NR e52 )R b52 、C(=NR e52 )NR c52 R d52 NR c52 C(=NR e52 )NR c52 R d52 NR c52 C(=NR e52 )R b52 NR c52 S(O)NR c52 R d52 NR c52 S(O)R b52 NR c52 S(O)2R b52 NR c52 S(O)(=NR e52 )R b52 NR c52S(O)2NR c52 R d52 、S(O)R b52 、S(O)NR c52 R d52 、S(O)2R b52 、S(O)2NR 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 the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R 5C Substituent substitution;

[0106] Each R a52 、R c52 and R d52 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Alkyl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R 5C Substituent substitution;

[0107] Alternatively, any R attached to the same N atom c52 and R d52 Together with the N atom to which it is attached, it forms a 4-7 membered heterocycloalkyl group, which is optionally substituted by 1, 2, 3 or 4 independently selected R 5C Substituent substitution;

[0108] Each R b52 Independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally substituted with 1, 2, 3 or 4 independently selected R 5C Substituent substitution;

[0109] Each R e52 Independently selected from H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl;

[0110] Each R f52 and R g52 Independently selected from H, C 1-6Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl;

[0111] Each R h52 and R i52 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl;

[0112] Each R j52 and R k52 Independently selected from OH, C 1-6 Alkoxy and C 1-6 haloalkoxy;

[0113] Alternatively, any R attached to the same B atom j52 and R k52 Together with the B atom to which it is attached, it forms a 5-membered or 6-membered heterocycloalkyl group, which is optionally substituted by 1, 2, 3 or 4 independently selected C 1-6 Alkyl and C 1-6 Substitution of haloalkyl groups;

[0114] Each R 5C Independently selected from H, D, halogen, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a53 SR 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 NR c53 R d53 NR c53 NR c53 R d53 NR c53 C(O)R b53 NR c53 C(O)OR a53 NR c53 C(O)NR c53 R d53 、C(=NR e53 )R b53 、C(=NR e53 )NR c53 R d53 NR c53 C(=NR e53 )NR c53 R d53 NR c53 C(=NR e53 )R b53 NR c53 S(O)NR c53 R d53 NR c53 S(O)R b53 NR c53 S(O)2R b53 NR c53 S(O)(=NR e53 )R b53 NR c53 S(O)2NR c53 R d53 、S(O)R b53 、S(O)NR c53 R d53 、S(O)2R b53 、S(O)2NR c53 R d53 、OS(O)(=NRe53 )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 the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R G Substituent substitution;

[0115] Each R a53 、R c53 and R d53 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Alkyl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R G Substituent substitution;

[0116] Alternatively, any R attached to the same N atom c53 and R d53 Together with the N atom to which it is attached, it forms a 4-7 membered heterocycloalkyl group, which is optionally substituted by 1, 2, 3 or 4 independently selected R G Substituent substitution;

[0117] Each R b53 Independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally substituted with 1, 2, 3 or 4 independently selected R G Substituent substitution;

[0118] Each R e53 Independently selected from H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl;

[0119] Each R f53 and R g53 Independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl;

[0120] Each R h53 and R i53 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl;

[0121] Each R j53 and R k53 Independently selected from OH, C 1-6 Alkoxy and C 1-6 haloalkoxy;

[0122] Alternatively, any R attached to the same B atom j53 and R k53 Together with the B atom to which it is attached, it forms a 5-membered or 6-membered heterocycloalkyl group, which is optionally substituted by 1, 2, 3 or 4 independently selected C 1-6 Alkyl and C 1-6 The substituent of the haloalkyl group is substituted; and

[0123] Each R G Independently selected from OH, NO2, CN, halogen, 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 Alkylsulfonyl, carbamoyl, C1-3 Alkylcarbamoyl, di(C 1-3 Alkyl)carbamoyl, carboxyl, 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 Alkylsulfonylamino, aminosulfonyl, 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.

[0124] In some embodiments, R 1 Independently selected from H, halogen, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a1 SR a1 、C(O)R b1 、C(O)NR c1 R d1 、C(O)OR a1 、OC(O)R b1 、OC(O)NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)2R b1 NR c1S(O)2NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 , wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R 1A Substituent substitution.

[0125] In some embodiments, R 1 Independently selected from H, halogen, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a1 、C(O)R b1 、C(O)NR c1 R d1 、C(O)OR a1 、OC(O)R b1 、OC(O)NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1、S(O)2R b1 and S(O)2NR c1 R d1 , wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R 1A Substituent substitution.

[0126] In some embodiments, R 1 Independently selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-3 Alkyl, phenyl-C 1-3 Alkyl, 4-7 membered heterocycloalkyl-C 1-3 Alkyl, 5-6 membered heteroaryl-C 1-3 Alkyl, OR a1 SR a1 and NR c1 R d1 , wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-3 Alkyl, phenyl-C 1-3 Alkyl, 4-7 membered heterocycloalkyl-C 1-3 Alkyl and 5-6 membered heteroaryl-C 1-3 Each alkyl group is optionally replaced by 1 or 2 independently selected R 1A Substituent substitution.

[0127] In some embodiments, R 1 Independently selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-3alkyl 、 Phenyl-C 1-3 Alkyl, 4-7 membered heterocycloalkyl-C 1-3 Alkyl, 5-6 membered heteroaryl-C 1-3 Alkyl, OR a1 and NR c1 R d1 , wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-3 Alkyl, phenyl-C 1-3 Alkyl, 4-7 membered heterocycloalkyl-C 1-3 Alkyl and 5-6 membered heteroaryl-C 1-3 Each alkyl group is optionally replaced by 1 or 2 independently selected R 1A Substituent substitution.

[0128] In some embodiments, R 1 Independently selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-4 Cycloalkyl and OR a1 , wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl and C 3-4 Each cycloalkyl group is optionally substituted with 1, 2, 3 or 4 independently selected R 1A Substituent substitution.

[0129] In some embodiments, R 1 Independently selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-4 Cycloalkyl and OR a1 , wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl and C 3-4 The cycloalkyl groups are each optionally substituted with 1 or 2 independently selected R 1A Substituent substitution.

[0130] In some embodiments, R 1 Independently selected from H, C1-6 Alkyl, phenyl, 5-7 membered heterocycloalkyl, OR a1 SR a1 and NR c1 R d1 , wherein the C 1-6 Alkyl, phenyl and 5-7 membered heterocycloalkyl are each optionally substituted by 1 or 2 independently selected R 1A Substituent substitution.

[0131] In some embodiments, R 1 Independently selected from H and OR a1 .

[0132] In some embodiments, each R a1 、R c1 and R d1 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Alkyl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R 1A Substituent substitution;

[0133] Each R b1 Independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally substituted with 1, 2, 3 or 4 independently selected R 1A Substituent substitution;

[0134] Each R 1A Independently selected from H, halogen, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a11 、C(O)R b11 、C(O)NR c11 R d11 、C(O)OR a11 、OC(O)R b11 、OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O)R b11 NR c11 C(O)OR a11 NR c11 C(O)NR c11 R d11 NR c11 S(O)2R b11 NR c11 S(O)2NR c11 R d11 、S(O)2R b11 and S(O)2NR c11 R d11 , wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R 1B Substituent substitution;

[0135] Each R a11 、R c11 and R d11 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Alkyl, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R 1B Substituent substitution;

[0136] Each R b11 Independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally substituted with 1, 2, 3 or 4 independently selected R 1B Substituent substitution;

[0137] Each R 1B Independently selected from H, halogen, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-4 Cycloalkyl, OR a12 、C(O)R b12 、C(O)NR c12R d12 、C(O)OR a12 、OC(O)R b12 NR c12 R d12 NR c12 C(O)R b12 NR c12 S(O)2R b12 、S(O)2R b12 and S(O)2NR c12 R d12 ;

[0138] Each R a12 、R c12 and R d12 Independently selected from H, C 1-6 Alkyl and C 1-6 haloalkyl; and

[0139] Each R b12 Independently selected from C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0140] In some embodiments, each R a1 、R c1 and R d1 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Alkyl, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R 1A Substituent substitution;

[0141] Each R b1 Independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally substituted with 1, 2, 3 or 4 independently selected R 1A Substituent substitution;

[0142] Each R 1A Independently selected from H, D, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a11 、C(O)R b11 、C(O)NR c11 R d11 、C(O)OR a11 、OC(O)R b11 、OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O)R b11 NR c11 C(O)OR a11 NR c11 C(O)NR c11 R d11 NR c11 S(O)2R b11 NR c11 S(O)2NR c11 R d11 、S(O)2R b11 and S(O)2NR c11 R d11 , wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4Alkyl and 5-6 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R 1B Substituent substitution;

[0143] Each R a11 、R c11 and R d11 Independently selected from H, C 1-6 Alkyl and C 1-6 alkyl halide;

[0144] Each R b11 Independently selected from C 1-6 Alkyl and C 1-6 alkyl halide;

[0145] Each R 1B Independently selected from H, D and OR a12 ;and

[0146] Each R a12 Independently selected from H and C 1-6 alkyl.

[0147] In some embodiments, each R a1 、R c1 and R d1 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Alkyl, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R 1A Substituent substitution;

[0148] Each R b1 Independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally substituted with 1, 2, 3 or 4 independently selected R 1A Substituent substitution;

[0149] Each R 1A Independently selected from H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a11 、C(O)R b11 、C(O)NR c11 R d11 、C(O)OR a11 、OC(O)R b11 、OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O)R b11 NR c11 C(O)OR a11 NR c11 C(O)NR c11 R d11 NR c11 S(O)2R b11 NR c11 S(O)2NR c11 R d11 、S(O)2R b11 and S(O)2NR c11 R d11 ;

[0150] Each R a11 、R c11 and R d11 Independently selected from H, C 1-6 Alkyl and C 1-6 haloalkyl; and

[0151] Each R b11Independently selected from C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0152] In some embodiments, each R a1 、R c1 and R d1 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Alkyl, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R 1A Substituent substitution;

[0153] Each R b1 Independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally substituted with 1, 2, 3 or 4 independently selected R 1A Substituents are substituted; and

[0154] Each R 1A Independently selected from H, halogen, CN, C 1-4 Alkyl, C 1-4 Halogenated alkyl, 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-C1-4 Alkyl, C 1-3 Alkoxy-C 1-4 Alkyl and C 3-4 Cycloalkyl.

[0155] In some embodiments, each R a1 、R c1 and R d1 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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 Each alkyl group is optionally replaced by 1, 2 or 3 independently selected R 1A Substituent substitution;

[0156] Each R b1 Independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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 substituted with 1 or 2 independently selected R 1A Substituents are substituted; and

[0157] Each R 1A Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OR a11 and C(O)OR a11 , wherein the C 1-6 Alkyl and C 1-6 Each haloalkyl group is optionally replaced by 1, 2 or 3 independently selected R 1B Substituent substitution;

[0158] Each R a11 Independently selected from H and C 1-4 Alkyl, wherein the C 1-4 The alkyl group is optionally substituted with 1, 2 or 3 independently selected R 1B Substituents are substituted; and

[0159] Each R 1B Independently selected from H, D and OC 1-4 alkyl.

[0160] In some embodiments, each R a1 、R c1 and R d1 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkyl and 4-6 membered heterocycloalkyl-C 1-3 Each alkyl group is optionally replaced by 1 or 2 independently selected R 1A Substituent substitution;

[0161] Each R b1 Independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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 substituted with 1 or 2 independently selected R 1A Substituents are substituted; and

[0162] Each R 1A are independently selected from H, halo, OH, C 1-3 Alkoxy and C 1-3 Halogenated alkoxy.

[0163] In some embodiments:

[0164] R 1 H, C 1-6 Alkyl, phenyl, 5-7 membered heterocycloalkyl, OR a1 SR a1 , or NR c1 R d1 , wherein the C 1-6 Alkyl, phenyl and 5-7 membered heterocycloalkyl are each optionally substituted by 1 or 2 independently selected R 1A Substituent substitution;

[0165] Each Ra1 、R c1 and R d1 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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 Each alkyl group is optionally replaced by 1, 2 or 3 independently selected R 1A Substituent substitution;

[0166] Each R 1A Independently selected from D, halogen, CN, C 1-4 Alkyl, C 1-4 Halogenated alkyl, OR a11 and C(O)OR a11 , wherein the C 1-4 Alkyl and C 1-4 Each haloalkyl group is optionally replaced by 1, 2 or 3 independently selected R 1B Substituent substitution;

[0167] Each R a11 Independently selected from H and C 1-4 alkyl; and

[0168] Each R 1B Independently selected from H, D and OC 1-4 alkyl.

[0169] In some embodiments:

[0170] R 1 H or OR a1 ;

[0171] Each R a1 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkyl and 4-6 membered heterocycloalkyl-C 1-3 Each alkyl group is optionally replaced by 1 or 2 independently selected R 1A Substituents are substituted; and

[0172] Each R 1A Independently selected from OH, C 1-3 Alkoxy and C 1-3 Halogenated alkoxy.

[0173] In some embodiments, R 1 Independently selected from H and OR a1 , where R a1 C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-3 Alkyl, phenyl-C 1-3 Alkyl, 4-7 membered heterocycloalkyl-C 1-3 Alkyl and 5-6 membered heteroaryl-C 1-3 alkyl.

[0174] In some embodiments, R 1 Independently selected from H, C 1-6 Alkyl, phenyl, 5-7 membered heterocycloalkyl, OR a1 SR a1 and NR c1 R d1 , wherein the C 1-6 Alkyl, phenyl and 5-7 membered heterocycloalkyl are each optionally substituted by 1 or 2 independently selected R 1A Substituent substitution;

[0175] R a1Selected from ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, CF3CH2-, CHF2CH2-, CF3CH2CH2-, CHF2CF2CH2-, CH3OCH2CH2-, CD3CD2-, (CH3)2-CD-, (CD3)2-CH-, (CD3)2-CD-, cyclopropyl, cyclobutyl, 3-methylcyclobutyl, 3-difluoromethylcyclobutyl, 3,3-difluorocyclobutyl, cyclopentyl, 3,3-difluorocyclopentyl, 4,4- difluorocyclohexyl, tetrahydro-1H-pyran-4-yl, tetrahydro-2H-pyran-4-yl, 2-methyltetrahydro-2H-pyran-4-yl, 3-methyltetrahydro-2H-pyran-4-yl, 2-(trifluoromethyl)tetrahydro-2H-pyran-4-yl, tetrahydrofuran-3-yl, MeO-C(O)-piperidin-4-yl, cyclopropyl-CH2-, cyclobutyl-CH2-, 1-trifluoromethylcyclobutyl-CH2-, cyclopentyl-CH2- and (tetrahydrofuran-3-yl)-CH2-;

[0176] R c1 is H;

[0177] R d1 is phenyl; and

[0178] Each R 1A independently selected from halogen, CN, C 1-3 Alkyl and C 1-3 Halogenated alkyl.

[0179] In some embodiments, R 1 Independently selected from H and OR a1 , where R a1 Selected from ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, CF3CH2-, CHF2CH2-, CF3CH2CH2-, CHF2CF2CH2-, CH3OCH2CH2-, CD3CD2-, (CH3)2-CD-, (CD3)2-CH-, (CD3)2-CD-, cyclopropyl, cyclobutyl, 3-methylcyclobutyl, 3-difluoromethylcyclobutyl, 3,3-difluorocyclobutyl, cyclopentyl, 3,3-difluorocyclopentyl, 4,4- difluorocyclohexyl, tetrahydro-1H-pyran-4-yl, tetrahydro-2H-pyran-4-yl, 2-methyltetrahydro-2H-pyran-4-yl, 3-methyltetrahydro-2H-pyran-4-yl, 2-(trifluoromethyl)tetrahydro-2H-pyran-4-yl, tetrahydrofuran-3-yl, MeO-C(O)-piperidin-4-yl, cyclopropyl-CH2-, cyclobutyl-CH2-, 1-trifluoromethylcyclobutyl-CH2-, cyclopentyl-CH2- and (tetrahydrofuran-3-yl)-CH2-.

[0180] In some embodiments, R 1Independently selected from H and OR a1 , where R a1 It is ethyl, isopropyl, isobutyl, tetrahydro-1H-pyran-4-yl, cyclopropyl-CH2-, (tetrahydrofuran-3-yl)-CH2-, CH3OCH2CH2-, CF3CH2- and CHF2CH2-.

[0181] In some embodiments, R 1 Selected from C 1-3 alkyl.

[0182] In some embodiments, R 1 Selected from propyl and isopropyl.

[0183] In some embodiments, R 1 is optionally 1 or 2 independently selected R 1A Substituent-substituted phenyl, wherein each R 1A independently selected from halo, CN and C 1-3 Halogenated alkyl.

[0184] In some embodiments, R 1 Selected from phenyl, 4-fluorophenyl, 3-trifluoromethylphenyl and 2-fluoro-3-cyano-phenyl.

[0185] In some embodiments, R 1 is selected from 5-7 membered heterocycloalkyl optionally substituted by 1 or 2 independently selected R 1A Substituents, where each R 1A independently selected from halogen, C 1-3 Alkyl and C 1-3 Halogenated alkyl.

[0186] In some embodiments, R 1 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]hept-7-yl, azabicyclo[2.2.1]hept-2-yl and (2-methoxyethyl)piperazin-1-yl.

[0187] In some embodiments, R 1 Selected from SR a1 , where R a1 Selected from C 1-3 alkyl.

[0188] In some embodiments, R 1 Selected from SRa1 , where R a1 Selected from ethyl, propyl and isopropyl.

[0189] In some embodiments, R 1 Selected from NR c1 R d1 , where R c1 and R d1 are each independently selected from H and phenyl.

[0190] In some embodiments, R 1 Selected from NR c1 R d1 , where R c1 H and R d1 It is phenyl.

[0191] In some embodiments, R 1 OR a1 .

[0192] In some embodiments, R 1 OR a1 And R a1 C 1-3 alkyl.

[0193] In some embodiments, R 2 Selected from H, halogen, CN, C 1-4 Alkyl, C 1-4 Halogenated alkyl, 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.

[0194] In some embodiments, R 2 Selected from H, halogen, CN, C 1-3 Alkyl and C 1-3 Halogenated alkyl.

[0195] In some embodiments, R 2 is H or halogen.

[0196] In some embodiments, R 2 H or F.

[0197] In some embodiments, R2 For H.

[0198] In some embodiments, ring portion B is a monocyclic 4-7 membered heterocycloalkyl.

[0199] In some embodiments, ring moiety B is azetidinyl, pyrrolidinyl, or piperidinyl.

[0200] In some embodiments, ring moiety B is piperidinyl.

[0201] In some embodiments, n is 0, 1, or 2.

[0202] In some embodiments, n is 0 or 1.

[0203] In some embodiments, n is 0.

[0204] In some embodiments, n is 1.

[0205] In some embodiments, each R 3 are independently selected from H, halogen, C 1-3 Alkyl and cyclopropyl.

[0206] In some embodiments, each R 3 Independently selected from H, F and methyl.

[0207] In some embodiments, each R 3 Independently selected from H and methyl.

[0208] In some embodiments, R 4 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Alkyl; wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R 4A Substituent substitution.

[0209] In some embodiments, R 4 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl-C 1-4 Alkyl; wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl and 5-6 membered heteroaryl are each optionally substituted by 1, 2, 3 or 4 independently selected R 4A Substituent substitution.

[0210] In some embodiments, R 4 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl and 5-6 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl and 5-6 membered heteroaryl are each optionally substituted by 1, 2, 3 or 4 independently selected R 4A Substituent substitution.

[0211] In some embodiments, R 4 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl-C 1-4 Alkyl; wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl-C 1-4 Each alkyl group is optionally replaced by 1 or 2 independently selected R 4A Substituent substitution.

[0212] In some embodiments, R 4 Selected from optionally 1 or 2 independently selected R 4A Substituent-substituted C 1-6 alkyl.

[0213] In some embodiments, R 4 C 1-6 Alkyl and C 3-6 Cycloalkyl.

[0214] In some embodiments, R 4 Selected from methyl, ethyl, propyl, butyl and cyclopropyl.

[0215] In some embodiments, R 4 is selected from methyl and cyclopropyl.

[0216] In some embodiments, R 4 Selected from optionally 1 or 2 independently selected R 4A The substituent is a 5-6 membered heteroaryl group substituted with a substituent.

[0217] In some embodiments, R 4 Selected from optionally 1 or 2 independently selected R 4A Substituted 4-7 membered heterocycloalkyl-C 1-4 alkyl.

[0218] In some embodiments:

[0219] Each R 4A Independently selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a41 SR a41 NHOR a41 、C(O)R b41 、C(O)NR c41 R d41 、C(O)OR a41 、OC(O)R b41 、OC(O)NR c41 R d41 NR c41 R d41 NR c41 C(O)R b41 NR c41 C(O)OR a41 NR c41 C(O)NR c41 R d41 NR c41 S(O)2R b41 NR c41 S(O)2NR c41R d41 、S(O)2R b41 and S(O)2NR c41 R d41 , wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R 4B Substituent substitution;

[0220] Each R a41 、R c41 and R d41 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Alkyl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R 4B Substituent substitution;

[0221] Each R b41 Independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally substituted with 1, 2, 3 or 4 independently selected R 4B Substituent substitution;

[0222] Each R 4B Independently selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a42 、C(O)R b42 、C(O)NR c42 R d42 、C(O)OR a42 、OC(O)R b42 、OC(O)NR c42 R d42 NR c42 R d42 NR c42 C(O)R b42 NR c42 C(O)OR a42 NR c42 C(O)NR c42 R d42 NR c42 S(O)2R b42 NR c42 S(O)2NR c42 R d42 、S(O)2R b42 and S(O)2NR c42 R d42 , wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R 4C Substituent substitution;

[0223] Each R a42 、R c42 and R d42 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Alkyl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R 4C Substituent substitution;

[0224] Each R b42 Independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally substituted with 1, 2, 3 or 4 independently selected R 4C Substituent substitution;

[0225] Each R 4C Independently selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-4 Cycloalkyl, OR a43 、C(O)R b43 、C(O)NR c43 R d43 、C(O)OR a43 、OC(O)R b43 NR c43 R d43 NR c43 C(O)R b43 NR c43 S(O)2R b43 、S(O)2R b43 and S(O)2NR c43 R d43 ;

[0226] Each R a43 、R c43 and R d43 Independently selected from H, C 1-6 Alkyl and C 1-6 haloalkyl; and

[0227] Each R b43 Independently selected from C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0228] In some embodiments:

[0229] Each R 4A Independently selected from H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a41 SR a41 NHOR a41 、C(O)R b41 、C(O)NR c41 R d41 、C(O)OR a41、OC(O)R b41 、OC(O)NR c41 R d41 NR c41 R d41 NR c41 C(O)R b41 NR c41 C(O)OR a41 NR c41 C(O)NR c41 R d41 NR c41 S(O)2R b41 NR c41 S(O)2NR c41 R d41 、S(O)2R b41 and S(O)2NR c41 R d41 , wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2 or 3 independently selected R 4B Substituent substitution;

[0230] Each R a41 、R c41 and R d41 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Alkyl, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C1-4 Each alkyl group is optionally replaced by 1, 2 or 3 independently selected R 4B Substituent substitution;

[0231] Each R b41 Independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally substituted with 1, 2 or 3 independently selected R 4B Substituent substitution;

[0232] Each R 4B Independently selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-4 Cycloalkyl, OR a42 、C(O)R b42 、C(O)NR c42 R d42 、C(O)OR a42 NR c42 R d42 NR c42 C(O)R b42 NR c42 C(O)OR a42 NR c42 C(O)NR c42 R d42 NR c42 S(O)2R b42 NR c42 S(O)2NR c42 R d42 、S(O)2R b42 and S(O)2NR c42 R d42 ;

[0233] Each R a42 、R c42 and R d42 Independently selected from H, C 1-6 Alkyl and C 1-6 haloalkyl; and

[0234] Each R b42 Independently selected from C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0235] In some embodiments:

[0236] Each R 4A Independently selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-4 Cycloalkyl, OR a41 、C(O)R b41 、C(O)NR c41 R d41 、C(O)OR a41 、OC(O)R b41 、OC(O)NR c41 R d41 NR c41 R d41 NR c41 C(O)R b41 NR c41 C(O)OR a41 NR c41 C(O)NR c41 R d41 NR c41 S(O)2R b41 NR c41 S(O)2NR c41 R d41 、S(O)2R b41 and S(O)2NR c41 R d41 , wherein the C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-4 Each cycloalkyl group is optionally substituted with 1, 2 or 3 independently selected R 4B Substituent substitution;

[0237] Each R a41 、R c41 and R d41 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-4 Cycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-4 The cycloalkyl groups are each optionally substituted with 1 or 2 independently selected R 4B Substituent substitution;

[0238] Each R b41 Independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-4Cycloalkyl, each of which is optionally substituted by 1 or 2 independently selected R 4B Substituent substitution;

[0239] Each R 4B Independently selected from H, halogen, CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, OR a42 and NR c42 R d42 ;

[0240] Each R a42 、R c42 and R d42 Independently selected from H, C 1-3 Alkyl and C 1-3 haloalkyl; and

[0241] Each R b42 Independently selected from C 1-3 Alkyl and C 1-3 Halogenated alkyl.

[0242] In some embodiments:

[0243] Each R 4A Independently selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-4 Cycloalkyl, OR a41 、C(O)R b41 、C(O)NR c41 R d41 、C(O)OR a41 、OC(O)R b41 、OC(O)NR c41 R d41 NR c41 R d41 NR c41 C(O)R b41 NR c41 C(O)OR a41 NR c41 C(O)NR c41 R d41 NR c41 S(O)2R b41 NR c41 S(O)2NR c41 R d41 、S(O)2R b41 and S(O)2NR c41 R d41 ;

[0244] Each R a41 、Rc41 and R d41 Independently selected from H, C 1-3 Alkyl and C 1-3 haloalkyl; and

[0245] Each R b41 Independently selected from C 1-3 Alkyl and C 1-3 Halogenated alkyl.

[0246] In some embodiments:

[0247] Each R 4A Independently selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OR a41 and NR c41 R d41 ;

[0248] Each R a41 、R c41 and R d41 Independently selected from H and C 1-3 Alkyl and C 1-3 haloalkyl; and

[0249] Each R b41 Independently C 1-3 alkyl.

[0250] In some embodiments, R 4 is optionally R 4A Substituted C 1-6 Alkyl, where R 4A NR c41 R d41 And R c41 and R d41 Each independently selected from H, C 1-3 Alkyl and C 1-3 Halogenated alkyl.

[0251] In some embodiments, R 4 Selected from dimethylaminopropyl, diethylaminopropyl, ethyl(methyl)aminopropyl, isopropyl(methyl)aminopropyl, 4-dimethylaminobutyl, 4-ethyl(methyl)aminobutyl and 2,2-difluoroethylaminobutyl.

[0252] In some embodiments, R 4 Selected from optionally 1 or 2 independently selected R 4A substituted 5-6 membered heteroaryl, wherein each R 4A Independently selected from C 1-3 alkyl.

[0253] In some embodiments, R 4 Selected from 1-methyl-1H-pyrazol-4-yl, 1-methyl-1H-imidazol-4-yl and 2-methyl-2H-1,2,3-triazol-4-yl.

[0254] In some embodiments, R 4 Selected from optionally 1 or 2 independently selected R 4A Substituted 4-7 membered heterocycloalkyl-C 1-4 Alkyl, where each R 4A Independently selected from C 1-3 Alkyl and OH.

[0255] In some embodiments, R 4 Selected from methyl, ethyl, propyl, butyl, cyclopropyl, pyrazol-4-yl, imidazol-4-yl, 1,2,3-triazol-4-yl, morpholin-4-yl-C 1-4 Alkyl, piperidinyl-C 1-4 Alkyl, piperazinyl-C 1-4 Alkyl, pyrrolidinyl-C 1-4 alkyl, each of which is optionally substituted with 1 or 2 independently selected R 4A Substituent substitution.

[0256] In some embodiments, R 4 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.

[0257] In some embodiments, R 4selected from 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, (pyrrolidone-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.

[0258] In some embodiments, ring portion A is a 5-10 membered heteroaryl.

[0259] In some embodiments, ring portion A is a 5-6 membered heteroaryl.

[0260] In some embodiments, ring moiety A is 1H-pyrrolo[2,3-b]pyridinyl, pyridinyl, or pyrazolyl.

[0261] In some embodiments, ring moiety A is 1H-pyrrolo[2,3-b]pyridin-4-yl, pyridin-4-yl, or 1H-pyrazol-4-yl.

[0262] In some embodiments, ring moiety A is 1H-pyrazol-4-yl.

[0263] In some embodiments, ring portion A is 1H-pyrazol-4-yl and ring portion B is selected from:

[0264]

[0265] In some embodiments, ring portion A is 1H-pyrazol-4-yl and ring portion B is piperidinyl.

[0266] In some embodiments, p is 0, 1, or 2.

[0267] In some embodiments, p is 0 or 1.

[0268] In some embodiments, p is 0.

[0269] In some embodiments, p is 1.

[0270] In some embodiments, each R 5 Independently selected from H, halogen, NO2, CN, C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a5 SR a5 NHOR a5 、C(O)R b5 、C(O)NR c5 R d5 、C(O)OR a5 、OC(O)R b5 、OC(O)NR c5 R d5 NR c5 R d5 NR c5 C(O)R b5 NR c5 C(O)OR a5 NR c5 C(O)NR c5 R d5 NR c5 S(O)2R b5 NR c5 S(O)2NR c5 R d5 、S(O)2R b5 and S(O)2NR c5 R d5 ; wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R 5A Substituent substitution.

[0271] In some embodiments, each R 5 Independently selected from H, halogen, NO2, CN, C 1-6Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, OR a5 、C(O)R b5 、C(O)NR c5 R d5 、C(O)OR a5 NR c5 R d5 NR c5 C(O)R b5 NR c5 S(O)2R b5 、S(O)2R b5 and S(O)2NR c5 R d5 ; wherein said C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl and 5-6 membered heteroaryl are each optionally substituted by 1, 2, 3 or 4 independently selected R 5A Substituent substitution.

[0272] In some embodiments, each R 5 Independently selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-4 Cycloalkyl, OR a5 and NR c5 R d5 , wherein the C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-4 Each cycloalkyl group is optionally substituted with 1, 2, 3 or 4 independently selected R 5A Substituent substitution.

[0273] In some embodiments, each R 5 Independently selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-4 Cycloalkyl, OR a5 and NR c5 R d5 ; and each R a5 、R c5 and R d5 Independently selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0274] In some embodiments, each R 5 Independently selected from H, C1-3 Alkyl and amino groups.

[0275] In some embodiments, each R 5 Independently selected from CH3 or NH2.

[0276] In some embodiments, each R 5 are independently selected from H and amino.

[0277] In some embodiments, each R 5 Independently selected from H and C 1-3 In some embodiments:

[0278] Each R a5 、R c5 and R d5 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Alkyl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R 5A Substituents are substituted; and

[0279] Each R b5 Independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally substituted with 1, 2, 3 or 4 independently selected R 5A Substituent substitution.

[0280] Each R 5A Independently selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a51 SR a51 NHOR a51 、C(O)R b51 、C(O)NR c51 R d51 、C(O)OR a51 、OC(O)R b51 、OC(O)NR c51 R d51 NR c51 R d51 NR c51 C(O)R b51 NR c51 C(O)OR a51 NR c51 C(O)NR c51 R d51 NR c51 S(O)2R b51 NR c51 S(O)2NR c51 R d51 、S(O)2R b51 and S(O)2NR c51 R d51 , wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R 5BSubstituent substitution;

[0281] Each R a51 、R c51 and R d51 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Alkyl, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R 5B Substituent substitution;

[0282] Each R b51 Independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally substituted with 1, 2, 3 or 4 independently selected R 5B Substituent substitution;

[0283] Each R 5B Independently selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-4 Cycloalkyl, OR a52 SR a52 NHOR a52 、C(O)R b52 、C(O)NR c52 R d52 、C(O)OR a52 、OC(O)Rb52 、OC(O)NR c52 R d52 NR c52 R d52 NR c52 C(O)R b52 NR c52 C(O)OR a52 NR c52 C(O)NR c52 R d52 NR c52 S(O)2R b52 NR c52 S(O)2NR c52 R d52 、S(O)2R b52 and S(O)2NR c52 R d52 ;

[0284] Each R a52 、R c52 and R d52 Independently selected from H, C 1-6 Alkyl and C 1-6 alkyl halide;

[0285] Each R b52 Independently selected from C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0286] In some embodiments:

[0287] Each R a5 、R c5 and R d5 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Alkyl, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R 5A Substituent substitution;

[0288] Each R b5 Independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally substituted with 1, 2, 3 or 4 independently selected R 5A Substituent substitution;

[0289] Each R 5A Independently selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-4 Cycloalkyl, OR a51 SR a51 NHOR a51 、C(O)R b51 、C(O)NR c51 R d51 、C(O)OR a51 、OC(O)R b51 、OC(O)NR c51 R d51 NR c51 R d51 NR c51 C(O)R b51 NR c51 C(O)OR a51 NR c51 C(O)NR c51 R d51 NR c51 S(O)2R b51 NR c51 S(O)2NR c51 R d51 、S(O)2R b51 and S(O)2NR c51 R d51 ;

[0290] Each R a51 、R c51 and R d51 Independently selected from H, C 1-6 Alkyl and C1-6 haloalkyl; and

[0291] Each R b51 Independently selected from C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0292] In some embodiments:

[0293] Each R a5 、R c5 and R d5 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl and 5-6 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl and 5-6 membered heteroaryl are each optionally substituted by 1, 2, 3 or 4 independently selected R 5A Substituents are substituted; and

[0294] Each R b5 Independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl and 5-6 membered heteroaryl, each of which is optionally substituted by 1, 2, 3 or 4 independently selected R 5A Substituent substitution.

[0295] Each R 5A Independently selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-4 Cycloalkyl, OR a51 and NR c51 R d51 ;

[0296] Each R a51 、R c51 and R d51 Independently selected from H and C 1-3 alkyl; and

[0297] Each R b51 Independently C 1-3 alkyl.

[0298] In some embodiments:

[0299] Each R a5 、R c5 and R d5 Independently selected from H, C1-6 Alkyl, C 1-6 Haloalkyl and C 3-4 cycloalkyl; and

[0300] Each R b5 Independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-4 Cycloalkyl.

[0301] In some embodiments:

[0302] n is 0, 1, or 2;

[0303] p is 0, 1, or 2;

[0304] The ring portion A is selected from C 3-10 cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl;

[0305] The ring portion B is a monocyclic 4-7 membered heterocycloalkyl group;

[0306] R 1 Independently selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a1 SR a1 and NR c1 R d1 , wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R 1A Substituent substitution;

[0307] Each R a1、R c1 and R d1 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Alkyl, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R 1A Substituent substitution;

[0308] Each R b1 Independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally substituted with 1, 2, 3 or 4 independently selected R 1A Substituent substitution;

[0309] Each R 1A Independently selected from H, D, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a11 、C(O)R b11 、C(O)NR c11R d11 、C(O)OR a11 、OC(O)R b11 、OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O)R b11 NR c11 C(O)OR a11 NR c11 C(O)NR c11 R d11 NR c11 S(O)2R b11 NR c11 S(O)2NR c11 R d11 、S(O)2R b11 and S(O)2NR c11 R d11 , wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R 1B Substituent substitution;

[0310] Each R a11 、R c11 and R d11 Independently selected from H, C 1-6 Alkyl and C 1-6 alkyl halide;

[0311] Each R b11 Independently selected from C 1-6 Alkyl and C 1-6 alkyl halide;

[0312] Each R 1B Independently selected from H, D and OR a12 ;

[0313] Each R a12 Independently selected from H and C 1-6 alkyl;

[0314] R 2 Selected from H, halogen, CN, C 1-3 Alkyl and C1-3 alkyl halide;

[0315] Each R 3 are independently selected from H, halogen, C 1-3 Alkyl and cyclopropyl;

[0316] R 4 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Alkyl; wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R 4A Substituent substitution;

[0317] Each R 4A Independently selected from H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a41 SR a41 NHOR a41 、C(O)R b41 、C(O)NR c41 R d41 、C(O)OR a41 、OC(O)R b41 、OC(O)NR c41R d41 NR c41 R d41 NR c41 C(O)R b41 NR c41 C(O)OR a41 NR c41 C(O)NR c41 R d41 NR c41 S(O)2R b41 NR c41 S(O)2NR c41 R d41 、S(O)2R b41 and S(O)2NR c41 R d41 , wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2 or 3 independently selected R 4B Substituent substitution;

[0318] Each R a41 、R c41 and R d41 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Alkyl, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2 or 3 independently selected R 4BSubstituent substitution;

[0319] Each R b41 Independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally substituted with 1, 2 or 3 independently selected R 4B Substituent substitution;

[0320] Each R 4B Independently selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-4 Cycloalkyl, OR a42 、C(O)R b42 、C(O)NR c42 R d42 、C(O)OR a42 NR c42 R d42 NR c42 C(O)R b42 NR c42 C(O)OR a42 NR c42 C(O)NR c42 R d42 NR c42 S(O)2R b42 NR c42 S(O)2NR c42 R d42 、S(O)2R b42 and S(O)2NR c42 R d42 ;

[0321] Each R a42 、R c42 and R d42 Independently selected from H, C 1-6 Alkyl and C 1-6 alkyl halide;

[0322] Each R b42 Independently selected from C 1-6 Alkyl and C 1-6 alkyl halide;

[0323] Each R 5Independently selected from H, halogen, NO2, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a5 SR a5 NHOR a5 、C(O)R b5 、C(O)NR c5 R d5 、C(O)OR a5 、OC(O)R b5 、OC(O)NR c5 R d5 NR c5 R d5 NR c5 C(O)R b5 NR c5 C(O)OR a5 NR c5 C(O)NR c5 R d5 NR c5 S(O)2R b5 NR c5 S(O)2NR c5 R d5 、S(O)2R b5 and S(O)2NR c5 R d5 ; wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R 5A Substituent substitution;

[0324] Each R a5 、Rc5 and R d5 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Alkyl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R 5A Substituents are substituted; and

[0325] Each R b5 Independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally substituted with 1, 2, 3 or 4 independently selected R 5A Substituent substitution.

[0326] Each R 5A Independently selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C1-4 Alkyl, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a51 SR a51 NHOR a51 、C(O)R b51 、C(O)NR c51 R d51 、C(O)OR a51 、OC(O)R b51 、OC(O)NR c51 R d51 NR c51 R d51 NR c51 C(O)R b51 NR c51 C(O)OR a51 NR c51 C(O)NR c51 R d51 NR c51 S(O)2R b51 NR c51 S(O)2NR c51 R d51 、S(O)2R b51 and S(O)2NR c51 R d51 , wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R 5B Substituent substitution;

[0327] Each R a51 、R c51 and R d51 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Alkyl, wherein the C1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R 5B Substituent substitution;

[0328] Each R b51 Independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally substituted with 1, 2, 3 or 4 independently selected R 5B Substituent substitution;

[0329] Each R 5B Independently selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-4 Cycloalkyl, OR a52 SR a52 NHOR a52 、C(O)R b52 、C(O)NR c52 R d52 、C(O)OR a52 、OC(O)R b52 、OC(O)NR c52 R d52 NR c52 R d52 NR c52 C(O)R b52 NR c52 C(O)OR a52 NR c52 C(O)NR c52 R d52 NR c52 S(O)2R b52 NR c52 S(O)2NR c52 R d52、S(O)2R b52 and S(O)2NR c52 R d52 ;

[0330] Each R a52 、R c52 and R d52 Independently selected from H, C 1-6 Alkyl and C 1-6 haloalkyl; and

[0331] Each R b52 Independently selected from C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0332] In some embodiments:

[0333] n is 0, 1, or 2;

[0334] p is 0, 1, or 2;

[0335] The ring portion A is selected from C 3-10 cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl;

[0336] The ring portion B is a monocyclic 4-7 membered heterocycloalkyl group;

[0337] R 1 Independently selected from H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a1 and NR c1 R d1 , wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R 1A Substituent substitution;

[0338] Each R a1 、R c1 and R d1 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Alkyl, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R 1A Substituent substitution;

[0339] Each R b1 Independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally substituted with 1, 2, 3 or 4 independently selected R 1A Substituent substitution;

[0340] Each R 1A Independently selected from H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C1-4 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 NR c11 R d11 NR c11 C(O)R b11 NR c11 C(O)OR a11 NR c11 C(O)NR c11 R d11 NR c11 S(O)2R b11 NR c11 S(O)2NR c11 R d11 、S(O)2R b11 and S(O)2NR c11 R d11 ;

[0341] Each R a11 、R c11 and R d11 Independently selected from H, C 1-6 Alkyl and C 1-6 alkyl halide;

[0342] Each R b11 Independently selected from C 1-6 Alkyl and C 1-6 alkyl halide;

[0343] R 2 Selected from H, halogen, CN, C 1-3 Alkyl and C 1-3 alkyl halide;

[0344] Each R 3 are independently selected from H, halogen, C 1-3 Alkyl and cyclopropyl;

[0345] R 4 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Alkyl; wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R 4A Substituent substitution;

[0346] Each R 4A Independently selected from H, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a41 SR a41 NHOR a41 、C(O)R b41 、C(O)NR c41 R d41 、C(O)OR a41 、OC(O)R b41 、OC(O)NR c41 R d41 NR c41 R d41 NR c41 C(O)R b41 NR c41 C(O)OR a41 NR c41 C(O)NR c41 R d41 NR c41 S(O)2R b41 NR c41 S(O)2NR c41 R d41 、S(O)2Rb41 and S(O)2NR c41 R d41 , wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2 or 3 independently selected R 4B Substituent substitution;

[0347] Each R a41 、R c41 and R d41 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Alkyl, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2 or 3 independently selected R 4B Substituent substitution;

[0348] Each R b41 Independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally substituted with 1, 2 or 3 independently selected R4B Substituent substitution;

[0349] Each R 4B Independently selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-4 Cycloalkyl, OR a42 、C(O)R b42 、C(O)NR c42 R d42 、C(O)OR a42 NR c42 R d42 NR c42 C(O)R b42 NR c42 C(O)OR a42 NR c42 C(O)NR c42 R d42 NR c42 S(O)2R b42 NR c42 S(O)2NR c42 R d42 、S(O)2R b42 and S(O)2NR c42 R d42 ;

[0350] Each R a42 、R c42 and R d42 Independently selected from H, C 1-6 Alkyl and C 1-6 alkyl halide;

[0351] Each R b42 Independently selected from C 1-6 Alkyl and C 1-6 alkyl halide;

[0352] Each R 5 Independently selected from H, halogen, NO2, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a5 SRa5 NHOR a5 、C(O)R b5 、C(O)NR c5 R d5 、C(O)OR a5 、OC(O)R b5 、OC(O)NR c5 R d5 NR c5 R d5 NR c5 C(O)R b5 NR c5 C(O)OR a5 NR c5 C(O)NR c5 R d5 NR c5 S(O)2R b5 NR c5 S(O)2NR c5 R d5 、S(O)2R b5 and S(O)2NR c5 R d5 ; wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R 5A Substituent substitution;

[0353] Each R a5 、R c5 and R d5 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Alkyl, wherein the C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R 5A Substituents are substituted; and

[0354] Each R b5 Independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally substituted with 1, 2, 3 or 4 independently selected R 5A Substituent substitution.

[0355] Each R 5A Independently selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a51 SR a51 NHOR a51 、C(O)R b51 、C(O)NR c51 R d51 、C(O)OR a51 、OC(O)R b51 、OC(O)NR c51 R d51 NR c51 R d51 NRc51 C(O)R b51 NR c51 C(O)OR a51 NR c51 C(O)NR c51 R d51 NR c51 S(O)2R b51 NR c51 S(O)2NR c51 R d51 、S(O)2R b51 and S(O)2NR c51 R d51 , wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R 5B Substituent substitution;

[0356] Each R a51 、R c51 and R d51 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Alkyl, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R 5B Substituent substitution;

[0357] Each R b51Independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally substituted with 1, 2, 3 or 4 independently selected R 5B Substituent substitution;

[0358] Each R 5B Independently selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-4 Cycloalkyl, OR a52 SR a52 NHOR a52 、C(O)R b52 、C(O)NR c52 R d52 、C(O)OR a52 、OC(O)R b52 、OC(O)NR c52 R d52 NR c52 R d52 NR c52 C(O)R b52 NR c52 C(O)OR a52 NR c52 C(O)NR c52 R d52 NR c52 S(O)2R b52 NR c52 S(O)2NR c52 R d52 、S(O)2R b52 and S(O)2NR c52 R d52 ;

[0359] Each R a52 、R c52 and R d52 Independently selected from H, C 1-6 Alkyl and C 1-6 haloalkyl; and

[0360] Each R b52 Independently selected from C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0361] In some embodiments:

[0362] n is 0, 1, or 2;

[0363] p is 0, 1, or 2;

[0364] The ring portion A is selected from C 3-10 cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl;

[0365] The ring portion B is azetidinyl, pyrrolidinyl or piperidinyl;

[0366] R 1 H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, phenyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl-C 1-3 Alkyl, phenyl-C 1-3 Alkyl, 4-7 membered heterocycloalkyl-C 1-3 Alkyl, 5-6 membered heteroaryl-C 1-3 Alkyl, OR a1 SR a1 and NR c1 R d1 , wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, phenyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl-C 1-3 Alkyl, phenyl-C 1-3 Alkyl, 4-7 membered heterocycloalkyl-C 1-3 Alkyl and 5-6 membered heteroaryl-C 1-3 Each alkyl group is optionally replaced by 1, 2 or 3 independently selected R 1A Substituent substitution;

[0367] Each R a1 、R c1 and R d1 Independently selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl and C 3-7 Cycloalkyl-C 1-4 Alkyl, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl and C 3-7 Cycloalkyl-C 1-4 Each alkyl group is optionally replaced by 1, 2 or 3 independently selected R 1A Substituent substitution;

[0368] Each R 1A Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-4 Cycloalkyl, OR a11 、C(O)R b11 、C(O)NR c11 R d11 、C(O)OR a11 、OC(O)R b11 、OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O)R b11 NR c11 C(O)OR a11 NR c11 C(O)NR c11 R d11 NR c11 S(O)2R b11 NR c11 S(O)2NR c11 R d11 、S(O)2R b11 and S(O)2NR c11 R d11 , wherein the C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-4 Each cycloalkyl group is optionally substituted with 1, 2 or 3 independently selected R 1B Substituent substitution;

[0369] Each R a11 、R c11 and R d11 Independently selected from H, C 1-6 Alkyl and C 1-6 alkyl halide;

[0370] Each R b11 Independently selected from C 1-6 Alkyl and C 1-6 alkyl halide;

[0371] Each R 1B Independently selected from H, D and OR a12 ;

[0372] Each R a12 Independently selected from H and C 1-6 alkyl;

[0373] R 2 Selected from H, halogen, CN, C 1-3 Alkyl and C 1-3 alkyl halide;

[0374] Each R 3 are independently selected from H, halogen, C 1-3 Alkyl and cyclopropyl;

[0375] R 4 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl-C 1-4 Alkyl; wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl-C 1-4 Each alkyl group is optionally replaced by 1 or 2 independently selected R 4A Substituent substitution;

[0376] Each R 4A Independently selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-4 Cycloalkyl, OR a41 、C(O)R b41 、C(O)NR c41 R d41 、C(O)OR a41 、OC(O)R b41 、OC(O)NR c41 R d41 NR c41 R d41 NR c41 C(O)R b41 NR c41 C(O)OR a41 NR c41 C(O)NR c41 R d41 NR c41 S(O)2R b41 NR c41 S(O)2NR c41 R d41 、S(O)2Rb41 and S(O)2NR c41 R d41 , wherein the C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-4 Each cycloalkyl group is optionally substituted with 1, 2 or 3 independently selected R 4B Substituent substitution;

[0377] Each R a41 、R c41 and R d41 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-4 Cycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-4 The cycloalkyl groups are each optionally substituted with 1 or 2 independently selected R 4B Substituent substitution;

[0378] Each R b41 Independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-4 Cycloalkyl, each of which is optionally substituted by 1 or 2 independently selected R 4B Substituent substitution;

[0379] Each R 4B Independently selected from H, halogen, CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, OR a42 and NR c42 R d42 ;

[0380] Each R a42 、R c42 and R d42 Independently selected from H, C 1-3 Alkyl and C 1-3 alkyl halide;

[0381] Each R b42 Independently selected from C 1-3 Alkyl and C 1-3 Halogenated alkyl.

[0382] Each R 5 Independently selected from H, halogen, NO2, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a5 SR a5 NHOR a5 、C(O)R b5 、C(O)NR c5 R d5 、C(O)OR a5 、OC(O)R b5 、OC(O)NR c5 R d5 NR c5 R d5 NR c5 C(O)R b5 NR c5 C(O)OR a5 NR c5 C(O)NR c5 R d5 NR c5 S(O)2R b5 NR c5 S(O)2NR c5 R d5 、S(O)2R b5 and S(O)2NR c5 R d5 ; wherein said C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R 5A Substituent substitution;

[0383] Each R a5 、R c5 and R d5 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4Alkyl and 5-6 membered heteroaryl-C 1-4 Alkyl, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R 5A Substituents are substituted; and

[0384] Each R b5 Independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally substituted with 1, 2, 3 or 4 independently selected R 5A Substituent substitution.

[0385] Each R 5A Independently selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-4 Cycloalkyl, OR a51 SR a51 NHOR a51 、C(O)R b51 、C(O)NR c51 R d51 、C(O)OR a51 、OC(O)R b51 、OC(O)NR c51 R d51 NR c51 R d51 NR c51 C(O)R b51 NR c51 C(O)OR a51 NR c51 C(O)NR c51 R d51 NR c51 S(O)2R b51 NRc51 S(O)2NR c51 R d51 、S(O)2R b51 and S(O)2NR c51 R d51 ;

[0386] Each R a51 、R c51 and R d51 Independently selected from H, C 1-6 Alkyl and C 1-6 haloalkyl; and

[0387] Each R b51 Independently selected from C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0388] In some embodiments:

[0389] n is 0, 1, or 2;

[0390] p is 0, 1, or 2;

[0391] The ring portion A is selected from C 3-10 cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl;

[0392] The ring portion B is azetidinyl, pyrrolidinyl or piperidinyl;

[0393] R 1 H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, phenyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl-C 1-3 Alkyl, phenyl-C 1-3 Alkyl, 4-7 membered heterocycloalkyl-C 1-3 Alkyl, 5-6 membered heteroaryl-C 1-3 Alkyl, OR a1 and NR c1 R d1 , wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, phenyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl-C 1-3 Alkyl, phenyl-C 1-3 Alkyl, 4-7 membered heterocycloalkyl-C 1-3Alkyl and 5-6 membered heteroaryl-C 1-3 Each alkyl group is optionally replaced by 1 or 2 independently selected R 1A Substituent substitution;

[0394] Each R 1A Independently selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-4 Cycloalkyl, OR a11 、C(O)R b11 、C(O)NR c11 R d11 、C(O)OR a11 、OC(O)R b11 、OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O)R b11 NR c11 C(O)OR a11 NR c11 C(O)NR c11 R d11 NR c11 S(O)2R b11 NR c11 S(O)2NR c11 R d11 、S(O)2R b11 and S(O)2NR c11 R d11 ;

[0395] Each R a11 、R c11 and R d11 Independently selected from H, C 1-6 Alkyl and C 1-6 alkyl halide;

[0396] Each R b11 Independently selected from C 1-6 Alkyl and C 1-6 alkyl halide;

[0397] R 2 Selected from H, halogen, CN, C 1-3 Alkyl and C 1-3 alkyl halide;

[0398] Each R 3 are independently selected from H, halogen, C 1-3 Alkyl and cyclopropyl;

[0399] R 4Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl and 5-6 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl and 5-6 membered heteroaryl are each optionally substituted by 1, 2, 3 or 4 independently selected R 4A Substituent substitution;

[0400] Each R 4A Independently selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-4 Cycloalkyl, OR a41 、C(O)R b41 、C(O)NR c41 R d41 、C(O)OR a41 、OC(O)R b41 、OC(O)NR c41 R d41 NR c41 R d41 NR c41 C(O)R b41 NR c41 C(O)OR a41 NR c41 C(O)NR c41 R d41 NR c41 S(O)2R b41 NR c41 S(O)2NR c41 R d41 、S(O)2R b41 and S(O)2NR c41 R d41 , wherein the C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-4 Each cycloalkyl group is optionally substituted with 1, 2 or 3 independently selected R 4B Substituent substitution;

[0401] Each R a41 、R c41 and R d41 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-4 Cycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl and C3-4 The cycloalkyl groups are each optionally substituted with 1 or 2 independently selected R 4B Substituent substitution;

[0402] Each R b41 Independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-4 Cycloalkyl, each of which is optionally substituted by 1 or 2 independently selected R 4B Substituent substitution;

[0403] Each R 4B Independently selected from H, halogen, CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, OR a42 and NR c42 R d42 ;

[0404] Each R a42 、R c42 and R d42 Independently selected from H, C 1-3 Alkyl and C 1-3 alkyl halide;

[0405] Each R b42 Independently selected from C 1-3 Alkyl and C 1-3 Halogenated alkyl.

[0406] Each R 5 Independently selected from H, halogen, NO2, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a5 SR a5 NHOR a5 、C(O)R b5 、C(O)NR c5 R d5 、C(O)OR a5 、OC(O)R b5 、OC(O)NR c5 R d5 NR c5 R d5 NR c5 C(O)R b5NR c5 C(O)OR a5 NR c5 C(O)NR c5 R d5 NR c5 S(O)2R b5 NR c5 S(O)2NR c5 R d5 、S(O)2R b5 and S(O)2NR c5 R d5 ; wherein said C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R 5A Substituent substitution;

[0407] Each R a5 、R c5 and R d5 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Alkyl, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R 5A Substituents are substituted; and

[0408] Each R b5 Independently selected from C 1-6 Alkyl, C1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally substituted with 1, 2, 3 or 4 independently selected R 5A Substituent substitution.

[0409] Each R 5A Independently selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-4 Cycloalkyl, OR a51 SR a51 NHOR a51 、C(O)R b51 、C(O)NR c51 R d51 、C(O)OR a51 、OC(O)R b51 、OC(O)NR c51 R d51 NR c51 R d51 NR c51 C(O)R b51 NR c51 C(O)OR a51 NR c51 C(O)NR c51 R d51 NR c51 S(O)2R b51 NR c51 S(O)2NR c51 R d51 、S(O)2R b51 and S(O)2NR c51 R d51 ;

[0410] Each R a51 、R c51 and R d51 Independently selected from H, C 1-6 Alkyl and C 1-6 haloalkyl; and

[0411] Each R b51 Independently selected from C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0412] In some embodiments:

[0413] n is 0 or 1;

[0414] p is 0 or 1;

[0415] The ring portion A is a 5-10 membered heteroaryl group;

[0416] The ring portion B is piperidinyl;

[0417] R 1 H, C 1-6 Alkyl, phenyl, 5-7 membered heterocycloalkyl, OR a1 SR a1 , or NR c1 R d1 , wherein the C 1-6 Alkyl, phenyl and 5-7 membered heterocycloalkyl are each optionally substituted by 1 or 2 independently selected R 1A Substituent substitution;

[0418] Each R a1 、R c1 and R d1 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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 Each alkyl group is optionally replaced by 1, 2 or 3 independently selected R 1A Substituents are substituted; and

[0419] Each R 1A Independently selected from H, D, halogen, CN, C 1-4 Alkyl, C 1-4 Halogenated alkyl, 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 3-4Cycloalkyl and C(O)OC 1-4 Alkyl, wherein the C 1-4 Alkyl, C 1-4 Halogenated alkyl, 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 Each alkyl group is optionally replaced by 1, 2 or 3 independently selected R 1B Substituent substitution;

[0420] Each R 1B Independently selected from H, D and OC 1-4 alkyl;

[0421] R 2 is H or halogen;

[0422] Each R 3 independently selected from H, F or methyl;

[0423] R 4 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl-C 1-4 Alkyl; wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl and 4-10 membered heterocycloalkyl-C 1-4 Each alkyl group is optionally replaced by 1 or 2 independently selected R 4A Substituent substitution;

[0424] Each R 4A Independently selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-4 Cycloalkyl, OR a41 、C(O)R b41 、C(O)NR c41 R d41 、C(O)OR a41 、OC(O)R b41 、OC(O)NR c41 R d41 NR c41 R d41 NRc41 C(O)R b41 NR c41 C(O)OR a41 NR c41 C(O)NR c41 R d41 NR c41 S(O)2R b41 NR c41 S(O)2NR c41 R d41 、S(O)2R b41 and S(O)2NR c41 R d41 , wherein the C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-4 Each cycloalkyl group is optionally substituted with 1, 2 or 3 independently selected R 4B Substituent substitution;

[0425] Each R a41 、R c41 and R d41 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-4 Cycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-4 The cycloalkyl groups are each optionally substituted with 1 or 2 independently selected R 4B Substituent substitution;

[0426] Each R b41 Independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-4 Cycloalkyl, each of which is optionally substituted by 1 or 2 independently selected R 4B Substituent substitution;

[0427] Each R 4B Independently selected from H, halogen, CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, OR a42 and NR c42 R d42 ;

[0428] Each R a42 、R c42 and R d42 Independently selected from H, C 1-3 Alkyl and C 1-3 alkyl halide;

[0429] Each Rb42 Independently selected from C 1-3 Alkyl and C 1-3 alkyl halide;

[0430] Each R 5 Independently selected from H, halogen, NO2, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, OR a5 、C(O)R b5 、C(O)NR c5 R d5 、C(O)OR a5 NR c5 R d5 NR c5 C(O)R b5 NR c5 S(O)2R b5 、S(O)2R b5 and S(O)2NR c5 R d5 ; wherein said C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl and 5-6 membered heteroaryl are each optionally substituted by 1, 2, 3 or 4 independently selected R 5A Substituent substitution;

[0431] Each R a5 、R c5 and R d5 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl and 5-6 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl and 5-6 membered heteroaryl are each optionally substituted by 1, 2, 3 or 4 independently selected R 5A Substituents are substituted; and

[0432] Each R b5 Independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl and 5-6 membered heteroaryl, each of which is optionally substituted by 1, 2, 3 or 4 independently selected R 5A Substituent substitution.

[0433] Each R 5A Independently selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-4 Cycloalkyl, OR a51 and NR c51 R d51 ;

[0434] Each R a51 、R c51 and R d51 Independently selected from H and C 1-3 alkyl; and

[0435] Each R b51 Independently C 1-3 alkyl.

[0436] In some embodiments:

[0437] n is 0 or 1;

[0438] p is 0 or 1;

[0439] The ring portion A is a 5-10 membered heteroaryl group;

[0440] The ring portion B is piperidinyl;

[0441] R 1 H or OR a1 ;

[0442] Each R a1 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkyl and 4-6 membered heterocycloalkyl-C 1-3 Each alkyl group is optionally replaced by 1 or 2 independently selected R 1A Substituents are substituted; and

[0443] Each R 1A Independently selected from H, halogen, CN, C 1-4 Alkyl, C 1-4 Halogenated alkyl, OH, C 1-3 Alkoxy, C 1-3 Haloalkoxy, amino, C1-3 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;

[0444] R 2 is H or halogen;

[0445] Each R 3 independently selected from H, F or methyl;

[0446] R 4 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl and 5-6 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl and 5-6 membered heteroaryl are each optionally substituted by 1, 2, 3 or 4 independently selected R 4A Substituent substitution;

[0447] Each R 4A Independently selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-4 Cycloalkyl, OR a41 、C(O)R b41 、C(O)NR c41 R d41 、C(O)OR a41 、OC(O)R b41 、OC(O)NR c41 R d41 NR c41 R d41 NR c41 C(O)R b41 NR c41 C(O)OR a41 NR c41 C(O)NR c41 R d41 NR c41 S(O)2R b41 NR c41 S(O)2NR c41 R d41 、S(O)2R b41 and S(O)2NR c41 R d41, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-4 Each cycloalkyl group is optionally substituted with 1, 2 or 3 independently selected R 4B Substituent substitution;

[0448] Each R a41 、R c41 and R d41 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-4 Cycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-4 The cycloalkyl groups are each optionally substituted with 1 or 2 independently selected R 4B Substituent substitution;

[0449] Each R b41 Independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-4 Cycloalkyl, each of which is optionally substituted by 1 or 2 independently selected R 4B Substituent substitution;

[0450] Each R 4B Independently selected from H, halogen, CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, OR a42 and NR c42 R d42 ;

[0451] Each R a42 、R c42 and R d42 Independently selected from H, C 1-3 Alkyl and C 1-3 alkyl halide;

[0452] Each R b42 Independently selected from C 1-3 Alkyl and C 1-3 alkyl halide;

[0453] Each R 5 Independently selected from H, halogen, NO2, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, OR a5 、C(O)R b5 、C(O)NR c5 R d5 、C(O)ORa5 NR c5 R d5 NR c5 C(O)R b5 NR c5 S(O)2R b5 、S(O)2R b5 and S(O)2NR c5 R d5 ; wherein said C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl and 5-6 membered heteroaryl are each optionally substituted by 1, 2, 3 or 4 independently selected R 5A Substituent substitution;

[0454] Each R a5 、R c5 and R d5 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl and 5-6 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl and 5-6 membered heteroaryl are each optionally substituted by 1, 2, 3 or 4 independently selected R 5A Substituents are substituted; and

[0455] Each R b5 Independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl and 5-6 membered heteroaryl, each of which is optionally substituted by 1, 2, 3 or 4 independently selected R 5A Substituent substitution.

[0456] Each R 5A Independently selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-4 Cycloalkyl, OR a51 and NR c51 R d51 ;

[0457] Each R a51 、R c51 and R d51 Independently selected from H and C 1-3 alkyl; and

[0458] Each Rb51 Independently C 1-3 alkyl.

[0459] In some embodiments:

[0460] n is 0 or 1;

[0461] p is 0 or 1;

[0462] The ring portion A is a 5-10 membered heteroaryl group;

[0463] The ring portion B is piperidinyl;

[0464] R 1 H or OR a1 ;

[0465] Each R a1 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkyl and 4-6 membered heterocycloalkyl-C 1-3 Each alkyl group is optionally replaced by 1, 2 or 3 independently selected R 1A Substituents are substituted; and

[0466] Each R 1A Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OR a11 and C(O)OR a11 , wherein the C 1-6 Alkyl and C 1-6 Each haloalkyl group is optionally replaced by 1, 2 or 3 independently selected R 1B Substituent substitution;

[0467] Each R a11 Independently selected from H and C 1-4 Alkyl, wherein the C 1-4 The alkyl group is optionally substituted with 1, 2 or 3 independently selected R 1B Substituent substitution;

[0468] Each R b11 Independently selected from C 1-6 Alkyl and C1-6 alkyl halide;

[0469] Each R 1B Independently selected from H, D and OR a12 ;

[0470] Each R a12 Independently selected from H and C 1-6 alkyl;

[0471] R 2 is H or halogen;

[0472] Each R 3 independently selected from H, F or methyl;

[0473] R 4 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl and 5-6 membered heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl and 5-6 membered heteroaryl are each optionally substituted by 1, 2, 3 or 4 independently selected R 4A Substituent substitution;

[0474] Each R 4A Independently selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-4 Cycloalkyl, OR a41 、C(O)R b41 、C(O)NR c41 R d41 、C(O)OR a41 、OC(O)R b41 、OC(O)NR c41 R d41 NR c41 R d41 NR c41 C(O)R b41 NR c41 C(O)OR a41 NR c41 C(O)NR c41 R d41 NR c41 S(O)2R b41 NR c41 S(O)2NR c41 R d41 、S(O)2R b41 and S(O)2NRc41 R d41 , wherein the C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-4 Each cycloalkyl group is optionally substituted with 1, 2 or 3 independently selected R 4B Substituent substitution;

[0475] Each R a41 、R c41 and R d41 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-4 Cycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-4 The cycloalkyl groups are each optionally substituted with 1 or 2 independently selected R 4B Substituent substitution;

[0476] Each R b41 Independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-4 Cycloalkyl, each of which is optionally substituted by 1 or 2 independently selected R 4B Substituent substitution;

[0477] Each R 4B Independently selected from H, halogen, CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, OR a42 and NR c42 R d42 ;

[0478] Each R a42 、R c42 and R d42 Independently selected from H, C 1-3 Alkyl and C 1-3 alkyl halide;

[0479] Each R b42 Independently selected from C 1-3 Alkyl and C 1-3 alkyl halide;

[0480] Each R 5 Independently selected from H, halogen, NO2, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, OR a5 、C(O)R b5 、C(O)NRc5 R d5 、C(O)OR a5 NR c5 R d5 NR c5 C(O)R b5 NR c5 S(O)2R b5 、S(O)2R b5 and S(O)2NR c5 R d5 ; wherein said C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl and 5-6 membered heteroaryl are each optionally substituted by 1, 2, 3 or 4 independently selected R 5A Substituent substitution;

[0481] Each R a5 、R c5 and R d5 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl and 5-6 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl and 5-6 membered heteroaryl are each optionally substituted by 1, 2, 3 or 4 independently selected R 5A Substituents are substituted; and

[0482] Each R b5 Independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl and 5-6 membered heteroaryl, each of which is optionally substituted by 1, 2, 3 or 4 independently selected R 5A Substituent substitution.

[0483] Each R 5A Independently selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-4 Cycloalkyl, OR a51 and NR c51 R d51 ;

[0484] Each R a51 、R c51 and R d51 Independently selected from H and C 1-3 alkyl; and

[0485] Each R b51 Independently C 1-3 alkyl.

[0486] In some embodiments:

[0487] n is 0 or 1;

[0488] p is 0 or 1;

[0489] The ring portion A is a 5-10 membered heteroaryl group having 1 or 2 N ring atoms;

[0490] The ring portion B is piperidinyl;

[0491] R 1 Independently selected from H, C 1-6 Alkyl, phenyl, 5-7 membered heterocycloalkyl, OR a1 SR a1 and NR c1 R d1 , wherein the C 1-6 Alkyl, phenyl and 5-7 membered heterocycloalkyl are each optionally substituted by 1 or 2 independently selected R 1A Substituent substitution;

[0492] Each R a1 、R c1 and R d1 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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 Each alkyl group is optionally replaced by 1, 2 or 3 independently selected R 1A Substituent substitution;

[0493] Each R 1A Independently selected from D, halogen, CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-4 Cycloalkyl, OR a11 and C(O)OR a11 , wherein the C 1-6 Alkyl and C1-6 Each haloalkyl group is optionally replaced by 1, 2 or 3 independently selected R 1B Substituent substitution;

[0494] Each R a11 Independently selected from H and C 1-4 Alkyl, wherein the C 1-4 The alkyl group is optionally substituted with 1, 2 or 3 independently selected R 1B Substituent substitution;

[0495] Each R 1B Independently selected from H, D and OC 1-4 alkyl;

[0496] R 2 H or F;

[0497] Each R 3 independently selected from H or methyl;

[0498] R 4 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl-C 1-4 Alkyl; wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R 4A Substituent substitution;

[0499] Each R 4A Independently selected from H, C 1-6 Alkyl, OH and NR c41 R d41 ;

[0500] Each R c41 and R d41 Independently selected from H, C 1-6 Alkyl and C 1-6 alkyl halide;

[0501] Each R 5 Independently selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-4 Cycloalkyl, OR a5 and NR c5 R d5 ;and

[0502] Each R a5 、R c5 and R d5 Independently selected from H, C1-6 Alkyl and C 1-6 Halogenated alkyl.

[0503] In some embodiments:

[0504] n is 0 or 1;

[0505] p is 0 or 1;

[0506] The ring portion A is a 5-10 membered heteroaryl group having 1 or 2 N ring atoms;

[0507] The ring portion B is piperidinyl;

[0508] R 1 Independently selected from H and OR a1 ;

[0509] Each R a1 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkyl and 4-6 membered heterocycloalkyl-C 1-3 Each alkyl group is optionally replaced by 1 or 2 independently selected R 1A Substituent substitution;

[0510] Each R 1A Independently selected from C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-4 Cycloalkyl, OH, C 1-3 Alkoxy and C 1-3 haloalkoxy;

[0511] R 2 H or F;

[0512] Each R 3 independently selected from H or methyl;

[0513] R 4 Selected from C 1-6 Alkyl and C 3-6 Cycloalkyl; wherein the C 1-6 Alkyl and C 3-6 Each cycloalkyl group is optionally substituted with 1, 2, 3 or 4 independently selected R4A Substituent substitution;

[0514] Each R 4A Independently selected from H and C 1-6 alkyl;

[0515] Each R 5 Independently selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-4 Cycloalkyl, OR a5 and NR c5 R d5 ;and

[0516] Each R a5 、R c5 and R d5 Independently selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0517] In some embodiments, the compound is a compound of formula (II):

[0518]

[0519] or a pharmaceutically acceptable salt thereof.

[0520] In some embodiments, the compound is a compound of formula (IIa):

[0521]

[0522] or a pharmaceutically acceptable salt thereof.

[0523] In some embodiments, the compound is a compound of formula (IIb):

[0524]

[0525] or a pharmaceutically acceptable salt thereof.

[0526] In some embodiments, the compound is a compound of formula (III):

[0527]

[0528] or a pharmaceutically acceptable salt thereof.

[0529] In some embodiments, the compound is a compound of formula (IIIa):

[0530]

[0531] or a pharmaceutically acceptable salt thereof.

[0532] In some embodiments, the compound is a compound of formula (IIIb):

[0533]

[0534] or a pharmaceutically acceptable salt thereof.

[0535] In some embodiments, the compound is a compound of formula (IV):

[0536]

[0537] or a pharmaceutically acceptable salt thereof, wherein:

[0538] X 1 is a bond, CH2, or CH2CH2; and

[0539] X 2 is a bond or CH2.

[0540] In some embodiments, the compound is a compound of formula (V):

[0541]

[0542] or a pharmaceutically acceptable salt thereof.

[0543] In some embodiments, the compound is a compound of formula (Va):

[0544]

[0545] or a pharmaceutically acceptable salt thereof.

[0546] In some embodiments, the compound is a compound of formula (Vb):

[0547]

[0548] or a pharmaceutically acceptable salt thereof.

[0549] In some embodiments, the compound is a compound of formula (Vc):

[0550]

[0551] or a pharmaceutically acceptable salt thereof.

[0552] In some embodiments, the compound is a compound of formula (Vd):

[0553]

[0554] or a pharmaceutically acceptable salt thereof.

[0555] In some embodiments, the compound is a compound of formula (VI):

[0556]

[0557] or a pharmaceutically acceptable salt thereof.

[0558] In some embodiments, the compound is a compound of formula (VIa):

[0559]

[0560] or a pharmaceutically acceptable salt thereof.

[0561] In some embodiments, the compound is a compound of formula (VIb):

[0562]

[0563] or a pharmaceutically acceptable salt thereof.

[0564] In some embodiments, the compound is a compound of formula (VIc):

[0565]

[0566] or a pharmaceutically acceptable salt thereof.

[0567] In some embodiments, the compound is a compound of formula (VIIa):

[0568]

[0569] or a pharmaceutically acceptable salt thereof.

[0570] In some embodiments, the compound is a compound of formula (VIIIa):

[0571]

[0572] or a pharmaceutically acceptable salt thereof.

[0573] In some embodiments, the compound is a compound of formula (VIIIb):

[0574]

[0575] or a pharmaceutically acceptable salt thereof.

[0576] In some embodiments, the compound is a compound of formula (VIIIc):

[0577]

[0578] or a pharmaceutically acceptable salt thereof.

[0579] In some embodiments, the compound is a compound of formula (IXa):

[0580]

[0581] or a pharmaceutically acceptable salt thereof.

[0582] In some embodiments, the compound is a compound of formula (IXb):

[0583]

[0584] or a pharmaceutically acceptable salt thereof.

[0585] In some embodiments, the compound is a compound of formula (IXc):

[0586]

[0587] or a pharmaceutically acceptable salt thereof.

[0588] In some embodiments, Z is CR 2 .

[0589] In some embodiments, Z is N.

[0590] In some embodiments, X is N; and Y is C.

[0591] In some embodiments, X is C; and Y is N.

[0592] In some embodiments, Z is N, X is N, and Y is C.

[0593] In some embodiments, Z is N, X is C, and Y is N.

[0594] In some embodiments, Z is CR 2 , X is N, and Y is C.

[0595] In some embodiments, Z is CR 2 , X is C, and Y is N.

[0596] In some embodiments, as described herein, a moiety connected to an "alkyl," "alkenyl," "alkynyl," "aryl," "phenyl," "cycloalkyl," "heterocycloalkyl," or "heteroaryl" substituent or a "-C 1-4 1, 2, 3, 4, 5, 6, 7 or 8 hydrogen atoms of the carbon atoms of the "alkyl-" and "alkylene" linking groups are optionally replaced by deuterium atoms.

[0597] It is further contemplated that certain features of the present invention, which for clarity are described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the present invention, which for brevity are described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0598] At various places in this specification, divalent linking substituents are described. Unless otherwise indicated, it is expressly intended that each divalent linking substituent includes both the forward and reverse forms of the linking substituent. For example, -NR(CR'R") n -Include-NR(CR'R") n -and-(CR'R") n NR - Both. When a structure explicitly requires a linking group, the Markush variable listed for that group is to be understood as the linking group.

[0599] The term "n-membered" (where n is an integer) generally describes the number of ring atoms in a moiety, where the number of ring atoms is n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl.

[0600] As used herein, the phrase "optionally substituted" means unsubstituted or substituted. Substituents are independently selected, and substitution may be at any chemically accessible position. As used herein, the term "substituted" means that a hydrogen atom is removed and replaced with a substituent. A single divalent substituent (e.g., oxo) may replace two hydrogen atoms. It will be understood that substitution at a given atom is limited to valences, does not exceed the normal valence of the designated atom, and that the substitution results in a stable compound.

[0601] As used herein, the term "independently selected" means that each occurrence of a variable or substituent is independently selected from the applicable list at each occurrence.

[0602] As used herein, the phrase "each 'variable' is independently selected from" means substantially the same as "at each occurrence the 'variable' is selected from".

[0603] When any variable (such as R G ) occurs more than once in any constituent or formula of a compound, its definition on each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be represented by 1, 2, 3, or 4 independently selected R G substituents, the group may be optionally substituted with up to four R G Group substituted and R G independently selected at each occurrence from R G Definition of .

[0604] In some embodiments, when optional multiple substituents are specified in the following form:

[0605]

[0606] It will be understood that the substituent R may appear p times on the ring and that R may be a different moiety at each occurrence. It will be understood that each R group may replace any hydrogen atom attached to a ring atom, including (CH2) n Furthermore, in the above examples, if the variable Q is defined to include hydrogen, such as when Q is referred to as CH2, NH, etc., then any floating substituent (such as R) in the above examples may replace a hydrogen in the Q variable as well as a hydrogen in any other non-variable component of the ring.

[0607] Throughout this definition, the term “C n-m " indicates a range including the endpoints, where n and m are integers and indicate the number of carbons. Examples include C 1-3 、C 1-4 、C 1-6 wait.

[0608] As used herein, the term "C n-m "Alkyl" refers to a saturated hydrocarbon group having n to m carbons which may be straight 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; higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, and the like. In some embodiments, the alkyl group contains 1 to 6 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms.

[0609] 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.

[0610] As used herein, “C n-m "Alkynyl" refers to an alkyl group having one or more carbon-carbon triple bonds and having n to m carbon atoms. Exemplary alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, 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, the term "C" alone or in combination with other terms refers to an alkyl group having from n to m carbon atoms. n-m"Alkoxy" refers to a radical of the formula -O-alkyl, where the alkyl radical has n to m carbon atoms. Exemplary alkoxy radicals 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 radical has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0611] As used herein, the term "amino" refers to a group of formula -NH2.

[0612] As used herein, the term "aryl," employed alone or in combination with other terms, refers to an aromatic hydrocarbon group which may be monocyclic or polycyclic (eg, having two fused rings). n-m "Aryl" refers to an aromatic radical having n to m ring carbon atoms. In some embodiments, an aromatic radical has 6 to 10 carbon atoms. In some embodiments, an aromatic radical is phenyl or naphthyl. In some embodiments, an aromatic radical is phenyl.

[0613] 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.

[0614] As used herein, “C n-m "Haloalkoxy" refers to a radical of the formula -O-haloalkyl having n to m carbon atoms. Exemplary haloalkoxy radicals include OCF3 and OCHF2. In some embodiments, the haloalkoxy radical is only fluorinated. In some embodiments, the alkyl radical has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0615] As used herein, the term "C n-m "Haloalkyl" refers to an alkyl group having from 1 halogen atom to 2s+1 halogen atoms, which may be the same or different, where "s" is the number of carbon atoms in the alkyl group, wherein the alkyl group has n to m carbon atoms. In some embodiments, the haloalkyl group is only fluorinated. In some embodiments, the alkyl group of the haloalkyl group 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.

[0616] As used herein, the term "C n-m "Fluoroalkyl" refers to an alkyl group having from one fluorine atom to 2s+1 fluorine atoms, where "s" is the number of carbon atoms in the alkyl group, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group of the fluoroalkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Exemplary fluoroalkyl groups include CF3, C2F5, CHF2, CH2F, and the like.

[0617] As used herein, the term "thio" refers to a group of formula -SH.

[0618] As used herein, the term "C n-m "Alkylamino" refers to a radical of the formula -NH(alkyl) wherein the alkyl radical has n to m carbon atoms. In some embodiments, the alkyl radical of the alkylamino radical has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0619] As used herein, the term "C n-m "Alkoxycarbonyl" refers to a radical of the formula -C(O)O-alkyl, wherein the alkyl radical has n to m carbon atoms. In some embodiments, the alkyl radical of the alkoxycarbonyl radical has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0620] As used herein, the term "C n-m "Alkylcarbonyl" refers to a radical of the formula -C(O)-alkyl, wherein the alkyl radical has n to m carbon atoms. In some embodiments, the alkyl radical of the alkylcarbonyl radical has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0621] As used herein, the term "C n-m "Alkylcarbonylamino" refers to a radical of the formula -NHC(O)-alkyl, wherein the alkyl radical has n to m carbon atoms. In some embodiments, the alkyl radical of the alkylcarbonylamino radical has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0622] As used herein, the term "C n-m "Alkoxycarbonylamino" refers to a group of the formula -NHC(O)O(C n-m In some embodiments, the alkyl group of the alkoxycarbonylamino group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0623] As used herein, the term "C n-m "Alkylsulfonylamino" refers to a radical of the formula -NHS(O)2-alkyl, wherein the alkyl radical has n to m carbon atoms. In some embodiments, the alkyl radical of the alkylsulfonylamino radical has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0624] As used herein, the term "aminosulfonyl" refers to a group of formula -S(O)2NH2.

[0625] As used herein, the term "C n-m "Alkylaminosulfonyl" refers to a radical of the formula -S(O)2NH(alkyl) wherein the alkyl radical has n to m carbon atoms. In some embodiments, the alkyl radical of the alkylaminosulfonyl radical has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0626] As used herein, the term "di(C n-m "dialkyl)aminosulfonyl" refers to a radical of the formula -S(O)2N(alkyl)2 wherein each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group of the dialkylaminosulfonyl radical independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0627] As used herein, the term "aminosulfonylamino" refers to a group of formula -NHS(O)2NH2.

[0628] As used herein, the term "C n-m "Alkylsulfonylamino" refers to a radical of the formula -NHS(O)2NH(alkyl), wherein the alkyl radical has n to m carbon atoms. In some embodiments, the alkyl radical of the alkylaminosulfonylamino radical has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0629] As used herein, the term "di(C n-m "Dialkyl)aminocarbonylamino" refers to a radical of the formula -NHS(O)2N(alkyl)2, wherein each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group of the dialkylaminosulfonylamino radical independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0630] As used herein, the term "aminocarbonylamino," employed alone or in combination with other terms, refers to a group of formula -NHC(O)NH2.

[0631] As used herein, the term "C n-m "Alkylaminocarbonylamino" refers to a radical of the formula -NHC(O)NH(alkyl) wherein the alkyl radical has n to m carbon atoms. In some embodiments, the alkyl radical of the alkylaminocarbonylamino radical has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0632] As used herein, the term "di(C n-m "dialkyl)aminocarbonylamino" refers to a radical of the formula -NHC(O)N(alkyl)2, wherein each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group of the dialkylaminocarbonylamino radical independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0633] As used herein, the term "C n-m "Alkylcarbamoyl" refers to a radical of the formula -C(O)-NH(alkyl) wherein the alkyl radical has n to m carbon atoms. In some embodiments, the alkyl radical of the alkylcarbamoyl radical has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0634] As used herein, the term "C n-m"Alkylthio" refers to a radical of the formula -S-alkyl, wherein the alkyl radical has n to m carbon atoms. In some embodiments, the alkyl radical of the alkylthio radical has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0635] As used herein, the term "C n-m "Alkylsulfinyl" refers to a radical of the formula -S(O)-alkyl, wherein the alkyl radical has n to m carbon atoms. In some embodiments, the alkyl radical of the alkylsulfinyl radical has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0636] As used herein, the term "C n-m "Alkylsulfonyl" refers to a radical of the formula -S(O)2-alkyl, wherein the alkyl radical has n to m carbon atoms. In some embodiments, the alkyl radical of the alkylsulfonyl radical has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0637] As used herein, the term "cyano C n-m "Alkyl" refers to a group of the formula -(C n-m As used herein, the term "cyano-C 1-6 "Alkyl" refers to a group of the formula -(C 1-6 As used herein, the term "cyano-C 1-3 "Alkyl" refers to a group of the formula -(C 1-3 alkylene)-CN group.

[0638] As used herein, the term "HO-C n-m "Alkyl" refers to a group of the formula -(C n-m As used herein, the term "HO-C 1-3 "Alkyl" refers to a group of the formula -(C 1-3 alkylene)-OH group.

[0639] As used herein, the term "C n-m Alkoxy-C o-p "Alkyl" refers to a group of the formula -(C n-m Alkylene)-O(C o-p As used herein, the term "C 1-6 Alkoxy-C 1-6 "Alkyl" refers to a group of the formula -(C 1-6 Alkylene)-O(C 1-6 As used herein, the term "C 1-3 Alkoxy-C 1-3 "Alkyl" refers to a group of the formula -(C 1-3 Alkylene)-O(C1-3 alkyl) groups.

[0640] As used herein, the term "carboxy" refers to a group of formula -C(O)OH.

[0641] As used herein, the term "di(C n-m "Dialkyl)amino" refers to a radical of the formula -N(alkyl)2, wherein each of the two alkyl groups independently has n to m carbon atoms. In some embodiments, each alkyl group of the dialkylamino group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0642] As used herein, the term "di(C n-m "Dialkylcarbamoyl" refers to a group of the formula -C(O)N(alkyl)2, wherein the two alkyl groups each independently have n to m carbon atoms. In some embodiments, each alkyl group of the dialkylcarbamoyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0643] As used herein, the term "C n-m "Alkylcarbonyloxy" refers to a radical of the formula -OC(O)-alkyl, wherein the alkyl radical has n to m carbon atoms. In some embodiments, the alkyl radical of the alkylcarbonyloxy radical has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0644] As used herein, "aminocarbonyloxy" refers to a group of formula -OC(O)-NH2.

[0645] As used herein, “C n-m "Alkylaminocarbonyloxy" refers to a radical of the formula -OC(O)-NH-alkyl, wherein the alkyl radical has n to m carbon atoms. In some embodiments, the alkyl radical of the alkylaminocarbonyloxy radical has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0646] As used herein, the term "di(C n-m "Dialkylaminocarbonyloxy" refers to a radical of the formula -OC(O)-N(alkyl)2, wherein each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group of the dialkylaminocarbonyloxy radical independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0647] As used herein, the term "C n-m "Alkoxycarbonylamino" refers to a radical of the formula -NHC(O)-O-alkyl, wherein the alkyl radical has n to m carbon atoms.

[0648] As used herein, the term "carbamyl" refers to a group of formula -C(O)NH2.

[0649] As used herein, the term "carbonyl," employed alone or in combination with other terms, refers to a -C(O)- group.

[0650] As used herein, "cycloalkyl" refers to a non-aromatic cyclic hydrocarbon including a cyclized alkyl and / or alkenyl group. Cycloalkyl can include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) groups, spirocycles, and bridged rings (e.g., bridged bicycloalkyls). The ring-forming carbon atoms of the cycloalkyl group can be optionally substituted with oxo or sulfide groups (e.g., C(O) or C(S)). The definition of cycloalkyl also includes a portion in which one or more aromatic rings are fused to a cycloalkyl ring (i.e., having a bond shared with the cycloalkyl ring), such as benzo or thienyl derivatives of cyclopentane, cyclohexane, etc. Cycloalkyl groups containing fused aromatic rings can be connected via any ring-forming atoms (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 group is C 3-10 In some embodiments, the cycloalkyl group is C 3-7 In some embodiments, the cycloalkyl group is C 4-7 In some embodiments, the cycloalkyl group is C 4-10 Spirocyclic or bridged ring cycloalkyl (e.g., bridged bicycloalkyl). Exemplary cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatraenyl, norbornyl, norpinanyl, norcarenyl, cubane, adamantane, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, spiro[3.3]heptyl, etc. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0651] As used herein, "heteroaryl" refers to a monocyclic or polycyclic ring (e.g., having 2, 3, or 4 fused rings) having at least one heteroatom ring member selected from N, O, or S. In some embodiments, any ring-forming N in the heteroaryl moiety may be an N oxide. In some embodiments, the heteroaryl group is a 5-10 membered monocyclic or bicyclic heteroaryl group having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, and S. In some embodiments, the heteroaryl group is a 5-6 monocyclic heteroaryl group having 1 or 2 heteroatom ring members selected from N, O, and S. In some embodiments, the heteroaryl group contains 5 to 10 or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to 4 ring-forming heteroatoms, 1 to 3 ring-forming heteroatoms, 1 to 2 ring-forming heteroatoms, or 1 ring-forming heteroatom. When the heteroaryl group contains more than one heteroatom ring member, these heteroatoms may be the same or different. Exemplary heteroaryl groups include, but are not limited to, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, oxazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, furanyl, thiophenyl, 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, isoquinolyl, indolyl, benzothiophenyl, benzofuranyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl, purinyl, triazinyl, thieno[3,2-b]pyridinyl, imidazo[1,2-a]pyridinyl, 1,5-naphthyridine, 1H-pyrazolo[4,3-b]pyridinyl, oxadiazole (e.g., 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole), 1,2-dihydro-1,2-azoboryl, and the like.

[0652] As used herein, "heterocycloalkyl" refers to a monocyclic or polycyclic heterocycle having at least one non-aromatic ring (saturated or partially unsaturated ring), wherein one or more of the ring-forming carbon atoms of the heterocycloalkyl are replaced by heteroatoms selected from N, O or S, and wherein the ring-forming carbon atoms and heteroatoms of the heterocycloalkyl are optionally substituted by one or more oxo or sulfide ion groups (e.g., C(O), S(O), C(S) or S(O)2, etc.). Heterocycloalkyl may include a monocyclic or polycyclic (e.g., having 2 fused rings) system. Heterocycloalkyl includes monocyclic and polycyclic 4-10, 4-7 and 5-6 membered heterocycloalkyls. Heterocycloalkyl may also include spirocycles and bridged rings. Heterocycloalkyl may be connected via ring-forming carbon atoms or ring-forming heteroatoms. In some embodiments, heterocycloalkyl contains 0 to 3 double bonds. In some embodiments, heterocycloalkyl contains 0 to 2 double bonds.

[0653] 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 heterocycle, such as benzo or thienyl derivatives of piperidine, morpholine, azophene, and the like. Heterocycloalkyl groups containing fused aromatic rings may be attached through any ring atom, including those of the fused aromatic ring. In some embodiments, heterocycloalkyl groups contain 4 to 10 ring heteroatoms, 4 to 7 ring heteroatoms, 4 to 6 ring heteroatoms, or 5 to 6 ring heteroatoms. In some embodiments, heterocycloalkyl groups have 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0654] 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, wherein 1, 2, 3 or 4 ring-forming carbon or heteroatoms may be optionally substituted with one or more oxo or sulfonium groups. 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, wherein 1, 2, 3 or 4 ring-forming carbon or heteroatoms may be optionally substituted with one or more oxo or sulfonium groups. In some embodiments, heterocycloalkyl is a 4-7 membered monocyclic heterocycloalkyl having 1 or 2 ring-forming heteroatoms independently selected from N, O and S, and wherein 1, 2 or 3 ring-forming carbon or heteroatoms may be optionally substituted with one or more oxo or sulfonium groups. In some embodiments, heterocycloalkyl is a monocyclic 4-6 membered heterocycloalkyl having 1 or 2 heteroatoms independently selected from N, O, S, and B, and having one or more oxygenated ring members.

[0655] Examples of heterocycloalkyl groups include pyrrolidin-2-one, 1,3-isoxazolidin-2-one, pyranyl, tetrahydropyran, oxetanyl, azetidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, benzazepine, 1,2, 3,4-tetrahydroisoquinoline, azabicyclo[3.1.0]hexyl, diazabicyclo[3.1.0]hexyl, oxabicyclo[2.1.1]hexyl, azabicyclo[2.2.1]heptyl, azabicyclo[2.2.1]hept-7-yl, azabicyclo[2.2.1]hept-2-yl, diazabicyclo[2.2.1]heptyl, azabicyclo[3.1.1]heptyl, diazabicyclo[ 3.1.1]heptyl, azabicyclo[3.2.1]octyl, diazabicyclo[3.2.1]octyl, oxabicyclo[2.2.2]octyl, azabicyclo[2.2.2]octyl, azaadamantyl, diazaadamantyl, oxa-adamantyl, azaspiro[3.3]heptyl, diazaspiro[3.3]heptyl, oxa-azaspiro[3.3]heptyl, azaspiro[3.4]octyl , diazaspiro[3.4]octyl, oxa-azaspiro[3.4]octyl, azaspiro[2.5]octyl, diazaspiro[2.5]octyl, azaspiro[4.4]nonyl, diazaspiro[4.4]nonyl, oxa-azaspiro[4.4]nonyl, azaspiro[4.5]decyl, diazaspiro[4.5]decyl, diazaspiro[4.4]nonyl, oxa-azaspiro[4.4]nonyl, etc.

[0656] As used herein, “C o-p Cycloalkyl-C n-m "Alkyl-" refers to a radical of the formula cycloalkyl-alkylene- wherein the cycloalkyl radical has o to p carbon atoms and the alkylene linking radical has n to m carbon atoms.

[0657] As used herein, “C o-p Aryl-C n-m "Alkyl-" refers to a radical of the formula aryl-alkylene- wherein the aryl has o to p carbon ring members and the alkylene has n to m carbon atoms.

[0658] As used herein, "heteroaryl-C n-m "Alkyl-" refers to a radical of the formula heteroaryl-alkylene- wherein the alkylene linking group has n to m carbon atoms.

[0659] As used herein, "heterocycloalkyl-C n-m "Alkyl-" refers to a radical of the formula heterocycloalkyl-alkylene- wherein the alkylene has n to m carbon atoms.

[0660] As used herein, the term "alkylene" refers to a divalent straight or branched chain alkyl linking group. Examples of "alkylene" 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.

[0661] As used herein, the term "alkenylene" refers to a divalent straight or branched alkenyl linking group. Examples of "alkenylene" include ethylene-1,1-diyl, ethylene-1,2-diyl, propylene-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.

[0662] As used herein, the term "alkynylene" refers to a divalent straight or branched chain alkynyl linking group. Examples of "alkynylene" include propyn-1,3-diyl, 2-butyn-1,4-diyl, 3-pentyn-1,5-diyl, 3-hexyn-1,6-diyl, 3-hexyn-1,5-diyl, and the like.

[0663] As used herein, an "alkyl linking group" is a divalent straight or branched chain alkyl linking group ("alkylene"). 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 group" or "alkylene" 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.

[0664] 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 (e.g., C=O or C(O)), or to a nitrogen or sulfur heteroatom forms a nitroso, sulfinyl, or sulfonyl group.

[0665] As used herein, the term "independently selected" means that each occurrence of a variable or substituent is independently selected from the applicable list at each occurrence.

[0666] In some cases, a definition or embodiment refers to a specific ring (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwise indicated, such rings may be attached to any ring member, provided that the valence of the atoms is not exceeded. For example, an azetidine ring may be attached at any position of the ring, while a pyridin-3-yl ring is attached at the 3-position.

[0667] The compounds described herein may 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 invention containing asymmetrically substituted carbon atoms can be separated in optically active or racemic forms. Methods for preparing optically active forms from optically active starting materials are known in the art, such as by resolving racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, etc. may also be present in the compounds described herein, and all of these stable isomers are encompassed by the present invention. The cis and trans geometric isomers of the compounds of the present invention are described and can be separated as isomer mixtures or as separated isomers. In some embodiments, the compound has an (R)-configuration. In some embodiments, the compound has an (S)-configuration. The formulas provided herein (e.g., formula (I), (II), etc.) include stereoisomers of the compound.

[0668] The resolution of the racemic mixture of compound can be carried out by any of a variety of methods known in the art. Exemplary methods include the fractional recrystallization using a chiral resolving acid, which is an optically active, salified organic acid. Suitable resolving agents for the fractional recrystallization method are, for example, optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, D and L forms, or various optically active camphorsulfonic acids, such as β-camphorsulfonic acid. Other resolving agents suitable for the fractional crystallization method include the stereoisomer-pure form (e.g., S and R forms, or diastereoisomer-pure forms) of α-methylbenzylamine, 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc.

[0669] Resolution of the racemic mixture can also be performed by elution on a column packed with an optically active resolving agent (eg nitrobenzoylphenylglycine). Suitable elution solvent compositions can be determined by one skilled in the art.

[0670] The compounds provided herein also include tautomeric forms. Tautomeric forms are produced by the exchange of a single bond with an adjacent double bond and accompanied by proton migration. Tautomeric forms include proton transfer tautomers, which are isomeric protonation states with the same empirical formula and total charge. Exemplary proton transfer tautomers include keto-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and ring forms in which protons can occupy two or more positions of a heterocyclic ring system, such as 1H-imidazole and 3H-imidazole, 1H-1,2,4-triazole, 2H-1,2,4-triazole and 4H-1,2,4-triazole, 1H-isoindole and 2H-isoindole, 2-hydroxypyridine and 2-pyridone, and 1H-pyrazole and 2H-pyrazole. Tautomeric forms can be in equilibrium or spatially locked into one form by appropriate substitution.

[0671] All compounds and pharmaceutically acceptable salts thereof may be found or isolated together with other substances such as water and solvents (eg, hydrates and solvates).

[0672] In some embodiments, preparation of the compounds may involve the addition of an acid or base to effect, for example, catalysis of the desired reaction or the formation of a salt form such as an acid addition salt.

[0673] In some embodiments, compound or its salt provided herein is separated substantially. " being separated substantially " means that compound is at least partially or substantially separated from the environment in which it is formed or detected. Partial separation can include, for example, a composition rich in the compound provided herein. Separation can include, substantially, a composition containing at least about 50 % by weight, at least about 60 % by weight, at least about 70 % by weight, at least about 80 % by weight, at least about 90 % by weight, at least about 95 % by weight, at least about 97 % by weight or at least about 99 % by weight of the compound or its salt provided herein. The method for separating compounds and their salts is conventional in this area.

[0674] As used herein, the term "compound" is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the depicted structure. Unless otherwise specified, a compound herein identified as one particular tautomeric form by name or structure is intended to include the other tautomeric forms.

[0675] The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0676] The present application also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds, wherein 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, inorganic or organic acid salts of basic residues (such as amines); alkali or organic salts of acidic residues (such as carboxylic acids); etc. The pharmaceutically acceptable salts of the present invention 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 invention can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. In general, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture of the two; in general, non-aqueous media such as ether, ethyl acetate, alcohols (e.g., methanol, ethanol, isopropanol, or butanol) or acetonitrile (ACN) are preferred. Lists of suitable salts are 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 herein incorporated by reference in its entirety.

[0677] synthesis

[0678] As will be appreciated by those skilled in the art, the compounds provided herein, including salts and stereoisomers thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of a number of possible synthetic routes, such as those provided in the following schemes.

[0679] The reactions for preparing the compounds described herein can be carried out in suitable solvents that can be readily selected by those skilled in the art of organic synthesis. Suitable solvents may be substantially non-reactive with the starting materials (reactants), intermediates, or products at temperatures 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 in a mixture of more than one solvent. Depending on the specific reaction step, a suitable solvent for a specific reaction step can be selected by a skilled person.

[0680] As used herein, the expression "ambient temperature" or "room temperature" or "rt" is understood in the art and generally refers to a temperature (e.g., reaction temperature) approximately the temperature of the space in which the reaction is carried out, e.g., a temperature of about 20°C to about 30°C.

[0681] The preparation of the compounds of the invention may involve the protection and deprotection of various chemical groups. The need for protection and deprotection and the selection of appropriate protecting groups are readily determined by those 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, 6th edition (Wiley, 2007); Peturssion et al., "Protecting Groups in Carbohydrate Chemistry", J. Chem. Educ., 1997, 74(11), 1297; and Wuts et al., Protective Groups in Organic Synthesis, 4th edition, (Wiley, 2006).

[0682] The reaction can be monitored by any suitable method known in the art. For example, product formation can be monitored by spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g. 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry; or by chromatographic methods such as high performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LCMS), or thin layer chromatography (TLC). Compounds can be purified by a variety of methods by those skilled in the art, including high performance liquid chromatography (HPLC) and normal phase silica chromatography.

[0683] The following schemes provide general guidance related to the preparation of the compounds of the present invention. One skilled in the art will appreciate that the preparations shown in the schemes can be modified or optimized using general knowledge of organic chemistry for the preparation of various compounds of the present invention.

[0684] Compounds of Formula 1-5 can be synthesized using methods as shown in Scheme 1. A palladium-catalyzed cross-coupling reaction of an appropriate aryl halide 1-1 with a boronic acid / ester 1-2 provides a compound of Formula 1-3. Transition metal (including but not limited to Pd and Cu)-catalyzed C-N bond formation reactions produce compounds of Formula 1-5.

[0685] Solution 1.

[0686]

[0687] Compounds of Formula 2-10 can also be synthesized using the method shown in Scheme 2. Nucleophilic substitution of compound 2-1 with O-ethyl carboisothiocyanate 2-2 provides intermediate compound 2-3. Cyclization of 2-3 using hydroxylamine hydrochloride / DIPEA provides the aminobicyclic core 2-4. Palladium-catalyzed cross-coupling of compound 2-4 with boronic acid / ester 2-5 provides compounds of Formula 2-6. Sandmeyer bromination of compound 2-6 generates aryl bromide 2-7, which can react 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.

[0688] Option 2.

[0689]

[0690] Compounds of Formula 3-10 can be synthesized using the method shown in Scheme 3. Nucleophilic substitution of compound 3-1 with O-ethyl carboisothiocyanate 3-2 provides intermediate compound 3-3. Cyclization of 3-3 using hydroxylamine hydrochloride / DIPEA provides the aminobicyclic core 3-4. Palladium-catalyzed cross-coupling of compound 3-4 with boronic acid / ester 3-5 provides compounds of Formula 3-6. Sandmeyer bromination of compound 3-6 generates aryl bromide 3-7, which can react 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.

[0691] Option 3.

[0692]

[0693] How to use

[0694] The compounds of the present disclosure can inhibit CDK2 and are therefore useful in treating diseases in which the underlying pathology is mediated entirely or in part by CDK2. Such diseases include cancer and other diseases with proliferative disorders. In some embodiments, the present disclosure provides treatment of an individual or patient in vivo using a compound of formula (I) or a salt thereof that inhibits the growth of a cancerous tumor. A compound of formula (I) or a compound of any formula as described herein or a compound as described in any one of the claims and as described herein or a salt thereof can be used to inhibit the growth of abnormal cancerous tumors with activated CDK2 kinase activity. These cancerous tumors include, but are not limited to, diseases characterized by amplification or overexpression of CCNE1 (e.g., cancer), such as ovarian cancer, uterine sarcoma, and breast cancer, and diseases characterized by p27 inactivation, such as breast cancer and melanoma. Therefore, in some embodiments of these methods, the patient has previously been determined to have amplification of the cyclin E1 (CCNE1) gene and / or a CCNE1 expression level that is higher than the control CCNE1 expression level in a biological sample obtained from a human subject. Alternatively, a compound of formula (I) or a compound of any formula as described herein or a compound as described in any one of the claims and as described herein, or a salt thereof, may 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 growth in vitro. The method comprises contacting tumor cells in vitro with a compound of formula (I) or a compound of any formula as described herein or a compound as described in any one of the claims and as described herein, or a salt thereof. In another embodiment, the present disclosure provides a method for inhibiting the growth of tumor cells having CCNE1 amplification and overexpression in an individual or patient. The method comprises administering a therapeutically effective amount of a compound of formula (I) or a compound of any formula as described herein or a compound as described in any one of the claims and as described herein, or a salt or stereoisomer thereof, to an individual or patient in need thereof.

[0695] In some embodiments, provided herein is a method of inhibiting CDK2, comprising contacting the CDK2 with a compound of formula (I), or any formula as described herein, or a compound as claimed in any one of the claims, or a salt thereof. In some embodiments, provided herein is a method of inhibiting CDK2 in a patient, comprising administering to the patient a compound of formula (I), or any formula as described herein, or a compound as claimed in any one of the claims, or a salt thereof.

[0696] 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 a compound of any formula as described herein, a compound as described in any one of the claims, or a salt thereof. In another embodiment, the cancer is characterized by amplification or overexpression of CCNE1. In some embodiments, the cancer is ovarian or breast cancer characterized by amplification or overexpression of CCNE1.

[0697] In some embodiments, provided herein is a method of treating a disease or condition associated with CDK2 in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (I) or a compound of any formula as described herein, a compound as described in any one of claims 1 and 2, or a salt thereof. In some embodiments, the disease or condition associated with CDK2 is associated with amplification of the cyclin E1 (CCNE1) gene and / or overexpression of CCNE1.

[0698] 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 mutant lung cancer (see Hu, S. et al., Mol Cancer Ther, 2015. 14(11):2576-85, and cancers with FBW7 mutations and CCNE1 overexpression (see Takada et al., Cancer Res, 2017. 77(18):4881-4893).

[0699] In some embodiments, the disease or disorder associated with CDK2 is squamous cell carcinoma of the lung, adenocarcinoma of the lung, pancreatic cancer, invasive breast cancer, uterine carcinosarcoma, ovarian serous cystadenocarcinoma, gastric adenocarcinoma, esophageal cancer, bladder urothelial carcinoma, mesothelioma, or sarcoma.

[0700] In some embodiments, the disease or disorder associated with CDK2 is lung adenocarcinoma, invasive breast carcinoma, uterine carcinosarcoma, ovarian serous cystadenocarcinoma, or gastric adenocarcinoma.

[0701] In some embodiments, the disease or disorder associated with CDK2 is adenocarcinoma, carcinoma, or cystadenocarcinoma.

[0702] 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.

[0703] In some embodiments, the disease or disorder associated with CDK2 is cancer.

[0704] 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.

[0705] In some embodiments, the breast cancer is chemotherapy or radiotherapy resistant breast cancer, endocrine 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.

[0706] Examples of cancers that can be treated using the compounds of the present disclosure include, but are not limited to, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, malignant melanoma of the skin or eye, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, fallopian tube cancer, carcinoma of the endometrium, and uterine carcinoma. The compounds of the present invention may be used to treat metastatic cancer.

[0707] In some embodiments, cancers that can be treated 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 adenocarcinoma), breast cancer, colon cancer, lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), squamous cell head and neck cancer, urothelial cancer (e.g., bladder cancer), and cancers with high microsatellite instability (MSI). 高 Additionally, the present disclosure encompasses refractory or recurrent malignancies whose growth can be inhibited using the compounds of the present disclosure.

[0708] In some embodiments, cancers that can be treated using the 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, kidney 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., lymphomas, leukemias such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), DLBCL, mantle cell lymphoma, non-Hodgkin lymphoma (including follicular lymphoma, including relapsed or refractory NHL and relapsed follicular lymphoma), Hodgkin lymphoma, or multiple myeloma), and combinations of these cancers.

[0709] In some embodiments, cancers that may be treated 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, islet cell carcinoma, oral cancer, mouth cancer, larynx cancer, laryngeal cancer, lip cancer, mesothelioma, neck cancer, nasal cancer, eye cancer, ocular melanoma, pelvic cancer, rectal cancer, renal cell carcinoma, salivary gland cancer, sinus cancer, spinal cord cancer, tongue cancer, mammary tubule cancer, urethral cancer, and urethral cancer.

[0710] In some embodiments, the compounds of the present disclosure are useful in treating sickle cell disease and sickle cell anemia.

[0711] In some embodiments, diseases and indications that may be treated using the compounds of the present disclosure include, but are not limited to, hematological cancers, sarcomas, lung cancers, gastrointestinal cancers, genitourinary tract cancers, liver cancers, bone cancers, cancers of the nervous system, gynecological cancers, and skin cancers.

[0712] Exemplary hematological cancers include lymphomas and leukemias, such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, non-Hodgkin lymphoma (including relapsed or refractory NHL and relapsed follicular lymphoma), Hodgkin lymphoma, myeloproliferative disorders (e.g., primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocythemia (ET)), myelodysplastic syndrome (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), and multiple myeloma (MM).

[0713] Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, rhabdosarcoma, fibroma, lipoma, hamartoma, and teratoma.

[0714] Exemplary lung cancers include non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), bronchogenic carcinoma, squamous cell adenocarcinoma, undifferentiated small cell adenocarcinoma, undifferentiated large cell adenocarcinoma, alveolar (bronchiolar) carcinoma, bronchial adenoma, enchondromatous hamartoma, and mesothelioma.

[0715] Exemplary gastrointestinal cancers include esophageal cancer (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (carcinoma, lymphoma, leiomyosarcoma), pancreatic cancer (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine cancer (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colorectal cancer (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), and colorectal cancer.

[0716] Exemplary genitourinary tract cancers include renal cancer (adenocarcinoma, Wilms' tumor [Nephroblastoma]), bladder and urethral cancer (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate cancer (adenocarcinoma, sarcoma), and testicular cancer (spermoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma).

[0717] Exemplary liver cancers include hepatoma (liver cell carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.

[0718] 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 chordoma, osteochondroma (osteocartilaginous exostosis), benign enchondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor.

[0719] Exemplary nervous system cancers include cancers of the skull (osteomas, hemangiomas, granulomas, xanthomas, osteitis deformans), meningeal cancers (meningiomas, meningiosarcomas, gliomatosis), brain cancers (astrocytomas, medulloblastomas, gliomas, ependymomas, blastomas (pinealomas), glioblastomas, glioblastomas multiforme, oligodendrogliomas, schwannomas, retinoblastomas, congenital tumors), and spinal cord cancers (neurofibromas, meningiomas, gliomas, sarcomas), as well as neuroblastoma and Lhermitte-Duclos disease.

[0720] Exemplary gynecological cancers include uterine cancer (endometrial cancer), cervical cancer (cervical carcinoma, preneoplastic cervical dysplasia), ovarian cancer (ovarian cancer (severe cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa cell and theca cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulvar cancer (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vaginal cancer (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma)), and fallopian tube cancer (carcinoma).

[0721] Exemplary skin cancers include melanoma, basal cell carcinoma, Merkel cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus dysplasia, lipoma, hemangioma, dermatofibroma, and keloid. In some embodiments, diseases and indications that can be treated 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, biliary tract cancer, esophageal cancer, and urothelial cancer.

[0722] It is believed that the compounds of formula (I) or any embodiment thereof may have a satisfactory pharmacological profile and promising biopharmaceutical properties, such as toxicological profile, metabolic and pharmacokinetic properties, solubility and permeability. It will be appreciated that the determination of appropriate biopharmaceutical properties is within the knowledge of those skilled in the art, for example, assaying cytotoxicity in cells or inhibition of certain targets or pathways to determine potential toxicity.

[0723] The terms "individual," "patient," or "subject," used interchangeably, refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, and most preferably humans.

[0724] The phrase "therapeutically effective amount" refers to that amount of an active compound or pharmaceutical agent that elicits in a tissue, system, animal, individual or human the biological or medical response that is being sought by the researcher, veterinarian, medical doctor or other clinician.

[0725] As used herein, the terms "treating" or "treatment" refer to one or more of the following: (1) inhibiting a disease; e.g., inhibiting a disease, disorder, or condition (i.e., arresting further development of the pathology and / or symptoms) in an individual who is experiencing or displaying the pathology or symptoms of the disease, disorder, or condition; and (2) ameliorating a disease; e.g., ameliorating a disease, disorder, or condition (i.e., reversing the pathology and / or symptoms) in an individual who is experiencing or displaying the pathology or symptoms of the disease, disorder, or condition, such as reducing the severity of the disease.

[0726] In some embodiments, the compounds of the invention are useful for preventing or reducing the risk of developing any of the diseases mentioned herein; for example, preventing or reducing the risk of developing a disease, disorder, or condition in an individual who may be susceptible to the disease, disorder, or condition but does not yet experience or display the pathology or symptoms of the disease.

[0727] Combination therapy

[0728] I. Cancer Therapy

[0729] The growth and survival of cancer cells can be affected by the dysfunction of multiple signaling pathways. Therefore, it is useful to combine different enzyme / protein / receptor inhibitors that exhibit different preferences for targets whose activity they modulate in order to treat such diseases. Targeting more than one signaling pathway (or more than one biomolecule involved in a given signaling pathway) can reduce the likelihood of drug resistance developing in a cell population and / or reduce the toxicity of treatment.

[0730] One or more additional pharmaceutical agents, such as, for example, chemotherapeutic agents, anti-inflammatory agents, steroids, immunosuppressants, immune-oncology agents, metabolic enzyme inhibitors, chemokine receptor inhibitors and phosphatase inhibitors, and targeted therapies, such as Bcr-Abl, Flt-3, EGFR, HER2, JAK, c-MET, VEGFR, PDGFR, c-Kit, IGF-1R, RAF, FAK and CDK4 / 6 kinase inhibitors, such as, for example, those described in WO 2006 / 056399, can be used in combination with the compounds of the present invention for the treatment of CDK2-related diseases, disorders or conditions. Other agents such as therapeutic antibodies can be used in combination with the compounds of the present invention for the treatment of CDK2-related diseases, disorders or conditions. The one or more additional pharmaceutical agents can be administered to the patient simultaneously or sequentially.

[0731] In some embodiments, a CDK2 inhibitor is administered or used in combination with a BCL2 inhibitor or a CDK4 / 6 inhibitor.

[0732] As disclosed herein, the compounds can be used in combination with one or more other enzyme / protein / receptor inhibitor therapies for the treatment of diseases such as cancer and other diseases or conditions described herein. Examples of diseases and indications that can be treated with combination therapy include those described herein. Examples of cancer include solid tumors and non-solid tumors, such as liquid tumors and blood cancers. Examples of infections include viral infections, bacterial infections, fungal infections, or parasitic infections. For example, the compounds of the present disclosure can be combined with one or more inhibitors of the following kinases for the treatment of cancer: Akt1, Akt2, Akt3, BCL2, CDK4 / 6, TGF-βR, PKA, PKG, PKC, CaM-kinases, phosphatase kinases, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IDH2, IGF-1R, IR-R, PDGFαR, PDGFβR, PI3K (α, β, γ, δ, and multiple or selective), CSF1R, KIT, FLK-1 1, 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. For example, the compounds of the present disclosure can be combined with one or more of the following inhibitors for the treatment of cancer or infection.Non-limiting examples of inhibitors that can be combined with the compounds of the present disclosure for the treatment of cancer and infection 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, orsimertinib, cetuximab, necituzumab, or panitumumab), VEGFR inhibitors or pathway blockers (e.g., bevacizumab, pazopanib, sunitinib, orthoclase), and EGFR inhibitors or pathway blockers (e.g., bevacizumab, pazopanib, orthoclase). tinib, 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, such as ruxolitinib or baricitinib; JAK1, such as itatinib (INCB39110), INCB052793, or INCB054707), IDO inhibitors (e.g., icadoline, NLG919, or BMS-986205, MK7162), LSD1 inhibitors ( For example, GSK2979552, INCB59872, and INCB60003), TDO inhibitors, PI3K-δ inhibitors (e.g., paxicillin (INCB50465) or INCB50797), PI3K-γ inhibitors such as PI3K-γ selective inhibitors, Pim inhibitors (e.g., INCB53914), CSF1R inhibitors, TAM receptor tyrosine kinases (Tyro-3, Axl, and Mer; for example, INCB081776), adenosine receptor antagonists (e.g., A2a / A2b receptor antagonists), HPK1 inhibitors, chemokine receptor inhibitors, agents (e.g., CCR2 or CCR5 inhibitors), SHP1 / 2 phosphatase inhibitors, histone deacetylase inhibitors (HDAC) such as HDAC8 inhibitors, angiogenesis inhibitors, interleukin receptor inhibitors, bromodomain and extra-terminal family member inhibitors (e.g., bromodomain inhibitors or BET inhibitors, such as INCB54329 and INCB57643), c-MET inhibitors (e.g., capmatinib), anti-CD19 antibodies (e.g., tafasitamab), ALK2 inhibitors (e.g., INCB00928); or a combination thereof.

[0733] 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 selective for more than JAK2.

[0734] 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 TM , such as anti-VEGF), panitumumab (such as anti-EGFR), cetuximab (such as anti-EGFR), rituxan (such as anti-CD20), and antibodies to c-MET.

[0735] One or more of the following agents may be used in combination with the compounds of the present disclosure and are provided as a non-limiting list: cytostatics, cisplatin, doxorubicin, taxotere, paclitaxel, etoposide, irinotecan, camptosar, topotecan, paclitaxel, docetaxel, epothilone, tamoxifen, 5-fluorouracil, methotrexate, temozolomide, cyclophosphamide, SCH 66336, R115777, L778,123, BMS214662, IRESSA TM (gefitinib), TARCEVA TM Erlotinib, EGFR antibody, intron, ara-C, doxorubicin, cytoxan, gemcitabine, uracil mustard, nitrogen mustard, ifosfamide, melphalan, chlorambucil, pipobroman, trotamide, triethylenethiophosphoramine, busulfan, carmustine, romustine, streptozotocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, oxaliplatin, folinic acid, eloxatin TM(oxaliplatin), pentostatin, vinblastine, vincristine, vindesine, bleomycin, actinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase, teniposide 17, alpha-ethinyl estradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, drostanolone propionate, testolactone, methylphenidate acetate Progesterone, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorpheniramine, hydroxyprogesterone, aminoglutethimide, estradiol mustard, medroxyprogesterone acetate, leuprolide, flutamide, toremifene, goserelin, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, vinpoxetine, anastrozole, letrazole, kecitabine, raloxifene, duloxifene, hexamidine, avastin, HERCEPTIN TM (trastuzumab), BEXXAR TM (tositumomab), VELCADE TM (bortezomib), ZEVALIN TM (ibritumomab tiuxetan), TRISENOX TM (arsenic trioxide), XELODA TM (capecitabine), vinorelbine, porfibrin sodium, ERBITUX TM (cetuximab), thiotepa, altretinoin, melphalan, trastuzumab, letrozole, fulvestrant, exemestane, ifosfamide, rituximab, C225 (cetuximab), Campath (alemtuzumab), clofarabine, cladribine, aphidicolon, rituxan, sunitinib, dasatinib, tezacitidine, Sml1, fludarabine, pentostatin, triapine, didox, trimidox, amidox, 3-AP, and MDL-101,731.

[0736] The compounds of the present disclosure can be further used in combination with other methods for treating cancer, such as by the following means: such as chemotherapy, radiotherapy, tumor-targeted therapy, adjuvant therapy, immunotherapy or surgery. The example of immunotherapy includes cytokine therapy (such as 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 virus therapy and immunomodulatory small molecule drugs (including thalidomide or JAK1 / 2 inhibitors), PI3Kδ inhibitors, etc. These compounds can be administered in combination with one or more anticancer drugs (such as chemotherapeutic agents). Examples of chemotherapeutic agents include any of the following: abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, hexamethylmelamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bevacizumab, bexarotene, baricitinib, bleomycin, bortezomib, intravenous busulfan, oral busulfan, captestosterone, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, actinomycin D, dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin, denileukin conjugates, diftitox), dexrazoxane, docetaxel, doxorubicin, drostanolone propionate, eculizumab, epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib mesylate, interferon alpha 2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, folinic acid, leuprolide acetate, levamisole, lomustine, meclofenac, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, Mitomycin C, mitotane, mitoxantrone, nandrolone phenylpropionate, nelarabine, novofluvimab, oxaliplatin, paclitaxel, pamidronate, panitumumab, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin, procarbazine, quinacrine, rasburicase, rituximab, ruxolitinib, sorafenib, streptozotocin, sunitinib, sunitinib malate, tamoxifen, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, vorinostat, and zoledronic acid.

[0737] Additional examples of chemotherapeutic agents include proteasome inhibitors (eg, bortezomib), thalidomide, lenalidomide; and DNA damaging agents such as melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide, carmustine, and the like.

[0738] Exemplary steroids include corticosteroids, such as dexamethasone or prednisone.

[0739] Exemplary Bcr-Abl inhibitors include imatinib mesylate (GLEEVAC TM ), nilotinib, dasatinib, bosutinib and ponatinib and pharmaceutically acceptable salts thereof. Other exemplary suitable Bcr-Abl inhibitors include compounds of the genera and classes disclosed in U.S. Patent No. 5,521,184, WO 04 / 005281 and US Serial No. 60 / 578,491 and pharmaceutically acceptable salts thereof.

[0740] Exemplary suitable Flt-3 inhibitors include midostaurin, lestaurinib, linifanib, sunitinib, sunitinib malate, sorafenib, quizartinib, crenolanib, pacritinib, tandutinib, PLX3397 and ASP2215 and pharmaceutically acceptable salts thereof. Other exemplary suitable Flt-3 inhibitors include compounds disclosed in WO 03 / 037347, WO 03 / 099771 and WO 04 / 046120 and pharmaceutically acceptable salts thereof.

[0741] Exemplary suitable RAF inhibitors include dabrafenib, sorafenib and vemurafenib and pharmaceutically acceptable salts thereof.Other exemplary suitable RAF inhibitors include compounds disclosed in WO 00 / 09495 and WO 05 / 028444 and pharmaceutically acceptable salts thereof.

[0742] Exemplary suitable FAK inhibitors include VS-4718, VS-5095, VS-6062, VS-6063, BI853520 and GSK2256098 and pharmaceutically acceptable salts thereof. Other exemplary suitable FAK inhibitors include compounds disclosed in WO 04 / 080980, WO 04 / 056786, WO 03 / 024967, WO 01 / 064655, WO 00 / 053595 and WO 01 / 014402 and pharmaceutically acceptable salts thereof.

[0743] Exemplary suitable CDK4 / 6 inhibitors include palbociclib, ribociclib, trilaciclib, lerociclib and abecilib and pharmaceutically acceptable salts thereof. Other exemplary suitable CDK4 / 6 inhibitors include compounds disclosed in WO 09 / 085185, WO 12 / 129344, WO 11 / 101409, WO 03 / 062236, WO 10 / 075074 and WO12 / 061156 and pharmaceutically acceptable salts thereof.

[0744] In some embodiments, the compounds of the present disclosure can be used in combination with one or more other kinase inhibitors, including imatinib, particularly for treating patients who are resistant to imatinib or other kinase inhibitors.

[0745] In some embodiments, the compounds of the present disclosure can be used in combination with chemotherapeutic agents in cancer treatment, and can improve the therapeutic response as compared to the response to a single chemotherapeutic agent without exacerbating its toxic effects. In some embodiments, the compounds of the present disclosure can be used in combination with chemotherapeutic agents provided herein. For example, additional pharmaceutical agents for the treatment of multiple myeloma may include but are not limited to melphalan, melphalan plus prednisone [MP], doxorubicin, dexamethasone, and velcro (bortezomib). Other additional agents for 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 immunomodulator. 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 immunomodulator is lenalidomide (LEN) or pomalidomide (POM). An additive or synergistic effect is a desired outcome of combining a CDK2 inhibitor of the present disclosure with another agent.

[0746] These agents may be combined with the compounds of this invention in a single or sequential dosage form, or these agents may be administered simultaneously or sequentially in separate dosage forms.

[0747] The compounds of the present disclosure may be used in combination with one or more other inhibitors or one or more therapies for treating infections.Examples of infections include viral infections, bacterial infections, fungal infections, or parasitic infections.

[0748] 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 as opposed to continuously.

[0749] The compound of formula (I) or any of the formulas described herein, the compound as described in any one of the claims and as described herein, or a salt thereof can be combined with another immunogenic agent 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 melanoma antigen peptides, such as gp100, MAGE antigens, Trp-2, MARTI and / or tyrosinase peptides or tumor cells transfected to express the cytokine GM-CSF.

[0750] Compounds of formula (I) or any of the formulas described herein, compounds as described in any of the claims and as described herein, or salts thereof can be used in combination with vaccination regimens 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 tumor tissue itself. In some embodiments, compounds of formula (I) or any of the formulas described herein, compounds as described in any of the claims and as described herein, or salts thereof can be combined with dendritic cell immunization to activate a potent anti-tumor response.

[0751] The compounds of the present disclosure can be used in combination with bispecific macrocyclic peptides that target Fcα or Fcγ receptor expressing effector cells to tumor cells. The compounds of the present disclosure can also be combined with macrocyclic peptides that activate the host immune response.

[0752] In some other embodiments, the compounds of the present disclosure in combination with other therapeutic agents may be administered to a patient before, during, and / or after a bone marrow transplant or stem cell transplant.The compounds of the present disclosure may be used in combination with a bone marrow transplant for the treatment of a variety of tumors of hematopoietic origin.

[0753] Compounds of formula (I) or any of the formulas described herein, compounds as described in any of the claims and as described herein, or salts thereof can be used in combination with vaccines to stimulate immune responses against pathogens, toxins, and autoantigens. Examples of pathogens for which this treatment method may be particularly useful include pathogens for which there are currently no effective vaccines or for which conventional vaccines are incompletely effective. These pathogens include, but are not limited to, HIV, hepatitis viruses (types A, B, and C), influenza viruses, herpes viruses, Giardia lamblia, malaria, Leishmania, Staphylococcus aureus, and Pseudomonas aeruginosa.

[0754] Viruses that cause infections treatable by the methods of the present disclosure include, but are not limited to, human papillomavirus, influenza virus, hepatitis A, B, C, or D virus, adenovirus, poxvirus, herpes simplex virus, human cytomegalovirus, severe acute respiratory syndrome virus, Ebola virus, measles virus, herpes viruses (e.g., VZV, HSV-1, HAV-6, HSV-II, and CMV, Estonia-Barr virus), flavivirus, enterocytopathic human orphan virus (echovirus), rhinovirus, coxsackievirus, coronavirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, pox virus, HTLV virus, dengue virus, papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus, and arboviral encephalitis virus.

[0755] Pathogenic bacteria that cause infections treatable by the methods of the present disclosure include, but are not limited to, Chlamydia, Rickettsia, Mycobacterium, Staphylococcus, Streptococcus, Pneumococcus, Meningococcus and Conococci, Klebsiella, Proteus, Serratia, Pseudomonas, Legionella, Diphtheria, Salmonella, Bacillus, Cholera, Tetanus, Botulinum, Anthrax, Plasmodium, Leptospirosis, and Lyme disease.

[0756] Pathogenic fungi that cause infections that can be treated by the methods of the present disclosure include, but are not limited to, Candida species (Candida albicans, Candida krusei, Candida glabrata, Candida tropicalis, etc.), Cryptococcus neoformans, Aspergillus species (Aspergillus fumigates, Aspergillus niger, etc.), Mucorales species (Mucor, Absidia, Rhizopus), Sporothrix schenckii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis, and Histoplasma capsulatum.

[0757] Pathogenic parasites that cause infections treatable by the methods of the present disclosure include, but are not limited to, Entamoeba histolytica, E. coli, Proteus, Acanthodea, Giardia lamblia, Cryptosporidium, Pneumocystis, Plasmodium vivax, Pirozoa molitor, Trypanosoma brucei, Trypanosoma cruzi, Kala-azar, Toxoplasma gondii, and Ancylostoma brasiliensis.

[0758] When more than one pharmaceutical agent is administered to a patient, they may be administered simultaneously, separately, sequentially, or in combination (eg, for more than two agents).

[0759] 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 literature. For example, the administration of various chemotherapeutic agents is described in "Physicians' Desk Reference" (PDR, e.g., 1996 edition, Medical Economics Company, Montvale, NJ), the disclosure of which is incorporated herein by reference as if set forth in full.

[0760] II. Immune Checkpoint Therapy

[0761] 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 infection.Exemplary immune checkpoint inhibitors include inhibitors for immune checkpoint molecules such as CBL-B, CD20, CD28, CD40, CD70, CD122, CD96, CD73, CD47, CDK2, GITR, CSF1R, JAK, PI3Kδ, PI3Kγ, TAM, arginase, HPK1, CD137 (also referred to 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, immune checkpoint molecules are selected from the following stimulating checkpoint molecules: CD27, CD28, CD40, ICOS, OX40, GITR and CD137. In some embodiments, the immune checkpoint molecule is an inhibitory checkpoint molecule selected from the following: A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, TIGIT and VISTA. In some embodiments, the compounds provided herein can be used in combination with one or more agents selected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors and TGFRβ inhibitors.

[0762] In some embodiments, the compounds provided herein can be used in combination with agonists of one or more immune checkpoint molecules, such as OX40, CD27, GITR, and CD137 (also known as 4-1BB).

[0763] 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.

[0764] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of PD-1 and PD-L1, such as an anti-PD-1 or anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-1 or anti-PD-L1 antibody is nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, cemiplimab, atezolizumab, avelumab, tislelizumab, spartalizumab (PDR001), cetrelimab (JNJ-63723283), toripalimab (JS001), camrelizumab (SHR-1210), sintilimab (IBI308), AB122(GLS-010), AMP-224, AMP-514 / MEDI-0680, BMS936559, JTX-4014, BGB-108, SHR-1210, MEDI4736, FAZ053, BCD-100, KN035, CS1001, BAT1306, LZ M009, AK105, HLX10, SHR-1316, CBT-502(TQB2450), A167(KL-A167), STI-A101(ZKAB001), CK-301, BGB-A333, MSB-2311, HLX20, TSR-042, or LY3300054. In some embodiments, the inhibitor of PD-1 or PD-L1 is an inhibitor disclosed in U.S. Patent Nos. 7,488,802, 7,943,743, 8,008,449, 8,168,757, 8,217,149, WO 03042402, WO 2008156712, WO 2010089411, WO2010036959, WO 2011066342, WO 2011159877, WO 2011082400, or WO 2011161699, each of which is herein incorporated by reference in its entirety.

[0765] In some embodiments, the antibody is an anti-PD-1 antibody, such as an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 antibody is nivolumab, pembrolizumab, cemipril limab, spartalizumab, camrelizumab, cerizumab, 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, cemipril limab, spartalizumab, camrelizumab, cerizumab, 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 cemiprizumab. 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 cerizumab. 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 anticancer agents include antibody therapeutics such as 4-1BB (e.g., urelumab, utomilumab). In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of PD-L1, such as 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.

[0766] In some embodiments, the inhibitor of immune checkpoint molecule is a small molecule or a pharmaceutically acceptable salt thereof that is bound to PD-L1. In some embodiments, the inhibitor of immune checkpoint molecule is a small molecule or a pharmaceutically acceptable salt thereof that is bound to PD-L1 and internalized. In some embodiments, the inhibitor of immune checkpoint molecule is a compound or a pharmaceutically acceptable salt thereof selected from US2018 / 0179201, US2018 / 0179197, US2018 / 0179179, US 2018 / 0179202, US2018 / 0177784, US2018 / 0177870, US Serial No. 16 / 369,654 (filed on March 29, 2019) and US Serial No. 62 / 688,164, each of which is incorporated herein by reference in its entirety.

[0767] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of KIR, TIGIT, LAIR1, CD160, 2B4, and TGFRβ.

[0768] In some embodiments, the inhibitor is MCLA-145.

[0769] 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, tesimumab, AGEN1884, or CP-675,206.

[0770] 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).

[0771] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CD73. In some embodiments, the inhibitor of CD73 is oleclumab.

[0772] 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.

[0773] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of VISTA. In some embodiments, the inhibitor of VISTA is JNJ-61610588 or CA-170.

[0774] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of B7-H3. In some embodiments, the inhibitor of B7-H3 is enoblituzumab, MGD009, or 8H9.

[0775] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of KIR. In some embodiments, the inhibitor of KIR is lirilumab or IPH4102.

[0776] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of A2aR. In some embodiments, the inhibitor of A2aR is CPI-444.

[0777] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of TGF-β. In some embodiments, the inhibitor of TGF-β is trabedersen, galusertinib, or M7824.

[0778] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PI3K-γ. In some embodiments, the inhibitor of PI3K-γ is IPI-549.

[0779] 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.

[0780] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CD73. In some embodiments, the inhibitor of CD73 is MEDI9447.

[0781] 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.

[0782] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of TIM3, such as an anti-TIM3 antibody. In some embodiments, the anti-TIM3 antibody is INCAGN2390, MBG453, or TSR-022.

[0783] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CD20, such as an anti-CD20 antibody. In some embodiments, the anti-CD20 antibody is obinutuzumab or rituximab.

[0784] 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).

[0785] In some embodiments, the agonist of CD137 is urelumab. In some embodiments, the agonist of CD137 is umetropin.

[0786] 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.

[0787] In some embodiments, the agonist of an immune checkpoint molecule is an agonist of CD40. In some embodiments, the agonist of CD40 is CP-870893, ADC-1013, CDX-1140, SEA-CD40, RO7009789, JNJ-64457107, APX-005M, or Chi Lob 7 / 4.

[0788] In some embodiments, the agonist of an immune checkpoint molecule is an agonist of ICOS. In some embodiments, the agonist of ICOS is GSK-3359609, JTX-2011, or MEDI-570.

[0789] In some embodiments, the agonist of an immune checkpoint molecule is an agonist of CD28. In some embodiments, the agonist of CD28 is theralizumab.

[0790] In some embodiments, the agonist of an immune checkpoint molecule is an agonist of CD27. In some embodiments, the agonist of CD27 is varlilumab.

[0791] In some embodiments, the agonist of an immune checkpoint molecule is an agonist of TLR7 / 8. In some embodiments, the agonist of TLR7 / 8 is MEDI9197.

[0792] The compounds of the present disclosure can be used in combination with bispecific antibodies. In some embodiments, one domain of the bispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3, CD137, ICOS, CD3, or 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.

[0793] In some embodiments, the compounds of the present disclosure may 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 icardostat, NLG919, BMS-986205, PF-06840003, IOM2983, RG-70099, and LY338196.

[0794] As provided throughout, additional compounds, inhibitors, agents, etc. can be combined with the compounds of the present invention in a single or sequential dosage form, or they can be administered simultaneously or sequentially as separate dosage forms.

[0795] Drug preparations and dosage forms

[0796] When used as a pharmaceutical agent, the compounds of the present disclosure can be administered in the form of a pharmaceutical composition. Such compositions can be prepared in a manner well known in the pharmaceutical art and can be administered by a variety of routes, depending on whether local or systemic treatment is required and the area to be treated. Administration can be topical (including transdermal, epidermal, ocular and mucous membranes, including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including use of a nebulizer; intratracheal or intranasal), oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or injection or infusion; or intracranial, such as intrathecal or intraventricular administration. Parenteral administration can be in the form of a single bolus dose, or can be achieved, for example, by a continuous infusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners, etc. may be necessary or desirable.

[0797] The present disclosure also includes pharmaceutical compositions, which contain a compound of the present disclosure or a pharmaceutically acceptable salt thereof as an active ingredient in combination with one or more pharmaceutically acceptable carriers (excipients). In some embodiments, the composition is suitable for topical administration. When preparing the composition of the present disclosure, the active ingredient is usually mixed with an excipient, diluted with an excipient or enclosed in a carrier in the form of, for example, a capsule, a sachet, paper or other container. When an excipient serves as a diluent, it can be a solid, semi-solid or liquid material, which is used as a vehicle, carrier or medium for the active ingredient. Therefore, the composition can be in the following forms: tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments containing, for example, up to 10% by weight of active compounds, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.

[0798] When preparing a formulation, the active compound may be ground to provide an appropriate particle size before combining with other ingredients. If the active compound is substantially insoluble, it may be ground to a particle size of less than 200 mesh. If the active compound is substantially water-soluble, the particle size may be adjusted by grinding to provide a generally uniform distribution in the formulation, for example, about 40 mesh.

[0799] The compounds of the present disclosure can be ground using known milling procedures (such as wet milling) to obtain particle sizes suitable for tablet formation and other formulation types. Finely dispersed (nanoparticulate) formulations of the compounds of the present disclosure can be prepared by processes known in the art, for example, see International Application No. WO 2002 / 000196.

[0800] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone, cellulose, water, syrup and methylcellulose. These formulations may additionally include: lubricants such as talc, magnesium stearate and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives such as methyl hydroxybenzoate and propyl hydroxybenzoate; sweeteners; and flavorings. The compositions of the present disclosure can be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to a patient using procedures known in the art.

[0801] These compositions can be formulated in unit dosage form, each dose containing from about 5 to about 1000 mg (1 g) or more, such as from about 100 to about 500 mg of active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.

[0802] In some embodiments, the compositions of the present disclosure contain about 5 to about 50 mg of active ingredient. One skilled 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 active ingredient.

[0803] In some embodiments, the compositions of the present disclosure contain about 50 to about 500 mg of active ingredient. Those skilled 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, about 450 to about 500 mg of active ingredient.

[0804] In some embodiments, the compositions of the present disclosure contain about 500 to about 1000 mg of active ingredient. Those skilled in the art will appreciate that this embodies 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 active ingredient.

[0805] Similar dosages of the compounds described herein can be used in the methods and uses of the present disclosure.

[0806] The active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. However, it will be understood that the actual amount of compound administered will generally be determined by a physician based on 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, and the like.

[0807] To prepare 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 compound of the invention. 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 invention.

[0808] The tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form that provides an advantage of prolonged action. For example, a tablet or pill can comprise an inner dose and an outer dose component, the latter being in the form of an exosome that coats the former. The two components can be separated by an enteric layer that resists disintegration in the stomach and allows the inner component to enter the duodenum intact or to delay release. Various materials can be used for such enteric layers or coatings, including mixtures of various polymeric acids and polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0809] Liquid forms in which the compounds and compositions of the present invention may be incorporated for oral or injection 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.

[0810] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the compositions are administered via the oral or nasal respiratory route to achieve local or systemic effect. The compositions can be aerosolized using an inert gas. Nebulized solutions can be breathed directly from the aerosolizing device, or the aerosolizing device can be connected to a mask, curtain, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0811] Topical preparations can contain one or more conventional carriers. In some embodiments, ointments can contain water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white petrolatum. The carrier composition of creams can be based on a combination of water and glycerol and one or more other components (for example, glyceryl monostearate, PEG-glyceryl monostearate and hexadecearyl alcohol). Isopropyl alcohol and water can be used, when appropriate, in combination with other components (such as glycerol, hydroxyethyl cellulose, etc.) to prepare a gel. In some embodiments, topical preparations contain at least about 0.1 % by weight, at least about 0.25 % by weight, at least about 0.5 % by weight, at least about 1 % by weight, at least about 2 % by weight or at least about 5 % by weight of the compound of the present disclosure. Topical preparations can be suitably packaged in, for example, 100 g tubes, which are optionally combined with instructions for treating selected indications (for example, psoriasis or other skin disorders).

[0812] The amount of compound or composition administered to a patient will vary depending on the substance being administered, the purpose of administration (such as prevention or therapy), the patient's condition, the mode of administration, and similar factors. In therapeutic applications, the composition can be administered to a patient already suffering from the 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 based on factors such as the severity of the disease, the patient's age, weight, and general condition, and similar factors.

[0813] The composition administered to the patient may be in the form of a pharmaceutical composition as described above. These compositions may be sterilized by conventional sterilization techniques or may be sterile filtered. Aqueous solutions may be packaged for use as is, or lyophilized, the lyophilized formulation being combined with a sterile aqueous vehicle prior to administration. The pH of the compound formulation will typically be between 3 and 11, more preferably 5 to 9, and most preferably 7 to 8. It will be understood that the use of some of the aforementioned excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.

[0814] The therapeutic dose of the disclosed compounds may vary according to, for example, the specific use to be achieved in the treatment, the mode of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The ratio or concentration of the disclosed compounds in the pharmaceutical composition may vary according to many factors, including dosage, chemical characteristics (e.g., hydrophobicity), and route of administration. For example, the disclosed compounds may be provided in a physiological buffered aqueous solution containing about 0.1 w / v% to about 10 w / v% compound for parenteral administration. Some typical dosage ranges are about 1 μg / kg to about 1 g / kg body weight per day. In some embodiments, the dosage range is about 0.01 mg / kg to about 100 mg / kg body weight per day. The dosage may depend on variables such as the type and degree of progression of the disease or condition, the overall health of the particular patient, the relative biological efficacy of the selected compound, the formulation of the excipient, and its route of administration. The effective dose can be extrapolated from a dose-response curve derived from an in vitro or animal model test system.

[0815] The compositions of the present disclosure may further include one or more additional pharmaceutical agents, such as chemotherapeutic agents, steroids, anti-inflammatory compounds, or immunosuppressants, examples of which are listed herein.

[0816] Labeled compounds and assays

[0817] Another aspect of the present disclosure relates to labeled compounds of the present disclosure (radioactive labels, fluorescent labels, etc.), which will be useful not only in imaging techniques, but also in in vitro and in vivo assays for localizing and quantifying CDK2 in tissue samples (including humans), and for identifying CDK2 activators by inhibiting the binding of labeled compounds. Substitution of one or more atoms of the compounds of the present disclosure can also be used to generate differentiated ADMEs (absorption, distribution, metabolism, and excretion). Thus, the present disclosure includes CDK2 assays containing such labeled or substituted compounds.

[0818] The present disclosure further includes isotopically labeled compounds of the present disclosure. An "isotopically" or "radiolabeled" compound is a compound of the present disclosure in which one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature (i.e., naturally occurring). Suitable radionuclides that may be incorporated into the compounds of the present disclosure include, but are not limited to 2 H (also written as D, i.e. deuterium), 3 H (also written as T, i.e. 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 131 I. For example, one or more hydrogen atoms in the compounds of the present disclosure may be replaced by deuterium atoms (e.g., C 1-6 One or more hydrogen atoms of an alkyl group may optionally be replaced with a deuterium atom, such as -CD3 replacing -CH3. In some embodiments, the alkyl groups of the disclosed formulae (e.g., Formula (I)) may be perdeuterated.

[0819] One or more constituent atoms of the compounds provided herein may be replaced or substituted with isotopes of these atoms in natural or unnatural abundance. In some embodiments, the compounds include at least one deuterium atom. For example, one or more hydrogen atoms in the compounds presented herein may be replaced with deuterium (e.g., C 1-6One or more hydrogen atoms of an alkyl group may be replaced with a deuterium atom, such as -CD3 replacing -CH3. In some embodiments, the compound includes two or more deuterium atoms. In some embodiments, the compound includes 1-2, 1-3, 1-4, 1-5, or 1-6 deuterium atoms. In some embodiments, all hydrogen atoms in the compound may be replaced or substituted with deuterium atoms.

[0820] In some embodiments, as described herein, the alkyl, alkenyl, alkynyl, aryl, phenyl, cycloalkyl, heterocycloalkyl, or heteroaryl substituent or -C 1-4 1, 2, 3, 4, 5, 6, 7 or 8 hydrogen atoms of the carbon atoms of the alkyl-, alkylene, alkenylene and alkynylene linking groups are optionally replaced by deuterium atoms.

[0821] 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 are useful in various studies such as NMR spectroscopy, metabolic experiments and / or assays.

[0822] Substitution with heavier isotopes, such as deuterium, may provide certain therapeutic advantages due to greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and may therefore be preferred in certain circumstances. (See, e.g., 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 may result in one or more therapeutic advantages.

[0823] The radionuclide incorporated into the radiolabeled compounds of the invention will depend on the specific application of the radiolabeled compound. For example, for in vitro CDK2 labeling and competition assays, incorporation of3 H. 14 C. 82 Br, 125 I. 131 I or 35 Compounds of S may be useful. For radioactive imaging applications, 11 C. 18 F. 125 I. 123 I. 124 I. 131 I. 75 Br, 76 Br or 77 Br may be useful.

[0824] It is understood that a "radiolabeled" or "labeled compound" is a compound that incorporates at least one radionuclide. In some embodiments, the radionuclide is selected from the group consisting of: 3 H. 14 C. 125 I. 35 S and 82 Br.

[0825] The present disclosure may 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 those skilled in the art will readily identify methods applicable to the compounds of the present disclosure.

[0826] The labeled compounds disclosed herein can be used to identify / evaluate compounds in screening assays. For example, a newly synthesized or identified compound (i.e., a test compound) that is labeled can be evaluated for its ability to bind to and activate CDK2 by monitoring its concentration changes via tracking the label when it is in contact with CDK2. For example, the ability of the test compound (labeled) to reduce binding to another compound (i.e., a standard compound) that is known to inhibit CDK2 can be evaluated. Accordingly, the ability of the test compound to compete with the standard compound for binding to CDK2 is directly related to its binding affinity. In contrast, in some other screening assays, the standard compound is labeled and the test compound is not labeled. Therefore, the concentration of the labeled standard compound is monitored to evaluate the competition between the standard compound and the test compound, and thereby determine the relative binding affinity of the test compound.

[0827] Reagent test kit

[0828] The present disclosure also includes pharmaceutical kits that can be used, for example, to treat or prevent CDK2-related diseases or conditions (such as, for example, cancer, inflammatory diseases, cardiovascular diseases, or neurodegenerative diseases), comprising one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present disclosure. Such kits may further include, if necessary, one or more of the various conventional pharmaceutical kit components, such as a container with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Instructions in the form of inserts or labels may also be included in the kit, indicating the amounts of the components to be administered, guidelines for administration, and / or guidelines for mixing the components.

[0829] Biomarkers and pharmacodynamic markers

[0830] 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) to identify those human subjects suffering from a disease or condition associated with CDK2, suspected of having the disease or condition, or at risk of developing the disease or condition, to whom administration of a CDK2 inhibitor (as used herein, "CDK2 inhibitor" refers to a compound of the present disclosure or a pharmaceutically acceptable salt thereof) may be effective. The present disclosure also provides pharmacodynamic markers (e.g., phosphorylation level) to identify those human subjects suffering from a disease or condition associated with CDK2, suspected of having the disease or condition, or at risk of developing the disease or condition, who respond to a CDK2 inhibitor. The use of CCNE1, p16, and Rb S780 is further described in WO 2020 / 168178 (and U.S. application No. 16 / 791,561), the drawings and disclosures of which are incorporated herein by reference in their entirety.

[0831] The methods are based, at least in part, on the discovery that the functional status of cyclin-dependent kinase inhibitor 2A ("CDKN2A," also known as "p16") is a biomarker for predicting sensitivity to CDK2-targeted therapies in G1 / S-specific cyclin-E1- ("CCNE1-") amplified cells and is useful for patient stratification. Additionally, the invention is based, at least in part, on the discovery that in CCNE1-amplified cell lines, the level of phosphorylation of human retinoblastoma-related protein ("Rb") at the serine corresponding to amino acid position 780 of SEQ ID NO: 3 is a pharmacodynamic marker of CDK2 activity and is useful for measuring CDK2 enzymatic activity in cell-based assays or in preclinical and clinical applications, such as, for example, monitoring the progress of or response to treatment with a CDK2 inhibitor.

[0832] CCNE1 and p16

[0833] CCNE1 and p16 have been identified in the Examples as genes that are useful in combination for predicting responsiveness (eg, disease improvement, as demonstrated by disease remission / regression) to CDK2 inhibitors in subjects with a disease or disorder associated with CDK2.

[0834] p16 (also known as cyclin-dependent kinase inhibitor 2A, cyclin-dependent kinase 4 inhibitor A, multiple tumor suppressor 1 and p16-INK4a) acts as a negative regulator of normal cell proliferation by interacting with CDK4 and CDK6. p16 is encoded by the cyclin-dependent kinase inhibitor 2A ("CDKN2A") gene (GenBank accession number NM_000077). The cell-generated position of the CDKN2A gene is 9p21.3, which is the position 21.3 of the short (p) arm of chromosome 9. The molecular position of the CDKN2A gene is base pairs 21,967,752 to 21,995,043 on chromosome 9 (Homo sapiens annotation version 109, GRCh38.p12). It is believed that genetic and epigenetic abnormalities of the gene encoding p16 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 described below in Table A. The amino acid sequence of human p16 is provided below (GenBank Accession No. NP_000068 / UniProtKB Accession No. P42771):

[0835]

[0836] CCNE1 is a cell cycle factor necessary for controlling the cell cycle at the G1 / S transition (Ohtsubo et al., 1995, Mol. Cell. Biol. 15: 2612-2624). CCNE1 acts as a regulatory subunit of CDK2, interacting with CDK2 to form a serine / threonine kinase holoenzyme complex. The CCNE1 subunit of this holoenzyme complex provides the substrate specificity of the complex (Honda et al., 2005, EMBO 24: 452-463). CCNE1 is encoded by the cyclin E1 ("CCNE1") gene (GenBank Accession No. NM_001238). The amino acid sequence of human CCNE1 is provided below (GenBank Accession No. NP_001229 / UniProtKB Accession No. P24864):

[0837]

[0838] These examples demonstrate that CDK2 knockout inhibits proliferation of CCNE1-amplified cell lines, but not CCNE1-non-amplified cell lines. Conversely, these examples show that CDK4 / 6 inhibition inhibits proliferation of CCNE1-non-amplified cell lines, but not CCNE1-amplified cell lines. These examples further demonstrate that the presence of a normal (e.g., non-mutated or non-deleted) p16 gene is required for the inhibition of cell proliferation observed in CCNE1-amplified cells treated with CDK2 inhibitors. Thus, CCNE1 and p16 together are a combination biomarker: cells that respond to treatment with a CDK2 inhibitor exhibit amplification of the CCNE1 gene and / or CCNE1 expression levels above a control CCNE1 expression level, and have a nucleotide sequence (e.g., 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 do not have amplification of the CCNE1 gene and / or CCNE1 expression levels above a control CCNE1 expression level, and tend to have a mutated or deleted gene encoding a p16 protein and / or lack expression of a p16 protein.

[0839] Thus, the present disclosure provides a method for treating a human subject having, suspected of having, or at risk of developing a disease or condition associated with CDK2, the method 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 p16 protein, and (ii) (a) have an amplification of the CCNE1 gene and / or (b) have a CCNE1 expression level that is higher than a control CCNE1 expression level in a biological sample obtained from the human subject. In certain embodiments, the prediction methods described herein predict that the subject will respond to treatment with a CDK2 inhibitor with an accuracy of at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or 100%. For example, in some embodiments, if a prediction method described herein is applied to 10 subjects who have, are suspected of having, or are at risk of developing a disease or condition associated with CDK2, and 8 of those 10 subjects are predicted to respond to treatment with a CDK2 inhibitor based on the prediction method described herein, and 7 of those 8 subjects actually respond to treatment with a CDK2 inhibitor, then the prediction method has an accuracy of 87.5% (divide 7 by 8). A subject is considered to respond to a CDK2 inhibitor if the subject shows any improvement in the disease state, as demonstrated by, for example, a decrease or alleviation of symptoms, disease remission / regression, etc.

[0840] In some embodiments, the subject has a disease or condition associated with CDK2. In some embodiments, the human subject has previously been determined to have: (i) (a) a nucleotide sequence encoding a p16 protein comprising the amino acid sequence of SEQ ID NO: 1, and / or (b) a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions, and (ii) 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 specific embodiments, the CDKN2A gene encodes a protein comprising the amino acid sequence of SEQ ID NO: 1.

[0841] In specific embodiments, the one or more inactivating nucleic acid substitutions and / or deletions in the CDKN2A gene are described in Table A. In specific embodiments, the one or more inactivating nucleic acid substitutions and / or deletions in the CDKN2A gene are 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.

[0842] Table A. CDKN2A gene substitutions, deletions, and modifications

[0843]

[0844]

[0845]

[0846] The present disclosure also provides a method for treating a subject having a disease or condition associated with CDK2, suspected of having the disease or condition, or at risk of developing the disease or condition, the method comprising: (i) identifying in a biological sample obtained from a human subject: (a) a nucleotide sequence encoding a p16 protein comprising the amino acid sequence SEQ ID NO: 1, (b) a CDKN2A gene lacking one or more inactivating nucleic acid substitutions, and / or (c) the presence of a p16 protein; (ii) identifying in a biological sample obtained from a human subject: (a) amplification of the CCNE1 gene and / or (b) a CCNE1 expression level greater than a control CCNE1 expression level; and (iii) administering a CDK2 inhibitor to the human subject. In some embodiments, the subject has a disease or condition associated with CDK2. In some embodiments, the subject is suspected of having a disease or condition associated with CDK2 or is at risk of developing the disease or condition. In some embodiments, the method comprises: (i) identifying in a biological sample obtained from a human subject: (a) a nucleotide sequence encoding a p16 protein comprising the amino acid sequence of SEQ ID NO: 1, (b) a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions, and / or (c) the presence of a p16 protein; (ii) identifying in a biological sample obtained from a human subject: (a) amplification of a CCNE1 gene; and (iii) administering a CDK2 inhibitor to the human subject.

[0847] The present disclosure also provides a method for predicting a response to a CDK2 inhibitor in a subject having, suspected of having, or at risk of developing a disease or condition associated with CDK2, the method comprising: (i) determining in a biological sample obtained from the human subject: (a) the nucleotide sequence of a 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 a p16 protein; and (ii) determining in a biological sample obtained from the human subject: (a) the copy number of a CCNE1 gene and / or (b) the expression level of CCNE1, wherein (1) 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) a CCNE1 expression level above a control CCNE1 expression level predicts that the human subject will respond to a CDK2 inhibitor. In some embodiments, the subject has a disease or condition associated with CDK2. In some embodiments, the subject is suspected of having a disease or condition associated with CDK2 or is at risk of developing the disease or condition. In some embodiments, the method comprises: (i) determining in a biological sample obtained from a human subject: (a) the nucleotide sequence of a CDKN2A gene, and / or (b) the presence of a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions; and (ii) determining in a biological sample obtained from a human subject: (a) the copy number of a CCNE1 gene, wherein (1) (a) the presence of a CDKN2A gene encoding a p16 protein comprising the amino acid sequence SEQ ID NO: 1 and / or (b) the presence of a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions, and (2) (a) amplification of the CCNE1 gene predicts that the human subject will respond to a CDK2 inhibitor.

[0848] In specific embodiments, (i) the presence 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 p16 protein is determined prior to administration of 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 specific embodiments, (ii) the copy number of the (a) CCNE1 gene and / or (b) the CCNE1 expression level is determined in a biological sample obtained from the human subject prior to administration of the 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).

[0849] Amplification of the CCNE1 gene and / or CCNE1 expression levels above a control CCNE1 expression level, combined with 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 amino 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), indicates / predicts that a human subject having, suspected of having, or at risk of developing a disease or condition associated with CDK2 will respond to a CDK2 inhibitor.

[0850] 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.

[0851] 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.

[0852] In some embodiments of the aforementioned methods, the control CCNE1 expression level is a pre-established cutoff value. In some embodiments of the aforementioned methods, the control CCNE1 expression level is the CCNE1 expression level in one or more samples obtained from one or more subjects that do not respond to treatment with a CDK2 inhibitor.

[0853] In some embodiments of the aforementioned methods, the expression level of CCNE1 is the expression level of CCNE1 mRNA. In some embodiments of the aforementioned methods, the expression level of CCNE1 is the expression level of CCNE1 protein. In some embodiments in which 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 in which the expression level of CCNE1 is the expression level of CCNE1 protein, the expression level of CCNE1 is measured by Western blotting, enzyme-linked immunosorbent assay, or immunohistochemical staining.

[0854] Rb S780

[0855] The present disclosure also provides a method for assessing the CDKN2A gene and the CCNE1 gene, the method comprising determining (i) (a) the nucleotide sequence of the CDKN2A gene or (b) the presence of a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions, and (ii) the copy number of the CCNE1 gene in a biological sample or multiple biological samples obtained from a human subject suffering from a disease or condition associated with CDK2.

[0856] The present disclosure also provides a method for evaluating the response of a human subject having a disease or condition associated with CDK2, suspected of having the disease or condition, or at risk of developing the disease or condition 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 amplification of the CCNE1 gene and / or a CCNE1 expression level that is higher than a control CCNE1 expression level; (b) measuring the level of retinoblastoma-related protein (Rb) phosphorylation at the serine corresponding to amino acid position 780 of SEQ ID NO: 3 in a biological sample obtained from the subject after administering step (a), wherein the level of Rb phosphorylation at the serine corresponding to amino acid position 780 of SEQ ID NO: 3 is reduced compared to the control Rb phosphorylation level at the serine corresponding to amino acid position 780 of SEQ ID NO: 3, indicating that the human subject is responsive to the CDK2 inhibitor. In some embodiments, the subject has a disease or condition associated with CDK2. In some embodiments, the subject is suspected of having a disease or condition associated with CDK2 or is at risk of developing the disease or condition. In some embodiments, the biological sample comprises a blood sample or a tumor biopsy sample.

[0857] Rb phosphorylation 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 pharmacodynamic marker that can be used to assess the response of human subjects having a disease or disorder with CCNE1 amplification to CDK2 inhibitors (e.g., inhibition by CDK2).

[0858] Rb is a regulator of the cell cycle and acts as a tumor suppressor. Rb is activated when phosphorylated by cyclin D-CDK4 / 6 at Ser780 and Ser795 and by cyclin E / CDK2 at Ser807 and Ser811. Rb is encoded by RB transcriptional corepressor 1 ("RB1") gene (GenBank accession number NM_000321). The amino acid sequence of human Rb is provided below (GenBank accession number NP_000312 / UniProtKB accession number P06400) (S780 is bold and underlined):

[0859]

[0860] As described above, these examples demonstrate that CDK2 knockout inhibits proliferation in CCNE1-amplified cell lines, but not in CCNE1-non-amplified cell lines. These examples demonstrate that CDK2 knockout or inhibition blocks phosphorylation at S780 in CCNE1-amplified cell lines, but not in CCNE1-non-amplified cell lines. Therefore, Rb phosphorylation at the serine corresponding to amino acid position 780 of SEQ ID NO: 3 is a pharmacodynamic marker for assessing the response to CDK2 inhibition in CCNE1-amplified cancer cells or patients with a disease or condition with CCNE1 amplification. Therefore, provided herein are methods involving the use of Rb phosphorylation levels at the serine corresponding to amino acid position 780 of SEQ ID NO: 3 as an indicator of the response of a human subject to a CDK2 inhibitor in those human subjects suffering from a disease or condition associated with CDK2, suspected of having the disease or condition, or at risk of developing the disease or condition, wherein the human subject has an increased CCNE1 expression level.

[0861] Thus, the present disclosure provides 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 condition 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 condition 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 amplification of the CCNE1 gene and / or a CCNE1 expression level that is higher than a control CCNE1 expression level; and (b) measuring the level of Rb phosphorylation at the serine corresponding to amino acid position 780 of SEQ ID NO: 3 in a biological sample obtained from the human subject after administering step (a), wherein the level of Rb phosphorylation at the serine corresponding to amino acid position 780 of SEQ ID NO: 3 is reduced as compared to the control level of Rb phosphorylation at the serine corresponding to amino acid position 780 of SEQ ID NO: 3, indicating that the human subject is responsive to the CDK2 inhibitor. In specific embodiments, the human subject has a disease or condition associated with CDK2.

[0862] A decreased level of Rb phosphorylation at the serine corresponding to amino acid position 780 of SEQ ID NO: 3, as compared to a control level of Rb phosphorylation at the serine corresponding to amino acid position 780 of SEQ ID NO: 3, combined with amplification of the CCNE1 gene and / or a level of CCNE1 expression above a control CCNE1 expression level, indicates that the human subject has, is suspected of having, or is at risk of developing a disease or condition associated with CDK2. For example, in a human subject with amplification of the CCNE1 gene and / or a level of CCNE1 expression above a control CCNE1 expression level, a biological sample obtained from the subject following treatment with a CDK2 inhibitor having a low (e.g., decreased compared to a control) or undetectable level of Rb phosphorylation at the serine corresponding to amino acid position 780 of SEQ ID NO: 3 indicates that the subject is responsive to the CDK2 inhibitor.

[0863] A biological sample obtained from the subject after administration of a CDK2 inhibitor to the subject in which the level of Rb phosphorylation at the serine corresponding to amino acid position 780 of SEQ ID NO:3 is reduced as compared to a control level of Rb phosphorylation at the serine corresponding to amino acid position 780 of SEQ ID NO:3, in combination with: (i) amplification of the CCNE1 gene and / or a level of CCNE1 expression above a control CCNE1 expression level, 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 amino 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), indicates that the human subject has, is suspected of having, or is at risk of developing a disease or condition associated with CDK2, is responsive to the CDK2 inhibitor. For example, in a human subject having (i) amplification of the CCNE1 gene and / or a level of CCNE1 expression that is higher than a control CCNE1 expression level, 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 that lacks one or more inactivating amino 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 that has a low (e.g., decreased compared to a control) or undetectable 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 CDK2 inhibitor.

[0864] 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 expression level of CCNE1 is the level of CCNE1 mRNA. In specific embodiments, the expression level of CCNE1 is the level of CCNE1 protein.

[0865] comparison

[0866] As described above, methods involving biomarkers and pharmacodynamic markers can involve measuring one or more markers (e.g., biomarkers and pharmacodynamic markers such as amplification of the CCNE1 gene, CCNE1 expression level, 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 who has a disease or condition associated with CDK2, is suspected of having such a disease or condition, or is at risk of developing such a disease or condition. In specific embodiments, the human subject has a disease or condition associated with CDK2. In specific embodiments, the human subject is suspected of having a disease or condition associated with CDK2 or is at risk of developing such a disease or condition. In certain aspects, the level of one or more biomarkers (e.g., amplification (e.g., CCNE1 gene), expression level (e.g., CCNE1 or p16 protein), or phosphorylation level (e.g., Rb)) is predictive / indicative of a human subject's response to a treatment comprising a CDK2 inhibitor, as compared to a control level of the one or more biomarkers. In certain embodiments, the human subject is identified as likely to respond to a CDK2 inhibitor when (i) CCNE1 gene amplification and / or CCNE1 expression level is higher than a control CCNE1 expression level, 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 amino 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, the human subject is identified as responsive to a CDK2 inhibitor when (i) the CCNE1 gene is amplified and / or the CCNE1 expression level is higher than a control CCNE1 expression level, and (ii) the level of Rb phosphorylation at the serine corresponding to amino acid position 780 of SEQ ID NO: 3 is lower than a control Rb phosphorylation level at the serine corresponding to amino acid position 780 of SEQ ID NO: 3 in a biological sample from the human subject after the CDK2 inhibitor has been administered to the human subject.In yet another embodiment, the human subject is identified as responsive to a CDK2 inhibitor when (i) the CCNE1 gene is amplified and / or the CCNE1 expression level is greater than a control CCNE1 expression level, (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 amino acid substitutions and / or deletions is present, and / or a p16 pr...

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: n is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; is a single bond or a double bond; X is N, Y is C, and the ring for or X is C, Y is N, and the ring for Z is CR 2 or N; The ring part A is selected from C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl; The ring portion B is a 4-10 membered heterocycloalkyl, wherein the ring portion B is attached to a -NH- group of formula (I) at a ring member of the saturated or partially saturated ring of the 4-10 membered heterocycloalkyl; R 1 independently selected from H, D, halogen, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, OR a1 , SR 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 NR c1 R d1 NR c1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 、C(=NR e1 )R b1 、C(=NR e1 )NR c1 R d1 NR c1 C(=NR e1 )NR c1 R d1 NR c1 C(=NR e1 )R b1 NR c1 S(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)(=NR e1 )R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 、S(O)2NR 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 the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 The alkyl groups are each optionally substituted with 1, 2, 3 or 4 independently selected R 1A Substituent substitution; Each R a1 , R c1 and R d1 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 Alkyl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 The alkyl group is each optionally replaced by 1, 2, 3, or 4 independently selected R 1A Substituent substitution; Alternatively, any R attached to the same N atom c1 and R d1 Together with the N atom to which it is attached, it forms a 4-10 membered heterocycloalkyl, wherein the 4-10 membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 independently selected R 1A Substituent substitution; Each R b1 Independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl, each of which is optionally substituted with 1, 2, 3 or 4 independently selected R 1A Substituent substitution; Each R e1 Independently selected from 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, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl; Each R f1 and R g1 Independently selected from 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, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl; Each R h1 and R i1 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl; Each R j1 and R k1 Independently selected from OH, C 1-6 Alkoxy and C 1-6 Haloalkoxy; Alternatively, any R attached to the same B atom j1 and R k1 Together with the B atom to which it is attached, it forms a 5- or 6-membered heterocycloalkyl group, which is optionally substituted by 1, 2, 3 or 4 independently selected 1-6 Alkyl and C 1-6 Substitution of haloalkyl groups; Each R 1A independently selected from H, D, halogen, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a11 , SR a11 NHOR a11 、C(O)R b11 、C(O)NR c11 R d11 、C(O)NR c11 (OR a11 )、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 the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 The alkyl groups are each optionally substituted with 1, 2, 3 or 4 independently selected R 1B Substituent substitution; Each R a11 , R c11 and R d11 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Alkyl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 The alkyl groups are each optionally substituted with 1, 2, 3 or 4 independently selected R 1B Substituent substitution; Alternatively, any R attached to the same N atom c11 and R d11 Together with the N atom to which it is attached, it forms a 4-7 membered heterocycloalkyl, wherein the 4-7 membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 independently selected R 1B Substituent substitution; Each R b11 Independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally substituted with 1, 2, 3 or 4 independently selected R 1B Substituent substitution; Each R e11 Independently selected from 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, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl; Each R f11 and R g11 Independently selected from 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, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl; Each R h11 and R i11 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl; Each R j11 and R k11 Independently selected from OH, C 1-6 Alkoxy and C 1-6 Haloalkoxy; Alternatively, any R attached to the same B atom j11 and R k11 Together with the B atom to which it is attached, it forms a 5- or 6-membered heterocycloalkyl group, which is optionally substituted by 1, 2, 3 or 4 independently selected 1-6 Alkyl and C 1-6 Substitution of haloalkyl groups; Each R 1B independently selected from H, D, halogen, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a12 , SR 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 NR c12 R d12 NR c12 NR c12 R d12 NR c12 C(O)R b12 NR c12 C(O)OR a12 NR c12 C(O)NR c12 R d12 、C(=NR e12 )R b12 、C(=NR e12 )NR c12 R d12 NR c12 C(=NR e12 )NR c12 R d12 NR c12 C(=NR e12 )R b12 NR c12 S(O)NR c12 R d12 NR c12 S(O)R b12 NR c12 S(O)2R b12 NR c12 S(O)(=NR e12 )R b12 NR c12 S(O)2NR c12 R d12 、S(O)R b12 、S(O)NR c12 R d12 、S(O)2R b12 、S(O)2NR 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 the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 The alkyl groups are each optionally substituted with 1, 2, 3 or 4 independently selected R G Substituent substitution; Each R a12 , R c12 and R d12 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Alkyl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 The alkyl groups are each optionally substituted with 1, 2, 3 or 4 independently selected R G Substituent substitution; Alternatively, any R attached to the same N atom c12 and R d12 Together with the N atom to which it is attached, it forms a 4-7 membered heterocycloalkyl, wherein the 4-7 membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 independently selected R G Substituent substitution; Each R b12 Independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally substituted with 1, 2, 3 or 4 independently selected R G Substituent substitution; Each R e12 Independently selected from 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, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl; Each R f12 and R g12 Independently selected from 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, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl; Each R h12 and R i12 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl; Each R j12 and R k12 Independently selected from OH, C 1-6 Alkoxy and C 1-6 Haloalkoxy; Alternatively, any R attached to the same B atom j12 and R k12 Together with the B atom to which it is attached, it forms a 5- or 6-membered heterocycloalkyl group, which is optionally substituted by 1, 2, 3 or 4 independently selected 1-6 Alkyl and C 1-6 Substitution of haloalkyl groups; R 2 independently selected from H, D, halogen, 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 Alkylsulfonyl, carbamoyl, C 1-4 Alkylcarbamoyl, di(C 1-4 Alkyl)carbamoyl, carboxyl, 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 Alkylsulfonylamino, aminosulfonyl, 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 independently selected from H, D, halogen, 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 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 Alkyl; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 The alkyl groups are each optionally substituted with 1, 2, 3 or 4 independently selected R 4A Substituent substitution; Each R 4A independently selected from H, D, halogen, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, OR a41 , SR 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 NR c41 R d41 NR c41 NR c41 R d41 NR c41 C(O)R b41 NR c41 C(O)OR a41 NR c41 C(O)NR c41 R d41 、C(=NR e41 )R b41 、C(=NR e41 )NR c41 R d41 NR c41 C(=NR e41 )NR c41 R d41 NR c41 C(=NR e41 )R b41 NR c41 S(O)NR c41 R d41 NR c41 S(O)R b41 NR c41 S(O)2R b41 NR c41 S(O)(=NR e41 )R b41 NR c41 S(O)2NR c41 R d41 、S(O)R b41 、S(O)NR c41 R d41 、S(O)2R b41 、S(O)2NR 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 the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 The alkyl groups are each optionally substituted with 1, 2, 3 or 4 independently selected R 4B Substituent substitution; Each R a41 , R c41 and R d41 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 Alkyl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 The alkyl groups are each optionally substituted with 1, 2, 3 or 4 independently selected R 4B Substituent substitution; Alternatively, any R attached to the same N atom c41 and R d41 Together with the N atom to which it is attached, it forms a 4-10 membered heterocycloalkyl, wherein the 4-10 membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 independently selected R 4B Substituent substitution; Each R b41 Independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl, each of which is optionally substituted with 1, 2, 3 or 4 independently selected R 4B Substituent substitution; Each R e41 Independently selected from 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, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl; Each R f41 and R g41 Independently selected from 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, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl; Each R h41 and R i41 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl; Each R j41 and R k41 Independently selected from OH, C 1-6 Alkoxy and C 1-6 Haloalkoxy; Alternatively, any R attached to the same B atom j41 and R k41 Together with the B atom to which it is attached, it forms a 5- or 10-membered heterocycloalkyl group, which is optionally substituted by 1, 2, 3 or 4 independently selected 1-6 Alkyl and C 1-6 Substitution of haloalkyl groups; Each R 4B independently selected from H, D, halogen, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a42 , SR a42 NHOR a42 、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)R f42 R g42 OP(O)(OR h42 )(OR i42 )、P(O)(OR h42 )(OR i42 ) and BR j42 R k42 , wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 The alkyl groups are each optionally substituted with 1, 2, 3 or 4 independently selected R 4C Substituent substitution; Each R a42 , R c42 and R d42 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Alkyl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 The alkyl groups are each optionally substituted with 1, 2, 3 or 4 independently selected R 4C Substituent substitution; Alternatively, any R attached to the same N atom c42 and R d42 Together with the N atom to which it is attached, it forms a 4-7 membered heterocycloalkyl, wherein the 4-7 membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 independently selected R 4C Substituent substitution; Each R b42 Independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally substituted with 1, 2, 3 or 4 independently selected R 4C Substituent substitution; Each R e42 Independently selected from 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, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl; Each R f42 and R g42 Independently selected from 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, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl; Each R h42 and R i42 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl; Each R j42 and R k42 Independently selected from OH, C 1-6 Alkoxy and C 1-6 Haloalkoxy; Alternatively, any R attached to the same B atom j42 and R k42 Together with the B atom to which it is attached, it forms a 5- or 6-membered heterocycloalkyl group, which is optionally substituted by 1, 2, 3 or 4 independently selected 1-6 Alkyl and C 1-6 Substitution of haloalkyl groups; Each R 4C independently selected from H, D, halogen, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a43 , SR 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 NR c43 R d43 NR c43 NR c43 R d43 NR c43 C(O)R b43 NR c43 C(O)OR a43 NR c43 C(O)NR c43 R d43 、C(=NR e43 )R b43 、C(=NR e43 )NR c43 R d43 NR c43 C(=NR e43 )NR c43 R d43 NR c43 C(=NR e43 )R b43 NR c43 S(O)NR c43 R d43 NR c43 S(O)R b43 NR c43 S(O)2R b43 NR c43 S(O)(=NR e43 )R b43 NR c43 S(O)2NR c43 R d43 、S(O)R b43 、S(O)NR c43 R d43 、S(O)2R b43 、S(O)2NR 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 the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 The alkyl groups are each optionally substituted with 1, 2, 3 or 4 independently selected R G Substituent substitution; Each R a43 , R c43 and R d43 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Alkyl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 The alkyl groups are each optionally substituted with 1, 2, 3 or 4 independently selected R G Substituent substitution; Alternatively, any R attached to the same N atom c43 and R d43 Together with the N atom to which it is attached, it forms a 4-7 membered heterocycloalkyl, wherein the 4-7 membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 independently selected R G Substituent substitution; Each R b43 Independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally substituted with 1, 2, 3 or 4 independently selected R G Substituent substitution; Each R e43 Independently selected from 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, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl; Each R f43 and R g43 Independently selected from 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, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl; Each R h43 and R i43 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl; Each R j43 and R k43 Independently selected from OH, C 1-6 Alkoxy and C 1-6 Haloalkoxy; Alternatively, any R attached to the same B atom j43 and R k43 Together with the B atom to which it is attached, it forms a 5- or 6-membered heterocycloalkyl group, which is optionally substituted by 1, 2, 3 or 4 independently selected 1-6 Alkyl and C 1-6 Substitution of haloalkyl groups; Each R 5 independently selected from H, D, halogen, NO2, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, OR a5 , SR 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 R d5 NR c5 R d5 NR c5 NR c5 R d5 NR c5 C(O)R b5 NR c5 C(O)OR a5 NR c5 C(O)NR c5 R d5 、C(=NR e5 )R b5 、C(=NR e5 )NR c5 R d5 NR c5 C(=NR e5 )NR c5 R d5 NR c5 C(=NR e5 )R b5 NR c5 S(O)NR c5 R d5 NR c5 S(O)R b5 NR c5 S(O)2R b5 NR c5 S(O)(=NR e5 )R b5 NR c5 S(O)2NR c5 R d5 、S(O)R b5 、S(O)NR c5 R d5 、S(O)2R b5 、S(O)2NR 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 said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 The alkyl groups are each optionally substituted with 1, 2, 3 or 4 independently selected R 5A Substituent substitution; Each R a5 , R c5 and R d5 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 Alkyl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 The alkyl groups are each optionally substituted with 1, 2, 3 or 4 independently selected R 5A Substituent substitution; Alternatively, any R attached to the same N atom c5 and R d5 Together with the N atom to which it is attached, it forms a 4-10 membered heterocycloalkyl group, which is optionally substituted by 1, 2, 3 or 4 independently selected R 5A Substituent substitution; Each R b5 Independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl, each of which is optionally substituted with 1, 2, 3 or 4 independently selected R 5A Substituent substitution; Each R e5 Independently selected from 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, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl; Each R f5 and R g5 Independently selected from 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, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl; Each R h5 and R i5 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl; Each R j5 and R k5 Independently selected from OH, C 1-6 Alkoxy and C 1-6 Haloalkoxy; Alternatively, any R attached to the same B atom j5 and R k5 Together with the B atom to which it is attached, it forms a 5- or 6-membered heterocycloalkyl group, which is optionally substituted by 1, 2, 3 or 4 independently selected 1-6 Alkyl and C 1-6 Substitution of haloalkyl groups; Each R 5A independently selected from H, D, halogen, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, OR a51 , SR 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 NR c51 R d51 NR c51 NR c51 R d51 NR c51 C(O)R b51 NR c51 C(O)OR a51 NR c51 C(O)NR c51 R d51 、C(=NR e51 )R b51 、C(=NR e51 )NR c51 R d51 NR c51 C(=NR e51 )NR c51 R d51 NR c51 C(=NR e51 )R b51 NR c51 S(O)NR c51 R d51 NR c51 S(O)R b51 NR c51 S(O)2R b51 NR c51 S(O)(=NR e51 )R b51 NR c51 S(O)2NR c51 R d51 、S(O)R b51 、S(O)NR c51 R d51 、S(O)2R b51 、S(O)2NR 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 the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 The alkyl groups are each optionally substituted with 1, 2, 3 or 4 independently selected R 5B Substituent substitution; Each R a51 , R c51 and R d51 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 Alkyl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 The alkyl groups are each optionally substituted with 1, 2, 3 or 4 independently selected R 5B Substituent substitution; Alternatively, any R attached to the same N atom c51 and R d51 Together with the N atom to which it is attached, it forms a 4-7 membered heterocycloalkyl group, which is optionally substituted by 1, 2, 3 or 4 independently selected R 5B Substituent substitution; Each R b51 Independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl, each of which is optionally substituted with 1, 2, 3 or 4 independently selected R 5B Substituent substitution; Each R e51 Independently selected from 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, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl; Each R f51 and R g51 Independently selected from 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, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl; Each R h51 and R i51 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl; Each R j51 and R k51 Independently selected from OH, C 1-6 Alkoxy and C 1-6 Haloalkoxy; Alternatively, any R attached to the same B atom j51 and R k51 Together with the B atom to which it is attached, it forms a 5- or 6-membered heterocycloalkyl group, which is optionally substituted by 1, 2, 3 or 4 independently selected 1-6 Alkyl and C 1-6 Substitution of haloalkyl groups; Each R 5B independently selected from H, D, halogen, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a52 , SR 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 NR c52 R d52 NR c52 NR c52 R d52 NR c52 C(O)R b52 NR c52 C(O)OR a52 NR c52 C(O)NR c52 R d52 、C(=NR e52 )R b52 、C(=NR e52 )NR c52 R d52 NR c52 C(=NR e52 )NR c52 R d52 NR c52 C(=NR e52 )R b52 NR c52 S(O)NR c52 R d52 NR c52 S(O)R b52 NR c52 S(O)2R b52 NR c52 S(O)(=NR e52 )R b52 NR c52 S(O)2NR c52 R d52 、S(O)R b52 、S(O)NR c52 R d52 、S(O)2R b52 、S(O)2NR 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 the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 The alkyl groups are each optionally substituted with 1, 2, 3 or 4 independently selected R 5C Substituent substitution; Each R a52 , R c52 and R d52 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Alkyl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 The alkyl groups are each optionally substituted with 1, 2, 3 or 4 independently selected R 5C Substituent substitution; Alternatively, any R attached to the same N atom c52 and R d52 Together with the N atom to which it is attached, it forms a 4-7 membered heterocycloalkyl group, which is optionally substituted by 1, 2, 3 or 4 independently selected R 5C Substituent substitution; Each R b52 Independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally substituted with 1, 2, 3 or 4 independently selected R 5C Substituent substitution; Each R e52 Independently selected from 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, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl; Each R f52 and R g52 Independently selected from 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, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl; Each R h52 and R i52 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl; Each R j52 and R k52 Independently selected from OH, C 1-6 Alkoxy and C 1-6 Haloalkoxy; Alternatively, any R attached to the same B atom j52 and R k52 Together with the B atom to which it is attached, it forms a 5- or 6-membered heterocycloalkyl group, which is optionally substituted by 1, 2, 3 or 4 independently selected 1-6 Alkyl and C 1-6 Substitution of haloalkyl groups; Each R 5C independently selected from H, D, halogen, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a53 , SR 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 NR c53 R d53 NR c53 NR c53 R d53 NR c53 C(O)R b53 NR c53 C(O)OR a53 NR c53 C(O)NR c53 R d53 、C(=NR e53 )R b53 、C(=NR e53 )NR c53 R d53 NR c53 C(=NR e53 )NR c53 R d53 NR c53 C(=NR e53 )R b53 NR c53 S(O)NR c53 R d53 NR c53 S(O)R b53 NR c53 S(O)2R b53 NR c53 S(O)(=NR e53 )R b53 NR c53 S(O)2NR c53 R d53 、S(O)R b53 、S(O)NR c53 R d53 、S(O)2R b53 、S(O)2NR 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 the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 The alkyl groups are each optionally substituted with 1, 2, 3 or 4 independently selected R G Substituent substitution; Each R a53 , R c53 and R d53 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Alkyl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 The alkyl groups are each optionally substituted with 1, 2, 3 or 4 independently selected R G Substituent substitution; Alternatively, any R attached to the same N atom c53 and R d53 Together with the N atom to which it is attached, it forms a 4-7 membered heterocycloalkyl group, which is optionally substituted by 1, 2, 3 or 4 independently selected R G Substituent substitution; Each R b53 Independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally substituted with 1, 2, 3 or 4 independently selected R G Substituent substitution; Each R e53 Independently selected from 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, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl; Each R f53 and R g53 Independently selected from 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, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl; Each R h53 and R i53 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl; Each R j53 and R k53 Independently selected from OH, C 1-6 Alkoxy and C 1-6 Haloalkoxy; Alternatively, any R attached to the same B atom j53 and R k53 Together with the B atom to which it is attached, it forms a 5- or 6-membered heterocycloalkyl group, which is optionally substituted by 1, 2, 3 or 4 independently selected 1-6 Alkyl and C 1-6 The substituent of the haloalkyl group is substituted; and Each R G independently selected from OH, NO2, CN, halogen, 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 Alkylsulfonyl, carbamoyl, C 1-3 Alkylcarbamoyl, di(C 1-3 Alkyl)carbamoyl, carboxyl, 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 Alkylsulfonylamino, aminosulfonyl, 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.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 independently selected from H, halogen, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a1 , SR a1 、C(O)R b1 、C(O)NR c1 R d1 、C(O)OR a1 、OC(O)R b1 、OC(O)NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 , wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 The alkyl groups are each optionally substituted with 1, 2, 3 or 4 independently selected R 1A Substituent substitution.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 are independently selected from H, halo, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-3 Alkyl, phenyl-C 1-3 Alkyl, 4-7 membered heterocycloalkyl-C 1-3 Alkyl, 5-6 membered heteroaryl-C 1-3 Alkyl, OR a1 , SR a1 and NR c1 R d1 , wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-3 Alkyl, phenyl-C 1-3 Alkyl, 4-7 membered heterocycloalkyl-C 1-3 Alkyl and 5-6 membered heteroaryl-C 1-3 The alkyl groups are each optionally substituted with 1 or 2 independently selected R 1A Substituent substitution.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 Independently selected from H, C 1-6 Alkyl, phenyl, 5-7 membered heterocycloalkyl, OR a1 , SR a1 and NR c1 R d1 , wherein the C 1-6 Alkyl, phenyl and 5-7 membered heterocycloalkyl are each optionally substituted with 1 or 2 independently selected R 1A Substituent substitution.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 Independently selected from H and OR a1 .

6. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein: Each R a1 , R c1 and R d1 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 Alkyl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 The alkyl groups are each optionally substituted with 1, 2, 3 or 4 independently selected R 1A Substituent substitution; Each R b1 Independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, each of which is optionally substituted with 1, 2, 3 or 4 independently selected R 1A Substituent substitution; Each R 1A independently selected from H, D, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a11 、C(O)R b11 、C(O)NR c11 R d11 、C(O)OR a11 、OC(O)R b11 、OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O)R b11 NR c11 C(O)OR a11 NR c11 C(O)NR c11 R d11 NR c11 S(O)2R b11 NR c11 S(O)2NR c11 R d11 、S(O)2R b11 and S(O)2NR c11 R d11 , wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 The alkyl groups are each optionally substituted with 1, 2, 3 or 4 independently selected R 1B Substituent substitution; Each R a11 , R c11 and R d11 Independently selected from H, C 1-6 Alkyl and C 1-6 Haloalkyl; Each R b11 Independently selected from C 1-6 Alkyl and C 1-6 Haloalkyl; Each R 1B Independently selected from H, D and OR a12 ;and Each R a12 Independently selected from H and C 1-6 alkyl.

7. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein: Each R a1 , R c1 and R d1 Independently selected from 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 1-3 Alkyl, wherein the 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 1-3 The alkyl groups are each optionally substituted with 1, 2 or 3 independently selected R 1A Substituent substitution; Each R b1 Independently selected from 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 substituted with 1 or 2 independently selected R 1A Substituents are substituted; and Each R 1A are independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, OR a11 and C(O)OR a11 , wherein the C 1-6 Alkyl and C 1-6 Each haloalkyl group is optionally substituted with 1, 2 or 3 independently selected R 1B Substituent substitution; Each R a11 Independently selected from H and C 1-4 Alkyl, wherein the C 1-4 The alkyl group is optionally substituted with 1, 2 or 3 independently selected R 1B Substituents are substituted; and Each R 1B Independently selected from H, D and OC 1-4 alkyl.

8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 OR a1 And R a1 C 1-3 alkyl.

9. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein R 2 Selected from H, halogen, 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.

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

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