Bicyclic amines as CDK2 inhibitors

Abstract

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

Description

[Technical Field]

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

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

[0003] Technical field This application relates to a bicyclic amine that inhibits cyclin-dependent kinase 2 (CDK2) and is useful in the treatment of cancer. [Background technology]

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

[0005] CDK2 is of particular interest because CDK2 activity dysregulation frequently occurs in various human cancers. CDK2 plays an essential role in promoting G1 / S transition and S phase progression. When complexed with cyclin E (CCNE), CDK2 phosphorylates retinoblastoma pocket protein family members (p107, p130, pRb), leading to derepression of E2F transcription factors, expression of G1 / S transition-related genes, and transition from G1 to S phase (Henley, SA and FADick, Cell Div, 2012, 7(1):p.10). This, in turn, enables the activation of CDK2 / cyclin A, which phosphorylates endogenous substrates, thereby enabling DNA synthesis, replication, and centrosome replication (Ekholm, SV and SIReed, Curr Opin Cell Biol, 2000, 12(6):676-84). The CDK2 pathway has been reported to influence tumorigenesis primarily through mutations that amplify and / or overexpress CCNE1 and inactivate endogenous CDK2 inhibitors (e.g., p27) (Xu, X., et al., Biochemistry, 1999.38(27):8713-22).

[0006] Increased copy number and overexpression of CCNE1 have been identified in ovarian cancer, gastric cancer, endometrial cancer, breast cancer, and other cancers, and are associated with poor outcomes in these tumors (Keyomarsi, K., et al., N Engl J Med, 2002.347(20):1566-75, Nakayama, N., et al., Cancer, 2010.116(11):2621-34, Au-Yeung, G., et al., Clin Cancer Res, 2017.23(7):1862-1874, Rosen, 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 methods targeting CDK2 have been shown to induce cell cycle arrest and inhibition of tumor growth (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). CDK2 inhibition has also been reported to restore sensitivity to trastuzumab treatment in resistant HER2+ breast tumors in preclinical models (Scaltriti (see above)).

[0007] These data provide evidence to consider CDK2 as a potential target for novel drug development in cancers associated with disregulated CDK2 activity. Interest in the development of CDK-selective inhibitors has grown over the past decade. Despite considerable effort, no approved drugs targeting CDK2 exist to date (Cicenas, J., et al., Cancers (Basel), 2014.6(4):p.2224-42). Therefore, there remains a need to discover CDK inhibitors with novel activity profiles, particularly CDK2-targeting CDK inhibitors. This application addresses this need and other needs. [Overview of the Initiative]

[0008] The present invention relates, in particular, to the compound of formula (I), [ka] With respect to the pharmaceutically acceptable salt thereof, the members are defined herein.

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

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

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

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

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

[0014] The present invention further provides the use of the compounds described herein, or pharmaceutically acceptable salts thereof, for preparing a medicament for use in any of the methods described herein. [Modes for carrying out the invention]

[0015] This application particularly concerns the compound of formula (I), [ka] or a pharmaceutically acceptable salt thereof, in the formula, n is 0, 1, 2, 3, or 4, p is 0, 1, 2, 3, or 4, [ka] However, it is either a single bond or a double bond. X is N, Y is C, and the ring [ka] but, [ka] is, or X is C, Y is N, and the ring [ka] but, [ka] And, Z, CR 2 or N, Ring portion A is C 3-10 Selected from cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, The ring moiety B is a 4- to 10-membered heterocycloalkyl, where the ring moiety B is bonded to the -NH- group of formula (I) at a ring member of the saturated or partially saturated ring of the 4- to 10-membered heterocycloalkyl, R 1 is independently H, D, halo, CN, NO2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, 6- to 10-membered aryl-C 1-4 alkyl, 4- to 10-membered heterocycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl, OR a1 , 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(=NRe1 )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 selected from, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, 6- to 10-membered aryl-C 1-4 alkyl, 4- to 10-membered heterocycloalkyl-C 1-4 alkyl, and 5- to 10-membered heteroaryl-C 1-4 alkyl is each optionally, independently, substituted with 1, 2, 3, or 4 selected R 1A [[ID=​​​​​​​are independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, 6- to 10-membered aryl-C 1-4 alkyl, 4- to 10-membered heterocycloalkyl-C 1-4 alkyl, and 5- to 10-membered heteroaryl-C 1-4 alkyl, selected from, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, 6- to 10-membered aryl-C 1-4 alkyl, 4- to 10-membered heterocycloalkyl-C 1-4 alkyl, and 5- to 10-membered heteroaryl-C 1-4 alkyls are each optionally, 1, 2, 3, or 4 independently selected R 1A substituents, or alternatively, any R c1 and R d1 bonded to the same N atom, together with the N atom to which they are bonded, form a 4- to 10-membered heterocycloalkyl group, and the 4- to 10-membered heterocycloalkyl group is optionally, 1, 2, 3, or 4 independently selected R 1A substituents, each R b1 is independently, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C1-4 Alkyl, 6-10 member aryl-C 1-4 Alkyl, 4-10 member heterocycloalkyl-C 1-4 Alkyl and 5-10 member heteroaryl-C 1-4 Selected from alkyl groups, these are each optionally selected as 1, 2, 3, or 4 independently R 1A Substituting with substituents, Each R e1 These are independently H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 2-6 Alkenil, C 2-6 Alkinyl, 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 member aryl-C 1-4 Alkyl, 4-10 member heterocycloalkyl-C 1-4 Alkyl and 5-10 member heteroaryl-C 1-4 Selected from alkyl groups, Each R f1 and R g1 H and C are independent. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 2-6 Alkenil, C 2-6 Alkinyl, 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 member aryl-C 1-4 Alkyl, 4-10 member heterocycloalkyl-C 1-4 Alkyl and 5-10 member heteroaryl-C 1-4 Selected from alkyl groups, Each R h1 and R i1 H and C are independent. 1-6 Alkyl, C1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, 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 member aryl-C 1-4 Alkyl, 4-10 member heterocycloalkyl-C 1-4 Alkyl and 5-10 member heteroaryl-C 1-4 Selected from alkyl groups, Each R j1 and R k1 OH and C are independent of each other. 1-6 Alkoxy, and C 1-6 Selected from haloalkoxys, Alternatively, any R bonded to the same B atom j1 and R k1 However, together with the B atom to which they are bonded, C 1-6 Alkyl and C 1-6 A 5-membered or 6-membered heterocycloalkyl group is formed, optionally substituted with 1, 2, 3, or 4 substituents independently selected from the haloalkyl group. Each R 1A They became independent as H, D, Haro, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl, 5-6 member 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 (ORa11 )、C(O)OR a11 、OC(O)R b11 、OC(O)NR c11 R d11 、NR c11 R d11 、NR c11 NR c11 R d11 、NR c11 C(O)R b11 、NR c11 C(O)OR a11 、NR c11 C(O)NR c11 R d11 、C(=NR e11 )R b11 、C(=NR e11 )NR c11 R d11 、NR c11 C(=NR e11 )NR c11 R d11 、NR c11 C(=NR e11 )R b11 、NR c11 S(O)NR c11 R d11 、NR c11 S(O)R b11 、NR c11 S(O)2R b11 、NR c11 S(O)(=NR e11 )R b11 、NR c11 S(O)2NR c11 R d11 、S(O)R b11 、S(O)NR c11 R d11 、S(O)2R b11 、S(O)2NR c11 R d11 、OS(O)(=NR e11 )R b11 、OS(O)2R b11 、S(O)(=NR e11 )R b11 、SF5、P(O)R f11 R g11 、OP(O)(OR h11 )(OR i11 )、P(O)(OR h11)(OR i11 ), and BR j11 R k11 Selected from, the C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, 3, or 4 independently selected R groups, each of which can be arbitrarily chosen. 1B Substituting with substituents, Each R a11 , R c11 , and R d11 H and C are independent. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl, the C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4The alkyl group consists of 1, 2, 3, or 4 independently selected R groups, each of which can be arbitrarily chosen. 1B Substituting with substituents, Alternatively, any R bonded to the same N atom c11 and R d11 However, together with the N atom to which they are bonded, they form a 4-7 member heterocycloalkyl group, and the 4-7 member heterocycloalkyl group can optionally consist of 1, 2, 3, or 4 independently selected R atoms. 1B Substituting with substituents, Each R b11 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl groups, these are each optionally selected as 1, 2, 3, or 4 independently R 1B Substituting with substituents, Each R e11 These are independently H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl groups, Each R f11 and R g11H and C are independent. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl groups, Each R h11 and R i11 H and C are independent. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl groups, Each R j11 and R k11 OH and C are independent of each other. 1-6 Alkoxy, and C 1-6 Selected from haloalkoxys, Alternatively, any R bonded to the same B atom j11 and R k11 However, together with the B atom to which they are bonded, C 1-6 Alkyl and C 1-6 A 5-membered or 6-membered heterocycloalkyl group is formed, optionally substituted with 1, 2, 3, or 4 substituents independently selected from the haloalkyl group. Each R 1B They became independent as H, D, Haro, CN, NO2, C 1-6Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl, 5-6 member 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)(=NRe12 )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 Selected from, the C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, 3, or 4 independently selected R groups, each of which can be arbitrarily chosen. G Substituting with substituents, Each R a12 , R c12 , and R d12 H and C are independent. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl, the C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, 3, or 4 independently selected R groups, each of which can be arbitrarily chosen. G Substituting with substituents, Alternatively, any R bonded to the same N atom c12 and R d12 However, together with the N atom to which they are bonded, they form a 4-7 member heterocycloalkyl group, and the 4-7 member heterocycloalkyl group can optionally consist of 1, 2, 3, or 4 independently selected R atoms. G Substituting with substituents, Each R b12 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl groups, these are each optionally selected as 1, 2, 3, or 4 independently R G Substituting with substituents, Each R e12 These are independently H, OH, CN, C1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl groups, Each R f12 and R g12 H and C are independent. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl groups, Each R h12 and R i12 H and C are independent. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl groups, Each R j12 and R k12 OH and C are independent of each other. 1-6 Alkoxy, and C 1-6 Selected from haloalkoxys, Alternatively, any R bonded to the same B atom j12 and R k12 However, together with the B atom to which they are bonded, C 1-6 Alkyl and C 1-6 A 5-membered or 6-membered heterocycloalkyl group is formed, optionally substituted with 1, 2, 3, or 4 substituents independently selected from the haloalkyl group. R 2 These are independent: H, D, Halo, CN, OH, NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 Alkenil, C 2-4 Alkinyl, 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 Alkyl sulfinyl, C 1-4 Alkyl sulfonyl, carbamyl, C 1-4 Alkylcarbamyl, di(C 1-4 Alkyl)carbamyl, carboxy, C 1-4 Alkylcarbonyl, C 1-4 Alkoxycarbonyl, C 1-4 Alkylcarbonyloxy, C 1-4 Alkylcarbonylamino, C 1-4 Alkoxycarbonylamino, C 1-4 Alkylaminocarbonyloxy, C 1-4 Alkylsulfonylamino, aminosulfonyl, C 1-4 Alkylaminosulfonyl, di(C 1-4Alkyl)aminosulfonyl, aminosulfonylamino, C 1-4 Alkylaminosulfonylamino, di(C 1-4 Alkyl)aminosulfonylamino, aminocarbonylamino, C 1-4 Alkylaminocarbonylamino, and di(C 1-4 Selected from alkyl)aminocarbonylamino, Each R 3 They became independent: H, D, Haro, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 Alkenil, C 2-4 Alkinyl, OH, C 1-3 Alkoxy, C 1-3 Haloalkoxy, amino, C 1-3 Alkylamino, di(C 1-3 Alkyl)amino, cyano-C 1-4 Alkyl, HO-C 1-4 Alkyl, C 1-3 Alkoxy-C 1-4 Alkyl and C 3-4 Selected from cycloalkyl groups, R 4 However, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, 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 member aryl-C 1-4 Alkyl, 4-10 member heterocycloalkyl-C 1-4 Alkyl and 5-10 member heteroaryl-C 1-4 Selected from alkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4Alkyl, 6-10 member aryl-C 1-4 Alkyl, 4-10 member heterocycloalkyl-C 1-4 Alkyl and 5-10 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, 3, or 4 independently selected R groups, each of which can be arbitrarily chosen. 4A Substituted by substituents, Each R 4A They became independent as H, D, Haro, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, 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 member aryl-C 1-4 Alkyl, 4-10 member heterocycloalkyl-C 1-4 Alkyl, 5-10 member 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(=NRe41 )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 Selected from, the C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, 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 member aryl-C 1-4 Alkyl, 4-10 member heterocycloalkyl-C 1-4 Alkyl and 5-10 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, 3, or 4 independently selected R groups, each of which can be arbitrarily chosen. 4BSubstituting with substituents, Each R a41 , R c41 , and R d41 H and C are independent. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, 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 member aryl-C 1-4 Alkyl, 4-10 member heterocycloalkyl-C 1-4 Alkyl and 5-10 member heteroaryl-C 1-4 Selected from alkyl, the C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, 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 member aryl-C 1-4 Alkyl, 4-10 member heterocycloalkyl-C 1-4 Alkyl and 5-10 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, 3, or 4 independently selected R groups, each of which can be arbitrarily chosen. 4B Substituting with substituents, Alternatively, any R bonded to the same N atom c41 and R d41 However, together with the N atom to which they are bonded, they form a 4-10 member heterocycloalkyl group, and the 4-10 member heterocycloalkyl group can optionally consist of 1, 2, 3, or 4 independently selected R atoms. 4B Substituting with substituents, Each R b41 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, 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 member aryl-C 1-4 Alkyl, 4-10 member heterocycloalkyl-C 1-4 Alkyl and 5-10 member heteroaryl-C 1-4 Selected from alkyl groups, these are each optionally selected as 1, 2, 3, or 4 independently R 4B Substituting with substituents, Each R e41 These are independently H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 2-6 Alkenil, C 2-6 Alkinyl, 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 member aryl-C 1-4 Alkyl, 4-10 member heterocycloalkyl-C 1-4 Alkyl and 5-10 member heteroaryl-C 1-4 Selected from alkyl groups, Each R f41 and R g41 H and C are independent. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 2-6 Alkenil, C 2-6 Alkinyl, 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 member aryl-C 1-4 Alkyl, 4-10 member heterocycloalkyl-C 1-4 Alkyl and 5-10 member heteroaryl-C1-4 Selected from alkyl groups, Each R h41 and R i41 H and C are independent. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, 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 member aryl-C 1-4 Alkyl, 4-10 member heterocycloalkyl-C 1-4 Alkyl and 5-10 member heteroaryl-C 1-4 Selected from alkyl groups, Each R j41 and R k41 OH and C are independent of each other. 1-6 Alkoxy, and C 1-6 Selected from haloalkoxys, Alternatively, any R bonded to the same B atom j41 and R k41 However, together with the B atom to which they are bonded, C 1-6 Alkyl and C 1-6 Forming a 5-membered or 10-membered heterocycloalkyl group, optionally substituted with 1, 2, 3, or 4 substituents independently selected from the haloalkyl group. Each R 4B They became independent as H, D, Haro, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl, 5-6 member heteroaryl-C 1-4 Alkyl, OR a42 , SR a42 NHORa42 、C(O)R b42 、C(O)NR c42 R d42 、C(O)NR c42 (OR a42 )、C(O)OR a42 、OC(O)R b42 、OC(O)NR c42 R d42 、NR c42 R d42 、NR c42 NR c42 R d42 、NR c42 C(O)R b42 、NR c42 C(O)OR a42 、NR c42 C(O)NR c42 R d42 、C(=NR e42 )R b42 、C(=NR e42 )NR c42 R d42 、NR c42 C(=NR e42 )NR c42 R d42 、NR c42 C(=NR e42 )R b42 、NR c42 S(O)NR c42 R d42 、NR c42 S(O)R b42 、NR c42 S(O)2R b42 、NR c42 S(O)(=NR e42 )R b42 、NR c42 S(O)2NR c42 R d42 、S(O)R b42 、S(O)NR c42 R d42 、S(O)2R b42 、S(O)2NR c42 R d42 、OS(O)(=NR e42 )R b42 、OS(O)2R b42 、S(O)(=NR e42 )R b42 、SF5、P(O)Rf42 R g42 , OP(O)(OR h42 )(OR i42 ), P(O)(OR h42 )(OR i42 ), and BR j42 R k42 Selected from, the C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, 3, or 4 independently selected R groups, each of which can be arbitrarily chosen. 4C Substituting with substituents, Each R a42 , R c42 , and R d42 H and C are independent. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl, the C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and 5- to 6-membered heteroaryl-C 1-4 The alkyls are each optionally substituted with 1, 2, 3, or 4 independently selected R 4C substituents, or any R and R c42 bonded to the same N atom together form a 4- to 7-membered heterocycloalkyl group, and the 4- to 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, or 4 independently selected R d42 substituents, 4C each R is independently C b42 alkyl, C 1-6 haloalkyl, C 1-6 alkenyl, C 2-6 alkynyl, C 2-6 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 3-7 alkyl, phenyl-C 1-4 alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 alkyl, and 5- to 6-membered heteroaryl-C 1-4 selected from alkyls, which are each optionally substituted with 1, 2, 3, or 4 independently selected R 1-4 substituents, 4C each R is independently H, OH, CN, C e42 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkenyl, C<000091i>alkynyl, C 2-6 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 3-7 alkyl, phenyl-C 1-4 alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 alkyl, and 5- to 6-membered heteroaryl-C 1-4 alkyl, and 5- to 6-membered heteroaryl-C1-4 Selected from alkyl groups, Each R f42 and R g42 H and C are independent. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl groups, Each R h42 and R i42 H and C are independent. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl groups, Each R j42 and R k42 OH and C are independent of each other. 1-6 Alkoxy, and C 1-6 Selected from haloalkoxys, Alternatively, any R bonded to the same B atom j42 and R k42 However, together with the B atom to which they are bonded, C 1-6 Alkyl and C 1-6Optionally substituted by one, two, three, or four substituents independently selected from haloalkyl to form a 5- or 6-membered heterocycloalkyl group, each R 4C is independently H, D, halo, CN, NO2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 alkyl, 5- to 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 c43S(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 Selected from, the C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, 3, or 4 independently selected R groups, each of which can be arbitrarily chosen. G Substituting with substituents, Each R a43 , R c43 , and R d43 H and C are independent. 1-6 Alkyl, C 1-6 Haloalkyl, C2-6 Alkenil, C 2-6 Alkinyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl, the C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, 3, or 4 independently selected R groups, each of which can be arbitrarily chosen. G Substituting with substituents, Alternatively, any R bonded to the same N atom c43 and R d43 However, together with the N atom to which they are bonded, they form a 4-7 member heterocycloalkyl group, and the 4-7 member heterocycloalkyl group can optionally consist of 1, 2, 3, or 4 independently selected R atoms. G Substituting with substituents, Each R b43 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl groups, these are each optionally selected as 1, 2, 3, or 4 independently R G Substituting with substituents, Each R e43 These are independently H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl groups, Each R f43 and R g43 H and C are independent. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl groups, Each R h43 and R i43 H and C are independent. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-7Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl groups, Each R j43 and R k43 OH and C are independent of each other. 1-6 Alkoxy, and C 1-6 Selected from haloalkoxys, Alternatively, any R bonded to the same B atom j43 and R k43 However, together with the B atom to which they are bonded, C 1-6 Alkyl and C 1-6 A 5-membered or 6-membered heterocycloalkyl group is formed, optionally substituted with 1, 2, 3, or 4 substituents independently selected from the haloalkyl group. Each R 5 They became independent as H, D, Haro, NO2, CN, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, 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 member aryl-C 1-4 Alkyl, 4-10 member heterocycloalkyl-C 1-4 Alkyl, 5-10 member 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 Rd5 , 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 Selected from, the C 1-6 Alkyl, C2-6 Alkenil, C 2-6 Alkinyl, 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 member aryl-C 1-4 Alkyl, 4-10 member heterocycloalkyl-C 1-4 Alkyl and 5-10 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, 3, or 4 independently selected R groups, each of which can be arbitrarily chosen. 5A Substituted by substituents, Each R a5 , R c5 , and R d5 H and C are independent. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, 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 member aryl-C 1-4 Alkyl, 4-10 member heterocycloalkyl-C 1-4 Alkyl and 5-10 member heteroaryl-C 1-4 Selected from alkyl, the C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, 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 member aryl-C 1-4 Alkyl, 4-10 member heterocycloalkyl-C 1-4 Alkyl and 5-10 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, 3, or 4 independently selected R groups, each of which can be arbitrarily chosen. 5ASubstituting with substituents, Alternatively, any R bonded to the same N atom c5 and R d5 However, together with the N atom to which they are bonded, they form a 4-10 member heterocycloalkyl group, which optionally consists of 1, 2, 3, or 4 independently selected R atoms. 5A Substituting with substituents, Each R b5 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, 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 member aryl-C 1-4 Alkyl, 4-10 member heterocycloalkyl-C 1-4 Alkyl and 5-10 member heteroaryl-C 1-4 Selected from alkyl groups, these are each optionally selected as 1, 2, 3, or 4 independently R 5A Substituting with substituents, Each R e5 These are independently H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 2-6 Alkenil, C 2-6 Alkinyl, 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 member aryl-C 1-4 Alkyl, 4-10 member heterocycloalkyl-C 1-4 Alkyl and 5-10 member heteroaryl-C 1-4 Selected from alkyl groups, Each R f5 and R g5 H and C are independent. 1-6 Alkyl, C 1-6Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 2-6 Alkenil, C 2-6 Alkinyl, 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 member aryl-C 1-4 Alkyl, 4-10 member heterocycloalkyl-C 1-4 Alkyl and 5-10 member heteroaryl-C 1-4 Selected from alkyl groups, Each R h5 and R i5 H and C are independent. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, 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 member aryl-C 1-4 Alkyl, 4-10 member heterocycloalkyl-C 1-4 Alkyl and 5-10 member heteroaryl-C 1-4 Selected from alkyl groups, Each R j5 and R k5 OH and C are independent of each other. 1-6 Alkoxy, and C 1-6 Selected from haloalkoxys, Alternatively, any R bonded to the same B atom j5 and R k5 However, together with the B atom to which they are bonded, C 1-6 Alkyl and C 1-6 A 5-membered or 6-membered heterocycloalkyl group is formed, optionally substituted with 1, 2, 3, or 4 substituents independently selected from the haloalkyl group. Each R 5A They became independent as H, D, Haro, CN, NO2, C 1-6 Alkyl, C2-6 Alkenil, C 2-6 Alkinyl, 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 member aryl-C 1-4 Alkyl, 4-10 member heterocycloalkyl-C 1-4 Alkyl, 5-10 member 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)(=NRe51 )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 Selected from, the C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, 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 member aryl-C 1-4 Alkyl, 4-10 member heterocycloalkyl-C 1-4 Alkyl and 5-10 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, 3, or 4 independently selected R groups, each of which can be arbitrarily chosen. 5B Substituting with substituents, Each R a51 , R c51 , and R d51 H and C are independent. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, 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 member aryl-C 1-4 Alkyl, 4-10 member heterocycloalkyl-C 1-4 Alkyl and 5-10 member heteroaryl-C 1-4 Selected from alkyl, the C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, 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 member aryl-C 1-4 Alkyl, 4-10 member heterocycloalkyl-C 1-4 Alkyl and 5-10 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, 3, or 4 independently selected R groups, each of which can be arbitrarily chosen. 5B Substituting with substituents, Alternatively, any R bonded to the same N atom c51 and R d51 However, together with the N atom to which they are bonded, they form a 4-7 member heterocycloalkyl group, which optionally consists of 1, 2, 3, or 4 independently selected R atoms. 5B Substituting with substituents, Each R b51 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, 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 member aryl-C 1-4 Alkyl, 4-10 member heterocycloalkyl-C 1-4 Alkyl and 5-10 member heteroaryl-C 1-4 Selected from alkyl groups, these are each optionally selected as 1, 2, 3, or 4 independently R 5B Substituting with substituents, Each R e51 These are independently H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 2-6 Alkenil, C 2-6 Alkinyl, 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 member aryl-C 1-4 Alkyl, 4-10 member heterocycloalkyl-C 1-4 Alkyl and 5-10 member heteroaryl-C 1-4 Selected from alkyl groups, Each R f51 and R g51 H and C are independent. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 2-6 Alkenil, C 2-6 Alkinyl, 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 member aryl-C 1-4 Alkyl, 4-10 member heterocycloalkyl-C 1-4 Alkyl and 5-10 member heteroaryl-C 1-4 Selected from alkyl groups, Each R h51 and R i51 H and C are independent. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, 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 member aryl-C 1-4Alkyl, 4-10 member heterocycloalkyl-C 1-4 Alkyl and 5-10 member heteroaryl-C 1-4 Selected from alkyl groups, Each R j51 and R k51 OH and C are independent of each other. 1-6 Alkoxy, and C 1-6 Selected from haloalkoxys, Alternatively, any R bonded to the same B atom j51 and R k51 However, together with the B atom to which they are bonded, C 1-6 Alkyl and C 1-6 A 5-membered or 6-membered heterocycloalkyl group is formed, optionally substituted with 1, 2, 3, or 4 substituents independently selected from the haloalkyl group. Each R 5B They became independent as H, D, Haro, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl, 5-6 member 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)Rb52 , 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 Selected from, the C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-7Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, 3, or 4 independently selected R groups, each of which can be arbitrarily chosen. 5C Substituting with substituents, Each R a52 , R c52 , and R d52 H and C are independent. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl, the C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, 3, or 4 independently selected R groups, each of which can be arbitrarily chosen. 5C Substituting with substituents, Alternatively, any R bonded to the same N atom c52 and R d52However, together with the N atom to which they are bonded, they form a 4-7 member heterocycloalkyl group, which optionally consists of 1, 2, 3, or 4 independently selected R atoms. 5C Substituting with substituents, Each R b52 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl groups, these are each optionally selected as 1, 2, 3, or 4 independently R 5C Substituting with substituents, Each R e52 These are independently H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl groups, Each R f52 and R g52 H and C are independent. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-7Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl groups, Each R h52 and R i52 H and C are independent. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl groups, Each R j52 and R k52 OH and C are independent of each other. 1-6 Alkoxy, and C 1-6 Selected from haloalkoxys, Alternatively, any R bonded to the same B atom j52 and R k52 However, together with the B atom to which they are bonded, C 1-6 Alkyl and C 1-6 A 5-membered or 6-membered heterocycloalkyl group is formed, optionally substituted with 1, 2, 3, or 4 substituents independently selected from the haloalkyl group. Each R 5C They became independent as H, D, Haro, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl, 5-6 member 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 Selected from, the C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, 3, or 4 independently selected R groups, each of which can be arbitrarily chosen. G Substituting with substituents, Each R a53 , R c53 , and R d53 H and C are independent. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl, the C 1-6 Alkyl, C 2-6 Alkenil, C 2-6Alkinyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, 3, or 4 independently selected R groups, each of which can be arbitrarily chosen. G Substituting with substituents, Alternatively, any R bonded to the same N atom c53 and R d53 However, together with the N atom to which they are bonded, they form a 4-7 member heterocycloalkyl group, which optionally consists of 1, 2, 3, or 4 independently selected R atoms. G Substituting with substituents, Each R b53 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl groups, these are each optionally selected as 1, 2, 3, or 4 independently R G Substituting with substituents, Each R e53 These are independently H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-7Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl groups, Each R f53 and R g53 H and C are independent. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl groups, Each R h53 and R i53 H and C are independent. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl groups, Each R j53 and R k53 OH and C are independent of each other. 1-6 Alkoxy, and C 1-6 Selected from haloalkoxys, Alternatively, any R bonded to the same B atom j53 and R k53 However, together with the B atom to which they are bonded, C 1-6 Alkyl and C 1-6 A 5-membered or 6-membered heterocycloalkyl group is formed, optionally substituted with 1, 2, 3, or 4 substituents independently selected from the haloalkyl group. Each R G These became independent: OH, NO2, CN, Halo, C 1-3 Alkyl, C 2-3 Alkenil, C 2-3 Alkinyl, 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 Alkyl sulfinyl, C 1-3 Alkyl sulfonyl, carbamyl, C 1-3 Alkylcarbamyl, di(C 1-3 Alkyl)carbamyl, carboxy, C 1-3 Alkylcarbonyl, C 1-3 Alkoxycarbonyl, C 1-3 Alkylcarbonyloxy, C 1-3 Alkylcarbonylamino, C 1-3 Alkoxycarbonylamino, C 1-3 Alkylaminocarbonyloxy, C 1-3 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 1-3Alkylaminocarbonylamino, and di(C 1-3 Selected from alkyl)aminocarbonylamino, The compound, or a pharmaceutically acceptable salt thereof, is provided.

[0016] In some embodiments, R 1 These are independently H, Haro, CN, NO2, and C. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl, 5-6 member heteroaryl-C 1-4 Alkyl, OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 ,OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , NR c1 S(O)2R b1 , NR c1 S(O)2NR c1 R d1 S(O)2R b1 , and S(O)2NR c1 R d1 Selected from, the C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-7Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Each alkyl group can be optionally selected from 1, 2, 3, or 4 independently selected R groups. 1A It is substituted with a substituent.

[0017] In some embodiments, R 1 These are independently H, Haro, CN, NO2, and C. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl, 5-6 member 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 Rd1 Selected from, the C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Each alkyl group can be optionally selected from 1, 2, 3, or 4 independently selected R groups. 1A It is substituted with a substituent.

[0018] In some embodiments, R 1 These are H, Haro, CN, and C, which are independent of each other. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-3 Alkyl, phenyl-C 1-3 Alkyl, 4-7 member heterocycloalkyl-C 1-3 Alkyl, 5-6 member heteroaryl-C 1-3 Alkyl, OR a1 , SR a1 , and NR c1 R d1 Selected from, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-3 Alkyl, phenyl-C 1-3 Alkyl, 4-7 member heterocycloalkyl-C 1-3 Alkyl and 5-6 member heteroaryl-C 1-3 The alkyl group consists of one or two independently selected R groups, each of which is optional. 1A It is substituted with a substituent.

[0019] In some embodiments, R 1 These are H, Haro, CN, and C, which are independent of each other. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-3 Alkyl, phenyl-C 1-3 Alkyl, 4-7 member heterocycloalkyl-C 1-3 Alkyl, 5-6 member heteroaryl-C 1-3 Alkyl, OR a1 , and NR c1 R d1 Selected from, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-3 Alkyl, phenyl-C 1-3 Alkyl, 4-7 member heterocycloalkyl-C 1-3 Alkyl and 5-6 member heteroaryl-C 1-3 The alkyl group consists of one or two independently selected R groups, each of which is optional. 1A It is substituted with a substituent.

[0020] In some embodiments, R 1 These are H, Haro, CN, and C, which are independent of each other. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-4 Cycloalkyl and OR a1 Selected from, the C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl and C 3-4 Each cycloalkyl group is optionally selected from 1, 2, 3, or 4 independently selected R groups. 1A It is substituted with a substituent.

[0021] In some embodiments, R 1 These are H, Haro, CN, and C, which are independent of each other. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-4 Cycloalkyl and OR a1 Selected from, the C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl and C 3-4 Each cycloalkyl group is optionally selected from one or two independently selected R groups. 1A It is substituted with a substituent.

[0022] In some embodiments, R 1 H and C are independent of each other. 1-6 Alkyl, phenyl, 5-7 member heterocycloalkyl, OR a1 , SR a1 , and NR c1 R d1 Selected from, the C 1-6 Alkyl, phenyl, and 5- to 7-membered heterocycloalkyl groups are each optionally selected as one or two independently selected R groups. 1A It is substituted with a substituent.

[0023] In some embodiments, R 1 H and OR are independent of each other. a1 Selected from.

[0024] Some implementation methods, each R a1 , R c1 , and R d1 H and C are independent. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl, the C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, 3, or 4 independently selected R groups, each of which can be arbitrarily chosen. 1A Substituting with substituents, Each R b1 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl groups, these are each optionally selected as 1, 2, 3, or 4 independently R 1A Substituting with substituents, Each R 1A They became independent as H, Haro, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl, 5-6 member heteroaryl-C 1-4 Alkyl, OR a11 , C(O)R b11 , C(O)NR c11 R d11 , C(O)OR a11 ,OC(O)R b11 , OC(O)NR c11 R d11 , NR c11 R d11 , NR c11 C(O)R b11 , NR c11 C(O)OR a11 , NR c11 C(O)NR c11 R d11 , NR c11 S(O)2R b11 , NR c11 S(O)2NR c11 R d11 S(O)2R b11 , and S(O)2NR c11 R d11 Selected from, the C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, 3, or 4 independently selected R groups, each of which can be arbitrarily chosen. 1B Substituting with substituents, Each R a11 , R c11 , and R d11 H and C are independent. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, 3, or 4 independently selected R groups, each of which can be arbitrarily chosen. 1B Substituting with substituents, Each R b11 C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl groups, these are each optionally selected as 1, 2, 3, or 4 independently R 1B Substituting with substituents, Each R 1B They became independent as H, Haro, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-4 Cycloalkyl, OR a12 , C(O)R b12 , C(O)NR c12 R d12, C(O)OR a12 ,OC(O)R b12 , NR c12 R d12 , NR c12 C(O)R b12 , NR c12 S(O)2R b12 S(O)2R b12 , and S(O)2NR c12 R d12 Selected from, Each R a12 , R c12 , and R d12 H and C are independent. 1-6 Alkyl and C 1-6 Selected from haloalkyls, Each R b12 C 1-6 Alkyl and C 1-6 Selected from haloalkyl groups.

[0025] Some implementation methods, each R a1 , R c1 , and R d1 H and C are independent. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, 3, or 4 independently selected R groups, each of which can be arbitrarily chosen.1A Substituting with substituents, Each R b1 C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl groups, these are each optionally selected as 1, 2, 3, or 4 independently R 1A Substituting with substituents, Each R 1A They became independent as H, D, Haro, CN, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl, 5-6 member heteroaryl-C 1-4 Alkyl, OR a11 , C(O)R b11 , C(O)NR c11 R d11 , C(O)OR a11 ,OC(O)R b11 , OC(O)NR c11 R d11 , NR c11 R d11 , NR c11 C(O)R b11 , NR c11 C(O)OR a11 , NR c11 C(O)NR c11 R d11 , NR c11 S(O)2R b11 , NR c11 S(O)2NR c11 R d11 S(O)2Rb11 , and S(O)2NR c11 R d11 Selected from, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, 3, or 4 independently selected R groups, each of which can be arbitrarily chosen. 1B Substituting with substituents, Each R a11 , R c11 , and R d11 H and C are independent. 1-6 Alkyl and C 1-6 Selected from haloalkyls, Each R b11 C 1-6 Alkyl and C 1-6 Selected from haloalkyls, Each R 1B H, D, and OR are independent of each other. a12 Selected from, Each R a12 H and C are independent of each other. 1-6 Selected from alkyl groups.

[0026] Some implementation methods, each R a1 , R c1 , and R d1 H and C are independent. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl, the C1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, 3, or 4 independently selected R groups, each of which can be arbitrarily chosen. 1A Substituting with substituents, Each R b1 C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl groups, these are each optionally selected as 1, 2, 3, or 4 independently R 1A Substituting with substituents, Each R 1A They became independent as H, Haro, CN, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl, 5-6 member heteroaryl-C 1-4 Alkyl, OR a11 , C(O)R b11 , C(O)NR c11 R d11 , C(O)OR a11 ,OC(O)R b11 , OC(O)NR c11 Rd11 , NR c11 R d11 , NR c11 C(O)R b11 , NR c11 C(O)OR a11 , NR c11 C(O)NR c11 R d11 , NR c11 S(O)2R b11 , NR c11 S(O)2NR c11 R d11 S(O)2R b11 , and S(O)2NR c11 R d11 Selected from, Each R a11 , R c11 , and R d11 H and C are independent. 1-6 Alkyl and C 1-6 Selected from haloalkyls, Each R b11 C 1-6 Alkyl and C 1-6 Selected from haloalkyl groups.

[0027] Some implementation methods, each R a1 , R c1 , and R d1 H and C are independent. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, 3, or 4 independently selected R groups, each of which can be arbitrarily chosen. 1A Substituting with substituents, Each R b1 C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl groups, these are each optionally selected as 1, 2, 3, or 4 independently R 1A Substituting with substituents, Each R 1A They became independent as H, Haro, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, OH, C 1-3 Alkoxy, C 1-3 Haloalkoxy, amino, C 1-3 Alkylamino, di(C 1-3 Alkyl)amino, cyano-C 1-4 Alkyl, HO-C 1-4 Alkyl, C 1-3 Alkoxy-C 1-4 Alkyl and C 3-4 Selected from cycloalkyl groups.

[0028] Some implementation methods, each R a1 , R c1 , and R d1 H and C are independent. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, phenyl, 4-6 member heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkyl and 4-6 member heterocycloalkyl-C 1-3Selected from alkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, phenyl, 4-6 member heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkyl and 4-6 member heterocycloalkyl-C 1-3 The alkyl group consists of 1, 2, or 3 independently selected R groups, each of which can be arbitrarily chosen. 1A Substituting with substituents, Each R b1 C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-6 member heterocycloalkyl, C 3-6 Cycloalkyl-C 1-2 Alkyl and 4-6 member heterocycloalkyl-C 1-2 Selected from alkyl groups, these are each optionally selected as one or two independently R groups. 1A Substituting with substituents, Each R 1A They became independent: H, D, Haro, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, OR a11 , and C(O)OR a11 Selected from, the C 1-6 Alkyl and C 1-6 The haloalkyl group consists of one, two, or three independently selected R groups, each of which can be arbitrarily chosen. 1B Substituting with substituents, Each R a11 H and C are independent of each other. 1-4 Selected from alkyl, the C 1-4 The alkyl group is optionally selected from 1, 2, or 3 independently selected R 1B Substituted by substituents, Each R 1B These are H, D, and OC, independently. 1-4 Selected from alkyl groups.

[0029] Some implementation methods, each R a1 , R c1 , and R d1 H and C are independent.1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-6 member heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkyl and 4-6 member heterocycloalkyl-C 1-3 Selected from alkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-6 member heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkyl and 4-6 member heterocycloalkyl-C 1-3 Alkyl is selected from one or two independently selected R components, each at will. 1A Substituting with substituents, Each R b1 C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-6 member heterocycloalkyl, C 3-6 Cycloalkyl-C 1-2 Alkyl and 4-6 member heterocycloalkyl-C 1-2 Selected from alkyl groups, these are each optionally selected as one or two independently R groups. 1A Substituting with substituents, Each R 1A These become independent: H, Halo, OH, C 1-3 Alkoxy, and C 1-3 Selected from haloalkoxys.

[0030] In some embodiments, R 1 However, H, C 1-6 Alkyl, phenyl, 5-7 member heterocycloalkyl, OR a1 , SR a1 , or NR c1 R d1 and C 1-6 Alkyl, phenyl, and 5- to 7-membered heterocycloalkyl groups are each optionally selected as one or two independently selected R groups. 1A Substituting with substituents, Each Ra1 , R c1 , and R d1 are each independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, phenyl, 4- to 6-membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkyl, and 4- to 6-membered heterocycloalkyl-C 1-3 alkyl, and are selected from 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, phenyl, 4- to 6-membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkyl, and 4- to 6-membered heterocycloalkyl-C 1-3 alkyl may each optionally be substituted with one, two, or three independently selected R 1A substituents, each R 1A is independently D, halo, CN, C 1-4 alkyl, C 1-4 haloalkyl, OR[[ID=NO:40]] a11 , and C(O)OR a11 and are selected from 1-4 alkyl and C 1-4 haloalkyl may each optionally be substituted with one, two, or three independently selected R 1B substituents, each R a11 is independently H and C 1-4 alkyl, each R 1B is independently H, D, and O-C 1-4 alkyl.

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

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

[0033] In some embodiments, R 1 is independently selected from H, C 1-6 alkyl, phenyl, 5- to 7-membered heterocycloalkyl, OR a1 , SR a1 and NR c1 R d1 wherein the C 1-6 alkyl, phenyl, and 5- to 7-membered heterocycloalkyl are each optionally substituted with one or two independently selected R 1A substituents, Ra1 However, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, CF3CH2-, CHF2CH2-, CF3CH2CH2-, CHF2CF2CH2-, CH3OCH2CH2-, CD3CD2-, (CH3)2-CD-, (CD3)2-CH-, (CD3)2-CD-, cyclopropyl, cyclobutyl, 3-methylcyclobutyl, 3-difluoromethylcyclobutyl, 3,3-difluorocyclobutyl, cyclopentyl, 3,3-difluorocyclopentyl, 4,4-difluorocyclohexyl, tetrahydro-1 Selected from H-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)-piperidine-4-yl, cyclopropyl-CH2-, cyclobutyl-CH2-, 1-trifluoromethylcyclobutyl-CH2-, cyclopentyl-CH2-, and (tetrahydrofuran-3-yl)-CH2-, R c1 However, H is, R d1 However, it is phenyl, Each R 1A They became independent as Hello, CN, and C 1-3 Alkyl and C 1-3 Selected from haloalkyl groups.

[0034] In some embodiments, R 1 H and OR are independent of each other. a1 Selected from, in the formula, R a1Ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, CF3CH2-, CHF2CH2-, CF3CH2CH2-, CHF2CF2CH2-, CH3OCH2CH2-, CD3CD2-, (CH3)2-CD-, (CD3)2-CH-, (CD3)2-CD-, cyclopropyl, cyclobutyl, 3-methylcyclobutyl, 3-difluoromethylcyclobutyl, 3,3-difluorocyclobutyl, cyclopentyl, 3,3-difluorocyclopentyl, 4,4-difluorocyclohexyl, tetrahydro-1 Selected from H-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)-piperidine-4-yl, cyclopropyl-CH2-, cyclobutyl-CH2-, 1-trifluoromethylcyclobutyl-CH2-, cyclopentyl-CH2-, and (tetrahydrofuran-3-yl)-CH2-.

[0035] In some embodiments, R 1 H and OR are independent of each other. a1 Selected from, in the formula, R a1 These are ethyl, isopropyl, isobutyl, tetrahydro-1H-pyran-4-yl, cyclopropyl-CH2-, (tetrahydrofuran-3-yl)-CH2-, CH3OCH2CH2-, CF3CH2-, and CHF2CH2-.

[0036] In some embodiments, R 1 C 1-3 Selected from alkyl groups.

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

[0038] In some embodiments, R 1 This involves one or two independently selected R 1A A phenyl compound optionally substituted by substituents, where each R in the formula1A These are independently: Halo, CN, and C 1-3 Selected from haloalkyl groups.

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

[0040] In some embodiments, R 1 This involves one or two independently selected R 1A Selected from 5- to 7-membered heterocycloalkyl groups that are optionally substituted by substituents, in the formula each R 1A They are independent, Hello, C 1-3 Alkyl and C 1-3 Selected from haloalkyl groups.

[0041] In some embodiments, R 1 The following are selected from pyrrolidine-1-yl, 3,3-difluoropyrrolidine-1-yl, piperidine-1-yl, 3-fluoropiperidine-1-yl, 4-fluoropiperidine-1-yl, 4-methylpiperidine-1-yl, (4-trifluoromethyl)piperidine-1-yl, 3,3-difluoropiperidine-1-yl, 3-(difluoromethyl)pyrrolidinyl, 2-methylpyrrolidinyl, 2-methylpiperidinyl, 3-(trifluoromethyl)piperidinyl, azabicyclo[2.2.1]heptan-7-yl, azabicyclo[2.2.1]heptan-2-yl, and (2-methoxyethyl)piperazine-1-yl.

[0042] In some embodiments, R 1 , SR a1 Selected from, in the formula, R a1 C 1-3 Selected from alkyl groups.

[0043] In some embodiments, R 1 , SR a1 Selected from, in the formula, R a1 The compound is selected from ethyl, propyl, and isopropyl.

[0044] In some embodiments, R 1 , NR c1 R d1 Selected from, in the formula, R c1 and R d1 Each of these is independently selected from H and phenyl.

[0045] In some embodiments, R 1 , NR c1 R d1 Selected from, in the formula, R c1 H is R d1 It is phenyl.

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

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

[0048] In some embodiments, R 2 H, Haro, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 Alkenil, C 2-4 Alkinyl, OH, C 1-3 Alkoxy, C 1-3 Haloalkoxy, amino, C 1-3 Alkylamino, di(C 1-3 Alkyl)amino, cyano-C 1-4 Alkyl, HO-C 1-4 Alkyl, C 1-3 Alkoxy-C 1-4 Alkyl and C 3-4 Selected from cycloalkyl groups.

[0049] In some embodiments, R 2 H, Haro, CN, C 1-3 Alkyl and C 1-3 Selected from haloalkyl groups.

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

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

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

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

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

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

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

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

[0058] In some embodiments, n is 0.

[0059] In some embodiments, n is 1.

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

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

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

[0063] In some embodiments, R4 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Each alkyl group can be optionally selected from 1, 2, 3, or 4 independently selected R groups. 4A Substituting with substituents.

[0064] In some embodiments, R 4 C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, and 4-7 member heterocycloalkyl-C 1-4 Selected from alkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyls, phenyls, 4-7 member heterocycloalkyls, and 5-6 member heteroaryls are each optionally selected from 1, 2, 3, or 4 independently selected R 4A Substituting with substituents.

[0065] In some embodiments, R 4 C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Selected from cycloalkyl, phenyl, 4-7 member heterocycloalkyl, and 5-6 member heteroaryl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyls, phenyls, 4-7 member heterocycloalkyls, and 5-6 member heteroaryls are each optionally selected from 1, 2, 3, or 4 independently selected R 4A Substituting with substituents.

[0066] In some embodiments, R 4 C 1-6 Alkyl, C 3-6 Cycloalkyl, 5-6 member heteroaryl, and 4-7 member heterocycloalkyl-C 1-4 Selected from alkyl, the C 1-6 Alkyl, C 3-6 Cycloalkyl, 5-6 member heteroaryl, and 4-7 member heterocycloalkyl-C 1-4 The alkyl group consists of one or two independently selected R groups, each of which is optional. 4A Substituting with substituents.

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

[0068] In some embodiments, R 4 C 1-6 Alkyl and C 3-6 It is a cycloalkyl group.

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

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

[0071] In some embodiments, R 4 This involves one or two independently selected R 4A Selected from 5- to 6-membered heteroaryl compounds, which are optionally substituted by substituents.

[0072] In some embodiments, R 4 This involves one or two independently selected R 4A A 4- to 7-membered heterocycloalkyl-C molecule that can be optionally substituted by substituents. 1-4 Selected from alkyl groups.

[0073] In some embodiments, Each R 4A They became independent as H, Haro, CN, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl, 5-6 member heteroaryl-C 1-4 Alkyl, OR a41 , SR a41 NHOR a41 , C(O)R b41 , C(O)NR c41 R d41 , C(O)OR a41 ,OC(O)R b41 , OC(O)NR c41 R d41 , NR c41 R d41 , NR c41 C(O)R b41 , NR c41 C(O)OR a41 , NR c41 C(O)NR c41 R d41 , NRc41 S(O)2R b41 , NR c41 S(O)2NR c41 R d41 S(O)2R b41 , and S(O)2NR c41 R d41 Selected from, the C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, 3, or 4 independently selected R groups, each of which can be arbitrarily chosen. 4B Substituting with substituents, Each R a41 , R c41 , and R d41 H and C are independent. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl, the C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, 3, or 4 independently selected R groups, each of which can be arbitrarily chosen. 4B Substituting with substituents, Each R b41 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl groups, these are each optionally selected as 1, 2, 3, or 4 independently R 4B Substituting with substituents, Each R 4B They became independent as H, Haro, CN, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl, 5-6 member heteroaryl-C 1-4 Alkyl, OR a42 , C(O)R b42 , C(O)NR c42 R d42 , C(O)OR a42 ,OC(O)R b42 , OC(O)NR c42 R d42 , NR c42 R d42 , NR c42 C(O)R b42, NR c42 C(O)OR a42 , NR c42 C(O)NR c42 R d42 , NR c42 S(O)2R b42 , NR c42 S(O)2NR c42 R d42 S(O)2R b42 , and S(O)2NR c42 R d42 Selected from, the C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, 3, or 4 independently selected R groups, each of which can be arbitrarily chosen. 4C Substituting with substituents, Each R a42 , R c42 , and R d42 H and C are independent. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl, the C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-7Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, 3, or 4 independently selected R groups, each of which can be arbitrarily chosen. 4C Substituting with substituents, Each R b42 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl groups, these are each optionally selected as 1, 2, 3, or 4 independently R 4C Substituting with substituents, Each R 4C They became independent as H, Haro, CN, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-4 Cycloalkyl, OR a43 , C(O)R b43 , C(O)NR c43 R d43 , C(O)OR a43 ,OC(O)R b43 , NR c43 R d43 , NR c43 C(O)R b43 , NR c43 S(O)2R b43 S(O)2R b43 , and S(O)2NR c43 R d43Selected from, Each R a43 , R c43 , and R d43 H and C are independent. 1-6 Alkyl and C 1-6 Selected from haloalkyls, Each R b43 C 1-6 Alkyl and C 1-6 Selected from haloalkyl groups.

[0074] In some embodiments, Each R 4A They became independent as H, Haro, CN, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl, 5-6 member heteroaryl-C 1-4 Alkyl, OR a41 , SR a41 NHOR a41 , C(O)R b41 , C(O)NR c41 R d41 , C(O)OR a41 ,OC(O)R b41 , OC(O)NR c41 R d41 , NR c41 R d41 , NR c41 C(O)R b41 , NR c41 C(O)OR a41 , NR c41 C(O)NR c41 R d41 , NR c41 S(O)2R b41 , NR c41 S(O)2NR c41 R d41 S(O)2R b41 , and S(O)2NR c41 R d41 Selected from, the C1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, or 3 independently selected R groups, each of which can be arbitrarily chosen. 4B Substituting with substituents, Each R a41 , R c41 , and R d41 H and C are independent. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, or 3 independently selected R groups, each of which can be arbitrarily chosen. 4B Substituting with substituents, Each R b41 C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl groups, these are each optionally selected as 1, 2, or 3 independently. 4B Substituting with substituents, Each R 4B They became independent as H, Haro, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-4 Cycloalkyl, OR a42 , C(O)R b42 , C(O)NR c42 R d42 , C(O)OR a42 , NR c42 R d42 , NR c42 C(O)R b42 , NR c42 C(O)OR a42 , NR c42 C(O)NR c42 R d42 , NR c42 S(O)2R b42 , NR c42 S(O)2NR c42 R d42 S(O)2R b42 , and S(O)2NR c42 R d42 Selected from, Each R a42 , R c42 , and R d42 H and C are independent. 1-6 Alkyl and C 1-6 Selected from haloalkyls, Each R b42 C 1-6 Alkyl and C 1-6 Selected from haloalkyl groups.

[0075] In some embodiments, Each R 4A They became independent as H, Haro, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C3-4 Cycloalkyl, OR a41 , C(O)R b41 , C(O)NR c41 R d41 , C(O)OR a41 ,OC(O)R b41 , OC(O)NR c41 R d41 , NR c41 R d41 , NR c41 C(O)R b41 , NR c41 C(O)OR a41 , NR c41 C(O)NR c41 R d41 , NR c41 S(O)2R b41 , NR c41 S(O)2NR c41 R d41 S(O)2R b41 , and S(O)2NR c41 R d41 Selected from, the C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-4 Each cycloalkyl group is optionally selected from 1, 2, or 3 independently selected R groups. 4B Substituting with substituents, Each R a41 , R c41 , and R d41 H and C are independent. 1-6 Alkyl, C 1-6 Haloalkyl and C 3-4 Selected from cycloalkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-4 The cycloalkyl group consists of one or two independently selected R groups, each of which can be arbitrarily chosen. 4B Substituting with substituents, Each R b41 C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-4 Selected from cycloalkyl groups, these are each optionally selected as one or two independently. 4B Substituting with substituents, Each R4B They became independent as H, Haro, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, OR a42 , and NR c42 R d42 Selected from, Each R a42 , R c42 , and R d42 H and C are independent. 1-3 Alkyl and C 1-3 Selected from haloalkyls, Each R b42 C 1-3 Alkyl and C 1-3 Selected from haloalkyl groups.

[0076] In some embodiments, Each R 4A They became independent as H, Haro, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-4 Cycloalkyl, OR a41 , C(O)R b41 , C(O)NR c41 R d41 , C(O)OR a41 ,OC(O)R b41 , OC(O)NR c41 R d41 , NR c41 R d41 , NR c41 C(O)R b41 , NR c41 C(O)OR a41 , NR c41 C(O)NR c41 R d41 , NR c41 S(O)2R b41 , NR c41 S(O)2NR c41 R d41 S(O)2R b41 , and S(O)2NR c41 R d41 Selected from, Each R a41 , R c41 , and R d41 H and C are independent. 1-3 Alkyl and C1-3 Selected from haloalkyls, Each R b41 C 1-3 Alkyl and C 1-3 Selected from haloalkyl groups.

[0077] In some embodiments, Each R 4A They became independent as H, Haro, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, OR a41 , and NR c41 R d41 Selected from, Each R a41 , R c41 , and R d41 H and C are independent of each other. 1-3 Alkyl and C 1-3 Selected from haloalkyls, Each R b41 However, independently C 1-3 It is alkyl.

[0078] In some embodiments, R 4 R 4A C is optionally replaced by 1-6 It is an alkyl, and in the formula, R 4A , NR c41 R d41 And R c41 and R d41 These are H and C, which are independent of each other. 1-3 Alkyl and C 1-3 Selected from haloalkyl groups.

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

[0080] In some embodiments, R 4 This involves one or two independently selected R 4ASelected from 5-6 member heteroaryls, which can be optionally substituted by substituents, in the formula each R 4A C 1-3 Selected from alkyl groups.

[0081] In some embodiments, R 4 The is selected from 1-methyl-1H-pyrazole-4-yl, 1-methyl-1H-imidazole-4-yl, and 2-methyl-2H-1,2,3-triazole-4-yl.

[0082] In some embodiments, R 4 This involves one or two independently selected R 4A A 4- to 7-membered heterocycloalkyl-C molecule that can be optionally substituted by substituents. 1-4 Selected from alkyl groups, in the formula, each R 4A C 1-3 Selected from alkyl and OH.

[0083] In some embodiments, R 4 These are methyl, ethyl, propyl, butyl, cyclopropyl, pyrazol-4-yl, imidazole-4-yl, 1,2,3-triazole-4-yl, and morpholin-4-yl-C. 1-4 Alkyl, piperidinyl-C 1-4 Alkyl, piperazinyl-C 1-4 Alkyl, pyrrolidinyl-C 1-4 Selected from alkyl groups, each of which is optionally one or two independently selected R groups. 4A Substituting with substituents.

[0084] In some embodiments, R 4The following are selected from (pyrrolidine-1-yl)CH2CH2, -(pyrrolidine-3-ol)CH2CH2-, (pyrrolidine-1-yl)CH2CH2CH2-, (3-difluoromethylpyrrolidine-1-yl)CH2CH2CH2CH2-, (piperidine-1-yl)CH2CH2CH2-, (4-methylpiperazine-1-yl)CH2CH2CH2-, (4-ethylpiperazine-1-yl)CH2CH2CH2-, and 4-morpholinobutyl.

[0085] In some embodiments, R 4 These include 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-pyrazole-4-yl, 1-methyl-1H-imidazole-4-yl, and 2-methyl-2H-1,2,3-triazole-4-yl. Selected from (pyrrolidine-1-yl)CH2CH2, (pyrrolidine-3-ol)CH2CH2, (pyrrolidine-1-yl)CH2CH2CH2, (3-difluoromethylpyrrolidine-1-yl)CH2CH2CH2CH2, (piperidine-1-yl)CH2CH2CH2, (4-methylpiperazine-1-yl)CH2CH2CH2, (4-ethylpiperazine-1-yl)CH2CH2CH2, and 4-morpholinobutyl.

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

[0087] In some embodiments, the ring portion A is a 5-6 member heteroaryl.

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

[0089] In some embodiments, ring portion A is 1H-pyrrolo[2,3-b]pyridine-4-yl, pyridine-4-yl, or 1H-pyrazole-4-yl.

[0090] In some embodiments, the ring portion A is 1H-pyrazole-4-yl.

[0091] In some embodiments, ring portion A is 1H-pyrazole-4-yl, and ring portion B is selected from the following. [ka] In some embodiments, ring portion A is 1H-pyrazole-4-yl and ring portion B is piperidinyl.

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

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

[0094] In some embodiments, p is 0.

[0095] In some embodiments, p is 1.

[0096] Some implementation methods, each R 5 These are independently H, Haro, NO2, CN, and C. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl, 5-6 member heteroaryl-C 1-4 Alkyl, OR a5 , SR a5 NHOR a5 , C(O)R b5, C(O)NR c5 R d5 , C(O)OR a5 ,OC(O)R b5 , OC(O)NR c5 R d5 , NR c5 R d5 , NR c5 C(O)R b5 , NR c5 C(O)OR a5 , NR c5 C(O)NR c5 R d5 , NR c5 S(O)2R b5 , NR c5 S(O)2NR c5 R d5 S(O)2R b5 , and S(O)2NR c5 R d5 Selected from, the C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Each alkyl group can be optionally selected from 1, 2, 3, or 4 independently selected R groups. 5A Substituting with substituents.

[0097] Some implementation methods, each R 5 These are independently H, Haro, NO2, CN, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, OR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , NRc5 R d5 , NR c5 C(O)R b5 , NR c5 S(O)2R b5 S(O)2R b5 , and S(O)2NR c5 R d5 Selected from, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyls, phenyls, 4-7 member heterocycloalkyls, and 5-6 member heteroaryls are each optionally selected from 1, 2, 3, or 4 independently selected R 5A Substituting with substituents.

[0098] Some implementation methods, each R 5 These are H, Haro, CN, and C, which are independent of each other. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-4 Cycloalkyl, OR a5 , and NR c5 R d5 Selected from, the C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-4 Each cycloalkyl group is optionally selected from 1, 2, 3, or 4 independently selected R groups. 5A Substituting with substituents.

[0099] Some implementation methods, each R 5 These are H, Haro, CN, and C, which are independent of each other. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-4 Cycloalkyl, OR a5 , and NR c5 R d5 Selected from, each R a5 , R c5 , and R d5 H and C are independent of each other. 1-6 Alkyl and C 1-6 Selected from haloalkyl groups.

[0100] Some implementation methods, each R 5 H and C are independent of each other.1-3 Selected from alkyl and amino.

[0101] Some implementation methods, each R 5 This is independently selected from CH3 or NH2.

[0102] Some implementation methods, each R 5 These are independently selected from H and amino.

[0103] Some implementation methods, each R 5 H and C are independent of each other. 1-3 Selected from alkyl groups.

[0104] In some embodiments, Each R a5 , R c5 , and R d5 H and C are independent. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl, the C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, 3, or 4 independently selected R groups, each of which can be arbitrarily chosen. 5ASubstituting with substituents, Each R b5 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl groups, these are each optionally selected as 1, 2, 3, or 4 independently R 5A Substituting with substituents, Each R 5A They became independent as H, Haro, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl, 5-6 member heteroaryl-C 1-4 Alkyl, OR a51 , SR a51 NHOR a51 , C(O)R b51 , C(O)NR c51 R d51 , C(O)OR a51 ,OC(O)R b51 , OC(O)NR c51 R d51 , NR c51 R d51 , NR c51 C(O)R b51 , NR c51 C(O)OR a51 , NR c51 C(O)NR c51 R d51 , NR c51 S(O)2R b51 , NRc51 S(O)2NR c51 R d51 S(O)2R b51 , and S(O)2NR c51 R d51 Selected from, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, 3, or 4 independently selected R groups, each of which can be arbitrarily chosen. 5B Substituting with substituents, Each R a51 , R c51 , and R d51 H and C are independent. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, 3, or 4 independently selected R groups, each of which can be arbitrarily chosen. 5B Substituting with substituents, Each R b51C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl groups, these are each optionally selected as 1, 2, 3, or 4 independently R 5B Substituting with substituents, Each R 5B They became independent as H, Haro, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-4 Cycloalkyl, OR a52 , SR a52 NHOR a52 , C(O)R b52 , C(O)NR c52 R d52 , C(O)OR a52 ,OC(O)R b52 , OC(O)NR c52 R d52 , NR c52 R d52 , NR c52 C(O)R b52 , NR c52 C(O)OR a52 , NR c52 C(O)NR c52 R d52 , NR c52 S(O)2R b52 , NR c52 S(O)2NR c52 R d52 S(O)2R b52 , and S(O)2NR c52 R d52 Selected from, Each R a52 , R c52 , and R d52 H and C are independent. 1-6 Alkyl and C 1-6 Selected from haloalkyls, Each R b52 C 1-6 Alkyl and C 1-6 Selected from haloalkyl groups.

[0105] In some embodiments, Each R a5 , R c5 , and R d5 H and C are independent. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, 3, or 4 independently selected R groups, each of which can be arbitrarily chosen. 5A Substituting with substituents, Each R b5 C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl groups, these are each optionally selected as 1, 2, 3, or 4 independently R5A Substituting with substituents, Each R 5A They became independent as H, Haro, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-4 Cycloalkyl, OR a51 , SR a51 NHOR a51 , C(O)R b51 , C(O)NR c51 R d51 , C(O)OR a51 ,OC(O)R b51 , OC(O)NR c51 R d51 , NR c51 R d51 , NR c51 C(O)R b51 , NR c51 C(O)OR a51 , NR c51 C(O)NR c51 R d51 , NR c51 S(O)2R b51 , NR c51 S(O)2NR c51 R d51 S(O)2R b51 , and S(O)2NR c51 R d51 Selected from, Each R a51 , R c51 , and R d51 H and C are independent. 1-6 Alkyl and C 1-6 Selected from haloalkyls, Each R b51 C 1-6 Alkyl and C 1-6 Selected from haloalkyl groups.

[0106] In some embodiments, Each R a5 , R c5 , and R d5 H and C are independent. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7Selected from cycloalkyl, phenyl, 4-7 member heterocycloalkyl, and 5-6 member heteroaryl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, and 5-6 member heteroaryl are each optionally selected from 1, 2, 3, or 4 independently selected R 5A Substituting with substituents, Each R b5 C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Selected from cycloalkyl, phenyl, 4-7 member heterocycloalkyl, and 5-6 member heteroaryl, each of which can be optionally selected as 1, 2, 3, or 4 independently. 5A Substituting with substituents, Each R 5A They became independent as H, Haro, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-4 Cycloalkyl, OR a51 , and NR c51 R d51 Selected from, Each R a51 , R c51 , and R d51 H and C are independent of each other. 1-3 Selected from alkyl groups, Each R b51 C 1-3 It is alkyl.

[0107] In some embodiments, Each R a5 , R c5 , and R d5 H and C are independent. 1-6 Alkyl, C 1-6 Haloalkyl and C 3-4 Selected from cycloalkyl groups, Each R b5 C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-4 Selected from cycloalkyl groups.

[0108] In some embodiments, n is 0, 1, or 2, p is 0, 1, or 2, Ring portion A is C 3-10 Selected from cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, Ring portion B is a monocyclic 4-7 member heterocycloalkyl group. R 1 They became independent as H, Haro, CN, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl, 5-6 member heteroaryl-C 1-4 Alkyl, OR a1 , SR a1 , and NR c1 R d1 Selected from, the C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, 3, or 4 independently selected R groups, each of which can be arbitrarily chosen. 1A Substituting with substituents, Each R a1 , R c1 , and R d1 H and C are independent.1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, 3, or 4 independently selected R groups, each of which can be arbitrarily chosen. 1A Substituting with substituents, Each R b1 C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl groups, these are each optionally selected as 1, 2, 3, or 4 independently R 1A Substituting with substituents, Each R 1A They became independent as H, D, Haro, CN, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl, 5-6 member heteroaryl-C 1-4 Alkyl, OR a11 , C(O)R b11 , C(O)NR c11 R d11 , C(O)OR a11 ,OC(O)R b11 , OC(O)NR c11 R d11 , NR c11 R d11 , NR c11 C(O)R b11 , NR c11 C(O)OR a11 , NR c11 C(O)NR c11 R d11 , NR c11 S(O)2R b11 , NR c11 S(O)2NR c11 R d11 S(O)2R b11 , and S(O)2NR c11 R d11 Selected from, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, 3, or 4 independently selected R groups, each of which can be arbitrarily chosen. 1B Substituted by substituents, Each R a11 , R c11 , and R d11 H and C are independent. 1-6 Alkyl and C 1-6 Selected from haloalkyls, Each R b11 C 1-6 Alkyl and C1-6 Selected from haloalkyls, Each R 1B H, D, and OR are independent of each other. a12 Selected from, Each R a12 H and C are independent of each other. 1-6 Selected from alkyl groups, R 2 However, H, Haro, CN, C 1-3 Alkyl and C 1-3 Selected from haloalkyls, Each R 3 They became independent as H, Haro, C 1-3 Selected from alkyl and cyclopropyl, R 4 However, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, 3, or 4 independently selected R groups, each of which can be arbitrarily chosen. 4A Substituted by substituents, Each R 4A They became independent as H, Haro, CN, NO2, C 1-6 Alkyl, C1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl, 5-6 member heteroaryl-C 1-4 Alkyl, OR a41 , SR a41 NHOR a41 , C(O)R b41 , C(O)NR c41 R d41 , C(O)OR a41 ,OC(O)R b41 , OC(O)NR c41 R d41 , NR c41 R d41 , NR c41 C(O)R b41 , NR c41 C(O)OR a41 , NR c41 C(O)NR c41 R d41 , NR c41 S(O)2R b41 , NR c41 S(O)2NR c41 R d41 S(O)2R b41 , and S(O)2NR c41 R d41 Selected from, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, or 3 independently selected R groups, each of which can be arbitrarily chosen. 4B Substituting with substituents, Each R a41 , R c41 , and Rd41 H and C are independent. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, or 3 independently selected R groups, each of which can be arbitrarily chosen. 4B Substituting with substituents, Each R b41 C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl groups, these are each optionally selected as 1, 2, or 3 independently. 4B Substituting with substituents, Each R 4B They became independent as H, Haro, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-4 Cycloalkyl, OR a42 , C(O)R b42 , C(O)NRc42 R d42 , C(O)OR a42 , NR c42 R d42 , NR c42 C(O)R b42 , NR c42 C(O)OR a42 , NR c42 C(O)NR c42 R d42 , NR c42 S(O)2R b42 , NR c42 S(O)2NR c42 R d42 S(O)2R b42 , and S(O)2NR c42 R d42 Selected from, Each R a42 , R c42 , and R d42 H and C are independent. 1-6 Alkyl and C 1-6 Selected from haloalkyls, Each R b42 C 1-6 Alkyl and C 1-6 Selected from haloalkyls, Each R 5 They became independent as H, Haro, NO2, CN, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl, 5-6 member 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)NRc5 R d5 , NR c5 R d5 , NR c5 C(O)R b5 , NR c5 C(O)OR a5 , NR c5 C(O)NR c5 R d5 , NR c5 S(O)2R b5 , NR c5 S(O)2NR c5 R d5 S(O)2R b5 , and S(O)2NR c5 R d5 Selected from, the C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, 3, or 4 independently selected R groups, each of which can be arbitrarily chosen. 5A Substituted by substituents, Each R a5 , R c5 , and R d5 H and C are independent. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl, the C 1-6Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, 3, or 4 independently selected R groups, each of which can be arbitrarily chosen. 5A Substituting with substituents, Each R b5 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl groups, these are each optionally selected as 1, 2, 3, or 4 independently R 5A Substituting with substituents, Each R 5A They became independent as H, Haro, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl, 5-6 member 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 Selected from, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, 3, or 4 independently selected R groups, each of which can be arbitrarily chosen. 5B Substituting with substituents, Each R a51 , R c51 , and R d51 H and C are independent. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl, the C 1-6Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, 3, or 4 independently selected R groups, each of which can be arbitrarily chosen. 5B Substituting with substituents, Each R b51 C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl groups, these are each optionally selected as 1, 2, 3, or 4 independently R 5B Substituting with substituents, Each R 5B They became independent as H, Haro, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-4 Cycloalkyl, OR a52 , SR a52 NHOR a52 , C(O)R b52 , C(O)NR c52 R d52 , C(O)OR a52 ,OC(O)R b52 , OC(O)NR c52 R d52 , NR c52 R d52 , NR c52 C(O)R b52 , NR c52 C(O)OR a52 , NR c52 C(O)NR c52R d52 , NR c52 S(O)2R b52 , NR c52 S(O)2NR c52 R d52 S(O)2R b52 , and S(O)2NR c52 R d52 Selected from, Each R a52 , R c52 , and R d52 H and C are independent. 1-6 Alkyl and C 1-6 Selected from haloalkyls, Each R b52 C 1-6 Alkyl and C 1-6 Selected from haloalkyl groups.

[0109] In some embodiments, n is 0, 1, or 2, p is 0, 1, or 2, Ring portion A is C 3-10 Selected from cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, Ring portion B is a monocyclic 4-7 member heterocycloalkyl group. R 1 They became independent as H, Haro, CN, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl, 5-6 member heteroaryl-C 1-4 Alkyl, OR a1 , and NR c1 R d1 Selected from, the C 1-6 Alkyl, C 2-6 Alkenil, C2-6 Alkinyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, 3, or 4 independently selected R groups, each of which can be arbitrarily chosen. 1A Substituting with substituents, Each R a1 , R c1 , and R d1 H and C are independent. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, 3, or 4 independently selected R groups, each of which can be arbitrarily chosen. 1A Substituting with substituents, Each R b1 C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl groups, these are each optionally selected as 1, 2, 3, or 4 independently R 1A Substituting with substituents, Each R 1A They became independent as H, Haro, CN, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl, 5-6 member heteroaryl-C 1-4 Alkyl, OR a11 , C(O)R b11 , C(O)NR c11 R d11 , C(O)OR a11 ,OC(O)R b11 , OC(O)NR c11 R d11 , NR c11 R d11 , NR c11 C(O)R b11 , NR c11 C(O)OR a11 , NR c11 C(O)NR c11 R d11 , NR c11 S(O)2R b11 , NR c11 S(O)2NR c11 R d11 S(O)2R b11 , and S(O)2NR c11 R d11 Selected from, Each R a11 , R c11 , and R d11 H and C are independent. 1-6 Alkyl and C 1-6Selected from haloalkyls, Each R b11 C 1-6 Alkyl and C 1-6 Selected from haloalkyls, R 2 However, H, Haro, CN, C 1-3 Alkyl and C 1-3 Selected from haloalkyls, Each R 3 They became independent as H, Haro, C 1-3 Selected from alkyl and cyclopropyl, R 4 However, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, 3, or 4 independently selected R groups, each of which can be arbitrarily chosen. 4A Substituted by substituents, Each R 4A They became independent as H, Haro, CN, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl, 5-6 member heteroaryl-C 1-4 Alkyl, OR a41 , SR a41 NHOR a41 , C(O)R b41 , C(O)NR c41 R d41 , C(O)OR a41 ,OC(O)R b41 , OC(O)NR c41 R d41 , NR c41 R d41 , NR c41 C(O)R b41 , NR c41 C(O)OR a41 , NR c41 C(O)NR c41 R d41 , NR c41 S(O)2R b41 , NR c41 S(O)2NR c41 R d41 S(O)2R b41 , and S(O)2NR c41 R d41 Selected from, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, or 3 independently selected R groups, each of which can be arbitrarily chosen. 4B Substituting with substituents, Each R a41 , R c41 , and R d41 H and C are independent.1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, or 3 independently selected R groups, each of which can be arbitrarily chosen. 4B Substituting with substituents, Each R b41 C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl groups, these are each optionally selected as 1, 2, or 3 independently. 4B Substituting with substituents, Each R 4B They became independent as H, Haro, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-4 Cycloalkyl, OR a42 , C(O)R b42 , C(O)NR c42 R d42, C(O)OR a42 , NR c42 R d42 , NR c42 C(O)R b42 , NR c42 C(O)OR a42 , NR c42 C(O)NR c42 R d42 , NR c42 S(O)2R b42 , NR c42 S(O)2NR c42 R d42 S(O)2R b42 , and S(O)2NR c42 R d42 Selected from, Each R a42 , R c42 , and R d42 H and C are independent. 1-6 Alkyl and C 1-6 Selected from haloalkyls, Each R b42 C 1-6 Alkyl and C 1-6 Selected from haloalkyls, Each R 5 They became independent as H, Haro, NO2, CN, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl, 5-6 member heteroaryl-C 1-4 Alkyl, OR a5 , SR a5 NHOR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 ,OC(O)R b5 , OC(O)NR c5 R d5, NR c5 R d5 , NR c5 C(O)R b5 , NR c5 C(O)OR a5 , NR c5 C(O)NR c5 R d5 , NR c5 S(O)2R b5 , NR c5 S(O)2NR c5 R d5 S(O)2R b5 , and S(O)2NR c5 R d5 Selected from, the C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, 3, or 4 independently selected R groups, each of which can be arbitrarily chosen. 5A Substituted by substituents, Each R a5 , R c5 , and R d5 H and C are independent. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl, the C 1-6 Alkyl, C 2-6 Alkenil, C2-6 Alkinyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, 3, or 4 independently selected R groups, each of which can be arbitrarily chosen. 5A Substituting with substituents, Each R b5 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl groups, these are each optionally selected as 1, 2, 3, or 4 independently R 5A Substituting with substituents, Each R 5A They became independent as H, Haro, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl, 5-6 member heteroaryl-C 1-4 Alkyl, OR a51 , SR a51 NHOR a51 , C(O)R b51 , C(O)NR c51 Rd51 , C(O)OR a51 ,OC(O)R b51 , OC(O)NR c51 R d51 , NR c51 R d51 , NR c51 C(O)R b51 , NR c51 C(O)OR a51 , NR c51 C(O)NR c51 R d51 , NR c51 S(O)2R b51 , NR c51 S(O)2NR c51 R d51 S(O)2R b51 , and S(O)2NR c51 R d51 Selected from, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, 3, or 4 independently selected R groups, each of which can be arbitrarily chosen. 5B Substituting with substituents, Each R a51 , R c51 , and R d51 H and C are independent. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl, the C 1-6 Alkyl, C 1-6Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, 3, or 4 independently selected R groups, each of which can be arbitrarily chosen. 5B Substituting with substituents, Each R b51 C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl groups, these are each optionally selected as 1, 2, 3, or 4 independently R 5B Substituting with substituents, Each R 5B They became independent as H, Haro, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-4 Cycloalkyl, OR a52 , SR a52 NHOR a52 , C(O)R b52 , C(O)NR c52 R d52 , C(O)OR a52 ,OC(O)R b52 , OC(O)NR c52 R d52 , NR c52 R d52 , NR c52 C(O)R b52 , NR c52 C(O)OR a52 , NR c52 C(O)NR c52 R d52 , NRc52 S(O)2R b52 , NR c52 S(O)2NR c52 R d52 S(O)2R b52 , and S(O)2NR c52 R d52 Selected from, Each R a52 , R c52 , and R d52 H and C are independent. 1-6 Alkyl and C 1-6 Selected from haloalkyls, Each R b52 C 1-6 Alkyl and C 1-6 Selected from haloalkyl groups.

[0110] In some embodiments, n is 0, 1, or 2, p is 0, 1, or 2, Ring portion A is C 3-10 Selected from cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, Ring portion B is azetidinil, pyrrolidinil, or piperidinil. R 1 However, H, Haro, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, phenyl, 4-6 member heterocycloalkyl, 5-6 member heteroaryl, C 3-6 Cycloalkyl-C 1-3 Alkyl, phenyl-C 1-3 Alkyl, 4-7 member heterocycloalkyl-C 1-3 Alkyl, 5-6 member heteroaryl-C 1-3 Alkyl, OR a1 , SR a1 , and NR c1 R d1 and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C3-6 Cycloalkyl, phenyl, 4-6 member heterocycloalkyl, 5-6 member heteroaryl, C 3-6 Cycloalkyl-C 1-3 Alkyl, phenyl-C 1-3 Alkyl, 4-7 member heterocycloalkyl-C 1-3 Alkyl and 5-6 member heteroaryl-C 1-3 The alkyl group consists of 1, 2, or 3 independently selected R groups, each of which can be arbitrarily chosen. 1A Substituting with substituents, Each R a1 , R c1 , and R d1 They become independent: H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, and C 3-7 Cycloalkyl-C 1-4 Selected from alkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, and C 3-7 Cycloalkyl-C 1-4 The alkyl group consists of 1, 2, or 3 independently selected R groups, each of which can be arbitrarily chosen. 1A Substituting with substituents, Each R 1A They became independent: H, D, Haro, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-4 Cycloalkyl, OR a11 , C(O)R b11 , C(O)NR c11 R d11 , C(O)OR a11 ,OC(O)R b11 , OC(O)NR c11 R d11 , NR c11 R d11 , NR c11 C(O)R b11 , NR c11 C(O)OR a11 , NR c11 C(O)NR c11 Rd11 , NR c11 S(O)2R b11 , NR c11 S(O)2NR c11 R d11 S(O)2R b11 , and S(O)2NR c11 R d11 Selected from, the C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-4 Each cycloalkyl group is optionally selected from 1, 2, or 3 independently selected R groups. 1B Substituted by substituents, Each R a11 , R c11 , and R d11 H and C are independent. 1-6 Alkyl and C 1-6 Selected from haloalkyls, Each R b11 C 1-6 Alkyl and C 1-6 Selected from haloalkyls, Each R 1B H, D, and OR are independent of each other. a12 Selected from, Each R a12 H and C are independent of each other. 1-6 Selected from alkyl groups, R 2 However, H, Haro, CN, C 1-3 Alkyl and C 1-3 Selected from haloalkyls, Each R 3 They became independent as H, Haro, C 1-3 Selected from alkyl and cyclopropyl, R 4 However, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, and 4-7 member heterocycloalkyl-C 1-4 Selected from alkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, and 4-7 member heterocycloalkyl-C 1-4 Alkyl is selected from one or two independently selected R components, each at will. 4A Substituted by substituents, Each R 4A They became independent as H, Haro, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-4 Cycloalkyl, OR a41 , C(O)R b41 , C(O)NR c41 R d41 , C(O)OR a41 ,OC(O)R b41 , OC(O)NR c41 R d41 , NR c41 R d41 , NR c41 C(O)R b41 , NR c41 C(O)OR a41 , NR c41 C(O)NR c41 R d41 , NR c41 S(O)2R b41 , NR c41 S(O)2NR c41 R d41 S(O)2R b41 , and S(O)2NR c41 R d41 Selected from, the C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-4 Each cycloalkyl group is optionally selected from 1, 2, or 3 independently selected R groups. 4B Substituting with substituents, Each R a41 , R c41 , and R d41 H and C are independent. 1-6 Alkyl, C 1-6 Haloalkyl and C 3-4 Selected from cycloalkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-4The cycloalkyl group consists of one or two independently selected R groups, each of which can be arbitrarily chosen. 4B Substituting with substituents, Each R b41 C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-4 Selected from cycloalkyl groups, these are each optionally selected as one or two independently. 4B Substituting with substituents, Each R 4B They became independent as H, Haro, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, OR a42 , and NR c42 R d42 Selected from, Each R a42 , R c42 , and R d42 H and C are independent. 1-3 Alkyl and C 1-3 Selected from haloalkyls, Each R b42 C 1-3 Alkyl and C 1-3 Selected from haloalkyls, Each R 5 They became independent as H, Haro, NO2, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl, 5-6 member heteroaryl-C 1-4 Alkyl, OR a5 , SR a5 NHOR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 ,OC(O)R b5 , OC(O)NR c5 R d5 , NRc5 R d5 , NR c5 C(O)R b5 , NR c5 C(O)OR a5 , NR c5 C(O)NR c5 R d5 , NR c5 S(O)2R b5 , NR c5 S(O)2NR c5 R d5 S(O)2R b5 , and S(O)2NR c5 R d5 Selected from, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, 3, or 4 independently selected R groups, each of which can be arbitrarily chosen. 5A Substituted by substituents, Each R a5 , R c5 , and R d5 H and C are independent. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, 3, or 4 independently selected R groups, each of which can be arbitrarily chosen. 5A Substituting with substituents, Each R b5 C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl groups, these are each optionally selected as 1, 2, 3, or 4 independently R 5A Substituting with substituents, Each R 5A They became independent as H, Haro, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-4 Cycloalkyl, OR a51 , SR a51 NHOR a51 , C(O)R b51 , C(O)NR c51 R d51 , C(O)OR a51 ,OC(O)R b51 , OC(O)NR c51 R d51 , NR c51 R d51 , NR c51 C(O)R b51 , NR c51 C(O)OR a51 , NR c51 C(O)NR c51 R d51 , NR c51 S(O)2R b51 , NR c51 S(O)2NR c51 R d51S(O)2R b51 , and S(O)2NR c51 R d51 Selected from, Each R a51 , R c51 , and R d51 H and C are independent. 1-6 Alkyl and C 1-6 Selected from haloalkyls, Each R b51 C 1-6 Alkyl and C 1-6 Selected from haloalkyl groups.

[0111] In some embodiments, n is 0, 1, or 2, p is 0, 1, or 2, Ring portion A is C 3-10 Selected from cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, Ring portion B is azetidinil, pyrrolidinil, or piperidinil. R 1 However, H, Haro, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, phenyl, 4-6 member heterocycloalkyl, 5-6 member heteroaryl, C 3-6 Cycloalkyl-C 1-3 Alkyl, phenyl-C 1-3 Alkyl, 4-7 member heterocycloalkyl-C 1-3 Alkyl, 5-6 member heteroaryl-C 1-3 Alkyl, OR a1 and NR c1 R d1 and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, phenyl, 4-6 member heterocycloalkyl, 5-6 member heteroaryl, C 3-6 Cycloalkyl-C 1-3 Alkyl, phenyl-C1-3 Alkyl, 4-7 member heterocycloalkyl-C 1-3 Alkyl and 5-6 member heteroaryl-C 1-3 Alkyl is selected from one or two independently selected R components, each at will. 1A Substituting with substituents, Each R 1A They became independent as H, Haro, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-4 Cycloalkyl, OR a11 , C(O)R b11 , C(O)NR c11 R d11 , C(O)OR a11 ,OC(O)R b11 , OC(O)NR c11 R d11 , NR c11 R d11 , NR c11 C(O)R b11 , NR c11 C(O)OR a11 , NR c11 C(O)NR c11 R d11 , NR c11 S(O)2R b11 , NR c11 S(O)2NR c11 R d11 S(O)2R b11 , and S(O)2NR c11 R d11 Selected from, Each R a11 , R c11 , and R d11 H and C are independent. 1-6 Alkyl and C 1-6 Selected from haloalkyls, Each R b11 C 1-6 Alkyl and C 1-6 Selected from haloalkyls, R 2 However, H, Haro, CN, C 1-3 Alkyl and C 1-3 Selected from haloalkyls, Each R 3 They became independent as H, Haro, C1-3 Selected from alkyl and cyclopropyl, R 4 However, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Selected from cycloalkyl, phenyl, 4-7 member heterocycloalkyl, and 5-6 member heteroaryl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, and 5-6 member heteroaryl are each optionally selected from 1, 2, 3, or 4 independently selected R 4A Substituted by substituents, Each R 4A They became independent as H, Haro, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-4 Cycloalkyl, OR a41 , C(O)R b41 , C(O)NR c41 R d41 , C(O)OR a41 ,OC(O)R b41 , OC(O)NR c41 R d41 , NR c41 R d41 , NR c41 C(O)R b41 , NR c41 C(O)OR a41 , NR c41 C(O)NR c41 R d41 , NR c41 S(O)2R b41 , NR c41 S(O)2NR c41 R d41 S(O)2R b41 , and S(O)2NR c41 R d41 Selected from, the C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-4 Each cycloalkyl group is optionally selected from 1, 2, or 3 independently selected R groups. 4B Substituting with substituents, Each R a41, R c41 , and R d41 H and C are independent. 1-6 Alkyl, C 1-6 Haloalkyl and C 3-4 Selected from cycloalkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-4 The cycloalkyl group consists of one or two independently selected R groups, each of which can be arbitrarily chosen. 4B Substituting with substituents, Each R b41 C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-4 Selected from cycloalkyl groups, these are each optionally selected as one or two independently. 4B Substituting with substituents, Each R 4B They became independent as H, Haro, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, OR a42 , and NR c42 R d42 Selected from, Each R a42 , R c42 , and R d42 H and C are independent. 1-3 Alkyl and C 1-3 Selected from haloalkyls, Each R b42 C 1-3 Alkyl and C 1-3 Selected from haloalkyls, Each R 5 They became independent as H, Haro, NO2, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl, 5-6 member heteroaryl-C 1-4 Alkyl, OR a5, SR a5 NHOR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 ,OC(O)R b5 , OC(O)NR c5 R d5 , NR c5 R d5 , NR c5 C(O)R b5 , NR c5 C(O)OR a5 , NR c5 C(O)NR c5 R d5 , NR c5 S(O)2R b5 , NR c5 S(O)2NR c5 R d5 S(O)2R b5 , and S(O)2NR c5 R d5 Selected from, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, 3, or 4 independently selected R groups, each of which can be arbitrarily chosen. 5A Substituted by substituents, Each R a5 , R c5 , and R d5 H and C are independent. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 The alkyl group consists of 1, 2, 3, or 4 independently selected R groups, each of which can be arbitrarily chosen. 5A Substituting with substituents, Each R b5 C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, 4-7 member heterocycloalkyl-C 1-4 Alkyl and 5-6 member heteroaryl-C 1-4 Selected from alkyl groups, these are each optionally selected as 1, 2, 3, or 4 independently R 5A Substituting with substituents, Each R 5A They became independent as H, Haro, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-4 Cycloalkyl, OR a51 , SR a51 NHOR a51 , C(O)R b51 , C(O)NR c51 R d51 , C(O)OR a51 ,OC(O)R b51 , OC(O)NR c51 R d51 , NR c51 R d51 , NR c51 C(O)R b51 , NRc51 C(O)OR a51 , NR c51 C(O)NR c51 R d51 , NR c51 S(O)2R b51 , NR c51 S(O)2NR c51 R d51 S(O)2R b51 , and S(O)2NR c51 R d51 Selected from, Each R a51 , R c51 , and R d51 H and C are independent. 1-6 Alkyl and C 1-6 Selected from haloalkyls, Each R b51 C 1-6 Alkyl and C 1-6 Selected from haloalkyl groups.

[0112] In some embodiments, n is 0 or 1, p is 0 or 1, The ring portion A is a 5-10 member heteroaryl compound. Ring portion B is piperidinyl, R 1 However, H, C 1-6 Alkyl, phenyl, 5-7 member heterocycloalkyl, OR a1 , SR a1 , or NR c1 R d1 and C 1-6 Alkyl, phenyl, and 5- to 7-membered heterocycloalkyl groups are each optionally selected as one or two independently selected R groups. 1A Substituting with substituents, Each R a1 , R c1 , and R d1 H and C are independent. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, phenyl, 4-6 member heterocycloalkyl, C 3-6 Cycloalkyl-C1-3 Alkyl and 4-6 member heterocycloalkyl-C 1-3 Selected from alkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, phenyl, 4-6 member heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkyl and 4-6 member heterocycloalkyl-C 1-3 The alkyl group consists of 1, 2, or 3 independently selected R groups, each of which can be arbitrarily chosen. 1A Substituting with substituents, Each R 1A They became independent: H, D, Haro, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, OH, C 1-3 Alkoxy, C 1-3 Haloalkoxy, amino, C 1-3 Alkylamino, di(C 1-3 Alkyl)amino, cyano-C 1-4 Alkyl, HO-C 1-4 Alkyl, C 1-3 Alkoxy-C 1-4 Alkyl, C 3-4 Cycloalkyl and C(O)OC 1-4 Selected from alkyl, the C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, amino, C 1-3 Alkylamino, di(C 1-3 Alkyl)amino, C 1-3 Alkoxy-C 1-4 Alkyl, C 3-4 Cycloalkyl and C(O)OC 1-4 The alkyl group consists of 1, 2, or 3 independently selected R groups, each of which can be arbitrarily chosen. 1B Substituting with substituents, Each R 1B These are H, D, and OC, independently. 1-4 Selected from alkyl groups, R 2 However, it is H or halo, Each R 3These are independently selected from H, F, or methyl. R 4 However, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, and 4-7 member heterocycloalkyl-C 1-4 Selected from alkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, and 4-10 member heterocycloalkyl-C 1-4 Alkyl is selected from one or two independently selected R components, each at will. 4A Substituted by substituents, Each R 4A They became independent as H, Haro, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-4 Cycloalkyl, OR a41 , C(O)R b41 , C(O)NR c41 R d41 , C(O)OR a41 ,OC(O)R b41 , OC(O)NR c41 R d41 , NR c41 R d41 , NR c41 C(O)R b41 , NR c41 C(O)OR a41 , NR c41 C(O)NR c41 R d41 , NR c41 S(O)2R b41 , NR c41 S(O)2NR c41 R d41 S(O)2R b41 , and S(O)2NR c41 R d41 Selected from, the C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-4Each cycloalkyl group is optionally selected from 1, 2, or 3 independently selected R groups. 4B Substituting with substituents, Each R a41 , R c41 , and R d41 H and C are independent. 1-6 Alkyl, C 1-6 Haloalkyl and C 3-4 Selected from cycloalkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-4 The cycloalkyl group consists of one or two independently selected R groups, each of which can be arbitrarily chosen. 4B Substituting with substituents, Each R b41 C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-4 Selected from cycloalkyl groups, these are each optionally selected as one or two independently. 4B Substituting with substituents, Each R 4B They became independent as H, Haro, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, OR a42 , and NR c42 R d42 Selected from, Each R a42 , R c42 , and R d42 H and C are independent. 1-3 Alkyl and C 1-3 Selected from haloalkyls, Each R b42 C 1-3 Alkyl and C 1-3 Selected from haloalkyls, Each R 5 They became independent as H, Haro, NO2, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, OR a5 , C(O)R b5 , C(O)NR c5 Rd5 , C(O)OR a5 , NR c5 R d5 , NR c5 C(O)R b5 , NR c5 S(O)2R b5 S(O)2R b5 , and S(O)2NR c5 R d5 Selected from, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, and 5-6 member heteroaryl are each optionally selected from 1, 2, 3, or 4 independently selected R 5A Substituted by substituents, Each R a5 , R c5 , and R d5 H and C are independent. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Selected from cycloalkyl, phenyl, 4-7 member heterocycloalkyl, and 5-6 member heteroaryl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, and 5-6 member heteroaryl are each optionally selected from 1, 2, 3, or 4 independently selected R 5A Substituting with substituents, Each R b5 C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Selected from cycloalkyl, phenyl, 4-7 member heterocycloalkyl, and 5-6 member heteroaryl, each of which can be optionally selected as 1, 2, 3, or 4 independently. 5A Substituting with substituents, Each R 5A They became independent as H, Haro, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-4 Cycloalkyl, OR a51 , and NR c51 Rd51 Selected from, Each R a51 , R c51 , and R d51 H and C are independent of each other. 1-3 Selected from alkyl groups, Each R b51 C 1-3 It is alkyl.

[0113] In some embodiments, n is 0 or 1, p is 0 or 1, The ring portion A is a 5-10 member heteroaryl compound. Ring portion B is piperidinyl, R 1 However, H or OR a1 And, Each R a1 H and C are independent. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-6 member heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkyl and 4-6 member heterocycloalkyl-C 1-3 Selected from alkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl C 3-6 Cycloalkyl, 4-6 member heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkyl and 4-6 member heterocycloalkyl-C 1-3 Alkyl is selected from one or two independently selected R components, each at will. 1A Substituting with substituents, Each R 1A They became independent as H, Haro, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, OH, C 1-3 Alkoxy, C 1-3 Haloalkoxy, amino, C 1-3 Alkylamino, di(C 1-3 Alkyl)amino, cyano-C 1-4 Alkyl, HO-C 1-4Alkyl, C 1-3 Alkoxy-C 1-4 Alkyl and C 3-4 Selected from cycloalkyl groups, R 2 However, it is H or halo, Each R 3 These are independently selected from H, F, or methyl. R 4 However, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Selected from cycloalkyl, phenyl, 4-7 member heterocycloalkyl, and 5-6 member heteroaryl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, and 5-6 member heteroaryl are each optionally selected from 1, 2, 3, or 4 independently selected R 4A Substituted by substituents, Each R 4A They became independent as H, Haro, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-4 Cycloalkyl, OR a41 , C(O)R b41 , C(O)NR c41 R d41 , C(O)OR a41 ,OC(O)R b41 , OC(O)NR c41 R d41 , NR c41 R d41 , NR c41 C(O)R b41 , NR c41 C(O)OR a41 , NR c41 C(O)NR c41 R d41 , NR c41 S(O)2R b41 , NR c41 S(O)2NR c41 R d41 S(O)2R b41 , and S(O)2NR c41 R d41 Selected from, the C1-6 Alkyl, C 1-6 Haloalkyl and C 3-4 Each cycloalkyl group is optionally selected from 1, 2, or 3 independently selected R groups. 4B Substituting with substituents, Each R a41 , R c41 , and R d41 H and C are independent. 1-6 Alkyl, C 1-6 Haloalkyl and C 3-4 Selected from cycloalkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-4 The cycloalkyl group consists of one or two independently selected R groups, each of which can be arbitrarily chosen. 4B Substituting with substituents, Each R b41 C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-4 Selected from cycloalkyl groups, these are each optionally selected as one or two independently. 4B Substituting with substituents, Each R 4B They became independent as H, Haro, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, OR a42 , and NR c42 R d42 Selected from, Each R a42 , R c42 , and R d42 H and C are independent. 1-3 Alkyl and C 1-3 Selected from haloalkyls, Each R b42 C 1-3 Alkyl and C 1-3 Selected from haloalkyls, Each R 5 They became independent as H, Haro, NO2, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, ORa5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , NR c5 R d5 , NR c5 C(O)R b5 , NR c5 S(O)2R b5 S(O)2R b5 , and S(O)2NR c5 R d5 Selected from, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, and 5-6 member heteroaryl are each optionally selected from 1, 2, 3, or 4 independently selected R 5A Substituted by substituents, Each R a5 , R c5 , and R d5 H and C are independent. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Selected from cycloalkyl, phenyl, 4-7 member heterocycloalkyl, and 5-6 member heteroaryl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, and 5-6 member heteroaryl are each optionally selected from 1, 2, 3, or 4 independently selected R 5A Substituting with substituents, Each R b5 C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Selected from cycloalkyl, phenyl, 4-7 member heterocycloalkyl, and 5-6 member heteroaryl, each of which can be optionally selected as 1, 2, 3, or 4 independently. 5A Substituting with substituents, Each R 5A They became independent as H, Haro, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C3-4 Cycloalkyl, OR a51 , and NR c51 R d51 Selected from, Each R a51 , R c51 , and R d51 H and C are independent of each other. 1-3 Selected from alkyl groups, Each R b51 C 1-3 It is alkyl.

[0114] In some embodiments, n is 0 or 1, p is 0 or 1, The ring portion A is a 5-10 member heteroaryl compound. Ring portion B is piperidinyl, R 1 However, H or OR a1 And, Each R a1 H and C are independent. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-6 member heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkyl and 4-6 member heterocycloalkyl-C 1-3 Selected from alkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl C 3-6 Cycloalkyl, 4-6 member heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkyl and 4-6 member heterocycloalkyl-C 1-3 The alkyl group consists of 1, 2, or 3 independently selected R groups, each of which can be arbitrarily chosen. 1A Substituting with substituents, Each R 1A They became independent: H, D, Haro, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, OR a11 , and C(O)OR a11 Selected from, the C 1-6 Alkyl and C 1-6The haloalkyl group consists of one, two, or three independently selected R groups, each of which can be arbitrarily chosen. 1B Substituting with substituents, Each R a11 H and C are independent of each other. 1-4 Selected from alkyl, the C 1-4 The alkyl group is optionally selected from 1, 2, or 3 independently selected R 1B Substituted by substituents, Each R b11 C 1-6 Alkyl and C 1-6 Selected from haloalkyls, Each R 1B H, D, and OR are independent of each other. a12 Selected from, Each R a12 H and C are independent of each other. 1-6 Selected from alkyl groups, R 2 However, it is H or halo, Each R 3 These are independently selected from H, F, or methyl. R 4 However, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Selected from cycloalkyl, phenyl, 4-7 member heterocycloalkyl, and 5-6 member heteroaryl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, and 5-6 member heteroaryl are each optionally selected from 1, 2, 3, or 4 independently selected R 4A Substituted by substituents, Each R 4A They became independent as H, Haro, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-4 Cycloalkyl, OR a41 , C(O)R b41 , C(O)NR c41 R d41 , C(O)OR a41 ,OC(O)R b41 , OC(O)NR c41R d41 , NR c41 R d41 , NR c41 C(O)R b41 , NR c41 C(O)OR a41 , NR c41 C(O)NR c41 R d41 , NR c41 S(O)2R b41 , NR c41 S(O)2NR c41 R d41 S(O)2R b41 , and S(O)2NR c41 R d41 Selected from, the C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-4 Each cycloalkyl group is optionally selected from 1, 2, or 3 independently selected R groups. 4B Substituting with substituents, Each R a41 , R c41 , and R d41 H and C are independent. 1-6 Alkyl, C 1-6 Haloalkyl and C 3-4 Selected from cycloalkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-4 The cycloalkyl group consists of one or two independently selected R groups, each of which can be arbitrarily chosen. 4B Substituting with substituents, Each R b41 C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-4 Selected from cycloalkyl groups, these are each optionally selected as one or two independently. 4B Substituting with substituents, Each R 4B They became independent as H, Haro, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, OR a42 , and NR c42 R d42 Selected from, Each R a42, R c42 , and R d42 H and C are independent. 1-3 Alkyl and C 1-3 Selected from haloalkyls, Each R b42 C 1-3 Alkyl and C 1-3 Selected from haloalkyls, Each R 5 They became independent as H, Haro, NO2, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, OR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , NR c5 R d5 , NR c5 C(O)R b5 , NR c5 S(O)2R b5 S(O)2R b5 , and S(O)2NR c5 R d5 Selected from, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, and 5-6 member heteroaryl are each optionally selected from 1, 2, 3, or 4 independently selected R 5A Substituted by substituents, Each R a5 , R c5 , and R d5 H and C are independent. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Selected from cycloalkyl, phenyl, 4-7 member heterocycloalkyl, and 5-6 member heteroaryl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, and 5-6 member heteroaryl are each optionally selected from 1, 2, 3, or 4 independently selected R 5A Substituting with substituents, Each R b5 C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Selected from cycloalkyl, phenyl, 4-7 member heterocycloalkyl, and 5-6 member heteroaryl, each of which can be optionally selected as 1, 2, 3, or 4 independently. 5A Substituting with substituents, Each R 5A They became independent as H, Haro, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-4 Cycloalkyl, OR a51 , and NR c51 R d51 Selected from, Each R a51 , R c51 , and R d51 H and C are independent of each other. 1-3 Selected from alkyl groups, Each R b51 C 1-3 It is alkyl.

[0115] In some embodiments, n is 0 or 1, p is 0 or 1, The ring portion A is a 5-10 membered heteroaryl having one or two N-ring forming atoms. Ring portion B is piperidinyl, R 1 H and C are independent. 1-6 Alkyl, phenyl, 5-7 member heterocycloalkyl, OR a1 , SR a1 , and NR c1 R d1 Selected from, the C 1-6 Alkyl, phenyl, and 5- to 7-membered heterocycloalkyl groups are each optionally selected as one or two independently selected R groups. 1ASubstituting with substituents, Each R a1 , R c1 , and R d1 H and C are independent. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, phenyl, 4-6 member heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkyl and 4-6 member heterocycloalkyl-C 1-3 Selected from alkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, phenyl, 4-6 member heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkyl and 4-6 member heterocycloalkyl-C 1-3 The alkyl group consists of 1, 2, or 3 independently selected R groups, each of which can be arbitrarily chosen. 1A Substituting with substituents, Each R 1A They became independent as D, Haro, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-4 Cycloalkyl, OR a11 , and C(O)OR a11 Selected from, the C 1-6 Alkyl and C 1-6 The haloalkyl group consists of one, two, or three independently selected R groups, each of which can be arbitrarily chosen. 1B Substituting with substituents, Each R a11 H and C are independent of each other. 1-4 Selected from alkyl, the C 1-4 The alkyl group is optionally selected from 1, 2, or 3 independently selected R 1B Substituted by substituents, Each R 1B These are H, D, and OC, independently. 1-4 Selected from alkyl groups, R 2 However, it is H or F, Each R 3 independently selected from H or methyl, R4 However, C 1-6 Alkyl, C 3-6 Cycloalkyl, 5-6 member heteroaryl, and 4-7 member heterocycloalkyl-C 1-4 Selected from alkyl, the C 1-6 Alkyl, C 3-6 Cycloalkyl, 5-6 member heteroaryl, and 4-7 member heterocycloalkyl-C 1-4 The alkyl group consists of 1, 2, 3, or 4 independently selected R groups, each of which can be arbitrarily chosen. 4A Substituted by substituents, Each R 4A H and C are independent. 1-6 Alkyl, OH, and NR c41 R d41 Selected from, Each R c41 and R d41 H and C are independent. 1-6 Alkyl and C 1-6 Selected from haloalkyls, Each R 5 They became independent as H, Haro, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-4 Cycloalkyl, OR a5 , and NR c5 R d5 Selected from, Each R a5 , R c5 , and R d5 H and C are independent. 1-6 Alkyl and C 1-6 Selected from haloalkyl groups.

[0116] In some embodiments, n is 0 or 1, p is 0 or 1, The ring portion A is a 5-10 membered heteroaryl having one or two N-ring forming atoms. Ring portion B is piperidinyl, R 1 H and OR a1 Selected from, Each R a1 H and C are independent.1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-6 member heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkyl and 4-6 member heterocycloalkyl-C 1-3 Selected from alkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl C 3-6 Cycloalkyl, 4-6 member heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkyl and 4-6 member heterocycloalkyl-C 1-3 Alkyl is selected from one or two independently selected R components, each at will. 1A Substituting with substituents, Each R 1A C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-4 Cycloalkyl, OH, C 1-3 Alkoxy, and C 1-3 Selected from haloalkoxys, R 2 However, it is H or F, Each R 3 independently selected from H or methyl, R 4 However, C 1-6 Alkyl and C 3-6 Selected from cycloalkyl, the C 1-6 Alkyl and C 3-6 Each cycloalkyl group is optionally selected from 1, 2, 3, or 4 independently selected R groups. 4A Substituted by substituents, Each R 4A H and C are independent of each other. 1-6 Selected from alkyl groups, Each R 5 They became independent as H, Haro, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-4 Cycloalkyl, OR a5 , and NR c5 R d5 Selected from, Each R a5 , R c5 , and R d5 H and C are independent. 1-6 Alkyl and C 1-6 Selected from haloalkyl groups.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0136] In some embodiments, the compound is a compound of formula (VIIIc), [Chemical formula] or a pharmaceutically acceptable salt thereof. [[ID=K19]]

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

[0138] In some embodiments, the compound is a compound of formula (IXb), [Chemical formula] [[ID=K39]] or a pharmaceutically acceptable salt thereof.

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

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

[0141] In some embodiments, Z is N.

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

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

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

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

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

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

[0148] In some embodiments, substituents such as "alkyl," "alkenyl," "alkynyl," "aryl," "phenyl," "cycloalkyl," "heterocycloalkyl," or "heteroaryl" substituents, or "-C" are used as described herein. 1-4 One, two, three, four, five, six, seven, or eight hydrogen atoms bonded to the carbon atoms of the alkyl- and alkylene linking groups can be optionally replaced with deutherium atoms.

[0149] It will be further understood that certain features of the present invention, described in the context of separate embodiments for clarity, may also be provided in combination in a single embodiment. Conversely, various features of the present invention, described in the context of a single embodiment for brevity, may also be provided separately or in any preferred partial combination.

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

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

[0152] As used herein, the phrase "optionally substituted" means either unsubstituted or substituted. Substituents are selected independently, and substitutions 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, can replace two hydrogen atoms. It should be understood that substitutions at a given atom are limited by their valence, never exceeding the normal valence of the specified atom, and that substitutions result in a stable compound.

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

[0154] When used herein, the phrase "each 'variable' is independently selected from..." is essentially the same as "in each instance, the 'variable' is selected from...".

[0155] In any component or formula relating to a certain compound, any variable (e.g., R) G If a given element appears more than once, its definition in each occurrence is independent of its definition in any other occurrence. Therefore, for example, if a given element is selected from 1, 2, 3, or 4 independently, G If indicated to be substituted with substituents, the group may optionally have up to four R GIt may be substituted with the base, and in each occurrence R G R G It is selected independently of the definition.

[0156] In some embodiments, if multiple substituents are optionally specified in the following form, [ka] Please understand that substituent R can appear p times on the ring, and that R can be a different part in each occurrence. Each R group is (CH2) n It should be understood that any hydrogen atom bonded to a ring atom may be replaced, including one or both of the hydrogen atoms in the given ring. Furthermore, if the variable Q is defined to include hydrogen, such as when Q is stated to be CH2, NH, etc., then any floating substituent such as R in the above example may replace the hydrogen in the Q variable of the ring, as well as any hydrogen in any other non-variable component.

[0157] Throughout the definition, "C n-m The term "C" indicates a range including the endpoint, where n and m are integers and represent the number of carbon atoms. For example, C 1-3 , C 1-4 , C 1-6 These are some examples.

[0158] When used herein, "C" is used alone or in combination with other terms. n-mThe term "alkyl" refers to a saturated hydrocarbon group having n to m carbon atoms, which may be linear or branched. Examples of alkyl groups 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, and sec-butyl, and higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, and 1,2,2-trimethylpropyl. In some embodiments, the alkyl group contains 1 to 6 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0187] When used herein, "cyano-C" n-m The term "alkyl" is derived from the formula -(Cn-m The term refers to the alkylene-CN group, where the alkylene group has n to m carbon atoms. When used herein, "cyano-C" is used to mean "C 1-6 The term "alkyl" is derived from the formula -(C 1-6 Refers to the alkylene-CN group. When used herein, "cyano-C 1-3 The term "alkyl" is derived from the formula -(C 1-3 This refers to the alkylene-CN group.

[0188] When used herein, "HO-C" n-m The term "alkyl" is derived from the formula -(C n-m The term refers to the alkylene-OH group, where the alkylene group has n to m carbon atoms. When used herein, "HO-C 1-3 The term "alkyl" is derived from the formula -(C 1-3 This refers to the alkylene-OH group.

[0189] When used herein, "C n-m Alkoxy-C o-p The term "alkyl" is derived from the formula -(C n-m Alkylene)-O(C) o-p The term refers to an alkyl group, where the alkylene group has n to m carbon atoms and the alkyl group has 0 to p carbon atoms. When used herein, "C 1-6 Alkoxy-C 1-6 The term "alkyl" is derived from the formula -(C 1-6 Alkylene)-O(C) 1-6 Refers to the alkyl group. When used herein, "C 1-3 Alkoxy-C 1-3 The term "alkyl" is derived from the formula -(C 1-3 Alkylene)-O(C) 1-3 It refers to the alkyl group.

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

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

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

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

[0194] As used herein, "aminocarbonyloxy" refers to the group of the formula -OC(O)-NH2.

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

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

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

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

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

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

[0201] As used herein, “heteroaryl” refers to a monocyclic or polycyclic (e.g., having two, three, or four fused rings) aromatic heterocycle having at least one heteroatom ring member selected from N, O, or S. In some embodiments, any ring-forming N in the heteroaryl moiety may be an N-oxide. In some embodiments, the heteroaryl is a 5- to 10-membered monocyclic or bicyclic heteroaryl having one, two, three, or four heteroatom ring members independently selected from N, O, and S. In some embodiments, the heteroaryl is a 5- to 6 monocyclic heteroaryl having one or two heteroatom ring members independently selected from N, O, and S. In some embodiments, the heteroaryl group contains 5- to 10 or 5-6 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. If a heteroaryl group contains more than one heteroatom ring member, those heteroatoms may be the same or different. Examples of heteroaryl groups include pyridyl, pyrimidinyl, pyrazinyl, pyridadinyl, pyrrolyl, pyrazolyl, azolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, furyl, thienyl, triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl), tetrazolyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl), quinolinyl, isoquinolinyl This includes, but is not limited to, oxadiazolyls, indolyl, benzothienyl, benzofuranyl, benzoisoxazolyl, imidazo[1,2-b]thiazolyl, prinyl, triazinyl, thieno[3,2-b]pyridinyl, imidazo[1,2-a]pyridinyl, 1,5-naphthilidinyl, 1H-pyrazolo[4,3-b]pyridinyl, oxadiazolyls (e.g., 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl), 1,2-dihydro-1,2-azobolinyl, etc.

[0202] As used herein, “heterocycloalkyl” means a monocyclic or polycyclic heterocycle having at least one non-aromatic ring (a saturated or partially unsaturated ring), wherein one or more of the ring-forming carbon atoms of the heterocycloalkyl are replaced with heteroatoms selected from N, O, or S, and the ring-forming carbon atoms and heteroatoms of the heterocycloalkyl may optionally be replaced with one or more oxo or sulfide atoms (e.g., C(O), S(O), C(S), or S(O)2). Heterocycloalkyls include monocyclic and polycyclic (e.g., having two fused rings) systems. Heterocycloalkyls include monocyclic and polycyclic 4- to 10-membered, 4- to 7-membered, and 5- to 6-membered heterocycloalkyls. Heterocycloalkyls may also include spirocycles and bridging rings. Heterocycloalkyls may be bonded via ring-forming carbon atoms or ring-forming heteroatoms. In some embodiments, heterocycloalkyls contain 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds.

[0203] Furthermore, the definition of heterocycloalkyl also includes moieties having one or more aromatic rings condensed (i.e., sharing a common bond) with a non-aromatic heterocyclic ring, such as piperidine, morpholine, and benzo or thienyl derivatives of azepines. Heterocycloalkyl groups containing condensed aromatic rings may be bonded via any ring-forming atoms, including the ring-forming atoms of the condensed aromatic ring. In some embodiments, heterocycloalkyl groups contain 4 to 10 ring-forming atoms, 4 to 7 ring-forming atoms, 4 to 6 ring-forming atoms, or 5 to 6 ring-forming atoms. In some embodiments, heterocycloalkyl groups have 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0204] In some embodiments, the heterocycloalkyl is a 4- to 10-membered monocyclic, bicyclic, or tricyclic heterocycloalkyl having 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, where the 1, 2, 3, or 4 ring-forming carbons or heteroatoms may optionally be substituted with one or more oxos or sulfides. In some embodiments, the heterocycloalkyl is a 4- to 7-membered monocyclic heterocycloalkyl having one or two ring-forming heteroatoms independently selected from N, O, and S, where one, two, or three ring-forming carbons or heteroatoms may optionally be substituted with one or more oxos or sulfides. In some embodiments, the heterocycloalkyl is a monocyclic 4- to 6-membered heterocycloalkyl having one or two heteroatoms independently selected from N, O, S, and B, and having one or more oxidized ring members.

[0205] Examples of heterocycloalkyl groups include pyrrolidine-2-one, 1,3-isoxazolidine-2-one, pyranyl, tetrahydropyran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, Benzazapen, 1,2,3,4-tetrahydroisoquinoline, azabicyclo[3.1.0]hexanyl, diazabicyclo[3.1.0]hexanyl, oxabicyclo[2.1.1]hexanyl, azabicyclo[2.2.1]heptanyl, azabicyclo[2.2.1]heptan-7-yl, azabicyclo[2.2.1]heptan-2-yl, diazabicyclo[2.2.1]heptanyl, azabicyclo[3.1.1]heptanyl, diaza Bicyclo[3.1.1]heptanil, azabicyclo[3.2.1]octanil, diazabicyclo[3.2.1]octanil, oxabicyclo[2.2.2]octanil, azaabicyclo[2.2.2]octanil, azaadamantanil, diazaadamantanil, oxa-adamantanil, azaspiro[3.3]heptanil, diazaspiro[3.3]heptanil, oxa-azaspiro[3.3]heptanil, azaspiro[3.4]octanil Examples include diazaspiro[3.4]octanyl, oxa-azaspiro[3.4]octanyl, azaspiro[2.5]octanyl, diazaspiro[2.5]octanyl, azaspiro[4.4]nonanyl, diazaspiro[4.4]nonanyl, oxa-azaspiro[4.4]nonanyl, azaspiro[4.5]decanyl, diazaspiro[4.5]decanyl, diazaspiro[4.4]nonanyl, and oxa-diazaspiro[4.4]nonanyl.

[0206] When used herein, "C o-p Cycloalkyl-C n-m "Alkyl-" refers to the group of the formula cycloalkyl-alkylene-, where the cycloalkyl group has 0 to p carbon atoms and the alkylene linking group has n to m carbon atoms.

[0207] When used herein, "C o-p Aryl-C n-m "Alkyl-" refers to the group of the formula aryl-alkylene-, where the aryl group has 0 to p carbon ring members and the alkylene linking group has n to m carbon atoms.

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

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

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

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

[0212] As used herein, the term "alkynylene" refers to a divalent linear or branched alkynyl linking group. Examples of "alkynylene groups" include propyne-1,3-diyl, 2-butyn-1,4-diyl, 3-pentyn-1,5-diyl, 3-hexyn-1,6-diyl, and 3-hexyn-1,5-diyl.

[0213] As used herein, “alkyl linking group” refers to a divalent linear or branched alkyl linking group (“alkylene group”). For example, “C o-p Cycloalkyl-C n-m Alkyl-", C o-p Aryl-C n-m Alkyl-, Phenyl-C n-m Alkyl-", "heteroaryl-C" n-m "alkyl-" and "heterocycloalkyl-C" n-m The "alkyl-" designation indicates the presence of an alkyl linking group. Examples of "alkyl linking groups" or "alkylene groups" include methylene, ethane-1,1-diyl, ethane-1,2-diyl, propane-1,3-diyl, propane-1,2-diyl, and propane-1,1-diyl.

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

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

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

[0217] 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 this disclosure containing asymmetrically substituted carbon atoms may be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically inert starting materials are known in the art, for example, by the separation of racemic mixtures or by stereoselective synthesis. Many geometric isomers, such as olefins and C=N double bonds, may also be present in the compounds described herein, and all such stable isomers are intended in the present invention. Cis and trans geometric isomers of the compounds of this disclosure are described, and these may be isolated as mixtures of isomers or as separated isomers. In some embodiments, the compounds have a (R) configuration. In some embodiments, the compounds have a (S) configuration. Formulas provided herein (e.g., formulas (I), (II), etc.) include stereoisomers of the compounds.

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

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

[0220] The compounds provided herein also include tautomerized forms. Tautomerized forms result from the exchange of a single bond with an adjacent double bond and the associated transfer of a proton. Tautomerized forms include prototropic tautomers, which are isomerized protonated states having the same empirical formula and total charge. Examples of prototropic tautomers include ketone-enol pairs, amide-imoid acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which a proton can occupy two or more positions in the heterocyclic system, such as 1H- and 3H-imidazoles, 1H-, 2H-, and 4H-1,2,4-triazoles, 1H- and 2H-isoindole, 2-hydroxypyridine and 2-pyridone, and 1H- and 2H-pyrazoles. Tautomerized forms may exist in equilibrium or may be sterically fixed into one form by appropriate substitution.

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

[0222] In some embodiments, the preparation of the compound may involve the addition of an acid or base to, for example, catalyze a desired reaction or to influence the formation of a salt form such as an acid addition salt.

[0223] In some embodiments, the compounds or salts thereof provided herein are substantially isolated. "Substantially isolated" means that the compound is separated at least partially or substantially from the environment in which it was formed or detected. Partial separation may include, for example, the concentration of a composition in the compounds provided herein. Substantial separation may include 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 compounds or salts thereof provided herein. Methods for isolating compounds and their salts are common in the art.

[0224] As used herein, the term “compound” is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of the illustrated structure. A compound identified herein by name or structure as a specific tautomer is intended to include other tautomers unless otherwise specified.

[0225] The term "pharmaceutically acceptable" is used herein to mean a compound, material, composition, and / or dosage form that, within the bounds of sound medical judgment, is suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic response, or other problems or complications, given a reasonable benefit-risk ratio.

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

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

[0228] 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 inactive with the starting materials (reactants), intermediates, or products at the temperature in which the reaction is carried out (for example, a temperature that may range from the freezing temperature to the boiling temperature of the solvent). A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the specific reaction step, a solvent suitable for that particular reaction step can be selected by those skilled in the art.

[0229] As used herein, the terms “ambient temperature,” “room temperature,” or “room temperature (rt)” are understood in the art and generally refer to temperature, such as reaction temperature, i.e., the temperature of the room in which the reaction is approximately carried out, e.g., about 20°C to about 30°C.

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

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

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

[0233] The compounds of formulas 1-5 can be synthesized using the process shown in Scheme 1. The compounds of formulas 1-3 were obtained by palladium-catalyzed cross-coupling reactions of suitable aryl halides 1-1 and boronic acid / ester 1-2. The compounds of formulas 1-5 were supplied by transition metal (including, but not limited to, Pd and Cu)-catalyzed CN bond formation reactions. Scheme 1. [ka]

[0234] The compound of formula 2-10 can also be synthesized using the process shown in Scheme 2. Intermediate compound 2-3 was obtained by nucleophilic substitution of compound 2-1 with O-ethyl carbonisothiocyanatidate 2-2. Cyclization of 2-3 with hydroxylamine hydrochloride / DIPEA provided the amino bicyclic core 2-4. Palladium-catalyzed cross-coupling of compound 2-4 and boronic acid / ester 2-5 yielded the compound of formula 2-6. Sandmeyer bromination of compound 2-6 produced aryl bromide 2-7, which could be reacted with amino compound 2-8 to provide compound 2-10 under transition metal-catalyzed CN bond formation conditions. Alternatively, the compound of formula 2-10 can be directly produced from amino compound 2-6 using a reductive amination protocol. Scheme 2. [ka]

[0235] The compounds of formula 3-10 can be synthesized using the process shown in scheme 3. Intermediate compound 3-3 was obtained by nucleophilic substitution of compound 3-1 with carbon 3-2 of ethyl isothiocyanatidic acid. Cyclization of 3-3 with hydroxylamine hydrochloride / DIPEA provided the amino bicyclic core 3-4. Palladium-catalyzed cross-coupling of compound 3-4 and boronic acid / ester 3-5 yielded the compound of formula 3-6. Sandmeyer bromination of compound 3-6 produced aryl bromide 3-7, which can be reacted with amino compound 3-8 to provide compound 3-10 under transition metal-catalyzed CN bond formation conditions. Alternatively, the compounds of formula 3-10 can be directly produced from amino compound 3-6 using a reductive amination protocol. Scheme 3. [ka]

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

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

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

[0239] In some embodiments, methods for treating CDK2-related diseases or disorders in patients are provided herein, the methods comprising administering to the patient a therapeutically effective amount of any compound of formula (I) or any of the formulas described herein, any of the compounds listed in any of the claims and described herein, or a salt thereof. In some embodiments, the CDK2-related diseases or disorders are related to amplification and / or overexpression of the cyclin E1 (CCNE1) gene.

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

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

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

[0243] In some embodiments, the disease or disorder associated with CDK2 is adenocarcinoma, carcinoma, or cystadenoma.

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

[0245] In some embodiments, the disease or disorder associated with CDK2 is cancer.

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

[0247] In some embodiments, breast cancer is breast cancer that is resistant to chemotherapy or radiotherapy, endocrine therapy, trastuzumab, or exhibits primary or acquired resistance to CDK4 / 6 inhibitors. In some embodiments, breast cancer is advanced or metastatic breast cancer.

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

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

[0250] In some embodiments, cancers treatable with the compounds of this 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., lymphoma, 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 such cancers.

[0251] In some embodiments, cancers treatable with the compounds of this 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 tumors, 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, pharyngeal cancer, laryngeal cancer, lip cancer, mesothelioma, cervical cancer, nasal cavity cancer, ocular cancer, melanoma, pelvic cancer, rectal cancer, renal cell carcinoma, salivary gland cancer, paranasal sinus cancer, spinal cancer, tongue cancer, tubular cancer, urethral cancer, and ureteral cancer.

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

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

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

[0255] Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyomas, rhabdomyomas, fibromas, lipomas, hamartomas, and teratomas.

[0256] Exemplary lung cancers include non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), bronchogenic carcinoma, squamous cell carcinoma, anaplastic small cell carcinoma, anaplastic large cell carcinoma, adenocarcinoma, alveolar (bronchial) carcinoma, bronchial adenoma, chondrotoxic hamartoma, and mesothelioma.

[0257] Typical gastrointestinal cancers include esophageal cancer (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (carcinoma, lymphoma, leiomyosarcoma), pancreatic cancer (pancreatic ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine cancer (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colorectal cancer (adenocarcinoma, tubular adenoma, chorioadenoma, hamartoma, leiomyoma), and colorectal cancer.

[0258] Exemplary urogenital tract cancers include kidney cancer (adenocarcinoma, Wilms' tumor [nephroblastoma]), bladder and urethral cancer (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate cancer (adenocarcinoma, sarcoma), and testicular cancer (seminocarcinoma, teratoma, fetal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoid tumor, lipoma).

[0259] Typical liver cancers include hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.

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

[0261] Exemplary cancers of the nervous system include skull cancer (osteoma, hemangioma, granuloma, xanthomas, osteoosteitis), meningeal cancer (meningioma, meningiosarcoma, glioma), brain cancer (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal glandoma), glioblastoma, glioblastoma multiforme, oligodendroglioma, Schwann cell tumor, retinoblastoma, congenital tumor), and spinal cord cancer (neurofibroma, meningioma, glioma, sarcoma), as well as neuroblastoma and Lhermitt-Dacros disease.

[0262] Exemplary gynecological cancers include uterine cancer (endometrial cancer), cervical cancer (cervical cancer, precancerous cervical dysplasia), ovarian cancer (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiable cancer), granulosa-theca cell tumor, Sertoli-Leydig cell tumor, undifferentiated germ cell tumor, malignant teratoma), vulvar cancer (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vaginal cancer (clear cell carcinoma, squamous cell carcinoma, staphylosarcoma (embryonic rhabdomyosarcoma), and fallopian tube cancer (carcinoma).

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

[0264] Any compound of formula (I), or any of its embodiments, is considered to have a satisfactory pharmacological profile and promising biologic properties, including toxicological profile, metabolic and pharmacokinetic properties, solubility, and permeability. It will be understood that determining appropriate biologic properties, such as determining inhibition of a specific target or channel to determine cytotoxicity in cells or potential toxicity, is within the scope of the knowledge of those skilled in the art.

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

[0266] The term "therapeutically effective dose" refers to the amount of an active compound or drug that elicits a biological or pharmaceutical response in a tissue, system, animal, individual, or human, as sought by researchers, veterinarians, physicians, or other clinicians.

[0267] As used herein, the term “to treat” or “treatment” means one or more of the following: (1) inhibiting a disease, for example, inhibiting a disease, condition, or disorder in an individual who is experiencing or exhibiting the pathology or overall symptoms of a disease, condition, or disorder (i.e., stopping the further progression of the pathology and / or overall symptoms); and (2) improving a disease, for example, improving a disease, condition, or disorder in an individual who is experiencing or exhibiting the pathology or overall symptoms of a disease, condition, or disorder (i.e., improving the pathology and / or overall symptoms), such as reducing the severity of the disease.

[0268] In some embodiments, the compounds of the present invention are useful in preventing or reducing the risk of developing any of the diseases mentioned herein, for example, in individuals who may have a predisposition to a disease, condition, or disorder but have not yet experienced or exhibited the pathology or overall symptoms of the disease.

[0269] Combination therapy I. Cancer Treatment The proliferation and survival of cancer cells can be affected by dysfunction in multiple signaling pathways. Therefore, it is useful to treat such conditions by combining different enzyme / protein / receptor inhibitors that exhibit different preferences for targets that modulate activity. Targeting more than one signaling pathway (or more than one biomolecule involved in a given signaling pathway) can reduce the potential for drug resistance to develop in the cell population and / or reduce the toxicity of the treatment.

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

[0271] In some embodiments, CDK2 inhibitors are administered or used in combination with BCL2 inhibitors or CDK4 / 6 inhibitors.

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

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

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

[0275] One or more of the following drugs may be used in combination with the compounds of this disclosure, and are presented as a non-limiting list: cell division inhibitors, cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, epotilon, tamoxifen, 5-fluorouracil, methotrexate, temozolomide, cyclophosphamide, SCH 66336, R115777, L778,123, BMS 214662, IRESSA (trademark) (gefitinib), TARCEVA (trademark) (erlotinib), antibody against EGFR, intron, Ara-C, adriamycin, cytoxane, gemcitabine, uracil mustard, chlormetine, ifosfamide, melphalan, chlorambucil, pipobromane, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, da Carbazine, phloxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, oxaliplatin, leucovorin, ELOXATIN (trademark) (oxaliplatin), pentostatin, vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, mitramycin, deoxycoformycin, mitomycin C, L-asparaginase, teniposide 17.alpha.- Ethinylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, dromostanolone propionate, testactone, megestrol acetate, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianicene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide, flutamide, toremifene, goserelin, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, navelbine, anastrozole, letrozole, capecitabine, raloxifene, droloxifene, hexamethylmelamine, Avastin, HERCEPTIN (trademark) (trastuzumab), BEXXAR (trademark) (tositumomab), VELCADE (trademark) (bortezomib), ZEVALIN (trademark) (ibritumomab tiuxetan), TRISENOX (trademark) (arsenic trioxide), XELODA (trademark) (capecitabine), vinorelbine, porfimer, ERBITUX (trademark) (cetuximab), thiotepa, altretamine, melphalan, trastuzumab, letrozo Lu, fulvestrant, exemestane, ifosfamide, rituximab, C225 (cetuximab), Campus (alemtuzumab), clofarabine, cladribine, aphidicolin, rituxan, sunitinib, dasatinib, tezacitabine, Sml1, fludarabine, pentostatin, triapin, zidox, trimidox, amidox, 3-AP, and MDL-101,731.

[0276] The compounds of this disclosure can also be used in combination with other methods of treating cancer, such as chemotherapy, radiotherapy, targeted tumor therapy, adjuvant therapy, immunotherapy, or surgery. Examples of immunotherapies include cytokine therapy (e.g., interferon, GM-CSF, G-CSF, IL-2), CRS-207 immunotherapy, cancer vaccines, monoclonal antibodies, bispecific or multispecific antibodies, antibody-drug conjugates, adoptive T cell transfer, Toll receptor agonists, RIG-I agonists, oncolytic virus therapy, and immunomodulatory small molecules including thalidomide or JAK1 / 2 inhibitors, PI3Kδ inhibitors, etc. The compounds can be administered in combination with one or more anticancer agents, such as chemotherapeutic agents. Examples of chemotherapy drugs include avalerix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bevacizumab, bexarotene, baricitinib, bleomycin, bortezomib, intravenous busulfan, oral busulfan, carsterone, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin, denileukin difutitox, dexrazoxane, docetaxel, doxorubicin, and propionate. Lomostanolone, eculizumab, epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib mesylate, interferon alpha-2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamizole, lomustine, mechloretamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen,Mitomycin C, Mitotane, Mitoxantrone, Nandrolone phenylpropionate, Nelarabine, Nofetumomab, Oxaliplatin, Paclitaxel, Pamidronate, Panitumumab, Pegaspargase, Pegfilgrastim, Pemetrexed disodium, Pentostatin, Pipobroman, Plicamycin, Procarbazine, Quinacrine, Rasburicase, Rituximab, Luxoli Any of the following are examples: tinib, sorafenib, streptozocin, sunitinib, sunitinib maleate, tamoxifen, temozolomide, teniposide, testactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tocitumomab, trastuzumab, tretinoin, uracil mustard, barrubicin, vinblastine, vincristine, vinorelbine, vorinostat, and zoledronate.

[0277] Examples of additional chemotherapy drugs include proteasome inhibitors (e.g., bortezomib), thalidomide, revlimid, and DNA damaging agents such as melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide, and carmustine.

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

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

[0280] Examples of suitable Flt-3 inhibitors include midostaurin, restaurtinib, linifanib, sunitinib, sunitinib, maleat, sorafenib, quizartinib, clenolanib, pacritinib, tandutinib, PLX3397 and ASP2215, and their pharmaceutically acceptable salts. Other examples of suitable Flt-3 inhibitors include compounds such as those disclosed in WO03 / 037347, WO03 / 099771 and WO04 / 046120, and their pharmaceutically acceptable salts.

[0281] Examples of suitable RAF inhibitors include dabrafenib, sorafenib, and vemurafenib, as well as pharmaceutically acceptable salts thereof. Other examples of suitable RAF inhibitors include compounds such as those disclosed in WO00 / 09495 and WO05 / 028444, as well as pharmaceutically acceptable salts thereof.

[0282] Examples of suitable FAK inhibitors include VS-4718, VS-5095, VS-6062, VS-6063, BI853520, and GSK2256098, as well as their pharmaceutically acceptable salts. Other examples of suitable FAK inhibitors include compounds such as those disclosed in WO04 / 080980, WO04 / 056786, WO03 / 024967, WO01 / 064655, WO00 / 053595, and WO01 / 014402, as well as their pharmaceutically acceptable salts.

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

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

[0285] In some embodiments, the compounds of this disclosure can be used in combination with chemotherapeutic agents in the treatment of cancer, improving the response to treatment compared to the response to the chemotherapeutic agent alone without exacerbating its toxic effects. In some embodiments, the compounds of this disclosure can be used in combination with chemotherapeutic agents provided herein. For example, additional pharmaceuticals used in the treatment of multiple myeloma may include, but are not limited to, melphalan, melphalan and prednisone [MP], doxorubicin, dexamethasone, and Velcade (bortezomib). Further additional agents used in the treatment of multiple myeloma include Bcr-Abl, Flt-3, RAF, and FAK kinase inhibitors. In some embodiments, this agent is an alkylating agent, a proteasome inhibitor, a corticosteroid, or an 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). Additive or synergistic effects are desirable outcomes of combining the CDK2 inhibitors of this disclosure with additional agents.

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

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

[0288] In some embodiments, a corticosteroid such as dexamethasone is administered to the patient in combination with the compounds of the Disclosure, where the dexamethasone is administered intermittently rather than continuously.

[0289] A compound of formula (I) or any of the formulas described herein, any compound listed in any of the claims and described herein, or a salt thereof, can be combined with other immunogenic substances such as cancer 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 peptide, MAGE antigen, Trp-2, MARTI, and / or tyrosinase, or tumor cells transfected to express the cytokine GM-CSF.

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

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

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

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

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

[0295] Pathogenic bacteria that cause infections treatable by the methods of this disclosure include, but are not limited to, Chlamydia, Rickettsia, Mycobacteria, Staphylococci, Streptococci, Pneumococci, Meningococci, and Conococci, Klebsiella, Proteus, Serratia, Pseudomonas, Legionella, Diphtheria, Salmonella, Bacillus, Cholera, Tetanus, Botulism, Anthrax, Leptospirosis, and Lyme disease.

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

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

[0298] If more than one medication is administered to a patient, they may be administered simultaneously, separately, sequentially, or in combination (for example, if more than two medications).

[0299] Methods for safely and effectively administering most of these chemotherapeutic agents are known to those skilled in the art. Furthermore, their administration is documented in standard literature. For example, the administration of many of these chemotherapeutic agents is described in the "Physicians' Desk Reference" (PDR, e.g., 1996 edition, Medical Economics Company, Montvale, NJ), and the disclosures of that document are incorporated herein by reference as if they were described in their entirety.

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

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

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

[0303] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of PD-1 or PD-L1, such as an anti-PD-1 or anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-1 or anti-PD-L1 antibody is nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, semiprimab, atezolizumab, avelumab, tislerizumab, spartalizumab (PDR001), cetrerimab (JNJ-63723283), tripalimab (JS001), camrelizumab (SHR-1210), cintilimab (IBI308), AB122 (GLS-010), AMP-224, AMP-514 / MEDI-0 These are 680, BMS936559, JTX-4014, BGB-108, SHR-1210, MEDI4736, FAZ053, BCD-100, KN035, CS1001, BAT1306, LZM009, AK105, HLX10, SHR-1316, CBT-502 (TQB2450), A167 (KL-A167), STI-A101 (ZKAB001), CK-301, BGB-A333, MSB-2311, HLX20, TSR-042, or LY3300054. In some embodiments, inhibitors of PD-1 or PD-L1 are disclosed in U.S. Patents 7,488,802, 7,943,743, 8,008,449, 8,168,757, 8,217,149, WO03042402, WO2008156712, WO2010089411, WO2010036959, WO2011066342, WO2011159877, WO2011082400, or WO2011161699, each of which is incorporated herein by reference in its entirety.

[0304] In some embodiments, the antibody is an anti-PD-1 antibody, such as an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 antibody is nivolumab, pembrolizumab, semiprimab, spartalizumab, camrelizumab, cetrelimab, tripalimab, scintirimab, 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, semiprimab, spartalizumab, camrelizumab, cetrelimab, tripalimab, or scintirimab. 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 semiprimab. In some embodiments, the anti-PD-1 antibody is spartalizumab. In some embodiments, the anti-PD-1 antibody is camrelizumab. In some embodiments, the anti-PD-1 antibody is cetrelimab. In some embodiments, the anti-PD-1 antibody is tripalimab. In some embodiments, the anti-PD-1 antibody is cintilimab. 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-PD-1 antibody is SHR-1210.Other anticancer agents include antibody therapies such as 4-1BB (e.g., urelumab, utomilumab). In some embodiments, the inhibitor of the immune checkpoint molecule is a PD-L1 inhibitor, such as an anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is atezolizumab, avelumab, durvalumab, tislerizumab, 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 tislerizumab. 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 tislerizumab. In some embodiments, the anti-PD-L1 antibody is BMS-935559. In some embodiments, the anti-PD-L1 antibody is MEDI4736. In some embodiments, the anti-PD-L1 antibody is FAZ053. In some embodiments, the anti-PD-L1 antibody is KN035. In some embodiments, the anti-PD-L1 antibody is CS1001. In some embodiments, the anti-PD-L1 antibody is SHR-1316. In some embodiments, the anti-PD-L1 antibody is CBT-502. In some embodiments, the anti-PD-L1 antibody is A167. In some embodiments, the anti-PD-L1 antibody is STI-A101. In some embodiments, the anti-PD-L1 antibody is CK-301. In some embodiments, the anti-PD-L1 antibody is BGB-A333. In some embodiments, the anti-PD-L1 antibody is MSB-2311. In some embodiments, the anti-PD-L1 antibody is HLX20. In some embodiments, the anti-PD-L1 antibody is LY3300054.

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

[0306] In some embodiments, the inhibitors of immune checkpoint molecules are inhibitors of KIR, TIGIT, LAIR1, CD160, 2B4, and TGFR beta.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0328] In some embodiments, the immune checkpoint molecule agonist is a CD28 agonist. In some embodiments, the CD28 agonist is ceralizumab.

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

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

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

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

[0333] As provided throughout, additional compounds, inhibitors, drugs, etc., can be combined with this compound in single or sequential dosage forms, or they can be administered simultaneously or sequentially in separate dosage forms.

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

[0335] The Disclosure also includes pharmaceutical compositions containing, in combination with one or more pharmaceutically acceptable carriers (excipients), the compounds of the Disclosure or pharmaceutically acceptable salts thereof as active ingredients. In some embodiments, the compositions are suitable for topical administration. When preparing the compositions of the Disclosure, the active ingredient is typically mixed with an excipient, diluted by an excipient, or encapsulated in such carrier in the form of, for example, a capsule, pouch, paper, or other container. If the excipient functions as a diluent, it may be a solid, semi-solid, or liquid material acting as a vehicle, carrier, or medium for the active ingredient. Thus, the compositions may be in the form of tablets, pills, powders, lozenges, pouches, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solid or in a liquid medium), for example, ointments, soft and hard gelatin capsules, suppositories, sterile injections, and sterile packaged powders containing up to 10% by weight of the active compound.

[0336] When preparing a formulation, the active compound may be ground to provide an appropriate particle size before being combined with other components. 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 substantially uniform distribution in the formulation, for example, about 40 mesh.

[0337] The compounds of this disclosure may be ground using known grinding procedures, such as wet grinding, to obtain particle sizes suitable for tablet formation and other formulation types. Finely divided (nanoparticle) preparations of the compounds of this disclosure can be prepared by processes known in the art; see, for example, International Application WO2002 / 000196.

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

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

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

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

[0342] In some embodiments, the compositions of this disclosure contain about 500 to about 1000 mg of the active ingredient. Those skilled in the art will understand 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 the active ingredient.

[0343] Similar dosages of the compounds described herein may be used in the methods and uses of this disclosure.

[0344] Active compounds can be effective across a wide range of dosages and are generally administered in pharmaceutically effective amounts. However, it should be understood that the actual amount of compound administered is usually determined by the physician based on relevant circumstances, including the condition being treated, the chosen route of administration, the actual compound being administered, the individual patient's age, weight, and response, and the severity of the patient's symptoms.

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

[0346] The tablets or pills of this disclosure may be coated or otherwise formulated to provide a dosage form that offers the benefit of long-lasting action. For example, the tablets or pills may contain an inner dosage and an outer dosage component, the latter in the form of a coating covering the former. These two components may be separated by an enteric coating, which functions to withstand disintegration in the stomach and allow the inner component to pass through the duodenum intact or to have its release delayed. Various materials may be used for such enteric coating or coating, and such materials include several polymer acids, as well as mixtures of polymer acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

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

[0348] Compositions for inhalation or inhalation include liquids and suspensions, as well as powders, in pharmaceutically acceptable aqueous solvents or organic solvents, or mixtures thereof. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, compositions are administered by oral or nasal respiratory pathways for topical or systemic effects. Compositions may be sprayed using an inert gas. The sprayed liquid may be inhaled directly from a spraying device, or the spraying device may be attached to a face mask, tent, or intermittent positive airway pressure (CPAP) device. Liquid, suspension, or powder compositions may be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0349] Topical formulations may contain one or more conventional carriers. In some embodiments, ointments may contain water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white petrolatum, etc. The carrier composition of creams may be based on water combined with glycerol and one or more other components, for example, glyceryl monostearate, PEG-glyceryl monostearate, and cetyl stearyl alcohol. Gels can be formulated using isopropyl alcohol and water in suitable combination with other components, for example, glycerol, hydroxyethylcellulose, etc. In some embodiments, topical formulations contain at least about 0.1, at least about 0.25, at least about 0.5, at least about 1, at least about 2, or at least about 5% by weight of the compounds of the Disclosure. Topical formulations may be suitably packaged, for example, in 100 g tubes, which is optional and associated with a description of a selected indication, for example, for the treatment of psoriasis or other skin conditions.

[0350] The amount of compound or composition administered to a patient will vary depending on what is being administered, the purpose of administration (prevention or treatment), the patient's condition, and the mode of administration. For therapeutic purposes, the composition may be administered to patients already suffering from a disease in an amount sufficient to cure or at least partially halt the symptoms of the disease and its complications. The effective dose will depend on the judgment of the attending physician, taking into account factors such as the medical condition being treated, the severity of the disease, the patient's age, weight, and overall health.

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

[0352] The therapeutic dose of the compounds disclosed herein may vary depending, for example, the specific use in which the treatment is performed, the mode of administration of the compound, the patient's health and condition, and the judgment of the prescribing physician. The proportion or concentration of the compounds disclosed herein in a pharmaceutical composition may vary depending on several factors, including the dose, chemical properties (e.g., hydrophobicity), and route of administration. For example, the compounds disclosed herein may be provided for parenteral administration in a physiologically buffered aqueous solution containing about 0.1 to about 10 w / v% of the compound. Some typical dose ranges are about 1 μg / kg body weight to about 1 g / kg body weight per day. In some embodiments, the dose range is about 0.01 mg / kg body weight to about 100 mg / kg body weight per day. The dose may depend on variable factors such as the type and degree of disease or disability progression, the overall health status of a particular patient, the biological efficacy ratio of the selected compound, the formulation of the excipients, and its route of administration. The effective dose can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

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

[0354] Labeled compounds and assay methods Another aspect of this disclosure relates to labeled compounds (radioactively labeled, fluorescently labeled, etc.) of this disclosure that would be useful in both in vitro and in vivo assays, as well as imaging techniques, for locating and quantifying CDK2 in tissue samples, including human tissue, and for identifying CDK2 activators, by inhibitory binding of the labeled compound. Substitution of one or more atoms in the compounds of this disclosure may also be useful in producing differentiated ADME (adsorption, distribution, metabolism, and excretion). Accordingly, this disclosure includes CDK2 assays containing such labeled or substituted compounds.

[0355] This disclosure further includes the isotope-labeled compounds of this disclosure. An “isotope-labeled” or “radio-labeled” compound is one in which one or more atoms in the compound of this disclosure are replaced or substituted with atoms having an atomic mass or mass number different from that typically found in nature (i.e., naturally occurring). Suitable radionuclides that may be incorporated into the compounds of this disclosure include: 2 H (also written as D, representing Deuterium), 3 H (also written as T, representing tritium), 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 18 F, 35 S, 36 Cl, 82 Br, 75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I, and 131This includes, but is not limited to, formula (I). For example, one or more hydrogen atoms in the compounds of this disclosure may be replaced with deuterium atoms (e.g., by substituting CH3 with -CD3, etc., C of formula (I)). 1-6 (One or more hydrogen atoms of the alkyl group may be optionally substituted with deutherium atoms.) In some embodiments, all alkyl groups of the disclosed formula (e.g., formula (I)) may be perdeuterated.

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

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

[0358] Methods for synthesizing 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). Isotopic-labeled compounds can be used in various studies such as NMR spectroscopy, metabolic experiments, and / or assays.

[0359] Substitution with heavier isotopes, such as deuterium, may result in certain therapeutic benefits stemming from greater metabolic stability, such as an increased in vivo half-life or reduced required dosage, and may therefore be preferable in some situations. (See, for example, A. Kerekes et al. J. Med. Chem. 2011, 54, 201-210 and 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 of these therapeutic benefits.

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

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

[0362] This disclosure may further include synthetic methods for incorporating radioactive isotopes into the compounds of this disclosure. Synthetic methods for incorporating radioactive isotopes into organic compounds are well known in the art, and those skilled in the art will readily recognize methods applicable to the compounds of this disclosure.

[0363] The labeled compounds of this disclosure can be used in screening assays to identify / evaluate compounds. 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 when in contact with CDK2 through tracking of the label. For example, a test compound (labeled) can be evaluated for its ability to reduce the binding of another compound (i.e., a standard compound) that is known to inhibit CDK2. Thus, the ability of a test compound to compete with a standard compound for binding to CDK2 is directly correlated with its binding affinity. Conversely, in some other screening assays, the standard compound is labeled and the test compound is not. Therefore, to evaluate competition between the standard compound and the test compound, the concentration of the labeled standard compound is monitored and the relative binding affinity of the test compound is thus confirmed.

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

[0365] Biomarkers and pharmacodynamic markers This disclosure further provides predictive markers (e.g., biomarkers and pharmacodynamic markers, e.g., gene copy number, gene sequence, expression level, or phosphorylation level) for identifying human subjects who have, are suspected of having, or are at risk of developing a CDK2-related disease or disorder, in which case administration of a CDK2 inhibitor (as used herein, “CDK2 inhibitor” means the compounds of this disclosure or pharmaceutically acceptable salts thereof) is likely to be effective. This disclosure also provides pharmacodynamic markers (e.g., phosphorylation level) for identifying human subjects who have, are suspected of having, or are at risk of developing a CDK2-related disease or disorder, in which case they are responding to a CDK2 inhibitor. The use of CCNE1, p16, and Rb S780 is further described in WO2020 / 168178 (and U.S. Patent Application No. 16 / 791,561), the figures and disclosures of which are incorporated herein by reference in their entirety.

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

[0367] CCNE1 and p16 CCNE1 and p16, together, were identified in the examples as genes useful in predicting the responsiveness to CDK2 inhibitors (e.g., improvement of the disease as evidenced by disease remission / disappearance) in subjects with CDK2-related diseases or disorders.

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

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

[0370] The examples demonstrate that CDK2 knockdown inhibits the proliferation of CCNE1-amplified cell lines, but not of CCNE1-non-amplified cell lines. Conversely, the examples show that CDK4 / 6 inhibition inhibits the proliferation of CCNE1-non-amplified cell lines, but not of CCNE1-amplified cell lines. The examples further demonstrate that the presence of a normal (e.g., non-mutant or non-deleted) p16 gene is required for the observed inhibition of cell proliferation in CCNE1-amplified cells treated with a CDK2 inhibitor. Therefore, CCNE1 and p16 together are combination biomarkers. In other words, cells that respond to treatment with CDK2 inhibitors exhibit amplification of the CCNE1 gene and / or CCNE1 expression levels higher than the control expression level of CCNE1, and have a nucleotide sequence (e.g., gene or mRNA) encoding the p16 protein (e.g., the p16 protein containing the amino acid sequence of SEQ ID NO: 1), and / or have the presence of the p16 protein, while control cells that do not respond to treatment with CDK2 inhibitors do not exhibit amplification of the CCNE1 gene and / or CCNE1 expression levels higher than the control expression level of CCNE1, and tend to have mutations or deletions in the gene encoding the p16 protein, and / or lack the expression of the p16 protein.

[0371] Therefore, this disclosure provides a method for treating a human subject having, suspected of having, or at risk of developing, a CDK2-related disease or disorder, the method comprising administering a CDK2 inhibitor to the human subject, the human subject having (i)(a) a nucleotide sequence encoding the 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) expressing the p16 protein, and (ii)(a) having amplification of the CCNE1 gene, and / or (b) having a CCNE1 expression level higher than the control expression level of CCNE1 in a biological sample obtained from the human subject. In certain embodiments, the predictive method described herein predicts with at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or 100% certainty that the subject will respond to treatment with the CDK2 inhibitor. For example, in some embodiments, the prediction method described herein is applied to 10 subjects who have, are suspected of having, or are at risk of developing a CDK2-related disease or disorder, and based on the prediction method described herein, 8 of those 10 subjects are predicted to respond to treatment with a CDK2 inhibitor, and 7 of those 8 subjects actually respond to treatment with a CDK2 inhibitor, then the prediction method has an accuracy of 87.5% (7 divided by 8). A subject is considered to respond to a CDK2 inhibitor if he or she shows any improvement in his or her condition, such as a reduction or alleviation of symptoms, or disease remission / disappearance.

[0372] In some embodiments, the subject has a disease or disorder related to CDK2. In some embodiments, the human subject has been previously determined to have (i)(a) a nucleotide sequence encoding the p16 protein containing 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 containing the amino acid sequence of SEQ ID NO: 1. In specific embodiments, the CDKN2A gene encodes a protein containing the amino acid sequence of SEQ ID NO: 1.

[0373] In specific embodiments, one or more inactivating nucleic acid substitutions and / or deletions in the CDKN2A gene are as shown in Table A. In specific embodiments, one or more inactivating nucleic acid substitutions and / or deletions in the CDKN2A gene are as described in Yarbrough et al., Journal of the National Cancer Institute, 91(18):1569-1574, 1999, Liggett and Sidransky, Biology of Neoplasia, Journal of Oncology, 16(3):1197-1206, 1998, and Cairns et al., Nature Genetics, 11:210-212, 1995, each of which is incorporated herein by reference in its entirety. [Table 1-1] [Table 1-2] [Table 1-3]

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

[0375] This disclosure also addresses a method for predicting the response to CDK2 inhibitors in human subjects who have, are suspected of having, or are at risk of developing a CDK2-related disease or disorder, the method comprising (i) determining from a biological sample obtained from a human subject (a) the nucleotide sequence of the CDKN2A gene, (b) the presence of the CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions, and / or (c) the presence of the p16 protein, and (ii) determining from a biological sample obtained from a human subject (a) the copy number of the CCNE1 gene and The method includes (b) determining the expression level of CCNE1, wherein (1) the presence of a CDKN2A gene encoding the p16 protein containing 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 the p16 protein, and (2) amplification of the CCNE1 gene, and / or (b) an expression level of CCNE1 higher than the control expression level of CCNE1, are predictions that the human subject will respond to a CDK2 inhibitor. In some embodiments, the subject has a CDK2-related disease or disorder. In some embodiments, the subject is suspected of having a CDK2-related disease or disorder, or is at risk of developing one. In some embodiments, the method includes (i) determining from a biological sample obtained from a human subject the presence of (a) the nucleotide sequence of the 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 from a biological sample obtained from a human subject the copy number of (a) the CCNE1 gene, where (1) the presence of a CDKN2A gene encoding the p16 protein containing the amino acid sequence of 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) the amplification of the CCNE1 gene, are predictions that the human subject will respond to a CDK2 inhibitor.

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

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

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

[0379] 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.

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

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

[0382] Rb S780 The disclosure also deals with methods for assessing the CDKN2A and CCNE1 genes, which include determining (i) (a) the nucleotide sequence of the CDKN2A gene, or (b) the presence of one or more inactive nucleic acid substitutions and / or deletions in the CDKN2A gene, and (ii) the copy number of the CCNE1 gene, from one or more biological samples obtained from human subjects having a CDK2-related disease or disorder.

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

[0384] Phosphorylation of Rb at the serine molecule corresponding to amino acid position 780 of Sequence ID No. 3 (referred to herein as "Ser780" or "S780") was identified in the examples as a useful pharmacodynamic marker for assessing responsiveness to CDK2 inhibitors (e.g., inhibition by CDK2) in human subjects with diseases or disorders involving CCNE1 amplification.

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

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

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

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

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

[0390] In some embodiments, the CCNE1 gene is amplified to 3 to 25 copies. In specific embodiments, the CCNE1 gene is amplified to at least 3 copies. In specific embodiments, the CCNE1 gene is amplified to at least 5 copies. In specific embodiments, the CCNE1 gene is amplified to at least 7 copies. In specific embodiments, the CCNE1 gene is amplified to at least 10 copies. In specific embodiments, the CCNE1 gene is amplified to at least 12 copies. In specific embodiments, the CCNE1 gene is amplified to at least 14 copies. In specific embodiments, the CCNE1 gene is amplified to at least 21 copies. 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.

[0391] contrast As described above, methods related to biomarkers and pharmacodynamic markers may involve measuring one or more markers (e.g., biomarkers or pharmacodynamic markers, e.g., amplification of the CCNE1 gene, CCNE1 expression level, presence of the CDKN2A gene encoding the p16 protein containing the amino acid sequence of SEQ ID NO: 1, presence of the CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions, presence of the p16 protein (e.g., the p16 protein containing 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 derived from a human subject having, suspecting, or being at risk of developing a CDK2-related disease or disorder. In certain embodiments, the level of one or more biomarkers (e.g., amplification (e.g., for the CCNE1 gene), expression level (e.g., for the CCNE1 or p16 protein), or phosphorylation level (e.g., for Rb)) compared to a control level of one or more biomarkers predicts / indicates a response in a human subject to treatment including a CDK2 inhibitor. In certain embodiments, a human subject is identified as likely to respond to a CDK2 inhibitor if (i) the CCNE1 gene is amplified and / or the expression level of CCNE1 is higher than the control expression level of CCNE1, and (ii) one or more CDKN2A genes lacking inactivating nucleic acid substitutions and / or deletions, which encode the p16 protein containing the amino acid sequence of SEQ ID NO: 1, and / or the p16 protein (e.g., the p16 protein containing the amino acid sequence of SEQ ID NO: 1) are present.In other embodiments, a human subject is identified as responsive to a CDK2 inhibitor if (i) the CCNE1 gene is amplified and / or the expression level of CCNE1 is higher than the control expression level of CCNE1, and (ii) the level of Rb phosphorylation at the serine corresponding to amino acid 780 of SEQ ID NO: 3 in a biological sample derived from the human subject after administration of the CDK2 inhibitor is less than the control level of Rb phosphorylation at the serine corresponding to amino acid 780 of SEQ ID NO: 3. In yet another embodiment, a human subject is identified as responsive to a CDK2 inhibitor if (i) the CCNE1 gene is amplified and / or has a higher expression level of CCNE1 than the control expression level of CCNE1, (ii) the CDKN2A gene encoding the p16 protein containing the amino acid sequence of SEQ ID NO: 1 is present, one or more CDKN2A genes lacking inactivating nucleic acid substitutions and / or deletions are present, and / or the p16 protein (e.g., the p16 protein containing the amino acid sequence of SEQ ID NO: 1) is present, and (iii) the level of Rb phosphorylation at the serine corresponding to amino acid position 780 of SEQ ID NO: 3 in a biological sample derived from the human subject after the human subject has been administered a CDK2 inhibitor is less than the control level of Rb phosphorylation at the serine corresponding to amino acid position 780 of SEQ ID NO: 3. In this context, the term “control” includes samples obtained from human subjects (from the same tissue species) that are known not to respond to a CDK2 inhibitor. The term “control” also includes samples (from the same tissue type) that have been previously obtained from ...

Claims

1. Equation (I): 【Chemistry 1】 A pharmaceutical composition for use in combination with one or more additional therapeutic agents for the treatment of diseases or disorders related to CDK2, comprising a compound of or a pharmaceutically acceptable salt thereof, If the disease or disorder is cancer In formula (I), n is 0, 1, 2, 3, or 4, p is 0, 1, 2, 3, or 4, 【Chemistry 2】 However, it is either a single bond or a double bond. X is N, Y is C, and the ring 【Transformation 3】 but, 【Chemistry 4】 is, or X is C, Y is N, and the ring 【Transformation 5】 but, 【Transformation 6】 And, Z is CR ２ or N, The ring portion A is a 5-10 member heteroaryl compound. Ring portion B is a monocyclic 4- to 7-membered heterocycloalkyl, where ring portion B is bonded to the -NH- group of formula (I) by a ring member of the saturated or partially saturated ring of the monocyclic 4- to 7-membered heterocycloalkyl. R １ is H, halo, CN, NO ２ , C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ３－７ cycloalkyl, phenyl, 4-7 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 , NR ２ R ｂ１ , NR ｃ１ , NR ２ , NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ , and S(O) ２ , NR ｃ１ R ｄ１ is selected from, and the C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ３－７ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C ３－７ cycloalkyl-C １－４ alkyl, phenyl-C １－４ Alkyl, 4-7 member heterocycloalkyl-C １－４ Alkyl and 5-6 member heteroaryl-C １－４ Each alkyl group is either unsubstituted or consists of 1, 2, 3, or 4 independently selected R groups. １Ａ Substituting with substituents, Each R ａ１ , R ｃ１ , and R ｄ１ H and C became independent. １－６ Alkyl, C １－６ Haloalkyl, C ３－７ Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4-7 member heterocycloalkyl-C １－４ Alkyl and 5-6 member heteroaryl-C １－４ Selected from alkyl, the C １－６ Alkyl, C １－６ Haloalkyl, C ３－７ Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4-7 member heterocycloalkyl-C １－４ Alkyl and 5-6 member heteroaryl-C １－４ Each alkyl group is either unsubstituted or consists of 1, 2, 3, or 4 independently selected R groups. １Ａ Substituting with substituents, Each R ｂ１ C １－６ Alkyl, C １－６ Haloalkyl, C ３－７ Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4-7 member heterocycloalkyl-C １－４ Alkyl and 5-6 member heteroaryl-C １－４ Selected from alkyl groups, each of which is either unsubstituted or one, two, three, or four independently selected R groups. １Ａ Substituting with substituents, Each R １Ａ is independently H, D, halo, CN, NO ２ , C １－６ alkyl, C １－６ haloalkyl, C ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－７ cycloalkyl-C １－４ alkyl, phenyl-C １－４ alkyl, 4- to 7-membered heterocycloalkyl-C １－４ alkyl, 5- to 6-membered heteroaryl-C １－４ alkyl, OR ａ１１ , C(O)R ｂ１１ , C(O)NR ｃ１１ R ｄ１１ , C(O)OR ａ１１ , 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)[[ID=�7]] ２ R ｂ１１ , NR ｃ１１ , S(O) ２ , NR ｃ１１ R ｄ１１ , S(O) ２ R ｂ１１ , and S(O) ２ , NR ｃ１１ R ｄ１１ selected from, said C １－６ alkyl, C １－６ haloalkyl, C ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－７ cycloalkyl-C １－４ alkyl, phenyl-C １－４ alkyl, 4- to 7-membered heterocycloalkyl-C １－４ alkyl, and 5- to 6-membered heteroaryl-C １－４ Each alkyl group is either unsubstituted or consists of 1, 2, 3, or 4 independently selected R groups. １Ｂ Substituting with substituents, Each R ａ１１ , R ｃ１１ , and R ｄ１１ H and C became independent. １－６ Alkyl and C １－６ Selected from haloalkyl groups, Each R ｂ１１ C １－６ Alkyl and C １－６ Selected from haloalkyl groups, Each R １Ｂ H, D, and OR are independent. ａ１２ Selected from, Each R ａ１２ H and C are independent of each other. １－６ Selected from alkyl groups, R ２ However, H, Halo, CN, C １－４ Alkyl, C １－４ Haloalkyl, C ２－４ Alkenil, C ２－４ Alkinyl, OH, C １－３ Alkoxy, C １－３ Haloalkoxy, amino, C １－３ Alkylamino, di(C) １－３ Alkyl)amino, cyano-C １－４ Alkyl, HO-C １－４ Alkyl, C １－３ Alkoxy-C １－４ Alkyl and C ３－４ Selected from cycloalkyl groups, Each R ３ These are independently selected from H, F, and methyl, R ４ However, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenil, C ２－６ Alkinyl, 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 member heterocycloalkyl-C １－４ Alkyl and 5-10 member heteroaryl-C １－４ Selected from alkyl, the C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenil, C ２－６ Alkinyl, 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 member heterocycloalkyl-C １－４ Alkyl and 5-10 member heteroaryl-C １－４ Each alkyl group is either unsubstituted or consists of 1, 2, 3, or 4 independently selected R groups. ４Ａ Substituting with substituents, Each R ４Ａ They became independent: H, Halo, CN, C １－６ Alkyl, C １－６ Haloalkyl, C ３－４ Cycloalkyl, OR ａ４１ , C(O)R ｂ４１ C(O)NR ｃ４１ R ｄ４１ , C(O)OR ａ４１ OC(O)R ｂ４１ , OC(O)NR ｃ４１ R ｄ４１ , NR ｃ４１ R ｄ４１ , NR ｃ４１ C(O)R ｂ４１ , NR ｃ４１ C(O)OR ａ４１ , NR ｃ４１ C(O)NR ｃ４１ R ｄ４１ , NR ｃ４１ S(O) ２ R ｂ４１ , NR ｃ４１ S(O) ２ NR ｃ４１ R ｄ４１ , S(O) ２ R ｂ４１ , and S(O) ２ NR ｃ４１ R ｄ４１ Selected from, the C １－６ Alkyl, C １－６ Haloalkyl and C ３－４ Each cycloalkyl group is either unsubstituted or consists of one, two, or three independently selected R groups. ４Ｂ Substituting with substituents, Each R ａ４１ , R ｃ４１ , and R ｄ４１ H and C became independent. １－６ Alkyl, C １－６ Haloalkyl and C ３－４ Selected from cycloalkyl, the C １－６ Alkyl, C １－６ Haloalkyl and C ３－４ Each cycloalkyl group is either unsubstituted or one or two independently selected R groups. ４Ｂ Substituting with substituents, Each R ｂ４１ C １－６ Alkyl, C １－６ Haloalkyl and C ３－４ Selected from cycloalkyl groups, each of which is either unsubstituted or one or two independently selected R groups. ４Ｂ Substituting with substituents, Each R ４Ｂ They became independent: H, Halo, CN, C １－３ Alkyl, C １－３ Haloalkyl, OR ａ４２ , and NR ｃ４２ R ｄ４２ Selected from, Each R ａ４２ , R ｃ４２ , and R ｄ４２ H and C became independent. １－３ Alkyl and C １－３ Selected from haloalkyl groups, Each R ５ They became independent: H, Halo, CN, C １－６ Alkyl, C １－６ Haloalkyl, C ３－４ Cycloalkyl, OR ａ５ , and NR ｃ５ R ｄ５ Selected from, and Each R ａ５ , R ｃ５ , and R ｄ５ H and C became independent. １－６ Alkyl and C １－６ Selected from haloalkyl groups, The aforementioned pharmaceutical composition.

2. R １ They became independent: H, Halo, CN, C １－６ Alkyl, C １－６ Haloalkyl, C ３－７ Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C ３－７ Cycloalkyl-C １－３ Alkyl, phenyl-C １－３ Alkyl, 4-7 member heterocycloalkyl-C １－３ Alkyl, 5-6 member heteroaryl-C １－３ Alkyl, OR ａ１ , SR ａ１ , and NR ｃ１ R ｄ１ Selected from, the C １－６ Alkyl, C １－６ Haloalkyl, C ３－７ Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C ３－７ Cycloalkyl-C １－３ Alkyl, phenyl-C １－３ Alkyl, 4-7 member heterocycloalkyl-C １－３ Alkyl and 5-6 member heteroaryl-C １－３ Each alkyl group is either unsubstituted or one or two independently selected R groups. １Ａ The pharmaceutical composition according to claim 1, which is substituted with a substituent.

3. R １ H and C became independent. １－６ Alkyl, phenyl, 5-7 member heterocycloalkyl, OR ａ１ , SR ａ１ , and NR ｃ１ R ｄ１ Selected from, the C １－６ Alkyl, phenyl, and 5- to 7-membered heterocycloalkyl groups are each unsubstituted or one or two independently selected R groups. １Ａ The pharmaceutical composition according to claim 1, which is substituted with a substituent.

4. R １ H and OR ａ１ A pharmaceutical composition according to claim 1, selected from the following.

5. Each R ａ１ , R ｃ１ , and R ｄ１ H and C became independent. １－６ Alkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, phenyl, 4-6 member heterocycloalkyl, C ３－６ Cycloalkyl-C １－３ Alkyl and 4-6 member heterocycloalkyl-C １－３ Selected from alkyl, the C １－６ Alkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, phenyl, 4-6 member heterocycloalkyl, C ３－６ Cycloalkyl-C １－３ Alkyl and 4-6 member heterocycloalkyl-C １－３ Each alkyl group is either unsubstituted or consists of one, two, or three independently selected R groups. １Ａ Substituting with substituents, Each R ｂ１ C １－６ Alkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, 4-6 member heterocycloalkyl, C ３－６ Cycloalkyl-C １－２ Alkyl and 4-6 member heterocycloalkyl-C １－２ Selected from alkyl groups, each of which is either unsubstituted or one or two independently selected R groups. １Ａ Substituting with substituents, Each R １Ａ These became independent: H, D, Halo, CN, C １－６ Alkyl, C １－６ Haloalkyl, OR ａ１１ , and C(O)OR ａ１１ Selected from, the C １－６ Alkyl and C １－６ Each haloalkyl is either unsubstituted or one, two, or three independently selected R １Ｂ Substituting with substituents, Each R ａ１１ H and C are independent of each other. １－４ Selected from alkyl, the C １－４ The alkyl group is either unsubstituted or consists of one, two, or three independently selected R groups. １Ｂ Substituting with substituents, Each R １Ｂ These are independently H, D, and O-C １－４ Selected from alkyl groups, A pharmaceutical composition according to any one of claims 1 to 4.

6. R １ However, OR ａ１ And R ａ１ However, C １－３ The pharmaceutical composition according to claim 1, wherein the alkyl group is alkyl.

7. R ２ The pharmaceutical composition according to any one of claims 1 to 6, wherein the element is H or a halo.

8. R ２ The pharmaceutical composition according to any one of claims 1 to 6, wherein the element is H or F.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein ring portion B is piperidinyl.

10. A pharmaceutical composition according to any one of claims 1 to 9, wherein n is 0 or 1.

11. Each R ３ The pharmaceutical composition according to any one of claims 1 to 10, wherein is independently selected from H and methyl.

12. R ４ However, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－７ Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4-7 member heterocycloalkyl-C １－４ Alkyl and 5-6 member heteroaryl-C １－４ Selected from alkyl, the C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－７ Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4-7 member heterocycloalkyl-C １－４ Alkyl and 5-6 member heteroaryl-C １－４ Each alkyl group is either unsubstituted or consists of 1, 2, 3, or 4 independently selected R groups. ４Ａ A pharmaceutical composition according to any one of claims 1 to 11, which is substituted with a substituent.

13. R ４ However, C １－６ Alkyl, C ３－６ Cycloalkyl, 5-6 member heteroaryl, and 4-7 member heterocycloalkyl-C １－４ Selected from alkyl, the C １－６ Alkyl, C ３－６ Cycloalkyl, 5-6 member heteroaryl, and 4-7 member heterocycloalkyl-C １－４ Each alkyl group is either unsubstituted or one or two independently selected R groups. ４Ａ A pharmaceutical composition according to any one of claims 1 to 11, which is substituted with a substituent.

14. R ４ However, C １－６ Alkyl and C ３－６ A pharmaceutical composition according to any one of claims 1 to 11, selected from cycloalkyl groups.

15. Each R ４Ａ They became independent: H, Halo, CN, C １－６ Alkyl, C １－６ Haloalkyl, C ３－４ Cycloalkyl, OR ａ４１ , C(O)R ｂ４１ C(O)NR ｃ４１ R ｄ４１ , C(O)OR ａ４１ OC(O)R ｂ４１ , OC(O)NR ｃ４１ R ｄ４１ , NR ｃ４１ R ｄ４１ , NR ｃ４１ C(O)R ｂ４１ , NR ｃ４１ C(O)OR ａ４１ , NR ｃ４１ C(O)NR ｃ４１ R ｄ４１ , NR ｃ４１ S(O) ２ R ｂ４１ , NR ｃ４１ S(O) ２ NR ｃ４１ R ｄ４１ , S(O) ２ R ｂ４１ , and S(O) ２ NR ｃ４１ R ｄ４１ Selected from, Each R ａ４１ , R ｃ４１ , and R ｄ４１ H and C became independent. １－３ Alkyl and C １－３ Selected from haloalkyl groups, Each R ｂ４１ C １－３ Alkyl and C １－３ Selected from haloalkyl groups, A pharmaceutical composition according to any one of claims 1 to 14.

16. Each R ４Ａ They became independent: H, Halo, CN, C １－６ Alkyl, C １－６ Haloalkyl, OR ａ４１ , and NR ｃ４１ R ｄ４１ Selected from, Each R ａ４１ , R ｃ４１ , and R ｄ４１ H and C became independent. １－３ Alkyl and C １－３ Selected from haloalkyl groups, Each R ｂ４１ However, C １－３ It is alkyl. A pharmaceutical composition according to any one of claims 1 to 14.

17. The pharmaceutical composition according to any one of claims 1 to 16, wherein the ring portion A is a 5- to 6-membered heteroaryl compound.

18. The pharmaceutical composition according to any one of claims 1 to 16, wherein ring portion A is 1H-pyrrolo[2,3-b]pyridinyl, pyridinyl, or pyrazolyl.

19. The pharmaceutical composition according to any one of claims 1 to 16, wherein ring portion A is pyrazolyl.

20. A pharmaceutical composition according to any one of claims 1 to 19, wherein p is 0 or 1.

21. Each R ５ CH became independent, ３ or NH ２ A pharmaceutical composition according to any one of claims 1 to 20, selected from the above.

22. n is 0, 1, or 2, p is 0, 1, or 2, The ring portion A is a 5-10 member heteroaryl compound. Ring portion B is azetidinil, pyrrolidinil, or piperidinil. R １ However, H, Halo, CN, C １－６ Alkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C ３－６ Cycloalkyl-C １－３ Alkyl, phenyl-C １－３ Alkyl, 4-7 member heterocycloalkyl-C １－３ Alkyl, 5-6 member heteroaryl-C １－３ Alkyl, OR ａ１ , SR ａ１ , and NR ｃ１ R ｄ１ And the above C １－６ Alkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, C ３－６ Cycloalkyl-C １－３ Alkyl, phenyl-C １－３ Alkyl, 4-7 member heterocycloalkyl-C １－３ Alkyl and 5-6 member heteroaryl-C １－３ Each alkyl group is either unsubstituted or consists of one, two, or three independently selected R groups. １Ａ Substituting with substituents, Each R ａ１ , R ｃ１ , and R ｄ１ H and C became independent. １－６ Alkyl, C １－６ Haloalkyl, C ３－７ Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, and C ３－７ Cycloalkyl-C １－４ Selected from alkyl, the C １－６ Alkyl, C １－６ Haloalkyl, C ３－７ Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, and C ３－７ Cycloalkyl-C １－４ Each alkyl group is either unsubstituted or consists of one, two, or three independently selected R groups. １Ａ Substituting with substituents, Each R １Ａ These became independent: H, D, Halo, CN, C １－６ Alkyl, C １－６ Haloalkyl, C ３－４ Cycloalkyl, OR ａ１１ , C(O)R ｂ１１ C(O)NR ｃ１１ R ｄ１１ , C(O)OR ａ１１ OC(O)R ｂ１１ , OC(O)NR ｃ１１ R ｄ１１ , NR ｃ１１ R ｄ１１ , NR ｃ１１ C(O)R ｂ１１ , NR ｃ１１ C(O)OR ａ１１ , NR ｃ１１ C(O)NR ｃ１１ R ｄ１１ , NR ｃ１１ S(O) ２ R ｂ１１ , NR ｃ１１ S(O) ２ NR ｃ１１ R ｄ１１ , S(O) ２ R ｂ１１ , and S(O) ２ NR ｃ１１ R ｄ１１ Selected from, the C １－６ Alkyl, C １－６ Haloalkyl and C ３－４ Each cycloalkyl group is either unsubstituted or consists of one, two, or three independently selected R groups. １Ｂ Substituting with substituents, Each R ａ１１ , R ｃ１１ , and R ｄ１１ H and C became independent. １－６ Alkyl and C １－６ Selected from haloalkyl groups, Each R ｂ１１ C １－６ Alkyl and C １－６ Selected from haloalkyl groups, Each R １Ｂ H, D, and OR are independent. ａ１２ Selected from, Each R ａ１２ H and C are independent of each other. １－６ Selected from alkyl groups, R ２ However, H, Halo, CN, C １－３ Alkyl and C １－３ Selected from haloalkyl groups, Each R ３ They became independent as H, Halo, and C １－３ Selected from alkyl and cyclopropyl, R ４ However, C １－６ Alkyl, C １－６ Haloalkyl, C ３－７ Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, and 4-7 member heterocycloalkyl-C １－４ Selected from alkyl, the C １－６ Alkyl, C １－６ Haloalkyl, C ３－７ Cycloalkyl, phenyl, 4-7 member heterocycloalkyl, 5-6 member heteroaryl, and 4-7 member heterocycloalkyl-C １－４ Each alkyl group is either unsubstituted or one or two independently selected R groups. ４Ａ Substituting with substituents, Each R ４Ａ They became independent: H, Halo, CN, C １－６ Alkyl, C １－６ Haloalkyl, C ３－４ Cycloalkyl, OR ａ４１ , C(O)R ｂ４１ C(O)NR ｃ４１ R ｄ４１ , C(O)OR ａ４１ OC(O)R ｂ４１ , OC(O)NR ｃ４１ R ｄ４１ , NR ｃ４１ R ｄ４１ , NR ｃ４１ C(O)R ｂ４１ , NR ｃ４１ C(O)OR ａ４１ , NR ｃ４１ C(O)NR ｃ４１ R ｄ４１ , NR ｃ４１ S(O) ２ R ｂ４１ , NR ｃ４１ S(O) ２ NR ｃ４１ R ｄ４１ , S(O) ２ R ｂ４１ , and S(O) ２ NR ｃ４１ R ｄ４１ Selected from, the C １－６ Alkyl, C １－６ Haloalkyl and C ３－４ Each cycloalkyl group is either unsubstituted or consists of one, two, or three independently selected R groups. ４Ｂ Substituting with substituents, Each R ａ４１ , R ｃ４１ , and R ｄ４１ H and C became independent. １－６ Alkyl, C １－６ Haloalkyl and C ３－４ Selected from cycloalkyl, the C １－６ Alkyl, C １－６ Haloalkyl and C ３－４ Each cycloalkyl group is either unsubstituted or one or two independently selected R groups. ４Ｂ Substituting with substituents, Each R ｂ４１ C １－６ Alkyl, C １－６ Haloalkyl and C ３－４ Selected from cycloalkyl groups, each of which is either unsubstituted or one or two independently selected R groups. ４Ｂ Substituting with substituents, Each R ４Ｂ They became independent: H, Halo, CN, C １－３ Alkyl, C １－３ Haloalkyl, OR ａ４２ , and NR ｃ４２ R ｄ４２ Selected from, Each R ａ４２ , R ｃ４２ , and R ｄ４２ H and C became independent. １－３ Alkyl and C １－３ Selected from haloalkyl groups, Each R ５ They became independent: H, Halo, CN, C １－６ Alkyl, C １－６ Haloalkyl, C ３－４ Cycloalkyl, OR ａ５ , and NR ｃ５ R ｄ５ Selected from, and Each R ａ５ , R ｃ５ , and R ｄ５ H and C became independent. １－６ Alkyl and C １－６ Selected from haloalkyl groups, The pharmaceutical composition according to claim 1.

23. n is 0 or 1, p is 0 or 1, Ring portion A is a 5- to 10-membered heteroaryl having one or two N-ring forming atoms. Ring portion B is piperidinyl, R １ H and C became independent. １－６ Alkyl, phenyl, 5-7 member heterocycloalkyl, OR ａ１ , SR ａ１ , and NR ｃ１ R ｄ１ Selected from, the C １－６ Alkyl, phenyl, and 5- to 7-membered heterocycloalkyl groups are each unsubstituted or one or two independently selected R groups. １Ａ Substituting with substituents, Each R ａ１ , R ｃ１ , and R ｄ１ H and C became independent. １－６ Alkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, phenyl, 4-6 member heterocycloalkyl, C ３－６ Cycloalkyl-C １－３ Alkyl and 4-6 member heterocycloalkyl-C １－３ Selected from alkyl, the C １－６ Alkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, phenyl, 4-6 member heterocycloalkyl, C ３－６ Cycloalkyl-C １－３ Alkyl and 4-6 member heterocycloalkyl-C １－３ Each alkyl group is either unsubstituted or consists of one, two, or three independently selected R groups. １Ａ Substituting with substituents, Each R １Ａ They became independent as D, Halo, CN, C １－３ Alkyl, C １－３ Haloalkyl, C ３－４ Cycloalkyl, OR ａ１１ , and C(O)OR ａ１１ Selected from, the C １－６ Alkyl and C １－６ Each haloalkyl is either unsubstituted or one, two, or three independently selected R １Ｂ Substituting with substituents, Each R ａ１１ H and C are independent of each other. １－４ Selected from alkyl, the C １－４ The alkyl group is either unsubstituted or consists of one, two, or three independently selected R groups. １Ｂ Substituting with substituents, Each R １Ｂ These are independently H, D, and O-C １－４ Selected from alkyl groups, R ２ However, it is H or F, Each R ３ independently selected from H or methyl, R ４ However, C １－６ Alkyl, C ３－６ Cycloalkyl, 5-6 member heteroaryl, and 4-7 member heterocycloalkyl-C １－４ Selected from alkyl, the C １－６ Alkyl, C ３－６ Cycloalkyl, 5-6 member heteroaryl, and 4-7 member heterocycloalkyl-C １－４ Each alkyl group is either unsubstituted or consists of 1, 2, 3, or 4 independently selected R groups. ４Ａ Substituting with substituents, Each R ４Ａ H and C became independent. １－６ Alkyl, OH, and NR ｃ４１ R ｄ４１ Selected from, Each R ｃ４１ and R ｄ４１ H and C became independent. １－６ Alkyl and C １－６ Selected from haloalkyl groups, Each R ５ They became independent: H, Halo, CN, C １－６ Alkyl, C １－６ Haloalkyl, C ３－４ Cycloalkyl, OR ａ５ , and NR ｃ５ R ｄ５ Selected from, Each R ａ５ , R ｃ５ , and R ｄ５ H and C became independent. １－６ Alkyl and C １－６ Selected from haloalkyl groups, The pharmaceutical composition according to claim 1.

24. n is 0 or 1, p is 0 or 1, Ring portion A is a 5- to 10-membered heteroaryl having one or two N-ring forming atoms. Ring portion B is piperidinyl, R １ H and OR ａ１ Selected from, Each R ａ１ H and C became independent. １－６ Alkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, 4-6 member heterocycloalkyl, C ３－６ Cycloalkyl-C １－３ Alkyl and 4-6 member heterocycloalkyl-C １－３ Selected from alkyl, the C １－６ Alkyl, C １－６ Haloalkyl C ３－６ Cycloalkyl, 4-6 member heterocycloalkyl, C ３－６ Cycloalkyl-C １－３ Alkyl and 4-6 member heterocycloalkyl-C １－３ Each alkyl group is either unsubstituted or one or two independently selected R groups. １Ａ Substituting with substituents, Each R １Ａ C １－３ Alkyl, C １－３ Haloalkyl, C ３－４ Cycloalkyl, OH, C １－３ Alkoxy and C １－３ Selected from haloalkoxys, R ２ However, it is H or F, Each R ３ independently selected from H or methyl, R ４ However, C １－６ Alkyl and C ３－６ Selected from cycloalkyl, the C １－６ Alkyl and C ３－６ Each cycloalkyl group is either unsubstituted or consists of 1, 2, 3, or 4 independently selected R groups. ４Ａ Substituting with substituents, Each R ４Ａ H and C are independent of each other. １－６ Selected from alkyl groups, Each R ５ They became independent: H, Halo, CN, C １－６ Alkyl, C １－６ Haloalkyl, C ３－４ Cycloalkyl, OR ａ５ , and NR ｃ５ R ｄ５ Selected from, Each R ａ５ , R ｃ５ , and R ｄ５ H and C became independent. １－６ Alkyl and C １－６ Selected from haloalkyl groups, The pharmaceutical composition according to claim 1.

25. A compound, or a pharmaceutically acceptable salt thereof, is of formula (Va), or (Vb), or (Vc), or (Vd): 【Transformation 7】 A pharmaceutical composition according to any one of claims 1 to 24, which is a compound of or a pharmaceutically acceptable salt of any of the above.

26. The compound, or a pharmaceutically acceptable salt thereof, is of formula (VIa), or (VIIa), or (VIIIIa), or (IXa): 【Transformation 8】 A pharmaceutical composition according to any one of claims 1 to 24, which is a compound of or a pharmaceutically acceptable salt of any of the above.

27. The compound, or a pharmaceutically acceptable salt thereof, is of formula (VIb), (VIIIb), or (IXb): 【Chemistry 9】 A pharmaceutical composition according to any one of claims 1 to 24, which is a compound of or a pharmaceutically acceptable salt of any of the above.

28. The compound, or a pharmaceutically acceptable salt thereof, is of formula (VIc), or (VIIIc), or (IXc): 【Chemistry 10】 A pharmaceutical composition according to any one of claims 1 to 24, which is a compound of or a pharmaceutically acceptable salt of any of the above.

29. A compound, or a pharmaceutically acceptable salt thereof, N-(1-(methylsulfonyl)piperidine-4-yl)-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, 8-Ethoxy-N-(1-(methylsulfonyl)piperidine-4-yl)-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, 8-Isobutoxy-N-(1-(methylsulfonyl)piperidine-4-yl)-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, 8-(cyclopropylmethoxy)-N-(1-(methylsulfonyl)piperidine-4-yl)-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, N-(1-(methylsulfonyl)piperidine-4-yl)-7-(1H-pyrazole-4-yl)-8-((tetrahydro-2H-pyran-4-yl)oxy)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, 8-(2-methoxyethoxy)-N-(1-(methylsulfonyl)piperidine-4-yl)-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, 6-Fluoro-N-(1-(methylsulfonyl)piperidine-4-yl)-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, N-(1-(methylsulfonyl)piperidine-4-yl)-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-2-amine, 8-(2,2-difluoroethoxy)-N-(1-(methylsulfonyl)piperidine-4-yl)-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, N-(1-(methylsulfonyl)piperidine-4-yl)-7-(1H-pyrazole-4-yl)-8-(2,2,2-trifluoroethoxy)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, N-(1-(methylsulfonyl)piperidine-4-yl)-7-(1H-pyrazole-4-yl)-8-((tetrahydrofuran-3-yl)methoxy)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, 8-Ethoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidine-4-yl)-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, N-((3R,4S)-1-(cyclopropylsulfonyl)-3-methylpiperidine-4-yl)-8-ethoxy-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, 8-Isopropoxy-N-(1-(methylsulfonyl)piperidine-4-yl)-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidine-2-amine, 8-Isobutoxy-N-(1-(methylsulfonyl)piperidine-4-yl)-7-(1H-pyrrolo[2,3-b]pyridine-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, and 7-(2-aminopyridine-4-yl)-8-isobutoxy-N-(1-(methylsulfonyl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, and Those pharmaceutically acceptable salts A pharmaceutical composition according to claim 1, selected from the following.

30. A compound, or a pharmaceutically acceptable salt thereof, 8-Ethoxy-7-(3-methyl-1H-pyrazole-4-yl)-N-(1-(methylsulfonyl)piperidine-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, 4-((2-((1-(methylsulfonyl)piperidine-4-yl)amino)-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-8-yl)oxy)piperidine-1-carboxylate methyl, (R)-1-(2-(((3R,4S)-4-((8-ethoxy-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl)amino)-3-methylpiperidine-1-yl)sulfonyl)ethyl)pyrrolidine-3-ol, 8-Ethoxy-N-((3R,4S)-3-methyl-1-((1-methyl-1H-pyrazole-4-yl)sulfonyl)piperidine-4-yl)-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, 8-Ethoxy-N-((3R,4S)-3-methyl-1-((2-methyl-2H-1,2,3-triazole-4-yl)sulfonyl)piperidine-4-yl)-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, N-(1-(methylsulfonyl)piperidine-4-yl)-8-phenyl-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, 8-(4-fluoropiperidine-1-yl)-N-(1-(methylsulfonyl)piperidine-4-yl)-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, N ２ -(1-(methylsulfonyl)piperidine-4-yl)-N ８ -phenyl-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine, 8-(4-fluorophenyl)-N-(1-(methylsulfonyl)piperidine-4-yl)-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, N-(1-(methylsulfonyl)piperidine-4-yl)-7-(1H-pyrazole-4-yl)-8-(3-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, 8-Ethoxy-N-((3R,4S)-3-methyl-1-((3-(piperidine-1-yl)propyl)sulfonyl)piperidine-4-yl)-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, N-((3R,4S)-1-((3-(dimethylamino)propyl)sulfonyl)-3-methylpiperidine-4-yl)-8-ethoxy-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, 8-Ethoxy-N-((3R,4S)-3-methyl-1-((3-(pyrrolidine-1-yl)propyl)sulfonyl)piperidine-4-yl)-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, N-(1-(methylsulfonyl)piperidine-4-yl)-7-(1H-pyrazole-4-yl)-8-(4-(trifluoromethyl)piperidine-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, 8-(3-fluoropiperidine-1-yl)-N-(1-(methylsulfonyl)piperidine-4-yl)-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, 8-Ethoxy-N-(1-(methylsulfonyl)piperidine-4-yl)-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidine-2-amine, 8-Isopropoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidine-4-yl)-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidine-2-amine, 8-(4-methylpiperidine-1-yl)-N-(1-(methylsulfonyl)piperidine-4-yl)-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidine-2-amine, N-(1-(methylsulfonyl)piperidine-4-yl)-7-(1H-pyrazole-4-yl)-8-(3-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-c]pyrimidine-2-amine, 2-Fluoro-4-(2-((1-(methylsulfonyl)piperidine-4-yl)amino)-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidine-8-yl)benzonitrile, N-(1-(methylsulfonyl)piperidine-4-yl)-8-propyl-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, 8-Isopropoxy-N-((3R,4S)-3-methyl-1-((2-(pyrrolidine-1-yl)ethyl)sulfonyl)piperidine-4-yl)-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidine-2-amine, 8-((4,4-difluorocyclohexyl)oxy)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidine-4-yl)-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidine-4-yl)-7-(1H-pyrazole-4-yl)-8-((tetrahydrofuran-3-yl)oxy)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, 8-(ethoxy-d5)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidine-4-yl)-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidine-4-yl)-7-(1H-pyrazole-4-yl)-8-((tetrahydro-2H-pyran-4-yl)oxy)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, 8-Isopropoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidine-4-yl)-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, 8-Isobutoxy-N-(1-(methylsulfonyl)piperidine-4-yl)-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidine-2-amine, 8-(2,2-difluoroethoxy)-N-(1-(methylsulfonyl)piperidine-4-yl)-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidine-2-amine, N-(1-(methylsulfonyl)piperidine-4-yl)-7-(1H-pyrazole-4-yl)-8-(3,3,3-trifluoropropoxy)-[1,2,4]triazolo[1,5-c]pyrimidine-2-amine, 8-Butoxy-N-(1-(methylsulfonyl)piperidine-4-yl)-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidine-2-amine, N-(1-(methylsulfonyl)piperidine-4-yl)-8-propoxy-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidine-2-amine, N-(1-(methylsulfonyl)piperidine-4-yl)-8-(piperidine-1-yl)-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidine-2-amine, N-(3-methyl-1-(methylsulfonyl)piperidine-4-yl)-8-(piperidine-1-yl)-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidine-2-amine, 8-(4-(2-methoxyethyl)piperazine-1-yl)-N-(1-(methylsulfonyl)piperidine-4-yl)-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidine-2-amine, N-(1-(methylsulfonyl)piperidine-4-yl)-7-(1H-pyrazole-4-yl)-8-(pyrrolidine-1-yl)-[1,2,4]triazolo[1,5-c]pyrimidine-2-amine, N-((3R,4S)-1-(cyclopropylsulfonyl)-3-methylpiperidine-4-yl)-8-isopropoxy-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidine-2-amine, N-((3R,4S)-1-(ethylsulfonyl)-3-methylpiperidine-4-yl)-8-isopropoxy-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidine-2-amine, N-((3R,4S)-1-((3-(ethyl(methyl)amino)propyl)sulfonyl)-3-methylpiperidine-4-yl)-8-isopropoxy-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidine-2-amine, N-((3R,4S)-1-((3-(dimethylamino)propyl)sulfonyl)-3-methylpiperidine-4-yl)-8-isopropoxy-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidine-2-amine, 8-Isopropoxy-N-((3R,4S)-1-((3-(isopropyl(methyl)amino)propyl)sulfonyl)-3-methylpiperidine-4-yl)-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidine-2-amine, 8-Isopropoxy-N-((3R,4S)-3-methyl-1-((3-(piperidine-1-yl)propyl)sulfonyl)piperidine-4-yl)-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidine-2-amine, 8-Isopropoxy-N-((3R,4S)-3-methyl-1-((3-(pyrrolidine-1-yl)propyl)sulfonyl)piperidine-4-yl)-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidine-2-amine, N-((3R,4S)-1-((3-(diethylamino)propyl)sulfonyl)-3-methylpiperidine-4-yl)-8-isopropoxy-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidine-2-amine, 8-Isopropoxy-N-((3R,4S)-3-methyl-1-((3-(4-methylpiperazine-1-yl)propyl)sulfonyl)piperidine-4-yl)-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidine-2-amine, N-((3R,4S)-1-((3-(4-ethylpiperazine-1-yl)propyl)sulfonyl)-3-methylpiperidine-4-yl)-8-isopropoxy-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidine-2-amine, 8-Isopropoxy-N-((3R,4S)-3-methyl-1-((4-morpholinobutyl)sulfonyl)piperidine-4-yl)-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidine-2-amine, N-((3R,4S)-1-((4-((2,2-difluoroethyl)amino)butyl)sulfonyl)-3-methylpiperidine-4-yl)-8-isopropoxy-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidine-2-amine, N-((3R,4S)-1-((4-(ethyl(methyl)amino)butyl)sulfonyl)-3-methylpiperidine-4-yl)-8-isopropoxy-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidine-2-amine, N-((3R,4S)-1-((4-(dimethylamino)butyl)sulfonyl)-3-methylpiperidine-4-yl)-8-isopropoxy-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidine-2-amine, N-((3R,4S)-1-((4-((R)-3-(difluoromethyl)pyrrolidine-1-yl)butyl)sulfonyl)-3-methylpiperidine-4-yl)-8-isopropoxy-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidine-2-amine, 5-Isopropoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidine-4-yl)-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, 5-Cyclobutoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidine-4-yl)-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, 5-Isobutoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidine-4-yl)-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidine-4-yl)-5-propoxy-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, 5-(2,2-difluoroethoxy)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidine-4-yl)-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidine-4-yl)-6-(1H-pyrazole-4-yl)-5-(2,2,3,3-tetrafluoropropoxy)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, 5-Cyclopropoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidine-4-yl)-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, 5-((3,3-difluorocyclopentyl)oxy)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidine-4-yl)-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, 5-(cyclobutylmethoxy)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidine-4-yl)-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, 5-(cyclopentylmethoxy)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidine-4-yl)-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, N-(1-(methylsulfonyl)piperidine-4-yl)-5-propoxy-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, 5-Isobutoxy-N-(1-(methylsulfonyl)piperidine-4-yl)-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, 5-(2,2-difluoroethoxy)-N-(1-(methylsulfonyl)piperidine-4-yl)-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, N-(1-(methylsulfonyl)piperidine-4-yl)-6-(1H-pyrazole-4-yl)-5-(2,2,3,3-tetrafluoropropoxy)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, 5-(cyclopropylmethoxy)-N-(1-(methylsulfonyl)piperidine-4-yl)-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidine-4-yl)-5-(piperidine-1-yl)-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, N-((3R,4S)-1-(ethylsulfonyl)-3-methylpiperidine-4-yl)-5-(piperidine-1-yl)-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, N-((3R,4S)-1-(cyclopropylsulfonyl)-3-methylpiperidine-4-yl)-5-(piperidine-1-yl)-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, N-((3R,4S)-3-methyl-1-((1-methyl-1H-imidazole-4-yl)sulfonyl)piperidine-4-yl)-5-(piperidine-1-yl)-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, 5-Isopropoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidine-4-yl)-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-2-amine, N-((3R,4S)-1-(ethylsulfonyl)-3-methylpiperidine-4-yl)-5-isopropoxy-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-2-amine, N-((3R,4S)-1-(cyclopropylsulfonyl)-3-methylpiperidine-4-yl)-5-isopropoxy-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-2-amine, N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidine-4-yl)-6-(1H-pyrazole-4-yl)-5-((tetrahydro-2H-pyran-4-yl)oxy)-[1,2,4]triazolo[1,5-a]pyrazine-2-amine, N-((3R,4S)-1-(ethylsulfonyl)-3-methylpiperidine-4-yl)-6-(1H-pyrazole-4-yl)-5-((tetrahydro-2H-pyran-4-yl)oxy)-[1,2,4]triazolo[1,5-a]pyrazine-2-amine, N-((3R,4S)-1-(cyclopropylsulfonyl)-3-methylpiperidine-4-yl)-6-(1H-pyrazole-4-yl)-5-((tetrahydro-2H-pyran-4-yl)oxy)-[1,2,4]triazolo[1,5-a]pyrazine-2-amine, 5-Cyclobutoxy-N-((3R,4S)-1-(ethylsulfonyl)-3-methylpiperidine-4-yl)-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-2-amine, 5-Cyclobutoxy-N-((3R,4S)-3-methyl-1-((1-methyl-1H-pyrazole-4-yl)sulfonyl)piperidine-4-yl)-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-2-amine, 5-Cyclobutoxy-N-((3R,4S)-3-methyl-1-((1-methyl-1H-imidazole-4-yl)sulfonyl)piperidine-4-yl)-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-2-amine, N-((3R,4S)-1-(ethylsulfonyl)-3-methylpiperidine-4-yl)-5-isopropoxy-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, N-((3R,4S)-1-(cyclopropylsulfonyl)-3-methylpiperidine-4-yl)-5-isopropoxy-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidine-4-yl)-6-(1H-pyrazole-4-yl)-5-((tetrahydro-2H-pyran-4-yl)oxy)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, N-((3R,4S)-3-methyl-1-((1-methyl-1H-pyrazole-4-yl)sulfonyl)piperidine-4-yl)-6-(1H-pyrazole-4-yl)-5-((tetrahydro-2H-pyran-4-yl)oxy)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, 5-Cyclobutoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidine-4-yl)-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-2-amine, 5-Isobutoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidine-4-yl)-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-2-amine, N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidine-4-yl)-5-propoxy-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-2-amine, 5-Butoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidine-4-yl)-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-2-amine, 5-Isobutoxy-N-(1-(methylsulfonyl)piperidine-4-yl)-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-2-amine, N-(1-(methylsulfonyl)piperidine-4-yl)-5-propoxy-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-2-amine, 5-Butoxy-N-(1-(methylsulfonyl)piperidine-4-yl)-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-2-amine, N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidine-4-yl)-5-(3-methylcyclobutoxy)-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-2-amine, 5-(3-(difluoromethyl)cyclobutoxy)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidine-4-yl)-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-2-amine, 5-Cyclopropoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidine-4-yl)-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-2-amine, 5-((4,4-difluorocyclohexyl)oxy)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidine-4-yl)-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-2-amine, N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidine-4-yl)-5-((3-methyltetrahydro-2H-pyran-4-yl)oxy)-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-2-amine, N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidine-4-yl)-5-((2-methyltetrahydro-2H-pyran-4-yl)oxy)-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-2-amine, N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidine-4-yl)-6-(1H-pyrazole-4-yl)-5-((2-(trifluoromethyl)tetrahydro-2H-pyran-4-yl)oxy)-[1,2,4]triazolo[1,5-a]pyrazine-2-amine, N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidine-4-yl)-6-(1H-pyrazole-4-yl)-5-((1-(trifluoromethyl)cyclobutyl)methoxy)-[1,2,4]triazolo[1,5-a]pyrazine-2-amine, 5-(cyclopropylmethoxy)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidine-4-yl)-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-2-amine, 5-(isopentyloxy)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidine-4-yl)-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-2-amine, 5-Cyclobutoxy-N-(1-(methylsulfonyl)piperidine-4-yl)-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-2-amine, 5-(3,3-difluorocyclobutoxy)-N-(1-(methylsulfonyl)piperidine-4-yl)-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-2-amine, N-(1-(methylsulfonyl)piperidine-4-yl)-6-(1H-pyrazole-4-yl)-5-((2-(trifluoromethyl)tetrahydro-2H-pyran-4-yl)oxy)-[1,2,4]triazolo[1,5-a]pyrazine-2-amine, N-(1-(methylsulfonyl)piperidine-4-yl)-6-(1H-pyrazole-4-yl)-5-((1-(trifluoromethyl)cyclobutyl)methoxy)-[1,2,4]triazolo[1,5-a]pyrazine-2-amine, 5-(isopentyloxy)-N-(1-(methylsulfonyl)piperidine-4-yl)-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-2-amine, 5-Ethoxy-N-(1-(methylsulfonyl)piperidine-4-yl)-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-2-amine, 5-(ethylthio)-N-(1-(methylsulfonyl)piperidine-4-yl)-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-2-amine, 5-(isopropylthio)-N-(1-(methylsulfonyl)piperidine-4-yl)-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-2-amine, N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidine-4-yl)-5-(piperidine-1-yl)-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-2-amine, N-(1-(methylsulfonyl)piperidine-4-yl)-5-(piperidine-1-yl)-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-2-amine, 5-(3,3-difluoropiperidine-1-yl)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidine-4-yl)-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-2-amine, (R)-5-(3-fluoropiperidine-1-yl)-N-(1-(methylsulfonyl)piperidine-4-yl)-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-2-amine, (S)-5-(3-fluoropiperidine-1-yl)-N-(1-(methylsulfonyl)piperidine-4-yl)-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-2-amine, 5-(3,3-difluoropyrroridine-1-yl)-N-(1-(methylsulfonyl)piperidine-4-yl)-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-2-amine, 5-(2-azabicyclo[2.2.1]heptan-2-yl)-N-(1-(methylsulfonyl)piperidine-4-yl)-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-2-amine, (S)-5-(2-methylpiperidine-1-yl)-N-(1-(methylsulfonyl)piperidine-4-yl)-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-2-amine, (S)-5-(2-methylpyrrolidine-1-yl)-N-(1-(methylsulfonyl)piperidine-4-yl)-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-2-amine, (S)-5-(3-(difluoromethyl)pyrroridine-1-yl)-N-(1-(methylsulfonyl)piperidine-4-yl)-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-2-amine, 5-(7-azabicyclo[2.2.1]heptan-7-yl)-N-(1-(methylsulfonyl)piperidine-4-yl)-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-2-amine, N-(1-(methylsulfonyl)piperidine-4-yl)-6-(1H-pyrazole-4-yl)-5-(3-(trifluoromethyl)piperidine-1-yl)-[1,2,4]triazolo[1,5-a]pyrazine-2-amine, N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidine-4-yl)-5-((propan-2-yl-2-d)oxy)-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-2-amine, N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidine-4-yl)-5-((propan-2-yl-1,1,1,3,3,3-d ６ )oxy)-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-2-amine, N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidine-4-yl)-5-((propan-2-yl-d ７ )oxy)-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-2-amine, 5-(cyclopentyloxy)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidine-4-yl)-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-2-amine, 5-Isopropoxy-N-(1-(methylsulfonyl)piperidine-4-yl)-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-2-amine, and N-(1-(methylsulfonyl)piperidine-4-yl)-5-((propan-2-yl-2-d)oxy)-6-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-2-amine, and Those pharmaceutically acceptable salts A pharmaceutical composition according to claim 1, selected from the following.

31. The pharmaceutical composition according to claim 1, wherein the compound, or a pharmaceutically acceptable salt thereof, is 8-ethoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidine-4-yl)-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, or a pharmaceutically acceptable salt thereof.

32. The pharmaceutical composition according to claim 1, wherein the compound, or a pharmaceutically acceptable salt thereof, is N-((3R,4S)-1-(cyclopropylsulfonyl)-3-methylpiperidine-4-yl)-8-ethoxy-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, or a pharmaceutically acceptable salt thereof.

33. The pharmaceutical composition according to claim 1, wherein the compound, or a pharmaceutically acceptable salt thereof, is 8-isopropoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidine-4-yl)-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, or a pharmaceutically acceptable salt thereof.

34. The pharmaceutical composition according to claim 1, wherein the compound, or a pharmaceutically acceptable salt thereof, is 8-(ethoxy-d5)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidine-4-yl)-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine, or a pharmaceutically acceptable salt thereof.

35. The pharmaceutical composition according to claim 1, wherein the compound, or a pharmaceutically acceptable salt thereof, is 8-isopropoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidine-4-yl)-7-(1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidine-2-amine, or a pharmaceutically acceptable salt thereof.

36. The pharmaceutical composition according to any one of claims 1 to 35, wherein one or more additional therapeutic agents are selected from palbociclib, fulvestrant, ribociclib, bevacizumab, olaparib, and paclitaxel.

37. The pharmaceutical composition according to claim 36, wherein one or more additional therapeutic agents are palbociclib.

38. The pharmaceutical composition according to claim 36, wherein one or more additional therapeutic agents are fulvestrant.

39. The pharmaceutical composition according to claim 36, wherein one or more additional therapeutic agents are ribociclib.

40. The pharmaceutical composition according to claim 36, wherein one or more additional therapeutic agents are bevacizumab.

41. The pharmaceutical composition according to claim 36, wherein one or more additional therapeutic agents are olaparib.

42. The pharmaceutical composition according to claim 36, wherein one or more additional therapeutic agents are paclitaxel.

43. The pharmaceutical composition according to any one of claims 1 to 42, wherein the cancer is breast cancer.

44. The pharmaceutical composition according to any one of claims 1 to 42, wherein the cancer is ovarian cancer.

45. The pharmaceutical composition according to claim 44, wherein the ovarian cancer is serous cystadenomatous carcinoma or mucinous cystadenomatous carcinoma.

46. The pharmaceutical composition according to any one of claims 1 to 42, wherein the cancer is lung cancer.

47. The pharmaceutical composition according to claim 46, wherein the lung cancer is non-small cell lung cancer or small cell lung cancer.

48. The pharmaceutical composition according to any one of claims 1 to 42, wherein the cancer is fallopian tube cancer.

49. The pharmaceutical composition according to any one of claims 1 to 42, wherein the cancer is endometrial cancer.

50. The pharmaceutical composition according to any one of claims 1 to 42, wherein the cancer is gastrointestinal cancer.

51. The pharmaceutical composition according to any one of claims 1 to 42, wherein the cancer is uterine cancer.

52. The pharmaceutical composition according to any one of claims 1 to 42, wherein the cancer is urothelial carcinoma.

53. The pharmaceutical composition according to any one of claims 1 to 42, wherein the cancer is anal cancer.

54. The pharmaceutical composition according to any one of claims 1 to 42, wherein the cancer is bile duct cancer.

55. The pharmaceutical composition according to any one of claims 1 to 42, wherein the cancer is small intestine cancer.

56. The pharmaceutical composition according to claim 55, wherein the small intestinal cancer is an adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, or fibroma.

57. The pharmaceutical composition according to any one of claims 1 to 42, wherein the cancer is colorectal cancer.

58. The pharmaceutical composition according to claim 57, wherein the colorectal cancer is an adenocarcinoma, tubular adenoma, chorioadenoma, hamartoma, or leiomyoma.

59. The pharmaceutical composition according to any one of claims 1 to 42, wherein the cancer is colon cancer.

60. The pharmaceutical composition according to any one of claims 1 to 42, wherein the cancer is colorectal cancer.

61. The pharmaceutical composition according to any one of claims 1 to 42, wherein the cancer is rectal cancer.

62. The pharmaceutical composition according to any one of claims 1 to 42, wherein the cancer is esophageal cancer.

63. The pharmaceutical composition according to any one of claims 1 to 42, wherein the cancer is islet cell carcinoma.

64. The pharmaceutical composition according to any one of claims 1 to 42, wherein the cancer is liver cancer.

65. The pharmaceutical composition according to any one of claims 1 to 42, wherein the cancer is hepatocellular carcinoma.

66. The pharmaceutical composition according to any one of claims 1 to 42, wherein the cancer is pancreatic cancer.

67. The pharmaceutical composition according to any one of claims 1 to 42, wherein the cancer is gastric cancer.

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