CDK inhibitors and their use as pharmaceuticals

Abstract

This disclosure relates, in part, to CDK inhibitors, pharmaceutical compositions containing same, and methods of use and preparation thereof.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Patent Application No. 63 / 005,577, filed April 6, 2020, and U.S. Provisional Patent Application No. 62 / 898,839, filed September 11, 2019, each of which is incorporated by reference herein in its entirety.

[0002] FIELD OF THE INVENTION The present disclosure relates to CDK inhibitors and methods of use thereof. [Background technology]

[0003] Cyclin-dependent kinases (CDKs) are a family of serine / threonine kinases whose activity depends on the association and activation of cyclins and plays an important role in regulating the cell cycle and gene transcription (Malumbres, M. (2014). "Cyclin-dependent kinases." Genome Biol 15(6):122.) CDK1, CDK2, CDK4, and CDK6 are directly involved in promoting cell division, while other members, such as CDK7, CDK8, and CDK9, comprise a second subgroup that regulates transcription.

[0004] Upon gene activation, transcription activators, a coactivator / mediator complex (MC), and RNA polymerase II (RNA Pol II) first assemble at the gene promoter to form the preinitiation complex (PIC). RNA Pol II is then released from the complex upon PIC activation to initiate initial transcription, which is then paused by factors such as negative elongation factor (NELF) and, shortly thereafter, DRB-sensitive inducing factor (DSIF). This is called promoter pausing. Productive elongation does not occur until the paused RNA Pol II is released by transcription elongation factor b (p-TEFb) (Harlen, KM and LS Churchman (2017). "The code and beyond: transcription regulation by the RNA polymerase II carboxy-terminal domain." Nat Rev Mol Cell Biol 18(4):263-273). During this process, CDK8, as a subunit of the mediator complex (MC), promotes PIC formation. Meanwhile, CDK7, a component of the transcription factor IIH (TFIIH) complex, phosphorylates serine 5 / 7 in the C-terminal domain (CTD) of RNA Pol II, triggering its release from the promoter. CDK9, a catalytic subunit of p-TEFb, phosphorylates serine 2 in the CTD, as well as NEFL and DSIF, to release RNA Pol II from pause and trigger productive elongation (Franco, LC, et al. (2018). "CDK9: A key player in cancer and other diseases." J Cell Biochem 119(2):1273-1284; Soutourina, J. (2018). "Transcription regulation by the Mediator complex." Nat Rev Mol Cell Biol 19(4):262-274).

[0005] As the master regulator of the release of paused Pol II from promoters, CDK9 plays a central role in promoting gene expression. Consistently, CDK9 inhibition causes a global downregulation of gene expression (Olson, C. M., et al. (2018). "Pharmacological perturbation of CDK9 using selective CDK9 inhibition or degradation." Nat Chem Biol 14(2):163-170.), among these are short-lived transcripts such as oncogenes, c-Myc, and Mcl-1, members of the pro-survival Bcl-2 family of proteins that promote cancer cell survival (Chen, R., et al. (2005). "Transcription inhibition by flavopiridol: mechanism of chronic lymphocytic leukemia cell death." Blood 106(7):2513-2519; Youle, R. J. and A. Strasser (2008). "The BCL-2 protein family: opposing activities that mediate cell death." Nat Rev Mol Cell Biol 9(1):47-59.), suggesting an indirect approach to targeting Mcl-1 for cancer treatment (Krystof, V., et al. (2012). "Perspective of cyclin-dependent kinase 9 (CDK9) as a drug target." Curr Pharm Des 18(20):2883-2890. In fact, several CDK9 inhibitors have been developed, shown promising anticancer activity in preclinical models, and are progressing to the clinic (Boffo, S., et al. (2018). "CDK9 inhibitors in acute myeloid leukemia." J Exp Clin Cancer Res 37(1):36.).Interestingly, recent studies have shown that CDK9 inhibition also reactivates tumor suppressor genes silenced by epigenetic modifications, adding another layer of evidence supporting CDK9 targeting in cancer therapy (Zhang, H., et al., (2018). "Targeting CDK9 Reactivates Epigenetically Silenced Genes in Cancer." Cell 175(5):1244-1258.e1226). Summary of the Invention

[0006] The present disclosure provides a compound of formula (I) or formula (II):

[0007] [ka] or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, X 1 , X 2 , and X 3 are each independently N or CR 3 and A 1 is N or CR 4 and B 1 is CR 6 R 7 , N.R. 5 , O, or S; A 2 is NR 8 , S, or O; B 2 is CR 9 or N, R 1 is C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, C 3~10 Cycloalkyl, 5 ~ 14-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6~10 Aryl -C 1~4 Alkyl, C 3~10 Cycloalkyl C 1~4 Alkyl, (5-14 membered heteroaryl)-C 1~4 Alkyl, and (4- to 14-membered heterocycloalkyl)-C 1~4 alkyl, At this time, R 1 is 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R b optionally substituted with substituents, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are each independently H, D, halo, oxo, or C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 6~10 Aryl, C 3~10 Cycloalkyl, 5-10 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl, C 1~4 Alkyl, (5-14 membered heteroaryl)-C 1~4 Alkyl, (4-14 membered heterocycloalkyl)-C 1~4 Alkyl, CN, NO2, OR a1 , S.R. a1 , NHOR a1 , C(O)R a1 , C(O)NR a1 R a1 , C(O)OR a1 ,OC(O)R a1 , OC(O)NR a1 R a1 , NHR a1 , N.R. a1 R a1 , N.R. a1 C(O)R a1 , N.R.a1 C(O)OR a1 , N.R. a1 C(O)NR a1 R a1 , C(=NR a1 )R a1 , C(=NR a1 )NR a1 R a1 , N.R. a1 C(=NR a1 )NR a1 R a1 , N.R. a1 C(=NOH)NR a1 R a1 , N.R. a1 C(=NCN)NR a1 R a1 , N.R. a1 S(O)R a1 , N.R. a1 S(O)2R a1 , N.R. a1 S(O)NR a1 R a1 , S(O)R a1 , S(O)NR a1 R a1 S(O)2R a1 , SF5, P(O)R a1 R a1 , P(O)(OR a1 )(OR a1 ), B(OR a1 )2 and S(O)2NR a1 R a1 is selected from R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 or R 9 But C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, C 3~10 Cycloalkyl, 5-10 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10Cycloalkyl-C 1~4 Alkyl, (5-14 membered heteroaryl)-C 1~4 Alkyl, or (4- to 14-membered heterocycloalkyl)-C 1~4 When it is alkyl, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 or R 9 is 1, 2, 3, 4, or 5 independently selected R b optionally substituted with substituents, Or R 4 and R 5 may be substituted with 1, 2, 3, 4, or 5 independently selected R b forming a 5-, 6-, or 7-membered heterocycloalkyl ring optionally substituted with substituents; Or R 6 and R 7 form a C3-C7 spirocyclic ring together with the carbon atoms to which they are both attached, Or R 8 and R 9 may be substituted with 1, 2, 3, 4, or 5 independently selected R b forming a 5-, 6-, or 7-membered heterocycloalkyl ring optionally substituted with substituents; Each R a1 are independently H, D, C 1~6 Alkyl, C 1~4 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, C 3~10 Cycloalkyl, 5-10 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4 Alkyl, (5-10 membered heteroaryl)-C 1~4 Alkyl, and (4- to 14-membered heterocycloalkyl)-C 1~4 alkyl, Ra1 But C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, C 3~10 Cycloalkyl, 5-10 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4 Alkyl, (5-10 membered heteroaryl)-C 1~4 Alkyl- or (4- to 14-membered heterocycloalkyl)-C 1~4 When it is alkyl, R a1 is 1, 2, 3, 4, or 5 independently selected R d optionally substituted with substituents, Each R b The substituents are independently D, halo, oxo, C 1~4 Alkyl, C 1~6 Alkoxy, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, C 6~10 Aryl, C 3~10 Cycloalkyl, 5-10 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4 Alkyl, (5-10 membered heteroaryl)-C 1~4 Alkyl, (4-14 membered heterocycloalkyl)-C 1~4 Alkyl, CN, OH, NH2, NO2, NHOR c , OR c , S.R. c , C(O)R c , C(O)NR c R c , C(O)OR c ,OC(O)R c , OC(O)NR c R c , C(=NR c )NR c R c , N.R. c C(=NR c )NRc R c , N.R. c C(=NOH)NR c R c , N.R. c C(=NCN)NR c R c , SF5, P(O)R c R c , P(O)(OR c )(OR c ), NHR c , N.R. c R c , N.R. c C(O)R c , N.R. c C(O)OR c , N.R. c C(O)NR c R c , N.R. c S(O)R c , N.R. c S(O)(=NR c )R c , N.R. c S(O)2R c , N.R. c S(O)NR c R c , S(O)R c , S(O)NR c R c , S(O)2R c or S(O)NR c R c is selected from R b But C 1~4 Alkyl, C 1~6 Alkoxy, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, C 6~10 Aryl, C 3~10 Cycloalkyl, 5-10 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4 Alkyl, (5-10 membered heteroaryl)-C 1~4 Alkyl- or (4- to 14-membered heterocycloalkyl)-C 1~4 When it is alkyl, Rb is one, two, or three independently selected R d optionally substituted with substituents, Each R c are independently H, D, OH, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~4 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, C 3~10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4 Alkyl, (5-10 membered heteroaryl)-C 1~4 Alkyl, and (4-10 membered heterocycloalkyl)-C 1~4 alkyl, R c But C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, C 3~10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4 Alkyl, (5-10 membered heteroaryl)-C 1~4 Alkyl- or (4- to 10-membered heterocycloalkyl)-C 1~4 When it is alkyl, R c is 1, 2, 3, 4, or 5 independently selected R f optionally substituted with substituents, Each R f independently, C 1~4 Alkyl, C 1~4 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, C 3~10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4 Alkyl, (5-10 membered heteroaryl)-C 1~4 Alkyl, and (4-10 membered heterocycloalkyl)-C 1~4 Alkyl, Halo, CN, NHOR g , OR g , S.R. g , C(O)R g , C(O)NR g R g , C(O)OR g ,OC(O)R g , OC(O)NR g R g , NHR g , N.R. g R g , N.R. g C(O)R g , N.R. g C(O)NR g R g , N.R. g C(O)OR g , C(=NR g )NR g R g , N.R. g C(=NR g )NR g R g , N.R. g C(=NOH)NR g R g , N.R. g C(=NCN)NR g R g , SF5, P(O)R g R g , P(O)(OR g )(OR g ), S(O)R g , S(O)NR g R g , S(O)2R g , N.R. g S(O)2R g , N.R. g S(O)NR g R g , and S(O)NR g R g is selected from R f But C 1~4 Alkyl, C 1~4 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, C 3~10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4 Alkyl, (5-10 membered heteroaryl)-C 1~4 Alkyl, and (4-10 membered heterocycloalkyl)-C 1~4 When it is alkyl, R f is 1, 2, 3, 4, or 5 independently selected R n optionally substituted with substituents, Each R n independently, C 1~4 Alkyl, C 1~4 Haloalkyl, Halo, CN, R o , NHOR o , OR o , S.R. o , C(O)R o , C(O)NR o R o , C(O)OR o ,OC(O)R o , OC(O)NR o R o , NHR o , N.R. o R o , N.R. o C(O)R o , N.R. o C(O)NR o R o , N.R. o C(O)OR o , C(=NR o )NR o R o , N.R. o C(=NR o )NR o R o , N.R. o C(=NOH)NR o Ro , N.R. o C(=NCN)NR o R o , SF5, P(O)R o R o , P(O)(OR o )(OR o ), S(O)R o , S(O)NR o R o , S(O)2R o , N.R. o S(O)2R o , N.R. o S(O)NR o R o , and S(O)NR o R o is selected from Each R d are independently D, oxo, C 1~6 Alkyl, C 1~6 Haloalkyl, Halo, C 3~10 Cycloalkyl, C 6~10 Aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4 Alkyl, (5-10 membered heteroaryl)-C 1~4 Alkyl, and (4-10 membered heterocycloalkyl)-C 1~4 Alkyl, CN, NH2, NHOR e , OR e , S.R. e , C(O)R e , C(O)NR e R e , C(O)OR e ,OC(O)R e , OC(O)NR e R e , NHR e , N.R. e R e , N.R. e C(O)R e , N.R. e C(O)NR e R e , N.R. e C(O)OR e, C(=NR e )NR e R e , N.R. e C(=NR e )NR e R e , N.R. e C(=NOH)NR e R e , N.R. e C(=NCN)NR e R e , SF5, P(O)R e R e , P(O)(OR e )(OR e ), S(O)R e , S(O)NR e R e , S(O)2R e , N.R. e S(O)2R e , N.R. e S(O)NR e R e , and S(O)NR e R e is selected from R d But C 1~6 Alkyl, C 3~10 Cycloalkyl, C 6~10 Aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4 Alkyl, (5-10 membered heteroaryl)-C 1~4 Alkyl, or (4- to 10-membered heterocycloalkyl)-C 1~4 When it is alkyl, R d is one, two, or three independently selected R f optionally substituted with substituents, Each R e are independently H, D, CN, and C 1~6 Alkyl, C 1~4 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, C 3~10Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4 Alkyl, (5-10 membered heteroaryl)-C 1~4 Alkyl, and (4-10 membered heterocycloalkyl)-C 1~4 alkyl, R e But C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, C 3~10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4 Alkyl, (5-10 membered heteroaryl)-C 1~4 Alkyl- or (4- to 10-membered heterocycloalkyl)-C 1~4 When it is alkyl, R e is one, two, or three independently selected R g optionally substituted with substituents, Each R g are independently H, D, C 1~6 Alkyl, C 1~4 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, C 3~10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4 Alkyl, (5-10 membered heteroaryl)-C 1~4 Alkyl, and (4-10 membered heterocycloalkyl)-C 1~4 alkyl, R g But C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6Alkynyl, C 6~10 Aryl, C 3~10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4 Alkyl, (5-10 membered heteroaryl)-C 1~4 Alkyl- or (4- to 10-membered heterocycloalkyl)-C 1~4 When it is alkyl, R g is one, two, or three independently selected R P optionally substituted with substituents, Each R P independently, C 1~4 Alkyl, C 1~4 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, C 3~10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4 Alkyl, (5-10 membered heteroaryl)-C 1~4 Alkyl, and (4-10 membered heterocycloalkyl)-C 1~4 Alkyl, Halo, CN, NHOR r , OR r , S.R. r , C(O)R r , C(O)NR r R r , C(O)OR r ,OC(O)R r , OC(O)NR r R r , NHR r , N.R. r R r , N.R. r C(O)R r , N.R. r C(O)NR r R r , N.R. r C(O)OR r , C(=NR r)NR r R r , N.R. r C(=NR r )NR r R r , N.R. r C(=NOH)NR r R r , N.R. r C(=NCN)NR r R r , SF5, P(O)R r R r , P(O)(OR r )(OR r ), S(O)R r , S(O)NR r R r , S(O)2R r , N.R. r S(O)2R r , N.R. r S(O)NR r R r , and S(O)NR r R r is selected from Each R o or R r are independently H, D, C 1~4 Alkyl, C 3~6 Cycloalkyl, C 6~10 Aryl, 5- or 6-membered heteroaryl, C 1~4 Haloalkyl, C 2~4 Alkenyl, and C 2~4 alkynyl, R o or R r But C 1~4 Alkyl, C 3~6 Cycloalkyl, C 6~10 Aryl, 5- or 6-membered heteroaryl, C 2~4 Alkenyl, and C 2~4 When R is alkynyl, o or R r is one, two, or three independently selected R q optionally substituted with substituents, Each R q are independently D, OH, CN, -COOH, NH2, halo, C 1~6 Alkyl, C1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~4 Alkylthio, phenyl, 5-6 membered heteroaryl, C 3~6 Cycloalkyl, 4-6 membered heterocycloalkyl, -CONHR 12 , -NHC(O)R 12 , -OC(O)R 12 , -C(O)OR 12 , -C(O)R 12 , -SO2R 12 , -NHSO2R 12 , -SO2NHR 12 and NR 12 R 12 is selected from R q But C 1~6 alkyl, phenyl, 4- to 6-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, R q are OH, CN, -COOH, NH2, C 1~6 Alkoxy, C 3~6 optionally substituted with cycloalkyl or 4- to 6-membered heterocycloalkyl; Each R 12 independently, C 1~6 It is alkyl.

[0008] In some embodiments,

[0009] [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein the variables are as defined herein.

[0010] In some embodiments,

[0011] [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein the variables are as defined herein.

[0012] In some embodiments, a compound having the formula of Formula (V), Formula (VI), Formula (VII), or Formula (XI):

[0013] [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein the variables are as defined herein.

[0014] In some embodiments, a compound having formula (VIII), formula (IX), formula (X), or formula (XII):

[0015] [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein the variables are as defined herein.

[0016] In some embodiments,

[0017] [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein the variables are as defined herein, and wherein two or more R b When there is a b are independent of each other.

[0018] In some embodiments, the compound has the solvate formula:

[0019] [ka] and has the formula During the ceremony, R 2 is Me or OMe, R 3 is H, D, or F, R 4 is H or C1-3 alkyl, R 5 is isopropyl, —CF3(CH)CH3, —C3-6 cycloalkyl, or —CH2—(C3-6 cycloalkyl); R b NHCOR 13 or CN, R 13 is H or optionally substituted C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, C 3~10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4 Alkyl, (5-10 membered heteroaryl)-C 1~4 Alkyl- or (4- to 10-membered heterocycloalkyl)-C 1~4 It is alkyl.

[0020] In some embodiments,

[0021] [ka] A compound having the formula: During the ceremony, R 2 is H, D, halogen, or Me; R 3 is H, D, or F, R 10 is H, D, Me, or C1-3 haloalkyl; R 11 is H, D, Me, or C1-3 haloalkyl; R b NHCOR 14and R 14 is H, -CHCN, or an optionally substituted C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, C 3~10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4 Alkyl, (5-10 membered heteroaryl)-C 1~4 Alkyl- or (4- to 10-membered heterocycloalkyl)-C 1~4 A compound that is alkyl.

[0022] In some embodiments,

[0023] [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein the variables are as defined herein.

[0024] In some embodiments, a method of inhibiting a CDK enzyme is provided, the method comprising contacting the CDK enzyme with an effective amount of a compound provided herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising same.

[0025] In some embodiments, a method is provided in a subject or in a subject in need of treatment for a disease or disorder associated with aberrant CDK activity, the method comprising administering to the subject a compound provided herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising either.

[0026] In some embodiments, a method is provided for treating cancer in a subject or a subject in need thereof, the method comprising administering to the subject a compound provided herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising same.

[0027] In some embodiments, pharmaceutical compositions are provided that include one or more compounds, or pharmaceutically acceptable salts or solvates thereof, or compounds of the various formulas provided herein, or pharmaceutically acceptable salts or solvates thereof.

[0028] Stereoisomers of the compounds of the various formulae provided herein, as well as pharmaceutical salts and solvates thereof, are also contemplated, described, and encompassed herein. Methods of using the compounds of the formulae provided herein, and pharmaceutical compositions containing the compounds of the formulae provided herein are described. DETAILED DESCRIPTION OF THE INVENTION

[0029] The present disclosure may be more fully understood by reference to the following description, including the following definitions and examples. Certain features of the disclosed compositions and methods that are described herein in the context of separate embodiments may also be provided in combination in a single embodiment. Alternatively, various features of the disclosed compositions and methods that are, for brevity, described in the context of a single embodiment may also be provided separately or in any subcombination.

[0030] At various places in this specification, substituents of compounds are disclosed in groups or ranges. Embodiments are specifically intended to include each and every individual subcombination of the members of such groups and ranges. For example, the terms "C1-6 alkyl" or "C1-C6 alkyl" are specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0031] It will be further understood that certain embodiments, which are, for brevity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of embodiments that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0032] All percentages and ratios used herein are by weight unless otherwise specified.

[0033] The term "alkyl," when used alone or as part of a substituent group, refers to a straight or branched chain hydrocarbon group, a spirocyclic group, or a fused or bridged bicyclic group, each of which contains from 1 to 12 carbon atoms ("C1-C 12"), preferably having 1 to 6 carbon atoms ("C1-C6"). Examples of alkyl groups include methyl (Me, C1 alkyl), ethyl (Et, C2 alkyl), n-propyl (C3 alkyl), isopropyl (C3 alkyl), butyl (C4 alkyl), isobutyl (C4 alkyl), sec-butyl (C4 alkyl), tert-butyl (C4 alkyl), pentyl (C5 alkyl), isopentyl (C5 alkyl), tert-pentyl (C5 alkyl), hexyl (C6 alkyl), isohexyl (C6 alkyl), and the like. The term "spirocyclic group" refers to a spirocyclic compound in which two rings share only one single atom (spiroatom), which is usually a quaternary carbon. Examples of spirocyclic compounds are spiro[2,3]undecane, spiro[3,3]heptane, and spiro[5,5]undecane. The term "fused bicyclic group" refers to a fused bicyclic compound in which two rings share two adjacent atoms. Examples of fused bicyclic compounds include bicyclo[4.4.0]decane, α-thujene, and decalin. The term "bridged bicyclic group" refers to a bridged bicyclic compound in which two rings share three or more atoms, with a bridge containing at least one atom separating the two bridgehead atoms. Examples of bridged bicyclic compounds include bicyclo[2.2.1]heptane, bicyclo[1,1,1]pentane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.3.1]nonane, bicyclo[3.3.3]undecane, and the like. The term "haloalkyl," when used alone or as part of a substituent, refers to a group of 1 to 12 carbon atoms ("C1-C 12 "), preferably 1 to 6 carbon atoms ("C1-C6"), in which one or more of the hydrogen atoms in the group is replaced by a halogen atom. Examples of haloalkyl groups include trifluoromethyl (-CF3, C1 haloalkyl), trifluoroethyl (-CH2CF3, C2 haloalkyl), and the like.

[0034] The term "halo" or "halogen" refers to chloro, fluoro, bromo, or iodo.

[0035] The term "oxo" refers to an oxygen atom (i.e., =O) as a divalent substituent, which forms a carbonyl group when attached to a carbon (e.g., C=O), or to a nitrogen or sulfur heteroatom to form nitroso, sulfinyl, or sulfonyl.

[0036] The term "cycloalkyl" when used alone or as part of a substituent group means a group containing 3 to 10 carbon atoms ("C 3~ C 10 "), preferably 3 to 6 carbon atoms (C 3~ "C6"), or 3 to 7 carbon atoms ("C3-C7"), monocyclic, bicyclic, or tricyclic non-aromatic hydrocarbon groups. Examples of cycloalkyl groups include, for example, cyclopropyl (C3), cyclobutyl (C4), cyclopropylmethyl (C4), cyclopentyl (C5), cyclohexyl (C6), 1-methylcyclopropyl (C4), 2-methylcyclopentyl (C4), adamantanyl (C6), and the like. 10 ) etc.

[0037] The term "heterocycloalkyl," when used alone or as part of a substituent, refers to any 3- to 14-membered monocyclic, bicyclic, or tricyclic saturated ring structure containing at least one heteroatom selected from the group consisting of O, N, and S. Heterocycloalkyl groups can be described in terms of the number of atoms in the group or in terms of the number of carbon atoms in the group. The term "bicyclic" ring structure refers to spirocyclic, fused bicyclic, or bridged bicyclic rings. For example, the term "4- to 10-membered heterocycloalkyl" refers to a heterocycloalkyl group containing 4 to 10 ring atoms. For example, the term -C4-C6 heterocycloalkyl refers to a heterocycloalkyl group containing 4 to 6 carbon atoms. The heterocycloalkyl group can be attached to any heteroatom or carbon atom of the ring that results in a stable structure. Examples of suitable heterocycloalkyl groups include, but are not limited to, azepanyl, aziridinyl, azetidinyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, piperazinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, oxazepanyl, oxolanyl, oxetanyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, decahydroquinoline, 2-azaspiro[5.5]undecane, 6-oxa-3-azabicyclo[3.1.1]heptane, and the like.

[0038] The term "aryl" when used alone or as part of a substituent group refers to a monocyclic or bicyclic aromatic hydrocarbon ring structure having 6 or 10 carbon atoms in the ring system. Examples of aryl groups are phenyl and naphthyl.

[0039] The term "heteroaryl," when used alone or as part of a substituent, refers to a monocyclic, bicyclic, or tricyclic aromatic ring structure containing carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur. The heteroaryl ring can contain a total of 5, 6, 9, 10, or 14 ring atoms. Heteroaryl groups can be described either by the number of atoms in the group or by the number of carbon atoms in the group. That is, the term "5-14-membered heteroaryl" refers to a heteroaryl group containing 5 to 14 ring atoms. For example, the term -C4-C6 heteroaryl refers to a heteroaryl group containing 4 to 6 carbon atoms. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thiophenyl (thienyl), oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furazanyl, indolizinyl, indolyl, and the like.

[0040] When a range of carbon atoms, such as C1 to C6, is used herein, all ranges as well as individual numbers of carbon atoms are included. For example, "C1 to C3" refers to C 1~ C3, C 1~ C2, C 2~ The range of carbon atoms may be expressed in alternative terms. For example, "C 1~6 The term " is an alternative expression for "C1-C6".

[0041] When a ring system is described herein as having a range of member numbers, e.g., "5-14 members," all ranges as well as individual numbers of atoms are encompassed. For example, "5-14 members" includes 5-6 members, 5-10 members, 6-9 members, 5 members, 6 members, 7 members, 8 members, etc.

[0042] As used herein, "alkoxy" refers to an --O-alkyl group. Exemplary alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like.

[0043] The term "alkenyl" when used alone or as part of a substituent group means an alkyl group having 2 to 12 carbon atoms ("C 2~ C 12 "), preferably refers to a straight or branched chain group having 2 to 6 carbon atoms ("C2-6"), in which the group contains at least one carbon-carbon double bond, and examples of alkenyl groups include vinyl (-CH=CH2, C2 alkenyl), allyl (-CH2-CH=CH2, C3 alkenyl), propenyl (-CH=CHCH3, C3 alkenyl), isopropenyl (-C(CH3)=CH2, C3 alkenyl), alkenyl), butenyl (-CH=CHCH2CH3, C4 alkenyl), sec-butenyl (-C(CH3)=CHCH3, C4 alkenyl), iso-butenyl (-CH=C(CH3)2, C4 alkenyl), 2-butenyl (-CH2CH=CHCH3, C4 alkyl), pentenyl (CH=CHCH2CH2CH3 or CH2=CHCH2CH2CH2-, C5 alkenyl), and the like.

[0044] The term "alkynyl" when used alone or as part of a substituent group refers to alkyl groups containing 2 to 12 carbon atoms ("C 2~ C 12 "), preferably refers to a straight or branched chain group having 2 to 6 carbon atoms ("C2-C6"), wherein the group contains at least one carbon-carbon triple bond. Examples of alkynyl groups include ethynyl (-C≡CH, C2 alkynyl), propargyl (-CH2-CH≡CH, C3 alkynyl), and the like.

[0045] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise specified. Compounds provided herein containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or stereoselective synthesis. Geometric isomers of olefins, C=N double bonds, and the like, may also be present in the compounds described herein, and all such stable isomers are contemplated in the present embodiments. Geometric isomers of the compounds of the present embodiments are described and can be isolated as a mixture of isomers or as separated isomeric forms.

[0046] The compounds provided herein may also include tautomeric forms. All tautomeric forms are included.

[0047] In some embodiments, the compounds may exist as rotamers. In some embodiments, the compounds exist as a mixture of rotamers in any proportion. In other embodiments, the compounds exist as a particular rotamer substantially free of other rotamers.

[0048] Compounds may also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0049] In some embodiments, the compounds and salts thereof are substantially isolated. "Substantially isolated" means that the compounds are at least partially or substantially separated from the environment in which they were formed or detected. Partial isolation can include, for example, compositions enriched for the compounds. Substantial isolation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compounds or salts thereof. Methods for isolating compounds and salts thereof are routine in the art.

[0050] Pharmaceutically acceptable salts of the compounds described herein are also provided herein. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds that have been modified by converting an acidic or basic moiety present in the parent compound into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. Pharmaceutically acceptable salts include, but are not limited to, conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of the two; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17 th 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.

[0051] The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and / or dosage forms that are suitable, within the scope of sound medical judgment, for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0052] "Pharmaceutically acceptable excipient" means a substance that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance that is added to a pharmaceutical composition or otherwise used as a solvent, carrier, or diluent to facilitate administration of a drug and is compatible therewith. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and starch types, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

[0053] "Solvate" refers to a physical association of a compound provided herein with one or more solvent molecules.

[0054] A "subject" includes a human. The terms "human," "patient," and "subject" are used interchangeably herein.

[0055] As used herein, the phrase "in need of" means that an animal or mammal (subject) has been identified as having a need for a particular method or treatment. In some embodiments, identification can be by any diagnostic means. The animal or mammal may be in need of any of the methods and treatments described herein. In some embodiments, the animal or mammal is in an environment or progresses to an environment where a particular disease, disorder, or condition is prevalent. In some embodiments, the subject in need thereof is suspected of having a condition that needs to be treated.

[0056] "Treating" or "treatment" of any disease or disorder, in some embodiments, refers to ameliorating the disease or disorder (i.e., arresting or reducing the disease or at least one of its clinical symptoms). In other embodiments, "treating" or "treatment" refers to improving at least one physical parameter, which may not be discernible by the subject. In yet other embodiments, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilization of a discernible symptom), physiologically (e.g., stabilization of a physical parameter), or both. In yet other embodiments, "treating" or "treatment" refers to delaying the onset of the disease or disorder.

[0057] As used herein, the phrase "an integer between X and Y" means any integer, inclusive of the endpoints. For example, the phrases "an integer between X and Y" or "1 to 5" or "1 to 5," when not modified by the term "integer," mean 1, 2, 3, 4, or 5, or any value within that range.

[0058] "Compounds of the disclosure" and equivalent expressions are meant to encompass any compound or structural representation described herein, and subgenera thereof, and these representations, where the context permits, include stereoisomers (e.g., enantiomers, diastereoisomers) and constitutional isomers (e.g., tautomers) of the various compounds of the formulae provided herein, and pharmaceutically acceptable salts thereof.

[0059] As used herein, the term "isotopic variant" refers to a compound that contains a proportion of an isotope at one or more of the atoms that constitute such compound that is greater than the natural abundance. For example, an "isotopic variant" of a compound can be radiolabeled, i.e., can contain one or more radioactive isotopes, or can contain, for example, deuterium ( 2 H or D), carbon-13 ( 13 C), nitrogen-15( 15In compounds where such isotopic substitution is made, the following atoms, if present, may be different, for example, any hydrogen may be 2 Any carbon may be H / D. 13 C or any nitrogen 15 It will be understood that N may be present and the presence and placement of such atoms may be determined by one skilled in the art.

[0060] It should also be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or in their arrangement through atomic space are referred to as "isomers." Isomers that differ in the arrangement of their atoms in space are referred to as "stereoisomers," e.g., diastereoisomers, enantiomers, and atropisomers. Compounds of the present disclosure may have one or more asymmetric centers; therefore, such compounds can be produced as individual (R)- or (S)-stereoisomers at each asymmetric center, or as mixtures thereof. Unless otherwise indicated, the description or name of a particular compound in the specification and claims is intended to include all stereoisomers and mixtures thereof, racemic or otherwise. While one chiral center is present in a structure, the specific stereochemistry at that center is not depicted, and both enantiomers, individually or as mixtures of enantiomers, are encompassed by the structure. Although two or more chiral centers are present in the structures, the specific stereochemistry at the centers is not depicted, and all enantiomers and diastereoisomers, individually or as mixtures, are encompassed by the structures. Methods for the determination of stereochemistry and separation of stereoisomers are well known in the art.

[0061] Throughout this specification, when a composition is described as having, listing, or including particular ingredients, or a process is described as having, listing, or including particular process steps, it is contemplated that the compositions described herein also consist essentially of or consist of the recited ingredients, and that the processes described herein also consist essentially of or consist of the recited processing steps. Furthermore, it should be understood that the order of steps or order of performing certain actions is immaterial so long as the process remains operable. Additionally, two or more steps or actions can be performed simultaneously.

[0062] In some embodiments, a compound of Formula (I) or Formula (II):

[0063] [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0064] In some embodiments, the present disclosure relates to compounds of formula (I):

[0065] In some embodiments, the present disclosure relates to pharmaceutically acceptable salts or solvates of compounds of formula (I).

[0066] In another aspect, the present disclosure relates to a compound of formula (II):

[0067] In some embodiments, the present disclosure relates to a pharmaceutically acceptable salt or solvate of a compound of formula (II).

[0068] In some embodiments, X in the compound of Formula (I) or Formula (II) 1 , X 2 , and X 3 are each independently N or CR 3 is.

[0069] In some embodiments, X 1is N. In other embodiments, X 1 is CR 3 is.

[0070] In some embodiments, X 2 is N. In other embodiments, X 2 is CR 3 is.

[0071] In some embodiments, X 3 is N. In other embodiments, X 3 is CR 3 is.

[0072] In some embodiments, A in the compound of formula (I) 1 is N or CR 4 is.

[0073] In some embodiments, A 1 is N.

[0074] In other embodiments, A 1 is CR 4 is.

[0075] In some embodiments, B in the compound of formula (I) 1 is CR 6 R 7 , N.R. 5 , O, or S.

[0076] In some embodiments, B 1 is CR 6 R 7 is.

[0077] In other embodiments, B 1 is NR 5 is.

[0078] In other embodiments, B 1 is O.

[0079] In other embodiments, B 1 is S.

[0080] In some embodiments, A in the compound of formula (II) 2 is NR 8 , S, or O.

[0081] In some embodiments, A 2 is NR 8 is.

[0082] In other embodiments, A 2 is S.

[0083] In other embodiments, A 2 is O.

[0084] In some embodiments, B in the compound of formula (II) 2 is CR 9 Or N.

[0085] In some embodiments, B 2 is CR 9 is.

[0086] In other embodiments, B 2 is N.

[0087] In some embodiments, R in a compound of Formula (I) or Formula (II) 1 is C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, C 3~10 Cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4 Alkyl, (5-14 membered heteroaryl)-C 1~4 Alkyl, and (4- to 14-membered heterocycloalkyl)-C 1~4 alkyl, wherein R 1is 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R b It is optionally substituted with a substituent.

[0088] In some embodiments, R 1 is C1-6 alkyl, for example, C6 alkyl, C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl, C1 alkyl, methyl, ethyl, isopropyl, etc., where R 1 is 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R b It is optionally substituted with a substituent.

[0089] In some embodiments, R 1 is C1-6 alkoxy, for example, C6 alkoxy, C5 alkoxy, C4 alkoxy, C3 alkoxy, C2 alkoxy, C1 alkoxy, methoxy, ethoxy, isopropoxy, etc., and in this case, R 1 is 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R b It is optionally substituted with a substituent.

[0090] In some embodiments, R 1 is C 2~6 Alkenyl, for example, C6 alkenyl, C5 alkenyl, C4 alkenyl, C3 alkenyl, C2 alkenyl, ethenyl, propenyl, isopropenyl, etc., wherein R 1 is 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R b It is optionally substituted with a substituent.

[0091] In some embodiments, R 1 is C 2~6 Alkynyl, for example, C alkynyl, C alkynyl, C alkynyl, C alkynyl, C alkynyl, ethynyl, 2-propynyl (i.e., propargyl), and the like, and 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R b It is substituted with a substituent.

[0092] In some embodiments, R 1 is C 6~10 Aryl, for example, C6 aryl, C7 aryl, C8 aryl, C9 aryl, C 10 aryl, phenyl, naphthyl, etc., and 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R b It is optionally substituted with a substituent.

[0093] In some embodiments, R 1 is C3~ 10 Cycloalkyl, e.g., C 10 cycloalkyl, C9 cycloalkyl, C8 cycloalkyl, C7 cycloalkyl, C6 cycloalkyl, C5 cycloalkyl, C4 cycloalkyl, C3 cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc., and 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R b It is optionally substituted with a substituent.

[0094] In some embodiments, R 1 is cyclopentyl and 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R b It is optionally substituted with a substituent.

[0095] In some embodiments, R 1 is cyclohexyl, and 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R b It is optionally substituted with a substituent.

[0096] In other embodiments, R 1is 5-14 membered heteroaryl, e.g., 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, 10-membered heteroaryl, 11-membered heteroaryl, 12-membered heteroaryl, 13-membered heteroaryl, 14-membered heteroaryl, pyrrolyl, furyl, thiophenyl (thienyl), oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyrazolyl, pyridinyl, pyradazinyl, pyrimidinyl, pyrazinyl, pyranyl, furazanyl, indolizinyl, indolyl, etc.; and 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R b It is optionally substituted with a substituent.

[0097] In other embodiments, R 1 is 4 to 10-membered heterocycloalkyl, e.g., 10-membered heterocycloalkyl, 9-membered heterocycloalkyl, 8-membered heterocycloalkyl, 7-membered heterocycloalkyl, 6-membered heterocycloalkyl, 5-membered heterocycloalkyl, 4-membered heterocycloalkyl, piperidinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, etc., and 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R b It is optionally substituted with a substituent.

[0098] In other embodiments, R 1 is C 6~10 Aryl-C 1~4 Alkyl, e.g., C 6~10 Aryl-C1 alkyl, C 6~10 Aryl-C2 alkyl, C 6~10 Aryl-C3 alkyl, C 6~10 Aryl-C4 alkyl, C6 aryl-C1 alkyl, C6 aryl-C2 alkyl, C6 aryl-C3 alkyl, C6 aryl-C4 alkyl, C 10 Aryl-C1 alkyl, C 10 Aryl-C2 alkyl, C 10 Aryl-C3 alkyl, C 10aryl-C4 alkyl, -CH2-phenyl, -CH2CH2-phenyl, -CH2-naphthyl, -CH2CH2-naphthyl, etc., and 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R b It is optionally substituted with a substituent.

[0099] In other embodiments, R 1 is C 3~10 Cycloalkyl-C 1~4 Alkyl, e.g., C 3~10 Cycloalkyl-C1 alkyl, C 3~10 Cycloalkyl-C2 alkyl, C 3~10 Cycloalkyl-C3 alkyl, C 3~10 Cycloalkyl-C4 alkyl, C 3-6 Cycloalkyl-C1 alkyl, C 3-6 Cycloalkyl-C2 alkyl, C 3-6 Cycloalkyl-C3 alkyl, C 3-6 Cycloalkyl-C4 alkyl, C 5-6 Cycloalkyl-C1 alkyl, C 5-6 Cycloalkyl-C2 alkyl, C 5-6 Cycloalkyl-C3 alkyl, C 5-6 cycloalkyl-C4 alkyl, and the like, and 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R b It is optionally substituted with a substituent.

[0100] In other embodiments, R 1 is (5-14 membered heteroaryl)-C 1~4Alkyl, for example, (5-14 membered heteroaryl)-C1 alkyl, (5-14 membered heteroaryl)-C2 alkyl, (5-14 membered heteroaryl)-C3 alkyl, (5-14 membered heteroaryl)-C4 alkyl, (5 membered heteroaryl)-C1 alkyl, (5 membered heteroaryl)-C2 alkyl, (5 membered heteroaryl)-C3 alkyl, (5 membered heteroaryl)-C4 alkyl, (6 membered heteroaryl)-C1 alkyl, (6 membered heteroaryl)-C2 alkyl, (6 membered heteroaryl)-C4 alkyl, and 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R b It is optionally substituted with a substituent.

[0101] In other embodiments, R 1 is (4-14 membered heterocycloalkyl)-C 1~4 alkyl, for example, (4-14 membered heterocycloalkyl)-C alkyl, (4-14 membered heterocycloalkyl)-C alkyl, (4-14 membered heterocycloalkyl)-C alkyl, (4-14 membered heterocycloalkyl)-C alkyl, (4-14 membered heterocycloalkyl)-C alkyl, etc., and 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R b It is optionally substituted with a substituent.

[0102] In some embodiments, R in a compound of Formula (I) or Formula (II) 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are each independently H, D, halo, oxo, or C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C2~6 Alkynyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 6~10 Aryl, C 3~10 Cycloalkyl, 5-10 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4 Alkyl, (5-14 membered heteroaryl)-C 1~4 Alkyl, (4-14 membered heterocycloalkyl)-C 1~4 Alkyl, CN, NO2, OR a1 , S.R. a1 , NHOR a1 , C(O)R a1 , C(O)NR a1 R a1 , C(O)OR a1 ,OC(O)R a1 , OC(O)NR a1 R a1 , NHR a1 , N.R. a1 R a1 , N.R. a1 C(O)R a1 , N.R. a1 C(O)OR a1 , N.R. a1 C(O)NR a1 R a1 , C(=NR a1 )R a1 , C(=NR a1 )NR a1 R a1 , N.R. a1 C(=NR a1 )NR a1 R a1 , N.R. a1 C(=NOH)NR a1 R a1 , N.R. a1 C(=NCN)NR a1 R a1 , N.R. a1 S(O)R a1 , N.R. a1 S(O)2R a1 , N.R. a1 S(O)NR a1 R a1,S(O)R a1 ,S(O)NR a1 R a1 S(O)2R a1 , SF5, P(O)R a1 R a1 , P(O)(OR a1 )(OR a1 ), B(OR a1 )2 and S(O)2NR a1 R a1 is selected from R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 or R 9 But C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, C 3~10 Cycloalkyl, 5-10 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4 Alkyl, (5-14 membered heteroaryl)-C 1~4 Alkyl, or (4- to 14-membered heterocycloalkyl)-C 1~4 When it is alkyl, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 or R 9 is 1, 2, 3, 4, or 5 independently selected R b In some embodiments, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 or R 9 is H.

[0103] In some embodiments, R 2 is not halo. In some embodiments, R 2 is an arbitrarily substituted C 1~6 In some embodiments, R 2 is an arbitrarily substituted C 1~4 In some embodiments, R 2 is an arbitrarily substituted C 1~3 It is alkyl.

[0104] In some embodiments, R 5 is optionally C 1~6 In some embodiments, R 5 is an arbitrarily substituted C 1~4 In some embodiments, R 5 is an arbitrarily substituted C 1~3 In some embodiments, optionally substituted C 1~6 Alkyl, optionally substituted C 1~4 Alkyl or optionally substituted C 1~3 Alkyl is a group consisting of two R b In some embodiments, an optionally substituted C 1~6 Alkyl, optionally substituted C 1~4 Alkyl or optionally substituted C 1~3 Alkyl is one R b In some embodiments, R b is not a carbocycle, heterocycle, or aryl.

[0105] In some embodiments, R 2 is H.

[0106] In some embodiments, R 3 is H.

[0107] In some embodiments, R 4 is H.

[0108] In some embodiments, R 2 , R3 , R 4 , R 5 , R 6 , R 7 , R 8 or R 9 is D.

[0109] In some embodiments, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 or R 9 is halo, (i.e., F, Cl, Br, or I).

[0110] In some embodiments, R 2 is halo. In some embodiments, R 2 is F. In other embodiments, R 2 is Cl.

[0111] In some embodiments, R 3 is halo. In some embodiments, R 3 is F. In other embodiments, R 3 is Cl.

[0112] In some embodiments, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 or R 9 is oxo.

[0113] In some embodiments, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 or R 9 is C 1~6alkyl, e.g., C alkyl, C alkyl, C alkyl, C alkyl, C alkyl, C alkyl, -methyl, -ethyl, -isopropyl, etc., and 1, 2, 3, 4, or 5 independently selected R b It is optionally substituted with a substituent.

[0114] In some embodiments, R 2 is methyl.

[0115] In some embodiments, R 3 is methyl.

[0116] In some embodiments, R 4 is methyl.

[0117] In some embodiments, R 5 is methyl. In another embodiment, R 5 is isopropyl.

[0118] In some embodiments, R 8 is methyl.

[0119] In some embodiments, R 9 is methyl. In another embodiment, R 9 is isopropyl.

[0120] In some embodiments, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 or R 9 is C 1~6 Alkoxy, for example, C alkoxy, C alkoxy, C alkoxy, C alkoxy, C alkoxy, C alkoxy, C alkoxy, C alkoxy, methoxy, ethoxy, isopropoxy, etc., and 1, 2, 3, 4, or 5 independently selected R b It is optionally substituted with a substituent.

[0121] In some embodiments, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 or R 9 is C 2~6 alkenyl, for example, C6 alkenyl, C5 alkenyl, C4 alkenyl, C3 alkenyl, C2 alkenyl, -ethenyl, -propenyl, -isopropenyl, etc., and 1, 2, 3, 4, or 5 independently selected R b It is optionally substituted with a substituent.

[0122] In some embodiments, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 or R 9 is C 2~6 Alkynyl, for example, C alkynyl, C alkynyl, C alkynyl, C alkynyl, C alkynyl, C alkynyl, -ethynyl, 2-propynyl (i.e., propargyl), and the like, and 1, 2, 3, 4, or 5 independently selected R b It is optionally substituted with a substituent.

[0123] In some embodiments, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 or R 9 is C 1~6 Haloalkyl, for example, C6 haloalkyl, C5 haloalkyl, C4 haloalkyl, C3 haloalkyl, C2 haloalkyl, C1 haloalkyl, halomethyl, haloethyl, haloisopropyl, and the like.

[0124] In some embodiments, R 2 , R 3 , R 4 , R 5 , R 6 , R7 , R 8 or R 9 is C 1~6 Haloalkoxy, for example, C6 haloalkoxy, C5 haloalkoxy, C4 haloalkoxy, C3 haloalkoxy, C2 haloalkoxy, C1 haloalkoxy, halomethoxy, haloethoxy, haloisopropoxy, and the like.

[0125] In some embodiments, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 or R 9 is C 6~10 Aryl, for example, C6 aryl, C7 aryl, C8 aryl, C9 aryl, C 10 aryl, phenyl, naphthyl, etc., and 1, 2, 3, 4, or 5 independently selected R b It is optionally substituted with a substituent.

[0126] In some embodiments, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 or R 9 is C 3~10 Cycloalkyl, e.g., C 10 cycloalkyl, C9 cycloalkyl, C8 cycloalkyl, C7 cycloalkyl, C6 cycloalkyl, C5 cycloalkyl, C4 cycloalkyl, C3 cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc., and 1, 2, 3, 4, or 5 independently selected R b It is optionally substituted with a substituent.

[0127] In some embodiments, R 2 , R 3 , R 4 , R 5 , R 6 , R7 , R 8 or R 9 is a 5- to 10-membered heteroaryl, e.g., a 5-membered heteroaryl, a 6-membered heteroaryl, a 7-membered heteroaryl, an 8-membered heteroaryl, a 9-membered heteroaryl, a 10-membered heteroaryl, pyrrolyl, furyl, thiophenyl (thienyl), oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyrazolyl, pyridinyl, pyradazinyl, pyrimidinyl, pyrazinyl, pyranyl, furazanyl, indolizinyl, indolyl, etc.; and one, two, three, four, or five independently selected R b It is optionally substituted with a substituent.

[0128] In some embodiments, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 or R 9 is 4 to 14 membered heterocycloalkyl, e.g., 10 membered heterocycloalkyl, 9 membered heterocycloalkyl, 8 membered heterocycloalkyl, 7 membered heterocycloalkyl, 6 membered heterocycloalkyl, 5 membered heterocycloalkyl, 4 membered heterocycloalkyl, piperidinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, etc., and 1, 2, 3, 4, or 5 independently selected R b It is optionally substituted with a substituent.

[0129] In some embodiments, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 or R 9 is C 6~10 Aryl-C 1~4 Alkyl, e.g., C 6~10 Aryl-C1 alkyl, C 6~10 Aryl-C2 alkyl, C 6~10 Aryl-C3 alkyl, C 6~10Aryl-C4 alkyl, C6 aryl-C1 alkyl, C6 aryl-C2 alkyl, C6 aryl-C3 alkyl, C6 aryl-C4 alkyl, C 10 Aryl-C1 alkyl, C 10 Aryl-C2 alkyl, C 10 Aryl-C3 alkyl, C 10 aryl-C4 alkyl, -CH2-phenyl, -CH2CH2-phenyl, -CH2-naphthyl, -CH2CH2-naphthyl, etc., and 1, 2, 3, 4, or 5 independently selected R b It is optionally substituted with a substituent.

[0130] In some embodiments, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 or R 9 is C 3~10 Cycloalkyl-C 1~4 Alkyl, e.g., C 3~10 Cycloalkyl-C1 alkyl, C 3~10 Cycloalkyl-C2 alkyl, C 3~10 Cycloalkyl-C3 alkyl, C 3~10 Cycloalkyl-C4 alkyl, C 3-6 Cycloalkyl-C1 alkyl, C 3-6 Cycloalkyl-C2 alkyl, C 3-6 Cycloalkyl-C3 alkyl, C 3-6 Cycloalkyl-C4 alkyl, C 5-6 Cycloalkyl-C1 alkyl, C 5-6 Cycloalkyl-C2 alkyl, C 5-6 Cycloalkyl-C3 alkyl, C 5-6 cycloalkyl-C4 alkyl, and the like, wherein 1, 2, 3, 4, or 5 independently selected R b It is optionally substituted with a substituent.

[0131] In some embodiments, R 2 , R 3 , R 4 , R5 , R 6 , R 7 , R 8 or R 9 is (5-14 membered heteroaryl)-C 1~4 Alkyl, for example, (5-14 membered heteroaryl)-C1 alkyl, (5-14 membered heteroaryl)-C2 alkyl, (5-14 membered heteroaryl)-C3 alkyl, (5-14 membered heteroaryl)-C4 alkyl, (5 membered heteroaryl)-C1 alkyl, (5 membered heteroaryl)-C2 alkyl, (5 membered heteroaryl)-C3 alkyl, (5 membered heteroaryl)-C4 alkyl, (6 membered heteroaryl)-C1 alkyl, (6 membered heteroaryl)-C2 alkyl, (6 membered heteroaryl)-C1 alkyl, (6 membered heteroaryl)-C2 alkyl, and 1, 2, 3, 4, or 5 independently selected R b It is optionally substituted with a substituent.

[0132] In some embodiments, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 or R 9 is (4-14 membered heterocycloalkyl)-C 1~4 alkyl, for example, (4-14 membered heterocycloalkyl)-C alkyl, (4-14 membered heterocycloalkyl)-C alkyl, (4-14 membered heterocycloalkyl)-C alkyl, (4-14 membered heterocycloalkyl)-C alkyl, etc., and 1, 2, 3, 4, or 5 independently selected R b It is optionally substituted with a substituent.

[0133] In some embodiments, R 2 , R3 , R 4 , R 5 , R 6 , R 7 , R 8 or R 9 is CN.

[0134] In some embodiments, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 or R 9 is NO2.

[0135] In some embodiments, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 or R 9 is OR a1 is.

[0136] In some embodiments, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 or R 9 is SR a1 is.

[0137] In some embodiments, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 or R 9 NHOR a1 is.

[0138] In some embodiments, R 2 , R 3 , R 4 , R 5 , R 6 , R7 , R 8 or R 9 is C(O)R a1 is.

[0139] In some embodiments, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 or R 9 is C(O)NR a1 R a1 is.

[0140] In some embodiments, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 or R 9 is C(O)OR a1 is.

[0141] In some embodiments, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 or R 9 is OC(O)R a1 is.

[0142] In some embodiments, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 or R 9 is OC(O)NR a1 R a1 is.

[0143] In some embodiments, R 2 , R 3 , R 4 , R 5 , R6 , R 7 , R 8 or R 9 is NHR a1 is.

[0144] In some embodiments, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 or R 9 is NR a1 R a1 is.

[0145] In some embodiments, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 or R 9 is NR a1 C(O)R a1 is.

[0146] In some embodiments, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 or R 9 is NR a1 C(O)OR a1 is.

[0147] In some embodiments, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 or R 9 is NR a1 C(O)NR a1 R a1 is.

[0148] In some embodiments, R 2 , R3 , R 4 , R 5 , R 6 , R 7 , R 8 or R 9 is C(=NR a1 )R a1 is.

[0149] In some embodiments, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 or R 9 is C(=NR a1 )NR a1 R a1 is.

[0150] In some embodiments, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 or R 9 is NR a1 C(=NR a1 )NR a1 R a1 is.

[0151] In some embodiments, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 or R 9 is NR a1 C(=NOH)NR a1 R a1 is.

[0152] In some embodiments, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 or R9 is NR a1 C(=NCN)NR a1 R a1 is.

[0153] In some embodiments, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 or R 9 is NR a1 S(O)R a1 is.

[0154] In some embodiments, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 or R 9 is NR a1 S(O)2R a1 is.

[0155] In some embodiments, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 or R 9 is NR a1 S(O)NR a1 R a1 is.

[0156] In some embodiments, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 or R 9 is S(O)R a1 is.

[0157] In some embodiments, R 2 , R 3 , R4 , R 5 , R 6 , R 7 , R 8 or R 9 is S(O)NR a1 R a1 S(O)2R a1 is.

[0158] In some embodiments, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 or R 9 is SF5.

[0159] In some embodiments, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 or R 9 is P(O)R a1 R a1 is.

[0160] In some embodiments, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 or R 9 is P(O)(OR a1 )(OR a1 )

[0161] In some embodiments, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 or R 9 is B(OR a1 )2.

[0162] In some embodiments, R2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 or R 9 is S(O)NR a1 R a1 is.

[0163] In some embodiments, R 4 and R 5 together with the atom to which they are attached form a 5-, 6-, or 7-membered heterocycloalkyl ring, and 1, 2, 3, 4, or 5 independently selected R b It is optionally substituted with a substituent.

[0164] In some embodiments, R 6 and R 7 together with the carbon atoms to which they are both attached form a C3-C7 spirocyclic ring, and 1, 2, 3, 4, or 5 independently selected R b It is optionally substituted with a substituent.

[0165] In some embodiments, R 8 and R 9 together with the atom to which they are attached form a 5-, 6-, or 7-membered heterocycloalkyl ring, and 1, 2, 3, 4, or 5 independently selected R b It is optionally substituted with a substituent.

[0166] In some embodiments of the present disclosure, each R a1 are independently H, D, C 1~6 Alkyl, C 1~4 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, C 3~10 Cycloalkyl, 5-10 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4Alkyl, (5-10 membered heteroaryl)-C 1~4 Alkyl, and (4- to 14-membered heterocycloalkyl)-C 1~4 alkyl, R a1 But C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, C 3~10 Cycloalkyl, 5-10 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4 Alkyl, (5-10 membered heteroaryl)-C 1~4 Alkyl- or (4- to 14-membered heterocycloalkyl)-C 1~4 When it is alkyl, R a1 is 1, 2, 3, 4, or 5 independently selected R d It is optionally substituted with a substituent.

[0167] In some embodiments of the present disclosure, each R b The substituents are independently D, halo, oxo, C 1~4 Alkyl, C 1~6 Alkoxy, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, C 6~10 Aryl, C 3~10 Cycloalkyl, 5-10 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4 Alkyl, (5-10 membered heteroaryl)-C 1~4 Alkyl, (4-14 membered heterocycloalkyl)-C 1~4 Alkyl, CN, OH, NH2, NO2, NHOR c , OR c , S.R. c , C(O)R c , C(O)NR c R c , C(O)OR c ,OC(O)Rc , OC(O)NR c R c , C(=NR c )NR c R c , N.R. c C(=NR c )NR c R c , N.R. c C(=NOH)NR c R c , N.R. c C(=NCN)NR c R c , SF5, P(O)R c R c , P(O)(OR c )(OR c ), NHR c , N.R. c R c , N.R. c C(O)R c , N.R. c C(O)OR c , N.R. c C(O)NR c R c , N.R. c S(O)R c , N.R. c S(O)(=NR c )R c , N.R. c S(O)2R c , N.R. c S(O)NR c R c , S(O)R c , S(O)NR c R c , S(O)2R c or S(O)NR c R c is selected from R b But C 1~4 Alkyl, C 1~6 Alkoxy, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, C 6~10 Aryl, C 3~10 Cycloalkyl, 5-10 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6~10 Aryl-C1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4 Alkyl, (5-10 membered heteroaryl)-C 1~4 Alkyl- or (4- to 14-membered heterocycloalkyl)-C 1~4 When it is alkyl, R b is one, two, or three independently selected R d It is optionally substituted with a substituent.

[0168] In some embodiments, R b is NR c C(=NR c )NR c R c , N.R. c C(=NOH)NR c R c , N.R. c C(=NCN)NR c R c , N.R. c C(O)R c , N.R. c C(O)OR c , N.R. c C(O)NR c R c , N.R. c S(O)R c , or NR c S(O)2R c , N.R. c S(O)NR c R c is.

[0169] In other embodiments, R b is NR c C(O)R c , N.R. c C(O)NR c R c , or NR c S(O)2R c is.

[0170] In some embodiments of the present disclosure, each R c are independently H, D, OH, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~4Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, C 3~10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4 Alkyl, (5-10 membered heteroaryl)-C 1~4 Alkyl, and (4-10 membered heterocycloalkyl)-C 1~4 alkyl, R c But C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, C 3~10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4 Alkyl, (5-10 membered heteroaryl)-C 1~4 Alkyl- or (4- to 10-membered heterocycloalkyl)-C 1~4 When it is alkyl, R c is 1, 2, 3, 4, or 5 independently selected R f It is optionally substituted with a substituent.

[0171] In some embodiments of the present disclosure, each R f independently, C 1~4 Alkyl, C 1~4 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, C 3~10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4 Alkyl, (5-10 membered heteroaryl)-C 1~4Alkyl, and (4-10 membered heterocycloalkyl)-C 1~4 Alkyl, Halo, CN, NHOR g , OR g , S.R. g , C(O)R g , C(O)NR g R g , C(O)OR g ,OC(O)R g , OC(O)NR g R g , NHR g , N.R. g R g , N.R. g C(O)R g , N.R. g C(O)NR g R g , N.R. g C(O)OR g , C(=NR g )NR g R g , N.R. g C(=NR g )NR g R g , N.R. g C(=NOH)NR g R g , N.R. g C(=NCN)NR g R g , SF5, P(O)R g R g , P(O)(OR g )(OR g ), S(O)R g , S(O)NR g R g , S(O)2R g , N.R. g S(O)2R g , N.R. g S(O)NR g R g , and S(O)NR g R g is selected from R f But C 1~4 Alkyl, C 1~4 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C6~10 Aryl, C 3~10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4 Alkyl, (5-10 membered heteroaryl)-C 1~4 Alkyl, and (4-10 membered heterocycloalkyl)-C 1~4 When it is alkyl, R f is 1, 2, 3, 4, or 5 independently selected R n It is optionally substituted with a substituent.

[0172] In some embodiments of the present disclosure, each R n independently, C 1~4 Alkyl, C 1~4 Haloalkyl, Halo, CN, R o , NHOR o , OR o , S.R. o , C(O)R o , C(O)NR o R o , C(O)OR o ,OC(O)R o , OC(O)NR o R o , NHR o , N.R. o R o , N.R. o C(O)R o , N.R. o C(O)NR o R o , N.R. o C(O)OR o , C(=NR o )NR o R o , N.R. o C(=NR o )NR o R o , N.R. o C(=NOH)NR o R o , N.R. o C(=NCN)NR o R o , SF5, P(O)Ro R o , P(O)(OR o )(OR o ), S(O)R o , S(O)NR o R o , S(O)2R o , N.R. o S(O)2R o , N.R. o S(O)NR o R o , and S(O)NR o R o is selected from.

[0173] In some embodiments of the present disclosure, each R d are independently D, oxo, C 1~6 Alkyl, C 1~6 Haloalkyl, Halo, C 3~10 Cycloalkyl, C 6~10 Aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4 Alkyl, (5-10 membered heteroaryl)-C 1~4 Alkyl, and (4-10 membered heterocycloalkyl)-C 1~4 Alkyl, CN, NH2, NHOR e , OR e , S.R. e , C(O)R e , C(O)NR e R e , C(O)OR e ,OC(O)R e , OC(O)NR e R e , NHR e , N.R. e R e , N.R. e C(O)R e , N.R. e C(O)NR e R e , N.R. e C(O)OR e , C(=NR e )NR e Re , N.R. e C(=NR e )NR e R e , N.R. e C(=NOH)NR e R e , N.R. e C(=NCN)NR e R e , SF5, P(O)R e R e , P(O)(OR e )(OR e ), S(O)R e , S(O)NR e R e , S(O)2R e , N.R. e S(O)2R e , N.R. e S(O)NR e R e , and S(O)NR e R e is selected from R d But C 1~6 Alkyl, C 3~10 Cycloalkyl, C 6~10 Aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4 Alkyl, (5-10 membered heteroaryl)-C 1~4 Alkyl, or (4- to 10-membered heterocycloalkyl)-C 1~4 When it is alkyl, R d is one, two, or three independently selected R f It is optionally substituted with a substituent.

[0174] In some embodiments of the present disclosure, each R e are independently H, D, CN, and C 1~6 Alkyl, C 1~4 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, C 3~10Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4 Alkyl, (5-10 membered heteroaryl)-C 1~4 Alkyl, and (4-10 membered heterocycloalkyl)-C 1~4 alkyl, R e But C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, C 3~10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4 Alkyl, (5-10 membered heteroaryl)-C 1~4 Alkyl- or (4- to 10-membered heterocycloalkyl)-C 1~4 When it is alkyl, R e is one, two, or three independently selected R g It is optionally substituted with a substituent.

[0175] In some embodiments of the present disclosure, each R g are independently H, D, C 1~6 Alkyl, C 1~4 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, C 3~10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4 Alkyl, (5-10 membered heteroaryl)-C 1~4 Alkyl, and (4-10 membered heterocycloalkyl)-C 1~4 alkyl, R g But C 1~6Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, C 3~10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4 Alkyl, (5-10 membered heteroaryl)-C 1~4 Alkyl- or (4- to 10-membered heterocycloalkyl)-C 1~4 When it is alkyl, R g is one, two, or three independently selected R P It is optionally substituted with a substituent.

[0176] In some embodiments of the present disclosure, each R P independently, C 1~4 Alkyl, C 1~4 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, C 3~10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4 Alkyl, (5-10 membered heteroaryl)-C 1~4 Alkyl, and (4-10 membered heterocycloalkyl)-C 1~4 Alkyl, Halo, CN, NHOR r , OR r , S.R. r , C(O)R r , C(O)NR r R r , C(O)OR r ,OC(O)R r , OC(O)NR r R r , NHR r , N.R. r R r , N.R. r C(O)R r , N.R. r C(O)NRr R r , N.R. r C(O)OR r , C(=NR r )NR r R r , N.R. r C(=NR r )NR r R r , N.R. r C(=NOH)NR r R r , N.R. r C(=NCN)NR r R r , SF5, P(O)R r R r , P(O)(OR r )(OR r ), S(O)R r , S(O)NR r R r , S(O)2R r , N.R. r S(O)2R r , N.R. r S(O)NR r R r , and S(O)NR r R r is selected from.

[0177] In some embodiments of the present disclosure, each R o or R r are independently H, D, C 1~4 Alkyl, C 3~6 Cycloalkyl, C 6~10 Aryl, 5- or 6-membered heteroaryl, C 1~4 Haloalkyl, C 2~4 Alkenyl, and C 2~4 alkynyl, R o or R r But C 1~4 Alkyl, C 3~6 Cycloalkyl, C 6~10 Aryl, 5- or 6-membered heteroaryl, C 2~4 Alkenyl, and C 2~4 When R is alkynyl, o or R ris one, two, or three independently selected R q It is optionally substituted with a substituent.

[0178] In some embodiments of the present disclosure, each R q are independently D, OH, CN, -COOH, NH2, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~4 Alkylthio, phenyl, 5-6 membered heteroaryl, C 3~6 Cycloalkyl, 4-6 membered heterocycloalkyl, -CONHR 12 , -NHC(O)R 12 , -OC(O)R 12 , -C(O)OR 12 , -C(O)R 12 , -SO2R 12 , -NHSO2R 12 , -SO2NHR 12 and NR 12 R 12 is selected from R q But C 1~6 alkyl, phenyl, 4- to 6-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, R q are OH, CN, -COOH, NH2, C 1~6 Alkoxy, C 3~6 It is optionally substituted with cycloalkyl or 4- to 6-membered heterocycloalkyl.

[0179] In some embodiments of the present disclosure, each R 12 independently, C 1~6 It is alkyl.

[0180] In some embodiments, the compound has the formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein: X 1 , X 2 , and X 3 are each independently N or CR 3 and A1 is N or CR 4 and B 1 is CR 6 R 7 , N.R. 5 and A 2 is NR 8 , S, or O; B 2 is CR 9 and R1 is C3~ 10 cycloalkyl or 4-10 membered heterocycloalkyl, and 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R b optionally substituted with substituents, R 2 is H, D, OH, halogen, CN, C1-6 alkyl, C3- 10 Cycloalkyl, C1-6 alkoxyl, C 1~6 haloalkyl or 4- to 14-membered heterocycloalkyl; R 3 is H, D, OH, halogen, CN, C1-6 alkyl, C3- 10 cycloalkyl, C alkoxyl, or 4- to 14-membered heterocycloalkyl; R 4 is H, D, C1-6 alkyl, C1-6 alkoxy, C 3~10 cycloalkyl, or 4- to 6-membered heterocycloalkyl; R 5 is C1-6 alkyl, C1-6 alkoxy, C 3~6 cycloalkyl, or 4- to 6-membered heterocycloalkyl; Or R 4 and R 5 may be substituted with 1, 2, 3, 4, or 5 independently selected R b forming a 5-, 6-, or 7-membered heterocycloalkyl ring optionally substituted with substituents; R 6 is C1-6 alkyl, C1-6 alkoxy, C 3~6 cycloalkyl, or 4- to 6-membered heterocycloalkyl; R 7is C1-6 alkyl, C1-6 alkoxy, C 3~6 cycloalkyl, or 4- to 6-membered heterocycloalkyl; Or R 6 and R 7 form a C4-7 spirocyclic ring together with the carbon atoms to which they are both attached, R 8 is C1-6 alkyl, R 9 is C1-6 alkyl, C1-6 alkoxy, C 3~6 cycloalkyl, or 4- to 6-membered heterocycloalkyl; Or R 8 and R 9 may be substituted with 1, 2, 3, 4, or 5 independently selected R b forming a 5-, 6-, or 7-membered heterocycloalkyl ring optionally substituted with substituents; R b represents 5- to 10-membered heteroaryl, 4- to 14-membered heterocycloalkyl, NR c C(=NR c )NR c R c , N.R. c C(=NOH)NR c R c , N.R. c C(=NCN)NR c R c , N.R. c C(O)R c , N.R. c C(O)OR c , N.R. c C(O)NR c R c , N.R. c S(O)R c , N.R. c S(O)(=NR c )R c , N.R. c S(O)2R c , or NR c S(O)NR c R c and Each R c are independently H, OH, C 1~6 Alkyl, C1~6 Alkoxy, C 3~10 cycloalkyl, 4- to 10-membered heterocycloalkyl, or (5- to 10-membered heteroaryl)-C 1~4 alkyl and 1, 2, 3, 4, or 5 independently selected R f optionally substituted with substituents, Each R f are independently halogen, CN, or OR g and Each R g are independently H or C 1~6 It is alkyl.

[0181] In some embodiments, the compound has the formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein: X 1 , X 2 , and X 3 are each independently N or CR 3 and A 1 is N or CR 4 and B 1 is CR 6 R 7 , N.R. 5 and A 2 is NR 8 , S, or O; B 2 is CR 9 and R1 is C3~ 10 cycloalkyl and 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R b optionally substituted with substituents, R 2 is H, D, OH, halogen, CN, C1-6 alkyl, C3- 10 cycloalkyl, C alkoxyl, or 4- to 14-membered heterocycloalkyl; R 3 is H, D, OH, halogen, CN, C1-6 alkyl, C3- 10cycloalkyl, C alkoxyl, or 4- to 14-membered heterocycloalkyl; R 4 is H, D, C1-6 alkyl, or C1-6 alkoxy; R 5 is C1-6 alkyl or C1-6 alkoxy, Or R 4 and R 5 may be substituted with 1, 2, 3, 4, or 5 independently selected R b forming a 5-, 6-, or 7-membered heterocycloalkyl ring optionally substituted with substituents; R 6 is C1-6 alkyl, R 7 is C1-6 alkyl, Or R 6 and R 7 form a C4-7 spirocyclic ring together with the carbon atoms to which they are both attached, R 8 is C1-6 alkyl, R 9 is C1-6 alkyl, Or R 8 and R 9 may be substituted with 1, 2, 3, 4, or 5 independently selected R b forming a 5-, 6-, or 7-membered heterocycloalkyl ring optionally substituted with substituents; R b is C 1~4 Alkyl, NR c C(=NR c )NR c R c , N.R. c C(=NOH)NR c R c , N.R. c C(=NCN)NR c R c , N.R. c C(O)R c , N.R. c C(O)OR c , N.R. c C(O)NR c R c, N.R. c S(O)R c , N.R. c S(O)(=NR c )R c , N.R. c S(O)2R c , or NR c S(O)NR c R c and Each R c are independently H, OH, C 1~6 Alkyl, C 1~6 Alkoxy, C 3~10 cycloalkyl, 4- to 10-membered heterocycloalkyl, or (5- to 10-membered heteroaryl)-C 1~4 alkyl and 1, 2, 3, 4, or 5 independently selected R f optionally substituted with substituents, Each R f are independently halogen, CN, C 1~4 Alkyl or OR g and Each R g are independently H or C 1~6 It is alkyl.

[0182] In some embodiments, the compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt or solvate thereof, is: X 1 , X 2 , and X 3 are each independently N or CR 3 and A 1 is N or CR 4 and B 1 is CR 6 R 7 , N.R. 5 and A 2 is NR 8 , S, or O; B 2 is CR 9 and R1 is C3-C7 cycloalkyl, and one Rb is substituted with a substituent, R b is NR c C(O)R c , N.R. c C(O)NR c R c , or NR c S(O)2R c and Each R c are independently H, OH, C 1~6 Alkyl, C 1~6 Alkoxy, C 3~10 cycloalkyl, 4- to 10-membered heterocycloalkyl, or (5- to 10-membered heteroaryl)-C 1~4 alkyl and 1, 2, 3, 4, or 5 independently selected R f optionally substituted with substituents, Each R f are independently halogen, CN, C 1~4 Alkyl or OR g and Each R g are independently H or C 1~6 is alkyl, R 2 is H, halogen, or C1-6 alkyl; R 3 is H, halogen, or C1-6 alkyl; R 4 is H or C1-6 alkyl, R 5 is C1-6 alkyl, Or R 4 and R 5 together with the atoms to which they are attached form a 5-, 6-, or 7-membered heterocycloalkyl ring optionally substituted with one or two methyl groups; R 6 is C1-6 alkyl, R 7 is C1-6 alkyl, Or R 6 and R 7 form a C4-7 spirocyclic ring together with the carbon atoms to which they are both attached, R8 is a C1-C6 alkyl, R 9 is a C1-C6 alkyl, Or R 8 and R 9 together with the atoms to which they are attached form a 5-, 6-, or 7-membered heterocycloalkyl ring optionally substituted with one or two methyl groups.

[0183] In some embodiments, the compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt or solvate thereof, is: X 1 , X 2 , and X 3 are each independently N or CR 3 and A 1 is N or CR 4 and B 1 is CR 6 R 7 , N.R. 5 , O, or S; A 2 is NR 8 , S, or O; B 2 is CR 9 or N, R1 is a C3-C7 cycloalkyl, and examples thereof include acetamide (-NHC(O)CH3), 3-hydroxybutanamide (-NHC(O)CH2CH(OH)CH3), propionamide (-NHC(O)CH2CH3), 2-methoxyacetamide (-NHC(O)CH2-OCH3), 2-cyanoacetamide (-NHC(O)CH2-CN), 1-hydroxycyclopropane-1-carboxamide,

[0184] [ka] 2-(thiazol-4-yl)acetamide,

[0185] [ka] Methylsulfonamide (-NSO2CH3), 3-methylureido (-NC(O)NHCH3), 3-methoxyureido (-NC(O)NHOCH3), 3,3-dimethylureido (-NC(O)N(CH3)2), or 3-ethylureido (-NC(O)NHCH2CH3), morpholine-4-carboxamide, i.e.,

[0186] [ka] or 4-methylpiperazine-1-carboxamide, i.e.,

[0187] [ka] is replaced by R 2 is H, halogen, or C1-C6 alkyl, R 3 is H, halogen, or C1-C6 alkyl, R 4 is H or C1-C6 alkyl, R 5 is a C1-C6 alkyl, Or R 4 and R 5 together with the atoms to which they are attached form a 5-membered heterocycloalkyl ring optionally substituted with one or two methyl groups; R 6 is a C1-C6 alkyl, R 7 is a C1-C6 alkyl, Or R 6 and R 7 form a C4-C7 spirocyclic ring together with the carbon atoms to which they are both attached, R 8 is a C1-C6 alkyl, R 9 is a C1-C6 alkyl, Or R 8 and R 9together with the atoms to which they are attached form a 5-, 6-, or 7-membered heterocycloalkyl ring optionally substituted with one or two methyl groups.

[0188] In some embodiments, R in the compound of Formula (I) or Formula (II) 1 are as follows:

[0189] [ka]

[0190] In other embodiments, R 1 are as follows:

[0191] [ka]

[0192] [ka]

[0193] In some embodiments, the compound is

[0194] [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 , R 2 , R 4 , R 5 , R 8 , R 9 , X 1 , X 2 , and X 3 is defined throughout this specification.

[0195] In some embodiments, the compound has the formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein X 1 is N, X 2 is CR 3 , and X3 is CR 3 is.

[0196] In some embodiments, the compound has the formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein X 1 is CR 3 , X 2 are N and X 3 is CR 3 is.

[0197] In some embodiments, the compound has the formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein X 1 is CR 3 , X 2 is CR 3 , and X 3 is N.

[0198] In some embodiments, the compound has the formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein X 1 is CR 3 , X 2 is CR 3 , and X 3 is CR 3 is.

[0199] In some embodiments, the compound has the formula (IV) or a pharmaceutically acceptable salt or solvate thereof, wherein X 1 is N, X 2 is CR 3 , and X 3 is CR 3 is.

[0200] In some embodiments, the compound has the formula (IV) or a pharmaceutically acceptable salt or solvate thereof, wherein X 1 is CR 3 , X 2 are N and X 3 is CR 3 is.

[0201] In some embodiments, the compound has the formula (IV) or a pharmaceutically acceptable salt or solvate thereof, wherein X 1 is CR 3 , X 2 is CR 3 , and X 3 is N.

[0202] In some embodiments, the compound has the formula (IV) or a pharmaceutically acceptable salt or solvate thereof, wherein X 1 is CR 3 , X 2 is CR 3 , and X 3 is CR 3 is.

[0203] In some embodiments, the compound has the formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is H, OH, halogen, CN, C1-6 alkyl, C3- 10 It is cycloalkyl, C1-6 alkoxyl, or 4- to 14-membered heterocycloalkyl.

[0204] In some embodiments, the compound has the formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is halogen or C1-6 alkyl.

[0205] In some embodiments, the compound has the formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C1-6 alkyl.

[0206] In some embodiments, the compound has the formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is chloro or fluoro.

[0207] In some embodiments, the compound has the formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C3~ 10 cycloalkyl, C1-6 alkoxyl.

[0208] In some embodiments, the compound has the formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is H or C alkyl, and R 5 is C1-6 alkyl, or R 4 and R 5 may be substituted with 1, 2, 3, 4, or 5 independently selected R b forming a 5- or 6-membered heterocycloalkyl ring optionally substituted with substituents, Each R b independently, C 1~4 Alkyl, NR c C(=NR c )NR c R c , N.R. c C(=NOH)NR c R c , N.R. c C(=NCN)NR c R c , N.R. c C(O)R c , N.R. c C(O)OR c , N.R. c C(O)NR c R c , N.R. c S(O)R c , or NR c S(O)2R c , N.R. c S(O)NR c R c and Each R c are independently H, C 1~6 Alkyl, C 3~10 cycloalkyl, 4- to 10-membered heterocycloalkyl, or (5- to 10-membered heteroaryl)-C 1~4alkyl and 1, 2, 3, 4, or 5 independently selected R f optionally substituted with substituents, Each R f are independently halogen, CN or OR g and Each R g are independently H or C 1~6 It is alkyl.

[0209] In some embodiments, the compound has the formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is H.

[0210] In some embodiments, the compound has the formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is C1-6 alkyl, for example, but not limited to, CH3.

[0211] In some embodiments, the compound has the formula (III) or a pharmaceutically acceptable salt or solvate thereof, and R 5 is C1-6 alkyl, for example, but not limited to, CH(CH3)2.

[0212] In some embodiments, the compound has the formula (III) or a pharmaceutically acceptable salt or solvate thereof, and R 4 and R 5 may be substituted with 1, 2, 3, 4, or 5 independently selected R b It forms a 5- or 6-membered heterocycloalkyl ring, optionally substituted with substituents.

[0213] In some embodiments, the compound has the formula (III) or a pharmaceutically acceptable salt or solvate thereof, and R 4 and R 5 are, together with the atoms to which they are attached, one or two R b In some embodiments, one or two Rb The substituent is C 1~4 Alkyl, for example, but not limited to, CH3.

[0214] In some embodiments, the compound has the formula (III) or a pharmaceutically acceptable salt or solvate thereof, and R 2 is H, OH, halogen, CN, C1-6 alkyl, C3- 10 It is cycloalkyl, C1-6 alkoxyl, or 4- to 14-membered heterocycloalkyl.

[0215] In some embodiments, the compound has the formula (III) or a pharmaceutically acceptable salt or solvate thereof, and R 2 is halogen or C1-6 alkyl.

[0216] In some embodiments, the compound has the formula (III) or a pharmaceutically acceptable salt or solvate thereof, and R 2 is C1-6 alkyl.

[0217] In some embodiments, the compound has the formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is chloro or fluoro.

[0218] In some embodiments, the compound has the formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is a C3- 10 cycloalkyl and 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R b optionally substituted with substituents, Each R b independently, C 1~4 Alkyl, NR c C(=NR c )NR c R c , N.R. c C(=NOH)NR c R c , N.R. c C(=NCN)NR c R c, N.R. c C(O)R c , N.R. c C(O)OR c , N.R. c C(O)NR c R c , N.R. c S(O)R c , or NR c S(O)2R c , N.R. c S(O)NR c R c and Each R c are independently H, C 1~6 Alkyl, C 3~10 cycloalkyl, 4- to 10-membered heterocycloalkyl, or (5- to 10-membered heteroaryl)-C 1~4 alkyl and 1, 2, 3, 4, or 5 independently selected R f optionally substituted with substituents, Each R f are independently halogen, CN or OR g and Each R g are independently H or C 1~6 It is alkyl.

[0219] In some embodiments, the compound has the formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is C 3~10 cycloalkyl and one R b It is optionally substituted with a substituent.

[0220] In some embodiments, the compound has the formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is C 3~7 cycloalkyl and one R b It is optionally substituted with a substituent.

[0221] In some embodiments, the compound has the formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is C5~6 cycloalkyl and one R b It is optionally substituted with a substituent.

[0222] In some embodiments, the compound has the formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is cyclopentanyl or cyclohexanyl, and one R b In another embodiment, R 1 R above b The substituent is NR c C(O)R c , N.R. c C(O)NR c R c , or NR c S(O)NR c R c In some embodiments, NR c C(O)R c , N.R. c C(O)NR c R c , or NR c S(O)NR c R c R in c are independently H, C 1~6 Alkyl, C 3~10 cycloalkyl, 4- to 10-membered heterocycloalkyl, or (5- to 10-membered heteroaryl)-C 1~4 alkyl and 1, 2, 3, 4, or 5 independently selected R f In some embodiments, R f The substituents are independently halogen, CN, or OR. g In some embodiments, R g are independently H or C 1~6 It is alkyl.

[0223] In some embodiments, the compound has the formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 One R above bThe substituents are acetamide (-NHC(O)CH3), 3-hydroxybutanamide (-NHC(O)CH2CH(OH)CH3), propionamide (-NHC(O)CH2CH3), 2-methoxyacetamide (-NHC(O)CH2-OCH3), 2-cyanoacetamide (-NHC(O)CH2-CN), 1-hydroxycyclopropane-1-carboxamide,

[0224] [ka] 2-(thiazol-4-yl)acetamide,

[0225] [ka] Methylsulfonamide (-NSO2CH3), 3-methylureido (-NC(O)NHCH3), 3-methoxyureido (-NC(O)NHOCH3), 3,3-dimethylureido (-NC(O)N(CH3)2), or 3-ethylureido (-NC(O)NHCH2CH3), morpholine-4-carboxamide, i.e.,

[0226] [ka] or 4-methylpiperazine-1-carboxamide, i.e.,

[0227] [ka] is.

[0228] In some embodiments, the compound has the formula (IV) or a pharmaceutically acceptable salt or solvate thereof, wherein R 8 is C1-6 alkyl, and R 9 is C1-6 alkyl, or R 8 and R 9 may be substituted with 1, 2, 3, 4, or 5 independently selected R bforming a 5- or 6-membered heterocycloalkyl ring optionally substituted with substituents, Each R b independently, C 1~4 Alkyl, NR c C(=NR c )NR c R c , N.R. c C(=NOH)NR c R c , N.R. c C(=NCN)NR c R c , N.R. c C(O)R c , N.R. c C(O)OR c , N.R. c C(O)NR c R c , N.R. c S(O)R c , or NR c S(O)2R c , N.R. c S(O)NR c R c and Each R c are independently H, C 1~6 Alkyl, C 3~10 cycloalkyl, 4- to 10-membered heterocycloalkyl, or (5- to 10-membered heteroaryl)-C 1~4 alkyl and 1, 2, 3, 4, or 5 independently selected R f optionally substituted with substituents, Each R f are independently halogen, CN or OR g and Each R g are independently H or C 1~6 It is alkyl.

[0229] In some embodiments, the compound has the formula (IV) or a pharmaceutically acceptable salt or solvate thereof, wherein R 8 is C1-6 alkyl, preferably CH3.

[0230] In some embodiments, the compound has the formula (IV) or a pharmaceutically acceptable salt or solvate thereof, wherein R 9 is C1-6 alkyl, preferably CH(CH3)2.

[0231] In some embodiments, the compound has the formula (IV) or a pharmaceutically acceptable salt or solvate thereof, wherein R 8 and R 9 may be substituted with 1, 2, 3, 4, or 5 independently selected R b In some embodiments, R 8 and R 9 are, together with the atoms to which they are attached, one or two R b In some embodiments, one or two R b The substituent is C 1~4 Alkyl, preferably CH3.

[0232] In some embodiments, the compound has the formula (IV) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is H, OH, halogen, CN, C1-6 alkyl, C3- 10 It is cycloalkyl, C1-6 alkoxyl, or 4- to 14-membered heterocycloalkyl.

[0233] In some embodiments, the compound has the formula (IV) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is halogen or C1-6 alkyl.

[0234] In some embodiments, the compound has the formula (IV) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C1-6 alkyl.

[0235] In some embodiments, the compound has the formula (IV) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is chloro or fluoro.

[0236] In some embodiments, the compound has the formula (IV) or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is a C3- 10 cycloalkyl and 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R b optionally substituted with substituents, Each R b independently, C 1~4 Alkyl, NR c C(=NR c )NR c R c , N.R. c C(=NOH)NR c R c , N.R. c C(=NCN)NR c R c , N.R. c C(O)R c , N.R. c C(O)OR c , N.R. c C(O)NR c R c , N.R. c S(O)R c , or NR c S(O)2R c , N.R. c S(O)NR c R c and Each R c are independently H, C 1~6 Alkyl, C 3~10 cycloalkyl, 4- to 10-membered heterocycloalkyl, or (5- to 10-membered heteroaryl)-C 1~4 alkyl and 1, 2, 3, 4, or 5 independently selected R f optionally substituted with substituents, Each R f are independently halogen, CN or OR g and Each R gare independently H or C 1~6 It is alkyl.

[0237] In some embodiments, the compound has the formula of Formula (IV) or a pharmaceutically acceptable salt thereof, wherein R 1 is C 3~10 cycloalkyl and one R b It is optionally substituted with a substituent.

[0238] In some embodiments, the compound has the formula (IV) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is C 3~7 cycloalkyl and one R b It is optionally substituted with a substituent.

[0239] In some embodiments, the compound has the formula (IV) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is C 5~6 cycloalkyl and one R b It is optionally substituted with a substituent.

[0240] In some embodiments, the compound has the formula of Formula (IV) or a pharmaceutically acceptable salt thereof, wherein R 1 is cyclopentanyl or cyclohexanyl, and one R b It is optionally substituted with a substituent.

[0241] In some embodiments, the compound has the formula (IV) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 One R above b The substituent is NR c C(O)R c , N.R. c C(O)NR c R c , or NR c S(O)NR c R c In some embodiments, NR c C(O)R c , N.R. cC(O)NR c R c , or NR c S(O)NR c R c R in c are independently H, C 1~6 Alkyl, C 3~10 cycloalkyl, 4- to 10-membered heterocycloalkyl, or (5- to 10-membered heteroaryl)-C 1~4 alkyl and 1, 2, 3, 4, or 5 independently selected R f In some embodiments, R f The substituents are independently halogen, CN, or OR. g In some embodiments, R g are independently H or C 1~6 In another embodiment, R 1 R above b The substituents are acetamide (-NHC(O)CH3), 3-hydroxybutanamide (-NHC(O)CH2CH(OH)CH3), propionamide (-NHC(O)CH2CH3), 2-methoxyacetamide (-NHC(O)CH2-OCH3), 2-cyanoacetamide (-NHC(O)CH2-CN), 1-hydroxycyclopropane-1-carboxamide,

[0242] [ka] 2-(thiazol-4-yl)acetamide,

[0243] [ka] Methylsulfonamide (-NSO2CH3), 3-methylureido (-NC(O)NHCH3), 3-methoxyureido (-NC(O)NHOCH3), 3,3-dimethylureido (-NC(O)N(CH3)2), or 3-ethylureido (-NC(O)NHCH2CH3), morpholine-4-carboxamide, i.e.,

[0244] [ka] or 4-methylpiperazine-1-carboxamide, i.e.,

[0245] [ka] is.

[0246] In some embodiments, the compound has the formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 are independently H, OH, halogen, CN, C1-6 alkyl, C3- 10 It is cycloalkyl, C1-6 alkoxyl, or 4- to 14-membered heterocycloalkyl.

[0247] In some embodiments, the compound has the formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 is independently H or halogen, such as, but not limited to, Cl or F.

[0248] In some embodiments, the compound has the formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 Only one of the following is OH, halogen, CN, C1-6 alkyl, C3- 10 cycloalkyl, C1-6 alkoxyl, or 4- to 14-membered heterocycloalkyl, the remainder being H.

[0249] In some embodiments, the compound has the formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 One of them is halogen, preferably Cl or F, and the rest are H.

[0250] In some embodiments, R 1 is a stereoisomer provided herein and above, for example in paragraph 00160.

[0251] In some embodiments, the compound is

[0252] [ka] or a pharmaceutically acceptable salt or solvate thereof, in which the variables are defined throughout the specification.

[0253] In some embodiments, the compound has the formula of any one of Formulas (V)-(XII) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is H, OH, halogen, CN, C1-6 alkyl, C3- 10 It is cycloalkyl, C1-6 alkoxyl, or 4- to 14-membered heterocycloalkyl.

[0254] In some embodiments, the compound has the formula of any one of Formulas (V)-(XII) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is halogen or C1-6 alkyl.

[0255] In some embodiments, the compound has the formula of any one of Formulas (V)-(XII) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C1-6 alkyl.

[0256] In some embodiments, the compound has the formula of any one of Formulas (V)-(XII) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is chloro or fluoro.

[0257] In some embodiments, the compound has the formula of any one of Formulas (V)-(XII) or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is a C3- 10 cycloalkyl and 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R b optionally substituted with substituents, Each R bindependently, C 1~4 Alkyl, NR c C(=NR c )NR c R c , N.R. c C(=NOH)NR c R c , N.R. c C(=NCN)NR c R c , N.R. c C(O)R c , N.R. c C(O)OR c , N.R. c C(O)NR c R c , N.R. c S(O)R c , or NR c S(O)2R c , N.R. c S(O)NR c R c and Each R c are independently H, C 1~6 Alkyl, C 3~10 cycloalkyl, 4- to 10-membered heterocycloalkyl, or (5- to 10-membered heteroaryl)-C 1~4 alkyl and 1, 2, 3, 4, or 5 independently selected R f optionally substituted with substituents, Each R f are independently halogen, CN or OR g and Each R g are independently H or C 1~6 It is alkyl.

[0258] In some embodiments, the compound has the formula of any one of Formulas (V)-(XII) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is C 3~10 cycloalkyl and one R b It is optionally substituted with a substituent.

[0259] In some embodiments, the compound has the formula of any one of Formulas (V)-(XII) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is C 3~7 cycloalkyl and one R b It is optionally substituted with a substituent.

[0260] In some embodiments, the compound has the formula of any one of Formulas (V)-(XII) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is C 5~6 cycloalkyl and one R b It is optionally substituted with a substituent.

[0261] In some embodiments, the compound has the formula of any one of Formulas (V)-(XII) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is cyclopentanyl or cyclohexanyl, and one R b It is optionally substituted with a substituent.

[0262] In some embodiments, the compound has the formula of any one of Formulas (V)-(XII) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 One R above b The substituent is NR c C(O)R c , N.R. c C(O)NR c R c , or NR c S(O)NR c R c In some embodiments, NR c C(O)R c , N.R. c C(O)NR c R c , or NR c S(O)NR c R c R in c are independently H, C 1~6 Alkyl, C 3~10cycloalkyl, 4- to 10-membered heterocycloalkyl, or (5- to 10-membered heteroaryl)-C 1~4 alkyl and 1, 2, 3, 4, or 5 independently selected R f In some embodiments, R f The substituents are independently halogen, CN, or OR. g In some embodiments, R g are independently H or C 1~6 In another embodiment, R 1 R above b The substituents are acetamide (-NHC(O)CH3), 3-hydroxybutanamide (-NHC(O)CH2CH(OH)CH3), propionamide (-NHC(O)CH2CH3), 2-methoxyacetamide (-NHC(O)CH2-OCH3), 2-cyanoacetamide (-NHC(O)CH2-CN), 1-hydroxycyclopropane-1-carboxamide,

[0263] [ka] 2-(thiazol-4-yl)acetamide,

[0264] [ka] Methylsulfonamide (-NSO2CH3), 3-methylureido (-NC(O)NHCH3), 3-methoxyureido (-NC(O)NHOCH3), 3,3-dimethylureido (-NC(O)N(CH3)2), or 3-ethylureido (-NC(O)NHCH2CH3), morpholine-4-carboxamide, i.e.,

[0265] [ka] or 4-methylpiperazine-1-carboxamide, i.e.,

[0266] [ka] is.

[0267] In some embodiments, the compound is

[0268] [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein A 1 is N.

[0269] In some embodiments, the compound has the formula (V), (VI), (VII), or (XI), or a pharmaceutically acceptable salt or solvate thereof, wherein A 1 is CR 4 is.

[0270] In some embodiments, the compound has the formula (V), (VI), (VII), or (XI), or a pharmaceutically acceptable salt or solvate thereof, wherein B 1 is CR 6 R 7 is.

[0271] In some embodiments, the compound has the formula (V), (VI), (VII), or (XI), or a pharmaceutically acceptable salt or solvate thereof, wherein B 1 is NR 5 is.

[0272] In some embodiments, the compound has the formula (V), (VI), (VII), or (XI), or a pharmaceutically acceptable salt or solvate thereof, wherein B 1 is O.

[0273] In some embodiments, the compound has the formula (V), (VI), (VII), or (XI), or a pharmaceutically acceptable salt or solvate thereof, wherein B 1 is S.

[0274] In some embodiments, the compound has the formula (V), (VI), (VII), or (XI), or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is H.

[0275] In some embodiments, the compound has the formula (V), (VI), (VII), or (XI), or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is C1-6 alkyl, preferably CH3.

[0276] In some embodiments, the compound has the formula (V), (VI), (VII), or (XI), or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 is C1-6 alkyl, preferably CH(CH3)2.

[0277] In some embodiments, the compound has the formula of Formula (V), Formula (VI), Formula (VII), or Formula (XI), or a pharmaceutically acceptable salt or solvate thereof, and R 4 and R 5 may be substituted with 1, 2, 3, 4, or 5 independently selected R b It forms a 5- or 6-membered heterocycloalkyl ring, optionally substituted with substituents.

[0278] In some embodiments, R 4 and R 5 are, together with the atoms to which they are attached, one or two R b In some embodiments, one or two R b The substituent is C 1~4 alkyl, preferably CH. In some embodiments, R 6 is C1-6 alkyl, preferably CH3, and R 7 is C alkyl, preferably CH. In some embodiments, or R 6 and R 7together with the carbon atoms to which they are both attached form a C4-C7 spirocyclic ring. In some embodiments, the C4-C7 spirocyclic ring is a spirocyclopentane ring.

[0279] In some embodiments, the compound is

[0280] [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein A 2 is NR 8 is.

[0281] In some embodiments, the compound has the formula (VIII), (IX), (X), or (XII), or a pharmaceutically acceptable salt or solvate thereof, wherein A 2 is S.

[0282] In some embodiments, the compound has the formula (VIII), (IX), (X), or (XII), or a pharmaceutically acceptable salt or solvate thereof, wherein A 2 is O.

[0283] In some embodiments, the compound has the formula (VIII), (IX), (X), or (XII), or a pharmaceutically acceptable salt or solvate thereof, wherein B 2 is CR 9 is.

[0284] In some embodiments, the compound has the formula (VIII), (IX), (X), or (XII), or a pharmaceutically acceptable salt or solvate thereof, wherein B 2 is N.

[0285] In some embodiments, the compound has the formula (VIII), (IX), (X), or (XII), or a pharmaceutically acceptable salt or solvate thereof, wherein R 8is C1-6 alkyl, preferably CH3.

[0286] In some embodiments, the compound has the formula (VIII), (IX), (X), or (XII), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9 is C1-6 alkyl, preferably CH(CH3)2.

[0287] In some embodiments, the compound has the formula of Formula (VIII), Formula (IX), Formula (X), or Formula (XII), or a pharmaceutically acceptable salt or solvate thereof, and R 8 and R 9 may be substituted with 1, 2, 3, 4, or 5 independently selected R b It forms a 5- or 6-membered heterocycloalkyl ring, optionally substituted with substituents.

[0288] In some embodiments, the compound has the formula of Formula (VIII), Formula (IX), Formula (X), or Formula (XII), or a pharmaceutically acceptable salt or solvate thereof, and R 8 and R 9 are, together with the atoms to which they are attached, one or two R b In some embodiments, one or two R b The substituent is C 1~4 Alkyl, preferably CH3.

[0289] In some embodiments, the compound has the formula of any one of Formulas (V)-(XII) or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is H, OH, halogen, CN, C1-6 alkyl, C3- 10 It is cycloalkyl, C1-6 alkoxyl, or 4- to 14-membered heterocycloalkyl.

[0290] In some embodiments, the compound has the formula of any one of Formulas (V)-(XII) or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is H or halogen, preferably Cl or F.

[0291] In some embodiments, the compound has the formula of any one of Formulas (I)-(XII) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 teeth,

[0292] [ka] where n is 0 or 1, and R b is as defined throughout the specification. In some embodiments, R 1 R above b The substituent is NR c C(O)R c , N.R. c C(O)NR c R c , or NR c S(O)NR c R c In some embodiments, NR c C(O)R c , N.R. c C(O)NR c R c , or NR c S(O)NR c R c R in c are independently H, C 1~6 Alkyl, C 3~10 cycloalkyl, 4- to 10-membered heterocycloalkyl, or (5- to 10-membered heteroaryl)-C 1~4 alkyl and 1, 2, 3, 4, or 5 independently selected R f In some embodiments, R f The substituents are independently halogen, CN, or OR. g In other embodiments, R g are independently H or C 1~6 In another embodiment, R 1 R above bThe substituents are acetamide (-NHC(O)CH3), 3-hydroxybutanamide (-NHC(O)CH2CH(OH)CH3), propionamide (-NHC(O)CH2CH3), 2-methoxyacetamide (-NHC(O)CH2-OCH3), 2-cyanoacetamide (-NHC(O)CH2-CN), 1-hydroxycyclopropane-1-carboxamide,

[0293] [ka] 2-(thiazol-4-yl)acetamide,

[0294] [ka] Methylsulfonamide (-NSO2CH3), 3-methylureido (-NC(O)NHCH3), 3-methoxyureido (-NC(O)NHOCH3), 3,3-dimethylureido (-NC(O)N(CH3)2), or 3-ethylureido (-NC(O)NHCH2CH3), morpholine-4-carboxamide, i.e.,

[0295] [ka] or 4-methylpiperazine-1-carboxamide, i.e.,

[0296] [ka] is.

[0297] In some aspects, the present disclosure is directed to a compound of formula (IA):

[0298] [ka] During the ceremony, R1 is C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6Alkynyl, C 6~10 Aryl, C 3~10 Cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4 Alkyl, (5-14 membered heteroaryl)-C 1~4 Alkyl, and (4- to 14-membered heterocycloalkyl)-C 1~4 alkyl, where R 1 is 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R b optionally substituted with substituents, R 2 is H, hydroxyl, halogen, CN, C1-C6 alkyl, C3-C 10 cycloalkyl, C1-C6 alkoxyl, or 4- to 14-membered heterocycloalkyl, and 10 Cycloalkyl, C1-C6 alkoxyl, or 4- to 14-membered heterocycloalkyl is selected from 1, 2, 3, 4, or 5 independently selected R b It is optionally substituted with a substituent. R 3 is H, hydroxyl, halogen, CN, C1-C6 alkyl, C3-C 10 cycloalkyl, C1-C6 alkoxyl, or 4- to 14-membered heterocycloalkyl, and 10 Cycloalkyl, C1-C6 alkoxyl, or 4- to 14-membered heterocycloalkyl is selected from 1, 2, 3, 4, or 5 independently selected R b It is optionally substituted with a substituent. R 4 is H, R 5 is a C1-C6 alkyl, Or R 4 and R 5 may be substituted with 1, 2, 3, 4, or 5 independently selected R b forming a 5-, 6-, or 7-membered heterocycloalkyl ring optionally substituted with substituents; Rb is C 1~6 Alkyl, NR c C(O)R c , N.R. c C(O)NR c R c , or NR c S(O)2R c and Each R c are independently H, OH, C 1~6 Alkyl, C 1~6 Alkoxy, C 3~10 cycloalkyl, 4- to 10-membered heterocycloalkyl, or (5- to 10-membered heteroaryl)-C 1~4 alkyl and 1, 2, 3, 4, or 5 independently selected R f optionally substituted with substituents, Each R f are independently halogen, CN, C 1~4 Alkyl or OR g and Each R g are independently H or C 1~6 It is alkyl.

[0299] In some embodiments, the compound of formula (IA) is: R1 is C3-C7 cycloalkyl, and one R b is substituted with a substituent, R b is C 1~6 Alkyl, NR c C(O)R c , N.R. c C(O)NR c R c , or NR c S(O)2R c and Each R c are independently H, OH, C 1~6 Alkyl, C 1~6 Alkoxy, C 3~10 cycloalkyl, 4- to 10-membered heterocycloalkyl, or (5- to 10-membered heteroaryl)-C 1~4 alkyl and 1, 2, 3, 4, or 5 independently selected Rf optionally substituted with substituents, Each R f are independently halogen, CN, CH3, OH, or OCH3; R 2 is H, halogen, or C1-C6 alkyl, R 3 is H or a halogen, R 4 is H or C1-C6 alkyl, R 5 is a C1-C6 alkyl, Or R 4 and R 5 together with the atoms to which they are attached form a 5-, 6-, or 7-membered heterocycloalkyl ring substituted with 1 or 2 methyl groups.

[0300] In some embodiments, the compound of formula (IA) is: 1 is a C3-C7 cycloalkyl, and examples thereof include acetamide (-NHC(O)CH3), 3-hydroxybutanamide (-NHC(O)CH2CH(OH)CH3), propionamide (-NHC(O)CH2CH3), 2-methoxyacetamide (-NHC(O)CH2-OCH3), 2-cyanoacetamide (-NHC(O)CH2-CN), 1-hydroxycyclopropane-1-carboxamide,

[0301] [ka] 2-(thiazol-4-yl)acetamide,

[0302] [ka] Methylsulfonamide (-NSO2CH3), 3-methylureido (-NC(O)NHCH3), 3-methoxyureido (-NC(O)NHOCH3), 3,3-dimethylureido (-NC(O)N(CH3)2), or 3-ethylureido (-NC(O)NHCH2CH3), morpholine-4-carboxamide, i.e.,

[0303] [ka] or 4-methylpiperazine-1-carboxamide, i.e.,

[0304] [ka] is substituted with R 2 is H, Cl, or Cl3, and R 3 is F and R 4 is H and R 5 is a C1-C6 alkyl, Or R 4 and R 5 together with the atoms to which they are attached form a 5-, 6-, or 7-membered heterocycloalkyl ring substituted with 1 or 2 methyl groups.

[0305] In some embodiments, the compound of formula (IA) is: 1 is a C5-C6 cycloalkyl, and examples thereof include acetamide (-NHC(O)CH3), 3-hydroxybutanamide (-NHC(O)CH2CH(OH)CH3), propionamide (-NHC(O)CH2CH3), 2-methoxyacetamide (-NHC(O)CH2-OCH3), 2-cyanoacetamide (-NHC(O)CH2-CN), 1-hydroxycyclopropane-1-carboxamide,

[0306] [ka] 2-(thiazol-4-yl)acetamide,

[0307] [ka] Methylsulfonamide (-NSO2CH3), 3-methylureido (-NC(O)NHCH3), 3-methoxyureido (-NC(O)NHOCH3), 3,3-dimethylureido (-NC(O)N(CH3)2), or 3-ethylureido (-NC(O)NHCH2CH3), morpholine-4-carboxamide, i.e.,

[0308] [ka] or 4-methylpiperazine-1-carboxamide, i.e.,

[0309] [ka] is substituted with R 2 is H, Cl, or Cl3, and R 3 is F and R 4 is H and R 5 is isopropyl.

[0310] In some embodiments, the compound of formula (IA) is: 1 is a C5-C6 cycloalkyl, and examples thereof include acetamide (-NHC(O)CH3), 3-hydroxybutanamide (-NHC(O)CH2CH(OH)CH3), propionamide (-NHC(O)CH2CH3), 2-methoxyacetamide (-NHC(O)CH2-OCH3), 2-cyanoacetamide (-NHC(O)CH2-CN), 1-hydroxycyclopropane-1-carboxamide,

[0311] [ka] 2-(thiazol-4-yl)acetamide,

[0312] [ka] Methylsulfonamide (-NSO2CH3), 3-methylureido (-NC(O)NHCH3), 3-methoxyureido (-NC(O)NHOCH3), 3,3-dimethylureido (-NC(O)N(CH3)2), or 3-ethylureido (-NC(O)NHCH2CH3), morpholine-4-carboxamide, i.e.,

[0313] [ka] or 4-methylpiperazine-1-carboxamide, i.e.,

[0314] [ka] is substituted with R 2 is H, Cl, or Cl3, and R 3 is F and R 4 and R 5 together with the atoms to which they are attached form a 5-membered heterocycloalkyl ring substituted with one or two methyl groups.

[0315] In some aspects, the present disclosure is directed to a compound of formula (XIII):

[0316] [ka] During the ceremony, R1 is C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, C 3~10 Cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4 Alkyl, (5-14 membered heteroaryl)-C 1~4 Alkyl, and (4- to 14-membered heterocycloalkyl)-C 1~4alkyl, where R 1 is 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R b optionally substituted with substituents, R 2 is H, hydroxyl, halogen, CN, C1-C6 alkyl, C3-C 10 cycloalkyl, C1-C6 alkoxyl, or 4- to 14-membered heterocycloalkyl, and 10 Cycloalkyl, C1-C6 alkoxyl, or 4- to 14-membered heterocycloalkyl is selected from 1, 2, 3, 4, or 5 independently selected R b It is optionally substituted with a substituent. R 3 is H, hydroxyl, halogen, CN, C1-C6 alkyl, C3-C 10 cycloalkyl, C1-C6 alkoxyl, or 4- to 14-membered heterocycloalkyl, and 10 Cycloalkyl, C1-C6 alkoxyl, or 4- to 14-membered heterocycloalkyl is selected from 1, 2, 3, 4, or 5 independently selected R b optionally substituted with substituents, R b is C 1~6 Alkyl, NR c C(O)R c , N.R. c C(O)NR c R c , or NR c S(O)2R c and Each R c are independently H, OH, C 1~6 Alkyl, C 1~6 Alkoxy, C 3~10 cycloalkyl, 4- to 10-membered heterocycloalkyl, or (5- to 10-membered heteroaryl)-C 1~4 alkyl and 1, 2, 3, 4, or 5 independently selected R f optionally substituted with substituents, Each R f are independently halogen, CN, C 1~4 Alkyl or OR gand Each R g are independently H or C 1~6 It is alkyl.

[0317] In some embodiments, the compound of formula (XIII) is: b is substituted with a substituent, R b is C 1~6 Alkyl, NR c C(O)R c , N.R. c C(O)NR c R c , or NR c S(O)2R c and Each R c are independently H, OH, C 1~6 Alkyl, C 1~6 Alkoxy, C 3~10 cycloalkyl, 4- to 10-membered heterocycloalkyl, or (5- to 10-membered heteroaryl)-C 1~4 alkyl and 1, 2, 3, 4, or 5 independently selected R f optionally substituted with substituents, Each R f are independently halogen, CN, CH3, OH, or OCH3; R 2 is H, halogen, or C1-C6 alkyl, and R 3 is H or a halogen.

[0318] In some embodiments, the compound of formula (XIII) is: 1 is a C5-C6 cycloalkyl, and examples thereof include acetamide (-NHC(O)CH3), 3-hydroxybutanamide (-NHC(O)CH2CH(OH)CH3), propionamide (-NHC(O)CH2CH3), 2-methoxyacetamide (-NHC(O)CH2-OCH3), 2-cyanoacetamide (-NHC(O)CH2-CN), 1-hydroxycyclopropane-1-carboxamide,

[0319] [ka] 2-(thiazol-4-yl)acetamide,

[0320] [ka] Methylsulfonamide (-NSO2CH3), 3-methylureido (-NC(O)NHCH3), 3-methoxyureido (-NC(O)NHOCH3), 3,3-dimethylureido (-NC(O)N(CH3)2), or 3-ethylureido (-NC(O)NHCH2CH3), morpholine-4-carboxamide, i.e.,

[0321] [ka] or 4-methylpiperazine-1-carboxamide, i.e.,

[0322] [ka] is substituted with R 2 is H, Cl, or Cl3, and R 3 is F.

[0323] In some aspects, the present disclosure is directed to a compound of formula (II-A):

[0324] [ka] During the ceremony, R1 is C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, C 3~10 Cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C1~4 Alkyl, (5-14 membered heteroaryl)-C 1~4 Alkyl, and (4- to 14-membered heterocycloalkyl)-C 1~4 alkyl, where R 1 is 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R b optionally substituted with substituents, R 2 is H, hydroxyl, halogen, CN, C1-C6 alkyl, C3-C 10 cycloalkyl, C1-C6 alkoxyl, or 4- to 14-membered heterocycloalkyl, and 10 Cycloalkyl, C1-C6 alkoxyl, or 4- to 14-membered heterocycloalkyl is selected from 1, 2, 3, 4, or 5 independently selected R b It is optionally substituted with a substituent. R 3 is H, hydroxyl, halogen, CN, C1-C6 alkyl, C3-C 10 cycloalkyl, C1-C6 alkoxyl, or 4- to 14-membered heterocycloalkyl, and 10 Cycloalkyl, C1-C6 alkoxyl, or 4- to 14-membered heterocycloalkyl is selected from 1, 2, 3, 4, or 5 independently selected R b optionally substituted with substituents, R b is C 1~6 Alkyl, NR c C(O)R c , N.R. c C(O)NR c R c , or NR c S(O)2R c and Each R c are independently H, OH, C 1~6 Alkyl, C 1~6 Alkoxy, C 3~10 cycloalkyl, 4- to 10-membered heterocycloalkyl, or (5- to 10-membered heteroaryl)-C 1~4 alkyl and 1, 2, 3, 4, or 5 independently selected R foptionally substituted with substituents, Each R f are independently halogen, CN, C 1~4 Alkyl or OR g and Each R g are independently H or C 1~6 It is alkyl. R 8 is a C1-C6 alkyl, R 9 is a C1-C6 alkyl, Or R 8 and R 9 together with the atoms to which they are attached form a 5-, 6-, or 7-membered heterocycloalkyl ring optionally substituted with one or two methyl groups.

[0325] In some embodiments, the compound of formula (II-A) is: b is substituted with a substituent, R b is C 1~6 Alkyl, NR c C(O)R c , N.R. c C(O)NR c R c , or NR c S(O)2R c and Each R c are independently H, OH, C 1~6 Alkyl, C 1~6 Alkoxy, C 3~10 cycloalkyl, 4- to 10-membered heterocycloalkyl, or (5- to 10-membered heteroaryl)-C 1~4 alkyl and 1, 2, 3, 4, or 5 independently selected R f optionally substituted with substituents, Each R f are independently halogen, CN, CH3, OH, or OCH3; R 2 is H, halogen, or C1-C6 alkyl, R 3is H or a halogen, R 8 is a C1-C6 alkyl, R 9 is a C1-C6 alkyl, Or R 8 and R 9 together with the atoms to which they are attached form a 5-, 6-, or 7-membered heterocycloalkyl ring substituted with 1 or 2 methyl groups.

[0326] In some embodiments, the compound of formula (II-A) is: R 1 is a C5-C6 cycloalkyl, and examples thereof include acetamide (-NHC(O)CH3), 3-hydroxybutanamide (-NHC(O)CH2CH(OH)CH3), propionamide (-NHC(O)CH2CH3), 2-methoxyacetamide (-NHC(O)CH2-OCH3), 2-cyanoacetamide (-NHC(O)CH2-CN), 1-hydroxycyclopropane-1-carboxamide,

[0327] [ka] 2-(thiazol-4-yl)acetamide,

[0328] [ka] Methylsulfonamide (-NSO2CH3), 3-methylureido (-NC(O)NHCH3), 3-methoxyureido (-NC(O)NHOCH3), 3,3-dimethylureido (-NC(O)N(CH3)2), or 3-ethylureido (-NC(O)NHCH2CH3), morpholine-4-carboxamide, i.e.,

[0329] [ka] or 4-methylpiperazine-1-carboxamide, i.e.,

[0330] [ka] is replaced by R 2 is H, Cl, or Cl3, R 3 is H or F, R 8 is Cl3, R 9 is isopropyl (i.e., Cl(CH3)2).

[0331] In other embodiments, the compound of formula (II-A) is: R 1 is a C5-C6 cycloalkyl, and examples thereof include acetamide (-NHC(O)CH3), 3-hydroxybutanamide (-NHC(O)CH2CH(OH)CH3), propionamide (-NHC(O)CH2CH3), 2-methoxyacetamide (-NHC(O)CH2-OCH3), 2-cyanoacetamide (-NHC(O)CH2-CN), 1-hydroxycyclopropane-1-carboxamide,

[0332] [ka] 2-(thiazol-4-yl)acetamide,

[0333] [ka] Methylsulfonamide (-NSO2CH3), 3-methylureido (-NC(O)NHCH3), 3-methoxyureido (-NC(O)NHOCH3), 3,3-dimethylureido (-NC(O)N(CH3)2), or 3-ethylureido (-NC(O)NHCH2CH3), morpholine-4-carboxamide, i.e.,

[0334] [ka] or 4-methylpiperazine-1-carboxamide, i.e.,

[0335] [ka] is replaced by R 2 is H, Cl, or Cl3, R 3 is H or F, R 8 and R 9 together with the atoms to which they are attached form a 5-membered heterocycloalkyl ring substituted with one or two methyl groups.

[0336] In some embodiments, the present disclosure provides:

[0337] [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein the variables are as defined herein, and wherein the compounds are provided having the formula: b When there is a b are independent of each other.

[0338] In some embodiments, the present disclosure provides:

[0339] [ka]

[0340] [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein the variables are as defined herein, and wherein the compounds are provided having the formula: b When there is a b are independent of each other. In some embodiments, R 2 is not halo. In some embodiments, R 2 is an arbitrarily substituted C 1~6In some embodiments, R 2 is an arbitrarily substituted C 1~4 In some embodiments, R 2 is an arbitrarily substituted C 1~3 In some embodiments, R 2 is an arbitrarily substituted C 1~3 In some embodiments, R 5 is optionally C 1~6 In some embodiments, R 5 is an arbitrarily substituted C 1~4 In some embodiments, R 5 is an arbitrarily substituted C 1~3 In some embodiments, optionally substituted C 1~6 Alkyl, optionally substituted C 1~4 Alkyl or optionally substituted C 1~3 Alkyl is a group consisting of two R b In some embodiments, an optionally substituted C 1~6 Alkyl, optionally substituted C 1~4 Alkyl or optionally substituted C 1~3 Alkyl is one R b In some embodiments, R b is not a carbocycle, heterocycle, or aryl. In some embodiments, R 2 is Me or OMe. In some embodiments, R 3 is H, D, or F. In some embodiments, R 4 is H or C alkyl. In some embodiments, R 5 is isopropyl, —CF3(CH)CH3, —C3-6 cycloalkyl, or —CH2—(C3-6 cycloalkyl). In some embodiments, R b NHCOR 13 or CN. In some embodiments, R 13 is H or optionally substituted C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6Alkynyl, C 6~10 Aryl, C 3~10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4 Alkyl, (5-10 membered heteroaryl)-C 1~4 Alkyl- or (4- to 10-membered heterocycloalkyl)-C 1~4 It is alkyl.

[0341] In some embodiments, the present disclosure provides:

[0342] [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0343] In some embodiments, the present disclosure provides:

[0344] [ka]

[0345] [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein the variables are as defined herein. In some embodiments, R 2 is H, D, halogen, or Me. In some embodiments, R 3 is H, D, or F. In some embodiments, R 10 is H, D, Me, or C haloalkyl. In some embodiments, R 11 is H, D, Me, or C haloalkyl. In some embodiments, R b NHCOR 14 In some embodiments, R 14is H, -CHCN, or an optionally substituted C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, C 3~10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4 Alkyl, (5-10 membered heteroaryl)-C 1~4 Alkyl- or (4- to 10-membered heterocycloalkyl)-C 1~4 It is alkyl.

[0346] In some embodiments, the present disclosure provides:

[0347] [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0348] In some embodiments, the compound is

[0349] [ka]

[0350] [ka]

[0351] [ka]

[0352] [ka]

[0353] [ka]

[0354] [ka]

[0355] [ka]

[0356] [ka]

[0357] [ka] It has the formula:

[0358] In some embodiments, the present disclosure provides: (1S,3R)-3-acetamido-N-[5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-indazol-5-yl)-2-pyridyl]cyclohexanecarboxamide, (1S,3R)-N-[5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-indazol-5-yl)-2-pyridyl]-3-[(1-hydroxycyclopropanecarbonyl)amino]-cyclohexanecarboxamide, (1S,3R)—N-(5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)-3-(2-(thiazol-4-yl)acetamide)cyclohexane-1-carboxamide, (1S,3R)—N-(5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)-3-(2-methoxyacetamido)cyclohexane-1-carboxamide, (1S,3R)—N-(5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)-3-propionamido-cyclohexane-1-carboxamide, (1S,3R)-N-[5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-indazol-5-yl)-2-pyridyl]-3-(methanesulfonamido)cyclohexanecarboxamide, N-[(1R,3S)-3-[[5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-indazol-5-yl)-2-pyridyl]carbamoyl]cyclohexyl]morpholine-4-carboxamide, N-((1R,3S)-3-((5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)carbamoyl)-cyclohexyl)-4-methylpiperazine-1-carboxamide, (1S,3R)—N-(5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)-3-(3-methylureido)cyclohexane-1-carboxamide, (1S,3R)—N-(5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)-3-(3,3-dimethylureido)cyclohexane-1-carboxamide, (1S,3R)—N-(5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)-3-(3-ethylureido)cyclohexane-1-carboxamide, (1S,3R)—N-(5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)-3-(3-methoxyureido)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-[5-chloro-4-(5-fluoro-1,1-dimethyl-2,3-dihydropyrrolo[1,2-a]benzimidazol-7-yl)-2-pyridyl]cyclohexanecarboxamide, (1S,3R)—N-(5-chloro-4-(5-fluoro-1,1-dimethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyridin-2-yl)-3-(2-cyanoacetamido)cyclohexane-1-carboxamide, (1S,3R)—N-(5-chloro-4-(5-fluoro-1,1-dimethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyridin-2-yl)-3-(3-hydroxybutanamido)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(5-chloro-4-(1,1-dimethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyridin-2-yl)cyclopentane-1-carboxamide, (1S,3R)—N-(5-chloro-4-(5-fluoro-1,1-dimethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyridin-2-yl)-3-propionamidocyclohexane-1-carboxamide, (1S,3R)—N-(5-chloro-4-(1,1-dimethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyridin-2-yl)-3-propionamidocyclopentane-1-carboxamide, (1S,3R)—N-(5-chloro-4-(5-fluoro-1,1-dimethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyridin-2-yl)-3-(1-hydroxycyclopropane-1-carboxamido)cyclohexane-1-carboxamide, (1S,3R)—N-(5-chloro-4-(5-fluoro-1,1-dimethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyridin-2-yl)-3-(2-methoxyacetamido)cyclohexane-1-carboxamide, (1S,3R)—N-(5-chloro-4-(5-fluoro-1,1-dimethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyridin-2-yl)-3-(methylsulfonamido)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(4-(5-fluoro-1,1-dimethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)-5-methylpyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)cyclopentane-1-carboxamide, (1S,3R)-3-acetamido-N-(5-chloro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl)pyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(5-chloro-4-(3-isopropylbenzo[c]isothiazol-5-yl)pyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(5-chloro-4-(1-methyl-2,3-dihydro-1H-pyrrolo[1,2-b]indazol-8-yl)pyridin-2-yl)cyclohexane-1-carboxamide (1S,3R)-3-(3,3-dimethylureido)-N-(4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)—N-(4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)-3-propionamidocyclohexane-1-carboxamide, (1S,3R)—N-(4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)-3-isobutyramidocyclohexane-1-carboxamide, (1S,3R)—N-(4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)-3-(2-methoxyacetamido)cyclohexane-1-carboxamide, (1S,3R)-3-(2-(dimethylamino)acetamido)-N-(4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)cyclohexane-1-carboxamide, methyl((1R,3S)-3-((4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)carbamoyl)cyclohexyl)carbamate, (1S,3R)—N-(4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)-3-(methylsulfonamido)cyclohexane-1-carboxamide, (1S,3R)—N-(4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)-3-(1-fluorocyclopropane-1-carboxamido)cyclohexane-1-carboxamide, (1S,3R)—N-(4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)-3-(1-hydroxycyclopropane-1-carboxamido)cyclohexane-1-carboxamide, N-((1R,3S)-3-((4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)carbamoyl)cyclohexyl)-1-methylazetidine-3-carboxamide, (1S,3R)-N-(4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)-3-((1r,3R)-3-hydroxycyclobutane-1-carboxamido)cyclohexane-1-carboxamide, (1S,3R)—N-(4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)-3-(2-hydroxyacetamido)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(4-(4-fluoro-1-(oxetan-3-yl)-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(4-(1-cyclopropyl-4-fluoro-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(4-(1-(cyclopropylmethyl)-4-fluoro-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)cyclohexane-1-carboxamide, (S)—N-((1R,3S)-3-((4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)carbamoyl)cyclohexyl)-3-hydroxypyrrolidine-1-carboxamide, (1S,3R)—N-(4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)-3-(3-methylureido)cyclohexane-1-carboxamide, N-((1R,3S)-3-((4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)carbamoyl)cyclohexyl)morpholine-4-carboxamide, N-((1R,3S)-3-((4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)carbamoyl)cyclohexyl)-4-methylpiperazine-1-carboxamide, (1S,3R)—N-[4-(7-fluoro-3-isopropyl-benzimidazol-5-yl)-5-methyl-2-pyridyl]-3-[(methylsulfonimidoyl)amino]cyclohexanecarboxamide, (1S,3R)-N1-(4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)-N3-methylcyclohexane-1,3-dicarboxamide, 3-cyano-N-(4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-(3,3-dimethylureido)-N-(4-(4-fluoro-1-(1,1,1-trifluoropropan-2-yl)-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(5-chloro-4-(1,1-dimethyl-2,3-dihydro-1H-pyrrolo[1,2-b]indazol-8-yl)pyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(5-chloro-4-(7-fluoro-3-(1-hydroxypropan-2-yl)-2-methyl-2H-indazol-5-yl)pyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(5-chloro-4-(7-fluoro-3-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-5-yl)pyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(5-chloro-4-(3-cyclopropyl-7-fluoro-2-methyl-2H-indazol-5-yl)pyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(5-chloro-4-(3-isopropyl-2-methyl-2H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)-5-methylpyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)—N-(5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)-3-(1-fluorocyclopropane-1-carboxamido)cyclohexane-1-carboxamide, N-((1R,3S)-3-((5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)carbamoyl)cyclohexyl)-2-methoxynicotinamide, N-((1R,3S)-3-((5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)carbamoyl)cyclohexyl)-5-methylisoxazole-3-carboxamide, N-((1R,3S)-3-((5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)carbamoyl)cyclohexyl)-6-methylnicotinamide, (1S,3R)—N-(4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)-5-methylpyridin-2-yl)-3-(2-methoxyacetamido)cyclohexane-1-carboxamide, (1S,3R)—N-(4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)-5-methylpyridin-2-yl)-3-(2-methoxyacetamido)cyclohexane-1-carboxamide, N-((1R,3S)-3-((4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)-5-methylpyridin-2-yl)carbamoyl)cyclohexyl)-5-methylisoxazole-3-carboxamide, N-((1R,3S)-3-((4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)-5-methylpyridin-2-yl)carbamoyl)cyclohexyl)-2-methoxynicotinamide, (1S,3R)—N-(5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)-3-(2-cyanoacetamido)cyclohexane-1-carboxamide, (1S,3R)-3-(2-cyanoacetamido)-N-(4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)-5-methylpyridin-2-yl)cyclohexane-1-carboxamide, N-((1R,3S)-3-((4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)-5-methylpyridin-2-yl)carbamoyl)cyclohexyl)morpholine-4-carboxamide, (1S,3R)-3-(3-ethylureido)-N-(4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)cyclohexane-1-carboxamide, N-((1R,3S)-3-((4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)carbamoyl)cyclohexyl)azetidine-1-carboxamide, methyl ((1R,3S)-3-((5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate, tetrahydro-2H-pyran-4-yl((1R,3S)-3-((5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate, (1-methyl-1H-pyrazol-3-yl)methyl ((1R,3S)-3-((5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate, (2,2-difluorocyclopropyl)methyl((1R,3S)-3-((5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate, (1S,3R)-3-acetamido-N-(5-chloro-4-(7-fluoro-2-methyl-3-(1,1,1-trifluoro-2-hydroxypropan-2-yl)-2H-indazol-5-yl)pyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(5-chloro-4-(3-(1,1-difluoro-2-hydroxypropan-2-yl)-7-fluoro-2-methyl-2H-indazol-5-yl)pyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-(2-cyanoacetamido)-N-(4-(7-fluoro-2-methyl-3-(1,1,1-trifluoro-2-hydroxypropan-2-yl)-2H-indazol-5-yl)-5-methylpyridin-2-yl)cyclohexane-1-carboxamide (P1), (1S,3R)-3-(2-cyanoacetamido)-N-(4-(7-fluoro-2-methyl-3-(1,1,1-trifluoro-2-hydroxypropan-2-yl)-2H-indazol-5-yl)-5-methylpyridin-2-yl)cyclohexane-1-carboxamide (P2), (1S,3R)-3-acetamido-N-(5-chloro-4-(7-fluoro-2-methyl-3-(1,1,1-trifluoro-2-hydroxypropan-2-yl)-2H-indazol-5-yl)pyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(5-chloro-4-(3-(1,1-difluoro-2-hydroxypropan-2-yl)-7-fluoro-2-methyl-2H-indazol-5-yl)pyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)—N-(5-chloro-4-(3-(1,1-difluoro-2-hydroxypropan-2-yl)-7-fluoro-2-methyl-2H-indazol-5-yl)pyridin-2-yl)-3-(2-cyanoacetamido)cyclohexane-1-carboxamide, (1S,3R)-3-(2-cyanoacetamido)-N-(4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methoxypyridin-2-yl)cyclohexane-1-carboxamide, N-((1R,3S)-3-((5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)carbamoyl)cyclohexyl)bicyclo[1.1.1]pentane-1-carboxamide, (1S,3R)-3-acetamido-N-(5-chloro-4-(4-fluoro-1-isopropyl-1H-benzo[d][1,2,3]triazol-6-yl)pyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(5-chloro-4-(3-isopropyl-3H-imidazo[4,5-b]pyridin-5-yl)pyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)—N-(5-chloro-4-(9-fluoro-4,4-dimethyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyridin-2-yl)-3-(2-cyanoacetamido)cyclohexane-1-carboxamide, (1S,3R)-3-(2-cyanoacetamido)-N-(4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)-5-methylpyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(5-chloro-4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyridin-2-yl)cyclohexane-1-carboxamide, The present invention relates to a compound selected from the group consisting of (1S,3R)-3-acetamido-N-(4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyridin-2-yl)cyclohexane-1-carboxamide, and pharmaceutically acceptable salts thereof.

[0359] It will be apparent that the compounds provided herein, including all subgenera described herein, may have multiple stereocenters. As a result, multiple stereoisomers (enantiomers and diastereoisomers) exist of the compounds of the various formulas provided herein (subgenera provided herein). The present disclosure contemplates and encompasses each stereoisomer of any compound of any formula provided herein (and subgenera provided herein), as well as mixtures of such stereoisomers. All enantiomers, diastereomers, and mixtures thereof are included within the scope of the compounds described herein.

[0360] Pharmaceutically acceptable salts and solvates of the compounds of any formula provided herein (including all subgenera provided herein) are also within the scope of this disclosure. Isotopic variations of the compounds of any formula provided herein (including all subgenera provided herein) are also contemplated by this disclosure.

[0361] Pharmaceutical compositions and methods of administration The subject pharmaceutical compositions are typically formulated to provide a therapeutically effective amount of the disclosed compound as the active ingredient, or to provide a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof. If desired, the pharmaceutical composition contains a pharmaceutically acceptable salt and / or coordination compound thereof, as well as one or more pharmaceutically acceptable excipients, carriers including inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers, and adjuvants.

[0362] The subject pharmaceutical composition can be administered alone or in combination with one or more other drugs, and is also typically administered in the form of a pharmaceutical composition. If desired, one or more compounds and other drugs can be mixed into a preparation, or both components can be formulated into separate preparations and used in combination, separately, or simultaneously.

[0363] In some embodiments, the concentration of one or more compounds provided in the pharmaceutical composition is 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.0%, by weight (w / w), weight / volume (w / v), or volume (v / v). 8%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% (or the number in a range defined by any two of the above numbers, and ranges inclusive).

[0364] In some embodiments, the concentration of one or more compounds is 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25%, 18%, 17.75%, 17.50%, 17.25%, 17%, 16.75%, 16.50%, 16.25%, 16%, 15.75%, 15.50% by weight (w / w), weight / volume (w / v), or volume (v / v). %,15.25%,15%,14.75%,14.50%,14.25%,14%,13.75%,13.50%,13.25%,13%,12.75%,12.50%,12.25%,12%,11.75%,11.50%,11.25%,11%,10.75%,10.50%,10.25%,10%,9.75%,9.50%,9.25%,9%,8.75%,8.50%,8.25%,8%,7.75%,7.50%,7.25%,7%,6. 75%, 6.50%, 6.25%, 6%, 5.75%, 5.50%, 5.25%, 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 1.25%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04 %, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% (or the number in a range defined by any two of the above numbers, and inclusive).

[0365] In some embodiments, the concentration of the one or more compounds is about 0.0001% to about 50%, about 0.001% to about 40%, about 0.01% to about 30%, about 0.02%, about 29%, about 0.03% to about 28%, about 0.04% to about 27%, about 0.05% to about 26%, about 0.06% to about 25%, about 0.07% to about 24%, about 0.08% to about 23%, about 0.09% to about 22%, about 0.1% to about 21%, about 0.2% to about 20%, about 0.3% to about 19%, about 0.4% to about 18%, about 0.5% to about 17%, about 0.6% to about 16%, about 0.7% to about 15%, about 0.8% to about 14%, about 0.9% to about 12%, and about 1% to about 10%.

[0366] In some embodiments, the concentration of one or more compounds ranges from about 0.001% to about 10%, about 0.01% to about 5%, about 0.02% to about 4.5%, about 0.03% to about 4%, about 0.04% to about 3.5%, about 0.05% to about 3%, about 0.06% to about 2.5%, about 0.07% to about 2%, about 0.08% to about 1.5%, about 0.09% to about 1%, or about 0.1% to about 0.9% by weight (w / w), weight / volume (w / v), or volume (v / v).

[0367] In some embodiments, the amount of one or more compounds is 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, or 10 g. g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g (or the number of a range defined by any two numbers above, and inclusive).

[0368] In some embodiments, the amount of one or more compounds is 0.0001g, 0.0002g, 0.0003g, 0.0004g, 0.0005g, 0.0006g, 0.0007g, 0.0008g, 0.0009g, 0.001g, 0.0015g, 0.002g, 0.0025g, 0.003g, 0.0035g, 0.0040g, 0.004 ... .004g, 0.0045g, 0.005g, 0.0055g, 0.006g, 0.0065g, 0.007g, 0.0075g, 0.008g, 0.008 5g, 0.009g, 0.0095g, 0.01g, 0.015g, 0.02g, 0.025g, 0.03g, 0.035g, 0.04g, 0.045g, 0. 05g, 0.055g, 0.06g, 0.065g, 0.07g, 0.075g, 0.08g, 0.085g, 0.09g, 0.095g, 0.1g, 0.1 5g, 0.2g, 0.25g, 0.3g, 0.35g, 0.4g, 0.45g, 0.5g, 0.55g, 0.6g, 0.65g, 0.7g, 0.75g, 0.8 g, 0.85 g, 0.9 g, 0.95 g, 1 g, 1.5 g, 2 g, 2.5 g, 3 g, 3.5 g, 4 g, 4.5 g, 5 g, 5.5 g, 6 g, 6.5 g, 7 g, 7.5 g, 8 g, 8.5 g, 9 g, 9.5 g, or 10 g (or the number in a range defined by any two of the above numbers, and inclusive).

[0369] In some embodiments, the amount of one or more compounds ranges from 0.0001 to 10 g, 0.0005 to 9 g, 0.001 to 8 g, 0.005 to 7 g, 0.01 to 6 g, 0.05 to 5 g, 0.1 to 4 g, 0.5 to 4 g, or 1 to 3 g.

[0370] In some embodiments, pharmaceutical compositions comprising the R enantiomer are free or substantially free of the S enantiomer.

[0371] In some embodiments, pharmaceutical compositions comprising the S enantiomer are free or substantially free of the R enantiomer.

[0372] In some embodiments, the pharmaceutical compositions comprise a particular enantiomer of a compound provided herein, such as the R or S enantiomer, in at least or about 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% enantiomeric excess. In some embodiments, the enantiomeric excess is at least or about 90%. In some embodiments, the enantiomeric excess is at least or about 95%. In some embodiments, the enantiomeric excess is at least or about 98%. In some embodiments, the enantiomeric excess is at least or about 99%.

[0373] The compounds may be effective over a wide dosage range. For example, in the treatment of adult humans, dosages of 0.01 to 1000 mg, 0.5 to 100 mg, 1 to 50 mg / day, and 5 to 40 mg / day are examples of dosages that may be used. An exemplary dosage is 10 to 30 mg / day. The exact dosage will depend on the route of administration, the form in which the compound is administered, the subject being treated, the body weight of the subject being treated, and the preference and experience of the attending physician.

[0374] Pharmaceutical compositions may contain an active ingredient provided herein (i.e., a compound of the present disclosure), or a pharmaceutically acceptable salt and / or coordination compound thereof, as well as one or more pharmaceutically acceptable excipients, carriers including, but not limited to, inert solid diluents and fillers, diluents, sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers, and adjuvants.

[0375] Below are described non-limiting exemplary pharmaceutical compositions and methods for their preparation.

[0376] A pharmaceutical composition for oral administration. In some embodiments, provided are pharmaceutical compositions for oral administration containing a compound provided herein and a pharmaceutical excipient suitable for oral administration.

[0377] In some embodiments, embodiments provide a solid pharmaceutical composition for oral administration containing (i) an amount (e.g., an effective amount) of a compound, optionally (ii) an amount of a second pharmaceutical agent, and (iii) a pharmaceutical excipient suitable for oral administration. In some embodiments, the composition further contains (iv) an amount of a third pharmaceutical agent.

[0378] In some embodiments, the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral ingestion. Pharmaceutical compositions suitable for oral administration may be in the form of discrete dosage forms such as capsules, cachets, or tablets, or may be in the form of a liquid or aerosol spray containing a predetermined amount of the active ingredient as a powder or granules, in solution, or as a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion, respectively. Such dosage forms may be prepared by any of the methods of a pharmacist, but all methods include the step of combining the active ingredient with a carrier, which constitutes one or more necessary ingredients. Generally, the compositions are prepared by uniformly and intimately admixing the active ingredient with a liquid carrier or finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired form. For example, tablets may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with excipients, such as, but not limited to, binders, lubricants, inert diluents, and / or surface-active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0379] The embodiments provided herein further encompass anhydrous pharmaceutical compositions and dosage forms containing active ingredients, as water can accelerate the degradation of some compounds. Water (e.g., 5%) may be added in the pharmaceutical arts as a means of simulating long-term storage to determine properties such as shelf life or the stability of a formulation over time. Anhydrous pharmaceutical compositions and dosage forms may be prepared using anhydrous or low-moisture-containing ingredients and low-moisture or low-humidity conditions. Pharmaceutical compositions and dosage forms containing lactose may be rendered anhydrous if they are expected to be in substantial contact with moisture and / or humidity during manufacturing, packaging, and / or storage. Anhydrous pharmaceutical compositions may be prepared and stored to maintain their anhydrous nature. Thus, anhydrous compositions may be packaged using materials known to prevent exposure to water, such that they may be included in suitable formulation kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit-dose containers, blister packs, and strip packs.

[0380] The active ingredient can be combined in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. Carriers can take a variety of forms, depending on the form of preparation desired for administration. When preparing compositions for oral administration, any of the usual pharmaceutical media, such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, etc., can be used as carriers for oral liquid preparations (such as suspensions, solutions, elixirs, etc.) or aerosols; or carriers such as starch, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents can be used in some embodiments without the use of lactose for oral solid preparations. For example, suitable carriers include powders, capsules, and tablets for solid oral preparations. If desired, tablets can be coated by standard aqueous or nonaqueous techniques.

[0381] Suitable binders for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose), polyvinylpyrrolidone, methylcellulose, pregelatinized starch, hydroxypropyl methylcellulose, microcrystalline cellulose, and mixtures thereof.

[0382] Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrose, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.

[0383] Disintegrants may be used in the compositions provided herein to provide tablets that disintegrate when exposed to an aqueous environment. If too much disintegrant is used, the provided tablets may disintegrate in the container. If too little disintegrant is used, disintegration may be insufficient, and thus the release rate and extent of the active ingredient(s) from the dosage form may vary. Therefore, to form a dosage form of a compound disclosed herein, a sufficient amount of disintegrant, neither too much nor too little, may be used so as not to adversely alter the release of the active ingredient(s). The amount of disintegrant used may vary based on the type of formulation and mode of administration and may be readily discernible to one of skill in the art. About 0.5 to about 15% by weight of disintegrant, or about 1 to about 5% by weight of disintegrant, may be used in the pharmaceutical composition. Disintegrants that can be used to form pharmaceutical compositions and dosage forms include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato starch or tapioca starch, other starches, pregelatinized starch, other starches, clays, other algins, other celluloses, gums, or mixtures thereof.

[0384] Lubricants that can be used to form pharmaceutical compositions and dosage forms include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureth, agar, or mixtures thereof. Additional lubricants include, for example, syloid silica gel, coagulated aerosol of synthetic silica, or mixtures thereof. Lubricants can optionally be added in an amount of less than about 1% by weight of the pharmaceutical composition.

[0385] When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredient therein may be combined with various sweetening or flavoring agents, coloring substances or dyes, and, if desired, the drug may be emulsified and / or precipitated with such diluents as water, ethanol, propylene glycol, glycerin, and various combinations thereof.

[0386] Tablets may be uncoated or may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect over a longer period of time. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate may be used. Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil.

[0387] Surfactants that can be used to form pharmaceutical compositions and dosage forms include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof, i.e., a mixture of hydrophilic surfactants can be used, a mixture of lipophilic surfactants can be used, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant can be used.

[0388] Suitable hydrophilic surfactants may generally have an HLB value of at least 10, while suitable lipophilic surfactants may generally have an HLB value of about 10 or less. An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of nonionic amphiphilic compounds is the hydrophilic-lipophilic balance ("HLB" value). Surfactants with lower HLB values ​​are more lipophilic or hydrophobic and have higher solubility in oil, while surfactants with higher HLB values ​​are more hydrophilic and have higher solubility in aqueous solutions.

[0389] Hydrophilic surfactants are generally considered to be compounds with an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable. Similarly, lipophilic (i.e., hydrophobic) surfactants are compounds with an HLB value of about 10 or less. However, the HLB value of a surfactant is a rough guideline commonly used to enable the formulation of industrial, pharmaceutical, and cosmetic emulsions.

[0390] The hydrophilic surfactant may be either ionic or nonionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts, fusidate salts, fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; lecithin and hydrogenated lecithin; lysolecithin and hydrogenated lysolecithin; phospholipids and their derivatives; lysophospholipids and their derivatives; carnitine fatty acid ester salts; alkyl sulfate salts; fatty acid salts; docusate sodium; acyl lactates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citrate esters of mono- and di-glycerides; and mixtures thereof.

[0391] Within the above group, examples of ionic surfactants include lecithin, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkyl sulfates; fatty acid salts; sodium docusate; acyl lactates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citrate esters of mono- and di-glycerides; and mixtures thereof.

[0392] Ionic surfactants include ionized forms of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactic acid esters of fatty acids, stearoyl-2-lactate, stearic acid ... The fatty acid esters may be selected from the group consisting of glyceryl stearate, ...

[0393] Hydrophilic nonionic surfactants may include, but are not limited to, alkyl glucosides; alkyl maltosides; alkyl thioglucosides; lauryl macrogol glycerides; polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethylene glycol alkylphenols; polyoxyalkylene alkylphenol fatty acid esters such as polyethylene glycol fatty acid monoesters and polyethylene glycol fatty acid diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of polyols having at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene sterols, derivatives, and analogs thereof; polyoxyethylated vitamins and derivatives thereof; polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; hydrophilic transesterification products of polyethylene glycol sorbitan fatty acid esters and polyols having at least one member of the group consisting of triglycerides, vegetable oils, and hydrogenated vegetable oils. The polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a sugar.

[0394] Other hydrophilic nonionic surfactants include, but are not limited to, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearic acid, PEG-32 distearate, PEG-40 stearic acid, PEG-100 stearic acid, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, P EG-40 Palm Kernel Oil, PEG-50 Hydrogenated Castor Oil, PEG-40 Castor Oil, PEG-35 Castor Oil, PEG-60 Castor Oil, PEG-40 Hydrogenated Castor Oil, PEG-60 Hydrogenated Castor Oil, PEG-60 Corn Oil, PEG-6 Capric / Caprylic Glycerides, PEG-8 Caprylic / Capric Glycerides, Polyglyceryl-10 Laurate, PEG-30 Cholesterol, PEG-25 Phytosterols, PEG-30 Soy Sterols, PE G-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, polyglyceryl-10 oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonylphenol, PEG 15-100 octylphenol, and poloxamer.

[0395] Suitable lipophilic surfactants include, by way of example only, fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acid esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- and diglycerides; glycerides, vegetable oils, hydrogenated vegetable oils, the hydrophobic transesterification product of polyols that have at least one member of the group consisting of fatty acids and sterols; oil-soluble vitamins / vitamin derivatives; and mixtures thereof.In this group, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or the hydrophobic transesterification product of polyols that have at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides.

[0396] In some embodiments, the composition may include a solubilizing agent to ensure good solubilization and / or dissolution of the compound and minimize precipitation of the compound. For example, this may be used in compositions for parenteral use, such as injectable compositions. Solubilizing agents may also be added to increase the solubility of other components, such as hydrophilic drugs and / or surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion.

[0397] Examples of suitable solubilizers include the following alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediol and their isomers, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrin and cyclodextrin derivatives; ethers of polyethylene glycol having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG; 2-pyrrolidone, 2-piperidone, ε-caprolactam, N-alkylpyrrolidone, N amides and other nitrogen-containing compounds such as hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide, and polyvinylpyrrolidone; esters such as ethyl propionate, tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, triethyl citrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and its isomers, δ-valerolactone and its isomers, β-butyrolactone and its isomers; and other solubilizing agents such as dimethylacetamide, dimethylisosorbide, N-methylpyrrolidone, monooctanoin, diethylene glycol monoethyl ether, and water.

[0398] Mixtures of solubilizers may also be used.Examples include, but are not limited to, triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcyclodextrin, ethanol, polyethylene glycol 200-100, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide.Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol, and propylene glycol.

[0399] The amount of solubilizer that can be included is not particularly limited. The amount of a given solubilizer may be limited to a biologically acceptable amount, which may be readily determined by one of ordinary skill in the art. In some circumstances, it may be advantageous to include an amount of solubilizer greater than the biologically acceptable amount in order to maximize drug concentration by removing excess solubilizer using conventional techniques, such as distillation or evaporation, before providing the composition to a subject or a patient in need thereof. Thus, when present, the solubilizer may be present in a weight ratio of 10%, 25%, 50%, 100%, or up to about 200% by weight, based on the combined weight of the drug and other excipients. If desired, very small amounts of solubilizer, such as 5%, 2%, 1%, or even less, can also be used. Typically, the solubilizer may be present in an amount of about 1% to about 100% by weight, more typically about 5% to about 25% by weight.

[0400] The composition may further comprise one or more pharmaceutically acceptable additives and excipients, including, but not limited to, adhesion reducers, antifoaming agents, buffers, polymers, antioxidants, preservatives, chelating agents, viscosity modifiers, tonicity agents, flavors, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

[0401] Additionally, acids or bases may be incorporated into the compositions to facilitate processing, improve stability, or for other reasons. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium bicarbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (Tris), and the like. Also suitable are bases that are salts of pharmaceutically acceptable acids such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, and uric acid. Salts of polyhydric acids such as sodium phosphate, disodium phosphate, and sodium dihydrogen phosphate may also be used. When the base is a salt, the cation can be any convenient and pharmaceutically acceptable cation, such as ammonium, an alkali metal, or an alkaline earth metal. Examples may include, but are not limited to, sodium, potassium, lithium, magnesium, calcium, and ammonium.

[0402] Suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, etc. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, etc.

[0403] A pharmaceutical composition for injection. In some embodiments, a pharmaceutical composition for injection is provided that contains a compound and a pharmaceutical excipient suitable for injection, wherein the components and amounts of the agents in the composition are as described herein.

[0404] Forms into which the composition may be incorporated for administration by injection include aqueous or oily suspensions or emulsions, including sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions and similar pharmaceutical vehicles.

[0405] Aqueous solutions in physiological saline are also commonly used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, etc. (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be used. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin to maintain the required particle size in the case of dispersion, and by the use of surfactants. Prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.

[0406] Sterile injectable solution is prepared by blending a certain amount of compound with various other ingredients as listed above, as needed, in a suitable solvent, followed by sterile filtration.Generally, dispersion is prepared by blending various sterilized active ingredients into a sterile-proof container containing a basic dispersion medium and the other ingredients required from those listed above.For the preparation of sterile powder for sterile injectable solution, the preferred method of preparation is vacuum drying and freeze-drying technology, which produces a powder of active ingredient and any additional desired ingredients from the previously sterile-filtered solution.

[0407] Pharmaceutical compositions for topical (eg, transdermal) delivery. In some embodiments, a pharmaceutical composition for transdermal delivery is provided that contains a compound and a pharmaceutical excipient suitable for transdermal delivery.

[0408] The composition can be formulated into a solid, semi-solid, or liquid form suitable for topical or local administration, such as gel, water-soluble jelly, cream, lotion, suspension, foam, powder, slurry, ointment, solution, oil, paste, suppository, spray, emulsion, saline solution, dimethyl sulfoxide (DMSO)-based solution, etc. Generally, a high-density carrier can provide an area with prolonged exposure to the active ingredient. In contrast, a solution formulation can provide a more immediate exposure of the active ingredient to the selected area.

[0409] The pharmaceutical composition may also include suitable solid or gel phase carriers or excipients, which are compounds that allow for increased penetration or aid in the delivery of therapeutic molecules across the stratum corneum permeability barrier of the skin. There are many of these penetration-enhancing molecules that are well known to those trained in the art of topical formulations.

[0410] Examples of such carriers and excipients include, but are not limited to, humectants (e.g., urea), glycols (e.g., propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleic acid), surfactants (e.g., isopropyl myristate and sodium lauryl sulfate), pyrrolidone, glycerol monolaurate, sulfoxides, terpenes (e.g., menthol), amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycol.

[0411] Another exemplary formulation for use in the methods employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds in controlled amounts, with or without another agent.

[0412] The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See U.S. Patent Nos. 5,023,252, 4,992,445, and 5,001,139. ​​Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

[0413] A pharmaceutical composition for inhalation. Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. Preferably, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions, preferably in pharmaceutically acceptable solvents, may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a face mask tent or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from a device that delivers the formulation in an appropriate manner.

[0414] Other pharmaceutical compositions. Pharmaceutical compositions may also be prepared from the compositions described herein and one or more pharmaceutically acceptable excipients suitable for sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intranasal administration. The preparation of such pharmaceutical compositions is well known in the art. For example, Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt And Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 20037ybg;Goodman and Gilman, eds.The Pharmacological Basis Of Therapeutics, Tenth Edition, McGraw Hill, 2001;Remington Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins, 2000;Martindale, The Extra Pharmacopoeia, Thirty-Second Edition(The Pharmaceutical Press, London, 1999).

[0415] The compound or pharmaceutical composition can be administered by any method that allows delivery of the compound to the site of action. These methods include rectal administration, local delivery by catheter or stent, or via inhalation, oral route, intraduodenal route, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion), topical (e.g., transdermal application). The compound can also be administered intraadiposely or intrathecally.

[0416] The amount of compound administered will depend on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound, and the discretion of the prescribing physician. However, effective doses range from about 0.001 to about 100 mg per kg of body weight per day, preferably 1 to about 35 mg / kg / day, in single or divided doses. For a 70 kg human, this would be about 0.05 to 7 g / day, preferably about 0.05 to about 2.5 g / day. In some cases, dosage levels below the lower end of the above range may be more than appropriate, while in other cases, higher doses may still be used without causing any adverse side effects, for example, by dividing such higher doses into several smaller doses to be administered throughout the day.

[0417] In some embodiments, the compound is administered in a single dose.

[0418] Typically, such administration may be by injection, e.g., intravenous injection, to rapidly introduce the drug. However, other routes, such as oral administration, may also be used as appropriate. A single dose of the compound may also be used to treat acute conditions.

[0419] In some embodiments, the compound is administered multiple times. Administration may be about once, twice, three times, four times, five times, six times, or more than six times per day. Administration may be about once per month, once every two weeks, once per week, or daily. In some embodiments, the compound and another agent are administered together about once to about six times per day. In some embodiments, administration of the compound and agent continues for less than about seven days. In yet other embodiments, administration continues for more than about 6, 10, 14, 28 days, 2 months, 6 months, or 1 year. In some cases, continuous administration is achieved and maintained as needed.

[0420] Administration of the compound may continue for as long as necessary. In some embodiments, the compound is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, the compound is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, the compound is administered over an ongoing, chronic period, for example, to treat a chronic effect.

[0421] The compounds may be administered in either single or multiple doses by any of the accepted modes of administration for drugs with similar efficacy, including rectal, buccal, intranasal, and transdermal routes, by intraarterial infusion, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, or inhalation.

[0422] The composition may also be delivered via an impregnated or coated device, such as a stent, or a cylindrical polymer inserted into the artery. Such administration methods can help prevent or ameliorate restenosis after procedures such as balloon angioplasty. Without being bound by theory, the compound may slow or inhibit the migration and proliferation of smooth muscle cells in the arterial wall, which contribute to restenosis. The compound may be administered by local delivery, for example, from the wall of the stent, from a stent graft, from a graft, or from a stent cover or sheath. In some embodiments, the compound is mixed with a matrix. Such a matrix may be a polymer matrix and may serve to bind the compound to the stent. Suitable polymer matrices for such uses include, for example, lactone-based polyesters or copolyesters, such as polylactides, polycaprolactone glycolides, polyorthoesters, polyanhydrides, polyamino acids, polysaccharides, polyphosphazenes, poly(ether-ester) copolymers (e.g., PEO-PLLA); fluorinated polymers, such as polydimethylsiloxanes, poly(ethylene-vinyl acetate), acrylate-based polymers or copolymers (e.g., polyhydroxyethylmethylmethacrylate, polyvinylpyrrolidone), polytetrafluoroethylene, and cellulose esters. Suitable matrices may be non-degradable or may degrade over time to release the compound or compounds. The compound may be applied to the surface of the stent by various methods, such as dip / spin coating, spray coating, dip coating, and / or brush coating. The compound may be applied in a solvent, and the solvent may evaporate to form a layer of the compound on the stent. Alternatively, the compound may be disposed within the body of the stent or graft, for example, within microchannels or micropores. When implanted, the compound diffuses out of the body of the stent and contacts the arterial wall. Such stents may be prepared by immersing a stent fabricated to contain such micropores or microchannels into a solution of the compound in a suitable solvent, followed by evaporation of the solvent.Excess drug on the surface of the stent may be removed via an additional brief solvent wash. In yet other embodiments, the compound may be covalently attached to the stent or graft. Biodegradable covalent linkers may be used to effect release of the compound. Any biolabile bond may be used, such as an ester, amide, or anhydride bond. The compound may additionally be administered intravascularly from a balloon used during angioplasty. Extravascular administration of the compound via the pericardium or adventitia of the formulation may also be performed to reduce restenosis.

[0423] Various stent devices that may be used as described are disclosed, for example, in the following references, all of which are incorporated herein by reference: U.S. Patent Nos. 5,451,233, 5,040,548, 5,061,273, 5,496,346, 5,292,331, 5,674,278, 3,657,744, 4,739,762, 5,195,984, 5,292,331, 5,674,278, 5,879,382, and 6,344,053.

[0424] Compound can be administered in dose.It is well known in the art that due to the inter-subject variability in the pharmacokinetics of compound, individualized administration regimen is necessary for optimal treatment.The administration of compound can be found by routine experiment in light of the present disclosure.

[0425] When the compound is administered in a composition containing one or more agents that have a shorter half-life than the agents in the unit dosage form of the compound, the compound may be adjusted accordingly.

[0426] The subject pharmaceutical compositions may be in a form suitable for oral administration, for example, as tablets, capsules, pills, powders, sustained-release formulations, solutions, and suspensions; or in a form suitable for parenteral injection, for example, as sterile solutions, suspensions, or emulsions; or in a form suitable for topical administration, for example, as ointments or creams; or in a form suitable for rectal administration, for example, as suppositories. The pharmaceutical composition may also be in a unit dosage form suitable for single administration of a precise dose. The pharmaceutical composition may include a conventional pharmaceutical carrier or excipient and the compound as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.

[0427] Exemplary parenteral dosage forms include solutions or suspensions of the active compounds in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired.

[0428] How to use In some embodiments, the method includes administering to a subject or subject in need thereof an amount, e.g., a therapeutically effective amount, of a compound, or a pharmaceutically acceptable salt or solvate thereof. The therapeutically effective amount of a subject combination of compounds may vary depending on the intended use (in vitro or in vivo), or the subject and disease state being treated, e.g., the subject's weight and age, the severity of the disease state, the mode of administration, etc., but can be readily determined by one of ordinary skill in the art. The term also applies to a dose that induces a particular response in a target cell, e.g., reduced proliferation or down-regulation of activity of a target protein. The particular dose may vary depending on the particular compound selected, the subsequent administration regimen, whether it is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.

[0429] As used herein, the term "IC 50" refers to the half-maximal inhibitory concentration of an inhibitor that inhibits a biological or biochemical function. This quantitative measurement indicates how much of a particular inhibitor is required to inhibit a given biological process (or component of a process, i.e., an enzyme, a cell, a cellular receptor, or a microorganism) by half. In other words, it is the half-maximal (50%) inhibitory concentration (IC) of a substance (50% IC or IC50). EC50 refers to the plasma concentration required to obtain >50% of the maximum effect in vivo.

[0430] In some embodiments, the subject methods utilize a CDK inhibitor that has an IC50 value at or below a predetermined value, as determined in an in vitro assay. In some embodiments, the CDK inhibitor is about 1 nM or less, 2 nM or less, 5 nM or less, 7 nM or less, 10 nM or less, 20 nM or less, 30 nM or less, 40 nM or less, 50 nM or less, 60 nM or less, 70 nM or less, 80 nM or less, 90 nM or less, 100 nM or less, 120 nM or less, 140 nM or less, 150 nM or less, 160 nM or less, 1 70nM or less, 180nM or less, 190nM or less, 200nM or less, 225nM or less, 250nM or less, 275nM or less, 300nM or less, 325nM or less, 350 nM or less, 375nM or less, 400nM or less, 425nM or less, 450nM or less, 475nM or less, 500nM or less, 550nM or less, 600nM or less, 650nM or less Bottom, 700nM or less, 750nM or less, 800nM or less, 850nM or less, 900nM or less, 950nM or less, 1μM or less, 1.1μM or less, 1.2μM or less, 1. 3μΜ or less, 1.4μΜ or less, 1.5μΜ or less, 1.6μΜ or less, 1.7μΜ or less, 1.8μΜ or less, 1.9μΜ or less, 2μΜ or less, 5μΜ or less, 10μΜ or less, 15 In some embodiments, the CDK enzyme is CDK9.

[0431] In some embodiments, a subject method of inhibiting a CDK enzyme comprises contacting the CDK enzyme with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments, the CDK enzyme is CDK9.

[0432] In some embodiments, the CDK inhibitor selectively inhibits a CDK with an IC50 value that is at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, or 1000 times lower (or the number in a range defined by any two numbers above, and inclusive) than its IC50 value for one, two, or three other CDKs. In some embodiments, the CDK inhibitor is a CDK9 inhibitor.

[0433] In some embodiments, the CDK inhibitor is at or below about 1 nM, 2 nM, 5 nM, 7 nM, 10 nM, 20 nM, 30 nM, 40 nM, 50 nM, 60 nM, 70 nM, 80 nM, 90 nM, 100 nM, 120 nM, 140 nM, 150 nM, 160 nM, 170 nM, 180 nM, 190 nM, 200 nM, 225 nM, 250 nM, 275 nM, 30 0nM, 325nM, 350nM, 375nM, 400nM, 425nM, 450nM, 475nM, 500nM, 550nM, 600nM, 650nM, 700nM, 75 0nM, 800nM, 850nM, 900nM, 950nM, 1μΜ, 1.1μΜ, 1.2μΜ, 1.3μΜ, 1.4μΜ, 1.5μΜ, 1.6μΜ, 1.7μΜ, 1.8μ 1.9 μM, 2 μM, 5 μM, 10 μM, 15 μM, 20 μM, 25 μM, 30 μM, 40 μM, 50 μM, 60 μM, 70 μM, 80 μM, 90 μM, 100 μM, 200 μM, 300 μM, 400 μM, or 500 μM (or the number of a range defined by any two numbers above, and inclusive), In some embodiments, the CDK inhibitor selectively inhibits K with an IC50 value at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, or 1000 times lower (or the number in a range defined by any two numbers above, and inclusive) than its IC50 value for one, two, or three other CDKs. In some embodiments, the CDK inhibitor is a CDK9 inhibitor.

[0434] In some embodiments, the compounds described herein are used to inhibit a CDK enzyme in a subject, which use comprises administering to the subject an effective amount of one or more compounds described herein, pharmaceutically acceptable salts, solvates, pharmaceutical compositions, or prodrugs thereof.

[0435] In some embodiments, the pharmaceutical compositions provided herein are used to inhibit a CDK enzyme in a subject, which use comprises administering to the subject an effective amount of one or more of the described pharmaceutical compositions.

[0436] In some embodiments, there is provided a use of a compound described herein in the manufacture of a formulation for inhibiting a CDK enzyme in a subject, the use comprising administering to the subject an effective amount of one or more compounds described herein, pharmaceutically acceptable salts, solvates, pharmaceutical compositions, or prodrugs thereof.

[0437] In some embodiments, there is provided a use of a pharmaceutical composition described herein for inhibiting a CDK enzyme in a subject, the use comprising administering to the subject an effective amount of one or more pharmaceutical compositions described herein. In some embodiments, the CDK enzyme is CDK9.

[0438] The subject methods are useful for treating a disease or disorder condition associated with CDK. Any disease or disorder condition that results directly or indirectly from an abnormal activity or expression level of CDK may be the intended disease or disorder condition. In some embodiments, the method for treating a disease or disorder condition associated with CDK in a subject or a subject in need thereof comprises administering to the subject a compound described herein or a pharmaceutically acceptable salt thereof.

[0439] Different disease or disorder states associated with CDKs have been reported, for example, CDKs are involved in autoimmune diseases, neurodegeneration (such as Parkinson's disease, Alzheimer's disease, and ischemia), inflammatory diseases, viral infections, and cancers such as colon cancer, breast cancer, small cell lung cancer, non-small cell lung cancer, bladder cancer, ovarian cancer, prostate cancer, chronic lymphocytic leukemia, lymphoma, myeloma, acute myeloid leukemia, or pancreatic cancer.

[0440] Non-limiting examples of such conditions include acanthoma, acinic cell carcinoma, acoustic neuroma, acral lentiginous melanoma, acral hidradenoma, acute eosinophilic leukemia, acute lymphoblastic leukemia, acute lymphocytic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute myeloblastic leukemia with maturation, acute myeloid dendritic cell leukemia, acute myeloid leukemia, acute myeloid leukemia, acute promyelocytic leukemia, adamantinoma, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenoid odontogenic tumor, adrenocortical carcinoma, adult T-cell leukemia, aggressive NK-cell leukemia, AIDS-related cancer, AIDS-related lymphoma, alveolar soft part sarcoma, ameloblastic fibrosis, and fibroblastic leukemia. tumor, anal cancer, anaplastic large cell lymphoma, anaplastic thyroid carcinoma, angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma, appendix cancer, astrocytoma, atypical teratoid rhabdoid tumor, basal cell carcinoma, basal-like carcinoma, B-cell leukemia, B-cell lymphoma, Bellini duct carcinoma, biliary tract cancer, bladder cancer, blastoma, bone cancer, bone tumor, brain stem glioma, brain tumor, breast cancer, Brenner tumor, bronchial tumor, bronchioloalveolar carcinoma, pheochromocytoma, Burkitt lymphoma, cancer of unknown primary site, carcinoid tumor, carcinoma, carcinoma in situ, penile cancer, carcinoma of unknown primary site, carcinosarcoma, Castleman disease, central nervous system embryonal tumor , cerebellar astrocytoma, cerebral astrocytoma, cervical cancer, bile duct carcinoma, chondroma, chondrosarcoma, chordoma, choriocarcinoma, choroid plexus papilloma, chronic lymphocytic leukemia, chronic monocytic leukemia, chronic myeloid leukemia, chronic myeloproliferative disorder, chronic neutrophilic leukemia, clear cell tumor, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, Degos disease, dermatofibrosarcoma protuberans, dermoid cyst, desmoplastic small round cell tumor, diffuse large B-cell lymphoma, dysembryoplastic neuroepithelial tumor, embryonal carcinoma, endodermal sinus tumor, uterine cancer, endometrial cancer, endometrial tumor, enteropathy-associated T-cell lymphoma, ependymoblastoma, ependymoma, epidermoid carcinoma, endodermal Epithelial sarcoma, erythroleukemia, esophageal cancer, esthesioneuroblastoma, Ewing's tumor, Ewing's sarcoma, Ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, extramammary Paget's disease, fallopian tube cancer, fetal inclusion malformation, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid cancer, gallbladder cancer, gallbladder carcinoma, ganglioglioma, ganglioneuroma, gastric cancer, gastrointestinal cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, gastrointestinal stromal tumor, germ cell tumor, germ cell tumor, gestational choriocarcinoma, gestational trophoblastic tumor, giant cell tumor of bone, glioblastoma multiforme, gliomatosis, glomus tumor, glucagonoma, gonadoblastoma, granulosa cell tumor,Hairy cell leukemia, head and neck cancer, heart cancer, hemoglobinopathies such as b-thalassemia and sickle cell disease (SCD), hemangioblastoma, hemangiopericytoma, angiosarcoma, hematologic malignancies, hepatocellular carcinoma, hepatosplenic T-cell lymphoma, hereditary breast and ovarian cancer syndrome, Hodgkin's lymphoma, hypopharyngeal cancer, hypothalamic glioma, inflammatory breast cancer, intraocular melanoma, pancreatic islet cell carcinoma, pancreatic islet cell tumor, juvenile myelomonocytic leukemia, Kaposi's sarcoma, kidney cancer, Krackin's tumor, Krukenberg's tumor, laryngeal cancer, laryngeal cancer, lentigo maligna melanoma, leukemia, lip and oral cavity cancer, liposarcoma, lung cancer, corpus luteum tumor, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphocytic leukemia, lymphoma, macroglobulinemia, malignant fibrous histiocytoma, malignant fibrous histiocytoma, malignant fibrous histiocytoma of bone, malignant glioma, malignant mesothelioma, malignant peripheral nerve sheath tumor, malignant rhabdoid tumor, malignant Triton tumor, MALT lymphoma, mantle cell lymphoma, mast cell leukemia, mastocytosis, mediastinal germ cell tumor, longitudinal wall tumor, medullary thyroid carcinoma, medulloblastoma, medulloepithelioma, melanoma, melanoma, meningioma, Merkel cell carcinoma, mesothelioma, metastatic squamous cell carcinoma of the neck of unknown primary, metastatic urothelial carcinoma, Müllerian duct Mixed tumor, monocytic leukemia, oral cancer, mucinous tumor, multiple endocrine neoplasia syndrome, multiple myeloma, multiple myeloma, mycosis fungoides, mycosis fungoides, myelodysplasia, myelodysplastic syndrome, myeloid leukemia, myeloid sarcoma, myeloproliferative disorders, myxoma, nasal cavity cancer, nasopharyngeal carcinoma, nasopharyngeal carcinoma, neoplasm, schwannoma, neuroblastoma, neuroblastoma, neurofibroma, neuroma, nodular melanoma, non-Hodgkin's lymphoma, non-Hodgkin's lymphoma, non-melanoma skin cancer, non-small cell lung cancer, ophthalmic oncology, oligoastrocytoma, oligodendroglioma, eosinophilic adenoma, optic nerve sheath meningioma, oral cavity cancer, oral cancer, oropharyngeal cancer, osteosarcoma, osteosarcoma, ovarian Cancer, ovarian cancer, epithelial ovarian cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, Paget's disease of the breast, Pancoast tumor, pancreatic cancer, pancreatic cancer, papillary thyroid carcinoma, papillomatosis, paraganglioma, sinus cancer, parathyroid carcinoma, penile cancer, perivascular epithelioid cell tumor, pharyngeal carcinoma, pheochromocytoma, moderately differentiated pineal parenchymal tumor, pineoblastoma, pituitary cell tumor, pituitary adenoma, pituitary tumor, plasma cell neoplasm, pleuropulmonary blastoma, polygerminoma, precursor T lymphoblastic lymphoma, primary central nervous system lymphoma, primary effusion lymphoma, primary hepatocellular carcinoma, primary liver cancer, primary peritoneal carcinoma, primitive neuroectodermal tumor, prostate cancer, peritoneal pseudomyxoma,Rectal cancer, renal cell carcinoma, respiratory carcinoma associated with the NUT gene on chromosome 15, retinoblastoma, rhabdomyoma, rhabdomyosarcoma, Richter transformation, sacrococcygeal teratoma, salivary gland carcinoma, sarcoma, schwannomatosis, sebaceous gland carcinoma, secondary neoplasms, seminoma, serous tumor, Sertoli-Leydig cell tumor, sex cord-stromal tumor, Sézary syndrome, signet ring cell carcinoma, skin cancer, small blue round cell tumor, small cell carcinoma, small cell lung cancer, small cell lymphoma, small intestine cancer, soft tissue sarcoma, somatostatinoma, sooty warts, spinal cord tumor, vertebral tumor, splenic marginal zone lymphoma, squamous cell carcinoma, gastric cancer, superficial spreading melanoma, supratentorial primitive neuroectodermal tumor, table These include, but are not limited to, facial epithelial-stromal tumor, synovial sarcoma, T-cell acute lymphoblastic leukemia, T-cell large granular lymphocytic leukemia, T-cell leukemia, T-cell lymphoma, T-cell prolymphocytic leukemia, teratoma, end-stage lymphoma, testicular cancer, theca cell tumor, laryngeal cancer, thymic carcinoma, thymoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, transitional cell carcinoma, urachal carcinoma, urethral cancer, genitourinary tumors, uterine sarcoma, uveal melanoma, vaginal cancer, Werner-Morrison syndrome, verrucous carcinoma, optic pathway glioma, vulvar cancer, Waldenstrom's macroglobulinemia, Warthin's tumor, Wilms' tumor, or any combination thereof.

[0441] In some embodiments, the method is for treating a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory diseases such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma, and ovarian, breast, lung, pancreatic, prostate, colon, and epidermoid carcinoma.

[0442] In other embodiments, the method is for treating a disease selected from breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer, ovarian cancer, uterine cancer, or cervical cancer. In some embodiments, the method comprises administering to a subject or a subject in need thereof a compound described herein or a pharmaceutically acceptable salt thereof.

[0443] In other embodiments, the method is for treating a leukemia, e.g., a disease selected from acute myeloid leukemia (AML), acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia, myelodysplasia, myeloproliferative disorders, acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), myelodysplastic syndromes (MDS), or epidermoid carcinoma.

[0444] In some embodiments, there is provided a compound described herein for use in treating a disease or disorder associated with aberrant CDK activity in a subject or in a subject in need thereof, the use comprising administering to the subject an effective amount of one or more compounds described herein, pharmaceutically acceptable salts, solvates, pharmaceutical compositions, or prodrugs thereof.

[0445] In some embodiments, there is provided a pharmaceutical composition as described herein for use in treating a disease or disorder associated with aberrant CDK activity in a subject or in a subject in need thereof, the use comprising administering to the subject an effective amount of one or more pharmaceutical compositions as described herein.

[0446] In some embodiments, there is provided a use of a compound described herein in the manufacture of a formulation for treating a disease or disorder associated with aberrant CDK activity in a subject or a subject in need thereof, comprising administering to the subject an effective amount of one or more compounds described herein, pharmaceutically acceptable salts, solvates, pharmaceutical compositions, or prodrugs thereof.

[0447] In some embodiments, there is provided a use of a pharmaceutical composition described herein for treating a disease or disorder associated with aberrant CDK activity in a subject or in a subject in need thereof, the use comprising administering to the subject an effective amount of one or more pharmaceutical compositions described herein. In some embodiments, the disease or disorder associated with aberrant CDK activity is colon cancer, breast cancer, small cell lung cancer, non-small cell lung cancer, bladder cancer, ovarian cancer, prostate cancer, chronic lymphocytic leukemia, lymphoma, myeloma, acute myeloid leukemia, or pancreatic cancer.

[0448] In some embodiments, there is provided a compound described herein for use in treating cancer in a subject or a subject in need thereof, the use comprising administering to the subject an effective amount of one or more compounds described herein, pharmaceutically acceptable salts, solvates, pharmaceutical compositions, or prodrugs thereof.

[0449] In some embodiments, there is provided a pharmaceutical composition described herein for use in treating cancer in a subject or in a subject in need thereof, the use comprising administering to the subject an effective amount of one or more pharmaceutical compositions described herein.

[0450] In some embodiments, there is provided a use of a compound described herein in the manufacture of a formulation for treating cancer in a subject or a subject in need thereof, comprising administering to the subject an effective amount of one or more compounds described herein, pharmaceutically acceptable salts, solvates, pharmaceutical compositions, or prodrugs thereof.

[0451] In some embodiments, there is provided a use of a pharmaceutical composition described herein for treating cancer in a subject or a subject in need thereof, comprising administering to the subject an effective amount of one or more pharmaceutical compositions described herein. In some embodiments, the cancer is colon cancer, breast cancer, small cell lung cancer, non-small cell lung cancer, bladder cancer, ovarian cancer, prostate cancer, chronic lymphocytic leukemia, lymphoma, myeloma, acute myeloid leukemia, or pancreatic cancer.

[0452] The compounds of the present disclosure, as well as pharmaceutical compositions containing them, can be administered alone or in combination with medical therapies, including, for example, surgery and radiation therapy (e.g., gamma irradiation, neutron radiation therapy, electron beam radiation therapy, proton radiation therapy, brachytherapy, systemic radioisotopes), to treat any of the diseases described.

[0453] In other aspects, the compounds of the present disclosure, as well as pharmaceutical compositions containing them, can be administered alone or in combination with one or more other drugs to treat any of the diseases described.

[0454] In other methods, the compounds of the present disclosure, as well as pharmaceutical compositions comprising same, can be administered in combination with an agonist of a nuclear receptor agent.

[0455] In other methods, the compounds of the present disclosure, as well as pharmaceutical compositions comprising same, can be administered in combination with an antagonist of a nuclear receptor agonist.

[0456] In other methods, the compounds of the present disclosure, as well as pharmaceutical compositions comprising same, can be administered in combination with an anti-proliferative agent.

[0457] Combination therapy To treat cancer and other proliferative diseases, the compounds can be used in combination with chemotherapeutic agents, nuclear receptor agonists or antagonists, or other antiproliferative agents. The compounds can also be used in combination with surgery or radiation therapy, such as gamma irradiation, neutron beam radiation therapy, electron beam radiation therapy, proton beam radiation therapy, brachytherapy, and whole-body radioisotope therapy. Examples of suitable chemotherapeutic agents include abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, all-trans retinoic acid, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bendamustine, bevacizumab, bexarotene, bleomycin, bortezombi, bortezomib, intravenous busulfan, oral busulfan, calsterone, capecitabine, carboplatin, and carmustine. , cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daltevarin sodium, dasatinib, daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolone propionate, eculizumab, epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane tamoxifen, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib mesylate, interferon alfa-2a, irinotecan, lapatinib tosylate, lenalidomide, letrozole, leucovorin, leucovorin acetate, levamizole ol, lomustine, mechlorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone phenpropionate, nelarabine, nofetumomab, oxaliplatin, paclitaxel, pamidronate, panobinostat, panitumumab, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin,Examples of the anti-cancer drug include procarbazine, quinacrine, rasburicase, rituximab, ruxolitinib, sorafenib, streptozocin, sunitinib, sunitinib malate, tamoxifen, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, vorinstat, and zoledronate.

[0458] In some embodiments, the compound can be used in combination with a therapeutic agent that targets an epigenetic regulator. Examples of epigenetic regulators include bromodomain inhibitors, histone lysine methyltransferase inhibitors, histone arginine methyltransferase inhibitors, histone demethylase inhibitors, histone deacetylase inhibitors, histone acetylase inhibitors, and DNA methyltransferase inhibitors. Histone deacetylase inhibitors include, for example, vorinostat. Histone arginine methyltransferase inhibitors include inhibitors of protein arginine methyltransferases (PRMTs), such as PRMT5, PRMT1, and PRMT4. DNA methyltransferase inhibitors include inhibitors of DNMT1 and DNMT3.

[0459] To treat cancer and other proliferative diseases, the compounds may be used in combination with targeted therapies such as JAK kinase inhibitors (e.g., ruxolitinib), PI3 kinase inhibitors, including PI3K-delta selective and broad-spectrum PI3K inhibitors, cyclin-dependent kinase inhibitors, including MEK inhibitors, CDK4 / 6 inhibitors and CDK9 inhibitors, BRAF inhibitors, mTOR inhibitors, proteasome inhibitors (e.g., bortezomib, carfilzomib), HDAC inhibitors (e.g., panobinostat, vorinostat), DNA methyltransferase inhibitors, dexamethasone, bromo- and extra-terminal family member BTK inhibitors (e.g., ibrutinib, acarbrutinib), BCL2 inhibitors (e.g., venetoclax), BCL2 family dual inhibitors (e.g., BCL2 / BCLxL), PARP inhibitors, FLT3 inhibitors, or LSD1 inhibitors.

[0460] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475), or PDR001. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab or pembrolizumab. In some embodiments, the anti-PD1 antibody is pembrolizumab. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is atezolizumab, durvalumab, or BMS-935559. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab.

[0461] In some embodiments, the agent is an alkylating agent, a proteasome inhibitor, a corticosteroid, or an immunomodulator. Examples of alkylating agents include cyclophosphamide (CY), melphalan (MEL), and bendamustine. In some embodiments, the proteasome inhibitor is carfilzomib. In some embodiments, the corticosteroid is dexamethasone (DEX). In some embodiments, the immunomodulator is lenalidomide (LEN) or pomalidomide (POM).

[0462] For treating autoimmune or inflammatory conditions, the compounds may be administered in combination with a corticosteroid, such as triamcinolone, dexamethasone, fluocinolone, cortisone, prednisolone, or flumetholone.

[0463] To treat autoimmune or inflammatory conditions, the compounds may be administered in combination with immunosuppressants such as fluoronolone acetonide (Retisert®), rimexolone (AL-2178, Vexol, Alcon), or cyclosporine (Restasis®).

[0464] In some embodiments, the compounds are used in methods for the prevention (preventing or preventing) or prophylaxis of the diseases, disorders, or conditions provided herein, hi some embodiments, the compounds are used to prevent the recurrence of the conditions or diseases provided herein.

[0465] The present disclosure also provides the following non-limiting embodiments. 1. A compound having formula (I) or formula (II), or a pharmaceutically acceptable salt or solvate thereof,

[0466] [ka] During the ceremony, X 1 , X 2 , and X 3 are each independently N or CR 3and A 1 is N or CR 4 and B 1 is CR 6 R 7 , N.R. 5 , O, or S; A 2 is NR 8 , S, or O; B 2 is CR 9 or N, R 1 is C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, C 3~10 Cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4 Alkyl, (5-14 membered heteroaryl)-C 1~4 Alkyl, and (4- to 14-membered heterocycloalkyl)-C 1~4 alkyl, At this time, R 1 is 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R b optionally substituted with substituents, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are each independently H, D, halo, oxo, or C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 6~10 Aryl, C 3~10Cycloalkyl, 5-10 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4 Alkyl, (5-14 membered heteroaryl)-C 1~4 Alkyl, (4-14 membered heterocycloalkyl)-C 1~4 Alkyl, CN, NO2, OR a1 , S.R. a1 , NHOR a1 , C(O)R a1 , C(O)NR a1 R a1 , C(O)OR a1 ,OC(O)R a1 , OC(O)NR a1 R a1 , NHR a1 , N.R. a1 R a1 , N.R. a1 C(O)R a1 , N.R. a1 C(O)OR a1 , N.R. a1 C(O)NR a1 R a1 , C(=NR a1 )R a1 , C(=NR a1 )NR a1 R a1 , N.R. a1 C(=NR a1 )NR a1 R a1 , N.R. a1 C(=NOH)NR a1 R a1 , N.R. a1 C(=NCN)NR a1 R a1 , N.R. a1 S(O)R a1 , N.R. a1 S(O)2R a1 , N.R. a1 S(O)NR a1 R a1 , S(O)R a1 , S(O)NR a1 R a1 S(O)2R a1 , SF5, P(O)R a1R a1 , P(O)(OR a1 )(OR a1 ), B(OR a1 )2 and S(O)2NR a1 R a1 is selected from R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 or R 9 But C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, C 3~10 Cycloalkyl, 5-10 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4 Alkyl, (5-14 membered heteroaryl)-C 1~4 Alkyl, or (4- to 14-membered heterocycloalkyl)-C 1~4 When it is alkyl, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 or R 9 is 1, 2, 3, 4, or 5 independently selected R b optionally substituted with substituents, Or R 4 and R 5 may be substituted with 1, 2, 3, 4, or 5 independently selected R b forming a 5-, 6-, or 7-membered heterocycloalkyl ring optionally substituted with substituents; Or R 6 and R 7 form a C3-C7 spirocyclic ring together with the carbon atoms to which they are both attached, Or R 8 and R 9may be substituted with 1, 2, 3, 4, or 5 independently selected R b forming a 5-, 6-, or 7-membered heterocycloalkyl ring optionally substituted with substituents; Each R a1 are independently H, D, C 1~6 Alkyl, C 1~4 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, C 3~10 Cycloalkyl, 5-10 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4 Alkyl, (5-10 membered heteroaryl)-C 1~4 Alkyl, and (4- to 14-membered heterocycloalkyl)-C 1~4 alkyl, R a1 But C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, C 3~10 Cycloalkyl, 5-10 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4 Alkyl, (5-10 membered heteroaryl)-C 1~4 Alkyl- or (4- to 14-membered heterocycloalkyl)-C 1~4 When it is alkyl, R a1 is 1, 2, 3, 4, or 5 independently selected R d optionally substituted with substituents, Each R b The substituents are independently D, halo, oxo, C 1~4 Alkyl, C 1~6 Alkoxy, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, C 6~10 Aryl, C 3~10Cycloalkyl, 5-10 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4 Alkyl, (5-10 membered heteroaryl)-C 1~4 Alkyl, (4-14 membered heterocycloalkyl)-C 1~4 Alkyl, CN, OH, NH2, NO2, NHOR c , OR c , S.R. c , C(O)R c , C(O)NR c R c , C(O)OR c ,OC(O)R c , OC(O)NR c R c , C(=NR c )NR c R c , N.R. c C(=NR c )NR c R c , N.R. c C(=NOH)NR c R c , N.R. c C(=NCN)NR c R c , SF5, P(O)R c R c , P(O)(OR c )(OR c ), NHR c , N.R. c R c , N.R. c C(O)R c , N.R. c C(O)OR c , N.R. c C(O)NR c R c , N.R. c S(O)R c , N.R. c S(O)(=NR c )R c , N.R. c S(O)2R c , N.R. c S(O)NR c Rc , S(O)R c , S(O)NR c R c , S(O)2R c or S(O)NR c R c is selected from R b But C 1~4 Alkyl, C 1~6 Alkoxy, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, C 6~10 Aryl, C 3~10 Cycloalkyl, 5-10 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4 Alkyl, (5-10 membered heteroaryl)-C 1~4 Alkyl- or (4- to 14-membered heterocycloalkyl)-C 1~4 When it is alkyl, R b is one, two, or three independently selected R d optionally substituted with substituents, Each R c are independently H, D, OH, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~4 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, C 3~10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4 Alkyl, (5-10 membered heteroaryl)-C 1~4 Alkyl, and (4-10 membered heterocycloalkyl)-C 1~4 alkyl, R c But C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10Aryl, C 3~10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4 Alkyl, (5-10 membered heteroaryl)-C 1~4 Alkyl- or (4- to 10-membered heterocycloalkyl)-C 1~4 When it is alkyl, R c is 1, 2, 3, 4, or 5 independently selected R f optionally substituted with substituents, Each R f are independently halogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, C 3~10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4 Alkyl, (5-10 membered heteroaryl)-C 1~4 Alkyl, and (4-10 membered heterocycloalkyl)-C 1~4 Alkyl, Halo, CN, NHOR g , OR g , S.R. g , C(O)R g , C(O)NR g R g , C(O)OR g ,OC(O)R g , OC(O)NR g R g , NHR g , N.R. g R g , N.R. g C(O)R g , N.R. g C(O)NR g R g , N.R. g C(O)OR g , C(=NR g )NRg R g , N.R. g C(=NR g )NR g R g , N.R. g C(=NOH)NR g R g , N.R. g C(=NCN)NR g R g , SF5, P(O)R g R g , P(O)(OR g )(OR g ), S(O)R g , S(O)NR g R g , S(O)2R g , N.R. g S(O)2R g , N.R. g S(O)NR g R g , and S(O)NR g R g is selected from R f But C 1~4 Alkyl, C 1~4 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, C 3~10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4 Alkyl, (5-10 membered heteroaryl)-C 1~4 Alkyl, and (4-10 membered heterocycloalkyl)-C 1~4 When it is alkyl, R f is 1, 2, 3, 4, or 5 independently selected R n optionally substituted with substituents, Each R n independently, C 1~4 Alkyl, C 1~4 Haloalkyl, Halo, CN, R o , NHOR o , OR o, S.R. o , C(O)R o , C(O)NR o R o , C(O)OR o ,OC(O)R o , OC(O)NR o R o , NHR o , N.R. o R o , N.R. o C(O)R o , N.R. o C(O)NR o R o , N.R. o C(O)OR o , C(=NR o )NR o R o , N.R. o C(=NR o )NR o R o , N.R. o C(=NOH)NR o R o , N.R. o C(=NCN)NR o R o , SF5, P(O)R o R o , P(O)(OR o )(OR o ), S(O)R o , S(O)NR o R o , S(O)2R o , N.R. o S(O)2R o , N.R. o S(O)NR o R o , and S(O)NR o R o is selected from Each R d are independently D, oxo, C 1~6 Alkyl, C 1~6 Haloalkyl, Halo, C 3~10 Cycloalkyl, C 6~10 Aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C3~10 Cycloalkyl-C 1~4 Alkyl, (5-10 membered heteroaryl)-C 1~4 Alkyl, and (4-10 membered heterocycloalkyl)-C 1~4 Alkyl, CN, NH2, NHOR e , OR e , S.R. e , C(O)R e , C(O)NR e R e , C(O)OR e ,OC(O)R e , OC(O)NR e R e , NHR e , N.R. e R e , N.R. e C(O)R e , N.R. e C(O)NR e R e , N.R. e C(O)OR e , C(=NR e )NR e R e , N.R. e C(=NR e )NR e R e , N.R. e C(=NOH)NR e R e , N.R. e C(=NCN)NR e R e , SF5, P(O)R e R e , P(O)(OR e )(OR e ), S(O)R e , S(O)NR e R e , S(O)2R e , N.R. e S(O)2R e , N.R. e S(O)NR e R e , and S(O)NR e R e is selected from R d But C 1~6Alkyl, C 3~10 Cycloalkyl, C 6~10 Aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4 Alkyl, (5-10 membered heteroaryl)-C 1~4 Alkyl, or (4- to 10-membered heterocycloalkyl)-C 1~4 When it is alkyl, R d is one, two, or three independently selected R f optionally substituted with substituents, Each R e are independently H, D, CN, and C 1~6 Alkyl, C 1~4 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, C 3~10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4 Alkyl, (5-10 membered heteroaryl)-C 1~4 Alkyl, and (4-10 membered heterocycloalkyl)-C 1~4 alkyl, R e But C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, C 3~10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4 Alkyl, (5-10 membered heteroaryl)-C 1~4 Alkyl- or (4- to 10-membered heterocycloalkyl)-C 1~4 When it is alkyl, R e is one, two, or three independently selected Rg optionally substituted with substituents, Each R g are independently H, D, C 1~6 Alkyl, C 1~4 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, C 3~10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4 Alkyl, (5-10 membered heteroaryl)-C 1~4 Alkyl, and (4-10 membered heterocycloalkyl)-C 1~4 alkyl, R g But C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, C 3~10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4 Alkyl, (5-10 membered heteroaryl)-C 1~4 Alkyl- or (4- to 10-membered heterocycloalkyl)-C 1~4 When it is alkyl, R g is one, two, or three independently selected R P optionally substituted with substituents, Each R P independently, C 1~4 Alkyl, C 1~4 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, C 3~10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C1~4 Alkyl, (5-10 membered heteroaryl)-C 1~4 Alkyl, and (4-10 membered heterocycloalkyl)-C 1~4 Alkyl, Halo, CN, NHOR r , OR r , S.R. r , C(O)R r , C(O)NR r R r , C(O)OR r ,OC(O)R r , OC(O)NR r R r , NHR r , N.R. r R r , N.R. r C(O)R r , N.R. r C(O)NR r R r , N.R. r C(O)OR r , C(=NR r )NR r R r , N.R. r C(=NR r )NR r R r , N.R. r C(=NOH)NR r R r , N.R. r C(=NCN)NR r R r , SF5, P(O)R r R r , P(O)(OR r )(OR r ), S(O)R r , S(O)NR r R r , S(O)2R r , N.R. r S(O)2R r , N.R. r S(O)NR r R r , and S(O)NR r R r is selected from Each R o or R r are independently H, D, C 1~4Alkyl, C 3~6 Cycloalkyl, C 6~10 Aryl, 5- or 6-membered heteroaryl, C 1~4 Haloalkyl, C 2~4 Alkenyl, and C 2~4 alkynyl, R o or R r But C 1~4 Alkyl, C 3~6 Cycloalkyl, C 6~10 Aryl, 5- or 6-membered heteroaryl, C 2~4 Alkenyl, and C 2~4 When R is alkynyl, o or R r is one, two, or three independently selected R q optionally substituted with substituents, Each R q are independently D, OH, CN, -COOH, NH2, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~4 Alkylthio, phenyl, 5-6 membered heteroaryl, C 3~6 Cycloalkyl, 4-6 membered heterocycloalkyl, -CONHR 12 , -NHC(O)R 12 , -OC(O)R 12 , -C(O)OR 12 , -C(O)R 12 , -SO2R 12 , -NHSO2R 12 , -SO2NHR 12 and NR 12 R 12 is selected from R q But C 1~6 alkyl, phenyl, 4- to 6-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, R q are OH, CN, -COOH, NH2, C 1~6 Alkoxy, C 3~6 optionally substituted with cycloalkyl or 4- to 6-membered heterocycloalkyl; Each R 12independently, C 1~6 A compound that is alkyl.

[0467] 2. The compound is

[0468] [ka] or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, X 1 , X 2 , and X 3 are each independently N or CR 3 and A 1 is N or CR 4 and B 1 is CR 6 R 7 , N.R. 5 and A 2 is NR 8 , S, or O; B 2 is CR 9 and R1 is C3~ 10 cycloalkyl or 4-10 membered heterocycloalkyl, and 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R b optionally substituted with substituents, R 2 is H, D, OH, halogen, CN, C1-6 alkyl, C3- 10 Cycloalkyl, C1-6 alkoxyl, C 1~6 haloalkyl, or 4- to 14-membered heterocycloalkyl; R 3 is H, D, OH, halogen, CN, C1-6 alkyl, C3- 10 Cycloalkyl, C1-6 alkoxyl, C 1~6 haloalkyl, or 4- to 14-membered heterocycloalkyl; R 4is H, D, C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, or 4-6 membered heterocycloalkyl; R 5 is C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, or 4-6 membered heterocycloalkyl, Or R 4 and R 5 may be substituted with 1, 2, 3, 4, or 5 independently selected R b forming a 5-, 6-, or 7-membered heterocycloalkyl ring optionally substituted with substituents; R 6 is C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, or 4-6 membered heterocycloalkyl, R 7 is C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, or 4-6 membered heterocycloalkyl, Or R 6 and R 7 form a C4-7 spirocyclic ring together with the carbon atoms to which they are both attached, R 8 is C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, or 4-6 membered heterocycloalkyl, R 9 is C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, or 4-6 membered heterocycloalkyl, Or R 8 and R 9 may be substituted with 1, 2, 3, 4, or 5 independently selected R b forming a 5- or 6-membered heterocycloalkyl ring optionally substituted with substituents, R b is C 1~4 Alkyl, 5-10 membered heteroaryl, 4-14 membered heterocycloalkyl, NR c C(=NR c )NR c R c , N.R. c C(=NOH)NR c R c, N.R. c C(=NCN)NR c R c , N.R. c C(O)R c , N.R. c C(O)OR c , N.R. c C(O)NR c R c , N.R. c S(O)R c , or NR c S(O)2R c , N.R. c S(O)NR c R c and Each R c are independently H, OH, C 1~6 Alkyl, C 1~6 Alkoxy, C 3~10 cycloalkyl, 4- to 10-membered heterocycloalkyl, or (5- to 10-membered heteroaryl)-C 1~4 is alkyl, Each R c But C 1~6 Alkyl, C 1~6 Alkoxy, C 3~10 cycloalkyl, 4- to 10-membered heterocycloalkyl, or (5- to 10-membered heteroaryl)-C 1~4 When it is alkyl, R c is 1, 2, 3, 4, or 5 independently selected R f optionally substituted with substituents, Each R f are independently halogen, CN or OR g and Each R g are independently H or C 1~6 The compound of embodiment 1, wherein the aryl group is alkyl.

[0469] 3. The compound is [ka] or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, X 1 , X2 , and X 3 are each independently N or CR 3 and A 1 is N or CR 4 and B 1 is CR 6 R 7 , N.R. 5 and A 2 is NR 8 , S, or O; B 2 is CR 9 and R1 is C3~ 10 cycloalkyl and 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R b optionally substituted with substituents, R 2 is H, D, OH, halogen, CN, C1-6 alkyl, C3- 10 cycloalkyl, C alkoxyl, or 4- to 14-membered heterocycloalkyl; R 3 is H, D, OH, halogen, CN, C1-6 alkyl, C3- 10 cycloalkyl, C alkoxyl, or 4- to 14-membered heterocycloalkyl; R 4 is H, D, C1-6 alkyl, or C 1~6 is an alkoxy, R 5 is C1-6 alkyl, or C 1~6 is an alkoxy, Or R 4 and R 5 may be substituted with 1, 2, 3, 4, or 5 independently selected R b forming a 5-, 6-, or 7-membered heterocycloalkyl ring optionally substituted with substituents; R 6 is C1-6 alkyl, R 7 is C1-6 alkyl, Or R 6 and R7 form a C4-7 spirocyclic ring together with the carbon atoms to which they are both attached, R 8 is C1-6 alkyl, R 9 is C1-6 alkyl, Or R 8 and R 9 may be substituted with 1, 2, 3, 4, or 5 independently selected R b forming a 5-, 6-, or 7-membered heterocycloalkyl ring optionally substituted with substituents; R b is C 1~4 Alkyl, NR c C(=NR c )NR c R c , N.R. c C(=NOH)NR c R c , N.R. c C(=NCN)NR c R c , N.R. c C(O)R c , N.R. c C(O)OR c , N.R. c C(O)NR c R c , N.R. c S(O)R c , N.R. c S(O)(=NR c )R c , N.R. c S(O)2R c , or NR c S(O)NR c R c and Each R c are independently H, C 1~6 Alkyl, C 1~6 Alkoxy, C 3~10 cycloalkyl, 4- to 10-membered heterocycloalkyl, or (5- to 10-membered heteroaryl)-C 1~4 is alkyl, Each R c But C 1~6 Alkyl, C 1~6 Alkoxy, C3~10 cycloalkyl, 4- to 10-membered heterocycloalkyl, or (5- to 10-membered heteroaryl)-C 1~4 When it is alkyl, R c is 1, 2, 3, 4, or 5 independently selected R f optionally substituted with substituents, Each R f are independently halogen, CN, C 1~4 Alkyl or OR g and Each R g are independently H or C 1~6 The compound of embodiment 1, wherein the aryl group is alkyl.

[0470] 4. X 1 The compound of embodiments 1-3, or a pharmaceutically acceptable salt or solvate thereof, wherein

[0471] 5. X 2 The compound of any one of embodiments 1 to 4, or a pharmaceutically acceptable salt or solvate thereof, wherein

[0472] 6. X 3 The compound of any one of embodiments 1 to 5, or a pharmaceutically acceptable salt or solvate thereof, wherein

[0473] 7. X 1 is CR 3 or a pharmaceutically acceptable salt or solvate thereof.

[0474] 8. X 2 is CR 3 or a pharmaceutically acceptable salt or solvate thereof.

[0475] 9. X 3 is CR 3 or a pharmaceutically acceptable salt or solvate thereof.

[0476] 10. R 1 But C 3~10 cycloalkyl, and 1, 2, 3, or 4 independently selected R b 10. The compound of any one of embodiments 1 to 9, or a pharmaceutically acceptable salt or solvate thereof, optionally substituted with a substituent.

[0477] 11. R 1 But C 3~7 cycloalkyl, and 1, 2, 3, or 4 independently selected R b The compound of embodiment 10, or a pharmaceutically acceptable salt or solvate thereof, optionally substituted by substituents.

[0478] 12. R 1 But C 5~6 cycloalkyl and one R b The compound of embodiment 11, or a pharmaceutically acceptable salt or solvate thereof, optionally substituted with substituents.

[0479] 13. The compound of embodiment 12, or a pharmaceutically acceptable salt or solvate thereof, wherein C5-6 cycloalkyl is cyclopentanyl or cyclohexanyl.

[0480] 14. R 1 One R above b The substituent is NR c C(O)R c , N.R. c C(O)NR c R c , or NR c S(O)NR c R c or a pharmaceutically acceptable salt or solvate thereof.

[0481] 15. NR c C(O)R c , N.R. c C(O)NR c R c , or NR c S(O)NRc R c R in c However, independently, H, C 1~6 Alkyl, C 3~10 cycloalkyl, 4- to 10-membered heterocycloalkyl, or (5- to 10-membered heteroaryl)-C 1~4 alkyl, and R c But C 1~6 Alkyl, C 1~6 Alkoxy, C 3~10 cycloalkyl, 4- to 10-membered heterocycloalkyl, or (5- to 10-membered heteroaryl)-C 1~4 When alkyl, R c is 1, 2, 3, 4, or 5 independently selected R f The compound of embodiment 14, or a pharmaceutically acceptable salt or solvate thereof, optionally substituted with substituents.

[0482] 16. R f The substituents are independently halogen, CN, or OR g or a pharmaceutically acceptable salt or solvate thereof.

[0483] 17. R g are independently H or C 1~6 The compound of embodiment 16, or a pharmaceutically acceptable salt or solvate thereof, wherein R is alkyl.

[0484] 18. R 1 One R above b The substituents are acetamide (-NHC(O)CH3), 3-hydroxybutanamide (-NHC(O)CH2CH(OH)CH3), propionamide (-NHC(O)CH2CH3), 2-methoxyacetamide (-NHC(O)CH2-OCH3), 2-cyanoacetamide (-NHC(O)CH2-CN), 1-hydroxycyclopropane-1-carboxamide,

[0485] [ka] 2-(thiazol-4-yl)acetamide,

[0486] [ka] Methylsulfonamide (-NSO2CH3), 3-methylureido (-NC(O)NHCH3), 3-methoxyureido (-NC(O)NHOCH3), 3,3-dimethylureido (-NC(O)N(CH3)2), or 3-ethylureido (-NC(O)NHCH2CH3), morpholine-4-carboxamide, i.e.,

[0487] [ka] or 4-methylpiperazine-1-carboxamide, i.e.,

[0488] [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0489] 19. R 2 The compound of any one of embodiments 1-18, or a pharmaceutically acceptable salt or solvate thereof, wherein is H, halogen (preferably Cl), or C1-6 alkyl (preferably CH3).

[0490] 20. R 2 20. The compound of any one of embodiments 1-19, or a pharmaceutically acceptable salt or solvate thereof, wherein is C1-6 alkyl, preferably CH3 or CH2CH3.

[0491] 21. R 3 The compound according to any one of embodiments 1 to 20, or a pharmaceutically acceptable salt or solvate thereof, wherein is H or halogen, preferably F.

[0492] 22. The compound is a compound of formula (I)

[0493] [ka] A compound of formula (I), according to any one of embodiments 1 to 21, or a pharmaceutically acceptable salt or solvate thereof.

[0494] 23. A 1 is N, or a pharmaceutically acceptable salt or solvate thereof.

[0495] 24. A 1 is CR 4 or a pharmaceutically acceptable salt or solvate thereof.

[0496] 25. B 1 is CR 6 R 7 25. The compound of any one of embodiments 22-24, wherein:

[0497] 26. B 1 NR 5 25. The compound of any one of embodiments 22-24, wherein:

[0498] 27. B 1 The compound of any one of embodiments 22-24, or a pharmaceutically acceptable salt or solvate thereof, wherein

[0499] 28. B 1 The compound of any one of embodiments 22-24, or a pharmaceutically acceptable salt or solvate thereof, wherein

[0500] 29. R 4 The compound of any one of embodiments 24-28, or a pharmaceutically acceptable salt or solvate thereof, wherein

[0501] 30. R 4The compound according to any one of embodiments 24-28, or a pharmaceutically acceptable salt or solvate thereof, wherein is C1-6 alkyl, preferably CH3.

[0502] 31. R 5 is C1-6 alkyl, preferably CH(CH3)2, or a pharmaceutically acceptable salt or solvate thereof.

[0503] 32. R 4 and R 5 together with the atoms to which they are attached, 1, 2, 3, 4, or 5 independently selected R b 27. The compound of any one of embodiments 24 or 26, or a pharmaceutically acceptable salt or solvate thereof, which forms a 5- or 6-membered heterocycloalkyl ring, optionally substituted with substituents.

[0504] 33. R 4 and R 5 together with the atoms to which they are attached, one or two R b The compound of embodiment 32, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound forms an optionally substituted 5-membered heterocycloalkyl ring, optionally substituted with substituents.

[0505] 34. One or two R's b The substituent is C 1~4 The compound according to embodiment 33, or a pharmaceutically acceptable salt or solvate thereof, wherein R is alkyl, preferably CH.

[0506] 35. R 6 is C1-6 alkyl, preferably CH3, and R 7 is C1-6 alkyl, preferably CH3; or a pharmaceutically acceptable salt or solvate thereof.

[0507] 36. R 6 and R 7together with the carbon atom to which they are both attached form a C4-C7 spirocyclic ring, or a pharmaceutically acceptable salt or solvate thereof.

[0508] 37. The compound according to embodiment 36, or a pharmaceutically acceptable salt or solvate thereof, wherein the C4-C7 spirocyclic ring is a spirocyclopentane ring.

[0509] 38. The compound is a compound of formula (II)

[0510] [ka] 22. A compound according to any one of embodiments 1 to 21, or a pharmaceutically acceptable salt or solvate thereof.

[0511] 39. A 2 NR 8 or a pharmaceutically acceptable salt or solvate thereof.

[0512] 40. A 2 or a pharmaceutically acceptable salt or solvate thereof.

[0513] 41. A 2 The compound of embodiment 38, or a pharmaceutically acceptable salt or solvate thereof, wherein

[0514] 42. B 2 is CR 9 42. The compound of any one of embodiments 38-41, wherein:

[0515] 43. B 2 The compound of any one of embodiments 38-41, or a pharmaceutically acceptable salt or solvate thereof, wherein is N.

[0516] 44. R 8is C1-6 alkyl, preferably CH3; or a pharmaceutically acceptable salt or solvate thereof.

[0517] 45. R 9 is C1-6 alkyl, preferably CH(CH3)2, or a pharmaceutically acceptable salt or solvate thereof.

[0518] 46. ​​R 8 and R 9 together with the atoms to which they are attached, 1, 2, 3, 4, or 5 independently selected R b The compound according to any one of embodiments 39 or 42, or a pharmaceutically acceptable salt or solvate thereof, which forms a 5- or 6-membered heterocycloalkyl ring, optionally substituted with substituents.

[0519] 47. R 8 and R 9 together with the atoms to which they are attached, one or two R b The compound of embodiment 46, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound forms a 5-membered heterocycloalkyl ring, optionally substituted with substituents.

[0520] 48. One or two R's b The substituent is C 1~4 The compound according to embodiment 47, or a pharmaceutically acceptable salt or solvate thereof, wherein R is alkyl, preferably CH3.

[0521] 49. The compound is

[0522] [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein the variables are as defined in embodiment 1.

[0523] 50. The compound has the formula (III) and X 1 is N and X2 is CR 3 and X 3 is CR 3 or a pharmaceutically acceptable salt or solvate thereof.

[0524] 51. The compound has the formula (III) and X 1 is CR 3 and X 2 is N and X 3 is CR 3 or a pharmaceutically acceptable salt or solvate thereof.

[0525] 52. The compound has the formula (III) and X 1 is CR 3 and X 2 is CR 3 and X 3 is N, or a pharmaceutically acceptable salt or solvate thereof.

[0526] 53. The compound has the formula (III) and X 1 is CR 3 and X 2 is CR 3 and X 3 is CR 3 or a pharmaceutically acceptable salt or solvate thereof.

[0527] 54. The compound has the formula (IV) and X 1 is N and X 2 is CR 3 and X 3 is CR 3 or a pharmaceutically acceptable salt or solvate thereof.

[0528] 55. The compound has the formula (IV) and X 1 is CR 3 and X 2 is N and X 3 is CR 3or a pharmaceutically acceptable salt or solvate thereof.

[0529] 56. The compound has the formula (IV) and X 1 is CR 3 and X 2 is CR 3 and X 3 is N, or a pharmaceutically acceptable salt or solvate thereof.

[0530] 57. The compound has the formula (IV) and X 1 is CR 3 and X 2 is CR 3 and X 3 is CR 3 or a pharmaceutically acceptable salt or solvate thereof.

[0531] 58. R 2 H, OH, halogen, CN, C1-6 alkyl, C3- 10 The compound of any one of embodiments 49-57, or a pharmaceutically acceptable salt or solvate thereof, wherein R is cycloalkyl, C1-6 alkoxyl, or 4- to 14-membered heterocycloalkyl.

[0532] 59. R 2 The compound of any one of embodiments 49-57, or a pharmaceutically acceptable salt or solvate thereof, wherein is halogen, or C1-6 alkyl.

[0533] 60. R 2 The compound of any one of embodiments 49-57, or a pharmaceutically acceptable salt or solvate thereof, wherein is C1-6 alkyl.

[0534] 61. R 2 The compound of any one of embodiments 49-57, or a pharmaceutically acceptable salt or solvate thereof, wherein is chloro or fluoro.

[0535] 62. R 4 is H or C alkyl, and R 5 is C1-6 alkyl, or R 4 and R 5 may be substituted with 1, 2, 3, 4, or 5 independently selected R b forming a 5- or 6-membered heterocycloalkyl ring optionally substituted with substituents, Each R b independently, C 1~4 Alkyl, NR c C(=NR c )NR c R c , N.R. c C(=NOH)NR c R c , N.R. c C(=NCN)NR c R c , N.R. c C(O)R c , N.R. c C(O)OR c , N.R. c C(O)NR c R c , N.R. c S(O)R c , or NR c S(O)2R c , N.R. c S(O)NR c R c and Each R c are independently H, C 1~6 Alkyl, C 3~10 cycloalkyl, 4- to 10-membered heterocycloalkyl, or (5- to 10-membered heteroaryl)-C 1~4 alkyl and 1, 2, 3, 4, or 5 independently selected R f optionally substituted with substituents, Each R f are independently halogen, CN or OR g and Each R g are independently H or C 1~6The compound according to any one of embodiments 49-53, of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R is alkyl.

[0536] 63. R 4 The compound according to any one of embodiments 49-53, of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein

[0537] 64. R 4 The compound according to any one of embodiments 49-53, of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein is C1-6 alkyl, preferably CH3.

[0538] 65. R 5 The compound according to any one of embodiments 49-53, of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein is C1-6 alkyl, preferably CH(CH3)2.

[0539] 66. R 4 and R 5 together with the atoms to which they are attached, 1, 2, 3, 4, or 5 independently selected R b The compound according to any one of embodiments 49-53, of formula (III), or a pharmaceutically acceptable salt or solvate thereof, which forms a 5- or 6-membered heterocycloalkyl ring, optionally substituted with substituents.

[0540] 67. R 4 and R 5 together with the atoms to which they are attached, one or two R b 54. The compound of any one of embodiments 49-53, of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0541] 68. One or two R's b The substituent is C 1~4The compound according to embodiment 67, or a pharmaceutically acceptable salt or solvate thereof, wherein R is alkyl, preferably CH3.

[0542] 69. R 2 H, OH, halogen, CN, C1-6 alkyl, C3- 10 The compound according to any one of embodiments 62-68, or a pharmaceutically acceptable salt or solvate thereof, wherein R is cycloalkyl, C1-6 alkoxyl, or 4-14 membered heterocycloalkyl.

[0543] 70. R 2 The compound according to any one of embodiments 62-68, or a pharmaceutically acceptable salt or solvate thereof, wherein is halogen, or C1-6 alkyl.

[0544] 71. R 2 The compound according to any one of embodiments 62-68, or a pharmaceutically acceptable salt or solvate thereof, wherein is C1-6 alkyl.

[0545] 72. R 2 The compound of any one of embodiments 62-68, or a pharmaceutically acceptable salt or solvate thereof, wherein is chloro or fluoro.

[0546] 73. The compound has the formula (III) and R1 is C3- 10 cycloalkyl and 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R b optionally substituted with substituents, Each R b independently, C 1~4 Alkyl, NR c C(=NR c )NR c R c , N.R. c C(=NOH)NR c R c , N.R. c C(=NCN)NR c R c , N.R. c C(O)R c , N.R.c C(O)OR c , N.R. c C(O)NR c R c , N.R. c S(O)R c , or NR c S(O)2R c , N.R. c S(O)NR c R c and Each R c are independently H, C 1~6 Alkyl, C 3~10 cycloalkyl, 4- to 10-membered heterocycloalkyl, or (5- to 10-membered heteroaryl)-C 1~4 alkyl and 1, 2, 3, 4, or 5 independently selected R f optionally substituted with substituents, Each R f are independently halogen, CN or OR g and Each R g are independently H or C 1~6 The compound of any one of embodiments 49-53 and 58-72, or a pharmaceutically acceptable salt or solvate thereof, wherein R is alkyl.

[0547] 74. R 1 But C 3~10 cycloalkyl and one R b A compound according to any one of embodiments 49 to 53 and 58 to 72 of formula (III), or a pharmaceutically acceptable salt or solvate thereof, optionally substituted with a substituent.

[0548] 75. R 1 But C 3~7 cycloalkyl and one R b A compound according to any one of embodiments 49 to 53 and 58 to 72 of formula (III), or a pharmaceutically acceptable salt or solvate thereof, optionally substituted with a substituent.

[0549] 76. R 1 But C 5~6cycloalkyl and one R b A compound according to any one of embodiments 49 to 53 and 58 to 72 of formula (III), or a pharmaceutically acceptable salt or solvate thereof, optionally substituted with a substituent.

[0550] 77. R 1 is cyclopentanyl or cyclohexanyl, and one R b A compound according to any one of embodiments 49 to 53 and 58 to 72 of formula (III), or a pharmaceutically acceptable salt or solvate thereof, optionally substituted with a substituent.

[0551] 78. R 1 One R above b The substituent is NR c C(O)R c , N.R. c C(O)NR c R c , or NR c S(O)NR c R c or a pharmaceutically acceptable salt or solvate thereof.

[0552] 79. NR c C(O)R c , N.R. c C(O)NR c R c , or NR c S(O)NR c R c R in c However, independently, H, C 1~6 Alkyl, C 3~10 cycloalkyl, 4- to 10-membered heterocycloalkyl, or (5- to 10-membered heteroaryl)-C 1~4 alkyl and 1, 2, 3, 4, or 5 independently selected R f The compound of embodiment 78, or a pharmaceutically acceptable salt or solvate thereof, optionally substituted by substituents.

[0553] 80. R fThe substituents are independently halogen, CN, or OR g or a pharmaceutically acceptable salt or solvate thereof.

[0554] 81. R g are independently H or C 1~6 The compound of embodiment 80, or a pharmaceutically acceptable salt or solvate thereof, wherein R is alkyl.

[0555] 82. R 1 One R above b The substituents are acetamide (-NHC(O)CH3), 3-hydroxybutanamide (-NHC(O)CH2CH(OH)CH3), propionamide (-NHC(O)CH2CH3), 2-methoxyacetamide (-NHC(O)CH2-OCH3), 2-cyanoacetamide (-NHC(O)CH2-CN), 1-hydroxycyclopropane-1-carboxamide,

[0556] [ka] 2-(thiazol-4-yl)acetamide,

[0557] [ka] Methylsulfonamide (-NSO2CH3), 3-methylureido (-NC(O)NHCH3), 3-methoxyureido (-NC(O)NHOCH3), 3,3-dimethylureido (-NC(O)N(CH3)2), or 3-ethylureido (-NC(O)NHCH2CH3), morpholine-4-carboxamide, i.e.,

[0558] [ka] or 4-methylpiperazine-1-carboxamide, i.e.,

[0559] [ka] 78. The compound of any one of embodiments 73-77, wherein:

[0560] 83. R 8 is C1-6 alkyl, and R 9 is C1-6 alkyl, or R 8 and R 9 may be substituted with 1, 2, 3, 4, or 5 independently selected R b forming a 5- or 6-membered heterocycloalkyl ring optionally substituted with substituents, Each R b independently, C 1~4 Alkyl, NR c C(=NR c )NR c R c , N.R. c C(=NOH)NR c R c , N.R. c C(=NCN)NR c R c , N.R. c C(O)R c , N.R. c C(O)OR c , N.R. c C(O)NR c R c , N.R. c S(O)R c , or NR c S(O)2R c , N.R. c S(O)NR c R c and Each R c are independently H, C 1~6 Alkyl, C 3~10 cycloalkyl, 4- to 10-membered heterocycloalkyl, or (5- to 10-membered heteroaryl)-C 1~4 alkyl and 1, 2, 3, 4, or 5 independently selected R f optionally substituted with substituents, Each R f are independently halogen, CN or OR g and Each R g are independently H or C 1~6 The compound according to any one of embodiments 49 or 54-57, of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R is alkyl.

[0561] 84. R 8 The compound according to any one of embodiments 49, 54-57, and 83 of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein is C1-6 alkyl, preferably CH3.

[0562] 85. R 9 The compound according to any one of embodiments 49, 54-57, and 83 of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein is C1-6 alkyl, preferably CH(CH3)2.

[0563] 86. R 8 and R 9 together with the atoms to which they are attached, 1, 2, 3, 4, or 5 independently selected R b A compound according to any one of embodiments 49, 54-57, and 83 of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, which forms a 5- or 6-membered heterocycloalkyl ring, optionally substituted with substituents.

[0564] 87. R 8 and R 9 together with the atoms to which they are attached, one or two R b The compound of embodiment 86, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound forms a 5-membered heterocycloalkyl ring, optionally substituted with substituents.

[0565] 88. 1 or 2 R b The substituent is C 1~4 The compound according to embodiment 87, or a pharmaceutically acceptable salt or solvate thereof, wherein R is alkyl, preferably CH3.

[0566] 89. R 2H, OH, halogen, CN, C1-6 alkyl, C3- 10 The compound according to any one of embodiments 83-88, or a pharmaceutically acceptable salt or solvate thereof, wherein R is cycloalkyl, C1-6 alkoxyl, or 4-14 membered heterocycloalkyl.

[0567] 90. R 2 The compound according to any one of embodiments 83-88, or a pharmaceutically acceptable salt or solvate thereof, wherein is halogen, or C1-6 alkyl.

[0568] 91. R 2 The compound according to any one of embodiments 83-88, or a pharmaceutically acceptable salt or solvate thereof, wherein is C1-6 alkyl.

[0569] 92. R 2 The compound of any one of embodiments 83-88, or a pharmaceutically acceptable salt or solvate thereof, wherein is chloro or fluoro.

[0570] 93. R1 is C3~ 10 cycloalkyl and 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R b optionally substituted with substituents, Each R b independently, C 1~4 Alkyl, NR c C(=NR c )NR c R c , N.R. c C(=NOH)NR c R c , N.R. c C(=NCN)NR c R c , N.R. c C(O)R c , N.R. c C(O)OR c , N.R. c C(O)NR c R c , N.R. c S(O)R c , or NRc S(O)2R c , N.R. c S(O)NR c R c and Each R c are independently H, C 1~6 Alkyl, C 3~10 cycloalkyl, 4- to 10-membered heterocycloalkyl, or (5- to 10-membered heteroaryl)-C 1~4 alkyl and 1, 2, 3, 4, or 5 independently selected R f optionally substituted with substituents, Each R f are independently halogen, CN or OR g and Each R g are independently H or C 1~6 The compound according to any one of embodiments 49, 54-57, and 83-92 of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R is alkyl.

[0571] 94. R 1 But C 3~10 cycloalkyl and one R b A compound according to any one of embodiments 49, 54-57 and 83-92 of formula (IV) or a pharmaceutically acceptable salt or solvate thereof, optionally substituted with a substituent.

[0572] 95. R 1 But C 3~7 cycloalkyl and one R b A compound according to any one of embodiments 49, 54-57 and 83-92 of formula (IV) or a pharmaceutically acceptable salt or solvate thereof, optionally substituted with a substituent.

[0573] 96. R 1 But C 5~6 cycloalkyl and one R b A compound according to any one of embodiments 49, 54-57 and 83-92 of formula (IV) or a pharmaceutically acceptable salt or solvate thereof, optionally substituted with a substituent.

[0574] 97. R 1 is cyclopentanyl or cyclohexanyl, and one R b A compound according to any one of embodiments 49, 54-57 and 83-92 of formula (IV) or a pharmaceutically acceptable salt or solvate thereof, optionally substituted with a substituent.

[0575] 98. R 1 One R above b The substituent is NR c C(O)R c , N.R. c C(O)NR c R c , or NR c S(O)NR c R c 98. The compound of any one of embodiments 93-97, wherein:

[0576] 99. NR c C(O)R c , N.R. c C(O)NR c R c , or NR c S(O)NR c R c R in c However, independently, H, C 1~6 Alkyl, C 3~10 cycloalkyl, 4- to 10-membered heterocycloalkyl, or (5- to 10-membered heteroaryl)-C 1~4 alkyl and 1, 2, 3, 4, or 5 independently selected R f The compound of embodiment 98, or a pharmaceutically acceptable salt or solvate thereof, optionally substituted by substituents.

[0577] 100. R f The substituents are independently halogen, CN, or OR g or a pharmaceutically acceptable salt or solvate thereof.

[0578] 101. R gare independently H or C 1~6 The compound of embodiment 100, or a pharmaceutically acceptable salt or solvate thereof, wherein R is alkyl.

[0579] 102. R 1 One R above b The substituents are acetamide (-NHC(O)CH3), 3-hydroxybutanamide (-NHC(O)CH2CH(OH)CH3), propionamide (-NHC(O)CH2CH3), 2-methoxyacetamide (-NHC(O)CH2-OCH3), 2-cyanoacetamide (-NHC(O)CH2-CN), 1-hydroxycyclopropane-1-carboxamide,

[0580] [ka] 2-(thiazol-4-yl)acetamide,

[0581] [ka] Methylsulfonamide (-NSO2CH3), 3-methylureido (-NC(O)NHCH3), 3-methoxyureido (-NC(O)NHOCH3), 3,3-dimethylureido (-NC(O)N(CH3)2), or 3-ethylureido (-NC(O)NHCH2CH3), morpholine-4-carboxamide, i.e.,

[0582] [ka] or 4-methylpiperazine-1-carboxamide, i.e.,

[0583] [ka] 98. The compound of any one of embodiments 93-97, wherein:

[0584] 103. Each R 3are independently H, OH, halogen, CN, C1-6 alkyl, C3- 10 The compound according to any one of embodiments 49-102, or a pharmaceutically acceptable salt or solvate thereof, wherein R is cycloalkyl, C1-6 alkoxyl, or 4-14 membered heterocycloalkyl.

[0585] 104. Each R 3 is independently H or halogen, preferably Cl or F; or a pharmaceutically acceptable salt or solvate thereof.

[0586] 105. R 3 Only one of the following is OH, halogen, CN, C1-6 alkyl, C3- 10 The compound according to any one of embodiments 49-102, or a pharmaceutically acceptable salt or solvate thereof, wherein R is cycloalkyl, C 1-6 alkoxyl, or 4-14 membered heterocycloalkyl, the remainder being H.

[0587] 106. R 3 or a pharmaceutically acceptable salt or solvate thereof, according to any one of embodiments 49-102, wherein one of is halogen, preferably Cl or F, and the rest are H.

[0588] 107. The compound is

[0589] [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein the variables are as defined in embodiment 1.

[0590] 108. R 2 H, OH, halogen, CN, C1-6 alkyl, C3- 10 The compound of Formulae (V)-(XII) according to embodiment 107, or a pharmaceutically acceptable salt or solvate thereof, wherein R is cycloalkyl, C1-6 alkoxyl, or 4- to 14-membered heterocycloalkyl.

[0591] 109. R 2 The compound of Formulae (V)-(XII) or a pharmaceutically acceptable salt or solvate thereof according to embodiment 106, wherein is halogen, or C1-6 alkyl.

[0592] 110. R 2 or a pharmaceutically acceptable salt or solvate thereof.

[0593] 111. R 2 The compound of Formulae (V)-(XII) or a pharmaceutically acceptable salt or solvate thereof according to embodiment 106, wherein is chloro or fluoro.

[0594] 112. R1 is C3~ 10 cycloalkyl and 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R b optionally substituted with substituents, Each R b independently, C 1~4 Alkyl, NR c C(=NR c )NR c R c , N.R. c C(=NOH)NR c R c , N.R. c C(=NCN)NR c R c , N.R. c C(O)R c , N.R. c C(O)OR c , N.R. c C(O)NR c R c , N.R. c S(O)R c , or NR c S(O)2R c , N.R. c S(O)NR c R c and Each R c are independently H, C1~6 Alkyl, C 3~10 cycloalkyl, 4- to 10-membered heterocycloalkyl, or (5- to 10-membered heteroaryl)-C 1~4 alkyl and 1, 2, 3, 4, or 5 independently selected R f optionally substituted with substituents, Each R f are independently halogen, CN or OR g and Each R g are independently H or C 1~6 The compound of any one of embodiments 107-111, or a pharmaceutically acceptable salt or solvate thereof, wherein R is alkyl.

[0595] 113. R 1 But C 3~10 cycloalkyl and one R b 112. The compound according to any one of embodiments 107 to 111, or a pharmaceutically acceptable salt or solvate thereof, optionally substituted with a substituent.

[0596] 114. R 1 But C 3~7 cycloalkyl and one R b 112. The compound according to any one of embodiments 107 to 111, or a pharmaceutically acceptable salt or solvate thereof, optionally substituted with a substituent.

[0597] 115. R 1 But C 5~6 cycloalkyl and one R b 112. The compound according to any one of embodiments 107 to 111, or a pharmaceutically acceptable salt or solvate thereof, optionally substituted with a substituent.

[0598] 116. R 1 is cyclopentanyl or cyclohexanyl, and one R b 112. The compound according to any one of embodiments 107 to 111, or a pharmaceutically acceptable salt or solvate thereof, optionally substituted with a substituent.

[0599] 117. R 1 One R above b The substituent is NR c C(O)R c , N.R. c C(O)NR c R c , or NR c S(O)NR c R c 117. The compound of any one of embodiments 112-116, wherein:

[0600] 118. NR c C(O)R c , N.R. c C(O)NR c R c , or NR c S(O)NR c R c R in c However, independently, H, C 1~6 Alkyl, C 3~10 cycloalkyl, 4- to 10-membered heterocycloalkyl, or (5- to 10-membered heteroaryl)-C 1~4 alkyl and 1, 2, 3, 4, or 5 independently selected R f The compound of embodiment 117, or a pharmaceutically acceptable salt or solvate thereof, optionally substituted by substituents.

[0601] 119. R f The substituents are independently halogen, CN, or OR g or a pharmaceutically acceptable salt or solvate thereof.

[0602] 120. R g are independently H or C 1~6 The compound of embodiment 119, or a pharmaceutically acceptable salt or solvate thereof, wherein R is alkyl.

[0603] 121. R 1 One R above bThe substituents are acetamide (-NHC(O)CH3), 3-hydroxybutanamide (-NHC(O)CH2CH(OH)CH3), propionamide (-NHC(O)CH2CH3), 2-methoxyacetamide (-NHC(O)CH2-OCH3), 2-cyanoacetamide (-NHC(O)CH2-CN), 1-hydroxycyclopropane-1-carboxamide,

[0604] [ka] 2-(thiazol-4-yl)acetamide,

[0605] [ka] Methylsulfonamide (-NSO2CH3), 3-methylureido (-NC(O)NHCH3), 3-methoxyureido (-NC(O)NHOCH3), 3,3-dimethylureido (-NC(O)N(CH3)2), or 3-ethylureido (-NC(O)NHCH2CH3), morpholine-4-carboxamide, i.e.,

[0606] [ka] or 4-methylpiperazine-1-carboxamide, i.e.,

[0607] [ka] 117. The compound of any one of embodiments 112-116, wherein:

[0608] 122. The compound is a compound of formula (V), formula (VI), formula (VII), or formula (XI)

[0609] [ka] 122. A compound according to any one of embodiments 107 to 121, or a pharmaceutically acceptable salt or solvate thereof.

[0610] 123. A 1 The compound of embodiment 122, or a pharmaceutically acceptable salt or solvate thereof, wherein

[0611] 124. A 1 is CR 4 or a pharmaceutically acceptable salt or solvate thereof.

[0612] 125. B 1 is CR 6 R 7 125. The compound of any one of embodiments 122-124, wherein:

[0613] 126. B 1 NR 5 125. The compound of any one of embodiments 122-124, wherein:

[0614] 127. B 1 The compound according to any one of embodiments 122-124, or a pharmaceutically acceptable salt or solvate thereof, wherein

[0615] 128. B 1 The compound according to any one of embodiments 122-124, or a pharmaceutically acceptable salt or solvate thereof, wherein

[0616] 129. R 4 The compound of any one of embodiments 124-128, or a pharmaceutically acceptable salt or solvate thereof, wherein

[0617] 130. R 4 The compound according to any one of embodiments 124-128, or a pharmaceutically acceptable salt or solvate thereof, wherein is C1-6 alkyl, preferably CH3.

[0618] 131. R 5 is C1-6 alkyl, preferably CH(CH3)2, or a pharmaceutically acceptable salt or solvate thereof.

[0619] 132. R 4 and R 5 together with the atoms to which they are attached, 1, 2, 3, 4, or 5 independently selected R b 127. The compound according to any one of embodiments 124 or 126, or a pharmaceutically acceptable salt or solvate thereof, which forms a 5- or 6-membered heterocycloalkyl ring, optionally substituted with substituents.

[0620] 133. R 4 and R 5 together with the atoms to which they are attached, one or two R b The compound according to embodiment 132, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound forms an optionally substituted 5-membered heterocycloalkyl ring, optionally substituted with substituents.

[0621] 134. One or two R's b The substituent is C 1~4 The compound according to embodiment 133, or a pharmaceutically acceptable salt or solvate thereof, wherein R is alkyl, preferably CH3.

[0622] 135. R 6 is C1-6 alkyl, preferably CH3, and R 7 is C1-6 alkyl, preferably CH3; or a pharmaceutically acceptable salt or solvate thereof.

[0623] 136. R 6 and R 7 But together with the carbon atom to which both are attached, C 4~ The compound according to embodiment 125, or a pharmaceutically acceptable salt or solvate thereof, which forms a C7 spirocyclic ring.

[0624] 137. The compound according to embodiment 136, or a pharmaceutically acceptable salt or solvate thereof, wherein the C4-C7 spirocyclic ring is a spirocyclopentane ring.

[0625] 138. The compound is a compound of formula (VIII), formula (IX), formula (X), or formula (XII).

[0626] [ka] 122. A compound according to any one of embodiments 107 to 121, or a pharmaceutically acceptable salt or solvate thereof.

[0627] 139. A 2 NR 8 or a pharmaceutically acceptable salt or solvate thereof.

[0628] 140. A 2 or a pharmaceutically acceptable salt or solvate thereof.

[0629] 141. A 2 The compound of embodiment 138, or a pharmaceutically acceptable salt or solvate thereof, wherein

[0630] 142. B 2 is CR 9 142. The compound of any one of embodiments 138-141, wherein:

[0631] 143. B 2 The compound according to any one of embodiments 138-141, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0632] 144. R 8 is C1-6 alkyl, preferably CH3; or a pharmaceutically acceptable salt or solvate thereof.

[0633] 145. R 9 is C1-6 alkyl, preferably CH(CH3)2, or a pharmaceutically acceptable salt or solvate thereof.

[0634] 146. R 8 and R 9 together with the atoms to which they are attached, 1, 2, 3, 4, or 5 independently selected R b 143. The compound according to any one of embodiments 139 or 142, or a pharmaceutically acceptable salt or solvate thereof, which forms a 5- or 6-membered heterocycloalkyl ring, optionally substituted with substituents.

[0635] 147. R 8 and R 9 together with the atoms to which they are attached, one or two R b The compound according to embodiment 146, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound forms a 5-membered heterocycloalkyl ring, optionally substituted with substituents.

[0636] 148. One or two R's b The substituent is C 1~4 The compound according to embodiment 147, or a pharmaceutically acceptable salt or solvate thereof, wherein R is alkyl, preferably CH3.

[0637] 149. R 3 H, OH, halogen, CN, C1-6 alkyl, C3- 10 The compound according to any one of embodiments 107-148, or a pharmaceutically acceptable salt or solvate thereof, wherein R is cycloalkyl, C1-6 alkoxyl, or 4- to 14-membered heterocycloalkyl.

[0638] 150. R 3 The compound according to any one of embodiments 107-148, or a pharmaceutically acceptable salt or solvate thereof, wherein is H or halogen, preferably Cl or F.

[0639] 151. R 1 but,

[0640] [ka] where n is 0 or 1, and R b The compound of any one of embodiments 1 to 13, 19 to 77, 83 to 97, 103 to 116, and 122 to 150, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0641] 152. R 1 One R above b The substituent is NR c C(O)R c , N.R. c C(O)NR c R c , or NR c S(O)NR c R c or a pharmaceutically acceptable salt or solvate thereof.

[0642] 153. NR c C(O)R c , N.R. c C(O)NR c R c , or NR c S(O)NR c R c R in c However, independently, H, C 1~6 Alkyl, C 3~10 cycloalkyl, 4- to 10-membered heterocycloalkyl, or (5- to 10-membered heteroaryl)-C 1~4 alkyl and 1, 2, 3, 4, or 5 independently selected R f The compound according to embodiment 152, or a pharmaceutically acceptable salt or solvate thereof, optionally substituted by substituents.

[0643] 154. R f The substituents are independently halogen, CN, or OR gor a pharmaceutically acceptable salt or solvate thereof.

[0644] 155. R g are independently H or C 1~6 The compound of embodiment 154, or a pharmaceutically acceptable salt or solvate thereof, wherein R is alkyl.

[0645] 156. R 1 One R above b The substituents are acetamide (-NHC(O)CH3), 3-hydroxybutanamide (-NHC(O)CH2CH(OH)CH3), propionamide (-NHC(O)CH2CH3), 2-methoxyacetamide (-NHC(O)CH2-OCH3), 2-cyanoacetamide (-NHC(O)CH2-CN), 1-hydroxycyclopropane-1-carboxamide,

[0646] [ka] 2-(thiazol-4-yl)acetamide,

[0647] [ka] Methylsulfonamide (-NSO2CH3), 3-methylureido (-NC(O)NHCH3), 3-methoxyureido (-NC(O)NHOCH3), 3,3-dimethylureido (-NC(O)N(CH3)2), or 3-ethylureido (-NC(O)NHCH2CH3), morpholine-4-carboxamide, i.e.,

[0648] [ka] or 4-methylpiperazine-1-carboxamide, i.e.,

[0649] [ka] 156. The compound of any one of embodiments 1-155, wherein:

[0650] 157. The compound is

[0651] [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0652] 158. The compound is

[0653] [ka] and has the formula During the ceremony, R 2 is Me or OMe, R 3 is H, D, or F, R 4 is H or C1-3 alkyl, R 5 is isopropyl, —CF3(CH)CH3, —C3-6 cycloalkyl, or —CH2—(C3-6 cycloalkyl); R b NHCOR 13 or CN, R 13 is H or optionally substituted C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, C 3~10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4 Alkyl, (5-10 membered heteroaryl)-C 1~4 Alkyl- or (4- to 10-membered heterocycloalkyl)-C 1~4The compound of embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R is alkyl.

[0654] 159. The compound is

[0655] [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0656] 160. The compound is

[0657] [ka] and has the formula During the ceremony, R 2 is H, D, halogen, or Me; R 3 is H, D, or F, R 10 is H, D, Me, or C1-3 haloalkyl; R 11 is H, D, Me, or C1-3 haloalkyl; R b NHCOR 14 and R 14 is H, -CHCN, or an optionally substituted C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, C 3~10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6~10 Aryl-C 1~4 Alkyl, C 3~10 Cycloalkyl-C 1~4 Alkyl, (5-10 membered heteroaryl)-C 1~4 Alkyl- or (4- to 10-membered heterocycloalkyl)-C 1~4 The compound of embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R is alkyl.

[0658] 161. The compound is

[0659] [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0660] 162. The compound is (1S,3R)-3-acetamido-N-[5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-indazol-5-yl)-2-pyridyl]cyclohexanecarboxamide, (1S,3R)-N-[5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-indazol-5-yl)-2-pyridyl]-3-[(1-hydroxycyclopropanecarbonyl)amino]-cyclohexanecarboxamide, (1S,3R)—N-(5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)-3-(2-(thiazol-4-yl)acetamide)cyclohexane-1-carboxamide, (1S,3R)—N-(5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)-3-(2-methoxyacetamido)cyclohexane-1-carboxamide, (1S,3R)—N-(5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)-3-propionamido-cyclohexane-1-carboxamide, (1S,3R)-N-[5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-indazol-5-yl)-2-pyridyl]-3-(methanesulfonamido)cyclohexanecarboxamide, N-[(1R,3S)-3-[[5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-indazol-5-yl)-2-pyridyl]carbamoyl]cyclohexyl]morpholine-4-carboxamide, N-((1R,3S)-3-((5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)carbamoyl)-cyclohexyl)-4-methylpiperazine-1-carboxamide, (1S,3R)—N-(5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)-3-(3-methylureido)cyclohexane-1-carboxamide, (1S,3R)—N-(5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)-3-(3,3-dimethylureido)cyclohexane-1-carboxamide, (1S,3R)—N-(5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)-3-(3-ethylureido)cyclohexane-1-carboxamide, (1S,3R)—N-(5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)-3-(3-methoxyureido)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-[5-chloro-4-(5-fluoro-1,1-dimethyl-2,3-dihydropyrrolo[1,2-a]benzimidazol-7-yl)-2-pyridyl]cyclohexanecarboxamide, (1S,3R)—N-(5-chloro-4-(5-fluoro-1,1-dimethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyridin-2-yl)-3-(2-cyanoacetamido)cyclohexane-1-carboxamide, (1S,3R)—N-(5-chloro-4-(5-fluoro-1,1-dimethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyridin-2-yl)-3-(3-hydroxybutanamido)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(5-chloro-4-(1,1-dimethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyridin-2-yl)cyclopentane-1-carboxamide, (1S,3R)—N-(5-chloro-4-(5-fluoro-1,1-dimethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyridin-2-yl)-3-propionamidocyclohexane-1-carboxamide, (1S,3R)—N-(5-chloro-4-(1,1-dimethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyridin-2-yl)-3-propionamidocyclopentane-1-carboxamide, (1S,3R)—N-(5-chloro-4-(5-fluoro-1,1-dimethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyridin-2-yl)-3-(1-hydroxycyclopropane-1-carboxamido)cyclohexane-1-carboxamide, (1S,3R)—N-(5-chloro-4-(5-fluoro-1,1-dimethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyridin-2-yl)-3-(2-methoxyacetamido)cyclohexane-1-carboxamide, (1S,3R)—N-(5-chloro-4-(5-fluoro-1,1-dimethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyridin-2-yl)-3-(methylsulfonamido)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(4-(5-fluoro-1,1-dimethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)-5-methylpyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)cyclopentane-1-carboxamide, (1S,3R)-3-acetamido-N-(5-chloro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl)pyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(5-chloro-4-(3-isopropylbenzo[c]isothiazol-5-yl)pyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(5-chloro-4-(1-methyl-2,3-dihydro-1H-pyrrolo[1,2-b]indazol-8-yl)pyridin-2-yl)cyclohexane-1-carboxamide (1S,3R)-3-(3,3-dimethylureido)-N-(4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)—N-(4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)-3-propionamidocyclohexane-1-carboxamide, (1S,3R)—N-(4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)-3-isobutyramidocyclohexane-1-carboxamide, (1S,3R)—N-(4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)-3-(2-methoxyacetamido)cyclohexane-1-carboxamide, (1S,3R)-3-(2-(dimethylamino)acetamido)-N-(4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)cyclohexane-1-carboxamide, methyl((1R,3S)-3-((4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)carbamoyl)cyclohexyl)carbamate, (1S,3R)—N-(4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)-3-(methylsulfonamido)cyclohexane-1-carboxamide, (1S,3R)—N-(4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)-3-(1-fluorocyclopropane-1-carboxamido)cyclohexane-1-carboxamide, (1S,3R)—N-(4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)-3-(1-hydroxycyclopropane-1-carboxamido)cyclohexane-1-carboxamide, N-((1R,3S)-3-((4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)carbamoyl)cyclohexyl)-1-methylazetidine-3-carboxamide, (1S,3R)-N-(4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)-3-((1r,3R)-3-hydroxycyclobutane-1-carboxamido)cyclohexane-1-carboxamide, (1S,3R)—N-(4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)-3-(2-hydroxyacetamido)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(4-(4-fluoro-1-(oxetan-3-yl)-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(4-(1-cyclopropyl-4-fluoro-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(4-(1-(cyclopropylmethyl)-4-fluoro-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)cyclohexane-1-carboxamide, (S)—N-((1R,3S)-3-((4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)carbamoyl)cyclohexyl)-3-hydroxypyrrolidine-1-carboxamide, (1S,3R)—N-(4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)-3-(3-methylureido)cyclohexane-1-carboxamide, N-((1R,3S)-3-((4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)carbamoyl)cyclohexyl)morpholine-4-carboxamide, N-((1R,3S)-3-((4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)carbamoyl)cyclohexyl)-4-methylpiperazine-1-carboxamide, (1S,3R)—N-[4-(7-fluoro-3-isopropyl-benzimidazol-5-yl)-5-methyl-2-pyridyl]-3-[(methylsulfonimidoyl)amino]cyclohexanecarboxamide, (1S,3R)-N1-(4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)-N3-methylcyclohexane-1,3-dicarboxamide, 3-cyano-N-(4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-(3,3-dimethylureido)-N-(4-(4-fluoro-1-(1,1,1-trifluoropropan-2-yl)-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(5-chloro-4-(1,1-dimethyl-2,3-dihydro-1H-pyrrolo[1,2-b]indazol-8-yl)pyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(5-chloro-4-(7-fluoro-3-(1-hydroxypropan-2-yl)-2-methyl-2H-indazol-5-yl)pyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(5-chloro-4-(7-fluoro-3-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-5-yl)pyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(5-chloro-4-(3-cyclopropyl-7-fluoro-2-methyl-2H-indazol-5-yl)pyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(5-chloro-4-(3-isopropyl-2-methyl-2H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)-5-methylpyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)—N-(5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)-3-(1-fluorocyclopropane-1-carboxamido)cyclohexane-1-carboxamide, N-((1R,3S)-3-((5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)carbamoyl)cyclohexyl)-2-methoxynicotinamide, N-((1R,3S)-3-((5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)carbamoyl)cyclohexyl)-5-methylisoxazole-3-carboxamide, N-((1R,3S)-3-((5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)carbamoyl)cyclohexyl)-6-methylnicotinamide, (1S,3R)—N-(4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)-5-methylpyridin-2-yl)-3-(2-methoxyacetamido)cyclohexane-1-carboxamide, (1S,3R)—N-(4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)-5-methylpyridin-2-yl)-3-(2-methoxyacetamido)cyclohexane-1-carboxamide, N-((1R,3S)-3-((4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)-5-methylpyridin-2-yl)carbamoyl)cyclohexyl)-5-methylisoxazole-3-carboxamide, N-((1R,3S)-3-((4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)-5-methylpyridin-2-yl)carbamoyl)cyclohexyl)-2-methoxynicotinamide, (1S,3R)—N-(5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)-3-(2-cyanoacetamido)cyclohexane-1-carboxamide, (1S,3R)-3-(2-cyanoacetamido)-N-(4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)-5-methylpyridin-2-yl)cyclohexane-1-carboxamide, N-((1R,3S)-3-((4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)-5-methylpyridin-2-yl)carbamoyl)cyclohexyl)morpholine-4-carboxamide, (1S,3R)-3-(3-ethylureido)-N-(4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)cyclohexane-1-carboxamide, N-((1R,3S)-3-((4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)carbamoyl)cyclohexyl)azetidine-1-carboxamide, methyl ((1R,3S)-3-((5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate, tetrahydro-2H-pyran-4-yl((1R,3S)-3-((5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate, (1-methyl-1H-pyrazol-3-yl)methyl ((1R,3S)-3-((5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate, (2,2-difluorocyclopropyl)methyl((1R,3S)-3-((5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate, (1S,3R)-3-acetamido-N-(5-chloro-4-(7-fluoro-2-methyl-3-(1,1,1-trifluoro-2-hydroxypropan-2-yl)-2H-indazol-5-yl)pyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(5-chloro-4-(3-(1,1-difluoro-2-hydroxypropan-2-yl)-7-fluoro-2-methyl-2H-indazol-5-yl)pyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-(2-cyanoacetamido)-N-(4-(7-fluoro-2-methyl-3-(1,1,1-trifluoro-2-hydroxypropan-2-yl)-2H-indazol-5-yl)-5-methylpyridin-2-yl)cyclohexane-1-carboxamide (P1), (1S,3R)-3-(2-cyanoacetamido)-N-(4-(7-fluoro-2-methyl-3-(1,1,1-trifluoro-2-hydroxypropan-2-yl)-2H-indazol-5-yl)-5-methylpyridin-2-yl)cyclohexane-1-carboxamide (P2), (1S,3R)-3-acetamido-N-(5-chloro-4-(7-fluoro-2-methyl-3-(1,1,1-trifluoro-2-hydroxypropan-2-yl)-2H-indazol-5-yl)pyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(5-chloro-4-(3-(1,1-difluoro-2-hydroxypropan-2-yl)-7-fluoro-2-methyl-2H-indazol-5-yl)pyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)—N-(5-chloro-4-(3-(1,1-difluoro-2-hydroxypropan-2-yl)-7-fluoro-2-methyl-2H-indazol-5-yl)pyridin-2-yl)-3-(2-cyanoacetamido)cyclohexane-1-carboxamide, (1S,3R)-3-(2-cyanoacetamido)-N-(4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methoxypyridin-2-yl)cyclohexane-1-carboxamide, N-((1R,3S)-3-((5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)carbamoyl)cyclohexyl)bicyclo[1.1.1]pentane-1-carboxamide, (1S,3R)-3-acetamido-N-(5-chloro-4-(4-fluoro-1-isopropyl-1H-benzo[d][1,2,3]triazol-6-yl)pyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(5-chloro-4-(3-isopropyl-3H-imidazo[4,5-b]pyridin-5-yl)pyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)—N-(5-chloro-4-(9-fluoro-4,4-dimethyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyridin-2-yl)-3-(2-cyanoacetamido)cyclohexane-1-carboxamide, (1S,3R)-3-(2-cyanoacetamido)-N-(4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)-5-methylpyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(5-chloro-4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyridin-2-yl)cyclohexane-1-carboxamide, 2. The compound of embodiment 1, selected from the group consisting of: (1S,3R)-3-acetamido-N-(4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyridin-2-yl)cyclohexane-1-carboxamide, or a pharmaceutically acceptable salt or solvate thereof.

[0661] 163. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 162, or a pharmaceutically acceptable salt or solvate thereof, and optionally a pharmaceutically acceptable excipient.

[0662] 164. The pharmaceutical composition according to embodiment 163, wherein the pharmaceutical composition comprises one enantiomer of the compound, or a pharmaceutically acceptable salt or solvate thereof, in at least 90% enantiomeric excess.

[0663] 165. The pharmaceutical composition according to embodiment 163, wherein the pharmaceutical composition comprises one enantiomer of the compound, or a pharmaceutically acceptable salt or solvate thereof, in at least 95% enantiomeric excess.

[0664] 166. The pharmaceutical composition according to embodiment 163, wherein the pharmaceutical composition comprises one enantiomer of the compound, or a pharmaceutically acceptable salt or solvate thereof, in enantiomeric excess of at least 98%.

[0665] 167. The pharmaceutical composition according to embodiment 163, wherein the pharmaceutical composition comprises one enantiomer of the compound, or a pharmaceutically acceptable salt or solvate thereof, in enantiomeric excess of at least 99%.

[0666] 168. A method for inhibiting a CDK enzyme, comprising contacting the CDK enzyme with an effective amount of a compound according to any one of embodiments 1 to 162 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to any one of embodiments 163 to 167.

[0667] 169. The method of embodiment 168, wherein the CDK enzyme is CDK9.

[0668] 170. A method for treating a disease or disorder associated with abnormal CDK activity in a subject or a subject in need thereof, comprising administering to the subject a compound of any one of embodiments 1-162 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of any one of embodiments 163-167.

[0669] 171. The method of embodiment 170, wherein the disease or disorder associated with abnormal CDK activity is colon cancer, breast cancer, small cell lung cancer, non-small cell lung cancer, bladder cancer, ovarian cancer, prostate cancer, chronic lymphocytic leukemia, lymphoma, myeloma, acute myeloid leukemia, or pancreatic cancer.

[0670] 172. A method of treating cancer in a subject or a subject in need thereof, comprising administering to the subject a compound according to any one of embodiments 1-162, or a pharmaceutically acceptable salt or solvate thereof.

[0671] 173. The method of embodiment 172, wherein the cancer is colon cancer, breast cancer, small cell lung cancer, non-small cell lung cancer, bladder cancer, ovarian cancer, prostate cancer, chronic lymphocytic leukemia, lymphoma, myeloma, acute myeloid leukemia, or pancreatic cancer.

[0672] 174. A compound according to any one of embodiments 1-162 for use in inhibiting a CDK enzyme in a subject, the use comprising administering to the subject an effective amount of a compound according to any one of embodiments 1-162, or a pharmaceutically acceptable salt, solvate, pharmaceutical composition, or prodrug thereof.

[0673] 175. A pharmaceutical composition described in any one of embodiments 163 to 167 for use in inhibiting a CDK enzyme in a subject, the use comprising administering to the subject an effective amount of the pharmaceutical composition described in any one of embodiments 163 to 167.

[0674] 176. Use of a compound according to any one of embodiments 1-162 in the manufacture of a formulation for inhibiting a CDK enzyme in a subject, the use comprising administering to the subject an effective amount of a compound according to any one of embodiments 1-162 or a pharmaceutically acceptable salt, solvate, pharmaceutical composition, or prodrug thereof.

[0675] 177. Use of a pharmaceutical composition described in any one of embodiments 163 to 167 for inhibiting a CDK enzyme in a subject, the use comprising administering to the subject an effective amount of a pharmaceutical composition described in any one of embodiments 163 to 167.

[0676] 178. The use of any one of embodiments 174 to 177, wherein the CDK enzyme is CDK9.

[0677] 179. A compound according to any one of embodiments 1-162 for use in treating a disease or disorder associated with abnormal CDK activity in a subject or in a subject in need thereof, the use comprising administering to the subject an effective amount of a compound according to any one of embodiments 1-162 or a pharmaceutically acceptable salt, solvate, pharmaceutical composition, or prodrug thereof.

[0678] 180. A pharmaceutical composition according to any one of embodiments 163 to 167 for use in treating a disease or disorder associated with abnormal CDK activity in a subject or a subject in need thereof, the use comprising administering to the subject an effective amount of the pharmaceutical composition according to any one of embodiments 163 to 167.

[0679] 181. Use of a compound according to any one of embodiments 1-162 in the manufacture of a formulation for treating a disease or disorder associated with abnormal CDK activity in a subject or in a subject in need thereof, the use comprising administering to the subject an effective amount of a compound according to any one of embodiments 1-162 or a pharmaceutically acceptable salt, solvate, pharmaceutical composition, or prodrug thereof.

[0680] 182. Use of a pharmaceutical composition described in any one of embodiments 163 to 167 for treating a disease or disorder associated with abnormal CDK activity in a subject or a subject in need thereof, the use comprising administering to the subject an effective amount of a pharmaceutical composition described in any one of embodiments 163 to 167.

[0681] 183. The use according to any one of embodiments 179 to 182, wherein the disease or disorder associated with abnormal CDK activity is colon cancer, breast cancer, small cell lung cancer, non-small cell lung cancer, bladder cancer, ovarian cancer, prostate cancer, chronic lymphocytic leukemia, lymphoma, myeloma, acute myeloid leukemia, or pancreatic cancer.

[0682] 184. A compound according to any one of embodiments 1-162 for use in treating cancer in a subject or in a subject in need thereof, the use comprising administering to the subject an effective amount of a compound according to any one of embodiments 1-162 or a pharmaceutically acceptable salt, solvate, pharmaceutical composition, or prodrug thereof.

[0683] 185. A pharmaceutical composition according to any one of embodiments 163 to 167 for use in treating cancer in a subject or a subject in need thereof, the use comprising administering to the subject an effective amount of the pharmaceutical composition according to any one of embodiments 163 to 167.

[0684] 186. Use of a compound according to any one of embodiments 1-162 in the manufacture of a formulation for treating cancer in a subject or a subject in need thereof, the use comprising administering to the subject an effective amount of a compound according to any one of embodiments 1-162 or a pharmaceutically acceptable salt, solvate, pharmaceutical composition, or prodrug thereof.

[0685] 187. Use of a pharmaceutical composition according to any one of embodiments 163 to 167 for treating cancer in a subject or a subject in need thereof, the use comprising administering to the subject an effective amount of a pharmaceutical composition according to any one of embodiments 163 to 167.

[0686] 188. The use according to any one of embodiments 183 to 187, wherein the cancer is colon cancer, breast cancer, small cell lung cancer, non-small cell lung cancer, bladder cancer, ovarian cancer, prostate cancer, chronic lymphocytic leukemia, lymphoma, myeloma, acute myeloid leukemia, or pancreatic cancer.

[0687] The following examples are illustrative, but not limiting, of the methods and compositions described herein. Other suitable adaptations and modifications of the variety of conditions and parameters normally encountered in the therapeutic, synthetic, and other embodiments disclosed herein are within the spirit and scope of the embodiments.

[0688] Compounds provided herein include, for example, Examples 1-88, exemplified or identified in Table A and Tables 1-8. In some embodiments, the compounds described herein can be prepared in trifluoroacetic acid ("TFA") salt form, although the TFA salt form is a non-limiting example of a salt form, and the compounds can also be prepared in other salt forms. For example, Examples 1-27, 43-46, 48, 50-75, 76-1, 76-2, 77-79, and 81-88 are prepared in TFA salt form.

[0689] [Table 1-1]

[0690] [Table 1-2]

[0691] [Table 1-3]

[0692] [Table 1-4]

[0693] synthesis The compounds of the present disclosure, including their salts, can be prepared using known organic synthesis techniques and can be synthesized according to any of a number of possible synthetic routes.

[0694] The reaction for preparing the compounds of the present disclosure can be carried out in a suitable solvent, which can be easily selected by those skilled in the art of organic synthesis.A suitable solvent can be substantially non-reactive with the starting material (reactant), intermediate, or product at the temperature at which the reaction is carried out, for example, a temperature that can range from the freezing temperature of the solvent to the boiling temperature of the solvent.A given reaction can be carried out in one solvent or a mixture of two or more solvents.Depending on the specific reaction step, a suitable solvent for a specific reaction step can be selected by those skilled in the art.

[0695] The preparation of compounds of the present disclosure may involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be easily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in T.W. Greene and P.G.M. Buts, Protective Groups in Organic Synthesis, 3rd Ed., Wiley & Sons, Inc., New York (1999), the entire contents of which are incorporated herein by reference.

[0696] The reaction can be monitored according to any suitable method known in the art. For example, product formation can be monitored by nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), can be monitored by spectroscopic means such as infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography such as high performance liquid chromatography ("HPLC") or thin layer chromatography.

[0697] As used herein, the expressions "ambient temperature," "room temperature," "RT," and "rt" are understood in the art and generally refer to a temperature that is near the room temperature at which a reaction is carried out, e.g., the reaction temperature, e.g., a temperature of about 20°C to about 30°C.

[0698] The compounds of the present disclosure can be prepared using a number of preparation reactions known in the literature.The following schemes provide general guidance related to the preparation of the compounds provided herein.Those skilled in the art will understand that they can use general knowledge of organic chemistry to prepare various compounds and modify or optimize the preparations shown in the schemes.Exemplary synthetic methods for preparing compounds are provided in the following schemes.

[0699] General Scheme

[0700] [ka]

[0701] Compounds of formula (I) or (II) can be prepared from an optionally protected bicyclic or tricyclic compound 1-1 or 1-2, as shown in Scheme I, where Y 1 is a halogen (e.g., Cl, Br, or I) or a pseudohalogen (e.g., OTf or OMs). 1-1 or 1-2 is M 1 can be coupled with 1-3, where is a boronic acid, boronate ester, potassium trifluoroborate, or an appropriately substituted metal such as Sn(Bu) or Zn, under standard Suzuki conditions (e.g., in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) or [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), a complex of dichloromethane and a base (e.g., a carbonate base)), or under standard Stille conditions (e.g., in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0)), or under standard Negishi conditions (e.g., in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) or [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)) to provide compounds of Formula (I) or (II).

[0702] Alternatively, 1-1 or 1-2 may be replaced with the appropriate 1-4 or 1-5 (e.g., M 2 is converted to B(OH)2, Bpin, BF3K, Sn(Bu)3, or Zn), and then Y 2is a halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can be coupled with 1-6 under standard Suzuki conditions (e.g., in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) or [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), a complex of dichloromethane with a base (e.g., a carbonate base)), or standard Stille conditions (e.g., in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0)), or standard Negishi conditions (e.g., in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0) or [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)) to provide compounds of Formula (I) or Formula (II).

[0703] [ka]

[0704] Some intermediates for the synthesis of compounds can be prepared as shown in Scheme II. 2 Optionally substituted 2-aminopyridines 2-1, in which Y is a halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs), can be coupled with Boc-protected amino acids 2-2 under standard amide-forming conditions (e.g., treatment with a suitable base such as DIPEA or trimethylamine in the presence of a coupling agent such as HATU, HOBt, or PyBOP). 2 The halo (e.g., Cl, Br, or I) or pseudohalo group (e.g., OTf or OMs) may be substituted with an appropriate substituted metal 2-4 (e.g., M 2can be converted to B(OH)2, Bpin, BF3K, Sn(Bu)3, or Zn) under standard conditions (e.g., in the presence of a diboron reagent such as bis(pinacolato)diboron, a palladium catalyst such as dichloro[bis(triphenylphosphoranyl)]palladium or bis(diphenylphosphino)ferrocene]dichloropalladium(II), or a complex of dichloromethane with a base such as potassium acetate). Compounds 2-5 or 2-6 can be synthesized from intermediate 2-4 using the method described in Scheme I. The Boc protecting group on 2-5 or 2-6 can be removed under acidic conditions (e.g., TFA or HCl) to afford intermediates 2-7 or 2-8.

[0705] [ka]

[0706] Some compounds of Formula (I) or Formula (II) can be prepared as shown in Scheme III. Intermediate 2-7 or 2-8 can be coupled with carboxylic acid 3-1 under standard amide-forming conditions (e.g., treatment with a suitable base such as DIPEA or trimethylamine in the presence of a coupling agent such as HATU, HOBt, or PyBOP) to give compound 3-2 or 3-3.

[0707] [ka]

[0708] Some compounds of Formula (I) or Formula (II) can be prepared as shown in Scheme IV. Amine 2-7 or 2-8 can be coupled with sulfonyl chloride 4-1 by a variety of methods (e.g., treatment with a suitable base such as pyridine or trimethylamine, and optionally with a catalyst such as 4-dimethylaminopyridine) to give compound 4-2 or 4-3.

[0709] [ka]

[0710] Some compounds of Formula (I) or Formula (II) can be prepared as shown in Scheme V. Intermediate 2-7 or 2-8 can be coupled with amine 5-1 under standard urea-forming conditions (e.g., treating amine 2-7 or 2-8 with a suitable base such as DIPEA or trimethylamine in the presence of a coupling agent such as CDI or triphosgene, followed by addition of amine 5-1) to give compound 3-2 or 3-3.

[0711] [ka]

[0712] Some intermediates for making compounds can be prepared as shown in Scheme VI. 1 Optionally substituted aniline 6-1, where is a halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs), can be coupled with lactam 6-2 under treatment with triethylamine and POCl to give compound 6-3. Compound 6-3 can be converted to tricyclic product 6-4 in the presence of a base such as CsCO or CuSO.

[0713] [ka]

[0714] As shown in Scheme VII, intermediate 7-3 can be prepared by reacting Y 1 is a halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs), can be prepared by coupling of hydrazine 7-1 with ketone 7-2 under acidic conditions (e.g., HOAC as solvent).

[0715] [ka]

[0716] As shown in Scheme VIII, intermediate 8-2 can be prepared by reacting Y 1 is a halogen (eg, Cl, Br, or I) or pseudohalogen (eg, OTf or OMs), can be prepared using aniline 8-1 and ketone 7-2 under treatment with MeSO2NH2 and SOCl2.

[0717] [ka]

[0718] Some intermediates for making the compounds can be prepared as shown in Scheme IX. Halogenation of compound 9-1 with a suitable reagent, such as N-chlorosuccinimide, N-bromosuccinimide, Br, or N-iodosuccinimide, can provide halide 9-2. Coupling of 9-2 with boronic ester 9-3 under standard Suzuki conditions (e.g., in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), a complex of dichloromethane and a base (e.g., a carbonate base)) can provide compound 9-4. The double bond in compound 9-4 can be reduced under standard hydrogenation conditions (e.g., in the presence of a catalyst such as PtO and H) to provide compound 9-5.

[0719] [ka]

[0720] Some intermediates for making compounds can be prepared as shown in Scheme X. Coupling of compound 9-1 with ketone 10-1 in the presence of a suitable base such as LDA can give alcohol 10-2. Deoxygenation of 10-2 using trifluoroacetic acid / triethylsilane can give compound 10-3.

[0721] [ka]

[0722] Compounds of formula (IA) can be prepared from an optionally protected bicyclic or tricyclic compound 11-1, as shown in Scheme I, where Y 1 is a halogen (e.g., Cl, Br, or I) or a pseudohalogen (e.g., OTf or OMs). Compound 11-1 is 1 can be coupled with 1-3, where is a boronic acid, boronate ester, potassium trifluoroborate, or an appropriately substituted metal such as Sn(Bu) or Zn, under standard Suzuki conditions (e.g., in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) or [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), a complex of dichloromethane and a base (e.g., a carbonate base)), or under standard Stille conditions (e.g., in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0)), or under standard Negishi conditions (e.g., in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) or [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)) to provide compounds of formula (IA).

[0723] Alternatively, compound 11-1 can be prepared by reacting compound 11-2 with a suitable compound (e.g., M 2 is converted to B(OH)2, Bpin, BF3K, Sn(Bu)3, or Zn), and then Y 2is a halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can be coupled with 1-6 under standard Suzuki conditions (e.g., in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) or [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), a complex of dichloromethane with a base (e.g., a carbonate base)), or standard Stille conditions (e.g., in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0)), or standard Negishi conditions (e.g., in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0) or [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)) to provide compounds of formula (IA).

[0724] [ka]

[0725] Compounds of formula (XIII) can be prepared from compound 12-4, where Y 1 is a halogen (e.g., Cl, Br, or I) or a pseudohalogen (e.g., OTf or OMs). 1 Optionally substituted aniline 12-1, where M is a halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs), can be coupled with lactam 12-2 under treatment with triethylamine and POCl to give compound 12-3. In the presence of a base such as CsCO, CuSO, compound 12-3 can be converted to tricyclic product 12-4. Compound 12-4 can be prepared by the reaction of M 1can be coupled with 1-3, which is a boronic acid, boronate ester, potassium trifluoroborate, or an appropriately substituted metal such as Sn(Bu) or Zn, under standard Suzuki conditions (e.g., in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) or [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), a complex of dichloromethane with a base (e.g., a carbonate base)), or under standard Stille conditions (e.g., in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0)), or under standard Negishi conditions (e.g., in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) or [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)) to provide compounds of formula (XIII).

[0726] Alternatively, compound 12-4 can be prepared by reacting a compound 12-5 (e.g., M 2 is converted to B(OH)2, Bpin, BF3K, Sn(Bu)3, or Zn), and then Y 2 is a halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can be coupled with 1-6 under standard Suzuki conditions (e.g., in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) or [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), a complex of dichloromethane with a base (e.g., a carbonate base)), or standard Stille conditions (e.g., in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0)), or standard Negishi conditions (e.g., in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0) or [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)) to provide compounds of formula (XIII).

[0727] [ka]

[0728] Compounds of formula (II-A) can be prepared from an optionally protected bicyclic or tricyclic compound 13-1, where Y 1 is a halogen (e.g., Cl, Br, or I) or a pseudohalogen (e.g., OTf or OMs). Compound 13-1 is 1 can be coupled with 1-3, where 1-3 is a boronic acid, boronate ester, potassium trifluoroborate, or an appropriately substituted metal such as Sn(Bu) or Zn, under standard Suzuki conditions (e.g., in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) or [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), a complex of dichloromethane with a base (e.g., a carbonate base)), or under standard Stille conditions (e.g., in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0)), or under standard Negishi conditions (e.g., in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) or [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)) to provide compounds of formula (II-A).

[0729] Alternatively, compound 13-1 can be prepared by reacting compound 13-2 (e.g., M 2 is converted to B(OH)2, Bpin, BF3K, Sn(Bu)3, or Zn), and then Y 2is a halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can be coupled with 1-6 under standard Suzuki conditions (e.g., in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) or [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), a complex of dichloromethane with a base (e.g., a carbonate base)), or standard Stille conditions (e.g., in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0)), or standard Negishi conditions (e.g., in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0) or [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)) to provide compounds of formula (II-A).

[0730] Examples of compounds: Example 1: (1S,3R)-3-acetamido-N-[5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-indazol-5-yl)-2-pyridyl]cyclohexanecarboxamide

[0731] [ka]

[0732] Step 1: 5-Bromo-7-fluoro-3-iodo-2-methyl-indazole

[0733] [ka] To a septum-capped 4 mL vial containing a solution of 5-bromo-7-fluoro-2-methyl-2H-indazole (102 mg, 0.45 mmol) in dichloromethane ("DCM") (1 mL) under nitrogen ("N") was charged pyridine (54 μL, 0.67 mmol), followed by (diacetoxyiodo)benzene (172 mg, 0.53 mmol). The reaction mixture was stirred at 30° C. for 30 minutes. Iodine (136 mg, 0.53 mmol) was charged to the reaction mixture and stirred at 30° C. for 20 hours. Additional pyridine (25 μL, 0.31 mmol) and (diacetoxyiodo)benzene (72 mg, 0.22 mmol) were added to the reaction mixture and stirred at 30° C. for 10 minutes. The mixture was then charged with iodine (56 mg, 0.22 mmol) and stirred at 30° C. for 2 hours. The reaction mixture was diluted with water (30 mL), saturated NaSO (5 mL), saturated NaHCO (5 mL), and extracted with DCM (2×30 mL). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The crude solid was rinsed with DCM (2×2 mL), and the liquid was purified by flash column chromatography (“FCC”) (12 g SiO, 0→20% EtOAc in hexanes, wet-loaded in DCM). Fractions containing the desired product were combined with the remaining solid to give 5-bromo-7-fluoro-3-iodo-2-methyl-indazole (146 mg, 0.41 mmol, 92% yield) as an off-white solid. Liquid chromatography-mass spectrometry (“LCMS”) m / z C8H6BrFIN2 (M+H) + Calculated values: 354.87 / 356.87; Measured values: 354.9 / 356.9.

[0734] Step 2: 5-Bromo-7-fluoro-3-isopropenyl-2-methyl-indazole

[0735] [ka] A septum-equipped 50 mL round-bottom flask ("RBF") containing a mixture of 5-bromo-7-fluoro-3-iodo-2-methyl-indazole (720 mg, 2.03 mmol), 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium (150 mg, 0.21 mmol), and potassium carbonate (727 mg, 5.26 mmol) under N was charged with tetrahydrofuran ("THF") (12 mL) and water (6 mL). The reaction mixture was purged with N for 2 minutes, charged with 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (450 μL, 2.4 mmol), and then stirred at 45° C. for 1 hour. The reaction mixture was charged with additional 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (50 μL, 0.27 mmol) and 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium (30 mg, 0.041 mmol) and stirred at 45° C. for an additional 1 h. The reaction mixture was diluted with ethyl acetate (“EtOAc”) (100 mL) and then washed with saturated NaHCO (30 mL), water (40 mL), water (70 mL), and brine (50 mL). The organic layer was dried over NaSO, filtered, concentrated under reduced pressure, and purified by FCC (40 g SiO, 0→20% EtOAc in hexanes, wet load in DCM+hexanes). Fractions containing the desired product were combined and concentrated under reduced pressure to give 5-bromo-7-fluoro-3-isopropenyl-2-methyl-indazole (483 mg, 1.8 mmol, 88% yield) as a clear yellow / orange oil. LCMS m / z C 11 H 11 BrFN2(M+H) + Calculated values: 269.01 / 271.01; Measured values: 269.0 / 271.0.

[0736] Step 3: 5-Bromo-7-fluoro-3-isopropyl-2-methyl-indazole

[0737] [ka] Ethyl acetate (11 mL) was added to a septum-capped 20 mL vial containing a mixture of 5-bromo-7-fluoro-3-isopropenyl-2-methyl-indazole (472 mg, 1.75 mmol) and anhydrous platinum(IV) oxide (14.4 mg, 0.063 mmol) under N2. The reaction mixture was sparged with H2 for 1 min, maintained under a H2 balloon, and stirred at room temperature ("RT") for 2 h. The reaction mixture was filtered through a 0.45 μm Pefe filter ("PTFE") and concentrated to dryness. The product, 5-bromo-7-fluoro-3-isopropyl-2-methyl-indazole (1.75 mmol, 100% yield), was used crude in subsequent reactions as a stock solution in dioxane, assuming 100% yield. LCMS m / z C 11 H 13 BrFN2(M+H) + Calculated values: 271.02 / 273.02; Measured values: 271.0 / 273.0.

[0738] Step 4: tert-butyl N-[(1R,3S)-3-[(4-bromo-5-chloro-2-pyridyl)carbamoyl]cyclohexyl]carbamate

[0739] [ka] To a mixture of (1S,3R)-3-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid (4.2 g, 17 mmol) in 120 mL of dry DCM at 0 °C, 1-chloro-N,N,2-trimethylprop-1-en-1-amine (2.77 g, 20.7 mmol) was added dropwise. The mixture was stirred at room temperature for 1.5 hours. Then, 4-bromo-5-chloro-pyridin-2-amine (3.58 g, 17.3 mmol) and pyridine (1.68 mL, 20.7 mmol) were added sequentially. The resulting mixture was stirred at room temperature for 12 hours. The volatiles were removed under reduced pressure, and the residue was dissolved in 150 mL of ethyl acetate and washed with water (50 mL). The organic layer was dried over Na2SO4 and concentrated. The residue was purified by reverse-phase high pressure liquid chromatography ("HPLC") (0.1% ammonia in water and methanol) to give tert-butyl N-[(1R,3S)-3-[(4-bromo-5-chloro-2-pyridyl)carbamoyl]cyclohexyl]carbamate (4.8 g, 10.6 mmol, 61.6% yield) as a white solid. LCMS C 13 H 16 BrClN3O3[M+H-tBu] + Calculated m / z = 376.0; Measured: 376.0. Proton nuclear magnetic resonance (" 1 H NMR”)(400MHz,DMSO-d6)δ1.03-1.13(m,1H),1.22-1.32(m,3H),1.37(s,9H),1.68-1.80(m,3H),1.88(d,J=12. 0Hz,1H),2.54-2.61(m,1H),3.21-3.29(m,1H),6.81(d,J=8.0Hz,1H),8.48(s,1H),8.50(s,1H),10.81(s,1H).

[0740] Step 5: (1S,3R)-3-amino-N-(4-bromo-5-chloropyridin-2-yl)cyclohexane-1-carboxamide

[0741] [ka] To a mixture of tert-butyl N-[(1R,3S)-3-[(4-bromo-5-chloro-2-pyridyl)carbamoyl]cyclohexyl]carbamate (500 mg, 1.16 mmol) in 10 mL of DCM was added TFA (0.88 mL, 11.55 mmol). The mixture was stirred at room temperature for 5 hours. The volatiles were removed under reduced pressure to give (1S,3R)-3-amino-N-(4-bromo-5-chloropyridin-2-yl)cyclohexane-1-carboxamide as the TFA salt (518 mg, 1.16 mmol, 100% yield). LCMS C 12 H 16 BrClNO[M+H] + Calculated m / z = 332.01; found: 332.0.

[0742] Step 6: (1S,3R)-3-acetamido-N-(4-bromo-5-chloropyridin-2-yl)cyclohexane-1-carboxamide

[0743] [ka] To a mixture of (1S,3R)-3-amino-N-(4-bromo-5-chloro-2-pyridyl)cyclohexanecarboxamide; 2,2,2-trifluoroacetic acid (518 mg, 1.16 mmol) in 15 mL of dry DCM at 0 °C, triethylamine (587 mg, 5.8 mmol) was added dropwise, followed by acetic anhydride (142 mg, 1.39 mmol). The mixture was stirred at 0 °C for 1 h. The volatiles were removed, and the residue was dissolved in 60 mL of ethyl acetate and washed with water (20 mL). The organic layer was dried over Na SO and concentrated. The residue was purified by reverse phase HPLC (0.1% ammonia in water and methanol) to give (1S,3R)-3-acetamido-N-(4-bromo-5-chloro-2-pyridyl)cyclohexanecarboxamide (361 mg, 0.96 mmol, 83% yield) as a white solid. LCMS C 14 H 18 BrClN3O2[M+H] + Calculated m / z = 374.02; found: 374.0. 1H NMR(400MHz,DMSO-d6)δ1.04-1.12(m,1H),1.21-1.32(m,3H),1.71-1.77(m,6H),1.84-1.93(m,1H), 2.56-2.63(m,1H),3.51-3.62(m,1H),7.78(d,J=7.6Hz,1H),8.49(s,1H),8.50(s,1H),10.83(s,1H).

[0744] Step 7: [2-[[(1S,3R)-3-acetamidocyclohexanecarbonyl]amino]-5-chl...

Claims

1. A compound, or a pharmaceutically acceptable salt or solvate thereof, The compound is 【Chemistry 1】 and has the formula During the ceremony, R ２ is Me or OMe, R ３ is H, D, or F, R ４ is H or C １ ~ ６ is alkyl, R ５ is C １ ~ ６ Alkyl, isopropyl, -CF ３ (CH)CH ３ , -C ３ ~ ６ cycloalkyl, or —CH ２ -(C ３ - ６ cycloalkyl), Or, R ４ and R ５ together with the atoms to which they are attached, are 1, 2, 3, 4, or 5 independently selected R ｂ forming a 5- or 6-membered heterocycloalkyl ring optionally substituted with substituents, R ｂ is NHCOR １３ or CN, R １３ is H or optionally substituted C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ６～１０ Aryl, C ３～１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６～１０ Aryl-C １～４ Alkyl, C ３～１０ Cycloalkyl-C １～４ alkyl, (5- to 10-membered heteroaryl)-C １～４ Alkyl- or (4- to 10-membered heterocycloalkyl)-C １～４ or a pharmaceutically acceptable salt or solvate thereof, wherein:

2. R ４ is H or C １ ~ ３ 2. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R is alkyl.

3. R ５ is C １ ~ ６ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein R is alkyl.

4. R ４ and R ５ together with the atoms to which they are attached, are 1, 2, 3, 4, or 5 independently selected R ｂ 2. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, which forms a 5- or 6-membered heterocycloalkyl ring, optionally substituted with substituents.

5. R ４ and R ５ together with the atoms to which they are attached, one or two R ｂ 5. The compound of claim 4, or a pharmaceutically acceptable salt or solvate thereof, optionally substituted with substituents forming an optionally substituted 5-membered heterocycloalkyl ring.

6. The one or two R ｂ The substituent is C １～４ 6. The compound of claim 5, or a pharmaceutically acceptable salt or solvate thereof, wherein R is alkyl.

7. The compound is 【Chemistry 2】 and R １３ is H or optionally substituted C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ６～１０ Aryl, C ３～１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６～１０ Aryl-C １～４ Alkyl, C ３～１０ Cycloalkyl-C １～４ alkyl, (5- to 10-membered heteroaryl)-C １～４ Alkyl- or (4- to 10-membered heterocycloalkyl)-C １～４ 2. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R is alkyl.

8. The compound is 【Transformation 3】 2. The compound of claim 1 having the formula: or a pharmaceutically acceptable salt or solvate thereof.

9. or a pharmaceutically acceptable salt or solvate thereof, The compound is 【Chemistry 4】 and has the formula During the ceremony, R ２ is H, D, halogen, or Me; R ３ is H, D, or F, R １０ is H, D, Me, or C １ ~ ３ is haloalkyl, R １１ is H, D, Me, or C １ ~ ３ is haloalkyl, R ｂ is NHCOR １４ and R １４ is H, -CH ２ CN, or optionally substituted C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ６～１０ Aryl, C ３～１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６～１０ Aryl-C １～４ Alkyl, C ３～１０ Cycloalkyl-C １～４ alkyl, (5- to 10-membered heteroaryl)-C １～４ Alkyl- or (4- to 10-membered heterocycloalkyl)-C １～４ or a pharmaceutically acceptable salt or solvate thereof, wherein:

10. The compound is 【Transformation 5】 and has the formula During the ceremony, R １１ is H, D, Me, or C １ ~ ３ is haloalkyl, R １４ is H, -CH ２ CN, or optionally substituted C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ６～１０ Aryl, C ３～１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６～１０ Aryl-C １～４ Alkyl, C ３～１０ Cycloalkyl-C １～４ alkyl, (5- to 10-membered heteroaryl)-C １～４ Alkyl- or (4- to 10-membered heterocycloalkyl)-C １～４ 10. The compound of claim 9, or a pharmaceutically acceptable salt or solvate thereof, wherein R is alkyl.

11. The compound is 【Transformation 6】 11. The compound of claim 10 having the formula: or a pharmaceutically acceptable salt or solvate thereof.

12. A compound, or a pharmaceutically acceptable salt or solvate thereof, The compound is (1S,3R)-3-acetamido-N-[5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-indazol-5-yl)-2-pyridyl]cyclohexanecarboxamide, (1S,3R)-N-[5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-indazol-5-yl)-2-pyridyl]-3-[(1-hydroxycyclopropanecarbonyl)amino]-cyclohexanecarboxamide, (1S,3R)—N-(5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)-3-(2-(thiazol-4-yl)acetamide)cyclohexane-1-carboxamide, (1S,3R)—N-(5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)-3-(2-methoxyacetamido)cyclohexane-1-carboxamide, (1S,3R)—N-(5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)-3-propionamido-cyclohexane-1-carboxamide, (1S,3R)-N-[5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-indazol-5-yl)-2-pyridyl]-3-(methanesulfonamido)cyclohexanecarboxamide, N-[(1R,3S)-3-[[5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-indazol-5-yl)-2-pyridyl]carbamoyl]cyclohexyl]morpholine-4-carboxamide, N-((1R,3S)-3-((5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)carbamoyl)-cyclohexyl)-4-methylpiperazine-1-carboxamide, (1S,3R)-N-(5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)-3-(3-methylureido)cyclohexane-1-carboxamide, (1S,3R)—N-(5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)-3-(3,3-dimethylureido)cyclohexane-1-carboxamide, (1S,3R)-N-(5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)-3-(3-ethylureido)cyclohexane-1-carboxamide, (1S,3R)-N-(5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)-3-(3-methoxyureido)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-[5-chloro-4-(5-fluoro-1,1-dimethyl-2,3-dihydropyrrolo[1,2-a]benzimidazol-7-yl)-2-pyridyl]cyclohexanecarboxamide, (1S,3R)—N-(5-chloro-4-(5-fluoro-1,1-dimethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyridin-2-yl)-3-(2-cyanoacetamido)cyclohexane-1-carboxamide, (1S,3R)-N-(5-chloro-4-(5-fluoro-1,1-dimethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyridin-2-yl)-3-(3-hydroxybutanamido)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(5-chloro-4-(1,1-dimethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyridin-2-yl)cyclopentane-1-carboxamide, (1S,3R)—N-(5-chloro-4-(5-fluoro-1,1-dimethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyridin-2-yl)-3-propionamidocyclohexane-1-carboxamide, (1S,3R)—N-(5-chloro-4-(1,1-dimethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyridin-2-yl)-3-propionamidocyclopentane-1-carboxamide, (1S,3R)-N-(5-chloro-4-(5-fluoro-1,1-dimethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyridin-2-yl)-3-(1-hydroxycyclopropane-1-carboxamido)cyclohexane-1-carboxamide, (1S,3R)—N-(5-chloro-4-(5-fluoro-1,1-dimethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyridin-2-yl)-3-(2-methoxyacetamido)cyclohexane-1-carboxamide, (1S,3R)—N-(5-chloro-4-(5-fluoro-1,1-dimethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyridin-2-yl)-3-(methylsulfonamido)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(4-(5-fluoro-1,1-dimethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)-5-methylpyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)cyclopentane-1-carboxamide, (1S,3R)-3-acetamido-N-(5-chloro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl)pyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(5-chloro-4-(3-isopropylbenzo[c]isothiazol-5-yl)pyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(5-chloro-4-(1-methyl-2,3-dihydro-1H-pyrrolo[1,2-b]indazol-8-yl)pyridin-2-yl)cyclohexane-1-carboxamide (1S,3R)-3-(3,3-dimethylureido)-N-(4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)—N-(4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)-3-propionamidocyclohexane-1-carboxamide, (1S,3R)—N-(4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)-3-isobutyramidocyclohexane-1-carboxamide, (1S,3R)—N-(4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)-3-(2-methoxyacetamido)cyclohexane-1-carboxamide, (1S,3R)-3-(2-(dimethylamino)acetamido)-N-(4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)cyclohexane-1-carboxamide, methyl((1R,3S)-3-((4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)carbamoyl)cyclohexyl)carbamate, (1S,3R)—N-(4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)-3-(methylsulfonamido)cyclohexane-1-carboxamide, (1S,3R)—N-(4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)-3-(1-fluorocyclopropane-1-carboxamido)cyclohexane-1-carboxamide, (1S,3R)—N-(4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)-3-(1-hydroxycyclopropane-1-carboxamido)cyclohexane-1-carboxamide, N-((1R,3S)-3-((4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)carbamoyl)cyclohexyl)-1-methylazetidine-3-carboxamide, (1S,3R)-N-(4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)-3-((1r,3R)-3-hydroxycyclobutane-1-carboxamido)cyclohexane-1-carboxamide, (1S,3R)—N-(4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)-3-(2-hydroxyacetamido)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(4-(4-fluoro-1-(oxetan-3-yl)-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(4-(1-cyclopropyl-4-fluoro-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(4-(1-(cyclopropylmethyl)-4-fluoro-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)cyclohexane-1-carboxamide, (S)—N-((1R,3S)-3-((4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)carbamoyl)cyclohexyl)-3-hydroxypyrrolidine-1-carboxamide, (1S,3R)—N-(4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)-3-(3-methylureido)cyclohexane-1-carboxamide, N-((1R,3S)-3-((4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)carbamoyl)cyclohexyl)morpholine-4-carboxamide, N-((1R,3S)-3-((4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)carbamoyl)cyclohexyl)-4-methylpiperazine-1-carboxamide, (1S,3R)-N-[4-(7-fluoro-3-isopropyl-benzimidazol-5-yl)-5-methyl-2-pyridyl]-3-[(methylsulfonimidoyl)amino]cyclohexanecarboxamide, (1S,3R)-N1-(4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)-N3-methylcyclohexane-1,3-dicarboxamide, 3-cyano-N-(4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-(3,3-dimethylureido)-N-(4-(4-fluoro-1-(1,1,1-trifluoropropan-2-yl)-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(5-chloro-4-(1,1-dimethyl-2,3-dihydro-1H-pyrrolo[1,2-b]indazol-8-yl)pyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(5-chloro-4-(7-fluoro-3-(1-hydroxypropan-2-yl)-2-methyl-2H-indazol-5-yl)pyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(5-chloro-4-(7-fluoro-3-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-5-yl)pyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(5-chloro-4-(3-cyclopropyl-7-fluoro-2-methyl-2H-indazol-5-yl)pyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(5-chloro-4-(3-isopropyl-2-methyl-2H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)-5-methylpyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)—N-(5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)-3-(1-fluorocyclopropane-1-carboxamido)cyclohexane-1-carboxamide, N-((1R,3S)-3-((5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)carbamoyl)cyclohexyl)-2-methoxynicotinamide, N-((1R,3S)-3-((5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)carbamoyl)cyclohexyl)-5-methylisoxazole-3-carboxamide, N-((1R,3S)-3-((5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)carbamoyl)cyclohexyl)-6-methylnicotinamide, (1S,3R)—N-(4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)-5-methylpyridin-2-yl)-3-(2-methoxyacetamido)cyclohexane-1-carboxamide, (1S,3R)—N-(4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)-5-methylpyridin-2-yl)-3-(2-methoxyacetamido)cyclohexane-1-carboxamide, N-((1R,3S)-3-((4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)-5-methylpyridin-2-yl)carbamoyl)cyclohexyl)-5-methylisoxazole-3-carboxamide, N-((1R,3S)-3-((4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)-5-methylpyridin-2-yl)carbamoyl)cyclohexyl)-2-methoxynicotinamide, (1S,3R)—N-(5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)-3-(2-cyanoacetamido)cyclohexane-1-carboxamide, (1S,3R)-3-(2-cyanoacetamido)-N-(4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)-5-methylpyridin-2-yl)cyclohexane-1-carboxamide, N-((1R,3S)-3-((4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)-5-methylpyridin-2-yl)carbamoyl)cyclohexyl)morpholine-4-carboxamide, (1S,3R)-3-(3-ethylureido)-N-(4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)cyclohexane-1-carboxamide, N-((1R,3S)-3-((4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)carbamoyl)cyclohexyl)azetidine-1-carboxamide, methyl((1R,3S)-3-((5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate, tetrahydro-2H-pyran-4-yl((1R,3S)-3-((5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate, (1-methyl-1H-pyrazol-3-yl)methyl ((1R,3S)-3-((5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate, (2,2-difluorocyclopropyl)methyl((1R,3S)-3-((5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate, (1S,3R)-3-acetamido-N-(5-chloro-4-(7-fluoro-2-methyl-3-(1,1,1-trifluoro-2-hydroxypropan-2-yl)-2H-indazol-5-yl)pyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(5-chloro-4-(3-(1,1-difluoro-2-hydroxypropan-2-yl)-7-fluoro-2-methyl-2H-indazol-5-yl)pyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-(2-cyanoacetamido)-N-(4-(7-fluoro-2-methyl-3-(1,1,1-trifluoro-2-hydroxypropan-2-yl)-2H-indazol-5-yl)-5-methylpyridin-2-yl)cyclohexane-1-carboxamide (P1), (1S,3R)-3-(2-cyanoacetamido)-N-(4-(7-fluoro-2-methyl-3-(1,1,1-trifluoro-2-hydroxypropan-2-yl)-2H-indazol-5-yl)-5-methylpyridin-2-yl)cyclohexane-1-carboxamide (P2), (1S,3R)-3-acetamido-N-(5-chloro-4-(7-fluoro-2-methyl-3-(1,1,1-trifluoro-2-hydroxypropan-2-yl)-2H-indazol-5-yl)pyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(5-chloro-4-(3-(1,1-difluoro-2-hydroxypropan-2-yl)-7-fluoro-2-methyl-2H-indazol-5-yl)pyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)—N-(5-chloro-4-(3-(1,1-difluoro-2-hydroxypropan-2-yl)-7-fluoro-2-methyl-2H-indazol-5-yl)pyridin-2-yl)-3-(2-cyanoacetamido)cyclohexane-1-carboxamide, (1S,3R)-3-(2-cyanoacetamido)-N-(4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methylpyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)-5-methoxypyridin-2-yl)cyclohexane-1-carboxamide, N-((1R,3S)-3-((5-chloro-4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)pyridin-2-yl)carbamoyl)cyclohexyl)bicyclo[1.1.1]pentane-1-carboxamide, (1S,3R)-3-acetamido-N-(5-chloro-4-(4-fluoro-1-isopropyl-1H-benzo[d][1,2,3]triazol-6-yl)pyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(5-chloro-4-(3-isopropyl-3H-imidazo[4,5-b]pyridin-5-yl)pyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)—N-(5-chloro-4-(9-fluoro-4,4-dimethyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyridin-2-yl)-3-(2-cyanoacetamido)cyclohexane-1-carboxamide, (1S,3R)-3-(2-cyanoacetamido)-N-(4-(7-fluoro-3-isopropyl-2-methyl-2H-indazol-5-yl)-5-methylpyridin-2-yl)cyclohexane-1-carboxamide, (1S,3R)-3-acetamido-N-(5-chloro-4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyridin-2-yl)cyclohexane-1-carboxamide, A compound selected from the group consisting of (1S,3R)-3-acetamido-N-(4-(4-fluoro-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyridin-2-yl)cyclohexane-1-carboxamide, or a pharmaceutically acceptable salt or solvate thereof.

13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

14. 14. The pharmaceutical composition of claim 13, wherein the pharmaceutical composition comprises at least 90%, at least 95%, at least 98%, or at least 99% enantiomeric excess of one enantiomer of the compound, or a pharmaceutically acceptable salt or solvate thereof.

15. A pharmaceutical for inhibiting a CDK enzyme, comprising a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to any one of claims 13 to 14.

16. The pharmaceutical according to claim 15, wherein the CDK enzyme is CDK9.

17. A medicament for treating a disease or disorder associated with abnormal CDK activity in a subject or a subject in need thereof, the medicament comprising a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to any one of claims 13 to 14.

18. The pharmaceutical composition of claim 17, wherein the disease or disorder associated with abnormal CDK activity is colon cancer, breast cancer, small cell lung cancer, non-small cell lung cancer, bladder cancer, ovarian cancer, prostate cancer, chronic lymphocytic leukemia, lymphoma, myeloma, acute myeloid leukemia, or pancreatic cancer.

19. 15. A medicament for treating cancer in a subject or a subject in need thereof, comprising a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to any one of claims 13 to 14.

20. 20. The pharmaceutical composition of claim 19, wherein the cancer is colon cancer, breast cancer, small cell lung cancer, non-small cell lung cancer, bladder cancer, ovarian cancer, prostate cancer, chronic lymphocytic leukemia, lymphoma, myeloma, acute myeloid leukemia, or pancreatic cancer.

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