Bicyclic heterocycles as FGFR inhibitors

Abstract

The present invention relates to bicyclic heterocycles, and pharmaceutical compositions thereof, which are inhibitors of FGFR enzymes and are useful in the treatment of FGFR-related diseases such as cancer. Formula (I): TIFF2022552324000476.tif54164

Description

[Technical Field]

[0001] The present disclosure relates to bicyclic heterocycles, and pharmaceutical compositions thereof, which are inhibitors of the enzyme FGFR and are useful in the treatment of FGFR-associated diseases, such as cancer. [Background technology]

[0002] Fibroblast growth factor receptors (FGFRs) are receptor tyrosine kinases that bind to fibroblast growth factor (FGF) ligands. There are four FGFR proteins (FGFR1-4) that can bind to the ligands, and they are involved in regulating many physiological processes, including tissue development, angiogenesis, wound healing, and metabolic control. Upon ligand binding, the receptors dimerize and become phosphorylated, leading to stimulation of protein kinase activity and recruitment of numerous intracellular docking proteins. These interactions promote the activation of a series of intracellular signaling pathways, including Ras-MAPK, AKT-PI3K, and phospholipase C, which are important for cell growth, proliferation, and survival (reviewed in Eswarakumar et al., Cytokine & Growth Factor Reviews, 2005, 16, 139-149). Aberrant activation of this pathway, either by overexpression of FGF ligands or FGFRs or by activating mutations in FGFRs, can lead to tumor initiation, progression, and resistance to conventional cancer therapies. Genetic alterations, including gene amplification, chromosomal translocations, and somatic mutations, that result in ligand-independent receptor activation have been described in human cancers (reviewed in Knights and Cook, Pharmacology & Therapeutics, 2010, 125, 105-117; Turner and Grose, Nature Reviews Cancer, 2010, 10, 116-129). Large-scale DNA sequencing of thousands of tumor samples has revealed alterations in FGFR genes in many cancers (Helsten et al. Clin Cancer Res. 2016, 22, 259-267). Some of these activating mutations are identical to germline mutations that cause bone dysplastic syndromes (Gallo et al. Cytokine & Growth Factor Reviews 2015, 26, 425-449). Mechanisms that cause aberrant ligand-dependent signaling in human disease include overexpression of FGFs and altered FGFR splicing that results in receptors with more promiscuous ligand binding capacity.Therefore, the development of inhibitors that target FGFRs may be useful in the clinical treatment of diseases associated with elevated FGF or FGFR activity.

[0003] Cancer types in which FGF / FGFR is involved include, but are not limited to, carcinomas (e.g., bladder, breast, colorectal, endometrial, gastric, head and neck, kidney, lung, ovarian, prostate), hematopoietic malignancies (e.g., multiple myeloma, acute myeloid leukemia, and myeloproliferative neoplasms), and other neoplasms (e.g., glioblastoma and sarcoma). In addition to its role in oncogenic neoplasms, FGFR activation has also been implicated in skeletal and chondrocyte disorders, including, but not limited to, achondroplasia and craniosynostosis syndrome.

[0004] There is a continuing need for the development of new drugs for the treatment of cancer, and the FGFR inhibitors described herein help to meet this need. Summary of the Invention

[0005] The present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein the constituent variables are defined herein.

[0006] The present disclosure is further directed to pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0007] The present disclosure is further directed to a method of inhibiting an FGFR enzyme (e.g., an FGFR3 enzyme), the method comprising contacting the enzyme with a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0008] The present disclosure is further directed to a method of treating a disease associated with abnormal activity or expression of an FGFR enzyme (e.g., an FGFR3 enzyme), the method comprising administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

[0009] The present disclosure is further directed to compounds of Formula (I) for use in treating diseases associated with abnormal activity or expression of FGFR enzymes (eg, FGFR3 enzymes).

[0010] The present disclosure is further directed to a method of treating a disorder mediated by an FGFR enzyme (e.g., an FGFR3 enzyme), or a mutant thereof, in a patient in need thereof, the method comprising administering to the patient a compound of formula (I), or a pharmaceutically acceptable composition thereof.

[0011] The present disclosure is further directed to a method of treating a disorder mediated by an FGFR enzyme (e.g., an FGFR3 enzyme), or a mutant thereof, in a patient in need thereof, the method comprising administering to the patient a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, in combination with another therapy or therapeutic agent as described herein.

[0012] Also provided herein is a method of treating cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of Formula I, wherein the cancer is characterized by alterations in FGFR2 and / or FGFR3.

[0013] The present disclosure is further directed to the use of compounds of formula (I) in the preparation of a medicament for use in therapy. DETAILED DESCRIPTION OF THE INVENTION

[0014] compound In one aspect, the present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: Cy 1 is selected from phenyl and 5- to 6-membered heteroaryl, wherein each 5- to 6-membered heteroaryl has at least one ring-forming carbon atom and 1, 2, or 3 ring-forming heteroatoms independently selected from N, O, and S, where N and S are optionally oxidized, and wherein a ring-forming carbon atom of the 5- to 6-membered heteroaryl is optionally substituted by oxo to form a carbonyl group, wherein the phenyl and the 5- to 6-membered heteroaryl are each selected from R 10 optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 1 But, Halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl, 4-5 membered heterocycloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~3 Alkoxy-C 1~3 Alkyl, C 1~3 Alkoxy-C 1~3 Alkoxy, HO-C 1~3 Alkoxy, HO-C 1~3 Alkyl, Cyano-C 1~3 Alkyl, H2N-C 1~3 Alkyl, C 1~6 Alkylamino, di(C 1~6 Alkyl)amino, C 1~6 Alkylthio, C 1~6 Alkylsulfonyl, C 1~6 Alkylcarbonyl, and C 1~6 alkoxycarbonyl, wherein optionally C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl, 4-5 membered heterocycloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~3Alkoxy-C 1~3 Alkyl, C 1~3 Alkoxy-C 1~3 Alkoxy, HO-C 1~3 Alkoxy, HO-C 1~3 Alkyl, Cyano-C 1~3 Alkyl, H2N-C 1~3 Alkyl, C 1~6 Alkylamino, di(C 1~6 Alkyl)amino, C 1~6 Alkylthio, C 1~6 Alkylsulfonyl, C 1~6 Alkylcarbonyl, and C 1~6 one or more H atoms of the alkoxycarbonyl are replaced by one or more D atoms; Each R 2 and R 3 But C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~10 Cycloalkyl-C 1~3 Alkylene, 4-10 membered heterocycloalkyl-C 1~3 Alkylene, C 6~10 Aryl-C 1~3 Alkylene, 5-10 membered heteroaryl-C 1~3 Alkylene, Halo, CN, NO2, OR a2 , S.R. a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 ,OC(O)R b2 , OC(O)NR c2 R d2 , N.R. c2 R d2 , N.R. c2 C(O)R b2 , N.R. c2 C(O)OR a2 , N.R. c2 C(O)NR c2 R d2 , C(=NRe2 )R b2 , C(=NOR a2 )R b2 , C(=NR e2 )NR c2 R d2 , N.R. c2 C(=NR e2 )NR c2 R d2 , N.R. c2 S(O)R b2 , N.R. c2 S(O)2R b2 , N.R. c2 S(O)NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O)2R b2 , and S(O)NR c2 R d2 are independently selected from, where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~10 Cycloalkyl-C 1~3 Alkylene, 4-10 membered heterocycloalkyl-C 1~3 Alkylene, C 6~10 Aryl-C 1~3 Alkylene and 5-10 membered heteroaryl-C 1~3 Each alkylene is R 21 optionally substituted with 1, 2, 3, or 4 substituents independently selected from or two adjacent R on a phenyl ring 2the substituents, together with the atoms to which they are attached, form a fused 5- or 6-membered cycloalkyl ring or a fused 5- or 6-membered heterocycloalkyl ring, wherein each fused 5- or 6-membered heterocycloalkyl ring has at least one ring-forming carbon atom and 1 or 2 ring-forming heteroatoms independently selected from N, O, and S, and wherein a ring-forming carbon atom of each fused 5- or 6-membered heterocycloalkyl ring is optionally substituted by oxo to form a carbonyl group, and wherein the fused 5- or 6-membered cycloalkyl ring and the fused 5- or 6-membered heterocycloalkyl ring each have R 21 optionally substituted with 1, 2, 3, or 4 substituents independently selected from n is selected from 0, 1, 2, and 3; Each R 10 But C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, 4-12 membered heterocycloalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~10 Cycloalkyl-C 1~3 Alkylene, 4-12 membered heterocycloalkyl-C 1~3 Alkylene, C 6~10 Aryl-C 1~3 Alkylene, 5-10 membered heteroaryl-C 1~3 Alkylene, Halo, D, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 ,OC(O)R b1 , OC(O)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , C(=NRe1 )R b1 , C(=NOR a1 )R b1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 , and S(O)NR c1 R d1 are independently selected from, where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, 4-12 membered heterocycloalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~10 Cycloalkyl-C 1~3 Alkylene, 4-12 membered heterocycloalkyl-C 1~3 Alkylene, C 6~10 Aryl-C 1~3 Alkylene and 5-10 membered heteroaryl-C 1~3 Each alkylene is R 11 optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 11 But C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~10 Cycloalkyl-C 1~3 Alkylene, 4-10 membered heterocycloalkyl-C1~3 Alkylene, C 6~10 Aryl-C 1~3 Alkylene, 5-10 membered heteroaryl-C 1~3 Alkylene, Halo, D, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)OR a3 , N.R. c3 S(O)R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 , and S(O)NR c3 R d3 are independently selected from, where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~10 Cycloalkyl-C 1~3 Alkylene, 4-10 membered heterocycloalkyl-C 1~3 Alkylene, C 6~10 Aryl-C 1~3 Alkylene and 5-10 membered heteroaryl-C 1~3 Each alkylene is R 12 optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 12 But C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C3~6 Cycloalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR a5 , S.R. a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , N.R. c5 R d5 , N.R. c5 C(O)R b5 , N.R. c5 C(O)OR a5 , N.R. c5 S(O)R b5 , N.R. c5 S(O)2R b5 , N.R. c5 S(O)NR c5 R d5 , S(O)R b5 , S(O)NR c5 R d5 , S(O)2R b5 , and S(O)NR c5 R d5 are independently selected from, where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 6~10 Aryl, 5- to 10-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each R g optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 21 But C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~10 Cycloalkyl-C 1~3 Alkylene, 4-10 membered heterocycloalkyl-C 1~3 Alkylene, C 6~10 Aryl-C 1~3Alkylene, 5-10 membered heteroaryl-C 1~3 Alkylene, Halo, D, CN, OR a4 , S.R. a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , N.R. c4 R d4 , N.R. c4 C(O)R b4 , N.R. c4 C(O)OR a4 , N.R. c4 S(O)R b4 , N.R. c4 S(O)2R b4 , N.R. c4 S(O)NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O)2R b4 , and S(O)NR c4 R d4 are independently selected from, where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~10 Cycloalkyl-C 1~3 Alkylene, 4-10 membered heterocycloalkyl-C 1~3 Alkylene, C 6~10 Aryl-C 1~3 Alkylene and 5-10 membered heteroaryl-C 1~3 Each alkylene is R 22 optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 22 But C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~6Cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR a6 , S.R. a6 , C(O)R b6 , C(O)NR c6 R d6 , C(O)OR a6 , N.R. c6 R d6 , N.R. c6 C(O)R b6 , N.R. c6 C(O)OR a6 , N.R. c6 S(O)R b6 , N.R. c6 S(O)2R b6 , N.R. c6 S(O)NR c6 R d6 , S(O)R b6 , S(O)NR c6 R d6 , S(O)2R b6 , and S(O)NR c6 R d6 are independently selected from, where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each R g optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a1 , R c1 and R d1 But H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10 aryl and 5- to 10-membered heteroaryl, wherein C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10Aryl and 5- to 10-membered heteroaryl are each R 11 optionally substituted with 1, 2, 3, or 4 substituents independently selected from or any R bonded to the same N atom c1 and R d1 together with the N atom to which they are attached, R 11 forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R b1 But C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10 aryl and 5- to 10-membered heteroaryl, wherein C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10 Aryl and 5- to 10-membered heteroaryl are each R 11 optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R e1 But H, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkylthio, C 1~6 Alkylsulfonyl, C 1~6 Alkyl carbonyl, C 1~6 Alkylaminosulfonyl, Carbamyl, C 1~6 Alkylcarbamyl, di(C 1~6 Alkyl)carbamyl, aminosulfonyl, C 1~6 Alkylaminosulfonyl and di(C 1~6 alkyl)aminosulfonyl; Each R a2 , R c2 and R d2 But H, C1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10 aryl and 5- to 10-membered heteroaryl, wherein C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10 Aryl and 5- to 10-membered heteroaryl are each R 21 optionally substituted with 1, 2, 3, or 4 substituents independently selected from or any R bonded to the same N atom c2 and R d2 together with the N atom to which they are attached, R 21 forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Each R b2 But C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10 aryl and 5- to 10-membered heteroaryl, wherein C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10 Aryl and 5- to 10-membered heteroaryl are each R 21 optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R e2 But H, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkylthio, C 1~6Alkylsulfonyl, C 1~6 Alkyl carbonyl, C 1~6 Alkylaminosulfonyl, Carbamyl, C 1~6 Alkylcarbamyl, di(C 1~6 Alkyl)carbamyl, aminosulfonyl, C 1~6 Alkylaminosulfonyl and di(C 1~6 alkyl)aminosulfonyl; Each R a3 , R c3 and R d3 But H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~6 independently selected from cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl, wherein C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each R 12 optionally substituted with 1, 2, 3, or 4 substituents independently selected from or any R bonded to the same N atom c3 and R d3 together with the N atom to which they are attached, R 12 forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Each R b3 But C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~6 independently selected from cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl, wherein C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each R 12 optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a4 , R c4 and R d4 But H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~6 independently selected from cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl, wherein C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each R 22 optionally substituted with 1, 2, 3, or 4 substituents independently selected from or any R bonded to the same N atom c4 and R d4 together with the N atom to which they are attached, R 22 forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Each R b4 But C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~6 independently selected from cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl, wherein C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each R 22 optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a5 , R c5 and R d5 But H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl and C 1~6 haloalkyl, wherein C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Each alkynyl is R g optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R b5 But C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl and C 1~6 haloalkyl, wherein C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Each alkynyl is R g optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a6 , R c6 and R d6 But H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl and C 1~6 haloalkyl, wherein C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Each alkynyl is R g optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R b6 But C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 1~6 haloalkyl, wherein C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Each alkynyl is R goptionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R g OH, NO2, CN, Halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl, C 3~6 Cycloalkyl-C 1~2 Alkylene, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~3 Alkoxy-C 1~3 Alkyl, C 1~3 Alkoxy-C 1~3 Alkoxy, HO-C 1~3 Alkoxy, HO-C 1~3 Alkyl, Cyano-C 1~3 Alkyl, H2N-C 1~3 Alkyl, Amino, C 1~6 Alkylamino, di(C 1~6 Alkyl)amino, thio, C 1~6 Alkylthio, C 1~6 Alkylsulfinyl, C 1~6 Alkyl sulfonyl, carbamyl, C 1~6 Alkylcarbamyl, di(C 1~6 Alkyl) carbamyl, carboxy, C 1~6 Alkyl carbonyl, C 1~6 Alkoxycarbonyl, C 1~6 Alkylcarbonylamino, C 1~6 Alkyl sulfonyl amino, amino sulfonyl, C 1~6 Alkylaminosulfonyl, di(C 1~6 Alkyl)aminosulfonyl, aminosulfonylamino, C 1~6 Alkylaminosulfonylamino, di(C 1~6 Alkyl)aminosulfonylamino, aminocarbonylamino, C 1~6 Alkylaminocarbonylamino, and di(C 1~6 alkyl)aminocarbonylamino.

[0015] In one aspect, the present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: Cy 1 is selected from phenyl, pyridinyl, and pyrazolyl, where phenyl, pyridinyl, and pyrazolyl are each selected from R 10 optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 1 But, Halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~5 Cycloalkyl, 4-5 membered heterocycloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~3 Alkoxy-C 1~3 Alkyl, HO-C 1~3 Alkyl, C 1~6 Alkylamino and di(C 1~6 alkyl)amino, wherein C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~5 Cycloalkyl, 4-5 membered heterocycloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~3 Alkoxy-C 1~3 Alkyl, HO-C 1~3 Alkyl, C 1~6 Alkylamino and di(C 1~6 Any of the H atoms of the alkyl)amino may be replaced by a D atom; Each R 2 and R 3 But C 1~6 Alkyl, C 2~6 Alkenyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl, 4-6 membered heterocycloalkyl, halo, CN, OR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2, N.R. c2 R d2 , and S(O)2R b2 are independently selected from, where C 1~6 Alkyl, C 2~6 Alkenyl, C 3~6 Cycloalkyl and 4- to 6-membered heterocycloalkyl are each R 21 optionally substituted with 1, 2, 3, or 4 substituents independently selected from or two adjacent R on a phenyl ring 2 the substituents, together with the atoms to which they are attached, form a fused 5- or 6-membered cycloalkyl ring or a fused 5- or 6-membered heterocycloalkyl ring, wherein each fused 5- or 6-membered heterocycloalkyl ring has at least one ring-forming carbon atom and 1 or 2 ring-forming heteroatoms independently selected from O and N, and wherein a ring-forming carbon atom of each fused 5- or 6-membered heterocycloalkyl ring is optionally substituted by oxo to form a carbonyl group, and wherein the fused 5- or 6-membered cycloalkyl ring and the fused 5- or 6-membered heterocycloalkyl ring are each R 21 optionally substituted with 1, 2, 3, or 4 substituents independently selected from n is selected from 0 and 1; Each R 10 But C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, 4-12 membered heterocycloalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~10 Cycloalkyl-C 1~3 Alkylene, 4-12 membered heterocycloalkyl-C 1~3 Alkylene, C 6~10 Aryl-C 1~3 Alkylene, 5-10 membered heteroaryl-C 1~3 Alkylene, Halo, D, CN, OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , N.R. c1 R d1, N.R. c1 C(O)R b1 , and S(O)2R b1 are independently selected from, where C 1~6 Alkyl, C 3~10 Cycloalkyl, 4-12 membered heterocycloalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~10 Cycloalkyl-C 1~3 Alkylene, 4-12 membered heterocycloalkyl-C 1~3 Alkylene, C 6~10 Aryl-C 1~3 Alkylene and 5-10 membered heteroaryl-C 1~3 Each alkylene is R 11 optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 11 But C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, halo, D, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)OR a3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)NR c3 R d3 , S(O)2R b3 , and S(O)NR c3 R d3 are independently selected from, where C 1~6 Alkyl, C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10 Aryl and 5- to 10-membered heteroaryl are each R 12optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 12 But C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl, 4-7 membered heterocycloalkyl, halo, D, CN, OR a5 , S.R. a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , N.R. c5 R d5 , N.R. c5 C(O)R b5 , S(O)2R b5 , and S(O)NR c5 R d5 are independently selected from, where C 1~6 Alkyl, C 3~6 Cycloalkyl and 4- to 7-membered heterocycloalkyl are each R g optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 21 But C 1~6 Alkyl, C 1~6 Haloalkyl, Halo, D, CN, OR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , N.R. c4 R d4 , and S(O)2R b4 are independently selected from, where C 1~6 Alkyl is R 22 optionally substituted with 1, 2, or 3 substituents independently selected from Each R 22 But C 1~6 Alkyl, C 1~6 Haloalkyl, Halo, D, CN, OR a6 , and NR c6 R d6 are independently selected from, where C 1~6 Alkyl is R goptionally substituted with one or two substituents independently selected from Each R a1 , R c1 and R d1 But H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 cycloalkyl, and 4- to 10-membered heterocycloalkyl, wherein C 1~6 Alkyl, C 3~10 Cycloalkyl and 4- to 10-membered heterocycloalkyl are each R 11 optionally substituted with 1, 2, 3, or 4 substituents independently selected from or any R bonded to the same N atom c1 and R d1 together with the N atom to which they are attached, R 11 forming a 4-, 5-, or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R b1 But C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 cycloalkyl, and 4- to 10-membered heterocycloalkyl, wherein C 1~6 Alkyl, C 3~10 Cycloalkyl and 4- to 10-membered heterocycloalkyl are each R 11 optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a2 , R c2 and R d2 But H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 cycloalkyl, and 4- to 10-membered heterocycloalkyl, wherein C 1~6 Alkyl, C 3~10 Cycloalkyl and 4- to 10-membered heterocycloalkyl are each R 21 optionally substituted with 1, 2, 3, or 4 substituents independently selected from or any R bonded to the same N atom c2 and R d2 together with the N atom to which they are attached, R 21 forming a 4-, 5-, or 6-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Each R b2 But C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 cycloalkyl, and 4- to 10-membered heterocycloalkyl, wherein C 1~6 Alkyl, C 3~10 Cycloalkyl and 4- to 10-membered heterocycloalkyl are each R 21 optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a3 , R c3 and R d3 But H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 cycloalkyl, and 4- to 7-membered heterocycloalkyl, wherein C 1~6 Alkyl, C 3~6 Cycloalkyl and 4- to 7-membered heterocycloalkyl are each R 12 optionally substituted with 1, 2, 3, or 4 substituents independently selected from or any R bonded to the same N atom c3 and R d3 together with the N atom to which they are attached, R 12 forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Each R b3 But C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 cycloalkyl, and 4- to 7-membered heterocycloalkyl, wherein C 1~6 Alkyl, C 3~6Cycloalkyl and 4- to 7-membered heterocycloalkyl are each R 12 optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a4 , R c4 and R d4 But H, C 1~6 Alkyl, and C 1~6 haloalkyl, wherein C 1~6 Alkyl is R 22 optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R b4 But C 1~6 Alkyl, and C 1~6 haloalkyl, wherein C 1~6 Alkyl is R 22 optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a5 , R c5 and R d5 But H, C 1~6 Alkyl, and C 1~6 haloalkyl, wherein C 1~6 Alkyl is R g optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R b5 But C 1~6 Alkyl, and C 1~6 haloalkyl, wherein C 1~6 Alkyl is R g optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a6 , R c6 and R d6 But H, C 1~6 Alkyl, and C 1~6 haloalkyl, wherein C 1~6 Alkyl is R g optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each Rb6 But C 1~6 Alkyl, and C 1~6 haloalkyl, wherein C 1~6 Alkyl is R g optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R g OH, CN, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~3 Alkoxy-C 1~3 Alkyl, HO-C 1~3 Alkyl, Cyano-C 1~3 Alkyl, H2N-C 1~3 Alkyl, Amino, C 1~6 Alkylamino, di(C 1~6 Alkyl)amino, C 1~6 Alkylthio, C 1~6 Alkyl sulfonyl, carboxy, C 1~6 Alkyl carbonyl, C 1~6 Alkoxycarbonyl, and C 1~6 alkylcarbonylamino.

[0016] In one aspect, the present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: Cy 1 is selected from phenyl, pyridin-3-yl and pyrazol-4-yl, wherein Cy 1 Phenyl, pyridin-3-yl and pyrazol-4-yl are each R 10 optionally substituted with one substituent selected from R 1 But Cl, C 1~3 Alkyl, C 1~3 Haloalkyl, cyclopropyl, azedinyl, hydroxymethyl, C 1~3 Alkoxy, C1~3 Haloalkoxy and C 1~3 alkylamino, wherein C 1~3 Alkyl, C 1~3 Haloalkyl, cyclopropyl, azedinyl, hydroxymethyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy and C 1~3 each alkylamino is optionally substituted with 1, 2, 3, 4, 5, 6, or 7 deuterium atoms; Each R 2 But C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 Cycloalkyl, F, Cl, CN, and OR a2 are independently selected from, where C 1~3 Alkyl, and C 3~6 Each cycloalkyl is R 21 optionally substituted with one, two, or three substituents independently selected from or R on the phenyl ring 2 the substituents, together with the atoms to which they are attached, form a fused 5- or 6-membered cycloalkyl ring or a fused 5- or 6-membered heterocycloalkyl ring, wherein each fused 5- or 6-membered heterocycloalkyl ring has at least one ring-forming carbon atom and one or two ring-forming O atoms, and wherein the fused 5- or 6-membered cycloalkyl ring and the fused 5- or 6-membered heterocycloalkyl ring each have R 21 optionally substituted with one or two substituents independently selected from n is 0, Each R 10 But C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 Cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 6-membered heteroaryl, 4- to 10-membered heterocycloalkyl-C 1~2 Alkylene, 5-6 membered heteroaryl-C 1~2 Alkylene, F, Cl, D, CN, OR a1 , C(O)NR c1 R d1 , and NR c1 Rd1 are independently selected from, where C 1~3 Alkyl, C 3~6 Cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 6-membered heteroaryl, 4- to 10-membered heterocycloalkyl-C 1~2 Alkylene and 5-6 membered heteroaryl-C 1~2 Each alkylene is R 11 optionally substituted with one or two substituents independently selected from Each R 11 But C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 Cycloalkyl, 4-10 membered heterocycloalkyl, 5-6 membered heteroaryl, F, Cl, D, CN, OR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 S(O)2R b3 , S(O)2R b3 , and S(O)NR c3 R d3 are independently selected from, where C 1~3 Alkyl, C 3~6 Cycloalkyl, 4- to 10-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each R 12 optionally substituted with one or two substituents independently selected from Each R 12 But C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 Cycloalkyl, 4-7 membered heterocycloalkyl, F, Cl, D, CN, OR a5 , C(O)R b5 , C(O)NR c5 R d5 , and NR c5 R d5 are independently selected from, where C 1~3 Alkyl, C 3~6Cycloalkyl and 4- to 7-membered heterocycloalkyl are each R g and optionally substituted with one substituent independently selected from R 21 But C 1~3 Alkyl, F, Cl, D, CN, and OR a4 are independently selected from, where C 1~3 Alkyl is R 22 optionally substituted with one or two substituents independently selected from Each R 22 F, Cl, D, CN, and OR a6 are independently selected from Each R a1 , R c1 and R d1 But H, C 1~3 Alkyl, C 1~3 independently selected from haloalkyl, and 4- to 6-membered heterocycloalkyl, wherein C 1~3 Alkyl and 4- to 6-membered heterocycloalkyl are each R 11 and optionally substituted with one substituent independently selected from Each R a2 But H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a3 , R c3 and R d3 But H, C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 cycloalkyl, and 4- to 6-membered heterocycloalkyl, wherein C 1~3 Alkyl, C 3~6 Cycloalkyl and 4- to 6-membered heterocycloalkyl are each R 12 optionally substituted with one or two substituents independently selected from or any R bonded to the same N atom c3 and R d3 together with the N atom to which they are attached, R 12forming a 4-, 5-, or 6-membered heterocycloalkyl group optionally substituted with one or two substituents independently selected from Each R b3 But C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 cycloalkyl, and 4- to 6-membered heterocycloalkyl, wherein C 1~3 Alkyl, C 3~6 Cycloalkyl and 4- to 6-membered heterocycloalkyl are each R 12 optionally substituted with one or two substituents independently selected from Each R a4 But H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a5 , R c5 and R d5 But H, C 1~3 Alkyl, and C 1~3 haloalkyl, wherein C 1~3 Alkyl is R g and optionally substituted with one substituent independently selected from Each R b5 But C 1~3 Alkyl, and C 1~3 haloalkyl, wherein C 1~3 Alkyl is R g and optionally substituted with one substituent independently selected from Each R a6 But H, and C 1~3 independently selected from alkyl, Each R g OH, CN, F, Cl, C 1~3 Alkyl, and C 1~3 haloalkyl.

[0017] In some embodiments, Cy 1 is selected from phenyl, pyridinyl, and pyrazolyl, where phenyl, pyridinyl, and pyrazolyl are each selected from R 10In some embodiments, Cy is optionally substituted with 1, 2, 3, or 4 substituents independently selected from 1 is selected from phenyl, pyridinyl, and pyrazolyl, where phenyl, pyridinyl, and pyrazolyl are each selected from R 10 In some embodiments, Cy is optionally substituted with one or two substituents independently selected from 1 is selected from phenyl, pyridinyl, and pyrazolyl, where phenyl, pyridinyl, and pyrazolyl are each selected from R 10 In some embodiments, Cy is optionally substituted with one substituent selected from 1 is selected from phenyl, pyridinyl, and pyrazolyl, where phenyl, pyridinyl, and pyrazolyl are each selected from R 10 is substituted with one substituent selected from

[0018] In some embodiments, Cy 1 is selected from phenyl, pyridin-3-yl, and pyrazol-4-yl, wherein phenyl, pyridin-3-yl, and pyrazol-4-yl are each selected from R 10 In some embodiments, Cy is optionally substituted with one substituent selected from 1 is selected from phenyl, pyridin-3-yl, and pyrazol-4-yl, wherein phenyl, pyridin-3-yl, and pyrazol-4-yl are each selected from R 10 is substituted with one substituent selected from

[0019] In some embodiments, Cy 1 is R 10 In some embodiments, Cy is a 5- to 6-membered heteroaryl optionally substituted with one or two substituents selected from 1 is selected from pyridin-3-yl and pyrazol-4-yl, where pyridin-3-yl and pyrazol-4-yl are each selected from R 10 is optionally substituted with one substituent selected from:

[0020] In some embodiments, Cy 1 is R 10 In some embodiments, Cy is pyrazol-4-yl optionally substituted with one or two substituents selected from 1 is selected from pyrazol-4-yl and pyridin-3-yl, where pyrazol-4-yl and pyridin-3-yl are each selected from R 10 In some embodiments, Cy is optionally substituted with one or two substituents selected from 1 is R 10 In some embodiments, Cy is pyridin-3-yl optionally substituted with one or two substituents selected from 1 is R 10 and n is 1 or 2.

[0021] In some embodiments, R 1 Ha, Halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~5 Cycloalkyl, 4-5 membered heterocycloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~3 Alkoxy-C 1~3 Alkyl, HO-C 1~3 Alkyl, C 1~6 Alkylamino and di(C 1~6 alkyl)amino, wherein optionally C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~5 Cycloalkyl, 4-5 membered heterocycloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~3 Alkoxy-C 1~3 Alkyl, HO-C 1~3 Alkyl, C 1~6 Alkylamino and di(C 1~6 One or more H atoms of the alkyl)amino are replaced by one or more D atoms.

[0022] In some embodiments, R 1 are Cl, C 1~3 Alkyl, C 1~3 Haloalkyl, cyclopropyl, azetidinyl, hydroxymethyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy and C 1~3 alkylamino, wherein optionally C 1~3 Alkyl, C 1~3 Haloalkyl, cyclopropyl, azetidinyl, hydroxymethyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy and C 1~3 One or more H atoms of the alkylamino are replaced by one or more D atoms.

[0023] In some embodiments, R 1 are Cl, C 1~2 Alkyl, C 1~2 Haloalkyl, cyclopropyl, hydroxymethyl, C 1~2 Alkoxy, C 1~2 Haloalkoxy and C 1~2 alkylamino, wherein optionally C 1~2 Alkyl, C 1~2 Haloalkyl, cyclopropyl, hydroxymethyl, C 1~2 Alkoxy, C 1~2 Haloalkoxy and C 1~2 One or more H atoms of the alkylamino are replaced by D atoms.

[0024] In some embodiments, R 1 are Cl, C 1~2 Alkyl, C 1~2 Haloalkyl, hydroxymethyl, C 1~2 Alkoxy, C 1~2 Haloalkoxy and C 1~2 alkylamino, wherein optionally C 1~2 Alkyl, C 1~2 Haloalkyl, hydroxymethyl, C 1~2 Alkoxy, C 1~2 Haloalkoxy and C 1~2One or more H atoms of the alkylamino are replaced by one or more D atoms.

[0025] In some embodiments, R 1 is selected from Cl, CH3, OCH3, OCD3, OCH2CH3, OCHF2, NHCH3, CHF2, and CH2OH.

[0026] In some embodiments, R 1 is C 1~2 In some embodiments, R 1 is OCH3. In some embodiments, R 1 is OCD3.

[0027] In some embodiments, each R 2 and R 3 is C 1~6 Alkyl, C 2~6 Alkenyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl, 4-6 membered heterocycloalkyl, halo, CN, OR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , N.R. c2 R d2 , and S(O)2R b2 are independently selected from, where C 1~6 Alkyl, C 2~6 Alkenyl, C 3~6 Cycloalkyl and 4- to 6-membered heterocycloalkyl are each R 21 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0028] In some embodiments, each R 2 is C 1~6 Alkyl, C 1~3 Haloalkyl, C 3~6 Cycloalkyl, halo, CN, and OR a2 are independently selected from, where C 1~6 Alkyl and C 3~6Each cycloalkyl is R 21 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0029] In some embodiments, each R 2 is C 1~6 Alkyl, C 3~6 Cycloalkyl, Halo, and OR a2 are independently selected from, where C 1~6 Alkyl and C 3~6 Each cycloalkyl is R 21 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0030] In some embodiments, two adjacent R on the phenyl ring 2 the substituents, together with the atoms to which they are attached, form a fused 5- or 6-membered cycloalkyl ring or a fused 5- or 6-membered heterocycloalkyl ring, wherein each fused 5- or 6-membered heterocycloalkyl ring has at least one ring-forming carbon atom and 1 or 2 ring-forming heteroatoms independently selected from O and N, and wherein a ring-forming carbon atom of each fused 5- or 6-membered heterocycloalkyl ring is optionally substituted by oxo to form a carbonyl group, and wherein the fused 5- or 6-membered cycloalkyl ring and the fused 5- or 6-membered heterocycloalkyl ring are each R 21 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0031] In some embodiments, two adjacent R on the phenyl ring 2 The substituents, together with the atoms to which they are attached, form a fused 5-membered cycloalkyl ring, or a fused 5- or 6-membered heterocycloalkyl ring, wherein each fused 5- or 6-membered heterocycloalkyl ring has at least one ring-forming carbon atom and one or two ring-forming O atoms, and wherein the fused 5-membered cycloalkyl ring and the fused 5- or 6-membered heterocycloalkyl ring each have R 21 and optionally substituted with one or two substituents independently selected from:

[0032] In some embodiments, each R 2 is C 3~6 Cycloalkyl, C 1~2 Alkyl, C 1~2 Haloalkyl, F, Cl, CN, and OR a2 are independently selected from, where C 1~2 Alkyl is R 21 is optionally substituted with one substituent selected from:

[0033] In some embodiments, each R 2 is C 1~3 Alkyl, C 1~3 Haloalkyl, F, Cl, CN, and OR a2 are independently selected from, where C 1~6 Alkyl is R 21 is optionally substituted with one substituent selected from:

[0034] In some embodiments, each R 2 is C 1~2 Alkyl, C 1~2 Haloalkyl, F, Cl, CN, and OR a2 are independently selected from, where C 1~2 Alkyl is R 21 is optionally substituted with one substituent selected from:

[0035] In some embodiments, each R 2 is C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 Cycloalkyl, F, Cl, CN, and OR a2 are independently selected from, where C 1~3 Alkyl, and C 3~6 Each cycloalkyl is R 21 and optionally substituted with one, two, or three substituents independently selected from:

[0036] In some embodiments, each R 2 is C 1~2independently selected from alkyl and F, where C 1~2 Alkyl is R 21 is optionally substituted with one substituent selected from:

[0037] In some embodiments, each R 2 are independently selected from F, methyl, CHCN, and CD.

[0038] In some embodiments, each R 2 are independently selected from F, methyl, CHCN, cyclopropyl, and CD.

[0039] In some embodiments, each R 2 are independently selected from F, methyl, CHCN, CD, OH, OCH, and cyclopropyl.

[0040] In some embodiments, each R 2 is C 1~2 In some embodiments, each R 2 is methyl.

[0041] In some embodiments, R on the phenyl ring 2 The substituents, together with the atoms to which they are attached, form a fused 5-membered cycloalkyl ring or a fused 5-membered heterocycloalkyl ring, wherein the fused 5-membered heterocycloalkyl ring has at least one ring-forming carbon atom and one or two ring-forming O atoms, and wherein the fused 5-membered cycloalkyl ring and the fused 5-membered heterocycloalkyl ring each have R 21 and optionally substituted with one or two substituents selected from:

[0042] In some embodiments, R on the phenyl ring 2The substituents, together with the atoms to which they are attached, form a fused 5- or 6-membered cycloalkyl ring or a fused 5- or 6-membered heterocycloalkyl ring, wherein each fused 5- or 6-membered heterocycloalkyl ring has at least one ring-forming carbon atom and one or two ring-forming O atoms, and wherein each fused 5- or 6-membered cycloalkyl ring or fused 5- or 6-membered heterocycloalkyl ring is selected from the group consisting of R 21 is optionally substituted with one substituent selected from:

[0043] In some embodiments, R 2 The substituents, together with the atoms to which they are attached, form a fused cyclopentyl or tetrahydrofuranyl group, each of which is R 21 and optionally substituted with one or two substituents selected from:

[0044] In some embodiments, R 2 The substituents, together with the atoms to which they are attached, form a fused cyclopentyl group, a fused tetrahydrofuranyl group, a fused 1,4-dioxanyl group, or a fused tetrahydropyranyl group, each of which is selected from the group consisting of R 21 and optionally substituted with one or two substituents selected from:

[0045] In some embodiments, R 2 The substituents, together with the atom to which they are attached, form a fused cyclopentyl group optionally substituted with one or two substituents independently selected from OH, CN, CH2OH, and F.

[0046] In some embodiments, R 2 The substituents, together with the atom to which they are attached, form a fused cyclopentyl group optionally substituted with one or two substituents independently selected from D, OH, CN, CH2OH, and F.

[0047] In some embodiments, R 2The substituents, together with the atoms to which they are attached, form a fused cyclopentyl or fused cyclohexyl group, wherein the fused cyclopentyl and fused cyclohexyl groups have at least one ring-forming carbon atom and each optionally has one or two ring-forming O atoms, and wherein the fused cyclopentyl and fused cyclohexyl groups are each optionally substituted with one or two substituents independently selected from D, OH, CN, CHOH, and F.

[0048] In some embodiments, R 2 The substituents, together with the atoms to which they are attached, form a fused cyclopentyl group.

[0049] In some embodiments, n is selected from 0 and 1.

[0050] In some embodiments, n is 0. In some embodiments, n is 1.

[0051] In some embodiments, each R 10 is C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, 4-12 membered heterocycloalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~10 Cycloalkyl-C 1~3 Alkylene, 4-12 membered heterocycloalkyl-C 1~3 Alkylene, C 6~10 Aryl-C 1~3 Alkylene, 5-10 membered heteroaryl-C 1~3 Alkylene, Halo, D, CN, OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , and S(O)2R b1 are independently selected from, where C 1~6 Alkyl, C 3~10Cycloalkyl, 4-12 membered heterocycloalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~10 Cycloalkyl-C 1~3 Alkylene, 4-12 membered heterocycloalkyl-C 1~3 Alkylene, C 6~10 Aryl-C 1~3 Alkylene and 5-10 membered heteroaryl-C 1~3 Each alkylene is R 11 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0052] In some embodiments, each R 10 is C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3~6 Cycloalkyl-C 1~3 Alkylene, 4-6 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene, 5-6 membered heteroaryl-C 1~3 Alkylene, Halo, D, CN, OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , and S(O)2R b1 are independently selected from, where C 1~6 Alkyl, C 3~6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3~6 Cycloalkyl-C 1~3 Alkylene, 4-6 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene and 5-6 membered heteroaryl-C 1~3 Each alkylene is R 11and optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0053] In some embodiments, each R 10 is C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3~6 Cycloalkyl-C 1~3 Alkylene, 4-6 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene, 5-6 membered heteroaryl-C 1~3 Alkylene, Halo, D, CN, OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , and S(O)2R b1 are independently selected from, where C 1~6 Alkyl, C 3~6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3~6 Cycloalkyl-C 1~3 Alkylene, 4-6 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene and 5-6 membered heteroaryl-C 1~3 Each alkylene is R 11 and optionally substituted with one or two substituents independently selected from:

[0054] In some embodiments, each R 10 is C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 Cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl-C 1~2 Alkylene, 5-6 membered heteroaryl-C1~2 Alkylene, Halo, D, CN, OR a1 , C(O)NR c1 R d1 , and NR c1 R d1 are independently selected from, where C 1~3 Alkyl, C 3~6 Cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl-C 1~2 Alkylene and 5-6 membered heteroaryl-C 1~2 Each alkylene is R 11 and optionally substituted with one or two substituents independently selected from:

[0055] In some embodiments, each R 10 is C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 Cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl-C 1~2 Alkylene, 5-6 membered heteroaryl-C 1~2 Alkylene, Halo, D, CN, C(O)NR c1 R d1 , and NR c1 R d1 are independently selected from, where C 1~3 Alkyl, C 3~6 Cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl-C 1~2 Alkylene and 5-6 membered heteroaryl-C 1~2 Each alkylene is R 11 and optionally substituted with one or two substituents independently selected from:

[0056] In some embodiments, each R 10 is C 1~3 Alkyl, C 1~3 Haloalkyl, OR a1 , C 3~6 Cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl-C1~2 Alkylene, 5-6 membered heteroaryl-C 1~2 Alkylene, Halo, D, CN, C(O)NR c1 R d1 , and NR c1 R d1 are independently selected from, where C 1~3 Alkyl, C 3~6 Cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl-C 1~2 Alkylene and 5-6 membered heteroaryl-C 1~2 Each alkylene is R 11 and optionally substituted with one or two substituents independently selected from:

[0057] In some embodiments, each R 10 is C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 Cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl-C 1~2 Alkylene, 5-6 membered heteroaryl-C 1~2 Alkylene, Halo, D, CN, C(O)NR c1 R d1 , and NR c1 R d1 are independently selected from, where C 1~3 Alkyl, C 3~6 Cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl-C 1~2 Alkylene and 5-6 membered heteroaryl-C 1~2 Each alkylene is R 11 and optionally substituted with one substituent selected from C 1~2 Optionally substituted with a second substituent selected from alkyl.

[0058] In some embodiments, each R 10 is C 1~3 Alkyl, C 1~3 Haloalkyl, OR a1 , C 3~6Cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl-C 1~2 Alkylene, 5-6 membered heteroaryl-C 1~2 Alkylene, Halo, D, CN, C(O)NR c1 R d1 , and NR c1 R d1 are independently selected from, where C 1~3 Alkyl, C 3~6 Cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl-C 1~2 Alkylene and 5-6 membered heteroaryl-C 1~2 Each alkylene is R 11 and optionally substituted with one substituent selected from C 1~2 Optionally substituted with a second substituent selected from alkyl.

[0059] In some embodiments, each R 10 is C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl-C 1~2 Alkylene, 5-6 membered heteroaryl-C 1~2 Alkylene, Halo, D, CN, C(O)NR c1 R d1 , and NR c1 R d1 are independently selected from, where C 1~3 Alkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl-C 1~2 Alkylene and 5-6 membered heteroaryl-C 1~2 Each alkylene is R 11 and optionally substituted with one or two substituents independently selected from:

[0060] In some embodiments, each R 10 is C 1~3 Alkyl, C1~3 Haloalkyl, Halo, D, CN, C(O)NR c1 R d1 , and NR c1 R d1 are independently selected from, where C 1~3 Alkyl is R 11 and optionally substituted with one or two substituents independently selected from:

[0061] In some embodiments, each R 10 is C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl-C 1~2 Alkylene and 5-6 membered heteroaryl-C 1~2 alkylene, wherein C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl-C 1~2 Alkylene and 5-6 membered heteroaryl-C 1~2 Each alkylene is R 11 and optionally substituted with one or two substituents independently selected from:

[0062] In some embodiments, each R 10 is C 1~2 Alkyl, C 1~2 Haloalkyl, C 3~6 Cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyridinyl, piperazinonyl, diazabicyclo[2.2.1]heptanyl(morpholinyl)ethyl, (pyridinyl)methyl, (triazolyl)methyl, 1-oxa-3,8-diazaspiro[4.5]decan-2-one, F, Cl, D, CN, and NR c1 R d1 are independently selected from, where C 1~2 Alkyl, C 3~6 Cycloalkyl, C 3~6Cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyridinyl, piperazinonyl, diazabicyclo[2.2.1]heptanyl(morpholinyl)ethyl, and (pyridinyl)methyl are each R 11 and optionally substituted with one or two substituents independently selected from:

[0063] In some embodiments, each R 10 is C 1~2 Alkyl, C 3~6 Cycloalkyl, halo, D, CN, OR a1 , C(O)NR c1 R d1 , N.R. c1 R d1 , azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyridinyl, piperazinonyl, diazabicyclo[2.2.1]heptanyl(morpholinyl)ethyl, (pyridinyl)methyl, (triazolyl)methyl, thiomorpholinyl, 1-oxa-3,8-diazaspiro[4.5]decan-2-one, and hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, wherein C 1~2 Alkyl, C 3~6 Cycloalkyl, C 3~6 Cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyridinyl, piperazinonyl, diazabicyclo[2.2.1]heptanyl(morpholinyl)ethyl, (pyridinyl)methyl, (triazolyl)methyl, thiomorpholinyl, 1-oxa-3,8-diazaspiro[4.5]decan-2-one, and hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl are each R 11 and optionally substituted with one or two substituents independently selected from:

[0064] In some embodiments, each R 10 is C 1~2 Alkyl, C 3~6independently selected from cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyridinyl, piperazinonyl, diazabicyclo[2.2.1]heptanyl(morpholinyl)ethyl, (pyridinyl)methyl, (triazolyl)methyl, thiomorpholinyl, 1-oxa-3,8-diazaspiro[4.5]decan-2-one, and hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, wherein C 1~2 Alkyl, C 3~6 Cycloalkyl, C 3~6 Cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyridinyl, piperazinonyl, diazabicyclo[2.2.1]heptanyl(morpholinyl)ethyl, (pyridinyl)methyl, (triazolyl)methyl, thiomorpholinyl, 1-oxa-3,8-diazaspiro[4.5]decan-2-one, and hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl are each R 11 and optionally substituted with one or two substituents independently selected from:

[0065] In some embodiments, R 10 When R is a 4- to 10-membered heterocycloalkyl, the heteroatoms of the heterocycloalkyl ring are within the range of R 11 In some embodiments, R 10 When R is a 4- to 6-membered heterocycloalkyl, the heteroatoms of the heterocycloalkyl ring are within the allowed valences of R 11 In some embodiments, the S atom of the heterocycloalkyl ring is substituted with NR. In some embodiments, the S atom of the heterocycloalkyl ring is substituted with NR and O.

[0066] In some embodiments, each R 10 is C 1~2 Alkyl, C 1~2 Haloalkyl, F, Cl, D, CN, and NR c1 R d1 are independently selected from, where C 1~2 Alkyl is R 11and optionally substituted with one or two substituents independently selected from:

[0067] In some embodiments, each R 10 is C 1~2 Alkyl, C 1~2 Haloalkyl, F, Cl, D, CN, OR a1 , and NR c1 R d1 are independently selected from, where C 1~2 Alkyl is R 11 and optionally substituted with one or two substituents independently selected from:

[0068] In some embodiments, each R 10 is C 3~6 independently selected from cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyridinyl, piperazinonyl, diazabicyclo[2.2.1]heptanyl(morpholinyl)ethyl, (pyridinyl)methyl, (triazinyl)methyl, and 1-oxa-3,8-diazaspiro[4.5]decan-2-one, wherein C 3~6 Cycloalkyl, C 3~6 Cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyridinyl, piperazinonyl, diazabicyclo[2.2.1]heptanyl(morpholinyl)ethyl, and (pyridinyl)methyl are each R 11 and optionally substituted with one or two substituents independently selected from:

[0069] In some embodiments, each R 10 is C 1~2 Alkyl, C 1~2 Haloalkyl, C 3~6 Cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyridinyl, piperazinonyl, diazabicyclo[2.2.1]heptanyl (morpholinyl)ethyl, (pyridinyl)methyl, (triazinyl)methyl, 1-oxa-3,8-diazaspiro[4.5]decan-2-one, F, Cl, D, CN, NR c1 Rd1 are independently selected from, where C 1~2 Alkyl, C 3~6 Cycloalkyl, C 3~6 Cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyridinyl, piperazinonyl, diazabicyclo[2.2.1]heptanyl(morpholinyl)ethyl, and (pyridinyl)methyl are each R 11 and optionally substituted with one substituent selected from C 1~2 Optionally substituted with a second substituent selected from alkyl.

[0070] In some embodiments, each R 10 is C 1~2 Alkyl, C 3~6 independently selected from cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyridinyl, piperazinonyl, diazabicyclo[2.2.1]heptanyl(morpholinyl)ethyl, (pyridinyl)methyl, (triazolyl)methyl, and 1-oxa-3,8-diazaspiro[4.5]decan-2-one, wherein C 1~2 Alkyl, C 3~6 Cycloalkyl, C 3~6 Cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyridinyl, piperazinonyl, diazabicyclo[2.2.1]heptanyl (morpholinyl)ethyl, (pyridinyl)methyl, and (triazolyl)methyl are each R 11 and optionally substituted with one or two substituents independently selected from:

[0071] In some embodiments, each R 10 is C 1~2 Alkyl, C 3~6 independently selected from cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyridinyl, piperazinonyl, diazabicyclo[2.2.1]heptanyl(morpholinyl)ethyl, (pyridinyl)methyl, (triazolyl)methyl, and 1-oxa-3,8-diazaspiro[4.5]decan-2-one, wherein C1~2 Alkyl, C 3~6 Cycloalkyl, C 3~6 Cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyridinyl, piperazinonyl, diazabicyclo[2.2.1]heptanyl (morpholinyl)ethyl, (pyridinyl)methyl, and (triazolyl)methyl are each R 11 and optionally substituted with one substituent selected from C 1~2 Optionally substituted with a second substituent selected from alkyl.

[0072] In some embodiments, each R 10are methyl, (1-methyl-1H-1,2,4-triazol-5-yl)methyl, pyrrolidin-3-yl, pyrrolidin-1-yl, 1-ethylpyrrolidin-3-yl, 1-methylazetidin-3-yl, 1-ethylazetidin-3-yl, 4-acetylpiperazin-1-yl, 3-cyanocyclobutyl, 1-(dimethylcarbamoyl)piperidin-4-yl, 1-(methoxycarbonyl)piperidin-4-yl, 1-(methoxycarbonyl) Azetidin-3-yl, 1-acetylazetidin-3-yl, 1-(methylsulfonyl)azetidin-3-yl, 1-(dimethylcarbamoyl)azetidin-3-yl, 1-(cyclopropanecarbonyl)azetidin-3-yl, pyridin-4-ylmethyl, 2-morpholinoethyl, cyclopropyl, 2-cyanoethyl, 2-hydroxyethyl, pyridin-4-yl, 4-hydroxycyclohexyl, 4-methylpiperazin-1-yl, 4-ethyl thylpiperazin-1-yl, morpholino, 4-methyl-3-oxopiperazin-1-yl, 4-hydroxypiperidin-1-yl, (R)-3,4-dimethylpiperazin-1-yl, (1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl, 4-(dimethylcarbamoyl)piperidin-1-yl, 4-carboxy-4-methylpiperidin-1-yl, (1S,4S)-4-acetamidocyclohexyl, 2, and 1-(methoxycarbonyl)piperazin-4-yl), independently selected from 4-dimethylpiperazin-1-yl, 4-(ethylcarbamoyl)piperazin-1-yl, 4-carbamoylpiperazin-1-yl, 4-isopropylpiperazin-1-yl, 4-ethylpiperazin-1-yl, 2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-8-yl, pyridin-2-ylmethyl, 1-acetylpiperidin-4-yl, and 1-(methoxycarbonyl)piperidin-4-yl.

[0073] In some embodiments, each R 10is methyl, (1-methyl-1H-1,2,4-triazol-5-yl)methyl, pyrrolidin-3-yl, pyrrolidin-1-yl, 1-ethylpyrrolidin-3-yl, 1-methylazetidin-3-yl, 1-ethylazetidin-3-yl, 4-acetylpiperazin-1-yl, 3-cyanocyclobutyl, 1-(dimethylcarbamoyl)piperidin-4-yl, 1-(methoxycarbonyl)piperidin-4-yl, 1-(methoxycarbonyl)azetidin-3-yl, 1-acetylazetidin-3-yl, 1-(methylsulfonyl)azetidin-3-yl, 1-(dimethylcarbamoyl)azetidin-3-yl, 1-(cyclopropanecarbonyl)azetidin-3-yl, pyridin-4-ylmethyl, 2-morpholinoethyl, cyclopropyl, 2-cyanoethyl, 2-hydroxyethyl, pyridine -4-yl, 4-hydroxycyclohexyl, 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl, morpholino, 4-methyl-3-oxopiperazin-1-yl, 4-hydroxypiperidin-1-yl, (R)-3,4-dimethylpiperazin-1-yl, (1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl, 4-(dimethylcarbamoyl)piperidin-1-yl, peridin-1-yl, 4-carboxy-4-methylpiperidin-1-yl, (1S,4S)-4-acetamidocyclohexyl, 2,4-dimethylpiperazin-1-yl, 4-(ethylcarbamoyl)piperazin-1-yl, 4-carbamoylpiperazin-1-yl, 4-isopropylpiperazin-1-yl, 4-ethylpiperazin-1-yl, 2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-8-yl, pyridin-2-ylmethyl, 1-acetylpiperidin-4-yl), 1-(methoxycarbonyl)piperidin-4-yl, (tetrahydrofuran-3-yl)oxy, 1-methyl-5-oxopyrrolidin-3-yl, 1-(2-hydroxypropanoyl)piperidin-4-yl, 1-(2-hydroxyacetyl)piperidin-4-yl, 4-carboxycyclohexyl, 3-amino-4-fluoropyrrolidin-1-yl, (7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, (7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, 4-imino-4-oxo-4λ. 6 -piperazin-1-yl, (2-hydroxy-N-methylacetamido)pyrrolidin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, 2-methoxyethoxy, (tetrahydro-2H-pyran-4-yl)oxy, cyclopropyl, and 3-(2-hydroxy-N-methylacetamido)azetidin-1-yl.

[0074] In some embodiments, each R 10are 1-(2-hydroxyacetyl)pyrrolidin-3-yl, 1-acetylpiperidin-3-yl, 1-(3'-pyrrolidin-2'-one)pyrrolidin-3-yl, 1-(1'-methyl-(3'-pyrrolidin-2'-one))pyrrolidin-3-yl, 1-(2-propanamido)pyrrolidin-3-yl, 1-(methyl-L-prolyl)piperidin-4-yl, 1-(4-methylmorpholin-3-yl)pyrrolidin-3-yl, 3-cyanocyclobut-1-yl, 1-(hydroxymethylcarbonyl)azetidin-3-yl, 1-(2-(dimethylamino) ethanecarbonyl)azetidin-3-yl, 1-(dimethylamino-methyl-acetyl)azetidin-3-yl, 1-((1-methylazetidin-2-yl)carbonyl)azetidin-3-yl, 1-(2-(4-methylpiperazin-1-yl)ethan-1-one)azetidin-3-yl, 1-(2-(4-hydroxypiperazin-1-yl)ethan-1-one)azetidin-3-yl, 1-((1-methylazetidin-2-yl)carbonyl)azetidin-3-yl, 1-(hydroxy-methyl-acetyl)azetidin-3-yl, 1-((trans )-3-hydroxycyclobutylcarbonyl)azetidin-3-yl, 1-((cis)-3-hydroxycyclobutylcarbonyl)azetidin-3-yl, 1-((4-methylmorpholin-3-yl)carbonyl)azetidin-3-yl, 1-(hydroxyl-acetyl)pyrrolidin-3-yl, 1-((tetrahydrofuran-2-yl)carbonyl)azetidin-3-yl, 1-((tetrahydrofuran-3-yl)carbonyl)azetidin-3-yl, 1-(hydroxy-methyl-acetyl)pyrrolidin-3-yl, 1-(3-hydroxybutanoyl 1-((-3-hydroxy-3-methylcyclobutyl)carbonyl)azetidin-3-yl, 1-(4-methylmorpholin-3-yl)carbonyl)pyrrolidin-3-yl, 1-((hydroxymethyl)cyclobutylcarbonyl)azetidin-3-yl, 1-((1-ethylazetidin-2-yl)carbonyl)azetidin-3-yl, 1-((1-(2-fluoroethyl)azetidin-2-yl)carbonyl)azetidin-3-yl, 1-((1-isopropylazetidin-2-yl)carbonyl)azetidin-3-yl,1-((1-(2-Fluoroethyl)azetidin-2-yl)carbonyl)pyrrolidin-3-yl, 1-((trans)-3-hydroxycyclobutylcarbonyl)pyrrolidin-3-yl, 1-((cis)-3-hydroxycyclobutylcarbonyl)pyrrolidin-3-yl, 1-((3-hydroxy-3-methylcyclobutyl)carbonyl)pyrrolidin-3-yl, 1-(2-methoxyethan-1-one)azetidin-3-yl, 1-(2-(dimethylamino)-2-methylpropan-1-one)azetidin-3-yl, 1-((cyclopropane -1-carbonitrile)carbonyl)azetidin-3-yl, 1-((ethan-1-ol)sulfonyl)azetidin-3-yl, 1-((N,N-dimethylethan-1-amine)sulfonyl)azetidin-3-yl, 1-((2-methoxyethyl)carboxylate)azetidin-3-yl, 1-((3-methoxycyclobutyl)carbonyl)azetidin-3-yl, 3-(2-hydroxy-N-methylacetamido)cyclopentyl, 3-(2-hydroxypropanamido)cyclopentyl, 3-(2-hydroxyacetamido)cyclopentyl, 3-(2-hydroxyethyl)-3-azabicyclo[3.1.0]hexan-1-yl, (4-hydroxypiperidin-1-yl)methyl, (2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl, 1-(morpholin-4-yl)ethyl, (5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-7-yl)methyl, 1-(2-hydroxyethyl)piperidin-4-yl-4-carbonitrile, 1-(2-hydroxyacetyl)piperidin-4-yl-4-carbonitrile, 2-methoxyethylpiperidin-4-yl perazin-1-yl, 1-(tetrahydro-2H-pyran-4-carbonyl)piperidin-4-yl-4-d, 1-(2-methoxyacetyl)pyrrolidin-3-yl, 1-(tetrahydrofuran-2-carbonyl)pyrrolidin-3-yl, 3-(2-hydroxy-N-methylacetamido)azetidin-1-yl, 1-((tetrahydrofuran-2-yl)carbonyl)azetidin-3-yl, 1-((1-methylpiperidin-2-yl)carbonyl)azetidin-3-yl, 1-(2-(dimethylamino)ethan-1-one)azetidin-3-yl,1-(3-hydroxypropan-1-one)azetidin-3-yl, 1-(2-hydroxyethan-1-one)azetidin-3-yl, 1-(2-hydroxypropan-1-one)azetidin-3-yl, 1-(2-hydroxy-N-methylacetamido)cyclobut-3-yl, 1-(2-hydroxyethan-1-one)-3-d-azetidin-3-yl, 1-carboxylate piperidin-4-yl, 1-(morpholine -4-carbonyl)piperidin-4-yl, 1-acetylpyrrolidin-3-yl, 1-(morpholine-4-carbonyl)pyrrolidin-3-yl, cyanomethyl, 1-propanenitrile-azetidin-3-yl, 1-(2-methoxy-N-methylacetamido)cyclobut-3-yl, 1-(3-hydroxy-N-methylpropanamido)cyclobut-3-yl, 1-(2-hydroxy-N-methylpropanamido)cyclobut-3-yl -3-yl, 1-(2-hydroxyethan-1-one)azabicyclo[3.1.0]hexan-3-yl, 1-((4-methylmorpholin-3-yl)carbonyl)azabicyclo[3.1.0]hexan-3-yl, 1-(tetrahydro-2H-pyran-4-yl)azabicyclo[3.1.0]hexan-3-yl, 1-(ethan-1-ol)azabicyclo[3.1.0]hexan-3-yl, 1-(4-methylmorpholin-3-yl)carbonyl)azabicyclo[3.1.0]hexan-3-yl 1-(4-methylmorpholine-3-carbonyl)-3-carbonitrile-pyrrolidin-3-yl, 1-(4-methylmorpholine-3-carbonyl)-4-carbonitrile-piperidin-4-yl, 1-(2-hydroxyacetyl)-3-carbonitrile-pyrrolidin-3-yl, (1,3-dimethylpiperazin-4-yl-2-one)methyl, and (2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl.

[0075] In some embodiments, each R 10is methyl, (1-methyl-1H-1,2,4-triazol-5-yl)methyl, pyrrolidin-3-yl, pyrrolidin-1-yl, 1-ethylpyrrolidin-3-yl, 1-methylazetidin-3-yl, 1-ethylazetidin-3-yl, 4-acetylpiperazin-1-yl, 3-cyanocyclobutyl, 1-(dimethylcarbamoyl)piperidin-4-yl, 1-(methoxycarbonyl)piperidin-4-yl, 1-(methoxycarbonyl)azetidin-3-yl, 1-acetylazetidin-3-yl, 1-(methylsulfonyl)azetidin-3-yl, 1-(dimethylcarbamoyl)azetidin-3-yl, 1-(cyclopropanecarbonyl)azetidin-3-yl, pyridin-4-ylmethyl, 2-morpholinoethyl, cyclopropyl, 2-cyanoethyl, 2-hydroxyethyl, pyridine -4-yl, 4-hydroxycyclohexyl, 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl, morpholino, 4-methyl-3-oxopiperazin-1-yl, 4-hydroxypiperidin-1-yl, (R)-3,4-dimethylpiperazin-1-yl, (1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl, 4-(dimethylcarbamoyl)piperidin-1-yl, peridin-1-yl, 4-carboxy-4-methylpiperidin-1-yl, (1S,4S)-4-acetamidocyclohexyl, 2,4-dimethylpiperazin-1-yl, 4-(ethylcarbamoyl)piperazin-1-yl, 4-carbamoylpiperazin-1-yl, 4-isopropylpiperazin-1-yl, 4-ethylpiperazin-1-yl, 2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-8-yl, pyridin-2-ylmethyl, 1-acetylpiperidin-4-yl), 1-(methoxycarbonyl)piperidin-4-yl, (tetrahydrofuran-3-yl)oxy, 1-methyl-5-oxopyrrolidin-3-yl, 1-(2-hydroxypropanoyl)piperidin-4-yl, 1-(2-hydroxyacetyl)piperidin-4-yl, 4-carboxycyclohexyl, 3-amino-4-fluoropyrrolidin-1-yl, (7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, (7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, 4-imino-4-oxo-4λ. 6-piperazin-1-yl, (2-hydroxy-N-methylacetamido)pyrrolidin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, 2-methoxyethoxy, (tetrahydro-2H-pyran-4-yl)oxy, cyclopropyl, and 3-(2-hydroxy-N-methylacetamido)azetidin-1-yl, 1-(2-hydroxyacetyl)pyrrolidin-3-yl, 1-acetylpiperidin-3-yl, 1-(3'-pyrrolidin-2'-one)pyrrolidin-3-yl, 1-(1'-methyl-(3'-pyrrolidin-2'-one) )pyrrolidin-3-yl, 1-(2-propanamido)pyrrolidin-3-yl, 1-(methyl-L-prolyl)piperidin-4-yl, 1-(4-methylmorpholin-3-yl)pyrrolidin-3-yl, 3-cyanocyclobut-1-yl, 1-(hydroxymethylcarbonyl)azetidin-3-yl, 1-(2-(dimethylamino)ethanecarbonyl)azetidin-3-yl, 1-(dimethylamino-methyl-acetyl)azetidin-3-yl, 1-((1-methylazetidin-2-yl)carbonyl)azetidin-3-yl, 1-(2-(4-methyl 1-(2-(4-hydroxypiperazin-1-yl)ethan-1-one)azetidin-3-yl, 1-((1-methylazetidin-2-yl)carbonyl)azetidin-3-yl, 1-(hydroxymethylacetyl)azetidin-3-yl, 1-((trans)-3-hydroxycyclobutylcarbonyl)azetidin-3-yl, 1-((cis)-3-hydroxycyclobutylcarbonyl)azetidin-3-yl, 1-((4-methylmorpholin-3-yl)carbonyl 1-(hydroxyl-acetyl)pyrrolidin-3-yl, 1-((tetrahydrofuran-2-yl)carbonyl)azetidin-3-yl, 1-((tetrahydrofuran-3-yl)carbonyl)azetidin-3-yl, 1-(hydroxy-methyl-acetyl)pyrrolidin-3-yl, 1-(3-hydroxybutanoyl)azetidin-3-yl, 1-((-3-hydroxy-3-methylcyclobutyl)carbonyl)azetidin-3-yl, 1-(4-methylmorpholin-3-yl)carbonyl)pyrrolidin-3-yl,1-((hydroxymethyl)cyclobutylcarbonyl)azetidin-3-yl, 1-((1-ethylazetidin-2-yl)carbonyl)azetidin-3-yl, 1-((1-(2-fluoroethyl)azetidin-2-yl)carbonyl)azetidin-3-yl, 1-((1-isopropylazetidin-2-yl)carbonyl)azetidin-3-yl, 1-((1-(2-fluoroethyl)azetidin-2-yl)carbonyl)pyrrolidin-3-yl, 1-((trans)-3-hydroxycyclobutylcarbonyl)pyrrolidin-3-yl , 1-((cis)-3-hydroxycyclobutylcarbonyl)pyrrolidin-3-yl, 1-((3-hydroxy-3-methylcyclobutyl)carbonyl)pyrrolidin-3-yl, 1-(2-methoxyethan-1-one)azetidin-3-yl, 1-(2-(dimethylamino)-2-methylpropan-1-one)azetidin-3-yl, 1-((cyclopropane-1-carbonitrile)carbonyl)azetidin-3-yl, 1-((ethan-1-ol)sulfonyl)azetidin-3-yl, 1-((N,N-dimethylethan-1-amine)sulfonyl)azetidin-3-yl (4-hydroxypiperidin-1-yl)methyl, (2-oxa-5-azabicyclo[3.1.0]hexan-1-yl, ... [2.2.1]heptan-5-yl)methyl, 1-(morpholin-4-yl)ethyl, (5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-7-yl)methyl, 1-(2-hydroxyethyl)piperidin-4-yl-4-carbonitrile, 1-(2-hydroxyacetyl)piperidin-4-yl-4-carbonitrile, 2-methoxyethylpiperazin-1-yl, 1-(tetrahydro-2H-pyran-4-carbonyl)piperidin-4-yl-4-d, 1-(2-methoxyacetyl)pyrrolidin-3-yl,1-(tetrahydrofuran-2-carbonyl)pyrrolidin-3-yl, 3-(2-hydroxy-N-methylacetamido)azetidin-1-yl, 1-((tetrahydrofuran-2-yl)carbonyl)azetidin-3-yl, 1-((1-methylpiperidin-2-yl)carbonyl)azetidin-3-yl, 1-(2-(dimethylamino)ethan-1-one)azetidin-3-yl, 1-(3-hydroxypropan-1-one)azetidin-3-yl, 1-(2-hydroxyethan-1-one)azetidin-3-yl , 1-(2-hydroxypropan-1-one)azetidin-3-yl, 1-(2-hydroxy-N-methylacetamido)cyclobut-3-yl, 1-(2-hydroxyethan-1-one)-3-d-azetidin-3-yl, 1-carboxylatepiperidin-4-yl, 1-(morpholine-4-carbonyl)piperidin-4-yl, 1-acetylpyrrolidin-3-yl, 1-(morpholine-4-carbonyl)pyrrolidin-3-yl, cyanomethyl, 1-propanenitrile-azetidin-3-yl, 1-(2-methoxy- N-methylacetamido)cyclobut-3-yl, 1-(3-hydroxy-N-methylpropanamido)cyclobut-3-yl, 1-(2-hydroxy-N-methylpropanamido)cyclobut-3-yl, 1-(2-hydroxyethan-1-one)azabicyclo[3.1.0]hexan-3-yl, 1-((4-methylmorpholin-3-yl)carbonyl)azabicyclo[3.1.0]hexan-3-yl, 1-(tetrahydro-2H-pyran-4-yl)azabicyclo[3.1.0]hexan-3-yl, 1-(ethano ... 1-(4-methylmorpholine-3-carbonyl)-3-carbonitrile-pyrrolidin-3-yl, 1-(4-methylmorpholine-3-carbonyl)-4-carbonitrile-piperidin-4-yl, 1-(2-hydroxyacetyl)-3-carbonitrile-pyrrolidin-3-yl, (1,3-dimethylpiperazin-4-yl-2-one)methyl, and (2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl.

[0076] In some embodiments, each R 11is C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, halo, D, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)OR a3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)NR c3 R d3 , S(O)2R b3 , and S(O)NR c3 R d3 are independently selected from, where C 1~6 Alkyl, C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10 Aryl and 5- to 10-membered heteroaryl are each R 12 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0077] In some embodiments, each R 11 is C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, halo, D, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)OR a3 , N.R.c3 S(O)R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 , and S(O)NR c3 R d3 are independently selected from, where C 1~6 Alkyl, C 3~6 Cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocycloalkyl are each R 12 and optionally substituted with 1, 2, or 3 substituents independently selected from:

[0078] In some embodiments, each R 11 is C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~4 Cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, halo, D, CN, OR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , and S(O)2R b3 are independently selected from, where C 1~3 Alkyl, C 3~4 Cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocycloalkyl are each R 12 is optionally substituted with one substituent selected from:

[0079] In some embodiments, each R 11 is C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~4 Cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, halo, D, CN, ORa3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , S(O)2R b3 , and NR c3 S(O)2R b3 are independently selected from, where C 1~3 Alkyl, C 3~4 Cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocycloalkyl are each R 12 is optionally substituted with one substituent selected from:

[0080] In some embodiments, each R 11 Ha, Halo, C 1~2 Alkyl, CN, OR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , and S(O)2R b3 are independently selected from, where C 1~2 Alkyl is OR a5 is optionally replaced by

[0081] In some embodiments, each R 11 Ha, Halo, C 1~2 Alkyl, CN, OR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , S(O)2R b3 , 1-methyl-pyrrolidin-3-yl-2-one, pyrrolidin-3-yl-2-one, 2-propanamide, NR c3 S(O)2Rb3 , D, and tetrahydropyran-4-yl, wherein C 1~2 Alkyl is OR a5 is optionally replaced by

[0082] In some embodiments, each R 11 is C 1~3 Alkyl, 4-10 membered heterocycloalkyl, F, D, CN, OR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 S(O)2R b3 , and S(O)2R b3 are independently selected from, where C 1~3 Alkyl and 4- to 10-membered heterocycloalkyl are each R 12 and optionally substituted with one or two substituents independently selected from:

[0083] In some embodiments, each R 11 is C 1~2 Alkyl, C 1~2 Haloalkyl, F, Cl, D, CN, OR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , and S(O)2R b3 are independently selected from

[0084] In some embodiments, each R 11 is C 1~2 Alkyl, CN, OR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , N.R.c3 C(O)R b3 , and S(O)2R b3 are independently selected from

[0085] In some embodiments, each R 11 are independently selected from methyl, ethyl, isopropyl, CN, OH, oxo, (1-methyl-1H-1,2,4-triazol-5-yl)methyl, C(O)CH, C(O)N(CH), C(O)NH, C(O)NHCHCH, C(O)OCH, C(O)OH, NHC(O)CH, S(O)CH, cyclopropanecarbonyl, pyridin-4-yl, pyridin-2-yl, and morpholino.

[0086] In some embodiments, each R 11 is independently selected from methyl, ethyl, isopropyl, CN, OH, oxo, (1-methyl-1H-1,2,4-triazol-5-yl)methyl, C(O)CH, C(O)N(CH), C(O)NH, C(O)NHCHCH, C(O)OCH, C(O)OH, NHC(O)CH, S(O)CH, cyclopropanecarbonyl, pyridin-4-yl, pyridin-2-yl, morpholino, 2-hydroxypropanoyl, 2-hydroxyacetyl, 2-hydroxyethyl, F, NH, and N(CH)C(O)CHOH.

[0087] In some embodiments, each R 11 are independently selected from methyl, ethyl, isopropyl, CN, OH, D, oxo, (1-methyl-1H-1,2,4-triazol-5-yl)methyl, C(O)CH, C(O)N(CH), C(O)NH, C(O)NHCHCH, C(O)OCH, C(O)OH, NHC(O)CH, S(O)CH, cyclopropanecarbonyl, pyridin-4-yl, pyridin-2-yl, and morpholino.

[0088] In some embodiments, each R 11are D, methyl, ethyl, isopropyl, CN, OH, oxo, (1-methyl-1H-1,2,4-triazol-5-yl)methyl, CH2CH2OH, C(O)CH3, C(O)N(CH3)2, C(O)NH2, C(O)NHCH2CH3, C(O)CH2CH2N(CH3)2, C(O)CH(CH3)N(CH3)2, C(O)OCH3, C(O)CH2OH, CH(CH3)C(O)NH2, C(O)OH, NHC(O)CH3, S(O)2CH3, cyclopropanecarbonyl, pyridin-4-yl, pyridin-2-yl, morpholino, 2-Hydroxypropanoyl, 2-hydroxyacetyl, 2-hydroxyethyl, F, NH2, N(CH3)C(O)CH2OH, 3'-pyrrolidin-2'-one, methyl-3'-pyrrolidin-2'-one, 1-methyl-prolyl, (4-methylmorpholin-3-yl)methyl-1-one, (1-methylazetidin-2-yl)methyl-1-one, 2-(4-methylpiperazin-1-yl)ethyl-1-one, 2-(4-hydroxypiperidin-1-yl)ethyl-1-one, 2-hydroxypropyl-1-one, (trans)-3-hydroxycithin (cyclobutyl)methyl-1-one, (cis)-3-hydroxycyclobutyl)methyl-1-one, (4-methylmorpholin-3-yl)methyl-1-one, (tetrahydrofuran-2-yl)methyl-1-one, 2-hydroxypropyl-1-one, 3-hydroxybutyl-1-one, 3-hydroxy-3-methylcyclobutyl)methyl-1-one, (hydroxymethyl)cyclobutyl)methyl-one, (1-ethylazetidin-2-yl)methyl-1-one, (2-fluoroethyl)azetidin-2-yl)methyl-1-one, (1-isopropyl Azetidin-2-yl)methyl-1-one, 2-methoxyethyl-1-one, 2-(dimethylamino)-2-methylpropyl-1-one, (cyclopropane-1-carbonitrile)methyl-1-one, S(O)2CH2CH2OH, S(O)2CH2CH2N(CH3)2, 2-methoxyethyl-carboxyl, N-methylmethanesulfonamide, 2-hydroxy-N-methylacetamide, 2-hydroxypropanamide, tetrahydro-2H-pyran-4-methyl-1-one, 2-methoxyacetyl, 2-hydroxy-N-methylacetamide,Independently selected from tetrahydrofuran-2-methyl-1-one, (1-methylpiperidin-2-yl)methyl-1-one, 2-(dimethylamino)ethyl-1-one, 3-hydroxypropyl-1-one, methoxymethyl-carboxyl, morpholine-4-carbonyl, propylnitrile, 2-methoxy-N-methylacetamide, 3-hydroxy-N-methylpropanamide, 2-hydroxy-N-methylpropanamide, tetrahydro-2H-pyran-4-yl, and 1,3-dimethylpiperazinyl-2-one.

[0089] In some embodiments, each R 12 is C 1~6 Alkyl, C 1~6 Haloalkyl, Halo, D, CN, OR a5 , and NR c5 R d5 are independently selected from, where C 1~6 Alkyl is R g and optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0090] In some embodiments, each R 12 is C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl, 4-7 membered heterocycloalkyl, halo, D, CN, OR a5 , S.R. a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , N.R. c5 R d5 , N.R. c5 C(O)R b5 , S(O)2R b5 , and S(O)NR c5 R d5 are independently selected from, where C 1~6 Alkyl, C 3~6 Cycloalkyl and 4- to 7-membered heterocycloalkyl are each R g and optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0091] In some embodiments, each R 12 is C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 Cycloalkyl, 4-7 membered heterocycloalkyl, F, Cl, D, CN, OR a5 , C(O)R b5 , C(O)NR c5 R d5 , and NR c5 R d5 are independently selected from, where C 1~3 Alkyl, C 3~6 Cycloalkyl and 4- to 7-membered heterocycloalkyl are each R g is optionally substituted with one substituent independently selected from

[0092] In some embodiments, each R 12 is C 1~3 Alkyl, Halo, D, and OR a5 are independently selected from

[0093] In some embodiments, R 12 is methyl.

[0094] In some embodiments, R 12 is OH.

[0095] In some embodiments, each R 21 is C 1~6 Alkyl, C 1~6 Haloalkyl, Halo, D, CN, OR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , N.R. c4 R d4 , and S(O)2R b4 are independently selected from, where C 1~6 Alkyl is R 22 and optionally substituted with 1, 2, or 3 substituents independently selected from:

[0096] In some embodiments, each R 21 is C 1~3 Alkyl, halo, D, CN, and OR a4 are independently selected from, where C 1~3 Alkyl is R 22 and optionally substituted with one or two substituents independently selected from:

[0097] In some embodiments, each R 21 is C 1~2 Alkyl, F, Cl, D, CN, and OR a4 are independently selected from, where C 1~2 Alkyl is R 22 is optionally substituted with one substituent selected from:

[0098] In some embodiments, each R 21 is C 1~2 Alkyl, halo, D, CN, and OR a4 are independently selected from, where C 1~3 Alkyl is R 22 and optionally substituted with one or two substituents independently selected from:

[0099] In some embodiments, each R 21 is C 1~3 Alkyl, halo, D, CN, and OR a4 are independently selected from, where C 1~3 Alkyl is R 22 and optionally substituted with one or two substituents independently selected from:

[0100] In some embodiments, each R 21 is C 1~3 Alkyl, F, Cl, D, CN, and OR a4 are independently selected from, where C 1~3 Alkyl is R 22 In some embodiments, each R 21 is C 1~2Alkyl, F, D, CN, and OR a4 are independently selected from, where C 1~2 Alkyl is R 22 is optionally substituted with one substituent selected from:

[0101] In some embodiments, each R 21 are independently selected from methyl, F, D, CN, and OH.

[0102] In some embodiments, each R 22 is C 1~6 Alkyl, C 1~6 Haloalkyl, Halo, D, CN, OR a6 , and NR c6 R d6 are independently selected from, where C 1~6 Alkyl is R g and optionally substituted with one or two substituents independently selected from:

[0103] In some embodiments, each R 22 are F, Cl, D, CN, and OR a6 are independently selected from

[0104] In some embodiments, each R 22 Halo, D, CN, and OR a6 are independently selected from

[0105] In some embodiments, each R 22 are F, Cl, CN, and OR a6 are independently selected from

[0106] In some embodiments, R 22 is OR a6 In some embodiments, R 22 is OH. In some embodiments, each R 22 is independently selected from F and Cl. In some embodiments, R 22 is CN.

[0107] In some embodiments, each R a1 , R c1 and R d1 is H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 cycloalkyl, and 4- to 6-membered heterocycloalkyl, wherein C 1~6 Alkyl, C 3~6 Cycloalkyl and 4- to 6-membered heterocycloalkyl are each R 11 and optionally substituted with 1, 2, or 3 substituents independently selected from:

[0108] In some embodiments, each R a1 , R c1 and R d1 is H and C 1~6 alkyl.

[0109] In some embodiments, each R a1 , R c1 and R d1 is H, C 1~6 alkyl, and 4- to 6-membered heterocycloalkyl.

[0110] In some embodiments, any R attached to the same N atom c1 and R d1 together with the N atom to which they are attached, R 11 and forming a 4-, 5-, or 6-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from:

[0111] In some embodiments, each R c1 and R d1 is H, C 1~3 Alkyl, and C 1~3 haloalkyl.

[0112] In some embodiments, R c1 and R d1 is H and C 1~2 alkyl.

[0113] In some embodiments, each R b1 is C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 cycloalkyl, and 4- to 6-membered heterocycloalkyl, wherein C 1~6 Alkyl, C 3~6 Cycloalkyl and 4- to 6-membered heterocycloalkyl are each R 11 In some embodiments, each R b1 is C 1~6 alkyl.

[0114] In some embodiments, each R a2 , R c2 and R d2 is H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 cycloalkyl, and 4- to 6-membered heterocycloalkyl, wherein C 1~6 Alkyl, C 3~6 Cycloalkyl and 4- to 6-membered heterocycloalkyl are each R 21 and optionally substituted with 1, 2, or 3 substituents independently selected from:

[0115] In some embodiments, each R a2 , R c2 and R d2 is H and C 1~6 alkyl.

[0116] In some embodiments, each R a2 is H and C 1~3 alkyl.

[0117] In some embodiments, each R a2 is H and C 1~2 alkyl.

[0118] In some embodiments, any R attached to the same N atom c2 and R d2 together with the N atom to which they are attached, R 21 and R 1 and R 2 form a 4-, 5-, or 6-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from:

[0119] In some embodiments, each R b2 is C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 cycloalkyl, and 4- to 6-membered heterocycloalkyl, wherein C 1~6 Alkyl, C 3~6 Cycloalkyl and 4- to 6-membered heterocycloalkyl are each R 21 and optionally substituted with 1, 2, or 3 substituents independently selected from:

[0120] In some embodiments, each R b2 is C 1~6 alkyl.

[0121] In some embodiments, each R a3 , R c3 and R d3 is H, C 1~6 Alkyl, C 1~6 Haloalkyl, and C 3~6 cycloalkyl, wherein C 1~6 Alkyl and C 3~6 Each cycloalkyl is R 12 and optionally substituted with one or two substituents independently selected from:

[0122] In some embodiments, each R a3 , R c3 and R d3 is H, C 1~3 Alkyl, C 1~3 Haloalkyl, and C 3~5 cycloalkyl.

[0123] In some embodiments, each R a3 , R c3 and R d3 is H and C 1~2 alkyl.

[0124] In some embodiments, any R attached to the same N atom c3 and R d3 together with the N atom to which they are attached, R 12 and forming a 4-, 5-, or 6-membered heterocycloalkyl group optionally substituted with one or two substituents independently selected from:

[0125] In some embodiments, each R b3 is C 1~6 Alkyl, C 1~6 Haloalkyl, and C 3~6 cycloalkyl, wherein C 1~6 Alkyl and C 3~6 Each cycloalkyl is R 12 and optionally substituted with one or two substituents independently selected from:

[0126] In some embodiments, each R b3 is C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 cycloalkyl, and 4- to 6-membered heterocycloalkyl, wherein C 1~3 Alkyl, C 3~6 Cycloalkyl and 4- to 6-membered heterocycloalkyl are each R 12 and optionally substituted with one or two substituents independently selected from:

[0127] In some embodiments, each R b3 is C 1~3 Alkyl and C 3~5 cycloalkyl.

[0128] In some embodiments, each R b3is C 1~2 In some embodiments, each R b3 is C 1~2 alkyl.

[0129] In some embodiments, each R a4 , R c4 and R d4 is H, C 1~6 Alkyl, and C 1~6 haloalkyl, wherein C 1~6 Alkyl is R 22 and optionally substituted with one or two substituents independently selected from:

[0130] In some embodiments, each R a4 , R c4 and R d4 is H, C 1~3 Alkyl, and C 1~3 haloalkyl, wherein C 1~3 Alkyl is R 22 and optionally substituted with one or two substituents independently selected from:

[0131] In some embodiments, each R a4 is H and C 1~3 alkyl.

[0132] In some embodiments, R a4 is H and C 1~2 In some embodiments, R a4 is H.

[0133] In some embodiments, each R b4 is C 1~6 Alkyl, and C 1~6 haloalkyl, wherein C 1~6 Alkyl is R 22 In some embodiments, each R b4is C 1~6 alkyl.

[0134] In some embodiments, each R a5 , R c5 and R d5 is H, C 1~6 Alkyl, and C 1~6 haloalkyl, wherein C 1~6 Alkyl is R g and optionally substituted with one or two substituents independently selected from:

[0135] In some embodiments, R a5 is H and C 1~3 alkyl.

[0136] In some embodiments, each R b5 is C 1~6 Alkyl, and C 1~6 haloalkyl, wherein C 1~6 Alkyl is R g and optionally substituted with one or two substituents independently selected from:

[0137] In some embodiments, each R a6 , R c6 and R d6 is H, C 1~6 Alkyl, and C 1~6 haloalkyl, wherein C 1~6 Alkyl is R g and optionally substituted with one or two substituents independently selected from:

[0138] In some embodiments, each R a6 is H and C 1~3 alkyl.

[0139] In some embodiments, R a6 is H and C 1~2 alkyl.

[0140] In some embodiments, each R b6 is C 1~6 Alkyl, and C 1~6 haloalkyl, wherein C 1~6 Alkyl is R g In some embodiments, each R b6 is C 1~6 alkyl.

[0141] In some embodiments, each R g OH, CN, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~3 Alkoxy-C 1~3 Alkyl, HO-C 1~3 Alkyl, Cyano-C 1~3 Alkyl, H2N-C 1~3 Alkyl, Amino, C 1~6 Alkylamino, di(C 1~6 Alkyl)amino, C 1~6 Alkylthio, C 1~6 Alkyl sulfonyl, carboxy, C 1~6 Alkyl carbonyl, C 1~6 Alkoxycarbonyl, and C 1~6 alkylcarbonylamino.

[0142] In some embodiments, each R g Ha, Halo, C 1~6 Alkyl, and C 1~6 haloalkyl.

[0143] In some embodiments, each R g OH, CN, F, Cl, C 1~3 Alkyl, and C 1~3 haloalkyl.

[0144] In some embodiments, the compound of Formula I has Formula Ia: [ka] or a pharmaceutically acceptable salt thereof, wherein Cy 1 , R 1 , and each R 2 is as defined herein.

[0145] In some embodiments, the compound of Formula I has Formula IIa: [ka] or a pharmaceutically acceptable salt thereof, wherein Cy 1 , each R 2 , R 3 , and n are as defined herein.

[0146] In some embodiments, the compound of Formula I has Formula IIb: [ka] or a pharmaceutically acceptable salt thereof, wherein Cy 1 and each R 2 is as defined herein.

[0147] In some embodiments, the compound of Formula I has Formula IIIa: [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , each R 2 , and R 10 is as defined herein.

[0148] In some embodiments, the compound of Formula I has Formula IIIb: [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , each R 2 , and R 10 is as defined herein.

[0149] In some embodiments, the compound of Formula I has Formula IIIc: [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , each R 2 , and R 10 is as defined herein.

[0150] In some embodiments, the compound of formula I has formula IVa: [ka] or a pharmaceutically acceptable salt thereof, wherein Cy 1 and R 1 is as defined herein.

[0151] In some embodiments, the compound of Formula I has Formula IVb: [ka] or a pharmaceutically acceptable salt thereof, wherein Cy 1 is as defined herein.

[0152] In some embodiments, the compound of formula I has formula Va: [ka] or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, or 2; 1 , R 1 , and R 21is as defined herein. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

[0153] In some embodiments, the compound of formula I has formula Vb: [ka] or a pharmaceutically acceptable salt thereof, wherein Cy 1 and R 1 is as defined herein.

[0154] In some embodiments, the compound of formula I has formula Vc: [ka] or a pharmaceutically acceptable salt thereof, wherein Cy 1 is as defined herein.

[0155] In some embodiments, the compound of formula I has formula VI: [ka] or a pharmaceutically acceptable salt thereof, wherein Cy 1 and R 1 is as defined herein.

[0156] In some embodiments, provided herein are compounds of formula (I), or pharmaceutically acceptable salts thereof, wherein: Cy 1 is selected from phenyl, pyridinyl, and pyrazolyl, where phenyl, pyridinyl, and pyrazolyl are each selected from R 10 optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 1 But, Halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~5Cycloalkyl, 4-5 membered heterocycloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~3 Alkoxy-C 1~3 Alkyl, HO-C 1~3 Alkyl, C 1~6 Alkylamino and di(C 1~6 alkyl)amino, wherein optionally C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~5 Cycloalkyl, 4-5 membered heterocycloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~3 Alkoxy-C 1~3 Alkyl, HO-C 1~3 Alkyl, C 1~6 Alkylamino and di(C 1~6 one or more H atoms of the alkyl)amino are replaced by one or more D atoms; Each R 2 and R 3 But C 1~6 Alkyl, C 2~6 Alkenyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl, 4-6 membered heterocycloalkyl, halo, CN, OR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , N.R. c2 R d2 , and S(O)2R b2 are independently selected from, where C 1~6 Alkyl, C 2~6 Alkenyl, C 3~6 Cycloalkyl and 4- to 6-membered heterocycloalkyl are each R 21 optionally substituted with 1, 2, 3, or 4 substituents independently selected from or two adjacent R on a phenyl ring 2the substituents, together with the atoms to which they are attached, form a fused 5- or 6-membered cycloalkyl ring or a fused 5- or 6-membered heterocycloalkyl ring, wherein each fused 5- or 6-membered heterocycloalkyl ring has at least one ring-forming carbon atom and 1 or 2 ring-forming heteroatoms independently selected from O and N, and wherein a ring-forming carbon atom of each fused 5- or 6-membered heterocycloalkyl ring is optionally substituted by oxo to form a carbonyl group, and wherein the fused 5- or 6-membered cycloalkyl ring and the fused 5- or 6-membered heterocycloalkyl ring are each R 21 optionally substituted with 1, 2, 3, or 4 substituents independently selected from n is selected from 0 and 1; Each R 10 But C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, 4-12 membered heterocycloalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~10 Cycloalkyl-C 1~3 Alkylene, 4-12 membered heterocycloalkyl-C 1~3 Alkylene, C 6~10 Aryl-C 1~3 Alkylene, 5-10 membered heteroaryl-C 1~3 Alkylene, Halo, D, CN, OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , and S(O)2R b1 are independently selected from, where C 1~6 Alkyl, C 3~10 Cycloalkyl, 4-12 membered heterocycloalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~10 Cycloalkyl-C 1~3 Alkylene, 4-12 membered heterocycloalkyl-C 1~3 Alkylene, C 6~10Aryl-C 1~3 Alkylene and 5-10 membered heteroaryl-C 1~3 Each alkylene is R 11 optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 11 But C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, halo, D, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)OR a3 , N.R. c3 S(O)R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 , and S(O)NR c3 R d3 are independently selected from, where C 1~6 Alkyl, C 3~6 Cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocycloalkyl are each R 12 optionally substituted with 1, 2, or 3 substituents independently selected from Each R 12 But C 1~6 Alkyl, C 1~6 Haloalkyl, Halo, D, CN, OR a5 , and NR c5 R d5 are independently selected from, where C 1~6 Alkyl is R goptionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 21 But C 1~6 Alkyl, C 1~6 Haloalkyl, Halo, D, CN, OR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , N.R. c4 R d4 , and S(O)2R b4 are independently selected from, where C 1~6 Alkyl is R 22 optionally substituted with 1, 2, or 3 substituents independently selected from Each R 22 But C 1~6 Alkyl, C 1~6 Haloalkyl, Halo, D, CN, OR a6 , and NR c6 R d6 are independently selected from, where C 1~6 Alkyl is R g optionally substituted with one or two substituents independently selected from Each R a1 , R c1 and R d1 But H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 cycloalkyl, and 4- to 6-membered heterocycloalkyl, wherein C 1~6 Alkyl, C 3~6 Cycloalkyl and 4- to 6-membered heterocycloalkyl are each R 11 optionally substituted with one, two, or three substituents independently selected from or any R bonded to the same N atom c1 and R d1 together with the N atom to which they are attached, R 11 forming a 4-, 5-, or 6-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Each Rb1 But C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 cycloalkyl, and 4- to 6-membered heterocycloalkyl, wherein C 1~6 Alkyl, C 3~6 Cycloalkyl and 4- to 6-membered heterocycloalkyl are each R 11 optionally substituted with 1, 2, or 3 substituents independently selected from Each R a2 , R c2 and R d2 But H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 cycloalkyl, and 4- to 6-membered heterocycloalkyl, wherein C 1~6 Alkyl, C 3~6 Cycloalkyl and 4- to 6-membered heterocycloalkyl are each R 21 optionally substituted with one, two, or three substituents independently selected from or any R bonded to the same N atom c2 and R d2 together with the N atom to which they are attached, R 21 forming a 4-, 5-, or 6-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Each R b2 But C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 cycloalkyl, and 4- to 6-membered heterocycloalkyl, wherein C 1~6 Alkyl, C 3~6 Cycloalkyl and 4- to 6-membered heterocycloalkyl are each R 21 optionally substituted with 1, 2, or 3 substituents independently selected from Each R a3 , R c3 and R d3 But H, C 1~6 Alkyl, C 1~6 Haloalkyl, and C 3~6cycloalkyl, wherein C 1~6 Alkyl and C 3~6 Each cycloalkyl is R 12 optionally substituted with one or two substituents independently selected from Each R b3 But C 1~6 Alkyl, C 1~6 Haloalkyl, and C 3~6 cycloalkyl, wherein C 1~6 Alkyl and C 3~6 Each cycloalkyl is R 12 optionally substituted with one or two substituents independently selected from Each R a4 , R c4 and R d4 But H, C 1~6 Alkyl, and C 1~6 haloalkyl, wherein C 1~6 Alkyl is R 22 optionally substituted with one or two substituents independently selected from Each R b4 But C 1~6 Alkyl, and C 1~6 haloalkyl, wherein C 1~6 Alkyl is R 22 optionally substituted with one or two substituents independently selected from Each R a5 , R c5 and R d5 But H, C 1~6 Alkyl, and C 1~6 haloalkyl, wherein C 1~6 Alkyl is R g optionally substituted with one or two substituents independently selected from Each R a6 , R c6 and R d6 But H, C 1~6 Alkyl, and C 1~6 haloalkyl, wherein C 1~6 Alkyl is R goptionally substituted with one or two substituents independently selected from Each R g OH, CN, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~3 Alkoxy-C 1~3 Alkyl, HO-C 1~3 Alkyl, Cyano-C 1~3 Alkyl, H2N-C 1~3 Alkyl, Amino, C 1~6 Alkylamino, di(C 1~6 Alkyl)amino, C 1~6 Alkylthio, C 1~6 Alkyl sulfonyl, carboxy, C 1~6 Alkyl carbonyl, C 1~6 Alkoxycarbonyl, and C 1~6 alkylcarbonylamino.

[0157] In some embodiments, provided herein are compounds of formula (I), or pharmaceutically acceptable salts thereof, wherein: Cy 1 is selected from phenyl, pyridin-3-yl and pyrazol-4-yl, wherein Cy 1 Phenyl, pyridin-3-yl and pyrazol-4-yl are each R 10 optionally substituted with one substituent selected from R 1 But Cl, C 1~3 Alkyl, C 1~3 Haloalkyl, cyclopropyl, azetidinyl, hydroxymethyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy and C 1~3 alkylamino, wherein optionally C 1~3 Alkyl, C 1~3 Haloalkyl, cyclopropyl, azetidinyl, hydroxymethyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy and C1~3 one or more H atoms of the alkylamino are replaced by one or more D atoms; Each R 2 But C 1~3 Alkyl, C 1~3 Haloalkyl, F, Cl, CN, and OR a2 are independently selected from, where C 1~6 Alkyl is R 21 or optionally substituted with one substituent selected from or R on the phenyl ring 2 the substituents, together with the atoms to which they are attached, form a fused 5- or 6-membered cycloalkyl ring or a fused 5- or 6-membered heterocycloalkyl ring, wherein each fused 5- or 6-membered heterocycloalkyl ring has at least one ring-forming carbon atom and one or two ring-forming O atoms, and wherein each fused 5- or 6-membered cycloalkyl ring or fused 5- or 6-membered heterocycloalkyl ring is selected from the group consisting of R 21 optionally substituted with one substituent selected from n is 0, R 10 But C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 Cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl-C 1~2 Alkylene, 5-6 membered heteroaryl-C 1~2 Alkylene, Halo, D, CN, C(O)NR c1 R d1 , and NR c1 R d1 are independently selected from, where C 1~3 Alkyl, C 3~6 Cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl-C 1~2 Alkylene and 5-6 membered heteroaryl-C 1~2 Each alkylene is R 11 optionally substituted with one or two substituents independently selected from Each R 11 But C 1~3Alkyl, C 1~3 Haloalkyl, C 3~4 Cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, halo, D, CN, OR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , and S(O)2R b3 are independently selected from, where C 1~3 Alkyl, C 3~4 Cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocycloalkyl are each R 12 optionally substituted with one substituent selected from Each R 12 But C 1~3 Alkyl, Halo, D, and OR a5 is selected from Each R 21 But C 1~3 Alkyl, halo, D, CN, and OR a4 are independently selected from, where C 1~3 Alkyl is R 22 optionally substituted with one or two substituents independently selected from Each R 22 Halo, D, CN, and OR a6 are independently selected from R c1 and R d1 But H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a2 However, H and C 1~3 independently selected from alkyl, Each R a3 , R c3 and R d3 But H, C 1~3 Alkyl, C 1~3 Haloalkyl, and C 3~5 cycloalkyl; Each Rb3 But C 1~3 Alkyl and C 3~5 cycloalkyl; Each R a4 However, H and C 1~3 independently selected from alkyl, Each R a5 However, H and C 1~3 alkyl, Each R a6 However, H and C 1~3 alkyl.

[0158] In some embodiments, provided herein are compounds of formula (I), or pharmaceutically acceptable salts thereof, wherein: Cy 1 is selected from phenyl, pyridin-3-yl and pyrazol-4-yl, wherein Cy 1 Phenyl, pyridin-3-yl and pyrazol-4-yl are each R 10 optionally substituted with one substituent selected from R 1 But Cl, C 1~3 Alkyl, C 1~3 Haloalkyl, cyclopropyl, azetidinyl, hydroxymethyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy and C 1~3 alkylamino, wherein optionally C 1~3 Alkyl, C 1~3 Haloalkyl, cyclopropyl, azetidinyl, hydroxymethyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy and C 1~3 one or more H atoms of the alkylamino are replaced by one or more D atoms; Each R 2 But C 1~3 Alkyl, C 1~3 Haloalkyl, F, Cl, CN, and OR a2 are independently selected from, where C 1~6 Alkyl is R 21 or optionally substituted with one substituent selected from or R on the phenyl ring 2 the substituents, together with the atoms to which they are attached, form a fused 5- or 6-membered cycloalkyl ring or a fused 5- or 6-membered heterocycloalkyl ring, wherein each fused 5- or 6-membered heterocycloalkyl ring has at least one ring-forming carbon atom and one or two ring-forming O atoms, and wherein each fused 5- or 6-membered cycloalkyl ring or fused 5- or 6-membered heterocycloalkyl ring is selected from the group consisting of R 21 optionally substituted with one substituent selected from n is 0, R 10 But C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl-C 1~2 Alkylene, 5-6 membered heteroaryl-C 1~2 Alkylene, Halo, D, CN, C(O)NR c1 R d1 , and NR c1 R d1 are independently selected from, where C 1~3 Alkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl-C 1~2 Alkylene and 5-6 membered heteroaryl-C 1~2 Each alkylene is R 11 optionally substituted with one or two substituents independently selected from Each R 11 But C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~4 Cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, halo, D, CN, OR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , N.R. c3 R d3 , N.R. c3 C(O)R b3, and S(O)2R b3 are independently selected from, where C 1~3 Alkyl, C 3~4 Cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocycloalkyl are each R 12 optionally substituted with one substituent selected from Each R 12 But C 1~3 Alkyl, Halo, D, and OR a5 is selected from Each R 21 But C 1~3 Alkyl, halo, D, CN, and OR a4 are independently selected from, where C 1~3 Alkyl is R 22 optionally substituted with one or two substituents independently selected from Each R 22 Halo, D, CN, and OR a6 are independently selected from R c1 and R d1 But H, C 1~3 Alkyl, and C 1~3 haloalkyl; Each R a2 However, H and C 1~3 independently selected from alkyl, Each R a3 , R c3 and R d3 But H, C 1~3 Alkyl, C 1~3 Haloalkyl, and C 3~5 cycloalkyl; Each R b3 But C 1~3 Alkyl and C 3~5 cycloalkyl; Each R a4 However, H and C 1~3 independently selected from alkyl, Each R a5 However, H and C 1~3 alkyl, Each R a6 However, H and C 1~3alkyl.

[0159] In some embodiments, provided herein are compounds of formula (I), or pharmaceutically acceptable salts thereof, wherein: Cy 1 is selected from phenyl, pyridin-3-yl and pyrazol-4-yl, wherein Cy 1 Phenyl, pyridin-3-yl and pyrazol-4-yl are each R 10 optionally substituted with one substituent selected from R 1 But Cl, C 1~2 Alkyl, C 1~2 Haloalkyl, cyclopropyl, hydroxymethyl, C 1~2 Alkoxy, C 1~2 Haloalkoxy and C 1~2 alkylamino, wherein optionally C 1~2 Alkyl, C 1~2 Haloalkyl, cyclopropyl, hydroxymethyl, C 1~2 Alkoxy, C 1~2 Haloalkoxy and C 1~2 one or more H atoms of the alkylamino are replaced by one or more D atoms; Each R 2 But C 1~2 Alkyl, C 1~2 Haloalkyl, F, Cl, CN, and OR a2 are independently selected from, where C 1~2 Alkyl is R 21 or optionally substituted with one substituent selected from or R on the phenyl ring 2 the substituents, together with the atoms to which they are attached, form a fused 5- or 6-membered cycloalkyl ring or a fused 5- or 6-membered heterocycloalkyl ring, wherein each fused 5- or 6-membered heterocycloalkyl ring has at least one ring-forming carbon atom and one or two ring-forming O atoms, and wherein each fused 5- or 6-membered cycloalkyl ring or fused 5- or 6-membered heterocycloalkyl ring is selected from the group consisting of R 21 optionally substituted with one substituent selected from n is 0, R 10 But C 1~2 Alkyl, C 1~2 Haloalkyl, C 3~6 Cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyridinyl, piperazinonyl, diazabicyclo[2.2.1]heptanyl, (morpholinyl)ethyl, (pyridinyl)methyl, (triazolyl)methyl, 1-oxa-3,8-diazaspiro[4.5]decan-2-one, F, Cl, D, CN, NR c1 R d1 are independently selected from, where C 1~2 Alkyl, C 3~6 Cycloalkyl, C 3~6 Cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyridinyl, piperazinonyl, diazabicyclo[2.2.1]heptanyl (morpholinyl)ethyl, (pyridinyl)methyl, and (triazolyl)methyl are each R 11 optionally substituted with one or two substituents independently selected from Each R 11 But C 1~2 Alkyl, C 1~2 Haloalkyl, F, Cl, D, CN, OR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , and S(O)2R b3 are independently selected from Each R 21 But C 1~2 Alkyl, F, Cl, D, CN, and OR a4 are independently selected from, where C 1~2 Alkyl is R 22 optionally substituted with one substituent selected from Each R 22 F, Cl, CN, and OR a6 are independently selected from R c1 and R d1 However, H and C 1~2 independently selected from alkyl, Each R a2 However, H and C 1~2 independently selected from alkyl, Each R a3 , R c3 and R d3 However, H and C 1~2 independently selected from alkyl, Each R b3 But C 1~2 alkyl, and cyclopropyl; Each R a4 However, H and C 1~2 independently selected from alkyl, Each R a6 However, H and C 1~2 alkyl.

[0160] In some embodiments, provided herein are compounds of formula (I), or pharmaceutically acceptable salts thereof, wherein: Cy 1 is selected from phenyl, pyridin-3-yl and pyrazol-4-yl, wherein Cy 1 Phenyl, pyridin-3-yl and pyrazol-4-yl are each R 10 and is substituted with one substituent selected from R 1 But Cl, C 1~2 Alkyl, C 1~2 Haloalkyl, hydroxymethyl, C 1~2 Alkoxy, C 1~2 Haloalkoxy and C 1~2 alkylamino, wherein optionally C 1~2 Alkyl, C 1~2 Haloalkyl, hydroxymethyl, C 1~2 Alkoxy, C 1~2 Haloalkoxy and C 1~2 one or more H atoms of the alkylamino are replaced by one or more D atoms; Each R 2 But C1~2 independently selected from alkyl and F, where C 1~2 Each alkyl is R 21 or optionally substituted with one substituent selected from or R on the phenyl ring 2 the substituents, together with the atoms to which they are attached, form a fused 5-membered cycloalkyl ring or a fused 5-membered heterocycloalkyl ring, wherein each fused 5-membered heterocycloalkyl ring has at least one ring-forming carbon atom and one or two ring-forming O atoms, and wherein the fused 5-membered cycloalkyl ring and the fused 5-membered heterocycloalkyl ring each have R 21 optionally substituted with one or two substituents each independently selected from n is 0, R 10 But C 1~2 Alkyl, C 3~6 independently selected from cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyridinyl, piperazinonyl, diazabicyclo[2.2.1]heptanyl(morpholinyl)ethyl, (pyridinyl)methyl, (triazinyl)methyl, and 1-oxa-3,8-diazaspiro[4.5]decan-2-one, wherein C 1~2 Alkyl, C 3~6 Cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyridinyl, piperazinonyl, diazabicyclo[2.2.1]heptanyl(morpholinyl)ethyl, and (pyridinyl)methyl are each R 11 optionally substituted with one or two substituents independently selected from Each R 11 But C 1~2 Alkyl, CN, OR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , N.R. c3 C(O)R b3 , and S(O)2R b3 are independently selected from Each R 21 But C1~2 Alkyl, F, D, CN, and OR a4 are independently selected from, where C 1~2 Alkyl is R 22 optionally substituted with one substituent selected from Each R 22 OR a6 and Each R a3 , R c3 and R d3 However, H and C 1~2 independently selected from alkyl, Each R b3 But C 1~2 alkyl, and cyclopropyl; Each R a6 However, H and C 1~2 alkyl.

[0161] In some embodiments, provided herein are compounds of formula (I), or pharmaceutically acceptable salts thereof, wherein: Cy 1 is selected from phenyl, pyridin-3-yl and pyrazol-4-yl, wherein Cy 1 Phenyl, pyridin-3-yl and pyrazol-4-yl are each R 10 optionally substituted with one substituent selected from R 1 But Cl, C 1~2 Alkyl, C 1~2 Haloalkyl, cyclopropyl, hydroxymethyl, C 1~2 Alkoxy, C 1~2 Haloalkoxy and C 1~2 alkylamino, wherein optionally C 1~2 Alkyl, C 1~2 Haloalkyl, cyclopropyl, hydroxymethyl, C 1~2 Alkoxy, C 1~2 Haloalkoxy and C 1~2 one or more H atoms of the alkylamino are replaced by one or more D atoms; Each R 2 But C 3~6 Cycloalkyl, C1~2 Alkyl, C 1~2 Haloalkyl, F, Cl, CN, and OR a2 are independently selected from, where C 1~2 Alkyl is R 21 or optionally substituted with one substituent selected from or R on the phenyl ring 2 the substituents, together with the atoms to which they are attached, form a fused 5- or 6-membered cycloalkyl ring or a fused 5- or 6-membered heterocycloalkyl ring, wherein each fused 5- or 6-membered heterocycloalkyl ring has at least one ring-forming carbon atom and one or two ring-forming O atoms, and wherein each fused 5- or 6-membered cycloalkyl ring or fused 5- or 6-membered heterocycloalkyl ring is selected from the group consisting of R 21 optionally substituted with one substituent selected from n is 0, R 10 But C 1~2 Alkyl, C 1~2 Haloalkyl, C 3~6 Cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyridinyl, piperazinonyl, diazabicyclo[2.2.1]heptanyl(morpholinyl)ethyl, (pyridinyl)methyl, (triazolyl)methyl, thiomorpholinyl, 1-oxa-3,8-diazaspiro[4.5]decan-2-one, hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, F, Cl, D, CN, OR a1 , and NR c1 R d1 are independently selected from, where C 1~2 Alkyl, C 3~6 Cycloalkyl, C 3~6 Cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyridinyl, piperazinonyl, diazabicyclo[2.2.1]heptanyl(morpholinyl)ethyl, (pyridinyl)methyl, (triazolyl)methyl, thiomorpholinyl, 1-oxa-3,8-diazaspiro[4.5]decan-2-one, and hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl are each R 11optionally substituted with one or two substituents independently selected from Each R 11 But C 1~2 Alkyl, C 1~2 Haloalkyl, F, Cl, D, CN, OR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , and S(O)2R b3 are independently selected from, where C 1~2 Alkyl is OR a5 optionally replaced by Each R 21 But C 1~2 Alkyl, F, Cl, D, CN, and OR a4 are independently selected from, where C 1~2 Alkyl is R 22 optionally substituted with one substituent selected from Each R 22 F, Cl, CN, and OR a6 are independently selected from Each R a1 , R c1 and R d1 But H, C 1~2 alkyl, and 4- to 6-membered heterocycloalkyl; Each R a2 However, H and C 1~2 independently selected from alkyl, Each R a3 , R c3 and R d3 However, H and C 1~2 independently selected from alkyl, Each R b3 But C 1~2 alkyl, and cyclopropyl; Each R a4 However, H and C 1~2 independently selected from alkyl, Each R a5 However, H and C 1~2independently selected from alkyl, Each R a6 However, H and C 1~2 alkyl.

[0162] In some embodiments, provided herein is a method for treating a pulmonary arthritis with a pulmonary arthritis recurrence syndrome (LARS-RES). 5-(2,3-dimethylphenyl)-6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine, 5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine, 5-(2,3-dimethylphenyl)-6-methoxy-3-(1-((1-methyl-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine, 5-(2,3-dihydrobenzofuran-7-yl)-6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine, 2-(3-(6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2-methylphenyl)acetonitrile, 1-(4-(5-(6-(difluoromethoxy)-5-(2,3-dimethylphenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperazin-1-yl)ethan-1-one, 4-(6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-1-ol, 4-(6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile, 4-(6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-2-ol, (4-(6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-1-yl)methanol, 2-fluoro-4-(6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-1-ol, 5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-3-(1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine, 5-(2,3-dihydro-1H-inden-4-yl)-3-(1-(1-ethylpyrrolidin-3-yl)-1H-pyrazol-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine, 3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)cyclobutanecarbonitrile, 5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-3-(1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine, 5-(2,3-dihydro-1H-inden-4-yl)-3-(1-(1-ethylazetidin-3-yl)-1H-pyrazol-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine, 4-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)-N,N-dimethylpiperidine-1-carboxamide, methyl 4-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate, methyl 3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate, 1-(3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)ethan-1-one, 5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-3-(1-(1-(methylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine, 3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)-N,N-dimethylazetidine-1-carboxamide, cyclopropyl(3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)methanone, 5-(2,3-dihydro-1H-inden-4-yl)-6-ethoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine, 5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-3-(1-(pyridin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine, 4-(2-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)ethyl)morpholine, 3-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine, 3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)propanenitrile, 2-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)ethan-1-ol, 5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-3-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine, (trans)-4-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)cyclohexan-1-ol, 5-(2,3-dimethylphenyl)-N-methyl-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-6-amine, 6-(difluoromethyl)-5-(2,3-dihydro-1H-inden-4-yl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine, (5-(2,3-dihydro-1H-inden-4-yl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-6-yl)methanol, 5-(2,3-dihydro-1H-inden-4-yl)-N-methyl-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-6-amine, (5-(2,3-dimethylphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-6-yl)methanol, 4-(6-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-2-ol, 5-(2,3-dimethylphenyl)-6-methyl-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine, 5-(2,3-dimethylphenyl)-6-methoxy-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine, 5-(2,3-dimethylphenyl)-3-(6-(4-ethylpiperazin-1-yl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine, 1-(4-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperazin-1-yl)ethan-1-one, 4-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)morpholine, 4-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-1-methylpiperazin-2-one, 1-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidin-4-ol, (R)-5-(2,3-dimethylphenyl)-3-(6-(3,4-dimethylpiperazin-1-yl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine, 5-(2,3-dimethylphenyl)-6-(methoxy-d3)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine, 5-(2,3-dimethylphenyl)-6-methoxy-3-(6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine, 1-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-N,N-dimethylpiperidine-4-carboxamide, 1-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-4-methylpiperidine-4-carboxylic acid, 3-(4-(5-(2-fluoro-3-methylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)-N,N-dimethylazetidine-1-carboxamide, N-((cis)-4-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)cyclohexyl)acetamide, 5-(2,3-dihydro-1H-inden-4-yl)-3-(6-(2,4-dimethylpiperazin-1-yl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine, 2-(3-(3-(6-(4-acetylpiperazin-1-yl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2-methylphenyl)acetonitrile, 2-(3-(6-methoxy-3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2-methylphenyl)acetonitrile, 5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-3-(6-(pyrrolidin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine, 4-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)morpholine, 4-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-N-ethylpiperazine-1-carboxamide, 4-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperazine-1-carboxamide, 1-(4-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)phenyl)piperazin-1-yl)ethan-1-one, 5-(2,3-dihydro-1H-inden-4-yl)-3-(4-(4-isopropylpiperazin-1-yl)phenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine, 5-(2,3-dihydro-1H-inden-4-yl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine, 1-(4-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperazin-1-yl)ethan-1-one, 8-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one, 5-(2,3-dimethylphenyl)-6-methoxy-3-(1-(pyridin-2-ylmethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine, 3-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine, 6-methoxy-5-(2-methyl-3-(methyl-d3)phenyl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine, 1-(4-(4-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethan-1-one, methyl 4-(4-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate, Methyl 3-(4-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate, and 3-(4-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)-N,N-dimethylazetidine-1-carboxamide or a pharmaceutically acceptable salt of any of the foregoing.

[0163] In some embodiments, provided herein is a method for treating a pulmonary arthritis with a pulmonary arthritis recurrence syndrome (LARS-RES). 2-fluoro-4-(6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-1-ol, 5-(2,3-dimethylphenyl)-6-methoxy-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine, 4-(6-methoxy-3-(6-((tetrahydrofuran-3-yl)oxy)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-2-ol, 4-(6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)2,3-dihydro-1H-inden-2-d-2-ol, 4-(6-methoxy-3-(6-(1-methyl-5-oxopyrrolidin-3-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile, (S)-1-(4-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidin-1-yl)-2-hydroxypropan-1-one, 1-(4-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidin-1-yl)-2-hydroxyethan-1-one, 4-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclohexane-1-carboxylic acid, (3S,4R)-1-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-4-fluoropyrrolidin-3-amine, (2S)-1-(4-(5-(5-(2-fluoro-2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidin-1-yl)-2-hydroxypropan-1-one, 1-(4-(5-(5-(2-fluoro-2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidin-1-yl)-2-hydroxyethan-1-one, (7R,8aS)-2-(5-(5-(2-fluoro-2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol, 5-(2-fluoro-2,3-dihydro-1H-inden-4-yl)-6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine, (7S,8aR)-2-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol, 4-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-1-imino-1λ 6 -thiomorpholine 1-oxide, (7R,8aS)-2-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol, (S)—N-(1-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)pyrrolidin-3-yl)-2-hydroxy-N-methylacetamide, 2-(3-(3-(6-(4-(2-hydroxyethyl)piperazin-1-yl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2-methylphenyl)acetonitrile, (7R,8aS)-2-(5-(6-methoxy-5-(3-methoxy-2-methylphenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol, (7R,8aS)-2-(5-(5-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol, (7R,8aS)-2-(5-(5-(2-cyclopropylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol, (7R,8aS)-2-(5-(5-(chroman-5-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol, (7R,8aS)-2-(5-(5-(2-fluoro-3-methylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol, 4-(6-methoxy-3-(6-(2-methoxyethoxy)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-2-ol, 4-(6-methoxy-3-(6-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-2-ol, 4-(3-(6-cyclopropylpyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-2-ol, and N-(1-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-3-yl)-2-hydroxy-N-methylacetamide or a pharmaceutically acceptable salt of any of the foregoing.

[0164] In some embodiments, provided herein is a method for treating a pulmonary arthritis with a pulmonary arthritis recurrence syndrome (LARS-RES). 1-(4-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidin-1-yl)ethan-1-one, 1-(4-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidin-1-yl)-2-hydroxyethan-1-one, 1-(3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)pyrrolidin-1-yl)-2-hydroxyethan-1-one (Peak 1), 1-(3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)pyrrolidin-1-yl)-2-hydroxyethan-1-one (peak 2), 1-(3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)pyrrolidin-1-yl)ethan-1-one (Peak 1), 1-(3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)pyrrolidin-1-yl)ethan-1-one (peak 2), 3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-[1,3'-bipyrrolidin]-2'-one (Peak 1), 3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-1'-methyl-[1,3'-bipyrrolidin]-2'-one (Peak 1), 2-(3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)pyrrolidin-1-yl)propanamide (Peak 1), 5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-3-(6-(1-(methyl-L-prolyl)piperidin-4-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine, (3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)pyrrolidin-1-yl)((R)-4-methylmorpholin-3-yl)methanone (peak 2), 4-(6-methoxy-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile, 4-(3-(1-(3-cyanocyclobutyl)-1H-pyrazol-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile, 4-(3-(1-(1-acetylpiperidin-4-yl)-1H-pyrazol-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile, 4-(3-(6-(4-hydroxycyclohexyl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile, 4-(3-(6-(4-(2-hydroxyethyl)piperazin-1-yl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile, 4-(3-(6-(1-(2-hydroxyacetyl)piperidin-4-yl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile, 1-(3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-2-hydroxyethan-1-one, 1-(3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-3-(dimethylamino)propan-1-one, (S)-1-(3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-2-(dimethylamino)propan-1-one, (S)-(3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(1-methylazetidin-2-yl)methanone, 1-(3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-2-(4-methylpiperazin-1-yl)ethan-1-one, 1-(3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-2-(4-hydroxypiperidin-1-yl)ethan-1-one, (R)-(3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(1-methylazetidin-2-yl)methanone, (R)-1-(3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-2-hydroxypropan-1-one, (S)-1-(3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-2-hydroxypropan-1-one, (3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)((trans)-3-hydroxycyclobutyl)methanone, (3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)((cis)-3-hydroxycyclobutyl)methanone, (R)-(3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(4-methylmorpholin-3-yl)methanone, (S)-(3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(4-methylmorpholin-3-yl)methanone, (S)-1-(3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)-2-hydroxyethan-1-one, (S)-(3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(tetrahydrofuran-2-yl)methanone, (S)-(3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(tetrahydrofuran-3-yl)methanone, (R)-1-((S)-3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)-2-hydroxypropan-1-one, (S)-1-((S)-3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)-2-hydroxypropan-1-one, (R)-1-(3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-3-hydroxybutan-1-one, (3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)((1r,3r)-3-hydroxy-3-methylcyclobutyl)methanone, (3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)((1s,3s)-3-hydroxy-3-methylcyclobutyl)methanone, ((R)-3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)((S)-4-methylmorpholin-3-yl)methanone, ((S)-3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)((R)-4-methylmorpholin-3-yl)methanone, (3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(1-(hydroxymethyl)cyclobutyl)methanone, (S)-(3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(1-ethylazetidin-2-yl)methanone, (S)-(3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(1-(2-fluoroethyl)azetidin-2-yl)methanone, (S)-(3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(1-isopropylazetidin-2-yl)methanone, ((S)-3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)((S)-1-(2-fluoroethyl)azetidin-2-yl)methanone, ((S)-3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)((trans)-3-hydroxycyclobutyl)methanone, ((S)-3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)((cis)-3-hydroxycyclobutyl)methanone, ((S)-3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)((1s,3r)-3-hydroxy-3-methylcyclobutyl)methanone, 1-(3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-2-methoxyethan-1-one, 1-(3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-2-(dimethylamino)-2-methylpropan-1-one, 1-(3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidine-1-carbonyl)cyclopropane-1-carbonitrile, 2-((3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)sulfonyl)ethan-1-ol, 2-((3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)sulfonyl)-N,N-dimethylethan-1-amine, 2-methoxyethyl 3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate, (3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)((1s,3s)-3-methoxycyclobutyl)methanone, N-(3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclopentyl)-N-methylmethanesulfonamide, N-(3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclopentyl)-2-hydroxy-N-methylacetamide (Peak 1), (2S)—N-(3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclopentyl)-2-hydroxypropanamide, N-(3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclopentyl)-2-hydroxyacetamide, 2-(1-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)phenyl)-3-azabicyclo[3.1.0]hexan-3-yl)ethan-1-ol, 4-(3-(4-((1R,5S)-3-(2-hydroxyethyl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile, 1-((5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)methyl)piperidin-4-ol, 5-((5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)methyl)-2-oxa-5-azabicyclo[2.2.1]heptane, 4-(1-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)ethyl)morpholine, 7-((5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine, 4-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-1-(2-hydroxyethyl)piperidine-4-carbonitrile, 4-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-1-(2-hydroxyacetyl)piperidine-4-carbonitrile, 2-(3-(6-methoxy-3-(6-(4-(2-methoxyethyl)piperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2-methylphenyl)acetonitrile, 4-(6-methoxy-3-(1-(1-(tetrahydro-2H-pyran-4-carbonyl)piperidin-4-yl-4-d)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile, 4-(6-methoxy-3-(1-((S)-1-(2-methoxyacetyl)pyrrolidin-3-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile, 4-(6-methoxy-3-(1-((S)-1-((S)-tetrahydrofuran-2-carbonyl)pyrrolidin-3-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile, (7R,8aS)-2-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol, N-(1-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-3-yl)-2-hydroxy-N-methylacetamide, (3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-1-yl)(tetrahydrofuran-2-yl)methanone, (S)-(3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-1-yl)(1-methylpiperidin-2-yl)methanone, 1-(3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-1-yl)-2-(dimethylamino)ethan-1-one, 1-(3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-1-yl)-3-hydroxypropan-1-one, 1-(3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-1-yl)-2-hydroxyethan-1-one, (S)-1-(3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-1-yl)-2-hydroxypropan-1-one, N-(3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclobutyl)-2-hydroxy-N-methylacetamide, 1-(3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-1-yl-3-d)-2-hydroxyethan-1-one, methyl 4-(5-(5-(1-cyano-2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidine-1-carboxylate, 4-(6-methoxy-3-(6-(1-(morpholine-4-carbonyl)piperidin-4-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile, peak 2, 4-(3-(6-(1-acetylpiperidin-4-yl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile, peak 2, 4-(3-(6-(1-acetylpyrrolidin-3-yl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile, 4-(6-methoxy-3-(6-(1-(morpholine-4-carbonyl)pyrrolidin-3-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile, 4-(3-(1-(cyanomethyl)-1H-pyrazol-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile, 4-(6-methoxy-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile, 3-(3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-1-yl)propanenitrile, N-(3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclobutyl)-2-methoxy-N-methylacetamide, N-(3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclobutyl)-3-hydroxy-N-methylpropanamide, (S)—N-(3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclobutyl)-2-hydroxy-N-methylpropanamide, 1-(1-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-hydroxyethan-1-one, (R) 1-(1-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-hydroxyethan-1-one, two enantiomers, (S) 1-(1-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-hydroxyethan-1-one, two enantiomers, (1-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)((R)-4-methylmorpholin-3-yl)methanone, 5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-3-(6-(3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine 2-(1-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)ethan-1-ol, (R) 2-(1-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)ethan-1-ol, two enantiomers, (S) 2-(1-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)ethan-1-ol, two enantiomers, 3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-1-((R)-4-methylmorpholine-3-carbonyl)pyrrolidine-3-carbonitrile, (R)-4-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-1-(4-methylmorpholine-3-carbonyl)piperidine-4-carbonitrile, 1-(1-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-hydroxyethan-1-one, 3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-1-(2-hydroxyacetyl)pyrrolidine-3-carbonitrile, (S)-4-((5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)methyl)-1,3-dimethylpiperazin-2-one, and (1R,4R)-5-((5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)methyl)-2-oxa-5-azabicyclo[2.2.1]heptane or a pharmaceutically acceptable salt of any of the foregoing.

[0165] It will be further understood that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0166] At various places in the present specification, substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include any and all individual subcombinations of the members of such groups and ranges. For example, "C 1~6The term "alkyl" is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0167] Various aryl, heteroaryl, cycloalkyl, and heterocycloalkyl rings are described in various places herein. Unless otherwise specified, these rings can be attached to the remainder of the molecule at any ring member as allowed by valence. For example, the term "pyridine ring" or "pyridinyl" can refer to a pyridin-2-yl ring, a pyridin-3-yl ring, or a pyridin-4-yl ring.

[0168] The term "n-membered," where n is an integer, typically describes the number of ring-forming atoms in a moiety where n is the number of ring-forming atoms. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.

[0169] In compounds of the invention where a variable occurs more than once, each variable may be a different moiety independently selected from the group defining the variable. For example, if a structure is described with two R groups occurring simultaneously on the same compound, the two R groups may represent different moieties independently selected from the group defined for R.

[0170] As used herein, the phrase "optionally substituted" means unsubstituted or substituted.

[0171] The term "substituted" means that an atom or group of atoms is formally replaced with hydrogen as a "substituent" bonded to another group. The term "substituted" refers to any level of substitution, e.g., mono-, di-, tri-, tetra-, or penta-substitution, unless otherwise indicated, in which case such substitution is permitted. Substituents are independently selected, and substitution may occur at any chemically accessible position. Substitution at a given atom should be understood to be limited by atomic valence. Substitution at a given atom should be understood to result in a chemically stable molecule. A single divalent substituent, e.g., oxo, can replace two hydrogen atoms.

[0172] As used herein, "C i~j The term "i" where i and j are integers, when used in conjunction with a chemical group, specifies a range of the number of carbon atoms in the chemical group, with i to j defining the range. For example, C 1~6 Alkyl refers to alkyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms.

[0173] As used herein, the term "alkyl," used alone or in combination with other terms, refers to a saturated hydrocarbon group, which may be straight-chain or branched. An alkyl group formally corresponds to an alkane with one C-H bond replaced at the point of attachment of the alkyl group to the remainder of the compound. In some embodiments, the alkyl group contains 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methyl-1-butyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, and the like. In some embodiments, the alkyl group is methyl, ethyl, or propyl.

[0174] As used herein, "C" when used alone or in combination with other terms i~jThe term "alkylene" refers to a saturated divalent linked hydrocarbon group, which may be straight or branched, having i to j carbons. In some embodiments, the alkylene group contains 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. Examples of alkylene moieties include, but are not limited to, chemical groups such as methylene, ethylene, 1,1-ethylene, 1,2-ethylene, 1,3-propylene, 1,2-propylene, 1,1-propylene, isopropylene, and the like.

[0175] As used herein, "alkenyl," used alone or in combination with other terms, refers to a straight- or branched-chain hydrocarbon group corresponding to an alkyl group having one or more carbon-carbon double bonds. An alkenyl group formally corresponds to an alkene with one C-H bond replaced at the point of attachment of the alkenyl group to the remainder of the compound. In some embodiments, the alkenyl moiety contains 2 to 6 or 2 to 4 carbon atoms. Exemplary alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

[0176] As used herein, "alkynyl," used alone or in combination with other terms, refers to a straight- or branched-chain hydrocarbon group corresponding to an alkyl group having one or more carbon-carbon triple bonds. An alkynyl group formally corresponds to an alkyne with one C-H bond replacing the point of attachment of the alkyl group to the remainder of the compound. In some embodiments, the alkynyl moiety contains 2 to 6 or 2 to 4 carbon atoms. Exemplary alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, and the like.

[0177] As used herein, "halo" or "halogen," employed alone or in combination with other terms, includes fluoro, chloro, bromo, and iodo. In some embodiments, halo is F or Cl. In some embodiments, halo is F.

[0178] As used herein, the term "haloalkyl," used alone or in combination with other terms, refers to an alkyl group in which one or more hydrogen atoms have been replaced with halogen atoms, with up to a full valence of halogen atom substituents, which may be the same or different. In some embodiments, the halogen atoms are fluoro atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Exemplary haloalkyl groups include CF, C2F5, CHF2, CCl3, CHCl2, C2Cl5, and the like.

[0179] As used herein, the term "alkoxy," employed alone or in combination with other terms, refers to a group of formula -O-alkyl. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Exemplary alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like. In some embodiments, the alkoxy is methoxy.

[0180] As used herein, "haloalkoxy," employed alone or in combination with other terms, refers to a group of formula -O-(haloalkyl). In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. An exemplary haloalkoxy group is -OCF.

[0181] As used herein, "amino," employed alone or in combination with other terms, refers to NH2.

[0182] As used herein, the term "alkylamino," employed alone or in combination with other terms, refers to a group of formula -NH(alkyl). In some embodiments, alkylamino groups have 1 to 6 or 1 to 4 carbon atoms. Exemplary alkylamino groups include methylamino, ethylamino, propylamino (e.g., n-propylamino and isopropylamino), and the like.

[0183] As used herein, the term "dialkylamino," employed alone or in combination with other terms, refers to a group of formula -N(alkyl). Exemplary dialkylamino groups include dimethylamino, diethylamino, dipropylamino (e.g., di(n-propyl)amino and di(isopropyl)amino), and the like. In some embodiments, each alkyl group independently has 1 to 6 or 1 to 4 carbon atoms.

[0184] As used herein, the term "alkylthio," employed alone or in combination with other terms, refers to a group of formula -S-alkyl. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

[0185] As used herein, the term "cycloalkyl," used alone or in combination with other terms, refers to non-aromatic cyclic hydrocarbons, including cyclized alkyl and alkenyl groups. n~mThe term "cycloalkyl" refers to a cycloalkyl having n to m ring carbon atoms. Cycloalkyl groups can include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused, bridged, or spiro rings) ring systems. Also included within the definition of cycloalkyl are moieties having one or more aromatic rings (e.g., aryl or heteroaryl rings) fused to (i.e., having a common bond with) the cycloalkyl ring, such as benzo derivatives of cyclopentane, cyclohexene, cyclohexane, or pyrido derivatives of cyclopentane or cyclohexane. Cycloalkyl groups containing fused aromatic rings can be bonded by any ring-forming atom, including the ring-forming atoms of the fused aromatic ring. Ring-forming carbon atoms of cycloalkyl groups can be optionally substituted by oxo. Cycloalkyl groups also include cycloalkylidenes. The term "cycloalkyl" also includes bridgehead cycloalkyl groups (e.g., non-aromatic cyclic hydrocarbon moieties containing at least one bridgehead carbon, such as admantan-1-yl) and spirocycloalkyl groups (e.g., non-aromatic hydrocarbon moieties containing at least two rings fused together through a single carbon atom, such as spiro[2.5]octane). In some embodiments, cycloalkyl groups have 3 to 10 ring members, or 3 to 7 ring members, or 3 to 6 ring members. In some embodiments, cycloalkyl groups are monocyclic or bicyclic. In some embodiments, cycloalkyl groups are monocyclic. In some embodiments, cycloalkyl groups are C 3~7 Monocyclic cycloalkyl groups. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, tetrahydronaphthalenyl, octahydronaphthalenyl, indanyl, and the like. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0186] As used herein, the term "heterocycloalkyl," used alone or in combination with other terms, refers to a non-aromatic ring or ring system, which may optionally contain one or more alkenylene or alkynylene groups as part of the ring structure, has at least one heteroatom ring member independently selected from nitrogen, sulfur, oxygen, and phosphorus, and has 4 to 14 ring members, 4 to 10 ring members, 4 to 7 ring members, or 4 to 6 ring members. The term "heterocycloalkyl" includes monocyclic 4-, 5-, 6-, and 7-membered heterocycloalkyl groups. Heterocycloalkyl groups can be monocyclic or polycyclic (e.g., having 2, 3, or 4 fused, bridged, or spiro rings) or spirocyclic ring systems. In some embodiments, heterocycloalkyl groups are monocyclic or bicyclic groups having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. Also included within the definition of heterocycloalkyl are moieties having one or more aromatic rings (e.g., aryl or heteroaryl rings) fused to (i.e., sharing a common bond with) a non-aromatic heterocycloalkyl ring, such as 1,2,3,4-tetrahydroquinoline. Heterocycloalkyl groups can also include bridgehead heterocycloalkyl groups (e.g., heterocycloalkyl moieties containing at least one bridgehead atom, such as azaadmantan-1-yl) and spiroheterocycloalkyl groups (e.g., heterocycloalkyl moieties containing at least two rings fused at a single atom, such as [1,4-dioxa-8-aza-spiro[4.5]decan-N-yl]). In some embodiments, heterocycloalkyl groups have 3 to 10 ring-forming atoms, 4 to 10 ring-forming atoms, or 3 to 8 ring-forming atoms. In some embodiments, heterocycloalkyl groups have 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 to 2 heteroatoms. Carbon atoms or heteroatoms in the ring(s) of a heterocycloalkyl group can be oxidized to form carbonyl, N-oxide, or sulfonyl groups (or other oxidized linkages), or nitrogen atoms can be quaternized. In some embodiments, S atoms in the ring of a heterocycloalkyl group can be oxidized to form imino-λ. 6-sulfanone groups (i.e., the S atom is replaced with ═O and ═NH groups). In some embodiments, the heterocycloalkyl moiety is C 2~7 It is a monocyclic heterocycloalkyl group. In some embodiments, the heterocycloalkyl group is a morpholine ring, a pyrrolidine ring, a piperazine ring, a piperidine ring, a dihydropyran ring, a tetrahydropyran ring, a tetrahydropyridine ring, an azetidine ring, or a tetrahydrofuran ring. In some embodiments, the heterocycloalkyl is a 4- to 7-membered heterocycloalkyl moiety having carbon and 1, 2, or 3 heteroatoms independently selected from N, O, and S. In some embodiments, the heterocycloalkyl is a 4- to 10-membered heterocycloalkyl moiety having carbon and 1, 2, or 3 heteroatoms independently selected from N, O, and S.

[0187] As used herein, the term "aryl," used alone or in combination with other terms, refers to a monocyclic or polycyclic (e.g., having two fused rings) aromatic hydrocarbon moiety, such as, but not limited to, phenyl, 1-naphthyl, 2-naphthyl, and the like. In some embodiments, an aryl group has 6 to 10 carbon atoms or 6 carbon atoms. In some embodiments, an aryl group is a monocyclic or bicyclic group. In some embodiments, an aryl group is phenyl.

[0188] As used herein, the term "genetic alteration", used alone or in combination with other terms, refers to gene mutations, fusions, rearrangements (translocations, deletions, inversions) and amplifications.

[0189] As used herein, the terms "heteroaryl" or "heteroaromatic," used alone or in combination with other terms, refer to a monocyclic or polycyclic (e.g., having two or three fused rings) aromatic hydrocarbon moiety having one or more heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl group is a monocyclic or bicyclic group having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. Exemplary heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, pyrrolyl, azolyl, quinolinyl, isoquinolinyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl, pyridone, etc. Carbon atoms or heteroatoms in the ring(s) of a heteroaryl group can be oxidized to form carbonyl, N-oxide, or sulfonyl groups (or other oxidized linkages), or nitrogen atoms can be quaternized, provided that the aromatic character of the ring is retained. In one embodiment, the heteroaryl group is a 5- to 10-membered heteroaryl group. In another embodiment, the heteroaryl group is a 5- to 6-membered heteroaryl group. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl moiety having carbon and 1, 2, or 3 heteroatoms independently selected from N, O, and S. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl moiety having carbon and 1, 2, or 3 heteroatoms independently selected from N, O, and S. In some embodiments, the heteroaryl has 5 to 6 ring atoms and 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, not more than two heteroatoms in the 5-membered heteroaryl moiety are N.

[0190] A 5-membered heteroaryl ring is a heteroaryl group having 5 ring atoms, wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary 5-membered heteroaryls include thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl.

[0191] A 6-membered heteroaryl ring is a heteroaryl group having 6 ring atoms, wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary 6-membered heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl, isoindolyl, and pyridazinyl.

[0192] The term "oxo" refers to an oxygen atom as a divalent substituent, which when attached to a carbon forms a carbonyl group, or when attached to a heteroatom forms a sulfoxide or sulfone group, or an N-oxide group. In some embodiments, heterocyclic groups can be optionally substituted with one or two oxo (=O) substituents.

[0193] The term "oxidized" in reference to a ring-forming N atom refers to a ring-forming N-oxide.

[0194] The term "oxidized" in reference to a ring-forming S atom refers to a ring-forming sulfonyl or ring-forming sulfinyl.

[0195] The term "aromatic" refers to a carbocyclic or heterocyclic ring having one or more polyunsaturated rings that have aromatic properties (i.e., have (4n+2) delocalized π (pi) electrons, where n is an integer).

[0196] In certain places, definitions or embodiments refer to specific rings (e.g., azetidine ring, pyridine ring, etc.). Unless otherwise specified, these rings can be bonded to any ring member, provided that the valence of the atom is not exceeded. For example, an azetidine ring can be bonded at any position on the ring, while an azetidin-3-yl ring is bonded at the 3-position.

[0197] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). Unless otherwise specified, all stereoisomers, such as enantiomers and diastereomers, are intended. Compounds of the present invention containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separate isomeric forms.

[0198] The resolution of a racemic mixture of a compound can be carried out by methods known in the art. An exemplary method includes fractional recrystallization using a chiral resolving acid, which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallization include, for example, optically active acids, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or various optically active camphorsulfonic acids in their D- and L-forms. Other suitable resolving agents for fractional recrystallization include stereoisomerically pure methylbenzylamine (e.g., S- and R-forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc.

[0199] Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent compositions can be determined by one skilled in the art.

[0200] In some embodiments, the compounds of the present invention have the (R) configuration. In other embodiments, the compounds have the (S) configuration. In compounds with two or more chiral centers, unless otherwise specified, each of the chiral centers in the compound may independently be (R) or (S).

[0201] The compounds of the present invention also include tautomeric forms. Tautomeric forms result from the exchange of a single bond with an adjacent double bond, accompanied by the migration of a proton. Tautomeric forms include prototropic tautomers, which are isomeric protonation states with the same empirical formula and total charge. Exemplary prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which protons can occupy more than one position in a heterocyclic ring system, such as 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms may be in equilibrium or sterically fixed into one form by appropriate substitution.

[0202] The compounds of the present invention also include all isotopes of atoms occurring in 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. One or more constituent atoms of the compounds of the present invention can be replaced or substituted with an isotope of that atom at natural or non-natural abundance. In some embodiments, the compounds contain at least one deuterium atom. For example, one or more hydrogen atoms in the compounds of the present disclosure can be replaced or substituted with deuterium. In some embodiments, the compounds contain two or more deuterium atoms. In some embodiments, the compounds contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 deuterium atoms. Synthetic methods for incorporating isotopes into organic compounds are known in the art (Deuterium Labeling in Organic Chemistry by Alan F. Thomas (New York, NY, Appleton-Century-Crofts, 1971); The Renaissance of H / D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistry of Isotopic Labelling by James R. Hanson, Royal Society of Chemistry, 2011). Isotopically labeled compounds can be used in a variety of studies, such as NMR spectroscopy, metabolic studies, and / or assays.

[0203] Substitution with heavier isotopes, such as deuterium, may confer certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be preferable in some circumstances (A. Kerekes et al. J. Med. Chem. 2011, 54, 201-210; R. Xu et al. J. Label Compd. Radiopharm. 2015, 58, 308-312).

[0204] The term "compound," as used herein, is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. The term is also meant to refer to compounds of the invention regardless of how they are prepared, for example, synthetically, by biological process (e.g., metabolic or enzymatic transformation), or a combination thereof.

[0205] All compounds and their pharmaceutically acceptable salts may be found together with other substances such as water and solvents (e.g., in the form of hydrates and solvates) or may be isolated. When in the solid state, the compounds described herein and their salts may occur in various forms, for example, in the form of solvates, including hydrates. Because the compounds may be in any solid state form, such as polymorphs or solvates, unless otherwise expressly indicated, references herein to compounds and their salts should be understood to encompass any solid state form of the compound.

[0206] In some embodiments, the compounds of the present invention, or salts thereof, are substantially isolated. "Substantially isolated" means that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial isolation can include, for example, compositions enriched for the compounds of the present invention. 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 of the present invention, or salts thereof. Methods for isolating compounds and their salts are routine in the art.

[0207] The phrase "pharmaceutically acceptable" is used herein to refer to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0208] The present invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds, in which the parent compound is modified by converting an existing acid or base moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutically acceptable salts of the present invention include non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing a basic or acid moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of the compound with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or in a mixture of the two; generally, non-aqueous media such as ether, ethyl acetate, alcohol (e.g., methanol, ethanol, isopropanol, or butanol), or acetonitrile (ACN) are preferred. Lists of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

[0209] The following abbreviations may be used herein: AcOH (acetic acid), AcO (acetic anhydride), aq. (aqueous), atm. (atmosphere(s)), Boc (t-butoxycarbonyl), br (broad line), Cbz (carboxybenzyl), calc. (calculated), d (double line), dd (double line of double line), DCM (dichloromethane), DEAD (diethyl azodicarboxylate), DIAD (N,N'-diisopropyl azidodicarboxylate), DIPEA (N,N-diisopropylethylamine), DMF (N,N-dimethyl azodicarboxylate), DIAD (N,N'-diisopropyl azidodicarboxylate), DIPEA (N,N-diisopropylethylamine), DMF (N,N-dimethyl azodicarboxylate), DMF (N,N-dimethyl azide ... N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate), HCl (hydrochloric acid), HPLC (high performance liquid chromatography), Hz (hertz), J (coupling constant), LCMS (liquid chromatography-mass spectrometry), m (multiplet), M (mol), mCPBA (3-chloroperoxybenzoic acid), MgSO4 (magnesium sulfate), MS (mass spectrometry), Me (methyl), MeCN (acetonitrile), MeOH (methanol), mg (milligram), min.(minute(s)), mL (milliliter(s)), mmol (millimole(s)), N (normal), NaHCO3 (sodium bicarbonate), NaOH (sodium hydroxide), Na2SO4 (sodium sulfate), NH4Cl (ammonium chloride), NH4OH (ammonium hydroxide), NIS (N-iodosuccinimide), nM (nanomole), NMR (nuclear magnetic resonance spectroscopy), OTf (trifluoromethanesulfonate), Pd (palladium), Ph (phenyl), pM (picomole), PMB (para-methoxybenzyl benzoate). diethyl), POCl3 (phosphoryl chloride), RP-HPLC (reverse-phase high-performance liquid chromatography), S (singlet), SEM (2-trimethylsilylethoxymethyl), t (triplet or tertiary), TBS (tert-butyldimethylsilyl), tert (tertiary), tt (triplet of triplets), t-Bu (tert-butyl), TFA (trifluoroacetic acid), THF (tetrahydrofuran), μg (microgram(s)), μL (microliter(s)), μM (micromoles), wt% (weight percent).

[0210] synthesis The compounds of the present invention, including their salts, can be prepared according to a variety of possible synthetic routes using known organic synthesis techniques.

[0211] The reaction for preparing the compound of the present invention can be carried out in a suitable solvent that can be easily selected by those skilled in the art of organic synthesis.Suitable solvents 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.

[0212] Preparation of the compounds of the present invention may involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be easily determined by one skilled in the art. The chemistry of protecting groups 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.

[0213] The reaction can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., ultraviolet-visible), or mass spectrometry, or by chromatography, e.g., high performance liquid chromatography (HPLC) or thin layer chromatography.

[0214] The expressions "ambient temperature," "room temperature," and "rt," as used herein, are understood in the art and generally refer to a temperature, e.g., a reaction temperature, near the temperature of the room in which the reaction is carried out, e.g., from about 20°C to about 30°C.

[0215] Location Cy 1Compounds of Formula (I) with various substitutions at 1 can be prepared using a process such as that illustrated in Scheme 1. In the process illustrated in Scheme 1, the halo substituent in a compound of Formula 1-1 can undergo a cross-coupling reaction involving Suzuki (Tetrahedron 2002, 58, 9633-9695) (e.g., in the presence of a palladium catalyst such as Xphos Pd G2 and a base such as potassium phosphate), Negishi (ACS Catalysis 2016, 6, 1540-1552) or Stille (ACS Catalysis 2015, 5, 3040-3053) (e.g., in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0)), or the like, to give a compound of Formula 1-2. The protecting group in a compound of Formula 1-2 can be removed under acidic conditions (e.g., in the presence of TFA or HCl) to give a compound of Formula 1-3. These compounds can be further halogenated with one of the halogenating agents (e.g., NIS or iodine), followed by NH protection with a suitable protecting group (e.g., Boc) to give compounds of formula 1-4. Cross-coupling reactions of 1-4, including Suzuki (e.g., in the presence of a palladium catalyst such as Xphos Pd G2 and a base such as potassium phosphate), Negishi, or Stille (e.g., in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0)), followed by deprotection of the protecting group, give compounds of formula (I). [ka]

[0216] Alternatively, compounds of Formula (I) can be prepared using a process as illustrated in Scheme 2. The protecting group in compounds of Formula 1-1 can be removed under acidic conditions (e.g., in the presence of TFA or HCl) to give compounds of Formula 2-1. These compounds can be further iodinated with an iodinating agent (e.g., NIS or iodine), followed by NH protection with a suitable protecting group (e.g., Boc), to give compounds of Formula 2-2. Cross-coupling reactions of 2-2, including Suzuki (e.g., in the presence of a palladium catalyst such as Pd(dppf)Cl2 and a base such as potassium phosphate), lead to the formation of compounds of Formula 2-3. A second cross-coupling reaction of 2-3, including Suzuki (e.g., in the presence of a palladium catalyst such as Xphos Pd G2 and a base such as potassium phosphate), Negishi, or Stille (e.g., in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0)), followed by deprotection of the protecting group, gives compounds of Formula (I). [ka]

[0217] How to use Compounds of the present disclosure can inhibit the activity of FGFR enzymes. For example, compounds of the present disclosure can be used to inhibit the activity of FGFR enzymes in cells, or in individuals or patients in need of enzyme inhibition by administering an inhibitory amount of one or more compounds of the present disclosure to the cells, individual, or patient. Compounds of the present disclosure can be used to inhibit the activity of FGFR3 enzymes in cells, or in individuals or patients in need of enzyme inhibition by administering an inhibitory amount of one or more compounds of the present disclosure to the cells, individual, or patient. Compounds of the present disclosure can be used to inhibit the activity of FGFR2 enzymes in cells, or in individuals or patients in need of enzyme inhibition by administering an inhibitory amount of one or more compounds of the present disclosure to the cells, individual, or patient. Compounds of the present disclosure can be used to inhibit the activity of FGFR3 and FGFR2 enzymes in cells, or in individuals or patients in need of enzyme inhibition by administering an inhibitory amount of a compound of the present disclosure to the cells, individual, or patient.

[0218] In some embodiments, compounds of the present disclosure have selective inhibitory activity against the enzyme FGFR3 over FGFR1. In some embodiments, the selectivity of compounds of the present disclosure for FGFR3 compared to FGFR1 is 10-fold to 25-fold, or 25-fold to 50-fold. In some embodiments, compounds of the present disclosure have selective inhibitory activity against the enzyme FGFR3 over FGFR4. In some embodiments, the selectivity of compounds of the present disclosure for FGFR3 compared to FGFR4 is 10-fold to 25-fold, 25-fold to 50-fold, or 50-fold to 100-fold. In some embodiments, compounds of the present disclosure have selective inhibitory activity against the enzyme FGFR3 over FGFR2. In some embodiments, the selectivity of compounds of the present disclosure for FGFR3 compared to FGFR2 is 1.5-fold to 2-fold, or 2-fold to 3-fold.

[0219] In some embodiments, the inhibitory activity of the compounds of Examples 1 to 98 against FGFR3 is 10 times or more, for example, 50 times, 100 times, 250 times, 500 times, 750 times, 1000 times, etc., compared to the inhibitory activity of the compounds of US2018 / 0072718 against FGFR3.

[0220] In some embodiments, compounds of the present disclosure have selective inhibitory activity against the enzyme FGFR3 over FGFR1. Without being bound by theory, FGFR1 is believed to be associated with certain side effects, such as FGFR1-induced hypophosphatemia. Compounds of the present disclosure may be advantageous over non-selective FGFR inhibitors (e.g., compounds that have similar inhibitory activity against both FGFR1 and FGFR3) because they have little or no side effect of FGFR1-induced hypophosphatemia, potentially allowing for higher maximum doses while avoiding side effects associated with FGFR1.

[0221] In some embodiments, compounds of the present disclosure have selective inhibitory activity against the enzyme FGFR2 over FGFR1. In some embodiments, the selectivity of compounds of the present disclosure for FGFR2 compared to FGFR1 is 10-fold to 25-fold, or 25-fold to 50-fold. In some embodiments, compounds of the present disclosure have selective inhibitory activity against the enzyme FGFR2 over FGFR4. In some embodiments, the selectivity of compounds of the present disclosure for FGFR2 compared to FGFR4 is 10-fold to 25-fold, 25-fold to 50-fold, or 50-fold to 100-fold.

[0222] As FGFR inhibitors, the compounds of the present disclosure are useful for treating various diseases associated with the abnormal expression or activity of FGFR enzymes or FGFR ligands. Compounds that inhibit FGFR are useful for providing a means of preventing tumor growth or inducing apoptosis, particularly by inhibiting angiogenesis. Therefore, it is expected that the compounds of the present disclosure will prove useful for treating or preventing proliferative disorders such as cancer. In particular, tumors with activating mutants of receptor tyrosine kinases or with upregulated receptor tyrosine kinases may be particularly sensitive to inhibitors.

[0223] In certain embodiments, the present disclosure provides a method of treating an FGFR-mediated disorder in a patient in need thereof, the method comprising administering to the patient a compound according to the present invention, or a pharmaceutically acceptable composition thereof.

[0224] In some embodiments, diseases and indications treatable using compounds of the present disclosure include, but are not limited to, hematological cancers, sarcomas, lung cancers, gastrointestinal cancers, genitourinary tract cancers, liver cancer, bone cancers, nervous system cancers, gynecological cancers, and skin cancers.

[0225] In some embodiments, the cancer treatable using the compounds of the present disclosure is selected from adenocarcinoma, bladder cancer, breast cancer, cervical cancer, bile duct cancer, colorectal cancer, endometrial cancer, esophageal cancer, gallbladder cancer, gastric cancer, glioma, head and neck cancer, hepatocellular carcinoma, kidney cancer, liver cancer, lung cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, rhabdomyosarcoma, skin cancer, thyroid cancer, leukemia, multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, B-cell lymphoma, acute myeloid leukemia, Hodgkin's or non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, hairy cell lymphoma, and Burkitt's lymphoma.

[0226] In some embodiments, the cancer treatable using the compounds of the present disclosure is selected from hepatocellular carcinoma, bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer, esophageal cancer, gallbladder cancer, pancreatic cancer, thyroid cancer, skin cancer, leukemia, multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, B-cell lymphoma, acute myeloid leukemia, Hodgkin's or non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, hairy cell lymphoma, Burkitt's lymphoma, glioblastoma, melanoma, and rhabdomyosarcoma.

[0227] In some embodiments, the cancer is selected from adenocarcinoma, bladder cancer, breast cancer, cervical cancer, cholangiocarcinoma, endometrial cancer, gastric cancer, glioma, head and neck cancer, lung cancer, ovarian cancer, leukemia, and multiple myeloma.

[0228] In some embodiments, the cancer treatable using the compounds of the present disclosure is selected from hepatocellular carcinoma, breast cancer, bladder cancer, colorectal cancer, melanoma, mesothelioma, lung cancer, prostate cancer, pancreatic cancer, testicular cancer, thyroid cancer, squamous cell carcinoma, glioblastoma, neuroblastoma, uterine cancer, and rhabdomyosarcoma.

[0229] Cancers characterized by alterations in FGFR2 and / or FGFR3 include bladder cancer (FGFR3 mutations or fusions), cholangiocarcinoma (FGFR2 fusions) and gastric cancer (FGFR2 amplification).

[0230] The compounds of the present invention can be used to treat cancer patients with FGFR2 / 3 alterations, including mutations, fusions, rearrangements, and amplifications. FGFR2 / 3 alterations have been found in a subset of cholangiocarcinoma, urothelial carcinoma, multiple myeloma, gastric adenocarcinoma, glioma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, and breast cancer. Furthermore, the compounds of the present invention can be used to target patients who are progressing on pan-FGFR inhibitor treatment due to the acquisition of gatekeeper mutations (V555M / L / F / I in FGFR3 and V564M / L / F / I in FGFR2). The compounds of the present invention can also be used to treat cancers in which FGFR2 / 3 signaling is involved in resistance to other targeted therapies; for example, the compounds have the potential to overcome resistance to CDK4 / 6 inhibitors in ER-positive breast cancer.

[0231] Exemplary hematological cancers include lymphomas and leukemias, such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, non-Hodgkin's lymphoma (including relapsed or refractory NHL and relapsed follicular), Hodgkin's lymphoma, myeloproliferative disorders ( Examples include primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocytosis (ET), 8p11 myeloproliferative syndrome (8p11), myelodysplastic syndrome (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), multiple myeloma, cutaneous T-cell lymphoma, adult T-cell leukemia, Waldenstrom's macroglobulinemia, hairy cell lymphoma, marginal zone lymphoma, chronic myeloid lymphoma, and Burkitt's lymphoma.

[0232] Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, rhabdosarcoma, fibroma, lipoma, hamartoma, lymphosarcoma, leiomyosarcoma, and teratoma.

[0233] Exemplary lung cancers include non-small cell lung cancer (NSCLC), small cell lung cancer, bronchogenic lung carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, chondroitin hamartoma, mesothelioma, small cell and non-small cell carcinoma, bronchial adenoma, and pleuropulmonary blastoma.

[0234] Exemplary gastrointestinal cancers include cancer of the esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), cancer of the stomach (carcinoma, lymphoma, leiomyosarcoma), cancer of the pancreas (exocrine pancreatic carcinoma, ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), cancer of the small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), cancer of the large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), colorectal cancer, gallbladder cancer, and anal cancer.

[0235] Exemplary genitourinary tract cancers include cancer of the kidney (adenocarcinoma, Wilms' tumor [nephroblastoma], renal cell carcinoma), cancer of the bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), cancer of the prostate (adenocarcinoma, sarcoma), cancer of the testes (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma), and urothelial carcinoma.

[0236] Exemplary liver cancers include hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.

[0237] Exemplary bone cancers include, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondral exostosis), benign cartilage tumor, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor.

[0238] Exemplary nervous system cancers include cancers of the skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), cancers of the meninges (meningioma, meningeal sarcoma, gliomatosis), cancers of the brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pinealoma), glioblastoma, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, neuroectodermal tumors), and cancers of the spinal cord (neurofibroma, meningioma, glioma, sarcoma), neuroblastoma, Lhermitte-Duclos disease, and pineal tumors.

[0239] Exemplary gynecological cancers include cancer of the breast (ductal carcinoma, lobular carcinoma, breast sarcoma, triple-negative breast cancer, HER2-positive breast cancer, inflammatory breast cancer, papillary carcinoma), cancer of the uterus (endometrial carcinoma), cancer of the cervix (cervical carcinoma, preneoplastic cervical dysplasia), cancer of the ovary (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), cancer of the vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), cancer of the vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma)), and cancer of the fallopian tubes (carcinoma).

[0240] Exemplary skin cancers include melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer, lenticular dysplastic nevi, lipoma, hemangioma, dermatofibroma, and keloids.

[0241] Exemplary head and neck cancers include glioblastoma, melanoma, rhabdomyosarcoma, lymphosarcoma, osteosarcoma, squamous cell carcinoma, adenocarcinoma, oral cavity cancer, laryngeal cancer, nasopharyngeal cancer, nasal cavity and paranasal sinus cancer, thyroid and parathyroid cancer, eye tumors, lip and oral cavity tumors, and squamous cell head and neck cancer.

[0242] Compounds of the present disclosure may also be useful in inhibiting tumor metastasis.

[0243] In addition to oncogenic neoplasms, the compounds of the present invention are useful for treating skeletal and chondrocyte disorders, including, but not limited to, achondroplasia, hypochondroplasia, dwarfism, thanatophoric dysplasia (TD) (clinical types TD I and TD II), Apert syndrome, Crouzon syndrome, Jackson-Weiss syndrome, Behle-Stevenson gyriform scalp syndrome, Pfeiffer syndrome, and craniosynostosis syndrome. In some embodiments, the present disclosure provides methods of treating patients suffering from skeletal and chondrocyte disorders.

[0244] In some embodiments, the compounds described herein may be used to treat Alzheimer's disease, HIV, or tuberculosis.

[0245] As used herein, the term "8p11 myeloproliferative syndrome" is meant to refer to myeloid / lymphoid neoplasms associated with eosinophilia and FGFR1 abnormalities.

[0246] As used herein, the term "cell" is meant to refer to an in vitro, ex vivo, or in vivo cell. In some embodiments, an ex vivo cell may be part of a tissue sample excised from an organism, such as a mammal. In some embodiments, an in vitro cell may be a cell in cell culture. In some embodiments, an in vivo cell is a cell that resides in an organism, such as a mammal.

[0247] As used herein, the term "contacting" refers to bringing the indicated moieties together in an in vitro system or in an in vivo system. For example, "contacting" an FGFR enzyme with a compound described herein includes administering a compound described herein to an individual or patient, such as a human, having an FGFR, as well as introducing a compound described herein into a sample containing, for example, a cell preparation or purified preparation containing an FGFR enzyme.

[0248] As used herein, the terms "individual" or "patient," used interchangeably, refer to a mammal, preferably any animal, including a mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse, or primate, most preferably a human.

[0249] As used herein, the phrase "therapeutically effective amount" refers to an amount of an active compound or pharmaceutical agent, such as an amount of any of the solid forms or salts thereof as disclosed herein, that elicits the biological or pharmaceutical response in a tissue, system, animal, individual, or human that is being sought by a researcher, veterinarian, physician, or other clinician. An appropriate "effective" amount in any individual case may be determined using techniques known to those of skill in the art.

[0250] The phrase "pharmaceutically acceptable" is used herein to refer to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, immunogenicity or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0251] As used herein, the phrase "pharmaceutically acceptable carrier or excipient" refers to a pharmaceutically acceptable substance, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. Excipients or carriers are generally safe, non-toxic, and not biologically or otherwise undesirable, and include excipients or carriers that are acceptable for human pharmaceutical use as well as veterinary use. In one embodiment, each component is "pharmaceutically acceptable" as defined herein. For example, Remington:The Science and Practice of Pharmacy,21st ed.;Lippincott Williams&Wilkins:Philadelphia,Pa.,2005;Handbook of Pharmaceutical Excipients,6th ed.;Rowe et al.,Eds.;The Pharmaceutical Press and the American Pharmaceutical Association:2009;Handbook of Pharmaceutical Additives,3rd ed.;Ash and Ash Eds.;Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, Fla., 2009.

[0252] As used herein, the term "treating" or "treatment" refers to inhibiting a disease, e.g., inhibiting a disease, condition, or disorder in an individual experiencing or exhibiting the pathogenesis or symptomology of the disease, condition, or disorder (i.e., preventing further development of the pathogenesis and / or symptomology), or ameliorating a disease, e.g., ameliorating a disease, condition, or disorder in an individual experiencing or exhibiting the pathogenesis or symptomology of the disease, condition, or disorder (i.e., reversing the pathogenesis and / or symptomology), e.g., reducing the severity of the disease.

[0253] It will be appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment (wherein the embodiments are intended to be combined as if described in multiple dependent form). Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0254] Combination therapy One or more additional pharmaceutical agents or treatment methods, such as antiviral agents, chemotherapeutic or other anti-cancer agents, immune enhancers, immunosuppressants, radiation, antitumor and antiviral vaccines, cytokine therapy (e.g., IL2, GM-CSF, etc.), and / or tyrosine kinase inhibitors, may be used in combination with the compounds described herein for the treatment of FGFR-related diseases, disorders, or conditions, or diseases or conditions as described herein. The agents may be combined with the compounds in a single dosage form, or the agents may be administered simultaneously or sequentially as separate dosage forms.

[0255] The compounds described herein can be used in combination with one or more other kinase inhibitors to treat diseases such as cancer that are affected by multiple signal transduction pathways. For example, the combination can include inhibitors of one or more of the following kinases for the treatment of cancer: Akt1, Akt2, Akt3, TGF-βR, Pim, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGFαR, PDGFβR, CSFIR, KIT, F LK-II, KDR / FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, Ron, Sea, TRKA, TRKB, TRKC, FLT3, VEGFR / Flt2, Flt4, EphA1, EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL, ALK, and B-Raf. Additionally, solid forms of FGFR inhibitors as described herein may be combined with inhibitors of kinases associated with the PIK3 / Akt / mTOR signaling pathway, such as PI3K, Akt (including Akt1, Akt2, and Akt3), and mTOR kinase.

[0256] In some embodiments, the compounds described herein may be used in combination with one or more inhibitors of enzymes or protein receptors, such as HPK1, SBLB, TUT4, A2A / A2B, CD47, CDK2, STING, ALK2, LIN28, ADAR1, MAT2a, RIOK1, HDAC8, WDR5, SMARCA2, and DCLK1, for the treatment of diseases and disorders. Exemplary diseases and disorders include cancer, infectious diseases, inflammation, and neurodegenerative disorders.

[0257] In some embodiments, the compounds described herein can be used in combination with therapeutic agents that target epigenetic regulators.Examples of epigenetic regulators include bromodomain inhibitors, histone lysine methyltransferases, histone arginine methyltransferases, histone demethylases, histone deacetylases, histone acetylases, and DNA methyltransferases.Histone deacetylase inhibitors include, for example, vorinostat.

[0258] For treating cancer and other proliferative diseases, the compounds described herein are useful in combination with JAK kinase inhibitors (e.g., ruxolitinib, additional JAK1 / 2 and JAK1-selective, baricitinib or INCB39110), Pim kinase inhibitors (e.g., LGH447, INCB053914 and SGI-1776), PI3K-delta selective and broad-spectrum PI3K inhibitors (e.g., INCB50465 and INCB54707), PI3K-gamma inhibitors (e.g., INCB50465 and INCB54707), and other PI3K inhibitors. PI3 kinase inhibitors, including PI3K-gamma inhibitors such as selective inhibitors, MEK inhibitors, CSF1R inhibitors (e.g., PLX3397 and LY3022855), TAM receptor tyrosine kinase inhibitors (Tyro-3, Axl, and Mer, e.g., INCB81776), angiogenesis inhibitors, interleukin receptor inhibitors, cyclin-dependent kinase inhibitors, BRAF inhibitors, mTOR inhibitors, proteasome inhibitors (bortezomib, carf iruzomib), HDAC inhibitors (panobinostat, vorinostat), DNA methyltransferase inhibitors, dexamethasone, bromo and extra-terminal family member inhibitors (e.g., bromodomain inhibitors or BET inhibitors, such as OTX015, CPI-0610, INCB54329, or INCB57643), LSD1 inhibitors (e.g., GSK2979552, INCB59872, and INCB60003), arginine Therapeutic agents may be used in combination with targeted therapies, including enzyme inhibitors (e.g., INCB1158), indoleamine 2,3-dioxygenase inhibitors (e.g., epacadostat, NLG919, or BMS-986205), PARP inhibitors (e.g., olaparib or rucaparib), inhibitors of BTK such as ibrutinib, c-MET inhibitors (e.g., capmatinib), ALK2 inhibitors (e.g., INCB00928), or combinations thereof.

[0259] To treat cancer and other proliferative diseases, the compounds described herein can be used in combination with chemotherapeutic agents, nuclear receptor agonists or antagonists, or other antiproliferative agents. The compounds described herein can also be used in combination with medical therapies, such as surgery or radiation therapy, including gamma irradiation, neutron radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy, and systemic radioisotopes.

[0260] Examples of suitable chemotherapeutic agents include abarelix, abiraterone, afatinib, aflibercept, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, amidox, amsacrine, anastrozole, aphidicolone, arsenic trioxide, asparaginase, axitinib, azacitidine, bevacizumab, bexarotene, baricitinib, bendamustine, bicalutamide, bleomycin, bortezomib, brivanib, buparlisib, busulfan, and the like. Note, oral busulfan, calsterone, camptosar, capecitabine, carboplatin, carmustine, cediranib, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, crizotinib, cyclophosphamide, cytarabine, dacarbazine, dacomitinib, dactinomycin, dalteparin sodium, dasatinib, dactinomycin, daunorubicin, decitabine, degarelix, denileukin, denileukin diftitox, deoxycoformycin, dexrazoxane, didox, docetaxel, doxorubicin, Droloxafine, dromostanolone propionate, eculizumab, enzalutamide, epidophyllotoxin, epirubicin, epothilone, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, flutamide, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuximab tamoxifen, idarubicin, idelalisib, ifosfamide, imatinib mesylate, interferon alpha 2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lonafarnib, lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mithramycin, mitomycin C, mitotane, mitoxantrone, nandrolone phenpropionate, navelbine, necitumumab,Nelarabine, neratinib, nilotinib, nilutamide, niraparib, nofetumomab, oserelin, oxaliplatin, paclitaxel, pamidronate, panitumumab, panobinostat, pazopanib, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, piralalisib, pipobroman, plicamycin, ponatinib, porfimer, prednisone, procarbazine, quinacrine, ranibizumab, rasburicase, regorafenib, reloxafine, revlimid, rituximab, rucaparib, ruxolitinib , sorafenib, streptozocin, sunitinib, sunitinib maleate, tamoxifan, tegafur, temozolomide, teniposide, testolactone, tezacitabine, thalidomide, thioguanine, thiotepa, tipifarnib, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, triapine, trimidox, triptorelin, uracil mustard, valrubicin, vandetanib, vinblastine, vincristine, vindesine, vinorelbine, vorinostat, veliparib, talazoparib, and zoledronate.

[0261] The proliferation and survival of cancer cells can be affected by the dysfunction of multiple signaling pathways. Therefore, it is useful to treat such conditions by combining different enzyme / protein / receptor inhibitors that exhibit different selectivity in the target that modulates the activity of the target. Targeting two or more signaling pathways (or two or more biomolecules involved in a given signaling pathway) may reduce the possibility of drug resistance occurring within a cell population and / or reduce the toxicity of the treatment.

[0262] One or more additional pharmaceutical agents, such as chemotherapeutic agents, anti-inflammatory agents, steroids, immunosuppressants, cancer immunotherapeutic agents, metabolic enzyme inhibitors, chemokine receptor inhibitors, and phosphatase inhibitors, as well as targeted therapies, such as Bcr-Abl, Flt-3, EGFR, HER2, JAK, c-MET, VEGFR, PDGFR, c-Kit, IGF-1R, RAF, FAK, CDK2, and CDK4 / 6 kinase inhibitors, such as those described in WO2006 / 056399, may be used in combination with the treatment methods and regimens of the present disclosure to treat cancer and solid tumors. Other agents, such as therapeutic antibodies, may be used in combination with the treatment methods and regimens of the present disclosure to treat cancer and solid tumors. One or more additional pharmaceutical agents may be administered to a patient simultaneously or sequentially.

[0263] The treatment methods as disclosed herein can be used in combination with one or more other enzyme / protein / receptor inhibitor therapies to treat diseases such as cancer and other diseases or disorders described herein. For example, the treatment methods and regimens of the present disclosure can be combined with inhibitors of one or more of the following kinases for the treatment of cancer: Akt1, Akt2, Akt3, BCL2, CDK2, CDK4 / 6, TGF-βR, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IDH2, IGF-1R, IR-R, PDGFαR, PDGFβR, PI3K (alpha, beta, gamma, delta, and multiple or multiple kinases). selective), CSF1R, KIT, FLK-II, KDR / FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, PARP, Ron, Sea, TRKA, TRKB, TRKC, TAM kinase (Axl, Mer , Tyro3), FLT3, VEGFR / Flt2, Flt4, EphA1, EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL, ALK and B-Raf.Non-limiting examples of inhibitors that may be combined with the treatment methods and regimens of the present disclosure to treat cancer include FGFR inhibitors (FGFR1, FGFR2, FGFR3, or FGFR4, e.g., pemigatinib (INCB54828), INCB62079), EGFR inhibitors (also known as ErB-1 or HER-1, e.g., erlotinib, gefitinib, vandetanib, orsimertinib, cetuximab, necitumumab, or panitumumab), VEGFR inhibitors or pathway blockers (e.g., bevacizumab, pazopanib, sunitinib, sorafenib, axitinib, regorafenib, ponatinib, cabozantinib, vandetanib, ramucirumab, lenvatinib, ziv-aflibercept), PARP inhibitors (e.g., olaparib, rucaparib, veliparib, or niraparib), JAK inhibitors (JAK1 and / or JAK2, e.g., ruxolitinib, baricitinib, itacitinib (INCB39110)), LSD1 inhibitors (e.g., INCB59872 and INCB60003), TD inhibitors (e.g., thiazol-1, 2-hydroxybenzoates ... O inhibitors, PI3K-delta inhibitors (e.g., INCB50465 and INCB50797), PI3K-gamma inhibitors, such as PI3K-gamma selective inhibitors, Pim inhibitors (e.g., INCB53914), CSF1R inhibitors, TAM receptor tyrosine kinases (Tyro-3, Axl, and Mer), adenosine receptor antagonists (e.g., A2a / A2b receptor antagonists), HPK1 inhibitors, chemokine receptor inhibitors (e.g., CCR2 or CCR5 inhibitors), SHP1 / 2 receptor antagonists, These include isoform inhibitors, histone deacetylase inhibitors (HDACs), such as HDAC8 inhibitors, angiogenesis inhibitors, interleukin receptor inhibitors, bromo and extraneous terminal family member inhibitors (e.g., bromodomain inhibitors or BET inhibitors, such as INCB54329 and INCB57643), c-MET inhibitors (e.g., capmatinib), anti-CD19 antibodies (e.g., tafasitamab), ALK2 inhibitors (e.g., INCB00928), or combinations thereof.

[0264] In some embodiments, the treatment methods described herein are combined with administration of a PI3Kδ inhibitor. In some embodiments, the treatment methods described herein are combined with administration of a JAK inhibitor. In some embodiments, the treatment methods described herein are combined with administration of a JAK1 or JAK2 inhibitor (e.g., baricitinib or ruxolitinib). In some embodiments, the treatment methods described herein are combined with administration of a JAK1 inhibitor. In some embodiments, the treatment methods described herein are combined with administration of a JAK1 inhibitor that is selective over JAK2.

[0265] Exemplary antibodies that may be administered in combination therapy include, but are not limited to, trastuzumab (e.g., anti-HER2), ranibizumab (e.g., anti-VEGF-A), bevacizumab (AVASTIN™, e.g., anti-VEGF), panitumumab (e.g., anti-EGFR), cetuximab (e.g., anti-EGFR), rituxan (e.g., anti-CD20), and antibodies directed against c-MET.

[0266] One or more of the following agents may be administered to a patient in combination with the treatment methods of the present disclosure, and are presented as a non-limiting list: the cytostatic agents cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan, camptosar, topotecan, paclitaxel, docetaxel, epothilone, tamoxifen, 5-fluorouracil, methotrexate, temozolomide, cyclophosphamide, SCH66336, R115777, L778,123, BMS 214662, IRESSA™ (gefitinib), TARCEVA™ (erlotinib), antibodies to EGFR, intron, ara-C, adriamycin, cytoxan, gemcitabine, uracil mustard, chlormethine, ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, floxolidin cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, oxaliplatin, leucovorin, ELOXATIN™ (oxaliplatin), pentostatin, vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase, teniposide 17 alpha.- ethinyl estradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, dromostanolone propionate, testolactone, megestrol acetate, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide, flutamide, toremifene, goserelin, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, navelbine, anastrazole, letrazole, capecitabine, reloxafine, droloxafine, hexamethylmelamine, avastin, HERCEPTIN™ (trastuzumab), BEXXAR™ VELCADE™ (tositumomab), VELCADE™ (bortezomib), ZEVALIN™ (ibritumomab tiuxetan), TRISENOX™ (arsenic trioxide), XELODA™ (capecitabine), vinorelbine, porfimer, ERBITUX™ (cetuximab), thiotepa, altretamine, melphalan, trastuzumab, lerozole, fulvestrant, etoxantrone, phenytoin ... Xemestane, ifosfamide, rituximab, C225 (cetuximab), Campath (alemtuzumab), clofarabine, cladribine, afidicolone, rituxan, sunitinib, dasatinib, tezacitabine, Sml1, fludarabine, pentostatin, triapine, didox, trimidox, amidox, 3-AP, and MDL-101,731.

[0267] The treatment methods and regimens of the present disclosure can be further used in combination with other methods of treating cancer, such as chemotherapy, radiation therapy, tumor-targeted therapy, adjuvant therapy, immunotherapy, or surgery. Examples of immunotherapies include cytokine treatment (e.g., interferon, GM-CSF, G-CSF, IL-2), CRS-207 immunotherapy, cancer vaccines, monoclonal antibodies, bispecific or multispecific antibodies, antibody-drug conjugates, adoptive T cell transfer, Toll receptor agonists, RIG-I agonists, oncolytic virotherapy, and immunomodulatory small molecules, such as thalidomide or JAK1 / 2 inhibitors, PI3Kδ inhibitors, etc. The compounds can be administered in combination with one or more anti-cancer drugs, such as chemotherapeutic agents. Examples of chemotherapy drugs include abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bevacizumab, bexarotene, baricitinib, bleomycin, bortezomib, intravenous busulfan, oral busulfan, calcitonin, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, and dromostan propionate. Nolon, eculizumab, epacadostat, epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib mesylate, interferon alpha 2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, mechlorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen,Mitomycin C, mitotane, mitoxantrone, nandrolone phenpropionate, nelarabine, nofetumomab, oxaliplatin, paclitaxel, pamidronate, panitumumab, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin, procarbazine, quinacrine, rasburicase, rituximab, ruxolitinib, sorafenib Examples of the anti-cancer drug include phenib, streptozocin, sunitinib, sunitinib maleate, tamoxifen, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, vorinostat, and zoledronate.

[0268] Additional examples of chemotherapeutic agents include proteosome inhibitors (eg, bortezomib), thalidomide, revlimid, and DNA damaging agents such as melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide, carmustine, and the like.

[0269] Exemplary steroids include corticosteroids such as dexamethasone or prednisone.

[0270] Exemplary Bcr-Abl inhibitors include imatinib mesylate (GLEEVAC™), nilotinib, dasatinib, bosutinib, and ponatinib, and pharmaceutically acceptable salts. Other exemplary suitable Bcr-Abl inhibitors include compounds of the genera and species disclosed in U.S. Pat. No. 5,521,184, WO 04 / 005281, and U.S. Ser. No. 60 / 578,491, and pharmaceutically acceptable salts thereof.

[0271] Exemplary suitable Flt-3 inhibitors include midostaurin, lestaurtinib, linifanib, sunitinib, sunitinib maleate, sorafenib, quizartinib, crenolanib, pacritinib, tanzutinib, PLX3397, and ASP2215, and pharmaceutically acceptable salts thereof. Other exemplary suitable Flt-3 inhibitors include compounds such as those disclosed in WO03 / 037347, WO03 / 099771, and WO04 / 046120, and pharmaceutically acceptable salts thereof.

[0272] Exemplary suitable RAF inhibitors include dabrafenib, sorafenib, and vemurafenib, and pharmaceutically acceptable salts thereof. Other exemplary suitable RAF inhibitors include compounds such as those disclosed in WO00 / 09495 and WO05 / 028444, and pharmaceutically acceptable salts thereof.

[0273] Exemplary suitable FAK inhibitors include VS-4718, VS-5095, VS-6062, VS-6063, BI853520, and GSK2256098, and pharmaceutically acceptable salts thereof. Other exemplary suitable FAK inhibitors include compounds such as those disclosed in WO04 / 080980, WO04 / 056786, WO03 / 024967, WO01 / 064655, WO00 / 053595, and WO01 / 014402, and pharmaceutically acceptable salts thereof.

[0274] Exemplary suitable CDK4 / 6 inhibitors include palbociclib, ribociclib, trilaciclib, relociclib, and abemaciclib, and pharmaceutically acceptable salts thereof. Other exemplary suitable CDK4 / 6 inhibitors include compounds such as those disclosed in WO09 / 085185, WO12 / 129344, WO11 / 101409, WO03 / 062236, WO10 / 075074, and WO12 / 061156, and pharmaceutically acceptable salts thereof.

[0275] In some embodiments, compounds of the present disclosure may be used in combination with one or more other kinase inhibitors, including imatinib, particularly to treat patients who are resistant to imatinib or other kinase inhibitors.

[0276] In some embodiments, the treatment methods of the present disclosure may be used in combination with chemotherapeutic agents in the treatment of cancer, and may improve treatment responses compared to the response of the chemotherapeutic agent alone without exacerbating its toxic effects. In some embodiments, the treatment methods of the present disclosure may be used in combination with the chemotherapeutic agents provided herein. For example, additional pharmaceutical agents used in the treatment of multiple myeloma may include, but are not limited to, melphalan, melphalan and prednisone [MP], doxorubicin, dexamethasone, and Velcade (bortezomib). Further additional agents used in the treatment of multiple myeloma include Bcr-Abl, Flt-3, RAF, and FAK kinase inhibitors. In some embodiments, the agent is an alkylating agent, a proteasome inhibitor, a corticosteroid, or an immunomodulatory agent. Examples of alkylating agents include cyclophosphamide (CY), melphalan (MEL), and bendamustine. In some embodiments, the proteasome inhibitor is carfilzomib. In some embodiments, the corticosteroid is dexamethasone (DEX). In some embodiments, the immunomodulatory agent is lenalidomide (LEN) or pomalidomide (POM). Additive or synergistic effects are desirable results when the treatment methods of the present disclosure are combined with additional agents.

[0277] The agents may be combined with Compound 1 and / or antibodies that bind to human PD-1 or human PD-L1, or antigen-binding fragments thereof, of the treatment method in a single or sequential dosage form, or the agents may be administered simultaneously or sequentially as separate dosage forms.

[0278] In some embodiments, a corticosteroid such as dexamethasone is administered to a patient in combination with the treatment methods of the present disclosure, where the dexamethasone is administered intermittently as opposed to continuously.

[0279] The treatment methods described herein can be combined with other immunogenic agents, such as cancerous cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells transfected with genes encoding immune-stimulating cytokines. Non-limiting examples of tumor vaccines that can be used include peptides of melanoma antigens, such as gp100, MAGE antigens, Trp-2, MARTI, and / or tyrosinase, or tumor cells transfected to express the cytokine GM-CSF.

[0280] The treatment methods described herein can be used in combination with vaccination protocols to treat cancer. In some embodiments, tumor cells are transduced to express GM-CSF. In some embodiments, tumor vaccines include proteins derived from viruses implicated in human cancers, such as human papillomavirus (HPV), hepatitis viruses (HBV and HCV), and Kaposi's herpes sarcoma virus (KHSV). In some embodiments, the treatment methods and regimens of the present disclosure can be used in combination with tumor-specific antigens, such as heat shock proteins isolated from the tumor tissue itself. In some embodiments, the treatment methods described herein can be combined with dendritic cell immunization to activate a potent anti-tumor response.

[0281] The disclosed treatment methods and regimens can be used in combination with bispecific macrocyclic peptides that target tumor cells with Fe alpha or Fe gamma receptor-expressing effector cells. The disclosed treatment methods and regimens can also be combined with macrocyclic peptides that activate host immune responsiveness.

[0282] In some further embodiments, the treatment methods of the present disclosure are combined with administering other therapeutic agents to the patient before, during, and / or after bone marrow or stem cell transplantation. The treatment methods and regimens of the present disclosure can be used in combination with bone marrow transplantation to treat various tumors of hematopoietic origin.

[0283] When two or more pharmaceutical agents are administered to a patient as set forth in any of the above embodiments, they may be administered simultaneously, separately, sequentially, or in combination (e.g., in the case of three or more agents).

[0284] Methods for safely and effectively administering many of these chemotherapeutic agents are known to those skilled in the art. In addition, their administration is described in standard literature. For example, the administration of many of the chemotherapeutic agents is described in the Physicians' Desk Reference (PDR, e.g., 1996 edition, Medical Economics Company, Montvale, NJ), the disclosure of which is incorporated herein by reference as if set forth in its entirety.

[0285] In some embodiments, the compounds described herein may be used in combination with immune checkpoint inhibitors. Exemplary immune checkpoint inhibitors include inhibitors of immune checkpoint molecules such as CD27, CD28, CD40, CD122, CD96, CD73, CD47, OX40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, CD137 (also known as 4-1BB), ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3 (e.g., INCAGN2385), TIM3 (e.g., INCB2390), VISTA, PD-1, PD-L1, and PD-L2. In some embodiments, the immune checkpoint molecule is a stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS, OX40 (e.g., INCAGN1949), GITR (e.g., INCAGN1876), and CD137. In some embodiments, the immune checkpoint molecule is an inhibitory checkpoint molecule selected from A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, and VISTA. In some embodiments, the compounds provided herein may be used in combination with one or more agents selected from a KIR inhibitor, a TIGIT inhibitor, a LAIR1 inhibitor, a CD160 inhibitor, a 2B4 inhibitor, and a TGFRbeta inhibitor.

[0286] In some embodiments, the inhibitor of an immune checkpoint molecule is a small molecule PD-L1 inhibitor. In some embodiments, the small molecule PD-L1 inhibitor has an IC50 of less than 1 μM, less than 100 nM, less than 10 nM, or less than 1 nM in the PD-L1 assay described in U.S. Patent Publication Nos. US20170107216, US20170145025, US20170174671, US20170174679, US20170320875, US20170342060, US20170362253, and US20180016260 (each of which is incorporated by reference in its entirety for all purposes).

[0287] 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 MGA012, nivolumab, pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001, ipilumimab, or AMP-224. 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 anti-PD1 antibody is nivolumab. In some embodiments, the anti-PD-1 monoclonal antibody is MGA012 (retifanlimab). In some embodiments, the anti-PD1 antibody is SHR-1210. Other anti-cancer agent(s) include antibody therapeutics such as 4-1BB (e.g., urelumab, utomilumab).

[0288] In some embodiments, compounds of the present disclosure may be used in combination with INCB086550.

[0289] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1, such as an anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments, the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI4736.

[0290] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CTLA-4, such as an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab, tremelimumab, AGEN1884, or CP-675,206.

[0291] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of LAG3, such as an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody is BMS-986016, LAG525, or INCAGN2385.

[0292] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of TIM3, such as an anti-TIM3 antibody. In some embodiments, the anti-TIM3 antibody is INCAGN2390, MBG453, or TSR-022.

[0293] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of GITR, such as an anti-GITR antibody. In some embodiments, the anti-GITR antibody is TRX518, MK-4166, INCAGN1876, MK-1248, AMG228, BMS-986156, GWN323, or MEDI1873.

[0294] In some embodiments, the inhibitor of an immune checkpoint molecule is an OX40 agonist, such as an OX40 agonist antibody or an OX40L fusion protein. In some embodiments, the anti-OX40 antibody is MEDI0562, MOXR-0916, PF-04518600, GSK3174998, or BMS-986178. In some embodiments, the OX40L fusion protein is MEDI6383.

[0295] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CD20, e.g., an anti-CD20 antibody. In some embodiments, the anti-CD20 antibody is obinutuzumab or rituximab.

[0296] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CD19, e.g., an anti-CD19 antibody. In some embodiments, the anti-CD19 antibody is tafasitamab.

[0297] The compounds of the present disclosure may be used in combination with bispecific antibodies, in some embodiments, one domain of the bispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3, CD137, ICOS, CD3, or a TGFβ receptor.

[0298] In some embodiments, the compounds of the present disclosure can be used in combination with one or more metabolic enzyme inhibitors. In some embodiments, the metabolic enzyme inhibitor is an inhibitor of IDO1, TDO, or arginase. Examples of IDO1 inhibitors include epacadostat, NLG919, BMS-986205, PF-06840003, IOM2983, RG-70099, and LY338196.

[0299] The compounds of the present disclosure may be used in combination with one or more immune checkpoint inhibitors to treat diseases such as cancer or infectious diseases. Exemplary immune checkpoint inhibitors include inhibitors against immune checkpoint molecules such as CBL-B, CD20, CD28, CD40, CD70, CD122, CD96, CD73, CD47, CDK2, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, HPK1, CD137 (also known as 4-1BB), ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, TLR (TLR7 / 8), TIGIT, CD112R, VISTA, PD-1, PD-L1, and PD-L2. In some embodiments, the immune checkpoint molecule is a stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS, OX40, GITR, and CD137. In some embodiments, the immune checkpoint molecule is an inhibitory checkpoint molecule selected from A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, TIGIT, and VISTA. In some embodiments, the compounds provided herein may be used in combination with one or more agents selected from a KIR inhibitor, a TIGIT inhibitor, a LAIR1 inhibitor, a CD160 inhibitor, a 2B4 inhibitor, and a TGFRbeta inhibitor.

[0300] In some embodiments, the compounds provided herein may be used in combination with one or more agonists of immune checkpoint molecules, such as OX40, CD27, GITR, and CD137 (also known as 4-1BB).

[0301] In some embodiments, the inhibitor of an immune checkpoint molecule is an anti-PD1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

[0302] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1 or PD-L1, e.g., an anti-PD-1 or anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-1 or anti-PD-L1 antibody is selected from the group consisting of nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, cemiplimab, atezolizumab, avelumab, tislelizumab, spartalizumab (PDR001), cetrelimab (JNJ-63723283), toripalimab (JS001), camrelizumab (SHR-1210), sintilimab (IBI308), AB122 (GLS-010), AMP-224, AMP-514 / MEDI- 0680, BMS936559, JTX-4014, BGB-108, SHR-1210, MEDI4736, FAZ053, BCD-100, KN035, CS1001, BAT1306, LZM009, AK105, HLX10, SHR-1316, CBT-502 (TQB2450), A167 (KL-A167), STI-A101 (ZKAB001), CK-301, BGB-A333, MSB-2311, HLX20, TSR-042, or LY3300054.In some embodiments, the PD-1 or PD-L1 inhibitor is a compound described in U.S. Patent Nos. 7,488,802, 7,943,743, 8,008,449, 8,168,757, 8,217,149, or 10,308,644; U.S. Publication Nos. 2017 / 0145025, 2017 / 0174671, 2017 / 0174672, 2017 / 0174673, 2017 / 0174674, 2017 / 0174675, 2017 / 0174676, 2017 / 0174677, 2017 / 0174678, 2017 / 0174679 ... No. 4679, No. 2017 / 0320875, No. 2017 / 0342060, No. 2017 / 0362253, No. 2018 / 0016260, No. 2018 / 005 No. 7486, No. 2018 / 0177784, No. 2018 / 0177870, No. 2018 / 0179179, No. 2018 / 0179201, No. 2018 / 0179 202, 2018 / 0273519, 2019 / 0040082, 2019 / 0062345, 2019 / 0071439, 2019 / 0127467, 2019 / 0144439, 2019 / 0202824, 2019 / 0225601, 2019 / 0300524, or 2019 / 0 345170, or PCT Publication Nos. WO03042402, WO2008156712, WO2010089411, WO2010036959, WO2011066342, WO2011159877, WO2011082400, or WO2011161699, each of which is incorporated by reference herein in its entirety. In some embodiments, the inhibitor of PD-L1 is INCB086550.

[0303] In some embodiments, the antibody is an anti-PD-1 antibody, e.g., an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 antibody is nivolumab, pembrolizumab, cemiplimab, spartalizumab, camrelizumab, cetrelimab, toripalimab, sintilimab, AB122, AMP-224, JTX-4014, BGB-108, BCD-100, BAT1306, LZM009, AK105, HLX10, or TSR-042. In some embodiments, the anti-PD-1 antibody is nivolumab, pembrolizumab, cemiplimab, spartalizumab, camrelizumab, cetrelimab, toripalimab, or sintilimab. In some embodiments, the anti-PD-1 antibody is pembrolizumab. In some embodiments, the anti-PD-1 antibody is nivolumab. In some embodiments, the anti-PD-1 antibody is cemiplimab. In some embodiments, the anti-PD-1 antibody is spartalizumab. In some embodiments, the anti-PD-1 antibody is camrelizumab. In some embodiments, the anti-PD-1 antibody is cetrelimab. In some embodiments, the anti-PD-1 antibody is toripalimab. In some embodiments, the anti-PD-1 antibody is sintilimab. In some embodiments, the anti-PD-1 antibody is AB122. In some embodiments, the anti-PD-1 antibody is AMP-224. In some embodiments, the anti-PD-1 antibody is JTX-4014. In some embodiments, the anti-PD-1 antibody is BGB-108. In some embodiments, the anti-PD-1 antibody is BCD-100. In some embodiments, the anti-PD-1 antibody is BAT1306. In some embodiments, the anti-PD-1 antibody is LZM009. In some embodiments, the anti-PD-1 antibody is AK105. In some embodiments, the anti-PD-1 antibody is HLX10. In some embodiments, the anti-PD-1 antibody is TSR-042. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab or pembrolizumab. In some embodiments, the anti-PD1 antibody is SHR-1210. Other anti-cancer agent(s) include antibody therapeutics such as 4-1BB (e.g., urelumab, utomilumab), etc.In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1, such as an anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is atezolizumab, avelumab, durvalumab, tislelizumab, BMS-935559, MEDI4736, atezolizumab (also known as MPDL3280A, RG7446), avelumab (MSB0010718C), FAZ053, KN035, CS1001, SHR-1316, CBT-502, A167, STI-A101, CK-301, BGB-A333, MSB-2311, HLX20, or LY3300054. In some embodiments, the anti-PD-L1 antibody is atezolizumab, avelumab, durvalumab, or tislelizumab. In some embodiments, the anti-PD-L1 antibody is atezolizumab. In some embodiments, the anti-PD-L1 antibody is avelumab. In some embodiments, the anti-PD-L1 antibody is durvalumab. In some embodiments, the anti-PD-L1 antibody is tislelizumab. In some embodiments, the anti-PD-L1 antibody is BMS-935559. In some embodiments, the anti-PD-L1 antibody is MEDI4736. In some embodiments, the anti-PD-L1 antibody is FAZ053. In some embodiments, the anti-PD-L1 antibody is KN035. In some embodiments, the anti-PD-L1 antibody is CS1001. In some embodiments, the anti-PD-L1 antibody is SHR-1316. In some embodiments, the anti-PD-L1 antibody is CBT-502. In some embodiments, the anti-PD-L1 antibody is A167. In some embodiments, the anti-PD-L1 antibody is STI-A101. In some embodiments, the anti-PD-L1 antibody is CK-301. In some embodiments, the anti-PD-L1 antibody is BGB-A333. In some embodiments, the anti-PD-L1 antibody is MSB-2311. In some embodiments, the anti-PD-L1 antibody is HLX20. In some embodiments, the anti-PD-L1 antibody is LY3300054.

[0304] In some embodiments, the inhibitor of an immune checkpoint molecule is a small molecule that binds to PD-L1, or a pharmaceutically acceptable salt thereof. In some embodiments, the inhibitor of an immune checkpoint molecule is a small molecule that binds to and internalizes PD-L1, or a pharmaceutically acceptable salt thereof. In some embodiments, the inhibitor of an immune checkpoint molecule is a compound selected from those in US2018 / 0179201, US2018 / 0179197, US2018 / 0179179, US2018 / 0179202, US2018 / 0177784, US2018 / 0177870, US Ser. No. 16 / 369,654 (filed March 29, 2019), and US Ser. No. 62 / 688,164, each of which is incorporated by reference herein in its entirety, or a pharmaceutically acceptable salt thereof.

[0305] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of KIR, TIGIT, LAIR1, CD160, 2B4, and TGFRbeta.

[0306] In some embodiments, the inhibitor is MCLA-145.

[0307] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CTLA-4, such as an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab, tremelimumab, AGEN1884, or CP-675,206.

[0308] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of LAG3, such as an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody is BMS-986016, LAG525, INCAGN2385, or eftiragimode alpha (IMP321).

[0309] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CD73. In some embodiments, the inhibitor of CD73 is oleclumab.

[0310] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of TIGIT. In some embodiments, the inhibitor of TIGIT is OMP-31M32.

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

[0312] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of B7-H3. In some embodiments, the inhibitor of B7-H3 is enoblituzumab, MGD009, or 8H9.

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

[0314] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of A2aR, hi some embodiments, the inhibitor of A2aR is CPI-444.

[0315] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of TGF-beta, hi some embodiments, the inhibitor of TGF-beta is travedersen, galusertinib, or M7824.

[0316] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PI3K-gamma. In some embodiments, the inhibitor of PI3K-gamma is IPI-549.

[0317] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CD47. In some embodiments, the inhibitor of CD47 is Hu5F9-G4 or TTI-621.

[0318] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CD73. In some embodiments, the inhibitor of CD73 is MEDI9447.

[0319] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CD70. In some embodiments, the inhibitor of CD70 is cusatuzumab or BMS-936561.

[0320] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of TIM3, such as an anti-TIM3 antibody. In some embodiments, the anti-TIM3 antibody is INCAGN2390, MBG453, or TSR-022.

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

[0322] In some embodiments, the agonist of an immune checkpoint molecule is an agonist of OX40, CD27, CD28, GITR, ICOS, CD40, TLR7 / 8, and CD137 (also known as 4-1BB).

[0323] In some embodiments, the CD137 agonist is urelumab. In some embodiments, the CD137 agonist is utomilumab.

[0324] In some embodiments, the agonist of the immune checkpoint molecule is an inhibitor of GITR. In some embodiments, the agonist of GITR is TRX518, MK-4166, INCAGN1876, MK-1248, AMG228, BMS-986156, GWN323, MEDI1873, or MEDI6469. In some embodiments, the agonist of the immune checkpoint molecule is an agonist of OX40, such as an OX40 agonist antibody or an OX40L fusion protein. In some embodiments, the anti-OX40 antibody is INCAGN01949, MEDI0562 (tavolimab), MOXR-0916, PF-04518600, GSK3174998, BMS-986178, or 9B12. In some embodiments, the OX40L fusion protein is MEDI6383.

[0325] In some embodiments, the agonist of an immune checkpoint molecule is an agonist of CD40, hi some embodiments, the CD40 agonist is CP-870893, ADC-1013, CDX-1140, SEA-CD40, RO7009789, JNJ-64457107, APX-005M, or Chi Lob 7 / 4.

[0326] In some embodiments, the agonist of the immune checkpoint molecule is an agonist of ICOS, hi some embodiments, the agonist of ICOS is GSK-3359609, JTX-2011, or MEDI-570.

[0327] In some embodiments, the agonist of the immune checkpoint molecule is an agonist of CD28. In some embodiments, the agonist of CD28 is celalizumab.

[0328] In some embodiments, the agonist of the immune checkpoint molecule is an agonist of CD27, hi some embodiments, the agonist of CD27 is varlilumab.

[0329] In some embodiments, the agonist of the immune checkpoint molecule is an agonist of TLR7 / 8. In some embodiments, the agonist of TLR7 / 8 is MEDI9197.

[0330] The compounds of the present disclosure may be used in combination with bispecific antibodies. In some embodiments, one domain of the bispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3, CD137, ICOS, CD3, or a TGFβ receptor. In some embodiments, the bispecific antibody binds to PD-1 and PD-L1. In some embodiments, the bispecific antibody that binds to PD-1 and PD-L1 is MCLA-136. In some embodiments, the bispecific antibody binds to PD-L1 and CTLA-4. In some embodiments, the bispecific antibody that binds to PD-L1 and CTLA-4 is AK104.

[0331] In some embodiments, the compounds of the present disclosure can be used in combination with one or more metabolic enzyme inhibitors. In some embodiments, the metabolic enzyme inhibitor is an inhibitor of IDO1, TDO, or arginase. Examples of IDO1 inhibitors include epacadostat, NLG919, BMS-986205, PF-06840003, IOM2983, RG-70099, and LY338196. Examples of arginase inhibitor inhibitors include INCB1158.

[0332] As provided throughout, the additional compounds, inhibitors, drugs, etc. may be combined with the present compounds in a single or sequential dosage form, or they may be administered simultaneously or sequentially as separate dosage forms.

[0333] In some embodiments, the compounds described herein may be used in combination with one or more drugs to treat diseases such as cancer. In some embodiments, the drug is an alkylating agent, a proteasome inhibitor, a corticosteroid, or an immunomodulatory agent. Examples of alkylating agents include cyclophosphamide (CY), melphalan (MEL), and bendamustine. In some embodiments, the proteasome inhibitor is carfilzomib. In some embodiments, the corticosteroid is dexamethasone (DEX). In some embodiments, the immunomodulatory agent is lenalidomide (LEN) or pomalidomide (POM).

[0334] Suitable antiviral agents contemplated for use in combination with the compounds of the present disclosure may include nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors, and other antiviral agents.

[0335] Exemplary suitable NRTIs include zidovudine (AZT), didanosine (ddl), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC), abacavir (1592U89), adefovir dipivoxil [bis(POM)-PMEA], lobucavir (BMS-180194), BCH-10652, emitricitabine [(-)-FTC], beta-L-FD4 (also called beta-L-D4C and named beta-L-2',3'-dicreoxy-5-fluoro-citidene), DAPD, ((-)-beta-D-2,6,-diamino-purine dioxolane), and rhodenosine (FddA). Exemplary and preferred NNRTIs include nevirapine (BI-RG-587), delaviradine (BHAP, U-90152), efavirenz (DMP-266), PNU-142721, AG-1549, MKC-442 (1-(ethoxymethyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione), and (+)-calanolide. A (NSC-675451) and B. Exemplary suitable protease inhibitors include saquinavir (Ro31-8959), ritonavir (ABT-538), indinavir (MK-639), nelfnavir (AG-1343), amprenavir (141W94), lasinavir (BMS-234475), DMP-450, BMS-2322623, ABT-378, and AG-1 549. Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside, and Yissum Project No. 11607.

[0336] Suitable drugs for use in combination with the compounds described herein to treat cancer include chemotherapy, targeted cancer therapy, immunotherapy, or radiation therapy.The compounds described herein may be effective in combination with antihormonal agents to treat breast cancer and other tumors.Suitable examples include antiestrogens, including but not limited to tamoxifen and toremifene, aromatase inhibitors, including but not limited to letrozole, anastrozole, and exemestane, corticosteroids (e.g., prednisone), progestins (e.g., megestrol acetate), and estrogen receptor antagonists (e.g., fulvestrant).Suitable antihormonal agents used to treat prostate cancer and other cancers may also be combined with the compounds described herein. These include antiandrogens, including but not limited to flutamide, bicalutamide, and nilutamide, luteinizing hormone-releasing hormone (LHRH) analogs, including leuprolide, goserelin, triptorelin, and histrelin, LHRH antagonists (e.g., degarelix), androgen receptor blockers (e.g., enzalutamide), and agents that inhibit androgen production (e.g., abiraterone).

[0337] The compounds described herein may be combined with or sequentially combined with other agents against membrane receptor kinases, particularly for patients who have developed primary or acquired resistance to targeted therapy. These therapeutic agents include inhibitors or antibodies against EGFR, Her2, VEGFR, c-Met, Ret, IGFR1, or Flt-3, as well as cancer-related fusion protein kinases such as Bcr-Abl and EML4-Alk. EGFR inhibitors include, but are not limited to, gefitinib and erlotinib, and EGFR / Her2 inhibitors include, but are not limited to, dacomitinib, afatinib, lapitinib, and neratinib. EGFR antibodies include, but are not limited to, cetuximab, panitumumab, and necitumumab. c-Met inhibitors may be used in combination with FGFR inhibitors. These include onartumzumab, tivantinib, and INC-280. Agents directed against Abl (or Bcr-Abl) include imatinib, dasatinib, nilotinib, and ponatinib, and agents directed against Alk (or EML4-ALK) include crizotinib.

[0338] Angiogenesis inhibitors may be effective in some tumors when combined with FGFR inhibitors. These include antibodies against VEGF or VEGFR or VEGFR kinase inhibitors. Antibodies against VEGF or other therapeutic proteins include bevacizumab and aflibercept. VEGFR kinase inhibitors and other antiangiogenesis inhibitors include, but are not limited to, sunitinib, sorafenib, axitinib, cediranib, pazopanib, regorafenib, brivanib, and vandetanib.

[0339] The activation of intracellular signal transduction pathways is frequent in cancer, and drugs that target components of these pathways are combined with receptor targeting agents to improve efficacy and reduce resistance. Examples of drugs that may be combined with the compounds described herein include inhibitors of the PI3K-AKT-mTOR pathway, inhibitors of the Raf-MAPK pathway, inhibitors of the JAK-STAT pathway, and inhibitors of protein chaperones and cell cycle progression.

[0340] Drugs against PI3 kinase include but are not limited to topilaralisib, idelalisib, and buparlisib. mTOR inhibitors, such as rapamycin, sirolimus, temsirolimus, and everolimus, can be combined with FGFR inhibitors. Other suitable examples include but are not limited to vemurafenib and dabrafenib (Raf inhibitors) and trametinib, selumetinib, and GDC-0973 (MEK inhibitors). One or more JAK inhibitors (e.g., ruxolitinib, baricitinib, tofacitinib), Hsp90 inhibitors (e.g., tanespimycin), cyclin-dependent kinase inhibitors (e.g., palbociclib), HDAC inhibitors (e.g., panobinostat), PARP inhibitors (e.g., olaparib), and proteasome inhibitors (e.g., bortezomib, carfilzomib) may also be combined with the compounds described herein. In some embodiments, the JAK inhibitor is selective for JAK1 over JAK2 and JAK3.

[0341] Other suitable agents for use in combination with the compounds described herein include chemotherapy combinations, such as platinum-based doublets used in lung cancer and other solid tumors (cisplatin or carboplatin and gemcitabine, cisplatin or carboplatin and docetaxel, cisplatin or carboplatin and paclitaxel, cisplatin or carboplatin and pemetrexed) or gemcitabine and paclitaxel-bound particles (Abraxane®).

[0342] Suitable chemotherapeutic or other anti-cancer agents include, for example, alkylating agents (including, but not limited to, nitrogen mustards, ethyleneimine derivatives, alkyl sulfonates, nitrosoureas, and triazenes), such as uracil mustard, chlormethine, cyclophosphamide (Cytoxan™), ifosfamide, melphalan, chlorambucil, pipobroman, triethylene-melamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

[0343] Other suitable agents for use in combination with the compounds described herein include steroids, such as 17alpha-ethinylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide, and medroxyprogesterone acetate.

[0344] Other suitable agents for use in combination with the compounds described herein include dacarbazine (DTIC), optionally with other chemotherapeutic agents such as carmustine (BCNU) and cisplatin, the "Dartmouth regimen" consisting of DTIC, BCNU, cisplatin, and tamoxifen, a combination of cisplatin, vinblastine, and DTIC, or temozolomide. The compounds described herein may also be combined with immunotherapeutic agents, including cytokines such as interferon alpha, interleukin 2, and tumor necrosis factor (TNF).

[0345] Suitable chemotherapeutic or other anti-cancer agents include, for example, antimetabolites (including, but not limited to, folate antagonists, pyrimidine analogs, purine analogs, and adenosine deaminase inhibitors), such as methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, and gemcitabine.

[0346] Suitable chemotherapeutic or other anti-cancer agents further include, for example, certain natural products and their derivatives (e.g., vinca alkaloids, antitumor antibiotics, enzymes, lymphokines, and epipodophyllotoxins), such as vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel (TAXOL™), mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase, interferons (especially IFN-α), etoposide, and teniposide.

[0347] Other cytotoxic agents include navelbine, CPT-11, anastrozole, letrazole, capecitabine, reloxafine, cyclophosphamide, ifosamide, and droloxafine.

[0348] Also suitable are cytotoxic agents such as epidophyllotoxins, antitumor enzymes, topoisomerase inhibitors, platinum coordination complexes such as procarbazine, mitoxantrone, cis-platin and carboplatin, biological response modifiers, growth inhibitory agents, antihormonal therapeutic agents, leucovorin, tegafur, and hematopoietic growth factors.

[0349] Other anti-cancer drug(s) include antibody therapeutics such as trastuzumab (Herceptin), antibodies against costimulatory molecules such as CTLA-4, 4-1BB, PD-L1 and PD-1 antibodies, or antibodies against cytokines (IL-10, TGF-β, etc.).

[0350] Other anti-cancer agents also include those that block immune cell migration, such as antagonists to chemokine receptors, including CCR2 and CCR4.

[0351] Other anti-cancer agents include those that enhance the immune system, such as adjuvants or adoptive T-cell transfer.

[0352] Anti-cancer vaccines include dendritic cells, synthetic peptides, DNA vaccines, and recombinant viruses. In some embodiments, tumor vaccines include proteins derived from viruses involved in human cancer, such as human papillomavirus (HPV), hepatitis viruses (HBV and HCV), and Kaposi's herpes sarcoma virus (KHSV). Non-limiting examples of tumor vaccines that can be used include peptides of melanoma antigens, such as gp100, MAGE antigens, Trp-2, MARTI, and / or tyrosinase, or tumor cells transfected to express the cytokine GM-CSF.

[0353] The compounds of the present disclosure may be used in combination with bone marrow transplantation to treat a variety of tumors of hematopoietic origin.

[0354] Methods for safely and effectively administering many of these chemotherapeutic agents are known to those skilled in the art. In addition, their administration is described in standard literature. For example, the administration of many of the chemotherapeutic agents is described in the Physicians' Desk Reference (PDR, e.g., 1996 edition, Medical Economics Company, Montvale, NJ), the disclosure of which is incorporated herein by reference as if set forth in its entirety.

[0355] As provided throughout, the additional compounds, inhibitors, drugs, etc. may be combined with the present compounds in a single or sequential dosage form, or they may be administered simultaneously or sequentially as separate dosage forms.

[0356] Pharmaceutical Preparations and Dosage Forms When used as pharmaceuticals, the compounds described herein can be administered in the form of a pharmaceutical composition, which refers to a combination of one or more compounds described herein and at least one pharmaceutically acceptable carrier or excipient. These compositions can be prepared by methods well known in the pharmaceutical arts and can be administered by various routes depending on whether local or systemic treatment is desired and the area to be treated. Administration can be topical (including transmucosal, including ocular and intranasal, intravaginal, and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer, intratracheal, intranasal, epidermal, and transdermal), ocular, oral, or parenteral. Methods of ocular delivery can include topical administration (eye drops), subconjunctival, periocular, or intravitreal injection, or introduction via a balloon catheter or ocular insert surgically placed in the conjunctival sac. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion, or intracranial, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose, or for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous, powder, or oily bases, thickeners, etc. may be necessary or desirable.

[0357] The present disclosure also includes pharmaceutical compositions containing one or more compounds described herein as an active ingredient in combination with one or more pharmaceutically acceptable carriers or excipients. When preparing the compositions described herein, the active ingredient is typically mixed with an excipient, diluted by the excipient, or enclosed within such a carrier, for example, in the form of a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments containing up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders. In some embodiments, the compositions are suitable for topical administration.

[0358] When preparing formulations, active compound can be milled to obtain suitable particle size before being combined with other components.If active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh.If active compound is substantially water-soluble, particle size can be adjusted by milling to obtain substantially uniform distribution in formulation, for example, about 40 mesh.

[0359] The compounds of the present invention may be milled using known milling procedures, such as wet milling, to obtain a particle size suitable for tablet formation and other formulation types. Micronized (nanoparticulate) preparations of the compounds of the present invention may be prepared by processes known in the art, see, for example, WO2002 / 000196.

[0360] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose.The formulation may further include lubricants such as talc, magnesium stearate, and mineral oil, wetting agents, emulsifying and suspending agents, preservatives such as methyl benzoate and propyl benzoate, sweeteners, and flavoring agents.The compositions described herein can be formulated to provide rapid, sustained, or delayed release of active ingredients after administration to patients by using procedures known in the art.

[0361] In some embodiments, the pharmaceutical composition comprises silicified microcrystalline cellulose (SMCC) and at least one compound described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the silicified microcrystalline cellulose comprises about 98 wt% microcrystalline cellulose and about 2 wt% silicon dioxide.

[0362] In some embodiments, the composition is a sustained-release composition comprising at least one compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient. In some embodiments, the composition comprises at least one compound described herein, or a pharmaceutically acceptable salt thereof, and at least one component selected from microcrystalline cellulose, lactose monohydrate, hydroxypropyl methylcellulose, and polyethylene oxide. In some embodiments, the composition comprises at least one compound described herein, or a pharmaceutically acceptable salt thereof, and microcrystalline cellulose, lactose monohydrate, and hydroxypropyl methylcellulose. In some embodiments, the composition comprises at least one compound described herein, or a pharmaceutically acceptable salt thereof, and microcrystalline cellulose, lactose monohydrate, and polyethylene oxide. In some embodiments, the composition further comprises magnesium stearate or silicon dioxide. In some embodiments, the microcrystalline cellulose is Avicel PH102™. In some embodiments, the lactose monohydrate is Fast-flo 316™. In some embodiments, the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose 2208 K4M (e.g., Methocel K4 M Premier™) and / or hydroxypropyl methylcellulose 2208 K100LV (e.g., Methocel K00LV™). In some embodiments, the polyethylene oxide is polyethylene oxide WSR 1105 (e.g., Polyox WSR 1105™).

[0363] In some embodiments, a wet granulation process is used to make the composition. In some embodiments, a dry granulation process is used to make the composition.

[0364] The compositions may be formulated in unit dosage form, each dosage containing, for example, about 5 mg to about 1000 mg, about 5 mg to about 100 mg, about 100 mg to about 500 mg, or about 10 to about 30 mg of active ingredient. In some embodiments, each dosage contains about 10 mg of active ingredient. In some embodiments, each dosage contains about 50 mg of active ingredient. In some embodiments, each dosage contains about 25 mg of active ingredient. The term "unit dosage form" refers to a physically discrete unit suitable as a unit dosage for human subjects and other mammals, each unit containing a predetermined amount of active agent calculated to produce a desired therapeutic effect in association with a suitable pharmaceutical excipient.

[0365] The components used to formulate pharmaceutical compositions are of high purity and substantially free of potentially harmful contaminants (e.g., at least national food grade, generally at least analytical grade, and more typically at least pharmaceutical grade). For human consumption in particular, compositions are preferably manufactured or formulated in accordance with good manufacturing practice as defined by applicable U.S. Food and Drug Administration regulations. For example, suitable formulations may be sterile and / or substantially isotonic and / or in full compliance with all U.S. Food and Drug Administration good manufacturing practice regulations.

[0366] The active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. However, it will be understood that the amount of compound actually administered will usually be determined by the physician according to the relevant circumstances, including the condition to be treated, the selected route of administration, the compound actually administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, etc.

[0367] Therapeutic dosages of the compounds of the invention can vary according to, for example, the particular application for which the treatment is given, the method of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the invention in a pharmaceutical composition can vary depending on numerous factors, including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. For example, a compound of the invention may be provided in an aqueous physiological buffer solution containing about 0.1 to about 10 wt.% compound for parenteral administration. Some typical dosage ranges are about 1 μg / kg to about 1 g / kg of body weight per day. In some embodiments, the dosage range is about 0.01 mg / kg to about 100 mg / kg of body weight per day. The dosage can depend on such variables as the type and progression of the disease or disorder, the overall health of the particular patient, the relative biological availability of the selected compound, the formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0368] To prepare solid compositions such as tablets, the primary active ingredient is mixed with pharmaceutical excipients to form a solid preformulation composition containing a homogeneous mixture of one or more compounds described herein. When these preformulation compositions are referred to as homogeneous, the active ingredient is typically dispersed evenly throughout the composition so that the composition can be easily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above, containing, for example, 0.1 to about 500 mg of the active ingredient of the present disclosure.

[0369] The tablets or pills of the present disclosure can be coated or otherwise compounded to provide a dosage form offering the advantage of prolonged action. For example, the tablets or pills can comprise an inner and outer dosage component, the latter being in the form of a coating over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and allow the inner component to pass intact into the duodenum or to delay its release. A variety of materials can be used for such enteric layers or coatings, including a number of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0370] Liquid forms into which the compounds or compositions described herein may be incorporated for oral or injectable administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0371] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the compositions are administered by oral or nasal respiratory route for local or systemic effect. Compositions may be nebulized by the use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a face mask tent or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0372] Topical formulations may contain one or more conventional carriers. In some embodiments, ointments may contain water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white petrolatum, etc. Cream carrier compositions may be based on a combination of water with glycerol and one or more other components, such as glycerol monostearate, PEG-glyceryl monostearate, and cetylstearyl alcohol. Gels may be formulated using isopropyl alcohol and water, preferably in combination with other components, such as glycerol, hydroxyethylcellulose, etc. In some embodiments, topical formulations contain at least about 0.1 wt%, at least about 0.25 wt%, at least about 0.5 wt%, at least about 1 wt%, at least about 2 wt%, or at least about 5 wt% of a compound of the present invention. Topical formulations may be suitably packaged, for example, in a 100 g tube, optionally accompanied by instructions for treating a selected indication, such as psoriasis or other skin conditions.

[0373] The amount of compound or composition administered to a patient will vary depending on what is being administered, the purpose of the administration, such as prophylaxis or therapy, the condition of the patient, the method of administration, etc. In therapeutic applications, compositions may be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. The effective dose will depend on the disease state being treated as well as the judgment of the attending clinician depending on factors such as the severity of the disease, the age, weight, and general condition of the patient, etc.

[0374] The compositions administered to patients may be in the form of pharmaceutical compositions described above. These compositions may be sterilized by conventional sterilization techniques or may be sterile filtered. Aqueous solutions may be packaged for immediate use or lyophilized, with the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the compound preparations will typically be 3-11, more preferably 5-9, and most preferably 7-8. It will be understood that the use of some of the aforementioned excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.

[0375] Therapeutic dosages of compounds of the present disclosure can vary according to, for example, the particular application for which the treatment is given, the method of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of the compound in a pharmaceutical composition can vary depending on numerous factors, including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. For example, compounds of the present disclosure can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10 wt.% of the compound for parenteral administration. Some typical dosage ranges are about 1 μg / kg to about 1 g / kg of body weight per day. In some embodiments, the dosage range is about 0.01 mg / kg to about 100 mg / kg of body weight per day. The dosage can depend on variables such as the type and progression of the disease or disorder, the overall health of the particular patient, the relative biological availability of the selected compound, the formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0376] The compounds described herein may also be formulated in combination with one or more additional active ingredients, which may include any pharmaceutical agent, such as an antiviral agent, a vaccine, an antibody, an immune enhancer, an immunosuppressant, an anti-inflammatory agent, etc.

[0377] Labeled Compounds and Assay Methods Another aspect of the present invention relates to the labeled compounds (radiolabeled, fluorescently labeled, etc.) of the present disclosure, which are useful for both in vitro and in vivo assays, as well as imaging techniques, to locate and quantify FGFR3 protein in tissue samples, including human tissue samples, and to identify FGFR3 ligands, by the inhibitory binding of the labeled compounds.The substitution of one or more atoms of the compounds of the present disclosure can also be useful in producing differentiated ADME (absorption, distribution, metabolism and excretion).Therefore, the present invention includes FGFR binding assays containing such labeled or substituted compounds.

[0378] The present disclosure further includes isotopically labeled compounds of the present disclosure. An "isotopically labeled" or "radiolabeled" compound is a compound of the present disclosure in which one or more atoms have been replaced or substituted by an atom having an atomic mass or mass number different from that normally found in nature (i.e., occurring in nature). Suitable radionuclides that may be incorporated into compounds of the present disclosure include: 2 H (also written as D for deuterium), 3 H (also written as T for tritium), 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 18 F, 35 S, 36 Cl, 82 Br, 75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I and 131 For example, one or more hydrogen atoms in the compounds of the present disclosure may be replaced by a deuterium atom (e.g., C in formula (I)). 1~6One or more hydrogen atoms of an alkyl group can be optionally replaced with a deuterium atom, such as -CH being replaced with -CD.) In some embodiments, the alkyl group of formula (I) can be fully deuterated.

[0379] One or more constituent atoms of the compounds presented herein may be replaced or substituted with a natural or non-natural abundance isotope of the atom. In some embodiments, the compound contains at least one deuterium atom. In some embodiments, the compound contains two or more deuterium atoms. In some embodiments, the compound contains 1-2, 1-3, 1-4, 1-5, or 1-6 deuterium atoms. In some embodiments, all hydrogen atoms in the compound may be replaced or substituted with deuterium atoms.

[0380] Synthetic methods for incorporating isotopes into organic compounds are known in the art (Deuterium Labeling in Organic Chemistry by Alan F. Thomas (New York, NY, Appleton-Century-Crofts, 1971); The Renaissance of H / D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistry of Isotopic Labelling by James R. Hanson, Royal Society of Chemistry, 2011). Isotopically labeled compounds can be used in a variety of studies, such as NMR spectroscopy, metabolic studies, and / or assays.

[0381] Substitution with heavier isotopes, such as deuterium, may confer certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be preferable in some circumstances. (See, e.g., A. Kerekes et al. J. Med. Chem. 2011, 54, 201-210; R. Xu et al. J. Label Compd. Radiopharm. 2015, 58, 308-312.) In particular, substitution at one or more metabolic sites may confer one or more therapeutic advantages.

[0382] The radionuclide that is incorporated into the present radiolabeled compounds will depend on the particular application of that radiolabeled compound. For example, for in vitro adenosine receptor labeling and competition assays: 3 H, 14 C. 82 Br, 125 I, 131 I or 35 Compounds incorporating S may be useful. For radioimaging applications, 11 C. 18 F, 125 I, 123 I, 124 I, 131 I, 75 Br, 76 Br or 77 Br may be useful.

[0383] A "radiolabel" or "labeled compound" is understood to be a compound that incorporates at least one radionuclide. In some embodiments, the radionuclide is 3 H, 14 C. 125 I, 35 S and 82 Br.

[0384] The present disclosure may further include synthetic methods for incorporating radioisotopes into the compounds of the present disclosure. Synthetic methods for incorporating radioisotopes into organic compounds are well known in the art, and one of ordinary skill in the art will readily recognize methods applicable to the compounds of the present disclosure.

[0385] The labeled compounds of the present invention can be used in screening assays to identify and / or evaluate compounds.For example, a labeled newly synthesized or identified compound (i.e., test compound) can be evaluated for its ability to bind to FGFR3 protein by monitoring its concentration change through label tracking when contacted with FGFR3.For example, a (labeled) test compound can be evaluated for its ability to reduce the binding of another compound (i.e., standard compound) known to bind to FGFR3 protein.Therefore, the ability of the test compound to compete with the standard compound for binding to FGFR3 protein is directly related to its binding affinity.Conversely, in some other screening assays, the standard compound is labeled, and the test compound is not labeled.Therefore, the concentration of the labeled standard compound is monitored to evaluate the competition between the standard compound and the test compound, thereby determining the relative binding affinity of the test compound.

[0386] kit The present invention also includes pharmaceutical kits useful for treating or preventing, e.g., FGFR-associated diseases or disorders referred to herein, such as cancer and other diseases, comprising one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present disclosure. Such kits may optionally further comprise one or more of a variety of conventional pharmaceutical kit components, e.g., containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to one of skill in the art. Instructions, either as an insert or label, indicating the amounts of components to be administered, administration guidelines, and / or guidelines for mixing of components, may also be included within the kit.

[0387] The present invention will be described in more detail by specific examples.The following examples are provided for illustrative purposes and are not intended to limit the present invention in any way.Those skilled in the art will easily recognize various non-critical parameters that can be changed or modified to achieve essentially the same results.The compound of example is found to be the inhibitor of FGFR3 as described below. [Example]

[0388] The experimental procedures for the compounds of the present invention are provided below. Preparative LC-MS purification of some of the prepared compounds was performed on a Waters mass spectrometric fractionation system. The basic instrument setup, protocols, and control software for operating these systems are well described in the literature. See, for example, "Two-Pump At Column Dilution Configuration for Preparative LC-MS", K. Blom, J. Combi. Chem., 4, 295 (2002), "Optimizing Preparative LC-MS Configurations and Methods for Parallel Synthesis Purification", K. Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi. Chem., 5, 670 (2003), and "Preparative LC-MS Purification: Improved Compound Specific Method Optimization", K. Blom, B. Glass, R. Sparks, A. Combs, J. Combi. Chem., 6, 874-883 (2004). The separated compounds were subjected to analytical liquid chromatography mass spectrometry (LCMS) for purity analysis, typically under the following conditions: Instrument: Agilent 1100 series, LC / MSD; Column: Waters Sunfire™ C 185 μm, 2.1 × 50 mm, buffer: mobile phase A: 0.025% TFA in water and mobile phase B: acetonitrile, gradient 2% to 80% B in 3 min, flow rate 2.0 mL / min.

[0389] Some of the prepared compounds were also separated on a preparative scale by reversed-phase high-performance liquid chromatography (RP-HPLC) or flash chromatography (silica gel) with MS detection, as shown in the Examples. Typical preparative reversed-phase high-performance liquid chromatography (RP-HPLC) column conditions are as follows:

[0390] Purification at pH=2: Waters Sunfire™ C 18 The 5 μm, 19 × 100 mm column was eluted with mobile phase A: 0.1% aqueous TFA (trifluoroacetic acid) and mobile phase B: acetonitrile at a flow rate of 30 mL / min. The separation gradient was optimized for each compound using a Compound Specific Method Optimization protocol as described in the literature [see "Preparative LCMS Purification: Improved Compound Specific Method Optimization," K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874-883 (2004)]. Typically, the flow rate used for the 30 × 100 mm column was 60 mL / min.

[0391] Purification at pH 10: Waters Xbridge C 18A 5 μm, 19 × 100 mm column was eluted with mobile phase A: 0.15% aqueous NH OH and mobile phase B: acetonitrile at a flow rate of 30 mL / min. The separation gradient was optimized for each compound using a compound-specific method optimization protocol as described in the literature [see "Preparative LCMS Purification: Improved Compound Specific Method Optimization," K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874-883 (2004)]. Typically, the flow rate used for a 30 × 100 mm column was 60 mL / min.

[0392] Example 1. 5-(2,3-dimethylphenyl)-6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine [ka] Step 1. 6-Bromo-1-trityl-1H-pyrazolo[4,3-b]pyridine [ka] NaH (60% in mineral oil, 2.46 g, 61.6 mmol) was slowly added to a solution of 6-bromo-1H-pyrazolo[4,3-b]pyridine (10.16 g, 51.3 mmol) in DMF (70 ml) at 0° C. After stirring at room temperature for 20 minutes, (chloromethanetriyl)tribenzene (15.73 g, 56.4 mmol) was slowly added, and the reaction mixture was stirred at room temperature for 1 hour. Water was then added, and the precipitated product was collected by filtration, washed with water, and air-dried. It was used in the next step without further purification. 25 H 19 BrN3(M+H) + LC-MS calculated for: m / z = 440.1 and 442.1; found 440.0 and 442.0.

[0393] Step 2. 6-Methoxy-1-trityl-1H-pyrazolo[4,3-b]pyridine [ka] 6-Bromo-1-trityl-1H-pyrazolo[4,3-b]pyridine (25.0 g, 56.8 mmol), cesium carbonate (25.9 g, 79 mmol), methanol (6.89 ml, 170 mmol) and t A mixture of BuXPhos Pd G3 (1.52 g, 1.7 mmol) was heated at 80° C. for 1 h. After cooling to room temperature, the reaction mixture was filtered, the solvent was evaporated in vacuo, and the crude material was purified by Biotage Isolera. 26 H 22 NO (M+H) + LCMS calculated for: m / z = 392.2; found: 392.1.

[0394] Step 3. 6-Methoxy-1-trityl-1H-pyrazolo[4,3-b]pyridine 4-oxide [ka] m-CPBA (14.5 g, 64.6 mmol) was slowly added to a solution of 6-methoxy-1-trityl-1H-pyrazolo[4,3-b]pyridine (16.8 g, 43.0 mmol) in DCM (150 ml) at 0 °C. After stirring overnight at room temperature, the reaction was quenched with NaSO solution and 1 M NaOH solution. After stirring for 30 minutes at room temperature, the organic phase was separated and washed three times with 1 M NaOH solution and twice with brine solution. The organic phase was then dried over sodium sulfate, filtered, and the solvent was removed in vacuo. The resulting product was used in the next step without further purification. 26 H 22 N3O2(M+H) + LC-MS calculated for: m / z = 408.2; found 408.2.

[0395] Step 4. 5-Chloro-6-methoxy-1-trityl-1H-pyrazolo[4,3-b]pyridine [ka] A solution of oxalyl chloride (5.36 ml, 61.3 mmol) in DCM was slowly added to a solution of 6-methoxy-1-trityl-1H-pyrazolo[4,3-b]pyridine 4-oxide (16.65 g, 40.9 mmol) and DIPEA (14.27 ml, 82 mmol) in DCM (100 ml) at 0 °C. After stirring at 0 °C for 1 h, the reaction was diluted with DCM and carefully quenched with water. The organic phase was separated, washed three times with water, twice with saturated NaHCO3 solution, twice with brine, and dried over sodium sulfate. After removing the solvent in vacuo, the resulting product was used in the next step without further purification. 26 H 21 ClNO (M+H) + LC-MS calculated for: m / z = 426.1; found 426.2.

[0396] Step 5. 5-Chloro-6-methoxy-1H-pyrazolo[4,3-b]pyridine [ka] TFA (29 ml, 376 mmol) and water (1.35 ml, 75 mmol) were added to a solution of 5-chloro-6-methoxy-1-trityl-1H-pyrazolo[4,3-b]pyridine (16 g, 37.6 mmol) in DCM (75 ml). After stirring at room temperature for 30 minutes, CHCN and water were added, and the DCM was evaporated in vacuo. The precipitated solid was collected by filtration. The reaction mixture was further diluted with water and washed three times with a 1:1 mixture of EtOAc / hexane. The aqueous phase was separated, and all solvent was removed in vacuo. The residue was redissolved in DCM and neutralized with NaHCO3 solution. The organic phase was further washed twice with NaHCO3 solution, brine, and then dried over sodium sulfate. The solvent was evaporated in vacuo. The crude product obtained was used in the next step without further purification. C7H7ClN3O (M+H) + LC-MS calculated for: m / z = 184.0; found 184.1.

[0397] Step 6. tert-Butyl 5-chloro-3-iodo-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate [ka] NIS (6.87 g, 30.6 mmol) was added to a solution of 5-chloro-6-methoxy-1H-pyrazolo[4,3-b]pyridine (5.5 g, 30.0 mmol) in DMF (60 mL). After stirring at 60° C. for 2 hours, the reaction mixture was cooled to room temperature, and triethylamine (6.26 mL, 44.9 mmol) and Boc anhydride (8.17 g, 37.4 mmol) were added. After stirring at room temperature for an additional hour, water was added, and the precipitated product was collected by filtration. The solid product was air-dried and used in the next step without further purification. 12 H 14 ClIN3O3(M+H) + LC-MS calculated for: m / z = 410.0; found 410.1.

[0398] Step 7. tert-Butyl 5-chloro-6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine-1-carboxylate [ka] tert-Butyl 5-chloro-3-iodo-6-methoxy-1H-pyrazolo[4,3-b]pyridine-1-carboxylate (8.73 g, 21.31 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (5.32 g, 25.6 mmol), PdCl(dppf)-CHCl adduct (3.48 g, 4.26 mmol), and potassium phosphate (6.79 g, 32.0 mmol) were placed in a flask, and the flask was evacuated and filled with N three times. 1,4-Dioxane (150 ml) and water (15 ml) were then added, and the reaction was stirred at 80 °C for 1 hour. After cooling to room temperature, water was added, and the desired product was extracted with EtOAc. The organic phase was washed with brine, dried over sodium sulfate, and the solvent was evaporated in vacuo. The crude material was purified by Biotage Isolera. 16 H 19 ClNO3(M+H) + LCMS calculated for: m / z = 364.1; found: 364.0.

[0399] Step 8. 5-(2,3-Dimethylphenyl)-6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine tert-Butyl 5-chloro-6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine-1-carboxylate (8 mg, 0.022 mmol), (2,3-dimethylphenyl)boronic acid (4.95 mg, 0.033 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium (1.7 mg, 2.2 μmol), and potassium phosphate (9.34 mg, 0.044 mmol) were placed in a vial, and the vial was evacuated and backfilled with N2 three times. 1,4-Dioxane (1 mL) and water (100 μL) were added, and the reaction mixture was stirred at 100 °C for 1 hour. The reaction was then filtered, and the solvent was evaporated in vacuo. DCM (1 ml) and TFA (0.5 ml) were added, and the reaction mixture was stirred at room temperature for 30 minutes. It was then diluted with CHCN and water and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% TFA at a flow rate of 60 mL / min). The product was isolated as the TFA salt. 19 H 20 NO (M+H) + LCMS calculated for: m / z = 334.2; found: 334.2. 1 H NMR (500 MHz, DMSO-d6) δ 8.27 (s, 1H), 8.00 (s, 1H), 7.45(s, 1H), 7.25 - 7.20 (m, 1H), 7.19 - 7.14 (t, J = 7.5 Hz, 1H), 7.12 - 7.09 (m, 1H), 3.89 (s, 3H), 3.82 (s, 3H), 2.31 (s, 3H), 1.96 (s, 3H) ppm.

[0400] Example 2. 5-(2,3-Dihydro-1H-inden-4-yl)-6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine [ka] This compound was prepared according to the procedure described in Example 1, except that 2-(2,3-dihydro-1H-inden-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was used instead of (2,3-dimethylphenyl)boronic acid as the starting material. The product was isolated as the TFA salt. 20 H 20 NO (M+H) + LCMS calculated for: m / z = 346.2; found: 346.2. 1 H NMR (500 MHz, DMSO-d6) δ 8.34 - 8.29 (s, 1H), 8.09 - 8.01 (s, 1H), 7.51 - 7.44 (s, 1H), 7.30 - 7.25 (m, 2H), 7.25 - 7.19 (m, 1H), 3.94 - 3.90 (s, 3H), 3.90 - 3.84 (s, 3H), 2.99 - 2.91 (t, J = 7.4 Hz, 2H), 2.85 - 2.75 (t, J = 7.4 Hz, 2H), 2.02 - 1.91 (p, J = 7.4 Hz, 2H) ppm.

[0401] Example 3. 5-(2,3-Dimethylphenyl)-6-methoxy-3-(1-((1-methyl-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine [ka] Step 1. 5-(2,3-dimethylphenyl)-6-methoxy-1-(4-methoxybenzyl)-3-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine [ka] To a solution of 5-(2,3-dimethylphenyl)-3-iodo-6-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine (Example 69, 100 mg, 0.2 mmol) in 1,4-dioxane (3 mL) and water (0.3 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (118 mg, 0.4 mmol), potassium phosphate (128 mg, 0.6 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (1:1) (16 mg, 0.02 mmol). The reaction was purged with N and stirred at 80° C. for 2 hours. It was then cooled to room temperature and diluted with EtOAc. It was then washed successively with water, saturated NaCl solution, and dried over Na2SO4. The organic phase was filtered and concentrated to dryness. The residue was purified by Biotage Isolera to give the desired product. 26 H 26 LC-MS calculated for N5O2 (M+H)+: m / z = 440.2; found 440.2.

[0402] Step 2. 5-(2,3-dimethylphenyl)-6-methoxy-3-(1-((1-methyl-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine To a solution of 5-(2,3-dimethylphenyl)-6-methoxy-1-(4-methoxybenzyl)-3-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine (90 mg, 0.2 mmol) in acetonitrile (3 mL) was added 5-(chloromethyl)-1-methyl-1H-1,2,4-triazole (70 mg, 0.53 mmol) and cesium carbonate (400 mg, 1.23 mmol). The reaction was stirred at 80°C for 12 hours. After that, it was cooled to room temperature and diluted with EtOAc. It was then washed successively with water, saturated NaCl solution, and dried over NaSO. The organic phase was filtered and concentrated to dryness. The residue was dissolved in TFA (1 mL) and heated to 80°C for 1 hour. The reaction mixture was then diluted with MeOH and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% TFA at a flow rate of 60 mL / min). The product was isolated as the TFA salt. 22 H 23 NO (M+H) + LC-MS calculated for: m / z = 415.2; found 415.2. 1 H NMR (600 MHz, DMSO-d6) δ 8.55 - 8.45 (s, 1H), 8.14 - 8.03 (s, 1H), 7.93 - 7.82 (s, 1H), 7.52 - 7.42 (s, 1H), 7.25 - 7.21 (d, J = 7.5 Hz, 1H), 7.19 - 7.14 (t, J = 7.5 Hz, 1H), 7.13 - 7.08 (d, J = 7.5 Hz, 1H), 5.75 - 5.60 (s, 2H), 3.91 - 3.86 (s, 2H), 3.86 - 3.76 (s, 3H), 2.34 - 2.27 (s, 3H), 2.01 - 1.90 (s, 3H) ppm.

[0403] Example 4. 5-(2,3-Dihydrobenzofuran-7-yl)-6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine [ka] This compound was prepared according to the procedure described in Example 1, except that (2,3-dihydrobenzofuran-7-yl)boronic acid was used as the starting material instead of (2,3-dimethylphenyl)boronic acid. The product was isolated as the TFA salt. 19 H 18 NO2(M+H) + LCMS calculated for: m / z = 348.1; found: 348.1. 1 H NMR (500 MHz, DMSO-d6) δ 8.33 - 8.29 (s, 1H), 8.06 - 8.02 (s, 1H), 7.45 - 7.40 (s, 1H), 7.31 - 7.25 (d, J = 5.8 Hz, 1H), 7.21 - 7.16 (d, J = 6.3 Hz, 1H), 6.96 - 6.86 (t, J = 7.5 Hz, 1H), 4.54 - 4.44 (t, J = 8.7 Hz, 2H), 3.94 - 3.90 (s, 3H), 3.87 - 3.82 (s, 3H), 3.29 - 3.20 (t, J = 8.7 Hz, 2H) ppm.

[0404] Intermediate 1. 2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetonitrile [ka] To a mixture of 4,4,5,5,4',4',5',5'-octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl] (1.28 g, 5.1 mmol), potassium acetate (0.57 g, 5.83 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (0.318 g, 0.389 mmol) under nitrogen, a solution of 2-(3-iodo-2-methylphenyl)acetonitrile (1 g, 3.89 mmol) in 1,4-dioxane (30 mL) was added. The reaction mixture was stirred at 100 °C under nitrogen for 3 days. After cooling to room temperature, the mixture was diluted with DCM and filtered. The filtrate was concentrated in vacuo, and the resulting residue was purified by Biotage Isolera to give the desired product.

[0405] Example 5. 2-(3-(6-Methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2-methylphenyl)acetonitrile [ka] This compound was prepared according to the procedure described in Example 1, except that 2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetonitrile (Intermediate 1) was used as the starting material instead of (2,3-dimethylphenyl)boronic acid. The product was isolated as the TFA salt. 20 H 19 NO (M+H) + LCMS calculated for: m / z = 359.2; found: 359.2. 1H NMR (500 MHz, DMSO-d6) δ 8.33 - 8.22 (s, 1H), 8.05 - 7.95 (s, 1H), 7.53 - 7.48 (s, 1H), 7.47 - 7.41 (d, J = 6.8 Hz, 1H), 7.36 - 7.30 (t, J = 7.6 Hz, 1H), 7.30 - 7.25 (d, J = 6.2 Hz, 1H), 4.13 - 4.05 (s, 2H), 3.92 - 3.87 (s, 3H), 3.85 - 3.80 (s, 3H), 2.08 - 2.01 (s, 3H) ppm.

[0406] Intermediate 2,4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-ol [ka] To a mixture of 4,4,5,5,4',4',5',5'-octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl] (626 mg, 2.46 mmol), potassium acetate (322 mg, 3.29 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex (1:1) with dichloromethane (201 mg, 0.246 mmol) under nitrogen was added a solution of 4-bromo-2,3-dihydro-1H-inden-1-ol (350 mg, 1.643 mmol) in 1,4-dioxane (15 mL). The reaction mixture was stirred overnight at 100 °C under nitrogen. After cooling to room temperature, the mixture was diluted with DCM and filtered. The filtrate was concentrated in vacuo, and the resulting residue was purified by Biotage Isolera to give the desired product.

[0407] Example 6. 1-(4-(5-(6-(difluoromethoxy)-5-(2,3-dimethylphenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperazin-1-yl)ethan-1-one [ka] Step 1. 1-Trityl-1H-pyrazolo[4,3-b]pyridin-6-ol [ka] 6-Bromo-1-trityl-1H-pyrazolo[4,3-b]pyridine (Example 1, Step 1, 20 g, 45.4 mmol), KOH (12.74 g, 227 mmol), and a solution of 6-bromo-1-trityl-1H-pyrazolo[4,3-b]pyridine (Example 1, Step 1, 20 g, 45.4 mmol) in 1,4-dioxane (100 mL) and water (100 mL) t A mixture of BuXPhos Pd G3 (0.727 g, 0.908 mmol) was heated at 100 °C for 3 hours. After that, it was cooled to room temperature, diluted with water, and extracted with EtOAc. The combined organic phases were washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated to dryness. The crude material was used in the next step without further purification. 25 H 20 NO (M+H) + LCMS calculated for: m / z = 378.2; found: 378.1.

[0408] Step 2. 6-(Difluoromethoxy)-1-trityl-1H-pyrazolo[4,3-b]pyridine [ka] To a mixture of 1-trityl-1H-pyrazolo[4,3-b]pyridin-6-ol (17 g, 45 mmol) and KOH (12.62 g, 225 mmol) in acetonitrile (100 mL) and water (10 mL) was added diethyl (bromodifluoromethyl)phosphonate (16.02 ml, 90 mmol) at 0° C. After the addition, the reaction was stirred at room temperature overnight. Water was then added, and the product was extracted with EtOAc. The organic phase was washed with brine, dried over sodium sulfate, and the solvent was evaporated in vacuo. The crude material was purified by Biotage Isolera. 26 H 20 F2N3O (M+H) + LCMS calculated for: m / z = 428.2; found: 428.2.

[0409] Step 3. 5-Chloro-6-(difluoromethoxy)-1-trityl-1H-pyrazolo[4,3-b]pyridine [ka] 3-Chlorobenzoperoxoic acid (7.64 g, 33.2 mmol) was slowly added to a solution of 6-(difluoromethoxy)-1-trityl-1H-pyrazolo[4,3-b]pyridine (7.1 g, 16.61 mmol) in DCM (100 mL) at 0 °C. After stirring overnight at room temperature, the reaction was treated with NaSO solution and 1 M NaOH solution. After stirring for 30 min at room temperature, the organic phase was separated and washed three times with 1 M NaOH solution and twice with brine solution. The organic phase was dried over sodium sulfate, filtered, and the solvent was removed in vacuo.

[0410] The resulting product was dissolved in DCM (100 mL). DIEA (7.25 ml, 41.5 mmol) and oxalyl chloride (2.91 ml, 33.2 mmol) were added sequentially to this solution at 0° C. The reaction mixture was allowed to warm to room temperature and stirred at this temperature overnight. The reaction mixture was diluted with DCM and carefully treated with water. The organic phase was separated, washed three times with water, twice with saturated NaHCO3 solution, twice with brine, and dried over sodium sulfate. After removing the solvent in vacuo, the crude material was purified by Biotage Isolera. 26 H 19 ClF2N3O (M+H) + LCMS calculated for: m / z = 462.1; found: 462.1.

[0411] Step 4. 6-(Difluoromethoxy)-5-(2,3-dimethylphenyl)-1H-pyrazolo[4,3-b]pyridine [ka] 5-Chloro-6-(difluoromethoxy)-1-trityl-1H-pyrazolo[4,3-b]pyridine (2.2 g, 4.76 mmol), (2,3-dimethylphenyl)boronic acid (1.072 g, 7.14 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium (0.38 g, 0.47 mmol), and KPO (2.1 g, 9.53 mmol) were placed in a flask, and the flask was evacuated and filled with N three times. After adding 1,4-dioxane (20 mL) and water (2 mL), the reaction mixture was stirred at 100 °C for 1 h. After cooling to room temperature, water was added, and the desired product was extracted with EtOAc. The organic phase was washed with brine, dried over sodium sulfate and the solvent was evaporated in vacuo.

[0412] The crude material was dissolved in TFA (2 mL), DCM (10 mL), and water (2 mL). After stirring at room temperature for 30 minutes, CHCN and water were added, and the DCM was evaporated in vacuo. The precipitated solid was collected by filtration. The reaction mixture was further diluted with water and washed three times with a 1:1 mixture of EtOAc / hexane. The aqueous phase was separated, and all solvents were removed in vacuo. The residue was dissolved in DCM and neutralized with NaHCO3 solution. The organic phase was washed twice with NaHCO3 solution and once with brine, dried over sodium sulfate, and concentrated in vacuo. The crude product obtained was used in the next step without further purification. C 15 H 14 F2N3O (M+H) + LC-MS calculated for: m / z = 290.1; found 290.1.

[0413] Step 5. 6-(Difluoromethoxy)-5-(2,3-dimethylphenyl)-3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine [ka] 1-Iodopyrrolidine-2,5-dione (1.5 g, 6.57 mmol) was added to a solution of 6-(difluoromethoxy)-5-(2,3-dimethylphenyl)-1H-pyrazolo[4,3-b]pyridine (1.9 g, 6.57 mmol) in DMF (25 mL). After stirring at 80 °C for 1 h, the reaction mixture was cooled to room temperature, and CsCO (5.35 g, 16.42 mmol) and 1-(chloromethyl)-4-methoxybenzene (1.714 mL, 13.14 mmol) were added. After further stirring at 80 °C for 1 h, water was added and the desired product was extracted with EtOAc. The organic phase was washed with brine, dried over sodium sulfate, and the solvent was evaporated in vacuo. The crude material was purified by Biotage Isolera. 23 H 21 F2IN3O2(M+H) + LCMS calculated for: m / z = 536.1; found: 536.1.

[0414] Step 6. 1-(4-(5-(6-(difluoromethoxy)-5-(2,3-dimethylphenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperazin-1-yl)ethan-1-one A solution of 6-(difluoromethoxy)-5-(2,3-dimethylphenyl)-3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine (27 mg, 0.050 mmol), 1-(4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazin-1-yl)ethan-1-one (56 mg, 0.17 mmol), Xphos Pd G2 (4 mg, 5 μmol), and potassium phosphate (44 mg, 0.21 mmol) in water (0.100 ml) and dioxane (1 ml) was heated to 80 °C for 2 h. It was then cooled to room temperature, diluted with water, and extracted with EtOAc. The combined organic phase was washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated to dryness. The residue was dissolved in triflic acid (0.5 mL). The mixture was stirred at room temperature for 1 hour, diluted with CH3CN, and purified by preparative LCMS (XBridge C18 column, eluted with a gradient of acetonitrile / water containing 0.1% TFA at a flow rate of 60 mL / min). The product was isolated as the TFA salt. 26 H 27 LCMS calculated for F2N6O2 (M+H)+: m / z = 493.2; found 493.3. 1 H NMR (500 MHz, DMSO-d6) δ 13.47 (s, 1H), 9.16 (d, J = 2.2 Hz, 1H), 8.50 (dd, J = 9.0, 2.4 Hz, 1H), 7.91 (s, 1H), 7.46-7.01 (m, 5H), 3.66 - 3.58 (m, 8H), 2.35 (s, 3H), 2.05 (s, 3H), 2.02 (s, 3H) ppm.

[0415] Examples 7 and 8. 4-(6-Methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-1-ol, two enantiomers [ka] tert-Butyl 5-chloro-6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine-1-carboxylate (35 mg, 0.096 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-ol (32 mg, 0.12 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium (15 mg, 0.02 mmol), and potassium phosphate (30 mg, 0.14 mmol) were placed in a vial, and the vial was evacuated and filled with N three times. After adding 1,4-dioxane (2 ml) and water (200 μl), the reaction mixture was stirred at 100° C. for 1 hour. After cooling to room temperature, the mixture was diluted with DCM and filtered. The filtrate was concentrated in vacuo, and the resulting residue was purified by Biotage Isolera.

[0416] The purified material was redissolved in 1,4-dioxane (2 ml) and water (2 ml). After the addition of cesium carbonate (31.3 mg, 0.096 mmol) and morpholine (0.3 ml), the reaction mixture was heated at 100° C. for 2 h. After cooling to room temperature, the mixture was diluted with DCM, washed with brine, dried over sodium sulfate, and the solvent was evaporated in vacuo.

[0417] The two enantiomers were then separated by chiral preparative HPLC (Phenomenex Lux 5 um Amylose-1, 21.2 x 250 mm, eluting with 25% EtOH in hexane at a flow rate of 20 mL / min, t R,ピーク1 =15.4 min, t R,ピーク2 =17.6 min). After evaporation of the solvent in vacuo, both enantiomers were purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% TFA at a flow rate of 60 mL / min). The product was isolated as the TFA salt.

[0418] Example 7. Peak 1: C 20 H 20NO2(M+H) + LCMS calculated for: m / z = 362.2; found: 362.2. 1 H NMR (500 MHz, DMSO-d6) δ 8.32 - 8.25 (s, 1H), 8.07 - 8.00 (s, 1H), 7.49 - 7.44 (s, 1H), 7.41 - 7.38 (d, J = 7.3 Hz, 1H), 7.38 - 7.35 (d, J = 7.5 Hz, 1H), 7.33 - 7.28 (m, 1H), 5.18 - 5.09 (t, J = 6.7 Hz, 1H), 3.95 - 3.88 (s, 3H), 3.88 - 3.82 (s, 3H), 2.87 - 2.75 (m, 1H), 2.75 - 2.65 (m, 1H), 2.35 - 2.28 (m, 1H), 1.83 - 1.68 (m, 1H) ppm.

[0419] Example 8. Peak 2: C 20 H 20 NO2(M+H) + LCMS calculated for: m / z = 362.2; found: 362.2. 1 H NMR (500 MHz, DMSO-d6) δ 8.33 - 8.28 (s, 1H), 8.06 - 8.02 (s, 1H), 7.49 - 7.45 (s, 1H), 7.42 - 7.38 (d, J = 7.2 Hz, 1H), 7.38 - 7.35 (m, 1H), 7.33 - 7.28 (m, 1H), 5.19 - 5.07 (t, J = 6.7 Hz, 1H), 3.93 - 3.89 (s, 3H), 3.89 - 3.85 (s, 3H), 2.86 - 2.75 (m, 1H), 2.75 - 2.66 (m, 1H), 2.36 - 2.22 (m, 1H), 1.82 - 1.67 (m, 1H) ppm.

[0420] Example 9. 4-(6-Methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile [ka] Methanesulfonyl chloride (5 mg, 0.04 mmol) was added to a solution of triethylamine (6.04 μL, 0.043 mmol) and tert-butyl 5-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)-6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine-1-carboxylate (intermediate from Example 8, 10 mg, 0.022 mmol) in DCM (1 mL). After stirring at room temperature for 30 minutes, the reaction mixture was filtered through a silica gel pad, the filter was washed with DCM and methanol, the organic fractions were combined, and the solvent was evaporated in vacuo. The resulting residue was dissolved in DMF (1 mL), and potassium cyanide (2.82 mg, 0.043 mmol) and 18-crown-6 (11 mg, 0.043 mmol) were added. The reaction mixture was stirred at 80°C for 2 hours, after which water was added and the desired product was extracted with DCM. The organic phase was washed with brine and the solvent was evaporated in vacuo. The resulting material was dissolved in DCM (1 ml) and TFA (0.5 ml), and the reaction mixture was stirred at room temperature for 30 minutes. It was then diluted with CHCN and water and purified by preparative LCMS (XBridge C18 column, eluted with a gradient of acetonitrile / water containing 0.1% TFA at a flow rate of 60 mL / min). The product was isolated as the TFA salt. 21 H 19 NO (M+H) + LCMS calculated for: m / z = 371.2; found: 371.2.

[0421] Intermediate 3. 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-ol [ka] This compound was prepared according to the procedure described in Intermediate 2, using 4-bromo-2,3-dihydro-1H-inden-2-ol instead of 4-bromo-2,3-dihydro-1H-inden-1-ol as the starting material.

[0422] Example 10. 4-(6-Methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-2-ol [ka] tert-Butyl 5-chloro-6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine-1-carboxylate (35 mg, 0.096 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-ol (32 mg, 0.12 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium (15 mg, 0.02 mmol), and potassium phosphate (30 mg, 0.14 mmol) were placed in a vial, and the vial was evacuated and filled with N three times. After adding 1,4-dioxane (2 ml) and water (200 μl), the reaction mixture was stirred at 100° C. for 1 hour. After cooling to room temperature, the mixture was diluted with DCM and filtered. The filtrate was concentrated in vacuo, and the resulting residue was purified by Biotage Isolera.

[0423] The two enantiomers were separated by chiral preparative HPLC (Phenomenex LUX Cellulose-1 5µm 21.2 x 250mm, eluted with 20% IPA (containing 2mM NH3) in hexane at a flow rate of 65mL / min, t R,ピーク1 =6.5 minutes, t R,ピーク2=7.5 min). Peak 2 was collected and the solvent was evaporated in vacuo. The resulting material was redissolved in 1,4-dioxane (2 ml) and water (2 ml). After the addition of cesium carbonate (31.3 mg, 0.096 mmol) and morpholine (0.3 ml), the reaction mixture was heated at 100° C. for 2 h. After cooling to room temperature, the mixture was diluted with CH3CN and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% TFA at a flow rate of 60 mL / min). The product was isolated as the TFA salt. C 20 H 20 NO2(M+H) + LCMS calculated for: m / z = 362.2; found: 362.2. 1 H NMR (500 MHz, DMSO-d6) δ 8.35 - 8.29 (s, 1H), 8.08 - 8.03 (s, 1H), 7.48 - 7.45 (s, 1H), 7.34 - 7.28 (d, J = 7.2 Hz, 1H), 7.29 - 7.25 (m, 1H), 7.25 - 7.20 (m, 1H), 4.52 - 4.45 (m, 1H), 3.94 - 3.90 (s, 3H), 3.89 - 3.84 (s, 3H), 3.21 - 3.11 (dd, J = 16.0, 6.0 Hz, 1H), 3.09 - 3.00 (dd, J = 16.4, 5.9 Hz, 1H), 2.88 - 2.78 (dd, J = 16.0, 3.6 Hz, 1H), 2.71 - 2.64 (dd, J = 16.4, 3.6 Hz, 1H) ppm.

[0424] Intermediate 4. (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)methanol [ka] Step 1. (4-Bromo-2,3-dihydro-1H-inden-1-yl)methanol [ka] A 1 M THF solution of LiHMDS (29.6 ml, 29.6 mmol) was slowly added to a suspension of (methoxymethyl)triphenylphosphonium chloride (10.15 g, 29.6 mmol) in THF (150 ml) at 0 °C. After stirring this solution at 0 °C for 1 h, a solution of 4-bromo-2,3-dihydro-1H-inden-1-one (5.0 g, 23.7 mmol) in THF (20 ml) was slowly added, and the reaction mixture was stirred at room temperature for 2 h. The reaction was then quenched with water, and the product was extracted with EtOAc. The combined organic phases were washed with brine, dried over anhydrous NaSO, and concentrated. The crude product was purified by Biotage Isolera.

[0425] A 1 M solution of BBr3 in DCM (21.2 ml, 21.2 mmol) was added to a solution of the purified material in DCM (50 ml) at -78 °C. After stirring at that temperature for 1 h, the reaction was quenched with water and the product was extracted with DCM. The organic phase was dried over sodium sulfate and the solvent was evaporated in vacuo. The crude product was purified by Biotage Isolera.

[0426] NaBH4 (0.630 g, 16.7 mmol) was added to a solution of the above material obtained in a mixture of THF (15 mL) and MeOH (15 mL). The reaction mixture was stirred at room temperature for 1 hour, and then water was added. The desired product was extracted with EtOAc, and the organic phase was washed with brine, dried over sodium sulfate, and the solvent was evaporated in vacuo. The crude product obtained was used in the next step without further purification.

[0427] Step 2. (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)methanol This compound was prepared according to the procedure described in Intermediate 2, using (4-bromo-2,3-dihydro-1H-inden-1-yl)methanol instead of (4-bromo-2,3-dihydro-1H-inden-1-ol) as the starting material.

[0428] Examples 11 and 12. (4-(6-Methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-1-yl)methanol, two enantiomers [ka] These compounds were prepared according to the procedure described in Example 7, using (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)methanol (Intermediate 4) instead of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-ol as the starting material.

[0429] The two enantiomers were separated by chiral preparative HPLC (Phenomenex Lux 5um Amylose-1, 21.2 x 250 mm, eluting with 60% EtOH in hexane at a flow rate of 20 mL / min, t R,ピーク1 =4.2 min, t R,ピーク2 =7.6 min). After evaporation of the solvent in vacuo, both enantiomers were purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% TFA at a flow rate of 60 mL / min). The product was isolated as the TFA salt.

[0430] Example 11. Peak 1: C 21 H 22 NO2(M+H) + LCMS calculated for: m / z = 376.2; found: 376.2. 11H NMR (500 MHz, DMSO-d6) δ 8.34 - 8.28 (s, 1H), 8.07 - 8.00 (s, 1H), 7.49 - 7.45 (s, 1H), 7.36 - 7.34 (d, J = 7.4 Hz, 1H), 7.31 - 7.28 (d, J = 7.5 Hz, 1H), 7.27 - 7.20 (t, J = 7.5 Hz, 1H), 3.95 - 3.89 (s, 3H), 3.89 - 3.84 (s, 3H), 3.74 - 3.66 (dd, J = 10.4, 5.8 Hz, 1H), 3.58 - 3.51 (dd, J = 10.4, 7.3 Hz, 1H), 3.34 - 3.20 (p, J = 6.9 Hz, 1H), 2.83 - 2.74 (t, J = 7.5 Hz, 2H), 2.23 - 2.06 (dq, J = 14.6, 7.3 Hz, 1H), 1.87 - 1.71 (dq, J = 14.4, 7.6 Hz, 1H) ppm.

[0431] Example 12. Peak 2: C 21 H 22 N5O2(M+H)[[ID=⑨]]<①⑥⑥⑥⑥⑥⑦> Calculated LCMS value for: m / z = 376.2; Observed value: 376.2. 1 It should be noted that there is an incorrect tag in the original text which is + and it is translated as <①⑥⑥⑥⑥⑥⑦> here as it seems to be an incorrect tag in the original. You may want to double-check the original text for accuracy.H NMR (500 MHz, DMSO-d6) δ 8.34 - 8.29 (s, 1H), 8.09 - 8.01 (s, 1H), 7.48 - 7.44 (s, 1H), 7.37 - 7.34 (d, J = 7.3 Hz, 1H), 7.32 - 7.27 (d, J = 7.4 Hz, 1H), 7.25 - 7.20 (t, J = 7.5 Hz, 1H), 3.94 - 3.87 (s, 3H), 3.88 - 3.83 (s, 3H), 3.74 - 3.67 (dd, J = 10.4, 5.8 Hz, 1H), 3.58 - 3.50 (dd, J = 10.4, 7.3 Hz, 1H), 3.35 - 3.23 (p, J = 6.8 Hz, 1H), 2.86 - 2.68 (t, J = 7.4 Hz, 2H), 2.19 - 2.05 (dq, J = 1...

Claims

1. Formula (I): 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, wherein: Cy １ is selected from phenyl and 5- to 6-membered heteroaryl, wherein each 5- to 6-membered heteroaryl has at least one ring-forming carbon atom and 1, 2, or 3 ring-forming heteroatoms independently selected from N, O, and S, wherein said N and S are optionally oxidized, and wherein a ring-forming carbon atom of the 5- to 6-membered heteroaryl is optionally substituted by oxo to form a carbonyl group, and wherein said phenyl and said 5- to 6-membered heteroaryl are each selected from R １０ and optionally substituted with 1, 2, 3 or 4 substituents independently selected from R １ But, Halo, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Haloalkyl, C ３～６ Cycloalkyl, 4- to 5-membered heterocycloalkyl, C １～６ Alkoxy, C １～６ Haloalkoxy, C １～３ Alkoxy-C １～３ Alkyl, C １～３ Alkoxy-C １～３ Alkoxy, HO-C １～３ Alkoxy, HO-C １～３ Alkyl, cyano-C １～３ Alkyl, H ２ N-C １～３ Alkyl, C １～６ Alkylamino, di(C １～６ alkyl)amino, C １～６ Alkylthio, C １～６ Alkylsulfonyl, C １～６ Alkylcarbonyl, and C １～６ alkoxycarbonyl, wherein optionally said C １～６ Alkyl, the C ２～６ Alkenyl, the above C ２～６ Alkynyl, the above C １～６ Haloalkyl, the C ３～６ cycloalkyl, the 4- to 5-membered heterocycloalkyl, the C １～６ Alkoxy, the above C １～６ Haloalkoxy, the above C １～３ Alkoxy-C １～３ Alkyl, the C １～３ Alkoxy-C １～３ Alkoxy, the HO-C １～３ Alkoxy, the HO-C １～３ Alkyl, the cyano-C １～３ Alkyl, the above H ２ N-C １～３ Alkyl, the C １～６ Alkylamino, the di(C １～６ alkyl)amino, １～６ Alkylthio, the above C １～６ Alkylsulfonyl, the above C １～６ Alkylcarbonyl, and the C １～６ one or more H atoms of the alkoxycarbonyl are replaced by one or more D atoms; Each R ２ and R ３ But, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Haloalkyl, C ３～１０ Cycloalkyl, 4-10 membered heterocycloalkyl, C ６～１０ Aryl, 5-10 membered heteroaryl, C ３～１０ Cycloalkyl-C １～３ Alkylene, 4- to 10-membered heterocycloalkyl-C １～３ Alkylene, C ６～１０ Aryl-C １～３ Alkylene, 5-10 membered heteroaryl-C １～３ Alkylene, halo, CN, NO ２ , OR ａ２ , S.R. ａ２ , C(O)R ｂ２ , C(O)NR ｃ２ R ｄ２ , C(O)OR ａ２ , O.C.(O)R ｂ２ , O.C.(O)NR ｃ２ R ｄ２ , N.R. ｃ２ R ｄ２ , N.R. ｃ２ C(O)R ｂ２ , N.R. ｃ２ C(O)OR ａ２ , N.R. ｃ２ C(O)NR ｃ２ R ｄ２ , C(=NR ｅ２ ) R ｂ２ , C(=NOR ａ２ ) R ｂ２ , C(=NR ｅ２ ) N.R. ｃ２ R ｄ２ , N.R. ｃ２ C (=NR ｅ２ ) N.R. ｃ２ R ｄ２ , N.R. ｃ２ S(O)R ｂ２ , N.R. ｃ２ S (O) ２ R ｂ２ , N.R. ｃ２ S (O) ２ N.R. ｃ２ R ｄ２ , S(O)R ｂ２ , S(O)NR ｃ２ R ｄ２ , S(O) ２ R ｂ２ , and S(O) ２ N.R. ｃ２ R ｄ２ wherein C is independently selected from １～６ Alkyl, the C ２～６ Alkenyl, the above C ２～６ Alkynyl, the above C ３～１０ cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C ６～１０ aryl, the 5- to 10-membered heteroaryl, the C ３～１０ Cycloalkyl-C １～３ alkylene, the 4- to 10-membered heterocycloalkyl-C １～３ Alkylene, ６～１０ Aryl-C １～３ Alkylene and the 5- to 10-membered heteroaryl-C １～３ Each alkylene is R ２１ or optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or two adjacent R on a phenyl ring ２ Substituents, together with the atoms to which they are attached, form a fused 5- or 6-membered cycloalkyl ring, or a fused 5- or 6-membered heterocycloalkyl ring, wherein each fused 5- or 6-membered heterocycloalkyl ring has at least one ring-forming carbon atom and 1 or 2 ring-forming heteroatoms independently selected from N, O, and S, and wherein a ring-forming carbon atom of each fused 5- or 6-membered heterocycloalkyl ring is optionally substituted by oxo to form a carbonyl group, and wherein said fused 5- or 6-membered cycloalkyl ring, and said fused 5- or 6-membered heterocycloalkyl ring are each independently selected from R ２１ and optionally substituted with 1, 2, 3 or 4 substituents independently selected from n is selected from 0, 1, 2, and 3; Each R １０ But, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Haloalkyl, C ３～１０ Cycloalkyl, 4- to 12-membered heterocycloalkyl, C ６～１０ Aryl, 5-10 membered heteroaryl, C ３～１０ Cycloalkyl-C １～３ Alkylene, 4- to 12-membered heterocycloalkyl-C １～３ Alkylene, C ６～１０ Aryl-C １～３ Alkylene, 5-10 membered heteroaryl-C １～３ Alkylene, halo, D, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O)R ｂ１ , O.C.(O)NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , N.R. ｃ１ C(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ ) R ｂ１ , C(=NOR ａ１ ) R ｂ１ , C(=NR ｅ１ ) N.R. ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ ) N.R. ｃ１ R ｄ１ , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S (O) ２ R ｂ１ , N.R. ｃ１ S (O) ２ N.R. ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ , and S(O) ２ N.R. ｃ１ R ｄ１ wherein C is independently selected from １～６ Alkyl, the C ２～６ Alkenyl, the above C ２～６ Alkynyl, the above C ３～１０ cycloalkyl, the 4- to 12-membered heterocycloalkyl, the C ６～１０ aryl, the 5- to 10-membered heteroaryl, the C ３～１０ Cycloalkyl-C １～３ alkylene, the 4- to 12-membered heterocycloalkyl-C １～３ Alkylene, ６～１０ Aryl-C １～３ Alkylene and the 5- to 10-membered heteroaryl-C １～３ Each alkylene is R １１ and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R １１ But, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Haloalkyl, C ３～１０ Cycloalkyl, 4-10 membered heterocycloalkyl, C ６～１０ Aryl, 5-10 membered heteroaryl, C ３～１０ Cycloalkyl-C １～３ Alkylene, 4- to 10-membered heterocycloalkyl-C １～３ Alkylene, C ６～１０ Aryl-C １～３ Alkylene, 5-10 membered heteroaryl-C １～３ Alkylene, halo, D, CN, OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)OR ａ３ , N.R. ｃ３ S(O)R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ N.R. ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , and S(O) ２ N.R. ｃ３ R ｄ３ wherein C is independently selected from １～６ Alkyl, the C ２～６ Alkenyl, the above C ２～６ Alkynyl, the above C ３～１０ cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C ６～１０ aryl, the 5- to 10-membered heteroaryl, the C ３～１０ Cycloalkyl-C １～３ alkylene, the 4- to 10-membered heterocycloalkyl-C １～３ Alkylene, ６～１０ Aryl-C １～３ Alkylene and the 5- to 10-membered heteroaryl-C １～３ Each alkylene is R １２ and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R １２ But, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Haloalkyl, C ３～６ Cycloalkyl, C ６～１０ Aryl, 5-10 membered heteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR ａ５ , S.R. ａ５ , C(O)R ｂ５ , C(O)NR ｃ５ R ｄ５ , C(O)OR ａ５ , N.R. ｃ５ R ｄ５ , N.R. ｃ５ C(O)R ｂ５ , N.R. ｃ５ C(O)OR ａ５ , N.R. ｃ５ S(O)R ｂ５ , N.R. ｃ５ S (O) ２ R ｂ５ , N.R. ｃ５ S (O) ２ N.R. ｃ５ R ｄ５ , S(O)R ｂ５ , S(O)NR ｃ５ R ｄ５ , S(O) ２ R ｂ５ , and S(O) ２ N.R. ｃ５ R ｄ５ wherein C is independently selected from １～６ Alkyl, the C ２～６ Alkenyl, the above C ２～６ Alkynyl, the above C ３～６ Cycloalkyl, the C ６～１０ The aryl, the 5- to 10-membered heteroaryl and the 4- to 7-membered heterocycloalkyl are each R ｇ and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ２１ But, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Haloalkyl, C ３～１０ Cycloalkyl, 4-10 membered heterocycloalkyl, C ６～１０ Aryl, 5-10 membered heteroaryl, C ３～１０ Cycloalkyl-C １～３ Alkylene, 4- to 10-membered heterocycloalkyl-C １～３ Alkylene, C ６～１０ Aryl-C １～３ Alkylene, 5-10 membered heteroaryl-C １～３ Alkylene, halo, D, CN, OR ａ４ , S.R. ａ４ , C(O)R ｂ４ , C(O)NR ｃ４ R ｄ４ , C(O)OR ａ４ , N.R. ｃ４ R ｄ４ , N.R. ｃ４ C(O)R ｂ４ , N.R. ｃ４ C(O)OR ａ４ , N.R. ｃ４ S(O)R ｂ４ , N.R. ｃ４ S (O) ２ R ｂ４ , N.R. ｃ４ S (O) ２ N.R. ｃ４ R ｄ４ , S(O)R ｂ４ , S(O)NR ｃ４ R ｄ４ , S(O) ２ R ｂ４ , and S(O) ２ N.R. ｃ４ R ｄ４ wherein C is independently selected from １～６ Alkyl, the C ２～６ Alkenyl, the above C ２～６ Alkynyl, the above C ３～１０ cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C ６～１０ aryl, the 5- to 10-membered heteroaryl, the C ３～１０ Cycloalkyl-C １～３ alkylene, the 4- to 10-membered heterocycloalkyl-C １～３ Alkylene, ６～１０ Aryl-C １～３ Alkylene and the 5- to 10-membered heteroaryl-C １～３ Each alkylene is R ２２ and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ２２ But, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Haloalkyl, C ３～６ Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, halo, D, CN, OR ａ６ , S.R. ａ６ , C(O)R ｂ６ , C(O)NR ｃ６ R ｄ６ , C(O)OR ａ６ , N.R. ｃ６ R ｄ６ , N.R. ｃ６ C(O)R ｂ６ , N.R. ｃ６ C(O)OR ａ６ , N.R. ｃ６ S(O)R ｂ６ , N.R. ｃ６ S (O) ２ R ｂ６ , N.R. ｃ６ S (O) ２ N.R. ｃ６ R ｄ６ , S(O)R ｂ６ , S(O)NR ｃ６ R ｄ６ , S(O) ２ R ｂ６ , and S(O) ２ N.R. ｃ６ R ｄ６ wherein C is independently selected from １～６ Alkyl, the C ２～６ Alkenyl, the above C ２～６ Alkynyl, the above C ３～６ cycloalkyl, said phenyl, said 5- to 6-membered heteroaryl and said 4- to 7-membered heterocycloalkyl are each R ｇ and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ａ１ , R ｃ１ and R ｄ１ But, H, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Haloalkyl, C ３～１０ Cycloalkyl, 4-10 membered heterocycloalkyl, C ６～１０ aryl and 5- to 10-membered heteroaryl, １～６ Alkyl, the C ２～６ Alkenyl, the above C ２～６ Alkynyl, the above C ３～１０ cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C ６～１０ The aryl and the 5- to 10-membered heteroaryl are each R １１ or optionally substituted with 1, 2, 3, or 4 substituents independently selected from or any R bonded to the same N atom ｃ１ and R ｄ１ together with the N atom to which they are attached, R １１ forming a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ｂ１ But, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Haloalkyl, C ３～１０ Cycloalkyl, 4-10 membered heterocycloalkyl, C ６～１０ aryl and 5- to 10-membered heteroaryl, １～６ Alkyl, the C ２～６ Alkenyl, the above C ２～６ Alkynyl, the above C ３～１０ cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C ６～１０ The aryl and the 5- to 10-membered heteroaryl are each R １１ and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ｅ１ But H, CN, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkylthio, C １～６ Alkylsulfonyl, C １～６ Alkylcarbonyl, C １～６ Alkylaminosulfonyl, carbamyl, C １～６ Alkylcarbamyl, di(C １～６ Alkyl) carbamyl, aminosulfonyl, C １～６ Alkylaminosulfonyl and di(C １～６ alkyl)aminosulfonyl; Each R ａ２ , R ｃ２ and R ｄ２ But, H, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Haloalkyl, C ３～１０ Cycloalkyl, 4-10 membered heterocycloalkyl, C ６～１０ aryl and 5- to 10-membered heteroaryl, １～６ Alkyl, the C ２～６ Alkenyl, the above C ２～６ Alkynyl, the above C ３～１０ cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C ６～１０ The aryl and the 5- to 10-membered heteroaryl are each R ２１ or optionally substituted with 1, 2, 3, or 4 substituents independently selected from or any R bonded to the same N atom ｃ２ and R ｄ２ together with the N atom to which they are attached, R ２１ forming a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 substituents independently selected from Each R ｂ２ But, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Haloalkyl, C ３～１０ Cycloalkyl, 4-10 membered heterocycloalkyl, C ６～１０ aryl and 5- to 10-membered heteroaryl, １～６ Alkyl, the C ２～６ Alkenyl, the above C ２～６ Alkynyl, the above C ３～１０ cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C ６～１０ The aryl and the 5- to 10-membered heteroaryl are each R ２１ and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ｅ２ But H, CN, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkylthio, C １～６ Alkylsulfonyl, C １～６ Alkylcarbonyl, C １～６ Alkylaminosulfonyl, carbamyl, C １～６ Alkylcarbamyl, di(C １～６ Alkyl) carbamyl, aminosulfonyl, C １～６ Alkylaminosulfonyl and di(C １～６ alkyl)aminosulfonyl; Each R ａ３ , R ｃ３ and R ｄ３ But, H, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Haloalkyl, C ３～６ cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl, wherein said C １～６ Alkyl, the C ２～６ Alkenyl, the above C ２～６ Alkynyl, the above C ３～６ cycloalkyl, said phenyl, said 5- to 6-membered heteroaryl and said 4- to 7-membered heterocycloalkyl are each R １２ or optionally substituted with 1, 2, 3, or 4 substituents independently selected from or any R bonded to the same N atom ｃ３ and R ｄ３ together with the N atom to which they are attached, R １２ forming a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 substituents independently selected from Each R ｂ３ But, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Haloalkyl, C ３～６ cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl, wherein said C １～６ Alkyl, the C ２～６ Alkenyl, the above C ２～６ Alkynyl, the above C ３～６ cycloalkyl, said phenyl, said 5- to 6-membered heteroaryl and said 4- to 7-membered heterocycloalkyl are each R １２ and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ａ４ , R ｃ４ and R ｄ４ But, H, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Haloalkyl, C ３～６ cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl, wherein said C １～６ Alkyl, the C ２～６ Alkenyl, the above C ２～６ Alkynyl, the above C ３～６ cycloalkyl, said phenyl, said 5- to 6-membered heteroaryl and said 4- to 7-membered heterocycloalkyl are each R ２２ or optionally substituted with 1, 2, 3, or 4 substituents independently selected from or any R bonded to the same N atom ｃ４ and R ｄ４ together with the N atom to which they are attached, R ２２ forming a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 substituents independently selected from Each R ｂ４ But, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Haloalkyl, C ３～６ cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl, wherein said C １～６ Alkyl, the C ２～６ Alkenyl, the above C ２～６ Alkynyl, the above C ３～６ cycloalkyl, said phenyl, said 5- to 6-membered heteroaryl and said 4- to 7-membered heterocycloalkyl are each R ２２ and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ａ５ , R ｃ５ and R ｄ５ But, H, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl and C １～６ haloalkyl, wherein said C １～６ Alkyl, the C ２～６ Alkenyl and the C ２～６ Each alkynyl is R ｇ and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ｂ５ But, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl and C １～６ haloalkyl, wherein said C １～６ Alkyl, the C ２～６ Alkenyl and the C ２～６ Each alkynyl is R ｇ and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ａ６ , R ｃ６ and R ｄ６ But, H, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl and C １～６ haloalkyl, wherein said C １～６ Alkyl, the C ２～６ Alkenyl and the C ２～６ Each alkynyl is R ｇ and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ｂ６ But, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, and C １～６ haloalkyl, wherein said C １～６ Alkyl, the C ２～６ Alkenyl and the C ２～６ Each alkynyl is R ｇ and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ｇ But, OH, NO ２ , C.N., Halo, C. １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Haloalkyl, C ３～６ Cycloalkyl, C ３～６ Cycloalkyl-C １～２ Alkylene, C １～６ Alkoxy, C １～６ Haloalkoxy, C １～３ Alkoxy-C １～３ Alkyl, C １～３ Alkoxy-C １～３ Alkoxy, HO-C １～３ Alkoxy, HO-C １～３ Alkyl, cyano-C １～３ Alkyl, H ２ N-C １～３ Alkyl, Amino, C １～６ Alkylamino, di(C １～６ Alkyl)amino, thio, C １～６ Alkylthio, C １～６ Alkylsulfinyl, C １～６ Alkyl sulfonyl, carbamyl, C １～６ Alkylcarbamyl, di(C １～６ Alkyl) carbamyl, carboxy, C １～６ Alkylcarbonyl, C １～６ Alkoxycarbonyl, C １～６ Alkylcarbonylamino, C １～６ Alkyl sulfonylamino, aminosulfonyl, C １～６ Alkylaminosulfonyl, di(C １～６ alkyl)aminosulfonyl, aminosulfonylamino, C １～６ Alkylaminosulfonylamino, di(C １～６ alkyl)aminosulfonylamino, aminocarbonylamino, C １～６ Alkylaminocarbonylamino, and di(C １～６ or a pharma- ceutically acceptable salt thereof, wherein the compound is independently selected from:

2. Cy １ is selected from phenyl, pyridinyl, and pyrazolyl, wherein said phenyl, said pyridinyl, and said pyrazolyl are each selected from R １０ 10. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, optionally substituted with one, two, three or four substituents independently selected from:

3. Cy １ is selected from phenyl, pyridin-3-yl, and pyrazol-4-yl, wherein said phenyl, said pyridin-3-yl, and said pyrazol-4-yl are each selected from R １０ 10. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, optionally substituted with one substituent selected from:

4. Cy １ But, R １０ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, which is a 5-6 membered heteroaryl optionally substituted with one or two substituents selected from:

5. Cy １ is selected from pyrazol-4-yl and pyridin-3-yl, wherein said pyrazol-4-yl and said pyridin-3-yl are each selected from R １０ 10. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, optionally substituted with one or two substituents selected from:

6. R １ But, Halo, C １～６ Alkyl, C １～６ Haloalkyl, C ３～５ Cycloalkyl, 4- to 5-membered heterocycloalkyl, C １～６ Alkoxy, C １～６ Haloalkoxy, C １～３ Alkoxy-C １～３ Alkyl, HO-C １～３ Alkyl, C １～６ Alkylamino and di(C １～６ (alkyl)amino, wherein optionally said C １～６ Alkyl, the C １～６ Haloalkyl, the C ３～５ cycloalkyl, the 4- to 5-membered heterocycloalkyl, the C １～６ Alkoxy, the above C １～６ Haloalkoxy, the above C １～３ Alkoxy-C １～３ Alkyl, the HO-C １～３ Alkyl, the C １～６ Alkylamino, and the di(C １～６ 6. The compound according to any one of claims 1 to 5, wherein one or more H atoms of the (alkyl)amino are replaced by one or more D atoms, or a pharma- ceutically acceptable salt thereof.

7. R １ But Cl, C １～２ Alkyl, C １～２ Haloalkyl, hydroxymethyl, C １～２ Alkoxy, C １～２ Haloalkoxy and C １～２ alkylamino, wherein optionally said C １～２ Alkyl, the C １～２ haloalkyl, hydroxymethyl, １～２ Alkoxy, the above C １～２ Haloalkoxy and the above C １～２ 6. The compound according to any one of claims 1 to 5, wherein one or more H atoms of the alkylamino are replaced by one or more D atoms, or a pharma- ceutically acceptable salt thereof.

8. R １ is Cl, CH ３ , O.C.H. ３ , O.C.D. ３ , O.C.H. ２ CH ３ , O.C.H.F. ２ , N.H.H. ３ , C.H.F. ２ , and C.H. ２ 6. The compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof, wherein: R is selected from the group consisting of: OH.

9. R １ OCH ３ 6. The compound according to any one of claims 1 to 5, which is: or a pharma- ceutically acceptable salt thereof.

10. Each R ２ But, C １～６ Alkyl, C ３～６ Cycloalkyl, halo, and OR ａ２ wherein C is independently selected from １～６ Alkyl and the C ３～６ Each cycloalkyl is R ２１ 10. The compound of any one of claims 1 to 9, or a pharma- ceutically acceptable salt thereof, optionally substituted with one, two, three, or four substituents independently selected from:

11. Two adjacent R ２ Substituents taken together with the atoms to which they are attached form a fused 5-membered cycloalkyl ring, or a fused 5- or 6-membered heterocycloalkyl ring, where each fused 5- or 6-membered heterocycloalkyl ring has at least one ring-forming carbon atom and 1 or 2 ring-forming O atoms, and where said fused 5-membered cycloalkyl ring, and said fused 5- or 6-membered heterocycloalkyl ring each have R ２１ 10. The compound of any one of claims 1 to 9, or a pharma- ceutically acceptable salt thereof, optionally substituted with one or two substituents independently selected from:

12. Each R ２ But, C １～３ Alkyl, C １～３ Haloalkyl, C ３～６ Cycloalkyl, F, Cl, CN, and OR ａ２ wherein C is independently selected from １～３ Alkyl, and the C ３～６ Each cycloalkyl is R ２１ 10. The compound of any one of claims 1 to 9, or a pharma- ceutically acceptable salt thereof, optionally substituted with one, two or three substituents independently selected from:

13. Each R ２ F, methyl, CH ２ C.N., C.D. ３ , O.H., O.C.H. ３ 10. The compound of any one of claims 1 to 9, or a pharma- ceutically acceptable salt thereof, wherein R is independently selected from:

14. The R ２ The substituents, together with the atoms to which they are attached, form a fused cyclopentyl group, a fused tetrahydrofuranyl group, a fused 1,4-dioxanyl group, or a fused tetrahydropyranyl group, each of which is selected from the group consisting of R ２１ 10. The compound of any one of claims 1 to 9, or a pharma- ceutically acceptable salt thereof, optionally substituted with one or two substituents selected from:

15. The R ２ Substituents, together with the atoms to which they are attached, are D, OH, CN, CH ２ 10. The compound according to any one of claims 1 to 9, which forms a fused cyclopentyl group optionally substituted with one or two substituents independently selected from OH, and F, or a pharma- ceutically acceptable salt thereof.

16. The R ２ Substituents, together with the atoms to which they are attached, form a fused cyclopentyl or fused cyclohexyl group, wherein said fused cyclopentyl and said fused cyclohexyl groups have at least one ring-forming carbon atom and each optionally has one or two ring-forming O atoms, and wherein said fused cyclopentyl and said fused cyclohexyl groups are each selected from the group consisting of D, OH, CN, CH ２ 10. The compound of any one of claims 1 to 9, optionally substituted with one or two substituents independently selected from OH and F, or a pharma- ceutically acceptable salt thereof.

17. The R ２ 10. The compound of any one of claims 1 to 9, wherein the substituents, together with the atom to which they are attached, form a fused cyclopentyl group, or a pharma- ceutically acceptable salt thereof.

18. 18. The compound according to any one of claims 1 to 17, or a pharma- ceutically acceptable salt thereof, wherein n is selected from 0 and 1.

19. The compound according to any one of claims 1 to 17, wherein n is 0, or a pharma- ceutically acceptable salt thereof.

20. Each R １０ But, C １～６ Alkyl, C １～６ Haloalkyl, C ３～１０ Cycloalkyl, 4- to 12-membered heterocycloalkyl, C ６～１０ Aryl, 5-10 membered heteroaryl, C ３～１０ Cycloalkyl-C １～３ Alkylene, 4- to 12-membered heterocycloalkyl-C １～３ Alkylene, C ６～１０ Aryl-C １～３ Alkylene, 5-10 membered heteroaryl-C １～３ Alkylene, halo, D, CN, OR ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , and S(O) ２ R ｂ１ wherein C is independently selected from １～６ Alkyl, the C ３～１０ cycloalkyl, the 4- to 12-membered heterocycloalkyl, the C ６～１０ aryl, the 5- to 10-membered heteroaryl, the C ３～１０ Cycloalkyl-C １～３ alkylene, the 4- to 12-membered heterocycloalkyl-C １～３ Alkylene, ６～１０ Aryl-C １～３ Alkylene and the 5- to 10-membered heteroaryl-C １～３ Each alkylene is R １１ 20. The compound of any one of claims 1 to 19, or a pharma- ceutically acceptable salt thereof, optionally substituted with one, two, three, or four substituents independently selected from:

21. R １０ But, C １～３ Alkyl, C １～３ Haloalkyl, C ３～６ Cycloalkyl, 4- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl-C １～２ Alkylene, 5-6 membered heteroaryl-C １～２ Alkylene, halo, D, CN, C(O)NR ｃ１ R ｄ１ , and N.R. ｃ１ R ｄ１ wherein C is independently selected from １～３ Alkyl, the C ３～６ cycloalkyl, the 4- to 6-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the 4- to 6-membered heterocycloalkyl-C １～２ alkylene, and the 5- to 6-membered heteroaryl-C １～２ Each alkylene is R １１ 20. The compound of any one of claims 1 to 19, or a pharma- ceutically acceptable salt thereof, optionally substituted with one or two substituents independently selected from:

22. Each R １０ But, C １～３ Alkyl, C １～３ Haloalkyl, C ３～６ Cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl-C １～２ Alkylene, 5-6 membered heteroaryl-C １～２ Alkylene, halo, D, CN, OR ａ１ , C(O)NR ｃ１ R ｄ１ , and N.R. ｃ１ R ｄ１ wherein C is independently selected from １～３ Alkyl, the C ３～６ cycloalkyl, the 4- to 10-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the 4- to 6-membered heterocycloalkyl-C １～２ alkylene, and the 5- to 6-membered heteroaryl-C １～２ Each alkylene is R １１ 20. The compound of any one of claims 1 to 19, or a pharma- ceutically acceptable salt thereof, optionally substituted with one or two substituents independently selected from:

23. Each R １０ But, C １～２ Alkyl, C １～２ Haloalkyl, F, Cl, D, CN, OR ａ１ and N.R. ｃ１ R ｄ１ wherein C is independently selected from １～２ Alkyl is R １１ 20. The compound of any one of claims 1 to 19, or a pharma- ceutically acceptable salt thereof, optionally substituted with one or two substituents independently selected from:

24. Each R １０ methyl, (1-methyl-1H-1,2,4-triazol-5-yl)methyl, pyrrolidin-3-yl, pyrrolidin-1-yl, 1-ethylpyrrolidin-3-yl, 1-methylazetidin-3-yl, 1-ethylazetidin-3-yl, 4-acetylpiperazin-1-yl, 3-cyanocyclobutyl, 1-(dimethylcarbamoyl)piperidin-4-yl, 1-(methoxycarbonyl)piperidin-4-yl, 1-(methoxycarbonyl)azetidin-3-yl, 1-acetylazetidin-3-yl, 1-(methylsulfonyl)azetidin-3-yl yl, 1-(dimethylcarbamoyl)azetidin-3-yl, 1-(cyclopropanecarbonyl)azetidin-3-yl, pyridin-4-ylmethyl, 2-morpholinoethyl, cyclopropyl, 2-cyanoethyl, 2-hydroxyethyl, pyridin-4-yl, 4-hydroxycyclohexyl, 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl, morpholino, 4-methyl-3-oxopiperazin-1-yl, 4-hydroxypiperidin-1-yl, (R)-3,4-dimethylpiperazin-1-yl, (1S,4S)-5-methyl-2 , 5-diazabicyclo[2.2.1]heptan-2-yl, 4-(dimethylcarbamoyl)piperidin-1-yl, 4-carboxy-4-methylpiperidin-1-yl, (1S,4S)-4-acetamidocyclohexyl, 2,4-dimethylpiperazin-1-yl, 4-(ethylcarbamoyl)piperazin-1-yl, 4-carbamoylpiperazin-1-yl, 4-isopropylpiperazin-1-yl, 4-ethylpiperazin-1-yl, 2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-8-yl, pyridin-2-ylmethyl, 1- acetylpiperidin-4-yl), 1-(methoxycarbonyl)piperidin-4-yl, (tetrahydrofuran-3-yl)oxy, 1-methyl-5-oxopyrrolidin-3-yl, 1-(2-hydroxypropanoyl)piperidin-4-yl, 1-(2-hydroxyacetyl)piperidin-4-yl, 4-carboxycyclohexyl, 3-amino-4-fluoropyrrolidin-1-yl, (7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, (7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl,2-a]pyrazin-2(1H)-yl, 4-imino-4-oxo-4λ, ６ -piperazin-1-yl, (2-hydroxy-N-methylacetamido)pyrrolidin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, 2-methoxyethoxy, (tetrahydro-2H-pyran-4-yl)oxy, cyclopropyl, and 3-(2-hydroxy-N-methylacetamido)azetidin-1-yl, 1-(2-hydroxyacetyl)pyrrolidin-3-yl, 1-acetylpiperidin-3-yl, 1-(3'-pyrrolidin-2'-one)pyrrolidin-3-yl, 1-(1'-methyl-(3'-pyrrolidin-2'-one) )pyrrolidin-3-yl, 1-(2-propanamido)pyrrolidin-3-yl, 1-(methyl-L-prolyl)piperidin-4-yl, 1-(4-methylmorpholin-3-yl)pyrrolidin-3-yl, 3-cyanocyclobut-1-yl, 1-(hydroxymethylcarbonyl)azetidin-3-yl, 1-(2-(dimethylamino)ethanecarbonyl)azetidin-3-yl, 1-(dimethylamino-methyl-acetyl)azetidin-3-yl, 1-((1-methylazetidin-2-yl)carbonyl)azetidin-3-yl, 1-(2-(4-methylazetidin-2-yl)carbonyl)azetidin-3-yl, 1-(2-(4-hydroxypiperazin-1-yl)ethan-1-one)azetidin-3-yl, 1-((1-methylazetidin-2-yl)carbonyl)azetidin-3-yl, 1-(hydroxymethylacetyl)azetidin-3-yl, 1-((trans)-3-hydroxycyclobutylcarbonyl)azetidin-3-yl, 1-((cis)-3-hydroxycyclobutylcarbonyl)azetidin-3-yl, 1-((4-methylmorpholin-3-yl)carbonyl 1-(hydroxyl-acetyl)pyrrolidin-3-yl, 1-((tetrahydrofuran-2-yl)carbonyl)azetidin-3-yl, 1-((tetrahydrofuran-3-yl)carbonyl)azetidin-3-yl, 1-(hydroxy-methyl-acetyl)pyrrolidin-3-yl, 1-(3-hydroxybutanoyl)azetidin-3-yl, 1-((-3-hydroxy-3-methylcyclobutyl)carbonyl)azetidin-3-yl, 1-(4-methylmorpholin-3-yl)carbonyl)pyrrolidin-3-yl,1-((hydroxymethyl)cyclobutylcarbonyl)azetidin-3-yl, 1-((1-ethylazetidin-2-yl)carbonyl)azetidin-3-yl, 1-((1-(2-fluoroethyl)azetidin-2-yl)carbonyl)azetidin-3-yl, 1-((1-isopropylazetidin-2-yl)carbonyl)azetidin-3-yl, 1-((1-(2-fluoroethyl)azetidin-2-yl)carbonyl)pyrrolidin-3-yl, 1-((trans)-3-hydroxycyclobutylcarbonyl)pyrrolidin-3-yl , 1-((cis)-3-hydroxycyclobutylcarbonyl)pyrrolidin-3-yl, 1-((3-hydroxy-3-methylcyclobutyl)carbonyl)pyrrolidin-3-yl, 1-(2-methoxyethan-1-one)azetidin-3-yl, 1-(2-(dimethylamino)-2-methylpropan-1-one)azetidin-3-yl, 1-((cyclopropane-1-carbonitrile)carbonyl)azetidin-3-yl, 1-((ethan-1-ol)sulfonyl)azetidin-3-yl, 1-((N,N-dimethylethan-1-amine)sulfonyl)azetidin-3-yl, 3-(2-hydroxy-N-methylacetamido)cyclopentyl, 3-(2-hydroxypropanamido)cyclopentyl, 3-(2-hydroxyacetamido)cyclopentyl, 3-(2-hydroxyethyl)-3-azabicyclo[3.1.0]hexan-1-yl, (4-hydroxypiperidin-1-yl)methyl, (2-oxa-5-azabicyclo[3.1.0]hexan-1-yl, (5-hydroxypiperidin-1-yl)methyl, (2-oxa-5-azabicyclo[3.1.0]hexan-1-yl, (6-hydroxypiperidin-1-yl)methyl, (2-oxa-5-azabicyclo[3.1.0]hexan-1-yl, (7-hydroxypiperidin-1-yl)methyl, (2-oxa-5-azabicyclo[3.1.0]hexan-1-yl, (8-hydroxypiperidin-1-yl)methyl, (2-oxa-5-azabicyclo[3.1.0]hexan-1-yl, (9-hydroxypiperidin-1-yl)methyl, (2-oxa-5-azabicyclo[3.1.0]hexan-1-yl, (10-hydroxypiperidin-1-yl)methyl, (2-oxa-5-azabicyclo[3.1.0]hexan-1-yl, (11-hydroxypiperidin-1-yl)methyl, (2-oxa-5-azabicyclo[3.1.0]hexan-1-yl, (12-hydroxypiperidin-1-yl)methyl, (2-oxa-5-azabicyclo[3.1.0]hexan-1-yl, (13-hydroxypiperidin-1-yl)methyl, (2-oxa-5-azabicyclo[3.1.0]hexan-1-yl, (14-hydroxypiperidin-1-yl)methyl, (2-oxa-5-azabicyclo[3.1.0]hexan-1- [2.2.1]heptan-5-yl)methyl, 1-(morpholin-4-yl)ethyl, (5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-7-yl)methyl, 1-(2-hydroxyethyl)piperidin-4-yl-4-carbonitrile, 1-(2-hydroxyacetyl)piperidin-4-yl-4-carbonitrile, 2-methoxyethylpiperazin-1-yl, 1-(tetrahydro-2H-pyran-4-carbonyl)piperidin-4-yl-4-d, 1-(2-methoxyacetyl)pyrrolidin-3-yl,1-(tetrahydrofuran-2-carbonyl)pyrrolidin-3-yl, 3-(2-hydroxy-N-methylacetamido)azetidin-1-yl, 1-((tetrahydrofuran-2-yl)carbonyl)azetidin-3-yl, 1-((1-methylpiperidin-2-yl)carbonyl)azetidin-3-yl, 1-(2-(dimethylamino)ethan-1-one)azetidin-3-yl, 1-(3-hydroxypropan-1-one)azetidin-3-yl, 1-(2-hydroxyethan-1-one)azetidin-3-yl, 1-(2-hydroxy cypropan-1-one)azetidin-3-yl, 1-(2-hydroxy-N-methylacetamido)cyclobut-3-yl, 1-(2-hydroxyethan-1-one)-3-d-azetidin-3-yl, 1-carboxylate piperidin-4-yl, 1-(morpholine-4-carbonyl)piperidin-4-yl, 1-acetylpyrrolidin-3-yl, 1-(morpholine-4-carbonyl)pyrrolidin-3-yl, cyanomethyl, 1-propanenitrile-azetidin-3-yl, 1-(2-methoxy-N-methylacetamido)cyclobut-3 -yl, 1-(3-hydroxy-N-methylpropanamido)cyclobut-3-yl, 1-(2-hydroxy-N-methylpropanamido)cyclobut-3-yl, 1-(2-hydroxyethan-1-one)azabicyclo[3.1.0]hexan-3-yl, 1-((4-methylmorpholin-3-yl)carbonyl)azabicyclo[3.1.0]hexan-3-yl, 1-(tetrahydro-2H-pyran-4-yl)azabicyclo[3.1.0]hexan-3-yl, 1-(ethan-1-ol)azabicyclo[3.1.0]hexan-3-yl 20. The compound according to any one of claims 1 to 19, wherein the compound is independently selected from 1-(4-methylmorpholine-3-carbonyl)-3-carbonitrile-pyrrolidin-3-yl, 1-(4-methylmorpholine-3-carbonyl)-4-carbonitrile-piperidin-4-yl, 1-(2-hydroxyacetyl)-3-carbonitrile-pyrrolidin-3-yl, (1,3-dimethylpiperazin-4-yl-2-one)methyl, and (2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl, or a pharma-ceutically acceptable salt thereof.

25. Each R １１ But, C １～６ Alkyl, C １～６ Haloalkyl, C ３～１０ Cycloalkyl, 4-10 membered heterocycloalkyl, C ６～１０ Aryl, 5-10 membered heteroaryl, halo, D, CN, OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)OR ａ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ N.R. ｃ３ R ｄ３ , S(O) ２ R ｂ３ , and S(O) ２ N.R. ｃ３ R ｄ３ wherein C is independently selected from １～６ Alkyl, the C ３～１０ cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C ６～１０ The aryl and the 5- to 10-membered heteroaryl are each R １２ 25. The compound of any one of claims 1 to 24, or a pharma- ceutically acceptable salt thereof, optionally substituted with one, two, three, or four substituents independently selected from:

26. Each R １１ But, C １～３ Alkyl, C １～３ Haloalkyl, C ３～４ Cycloalkyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl, halo, D, CN, OR ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , S(O) ２ R ｂ３ , and N.R. ｃ３ S (O) ２ R ｂ３ wherein C is independently selected from １～３ Alkyl, the C ３～４ The cycloalkyl, the 5- to 6-membered heteroaryl, and the 4- to 6-membered heterocycloalkyl are each R １２ 25. The compound of any one of claims 1 to 24, or a pharma- ceutically acceptable salt thereof, optionally substituted with one substituent selected from:

27. Each R １１ But, Halo, C １～２ Alkyl, CN, OR ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , S(O) ２ R ｂ３ , 1-methyl-pyrrolidin-3-yl-2-one, pyrrolidin-3-yl-2-one, 2-propanamide, NR ｃ３ S (O) ２ R ｂ３ , D, and tetrahydropyran-4-yl, １～２ Alkyl is OR ａ５ 25. The compound of any one of claims 1 to 24, or a pharma- ceutically acceptable salt thereof, optionally substituted with:

28. Each R １１ But, C １～３ Alkyl, 4-10 membered heterocycloalkyl, F, D, CN, OR ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , and S(O) ２ R ｂ３ wherein C is independently selected from １～３ alkyl, and the 4- to 10-membered heterocycloalkyl are each R １２ 25. The compound of any one of claims 1 to 24, or a pharma- ceutically acceptable salt thereof, optionally substituted with one or two substituents independently selected from:

29. Each R １１ D, methyl, ethyl, isopropyl, CN, OH, oxo, (1-methyl-1H-1,2,4-triazol-5-yl)methyl, CH ２ CH ２ OH, C(O)CH ３ , C(O)N(CH ３ ) ２ , C(O)NH ２ , C(O)NHCH ２ CH ３ , C(O)CH ２ CH ２ N (CH ３ ) ２ , C(O)CH(CH ３ ) N(CH ３ ) ２ , C(O)OCH ３ , C(O)CH ２ OH, CH(CH ３ )C(O)NH ２ , C(O)OH, NHC(O)CH ３ , S(O) ２ CH ３ , cyclopropanecarbonyl, pyridin-4-yl, pyridin-2-yl, morpholino, 2-hydroxypropanoyl, 2-hydroxyacetyl, 2-hydroxyethyl, F, NH ２ , N(CH ３ )C(O)CH ２ OH, 3'-pyrrolidin-2'-one, methyl-3'-pyrrolidin-2'-one, 1-methyl-prolyl, (4-methylmorpholin-3-yl)methyl-1-one, (1-methylazetidin-2-yl)methyl-1-one, 2-(4-methylpiperazin-1-yl)ethyl-1-one, 2-(4-hydroxypiperidin-1-yl)ethyl-1-one, 2-hydroxypropyl-1-one, (trans)-3-hydroxycyclobutyl)methyl-1-one, (cis)-3-hydroxycyclobutyl)methyl-1-one, (4-methylmorpholin-3-yl)methyl-1-one, (tetrahydrofuran 2-(2-fluoroethyl)azetidin-2-yl)methyl-1-one, 2-(dimethylamino)-2-methylpropyl-1-one, (cyclopropane-1-carbonitrile)methyl-1-one, S(O) ２ CH ２ CH ２ OH, S(O) ２ CH ２ CH ２ N (CH ３ ) ２ 25. The compound of claim 1, wherein the compound is independently selected from 1,3-dimethylpiperazinyl-2-one, 2-methoxyethyl-carboxyl, N-methylmethanesulfonamide, 2-hydroxy-N-methylacetamide, 2-hydroxypropanamide, tetrahydro-2H-pyran-4-methyl-1-one, 2-methoxyacetyl, 2-hydroxy-N-methylacetamide, tetrahydrofuran-2-methyl-1-one, (1-methylpiperidin-2-yl)methyl-1-one, 2-(dimethylamino)ethyl-1-one, 3-hydroxypropyl-1-one, methoxymethyl-carboxyl, morpholine-4-carbonyl, propylnitrile, 2-methoxy-N-methylacetamide, 3-hydroxy-N-methylpropanamide, 2-hydroxy-N-methylpropanamide, tetrahydro-2H-pyran-4-yl, and 1,3-dimethylpiperazinyl-2-one, or a pharma-ceutically acceptable salt thereof.

30. Each R ｂ３ But, C １～３ Alkyl, C １～３ Haloalkyl, C ３～６ cycloalkyl, and 4- to 6-membered heterocycloalkyl, １～３ Alkyl, the C ３～６ cycloalkyl, and the 4- to 6-membered heterocycloalkyl are each R １２ 30. The compound of any one of claims 1 to 29, or a pharma- ceutically acceptable salt thereof, optionally substituted with one or two substituents independently selected from:

31. Any R bonded to the same N atom ｃ３ and R ｄ３ together with the N atom to which they are attached, R １２ 31. The compound according to any one of claims 1 to 30, or a pharma- ceutically acceptable salt thereof, which forms a 4-, 5- or 6-membered heterocycloalkyl group, optionally substituted with one or two substituents independently selected from:

32. Each R １２ But, C １～６ Alkyl, C １～６ Haloalkyl, C ３～６ Cycloalkyl, 4-7 membered heterocycloalkyl, halo, D, CN, OR ａ５ , S.R. ａ５ , C(O)R ｂ５ , C(O)NR ｃ５ R ｄ５ , C(O)OR ａ５ , N.R. ｃ５ R ｄ５ , N.R. ｃ５ C(O)R ｂ５ , S(O) ２ R ｂ５ , and S(O) ２ N.R. ｃ５ R ｄ５ wherein C is independently selected from １～６ Alkyl, the C ３～６ cycloalkyl, and the 4- to 7-membered heterocycloalkyl are each R ｇ 32. The compound of any one of claims 1 to 31, or a pharma- ceutically acceptable salt thereof, optionally substituted with one, two, three, or four substituents independently selected from:

33. Each R １２ But, C １～３ Alkyl, C １～３ Haloalkyl, C ３～６ Cycloalkyl, 4- to 7-membered heterocycloalkyl, F, Cl, D, CN, OR ａ５ , C(O)R ｂ５ , C(O)NR ｃ５ R ｄ５ , and N.R. ｃ５ R ｄ５ wherein C is independently selected from １～３ Alkyl, the C ３～６ cycloalkyl, and the 4- to 7-membered heterocycloalkyl are each R ｇ 32. The compound of any one of claims 1 to 31, or a pharma- ceutically acceptable salt thereof, optionally substituted with one substituent independently selected from:

34. Each R ２１ But, C １～６ Alkyl, C １～６ Haloalkyl, Halo, D, CN, OR ａ４ , C(O)R ｂ４ , C(O)NR ｃ４ R ｄ４ , C(O)OR ａ４ , N.R. ｃ４ R ｄ４ , and S(O) ２ R ｂ４ wherein C is independently selected from １～６ Alkyl is R ２２ 34. The compound of any one of claims 1 to 33, or a pharma- ceutically acceptable salt thereof, optionally substituted with one, two, or three substituents independently selected from:

35. Each R ２１ But, C １～３ Alkyl, halo, D, CN, and OR ａ４ wherein C is independently selected from １～３ Alkyl is R ２２ 34. The compound of any one of claims 1 to 33, or a pharma- ceutically acceptable salt thereof, optionally substituted with one or two substituents independently selected from:

36. Each R ２１ But, C １～３ Alkyl, F, Cl, D, CN, and OR ａ４ wherein C is independently selected from １～３ Alkyl is R ２２ 34. The compound of any one of claims 1 to 33, or a pharma- ceutically acceptable salt thereof, optionally substituted with one or two substituents independently selected from:

37. Each R ２２ is halo, D, CN, and OR ａ６ 37. The compound of any one of claims 1 to 36, or a pharma- ceutically acceptable salt thereof, independently selected from:

38. Each R ２２ is F, Cl, D, CN, and OR ａ６ 37. The compound of any one of claims 1 to 36, or a pharma- ceutically acceptable salt thereof, independently selected from:

39. R ２２ OR ａ６ 37. The compound according to any one of claims 1 to 36, which is: or a pharma- ceutically acceptable salt thereof.

40. Each R ｇ OH, CN, F, Cl, C １～３ Alkyl, and C １～３ 40. The compound of any one of claims 1 to 39, or a pharma- ceutically acceptable salt thereof, independently selected from haloalkyl.

41. Formula IIb: 【Chemistry 2】 or a pharma- ceutically acceptable salt thereof. The compound according to any one of claims 1 to 5, 10 to 17, and 20 to 40, or a pharma- ceutically acceptable salt thereof.

42. Formula IIIa: 【Chemistry 3】 41. The compound of any one of claims 1, 6-17, and 20-40, or a pharma- ceutically acceptable salt thereof.

43. Formula IIIb: 【Chemistry 4】 41. The compound of any one of claims 1, 6-17, and 20-40, or a pharma- ceutically acceptable salt thereof.

44. Formula IIIc: 【Chemistry 5】 41. The compound of any one of claims 1, 6-17, and 20-40, or a pharma- ceutically acceptable salt thereof.

45. Formula IVa: 【Chemistry 6】 41. The compound according to any one of claims 1 to 9 and 20 to 40, or a pharma- ceutically acceptable salt thereof.

46. Formula Va: 【Chemistry 7】 or a pharma- ceutically acceptable salt thereof, wherein m is 0, 1, or 2. The compound of any one of claims 1 to 9 and 20 to 40, or a pharma- ceutically acceptable salt thereof.

47. Cy １ is selected from phenyl, pyridinyl, and pyrazolyl, wherein said phenyl, said pyridinyl, and said pyrazolyl are each selected from R １０ and optionally substituted with 1, 2, 3 or 4 substituents independently selected from R １ But, Halo, C １～６ Alkyl, C １～６ Haloalkyl, C ３～５ Cycloalkyl, 4- to 5-membered heterocycloalkyl, C １～６ Alkoxy, C １～６ Haloalkoxy, C １～３ Alkoxy-C １～３ Alkyl, HO-C １～３ Alkyl, C １～６ Alkylamino and di(C １～６ (alkyl)amino, wherein said C １～６ Alkyl, the C １～６ Haloalkyl, the C ３～５ cycloalkyl, the 4- to 5-membered heterocycloalkyl, the C １～６ Alkoxy, the above C １～６ Haloalkoxy, the above C １～３ Alkoxy-C １～３ Alkyl, the HO-C １～３ Alkyl, the C １～６ Alkylamino, and the di(C １～６ Any of the H atoms of the alkyl)amino may be replaced by a D atom; Each R ２ and R ３ But, C １～６ Alkyl, C ２～６ Alkenyl, C １～６ Haloalkyl, C ３～６ Cycloalkyl, 4-6 membered heterocycloalkyl, halo, CN, OR ａ２ , C(O)R ｂ２ , C(O)NR ｃ２ R ｄ２ , C(O)OR ａ２ , N.R. ｃ２ R ｄ２ , and S(O) ２ R ｂ２ wherein C is independently selected from １～６ Alkyl, the C ２～６ Alkenyl, the above C ３～６ cycloalkyl, and the 4- to 6-membered heterocycloalkyl are each R ２１ or optionally substituted with 1, 2, 3, or 4 substituents independently selected from Alternatively, two adjacent R ２ Substituents, together with the atoms to which they are attached, form a fused 5- or 6-membered cycloalkyl ring, or a fused 5- or 6-membered heterocycloalkyl ring, wherein each fused 5- or 6-membered heterocycloalkyl ring has at least one ring-forming carbon atom and 1 or 2 ring-forming heteroatoms independently selected from O and N, and wherein a ring-forming carbon atom of each fused 5- or 6-membered heterocycloalkyl ring is optionally substituted by oxo to form a carbonyl group, and wherein said fused 5- or 6-membered cycloalkyl ring, and said fused 5- or 6-membered heterocycloalkyl ring are each independently selected from R ２１ and optionally substituted with 1, 2, 3 or 4 substituents independently selected from n is selected from 0 and 1; Each R １０ But, C １～６ Alkyl, C １～６ Haloalkyl, C ３～１０ Cycloalkyl, 4- to 12-membered heterocycloalkyl, C ６～１０ Aryl, 5-10 membered heteroaryl, C ３～１０ Cycloalkyl-C １～３ Alkylene, 4- to 12-membered heterocycloalkyl-C １～３ Alkylene, C ６～１０ Aryl-C １～３ Alkylene, 5-10 membered heteroaryl-C １～３ Alkylene, halo, D, CN, OR ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , and S(O) ２ R ｂ１ wherein C is independently selected from １～６ Alkyl, the C ３～１０ cycloalkyl, the 4- to 12-membered heterocycloalkyl, the C ６～１０ aryl, the 5- to 10-membered heteroaryl, the C ３～１０ Cycloalkyl-C １～３ alkylene, the 4- to 12-membered heterocycloalkyl-C １～３ Alkylene, ６～１０ Aryl-C １～３ Alkylene and the 5- to 10-membered heteroaryl-C １～３ Each alkylene is R １１ and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R １１ But, C １～６ Alkyl, C １～６ Haloalkyl, C ３～１０ Cycloalkyl, 4-10 membered heterocycloalkyl, C ６～１０ Aryl, 5-10 membered heteroaryl, halo, D, CN, OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)OR ａ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ N.R. ｃ３ R ｄ３ , S(O) ２ R ｂ３ , and S(O) ２ N.R. ｃ３ R ｄ３ wherein C is independently selected from １～６ Alkyl, the C ３～１０ cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C ６～１０ The aryl and the 5- to 10-membered heteroaryl are each R １２ and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R １２ But, C １～６ Alkyl, C １～６ Haloalkyl, C ３～６ Cycloalkyl, 4-7 membered heterocycloalkyl, halo, D, CN, OR ａ５ , S.R. ａ５ , C(O)R ｂ５ , C(O)NR ｃ５ R ｄ５ , C(O)OR ａ５ , N.R. ｃ５ R ｄ５ , N.R. ｃ５ C(O)R ｂ５ , S(O) ２ R ｂ５ , and S(O) ２ N.R. ｃ５ R ｄ５ wherein C is independently selected from １～６ Alkyl, the C ３～６ cycloalkyl, and the 4- to 7-membered heterocycloalkyl are each R ｇ and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ２１ But, C １～６ Alkyl, C １～６ Haloalkyl, Halo, D, CN, OR ａ４ , C(O)R ｂ４ , C(O)NR ｃ４ R ｄ４ , C(O)OR ａ４ , N.R. ｃ４ R ｄ４ , and S(O) ２ R ｂ４ wherein C is independently selected from １～６ Alkyl is R ２２ and optionally substituted with 1, 2, or 3 substituents independently selected from Each R ２２ But, C １～６ Alkyl, C １～６ Haloalkyl, Halo, D, CN, OR ａ６ , and N.R. ｃ６ R ｄ６ wherein C is independently selected from １～６ Alkyl is R ｇ and optionally substituted with one or two substituents independently selected from Each R ａ１ , R ｃ１ and R ｄ１ But, H, C １～６ Alkyl, C １～６ Haloalkyl, C ３～１０ cycloalkyl, and 4- to 10-membered heterocycloalkyl, １～６ Alkyl, the C ３～１０ cycloalkyl, and the 4- to 10-membered heterocycloalkyl are each R １１ or optionally substituted with 1, 2, 3, or 4 substituents independently selected from or any R bonded to the same N atom ｃ１ and R ｄ１ together with the N atom to which they are attached, R １１ forming a 4-, 5-, or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ｂ１ But, C １～６ Alkyl, C １～６ Haloalkyl, C ３～１０ cycloalkyl, and 4- to 10-membered heterocycloalkyl, １～６ Alkyl, the C ３～１０ cycloalkyl, and the 4- to 10-membered heterocycloalkyl are each R １１ and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ａ２ , R ｃ２ and R ｄ２ But, H, C １～６ Alkyl, C １～６ Haloalkyl, C ３～１０ cycloalkyl, and 4- to 10-membered heterocycloalkyl, １～６ Alkyl, the C ３～１０ cycloalkyl, and the 4- to 10-membered heterocycloalkyl are each R ２１ or optionally substituted with 1, 2, 3, or 4 substituents independently selected from or any R bonded to the same N atom ｃ２ and R ｄ２ together with the N atom to which they are attached, R ２１ forming a 4-, 5-, or 6-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Each R ｂ２ But, C １～６ Alkyl, C １～６ Haloalkyl, C ３～１０ cycloalkyl, and 4- to 10-membered heterocycloalkyl, １～６ Alkyl, the C ３～１０ cycloalkyl, and the 4- to 10-membered heterocycloalkyl are each R ２１ and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ａ３ , R ｃ３ and R ｄ３ But, H, C １～６ Alkyl, C １～６ Haloalkyl, C ３～６ cycloalkyl, and 4- to 7-membered heterocycloalkyl, １～６ Alkyl, the C ３～６ cycloalkyl, and the 4- to 7-membered heterocycloalkyl are each R １２ or optionally substituted with 1, 2, 3, or 4 substituents independently selected from or any R bonded to the same N atom ｃ３ and R ｄ３ together with the N atom to which they are attached, R １２ forming a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 substituents independently selected from Each R ｂ３ But, C １～６ Alkyl, C １～６ Haloalkyl, C ３～６ cycloalkyl, and 4- to 7-membered heterocycloalkyl, １～６ Alkyl, the C ３～６ cycloalkyl, and the 4- to 7-membered heterocycloalkyl are each R １２ and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ａ４ , R ｃ４ and R ｄ４ But, H, C １～６ Alkyl, and C １～６ haloalkyl, wherein said C １～６ Alkyl is R ２２ and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ｂ４ But, C １～６ Alkyl, and C １～６ haloalkyl, wherein said C １～６ Alkyl is R ２２ and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ａ５ , R ｃ５ and R ｄ５ But, H, C １～６ Alkyl, and C １～６ haloalkyl, wherein said C １～６ Alkyl is R ｇ and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ｂ５ But, C １～６ Alkyl, and C １～６ haloalkyl, wherein said C １～６ Alkyl is R ｇ and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ａ６ , R ｃ６ and R ｄ６ But, H, C １～６ Alkyl, and C １～６ haloalkyl, wherein said C １～６ Alkyl is R ｇ and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ｂ６ But, C １～６ Alkyl, and C １～６ haloalkyl, wherein said C １～６ Alkyl is R ｇ and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ｇ OH, CN, halo, C １～６ Alkyl, C １～６ Haloalkyl, C ３～６ Cycloalkyl, C １～６ Alkoxy, C １～６ Haloalkoxy, C １～３ Alkoxy-C １～３ Alkyl, HO-C １～３ Alkyl, cyano-C １～３ Alkyl, H ２ N-C １～３ Alkyl, Amino, C １～６ Alkylamino, di(C １～６ Alkyl)amino, C １～６ Alkylthio, C １～６ Alkyl sulfonyl, carboxy, C １～６ Alkylcarbonyl, C １～６ Alkoxycarbonyl, and C １～６ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, independently selected from alkylcarbonylamino.

48. Cy １ is selected from phenyl, pyridin-3-yl and pyrazol-4-yl, where Cy １ The phenyl, the pyridin-3-yl and the pyrazol-4-yl are each R １０ and optionally substituted with one substituent selected from R １ But Cl, C １～３ Alkyl, C １～３ Haloalkyl, cyclopropyl, azedinyl, hydroxymethyl, C １～３ Alkoxy, C １～３ Haloalkoxy and C １～３ alkylamino, wherein said C １～３ Alkyl, the C １～３ haloalkyl, cyclopropyl, azedinyl, hydroxymethyl, １～３ Alkoxy, the above C １～３ Haloalkoxy and the above C １～３ each alkylamino is optionally substituted with 1, 2, 3, 4, 5, 6, or 7 deuterium; Each R ２ But, C １～３ Alkyl, C １～３ Haloalkyl, C ３～６ Cycloalkyl, F, Cl, CN, and OR ａ２ wherein C is independently selected from １～３ Alkyl, and the C ３～６ Each cycloalkyl is R ２１ or optionally substituted with one, two or three substituents independently selected from Alternatively, the R on the phenyl ring ２ Substituents, together with the atoms to which they are attached, form a fused 5- or 6-membered cycloalkyl ring, or a fused 5- or 6-membered heterocycloalkyl ring, wherein each fused 5- or 6-membered heterocycloalkyl ring has at least one ring-forming carbon atom and 1 or 2 ring-forming O atoms, and wherein said fused 5- or 6-membered cycloalkyl ring, and said fused 5- or 6-membered heterocycloalkyl ring, each are selected from the group consisting of R ２１ and optionally substituted with one or two substituents independently selected from n is 0, Each R １０ But, C １～３ Alkyl, C １～３ Haloalkyl, C ３～６ Cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 6-membered heteroaryl, 4- to 10-membered heterocycloalkyl-C １～２ Alkylene, 5-6 membered heteroaryl-C １～２ Alkylene, F, Cl, D, CN, OR ａ１ , C(O)NR ｃ１ R ｄ１ , and N.R. ｃ１ R ｄ１ wherein C is independently selected from １～３ Alkyl, the C ３～６ cycloalkyl, the 4- to 10-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the 4- to 10-membered heterocycloalkyl-C １～２ alkylene, and the 5- to 6-membered heteroaryl-C １～２ Each alkylene is R １１ and optionally substituted with one or two substituents independently selected from Each R １１ But, C １～３ Alkyl, C １～３ Haloalkyl, C ３～６ Cycloalkyl, 4-10 membered heterocycloalkyl, 5-6 membered heteroaryl, F, Cl, D, CN, OR ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , S(O) ２ R ｂ３ , and S(O) ２ N.R. ｃ３ R ｄ３ wherein C is independently selected from １～３ Alkyl, the C ３～６ cycloalkyl, the 4- to 10-membered heterocycloalkyl, and the 5- to 6-membered heteroaryl are each R １２ and optionally substituted with one or two substituents independently selected from Each R １２ But, C １～３ Alkyl, C １～３ Haloalkyl, C ３～６ Cycloalkyl, 4- to 7-membered heterocycloalkyl, F, Cl, D, CN, OR ａ５ , C(O)R ｂ５ , C(O)NR ｃ５ R ｄ５ , and N.R. ｃ５ R ｄ５ wherein C is independently selected from １～３ Alkyl, the C ３～６ cycloalkyl, and the 4- to 7-membered heterocycloalkyl are each R ｇ and optionally substituted with one substituent independently selected from R ２１ But, C １～３ Alkyl, F, Cl, D, CN, and OR ａ４ wherein C is independently selected from １～３ Alkyl is R ２２ and optionally substituted with one or two substituents independently selected from Each R ２２ is F, Cl, D, CN, and OR ａ６ are independently selected from Each R ａ１ , R ｃ１ and R ｄ１ But, H, C １～３ Alkyl, C １～３ haloalkyl, and 4- to 6-membered heterocycloalkyl, １～３ alkyl, and the 4- to 6-membered heterocycloalkyl are each R １１ and optionally substituted with one substituent independently selected from Each R ａ２ But, H, C １～３ Alkyl, and C １～３ haloalkyl; Each R ａ３ , R ｃ３ and R ｄ３ But, H, C １～３ Alkyl, C １～３ Haloalkyl, C ３～６ cycloalkyl, and 4- to 6-membered heterocycloalkyl, １～３ Alkyl, the C ３～６ cycloalkyl, and the 4- to 6-membered heterocycloalkyl are each R １２ or or any R bonded to the same N atom ｃ３ and R ｄ３ together with the N atom to which they are attached, R １２ forming a 4-, 5- or 6-membered heterocycloalkyl group, optionally substituted with 1 or 2 substituents independently selected from Each R ｂ３ But, C １～３ Alkyl, C １～３ Haloalkyl, C ３～６ cycloalkyl, and 4- to 6-membered heterocycloalkyl, １～３ Alkyl, the C ３～６ cycloalkyl, and the 4- to 6-membered heterocycloalkyl are each R １２ and optionally substituted with one or two substituents independently selected from Each R ａ４ But, H, C １～３ Alkyl, and C １～３ haloalkyl; Each R ａ５ , R ｃ５ and R ｄ５ But, H, C １～３ Alkyl, and C １～３ haloalkyl, wherein said C １～３ Alkyl is R ｇ and optionally substituted with one substituent independently selected from Each R ｂ５ But, C １～３ Alkyl, and C １～３ haloalkyl, wherein said C １～３ Alkyl is R ｇ and optionally substituted with one substituent independently selected from Each R ａ６ H, and C １～３ independently selected from alkyl, Each R ｇ OH, CN, F, Cl, C １～３ Alkyl, and C １～３ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, independently selected from haloalkyl.

49. 5-(2,3-dimethylphenyl)-6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine, 5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine, 5-(2,3-dimethylphenyl)-6-methoxy-3-(1-((1-methyl-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine, 5-(2,3-dihydrobenzofuran-7-yl)-6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine, 2-(3-(6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2-methylphenyl)acetonitrile, 1-(4-(5-(6-(difluoromethoxy)-5-(2,3-dimethylphenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperazin-1-yl)ethan-1-one, 4-(6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-1-ol, 4-(6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile, 4-(6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-2-ol, (4-(6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-1-yl)methanol, 2-fluoro-4-(6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-1-ol, 5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-3-(1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine, 5-(2,3-dihydro-1H-inden-4-yl)-3-(1-(1-ethylpyrrolidin-3-yl)-1H-pyrazol-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine, 3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)cyclobutanecarbonitrile, 5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-3-(1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine, 5-(2,3-dihydro-1H-inden-4-yl)-3-(1-(1-ethylazetidin-3-yl)-1H-pyrazol-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine, 4-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)-N,N-dimethylpiperidine-1-carboxamide, methyl 4-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate, methyl 3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate, 1-(3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)ethan-1-one, 5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-3-(1-(1-(methylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine, 3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)-N,N-dimethylazetidine-1-carboxamide, cyclopropyl(3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)methanone, 5-(2,3-dihydro-1H-inden-4-yl)-6-ethoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine, 5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-3-(1-(pyridin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine, 4-(2-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)ethyl)morpholine, 3-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine, 3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)propanenitrile, 2-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)ethan-1-ol, 5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-3-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine, (trans)-4-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)cyclohexan-1-ol, 5-(2,3-dimethylphenyl)-N-methyl-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-6-amine, 6-(difluoromethyl)-5-(2,3-dihydro-1H-inden-4-yl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine, (5-(2,3-dihydro-1H-inden-4-yl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-6-yl)methanol, 5-(2,3-dihydro-1H-inden-4-yl)-N-methyl-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-6-amine, (5-(2,3-dimethylphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-6-yl)methanol, 4-(6-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-2-ol, 5-(2,3-dimethylphenyl)-6-methyl-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine, 5-(2,3-dimethylphenyl)-6-methoxy-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine, 5-(2,3-dimethylphenyl)-3-(6-(4-ethylpiperazin-1-yl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine, 1-(4-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperazin-1-yl)ethan-1-one, 4-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)morpholine, 4-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-1-methylpiperazin-2-one, 1-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidin-4-ol, (R)-5-(2,3-dimethylphenyl)-3-(6-(3,4-dimethylpiperazin-1-yl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine, 5-(2,3-dimethylphenyl)-6-(methoxy-d3)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine, 5-(2,3-dimethylphenyl)-6-methoxy-3-(6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine, 1-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-N,N-dimethylpiperidine-4-carboxamide, 1-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-4-methylpiperidine-4-carboxylic acid, 3-(4-(5-(2-fluoro-3-methylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)-N,N-dimethylazetidine-1-carboxamide, N-((cis)-4-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)cyclohexyl)acetamide, 5-(2,3-dihydro-1H-inden-4-yl)-3-(6-(2,4-dimethylpiperazin-1-yl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine, 2-(3-(3-(6-(4-acetylpiperazin-1-yl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2-methylphenyl)acetonitrile, 2-(3-(6-methoxy-3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2-methylphenyl)acetonitrile, 5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-3-(6-(pyrrolidin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine, 4-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)morpholine, 4-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-N-ethylpiperazine-1-carboxamide, 4-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperazine-1-carboxamide, 1-(4-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)phenyl)piperazin-1-yl)ethan-1-one, 5-(2,3-dihydro-1H-inden-4-yl)-3-(4-(4-isopropylpiperazin-1-yl)phenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine, 5-(2,3-dihydro-1H-inden-4-yl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine, 1-(4-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperazin-1-yl)ethan-1-one, 8-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one, 5-(2,3-dimethylphenyl)-6-methoxy-3-(1-(pyridin-2-ylmethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine, 3-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridine, 6-methoxy-5-(2-methyl-3-(methyl-d3)phenyl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine, 1-(4-(4-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethan-1-one, methyl 4-(4-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate, Methyl 3-(4-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate, and 3-(4-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)-N,N-dimethylazetidine-1-carboxamide 2. The compound of claim 1 selected from:

50. 2-fluoro-4-(6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-1-ol, 5-(2,3-dimethylphenyl)-6-methoxy-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine, 4-(6-methoxy-3-(6-((tetrahydrofuran-3-yl)oxy)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-2-ol, 4-(6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)2,3-dihydro-1H-inden-2-d-2-ol, 4-(6-methoxy-3-(6-(1-methyl-5-oxopyrrolidin-3-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile, (S)-1-(4-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidin-1-yl)-2-hydroxypropan-1-one, 1-(4-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidin-1-yl)-2-hydroxyethan-1-one, 4-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclohexane-1-carboxylic acid, (3S,4R)-1-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-4-fluoropyrrolidin-3-amine, (2S)-1-(4-(5-(5-(2-fluoro-2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidin-1-yl)-2-hydroxypropan-1-one, 1-(4-(5-(5-(2-fluoro-2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidin-1-yl)-2-hydroxyethan-1-one, (7R,8aS)-2-(5-(5-(2-fluoro-2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol, 5-(2-fluoro-2,3-dihydro-1H-inden-4-yl)-6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine, (7S,8aR)-2-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol, 4-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-1-imino-1λ ６ -thiomorpholine 1-oxide, (7R,8aS)-2-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol, (S)—N-(1-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)pyrrolidin-3-yl)-2-hydroxy-N-methylacetamide, 2-(3-(3-(6-(4-(2-hydroxyethyl)piperazin-1-yl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2-methylphenyl)acetonitrile, (7R,8aS)-2-(5-(6-methoxy-5-(3-methoxy-2-methylphenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol, (7R,8aS)-2-(5-(5-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol, (7R,8aS)-2-(5-(5-(2-cyclopropylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol, (7R,8aS)-2-(5-(5-(chroman-5-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol, (7R,8aS)-2-(5-(5-(2-fluoro-3-methylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol, 4-(6-methoxy-3-(6-(2-methoxyethoxy)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-2-ol, 4-(6-methoxy-3-(6-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-2-ol, 4-(3-(6-cyclopropylpyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-2-ol, and N-(1-(5-(5-(2,3-dimethylphenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-3-yl)-2-hydroxy-N-methylacetamide or a pharma- ceutically acceptable salt of any of the above.

51. 1-(4-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidin-1-yl)ethan-1-one, 1-(4-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidin-1-yl)-2-hydroxyethan-1-one, 1-(3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)pyrrolidin-1-yl)-2-hydroxyethan-1-one (Peak 1), 1-(3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)pyrrolidin-1-yl)-2-hydroxyethan-1-one (peak 2), 1-(3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)pyrrolidin-1-yl)ethan-1-one (Peak 1), 1-(3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)pyrrolidin-1-yl)ethan-1-one (peak 2), 3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-[1,3'-bipyrrolidin]-2'-one (Peak 1), 3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-1'-methyl-[1,3'-bipyrrolidin]-2'-one (Peak 1), 2-(3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)pyrrolidin-1-yl)propanamide (Peak 1), 5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-3-(6-(1-(methyl-L-prolyl)piperidin-4-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine, (3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)pyrrolidin-1-yl)((R)-4-methylmorpholin-3-yl)methanone (peak 2), 4-(6-methoxy-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile, 4-(3-(1-(3-cyanocyclobutyl)-1H-pyrazol-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile, 4-(3-(1-(1-acetylpiperidin-4-yl)-1H-pyrazol-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile, 4-(3-(6-(4-hydroxycyclohexyl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile, 4-(3-(6-(4-(2-hydroxyethyl)piperazin-1-yl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile, 4-(3-(6-(1-(2-hydroxyacetyl)piperidin-4-yl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile, 1-(3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-2-hydroxyethan-1-one, 1-(3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-3-(dimethylamino)propan-1-one, (S)-1-(3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-2-(dimethylamino)propan-1-one, (S)-(3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(1-methylazetidin-2-yl)methanone, 1-(3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-2-(4-methylpiperazin-1-yl)ethan-1-one, 1-(3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-2-(4-hydroxypiperidin-1-yl)ethan-1-one, (R)-(3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(1-methylazetidin-2-yl)methanone, (R)-1-(3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-2-hydroxypropan-1-one, (S)-1-(3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-2-hydroxypropan-1-one, (3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)((trans)-3-hydroxycyclobutyl)methanone, (3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)((cis)-3-hydroxycyclobutyl)methanone, (R)-(3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(4-methylmorpholin-3-yl)methanone, (S)-(3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(4-methylmorpholin-3-yl)methanone, (S)-1-(3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)-2-hydroxyethan-1-one, (S)-(3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(tetrahydrofuran-2-yl)methanone, (S)-(3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(tetrahydrofuran-3-yl)methanone, (R)-1-((S)-3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)-2-hydroxypropan-1-one, (S)-1-((S)-3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)-2-hydroxypropan-1-one, (R)-1-(3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-3-hydroxybutan-1-one, (3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)((1r,3r)-3-hydroxy-3-methylcyclobutyl)methanone, (3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)((1s,3s)-3-hydroxy-3-methylcyclobutyl)methanone, ((R)-3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)((S)-4-methylmorpholin-3-yl)methanone, ((S)-3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)((R)-4-methylmorpholin-3-yl)methanone, (3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(1-(hydroxymethyl)cyclobutyl)methanone, (S)-(3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(1-ethylazetidin-2-yl)methanone, (S)-(3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(1-(2-fluoroethyl)azetidin-2-yl)methanone, (S)-(3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(1-isopropylazetidin-2-yl)methanone, ((S)-3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)((S)-1-(2-fluoroethyl)azetidin-2-yl)methanone, ((S)-3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)((trans)-3-hydroxycyclobutyl)methanone, ((S)-3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)((cis)-3-hydroxycyclobutyl)methanone, ((S)-3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)((1s,3r)-3-hydroxy-3-methylcyclobutyl)methanone, 1-(3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-2-methoxyethan-1-one, 1-(3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-2-(dimethylamino)-2-methylpropan-1-one, 1-(3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidine-1-carbonyl)cyclopropane-1-carbonitrile, 2-((3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)sulfonyl)ethan-1-ol, 2-((3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)sulfonyl)-N,N-dimethylethan-1-amine, 2-methoxyethyl 3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate, (3-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)azetidin-1-yl)((1s,3s)-3-methoxycyclobutyl)methanone, N-(3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclopentyl)-N-methylmethanesulfonamide, N-(3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclopentyl)-2-hydroxy-N-methylacetamide (Peak 1), (2S)—N-(3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclopentyl)-2-hydroxypropanamide, N-(3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclopentyl)-2-hydroxyacetamide, 2-(1-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)phenyl)-3-azabicyclo[3.1.0]hexan-3-yl)ethan-1-ol, 4-(3-(4-((1R,5S)-3-(2-hydroxyethyl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile, 1-((5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)methyl)piperidin-4-ol, 5-((5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)methyl)-2-oxa-5-azabicyclo[2.2.1]heptane, 4-(1-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)ethyl)morpholine, 7-((5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine, 4-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-1-(2-hydroxyethyl)piperidine-4-carbonitrile, 4-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-1-(2-hydroxyacetyl)piperidine-4-carbonitrile, 2-(3-(6-methoxy-3-(6-(4-(2-methoxyethyl)piperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2-methylphenyl)acetonitrile, 4-(6-methoxy-3-(1-(1-(tetrahydro-2H-pyran-4-carbonyl)piperidin-4-yl-4-d)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile, 4-(6-methoxy-3-(1-((S)-1-(2-methoxyacetyl)pyrrolidin-3-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile, 4-(6-methoxy-3-(1-((S)-1-((S)-tetrahydrofuran-2-carbonyl)pyrrolidin-3-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile, (7R,8aS)-2-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol, N-(1-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-3-yl)-2-hydroxy-N-methylacetamide, (3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-1-yl)(tetrahydrofuran-2-yl)methanone, (S)-(3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-1-yl)(1-methylpiperidin-2-yl)methanone, 1-(3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-1-yl)-2-(dimethylamino)ethan-1-one, 1-(3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-1-yl)-3-hydroxypropan-1-one, 1-(3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-1-yl)-2-hydroxyethan-1-one, (S)-1-(3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-1-yl)-2-hydroxypropan-1-one, N-(3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclobutyl)-2-hydroxy-N-methylacetamide, 1-(3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-1-yl-3-d)-2-hydroxyethan-1-one, methyl 4-(5-(5-(1-cyano-2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)piperidine-1-carboxylate, 4-(6-methoxy-3-(6-(1-(morpholine-4-carbonyl)piperidin-4-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile, peak 2, 4-(3-(6-(1-acetylpiperidin-4-yl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile, peak 2, 4-(3-(6-(1-acetylpyrrolidin-3-yl)pyridin-3-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile, 4-(6-methoxy-3-(6-(1-(morpholine-4-carbonyl)pyrrolidin-3-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile, 4-(3-(1-(cyanomethyl)-1H-pyrazol-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile, 4-(6-methoxy-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-indene-1-carbonitrile, 3-(3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)azetidin-1-yl)propanenitrile, N-(3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclobutyl)-2-methoxy-N-methylacetamide, N-(3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclobutyl)-3-hydroxy-N-methylpropanamide, (S)—N-(3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)cyclobutyl)-2-hydroxy-N-methylpropanamide, 1-(1-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-hydroxyethan-1-one, (R) 1-(1-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-hydroxyethan-1-one, two enantiomers; (S) 1-(1-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-hydroxyethan-1-one, two enantiomers; (1-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)((R)-4-methylmorpholin-3-yl)methanone, 5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-3-(6-(3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine 2-(1-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)ethan-1-ol, (R) 2-(1-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)ethan-1-ol, two enantiomers; (S) 2-(1-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)ethan-1-ol, two enantiomers; 3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-1-((R)-4-methylmorpholine-3-carbonyl)pyrrolidine-3-carbonitrile, (R)-4-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-1-(4-methylmorpholine-3-carbonyl)piperidine-4-carbonitrile, 1-(1-(4-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-hydroxyethan-1-one, 3-(5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)-1-(2-hydroxyacetyl)pyrrolidine-3-carbonitrile, (S)-4-((5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)methyl)-1,3-dimethylpiperazin-2-one, and (1R,4R)-5-((5-(5-(2,3-dihydro-1H-inden-4-yl)-6-methoxy-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2-yl)methyl)-2-oxa-5-azabicyclo[2.2.1]heptane 2. The compound of claim 1 selected from:

52. 52. A pharmaceutical composition comprising a compound according to any one of claims 1 to 51, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier or excipient.

53. A pharmaceutical for inhibiting FGFR3 enzyme, comprising a compound according to any one of claims 1 to 51 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 52.

54. A medicament for treating cancer in a patient, comprising a compound according to any one of claims 1 to 51 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 52.

55. 52. A medicament for treating cancer in a patient, comprising a compound according to any one of claims 1 to 51 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 52, wherein said medicament is administered in combination with another therapy or therapeutic agent.

56. 56. The pharmaceutical agent of claim 54 or 55, wherein the cancer is selected from adenocarcinoma, bladder cancer, breast cancer, cervical cancer, bile duct cancer, colorectal cancer, endometrial cancer, esophageal cancer, gallbladder cancer, gastric cancer, glioma, head and neck cancer, hepatocellular carcinoma, kidney cancer, liver cancer, lung cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, rhabdomyosarcoma, skin cancer, thyroid cancer, leukemia, multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, B-cell lymphoma, acute myeloid leukemia, Hodgkin's or non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, hairy cell lymphoma, and Burkitt's lymphoma.

57. The pharmaceutical agent of claim 54 or 55, wherein the cancer is selected from adenocarcinoma, bladder cancer, breast cancer, cervical cancer, bile duct cancer, endometrial cancer, gastric cancer, glioma, head and neck cancer, lung cancer, ovarian cancer, leukemia, and multiple myeloma.

58. 52. A medicament for treating a skeletal or chondrocyte disorder in a patient, said medicament comprising a compound according to any one of claims 1 to 51 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 52.

59. 59. The pharmaceutical composition of claim 58, wherein the skeletal or chondrocyte disorder is selected from achondroplasia, hypochondroplasia, dwarfism, thanatophoric dysplasia (TD), Apert syndrome, Crouzon syndrome, Jackson-Weiss syndrome, Behle-Stevenson gyriform scalp syndrome, Pfeiffer syndrome, and craniosynostosis syndrome.

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