Tricyclic heterocycles as FGFR inhibitors

Abstract

The present disclosure relates to tricyclic heterocycles and pharmaceutical compositions thereof that are inhibitors of FGFR enzymes and are useful in the treatment of FGFR-associated diseases, such as cancer. TIFF2023505258000208.tif40164

Description

[Background technology]

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

[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 ligands and are involved in the control of many physiological processes, including tissue development, angiogenesis, wound healing, and metabolic regulation. Upon ligand binding, the receptor undergoes dimerization and phosphorylation, 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 through overexpression of FGF ligands or FGFRs, or through 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 leading to 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 that FGFR genes are altered 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 skeletal dysplasia syndromes (Gallo et al. Cytokine & Growth Factor Reviews 2015, 26, 425-449). Mechanisms leading to aberrant ligand-dependent signaling in human disease include overexpression of FGFs and altered FGFR splicing, leading to receptors with more promiscuous ligand-binding capacity.Therefore, the development of inhibitors that target FGFR may be useful in the clinical treatment of diseases in which FGF or FGFR activity is elevated.

[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 syndromes.

[0004] There is a continuing need for the development of new drugs for the treatment of cancer, and the FGFR inhibitors described herein are useful in addressing 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 a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

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

[0009] The present disclosure is further directed to compounds of Formula (I) for use in the treatment of 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 disease mediated by an FGFR enzyme (e.g., an FGFR3 enzyme) or a mutant thereof in a patient in need thereof, comprising administering to said 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 disease mediated by an FGFR enzyme (e.g., an FGFR3 enzyme) or a mutant thereof in a patient in need thereof, comprising administering to said 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 treatment described herein.

[0012] 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

[0013] compound In one aspect, the present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein Ring A is aromatic; Y is N or C; When Y is N, X is CR 4 is, or When Y is C, X is NR 5 and [ka] represents a single or double bond, Z is N or CR6 and Cy 1 is C 6-10 aryl and 5- to 10-membered heteroaryl; each 5- to 10-membered heteroaryl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; N and S are optionally oxidized; a ring-forming carbon atom of the 5- to 10-membered heteroaryl is optionally substituted with oxo to form a carbonyl group; C 6-10 The aryl and the 5- to 10-membered heteroaryl are each optionally independently R 10 and is substituted with 1, 2, 3 or 4 substituents selected from Cy A is C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; said 4- to 10-membered heterocycloalkyl and said 5- to 10-membered heteroaryl each have at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; said N and said S are optionally oxidized; ring-forming carbon atoms of the 5- to 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl are optionally substituted with oxo to form a carbonyl group; said 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 optionally independently represented by R 20 and is substituted with 1, 2, 3 or 4 substituents selected from R 1 , R 2 , R 3 and R 6 are independently H, D, and 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, halo, CN, OR a9 , S.R.a9 , C(O)R b9 , C(O)NR c9 R d9 , C(O)OR a9 , N.R. c9 R d9 , N.R. c9 C(O)R b9 , N.R. c9 C(O)OR a9 , N.R. c9 C(O)NR c9 R d9 , N.R. c9 S(O)R b9 , N.R. c9 S(O)2R b9 , N.R. c9S (O)2NR c9 R d9 , S(O)R b9 , S(O)NR c9 R d9 , S(O)2R b9 and S(O)2NR c9 R d9 C is selected from 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 3-10 cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C 6-10 The aryl and the 5- to 10-membered heteroaryl are each optionally independently represented by R 30 and is substituted with 1, 2, 3 or 4 substituents selected from R 4 H, D, 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, halo, CN, OR a7 , S.R. a7 , C(O)R b7 , C(O)NR c7 R d7 , C(O)OR a7 , N.R. c7 R d7 , N.R. c7(O)R b7 , N.R. c7 C(O)OR a7 , N.R. c7 C(O)NR c7 R d7 , N.R. c7 S(O)R b7 , N.R. c7 S(O)2R b7 , N.R. c7 S(O)NR c7 R d7 , S(O)R b7 , S(O)NR c7 R d7 , S(O)2R b7 and S(O)2NR c7 R d7 C is selected from 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 3-10 cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C 6-10 The aryl and the 5- to 10-membered heteroaryl are each optionally independently represented by R 40 and is substituted with 1, 2, 3 or 4 substituents selected from R 5 H, D, 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, 2-6 Alkynyl, 3-10 cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C 6-10 The aryl and the 5- to 10-membered heteroaryl are each optionally independently represented by R 50 and is substituted with 1, 2, 3 or 4 substituents selected from Each R 10 independently, C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 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, 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(=NR e1 )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 C is selected from1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 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 optionally independently R 11 and is substituted with 1, 2, 3 or 4 substituents selected from Each R 11 independently, 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, 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 C(O)NR c3 R d3 , N.R. c3 S(O)R b3 , N.R. c3S(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)2NR c3 R d3 C is selected from 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 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 optionally independently R 12 and is substituted with 1, 2, 3 or 4 substituents selected from Each R 12 independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 5-6 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 C(O)NR c5 R d5 , N.R. c5S(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)2NR c5 R d5 C is selected from 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 3-6 Cycloalkyl, the C 6-10 The aryl, the 5- to 6-membered heteroaryl, and the 4- to 7-membered heterocycloalkyl are each optionally independently represented by R g and is substituted with 1, 2, 3 or 4 substituents selected from Each R 20 independently, 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, D, 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. c2C(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 )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 C is selected from 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 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 optionally independently R 21 and is substituted with 1, 2, 3, or 4 substituents selected from Each R 21 independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 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, D, CN, OR a4 , S.R. a4 , C(O)R b4 , C(O)NR c4Rd4 , 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 C(O)NR c4 R d4 , 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)2NR c4 R d4 C is selected from 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 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 optionally independently R 22and is substituted with 1, 2, 3 or 4 substituents selected from Each R 22 independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 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 C(O)NR c6 R d6 , 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)2NR c6 R d6 C is selected from 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 3-6 The cycloalkyl, the phenyl, the 5- to 6-membered heteroaryl, and the 4- to 7-membered heterocycloalkyl are each optionally independently represented by R g and is substituted with 1, 2, 3 or 4 substituents selected from Each R 30 independently, 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 a10 , S.R. a10 , C(O)R b10 , C(O)NR c10 R d10 , C(O)OR a10 , N.R. c10 R d10 , N.R. c10 C(O)R b10 , N.R. c10 C(O)OR a10 , N.R. c10 C(O)NR c10 R d10 , N.R. c10 S(O)R b10 , N.R. c10 S(O)2R b10 , N.R. c10 S(O)NR c10 R d10 , S(O)R b10 , S(O)NR c10 R d10 , S(O)2R b10 and S(O)2NR c10 R d10 C is selected from 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 3-6 The cycloalkyl, the phenyl, the 5- to 6-membered heteroaryl, and the 4- to 7-membered heterocycloalkyl are each optionally independently represented by R g and is substituted with 1, 2, 3 or 4 substituents selected from Each R 40 independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR a8 , S.R. a8 , C(O)R b8 , C(O)NR c8 R d8 , C(O)OR a8 , N.R.c8 R d8 , N.R. c8 C(O)R b8 , N.R. c8 C(O)OR a8 , N.R. c8 C(O)NR c8 R d8 , N.R. c8 S(O)R b8 , N.R. c8 S(O)2R b8 , N.R. c8 S(O)NR c8 R d8 , S(O)R b8 , S(O)NR c8 R d8 , S(O)2R b8 and S(O)2NR c8 R d8 C is selected from 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 3-6 The cycloalkyl, the phenyl, the 5- to 6-membered heteroaryl, and the 4- to 7-membered heterocycloalkyl are each optionally independently represented by R g and is substituted with 1, 2, 3 or 4 substituents selected from Each R 50 independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR a11 , S.R. a11 , C(O)R b11 , C(O)NR c11 R d11 , C(O)OR a11 , N.R. c11 R d11 , N.R. c11 C(O)R b11 , N.R. c11 C(O)OR a11 , N.R. c11 C(O)NR c11 R d11 , N.R.c11 S(O)R b11 , N.R. c11 S(O)2R b11 , N.R. c11 S(O)NR c11 R d11 , S(O)R b11 , S(O)NR c11 R d11 , S(O)2R b11 and S(O)2NR c11 R d11 C is selected from 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 3-6 The cycloalkyl, the phenyl, the 5- to 6-membered heteroaryl, and the 4- to 7-membered heterocycloalkyl are each optionally independently represented by R g and is substituted with 1, 2, 3 or 4 substituents selected from Each R a1 , R c1 and R d1 are independently 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, 2-6 Alkynyl, 3-10 cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C 6-10 The aryl and the 5- to 10-membered heteroaryl are each optionally independently represented by R 11 and is substituted with 1, 2, 3 or 4 substituents selected from Or any R bonded to the same N atom c1 and R d1 are independently R together with the N atom to which they are attached. 11 forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents selected from Each R b1 independently, 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, 2-6 Alkynyl, 3-10 cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C 6-10 The aryl and the 5- to 10-membered heteroaryl are each optionally independently represented by R 11 and is substituted with 1, 2, 3 or 4 substituents selected from Each R e1 are independently H, CN, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkylthio, C 1-6 Alkyl sulfonyl, 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 are independently 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, 2-6 Alkynyl, 3-10cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C 6-10 The aryl and the 5- to 10-membered heteroaryl are each optionally independently represented by R 21 and is substituted with 1, 2, 3 or 4 substituents selected from Or any R bonded to the same N atom c2 and R d2 are independently R together with the N atom to which they are attached. 21 forming a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 substituents selected from Each R b2 independently, 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, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 The aryl and the 5- to 10-membered heteroaryl are each optionally independently R 21 and is substituted with 1, 2, 3 or 4 substituents selected from Each R e2 are independently H, CN, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkylthio, C 1-6 Alkyl sulfonyl, 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 c3and R d3 are independently 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; 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 3-6 The cycloalkyl, the phenyl, the 5- to 6-membered heteroaryl, and the 4- to 7-membered heterocycloalkyl are each optionally independently represented by R 12 and is substituted with 1, 2, 3 or 4 substituents selected from Or any R bonded to the same N atom c3 and R d3 are independently R together with the N atom to which they are attached. 12 forming a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 substituents selected from Each R b3 independently, 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; 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 3-6 The cycloalkyl, the phenyl, the 5- to 6-membered heteroaryl, and the 4- to 7-membered heterocycloalkyl are each optionally independently represented by R 12 and is substituted with 1, 2, 3 or 4 substituents selected from Each R a4 , R c4 and R d4 are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C1-6 Haloalkyl, C 3-6 cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl; 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 3-6 The cycloalkyl, the phenyl, the 5- to 6-membered heteroaryl, and the 4- to 7-membered heterocycloalkyl are each optionally independently represented by R 22 and is substituted with 1, 2, 3 or 4 substituents selected from Or any R bonded to the same N atom c4 and R d4 are independently R together with the N atom to which they are attached. 22 forming a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents selected from Each R b4 independently, 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; 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 3-6 The cycloalkyl, the phenyl, the 5- to 6-membered heteroaryl, and the 4- to 7-membered heterocycloalkyl are each optionally independently represented by R 22 and is substituted with 1, 2, 3 or 4 substituents selected from Each R a5 , R c5 and R d5 are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 1-6 haloalkyl; 1-6 Alkyl, the C 2-6 alkenyl, and the C 2-6Each alkynyl is optionally independently R g and is substituted with 1, 2, 3, or 4 substituents selected from Or any R bonded to the same N atom c5 and R d5 are independently R together with the N atom to which they are attached. g forming a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, 3 or 4 substituents selected from Each R b5 independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 1-6 haloalkyl; 1-6 Alkyl, the C 2-6 alkenyl, and the C 2-6 Each alkynyl is optionally independently R g and is substituted with 1, 2, 3, or 4 substituents selected from Each R a6 , R c6 and R d6 are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 1-6 haloalkyl; 1-6 Alkyl, the C 2-6 alkenyl, and the C 2-6 Each alkynyl is optionally independently R g and is substituted with 1, 2, 3 or 4 substituents selected from Each R b6 independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 1-6 haloalkyl; 1-6 Alkyl, the C 2-6 alkenyl, and the C 2-6 Each alkynyl is optionally independently R g and is substituted with 1, 2, 3, or 4 substituents selected from Each R a7 , R c7 and R d7 are independently 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, 2-6 Alkynyl, 3-10 cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C 6-10 The aryl and the 5- to 10-membered heteroaryl are each optionally independently represented by R 40 and is substituted with 1, 2, 3 or 4 substituents selected from Or any R bonded to the same N atom c7 and R d7 are independently R together with the N atom to which they are attached. 40 forming a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 substituents selected from Each R b7 independently, 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, 2-6 Alkynyl, 3-10 cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C 6-10 The aryl and the 5- to 10-membered heteroaryl are each optionally independently represented by R 40 and is substituted with 1, 2, 3 or 4 substituents selected from Each R a8 , R c8and R d8 are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 1-6 haloalkyl; 1-6 Alkyl, the C 2-6 alkenyl, and the C 2-6 Each alkynyl is optionally independently R g and is substituted with 1, 2, 3 or 4 substituents selected from Each R b8 independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 1-6 haloalkyl; 1-6 Alkyl, the C 2-6 alkenyl, and the C 2-6 Each alkynyl is optionally independently R g and is substituted with 1, 2, 3 or 4 substituents selected from Each R a9 , R c9 and R d9 are independently 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, 2-6 Alkynyl, 3-10 cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C 6-10 The aryl and the 5- to 10-membered heteroaryl are each optionally independently represented by R 30 and is substituted with 1, 2, 3 or 4 substituents selected from Or any R bonded to the same N atom c9 and R d9 are independently R together with the N atom to which they are attached. 30forming a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 substituents selected from Each R b9 independently, 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, 2-6 Alkynyl, 3-10 cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C 6-10 The aryl and the 5- to 10-membered heteroaryl are each optionally independently represented by R 30 and is substituted with 1, 2, 3 or 4 substituents selected from Each R a10 , R c10 and R d10 are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 1-6 haloalkyl; 1-6 Alkyl, the C 2-6 alkenyl, and the C 2-6 Each alkynyl is optionally independently R g and is substituted with 1, 2, 3 or 4 substituents selected from Each R b10 independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 1-6 haloalkyl; 1-6 Alkyl, the C 2-6 alkenyl, and the C 2-6 Each alkynyl is optionally independently R g and is substituted with 1, 2, 3 or 4 substituents selected from Each R a11 , Rc11 and R d11 are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 1-6 haloalkyl; 1-6 Alkyl, the C 2-6 alkenyl, and the C 2-6 Each alkynyl is optionally independently R g and is substituted with 1, 2, 3 or 4 substituents selected from Each R b11 independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 1-6 haloalkyl; 1-6 Alkyl, the C 2-6 alkenyl, and the C 2-6 Each alkynyl is optionally independently R g and is substituted with 1, 2, 3 or 4 substituents selected from Each R g are independently D, 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, C1-6 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 Alkoxycarbonylamino, C 1-6 Alkylcarbonyloxy, aminocarbonyloxy, C 1-6 Alkylaminocarbonyloxy, di(C 1-6 alkyl)aminocarbonyloxy, 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 The present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: (a) (alkyl) aminocarbonyl amino;

[0014] In another aspect, the present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein Ring A is aromatic; Y is N or C; When Y is N, X is CR 4 is, or When Y is C, X is NR 5 and [ka] represents a single or double bond, Z is N or CR 6 and Cy 1is C 6-10 aryl and 5- to 10-membered heteroaryl; each 5- to 10-membered heteroaryl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; N and S are optionally oxidized; a ring-forming carbon atom of the 5- to 10-membered heteroaryl is optionally substituted with oxo to form a carbonyl group; C 6-10 The aryl and the 5- to 10-membered heteroaryl are each optionally independently R 10 and is substituted with 1, 2, 3, or 4 substituents selected from Cy A is C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; said 4- to 10-membered heterocycloalkyl and said 5- to 10-membered heteroaryl each have at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; said N and said S are optionally oxidized; ring-forming carbon atoms of the 5- to 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl are optionally substituted with oxo to form a carbonyl group; said 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 optionally independently represented by R 20 and is substituted with 1, 2, 3 or 4 substituents selected from R 1 , R 2 , R 3 and R 6 are independently H, D, and 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, halo, CN, OR a9 , S.R. a9 , C(O)R b9 , C(O)NR c9R d9 , C(O)OR a9 , N.R. c9 R d9 , N.R. c9 C(O)R b9 , N.R. c9 C(O)OR a9 , N.R. c9 S(O)R b9 , N.R. c9 S(O)2R b9 , N.R. c9 S(O)NR c9 R d9 , S(O)R b9 , S(O)NR c9 R d9 , S(O)2R b9 and S(O)2NR c9 R d9 C is selected from 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 3-10 cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C 6-10 The aryl and the 5- to 10-membered heteroaryl are each optionally independently represented by R 30 and is substituted with 1, 2, 3 or 4 substituents selected from R 4 H, D, 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, halo, CN, OR a7 , S.R. a7 , C(O)R b7 , C(O)NR c7 R d7 , C(O)OR a7 , N.R. c7 R d7 , N.R. c7 (O)R b7 , N.R. c7 C(O)OR a7 , N.R. c7 S(O)R b7 , N.R.c7 S(O)2R b7 , N.R. c7 S(O)NR c7 R d7 , S(O)R b7 , S(O)NR c7 R d7 , S(O)2R b7 and S(O)2NR c7 R d7 C is selected from 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 3-10 cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C 6-10 The aryl and the 5- to 10-membered heteroaryl are each optionally independently represented by R 40 and is substituted with 1, 2, 3 or 4 substituents selected from R 5 is 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, 2-6 Alkynyl, 3-10 cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C 6-10 The aryl and the 5- to 10-membered heteroaryl are each optionally independently represented by R 50 and is substituted with 1, 2, 3 or 4 substituents selected from Each R 10 independently, 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 1-3Alkylene, 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, 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(=NR e1 )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 C is selected from 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 3-10 cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C 6-10 aryl, the 5- to 10-membered heteroaryl, the C3-10 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 optionally independently R 11 and is substituted with 1, 2, 3 or 4 substituents selected from Each R 11 independently, 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, 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 C is selected from1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 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 optionally independently R 12 and is substituted with 1, 2, 3 or 4 substituents selected from Each R 12 independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 5-6 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)2NR c5 R d5 C is selected from 1-6Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 3-6 Cycloalkyl, the C 6-10 The aryl, the 5- to 6-membered heteroaryl, and the 4- to 7-membered heterocycloalkyl are each optionally independently represented by R g and is substituted with 1, 2, 3 or 4 substituents selected from Each R 20 independently, 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, D, 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(=NR e2 )R b2 , C(=NOR a2 )R b2 , C(=NR e2 )NR c2 R d2 , N.R. c2 C(=NR e2 )NR c2R 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 C is selected from 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 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 optionally independently R 21 and is substituted with 1, 2, 3 or 4 substituents selected from Each R 21 independently, 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, 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 C is selected from 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 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 optionally independently R 22 optionally substituted with 1, 2, 3 or 4 substituents selected from Each R 22 independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 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 Rd6 , 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)2NR c6 R d6 C is selected from 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 3-6 The cycloalkyl, the phenyl, the 5- to 6-membered heteroaryl, and the 4- to 7-membered heterocycloalkyl are each optionally independently represented by R g and is substituted with 1, 2, 3 or 4 substituents selected from Each R 30 independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR a10 , S.R. a10 , C(O)R b10 , C(O)NR c10 R d10 , C(O)OR a10 , N.R. c10 R d10 , N.R. c10 C(O)R b10 , N.R. c10 C(O)OR a10 , N.R. c10 S(O)R b10 , N.R. c10 S(O)2R b10 , N.R.c10 S(O)NR c10 R d10 , S(O)R b10 , S(O)NR c10 R d10 , S(O)2R b10 and S(O)2NR c10 R d10 C is selected from 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 3-6 The cycloalkyl, the phenyl group, the 5- to 6-membered heteroaryl, and the 4- to 7-membered heterocycloalkyl are each optionally independently represented by R g and is substituted with 1, 2, 3 or 4 substituents selected from Each R 40 independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR a8 , S.R. a8 , C(O)R b8 , C(O)NR c8 R d8 , C(O)OR a8 , N.R. c8 R d8 , N.R. c8 C(O)R b8 , N.R. c8 C(O)OR a8 , N.R. c8 S(O)R b8 , N.R. c8 S(O)2R b8 , N.R. c8 S(O)NR c8 R d8 , S(O)R b8 , S(O)NR c8 R d8 , S(O)2R b8 and S(O)2NR c8 R d8 C is selected from 1-6 Alkyl, the C 2-6Alkenyl, 2-6 Alkynyl, 3-6 The cycloalkyl, the phenyl, the 5- to 6-membered heteroaryl, and the 4- to 7-membered heterocycloalkyl are each optionally independently represented by R g and is substituted with 1, 2, 3 or 4 substituents selected from Each R 50 independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR a11 , S.R. a11 , C(O)R b11 , C(O)NR c11 R d11 , C(O)OR a11 , N.R. c11 R d11 , N.R. c11 C(O)R b11 , N.R. c11 C(O)OR a11 , N.R. c11 S(O)R b11 , N.R. c11 S(O)2R b11 , N.R. c11 S(O)NR c11 R d11 , S(O)R b11 , S(O)NR c11 R d11 , S(O)2R b11 and S(O)2NR c11 R d11 C is selected from 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 3-6 The cycloalkyl, the phenyl, the 5- to 6-membered heteroaryl, and the 4- to 7-membered heterocycloalkyl are each optionally independently represented by R g and is substituted with 1, 2, 3 or 4 substituents selected from Each R a1 , R c1 and R d1are independently 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, 2-6 Alkynyl, 3-10 cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C 6-10 The aryl and the 5- to 10-membered heteroaryl are each optionally independently represented by R 11 and is substituted with 1, 2, 3 or 4 substituents selected from Or any R bonded to the same N atom c1 and R d1 are independently R together with the N atom to which they are attached. 11 forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents selected from Each R b1 independently, 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, 2-6 Alkynyl, 3-10 cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C 6-10 The aryl and the 5- to 10-membered heteroaryl are each optionally independently represented by R 11 and is substituted with 1, 2, 3 or 4 substituents selected from Each R e1 are independently H, CN, and C 1-6 Alkyl, C 1-6 Haloalkyl, C1-6 Alkylthio, C 1-6 Alkyl sulfonyl, 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 are independently 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, 2-6 Alkynyl, 3-10 cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C 6-10 The aryl and the 5- to 10-membered heteroaryl are each optionally independently represented by R 21 and is substituted with 1, 2, 3 or 4 substituents selected from Or any R bonded to the same N atom c2 and R d2 are independently R together with the N atom to which they are attached. 21 forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents selected from Each R b2 independently, 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 6-10aryl and 5- to 10-membered heteroaryl; 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 3-10 cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C 6-10 The aryl and the 5- to 10-membered heteroaryl are each optionally independently represented by R 21 and is substituted with 1, 2, 3 or 4 substituents selected from Each R e2 are independently H, CN, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkylthio, C 1-6 Alkyl sulfonyl, 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 are independently 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; 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 3-6 The cycloalkyl, the phenyl, the 5- to 6-membered heteroaryl, and the 4- to 7-membered heterocycloalkyl are each optionally independently represented by R 12 and is substituted with 1, 2, 3 or 4 substituents selected from Or any R bonded to the same N atom c3 and R d3are independently R together with the N atom to which they are attached. 12 forming a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 substituents selected from Each R b3 independently, 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; 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 3-6 The cycloalkyl, the phenyl, the 5- to 6-membered heteroaryl, and the 4- to 7-membered heterocycloalkyl are each optionally independently represented by R 12 and is substituted with 1, 2, 3 or 4 substituents selected from Each R a4 , R c4 and R d4 are independently 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; 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 3-6 The cycloalkyl, the phenyl, the 5- to 6-membered heteroaryl, and the 4- to 7-membered heterocycloalkyl are each optionally independently represented by R 22 and is substituted with 1, 2, 3 or 4 substituents selected from Or any R bonded to the same N atom c4 and R d4 are independently R together with the N atom to which they are attached. 22forming a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents selected from Each R b4 independently, 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; 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 3-6 The cycloalkyl, the phenyl, the 5- to 6-membered heteroaryl, and the 4- to 7-membered heterocycloalkyl are each optionally independently represented by R 22 and is substituted with 1, 2, 3 or 4 substituents selected from Each R a5 , R c5 and R d5 are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 1-6 haloalkyl; 1-6 Alkyl, the C 2-6 alkenyl, and the C 2-6 Each alkynyl is optionally independently R g and is substituted with 1, 2, 3 or 4 substituents selected from Or any R bonded to the same N atom c5 and R d5 are independently R together with the N atom to which they are attached. g forming a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, 3 or 4 substituents selected from Each R b5 independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 1-6 haloalkyl; 1-6Alkyl, the C 2-6 alkenyl, and the C 2-6 Each alkynyl is optionally independently R g and is substituted with 1, 2, 3 or 4 substituents selected from Each R a6 , R c6 and R d6 are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 1-6 haloalkyl; 1-6 Alkyl, the C 2-6 alkenyl, and the C 2-6 Each alkynyl is optionally independently R g and is substituted with 1, 2, 3 or 4 substituents selected from Each R b6 independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 1-6 haloalkyl; 1-6 Alkyl, the C 2-6 alkenyl, and the C 2-6 Each alkynyl is optionally independently R g and is substituted with 1, 2, 3 or 4 substituents selected from Each R a7 , R c7 and R d7 are independently 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, 2-6 Alkynyl, 3-10 cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C 6-10The aryl and the 5- to 10-membered heteroaryl are each optionally independently represented by R 40 and is substituted with 1, 2, 3 or 4 substituents selected from Or any R bonded to the same N atom c7 and R d7 are independently R together with the N atom to which they are attached. 40 forming a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 substituents selected from Each R b7 independently, 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, 2-6 Alkynyl, 3-10 cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C 6-10 The aryl and the 5- to 10-membered heteroaryl are each optionally independently represented by R 40 and is substituted with 1, 2, 3 or 4 substituents selected from Each R a8 , R c8 and R d8 are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 1-6 haloalkyl; 1-6 Alkyl, the C 2-6 alkenyl, and the C 2-6 Each alkynyl is optionally independently R g and is substituted with 1, 2, 3 or 4 substituents selected from Each R b8 independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C1-6 haloalkyl; 1-6 Alkyl, the C 2-6 alkenyl, and the C 2-6 Each alkynyl is optionally independently R g and is substituted with 1, 2, 3 or 4 substituents selected from Each R a9 , R c9 and R d9 are independently 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, 2-6 Alkynyl, 3-10 cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C 6-10 The aryl and the 5- to 10-membered heteroaryl are each optionally independently represented by R 30 and is substituted with 1, 2, 3 or 4 substituents selected from Or any R bonded to the same N atom c9 and R d9 are independently R together with the N atom to which they are attached. 30 forming a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 substituents selected from Each R b9 independently, 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, 2-6 Alkynyl, 3-10cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C 6-10 The aryl and the 5- to 10-membered heteroaryl are each optionally independently represented by R 30 and is substituted with 1, 2, 3 or 4 substituents selected from Each R a10 , R c10 and R d10 are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 1-6 haloalkyl; 1-6 Alkyl, the C 2-6 alkenyl, and the C 2-6 Each alkynyl is optionally independently R g and is substituted with 1, 2, 3 or 4 substituents selected from Each R b10 independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 1-6 haloalkyl; 1-6 Alkyl, the C 2-6 alkenyl, and the C 2-6 Each alkynyl is optionally independently R g and is substituted with 1, 2, 3 or 4 substituents selected from Each R a11 , R c11 and R d11 are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 1-6 haloalkyl; 1-6 Alkyl, the C 2-6 alkenyl, and the C 2-6 Each alkynyl is optionally independently R g and is substituted with 1, 2, 3 or 4 substituents selected from Each R b11 independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, and C 1-6 haloalkyl; 1-6 Alkyl, the C 2-6 alkenyl, and the C 2-6 Each alkynyl is optionally independently R g and is substituted with 1, 2, 3 or 4 substituents selected from Each R g are independently D, 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 Alkoxycarbonylamino, C 1-6 Alkylcarbonyloxy, aminocarbonyloxy, C 1-6 Alkylaminocarbonyloxy, di(C 1-6 alkyl)aminocarbonyloxy, C 1-6 Alkyl sulfonyl amino, amino sulfonyl, C1-6 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 The present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: (a) (alkyl) aminocarbonyl amino;

[0015] In one embodiment, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: Ring A is aromatic; Y is N or C; When Y is N, X is CR 4 is, or When Y is C, X is NR 5 and [ka] represents a single or double bond, Z is N or CR 6 and Cy 1 is selected from 5-10 membered heteroaryl; each 5-10 membered heteroaryl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; N and S are optionally oxidized; a ring-forming carbon atom of a 5-10 membered heteroaryl is optionally substituted with oxo to form a carbonyl group; each 5-10 membered heteroaryl is optionally independently selected from R 10 and is substituted with 1, 2, 3, or 4 substituents selected from Cy A is C 6-10selected from aryl and 5- to 10-membered heteroaryl; each 5- to 10-membered heteroaryl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; N and S are optionally oxidized; a ring-forming carbon atom of the 5- to 10-membered heteroaryl is optionally substituted with oxo to form a carbonyl group; C 6-10 The aryl and the 5- to 10-membered heteroaryl are each independently R 20 optionally substituted with 1, 2, 3, or 4 substituents selected from R 1 , R 2 , R 3 , and R 6 are independently H, D, and C 1-6 Alkyl, C 1-6 Haloalkyl, Halo, CN, OR a9 and NR c9 R d9 Selected from; R 4 H, D, 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, halo, CN, OR a7 and NR c7 R d7 C is selected from 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 3-10 cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C 6-10 The aryl and the 5- to 10-membered heteroaryl are each optionally independently represented by R 40 and is substituted with 1, 2, 3 or 4 substituents selected from R 5 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl and C 6-10aryl; 1-6 Alkyl, the C 3-10 Cycloalkyl and the C 6-10 Each aryl is optionally independently R 50 and is substituted with 1, 2, 3 or 4 substituents selected from Each R 10 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, halo, D, CN, OR a1 and NR c1 R d1 C is selected from 1-6 Alkyl, the C 3-10 The cycloalkyl and the 4- to 10-membered heterocycloalkyl are each optionally independently R 11 and is substituted with 1, 2, 3 or 4 substituents selected from Each R 11 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, halo, D, CN, OR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , N.R. c3 R d3 and NR c3 C(O)R b3 C is selected from 1-6 Alkyl and the C 3-10 Each cycloalkyl is optionally independently R 12 and is substituted with 1, 2, 3 or 4 substituents selected from Each R 12 independently, C 1-6 Alkyl, Halo, D, CN, OR a5 and NR c5 R d5 is selected from Each R 20 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10Cycloalkyl, halo, D, CN, OR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , S(O)NR c2 R d2 and S(O)2R b2 C is selected from 1-6 Alkyl and the C 3-10 Each cycloalkyl is optionally independently R 21 and is substituted with 1, 2, 3 or 4 substituents selected from Each R 21 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, Halo, D, CN, OR a4 and NR c4 R d4 is selected from Each R 40 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, Halo, D, CN, OR a8 and NR c8 R d8 is selected from Each R 50 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, Halo, D, CN, OR a11 and NR c11 R d11 is selected from Each R a1 , R c1 and R d1 are independently 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 The cycloalkyl and the 4- to 10-membered heterocycloalkyl are each optionally independently R 11 and is substituted with 1, 2, 3 or 4 substituents selected from Or any R bonded to the same N atom c1 and Rd1 are independently R together with the N atom to which they are attached. 11 forming a 4-, 5-, or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents selected from Each R a2 , R c2 and R d2 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 cycloalkyl; 1-6 Alkyl and the C 3-10 Each cycloalkyl is optionally independently R 21 and is substituted with 1, 2, 3 or 4 substituents selected from Each R b2 independently, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 cycloalkyl; 1-6 Alkyl and the C 3-10 Each cycloalkyl is optionally independently R 21 and is substituted with 1, 2, 3 or 4 substituents selected from Each R a3 , R c3 and R d3 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 cycloalkyl; 1-6 Alkyl and the C 3-6 Each cycloalkyl is optionally independently R 12 and is substituted with 1, 2, 3 or 4 substituents selected from Each R b3 independently, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 cycloalkyl; 1-6 Alkyl and the C 3-6 Each cycloalkyl is optionally independently R 12 and is substituted with 1, 2, 3 or 4 substituents selected from Each R a4 , R c4 , and R d4 are independently H, C 1-6 Alkyl, and C 1-6 haloalkyl; Each R a5 , R c5 , and R d5 are independently H, C 1-6 Alkyl, and C 1-6 haloalkyl; Each R a7 , R c7 , and R d7 are independently H, C 1-6 Alkyl, and C 1-6 haloalkyl; Each R a8 , R c8 , and R d8 are independently H, C 1-6 Alkyl, and C 1-6 haloalkyl; Each R a9 , R c9 , and R d9 are independently H, C 1-6 Alkyl, and C 1-6 haloalkyl; Each R a11 , R c11 , and R d11 are independently H, C 1-6 Alkyl, and C 1-6 haloalkyl, or a pharmaceutically acceptable salt thereof.

[0016] In one embodiment, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: Ring A is aromatic; Y is N or C; When Y is N, X is CR 4 is, or When Y is C, X is NR 5 and [ka] represents a single or double bond, Z is N or CH; Cy 1 is selected from 5- to 6-membered heteroaryls; each 5- to 6-membered heteroaryl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; each 5- to 6-membered heteroaryl is optionally independently selected from R 10 and is substituted with 1, 2, 3 or 4 substituents selected from Cy A is selected from phenyl and 5- to 6-membered heteroaryl; each of the 5- to 6-membered heteroaryls has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; each of the phenyl and 5- to 6-membered heteroaryls is optionally independently selected from R 20 and is substituted with 1, 2, 3 or 4 substituents selected from R 1 , R 2 , R 3 are H, respectively, R 4 H, halo, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-7 cycloalkyl, phenyl, and 5- to 6-membered heteroaryl, 1-6 Alkyl, the C 2-6 Alkenyl, 3-7 The cycloalkyl, the phenyl and the 5- to 6-membered heteroaryl are each optionally represented by R 40 and is substituted with one or two substituents selected from R 5 is C 1-6 is alkyl, Each R 10 independently, C 1-6 Alkyl, 4-6 membered heterocycloalkyl and C 3-7 cycloalkyl, each of which is optional and independently selected from R 11 and is substituted with one or two substituents selected from Each R 11 independently, C1-6 Alkyl, C 3-7 Cycloalkyl, CN, OR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 and S(O)2R b3 C is selected from 1-6 Alkyl and the C 3-7 Each cycloalkyl is optionally independently R 12 and is substituted with one or two substituents selected from Each R 12 independently, C 1-6 Alkyl, Halo, D, CN, OR a5 and NR c5 R d5 Selected from; Each R 20 independently, halo, C 1-6 Alkyl and OR a2 is selected from Each R 21 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, Halo, D, CN, OR a4 and NR c4 R d4 is selected from Each R 40 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, Halo, D, CN, OR a8 and NR c8 R d8 is selected from Each R a2 is H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 cycloalkyl; 1-6 Alkyl and the C 3-10 Each cycloalkyl is optionally independently R 21 and is substituted with 1, 2, 3 or 4 substituents selected from Each R a3 , R c3 and R d3 are independently H, C1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 cycloalkyl; 1-6 Alkyl and the C 3-6 Each cycloalkyl is optionally independently R 12 and is substituted with 1, 2, 3 or 4 substituents selected from Each R b3 independently, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 cycloalkyl; 1-6 Alkyl and the C 3-6 Each cycloalkyl is optionally independently R 12 and is substituted with 1, 2, 3 or 4 substituents selected from Each R a4 , R c4 , and R d4 are independently H, C 1-6 Alkyl, and C 1-6 haloalkyl; Each R a5 , R c5 , and R d5 are independently H, C 1-6 Alkyl, and C 1-6 haloalkyl; Each R a8 , R c8 , and R d8 are independently H, C 1-6 Alkyl, and C 1-6 haloalkyl, or a pharmaceutically acceptable salt thereof.

[0017] In one embodiment, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: Ring A is aromatic; Y is N or C; When Y is N, X is CR 4 is, or When Y is C, X is NR 5 and [ka] represents a single or double bond, Z is N or CH; Cy 1 is selected from phenyl and 5- to 6-membered heteroaryl; each 5- to 6-membered heteroaryl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; each phenyl and 5- to 6-membered heteroaryl is optionally independently selected from R 10 and is substituted with 1, 2, 3 or 4 substituents selected from Cy A is phenyl, 5- to 6-membered heteroaryl, 4- to 10-membered heterocycloalkyl, and C 3-7 cycloalkyl; 5-6 membered heteroaryl having at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; phenyl, 5-6 membered heteroaryl, 4-10 membered heterocycloalkyl, and C 3-7 Each cycloalkyl is optionally independently R 20 and is substituted with 1, 2, 3 or 4 substituents selected from R 1 H, OR a9 or NR c9 R d9 and R 2 and R 3 are H, respectively, R 4 H, halo, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-7 cycloalkyl, phenyl, and 5- to 6-membered heteroaryl, 1-6 Alkyl, the C 2-6 Alkenyl, 3-7 The cycloalkyl, the phenyl and the 5- to 6-membered heteroaryl are each optionally represented by R 40 and is substituted with one or two substituents selected from R 5 is C 1-6 is alkyl, Each R 10 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, phenyl, 4-6 membered heterocycloalkyl and C 3-7 cycloalkyl, each of which is optional and independently selected from R 11 and is substituted with one or two substituents selected from Each R 11 independently, C 1-6 Alkyl, CN, C(O)R b3 , C(O)OR a3 , N.R. c3 C(O)R b3 , OR a3 , C(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)NR c3 R d3 , S(O)NR c3 R d3 , S(O)2R b3 , phenyl, and 4- to 6-membered heterocycloalkyl; 1-6 The alkyl, the phenyl and the 4- to 6-membered heterocycloalkyl are each optionally independently R 12 and is substituted with one or two substituents selected from Each R 12 independently, C 1-6 Alkyl, Halo, D, CN, OR a5 , N.R. c5 R d5 and 5-6 membered heteroaryl; Each R 20 are independently halo, CN, C 1-6 Alkyl, C 1-6 Haloalkyl and NR c2 C(O)R b2 Selected from C 1-6 Alkyl is optionally OR a4 is replaced by Each R 21 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, Halo, D, CN, ORa4 and NR c4 R d4 is selected from Each R 40 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, Halo, D, CN, OR a8 and NR c8 R d8 is selected from Each R a2 is H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 cycloalkyl; 1-6 Alkyl and the C 3-10 Each cycloalkyl is optionally independently R 21 and is substituted with 1, 2, 3 or 4 substituents selected from Each R a3 , R c3 and R d3 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 cycloalkyl; 1-6 Alkyl and the C 3-6 Each cycloalkyl is optionally independently R 12 and is substituted with 1, 2, 3 or 4 substituents selected from Each R b3 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocycloalkyl; each optionally and independently R 12 and is substituted with 1, 2, 3 or 4 substituents selected from Each R a4 , R c4 , and R d4 are independently H, C 1-6 Alkyl, and C 1-6 haloalkyl; Each R a5 , R c5 , and R d5 are independently H, C1-6 Alkyl, and C 1-6 haloalkyl; Each R a8 , R c8 , and R d8 are independently H, C 1-6 Alkyl, and C 1-6 haloalkyl, or a pharmaceutically acceptable salt thereof.

[0018] In one aspect, the present disclosure provides a compound of formula (IA) or formula (IB): [ka] or a pharmaceutically acceptable salt thereof.

[0019] In one aspect, the present disclosure provides a compound of formula (IA): [ka] or a pharmaceutically acceptable salt thereof.

[0020] In one aspect, the present disclosure provides a compound of formula (IB): [ka] or a pharmaceutically acceptable salt thereof.

[0021] In one aspect, the disclosure provides a compound of formula (IA) or a pharmaceutically acceptable salt thereof, wherein: Z is N, Cy 1 is C 6-10 aryl and 5- to 10-membered heteroaryl; each 5- to 10-membered heteroaryl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; N and S are optionally oxidized; a ring-forming carbon atom of the 5- to 10-membered heteroaryl is optionally substituted with oxo to form a carbonyl group; C 6-10The aryl and the 5- to 10-membered heteroaryl are each optionally independently R 10 and is substituted with 1, 2, 3, or 4 substituents selected from Cy A is C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl, and 5-10-membered heteroaryl; the 4-10-membered heterocycloalkyl and 5-10-membered heteroaryl each have at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; N and S are optionally oxidized; the ring-forming carbon atoms of the 5-10-membered heteroaryl and 4-10-membered heterocycloalkyl are optionally substituted with oxo to form a carbonyl group; C3-10 cycloalkyl, 4-10-membered heterocycloalkyl, C6-10 The aryl and 5- to 10-membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R20; R 1 , R 2 , R 3 and R 6 are independently H, D, and 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, halo, CN, OR a9 , S.R. a9 , C(O)R b9 , C(O)NR c9 R d9 , C(O)OR a9 , N.R. c9 R d9 , N.R. c9 C(O)R b9 , N.R. c9 C(O)OR a9 , N.R. c9 C(O)NR c9 R d9 , N.R. c9 S(O)R b9 , N.R.c9 S(O)2R b9 , N.R. c9S (O)2NR c9 R d9 , S(O)R b9 , S(O)NR c9 R d9 , S(O)2R b9 and S(O)2NR c9 R d9 C is selected from 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 3-10 cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C 6-10 The aryl and the 5- to 10-membered heteroaryl are each optionally independently represented by R 30 and is substituted with 1, 2, 3 or 4 substituents selected from R 5 H, D, 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, 2-6 Alkynyl, 3-10 cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C 6-10 The aryl and the 5- to 10-membered heteroaryl are each optionally independently represented by R 50 and is substituted with 1, 2, 3 or 4 substituents selected from Each R 10 independently, 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 1-3Alkylene, 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, 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(=NR e1 )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 C is selected from 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 3-10 cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C 6-10 aryl, the 5- to 10-membered heteroaryl, the C3-10 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 optionally independently R 11 and is substituted with 1, 2, 3 or 4 substituents selected from Each R 11 independently, 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, 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 C(O)NR c3 R d3 , 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 b3and S(O)2NR c3 R d3 C is selected from 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 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 optionally independently R 12 and is substituted with 1, 2, 3 or 4 substituents selected from Each R 12 independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 5-6 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 C(O)NR c5 R d5 , N.R. c5 S(O)R b5 , N.R. c5 S(O)2R b5 , N.R. c5 S(O)NR c5 R d5 , S(O)R b5 , S(O)NR c5 Rd5 , S(O)2R b5 and S(O)2NR c5 R d5 C is selected from 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 3-6 Cycloalkyl, the C 6-10 The aryl, the 5- to 6-membered heteroaryl, and the 4- to 7-membered heterocycloalkyl are each optionally independently represented by R g and is substituted with 1, 2, 3 or 4 substituents selected from Each R 20 independently, 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, D, 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(=NR e2 )R b2 , C(=NOR a2 )R b2 , C(=NRe2 )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 C is selected from 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 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 optionally independently R 21 and is substituted with 1, 2, 3, or 4 substituents selected from Each R 21 independently, 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 C(O)NR c4 R d4 , 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)2NR c4 R d4 C is selected from 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 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 optionally independently R 22 and is substituted with 1, 2, 3 or 4 substituents selected from Each R 22 independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6Haloalkyl, C 3-6 Cycloalkyl, 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 C(O)NR c6 R d6 , 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)2NR c6 R d6 C is selected from 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 3-6 The cycloalkyl, the phenyl, the 5- to 6-membered heteroaryl, and the 4- to 7-membered heterocycloalkyl are each optionally independently represented by R g and is substituted with 1, 2, 3 or 4 substituents selected from Each R 30 independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR a10 , S.R. a10 , C(O)R b10 , C(O)NR c10 R d10, C(O)OR a10 , N.R. c10 R d10 , N.R. c10 C(O)R b10 , N.R. c10 C(O)OR a10 , N.R. c10 C(O)NR c10 R d10 , N.R. c10 S(O)R b10 , N.R. c10 S(O)2R b10 , N.R. c10 S(O)NR c10 R d10 , S(O)R b10 , S(O)NR c10 R d10 , S(O)2R b10 and S(O)2NR c10 R d10 C is selected from 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 3-6 The cycloalkyl, the phenyl, the 5- to 6-membered heteroaryl, and the 4- to 7-membered heterocycloalkyl are each optionally independently represented by R g and is substituted with 1, 2, 3 or 4 substituents selected from Each R 50 independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR a11 , S.R. a11 , C(O)R b11 , C(O)NR c11 R d11 , C(O)OR a11 , N.R. c11 R d11 , N.R. c11 C(O)R b11 , N.R. c11 C(O)OR a11 , N.R. c11 C(O)NR c11 Rd11 , N.R. c11 S(O)R b11 , N.R. c11 S(O)2R b11 , N.R. c11 S(O)NR c11 R d11 , S(O)R b11 , S(O)NR c11 R d11 , S(O)2R b11 and S(O)2NR c11 R d11 C is selected from 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 3-6 The cycloalkyl, the phenyl, the 5- to 6-membered heteroaryl, and the 4- to 7-membered heterocycloalkyl are each optionally independently represented by R g and is substituted with 1, 2, 3 or 4 substituents selected from Each R a1 , R c1 and R d1 are independently 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, 2-6 Alkynyl, 3-10 cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C 6-10 The aryl and the 5- to 10-membered heteroaryl are each optionally independently represented by R 11 and is substituted with 1, 2, 3 or 4 substituents selected from Or any R bonded to the same N atom c1 and R d1 are independently R together with the N atom to which they are attached. 11forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents selected from Each R b1 independently, 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, 2-6 Alkynyl, 3-10 cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C 6-10 The aryl and the 5- to 10-membered heteroaryl are each optionally independently represented by R 11 and is substituted with 1, 2, 3 or 4 substituents selected from Each R e1 are independently H, CN, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkylthio, C 1-6 Alkyl sulfonyl, 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 are independently 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; 1-6Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 3-10 cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C 6-10 The aryl and the 5- to 10-membered heteroaryl are each optionally independently represented by R 21 and is substituted with 1, 2, 3 or 4 substituents selected from Or any R bonded to the same N atom c2 and R d2 are independently R together with the N atom to which they are attached. 21 forming a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 substituents selected from Each R b2 independently, 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, 2-6 Alkynyl, 3-10 cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C 6-10 The aryl and the 5- to 10-membered heteroaryl are each optionally independently represented by R 21 and is substituted with 1, 2, 3 or 4 substituents selected from Each R e2 are independently H, CN, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkylthio, C 1-6 Alkyl sulfonyl, C 1-6 Alkyl carbonyl, C 1-6 Alkylaminosulfonyl, Carbamyl, C 1-6 Alkylcarbamyl, di(C 1-6 Alkyl)carbamyl, aminosulfonyl, C 1-6Alkylaminosulfonyl, and di(C 1-6 alkyl)aminosulfonyl; Each R a3 , R c3 and R d3 are independently 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; 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 3-6 The cycloalkyl, the phenyl, the 5- to 6-membered heteroaryl, and the 4- to 7-membered heterocycloalkyl are each optionally independently represented by R 12 and is substituted with 1, 2, 3 or 4 substituents selected from Or any R bonded to the same N atom c3 and R d3 are independently R together with the N atom to which they are attached. 12 forming a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents selected from Each R b3 independently, 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; 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 3-6 The cycloalkyl, the phenyl, the 5- to 6-membered heteroaryl, and the 4- to 7-membered heterocycloalkyl are each optionally independently represented by R 12 and is substituted with 1, 2, 3 or 4 substituents selected from Each R a4 , R c4and R d4 are independently 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; 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 3-6 The cycloalkyl, the phenyl, the 5- to 6-membered heteroaryl, and the 4- to 7-membered heterocycloalkyl are each optionally independently represented by R 22 and is substituted with 1, 2, 3 or 4 substituents selected from Or any R bonded to the same N atom c4 and R d4 are independently R together with the N atom to which they are attached. 22 forming a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents selected from Each R b4 independently, 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; 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 3-6 The cycloalkyl, the phenyl, the 5- to 6-membered heteroaryl, and the 4- to 7-membered heterocycloalkyl are each optionally independently represented by R 22 and is substituted with 1, 2, 3 or 4 substituents selected from Each R a5 , R c5 and R d5 are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C1-6 haloalkyl; 1-6 Alkyl, the C 2-6 alkenyl, and the C 2-6 Each alkynyl is optionally independently R g and is substituted with 1, 2, 3 or 4 substituents selected from Or any R bonded to the same N atom c5 and R d5 are independently R together with the N atom to which they are attached. g forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents selected from Each R b5 independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 1-6 haloalkyl; 1-6 Alkyl, the C 2-6 alkenyl, and the C 2-6 Each alkynyl is optionally independently R g and is substituted with 1, 2, 3, or 4 substituents selected from Each R a6 , R c6 and R d6 are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 1-6 haloalkyl; 1-6 Alkyl, the C 2-6 alkenyl, and the C 2-6 Each alkynyl is optionally independently R g and is substituted with 1, 2, 3 or 4 substituents selected from Each R b6 independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 1-6 haloalkyl; 1-6 Alkyl, the C 2-6 alkenyl, and the C2-6 Each alkynyl is optionally independently R g and is substituted with 1, 2, 3 or 4 substituents selected from Each R a9 , R c9 and R d9 are independently 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, 2-6 Alkynyl, 3-10 cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C 6-10 The aryl and the 5- to 10-membered heteroaryl are each optionally independently represented by R 30 and is substituted with 1, 2, 3 or 4 substituents selected from Or any R bonded to the same N atom c9 and R d9 are independently R together with the N atom to which they are attached. 30 forming a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents selected from Each R b9 independently, 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, 2-6 Alkynyl, 3-10 cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C 6-10The aryl and the 5- to 10-membered heteroaryl are each optionally independently represented by R 30 and is substituted with 1, 2, 3 or 4 substituents selected from Each R a10 , R c10 and R d10 are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 1-6 haloalkyl; 1-6 Alkyl, the C 2-6 alkenyl, and the C 2-6 Each alkynyl is optionally independently R g and is substituted with 1, 2, 3 or 4 substituents selected from Each R b10 independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 1-6 haloalkyl; 1-6 Alkyl, the C 2-6 alkenyl, and the C 2-6 Each alkynyl is independently R g optionally substituted with 1, 2, 3 or 4 substituents selected from Each R a11 , R c11 and R d11 are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 1-6 haloalkyl; 1-6 Alkyl, the C 2-6 alkenyl, and the C 2-6 Each alkynyl is optionally independently R g and is substituted with 1, 2, 3 or 4 substituents selected from Each R b11 independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 1-6 haloalkyl;1-6 Alkyl, the C 2-6 alkenyl, and the C 2-6 Each alkynyl is optionally independently R g and is substituted with 1, 2, 3 or 4 substituents selected from Each R g are independently D, 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 Alkoxycarbonylamino, C 1-6 Alkylcarbonyloxy, aminocarbonyloxy, C 1-6 Alkylaminocarbonyloxy, di(C 1-6 alkyl)aminocarbonyloxy, C1 -6 Alkyl sulfonyl amino, amino sulfonyl, C 1-6 Alkylaminosulfonyl, di(C 1-6Alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 Alkylaminosulfonylamino, di(C 1-6 Alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 Alkylaminocarbonylamino and di(C 1-6 The present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: (a) (alkyl) aminocarbonyl amino;

[0022] In one aspect, the disclosure provides a compound of formula (IA) or a pharmaceutically acceptable salt thereof, wherein: Z is N, Cy 1 is selected from 5- to 10-membered heteroaryls; each 5- to 10-membered heteroaryl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; a ring-forming carbon atom of a 5- to 10-membered heteroaryl is optionally substituted with oxo to form a carbonyl group; each 5- to 10-membered heteroaryl is optionally independently selected from R 10 and is substituted with one or two substituents selected from Cy A is a 4- to 10-membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; 4- to 10-membered heterocycloalkyl and 5- to 10-membered heteroaryl each have at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; ring-forming carbon atoms of 5- to 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl are optionally substituted with oxo to form a carbonyl group; 4- to 10-membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are each optionally independently R 20 and is substituted with one, two, or three substituents selected from R 1 , R 2 , and R 3 are independently H, D, and C 1-6 Alkyl, C 1-6selected from haloalkyl, halo, and CN; R 5 H, D, C 1-6 Alkyl and C 1-6 haloalkyl; Each R 10 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, halo, D, CN, OR a1 and NR c1 R d1 C is selected from 1-6 Alkyl, the C 3-10 The cycloalkyl and the 4- to 10-membered heterocycloalkyl are each optionally independently R 11 and is substituted with one, two or three substituents selected from Each R 11 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, Halo, D, CN, OR a3 , C(O)R b3 , C(O)NR c3 R d3 and NR c3 R d3 is selected from Each R 20 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, Halo, D, CN, OR a2 and NR c2 R d2 is selected from Each R a1 , R c1 and R d1 are independently 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 The cycloalkyl and the 4- to 10-membered heterocycloalkyl are each optionally independently R 11 and is substituted with one or two substituents selected from Or any R bonded to the same N atom c1 and R d1 are independently R together with the N atom to which they are attached. 11 forming a 4-, 5-, or 6-membered heterocycloalkyl group optionally substituted with one or two substituents selected from Each R a2 , R c2 , and R d2 are independently H, C 1-6 Alkyl, and C 1-6 haloalkyl; Each R a3 , R c3 and R d3 are independently H, C 1-6 Alkyl and C 1-6 haloalkyl; Each R b3 independently, C 1-6 Alkyl and C 1-6 haloalkyl, or a pharmaceutically acceptable salt thereof.

[0023] In one aspect, the disclosure provides a compound of formula (IA), or a pharmaceutically acceptable salt thereof, wherein: Z is N, Cy 1 is a 5- to 10-membered heteroaryl; each 5- to 10-membered heteroaryl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; N and S are optionally oxidized; a ring-forming carbon atom of a 5- to 10-membered heteroaryl is optionally substituted with oxo to form a carbonyl group; C 6-10 The aryl and the 5- to 10-membered heteroaryl are each optionally independently R 10 and is substituted with 1, 2, 3, or 4 substituents selected from Cy A is C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10aryl, and 5- to 10-membered heteroaryl; said 4- to 10-membered heterocycloalkyl and said 5- to 10-membered heteroaryl each have at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; said N and said S are optionally oxidized; ring-forming carbon atoms of the 5- to 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl are optionally substituted with oxo to form a carbonyl group; said 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 optionally independently represented by R 20 and is substituted with 1, 2, 3 or 4 substituents selected from R 1 , R 2 , and R 3 are independently H, D, and C 1-6 Alkyl, C 1-6 Haloalkyl, Halo, CN, OR a9 and NR c9 R d9 is selected from R 5 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl and C 6-10 aryl; 1-6 Alkyl, the C 3-10 Cycloalkyl and the C 6-10 Each aryl is optionally independently R 50 and is substituted with 1, 2, 3 or 4 substituents selected from Each R 10 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, halo, D, CN, OR a1 and NR c1 R d1 C is selected from 1-6 Alkyl, the C 3-10The cycloalkyl and the 4- to 10-membered heterocycloalkyl are each optionally independently R 11 and is substituted with 1, 2, 3 or 4 substituents selected from Each R 11 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, halo, D, CN, OR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , N.R. c3 R d3 and S(O)R2R b3 C is selected from 1-6 Alkyl and the C 3-10 Each cycloalkyl is optionally independently R 12 and is substituted with 1, 2, 3 or 4 substituents selected from Each R 12 independently, C 1-6 Alkyl, Halo, D, CN, OR a5 and NR c5 R d5 is selected from Each R 20 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, halo, D, CN, OR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , S(O)NR c2 R d2 and S(O)2R b2 C is selected from 1-6 Alkyl and the C 3-10 Each cycloalkyl is optionally independently R 21 and is substituted with 1, 2, 3 or 4 substituents selected from Each R 21 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, Halo, D, CN, OR a4and NR c4 R d4 is selected from Each R 50 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, Halo, D, CN, OR a11 and NR c11 R d11 is selected from Each R a1 , R c1 and R d1 are independently 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 The cycloalkyl and the 4- to 10-membered heterocycloalkyl are each optionally independently R 11 and is substituted with 1, 2, 3 or 4 substituents selected from Or any R bonded to the same N atom c1 and R d1 are independently R together with the N atom to which they are attached. 11 forming a 4-, 5-, or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents selected from Each R a2 , R c2 and R d2 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 cycloalkyl; 1-6 Alkyl and the C 3-10 Each cycloalkyl is optionally independently R 21 and is substituted with 1, 2, 3 or 4 substituents selected from Each R b2 independently, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 cycloalkyl; 1-6 Alkyl and the C 3-10Each cycloalkyl is optionally independently R 21 and is substituted with 1, 2, 3 or 4 substituents selected from Each R a3 , R c3 and R d3 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 cycloalkyl; 1-6 Alkyl and the C 3-6 Each cycloalkyl is optionally independently R 12 and is substituted with 1, 2, 3 or 4 substituents selected from Each R b3 independently, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 cycloalkyl; 1-6 Alkyl and the C 3-6 Each cycloalkyl is optionally independently R 12 and is substituted with 1, 2, 3 or 4 substituents selected from Each R a4 , R c4 , and R d4 are independently H, C 1-6 Alkyl, and C 1-6 haloalkyl; Each R a5 , R c5 , and R d5 are independently H, C 1-6 Alkyl, and C 1-6 haloalkyl; Each R a9 , R c9 , and R d9 are independently H, C 1-6 Alkyl, and C 1-6 haloalkyl; Each R a11 , R c11 , and R d11 are independently H, C 1-6 Alkyl, and C 1-6 haloalkyl, or a pharmaceutically acceptable salt thereof.

[0024] In one aspect, the disclosure provides a compound of formula (IB), or a pharmaceutically acceptable salt thereof, wherein: Z is N or CR 6 and Cy 1 is C 6-10 aryl and 5- to 10-membered heteroaryl; each 5- to 10-membered heteroaryl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; N and S are optionally oxidized; a ring-forming carbon atom of the 5- to 10-membered heteroaryl is optionally substituted with oxo to form a carbonyl group; C 6-10 The aryl and the 5- to 10-membered heteroaryl are each optionally independently R 10 and is substituted with 1, 2, 3, or 4 substituents selected from Cy A is C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl, and 5-10-membered heteroaryl; the 4-10-membered heterocycloalkyl and 5-10-membered heteroaryl each have at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; N and S are optionally oxidized; the ring-forming carbon atoms of the 5-10-membered heteroaryl and 4-10-membered heterocycloalkyl are optionally substituted with oxo to form a carbonyl group; C3-10 cycloalkyl, 4-10-membered heterocycloalkyl, C6-10 The aryl and 5- to 10-membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R20; R 1 , R 2 , R 3 and R 6 are independently H, D, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, halo, CN, OR a9 , S.R. a9 , C(O)R b9 , C(O)NR c9 R d9 , C(O)OR a9 , N.R. c9 R d9 , N.R. c9 C(O)R b9 , N.R. c9 C(O)OR a9 , N.R. c9 C(O)NR c9 R d9 , N.R. c9 S(O)R b9 , N.R. c9 S(O)2R b9 , N.R. c9 S(O)NR c9 R d9 , S(O)R b9 , S(O)NR c9 R d9 , S(O)2R b9 and S(O)2NR c9 R d9 C is selected from 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 3-10 cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C 6-10 The aryl and the 5- to 10-membered heteroaryl are each optionally independently represented by R 30 and is substituted with 1, 2, 3 or 4 substituents selected from R 4 H, D, 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, halo, CN, OR a7 , S.R. a7 , C(O)R b7 , C(O)NRc7 R d7 , C(O)OR a7 , N.R. c7 R d7 , N.R. c7 (O)R b7 , N.R. c7 C(O)OR a7 , N.R. c7 C(O)NR c7 R d7 , N.R. c7 S(O)R b7 , N.R. c7 S(O)2R b7 , N.R. c7 S(O)NR c7 R d7 , S(O)R b7 , S(O)NR c7 R d7 , S(O)2R b7 and S(O)2NR c7 R d7 C is selected from 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 3-10 cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C 6-10 The aryl and the 5- to 10-membered heteroaryl are each optionally independently represented by R 40 and is substituted with 1, 2, 3 or 4 substituents selected from Each R 10 independently, 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, 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(=NR e1 )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 C is selected from 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 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 1-3Each alkylene is optionally independently R 11 and is substituted with 1, 2, 3 or 4 substituents selected from Each R 11 independently, 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, 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 C(O)NR c3 R d3 , 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)2NR c3 R d3 C is selected from 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 3-10 cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C6-10 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 optionally independently R 12 and is substituted with 1, 2, 3 or 4 substituents selected from Each R 12 independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 5-6 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 C(O)NR c5 R d5 , N.R. c5 S(O)R b5 , N.R. c5 S(O)2R b5 , N.R. c5 S(O)NR c5 R d5 , S(O)R b5 , S(O)NR c5 R d5 , S(O)2R b5 and S(O)2NR c5 R d5 C is selected from 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 3-6Cycloalkyl, the C 6-10 The aryl, the 5- to 6-membered heteroaryl, and the 4- to 7-membered heterocycloalkyl are each optionally independently represented by R g and is substituted with 1, 2, 3 or 4 substituents selected from Each R 20 independently, 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, D, 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(=NR e2 )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. c2S(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 C is selected from 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 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 optionally independently R 21 and is substituted with 1, 2, 3 or 4 substituents selected from Each R 21 independently, 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, 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 C(O)NR c4 R d4 , 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)2NR c4 R d4 C is selected from 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 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 optionally independently R 22 and is substituted with 1, 2, 3 or 4 substituents selected from Each R 22 independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 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 C(O)NR c6 R d6 , 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)2NR c6 R d6 C is selected from 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 3-6 The cycloalkyl, the phenyl, the 5- to 6-membered heteroaryl, and the 4- to 7-membered heterocycloalkyl are each optionally independently represented by R g and is substituted with 1, 2, 3 or 4 substituents selected from Each R 30 independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR a10 , S.R. a10 , C(O)R b10 , C(O)NR c10 R d10 , C(O)OR a10 , N.R. c10 R d10 , N.R. c10 C(O)R b10 , N.R. c10 C(O)OR a10 , N.R. c10 C(O)NR c10 Rd10 , N.R. c10 S(O)R b10 , N.R. c10 S(O)2R b10 , N.R. c10 S(O)NR c10 R d10 , S(O)R b10 , S(O)NR c10 R d10 , S(O)2R b10 and S(O)2NR c10 R d10 C is selected from 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 3-6 The cycloalkyl, the phenyl, the 5- to 6-membered heteroaryl, and the 4- to 7-membered heterocycloalkyl are each optionally independently represented by R g and is substituted with 1, 2, 3 or 4 substituents selected from Each R 40 independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR a8 , S.R. a8 , C(O)R b8 , C(O)NR c8 R d8 , C(O)OR a8 , N.R. c8 R d8 , N.R. c8 C(O)R b8 , N.R. c8 C(O)OR a8 , N.R. c8 C(O)NR c8 R d8 , N.R. c8 S(O)R b8 , N.R. c8 S(O)2R b8 , N.R. c8 S(O)NR c8 R d8 , S(O)R b8, S(O)NR c8 R d8 , S(O)2R b8 and S(O)2NR c8 R d8 C is selected from 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 3-6 The cycloalkyl, the phenyl, the 5- to 6-membered heteroaryl, and the 4- to 7-membered heterocycloalkyl are each optionally independently represented by R g and is substituted with 1, 2, 3 or 4 substituents selected from Each R a1 , R c1 and R d1 are independently 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, 2-6 Alkynyl, 3-10 cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C 6-10 The aryl and the 5- to 10-membered heteroaryl are each optionally independently represented by R 11 and is substituted with 1, 2, 3 or 4 substituents selected from Or any R bonded to the same N atom c1 and R d1 are independently R together with the N atom to which they are attached. 11 forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents selected from Each R b1 independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl; 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 3-10 cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C 6-10 The aryl and the 5- to 10-membered heteroaryl are each optionally independently represented by R 11 and is substituted with 1, 2, 3 or 4 substituents selected from Each R e1 are independently H, CN, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkylthio, C 1-6 Alkyl sulfonyl, 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 are independently 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, 2-6 Alkynyl, 3-10 cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C 6-10 The aryl and the 5- to 10-membered heteroaryl are each optionally independently represented by R 21 and is substituted with 1, 2, 3 or 4 substituents selected from Or any R bonded to the same N atom c2 and R d2 are independently R together with the N atom to which they are attached. 21 forming a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents selected from Each R b2 independently, 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, 2-6 Alkynyl, 3-10 cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C 6-10 The aryl and the 5- to 10-membered heteroaryl are each optionally independently represented by R 21 and is substituted with 1, 2, 3 or 4 substituents selected from Each R e2 are independently H, CN, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkylthio, C 1-6 Alkyl sulfonyl, 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 are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6Haloalkyl, C 3-6 cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl; 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 3-6 The cycloalkyl, the phenyl, the 5- to 6-membered heteroaryl, and the 4- to 7-membered heterocycloalkyl are each optionally independently represented by R 12 and is substituted with 1, 2, 3 or 4 substituents selected from Or any R bonded to the same N atom c3 and R d3 are independently R together with the N atom to which they are attached. 12 forming a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents selected from Each R b3 independently, 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; 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 3-6 The cycloalkyl, the phenyl, the 5- to 6-membered heteroaryl, and the 4- to 7-membered heterocycloalkyl are each optionally independently represented by R 12 and is substituted with 1, 2, 3 or 4 substituents selected from Each R a4 , R c4 and R d4 are independently 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; 1-6 Alkyl, the C2-6 Alkenyl, 2-6 Alkynyl, 3-6 The cycloalkyl, the phenyl, the 5- to 6-membered heteroaryl, and the 4- to 7-membered heterocycloalkyl are each optionally independently represented by R 22 and is substituted with 1, 2, 3 or 4 substituents selected from Or any R bonded to the same N atom c4 and R d4 are independently R together with the N atom to which they are attached. 22 forming a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents selected from Each R b4 independently, 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; 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 3-6 The cycloalkyl, the phenyl, the 5- to 6-membered heteroaryl, and the 4- to 7-membered heterocycloalkyl are each optionally independently represented by R 22 and is substituted with 1, 2, 3 or 4 substituents selected from Each R a5 , R c5 and R d5 are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 1-6 haloalkyl; 1-6 Alkyl, the C 2-6 alkenyl, and the C 2-6 Each alkynyl is optionally independently R g and is substituted with 1, 2, 3 or 4 substituents selected from Or any R bonded to the same N atom c5 and Rd5 are independently R together with the N atom to which they are attached. g forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents selected from Each R b5 independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 1-6 haloalkyl; 1-6 Alkyl, the C 2-6 alkenyl, and the C 2-6 Each alkynyl is optionally independently R g and is substituted with 1, 2, 3 or 4 substituents selected from Each R a6 , R c6 and R d6 are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 1-6 haloalkyl; 1-6 Alkyl, the C 2-6 alkenyl, and the C 2-6 Each alkynyl is optionally independently R g and is substituted with 1, 2, 3 or 4 substituents selected from Each R b6 independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 1-6 haloalkyl; 1-6 Alkyl, the C 2-6 alkenyl, and the C 2-6 Each alkynyl is optionally independently R g and is substituted with 1, 2, 3 or 4 substituents selected from Each R a7 , R c7 and R d7 are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, 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, 2-6 Alkynyl, 3-10 cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C 6-10 The aryl and the 5- to 10-membered heteroaryl are each optionally independently represented by R 40 and is substituted with 1, 2, 3 or 4 substituents selected from Or any R bonded to the same N atom c7 and R d7 are independently R together with the N atom to which they are attached. 40 forming a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 substituents selected from Each R b7 independently, 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, 2-6 Alkynyl, 3-10 cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C 6-10 The aryl and the 5- to 10-membered heteroaryl are each optionally independently represented by R 40 and is substituted with 1, 2, 3 or 4 substituents selected from Each R a8 , R c8 and R d8 are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 1-6haloalkyl; 1-6 Alkyl, the C 2-6 alkenyl, and the C 2-6 Each alkynyl is optionally independently R g and is substituted with 1, 2, 3 or 4 substituents selected from Each R b8 independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 1-6 haloalkyl; 1-6 Alkyl, the C 2-6 alkenyl, and the C 2-6 Each alkynyl is optionally independently R g and is substituted with 1, 2, 3 or 4 substituents selected from Each R a9 , R c9 and R d9 are independently 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, 2-6 Alkynyl, 3-10 cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C 6-10 The aryl and the 5- to 10-membered heteroaryl are each optionally independently represented by R 30 and is substituted with 1, 2, 3 or 4 substituents selected from Or any R bonded to the same N atom c9 and R d9 are independently R together with the N atom to which they are attached. 30 forming a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents selected from Each R b9 independently, 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; 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 3-10 cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C 6-10 The aryl and the 5- to 10-membered heteroaryl are each optionally independently represented by R 30 and is substituted with 1, 2, 3 or 4 substituents selected from Each R a10 , R c10 and R d10 are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 1-6 haloalkyl; 1-6 Alkyl, the C 2-6 alkenyl, and the C 2-6 Each alkynyl is optionally independently R g and is substituted with 1, 2, 3 or 4 substituents selected from Each R b10 independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 1-6 haloalkyl; 1-6 Alkyl, the C 2-6 alkenyl, and the C 2-6 Each alkynyl is optionally independently R g and is substituted with 1, 2, 3 or 4 substituents selected from Each R g are independently D, OH, NO2, CN, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6Haloalkyl, 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 Alkoxycarbonylamino, C 1-6 Alkylcarbonyloxy, aminocarbonyloxy, C 1-6 Alkylaminocarbonyloxy, di(C 1-6 alkyl)aminocarbonyloxy, 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 The present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: (a) (alkyl) aminocarbonyl amino;

[0025] In one aspect, the disclosure provides a compound of formula (IB), or a pharmaceutically acceptable salt thereof, wherein: Z is N or CR 6 and Cy 1 is selected from 5-10 membered heteroaryl; each 5-10 membered heteroaryl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; N and S are optionally oxidized; a ring-forming carbon atom of a 5-10 membered heteroaryl is optionally substituted with oxo to form a carbonyl group; each 5-10 membered heteroaryl is optionally independently selected from R 10 and is substituted with 1, 2, 3 or 4 substituents selected from Cy A is C 6-10 selected from aryl and 5- to 10-membered heteroaryl; each 5- to 10-membered heteroaryl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; N and S are optionally oxidized; a ring-forming carbon atom of the 5- to 10-membered heteroaryl is optionally substituted with oxo to form a carbonyl group; C 6-10 The aryl and the 5- to 10-membered heteroaryl are each independently R 20 optionally substituted with 1, 2, 3, or 4 substituents selected from R 1 , R 2 , R 3 , and R 6 are independently H, D, and C 1-6 Alkyl, C 1-6 Haloalkyl, Halo, CN, OR a9 and NR c9 R d9 is selected from R 4 H, D, 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 6-10Aryl, 5-10 membered heteroaryl, halo, CN, OR a7 and NR c7 R d7 C is selected from 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 3-10 cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C 6-10 The aryl and the 5- to 10-membered heteroaryl are each optionally independently represented by R 40 and is substituted with 1, 2, 3 or 4 substituents selected from Each R 10 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, halo, D, CN, OR a1 and NR c1 R d1 C is selected from 1-6 Alkyl, the C 3-10 The cycloalkyl and the 4- to 10-membered heterocycloalkyl are each optionally independently R 11 and is substituted with 1, 2, 3 or 4 substituents selected from Each R 11 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, halo, D, CN, OR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , N.R. c3 R d3 and NR c3 C(O)R b3 C is selected from 1-6 Alkyl and the C 3-10 Each cycloalkyl is optionally independently R 12 and is substituted with 1, 2, 3 or 4 substituents selected from Each R 12 independently, C 1-6 Alkyl, Halo, D, CN, ORa5 and NR c5 R d5 is selected from Each R 20 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, halo, D, CN, OR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , S(O)NR c2 R d2 and S(O)2R b2 C is selected from 1-6 Alkyl and the C 3-10 Each cycloalkyl is optionally independently R 21 and is substituted with 1, 2, 3 or 4 substituents selected from Each R 21 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, Halo, D, CN, OR a4 and NR c4 R d4 is selected from Each R 40 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, Halo, D, CN, OR a8 and NR c8 R d8 is selected from Each R a1 , R c1 and R d1 are independently 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 The cycloalkyl and the 4- to 10-membered heterocycloalkyl are each optionally independently R 11 and is substituted with 1, 2, 3 or 4 substituents selected from Or any R bonded to the same N atom c1 and Rd1 are independently R together with the N atom to which they are attached. 11 forming a 4-, 5-, or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents selected from Each R a2 , R c2 and R d2 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 cycloalkyl; 1-6 Alkyl and the C 3-10 Each cycloalkyl is optionally independently R 21 and is substituted with 1, 2, 3 or 4 substituents selected from Each R b2 independently, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 cycloalkyl; 1-6 Alkyl and the C 3-10 Each cycloalkyl is optionally independently R 21 and is substituted with 1, 2, 3 or 4 substituents selected from Each R a3 , R c3 and R d3 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 cycloalkyl; 1-6 Alkyl and the C 3-6 Each cycloalkyl is optionally independently R 12 and is substituted with 1, 2, 3 or 4 substituents selected from Each R b3 independently, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 cycloalkyl; 1-6 Alkyl and the C 3-6 Each cycloalkyl is optionally independently R 12 and is substituted with 1, 2, 3 or 4 substituents selected from Each R a4 , R c4 , and R d4 are independently H, C 1-6 Alkyl, and C 1-6 haloalkyl; Each R a5 , R c5 , and R d5 are independently H, C 1-6 Alkyl, and C 1-6 haloalkyl; Each R a7 , R c7 , and R d7 are independently H, C 1-6 Alkyl, and C 1-6 haloalkyl; Each R a8 , R c8 , and R d8 are independently H, C 1-6 Alkyl, and C 1-6 haloalkyl; Each R a9 , R c9 , and R d9 are independently H, C 1-6 Alkyl, and C 1-6 haloalkyl, or a pharmaceutically acceptable salt thereof.

[0026] In one aspect, the disclosure provides a compound of formula (IB), or a pharmaceutically acceptable salt thereof, wherein: Z is N or CR 6 and Cy 1 is C 6-10 aryl and 5- to 10-membered heteroaryl; each 5- to 10-membered heteroaryl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; a ring-forming carbon atom of a 5- to 10-membered heteroaryl is optionally substituted with oxo to form a carbonyl group; C 6-10 The aryl and the 5- to 10-membered heteroaryl are each optionally independently R 10 and is substituted with one or two substituents selected from Cy A is C 3-10 Cycloalkyl and C 6-10 aryl; C 3-10 Cycloalkyl and C 6-10 Each aryl is optionally independently R 20 and is substituted with one, two or three substituents selected from R 1 are independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, Halo, CN, OR a9 and NR c9 R d9 is selected from R 2 and R 3 are each independently H, D and C 1-6 alkyl, R 6 are independently H, D, and C 1-6 Alkyl, C 1-6 Haloalkyl, Halo, CN, OR a9 and NR c9 R d9 is selected from R 4 H, D, 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, halo, CN, OR a7 and NR c7 R d7 C is selected from 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 3-10 cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C 6-10 The aryl and the 5- to 10-membered heteroaryl are each optionally independently represented by R 40 and is substituted with one or two substituents selected from Each R 10independently, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl, halo, D, CN, OR a1 and NR c1 R d1 C is 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 optionally independently represented by R 11 and is substituted with one, two or three substituents selected from Each R 11 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl, 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 , N.R. c3 C(O)NR c3 R d3 , S(O)2R b3 and S(O)2NR c3 R d3 C is selected from 1-6 Alkyl and the C 6-10 Each aryl is optionally independently R 12 and is substituted with one or two substituents selected from Each R 12 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, 5-6 membered heteroaryl, halo, D, CN, OR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 and NRc5 R d5 is selected from Each R 20 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, Halo, D, CN, OR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , N.R. c2 R d2 and NR c2 C(O)R b2 C is selected from 1-6 The alkyl is optionally independently R 21 and is substituted with one or two substituents selected from Each R 21 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, Halo, D, CN, OR a4 and NR c4 R d4 is selected from Each R 40 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, Halo, D, CN, OR a8 and NR c8 R d8 is selected from Each R a1 , R c1 and R d1 are independently 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 The cycloalkyl and the 4- to 10-membered heterocycloalkyl are each optionally independently R 11 and is substituted with one or two substituents selected from Or any R bonded to the same N atom c1 and R d1 are independently R together with the N atom to which they are attached. 11forming a 4-, 5- or 6-membered heterocycloalkyl group optionally substituted with one or two substituents selected from Each R a2 , R c2 , and R d2 are independently H, C 1-6 Alkyl, and C 1-6 haloalkyl; 1-6 Alkyl is independently R 21 optionally substituted with one or two substituents selected from Each R b2 independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 1-6 haloalkyl; 1-6 Alkyl, the C 2-6 alkenyl, and the C 2-6 Each alkynyl is optionally independently R 21 and is substituted with one or two substituents selected from Each R a3 , R c3 , and R d3 are independently H, C 1-6 Alkyl, and C 1-6 haloalkyl; 1-6 Alkyl is independently R 12 optionally substituted with one or two substituents selected from Or any R bonded to the same N atom c3 and R d3 are independently R together with the N atom to which they are attached. 12 forming a 4-, 5-, or 6-membered heterocycloalkyl group optionally substituted with one or two substituents selected from Each R b3 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl; 1-6 Alkyl, the C 3-6The cycloalkyl, the phenyl, the 5- to 6-membered heteroaryl, and the 4- to 7-membered heterocycloalkyl are each optionally independently selected from R 12 and is substituted with one or two substituents selected from Each R a4 , R c4 , and R d4 are independently H, C 1-6 Alkyl, and C 1-6 haloalkyl; Each R a5 , R c5 , and R d5 are independently H, C 1-6 Alkyl, and C 1-6 haloalkyl; Each R b5 independently, C 1-6 Alkyl and C 1-6 haloalkyl; Each R a7 , R c7 , and R d7 are independently H, C 1-6 Alkyl, and C 1-6 haloalkyl; 1-6 Alkyl is independently R 40 optionally substituted with one or two substituents selected from Each R a8 , R c8 , and R d8 are independently H, C 1-6 Alkyl, and C 1-6 haloalkyl; Each R a9 , R c9 and R d9 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 selected from cycloalkyl and 4- to 10-membered heterocycloalkyl; Or any R bonded to the same N atom c9 and R d9together with the N atom to which they are attached form a 4-, 5-, or 6-membered heterocycloalkyl group, or a pharmaceutically acceptable salt thereof.

[0027] In some embodiments, X is CR 4 and Y is N.

[0028] In some embodiments, X is NR 5 and Y is C.

[0029] In some embodiments, Z is N.

[0030] In some embodiments, Z is CR 6 is.

[0031] In some embodiments, Cy 1 is a 5- to 10-membered heteroaryl; each 5- to 10-membered heteroaryl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; N and S are optionally oxidized; a ring-forming carbon atom of a 5- to 10-membered heteroaryl is optionally substituted with oxo to form a carbonyl group; and a 5- to 10-membered heteroaryl is independently selected from R 10 is optionally substituted with 1, 2, 3, or 4 substituents selected from:

[0032] In some embodiments, Cy 1 is a 5- to 6-membered heteroaryl; each 5- to 6-membered heteroaryl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; N and S are optionally oxidized; a ring-forming carbon atom of a 5- to 6-membered heteroaryl is optionally substituted with oxo to form a carbonyl group; and a 5- to 6-membered heteroaryl is independently selected from R 10 is optionally substituted with 1, 2, 3, or 4 substituents selected from:

[0033] In some embodiments, Cy 1are optional and independently R 10 In some embodiments, Cy is a 5- to 10-membered heteroaryl substituted with 1, 2, 3, or 4 substituents selected from 1 are optional and independently R 10 is a 5- to 6-membered heteroaryl substituted with 1, 2, 3 or 4 substituents selected from:

[0034] In some embodiments, Cy 1 are optional and independently R 10 In some embodiments, Cy is a 5- to 10-membered heteroaryl substituted with one or two substituents selected from 1 are optional and independently R 10 In some embodiments, Cy is a 5- to 6-membered heteroaryl substituted with one or two substituents selected from 1 are optional and independently R 10 In some embodiments, Cy is a 5-membered heteroaryl substituted with one or two substituents selected from 1 are optional and independently R 10 and wherein the aryl is a 6-membered heteroaryl substituted with one or two substituents selected from:

[0035] In some embodiments, Cy 1 are each arbitrary and independently R 10 In some embodiments, Cy is a 5- to 10-membered heteroaryl or phenyl substituted with 1, 2, 3, or 4 substituents selected from: 1 are each arbitrary and independently R 10 and R is a 5- to 10-membered heteroaryl or phenyl substituted with one or two substituents selected from:

[0036] In some embodiments, Cy 1 are each arbitrary and independently R 10 In some embodiments, Cy is a 5- to 6-membered heteroaryl or phenyl substituted with 1, 2, 3, or 4 substituents selected from 1 are each arbitrary and independently R 10and R is a 5- to 6-membered heteroaryl or phenyl substituted with one or two substituents selected from:

[0037] In some embodiments, Cy 1 are optional and independently R 10 In some embodiments, Cy is phenyl substituted with 1, 2, 3, or 4 substituents selected from 1 are optional and independently R 10 and n is 1 or 2.

[0038] In some embodiments, Cy 1 are each arbitrary and independently R 10 In some embodiments, Cy is pyrazolyl or pyridinyl substituted with one or two substituents selected from 1 are independently 10 In some embodiments, Cy is pyrazolyl optionally substituted with one or two substituents selected from 1 are independently 10 and pyridinyl optionally substituted with one or two substituents selected from:

[0039] In some embodiments, Cy 1 are each arbitrary and independently R 10 and R is a pyrazolyl, pyridinyl, or phenyl substituted with one or two substituents selected from:

[0040] In some embodiments, Cy 1 are 1-methyl-1H-pyrazol-4-yl, 1,3-dimethyl-1H-pyrazol-4-yl, 1-(1-acetylpyrrolidin-3-yl)-1H-pyrazol-4-yl, 1-(4-carboxycyclohexyl)-1H-pyrazol-4-yl, 1-(4-acetamido)-1H-pyrazol-4-yl, S cyclohexyl)-1H-pyrazol-4-yl, 1-(3-hydroxycyclobutyl)-1H-pyrazol-4-yl, and 6-(4-acetylpiperazin-1-yl)pyridin-3-yl.

[0041] In some embodiments, Cy 1 are 1-methyl-1H-pyrazol-4-yl, 1,3-dimethyl-1H-pyrazol-4-yl, 1-(1-acetylpyrrolidin-3-yl)-1H-pyrazol-4-yl, 1-(4-carboxycyclohexyl)-1H-pyrazol-4-yl, 1-(4-acetamido)-1H-pyrazol-4-yl, Scyclohexyl)-1H-pyrazol-4-yl, 1-(3-hydroxycyclobutyl)-1H-pyrazol-4-yl, 6-(4-acetylpiperazin-1-yl)pyridin-3-yl, 1-(1-(2-hydroxyacetyl)pyrrolidin-3-yl)-1H-pyrazol-4-yl, 1-(1-(1-aminocyclopropane-1-carbonyl)azetidin-3-yl)-1H-pyrazol-4-yl, 1-(1-(2-(1H-imidazol-1-yl)acetyl)azetidin-3-yl)-1H-pyrazol-4-yl, 1-(1-(oxazole- 4-carbonyl)azetidin-3-yl)-1H-pyrazol-4-yl, 1-(1-(4-aminotetrahydro-2H-pyran-4-carbonyl)azetidin-3-yl)-1H-pyrazol-4-yl, 1-(1-(2-cyanoacetyl)azetidin-3-yl)-1H-pyrazol-4-yl, 1-(4-carboxy-3-fluorobenzyl)-1H-pyrazol-4-yl, 1-(4-(dimethylcarbamoyl)phenyl)-1H-pyrazol-4-yl, 1-((1r,4r)-4-(2-methoxyacetamido)cyclohexyl)-1H-pyrazol-4-yl 1-((1r,4r)-4-(3,3-dimethylureido)cyclohexyl)-1H-pyrazol-4-yl, 1-(2-acetyl-2-azaspiro[3.5]nonan-7-yl)-1H-pyrazol-4-yl, 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl, 1-((1r,4r)-4-hydroxycyclohexyl)-1H-pyrazol-4-yl, 1-(4-carboxy-4-methylcyclohexyl)-1H-pyrazol-4-yl, 1-(1-(dimethylcarbamoyl)pyrrolidin-3-yl) -1H-pyrazol-4-yl, 1-(1-(N,N-dimethylsulfamoyl)pyrrolidin-3-yl)-1H-pyrazol-4-yl, 1-(3-(2-hydroxyacetyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1H-pyrazol-4-yl, 1-(1-(morpholine-4-carbonyl)pyrrolidin-3-yl)-1H-pyrazol-4-yl, 1-(3-(2-hydroxyacetyl)-3-azabicyclo[4.1.0]heptan-6-yl)-1H-pyrazol-4-yl, 1-(3-acetyl-3-azabicyclo[4.1.0]heptan-1-yl)-1H-pyrazol-4-yl, 6-(1-(2-hydroxyacetyl)azetidin-3-yl)pyridin-3-yl, 5-(1-acetylazetidin-3-yl)pyridin-3-yl, 4-(1-acetylazetidin-3-yl)phenyl), 1-cyclopropyl-1H-pyrazol-4-yl, 1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl, 1-(oxetan-3-yl)-1H-pyrazol-4-yl, 1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl, 1-isopropyl-1H-pyrazol-4-yl, 1-(difluoromethyl)-1H-pyrazol-4-yl, 1-( 2-cyanoethyl)-1H-pyrazol-4-yl, 1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl, 1-(cyanomethyl)-1H-pyrazol-4-yl, 1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl, 1-(1-hydroxy-2-methylpropan-2-yl)-1H-pyrazol-4-yl, 1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-4-yl, 1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl, 1-(2-morpholinoethyl)-1H-pyrazol-4-yl, and 1-(2-hydroxyethyl)-1H-pyrazol-4-yl.

[0042] In some embodiments, Cy 1 are 1-methyl-1H-pyrazol-4-yl, 1,3-dimethyl-1H-pyrazol-4-yl, 1-(1-acetylpyrrolidin-3-yl)-1H-pyrazol-4-yl, 1-(4-carboxycyclohexyl)-1H-pyrazol-4-yl, 1-(4-acetamido)-1H-pyrazol-4-yl, Scyclohexyl)-1H-pyrazol-4-yl, 1-(3-hydroxycyclobutyl)-1H-pyrazol-4-yl, 6-(4-acetylpiperazin-1-yl)pyridin-3-yl, 1-(1-(2-hydroxyacetyl)pyrrolidin-3-yl)-1H-pyrazol-4-yl, 1-(1-(1-aminocyclopropane-1-carbonyl)azetidin-3-yl)-1H-pyrazol-4-yl, 1-(1-(2-(1H-imidazol-1-yl)acetyl)azetidin-3-yl)-1H-pyrazol-4-yl, 1-(1-(oxazole- 4-carbonyl)azetidin-3-yl)-1H-pyrazol-4-yl, 1-(1-(4-aminotetrahydro-2H-pyran-4-carbonyl)azetidin-3-yl)-1H-pyrazol-4-yl, 1-(1-(2-cyanoacetyl)azetidin-3-yl)-1H-pyrazol-4-yl, 1-(4-carboxy-3-fluorobenzyl)-1H-pyrazol-4-yl, 1-(4-(dimethylcarbamoyl)phenyl)-1H-pyrazol-4-yl, 1-((1r,4r)-4-(2-methoxyacetamido)cyclohexyl)-1H-pyrazol-4-yl 1-((1r,4r)-4-(3,3-dimethylureido)cyclohexyl)-1H-pyrazol-4-yl, 1-(2-acetyl-2-azaspiro[3.5]nonan-7-yl)-1H-pyrazol-4-yl, 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl, 1-((1r,4r)-4-hydroxycyclohexyl)-1H-pyrazol-4-yl, 1-(4-carboxy-4-methylcyclohexyl)-1H-pyrazol-4-yl, 1-(1-(dimethylcarbamoyl)pyrrolidin-3-yl) -1H-pyrazol-4-yl, 1-(1-(N,N-dimethylsulfamoyl)pyrrolidin-3-yl)-1H-pyrazol-4-yl, 1-(3-(2-hydroxyacetyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1H-pyrazol-4-yl, 1-(1-(morpholine-4-carbonyl)pyrrolidin-3-yl)-1H-pyrazol-4-yl, 1-(3-(2-hydroxyacetyl)-3-azabicyclo[4.1.0]heptan-6-yl)-1H-pyrazol-4-yl, 1-(3-acetyl-3-azabicyclo[4.1.0]heptan-1-yl)-1H-pyrazol-4-yl, 6-(1-(2-hydroxyacetyl)azetidin-3-yl)pyridin-3-yl, 5-(1-acetylazetidin-3-yl)pyridin-3-yl, 1-cyclopropyl-1H-pyrazol-4-yl, 1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl, 1-(oxetan-3-yl)-1H-pyrazol-4-yl, 1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl, 1-isopropyl-1H-pyrazol-4-yl, 1-(difluoromethyl)-1H-pyrazol-4-yl, 1-(2-cyanoethyl)-1H- The pyrazol-4-yl is selected from pyrazol-4-yl, 1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl, 1-(cyanomethyl)-1H-pyrazol-4-yl, 1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl, 1-(1-hydroxy-2-methylpropan-2-yl)-1H-pyrazol-4-yl, 1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-4-yl, 1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl, 1-(2-morpholinoethyl)-1H-pyrazol-4-yl, and 1-(2-hydroxyethyl)-1H-pyrazol-4-yl.

[0043] In some embodiments, each R 10 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, halo, D, CN, OR a1 and NR c1 R d1 C is selected from 1-6 Alkyl, the C 3-10 The cycloalkyl and the 4- to 10-membered heterocycloalkyl are each optionally independently R 11 is substituted with 1, 2, 3 or 4 substituents selected from:

[0044] In some embodiments, each R 10 independently, C 1-6 Alkyl, C 1-6Haloalkyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, halo, D, CN, OR a1 and NR c1 R d1 C is selected from 1-6 Alkyl, the C 6-10 Aryl, the C 3-10 The cycloalkyl and the 4- to 10-membered heterocycloalkyl are each optionally independently R 11 is substituted with 1, 2, 3 or 4 substituents selected from:

[0045] In some embodiments, each R 10 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 4-6 membered heterocycloalkyl, halo, D, CN, OR a1 and NR c1 R d1 C is selected from 1-6 Alkyl, the C 3-7 The cycloalkyl and the 4- to 6-membered heterocycloalkyl are each optionally independently R 11 and is substituted with one or two substituents selected from:

[0046] In some embodiments, each R 10 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 4-6 membered heterocycloalkyl, halo, D, CN, OR a1 and NR c1 R d1 C is selected from 1-6 Alkyl, the C 6-10 Aryl, the C 3-7 The cycloalkyl and the 4- to 6-membered heterocycloalkyl are each optionally independently R 11 and is substituted with one or two substituents selected from:

[0047] In some embodiments, each R 10 independently, C 1-6 Alkyl, 4-10 membered heterocycloalkyl and C 3-10 cycloalkyl, each of which is optional and independently selected from R 11 and is substituted with one or two substituents selected from:

[0048] In some embodiments, each R 10 independently, C 1-6 Alkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and C 3-10 cycloalkyl, each of which is optional and independently selected from R 11 and is substituted with one or two substituents selected from:

[0049] In some embodiments, each R 10 independently, C 1-6 Alkyl, 4-6 membered heterocycloalkyl and C 3-7 cycloalkyl, each of which is optional and independently selected from R 11 In some embodiments, each R 10 is independently R 11 C optionally substituted with one or two substituents selected from 1-6 In some embodiments, each R 10 is independently R 11 In some embodiments, each R 10 is independently R 11 C optionally substituted with one or two substituents selected from 3-7 cycloalkyl.

[0050] In some embodiments, each R 10 independently, C 1-6 Alkyl, 4-6 membered heterocycloalkyl, C 6-10 Aryl and C3-7 cycloalkyl, each of which is optional and independently selected from R 11 In some embodiments, each R 10 independently, C 1-6 Alkyl, 4-6 membered heterocycloalkyl, phenyl, and C 3-7 cycloalkyl, each of which is optional and independently selected from R 11 and is substituted with one or two substituents selected from:

[0051] In some embodiments, each R 10 are independently selected from methyl, pyrrolidinyl, cyclohexyl, cyclobutyl, and piperazinyl, each of which is optional, and independently R 11 In some embodiments, each R 10 are independently selected from methyl, pyrrolidinyl, cyclohexyl, and cyclobutyl, each of which is optional, and independently R 11 In some embodiments, each R 10 is independently selected from methyl and piperazinyl, each of which is optional, and independently R 11 and is substituted with one or two substituents selected from:

[0052] In some embodiments, each R 10 are independently methyl, ethyl, isopropyl, 2-methylpropyl, difluoromethyl, cyclopropyl, cyclobutyl, cyclohexyl, phenyl, piperzinyl, azaspiro[3.5]nona D Tetrahydro-2H-pyranyl, azabicyclo[3.1.0]hexa D Azabicyclo[4.1.0]hepta D aryl, tetrahydrofuranyl, oxetanyl, and piperidinyl, each of which is optional and independently R 11 and is substituted with one or two substituents selected from:

[0053] In some embodiments, each R 10 are independently selected from methyl, ethyl, isopropyl, 2-methylpropyl, and difluoromethyl, and methyl and ethyl are each optionally independently selected from R 11 In some embodiments, each R 10 is independently selected from methyl, ethyl, isopropyl, 2-methylpropyl, and difluoromethyl.

[0054] In some embodiments, each R 10 are independently cyclopropyl, cyclobutyl, cyclohexyl, phenyl, piperzinyl, azaspiro[3.5]nona D Tetrahydro-2H-pyranyl, azabicyclo[3.1.0]hexa D Azabicyclo[4.1.0]hepta D aryl, tetrahydrofuranyl, oxetanyl, and piperidinyl, each of which is optional and independently R 11 and is substituted with one or two substituents selected from:

[0055] In some embodiments, each R 11 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, C 6-10 Aryl, 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)2R b3 and S(O)2NR c3 R d3 C is selected from 1-6 Alkyl and the C 6-10Each aryl is optionally independently R 12 and is substituted with one or two substituents selected from:

[0056] In some embodiments, each R 11 independently, C 1-6 Alkyl, C 3-7 Cycloalkyl, CN, OR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 and S(O)2R b3 C is selected from 1-6 Alkyl and the C 3-7 Each cycloalkyl is optionally independently R 12 and is substituted with one or two substituents selected from:

[0057] In some embodiments, each R 11 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, C 6-10 Aryl, 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)2R b3 and S(O)2NR c3 R d3 C is selected from 1-6 Alkyl and the C 6-10 Each aryl is optionally independently R 12 and is substituted with one or two substituents selected from:

[0058] In some embodiments, each R 11 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, halo, D, CN, OR a3, C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , N.R. c3 R d3 and S(O)2R b is selected from.

[0059] In some embodiments, each R 11 are independently C(O)R b3 , C(O)OR a3 , N.R. c3 C(O)R b3 and OR a3 In some embodiments, each R 11 is independently selected from C(O)CH3, C(O)OH, NHC(O)CH3, and OH.

[0060] Each R 11 independently, C 1-6 Alkyl, CN, C(O)R b3 , C(O)OR a3 , N.R. c3 C(O)R b3 , OR a3 , C(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)NR c3 R d3 , S(O)NR c3 R d3 , S(O)2R b3 , phenyl, and 4- to 6-membered heterocycloalkyl; 1-6 The alkyl, the phenyl and the 4- to 6-membered heterocycloalkyl are each optionally independently R 12 and is substituted with one or two substituents selected from:

[0061] In some embodiments, each R 11 are independently C(O)R b3 , C(O)OR a3 , N.R. c3 C(O)R b3 , OR a3, C(O)NR c3 R d3 , S(O)NR c3 R d3 , N.R. c3 R d3 , CN and S(O)R b3 is selected from.

[0062] In some embodiments, each R 11 are independently C(O)R b3 , C(O)OR a3 , and NR c3 C(O)R b3 In some embodiments, each R 11 is independently selected from C(O)CH3, C(O)OH, and NHC(O)CH3.

[0063] In some embodiments, each R 11 are independently selected from methyl, CN, OH, C(O)CH, C(O)OH, NHC(O)CH, C(O)CHOH, C(O)N(CH), NHC(O)CHOCH, NHC(O)N(CH), S(O)N(CH), N(CH), S(O)CH, 2-cyanoacetyl, morpholine-4-carbonyl, morpholinyl, 1-aminocyclopropane-1-carbonyl, (1H-imidazol-1-yl)acetyl, oxazole-4-carbonyl, 4-aminotetrahydro-2H-pyran-4-carbonyl, and 4-carboxy-3-fluorophenyl.

[0064] In some embodiments, R 11 is OR a3 In some embodiments, R 11 is OH.

[0065] In some embodiments, each R 12 independently, C 1-6 Alkyl, Halo, D, CN, OR a5 and NR c5 R d5 is selected from.

[0066] In some embodiments, each R 12 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, 5-6 membered heteroaryl, halo, D, CN, OR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 and NR c5 R d5 is selected from.

[0067] In some embodiments, Cy A is C 3-7 selected from cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; the 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl each have at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; N and S are optionally oxidized; the ring-forming carbon atoms of the 5- to 6-membered heteroaryl and 4- to 6-membered heterocycloalkyl are optionally substituted with oxo to form a carbonyl group; C 3-7 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each optionally independently R 20 is substituted with 1, 2, 3 or 4 substituents selected from:

[0068] In some embodiments, Cy A is C 3-7 selected from cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; the 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl each have at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; N and S are optionally oxidized; the ring-forming carbon atoms of the 5- to 6-membered heteroaryl and 4- to 6-membered heterocycloalkyl are optionally substituted with oxo to form a carbonyl group; C 3-7Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each optionally independently R 20 and is substituted with one or two substituents selected from:

[0069] In some embodiments, Cy A is C 6-10 selected from aryl and 5- to 10-membered heteroaryl; each 5- to 10-membered heteroaryl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; N and S are optionally oxidized; a ring-forming carbon atom of the 5- to 10-membered heteroaryl is optionally substituted with oxo to form a carbonyl group; C 6-10 The aryl and the 5- to 10-membered heteroaryl are each independently R 20 and optionally substituted with 1, 2, 3, or 4 substituents selected from:

[0070] In some embodiments, Cy A is selected from phenyl and 5- to 6-membered heteroaryl; each 5- to 6-membered heteroaryl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; N and S are optionally oxidized; a ring-forming carbon atom of the 5- to 6-membered heteroaryl is optionally substituted with oxo to form a carbonyl group; each phenyl and 5- to 6-membered heteroaryl is optionally independently selected from R 20 and is substituted with 1, 2, 3, or 4 substituents selected from:

[0071] In some embodiments, Cy A is selected from phenyl and 5- to 6-membered heteroaryl, each of which is optional and independently R 20 In some embodiments, Cy is substituted with 1, 2, 3, or 4 substituents selected from A is selected from phenyl and 5- to 6-membered heteroaryl, each of which is optional and independently R20 and is substituted with one or two substituents selected from:

[0072] In some embodiments, Cy A is phenyl or furanyl, each optionally independently R 20 In some embodiments, Cy is substituted with one, two, or three substituents selected from A is phenyl or furanyl, each optionally independently R 20 and is substituted with one or two substituents selected from:

[0073] In some embodiments, Cy A is phenyl, furanyl, piperidinyl, 2-oxo-3,8-diazabicyclo[3.2.1]octanyl, or cyclopropyl, each of which is optional, and independently R 20 In some embodiments, Cy is substituted with one, two, or three substituents selected from A is phenyl, furanyl, piperidinyl, 2-oxo-3,8-diazabicyclo[3.2.1]octanyl, or cyclopropyl, each of which is optional, and independently R 20 and is substituted with one or two substituents selected from:

[0074] In some embodiments, Cy A is independently R 20 In some embodiments, Cy is phenyl optionally substituted with 1, 2, or 3 substituents selected from 1 is independently R 20 In some embodiments, Cy is phenyl substituted with one or two substituents selected from A The ortho and / or para positions of the phenyl are independently R 20 For example, Cy is phenyl substituted with one or two substituents selected from A The ortho and para positions of the phenyl are independently R 20 and phenyl substituted with two substituents selected from:

[0075] In some embodiments, Cy A The ortho position of the phenyl is independently R 20 For example, Cy is phenyl substituted with one or two substituents selected from A The ortho position of the phenyl is independently R 20 For example, Cy A The ortho position of the phenyl is independently R 20 and phenyl substituted with two substituents selected from:

[0076] In some embodiments, Cy A is selected from 2-chlorophenyl, 2,6-difluorophenyl, 2-chloro-6-fluorophenyl, 2,6-dichlorophenyl, 2-fluoro-6-methylphenyl, 2-chloro-4-methoxyphenyl and 3-methylfuran-2-yl.

[0077] In some embodiments, Cy A is selected from 2-chlorophenyl, 2,6-difluorophenyl, 2-chloro-6-fluorophenyl, 2,6-dichlorophenyl, 2-fluoro-6-methylphenyl, 2-chloro-4-methoxyphenyl, 3-methylfuran-2-yl, 1-methylpiperidin-4-yl, (1S,5R)-2-oxo-3,8-diazabicyclo[3.2.1]octan-8-yl, 2-chloro-6-(trifluoromethyl)phenyl, 2,6-dimethylphenyl, 2-cyano-6-fluorophenyl, 2-fluoro-6-methoxyphenyl, 2,3-dimethylphenyl, 4-(hydroxymethyl)-2-methylphenyl, 3-acrylamido-2,6-dichlorophenyl, 3-acrylamidophenyl, 2-acrylamidophenyl, and cyclopropyl.

[0078] Each R 20 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, halo, D, CN, OR a2, C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , S(O)NR c2 R d2 and S(O)2R b2 C is selected from 1-6 Alkyl and the C 3-10 Each cycloalkyl is optionally independently R 21 is substituted with 1, 2, 3 or 4 substituents selected from:

[0079] In some embodiments, each R 20 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, halo, D, CN, OR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , N.R. c2 C(O)R b2 , S(O)NR c2 R d2 and S(O)2R b2 C is selected from 1-6 Alkyl and the C 3-10 Each cycloalkyl is optionally independently R 21 is substituted with 1, 2, 3 or 4 substituents selected from:

[0080] In some embodiments, each R 20 are independently halo, CN, C 1-6 Alkyl, C 1-6 Haloalkyl and NR c2 C(O)R b2 Selected from C 1-6 Alkyl is optionally OR a4 is replaced by .

[0081] In some embodiments, each R 20 independently, halo, C 1-6 Alkyl and OR a2 is selected from.

[0082] In some embodiments, each R 20 is independently selected from chloro, fluoro, methyl and methoxy.

[0083] In some embodiments, each R 20 is independently selected from CN, chloro, fluoro, methyl, methoxy, trifluoromethyl, hydroxymethyl, and acrylamide.

[0084] In some embodiments, each R 21 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, Halo, D, CN, OR a4 and NR c4 R d4 is selected from.

[0085] In some embodiments, R 1 , R 2 , R 3 , and R 6 are independently H, D, and C 1-6 Alkyl, C 1-6 Haloalkyl, Halo, CN, OR a9 and NR c9 R d9 is selected from.

[0086] In some embodiments, R 1 , R 2 and R 3 are independently H, D, and C 1-6 Alkyl, C 1-6 Haloalkyl, Halo, CN, OR a9 and NR c9 R d9 is selected from.

[0087] In some embodiments, R 1 is H. In some embodiments, R 1 H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, Halo, CN, OR a9and NR c9 R d9 is selected from.

[0088] In some embodiments, R 1 H, OR a9 , or NR c9 R d9 In some embodiments, R 1 is H, OH, or N(CH3)2.

[0089] In some embodiments, R 2 is H. In some embodiments, R 2 H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, Halo, CN, OR a9 and NR c9 R d9 is selected from.

[0090] In some embodiments, R 3 is H. In some embodiments, R 3 H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, Halo, CN, OR a9 and NR c9 R d9 is selected from.

[0091] In some embodiments, R 4 H, D, 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, halo, CN, OR a7 and NR c7 R d7 C is selected from 1-6 Alkyl, the C 2-6 Alkenyl, 2-6 Alkynyl, 3-10cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C 6-10 The aryl and the 5- to 10-membered heteroaryl are each optionally independently represented by R 40 is substituted with 1, 2, 3 or 4 substituents selected from:

[0092] In some embodiments, R 4 H, halo, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl, 1-6 Alkyl, the C 2-6 Alkenyl, 3-10 Cycloalkyl, the C 6-10 The aryl and the 5- to 10-membered heteroaryl are each optionally represented by R 40 and is substituted with one or two substituents selected from:

[0093] In some embodiments, R 4 H, halo, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-7 cycloalkyl, phenyl, and 5- to 6-membered heteroaryl, 1-6 Alkyl, the C 2-6 Alkenyl, 3-7 The cycloalkyl, the phenyl and the 5- to 6-membered heteroaryl are each optionally represented by R 40 and is substituted with one or two substituents selected from:

[0094] In some embodiments, R 4 are independently selected from H, methyl, ethyl, chloro, CN, cyclopropyl, cyclopentenyl, propenyl, phenyl, pyrazolyl, and furanyl; and said methyl, said ethyl, said cyclopropyl, said cyclopentenyl, said propenyl, said phenyl, said pyrazolyl, and said furanyl are each optionally selected from R 40 and is substituted with one or two substituents selected from:

[0095] In some embodiments, R 4 is selected from H, methyl, ethyl, chloro, CN, cyclopent-1-en-1-yl, prop-1-en-1-yl, 3,5-dimethoxyphenyl, 1-methyl-1H-pyrazol-4-yl, furan-2-yl, and cyclopropyl.

[0096] In some embodiments, R 4 is selected from H, methyl, ethyl, isopropyl, hydroxymethyl, 1-hydroxyethyl, chloro, bromo, CN, cyclopent-1-en-1-yl, prop-1-en-1-yl, 3,5-dimethoxyphenyl, 1-methyl-1H-pyrazol-4-yl, furan-2-yl, and cyclopropyl.

[0097] In some embodiments, each R 40 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, Halo, D, CN, OR a8 and NR c8 R d8 is selected from.

[0098] In some embodiments, each R 40 independently, C 1-6 Alkyl and OR a8 is selected from.

[0099] In some embodiments, R 5 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl and C 6-10 aryl; 1-6 Alkyl, the C 3-10 Cycloalkyl and the C 6-10 Each aryl is optionally independently R 50 is substituted with 1, 2, 3 or 4 substituents selected from:

[0100] In some embodiments, R5 is C 1-6 It is alkyl.

[0101] In some embodiments, R 5 is methyl.

[0102] In some embodiments, each R 50 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, Halo, D, CN, OR a11 and NR c11 R d11 is selected from.

[0103] In some embodiments, R 6 is H.

[0104] In some embodiments, R 6 is H or OR a9 In some embodiments, R 6 is H or (tetrahydrofuran-3-yl)oxy.

[0105] In some embodiments, each R a1 , R c1 and R d1 are independently 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 The cycloalkyl and the 4- to 10-membered heterocycloalkyl are each optionally independently R 11 and is substituted with 1, 2, 3, or 4 substituents selected from:

[0106] In some embodiments, each R a1 , R c1 and R d1 are independently H, C 1-6 Alkyl and C 1-6 haloalkyl.

[0107] In some embodiments, any R attached to the same N atom c1 and R d1 are independently R together with the N atom to which they are attached. 11 and forming a 4-, 5-, or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents selected from:

[0108] In some embodiments, each R b1 independently, C 1-6 Alkyl and C 1-6 haloalkyl.

[0109] In some embodiments, each R e1 are independently H and C 1-6 alkyl.

[0110] In some embodiments, each R a2 , R c2 and R d2 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 cycloalkyl; 1-6 Alkyl and the C 3-10 Each cycloalkyl is optionally independently R 21 is substituted with 1, 2, 3 or 4 substituents selected from:

[0111] In some embodiments, each R a2 , R c2 and R d2 are independently H, C 1-6 Alkyl and C 1-6 haloalkyl.

[0112] In some embodiments, each R b2 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 cycloalkyl; 1-6 Alkyl and the C 3-10Each cycloalkyl is optionally independently R 21 is substituted with 1, 2, 3 or 4 substituents selected from:

[0113] In some embodiments, each R b2 independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 1-6 haloalkyl; 1-6 Alkyl, the C 2-6 alkenyl, and the C 2-6 Each alkynyl is optionally independently R 21 In some embodiments, each R b2 is C 2-6 It is alkenyl.

[0114] In some embodiments, each R b2 independently, C 1-6 Alkyl and C 1-6 haloalkyl.

[0115] In some embodiments, each R e2 are independently H and C 1-6 alkyl.

[0116] In some embodiments, each R a3 , R c3 and R d3 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 cycloalkyl; 1-6 Alkyl and the C 3-6 Each cycloalkyl is optionally independently R 12 is substituted with 1, 2, 3 or 4 substituents selected from:

[0117] In some embodiments, each R a3 , R c3 and R d3are independently H, C 1-6 Alkyl and C 1-6 haloalkyl.

[0118] In some embodiments, any R attached to the same N atom c3 and R d3 are independently R together with the N atom to which they are attached. 12 In some embodiments, any R bonded to the same N atom form a 4-, 5-, or 6-membered heterocycloalkyl group, optionally substituted with one or two substituents selected from: c3 and R d3 together with the N atom to which they are attached form a 6-membered heterocycloalkyl group.

[0119] In some embodiments, each R b3 independently, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 cycloalkyl; 1-6 Alkyl and the C 3-6 Each cycloalkyl is optionally independently R 12 is substituted with 1, 2, 3 or 4 substituents selected from:

[0120] In some embodiments, each R b3 independently, C 1-6 Alkyl and C 1-6 haloalkyl.

[0121] In some embodiments, each R b3 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl; 1-6 Alkyl, the C 3-6 The cycloalkyl, the phenyl, the 5- to 6-membered heteroaryl, and the 4- to 7-membered heterocycloalkyl are each optionally independently selected from R 12In some embodiments, each R b3 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 It is selected from cycloalkyl, phenyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl.

[0122] In some embodiments, each R a4 , R c4 and R d4 are independently H, C 1-6 Alkyl and C 1-6 haloalkyl.

[0123] In some embodiments, each R b4 independently, C 1-6 Alkyl and C 1-6 haloalkyl.

[0124] In some embodiments, each R a5 , R c5 and R d5 are independently H, C 1-6 Alkyl and C 1-6 haloalkyl.

[0125] In some embodiments, each R b5 independently, C 1-6 Alkyl and C 1-6 haloalkyl.

[0126] In some embodiments, each R a6 , R c6 and R d6 are independently H, C 1-6 Alkyl and C 1-6 haloalkyl.

[0127] In some embodiments, each R b6 independently, C 1-6 Alkyl and C 1-6 haloalkyl.

[0128] In some embodiments, each R a7 , R c7 and R d7 are independently H, C 1-6 Alkyl and C 1-6 haloalkyl.

[0129] In some embodiments, each R b7 independently, C 1-6 Alkyl and C 1-6 haloalkyl.

[0130] In some embodiments, each R a8 , R c8 and R d8 are independently H, C 1-6 Alkyl and C 1-6 haloalkyl.

[0131] In some embodiments, each R b8 independently, C 1-6 Alkyl and C 1-6 haloalkyl.

[0132] In some embodiments, each R a9 , R c9 and R d9 are independently H, C 1-6 Alkyl and C 1-6 haloalkyl.

[0133] In some embodiments, each R a9 , R c9 and R d9 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 In some embodiments, each R a9 , R c9 and R d9 are independently H, C 1-6 alkyl, and 4- to 10-membered heterocycloalkyl.

[0134] In some embodiments, each R b9 independently, C 1-6 Alkyl and C 1-6 haloalkyl.

[0135] In some embodiments, each R a10 , R c10 and R d10 are independently H, C 1-6 Alkyl and C 1-6 haloalkyl.

[0136] In some embodiments, each R b11 independently, C 1-6 Alkyl and C 1-6 haloalkyl.

[0137] In some embodiments, each R a11 , R c11 and R d11 are independently H, C 1-6 Alkyl and C 1-6 haloalkyl.

[0138] In some embodiments, each R b11 independently, C 1-6 Alkyl and C 1-6 haloalkyl.

[0139] Provided herein are compounds of formula IIa: [ka] or a pharmaceutically acceptable salt thereof, wherein Cy A , X, Y, Z and R 10 is defined herein, and ring A is aromatic.

[0140] Provided herein are compounds of formula IIb: [ka] IIb or a pharmaceutically acceptable salt thereof, wherein Cy 1 , X, Y, Z and each R 20 is defined herein, ring A is aromatic, and n is 0, 1, 2, or 3. In some embodiments, n is 1 or 2.

[0141] Provided herein are compounds of formula IIc: [ka] IIc or a pharmaceutically acceptable salt thereof, wherein X, Y, Z, R 10 and each R 20 is defined herein, ring A is aromatic, and n is 0, 1, 2, or 3. In some embodiments, n is 1 or 2.

[0142] Provided herein are compounds of formula IIIa: [ka] or a pharmaceutically acceptable salt thereof, wherein Cy A , Z, R 5 , and R 10 is defined herein.

[0143] Provided herein are compounds of formula IIIb: [ka] or a pharmaceutically acceptable salt thereof, wherein Cy 1 , Z, R 5 , and each R 20 is defined herein, and n is 0, 1, 2, or 3. In some embodiments, n is 1 or 2.

[0144] Provided herein are compounds of formula IIIc: [ka] or a pharmaceutically acceptable salt thereof, wherein Z, R 5 , R 10 , and each R 20 is defined herein, and n is 0, 1, 2, or 3. In some embodiments, n is 1 or 2.

[0145] Provided herein are compounds of formula IVa: [ka] or a pharmaceutically acceptable salt thereof, wherein Cy A , Z, R 4 , and R 10 is defined herein.

[0146] Provided herein are compounds of formula IVb: [ka] or a pharmaceutically acceptable salt thereof, wherein Cy 1 , Z, R 4 , and each R 20 is defined herein, and n is 0, 1, 2, or 3. In some embodiments, n is 1 or 2.

[0147] Provided herein are compounds of formula IVc: [ka] or a pharmaceutically acceptable salt thereof, wherein Z, R 4 , R 10 , and each R 20 is defined herein, and n is 0, 1, 2, or 3. In some embodiments, n is 1 or 2.

[0148] In some embodiments, provided herein are 2-(2-chlorophenyl)-3-methyl-9-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine, 2-(2-chlorophenyl)-3-(cyclopent-1-en-1-yl)-9-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine, (E)-2-(2-chlorophenyl)-9-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine, [2,1-f][1,6]naphthyridine, 2-(2-chlorophenyl)-3-(3,5-dimethoxyphenyl)-9-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine, 2-(2-chlorophenyl)-3,9-bis(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine, 2-(2-chlorophenyl)-3-(furan-2-yl)-9-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine, 2- (2-chlorophenyl)-9-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carbonitrile, 2-(2-chlorophenyl)-3-cyclopropyl-9-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine, 2-(2-chlorophenyl)-3-ethyl-9-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine, 3-chloro-2-(2-chlorophenyl)-9-(1-methyl-1H- pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine, 2-(2,6-difluorophenyl)-9-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine, 2-(2-chloro-6-fluorophenyl)-9-(1,3-dimethyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine, 9-(2-chlorophenyl)-8-cyclopropyl-2-(1-methyl-1H-pyrazol-4-yl)imidazo[1',2':1,2]pyrido[3,4-b]pyrazine, 9-(2-chloro-6-fluorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)imidazo[1',2':1,2]pyrido[3,4-b]pyrazine, 1-(3-(4-(2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)ethan-1-one, (1R,4R)-4-(4-(2-(2-chlorophenyl) -3-cyclopropylimidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)cyclohexane-1-carboxylic acid, N-((1R,4R)-4-(4-(2-(2-chlorophenyl)-3-cyclopropylimidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)cyclohexyl)acetamide, 2-(2-fluoro-6-methylphenyl)-3-methyl-8-(1- Methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-f]quinoxaline, 2-(2-chloro-4-methoxyphenyl)-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-f]quinoxaline, 3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-2-(3-methylfuran-2-yl)-3H-imidazo[4,5-f]quinoxaline, 3-(4-(2-(2-chloro-6- 1-(4-(5-(2-(2-chloro-6-fluorophenyl)-3-methyl-3H-imidazo[4,5-f]quinoxalin-8-yl)-1H-pyrazol-1-yl)cyclobutan-1-ol, and 1-(4-(5-(2-(2-chloro-6-fluorophenyl)-3-methyl-3H-imidazo[4,5-f]quinoxalin-8-yl)pyridin-2-yl)piperazin-1-yl)ethan-1-one, or a pharmaceutically acceptable salt of any of the foregoing.

[0149] In some embodiments, provided herein are 3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-2-(1-methylpiperidin-4-yl)-3H-imidazo[4,5-f]quinoxaline, (1S,5R)-8-(3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-f]quinoxalin-2-yl)-3,8-diazabicyclo[3.2.1]octan-2-one, (S)-1-(3-(4-(2-(2-chloro-6-(trifluoromethyl)phenyl)-3-methylimidazo [2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)-2-hydroxyethan-1-one, (S)-1-(3-(4-(2-(2,6-dimethylphenyl)-3-methylimidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)-2-hydroxyethan-1-one, (S)-3-fluoro-2-(9-(1-(1-(2-hydroxyacetyl)pyrrolidin-3-yl)-1H-pyrazol-4-yl ... 2-(2,3-dimethylphenyl)-3-methyl-9-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-2-yl)benzonitrile, (S)-1-(3-(4-(2-(2-fluoro-6-methoxyphenyl)-3-methylimidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)-2-hydroxyethan-1-one, 2-(2,3-dimethylphenyl)-3-methyl-9-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-2-yl ... (S)-2-(2,6-dichlorophenyl)-3-methyl-9-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-2-yl)phenyl)methanol, 2-(2,6-dichlorophenyl)-3-methyl-9-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-8-ol, (S)-2-(2,6-dichlorophenyl)-3-methyl-9-(1-methyl-1H-pyrazol-4-yl)-10-((tetrahydrofuran-3-yl)oxy)imidazo[2,1-f][1,6]naphthyridin-2-yl ...3-Trimethyl-9-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-8-amine, N-(2,4-dichloro-3-(3-methyl-9-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-2-yl)phenyl)acrylamide, N-(3-(3-methyl-9-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-2-yl)phenyl)acrylamide, N-(2-(3-methyl-9-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-2-yl)phenyl)acrylamide 1-(3-(4-(2-(2,6-dichlorophenyl)-3-methylimidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-2-(1H-imidazole- 1-yl)ethan-1-one, (3-(4-(2-(2,6-dichlorophenyl)-3-methylimidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(oxazol-4-yl)methanone, (4-aminotetrahydro-2H-pyran-4-yl)(3-(4-(2-(2,6-dichlorophenyl)-3-methylimidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)azetidin-1-yl)methanone, 3-(3-(4-(2-(2,6-dichlorophenyl)-3-methylimidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)azetidin-1-yl)methanone phenyl)-3-methylimidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-3-oxopropanenitrile, 4-((4-(2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoic acid, 4-(4-(2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)-N,N-dimethylbenzamide, N-((1r,4r)-4-(4-(2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)cyclohexyl)-2-methoxyacetamide, 3-((1r,4r)-4-(4-(2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)cyclohexyl)-1,1-dimethylurea, 1-(7-(4-(2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)cyclohexyl) (1r,4r)-4-(4-(2-(2,6-dichlorophenyl)-3-methylimidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)cyclohexan-1-ol, 4-(4-(2-(2,6-dichlorophenyl)-3-methylimidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)cyclohexan-1-ol, 4-(4-(2-(2,6-dichlorophenyl)-3-methylimidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)cyclohexan-1-ol, 4-(4-(2-(2,6-dichlorophenyl)-3-methylimidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)cyclohexan-1-ol Imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)-1-methylcyclohexane-1-carboxylic acid, 3-(4-(2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)-N,N-dimethylpyrrolidine-1-carboxamide, 3-(4-(2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)-N,N-dimethylpyrrolidine-1-sulfonamide, (S )-1-(3-(4-(2-(2,6-dichlorophenyl)-3-methylimidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)ethan-1-one, (S)-1-(3-(4-(2-(2,6-dichlorophenyl)-3-methylimidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)-2-hydroxyethan-1-one, 1-(1-(4-(2-(2,6-dichlorophenyl)-3-methylimidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)6]naphthyridin-9-yl)-1H-pyrazol-1-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-hydroxyethan-1-one, (S)-1-(3-(4-(2-(2,6-dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)-2-hydroxyethan-1-one, (S)-1-(3-(4-(2-(2,6-dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl) ]naphthyridin-9-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)ethan-1-one, (S)-(3-(4-(2-(2,6-dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)(morpholino)methanone, 1-((3S)-3-(4-(2-(2,6-dichlorophenyl)-3-(1-hydroxyethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl) pyrrolidin-1-yl)-2-hydroxyethan-1-one, 1-(6-(4-(2-(2,6-dichlorophenyl)-3-methylimidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)-3-azabicyclo[4.1.0]heptan-3-yl)-2-hydroxyethan-1-one, 1-(1-(4-(2-(2,6-dichlorophenyl)-3-methylimidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)-3-azabicyclo[4.1.0]heptan-3-yl)-2-hydroxyethan-1-one, yl)ethan-1-one, 1-(3-(5-(2-(2,6-dichlorophenyl)-3-methylimidazo[2,1-f][1,6]naphthyridin-9-yl)pyridin-2-yl)azetidin-1-yl)-2-hydroxyethan-1-one, 1-(3-(5-(2-(2,6-dichlorophenyl)-3-methylimidazo[2,1-f][1,6]naphthyridin-9-yl)pyridin-3-yl)azetidin-1-yl)ethan-1-one, 1-(3-(5-(2-(2,6-dichlorophenyl)-3-methylimidazo[2,1-f][1,6]naphthyridin-9-yl)pyridin-3-yl)azetidin-1-yl)ethan-1-one, 1-(3-(5-(2-(2,6-dichlorophenyl)-3-methylimidazo[2,1-f][1,6]naphthyridin-9-yl)phenyl)azetidin-1-yl)ethan-1-one, (S)-1-(3-(4-(2-(2-chlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)ethan-1-one, (S)-1-(3-(4-(2-(2-chlorophenyl)-3-isopropylimidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)-2-hydroxyethane-1 -one, (S)-1-(3-(4-(3-bromo-2-(2-chloro-6-fluorophenyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)-2-hydroxyethan-1-one, 2-cyclopropyl-3-methyl-9-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-3-yl, (2-(2,6-dichlorophenyl)-9-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-3-yl (9-(1-cyclopropyl-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridin-3-yl)methanol, (2-(2,6-dichlorophenyl)-9-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-3-yl)methanol, (2-(2,6-dichlorophenyl)-9-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-3-yl)methanol, (2-(2,6-dichlorophenyl)-9-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-3-yl)methanol, (2-(2,6-dichlorophenyl)-9-(1-isopropyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-3-yl)methanol, (2-(2,6-dichlorophenyl)-9-(1-(difluoromethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-3-yl)methanol, 3-(4-(2-(2,6-dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)propanenitrile, 1-(4-(2-(2,6-dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol, 2-(4-(2-(2,6-dichlorophenyl)-3, -(Hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)acetonitrile, (2-(2,6-dichlorophenyl)-9-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-3-yl)methanol, 2-(4-(2-(2,6-dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)-2-methylpropan-1-ol, (2-(2,6-dichlorophenyl)-9-(1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6 ]naphthyridin-3-yl)methanol, (2-(2,6-dichlorophenyl)-9-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-3-yl)methanol, (2-(2,6-dichlorophenyl)-9-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-3-yl)methanol and 2-(4-(2-(2,6-dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)ethan-1-ol, or a pharmaceutically acceptable salt of any of the foregoing.

[0150] It will be further understood that certain features of the present disclosure, 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 present disclosure, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0151] At various places in the present specification, alternatives of the compounds of the present disclosure are disclosed in groups or in ranges. It is specifically intended that the present disclosure include each and every individual subcombination of the members of such groups and ranges. For example, "C 1-6 The term "alkyl" is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0152] Various aryl, heteroaryl, cycloalkyl, and heterocycloalkyl rings are described in various places herein. Unless otherwise specified, these rings may be attached to the remainder of the molecule at any ring member, valence permitting. For example, the term "pyridine ring" or "pyridinyl" may refer to a pyridin-2-yl ring, a pyridin-3-yl ring, or a pyridin-4-yl ring.

[0153] 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.

[0154] For compounds of the present disclosure in which a variable occurs multiple times, each variable can be a different moiety independently selected from the group defining the variable. For example, when a structure is described having two R groups co-occurring in the same compound, the two R groups can represent different moieties independently selected from the group defined for the R group.

[0155] As used herein, the phrase "optionally substituted" means unsubstituted or substituted.

[0156] The term "substituted" formally means that an atom or group of atoms replaces hydrogen as a "substituent" attached to another group. The term "substituted" indicates any level of substitution, for example, mono-, di-, tri-, tetra-, or penta-substitution, unless otherwise specified, where substitution is permitted. Substituents are independently selected, and substitution may occur at any chemically accessible position. It should be understood that substitution at a given atom is limited by valency. It should be understood that substitution at a given atom results in a chemically stable molecule. A single divalent substituent, for example, oxo, can replace two hydrogen atoms.

[0157] As used herein, "C" refers to a group where i and j are integers and are used in combination with chemical groups. i-j The term "ij" refers to a range of carbon atoms in a chemical group having a specified range. For example, C 1-6 Alkyl denotes alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms.

[0158] As used herein, the term "alkyl," used alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chained or branched. An alkyl group formally corresponds to an alkane with one C-H bond replaced by 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, and 1,2,2-trimethylpropyl. In some embodiments, the alkyl group is methyl, ethyl, or propyl.

[0159] As used herein, "C" when used alone or in combination with other terms i-j The term "alkylene" refers to a divalent linked saturated hydrocarbon group having i-j carbons, which may be straight-chained or branched. In some embodiments, the alkylene group contains 1 to 4 carbon atoms, or 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, and isopropylene.

[0160] As used herein, the term "alkenyl," used alone or in combination with other terms, refers to a straight-chain or branched 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 by 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.

[0161] As used herein, the term "alkynyl," used alone or in combination with other terms, refers to a straight-chain or branched 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 replaced at 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.

[0162] As used herein, the terms "carbamoyl" and "carbamyl" refer interchangeably to a group of formula -C(O)NH2.

[0163] As used herein, the term "carboxy" refers to a group of formula -C(O)OH.

[0164] The term "cyano" or "nitrile" refers to a group of formula -C≡N, which may also be written as -CN.

[0165] As used herein, "C 1-3 Alkoxy-C 1-3 The term "alkyl" refers to a group of the formula -(C 1-3 alkylene)-O(C 1-3 This represents an alkoxy group.

[0166] As used herein, "C 1-3 Alkoxy-C 1-3 The term "alkoxy" refers to a group of the formula -(C 1-3 Alkoxylene)-(C 1-3 This represents an alkoxy group.

[0167] As used herein, "HO-C 1-3 The term "alkoxy" refers to a group of the formula -(C 1-3 represents the alkoxylene)-OH group.

[0168] As used herein, "HO-C 1-3 The term "alkyl" refers to a group of the formula -(C 1-3 represents the group alkylene-OH.

[0169] As used herein, "cyano-C" 1-3 The term "alkyl" refers to a group of the formula -(C 1-3 represents the group alkylene-CN.

[0170] As used herein, "H2N-C 1-3 The term "alkyl" refers to a group of the formula -(C 1-3 represents the group alkylene-NH2.

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

[0172] As used herein, "C n-m The term "alkoxycarbonyl" refers to a group of formula -C(O)O-alkyl, where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

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

[0174] As used herein, "C n-m The term "alkylcarbonylamino" refers to a group of formula -NHC(O)-alkyl, where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

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

[0176] As used herein, the term "aminocarbonyloxy" refers to a group of formula -OC(O)NH2.

[0177] As used herein, "C n-mThe term "alkylaminocarbonyloxy" refers to a group of formula -OC(O)-NH-alkyl, where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

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

[0179] As used herein, the term "aminosulfonyl" refers to a group of formula -S(O)2NH2.

[0180] As used herein, "C n-m The term "alkylaminosulfonyl" refers to a group of formula -S(O)NH(alkyl), where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0181] As used herein, "di(C n-m The term "(alkyl)aminosulfonyl" refers to a group of formula -S(O)N(alkyl), where each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0182] As used herein, the term "aminosulfonylamino" refers to a group of formula -NHS(O)2NH2.

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

[0184] As used herein, "di(C n-m The term "NHS(O)N(alkyl)aminosulfonylamino" refers to a group of formula -NHS(O)N(alkyl), where each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0185] As used herein, the term "aminocarbonylamino," employed alone or in combination with other terms, refers to a group of formula -NHC(O)NH2.

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

[0187] As used herein, "di(C n-m The term "NHC(O)N(alkyl)aminocarbonylamino" refers to a group of formula -NHC(O)N(alkyl), where each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0188] As used herein, "C n-m The term "alkylcarbamyl" refers to a group of formula -C(O)-NH(alkyl), where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0189] As used herein, "di(C n-m The term "-C(O)N(alkyl)carbamyl" refers to a group of formula -C(O)N(alkyl), where the two alkyl groups each independently have n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0190] As used herein, the term "thio" refers to a group of formula -SH.

[0191] As used herein, "C n-m The term "alkylthio" refers to an alkyl group of formula -S-, where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0192] As used herein, "C n-m The term "alkylsulfinyl" refers to a group of formula -S(O)-alkyl, where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

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

[0194] As used herein, "halo" or "halogen," used 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.

[0195] 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 are replaced by halogen atoms, which may be replaced by halogen atom substituents, which may be the same or different, up to the maximum valence. In some embodiments, the halogen atom is a fluoro atom. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of haloalkyl groups include CF, CF, CHF, CCl, CHCl, CCl, and the like.

[0196] As used herein, the term "alkoxy," used 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.

[0197] As used herein, "haloalkoxy," used alone or in combination with other terms, refers to a group of the 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.

[0198] As used herein, "amino," used alone or in combination with other terms, refers to NH2.

[0199] As used herein, the term "alkylamino," used 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. Examples of alkylamino groups include methylamino, ethylamino, propylamino (e.g., n-propylamino and isopropylamino), and the like.

[0200] As used herein, the term "alkylthio," used 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.

[0201] As used herein, the term "cycloalkyl," used alone or in combination with other terms, refers to a non-aromatic cyclic hydrocarbon, including cyclized alkyl and alkenyl groups. n-m The term "cycloalkyl" refers to a cycloalkyl having n to m ring carbon atoms. Cycloalkyl groups include monocyclic or polycyclic (e.g., 2, 3, or 4 fused, bridged, or spiro) rings. The definition of cycloalkyl also includes moieties having one or more aromatic rings (e.g., aryl or heteroaryl rings) fused to (i.e., sharing a 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 through any ring-forming atom, including those of the fused aromatic rings. Ring-forming carbon atoms of cycloalkyl groups can be optionally substituted with oxo. Cycloalkyl groups also include cycloalkylidenes. The term "cycloalkyl" further includes bridgehead cycloalkyl groups (e.g., non-aromatic cyclic hydrocarbon moieties containing at least one bridgehead carbon, such as adamantan-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, 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 3-7Monocyclic cycloalkyl groups. Examples of 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.

[0202] As used herein, the term "heterocycloalkyl," used alone or in combination with other terms, refers to a non-aromatic ring or ring system having 4 to 14 ring members, 4 to 10 ring members, 4 to 7 ring members, or 4 to 6 ring members, which may optionally contain one or more alkenylene or alkynylene groups as part of the ring structure and have at least one heteroatom ring member independently selected from nitrogen, sulfur, oxygen, and phosphorus. The term "heterocycloalkyl" includes monocyclic 4-, 5-, 6-, and 7-membered heterocycloalkyl groups. Heterocycloalkyl groups can include monocyclic or polycyclic ring systems (e.g., 2, 3, or 4 fused, bridged, or spiro rings) or spiro 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. The definition of heterocycloalkyl also includes moieties having one or more aromatic rings (e.g., aryl or heteroaryl rings) fused to (i.e., sharing a bond with) a non-aromatic heterocycloalkyl ring, such as 1,2,3,4-tetrahydroquinoline. Heterocycloalkyl groups also include bridgehead heterocycloalkyl groups (e.g., heterocycloalkyl moieties containing at least one bridgehead atom, such as azaadamantan-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-azaspiro[4.5]decane-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 of a heterocycloalkyl group can be oxidized to form a carbonyl, N-oxide, or sulfonyl group (or other oxidized bond), or a nitrogen atom can be quaternized. In some embodiments, the heterocycloalkyl moiety is C 2-7It 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.

[0203] 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, including, 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.

[0204] As used herein, the term "heteroaryl" or "heteroaromatic compound," used alone or in combination with other terms, refers 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. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, 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 of a heteroaryl group can be oxidized to form carbonyl, N-oxide, or sulfonyl groups (or other oxidized bonds), or nitrogen atoms can be quaternized, provided that the aromatic character of the ring is maintained. 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, no more than two heteroatoms in the 5-membered heteroaryl moiety are N.

[0205] 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.

[0206] A 6-membered heteroaryl ring is a heteroaryl group having 6 ring atoms, where one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary 6-membered heteroaryls include pyridyl, pyrazinyl, pyrimidinyl, triazinyl, isoindolyl, and pyridazinyl.

[0207] 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 may be optionally substituted with one or two oxo (=O) substituents.

[0208] The term "oxidized" in reference to a ring-forming N atom refers to a ring-forming N-oxide.

[0209] The term "oxidized" in reference to a ring-forming S atom refers to a ring-forming sulfonyl or ring-forming sulfinyl.

[0210] The term "aromatic" refers to a carbocyclic or heterocyclic ring having one or more polyunsaturated rings with aromatic character (i.e., having (4n+2) delocalized π (pi) electrons, where n is an integer).

[0211] In certain places, definitions or embodiments refer to certain rings (e.g., azetidine ring, pyridine ring, etc.). Unless otherwise specified, these rings can be attached to any ring member, provided that the valence of the atom is not exceeded. For example, an azetidine ring can be attached at any position on the ring, while an azetidin-3-yl ring is attached at the 3-position.

[0212] 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 disclosure containing asymmetrically substituted atoms can be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or 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 disclosure are described and can be isolated as a mixture of isomers or as separated isomeric forms.

[0213] Resolution of racemic mixtures of compounds can be carried out by methods well known in the art. Exemplary methods include fractional recrystallization using chiral resolving acids, which are optically active, salt-forming organic acids. Suitable resolving agents for partial recrystallization methods are optically active acids, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or the D- and L-forms of various optically active camphorsulfonic acids. Other resolving agents suitable for fractional crystallization include stereoisomerically pure forms of methylbenzylamine (e.g., S- and R-forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

[0214] 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.

[0215] In some embodiments, the compounds of the present disclosure have the (R) configuration. In other embodiments, the compounds have the (S) configuration. In compounds with multiple chiral centers, unless otherwise specified, each of the chiral centers in the compound may independently be (R) or (S).

[0216] The compounds of the present invention also include tautomeric forms. Tautomeric forms are obtained by the interchange of adjacent double and single bonds with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers, which are isomeric protonation states with the same empirical formula and total charge. Exemplary prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which protons can occupy more than one position on a heterocyclic ring system, such as 1H- and 3H-imidazole, 1H-, 2H-, and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms may be in equilibrium or sterically fixed into one form by appropriate substitution.

[0217] The compounds of the present disclosure may also include all isotopes of atoms occurring in intermediates or final compounds. Isotopes include atoms with 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 disclosure can be replaced or substituted with an isotope of the 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 may 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 well 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 experiments, and / or assays.

[0218] Substitution with heavier isotopes, such as deuterium, may confer certain therapeutic benefits, such as increased in vivo half-life or reduced dosage requirements, resulting from greater metabolic stability, and therefore may be preferable in some cases (see A. Kerekes et al. J. Med. Chem. 2011, 54, 201-210; R. Xu et al. J. Label Compd. Radiopharm. 2015, 58, 308-312).

[0219] 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 present disclosure regardless of how they are prepared, for example, by synthetic, biological process (e.g., metabolic or enzymatic transformation), or a combination thereof.

[0220] All compounds and pharmaceutically acceptable salts thereof may be found together with other substances such as water and solvents (e.g., hydrates and solvates) or may be isolated. When in the solid state, the compounds and salts thereof described herein may occur in various forms, for example, in the form of solvates, including hydrates. The compounds may be in any solid state, such as polymorphs or solvates, and unless expressly indicated otherwise, references in the specification to compounds and salts thereof should be understood to include any solid state of the compounds.

[0221] In some embodiments, the compounds of the present disclosure or salts thereof are substantially isolated. "Substantially isolated" means that the compounds are at least partially or substantially separated from the environment in which epacadostat and its salts were formed or detected. Partial separation can include, for example, compositions enriched for the compounds of the present disclosure. Substantial separation 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 disclosure or salts thereof. Methods for isolating compounds and their salts are routine in the art.

[0222] 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.

[0223] The present disclosure 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 has been modified by converting an existing acid or base moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutically acceptable salts of the present disclosure 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 disclosure can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or 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.

[0224] The following abbreviations may be used herein: AcOH (acetic acid); AcO (acetic anhydride); aq. (water); atm. (gas); Boc (t-butoxycarbonyl); br (broad); Cbz (carboxybenzyl); calc. (calculated); d (doublet); dd (double doublet); DCM (dichloromethane); DEAD (diethyl azodicarboxylate); DIAD (N,N'-diisopropyl azidodicarboxylate); DIPEA (N,N-diisopropylethylamine); DMF (N,N-dimethylformamide); Et (ethyl); EtOAc (ethyl acetate); g (gram); h (hour); HATU (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 (molar); mCPBA (3-chloroperbenzoic acid); MgSO4 (magnesium sulfate); MS (mass spectrometry); Me (methyl); MeCN (acetonitrile); MeOH (methanol); unsplit blank -U+00A0mg (milligram); min. (minute); mL (milliliter); mmol (millimol); N (standard); NaHCO3 (sodium bicarbonate); NaOH (sodium hydroxide); Na2SO4 (sodium sulfate); NH4Cl (ammonium chloride); NH4OH (ammonium hydroxide); NI (N-iodosuccinimide); nm (nanomole); NMR (nuclear magnetic resonance spectroscopy); OTf (thiazolinone) trifluoromethanesulfonate; Pd (palladium); Ph (phenyl); pm (picomole); PMB (paramethoxybenzyl); 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); μL (microliter); μm (micromole); wt% (weight percent).

[0225] synthesis As will be appreciated by those skilled in the art, the compounds provided herein, including their salts and stereoisomers, can be prepared using known organic synthesis techniques, or can be synthesized according to any of a number of possible synthetic routes.

[0226] The reaction for preparing the compounds of the present disclosure 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 starting materials (reactants), intermediates or products 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.

[0227] The preparation of compounds of the present disclosure may involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be easily determined by those 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.

[0228] 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.

[0229] As used herein, the expressions "ambient temperature," "room temperature," and "rt" are art-recognized and generally refer to a temperature near the temperature of the room in which the reaction is carried out, e.g., from about 20° C. to about 30° C., e.g., the reaction temperature.

[0230] Compounds of formula S-11 can be prepared via the synthetic route outlined in Scheme 1. Commercially available starting material S-1 can be coupled to adduct S-2, where M is a boronic acid, boronic ester, or appropriately substituted metal (e.g., M is B(OR)2, Sn(alkyl)3, Zn-Hal, etc.), under standard Suzuki cross-coupling conditions (e.g., in the presence of a palladium catalyst and a suitable base) (Tetrahedron 2002, 58, 9633-9695), or standard Stille cross-coupling conditions (e.g., in the presence of a palladium catalyst) (ACS Catalysis 2015, 5, 3040-3053), or standard Negishi cross-coupling conditions (e.g., in the presence of a palladium catalyst) (ACS Catalysis 2016, 6, 1540-1552), to give derivative S-3. Reduction of the nitro group of compound S-3 under appropriate conditions can provide compound S-4. Compound S-4 can be prepared by electrophilic aromatic substitution (S E Ar) to provide compound S-5 (Hal is a halide such as F, Cl, Br, or I). NIntermediate S-5 is substituted with the halide of reagent S-6 via 2) to produce intermediate S-7. Compound S-7 can undergo an amination reaction, such as a Buchwald-Hartwig coupling (Chem. Sci. 2011, 2, 27-50), in the presence of a palladium catalyst (e.g., tris(dibenzylideneacetone)dipalladium(0)), a suitable ligand (e.g., 2'-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine), and a base (e.g., sodium tert-butoxide), to produce diamine S-8. Compound S-8 can be coupled with a carboxylic acid adduct of formula S-9 using an appropriate coupling reagent (e.g., HATU, BOP, or PyBOP) to produce compound S-10. Finally, compound S-10 can be cyclized at elevated temperature in the presence of a suitable reagent, such as acetic acid, to produce compound S-11.

[0231] Scheme 1 [ka] Alternatively, compound S-11 can be prepared via a synthetic route as outlined in Scheme 2. Acylation of compound S-8 with adduct S-12 (Hal is a halide such as F, Cl, Br, or I) provides intermediate S-10. Cyclization of compound S-10 at elevated temperature in the presence of a suitable reagent such as acetic acid generates compound S-11.

[0232] Scheme 2 [ka] Compounds of formula S-21 can be prepared via synthetic routes such as those outlined in Scheme 3. Treatment of commercially available compound S-13 with an appropriate reagent, such as phosphoryl chloride (POCl), at elevated temperatures can provide the chloride adduct S-14.

[0233] The chloride of compound S-14 can be displaced via nucleophilic substitution with aqueous ammonia at elevated temperatures to give amine S-15. Compound S-15 can then be selectively coupled with adduct S-2, where M is a boronic acid, boronic ester, or appropriately substituted metal (e.g., M is B(OR)2, Sn(alkyl)3, Zn-Hal, etc.), under standard Suzuki cross-coupling conditions (e.g., in the presence of a palladium catalyst and a suitable base), or under standard Stille cross-coupling conditions (e.g., in the presence of a palladium catalyst), or under standard Negishi cross-coupling conditions (e.g., in the presence of a palladium catalyst), to give derivatives of S-16. Condensation of compound S-16 with a carbonyl adduct of formula S-17 (Hal is a halide such as F, Cl, Br, or I) at elevated temperatures can produce compound S-18. Tricyclic compound S-18 can be converted to tricyclic compound S-18 by electrophilic aromatic substitution (S E R can undergo a halogenation reaction such as with Hal (Ar) to provide compound S-19 (Hal is a halide such as F, Cl, Br, or I). 1 Introduction of can be achieved by coupling compound S-19 with adduct S-20 to provide compound S-21 using conditions similar to those described for the preparation of compound S-16 from compound S-15.

[0234] Scheme 3 [ka] Alternatively, compounds of formula S-21 can be prepared via a synthetic route such as that outlined in Scheme 4. Condensation of compound S-15 with a carbonyl adduct of formula S-17 (where Hal is a halide such as Cl, Br, or I) at elevated temperatures can produce compound S-22. Compound S-22 can then be selectively coupled with adduct S-2, where M is a boronic acid, boronic ester, or appropriately substituted metal (e.g., M is B(OR)2, Sn(alkyl)3, Zn-Hal, etc.), under standard Suzuki cross-coupling conditions (e.g., in the presence of a palladium catalyst and a suitable base), or under standard Stille cross-coupling conditions (e.g., in the presence of a palladium catalyst), or under standard Negishi cross-coupling conditions (e.g., in the presence of a palladium catalyst), to give derivatives of formula S-18. Compounds of formula S-21 can then be prepared from compounds of formula S-18 via a synthetic route such as that outlined in Scheme 3.

[0235] Scheme 4 [ka] Additionally, compound S-21 can be prepared by using the above steps in a different order. Compound S-22 can be first halogenated with an appropriate reagent, such as N-iodosuccinimide (NIS), to generate a dihalide intermediate, which can undergo selective coupling with adduct S-20 following the synthetic sequence from S-18 to S-21 as shown in Scheme 3 above. Compound S-21 can also be obtained following a similar coupling strategy to adduct S-2 as shown in Scheme 4 above.

[0236] Alternatively, compound S-21 can be prepared via a synthetic route such as that outlined in Scheme 5. Condensation of compound S-15 with a carbonyl adduct of formula S-23 (where Hal is a halide such as Cl, Br, or I) at elevated temperatures can produce compound S-24. Compound S-24 can then be selectively coupled with adduct S-2, where M is a boronic acid, boronic ester, or appropriately substituted metal (e.g., M is B(OR)2, Sn(alkyl)3, Zn-Hal, etc.), under standard Suzuki cross-coupling conditions (e.g., in the presence of a palladium catalyst and a suitable base), or under standard Stille cross-coupling conditions (e.g., in the presence of a palladium catalyst), or under standard Negishi cross-coupling conditions (e.g., in the presence of a palladium catalyst), to give derivatives of S-25. Compound S-25 can be selectively coupled with adduct S-2, where M is a boronic acid, boronic ester, or appropriately substituted metal (e.g., M is B(OR)2, Sn(alkyl)3, Zn-Hal, etc.), under standard Suzuki cross-coupling conditions (e.g., in the presence of a palladium catalyst), or under standard Negishi cross-coupling conditions (e.g., in the presence of a palladium catalyst), to give derivatives of S-25. Compound S-25 can be selectively converted to S-25 by electrophilic aromatic substitution (S E R can undergo a halogenation reaction such as with Hal (Ar) to provide compound S-26 (Hal is a halide such as Cl, Br, or I). 1 Introduction of S-26 can be achieved by coupling S-26 with adduct S-20 to provide S-27, using conditions similar to those described for the preparation of S-25 from S-24. S-27 can be obtained by electrophilic aromatic substitution (S E The compound S-28 can undergo a second halogenation reaction, such as with Hal (Ar), to provide compound S-28 (Hal is a halide such as Cl, Br, or I). 2 Introduction of can be achieved by coupling compound S-28 with adduct S-29 to provide compound S-21 using conditions similar to those described for the preparation of compound S-25 from compound S-24.

[0237] Scheme 5 [ka] Compounds of formula S-33 can be prepared via synthetic routes such as those outlined in Scheme 6. Commercially available starting material S-30 can undergo selective coupling reactions with adduct S-2, where M is a boronic acid, a boronic ester, or an appropriately substituted metal (e.g., M is B(OR)2, Sn(alkyl)3, Zn-Hal, etc.), under standard Suzuki cross-coupling conditions (e.g., in the presence of a palladium catalyst and a suitable base), or under standard Stille cross-coupling conditions (e.g., in the presence of a palladium catalyst), or under standard Negishi cross-coupling conditions (e.g., in the presence of a palladium catalyst), to give derivatives S-31. Compound S-32 can be prepared by reacting compound S-31 with aqueous ammonia using conditions similar to those described for preparing compound S-15 from compound S-14 in Scheme 3. Compound S-33 can then be prepared from compound S-32 using synthetic routes such as those outlined in Scheme 3, starting from compound S-16.

[0238] Scheme 6 [ka]

[0239] How to use The compounds of the present disclosure can inhibit the activity of FGFR enzyme.For example, the compounds of the present disclosure can be used to inhibit the activity of FGFR enzyme in cells, individuals, or patients that require enzyme inhibition by administering an inhibitory amount of one or more compounds of the present disclosure to cells, individuals, or patients.The compounds of the present disclosure can be used to inhibit the activity of FGFR3 enzyme in cells, individuals, or patients that require enzyme inhibition by administering an inhibitory amount of one or more compounds of the present disclosure to cells, individuals, or patients.

[0240] As FGFR inhibitors, the compounds of the present disclosure are useful for treating various diseases associated with abnormal expression or activity of FGFR enzymes or FGFR ligands. Compounds that inhibit FGFR may be useful for preventing tumor growth or inducing apoptosis, particularly by inhibiting angiogenesis. Thus, 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 activated mutants of receptor tyrosine kinases or upregulated receptor tyrosine kinases may be particularly sensitive to inhibitors.

[0241] In certain embodiments, the present disclosure provides a method for treating an FGFR-mediated disorder in a patient in need thereof, the method comprising administering to the patient a compound according to the present disclosure or a pharmaceutically acceptable composition thereof.

[0242] 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 cancers, liver cancers, bone cancers, nervous system cancers, gynecological cancers, and skin cancers.

[0243] 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, 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 leukemia, marginal zone lymphoma, chronic myeloid lymphoma, and Burkitt's lymphoma.

[0244] Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, rhabdosarcoma, fibroma, lipoma, hamartoma, lymphosarcoma, leiomyosarcoma, and teratoma.

[0245] Exemplary lung cancers include non-small cell lung cancer (NSCLC), small cell lung cancer, bronchial carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchial) carcinoma, bronchial adenoma, chondromatous hamartoma, mesothelioma, small cell and non-small cell carcinoma, bronchial adenoma, and pleuropulmonary blastoma.

[0246] 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.

[0247] 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.

[0248] Exemplary liver cancers include hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.

[0249] 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.

[0250] Exemplary nervous system cancers include cancer of the skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, neuroectodermal tumors), and spinal cord (neurofibroma, meningioma, glioma, sarcoma), neuroblastoma, Lhermitte-Dacros disease, and pineal tumor.

[0251] 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).

[0252] 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.

[0253] Exemplary head and neck cancers include glioblastoma, melanoma, rhabdomyosarcoma, lymphosarcoma, osteosarcoma, squamous cell carcinoma, adenocarcinoma, oral cancer, laryngeal cancer, nasopharyngeal cancer, nasal cavity and paranasal sinus cancer, thyroid and parathyroid cancer, eye tumors, lip and mouth tumors, and squamous cell head and neck cancer.

[0254] The compounds of the present disclosure may also be useful in inhibiting tumor metastasis.

[0255] In addition to oncogenic neoplasms, compounds of the present disclosure are useful for treating skeletal and chondrocyte disorders, including, but not limited to, achondroplasia, hypochondroplasia, dwarfism, thanatophoric dysplasia (TD) (clinical forms 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.

[0256] In some embodiments, the compounds described herein can be used to treat Alzheimer's disease, HIV, or tuberculosis.

[0257] As used herein, the term "8p11 myeloproliferative syndrome" is meant to refer to myeloid / lymphoid neoplasms associated with eosinophilia and FGFR1 abnormalities.

[0258] As used herein, the term "cell" refers to a cell that is in vitro, ex vivo, or in vivo. 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.

[0259] As used herein, the term "contacting" refers to bringing the indicated moieties together in an in vitro system or 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, including, for example, a cell preparation or purified preparation containing an FGFR enzyme.

[0260] 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.

[0261] As used herein, the phrase "therapeutically effective amount" refers to an amount of an active compound or pharmaceutical agent, such as any of the solid forms disclosed herein or salts thereof, that elicits the biological or medicinal response that a researcher, veterinarian, physician, or other clinician is seeking in a tissue, system, animal, individual, or human. An appropriate "effective" amount in any individual case can be determined using techniques known to those of ordinary skill in the art.

[0262] As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problem or complication, within the scope of safe medical judgment, and commensurate with a reasonable benefit / risk ratio.

[0263] As used herein, a "pharmaceutically acceptable carrier or excipient" refers to a pharmaceutically acceptable material, 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 veterinary use as well as human pharmaceutical 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.

[0264] As used herein, the term "treat" or "treatment" refers to inhibiting a disease, e.g., inhibiting a disease, condition, or disorder (i.e., halting further development of the pathology and / or symptomology) in an individual experiencing or exhibiting the pathology or symptomology of the disease, condition, or disorder, or ameliorating a disease, e.g., ameliorating a disease, condition, or disorder (i.e., reversing the pathology and / or symptomology) in an individual experiencing or exhibiting the pathology or symptomology of the disease, condition, or disorder, e.g., reducing the severity of the disease.

[0265] It will be appreciated that certain features of the present disclosure, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment (while those embodiments are intended to be combined as if described in multiple dependent fashion). Conversely, various features of the present disclosure, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0266] 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, can be used in combination with the compounds described herein for the treatment of FGFR-associated diseases, disorders, or conditions, or the diseases or conditions described herein. The agents can be combined with the compounds in a single dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms.

[0267] The compounds described herein can be used in combination with one or more other kinase inhibitors for the treatment of diseases such as cancer that are affected by multiple signal transduction pathways. For example, the combination can include one or more inhibitors 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, FL K-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, the solid forms of the FGFR inhibitors described herein can 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.

[0268] In some embodiments, the compounds described herein can 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.

[0269] 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.Histone deacetylase inhibitors include, for example, vorinostat.

[0270] For the treatment of cancer and other proliferative disorders, the compounds described herein may be used in combination with JAK kinase inhibitors (ruxolitinib, additional JAK1 / 2 and JAK1-selective baricitinib or INCB39110), Pim kinase inhibitors (e.g., LGH447, INCB053914, and SGI-1776), Pim kinase inhibitors (e.g., INCB53914), PI3 kinase inhibitors (PI3K-δ selective and broad-spectrum P I3K inhibitors), (e.g., INCB50465 and INCB54707), PI3K-γ inhibitors (such as PI3K-γ 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, B It may be used in combination with targeted therapies, including RAF inhibitors, mTOR inhibitors, proteasome inhibitors (bortezomib, carfilzomib), HDAC inhibitors (panobinostat, vorinostat), DNA methyltransferase inhibitors, dexamethasone, bromo and specific terminal family member inhibitors (e.g., bromodomain inhibitors or BET inhibitors, e.g., OTX015, CPI-0610, INCB54329, or INCB57643), LSD1 inhibitors (e.g., GSK2979552, INCB59872, and INCB60003), arginase inhibitors (e.g., INCB1158), indoleamine 2,3-dioxygenase inhibitors (e.g., epacadostat, NLG919, or BMS-986205), PARP inhibitors (e.g., olaparib, or rucaparib), and BTK inhibitors such as ibrutinib. Additionally, to treat cancer and other proliferative diseases, the compounds described herein may be used in combination with targeted therapies, such as c-MET inhibitors (e.g., capmatinib), anti-CD19 antibodies (e.g., tafasitamab), ALK2 inhibitors (e.g., INCB00928), or combinations thereof.

[0271] 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 of the present invention can also be used in combination with medical therapies such as surgery or radiation therapy, for example, gamma radiation, neutron radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy, and systemic radioactive isotopes.

[0272] Examples of chemotherapeutic agents include abarelix, abiraterone, afatinib, aflibercept, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, amidox, amsacrine, anastrozole, aphidicolin, arsenic trioxide, asparaginase, axitinib, azacitidine, bevacizumab, bexarotene, baricitinib, bendamustine, bicalutamide, bleomycin, bortezomib, Brivanib, buparlisib, intravenous busulfan, oral busulfan, calucinone, irinotecan, 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, floxiridine, fludarabine, fluorouracil, flutamide, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, hysterelin acetate, ibritumomab tiuxetan, idarubicin , idelalisib, ifosfamide, imatinib mesylate, interferon alpha 2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lonafarnib, lomustine, mechlorethamine, 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, rasbricase, regorafenib, reloxafin, Revlimid, rituximab, rucaparib, ruxolitinib, sorafenib, streptozocin, sunitinib, sunitinib maleate, tacrolimus The present invention includes any of moxifen, 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.

[0273] In some embodiments, the compounds described herein can 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, PI3Kδ, PI3Kγ, TAM, arginase, CD137 (also known as 4-1BB), ICOS, A2AP, 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.

[0274] 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. US 20170107216, US 20170145025, US 20170174671, US 20170174679, US 20170320875, US 20170342060, US 20170362253, and US 20180016260, each of which is incorporated by reference in its entirety for all purposes.

[0275] 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 (retifanlimab), 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).

[0276] In some embodiments, compounds of the present disclosure can be used in combination with INCB086550.

[0277] 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.

[0278] 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.

[0279] 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.

[0280] 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.

[0281] 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.

[0282] In some embodiments, the inhibitor of the 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.

[0283] 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.

[0284] 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.

[0285] 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.

[0286] In some embodiments, the compounds described herein can be used in combination with one or more drugs for the treatment of 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).

[0287] 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 drugs.

[0288] Examples of 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; emtricitabine [(-)-FTC]; beta-L-FD4 (also called beta-L-D4C, beta-L-2',3'-dicreoxy-5-fluoro-citidene); DAPD, ((-)-beta-D-2,6,-diamino-purine dioxolane); and rhodenosine (FddA). Exemplary suitable NNRTIs include nevirapine (BI-RG-587), delavirdine (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 (Ro 31-8959), ritonavir (ABT-538), indinavir (MK-639), nelfinavir (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.

[0289] Suitable drugs for use in combination with the compounds described herein for the treatment of cancer include chemotherapy, targeted cancer therapy, immunotherapy, or radiation therapy.The compounds described herein can be effective in combination with antihormonal agents for the treatment of 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, adrenocorticosteroids (e.g., prednisone), progestins (e.g., megastrol acetate), and estrogen receptor antagonists (e.g., fulvestrant).Suitable antihormonal agents used in the treatment of prostate cancer and other cancers can 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).

[0290] The compounds described herein may be combined or sequenced 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 against Flt-3 and cancer-associated 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 can be used in combination with FGFR inhibitors. These include onartumuzumab, 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.

[0291] Angiogenesis inhibitors, in combination with FGFR inhibitors, can be effective in some tumors. These include antibodies against VEGF or VEGFR, or VEGFR kinase inhibitors. Antibodies or other therapeutic proteins against VEGF include bevacizumab and aflibercept. Inhibitors of VEGFR kinase and other anti-angiogenesis inhibitors include, but are not limited to, sunitinib, sorafenib, axitinib, cediranib, pazopanib, regorafenib, brivanib, and vandetanib.

[0292] Activation of intracellular signaling pathways frequently occurs in cancer, and drugs that target components of these pathways have been combined with receptor-targeting agents to increase efficacy and reduce resistance. Examples of drugs that can 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.

[0293] Drugs against PI3 kinase include, but are not limited to, topiralisib, idelalisib, and buparlisib.Inhibitors of mTOR, 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 inhibitors of JAK (e.g., ruxolitinib, baricitinib, tofacitinib), inhibitors of Hsp90 (e.g., tanespimycin), inhibitors of cyclin-dependent kinases (e.g., palbociclib), inhibitors of HDAC (e.g., panobinostat), inhibitors of PARP (e.g., olaparib), and inhibitors of proteasomes (e.g., bortezomib, carfilzomib) can also be combined with the compounds described herein. In some embodiments, the JAK inhibitor is selective for JAK1 over JAK2 and JAK3.

[0294] 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 plus gemcitabine; cisplatin or carboplatin plus docetaxel; cisplatin or carboplatin plus paclitaxel; cisplatin or carboplatin plus pemetrexed), or gemcitabine plus paclitaxel-bound particles (Abraxane®).

[0295] Suitable chemotherapeutic or other anti-cancer agents include, for example, alkylating agents (including but not limited to nitrogen mustards, ethyleneimine derivatives, alkylsulfonates, nitrosoureas, and triazenes), such as uracil mustard, chlormethine, cyclophosphamide (Cytoxan™), ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

[0296] Other agents suitable 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.

[0297] 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).

[0298] Suitable chemotherapeutic or other anti-cancer agents include, for example, antimetabolites (including but not limited to antifolates, pyrimidine analogs, purine analogs, and adenosine deaminase inhibitors), such as methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, and gemcitabine.

[0299] 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.

[0300] Other cytotoxic agents include navelbine, CPT-11, anastrozole, letrozole, capecitabine, reloxafine, cyclophosphamide, ifosfamide, and droloxafine.

[0301] Also suitable are cytotoxic agents such as epidophyllotoxins; antitumor enzymes; topoisomerase inhibitors; procarbazine; mitoxantrone; platinum coordination complexes such as cisplatin and carboplatin; biological response modifiers; growth inhibitory agents; antihormonal therapeutic agents; leucovorin; tegafur; and hematopoietic growth factors.

[0302] 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 (such as IL-10, TGF-β).

[0303] Other anti-cancer drugs include those that block immune cell migration, such as antagonists against chemokine receptors such as CCR2 and CCR4.

[0304] Other anti-cancer agents also include those that further enhance the immune system, such as adjuvants or adoptive T cell transfer.

[0305] 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.

[0306] The compounds of the present disclosure can be used in combination with bone marrow transplantation for the treatment of various tumors of hematopoietic origin.

[0307] Methods for safely and effectively administering most of these chemotherapeutic agents are known to those skilled in the art. In addition, their administration is described in standard literature. For example, the administration of many chemotherapeutic agents is described in the "Physicians' Desk Reference" (PDR, e.g., 1996 ed., Medical Economics Company, Montvale, NJ), the disclosure of which is incorporated herein by reference as if set forth in its entirety.

[0308] 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.

[0309] 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 with at least one pharmaceutically acceptable carrier or excipient. These compositions can be prepared in a manner well known in the pharmaceutical arts and can be administered by various routes, depending on whether local or systemic treatment is desired and the area to be treated. Administration can be topical (including transmucosal, including ophthalmic, intranasal, intravaginal, and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including those via nebulizers; intratracheal, intranasal, epithelial, and transdermal), ocular, oral, or parenteral. Methods of ocular delivery can include topical administration (eye drops), subconjunctival, periorbital, 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, and intracranial, e.g., intrathecal, or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose, or can be, 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 bases, powder bases, or oily bases, thickeners, etc. may be necessary or desirable.

[0310] 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. In preparing the compositions described herein, the active ingredient is typically mixed with an excipient, diluted by an excipient, or enclosed in 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 solid or liquid vehicles), 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.

[0311] When preparing formulation, active compound can be milled to obtain suitable particle size before being combined with other components.If active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh.If active compound is substantially water-soluble, particle size can be adjusted by milling to obtain substantially uniform distribution in formulation, for example, about 40 mesh.

[0312] The compounds of the present disclosure can be milled using known milling procedures, such as wet milling, to obtain a particle size suitable for tablet formation and other formulation types. Finely divided (nanoparticulate) preparations of the compounds of the present invention can be prepared by processes known in the art (see, for example, WO2002 / 000196).

[0313] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose.The formulation can further comprise lubricants such as talc, magnesium stearate, and mineral oil, wetting agents, emulsifying and suspending agents, preservatives such as methylbenzoate and propylhydroxybenzoate, sweeteners, and flavoring agents.The compositions described herein can be formulated to provide quick, sustained, or delayed release of active ingredients after administration to patients by using procedures known in the art.

[0314] 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% microcrystalline cellulose and about 2% silicon dioxide w / w.

[0315] 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™).

[0316] In some embodiments, a wet granulation process is used to produce the composition. In some embodiments, a dry granulation process is used to manufacture the composition.

[0317] The compositions can be prepared 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 unitary dosage for human subjects and other mammals, each unit containing a predetermined quantity of active ingredient calculated to produce a desired therapeutic effect in association with a suitable pharmaceutical excipient.

[0318] 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). Particularly for human consumption, compositions are preferably manufactured or formulated in accordance with Good Manufacturing Practice standards as defined in 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.

[0319] The active compound can be effective over a wide dosage range and is therefore 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 being 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 condition, etc.

[0320] Therapeutic dosages of compounds of the present disclosure may vary according to, for example, the particular application for which the treatment is being administered, the mode of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the present disclosure in a pharmaceutical composition can vary depending on several factors, including dosage, chemical properties (e.g., hydrophobicity), and the route of administration. For example, compounds of the present disclosure can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w / v 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. Dosages can depend on variables such as the type and progression of the disease or disorder, the overall health of the particular patient, the relative bioefficacy of the selected compound, the formulation of excipients, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0321] 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, allowing the composition to be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above, containing, for example, from about 0.1 to about 500 mg of the active ingredient of the present disclosure.

[0322] The tablets or pills of the present disclosure can be coated or otherwise compounded to provide a dosage form that provides the advantage of prolonged action.For example, the tablets or pills can comprise an inner dose and an outer dose component, the latter being in the form of an envelope over the former.The two components can be separated by an enteric layer that resists disintegration in the stomach and allows the inner component to pass intact into the duodenum or be delayed in release.A variety of materials can be used as such enteric layers or coatings, including numerous polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0323] Liquid forms into which the compounds and 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.

[0324] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions may be nebulized by use of an inert gas. 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.

[0325] 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-glycerol 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, at least about 0.25, at least about 0.5, at least about 1, at least about 2, or at least about 5% by weight of a compound of the present disclosure. Topical formulations may be suitably packaged in 100g tubes, optionally accompanied by instructions for treating a selected indication, such as psoriasis or other skin conditions.

[0326] The amount of compound or composition administered to a patient will vary depending on what is being administered, the purpose of the administration, such as prophylaxis or treatment, the condition of the patient, the method of administration, etc. In therapeutic applications, compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. The effective dose will depend on the disease state being treated and the judgment of the attending physician based on factors such as the severity of the disease, the age, weight, and general condition of the patient.

[0327] The compositions administered to patients can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques or can be sterile filtered. Aqueous solutions can 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 preparation will typically be 3-11, more preferably 5-9, and most preferably 7-8. It will be appreciated that the use of certain of the aforementioned excipients, carriers, or stabilizers can result in the formulation of pharmaceutical salts.

[0328] Therapeutic amounts of compounds of the invention can vary according to, for example, the particular application for which treatment is being performed, 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 several factors, including dosage, chemical properties (e.g., hydrophobicity), and 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% w / v 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 bioefficacy of the selected compound, the formulation of excipients, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0329] The compounds described herein can 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 immunoenhancing agent, an immunosuppressant, an anti-inflammatory agent, etc.

[0330] Labeled Compounds and Assay Methods Another aspect of the present disclosure relates to the labeled compounds (radiolabeled, fluorescently labeled, etc.) of the present disclosure, which may be useful in both in vitro and in vivo assays as well as imaging techniques to locate and quantify FGFR3 protein in tissue samples, including humans, and to identify FGFR3 ligands through the inhibitory binding of the labeled compounds. Substitution of one or more atoms of the compounds of the present disclosure may also be useful in generating differentiated ADME (adsorption, distribution, metabolism, and excretion). Thus, the present disclosure includes FGFR binding assays that include such labeled or substituted compounds.

[0331] 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, i.e., substituted, with an atom having an atomic mass or mass number different from that normally found in nature (i.e., naturally occurring). Suitable radionuclides that can be incorporated into compounds of the present disclosure include, but are not limited to: 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 can be replaced with deuterium atoms (e.g., one or more hydrogen atoms in the C alkyl groups of formula (I) can be replaced with deuterium atoms as needed, such as replacing -CH with -CD). In some embodiments, all alkyl groups in formula (I) can be perdeuterated.

[0332] One or more constituent atoms of the compounds presented herein can be replaced or substituted with a natural or non-natural abundance isotope of the atom. In some embodiments, the compounds contain at least one deuterium atom. In some embodiments, the compounds contain two or more deuterium atoms. In some embodiments, the compounds contain 1 to 2, 1 to 3, 1 to 4, 1 to 5, or 1 to 6 deuterium atoms. In some embodiments, all hydrogen atoms in the compounds can be replaced or substituted with deuterium atoms.

[0333] Synthetic methods for incorporating isotopes into organic compounds are well 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 experiments, and / or assays.

[0334] Substitution with heavier isotopes, such as deuterium, can confer certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be preferable in some cases (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.

[0335] The radionuclide incorporated into the radiolabeled compound 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.

[0336] 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.

[0337] The present disclosure can further include synthetic methods for incorporating radioisotopes into the disclosed compounds. 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 disclosed compounds.

[0338] The labeled compounds of the present disclosure 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 upon contact with FGFR3 protein through tracking the label. For example, a (labeled) test compound can be evaluated for its ability to reduce the binding of another compound known to bind to FGFR3 protein (i.e., standard compound). Thus, the ability of the test compound to compete with the standard compound for binding to FGFR3 protein is directly correlated with its binding affinity. Conversely, in some other screening assays, the standard compound is labeled, and the test compound is not labeled. Thus, 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.

[0339] kit The present disclosure also includes pharmaceutical kits useful in the treatment or prevention of FGFR-related diseases or disorders, such as, for example, cancer and other diseases mentioned herein, which include one or more containers housing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present disclosure. As will be apparent to those skilled in the art, such kits can optionally further include one or more of a variety of conventional pharmaceutical kit components, such as, for example, a container with one or more pharmaceutically acceptable carriers, additional containers, etc. Instructions, either as an insert or label, indicating the amounts of components to be administered, administration guidelines, and / or guidelines for mixing the components, can also be included in the kit.

[0340] The present disclosure will be explained in more detail by specific examples.The following examples are provided for illustrative purposes and are not intended to limit the present disclosure 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 has been found to be an FGFR3 inhibitor, as described below. [Example]

[0341] The experimental procedures for the compounds of the present disclosure are provided below. Preparative LC-MS purification of some of the prepared compounds was carried out on a Waters mass fractionation system. The basic instrument setup, protocols, and control software for operating these systems are described in detail in the literature. 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” Chem., 5, 670 (2003); and “Preparative LC-MS Purification:Improved Compound Specific Method Optimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Combi. See Chem., 6, 874-883 (2004). The separated compounds were typically subjected to analytical liquid chromatography mass spectrometry (LCMS) for purity analysis under the following conditions: Instrument: Agilent 1100 series, LC / MSD; Column: Waters Sunfire™ C 18 5 μm, 2.1 × 50 mm, buffer: mobile phase A: 0.025% TFA in water, and mobile phase B: acetonitrile; flow rate 2.0 mL / min, gradient 2% to 80% B in 3 min.

[0342] 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 indicated in the examples. Typical preparative reversed-phase high-performance liquid chromatography (RP-HPLC) column conditions are as follows: Purification at pH=2: Waters Sunfire™ C 18The 5 μm, 19 × 100 mm column was eluted with mobile phase A: 0.1% TFA (trifluoroacetic acid) in water 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 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 on the 30 × 100 mm column was 60 mL / min.

[0343] pH=10 purification: Waters XBridge C 18 A 5 μm, 19 × 100 mm column was eluted with mobile phase A: 0.15% NH OH in water 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 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 on a 30 × 100 mm column was 60 mL / min.

[0344] Example 1: 2-(2-chlorophenyl)-3-methyl-9-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine [ka] Step 1: 3-Bromo-5-chloro-1,6-naphthyridine [ka] A flask containing a mixture of phosphorus(V) oxychloride (41.4 mL, 444 mmol) and 3-bromo-1,6-naphthyridin-5(6H)-one (5.0 g, 22.2 mmol) was stirred at 100 °C for 3 hours. The reaction mixture was cooled to room temperature, and the reaction mixture was concentrated in vacuo. The resulting residue was treated with saturated aqueous NaHCO3, and the mixture was extracted with EtOAc. The organic phase was washed with brine, dried over MgSO4, filtered, and the solvent was evaporated in vacuo. The crude product obtained was used in the next step without further purification. CHBrClN2 (M+H) + LCMS calculated for m / z = 242.9 / 244.9; found 243.0 / 244.9.

[0345] Step 2: 3-Bromo-1,6-naphthyridin-5-amine [ka] A mixture of 3-bromo-5-chloro-1,6-naphthyridine (2.68 g, 11.0 mmol), 1,4-dioxane (9 mL), and ammonium hydroxide solution (9 mL) was placed in a sealed microwave vessel and irradiated at 150 °C for 3 h using a Biotage Initator+ microwave synthesizer. The reaction mixture was cooled to room temperature and the solvent was evaporated in vacuo. The crude product obtained was used in the next step without further purification. C8H7BrN3 (M+H) + LCMS calculated for m / z = 224.0 / 226.0; found 224.2 / 226.2.

[0346] Step 3: 3-(1-methyl-1H-pyrazol-4-yl)-1,6-naphthyridin-5-amine [ka] A vial containing a mixture of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.0 g, 4.91 mmol), 3-bromo-1,6-naphthyridin-5-amine (1.0 g, 4.46 mmol), XPhos Pd G2 (351 mg, 0.45 mmol), and sodium carbonate (1.42 g, 13.4 mmol) was evacuated and backfilled with nitrogen three times, followed by the addition of 1,4-dioxane (20 mL) and water (2.0 mL). The vial was sealed and heated to 100° C. for 1 hour. After cooling to room temperature, the mixture was directly filtered, and the filter cake was washed with water, ether, and hexane and then air-dried overnight. The resulting crude product was used in the next step without further purification. 12 H 12 N5(M+H) + LCMS calculated for m / z = 226.1; found 226.3.

[0347] Step 4: 2-(2-chlorophenyl)-9-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine [ka] A vial containing a mixture of 3-(1-methyl-1H-pyrazol-4-yl)-1,6-naphthyridin-5-amine (255 mg, 1.13 mmol), sodium bicarbonate (1.43 g, 1.70 mmol), 2-bromo-1-(2-chlorophenyl)ethan-1-one (214 μL, 1.47 mmol), and absolute ethanol (3 mL) was heated to 100° C. for 3 hours. After cooling to room temperature, the solvent was evaporated in vacuo, and the remaining residue was filtered. The filter cake was washed with ether and then air-dried overnight. The resulting crude product was used in the next step without further purification. 20 H 15 ClN5(M+H) + LCMS calculated for m / z = 360.1 / 362.1; found 360.2 / 362.3.

[0348] Step 5: 3-Bromo-2-(2-chlorophenyl)-9-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine [ka] To a solution of 2-(2-chlorophenyl)-9-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]-naphthyridine (407 mg, 1.13 mmol) in CHCl (7.5 mL) was added N-bromosuccinimide (242 mg, 1.36 mmol) at 0° C., followed by stirring at room temperature for 10 minutes. The solvent was evaporated in vacuo, and the resulting residue was purified by Biotage Isolera to give the desired product as a brown solid (411 mg, 83% yield). 20 H 14 BrClN5(M+H) + LCMS calculated for m / z = 438.0 / 440.0 / 442.0; found 438.0 / 439.9 / 442.0.

[0349] Step 6: 2-(2-chlorophenyl)-3-methyl-9-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine A vial containing a mixture of 3-bromo-2-(2-chlorophenyl)-9-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine (10 mg, 0.023 mmol), tetrakis(triphenylphosphine)-palladium(0) (5.3 mg, 0.0046 mmol), and potassium carbonate (6.3 mg, 0.043 mmol) was evacuated and backfilled with nitrogen three times, followed by the addition of 1,4-dioxane (1 mL), water (150 μL), and trimethylboroxine (4.8 μL, 0.034 mmol). The vial was sealed and heated to 100° C. for 1.5 hours. After cooling to room temperature, the mixture was filtered through Celite, washing with CHCl, and the filtrate was concentrated in vacuo. The reaction mixture was then diluted with CH3CN and water and purified by prep-LCMS (XBridge C18 column, eluted with a gradient of acetonitrile / water containing 0.1% TFA at a flow rate of 60 mL / min). The title compound was isolated as the TFA salt. 21 H 17 ClN5(M+H) + LCMS calculated for m / z = 374.1 / 376.1; found 374.3 / 376.3.

[0350] Example 2: 2-(2-chlorophenyl)-3-(cyclopent-1-en-1-yl)-9-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine [ka] This compound was prepared according to the procedure described in Example 1, substituting 2-(cyclopent-1-en-1-yl)4,4,5,5-tetramethyl-1,3,2-dioxaborolane for trimethylboroxine in step 6. The title compound was isolated as the TFA salt. 25 H 21 ClN5(M+H) + LCMS calculated for m / z = 426.1 / 428.1; found 426.3 / 428.4.

[0351] Example 3: (E)-2-(2-chlorophenyl)-9-(1-methyl-1H-pyrazol-4-yl)-3-(prop-1-en-1-yl)imidazo[2,1-f][1,6]naphthyridine [ka] This compound was prepared according to the procedure described in Example 1, substituting potassium (E)-trifluoro(prop-1-en-1-yl)borate for trimethylboroxine in step 6. The title compound was isolated as the TFA salt. 23 H 19 ClN5(M+H) + LCMS calculated for m / z = 400.1 / 402.1; found 400.3 / 402.4.

[0352] Example 4: 2-(2-chlorophenyl)-3-(3,5-dimethoxyphenyl)-9-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine [ka] This compound was prepared according to the procedure described in Example 1, substituting 2-(3,5-dimethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane for trimethylboroxine in step 6. The title compound was isolated as the TFA salt. 28 H 23 ClNO2(M+H) + LCMS calculated for m / z = 496.2 / 498.2; found 496.1 / 498.1.

[0353] Example 5: 2-(2-chlorophenyl)-3,9-bis(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine [ka] This compound was prepared according to the procedure described in Example 1, substituting 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole for trimethylboroxine in step 6. The title compound was isolated as the TFA salt. 24 H 19 ClN7(M+H) + LCMS calculated for m / z = 440.1 / 442.1; found 440.4 / 442.3.

[0354] Example 6: 2-(2-chlorophenyl)-3-(furan-2-yl)-9-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine [ka] A vial containing a mixture of 3-bromo-2-(2-chlorophenyl)-9-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine (10 mg, 0.023 mmol, Example 1, Step 5) and tetrakis(triphenylphosphine)palladium(0) (2.6 mg, 0.0023 mmol) was evacuated and backfilled with nitrogen three times, followed by the addition of 1,4-dioxane (1 mL) and tributyl(furan-2-yl)stannane (7.9 μL, 0.025 mmol). The vial was sealed and heated to 100° C. for 1 h. After the mixture was cooled to room temperature, it was filtered through Celite, washing with CHCl, and the filtrate was concentrated in vacuo. The reaction mixture was then diluted with CH3CN and water and purified by prep-LCMS (XBridge C18 column, eluted with a gradient of acetonitrile / water containing 0.1% TFA at a flow rate of 60 mL / min). The title compound was isolated as the TFA salt. 24 H 17 ClN5(M+H) + LCMS calculated for m / z = 426.1 / 428.1; found 426.2 / 428.1.

[0355] Example 7: 2-(2-chlorophenyl)-9-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carbonitrile [ka] A microwave vessel containing a mixture of 3-bromo-2-(2-chlorophenyl)-9-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine (Example 1, Step 5) (20 mg, 0.046 mmol), tris(dibenzylideneacetone)dipalladium(0) (2.1 mg, 2.3 μmol), 1,1′-bis(diphenylphosphino)ferrocene (2.5 mg, 4.5 μmol), zinc powder (1.2 mg, 0.02 mmol), and zinc cyanide (5.3 mg, 0.046 mmol) was evacuated and backfilled with nitrogen three times, followed by the addition of DMF (1 mL). The vial was sealed and irradiated at 150 °C for 2 h using a Biotage Initator+ microwave synthesizer. After the mixture was cooled to room temperature, it was filtered through Celite, washed with CH2Cl2, and the filtrate was then concentrated in vacuo. The reaction mixture was then diluted with CH3CN and water and purified by prep-LCMS (XBridge C18 column, eluted with a gradient of acetonitrile / water containing 0.1% TFA at a flow rate of 60 mL / min). The title compound was isolated as the TFA salt. 21 H 14 ClN6(M+H) + LCMS calculated for m / z = 385.1 / 387.1; found 385.1 / 387.1.

[0356] Example 8: 2-(2-chlorophenyl)-3-cyclopropyl-9-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine [ka] A vial containing a mixture of 3-bromo-2-(2-chlorophenyl)-9-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine (Example 1, Step 5) (10 mg, 0.023 mmol), palladium(II) acetate (1.0 mg, 4.6 μmol), potassium cyclopropyltrifluoroborate (3.4 mg, 0.023 mmol), and di(1-adamantyl)-n-butylphosphine (2.0 mg, 5.7 μmol) was evacuated and backfilled with nitrogen three times, followed by the addition of 1,4-dioxane (1 mL) and water (100 μL). The vial was sealed and heated to 100° C. for 16 hours. After the mixture was cooled to room temperature, it was filtered through Celite, washing with CHCl, and the filtrate was concentrated in vacuo. The reaction mixture was then diluted with CH3CN and water and purified by prep-LCMS (XBridge C18 column, eluted with a gradient of acetonitrile / water containing 0.1% TFA at a flow rate of 60 mL / min). The title compound was isolated as the TFA salt. 23 H 19 ClN5(M+H) + LCMS calculated for m / z = 400.1 / 402.1; found 400.2 / 402.2.

[0357] Example 9: 2-(2-chlorophenyl)-3-ethyl-9-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine [ka] Step 1: 2-(2-chlorophenyl)-9-(1-methyl-1H-pyrazol-4-yl)-3-vinylimidazo[2,1-f][1,6]naphthyridine [ka] This compound was prepared according to the procedure described in Example 1, substituting 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane for trimethylboroxine in step 6. 22 H 17 ClN5(M+H) +LCMS calculated for m / z = 386.1 / 388.1; found 386.2 / 386.1.

[0358] Step 2: 2-(2-chlorophenyl)-3-ethyl-9-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine To a solution of 2-(2-chlorophenyl)-9-(1-methyl-1H-pyrazol-4-yl)-3-vinylimidazo[2,1-f][1,6]naphthyridine (13 mg, 0.034 mmol) in absolute ethanol (2 mL) was added palladium hydroxide on carbon (20 wt%, 2.4 mg, 3.4 μmol). The reaction flask was connected to a balloon of hydrogen and evacuated and filled three times. The reaction mixture was stirred at 60 °C for 2 h. After the mixture was cooled to room temperature, it was filtered through Celite, washed with CHCl, and the filtrate was concentrated in vacuo. The reaction mixture was then diluted with CHCN and water and purified by prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% TFA at a flow rate of 60 mL / min). The title compound was isolated as the TFA salt. 22 H 19 ClN5(M+H) + LCMS calculated for m / z = 388.1 / 390.1; found 388.2 / 390.2.

[0359] Example 10: 3-chloro-2-(2-chlorophenyl)-9-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine [ka] To a solution of 2-(2-chlorophenyl)-9-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine (Example 1, Step 4) (10 mg, 0.028 mmol) in 1,2-dichloroethane (500 μL) was added N-chlorosuccinimide (4.5 mg, 0.033 mmol), followed by heating to 100° C. for 1 h. The solvent was evaporated in vacuo, and the residue was subsequently purified by prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% TFA at a flow rate of 60 mL / min). The title compound was isolated as the TFA salt. 20 H 14 Cl2N5(M+H) + LCMS calculated for m / z = 394.1 / 396.1; found 394.3 / 396.3.

[0360] Example 11: 2-(2,6-difluorophenyl)-9-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine [ka] This compound was prepared according to the procedure described in Example 1, substituting 2-bromo-1-(2,6-difluorophenyl)ethan-1-one for 2-bromo-1-(2-chlorophenyl)ethan-1-one in step 4. The title compound was isolated as the TFA salt. 20 H 14 F2N5(M+H) + LCMS calculated for m / z = 362.1; found 362.2.

[0361] Example 12: 2-(2-chloro-6-fluorophenyl)-9-(1,3-dimethyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine [ka] Step 1: 3-(1,3-dimethyl-1H-pyrazol-4-yl)-1,6-naphthyridin-5-amine [ka] This compound was prepared according to the procedure described in Example 1, substituting 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole for 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in step 3. 13 H 14 N5(M+H) + LCMS calculated for m / z = 240.1; found 240.1.

[0362] Step 2: 2-(2-chloro-6-fluorophenyl)-9-(1,3-dimethyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine This compound was prepared according to the procedure described in Example 1, substituting 2-bromo-1-(2-chlorophenyl)ethan-1-one for 2-bromo-1-(2-chloro-6-fluorophenyl)ethan-1-one in step 4. The title compound was isolated as the TFA salt. 21 H 16 ClFN5(M+H) + LCMS calculated for m / z = 392.1 / 394.1; found 392.2 / 394.2.

[0363] Intermediate 1: 3-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-b]pyrazin-5-amine [ka] Step 1: 5-chloro-3-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-b]pyrazine [ka] This compound was prepared according to the procedure described in Example 1, substituting 3,5-dichloropyrido[3,4-b]pyrazine for 3-bromo-1,6-naphthyridin-5-amine in step 3.11 H9ClN5(M+H) + LCMS calculated for m / z = 246.1 / 248.1; found 246.2 / 248.2.

[0364] Step 2: 3-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-b]pyrazin-5-amine This compound was prepared according to the procedure described in Example 1, substituting 5-chloro-3-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-b]pyrazine for 3-bromo-5-chloro-1,6-naphthyridine in step 2. 11 H 11 N6(M+H) + LCMS calculated for m / z = 227.1; found 227.2.

[0365] Example 13: 9-(2-chlorophenyl)-8-cyclopropyl-2-(1-methyl-1H-pyrazol-4-yl)imidazo[1',2':1,2]pyrido[3,4-b]pyrazine [ka] This compound was prepared according to the procedures described in Examples 1 and 8, substituting 3-(1-methyl-1H-pyrazol-4-yl)-1,6-naphthyridin-5-amine with 3-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-b]pyrazin-5-amine in Example 1, Step 4. The title compound was isolated as the TFA salt. 22 H 18 ClN6(M+H) + LCMS calculated for m / z = 401.1 / 403.1; found 401.2 / 403.1.

[0366] Example 14: 9-(2-chloro-6-fluorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)imidazo[1',2':1,2]pyrido[3,4-b]pyrazine [ka] This compound was prepared according to the procedure described in Example 1, substituting 3-(1-methyl-1H-pyrazol-4-yl)-1,6-naphthyridin-5-amine for 3-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-b]pyrazin-5-amine in step 4. The title compound was isolated as the TFA salt. 19 H 13 ClFN6(M+H) + LCMS calculated for m / z = 379.1 / 381.1; found 379.2 / 381.1.

[0367] Example 15: 1-(3-(4-(2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)ethan-1-one [ka] Step 1: 9-Bromo-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine [ka] A microwave vessel containing a mixture of 3-bromo-1,6-naphthyridin-5-amine (Example 1, Step 2) (1.32 g, 5.89 mmol), sodium bicarbonate (742 mg, 8.84 mmol), 2-bromo-1-(2,6-dichlorophenyl)ethan-1-one (1.89 g, 7.07 mmol), and tert-butanol (8 mL) was irradiated at 150 °C for 9 hours using a Biotage Initator+ microwave synthesizer. After cooling to room temperature, the solid was filtered and washed with CHCl, followed by concentration of the filtrate in vacuo. The resulting residue was purified by Biotage Isolera to give the desired product as an orange solid. 16 H9BrCl2N3(M+H) + LCMS calculated for m / z = 391.9 / 393.9 / 395.9; found 392.1 / 394.1 / 396.1.

[0368] Step 2: 2-(2,6-dichlorophenyl)-9-(1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine [ka] A vial containing a mixture of tert-butyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (102 mg, 0.280 mmol), 9-bromo-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine (100 mg, 0.254 mmol), tetrakis(triphenylphosphine)palladium(0) (29 mg, 0.025 mmol), and potassium carbonate (81.0 mg, 0.763 mmol) was evacuated and backfilled with nitrogen three times, followed by the addition of 1,4-dioxane (2 mL) and water (200 μL). The vial was sealed and heated to 100° C. for 2 hours. After the mixture was cooled to room temperature, it was filtered through Celite, washed with CH2Cl2, and then the filtrate was concentrated in vacuo. The resulting residue was purified by Biotage Isolera to give the desired product as a brown solid. The purified material was then diluted with CH2Cl2 (3 mL) and TFA (1 mL) and stirred at room temperature for 1 h. Upon completion, the volatiles were removed in vacuo. The resulting product was used in the next step without further purification. 23 H 19 Cl2N6(M+H) + LCMS calculated for m / z = 449.1 / 451.1; found 449.3 / 451.3.

[0369] Step 3: 1-(3-(4-(2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)ethan-1-one To a vial containing a mixture of 2-(2,6-dichlorophenyl)-9-(1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine (10 mg, 0.022 mmol) and diisopropylethylamine (19 μL, 0.111 mmol) in CHCN (1 mL) was added acetyl chloride (3 μL, 0.049 mmol). The solution was stirred at room temperature for 2 hours. The reaction mixture was then diluted with CHCN and purified by prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% TFA at a flow rate of 60 mL / min). The title compound was isolated as the TFA salt. 25 H 21 Cl2N6O(M+H) + LCMS calculated for m / z = 491.1 / 493.1; found 491.1 / 493.1.

[0370] Example 16: (1R,4R)-4-(4-(2-(2-chlorophenyl)-3-cyclopropylimidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)cyclohexane-1-carboxylic acid [ka] Step 1: 2-(2-chlorophenyl)-3-cyclopropyl-9-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine [ka] This compound was prepared according to the procedures described in Examples 1 and 8, substituting 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole for 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in Example 1, Step 3. 28 H 31 ClN5OSi(M+H)+ LCMS calculated for m / z = 516.2 / 518.2; found 516.4 / 518.4.

[0371] Step 2: 2-(2-chlorophenyl)-3-cyclopropyl-9-(1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine [ka] To a vial containing a mixture of 2-(2-chlorophenyl)-3-cyclopropyl-9-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine (1.39 g, 2.70 mmol) as a solution in CHCl (10 mL) was added 4 M HCl in dioxane (10 mL). The solution was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The resulting residue was treated with saturated aqueous NaHCO and the organic material was extracted into EtOAc. The organic phase was washed with brine, dried over MgSO, filtered, and the solvent was evaporated in vacuo. The resulting crude product was used in the next step without further purification. 22 H 17 ClN5(M+H) + LCMS calculated for m / z = 386.1 / 388.1; found 386.1 / 388.1.

[0372] Step 3: (1R,4R)-4-(4-(2-(2-chlorophenyl)-3-cyclopropylimidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)cyclohexane-1-carboxylic acid To a vial containing a mixture of 2-(2-chlorophenyl)-3-cyclopropyl-9-(1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine (20 mg, 0.052 mmol) and cesium carbonate (51 mg, 0.155 mmol) in CHCN (1 mL) was added ethyl (1S,4S)-4-((methylsulfonyl)oxy)cyclohexane-1-carboxylate (19.5 mg, 0.078 mmol). The vial was sealed and heated to 80 °C for 16 h. After cooling to room temperature, the mixture was filtered, washed with CHCN, and the filtrate was concentrated in vacuo. The resulting residue was treated with 1,4-dioxane (1 mL) and 2 M aqueous LiOH (1 mL) and stirred at room temperature for 2 h. The reaction mixture was then diluted with CH3CN and purified by prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile / water containing 0.1% TFA at a flow rate of 60 mL / min). The title compound was isolated as the TFA salt. 29 H 27 ClNO2(M+H) + LCMS calculated for m / z = 512.2 / 514.2; found 512.4 / 514.4.

[0373] Example 17: N-((1R,4R)-4-(4-(2-(2-chlorophenyl)-3-cyclopropylimidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)cyclohexyl)acetamide [ka] Step 1: tert-butyl ((1R,4R)-4-(4-(2-(2-chlorophenyl)-3-cyclopropylimidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)cyclohexyl)carbamate [ka] To a vial containing a mixture of 2-(2-chlorophenyl)-3-cyclopropyl-9-(1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine (20 mg, 0.052 mmol) and cesium carbonate (51 mg, 0.155 mmol) as a solution in CHCN (1 mL) was added (1S,4S)-4-((tert-butoxycarbonyl)amino)-cyclohexylmethanesulfonate (22.8 mg, 0.078 mmol). The vial was sealed and heated to 80° C. for 16 hours. After cooling to room ...

Claims

1. Formula (I): 【Chemical 1】 or a pharmaceutically acceptable salt thereof, wherein Ring A is aromatic; Y is N or C; When Y is N, X is CR ４ is, or When Y is C, X is NR ５ and 【Chemistry 2】 represents a single or double bond, Z is N or CR ６ and Cy １ is selected from phenyl and 5- to 6-membered heteroaryl; said 5- to 6-membered heteroaryl having at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; said phenyl and said 5- to 6-membered heteroaryl are each independently selected from R １０ and optionally substituted with 1, 2, 3 or 4 substituents selected from Cy Ａ is selected from C cycloalkyl, 4- to 10-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; said 4- to 10-membered heterocycloalkyl and said 5- to 6-membered heteroaryl each have at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; said N and said S are optionally oxidized; ring-forming carbon atoms of said 5- to 6-membered heteroaryl and said 4- to 10-membered heterocycloalkyl are optionally substituted with oxo to form a carbonyl group; said C cycloalkyl, said 4- to 10-membered heterocycloalkyl, said phenyl, and said 5- to 6-membered heteroaryl each independently are R ２０ and optionally substituted with 1, 2, 3 or 4 substituents selected from R 1 is H, OR a9 or NR c9 R d9 ; R 2 and R 3 are each H; R ４ is H, C １－６ Alkyl, C ２－６ alkenyl, C 3-7 cycloalkyl, phenyl, 5-6 membered heteroaryl, halo, and CN; １－６ alkyl, the C ２－６ alkenyl, the C cycloalkyl, the phenyl and the 5- to 6-membered heteroaryl are each independently R ４０ and optionally substituted with one or two substituents selected from R ５ is C １－６ is alkyl, R 6 is H or OR a9 ; Each R １０ are independently １－６ Alkyl, C １－６ haloalkyl, C cycloalkyl, 4- to 6-membered heterocycloalkyl, and phenyl; １－６ alkyl, the C cycloalkyl, the 4- to 6-membered heterocycloalkyl, and the phenyl are each independently R １１ and optionally substituted with one or two substituents selected from Each R １１ are independently １－６ Alkyl, 4- to 6-membered heterocycloalkyl, phenyl, 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 C(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ and S(O) ２ NR ｃ３ R ｄ３ C １－６ The alkyl, the 4- to 6-membered heterocycloalkyl, and the phenyl are each independently R １２ and optionally substituted with one or two substituents selected from Each R １２ are independently １－６ Alkyl, 5-6 membered heteroaryl, halo, D, CN, OR ａ５ , and N.R. ｃ５ R ｄ５ is selected from Each R ２０ are independently １－６ Alkyl, C １－６ Haloalkyl, Halo, CN, OR ａ２ , and N.R. ｃ２ C(O)R ｂ２ C １－６ The alkyl may be substituted with OR a4 ; Each R ４０ are independently １－６ Alkyl, C １－６ Haloalkyl, Halo, D, CN, OR ａ８ , and N.R. ｃ８ R ｄ８ is selected from Each R ａ２ and R ｃ２ are independently H, C １－６ Alkyl, C １－６ Haloalkyl and C ３－１０ cycloalkyl; １－６ Alkyl and the C ３－１０ Each cycloalkyl is independently R ２１ and optionally substituted with 1, 2, 3 or 4 substituents selected from each R 21 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, D, CN, OR a4 and NR c4 R d4 ; Each R ｂ２ are independently １－６ Alkyl and C ２－６ alkenyl; Each R ａ３ , R ｃ３ and R ｄ３ are independently H, C １－６ Alkyl, C １－６ Haloalkyl, and C ３－６ cycloalkyl; １－６ Alkyl, and the C ３－６ Each cycloalkyl is independently R １２ and optionally substituted with 1, 2, 3 or 4 substituents selected from Each R ｂ３ are independently １－６ Alkyl, C １－６ Haloalkyl, C ３－６ cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl; １－６ alkyl, the C ３－６ cycloalkyl, the 5- to 6-membered heteroaryl, and the 4- to 7-membered heterocycloalkyl are each independently R １２ and optionally substituted with 1, 2, 3 or 4 substituents selected from Each R ａ４ , R ｃ４ and R ｄ４ are independently H, C １－６ Alkyl, and C １－６ haloalkyl; Each R ａ５ , R ｃ５ and R ｄ５ are independently H, C １－６ Alkyl, and C １－６ haloalkyl; Each R ａ８ , R ｃ８ and R ｄ８ are independently H, C １－６ Alkyl, and C １－６ haloalkyl, and Each R ａ９ , R ｃ９ and R ｄ９ are independently H, C １－６ alkyl, and 4- to 10-membered heterocycloalkyl The compound or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein the compound has formula (IA): 【Chemistry 3】 2. The compound of claim 1, having the formula:

3. The compound of claim 2, wherein the compound has formula (IB): 【Chemistry 4】 2. The compound of claim 1, having the formula:

4. The compound according to any one of claims 1 to 3, wherein Z is N, or a pharmaceutically acceptable salt thereof.

5. Z is CR ６ 4. The compound according to claim 1, wherein:

6. Cy １ is a 5- to 6-membered heteroaryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 10 , or a pharmaceutically acceptable salt thereof.

7. Cy １ is pyrazolyl or pyridinyl, optionally substituted with one or two substituents independently selected from R 10 , or a pharmaceutically acceptable salt thereof.

8. Cy １ is pyrazolyl, pyridinyl or phenyl, optionally substituted with one or two substituents independently selected from R 10 , or a pharmaceutically acceptable salt thereof.

9. Cy １ is selected from 1-methyl-1H-pyrazol-4-yl, 1,3-dimethyl-1H-pyrazol-4-yl, 1-(1-acetylpyrrolidin-3-yl)-1H-pyrazol-4-yl, 1-(4-carboxycyclohexyl)-1H-pyrazol-4-yl, 1-(4-acetamidocyclohexyl)-1H-pyrazol-4-yl, 1-(3-hydroxycyclobutyl)-1H-pyrazol-4-yl, and 6-(4-acetylpiperazin-1-yl)pyridin-3-yl, or a pharmaceutically acceptable salt thereof.

10. Cy １ Examples of the compounds include 1-methyl-1H-pyrazol-4-yl, 1,3-dimethyl-1H-pyrazol-4-yl, 1-(1-acetylpyrrolidin-3-yl)-1H-pyrazol-4-yl, 1-(4-carboxycyclohexyl)-1H-pyrazol-4-yl, 1-(4-acetamidocyclohexyl)-1H-pyrazol-4-yl, 1-(3-hydroxycyclobutyl)-1H-pyrazol-4-yl, 6-(4-acetylpiperazin-1-yl)pyridin-3-yl, 1-(1-(2-hydroxyacetone)-1H-yl)-4-yl, 1-(4-acetylpyrrolidin-3-yl)-1H-pyrazol ... 1-(1-(1-aminocyclopropane-1-carbonyl)azetidin-3-yl)-1H-pyrazol-4-yl, 1-(1-(2-(1H-imidazol-1-yl)acetyl)azetidin-3-yl)-1H-pyrazol-4-yl, 1-(1-(oxazole-4-carbonyl)azetidin-3-yl)-1H-pyrazol-4-yl, 1-(1-(4-aminotetrahydro-2H-pyran-4-carbonyl)azetidin-3 -yl)-1H-pyrazol-4-yl, 1-(1-(2-cyanoacetyl)azetidin-3-yl)-1H-pyrazol-4-yl, 1-(4-carboxy-3-fluorobenzyl)-1H-pyrazol-4-yl, 1-(4-(dimethylcarbamoyl)phenyl)-1H-pyrazol-4-yl, 1-((1r,4r)-4-(2-methoxyacetamido)cyclohexyl)-1H-pyrazol-4-yl, 1-((1r,4r)-4-(3,3-dimethylureido)cyclohexyl)-1H- pyrazol-4-yl, 1-(2-acetyl-2-azaspiro[3.5]nonan-7-yl)-1H-pyrazol-4-yl, 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl, 1-((1r,4r)-4-hydroxycyclohexyl)-1H-pyrazol-4-yl, 1-(4-carboxy-4-methylcyclohexyl)-1H-pyrazol-4-yl, 1-(1-(dimethylcarbamoyl)pyrrolidin-3-yl)-1H-pyrazol-4-yl, 1-(1-(N,N-dimethylsulfamoyl)pyrrolidin-3-yl)-1H-pyrazol-4-yl, 1-(3-(2-hydroxyacetyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1H-pyrazol-4-yl, 1-(1-(morpholine-4-carbonyl)pyrrolidin-3-yl)-1H-pyrazol-4-yl, 1-(3-(2-hydroxyacetyl)-3-azabicyclo[4.1.0]heptan-6-yl)-1H-pyrazol-4-yl, 1-(3-acetyl -3-azabicyclo[4.1.0]heptan-1-yl)-1H-pyrazol-4-yl, 6-(1-(2-hydroxyacetyl)azetidin-3-yl)pyridin-3-yl, 5-(1-acetylazetidin-3-yl)pyridin-3-yl, 4-(1-acetylazetidin-3-yl)phenyl), 1-cyclopropyl-1H-pyrazol-4-yl, 1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl, 1-(oxetan-3-yl)-1H-pyrazol-4-yl 1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl, 1-isopropyl-1H-pyrazol-4-yl, 1-(difluoromethyl)-1H-pyrazol-4-yl, 1-(2-cyanoethyl)-1H-pyrazol-4-yl, 1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl, 1-(cyanomethyl)-1H-pyrazol-4-yl, 1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl 6. The compound according to any one of claims 1 to 5, selected from 1-(1-hydroxy-2-methylpropan-2-yl)-1H-pyrazol-4-yl, 1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-4-yl, 1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl, 1-(2-morpholinoethyl)-1H-pyrazol-4-yl, and 1-(2-hydroxyethyl)-1H-pyrazol-4-yl, or a pharmaceutically acceptable salt thereof.

11. Each R １０ But independently, C １－６ alkyl, 4- to 6-membered heterocycloalkyl, and C cycloalkyl, each of which is independently selected from R １１ The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, optionally substituted with one or two substituents selected from:

12. Each R １０ are independently selected from methyl, ethyl, isopropyl, 2-methylpropyl, difluoromethyl, cyclopropyl, cyclobutyl, cyclohexyl, phenyl, piperzinyl, azetidinyl, pyrrolidinyl, azaspiro[3.5]nonanyl, tetrahydro-2H-pyranyl, azabicyclo[3.1.0]hexanyl, azabicyclo[4.1.0]heptanyl, tetrahydrofuranyl, oxetanyl, and piperidinyl, each of which is independently selected from R １１ The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, optionally substituted with one or two substituents selected from:

13. Each R １１ But independently, C(O)R ｂ３ , C(O)OR ａ３ , N.R. ｃ３ C(O)R ｂ３ and OR ａ３ 12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, selected from:

14. Each R １１ are independently C(O)CH ３ , C(O)OH, NHC(O)CH ３ 12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

15. Each R １１ are independently methyl, CN, OH, C(O)CH ３ , C(O)OH, NHC(O)CH ３ , C(O)CH ２ OH, C(O)N(CH ３ ) ２ , NHC(O)CH ２ OCH ３ ,NHC(O)N(CH ３ ) ２ , S(O) ２ N (CH ３ ) ２ , N(CH ３ ) ２ , S(O) ２ CH ３ , 2-cyanoacetyl, morpholine-4-carbonyl, morpholinyl, 1-aminocyclopropane-1-carbonyl, (1H-imidazol-1-yl)acetyl, oxazole-4-carbonyl, 4-aminotetrahydro-2H-pyran-4-carbonyl, and 4-carboxy-3-fluorophenyl, or a pharmaceutically acceptable salt thereof.

16. Cy Ａ is selected from phenyl and 5- to 6-membered heteroaryl, and said phenyl and said 5- to 6-membered heteroaryl are each independently selected from R ２０ 16. The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, optionally substituted with 1, 2, 3 or 4 substituents selected from:

17. Cy Ａ is phenyl or furanyl, optionally substituted with 1, 2 or 3 substituents independently selected from R 20 , or a pharmaceutically acceptable salt thereof.

18. Cy Ａ is selected from 2-chlorophenyl, 2,6-difluorophenyl, 2-chloro-6-fluorophenyl, 2,6-dichlorophenyl, 2-fluoro-6-methylphenyl, 2-chloro-4-methoxyphenyl, and 3-methylfuran-2-yl, or a pharmaceutically acceptable salt thereof.

19. Cy Ａ is selected from 2-chlorophenyl, 2,6-difluorophenyl, 2-chloro-6-fluorophenyl, 2,6-dichlorophenyl, 2-fluoro-6-methylphenyl, 2-chloro-4-methoxyphenyl, 3-methylfuran-2-yl, 1-methylpiperidin-4-yl, (1S,5R)-2-oxo-3,8-diazabicyclo[3.2.1]octan-8-yl, 2-chloro-6-(trifluoromethyl)phenyl, 2,6-dimethylphenyl, 2-cyano-6-fluorophenyl, 2-fluoro-6-methoxyphenyl, 2,3-dimethylphenyl, 4-(hydroxymethyl)-2-methylphenyl, 3-acrylamido-2,6-dichlorophenyl, 3-acrylamidophenyl, 2-acrylamidophenyl, and cyclopropyl; or a pharmaceutically acceptable salt thereof.

20. Each R ２０ But independently, Halo, C １－６ Alkyl and OR ａ２ 20. The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, selected from:

21. Each R ２０ 20. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein is independently selected from chloro, fluoro, methyl and methoxy.

22. Each R ２０ is independently selected from CN, chloro, fluoro, methyl, methoxy, trifluoromethyl, hydroxymethyl, and acrylamide, or a pharmaceutically acceptable salt thereof.

23. R １ The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein

24. R ４ are independently selected from H, methyl, ethyl, chloro, CN, cyclopropyl, cyclopentenyl, propenyl, phenyl, pyrazolyl, and furanyl, and said methyl, said ethyl, said cyclopropyl, said cyclopentenyl, said propenyl, said phenyl, said pyrazolyl, and said furanyl are each selected from R ４０ The compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, optionally substituted with one or two substituents selected from:

25. R ４ is selected from H, methyl, ethyl, chloro, CN, cyclopent-1-en-1-yl, prop-1-en-1-yl, 3,5-dimethoxyphenyl, 1-methyl-1H-pyrazol-4-yl, furan-2-yl, and cyclopropyl, or a pharmaceutically acceptable salt thereof.

26. R ４ is selected from H, methyl, ethyl, isopropyl, hydroxymethyl, 1-hydroxyethyl, chloro, bromo, CN, cyclopent-1-en-1-yl, prop-1-en-1-yl, 3,5-dimethoxyphenyl, 1-methyl-1H-pyrazol-4-yl, furan-2-yl, and cyclopropyl, or a pharmaceutically acceptable salt thereof.

27. Each R ４０ But independently, C １－６ Alkyl and OR ａ８ 25. The compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, selected from:

28. R ５ 28. The compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein is methyl.

29. R ６ The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein 30. The compound of claim 30, wherein the compound has Formula IIIa or Formula IVa: 【Chemistry 5】 29. The compound of any one of claims 1, 4, 5, 11 to 22 and 24 to 28, or a pharmaceutically acceptable salt thereof, having the formula:

31. The compound of claim 31, wherein the compound has Formula IIIb or Formula IVb: 【Chemistry 6】 29. The compound according to any one of claims 1, 4 to 15, 20 to 22 and 24 to 28, or a pharmaceutically acceptable salt thereof, having the formula:

32. The compound of claim 31, wherein the compound has formula IIIc or formula IVc: 【Chemistry 7】 29. The compound according to any one of claims 1, 4, 5, 11 to 15, 20 to 22 and 24 to 28, or a pharmaceutically acceptable salt thereof, having the formula:

33. Formula (IA): 【Chemistry 8】 or a pharmaceutically acceptable salt thereof, wherein Z is N; Cy １ is a 5- to 6-membered heteroaryl; said 5- to 6-membered heteroaryl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; said 5- to 6-membered heteroaryl is independently selected from R １０ and optionally substituted with 1, 2, 3, or 4 substituents selected from Cy Ａ is selected from C cycloalkyl, 4- to 10-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; said 4- to 10-membered heterocycloalkyl and said 5- to 6-membered heteroaryl each have at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; said N and said S are optionally oxidized; ring-forming carbon atoms of said 5- to 6-membered heteroaryl and said 4- to 10-membered heterocycloalkyl are optionally substituted with oxo to form a carbonyl group; said C cycloalkyl, said 4- to 10-membered heterocycloalkyl, said phenyl, and said 5- to 6-membered heteroaryl each independently are selected from R ２０ and optionally substituted with 1, 2, 3 or 4 substituents selected from R 1 is H, OR a9 or NR c9 R d9 ; R ２ and R ３ are H, respectively, R ５ is C １－６ is alkyl, Each R １０ are independently １－６ Alkyl, C １－６ haloalkyl, C cycloalkyl, and 4- to 6-membered heterocycloalkyl; １－６ alkyl, the C cycloalkyl and the 4- to 6-membered heterocycloalkyl are each independently R １１ and optionally substituted with one or two substituents selected from Each R １１ are independently １－６ Alkyl, CN, OR ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , N.R. ｃ３ R ｄ３ and S(O) 2 R b3; １－６ Alkyl is independently R １２ and optionally substituted with one or two substituents selected from Each R １２ are independently １－６ Alkyl, halo, D, CN, OR ａ５ and NR ｃ５ R ｄ５ is selected from Each R ２０ are independently １－６ Alkyl, C １－６ Haloalkyl, halo, CN, and OR ａ２ C １－６ The alkyl may be substituted with OR a4; R ａ２ is H, C １－６ Alkyl, C １－６ Haloalkyl and C ３－１０ cycloalkyl; １－６ Alkyl and the C ３－１０ Each cycloalkyl is independently R ２１ and optionally substituted with 1, 2, 3 or 4 substituents selected from each R 21 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, D, CN, OR a4 and NR c4 R d4 ; Each R ａ３ , R ｃ３ and R ｄ３ are independently H, C １－６ Alkyl, C １－６ Haloalkyl and C ３－６ cycloalkyl; １－６ Alkyl and the C ３－６ Each cycloalkyl is independently R １２ and optionally substituted with 1, 2, 3 or 4 substituents selected from Each R ｂ３ are independently １－６ Alkyl, C １－６ Haloalkyl and C ３－６ cycloalkyl; １－６ Alkyl and the C ３－６ Each cycloalkyl is independently R １２ and optionally substituted with 1, 2, 3 or 4 substituents selected from Each R ａ４ , R ｃ４ , and R ｄ４ are independently H, C １－６ Alkyl, and C １－６ haloalkyl; Each R ａ５ , R ｃ５ , and R ｄ５ are independently H, C １－６ Alkyl, and C １－６ haloalkyl, and Each R ａ９ , R ｃ９ , and R ｄ９ are independently H, C １－６ Alkyl, and C １－６ haloalkyl, 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

34. Formula (IB): 【Chemistry 9】 or a pharmaceutically acceptable salt thereof, wherein Z is N or CR ６ and Cy １ is a 5- to 6-membered heteroaryl; said 5- to 6-membered heteroaryl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; said 5- to 6-membered heteroaryl is independently selected from R １０ and optionally substituted with 1, 2, 3 or 4 substituents selected from Cy Ａ is selected from phenyl and 5- to 6-membered heteroaryl; said 5- to 6-membered heteroaryl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; said N and said S are optionally oxidized; said ring-forming carbon atoms of said 5- to 6-membered heteroaryl are optionally substituted with oxo to form a carbonyl group; said phenyl and said 5- to 6-membered heteroaryl are each independently selected from R ２０ and optionally substituted with 1, 2, 3 or 4 substituents selected from R 1 is H, OR a9 or NR c9 R d9 ; R 2 and R 3 are each H; R ４ is H, C １－６ Alkyl, C ２－６ alkenyl, C cycloalkyl, phenyl, 5-6 membered heteroaryl, halo, and CN; １－６ alkyl, the C ２－６ alkenyl, the C cycloalkyl, the phenyl and the 5- to 6-membered heteroaryl are each independently R ４０ and optionally substituted with one or two substituents selected from R 6 is H or OR a9 ; Each R １０ are independently １－６ Alkyl, C １－６ haloalkyl, C cycloalkyl, and 4- to 10-membered heterocycloalkyl; １－６ alkyl, the C cycloalkyl and the 4- to 10-membered heterocycloalkyl are each independently R １１ and optionally substituted with one or two substituents selected from Each R １１ are independently １－６ Alkyl, CN, OR ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , N.R. ｃ３ R ｄ３ and NR ｃ３ C(O)R ｂ３ C １－６ Alkyl is independently R １２ and optionally substituted with one or two substituents selected from Each R １２ are independently １－６ Alkyl, halo, D, CN, OR ａ５ and NR ｃ５ R ｄ５ Selected from: Each R ２０ are independently １－６ Alkyl, C １－６ Haloalkyl, halo, CN, and OR ａ２ C １－６ The alkyl may be substituted with OR a4 ; Each R ４０ are independently １－６ Alkyl, C １－６ Haloalkyl, Halo, D, CN, OR ａ８ and NR ｃ８ R ｄ８ is selected from R ａ２ is H, C １－６ Alkyl, C １－６ Haloalkyl and C ３－１０ cycloalkyl; １－６ Alkyl and the C ３－１０ Each cycloalkyl is independently R ２１ and optionally substituted with 1, 2, 3 or 4 substituents selected from Each R ｂ２ are independently １－６ Alkyl, C １－６ Haloalkyl and C ３－１０ cycloalkyl; １－６ Alkyl and the C ３－１０ Each cycloalkyl is independently R ２１ and optionally substituted with 1, 2, 3 or 4 substituents selected from each R 21 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, D, CN, OR a4 and NR c4 R d4 ; Each R ａ３ , R ｃ３ and R ｄ３ are independently H, C １－６ Alkyl, C １－６ Haloalkyl and C ３－６ cycloalkyl; １－６ Alkyl and the C ３－６ Each cycloalkyl is independently R １２ and optionally substituted with 1, 2, 3 or 4 substituents selected from Each R ｂ３ are independently １－６ Alkyl, C １－６ Haloalkyl and C ３－６ cycloalkyl; １－６ Alkyl and the C ３－６ Each cycloalkyl is independently R １２ and optionally substituted with 1, 2, 3 or 4 substituents selected from Each R ａ４ , R ｃ４ , and R ｄ４ are independently H, C １－６ Alkyl, and C １－６ haloalkyl; Each R ａ５ , R ｃ５ , and R ｄ５ are independently H, C １－６ Alkyl, and C １－６ haloalkyl; Each R ａ８ , R ｃ８ , and R ｄ８ are independently H, C １－６ Alkyl, and C １－６ haloalkyl, and Each R ａ９ , R ｃ９ , and R ｄ９ are independently H, C １－６ Alkyl, and C １－６ haloalkyl, 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

35. 2-(2-chlorophenyl)-3-methyl-9-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine, 2-(2-chlorophenyl)-3-(cyclopent-1-en-1-yl)-9-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine, (E)-2-(2-chlorophenyl)-9-(1-methyl-1H-pyrazol-4-yl)-3-(prop-1-en-1-yl)imidazo[2,1-f][1,6]naphthyridine, 2-(2-chlorophenyl)-3-(3, 5-dimethoxyphenyl)-9-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine, 2-(2-chlorophenyl)-3,9-bis(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine, 2-(2-chlorophenyl)-3-(furan-2-yl)-9-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine, 2-(2-chlorophenyl)-9-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine ]naphthyridine-3-carbonitrile, 2-(2-chlorophenyl)-3-cyclopropyl-9-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine, 2-(2-chlorophenyl)-3-ethyl-9-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine, 3-chloro-2-(2-chlorophenyl)-9-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine, 2-(2,6-difluorophenyl)-9-(1-methyl-1 2-(2-chloro-6-fluorophenyl)-9-(1,3-dimethyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine, 2-(2-chloro-6-fluorophenyl)-9-(1,3-dimethyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine, 9-(2-chlorophenyl)-8-cyclopropyl-2-(1-methyl-1H-pyrazol-4-yl)imidazo[1',2':1,2]pyrido[3,4-b]pyrazine, 9-(2-chloro-6-fluorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)imidazo[1',2':1,2]pyrido[3,4-b]pyrazine, 1-(3-(4-(2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)ethan-1-one, (1R,4R)-4-(4-(2-(2-chlorophenyl)-3-cyclopropylimidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazole- 1-yl)cyclohexane-1-carboxylic acid, N-((1R,4R)-4-(4-(2-(2-chlorophenyl)-3-cyclopropylimidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)cyclohexyl)acetamide, 2-(2-fluoro-6-methylphenyl)-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-3H -imidazo[4,5-f]quinoxaline, 2-(2-chloro-4-methoxyphenyl)-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-f]quinoxaline, 3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-2-(3-methylfuran-2-yl)-3H-imidazo[4,5-f]quinoxaline, 3-(4-(2-(2-chloro 1-(4-(5-(2-(2-chloro-6-fluorophenyl)-3-methyl-3H-imidazo[4,5-f]quinoxalin-8-yl)-1H-pyrazol-1-yl)cyclobutan-1-ol, and 1-(4-(5-(2-(2-chloro-6-fluorophenyl)-3-methyl-3H-imidazo[4,5-f]quinoxalin-8-yl)pyridin-2-yl)piperazin-1-yl)ethan-1-one; and pharmaceutically acceptable salts thereof 2. The compound of claim 1, selected from: or a pharmaceutically acceptable salt thereof.

36. 3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-2-(1-methylpiperidin-4-yl)-3H-imidazo[4,5-f]quinoxaline, (1S,5R)-8-(3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-f]quinoxalin-2-yl)-3,8-diazabicyclo[3.2.1]octan-2-one, (S)-1-(3-(4-(2-(2-chloro-6-(trifluoromethyl)phenyl)-3-methylimidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-4-yl) (S)-1-(3-(4-(2-(2,6-dimethylphenyl)-3-methylimidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)-2-hydroxyethan-1-one, (S)-1-(3-(4-(2-(2,6-dimethylphenyl)-3-methylimidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)-2-hydroxyethan-1-one, (S)-3-fluoro-2-(9-(1-(1-(2-hydroxyacetyl)pyrrolidin-3-yl)-1H-pyrazol-4-yl)-3-methylimidazo[2,1-f][1,6]naphthyridin-2-yl)benzonitrile ... )-1-(3-(4-(2-(2-fluoro-6-methoxyphenyl)-3-methylimidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)-2-hydroxyethan-1-one, 2-(2,3-dimethylphenyl)-3-methyl-9-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine, (3-methyl-4-(3-methyl-9-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-2-yl)phenyl N,N,3-trimethyl-9-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-8-ol, (S)-2-(2,6-dichlorophenyl)-3-methyl-9-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-8-ol, (S)-2-(2,6-dichlorophenyl)-3-methyl-9-(1-methyl-1H-pyrazol-4-yl)-10-((tetrahydrofuran-3-yl)oxy)imidazo[2,1-f][1,6]naphthyridine, 2-(2,6-dichlorophenyl)-N,N,3-trimethyl-9-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-8-amine, N-(2,4-dichloro-3-(3-methyl-9-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-2-yl)phenyl)acrylamide, N-(3-(3-methyl-9-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-2-yl)phenyl)acrylamide, N-(2-(3-methyl-9-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-2-yl)phenyl)acrylamide amide, (1-aminocyclopropyl)(3-(4-(2-(2,6-dichlorophenyl)-3-methylimidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)azetidin-1-yl)methanone, 1-(3-(4-(2-(2,6-dichlorophenyl)-3-methylimidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-2-(1H-imidazol-1-yl)ethan-1-one, (3-(4-(2-(2,6-dichlorophenyl)-3-methylimidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-2-(1H-imidazol-1-yl)ethan-1-one, imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)azetidin-1-yl)(oxazol-4-yl)methanone, (4-aminotetrahydro-2H-pyran-4-yl)(3-(4-(2-(2,6-dichlorophenyl)-3-methylimidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)azetidin-1-yl)methanone, 3-(3-(4-(2-(2,6-dichlorophenyl)-3-methylimidazo[2,1-f][1,6]naphthyridin-9-yl)-1H -pyrazol-1-yl)azetidin-1-yl)-3-oxopropanenitrile, 4-((4-(2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)methyl)-2-fluorobenzoic acid, 4-(4-(2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)-N,N-dimethylbenzamide, N-((1r,4r)-4-(4-(2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)azetidin-1-yl)-3-oxopropanenitrile6]naphthyridin-9-yl)-1H-pyrazol-1-yl)cyclohexyl)-2-methoxyacetamide, 3-((1r,4r)-4-(4-(2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)cyclohexyl)-1,1-dimethylurea, 1-(7-(4-(2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.5]non-2-yl ) ethan-1-one, 2-(2,6-dichlorophenyl)-3-methyl-9-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine, (1r,4r)-4-(4-(2-(2,6-dichlorophenyl)-3-methylimidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)cyclohexan-1-ol, 4-(4-(2-(2,6-dichlorophenyl)-3-methylimidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)cyclohexan-1-ol, (S)-1-(3-(4-(2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)-1-methylcyclohexane-1-carboxylic acid, 3-(4-(2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)-N,N-dimethylpyrrolidine-1-carboxamide, 3-(4-(2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)-N,N-dimethylpyrrolidine-1-sulfonamide, (S)-1-(3-(4- (2-(2,6-dichlorophenyl)-3-methylimidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)ethan-1-one, (S)-1-(3-(4-(2-(2,6-dichlorophenyl)-3-methylimidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)-2-hydroxyethan-1-one, 1-(1-(4-(2-(2,6-dichlorophenyl)-3-methylimidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)6]naphthyridin-9-yl)-1H-pyrazol-1-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-hydroxyethan-1-one, (S)-1-(3-(4-(2-(2,6-dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)-2-hydroxyethan-1-one, (S)-1-(3-(4-(2-(2,6-dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6 ]naphthyridin-9-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)ethan-1-one, (S)-(3-(4-(2-(2,6-dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)(morpholino)methanone, 1-((3S)-3-(4-(2-(2,6-dichlorophenyl)-3-(1-hydroxyethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl) pyrrolidin-1-yl)-2-hydroxyethan-1-one, 1-(6-(4-(2-(2,6-dichlorophenyl)-3-methylimidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)-3-azabicyclo[4.1.0]heptan-3-yl)-2-hydroxyethan-1-one, 1-(1-(4-(2-(2,6-dichlorophenyl)-3-methylimidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)-3-azabicyclo[4.1.0]heptan-3-yl)-2-hydroxyethan-1-one, 1-(3-(5-(2-(2,6-dichlorophenyl)-3-methylimidazo[2,1-f][1,6]naphthyridin-9-yl)pyridin-2-yl)azetidin-1-yl)-2-hydroxyethan-1-one, 1-(3-(5-(2-(2,6-dichlorophenyl)-3-methylimidazo[2,1-f][1,6]naphthyridin-9-yl)pyridin-3-yl)azetidin-1-yl)ethan-1-one, 1-(3-(5-(2-(2,6-dichlorophenyl)-3-methylimidazo[2,1-f][1,6]naphthyridin-9-yl)pyridin-3-yl)azetidin-1-yl)ethan-1-one, 1-(3-(5-(2-(2,6-dichlorophenyl)-3-methylimidazo[2,1-f][1,6]naphthyridin-9-yl)phenyl)azetidin-1-yl)ethan-1-one, (S)-1-(3-(4-(2-(2-chlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)ethan-1-one, (S)-1-(3-(4-(2-(2-chlorophenyl)-3-isopropylimidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)-2-hydroxyethane-1 -one, (S)-1-(3-(4-(3-bromo-2-(2-chloro-6-fluorophenyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)pyrrolidin-1-yl)-2-hydroxyethan-1-one, 2-cyclopropyl-3-methyl-9-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine, (2-(2,6-dichlorophenyl)-9-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-3-yl (9-(1-cyclopropyl-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridin-3-yl)methanol, (2-(2,6-dichlorophenyl)-9-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-3-yl)methanol, (2-(2,6-dichlorophenyl)-9-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-3-yl)methanol, (2-(2,6-dichlorophenyl)-9-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-3-yl)methanol (2-(2,6-dichlorophenyl)-9-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-3-yl)methanol, (2-(2,6-dichlorophenyl)-9-(1-isopropyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-3-yl)methanol, (2-(2,6-dichlorophenyl)-9-(1-(difluoromethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-3-yl)methanol, 3-(4-(2-(2,6-dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)propanenitrile, 1-(4-(2-(2,6-dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol, 2-(4-(2-(2,6-dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl) ,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)acetonitrile, (2-(2,6-dichlorophenyl)-9-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-3-yl)methanol, 2-(4-(2-(2,6-dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)-2-methylpropan-1-ol, (2-(2,6-dichlorophenyl)-9-(1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-4-yl)imidazo[2,1-f] [1,6]naphthyridin-3-yl)methanol, (2-(2,6-dichlorophenyl)-9-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-3-yl)methanol, (2-(2,6-dichlorophenyl)-9-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridin-3-yl)methanol and 2-(4-(2-(2,6-dichlorophenyl)-3-(hydroxymethyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)-1H-pyrazol-1-yl)ethan-1-ol; and pharmaceutically acceptable salts thereof 2. The compound of claim 1, selected from: or a pharmaceutically acceptable salt thereof.

37. 37. A pharmaceutical composition comprising a compound according to any one of claims 1 to 36 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

38. A pharmaceutical agent for inhibiting FGFR3 enzyme, comprising the compound according to any one of claims 1 to 36 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 37.

39. A medicament for treating cancer in a patient, comprising a compound according to any one of claims 1 to 36 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 37.

40. 38. A medicament for treating cancer in a patient, comprising a compound of any one of claims 1 to 36 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 37, wherein the medicament is administered to the patient in combination with another therapy or therapeutic agent.

41. 41. The pharmaceutical composition of claim 39 or 40, wherein the cancer 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 lymphoma or non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, hairy cell lymphoma, Burkitt's lymphoma, glioblastoma, melanoma, and rhabdomyosarcoma.

42. 41. The pharmaceutical composition of claim 39 or 40, wherein the cancer 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.

43. A medicament for treating a skeletal or chondrocyte disorder in a patient, the medicament comprising a compound according to any one of claims 1 to 36 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 37.

44. 44. The pharmaceutical composition of claim 43, 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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