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. TIFF2024522189000102.tif53163

Description

[Technical field]

[0001] 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.

[0002] Sequence Listing This application contains a Sequence Listing that has been submitted electronically as an ASCII text file titled "Sequence_Listing.txt". The ASCII text file was created on Jun. 6, 2022 and is 1 kilobyte in size. The contents of the ASCII text file are incorporated herein by reference in their entirety. [Background technology]

[0003] Fibroblast growth factor receptors (FGFRs) are receptor tyrosine kinases that bind fibroblast growth factor (FGF) ligands. There are four FGFR proteins (FGFR1-4) that can bind ligands and are involved in the regulation of many physiological processes, including tissue development, angiogenesis, wound healing, and metabolic control. Upon ligand binding, the receptors dimerize, phosphorylation occurs, stimulating protein kinase activity, and recruiting a number of intracellular docking proteins. These interactions promote the activation of a series of intracellular signaling pathways (including Ras-MAPK, AKT-PI3K, and phospholipase C) that 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 activating mutations in FGFRs, can result in tumor formation, progression, and resistance to conventional cancer treatments. Genetic alterations (including gene amplifications, chromosomal translocations, and somatic mutations) that lead to ligand-independent receptor activation have been reported 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 bone dysplastic syndromes (Gallo et al. Cytokine & Growth Factor Reviews 2015, 26, 425-449). Mechanisms that lead to aberrant ligand-dependent signaling in human disease include overexpression of FGFs and alterations in FGFR splicing that give rise to receptors with increased promiscuity in ligand binding capacity.Therefore, for the clinical treatment of diseases in which FGF or FGFR activity is elevated, it may be useful to develop inhibitors that target FGFR.

[0004] 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, renal, lung, ovarian, prostate), hematopoietic malignancies (e.g., multiple myeloma, acute myeloid leukemia, and myeloproliferative neoplasms), and other neoplasms (e.g., glioblastoma and sarcoma). In addition to its role in oncogenic neoplasms, FGFR activation has also been implicated in skeletal and chondrocyte disorders (including, but not limited to, achondroplasia and craniosynostosis syndrome).

[0005] There is a continuing need to develop new drugs to treat cancer, and the FGFR inhibitors described herein help address this need. Summary of the Invention

[0006] The present disclosure provides a compound of formula (I): [ka] or a pharma- ceutical acceptable salt thereof, wherein the constituent variables are defined herein.

[0007] The present disclosure is further directed to pharmaceutical compositions comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof and at least one pharma- ceutically acceptable carrier.

[0008] The present disclosure is further directed to a method of inhibiting an FGFR enzyme (eg, an FGFR3 enzyme), the method comprising contacting the enzyme with a compound of formula (I) or a pharma- ceutically acceptable salt thereof.

[0009] 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 pharma- ceutically acceptable salt thereof.

[0010] The present disclosure is further directed to the compounds of formula (I) for use in treating diseases associated with abnormal activity or expression of FGFR enzymes (e.g., FGFR3 enzymes).The present disclosure is further directed to the use of the compounds of formula (I) in the preparation of a medicament for use in treatment.

[0011] The present disclosure is further directed to a method of treating a disorder mediated by an FGFR enzyme (e.g., an FGFR3 enzyme) or a mutant thereof in a patient in need of such treatment, comprising administering to the patient a compound of formula (I) or a pharma- ceutical acceptable composition thereof.

[0012] The present disclosure is further directed to a method of treating a disorder mediated by an FGFR enzyme (e.g., an FGFR3 enzyme) or a mutant thereof in a patient in need of such treatment, comprising administering to the patient a compound of formula (I) or a pharma- ceutical acceptable salt thereof, or a composition comprising a compound of formula (I) or a pharma-ceutical acceptable salt thereof, in combination with another treatment or therapeutic agent as described herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] compound In one aspect, the present disclosure provides a compound of formula (I): [ka] or a pharma- ceutical acceptable salt thereof, wherein R 1 , 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, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-3 Alkylene, 4-10 membered heterocycloalkyl-C 1-3Alkylene, C 6-10 Aryl-C 1-3 Alkylene, 5-10 membered heteroaryl-C 1-3 Alkylene, Halo, D, CN, NO 2 , OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , C(=NR e1 )R b1 , C(=NOR a1 )R b1 , C(=NR e1 )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) 2 R b1 , N.R. c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 C is selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-3 Alkylene, 4-10 membered heterocycloalkyl-C 1-3 Alkylene, C 6-10 Aryl-C 1-3 Alkylene and 5-10 membered heteroaryl-C 1-3 Each alkylene is R 10 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from R 2 , 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, 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, NO 2 , OR a2 , S.R. a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , O.C.(O)R b2 , O-C(O)NR c2 R d2 , N.R. c2 R d2 , N.R. c2 C(O)R b2 , N.R. c2 C(O)OR a2 , N.R. c2 C(O)NR c2 R d2 , C(=NR e2 )R b2 , C(=NOR a2 )R b2 , C(=NR e2 )NR c2R d2 , N.R. c2 C(=NR e2 )NR c2 R d2 , N.R. c2 S(O)R b2 , N.R. c2 S(O) 2 R b2 , N.R. c2 S(O) 2 NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 C is selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-3 Alkylene, 4-10 membered heterocycloalkyl-C 1-3 Alkylene, C 6-10 Aryl-C 1-3 Alkylene and 5-10 membered heteroaryl-C 1-3 Each alkylene is R 20 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from R 3 , 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, 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, NO 2 , OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , O.C.(O)R b3 , O-C(O)NR c3 R d3 , 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 , C(=NR e3 )R b3 , C(=NOR a3 )R b3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , N.R. c3 S(O)R b3 , N.R. c3 S(O) 2 R b3 , N.R. c3 S(O) 2 NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , and S(O) 2 NR c3 R d3 C is selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-3Alkylene, 4-10 membered heterocycloalkyl-C 1-3 Alkylene, C 6-10 Aryl-C 1-3 Alkylene and 5-10 membered heteroaryl-C 1-3 Each alkylene is R 30 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from R 4 , 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, 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, NO 2 , OR a4 , S.R. a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , O.C.(O)R b4 , O-C(O)NR c4 R d4 , 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 , C(=NR e4 )R b4 , C(=NOR a4 )R b4 , C(=NR e4 )NR c4 R d4 , N.R. c4 C(=NR e4 )NRc4 R d4 , N.R. c4 S(O)R b4 , N.R. c4 S(O) 2 R b4 , N.R. c4 S(O) 2 NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , and S(O) 2 NR c4 R d4 C is selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-3 Alkylene, 4-10 membered heterocycloalkyl-C 1-3 Alkylene, C 6-10 Aryl-C 1-3 Alkylene and 5-10 membered heteroaryl-C 1-3 Each alkylene is R 40 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from R 5 , 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, 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 a5 , S.R. a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , O.C.(O)R b5 , O-C(O)NR c5 R d5 , 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 , C(=NR e5 )R b5 , C(=NOR a5 )R b5 , C(=NR e5 )NR c5 R d5 , N.R. c5 C(=NR e5 )NR c5 R d5 , N.R. c5 S(O)R b5 , N.R. c5 S(O) 2 R b5 , N.R. c5 S(O) 2 NR c5 R d5 , S(O)R b5 , S(O)NR c5 R d5 , S(O) 2 R b5 , and S(O) 2 NR c5 R d5 C is selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-3 Alkylene, 4-10 membered heterocycloalkyl-C 1-3 Alkylene, C6-10 Aryl-C 1-3 Alkylene and 5-10 membered heteroaryl-C 1-3 Each alkylene is R 50 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from Z is N or CR 6 and R 6 , 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, 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, NO 2 , OR a6 , S.R. a6 , C(O)R b6 , C(O)NR c6 R d6 , C(O)OR a6 , O.C.(O)R b6 , O-C(O)NR c6 R d6 , 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 , C(=NR e6 )R b6 , C(=NOR a6 )R b6 , C(=NR e6 )NR c6 R d6 , N.R. c6 C(=NR e6 )NRc6 R d6 , N.R. c6 S(O)R b6 , N.R. c6 S(O) 2 R b6 , N.R. c6 S(O) 2 NR c6 R d6 , S(O)R b6 , S(O)NR c6 R d6 , S(O) 2 R b6 , and S(O) 2 NR c6 R d6 C is selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-3 Alkylene, 4-10 membered heterocycloalkyl-C 1-3 Alkylene, C 6-10 Aryl-C 1-3 Alkylene and 5-10 membered heteroaryl-C 1-3 Each alkylene is R 60 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R 10 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, 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 a10 , S.R. a10 , C(O)R b10 , C(O)NR c10 R d10 , C(O)OR a10 , O.C.(O)R b10 , O-C(O)NR c10 R d10 , 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 , C(=NR e10 )R b10 , C(=NOR a10 )R b10 , C(=NR e10 )NR c10 R d10 , N.R. c10 C(=NR e10 )NR c10 R d10 , N.R. c10 S(O)R b10 , N.R. c10 S(O) 2 R b10 , N.R. c10 S(O) 2 NR c10 R d10 , S(O)R b10 , S(O)NR c10 R d10 , S(O) 2 R b10 , and S(O) 2 NR c10 R d10 Independently selected from the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-3 Alkylene, 4-10 membered heterocycloalkyl-C 1-3 Alkylene, C6-10 Aryl-C 1-3 Alkylene and 5-10 membered heteroaryl-C 1-3 Each alkylene is R 11 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R 11 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, 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 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) 2 R b11 , N.R. c11 S(O) 2 NR c11 R d11 , S(O)R b11 , S(O)NR c11 R d11 , S(O) 2 R b11 , and S(O) 2 NR c11 R d11Independently selected from the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-3 Alkylene, 4-10 membered heterocycloalkyl-C 1-3 Alkylene, C 6-10 Aryl-C 1-3 Alkylene and 5-10 membered heteroaryl-C 1-3 Each alkylene is R 12 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R 12 is 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 a12 , S.R. a12 , C(O)R b12 , C(O)NR c12 R d12 , C(O)OR a12 , N.R. c12 R d12 , N.R. c12 C(O)R b12 , N.R. c12 C(O)OR a12 , N.R. c12 C(O)NR c12 R d12 , N.R. c12 S(O)R b12 , N.R. c12 S(O) 2 R b12 , N.R. c12 S(O) 2 NR c12 R d12 , S(O)R b12 , S(O)NR c12 R d12 , S(O)2 R b12 , and S(O) 2 NR c12 R d12 Independently selected from the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each R g and optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R 20 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, 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, NO 2 , OR a20 , S.R. a20 , C(O)R b20 , C(O)NR c20 R d20 , C(O)OR a20 , O.C.(O)R b20 , O-C(O)NR c20 R d20 , N.R. c20 R d20 , N.R. c20 C(O)R b20 , N.R. c20 C(O)OR a20 , N.R. c20 C(O)NR c20 R d20 , C(=NR e20 )R b20 , C(=NOR a20 )Rb20 , C(=NR e20 )NR c20 R d20 , N.R. c20 C(=NR e20 )NR c20 R d20 , N.R. c20 S(O)R b20 , N.R. c20 S(O) 2 R b20 , N.R. c20 S(O) 2 NR c20 R d20 , S(O)R b20 , S(O)NR c20 R d20 , S(O) 2 R b20 , and S(O) 2 NR c20 R d20 Independently selected from the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-3 Alkylene, 4-10 membered heterocycloalkyl-C 1-3 Alkylene, C 6-10 Aryl-C 1-3 Alkylene and 5-10 membered heteroaryl-C 1-3 Each alkylene is R 21 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R 21 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, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-3 Alkylene, 4-10 membered heterocycloalkyl-C1-3 Alkylene, C 6-10 Aryl-C 1-3 Alkylene, 5-10 membered heteroaryl-C 1-3 Alkylene, Halo, D, CN, OR a21 , S.R. a21 , C(O)R b21 , C(O)NR c21 R d21 , C(O)OR a21 , N.R. c21 R d21 , N.R. c21 C(O)R b21 , N.R. c21 C(O)OR a21 , N.R. c21 C(O)NR c21 R d21 , N.R. c21 S(O)R b21 , N.R. c21 S(O) 2 R b21 , N.R. c21 S(O) 2 NR c21 R d21 , S(O)R b21 , S(O)NR c21 R d21 , S(O) 2 R b21 , and S(O) 2 NR c21 R d21 Independently selected from the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-3 Alkylene, 4-10 membered heterocycloalkyl-C 1-3 Alkylene, C 6-10 Aryl-C 1-3 Alkylene and 5-10 membered heteroaryl-C 1-3 Each alkylene is R 22 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R22 is 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 a22 , S.R. a22 , C(O)R b22 , C(O)NR c22 R d22 , C(O)OR a22 , N.R. c22 R d22 , N.R. c22 C(O)R b22 , N.R. c22 C(O)OR a22 , N.R. c22 C(O)NR c22 R d22 , N.R. c22 S(O)R b22 , N.R. c22 S(O) 2 R b22 , N.R. c22 S(O) 2 NR c22 R d22 , S(O)R b22 , S(O)NR c22 R d22 , S(O) 2 R b22 , and S(O) 2 NR c22 R d22 Independently selected from the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each R g and optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R 30 is 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, 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, NO 2 , OR a30 , S.R. a30 , C(O)R b30 , C(O)NR c30 R d30 , C(O)OR a30 , O.C.(O)R b30 , O-C(O)NR c30 R d30 , N.R. c30 R d30 , N.R. c30 C(O)R b30 , N.R. c30 C(O)OR a30 , N.R. c30 C(O)NR c30 R d30 , C(=NR e30 )R b30 , C(=NOR a30 )R b30 , C(=NR e30 )NR c30 R d30 , N.R. c30 C(=NR e30 )NR c30 R d30 , N.R. c30 S(O)R b30 , N.R. c30 S(O) 2 R b30 , N.R. c30 S(O) 2 NR c30 R d30 , S(O)R b30 , S(O)NR c30 R d30 , S(O) 2 R b30 , and S(O) 2 NR c30 R d30Independently selected from the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-3 Alkylene, 4-10 membered heterocycloalkyl-C 1-3 Alkylene, C 6-10 Aryl-C 1-3 Alkylene and 5-10 membered heteroaryl-C 1-3 Each alkylene is R 31 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R 31 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, 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 a31 , S.R. a31 , C(O)R b31 , C(O)NR c31 R d31 , C(O)OR a31 , N.R. c31 R d31 , N.R. c31 C(O)R b31 , N.R. c31 C(O)OR a31 , N.R. c31 C(O)NR c31 R d31 , N.R. c31 S(O)R b31 , N.R. c31S(O) 2 R b31 , N.R. c31 S(O) 2 NR c31 R d31 , S(O)R b31 , S(O)NR c31 R d31 , S(O) 2 R b31 , and S(O) 2 NR c31 R d31 Independently selected from the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-3 Alkylene, 4-10 membered heterocycloalkyl-C 1-3 Alkylene, C 6-10 Aryl-C 1-3 Alkylene and 5-10 membered heteroaryl-C 1-3 Each alkylene is R 32 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R 32 is 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 a32 , S.R. a32 , C(O)R b32 , C(O)NR c32 R d32 , C(O)OR a32 , N.R. c32 R d32 , N.R. c32 C(O)R b32 , N.R. c32 C(O)OR a32 , N.R. c32 C(O)NRc32 R d32 , N.R. c32 S(O)R b32 , N.R. c32 S(O) 2 R b32 , N.R. c32 S(O) 2 NR c32 R d32 , S(O)R b32 , S(O)NR c32 R d32 , S(O) 2 R b32 , and S(O) 2 NR c32 R d32 Independently selected from the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each R g and optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R 40 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, 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, NO 2 , OR a40 , S.R. a40 , C(O)R b40 , C(O)NR c40 R d40 , C(O)OR a40 , O.C.(O)R b40 , O-C(O)NRc40 R d40 , N.R. c40 R d40 , N.R. c40 C(O)R b40 , N.R. c40 C(O)OR a40 , N.R. c40 C(O)NR c40 R d40 , C(=NR e40 )R b40 , C(=NOR a40 )R b40 , C(=NR e40 )NR c40 R d40 , N.R. c40 C(=NR e40 )NR c40 R d40 , N.R. c40 S(O)R b40 , N.R. c40 S(O) 2 R b40 , N.R. c40 S(O) 2 NR c40 R d40 , S(O)R b40 , S(O)NR c40 R d40 , S(O) 2 R b40 , and S(O) 2 NR c40 R d40 Independently selected from the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-3 Alkylene, 4-10 membered heterocycloalkyl-C 1-3 Alkylene, C 6-10 Aryl-C 1-3 Alkylene and 5-10 membered heteroaryl-C 1-3 Each alkylene is R 41 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R 41 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, 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 a41 , S.R. a41 , C(O)R b41 , C(O)NR c41 R d41 , C(O)OR a41 , N.R. c41 R d41 , N.R. c41 C(O)R b41 , N.R. c41 C(O)OR a41 , N.R. c41 C(O)NR c41 R d41 , N.R. c41 S(O)R b41 , N.R. c41 S(O) 2 R b41 , N.R. c41 S(O) 2 NR c41 R d41 , S(O)R b41 , S(O)NR c41 R d41 , S(O) 2 R b41 , and S(O) 2 NR c41 R d41 Independently selected from the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-3 Alkylene, 4-10 membered heterocycloalkyl-C 1-3 Alkylene, C 6-10 Aryl-C 1-3 Alkylene and 5-10 membered heteroaryl-C 1-3 Each alkylene is R 42 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R 42 is 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 a42 , S.R. a42 , C(O)R b42 , C(O)NR c42 R d42 , C(O)OR a42 , N.R. c42 R d42 , N.R. c42 C(O)R b42 , N.R. c42 C(O)OR a42 , N.R. c42 C(O)NR c42 R d42 , N.R. c42 S(O)R b42 , N.R. c42 S(O) 2 R b42 , N.R. c42 S(O) 2 NR c42 R d42 , S(O)R b42 , S(O)NR c42 R d42 , S(O) 2 R b42 , and S(O) 2 NR c42 R d42 Independently selected from the C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each R g and optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R 50 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, 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, NO 2 , OR a50 , S.R. a50 , C(O)R b50 , C(O)NR c50 R d50 , C(O)OR a50 , O.C.(O)R b50 , O-C(O)NR c50 R d50 , N.R. c50 R d50 , N.R. c50 C(O)R b50 , N.R. c50 C(O)OR a50 , N.R. c50 C(O)NR c50 R d50 , C(=NR e50 )R b50 , C(=NOR a50 )R b50 , C(=NR e50 )NR c50 R d50 , N.R. c50 C(=NR e50 )NR c50 Rd50 , N.R. c50 S(O)R b50 , N.R. c50 S(O) 2 R b50 , N.R. c50 S(O) 2 NR c50 R d50 , S(O)R b50 , S(O)NR c50 R d50 , S(O) 2 R b50 , and S(O) 2 NR c50 R d50 Independently selected from the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-3 Alkylene, 4-10 membered heterocycloalkyl-C 1-3 Alkylene, C 6-10 Aryl-C 1-3 Alkylene and 5-10 membered heteroaryl-C 1-3 Each alkylene is R 51 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R 51 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, 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 a51, S.R. a51 , C(O)R b51 , C(O)NR c51 R d51 , C(O)OR a51 , N.R. c51 R d51 , N.R. c51 C(O)R b51 , N.R. c51 C(O)OR a51 , N.R. c51 C(O)NR c51 R d51 , N.R. c51 S(O)R b51 , N.R. c51 S(O) 2 R b51 , N.R. c51 S(O) 2 NR c51 R d51 , S(O)R b51 , S(O)NR c51 R d51 , S(O) 2 R b51 , and S(O) 2 NR c51 R d51 Independently selected from the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-3 Alkylene, 4-10 membered heterocycloalkyl-C 1-3 Alkylene, C 6-10 Aryl-C 1-3 Alkylene and 5-10 membered heteroaryl-C 1-3 Each alkylene is R 52 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R 52 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR a52 , S.R. a52 , C(O)R b52 , C(O)NR c52 R d52 , C(O)OR a52 , N.R. c52 R d52 , N.R. c52 C(O)R b52 , N.R. c52 C(O)OR a52 , N.R. c52 C(O)NR c52 R d52 , N.R. c52 S(O)R b52 , N.R. c52 S(O) 2 R b52 , N.R. c52 S(O) 2 NR c52 R d52 , S(O)R b52 , S(O)NR c52 R d52 , S(O) 2 R b52 , and S(O) 2 NR c52 R d52 Independently selected from the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each R g and optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R 60 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, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C1-3 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, NO 2 , OR a60 , S.R. a60 , C(O)R b60 , C(O)NR c60 R d60 , C(O)OR a60 , O.C.(O)R b60 , O-C(O)NR c60 R d60 , N.R. c60 R d60 , N.R. c60 C(O)R b60 , N.R. c60 C(O)OR a60 , N.R. c60 C(O)NR c60 R d60 , C(=NR e60 )R b60 , C(=NOR a60 )R b60 , C(=NR e60 )NR c60 R d60 , N.R. c60 C(=NR e60 )NR c60 R d60 , N.R. c60 S(O)R b60 , N.R. c60 S(O) 2 R b60 , N.R. c60 S(O) 2 NR c60 R d60 , S(O)R b60 , S(O)NR c60 R d60 , S(O) 2 R b60 , and S(O) 2 NR c60 R d60 Independently selected from the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-3 Alkylene, 4-10 membered heterocycloalkyl-C 1-3 Alkylene, C 6-10 Aryl-C 1-3 Alkylene and 5-10 membered heteroaryl-C 1-3 Each alkylene is R 61 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R 61 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, 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 a61 , S.R. a61 , C(O)R b61 , C(O)NR c61 R d61 , C(O)OR a61 , N.R. c61 R d61 , N.R. c61 C(O)R b61 , N.R. c61 C(O)OR a61 , N.R. c61 C(O)NR c61 R d61 , N.R. c61 S(O)R b61 , N.R. c61 S(O) 2 R b61 , N.R. c61 S(O) 2 NR c61 Rd61 , S(O)R b61 , S(O)NR c61 R d61 , S(O) 2 R b61 , and S(O) 2 NR c61 R d61 Independently selected from the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-3 Alkylene, 4-10 membered heterocycloalkyl-C 1-3 Alkylene, C 6-10 Aryl-C 1-3 Alkylene and 5-10 membered heteroaryl-C 1-3 Each alkylene is R 62 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R 62 is 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 a62 , S.R. a62 , C(O)R b62 , C(O)NR c62 R d62 , C(O)OR a62 , N.R. c62 R d62 , N.R. c62 C(O)R b62 , N.R. c62 C(O)OR a62 , N.R. c62 C(O)NR c62 R d62 , N.R. c62 S(O)R b62 , N.R. c62 S(O)2 R b62 , N.R. c62 S(O) 2 NR c62 R d62 , S(O)R b62 , S(O)NR c62 R d62 , S(O) 2 R b62 , and S(O) 2 NR c62 R d62 Independently selected from the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each R g and optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R a1 , R b1 , R c1 , and R d1 , 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, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are each R 10 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from or any R attached to the same N atom c1 and R d1 together with the N atom to which they are attached form R 10forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R e1 H, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkylthio, C 1-6 Alkylsulfonyl, C 1-6 Alkyl carbonyl, C 1-6 Alkylaminosulfonyl, Carbamyl, C 1-6 Alkylcarbamyl, di(C 1-6 Alkyl)carbamyl, aminosulfonyl, C 1-6 Alkylaminosulfonyl, and di(C 1-6 alkyl)aminosulfonyl; Each R a2 , R b2 , R c2 , and R d2 , 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, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are each R 20 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from or any R attached to the same N atom c2 and R d2 together with the N atom to which they are attached form R 20 forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by 1, 2, or 3 substituents independently selected from Each R e2 H, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkylthio, C 1-6 Alkylsulfonyl, C 1-6 Alkyl carbonyl, C 1-6 Alkylaminosulfonyl, Carbamyl, C 1-6 Alkylcarbamyl, di(C 1-6 Alkyl)carbamyl, aminosulfonyl, C 1-6 Alkylaminosulfonyl, and di(C 1-6 alkyl)aminosulfonyl; Each R a3 , R b3 , R c3 and R d3 , 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, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are each R 30 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from or any R attached to the same N atom c3 and R d3 together with the N atom to which they are attached form R 30 forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R e3 H, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C1-6 Alkylthio, C 1-6 Alkylsulfonyl, C 1-6 Alkyl carbonyl, C 1-6 Alkylaminosulfonyl, Carbamyl, C 1-6 Alkylcarbamyl, di(C 1-6 Alkyl)carbamyl, aminosulfonyl, C 1-6 Alkylaminosulfonyl, and di(C 1-6 alkyl)aminosulfonyl; Each R a4 , R b4 , R c4 , and R d4 , 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, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are each R 40 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from or any R attached to the same N atom c4 and R d4 together with the N atom to which they are attached form R 40 forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R e4 H, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkylthio, C 1-6 Alkylsulfonyl, C 1-6 Alkyl carbonyl, C 1-6Alkylaminosulfonyl, 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 a5 , R b5 , R c5 , and R d5 , 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, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are each R 50 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from or any R attached to the same N atom c5 and R d5 together with the N atom to which they are attached form R 50 forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R e5 H, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkylthio, C 1-6 Alkylsulfonyl, C 1-6 Alkyl carbonyl, C 1-6 Alkylaminosulfonyl, Carbamyl, C 1-6 Alkylcarbamyl, di(C 1-6Alkyl)carbamyl, aminosulfonyl, C 1-6 Alkylaminosulfonyl, and di(C 1-6 alkyl)aminosulfonyl; Each R a6 , R b6 , R c6 , and R d6 , 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, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are each R 60 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from or any R attached to the same N atom c6 and R d6 together with the N atom to which they are attached form R 60 forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R e6 H, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkylthio, C 1-6 Alkylsulfonyl, C 1-6 Alkyl carbonyl, C 1-6 Alkylaminosulfonyl, Carbamyl, C 1-6 Alkylcarbamyl, di(C 1-6 Alkyl)carbamyl, aminosulfonyl, C 1-6 Alkylaminosulfonyl, and di(C 1-6alkyl)aminosulfonyl; Each R a10 , R b10 , R c10 , and R d10 , 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, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are each R 11 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from or any R attached to the same N atom c10 and R d10 together with the N atom to which they are attached form R 11 forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R e10 H, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkylthio, C 1-6 Alkylsulfonyl, C 1-6 Alkyl carbonyl, C 1-6 Alkylaminosulfonyl, Carbamyl, C 1-6 Alkylcarbamyl, di(C 1-6 Alkyl)carbamyl, aminosulfonyl, C 1-6 Alkylaminosulfonyl, and di(C 1-6 alkyl)aminosulfonyl; Each R a11 , R b11 , Rc11 , and R d11 , 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, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each R 12 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from or any R attached to the same N atom c11 and R d11 together with the N atom to which they are attached form R 12 forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by 1, 2, or 3 substituents independently selected from Each R a12 , R b12 , R c12 , and R d12 , H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 1-6 haloalkyl, 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl is R g and optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R a20 , R b20 , R c20 , and R d20 , H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C3-10 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 Aryl and 5- to 10-membered heteroaryl are each R 21 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from or any R attached to the same N atom c20 and R d20 together with the N atom to which they are attached form R 21 forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R e20 H, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkylthio, C 1-6 Alkylsulfonyl, C 1-6 Alkyl carbonyl, C 1-6 Alkylaminosulfonyl, Carbamyl, C 1-6 Alkylcarbamyl, di(C 1-6 Alkyl)carbamyl, aminosulfonyl, C 1-6 Alkylaminosulfonyl, and di(C 1-6 alkyl)aminosulfonyl; Each R a21 , R b21 , R c21 , and R d21 , 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; 1-6Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each R 22 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from or any R attached to the same N atom c21 and R d21 together with the N atom to which they are attached form R 22 forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by 1, 2, or 3 substituents independently selected from Each R a22 , R b22 , R c22 , and R d22 , H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 1-6 haloalkyl, 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl is R g and optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R a30 , R b30 , R c30 , and R d30 , 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, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10Aryl and 5- to 10-membered heteroaryl are each R 31 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from or any R attached to the same N atom c30 and R d30 together with the N atom to which they are attached form R 31 forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R e30 H, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkylthio, C 1-6 Alkylsulfonyl, C 1-6 Alkyl carbonyl, C 1-6 Alkylaminosulfonyl, Carbamyl, C 1-6 Alkylcarbamyl, di(C 1-6 Alkyl)carbamyl, aminosulfonyl, C 1-6 Alkylaminosulfonyl, and di(C 1-6 alkyl)aminosulfonyl; Each R a31 , R b31 , R c31 , and R d31 , 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, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each R 32 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from or any R attached to the same N atom c31 and R d31 together with the N atom to which they are attached form R 32 forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by 1, 2, or 3 substituents independently selected from Each R a32 , R b32 , R c32 , and R d32 , H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 1-6 haloalkyl, 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl is R g and optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R a40 , R b40 , R c40 , and R d40 , 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, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are each R 41 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from or any R attached to the same N atom c40 and R d40 together with the N atom to which they are attached form R 41forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R e40 H, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkylthio, C 1-6 Alkylsulfonyl, C 1-6 Alkyl carbonyl, C 1-6 Alkylaminosulfonyl, Carbamyl, C 1-6 Alkylcarbamyl, di(C 1-6 Alkyl)carbamyl, aminosulfonyl, C 1-6 Alkylaminosulfonyl, and di(C 1-6 alkyl)aminosulfonyl; Each R a41 , R b41 , R c41 , and R d41 , 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, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each R 42 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from or any R attached to the same N atom c41 and R d41 together with the N atom to which they are attached form R 42 forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by 1, 2, or 3 substituents independently selected from Each R a42 , Rb42 , R c42 , and R d42 , H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 1-6 haloalkyl, 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl is R g and optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R a50 , R b50 , R c50 , and R d50 , 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, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are each R 51 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from or any R attached to the same N atom c50 and R d50 together with the N atom to which they are attached form R 51 forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R e50 H, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkylthio, C 1-6Alkylsulfonyl, C 1-6 Alkyl carbonyl, C 1-6 Alkylaminosulfonyl, Carbamyl, C 1-6 Alkylcarbamyl, di(C 1-6 Alkyl)carbamyl, aminosulfonyl, C 1-6 Alkylaminosulfonyl, and di(C 1-6 alkyl)aminosulfonyl; Each R a51 , R b51 , R c51 , and R d51 , 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, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each R 52 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from or any R attached to the same N atom c51 and R d51 together with the N atom to which they are attached form R 52 forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by 1, 2, or 3 substituents independently selected from Each R a52 , R b52 , R c52 , and R d52 , H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 1-6 haloalkyl, 1-6 Alkyl, C 2-6 Alkenyl, and C2-6 Each alkynyl is R g and optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R a60 , R b60 , R c60 , and R d60 , 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, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are each R 61 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from or any R attached to the same N atom c60 and R d60 together with the N atom to which they are attached form R 61 forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R e60 H, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkylthio, C 1-6 Alkylsulfonyl, C 1-6 Alkyl carbonyl, C 1-6 Alkylaminosulfonyl, Carbamyl, C 1-6 Alkylcarbamyl, di(C 1-6 Alkyl)carbamyl, aminosulfonyl, C 1-6 Alkylaminosulfonyl, and di(C 1-6alkyl)aminosulfonyl; Each R a61 , R b61 , R c61 , and R d61 , 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, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each R 62 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from or any R attached to the same N atom c61 and R d61 together with the N atom to which they are attached form R 62 forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by 1, 2, or 3 substituents independently selected from Each R a62 , R b62 , R c62 , and R d62 , H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 1-6 haloalkyl, 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl is R g and optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R g D, OH, NO 2 ,CN,Haro,C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl-C 1-2 Alkylene, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-3 Alkoxy-C 1-3 Alkyl, C 1-3 Alkoxy-C 1-3 Alkoxy, HO-C 1-3 Alkoxy, HO-C 1-3 Alkyl, Cyano-C 1-3 Alkyl, H 2 NC 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 sulfonylamino, aminosulfonyl, C 1-6 Alkylaminosulfonyl, di(C 1-6 Alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 Alkylaminosulfonylamino, di(C 1-6 Alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 Alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino.

[0014] In some embodiments, Z is CR 6 In some embodiments, Z is CH. In some embodiments, Z is N.

[0015] In some embodiments, R 1 , 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, 5-10 membered heteroaryl, halo, D, CN, NO 2 , OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 C is selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are each R 10 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from:

[0016] In some embodiments, R 1 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 6-10Aryl, 5-10 membered heteroaryl, halo, D, CN, NO 2 , OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 C is selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are each R 10 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from:

[0017] In some embodiments, R 1 , 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, 5-10 membered heteroaryl, halo, D, CN, NO 2 , OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1C is selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are each R 10 and optionally substituted by one or two substituents independently selected from:

[0018] In some embodiments, R 1 , H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl, halo, D, CN, NO 2 , OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 C is selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, C 6-10 Aryl and 5- to 6-membered heteroaryl are each R 10 and optionally substituted by one or two substituents independently selected from:

[0019] In some embodiments, R 1 , H, C 1-6 Alkyl, C 2-6 Alkynyl, C3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl, and 5-10 membered heteroaryl, 1-6 Alkyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are each R 10 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from:

[0020] In some embodiments, R 1 , H, C 1-6 Alkyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl, and 5-10 membered heteroaryl, 1-6 Alkyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are each R 10 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from:

[0021] In some embodiments, R 1 , H, C 1-6 Alkyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl, and 5-10 membered heteroaryl, 1-6 Alkyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are each R 10 and optionally substituted by one or two substituents independently selected from:

[0022] In some embodiments, R 1 , H, C 1-6 Alkyl, C 2-6 Alkynyl, C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl, 1-6 Alkyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each R 10 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from:

[0023] In some embodiments, R 1 , H, C 1-6 Alkyl, C 2-6 Alkynyl, C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl, 1-6 Alkyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each R 10 and optionally substituted by one or two substituents independently selected from:

[0024] In some embodiments, R 1 is C 1-6 Alkyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl, and 5-10 membered heteroaryl, 1-6 Alkyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are each R 10 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from:

[0025] In some embodiments, R 1 is C 1-6 Alkyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl, and 5-10 membered heteroaryl, 1-6 Alkyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are each R 10 and optionally substituted by one or two substituents independently selected from:

[0026] In some embodiments, R 1 is C 1-6 Alkyl, C 2-6 Alkynyl, C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl, 1-6 Alkyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each R 10 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from:

[0027] In some embodiments, R 1 is C 1-6 Alkyl, C 2-6 Alkynyl, C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl, 1-6 Alkyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each R 10and optionally substituted by one or two substituents independently selected from:

[0028] In some embodiments, R 1 is C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl, 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each R 10 and optionally substituted by one or two substituents independently selected from:

[0029] In some embodiments, R 1 is selected from phenyl and 5- to 6-membered heteroaryl, each of which is R 10 and optionally substituted by one or two substituents independently selected from:

[0030] In some embodiments, R 1 is a 5- to 6-membered heteroaryl, and the 5- to 6-membered heteroaryl is R 10 and optionally substituted by one or two substituents independently selected from:

[0031] In some embodiments, R 1 is C 1-6 Alkyl, C 2-6 alkynyl, phenyl, cyclohexenyl, pyrazol-4-yl, imidazol-4-yl, 6-oxo-1,6-dihydropyridin-3-yl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl, pyridin-3-yl, and pyrimidin-5-yl, each of which is selected from R 10 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from:

[0032] In some embodiments, R 1 is C 1-6 Alkyl, C 2-6alkynyl, phenyl, cyclohexenyl, pyrazol-4-yl, imidazol-4-yl, 6-oxo-1,6-dihydropyridin-3-yl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl, pyridin-3-yl, and pyrimidin-5-yl, each of which is selected from R 10 and optionally substituted by one or two substituents independently selected from:

[0033] In some embodiments, R 1 is selected from pyrazol-4-yl, imidazol-4-yl, 6-oxo-1,6-dihydropyridin-3-yl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl, pyridin-3-yl, and pyrimidin-5-yl, each of which is selected from R 10 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from:

[0034] In some embodiments, R 1 is selected from pyrazol-4-yl, imidazol-4-yl, 6-oxo-1,6-dihydropyridin-3-yl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl, pyridin-3-yl, and pyrimidin-5-yl, each of which is selected from R 10 and optionally substituted by one or two substituents independently selected from:

[0035] In some embodiments, R 1 is R 10 In some embodiments, R is optionally substituted with one or two substituents independently selected from 1 is R 10 and wherein R is an integer from 1 to 2.

[0036] In some embodiments, R 1 is R 10In some embodiments, R is phenyl optionally substituted with one or two substituents independently selected from 1 is R 10 and wherein R is an integer from 1 to 2.

[0037] In some embodiments, R 1H, 1-(2-hydroxyethyl)-1H-pyrazol-4-yl, 1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl, 1-(1-amino-2-methyl-1-oxopropan-2-yl)-1H-pyrazol-4-yl, 4-(morpholine-4-carbonyl)phenyl, 1H-pyrazol-4-yl, 1-(1-cyanopropan-2-yl)-1H-pyrazol-4-yl 1-(2-hydroxybutyl)-1H-pyrazol-4-yl, 1-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-yl, 1-((5-cyanopyridin-3-yl)methyl)-1H-pyrazol-4-yl, 1-((2-cyanopyridin-4-yl)methyl)-1H-pyrazol-4-yl, 1-(pyrimidin-4-ylmethyl)-1H-pyrazol 1-(1-(2-cyanopyridin-4-yl)ethyl)-1H-pyrazol-4-yl, 4-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)phenyl, 4-(1,1-dioxidethiomorpholino)phenyl, 1-(pyrimidin-2-ylmethyl)-1H-pyrazol-4-yl, 1-((6-cyanopyridin-2-yl)methyl ...4-(1,1-dioxidethiomorpholin -(4-acetylpiperazin-1-yl)phenyl, 4-(4-(2-hydroxyacetyl)piperazin-1-yl)phenyl, 4-((4-acetylpiperazin-1-yl)methyl)phenyl, 4-((4-(2-hydroxyacetyl)piperazin-1-yl)methyl)phenyl, 4-(4-methylpiperazin-1-yl)phenyl, 4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl)phenyl, 1-(cyanomethyl)-1H-pyrazol-4-yl, 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl, 1-benzyl-1H-pyrazol-4-yl, 1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-4-yl, 1-(1-cyanoethyl)-1H-pyrazol-4-yl, 1-(2,2-difluoroethyl)-1H-pyrazol-4-yl, 1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl, 1-(1-hydroxy-2-methylpropane- 2-yl)-1H-pyrazol-4-yl, 1-(2-cyanopropan-2-yl)-1H-pyrazol-4-yl, 1-cyclopropyl-1H-pyrazol-4-yl, 1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl, 1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl, 1-(1-methoxy-2-methylpropan-2-yl)-1H-pyrazol-4-yl, 9-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl, 1-(3-(dimethylamino)propyl)-1H-pyrazol-4-yl , 1-methyl-1H-imidazol-4-yl, 6-oxo-1,6-dihydropyridin-3-yl, 5-isopropyl-1H-pyrazol-4-yl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl, 5-(2-hydroxypropan-2-yl)pyridin-3-yl, 2-(methylamino)pyrimidin-5-yl, 1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl, 1-(2-morpholinoethyl)-1H-pyrazol-4-yl, 1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-pyrazole 4-hydroxycyclohex-1-en-1-yl, 5-hydroxypent-1-yn-1-yl, and 2-hydroxypropan-2-yl.

[0038] In some embodiments, R 1are 1-(2-hydroxyethyl)-1H-pyrazol-4-yl, 1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl, 1-(1-amino-2-methyl-1-oxopropan-2-yl)-1H-pyrazol-4-yl, 4-(morpholine-4-carbonyl)phenyl, 1H-pyrazol-4-yl, 1-(1-cyanopropan-2-yl)-1H-pyrazol-4-yl , 1-(2-hydroxybutyl)-1H-pyrazol-4-yl, 1-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-yl, 1-((5-cyanopyridin-3-yl)methyl)-1H-pyrazol-4-yl, 1-((2-cyanopyridin-4-yl)methyl)-1H-pyrazol-4-yl, 1-(pyrimidin-4-ylmethyl)-1H-pyrazole -4-yl, 1-(1-(2-cyanopyridin-4-yl)ethyl)-1H-pyrazol-4-yl, 4-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)phenyl, 4-(1,1-dioxidethiomorpholino)phenyl, 1-(pyrimidin-2-ylmethyl)-1H-pyrazol-4-yl, 1-((6-cyanopyridin-2-yl)methyl)-1H-pyrazol-4-yl, 4 -(4-acetylpiperazin-1-yl)phenyl, 4-(4-(2-hydroxyacetyl)piperazin-1-yl)phenyl, 4-((4-acetylpiperazin-1-yl)methyl)phenyl, 4-((4-(2-hydroxyacetyl)piperazin-1-yl)methyl)phenyl, 4-(4-methylpiperazin-1-yl)phenyl, 4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl)phenyl, 1-(cyanomethyl)-1H-pyrazol-4-yl, 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl, 1-benzyl-1H-pyrazol-4-yl, 1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-4-yl, 1-(1-cyanoethyl)-1H-pyrazol-4-yl, 1-(2,2-difluoroethyl)-1H-pyrazol-4-yl, 1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl, 1-(1-hydroxy-2-methylpropane- 2-yl)-1H-pyrazol-4-yl, 1-(2-cyanopropan-2-yl)-1H-pyrazol-4-yl, 1-cyclopropyl-1H-pyrazol-4-yl, 1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl, 1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl, 1-(1-methoxy-2-methylpropan-2-yl)-1H-pyrazol-4-yl, 9-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl, 1-(3-(dimethylamino)propyl)-1H-pyrazol-4-yl , 1-methyl-1H-imidazol-4-yl, 6-oxo-1,6-dihydropyridin-3-yl, 5-isopropyl-1H-pyrazol-4-yl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl, 5-(2-hydroxypropan-2-yl)pyridin-3-yl, 2-(methylamino)pyrimidin-5-yl, 1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl, 1-(2-morpholinoethyl)-1H-pyrazol-4-yl, 1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-pyrazole 4-hydroxycyclohex-1-en-1-yl, 5-hydroxypent-1-yn-1-yl, and 2-hydroxypropan-2-yl.

[0039] In some embodiments, R 1 is selected from 4-(morpholine-4-carbonyl)phenyl, 4-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)phenyl, 4-(1,1-dioxidethiomorpholino)phenyl, 4-(4-acetylpiperazin-1-yl)phenyl, 4-(4-(2-hydroxyacetyl)piperazin-1-yl)phenyl, 4-((4-acetylpiperazin-1-yl)methyl)phenyl, 4-((4-(2-hydroxyacetyl)piperazin-1-yl)methyl)phenyl, 4-(4-methylpiperazin-1-yl)phenyl, and 4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl)phenyl.

[0040] In some embodiments, R 1are 1-(2-hydroxyethyl)-1H-pyrazol-4-yl, 1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl, 1-(1-amino-2-methyl-1-oxopropan-2-yl)-1H-pyrazol-4-yl, 1-(1-cyanopropan-2-yl)-1H-pyrazol-4-yl, 1-(2-hydroxybutyl)-1H-pyrazol-4-yl, 1-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-yl, 1-((5 -cyanopyridin-3-yl)methyl)-1H-pyrazol-4-yl, 1-((2-cyanopyridin-4-yl)methyl)-1H-pyrazol-4-yl, 1-(pyrimidin-4-ylmethyl)-1H-pyrazol-4-yl, 1-(1-(2-cyanopyridin-4-yl)ethyl)-1H-pyrazol-4-yl, 1-(pyrimidin-2-ylmethyl)-1H-pyrazol-4-yl, 1-((6-cyanopyridin-2-yl)methyl)-1H-pyrazol-4-yl, 1-(cyanomethyl)-1H-pyrazol-4-yl, 1-( Tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl, 1-benzyl-1H-pyrazol-4-yl, 1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-4-yl, 1-(1-cyanoethyl)-1H-pyrazol-4-yl, 1-(2,2-difluoroethyl)-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-cyanopropan-2-yl)- 1H-pyrazol-4-yl, 1-cyclopropyl-1H-pyrazol-4-yl, 1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl, 1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl, 1-(1-methoxy-2-methylpropan-2-yl)-1H-pyrazol-4-yl, 9-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl, 1-(3-(dimethylamino)propyl)-1H-pyrazol-4-yl, 1-methyl-1H-imidazol-4-yl, 6-oxo-1,6-Dihydropyridin-3-yl, 5-isopropyl-1H-pyrazol-4-yl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl, 5-(2-hydroxypropan-2-yl)pyridin-3-yl, 2-(methylamino)pyrimidin-5-yl, 1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl, 1-(2-morpholinoethyl)-1H-pyrazol-4-yl, 1-(2-(4-methylpiperazine-1 1-(2-hydroxypropyl)-1H-pyrazol-4-yl, 1-(3-hydroxypropyl)-1H-pyrazol-4-yl, 1-(2-cyanoethyl)-1H-pyrazol-4-yl, 1-(2-amino-2-oxoethyl)-1H-pyrazol-4-yl, 6-(2-hydroxypropan-2-yl)pyridin-3-yl, 6-(2,2,2-trifluoroethyl)pyridin-3-yl, and 6-(methylcarbamoyl)pyridin-3-yl.

[0041] In some embodiments, R 2 , H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, Halo, D, CN, NO 2 , OR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , N.R. c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 In some embodiments, R 2 , H, C 1-6 It is selected from alkyl, halo, and CN.

[0042] In some embodiments, R 2 is H.

[0043] In some embodiments, R 3 , H, C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, Halo, D, CN, NO 2 , OR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , N.R. c3 R d3 , S(O) 2 R b3 , and S(O) 2 NR c3 R d3 In some embodiments, R 3 , H, C 1-6 It is selected from alkyl, halo, and CN.

[0044] In some embodiments, R 3 is H.

[0045] In some embodiments, R 4 , H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, Halo, D, CN, NO 2 , OR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , N.R. c4 R d4 , S(O) 2 R b4 , and S(O) 2 NR c4 R d4 In some embodiments, R 4 , H, C 1-6 It is selected from alkyl, halo, and CN.

[0046] In some embodiments, R 4 is H.

[0047] In some embodiments, R 5 , 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, 5-10 membered heteroaryl, halo, D, CN, NO 2 , OR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , N.R. c5 R d5 , S(O) 2 R b5 , and S(O) 2 NR c5 R d5 C is selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are each R 50 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from:

[0048] In some embodiments, R 5 , 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, 5-10 membered heteroaryl, halo, D, CN, NO 2 , OR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , N.R. c5 R d5 , S(O) 2 R b5, and S(O) 2 NR c5 R d5 C is selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are each R 50 and optionally substituted by one or two substituents independently selected from:

[0049] In some embodiments, R 5 , H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, halo, D, CN, NO 2 , OR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , N.R. c5 R d5 , S(O) 2 R b5 , and S(O) 2 NR c5 R d5 C is selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each R 50 and optionally substituted by one or two substituents independently selected from:

[0050] In some embodiments, R 5 , H, C 1-6 Alkyl, and C 6-10 aryl, 1-6 Alkyl and C6-10 Each aryl is R 50 In some embodiments, R is optionally substituted with 1, 2, 3, or 4 substituents independently selected from 5 , H, C 1-6 Alkyl, and C 6-10 aryl, 1-6 Alkyl and C 6-10 Each aryl is R 50 and optionally substituted by one or two substituents independently selected from:

[0051] In some embodiments, R 5 is C 1-6 alkyl and phenyl, 1-6 Alkyl and phenyl are R 50 In some embodiments, R is optionally substituted with 1, 2, 3, or 4 substituents independently selected from 5 is C 1-6 alkyl and phenyl, 1-6 Alkyl and phenyl are R 50 and optionally substituted by one or two substituents independently selected from:

[0052] In some embodiments, R 5 is R 50 In some embodiments, R is phenyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from 5 is R 50 In some embodiments, R is phenyl optionally substituted with one or two substituents independently selected from 5 is R 50 and wherein R is an integer from 1 to 2.

[0053] In some embodiments, R 5 is H, methyl, or 2,6-dichlorophenyl. In some embodiments, R5 is methyl or 2,6-dichlorophenyl.

[0054] In some embodiments, each R 10 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, 5-10 membered heteroaryl, halo, D, CN, NO 2 , OR a10 , C(O)R b10 , C(O)NR c10 R d10 , C(O)OR a10 , O.C.(O)R b10 , N.R. c10 R d10 , N.R. c10 C(O)R b10 , S(O) 2 R b10 , and S(O) 2 NR c10 R d10 Independently selected from the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are each R 11 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from:

[0055] In some embodiments, each R 10 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, 5-10 membered heteroaryl, halo, D, CN, NO 2 , OR a10, C(O)R b10 , C(O)NR c10 R d10 , C(O)OR a10 , O.C.(O)R b10 , N.R. c10 R d10 , N.R. c10 C(O)R b10 , S(O) 2 R b10 , and S(O) 2 NR c10 R d10 Independently selected from the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are each R 11 and optionally substituted by one or two substituents independently selected from:

[0056] In some embodiments, each R 10 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl, halo, D, CN, NO 2 , OR a10 , C(O)R b10 , C(O)NR c10 R d10 , C(O)OR a10 , O.C.(O)R b10 , N.R. c10 R d10 , N.R. c10 C(O)R b10 , S(O) 2 R b10 , and S(O) 2 NR c10 R d10 Independently selected from the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, C 6-10 Aryl and 5- to 6-membered heteroaryl are each R 11 and optionally substituted by one or two substituents independently selected from:

[0057] In some embodiments, each R 10 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, OR a10 , C(O)NR c10 R d10 , and N.R. c10 R d10 Independently selected from the C 1-6 Alkyl, C 3-10 Cycloalkyl and 4-10 membered heterocycloalkyl are each R 11 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from:

[0058] In some embodiments, each R 10 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, OR a10 , C(O)NR c10 R d10 , and N.R. c10 R d10 Independently selected from the C 1-6 Alkyl, C 3-10 Cycloalkyl and 4-10 membered heterocycloalkyl are each R 11 and optionally substituted by one or two substituents independently selected from:

[0059] In some embodiments, each R 10 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6Cycloalkyl, 4-7 membered heterocycloalkyl, OR a10 , C(O)NR c10 R d10 , and N.R. c10 R d10 Independently selected from the C 1-6 Alkyl, C 3-6 Cycloalkyl and 4- to 7-membered heterocycloalkyl are each R 11 and optionally substituted by one or two substituents independently selected from:

[0060] In some embodiments, each R 10 is C 1-6 Alkyl, C 1-6 Haloalkyl, OR a10 , C(O)NR c10 R d10 , N.R. c10 R d10 , 1,1-dioxidetetrahydro-2H-thiopyranyl, 1,1-dioxidethiomorpholino, piperazinyl, tetrahydro-2H-pyranyl, piperidinyl, cyclopropyl, tetrahydrofuran-3-yl, and cyclohexenyl, each of which is independently selected from R 11 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from:

[0061] In some embodiments, each R 10 is C 1-6 Alkyl, C 1-6 Haloalkyl, OR a10 , C(O)NR c10 R d10 , N.R. c10 R d10 , 1,1-dioxidetetrahydro-2H-thiopyranyl, 1,1-dioxidethiomorpholino, piperazinyl, tetrahydro-2H-pyranyl, piperidinyl, cyclopropyl, tetrahydrofuran-3-yl, and cyclohexenyl, each of which is independently selected from R 11 and optionally substituted by one or two substituents independently selected from:

[0062] In some embodiments, each R 11 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, 5-10 membered heteroaryl, halo, D, CN, OR a11 , C(O)R b11 , C(O)NR c11 R d11 , C(O)OR a11 , N.R. c11 R d11 , S(O)NR c11 R d11 , S(O) 2 R b11 , and S(O) 2 NR c11 R d11 Independently selected from the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are each R 12 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from:

[0063] In some embodiments, each R 11 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, 5-10 membered heteroaryl, halo, D, CN, OR a11 , C(O)R b11 , C(O)NR c11 R d11 , C(O)OR a11 , N.R. c11 R d11 , S(O)NRc11 R d11 , S(O) 2 R b11 , and S(O) 2 NR c11 R d11 Independently selected from the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are each R 12 and optionally substituted by one or two substituents independently selected from:

[0064] In some embodiments, each R 11 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl, halo, D, CN, OR a11 , C(O)R b11 , C(O)NR c11 R d11 , C(O)OR a11 , N.R. c11 R d11 , S(O)NR c11 R d11 , S(O) 2 R b11 , and S(O) 2 NR c11 R d11 Independently selected from the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, C 6-10 Aryl and 5- to 6-membered heteroaryl are each R 12 and optionally substituted by one or two substituents independently selected from:

[0065] In some embodiments, each R 11 is C 1-6 Alkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, CN, OR a11 , C(O)R b11 , C(O)NR c11 R d11 , N.R. c11 R d11 , and S(O) 2 R b11 Independently selected from the C 1-6 Alkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are each R 12 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from:

[0066] In some embodiments, each R 11 is C 1-6 Alkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, CN, OR a11 , C(O)R b11 , C(O)NR c11 R d11 , N.R. c11 R d11 , and S(O) 2 R b11 Independently selected from the C 1-6 Alkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are each R 12 and optionally substituted by one or two substituents independently selected from:

[0067] In some embodiments, each R 11 is C 1-6 Alkyl, 4-7 membered heterocycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl, CN, OR a11 , C(O)R b11 , C(O)NR c11 R d11, N.R. c11 R d11 , and S(O) 2 R b11 Independently selected from the C 1-6 Alkyl, 4-7 membered heterocycloalkyl, C 6-10 Aryl and 5- to 6-membered heteroaryl are each R 12 and optionally substituted by one or two substituents independently selected from:

[0068] In some embodiments, each R 11 is C 1-6 Alkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, CN, OR a11 , C(O)R b11 , C(O)NR c11 R d11 , N.R. c11 R d11 , and S(O) 2 R b11 Independently selected from the C 1-6 Alkyl, 4- to 7-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each R 12 and optionally substituted by one or two substituents independently selected from:

[0069] In some embodiments, each R 12 is C 1-6 Alkyl, halo, CN, OR a12 , and C(O)R b12 Independently selected from the C 1-6 Alkyl is R g and optionally substituted by one or two substituents independently selected from:

[0070] In some embodiments, each R 12 is C 1-6 Alkyl, halo, CN, OR a12 , and C(O)R b12 Independently selected from the C 1-6 The alkyl is optionally substituted with a substituent that is OH.

[0071] In some embodiments, each R 20 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, Halo, D, CN, NO 2 , OR a20 , C(O)R b20 , C(O)NR c20 R d20 , C(O)OR a20 , O.C.(O)R b20 , N.R. c20 R d20 , N.R. c20 C(O)R b20 , SS(O) 2 R b20 , and S(O) 2 NR c20 R d20 Independently selected from the C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl is R 21 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from:

[0072] In some embodiments, each R 20 is C 1-6 Alkyl, C 1-6 Independently selected from haloalkyl, halo, D, and CN.

[0073] In some embodiments, each R 21 is C 1-6 Alkyl, C 1-6 Independently selected from haloalkyl, halo, D, and CN.

[0074] In some embodiments, each R 22 is C 1-6 Alkyl, C 1-6 Independently selected from haloalkyl, halo, D, and CN.

[0075] In some embodiments, each R 30is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, Halo, D, CN, NO 2 , OR a30 , C(O)R b30 , C(O)NR c30 R d30 , C(O)OR a30 , O.C.(O)R b30 , N.R. c30 R d30 , N.R. c30 C(O)R b30 , S(O) 2 R b30 , and S(O) 2 NR c30 R d30 Independently selected from the C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl is R 31 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from:

[0076] In some embodiments, each R 30 is C 1-6 Alkyl, C 1-6 Independently selected from haloalkyl, halo, D, and CN.

[0077] In some embodiments, each R 31 is C 1-6 Alkyl, C 1-6 Independently selected from haloalkyl, halo, D, and CN.

[0078] In some embodiments, each R 32 is C 1-6 Alkyl, C 1-6 Independently selected from haloalkyl, halo, D, and CN.

[0079] In some embodiments, each R 40 is C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 1-6 Haloalkyl, Halo, D, CN, NO 2 , OR a40 , C(O)R b40 , C(O)NR c40 R d40 , C(O)OR a40 , O.C.(O)R b40 , N.R. c40 R d40 , N.R. c40 C(O)R b40 , S(O) 2 R b40 , and S(O) 2 NR c40 R d40 Independently selected from the C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl is R 41 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from:

[0080] In some embodiments, each R 40 is C 1-6 Alkyl, C 1-6 Independently selected from haloalkyl, halo, D, and CN.

[0081] In some embodiments, each R 41 is C 1-6 Alkyl, C 1-6 Independently selected from haloalkyl, halo, D, and CN.

[0082] In some embodiments, each R 42 is C 1-6 Alkyl, C 1-6 Independently selected from haloalkyl, halo, D, and CN.

[0083] In some embodiments, each R 50 is C 1-6 Alkyl, C 1-6 Haloalkyl, Halo, D, CN, OR a50 , C(O)R b50 , C(O)NRc50 R d50 , C(O)OR a50 , N.R. c50 R d50 , N.R. c50 C(O)R b50 , S(O) 2 R b50 , and S(O) 2 NR c50 R d50 are independently selected from

[0084] In some embodiments, each R 50 is C 1-6 Alkyl, C 1-6 Independently selected from haloalkyl, halo, D, and CN.

[0085] In some embodiments, each R 50 is independently selected from halo.

[0086] In some embodiments, each R 50 is Cl.

[0087] In some embodiments, each R 51 is C 1-6 Alkyl, C 1-6 Independently selected from haloalkyl, halo, D, and CN.

[0088] In some embodiments, each R 52 is C 1-6 Alkyl, C 1-6 Independently selected from haloalkyl, halo, D, and CN.

[0089] In some embodiments, each R 60 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, Halo, D, CN, NO 2 , OR a60 , C(O)R b60 , C(O)NR c60 R d60 , C(O)ORa60 , O.C.(O)R b60 , N.R. c60 R d60 , N.R. c60 C(O)R b60 , S(O) 2 R b60 , and S(O) 2 NR c60 R d60 Independently selected from the C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl is R 61 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from:

[0090] In some embodiments, each R 60 is C 1-6 Alkyl, C 1-6 Independently selected from haloalkyl, halo, D, and CN.

[0091] In some embodiments, each R 61 is C 1-6 Alkyl, C 1-6 Independently selected from haloalkyl, halo, D, and CN.

[0092] In some embodiments, each R 62 is C 1-6 Alkyl, C 1-6 Independently selected from haloalkyl, halo, D, and CN.

[0093] In some embodiments, each R a1 , R b1 , R c1 , and R d1 H and C 1-6 alkyl.

[0094] In some embodiments, each R a2 , R b2 , R c2 , and R d2 H and C 1-6 alkyl.

[0095] In some embodiments, each R a3 , R b3 , R c3 , and R d3 H and C 1-6 alkyl.

[0096] In some embodiments, each R a4 , R b4 , R c4 , and R d4 H and C 1-6 alkyl.

[0097] In some embodiments, each R a5 , R b5 , R c5 , and R d5 H and C 1-6 alkyl.

[0098] In some embodiments, each R a6 , R b6 , R c6 , and R d6 H and C 1-6 alkyl.

[0099] In some embodiments, each R a10 , R b10 , R c10 , and R d10 H and C 1-6 alkyl.

[0100] In some embodiments, any R attached to the same N atom c10 and R d10 together with the N atom to which they are attached form R 11 In some embodiments, any R attached to the same N atom forms a 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from: c10 and R d10together with the N atom to which they are attached form a 6- or 7-membered heterocycloalkyl group.

[0101] In some embodiments, each R a11 , R b11 , R c11 , and R d11 H and C 1-6 alkyl.

[0102] In some embodiments, each R a12 , R b12 , R c12 , and R d12 H and C 1-6 alkyl.

[0103] In some embodiments, each R a20 , R b20 , R c20 , and R d20 H and C 1-6 alkyl.

[0104] In some embodiments, each R a21 , R b21 , R c21 , and R d21 H and C 1-6 alkyl.

[0105] In some embodiments, each R a22 , R b22 , R c22 , and R d22 H and C 1-6 alkyl.

[0106] In some embodiments, each R a30 , R b30 , R c30 , and R d30 H and C 1-6 alkyl.

[0107] In some embodiments, each Ra31 , R 31 , R c31 , and R d31 H and C 1-6 alkyl.

[0108] In some embodiments, each R a32 , R b32 , R c32 , and R d32 H and C 1-6 alkyl.

[0109] In some embodiments, each R a40 , R b40 , R c40 , and R d40 H and C 1-6 alkyl.

[0110] In some embodiments, each R a41 , R 41 , R c41 , and R d41 H and C 1-6 alkyl.

[0111] In some embodiments, each R a42 , R b42 , R c42 , and R d42 H and C 1-6 alkyl.

[0112] In some embodiments, each R a50 , R b50 , R c50 , and R d50 H and C 1-6 alkyl.

[0113] In some embodiments, each R a51 , R 51 , R c51 , and R d51 H and C 1-6 alkyl.

[0114] In some embodiments, each R a52 , R b52 , R c52 , and R d52 H and C 1-6 alkyl.

[0115] In some embodiments, each R a60 , R b60 , R c60 , and R d60 H and C 1-6 alkyl.

[0116] In some embodiments, each R a61 , R 61 , R c61 , and R d61 H and C 1-6 alkyl.

[0117] In some embodiments, each R a62 , R b62 , R c62 , and R d62 H and C 1-6 alkyl.

[0118] In some embodiments, each R g is OH.

[0119] In one aspect, the present disclosure provides a compound of formula II: [ka] or a pharma- ceutical acceptable salt thereof, wherein Z, R 1 , R 2 , R 3 , and R 4 is as defined herein.

[0120] In one aspect, the present disclosure provides a compound of formula IIIa: [ka] or a pharma- ceutical acceptable salt thereof, wherein R 2 , R 3 , R 4 , R 5 , R 6 , and R 10 is as defined herein.

[0121] In one aspect, the present disclosure provides a compound of formula IIIb: [ka] or a pharma- ceutical acceptable salt thereof, wherein R 2 , R 3 , R 4 , R 5 , R 6 , and R 10 is as defined herein.

[0122] In one aspect, the present disclosure provides a compound of formula IVa: [ka] or a pharma- ceutical acceptable salt thereof, wherein R 2 , R 3 , R 4 , R 6 , and R 10 is as defined herein.

[0123] In one aspect, the present disclosure provides a compound of formula IVb: [ka] or a pharma- ceutical acceptable salt thereof, wherein R 2 , R 3 , R 4 , R 6 , and R 10 is as defined herein.

[0124] In some embodiments, R 1 , H, C 1-6 Alkyl, C2-6 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, D, CN, NO 2 , OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 C is selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are each R 10 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from R 2 , H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, Halo, D, CN, NO 2 , OR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , N.R. c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 is selected from R 3 , H, C 1-6Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, Halo, D, CN, NO 2 , OR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , N.R. c3 R d3 , S(O) 2 R b3 , and S(O) 2 NR c3 R d3 is selected from R 4 , H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, Halo, D, CN, NO 2 , OR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , N.R. c4 R d4 , S(O) 2 R b4 , and S(O) 2 NR c4 R d4 is selected from R 5 , 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, 5-10 membered heteroaryl, halo, D, CN, NO 2 , OR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , N.R. c5 R d5 , S(O) 2 R b5 , and S(O)2 NR c5 R d5 C is selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are each R 50 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from Z is CR 6 and R 6 , H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, Halo, D, CN, NO 2 , OR a6 , C(O)R b6 , C(O)NR c6 R d6 , C(O)OR a6 , N.R. c6 R d6 , S(O) 2 R b6 , and S(O) 2 NR c6 R d6 is selected from Each R 10 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, 5-10 membered heteroaryl, halo, D, CN, NO 2 , OR a10 , C(O)R b10 , C(O)NR c10 R d10 , C(O)OR a10 , O.C.(O)R b10 , N.R. c10 R d10 , N.R. c10 C(O)R b10, S(O) 2 R b10 , and S(O) 2 NR c10 R d10 Independently selected from the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are each R 11 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R 11 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, 5-10 membered heteroaryl, halo, D, CN, OR a11 , C(O)R b11 , C(O)NR c11 R d11 , C(O)OR a11 , N.R. c11 R d11 , S(O)NR c11 R d11 , S(O) 2 R b11 , and S(O) 2 NR c11 R d11 Independently selected from the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are each R 12 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R 12 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR a12 , C(O)R b12 , C(O)NR c12 R d12 , C(O)OR a12 , N.R. c12 R d12 , N.R. c12 C(O)R b12 , S(O)NR c12 R d12 , S(O) 2 R b12 , and S(O) 2 NR c12 R d12 Independently selected from the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each R g and optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R 50 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, 5-10 membered heteroaryl, halo, D, CN, NO 2 , OR a50 , C(O)R b50 , C(O)NR c50 R d50 , C(O)OR a50 , O.C.(O)R b50 , N.R. c50 R d50 , N.R. c50 C(O)R b50 , S(O) 2 R b50 , and S(O)2 NR c50 R d50 Independently selected from the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are each R 51 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R 51 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, 5-10 membered heteroaryl, halo, D, CN, OR a51 , C(O)R b51 , C(O)NR c51 R d51 , C(O)OR a51 , N.R. c51 R d51 , N.R. c51 C(O)R b51 , S(O) 2 R b51 , and S(O) 2 NR c51 R d51 Independently selected from the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are each R 52 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R 52 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR a52 , C(O)R b52 , C(O)NR c52 R d52 , C(O)OR a52 , N.R. c52 R d52 , N.R. c52 C(O)R b52 , S(O) 2 R b52 , and S(O) 2 NR c52 R d52 Independently selected from the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each R g and optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R a1 , R b1 , R c1 , and R d1 , 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, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are each R 10 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from or any R attached to the same N atom c1 and R d1together with the N atom to which they are attached form R 10 forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R a2 , R b2 , R c2 , and R d2 , 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, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are each R 20 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from or any R attached to the same N atom c2 and R d2 together with the N atom to which they are attached form R 20 forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by 1, 2, or 3 substituents independently selected from Each R a3 , R b3 , R c3 , and R d3 , 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, C2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are each R 30 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from or any R attached to the same N atom c3 and R d3 together with the N atom to which they are attached form R 30 forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R a4 , R b4 , R c4 , and R d4 , 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, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are each R 40 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from or any R attached to the same N atom c4 and R d4 together with the N atom to which they are attached form R 40 forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R a5 , Rb5 , R c5 , and R d5 , 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, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are each R 50 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from or any R attached to the same N atom c5 and R d5 together with the N atom to which they are attached form R 50 forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R a6 , R b6 , R c6 , and R d6 , 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, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are each R 60and optionally substituted by 1, 2, 3, or 4 substituents independently selected from or any R attached to the same N atom c6 and R d6 together with the N atom to which they are attached form R 60 forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R a10 , R b10 , R c10 , and R d10 , 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, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are each R 11 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from or any R attached to the same N atom c10 and R d10 together with the N atom to which they are attached form R 11 forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R a11 , R b11 , R c11 , and R d11 , H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C3-6 cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl; 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each R 12 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from or any R attached to the same N atom c11 and R d11 together with the N atom to which they are attached form R 12 forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by 1, 2, or 3 substituents independently selected from Each R a12 , R b12 , R c12 , and R d12 , H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 1-6 haloalkyl, 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl is R g and optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R a50 , R b50 , R c50 , and R d50 , 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, C 2-6Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are each R 51 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from or any R attached to the same N atom c50 and R d50 together with the N atom to which they are attached form R 51 forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R a51 , R b51 , R c51 , and R d51 , 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, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each R 52 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from or any R attached to the same N atom c51 and R d51 together with the N atom to which they are attached form R 52 forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by 1, 2, or 3 substituents independently selected from Each R a52 , R b52 , R c52 , and R d52, H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 1-6 haloalkyl, 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl is R g and optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R a60 , R b60 , R c60 , and R d60 , 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, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are each R 61 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from or any R attached to the same N atom c60 and R d60 together with the N atom to which they are attached form R 61 forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R g D, OH, NO 2 ,CN,Haro,C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C1-6 Haloalkoxy, C 1-3 Alkoxy-C 1-3 Alkyl, C 1-3 Alkoxy-C 1-3 Alkoxy, HO-C 1-3 Alkoxy, HO-C 1-3 Alkyl, Cyano-C 1-3 Alkyl, H 2 NC 1-3 Alkyl, Amino, C 1-6 Alkylamino and di(C 1-6 alkyl)amino.

[0125] In some embodiments, R 1 , 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, 5-10 membered heteroaryl, halo, D, CN, NO 2 , OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 C is selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are each R 10 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from R2 is H, R 3 is H, R 4 is H, R 5 , 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, 5-10 membered heteroaryl, halo, D, CN, NO 2 , OR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , N.R. c5 R d5 , S(O) 2 R b5 , and S(O) 2 NR c5 R d5 C is selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are each R 50 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from Z is CR 6 and R 6 is H, Each R 10 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, 5-10 membered heteroaryl, halo, D, CN, NO 2 , OR a10 , C(O)R b10, C(O)NR c10 R d10 , C(O)OR a10 , O.C.(O)R b10 , N.R. c10 R d10 , N.R. c10 C(O)R b10 , S(O) 2 R b10 , and S(O) 2 NR c10 R d10 Independently selected from the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are each R 11 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R 11 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, 5-10 membered heteroaryl, halo, D, CN, OR a11 , C(O)R b11 , C(O)NR c11 R d11 , C(O)OR a11 , N.R. c11 R d11 , S(O)NR c11 R d11 , S(O) 2 R b11 , and S(O) 2 NR c11 R d11 Independently selected from the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are each R12 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R 12 is 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 a12 , C(O)R b12 , C(O)NR c12 R d12 , C(O)OR a12 , N.R. c12 R d12 , N.R. c12 C(O)R b12 , S(O)NR c12 R d12 , S(O) 2 R b12 , and S(O) 2 NR c12 R d12 Independently selected from the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each R g and optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R 50 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, 5-10 membered heteroaryl, halo, D, CN, NO 2 , OR a50 , C(O)R b50 , C(O)NR c50 R d50 , C(O)ORa50 , O.C.(O)R b50 , N.R. c50 R d50 , N.R. c50 C(O)R b50 , S(O) 2 R b50 , and S(O) 2 NR c50 R d50 Independently selected from the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are each R 51 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R 51 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, 5-10 membered heteroaryl, halo, D, CN, OR a51 , C(O)R b51 , C(O)NR c51 R d51 , C(O)OR a51 , N.R. c51 R d51 , N.R. c51 C(O)R b51 , S(O) 2 R b51 , and S(O) 2 NR c51 R d51 Independently selected from the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are each R 52and optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R 52 is 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 a52 , C(O)R b52 , C(O)NR c52 R d52 , C(O)OR a52 , N.R. c52 R d52 , N.R. c52 C(O)R b52 , S(O) 2 R b52 , and S(O) 2 NR c52 R d52 Independently selected from the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each R g and optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R a1 , R b1 , R c1 , and R d1 , 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, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are each R 10 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from or any R attached to the same N atom c1 and R d1 together with the N atom to which they are attached form R 10 forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R a5 , R b5 , R c5 , and R d5 , 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, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are each R 50 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from or any R attached to the same N atom c5 and R d5 together with the N atom to which they are attached form R 50 forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R a10 , R b10 , R c10 , and R d10 , H, C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are each R 11 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from or any R attached to the same N atom c10 and R d10 together with the N atom to which they are attached form R 11 forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R a11 , R b11 , R c11 , and R d11 , 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, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each R 12 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from or any R attached to the same N atom c11 and R d11together with the N atom to which they are attached form R 12 forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by 1, 2, or 3 substituents independently selected from Each R a12 , R b12 , R c12 , and R d12 , H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 1-6 haloalkyl, 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl is R g and optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R a50 , R b50 , R c50 , and R d50 , 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, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are each R 51 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from or any R attached to the same N atom c50 and R d50 together with the N atom to which they are attached form R 51forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R a51 , R b51 , R c51 , and R d51 , 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, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each R 52 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from or any R attached to the same N atom c51 and R d51 together with the N atom to which they are attached form R 52 forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by 1, 2, or 3 substituents independently selected from Each R a52 , R b52 , R c52 , and R d52 , H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 1-6 haloalkyl, 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl is R g and optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R gD, OH, CN, halo, C 1-6 Alkyl, and C 1-6 haloalkyl.

[0126] In some embodiments, R 1 , H, C 1-6 Alkyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl, and 5-10 membered heteroaryl, 1-6 Alkyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are each R 10 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from R 2 is H, R 3 is H, R 4 is H, R 5 , H, C 1-6 Alkyl, and C 6-10 aryl, 1-6 Alkyl and C 6-10 Each aryl is R 50 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from Z is CR 6 and R 6 is H, Each R 10 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, OR a10 , C(O)NR c10 R d10 , and N.R. c10 R d10 Independently selected from the C1-6 Alkyl, C 3-10 Cycloalkyl and 4-10 membered heterocycloalkyl are each R 11 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R 11 is C 1-6 Alkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, CN, OR a11 , C(O)R b11 , C(O)NR c11 R d11 , N.R. c11 R d11 , and S(O) 2 R b11 Independently selected from the C 1-6 Alkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are each R 12 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R 12 is C 1-6 Alkyl, halo, CN, OR a12 , and C(O)R b12 Independently selected from the C 1-6 Alkyl is R g and optionally substituted by one or two substituents independently selected from Each R 50 is selected independently from the halo, Each R a10 , R c10 , and R d10 H and C 1-6 alkyl, 1-6 Alkyl is R 11 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from or any R attached to the same N atom c10 and R d10 together with the N atom to which they are attached form R 11forming a 6- or 7-membered heterocycloalkyl group optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R a11 , R b11 , R c11 , and R d11 H and C 1-6 alkyl, 1-6 Alkyl is R 12 and optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R a12 and R b12 H and C 1-6 alkyl, 1-6 Alkyl is R g is optionally replaced by R g is OH.

[0127] It will be further understood that certain features of the present disclosure, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the present disclosure, which are, for clarity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

[0128] At various places in the present specification, substituents of compounds of the present disclosure are disclosed in groups or in ranges. It is expressly intended that the present disclosure includes any and all individual subcombinations of the members of such groups or ranges. For example, "C 1-6 The term "alkyl" includes methyl, ethyl, C 3 Alkyl, C 4 Alkyl, C 5 Alkyl, and C 6 It is specifically intended to disclose alkyl individually.

[0129] Various aryl, heteroaryl, cycloalkyl, and heterocycloalkyl rings are described in various places herein. Unless otherwise specified, such rings may be attached to the remainder of the molecule at any ring member as valence permits. 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.

[0130] The term "n-membered" (where n is typically an integer) describes the number of ring-forming atoms in a moiety, where the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.

[0131] 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 that occur simultaneously on the same compound, the two R groups can represent different moieties independently selected from the group defined for R.

[0132] As used herein, the phrase "optionally substituted" means unsubstituted or substituted.

[0133] The term "substituted" means that an atom or group of atoms formally replaces hydrogen as a "substituent" attached to another group. The term "substituted" refers to any level of substitution (e.g., mono-, di-, tri-, tetra-, or penta-substitution) (where such substitution is permitted) unless otherwise specified. Substituents are independently selected, and substitution may be at any chemically accessible position. It is understood that substitution for a given atom is limited by atomic valence. It is understood that substitution for a given atom results in a chemically stable molecule. A single divalent substituent (e.g., oxo) may replace two hydrogen atoms.

[0134] As used herein, "C i-j " (where i and j are integers) is used in conjunction with a chemical group to specify a range of the number of carbon atoms in the chemical group, with i through j defining the range. For example, C 1-6 Alkyl refers to alkyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms.

[0135] The term "alkyl" as used herein, alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight or branched. An alkyl group formally corresponds to an alkane with one C-H bond replaced by the point at which the alkyl group is attached to the remainder of the compound. In some embodiments, the alkyl group contains 1-6, 1-4, or 1-3 carbon atoms. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methyl-1-butyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, and the like. In some embodiments, the alkyl group is methyl, ethyl, or propyl.

[0136] As used herein, "C i-jThe term "alkylene," alone or in combination with other terms, means a saturated divalent linked hydrocarbon group having i to j carbons, which may be straight or branched. In some embodiments, an alkylene group contains 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. Examples of alkylene moieties include, but are not limited to, chemical groups such as methylene, ethylene, 1,1-ethylene, 1,2-ethylene, 1,3-propylene, 1,2-propylene, 1,1-propylene, isopropylene, and the like.

[0137] As used herein, "alkenyl," alone or in combination with other terms, refers to a straight or branched chain hydrocarbon group corresponding to an alkyl group having one or more carbon-carbon double bonds. An alkenyl group formally corresponds to an alkene with one C-H bond replaced by the point at which the alkenyl group is attached to the remainder of the compound. In some embodiments, the alkenyl moiety contains 2-6 or 2-4 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

[0138] As used herein, "alkynyl," alone or in combination with other terms, refers to a straight or branched chain hydrocarbon group corresponding to an alkyl group having one or more carbon-carbon triple bonds. An alkynyl group formally corresponds to an alkyne with one C-H bond replaced by the point at which the alkyl group is attached to the remainder of the compound. In some embodiments, the alkynyl moiety contains 2-6 or 2-4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, and the like.

[0139] As used herein, the terms "carbamoyl" and "carbamyl" refer to -C(O)NH 2 These terms interchangeably refer to the bases of the formula:

[0140] As used herein, the term "carboxy" refers to a group of the formula -C(O)OH.

[0141] The term "cyano" or "nitrile" refers to a group of the formula -C≡N (which may also be written -CN).

[0142] As used herein, "C 1-3 Alkoxy-C 1-3 The term "alkyl" refers to -(C 1-3 Alkylene)-(C 1-3 It refers to a group of the formula:

[0143] As used herein, "C 1-3 Alkoxy-C 1-3 The term "alkoxy" refers to -(C 1-3 Alkoxylen)-(C 1-3 It refers to a group of the formula:

[0144] As used herein, "HO-C 1-3 The term "alkoxy" refers to -(C 1-3 It refers to the group of the formula alkoxylene-OH.

[0145] As used herein, "HO-C 1-3 The term "alkyl" refers to -(C 1-3 It refers to the group of the formula -(alkylene)-OH.

[0146] As used herein, "cyano-C 1-3 The term "alkyl" refers to -(C 1-3 It refers to the group of the formula alkylene-CN.

[0147] As used herein, "H 2 NC 1-3 The term "alkyl" refers to -(C 1-3 (alkylene)-NH 2 This refers to the base of the formula:

[0148] As used herein, "C n-mThe term "alkylamino" refers to a group of the formula -NH(alkyl), where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0149] As used herein, "C n-m The term "alkoxycarbonyl" refers to a group of the formula -C(O)O-alkyl, where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0150] As used herein, "C n-m The term "alkylcarbonyl" refers to a group of the formula -C(O)-alkyl, where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0151] As used herein, "C n-m The term "alkylcarbonylamino" refers to a group of the formula -NHC(O)-alkyl, where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0152] As used herein, "C n-m The term "alkylcarbonyloxy" refers to a group of the formula -OC(O)-alkyl, where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0153] As used herein, the term "aminocarbonyloxy" refers to -OC(O)NH 2 This refers to the base of the formula:

[0154] As used herein, "C n-mThe term "alkylaminocarbonyloxy" refers to a group of the formula -OC(O)NH-alkyl, where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0155] As used herein, "C n-m The term "alkylsulfonylamino" refers to -NHS(O) 2 "Alkyl" refers to a group of the formula -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.

[0156] As used herein, the term "aminosulfonyl" refers to -S(O) 2 NH 2 This refers to the base of the formula:

[0157] As used herein, "C n-m The term "alkylaminosulfonyl" refers to -S(O) 2 It refers to a group of the formula NH(alkyl), where the alkyl group has n to m carbon atoms, in some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0158] As used herein, "di(C n-m The term "aminosulfonyl" refers to -S(O) 2 N(alkyl) 2 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.

[0159] As used herein, the term "aminosulfonylamino" refers to -NHS(O) 2 NH 2 This refers to the base of the formula:

[0160] As used herein, "C n-mThe term "alkylaminosulfonylamino" refers to -NHS(O) 2 It refers to a group of the formula NH(alkyl), where the alkyl group has n to m carbon atoms, in some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0161] As used herein, "di(C n-m The term "NHS(O) alkyl)aminosulfonylamino" refers to -NHS(O) 2 N(alkyl) 2 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.

[0162] As used herein, the term "aminocarbonylamino" alone or in combination with other terms, refers to -NHC(O)NH 2 This refers to the base of the formula:

[0163] As used herein, "C n-m The term "alkylaminocarbonylamino" refers to a group of the formula -NHC(O)NH(alkyl), where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0164] As used herein, "di(C n-m The term "NHC(O)N(alkyl)aminocarbonylamino" refers to -NHC(O)N(alkyl)aminocarbonylamino. 2 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.

[0165] As used herein, "C n-mThe term "alkylcarbamyl" refers to a group of the formula -C(O)-NH(alkyl), where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0166] As used herein, "di(C n-m The term "-C(O)N(alkyl)carbamyl" refers to 2 wherein each of the two alkyl groups 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.

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

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

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

[0170] As used herein, "C n-m The term "alkylsulfonyl" refers to -S(O) 2 "Alkyl" refers to a group of the formula -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.

[0171] As used herein, "halo" or "halogen," 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.

[0172] As used herein, the term "haloalkyl," alone or in combination with other terms, refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a halogen atom and has halogen atom substituents, which may be the same or different, up to the full 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 3 , C 2 F 5 , CHF 2 , CCl 3 , CHCl 2 , C 2 Cl 5 , and the like.

[0173] As used herein, the term "alkoxy," alone or in combination with other terms, refers to a group of the formula -O-alkyl. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like. In some embodiments, the alkoxy is methoxy.

[0174] As used herein, "haloalkoxy," 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 example of a haloalkoxy group is -OCF 3 It is.

[0175] As used herein, "amino" used alone or in combination with other terms means NH 2Refers to...

[0176] As used herein, the term "alkylamino," alone or in combination with other terms, refers to a group of the 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.

[0177] As used herein, the term "alkylthio," alone or in combination with other terms, refers to a group of the formula -S-alkyl. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

[0178] As used herein, the term "cycloalkyl," used alone or in combination with other terms, refers to non-aromatic cyclic hydrocarbons, including cyclized alkyl and alkenyl groups. n-mThe term "cycloalkyl" refers to a cycloalkyl having n to m ring carbon atoms. Cycloalkyl groups can include monocyclic or polycyclic ring systems (e.g., those having 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 (i.e., having a common bond with) the cycloalkyl ring (e.g., benzo derivatives of cyclopentane, cyclohexene, cyclohexane, and the like, or pyrido derivatives of cyclopentane or cyclohexane). Cycloalkyl groups containing fused aromatic rings can be attached through any ring-forming atom, including the ring-forming atoms of the fused aromatic ring. The ring-forming carbon atoms of the cycloalkyl group can be optionally substituted by oxo. Cycloalkyl groups also include cycloalkylidenes. The term "cycloalkyl" also includes bridgehead cycloalkyl groups (e.g., non-aromatic cyclic hydrocarbon moieties that contain at least one bridgehead carbon, such as adamantan-1-yl) as well as spirocycloalkyl groups (e.g., non-aromatic hydrocarbon moieties that contain at least two rings fused at a single carbon atom, such as spiro[2.5]octane and the like). In some embodiments, cycloalkyl groups have 3-10 ring members, or 3-7 ring members, or 3-6 ring members. In some embodiments, cycloalkyl groups are monocyclic or bicyclic. In some embodiments, cycloalkyl groups are monocyclic. In some embodiments, cycloalkyl groups are C 3-7 It is a monocyclic cycloalkyl group. In some embodiments, the cycloalkyl group is cyclopropyl or cyclohexenyl.

[0179] As used herein, the term "heterocycloalkyl", alone or in combination with other terms, refers to a non-aromatic ring or ring system having at least one heteroatom ring member independently selected from nitrogen, sulfur, oxygen, and phosphorus, and having 4 to 14, 4 to 10, 4 to 7, or 4 to 6 ring members, which may optionally include one or more alkenylene or alkynylene groups as part of the ring structure. The term "heterocycloalkyl" includes 4-, 5-, 6-, and 7-membered monocyclic heterocycloalkyl groups. Heterocycloalkyl groups may include monocyclic or polycyclic ring systems (e.g., those having 2, 3, or 4 fused, bridged, or spiro rings) or spirocyclic ring systems. In some embodiments, the heterocycloalkyl group is a monocyclic or bicyclic group having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. Also included within the definition of heterocycloalkyl are moieties having one or more aromatic rings (e.g., aryl or heteroaryl rings) fused (i.e., having a bond in common with) a non-aromatic heterocycloalkyl ring (e.g., 1,2,3,4-tetrahydro-quinoline and the like). Heterocycloalkyl groups can also include bridgehead heterocycloalkyl groups (e.g., heterocycloalkyl moieties that contain at least one bridgehead atom, such as azaadamantan-1-yl and the like) as well as spiroheterocycloalkyl groups (e.g., heterocycloalkyl moieties that contain at least two rings fused at a single atom, such as [1,4-dioxa-8-aza-spiro[4.5]decane-N-yl] and the like). 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, a heterocycloalkyl group has 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 to 2 heteroatoms. Carbon atoms or heteroatoms in the ring(s) of a heterocycloalkyl group can be oxidized to form 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. 2-7 It is a monocyclic heterocycloalkyl group. In some embodiments, the heterocycloalkyl group is a morpholine ring, a pyrrolidine ring, a piperazine ring, a piperidine ring, a dihydropyran ring, a tetrahydropyran ring, a tetrahyropyridine, an azetidine ring, or a tetrahydrofuran ring. In some embodiments, the heterocycloalkyl is a 4-7 membered heterocycloalkyl moiety having carbon and one, two, or three heteroatoms independently selected from N, O, and S. In some embodiments, the heterocycloalkyl is a 4-10 membered heterocycloalkyl moiety having carbon and one, two, or three heteroatoms independently selected from N, O, and S.

[0180] As used herein, the term "aryl", alone or in combination with other terms, refers to a monocyclic aromatic hydrocarbon moiety or a polycyclic aromatic hydrocarbon moiety (e.g., having two fused rings), such as, but not limited to, phenyl, 1-naphthyl, 2-naphthyl, and the like. In some embodiments, an aryl group has 6-10 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.

[0181] As used herein, the terms "heteroaryl" or "heteroaromatic," alone or in combination with other terms, refer to a monocyclic or polycyclic aromatic hydrocarbon moiety (e.g., having two or three fused rings) 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 one, two, three, or four 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, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, pyrrolyl, azolyl, quinolinyl, isoquinolinyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl, pyridone, or the like. Carbon atoms or heteroatoms in the ring(s) of the heteroaryl group may be oxidized to form carbonyl, N-oxide, or sulfonyl groups (or other oxidized bonds), or nitrogen atoms may be quaternized, provided that the aromatic nature of the ring is maintained. In some embodiments, the heteroaryl group is a 5-10 membered heteroaryl group. In other embodiments, the heteroaryl group is a 5-6 membered heteroaryl group. In some embodiments, the heteroaryl is a 5-6 membered heteroaryl moiety having carbon and one, two, or three heteroatoms independently selected from N, O, and S. In some embodiments, the heteroaryl is a 5-10 membered heteroaryl moiety having carbon and one, two, or three heteroatoms independently selected from N, O, and S. In some embodiments, the heteroaryl has 5-6 ring atoms and one or two heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, up to two heteroatoms in the 5-membered heteroaryl moiety are N.

[0182] 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. Examples of 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.

[0183] A 6-membered heteroaryl ring is a heteroaryl group having 6 ring atoms, in which one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Examples of 6-membered heteroaryl rings are pyridyl, pyrazinyl, pyrimidinyl, triazinyl, isoindolyl, and pyridazinyl.

[0184] The term "oxo" refers to an oxygen atom as a divalent substituent that forms a carbonyl group when attached to a carbon, or a sulfoxide or sulfone group or an N-oxide group when attached to a heteroatom. In some embodiments, heterocyclic groups can be optionally substituted with one or two oxo (=O) substituents.

[0185] The term "oxidized" with respect to a ring-forming N-atom refers to a ring-forming N-oxide.

[0186] The term "oxidized" with respect to a ring-forming S atom refers to a ring-forming sulfonyl or ring-forming sulfinyl.

[0187] The term "aromatic" refers to a carbocycle or heterocycle having one or more polyunsaturated rings with aromatic character (i.e., having (4n+2) delocalized □(π) electrons, where n is an integer).

[0188] In certain places, definitions or embodiments refer to certain rings (e.g., azetidine ring, pyridine ring, etc.).Unless otherwise specified, such 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 of the ring, and an azetidin-3-yl ring is attached at the 3-position.

[0189] The compounds described herein may be asymmetric (e.g., have one or more stereocenters). All stereoisomers (enantiomers, diastereomers, etc.) are intended unless otherwise specified. Compounds of the present disclosure that contain asymmetrically substituted carbon atoms may be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolving racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like may also exist in the compounds described herein, and all such stable isomers are contemplated in the present disclosure. Cis and trans geometric isomers of the compounds of the present disclosure are described, and such cis and trans geometric isomers may be isolated as mixtures of isomers or as separate isomers.

[0190] The resolution of racemic mixtures of compounds can be carried out by methods known in the art. One example of the method is fractional recrystallization using chiral resolving acids that are optically active salt-forming organic acids. Suitable resolving agents for fractional recrystallization are, for example, optically active acids, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or various optically active camphorsulfonic acids in their D and L forms. Other suitable resolving agents for fractional recrystallization include stereoisomerically pure forms of methyl-benzylamine (e.g., S and R forms or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

[0191] Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Appropriate elution solvent compositions can be determined by one skilled in the art.

[0192] 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 chiral center in the compound can be independently (R) or (S).

[0193] The compounds of the present disclosure also include tautomers. Tautomers arise from the switching of a single bond and an adjacent double bond with the concomitant displacement of a proton. Tautomers include prototropic tautomers, which are isomeric protonation states with the same empirical formula and overall charge. Examples of prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which protons can occupy more than one position in a heterocyclic system (e.g., 1H-imidazole and 3H-imidazole, 1H-1,2,4-triazole and 2H-1,2,4-triazole and 4H-1,2,4-triazole, 1H-isoindole and 2H-isoindole, and 1H-pyrazole and 2H-pyrazole). Tautomers can be in equilibrium or sterically locked into one form by appropriate substitution.

[0194] The compounds of the present disclosure include all those containing isotopes of atoms 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 isotopes of such atoms in natural or non-natural abundance ratios. In some embodiments, the compounds contain at least one deuterium atom. For example, one or more of the hydrogen atoms in the compounds of the present disclosure can be replaced or substituted with deuterium. In some embodiments, the compounds contain two or more deuterium atoms. In some embodiments, the compounds contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 deuterium atoms. Synthetic methods for incorporating isotopes into organic compounds are known in the art (Deuterium Labeling in Organic Chemistry by Alan F. Thomas (New York, NY, Appleton-Century-Crofts, 1971; The Renaissance of H / D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistry of Isotopic Labelling by James R. Hanson, Royal Society of Chemistry, 2011). Isotopically labeled compounds can be used in a variety of tests (such as NMR spectroscopy), metabolic experiments, and / or assays.

[0195] Substitution with heavy isotopes (such as deuterium) may confer certain therapeutic advantages due to increased metabolic stability (e.g., increased in vivo half-life) or reduced dosage requirements and therefore may be preferred in some circumstances (A. Kerekes et.al. J. Med. Chem. 2011, 54, 201-210; R. Xu et.al. J. Label Compd. Radiopharm. 2015, 58, 308-312).

[0196] The term "compound" as used herein is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of the depicted structure. The term is also intended to refer to compounds of the present disclosure regardless of how they are prepared (e.g., synthetically, via a biological process (e.g., metabolic or enzymatic transformation), or a combination thereof).

[0197] All compounds and their pharma- ceutically acceptable salts may be found together with other substances (such as water and solvents) (e.g., in the form of hydrates and in the form of solvates) or may be isolated. When in the solid state, the compounds and their salts described herein may exist in various forms, for example, in the form of solvates (including hydrates). Because the compounds may exist in any solid state form (such as polymorphs or solvates), references herein to the compounds and their salts should be understood to encompass any solid state form of the compounds, unless expressly specified otherwise.

[0198] In some embodiments, the disclosed compound or salt thereof is substantially isolated. "Substantially isolated" means that the compound is at least partially or substantially separated from its formation or detection environment. Partial separation can include, for example, increasing the abundance of the disclosed compound in the composition. Substantial separation can include making the disclosed compound or salt thereof present in the composition at least about 50% by weight, at least about 60% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 95% by weight, at least about 97% by weight, or at least about 99% by weight. Methods for isolating compounds and their salts are routine in the art.

[0199] The phrase "pharmacologically acceptable" is used herein to mean that a compound, material, composition, and / or dosage form is suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, within the scope of sound medical judgment, and is commensurate with a reasonable benefit / risk ratio.

[0200] The present disclosure also includes pharma- ceutically acceptable salts of the compounds described herein. As used herein, "pharma- ceutically acceptable salts" refers to derivatives of the disclosed compounds, in which the parent compound is modified by converting an existing acid or base moiety into its salt form. Examples of pharma- ceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues (such as amines), alkali or organic salts of acidic residues (such as carboxylic acids), and the like. The pharma- ceutical acceptable salts of the present disclosure include non-toxic salts of the parent compound (e.g., formed from non-toxic inorganic or organic acids). The pharma- ceutical acceptable salts of the present disclosure can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. In general, such salts can be prepared by reacting the compound in its free acid or base form with a stoichiometric amount of an appropriate base or acid in water or an organic solvent, or a mixture of the two, generally with non-aqueous media such as ether, ethyl acetate, alcohol (e.g., methanol, ethanol, iso-propanol, or butanol), or acetonitrile (ACN). 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.

[0201] The following abbreviations may be used herein: AcOH (acetic acid); 2O(acetic anhydride);aq.(aqueous);atm.(atmosphere(s));Boc(t-butoxycarbonyl);br(broad);Cbz(carboxybenzyl);calc.(calculated value);d(doublet);dd(doublet of 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(s);h (hour(s));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 (multiplets);M (molar concentration);mCPBA (3-chloroperbenzoic acid);MgSO 4 (Magnesium sulfate); MS (Mass spectrometry); Me (Methyl); MeCN (Acetonitrile); MeOH (Methanol); mg (Milligram(s); min. (Minute(s); mL (Milliliter(s); mmol (Millimoles(s); N (Normalized); NaHCO 3 (Sodium bicarbonate);NaOH (Sodium hydroxide);Na 2 SO 4 (Sodium sulfate);NH 4 Cl (ammonium chloride);NH 4 OH (ammonium hydroxide); NIS (N-iodosuccinimide); nM (nanomolar); NMR (nuclear magnetic resonance spectroscopy); OTf (trifluoromethanesulfonate); Pd (palladium); Ph (phenyl); pM (picomolar); PMB (para-methoxybenzyl), POCl 3(phosphoryl chloride); RP-HPLC (reverse-phase high-performance liquid chromatography); s (singlet); SEM (2-trimethylsilylethoxymethyl); t (triplet or tertiary); TBS (tert-butyldimethylsilyl); tert (tertiary); tt (triplet of triplets); t-Bu (tert-butyl); TFA (trifluoroacetic acid); THF (tetrahydrofuran); μg (microgram(s)); μL (microliter(s)); μM (micromolar); wt% (weight percent).

[0202] synthesis Those skilled in the art will appreciate that the compounds provided herein, including their salts and stereoisomers, can be prepared using known organic synthesis techniques, or can be synthesized along any of a number of possible synthetic routes.

[0203] The reaction for preparing the compounds of the present disclosure can be carried out in a suitable solvent, and those skilled in the art of organic synthesis can easily select such a suitable solvent. A suitable solvent can be substantially non-reactive with the starting materials (reactants), intermediates, or products at the temperature at which the reaction is carried out (e.g., 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 multiple solvents. Those skilled in the art can select a suitable solvent for a particular reaction step depending on the particular reaction step.

[0204] Preparation of the compounds of the present disclosure may involve the protection and deprotection of various chemical groups. Those skilled in the art can easily determine the need for protection and deprotection, and the selection of suitable protecting groups. The chemistry of protecting groups can be found, for example, in TW Greene and PG M Huts, Protective Groups in Organic Synthesis, 3rd.Ed., Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety.

[0205] The reaction may be monitored according to any suitable method known in the art, for example, by spectroscopic means (e.g., nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or chromatography (such as high performance liquid chromatography (HPLC) or thin layer chromatography).

[0206] As used herein, the expressions "ambient temperature," "room temperature," and "rt" are understood in the art and generally refer to a temperature (e.g., the reaction temperature) that is close to the temperature of the room in which the reaction is carried out (e.g., a temperature of about 20° C. to about 30° C.).

[0207] Compounds of formula I can be prepared via the synthetic route outlined in Scheme 1. [ka]

[0208] The appropriate reagent (phosphoryl chloride (POCl) 3) at high temperature to give compound S-2. Substitution of the chlorine of compound S-2 by nucleophilic substitution with aqueous ammonia at high temperature to give compound S-3. Condensation of compound S-3 with compound S-4 (Hal is a halide, such as Cl, Br, or I) at high temperature to give compound S-5, which can be reacted with a suitable reagent (such as N-iodosuccinimide (NIS)) to give compound S-6 (Hal is a halide, such as Cl, Br, or I). Carbonylation of compound S-6 with CO under palladium catalysis (Angew. Chem. Int. Ed. 2009, 48, 4114-4133) gives derivatives of formula S-7, which can be transformed using known organic synthesis techniques to give compounds of formula S-8. Compound S-8 can then be reacted with an adduct of formula S-9 (where M is a boronic acid, a boronic ester, or a suitable reagent [e.g., M is B(OR)) 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). 2 , Sn(alkyl) 3 Zn-Hal, etc.) to form R 2 can be introduced to give compounds of formula S-10.

[0209] How to use The compounds of the present disclosure may inhibit the activity of FGFR enzymes. For example, the compounds of the present disclosure may be used to inhibit the activity of enzymes in cells, individuals, or patients by administering one or more compounds of the present disclosure in an inhibitory amount to a cell or an individual or patient in need of inhibition of FGFR enzymes. The compounds of the present disclosure may be used to inhibit the activity of enzymes in cells, individuals, or patients by administering one or more compounds of the present disclosure in an inhibitory amount to a cell or an individual or patient in need of inhibition of FGFR3 enzymes. The compounds of the present disclosure may be used to inhibit the activity of enzymes in cells, individuals, or patients by administering one or more compounds of the present disclosure in an inhibitory amount to a cell or an individual or patient in need of inhibition of FGFR2 enzymes. The compounds of the present disclosure may be used to inhibit the activity of enzymes in cells, individuals, or patients by administering one or more compounds of the present disclosure in an inhibitory amount to a cell or an individual or patient in need of inhibition of FGFR3 enzymes and FGFR2 enzymes.

[0210] 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 FGFRs will be useful in providing a means to cause tumor growth inhibition or apoptosis induction, particularly by suppressing 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 activating mutants of receptor tyrosine kinases or upregulation of receptor tyrosine kinases may be particularly sensitive to such inhibitors.

[0211] In certain embodiments, the present disclosure provides a method for treating an FGFR-mediated disorder in a patient in need of such treatment, the method comprising administering to the patient a compound according to the invention or a pharma- ceutical acceptable composition thereof.

[0212] In some embodiments, diseases and indications that can be treated using the compounds of the present disclosure include, but are not limited to, hematological cancers, sarcomas, lung cancer, gastrointestinal cancer, genitourinary cancer, liver cancer, bone cancer, nervous system cancer, gynecological cancer, and skin cancer.

[0213] In some embodiments, the cancer that can be treated using the compounds of the present disclosure is selected from adenocarcinoma, bladder cancer, breast cancer, cervical cancer, bile duct cancer, colorectal cancer, endometrial cancer, esophageal cancer, gallbladder cancer, gastric cancer, glioma, head and neck cancer, hepatocellular carcinoma, renal cancer, liver cancer, lung cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, rhabdomyosarcoma, skin cancer, thyroid cancer, leukemia, multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, B-cell lymphoma, acute myeloid leukemia, Hodgkin's or non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, hairy cell lymphoma, and Burkitt's lymphoma.

[0214] In some embodiments, the cancer that can be treated using the compounds of the present disclosure is selected from hepatocellular carcinoma, bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, head and neck cancer, renal 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.

[0215] In some embodiments, the cancer is selected from adenocarcinoma, bladder cancer, breast cancer, cervical cancer, cholangiocarcinoma, endometrial cancer, gastric cancer, glioma, head and neck cancer, lung cancer, ovarian cancer, leukemia, and multiple myeloma.

[0216] In some embodiments, cancers that can be treated using the compounds of the present disclosure are 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.

[0217] Cancers characterized by alterations in FGFR2 and / or FGFR3 include bladder cancer (FGFR3 mutations or fusions), cholangiocarcinoma (FGFR2 fusions), and gastric cancer (FGFR2 amplification).

[0218] The compounds of the present invention can be used to treat cancer patients with FGFR2 / 3 alterations, including mutations, fusions, rearrangements, and amplifications. FGFR2 / 3 alterations have been found in a subset of cholangiocarcinoma, urothelial carcinoma, multiple myeloma, gastric adenocarcinoma, glioma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, and breast cancer. In addition, the compounds of the present invention can be used to target patients undergoing treatment with pan-FGFR inhibitors due to the acquisition of gatekeeper mutations (V555M / L / F / I in FGFR3, V564M / L / F / I in FGFR2). The compounds of the present invention can also be used to treat cancers in which FGFR2 / 3 signaling is involved in resistance to other targeted therapies, for example, the compounds of the present invention have the potential to overcome CDK4 / 6 inhibitor resistance in ER-positive breast cancer.

[0219] Examples of blood cancers include lymphomas and leukemias, including 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, bone marrow cancer, and lymphomas of the 1st generation. Myeloproliferative disorders (e.g., primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocytosis (ET), 8p11 myeloproliferative syndrome), myelodysplastic syndromes (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), multiple myeloma, cutaneous T-cell lymphoma, adult T-cell leukemia, Waldenstrom's macroglobulinemia, hairy cell lymphoma, marginal zone lymphoma, chronic myeloid lymphoma, and Burkitt's lymphoma.

[0220] Examples of sarcomas include chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, rhabdomyosarcoma, fibroma, lipoma, hamartoma, lymphosarcoma, leiomyosarcoma, and teratoma.

[0221] Examples of lung cancer include non-small cell lung cancer (NSCLC), small cell lung carcinoma, bronchial carcinoma (squamous cell, small undifferentiated cell, large undifferentiated cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, chondroitin hamartoma, mesothelioma, small cell and non-small cell carcinoma, bronchial adenoma, and pleuropulmonary blastoma.

[0222] Examples of 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.

[0223] Examples of genitourinary 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.

[0224] Examples of liver cancer include hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.

[0225] Examples of bone cancer include, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell chordoma, osteochondroma (osteochondral exostosis), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor.

[0226] Examples of nervous system cancers include cancer of the skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), cancer of the meninges (meningioma, meningeal sarcoma, gliomatosis), cancer of the brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, neuroectodermal tumors), and cancer of the spinal cord (neurofibroma, meningioma, glioma, sarcoma), neuroblastoma, Lhermitte-Duclos disease, and pineal tumors.

[0227] Examples of 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 ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-theca cell tumor, Sertoli-Leydig cell, 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, sarcoma botryoides (embryonal rhabdomyosarcoma), and cancer of the fallopian tubes (carcinoma).

[0228] Examples of skin cancer include melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer, dysplastic nevi, lipoma, hemangioma, dermatofibroma, and keloids.

[0229] Examples of 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 head and neck squamous cell carcinoma.

[0230] Compounds of the present disclosure may also be useful in inhibiting tumor metastasis.

[0231] In addition to oncogenic neoplasms, the compounds of the present invention are also useful for treating skeletal and chondrocyte disorders, including, but not limited to, achondroplasia, hypochondroplasia, dwarfism, thanatophoric dysplasia (TD) (clinical types TD I and TD II), Apert syndrome, Crouzon syndrome, Jackson-Weiss syndrome, Bear-Stevenson-Cutis-Gyrata syndrome, Pfeiffer syndrome, and craniosynostosis syndrome. In some embodiments, the present disclosure provides methods of treating patients suffering from skeletal and chondrocyte disorders.

[0232] In some embodiments, the compounds described herein may be used to treat Alzheimer's disease, HIV, or tuberculosis.

[0233] As used herein, the term "8p11 myeloproliferative syndrome" is intended to refer to myeloid / lymphoid neoplasms associated with eosinophilia and FGFR1 abnormalities.

[0234] The term "cell" as used herein is intended to refer to an in vitro, ex vivo, or in vivo cell. In some embodiments, an ex vivo cell may be part of a tissue sample that has been dissociated 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 living cell in an organism (such as a mammal).

[0235] The term "contacting" as used herein refers to bringing together the specified moieties in an in vitro 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 that contains an FGFR enzyme.

[0236] As used herein, the terms "individual" or "patient" are used interchangeably and refer to any animal, including a mammal, preferably a mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse, or primate, and most preferably a human.

[0237] As used herein, the phrase "therapeutically effective amount" refers to an amount of an active compound or pharmaceutical agent (such as an amount of any of the solid forms or salts thereof disclosed herein) that elicits the biological or medicinal response in a tissue, system, animal, individual, or human being that is being sought by a researcher, veterinarian, physician, or other clinician. An appropriate "effective" amount in any individual case may be determined using techniques known to those of skill in the art.

[0238] The phrase "pharmacologically acceptable" is used herein to mean that a compound, material, composition, and / or dosage form is 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 sound medical judgment, and is commensurate with a reasonable benefit / risk ratio.

[0239] As used herein, the phrase "pharmaceutically acceptable carrier or excipient" refers to a pharma- ceutically acceptable material, composition, or vehicle, such as a liquid or solid excipient, diluent, solvent, or encapsulating material. Excipients or carriers are generally safe, non-toxic, and non-harmful biologically or otherwise, and include excipients or carriers acceptable for veterinary use and for 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.

[0240] The term "treating" or "treatment" as used herein refers to inhibiting a disease (e.g., inhibiting a disease, condition, or disorder in an individual suffering from or exhibiting the pathology or symptomology of the disease, condition, or disorder (i.e., arresting further progression of the pathology and / or symptomology)) or to ameliorating a disease (e.g., ameliorating a disease, condition, or disorder in an individual suffering from or exhibiting the pathology or symptomology of the disease, condition, or disorder (i.e., improving the pathology and / or symptomology) (such as reducing the severity of the disease)).

[0241] It will be understood that certain features of the invention, which are for clarity described in the context of separate embodiments, can also be provided in combination in a single embodiment (while such embodiments are intended to be combined in the same manner as if described in a multiplicity dependent manner). Conversely, various features of the invention, which are for clarity described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

[0242] Combination therapy One or more additional pharmaceutical agents or therapeutic methods (e.g., antiviral agents, chemotherapeutic or other anti-cancer agents, immunostimulants, immunosuppressants, radiation, antitumor and antiviral vaccines, cytokine therapy (e.g., IL2, GM-CSF, etc.), and / or tyrosine kinase inhibitors, etc.) may be combined with the compounds described herein to treat a disease, disorder, or condition associated with FGFR, or a disease or condition described herein. The agents may be combined with the compounds of the present disclosure in a single dosage form, or the agents may be administered simultaneously or sequentially as separate dosage forms.

[0243] The compounds described herein may be combined with one or more other kinase inhibitors to treat diseases that are affected by multiple signal transduction pathways, such as cancer. For example, the combination may include one or more inhibitors of the following kinases to treat 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, FLK- 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 may be used in combination with inhibitors of kinases associated with the PIK3 / Akt / mTOR signaling pathway, such as PI3K, Akt (including Akt1, Akt2, and Akt3), and mTOR kinase.

[0244] In some embodiments, the compounds described herein may be used in combination with one or more inhibitors of enzymes or protein receptors (such as HPK1, SBLB, TUT4, A2A / A2B, CD47, CDK2, STING, ALK2, LIN28, ADAR1, MAT2a, RIOK1, HDAC8, WDR5, SMARCA2, and DCLK1) to treat diseases and disorders. Examples of diseases and disorders include cancer, infectious diseases, inflammation, and neurodegenerative disorders.

[0245] 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 methyltransferase, histone arginine methyltransferase, histone demethylase, histone deacetylase, histone acetylase, and DNA methyltransferase.Histone deacetylase inhibitors include, for example, vorinostat.

[0246] For the treatment of cancer and other proliferative diseases, the compounds described herein may be used in combination with targeted therapeutic agents, including JAK kinase inhibitors (ruxolitinib, additional JAK1 / 2-selective and JAK1-selective baricitinib or INCB39110), Pim kinase inhibitors (e.g., LGH447, INCB053914, and SGI-1776), PI3 kinase inhibitors (PI3K-delta selective inhibitors and broad-spectrum PI3K inhibitors (e.g., INCB50465 and INCB54707), PI3K-gamma inhibitors, and combinations thereof. Inhibitors of inflammatory bowel diseases (e.g., PI3K-gamma selective inhibitors), MEK inhibitors, CSF1R inhibitors (e.g., PLX3397 and LY3022855), TAM receptor tyrosine kinase inhibitors (Tyro-3, Axl, and Mer (e.g., INCB81776)), angiogenesis inhibitors, interleukin receptor inhibitors, cyclin-dependent kinase inhibitors, BRAF inhibitors, mTOR inhibitors, proteasome inhibitors (bortezomib, carfilzomib, ), HDAC inhibitors (panobinostat, vorinostat), DNA methyltransferase inhibitors, dexamethasone, inhibitors of members of the bromodomain and extraterminal domain families (e.g., bromodomain inhibitors or BET inhibitors (such as OTX015, CPI-0610, INCB54329, or INCB57643)), LSD1 inhibitors (e.g., GSK2979552, INCB59872, and INCB60 003), arginase inhibitors (e.g., INCB1158), indoleamine 2,3-dioxygenase inhibitors (e.g., epacadostat, NLG919, or BMS-986205), PARP inhibitors (e.g., olaparib or rucaparib), inhibitors of BTK (such as ibrutinib), c-MET inhibitors (e.g., capmatinib), ALK2 inhibitors (e.g., INCB00928), or combinations thereof.

[0247] For the treatment of cancer and other proliferative diseases, the compounds described herein may be combined with chemotherapeutic agents, nuclear receptor agonists or antagonists, or other anti-proliferative agents. The compounds described herein may also be combined with medical treatments, such as surgery or radiation therapy (e.g., gamma radiation, neutron radiation therapy, electron beam radiation therapy, proton radiation therapy, brachytherapy, and systemic radioisotope therapy).

[0248] Examples of suitable chemotherapeutic agents include abarelix, abiraterone, afatinib, aflibercept, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, amidox, amsacrine, anastrozole, aphidicolon, arsenic trioxide, asparaginase, axitinib, azacitidine, bevacizumab, bexarotene, baricitinib, bendamustine, bicalutamide, bleomycin, bortezomib, bortezomib, brivanib, bupallisib, intravenous busulfan, and bronchodilator. , oral busulfan, calsterone, camptosar, capecitabine, carboplatin, carmustine, cediranib, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, crizotinib, cyclophosphamide, cytarabine, dacarbazine, dacomitinib, dactinomycin, dalteparin sodium, dasatinib, dactinomycin, daunorubicin, decitabine, degarelix, denileukin, denileukin diftitox, deoxycoformycin, dexrazoxane, didox , docetaxel, doxorubicin, droloxafine, dromostanolone propionate, eculizumab, enzalutamide, epidophyllotoxin, epirubicin, epothilone, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, flutamide, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab 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, navelbene, necitumumab, nelarabine, neratinib,Nilotinib, nilutamide, niraparib, nofetumomab, oserelin, oxaliplatin, paclitaxel, pamidronate, panitumumab, panobinostat, pazopanib, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, piralalisib, pipobroman, plicamycin, ponatinib, porfimer, prednisone, procarbazine, quinacrine, ranibizumab, rasburicase, regorafenib, reloxafine, revlimid, rituximab, rucaparib, ruxolitinib, sorafe nib, streptozocin, sunitinib, sunitinib maleate, tamoxifen, 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.

[0249] Cancer cell growth and survival can be affected by the dysfunction of multiple signaling pathways. Therefore, it is useful to treat such conditions by combining different enzyme / protein / receptor inhibitors that show different selectivity for the targets that regulate their activity. Targeting multiple signaling pathways (or multiple biomolecules involved in a given signaling pathway) can reduce the possibility of drug resistance in cell populations and / or reduce the toxicity of treatment.

[0250] One or more additional pharmaceutical agents (such as chemotherapeutic agents, anti-inflammatory agents, steroids, immunosuppressants, cancer immunotherapy agents, metabolic enzyme inhibitors, chemokine receptor inhibitors, and phosphatase inhibitors), as well as targeted therapies (such as Bcr-Abl, Flt-3, EGFR, HER2, JAK, c-MET, VEGFR, PDGFR, c-Kit, IGF-1R, RAF, FAK, CDK2, and CDK4 / 6 kinase inhibitors (such as those described in WO2006 / 056399)) can be used in combination with the disclosed therapeutic methods and regimens for treating cancer and solid tumors. Other agents (such as therapeutic antibodies) can also be used in combination with the disclosed therapeutic methods and regimens for treating cancer and solid tumors. One or more additional pharmaceutical agents can be administered to the patient simultaneously or sequentially.

[0251] The therapeutic methods disclosed herein may be combined with one or more other enzyme / protein / receptor inhibitor treatments to treat diseases (such as cancer) and other diseases or disorders described herein. For example, the therapeutic methods and regimens disclosed herein may be combined with one or more inhibitors of the following kinases to treat cancer: Akt1, Akt2, Akt3, BCL2, CDK2, CDK4 / 6, TGF-□R, PKA, PKG, PKC, CaM kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IDH2, IGF-1R, IR-R, PDGF□R, PDGF□R, PI3K (alpha, beta, gamma, delta, and multiple or selected kinases). selective), CSF1R, KIT, FLK-II, KDR / FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, PARP, Ron, Sea, TRKA, TRKB, TRKC, TAM kinase (Axl, Mer , Tyro3), FLT3, VEGFR / Flt2, Flt4, EphA1, EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL, ALK, and B-Raf.Examples of inhibitors that may be used in combination with the disclosed therapeutic methods and regimens for treating cancer include, but are not limited to, FGFR inhibitors (FGFR1, FGFR2, FGFR3, or FGFR4 (e.g., pemigatinib (INCB54828), INCB62079)), EGFR inhibitors (also known as ErB-1 or HER-1 (e.g., erlotinib, gefitinib, vandetanib, orsimertinib, cetuximab, necitumumab, or panitumumab)), VEGFR inhibitors, or or pathway blockers (e.g., bevacizumab, pazopanib, sunitinib, sorafenib, axitinib, regorafenib, ponatinib, cabozantinib, vandetanib, ramucirumab, lenvatinib, ziv-aflibercept), PARP inhibitors (e.g., olaparib, rucaparib, veliparib, or niraparib), JAK inhibitors (JAK1 and / or JAK2 (e.g., ruxolitinib, baricitinib, itacitinib (INCB39110)), LSD1 inhibitors (e.g., INCB59872 and INCB600 03), TDO inhibitors, PI3K-delta inhibitors (e.g., INCB50465 and INCB50797), PI3K-gamma inhibitors (such as PI3K-gamma selective inhibitors), Pim inhibitors (e.g., INCB53914), CSF1R inhibitors, TAM receptor tyrosine kinases (Tyro-3, Axl, and Mer), adenosine receptor antagonists (e.g., A2a / A2b receptor antagonists), HPK1 inhibitors, chemokine receptor inhibitors (e.g., CCR2 inhibitors or CCR5 inhibitors), SHP1 / 2 These include phosphatase inhibitors, histone deacetylase inhibitors (HDACs) (such as HDAC8 inhibitors), angiogenesis inhibitors, interleukin receptor inhibitors, inhibitors of members of the bromodomain and extraterminal domain family (e.g., bromodomain inhibitors or BET inhibitors (such as INCB54329 and INCB57643)), c-MET inhibitors (e.g., capmatinib), anti-CD19 antibodies (e.g., tafasitamab), ALK2 inhibitors (e.g., INCB00928), or combinations thereof.

[0252] In some embodiments, the methods of treatment described herein are combined with administration of a PI3Kδ inhibitor. In some embodiments, the methods of treatment described herein are combined with administration of a JAK inhibitor. In some embodiments, the methods of treatment described herein are combined with administration of a JAK1 inhibitor or a JAK2 inhibitor (e.g., baricitinib or ruxolitinib). In some embodiments, the methods of treatment described herein are combined with administration of a JAK1 inhibitor. In some embodiments, the methods of treatment described herein are combined with administration of a JAK1 inhibitor that has higher selectivity than that for JAK2.

[0253] Examples of antibodies that may be administered in combination therapy include, but are not limited to, trastuzumab (e.g., anti-HER2), ranibizumab (e.g., anti-VEGF-A), bevacizumab (AVASTIN™, e.g., anti-VEGF), panitumumab (e.g., anti-EGFR), cetuximab (e.g., anti-EGFR), Rituxan (e.g., anti-CD20), and antibodies directed against c-MET.

[0254] One or more of the following agents may be administered to the patient in combination with the therapeutic methods of the present disclosure, including, but not limited to, the following list: cytostatics, cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, epothilone, tamoxifen, 5-fluorouracil, methoxtrexate, temozolomide, cyclophosphamide, SCH66336, R115777, L778,123, BMS214662, IRESSA™ (gefitinib), TARCEVA™ (erlotinib), antibodies against EGFR, intron, ara-C, adriamycin, cytoxan, gemcitabine, ribavirin ... Cytabine, uracil mustard, chlormethine, ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, oxaliplatin, leucovirin, ELOXATIN™ (oxaliplatin), pentostatin, vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase, teniposide 17. alpha.-ethinyl estradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, dromostanolone propionate, testolactone, megestrol acetate, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide, flutamide, toremifene, goserelin, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, navelbene, anastrazole, letrazole, capecitabine, reloxafine, droloxafine, hexamethylmelamine, avastin, HERCEPTIN (trademark) (trastuzumab) (ibritumomab), BEXXAR™ (tositumomab), VELCADE™ (bortezomib), ZEVALIN™ (ibritumomab tiuxetan), TRISENOX™ (arsenic trioxide), XELODA™ (capecitabine), vinorelbine, porfimer, ERBITUX™ (cetuximab), thiotepa, altretamine, melphalan, trastuzumab, lerozole, fulvestrant, exemestane , ifosfomide, rituximab, C225 (cetuximab), Campath (alemtuzumab), clofarabine, cladribine, aphidicolon, rituxan, sunitinib, dasatinib, tezacitabine, Sml1, fludarabine, pentostatin, triapine, didox, trimidox, amidox, 3-AP, and MDL-101,731.

[0255] The disclosed treatment methods and regimens can further be combined with other cancer treatment methods. Such cancer treatment methods are, for example, chemotherapy, radiation therapy, tumor targeting therapy, adjuvant therapy, immunotherapy, or surgery. Examples of immunotherapy include cytokine therapy (e.g., interferon, GM-CSF, G-CSF, IL-2), CRS-207 immunotherapy, cancer vaccines, monoclonal antibodies, bispecific or multispecific antibodies, antibody drug conjugates, adoptive T cell transfer, Toll receptor agonists, RIG-I agonists, oncolytic virus therapy, and immunomodulatory small molecules (including thalidomide or JAK1 / 2 inhibitors, PI3Kδ inhibitors, and the like). The compound can be administered in combination with one or more anti-cancer agents (such as chemotherapeutic agents). Examples of chemotherapeutic agents include abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bevacizumab, bexarotene, baricitinib, bleomycin, bortezomib, intravenous busulfan, oral busulfan, calcitinib, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, propionic acid Dromostanolone, eculizumab, epacadostat, epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib mesylate, interferon alpha 2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, mechlorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate,Methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone phenpropionate, nelarabine, nofetumomab, oxaliplatin, paclitaxel, pamidronate, panitumumab, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin, procarbazine, quinacrine, rasburicase, rituximab, ruxolitinib, Sorafenib, streptozocin, sunitinib, sunitinib maleate, tamoxifen, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, vorinostat, and zoledronate.

[0256] Additional examples of chemotherapeutic agents include proteosome inhibitors (e.g., bortezomib), thalidomide, revlimid, and DNA damaging agents (such as melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide, carmustine, and the like).

[0257] Examples of steroids include corticosteroids (such as dexamethasone or prednisone).

[0258] Examples of Bcr-Abl inhibitors include imatinib mesylate (GLEEVAC™), nilotinib, dasatinib, bosutinib, and ponatinib, and pharmaceutically acceptable salts. Other suitable Bcr-Abl inhibitors include the genera and species of compounds disclosed in U.S. Patent No. 5,521,184, WO04 / 005281, and U.S. Patent No. 60 / 578,491, and pharmaceutically acceptable salts thereof.

[0259] Examples of suitable Flt-3 inhibitors include midostaurin, lestaurtinib, linifanib, sunitinib, sunitinib maleate, sorafenib, quizartinib, crenolanib, pacritinib, tanzutinib, PLX3397 and ASP2215, and pharmaceutically acceptable salts thereof. Examples of other suitable Flt-3 inhibitors include the compounds disclosed in WO03 / 037347, WO03 / 099771, and WO04 / 046120, and pharmaceutically acceptable salts thereof.

[0260] Examples of suitable RAF inhibitors include dabrafenib, sorafenib, and vemurafenib, and pharmaceutically acceptable salts thereof. Examples of other suitable RAF inhibitors include the compounds disclosed in WO00 / 09495 and WO05 / 028444, and pharmaceutically acceptable salts thereof.

[0261] Examples of suitable FAK inhibitors include VS-4718, VS-5095, VS-6062, VS-6063, BI853520, and GSK2256098, and pharma- ceutically acceptable salts thereof. Other examples of suitable FAK inhibitors include the compounds disclosed in WO04 / 080980, WO04 / 056786, WO03 / 024967, WO01 / 064655, WO00 / 053595, and WO01 / 014402, and pharma- ceutically acceptable salts thereof.

[0262] Examples of suitable CDK4 / 6 inhibitors include palbociclib, ribociclib, trilaciclib, relociclib, and abemaciclib, and pharmaceutically acceptable salts thereof. Examples of other suitable CDK4 / 6 inhibitors include compounds disclosed in WO09 / 085185, WO12 / 129344, WO11 / 101409, WO03 / 062236, WO10 / 075074, and WO12 / 061156, and pharmaceutically acceptable salts thereof.

[0263] In some embodiments, compounds of the present disclosure may be combined with one or more other kinase inhibitors, including imatinib, particularly for treating patients resistant to imatinib or other kinase inhibitors.

[0264] In some embodiments, the therapeutic methods of the present disclosure can be combined with chemotherapeutic agents in the treatment of cancer, and can improve the therapeutic response compared to the response to the chemotherapeutic agent alone without worsening its toxic effects. In some embodiments, the therapeutic methods of the present disclosure can be combined with chemotherapeutic agents provided herein. For example, additional pharmaceutical agents used in the treatment of multiple myeloma can include, but are not limited to, melphalan, melphalan + prednisone [MP], doxorubicin, dexamethasone, and Velcade (bortezomib). Further additional agents used in the treatment of multiple myeloma include Bcr-Abl, Flt-3, RAF, and FAK kinase inhibitors. In some embodiments, the agent is an alkylating agent, a proteasome inhibitor, a corticosteroid, or an immunomodulatory agent. Examples of alkylating agents include cyclophosphamide (CY), melphalan (MEL), and bendamustine. In some embodiments, the proteasome inhibitor is carfilzomib. In some embodiments, the corticosteroid is dexamethasone (DEX). In some embodiments, the immunomodulatory agent is lenalidomide (LEN) or pomalidomide (POM).Additive or synergistic effects are desirable results of combining the therapeutic methods of the present disclosure with additional agents.

[0265] The agents may be combined with Compound 1 and / or an antibody or antigen-binding fragment thereof that binds human PD-1 or human PD-L1 in the treatment methods of the disclosure in a single dosage form or in sequential dosage forms, or the agents may be administered simultaneously or sequentially as separate dosage forms.

[0266] In some embodiments, a corticosteroid (such as dexamethasone) is administered to a patient in combination with the therapeutic methods of the present disclosure, and the dexamethasone is administered intermittently as opposed to continuously.

[0267] The therapeutic methods described herein can be combined with other immunogenic agents, such as cancerous cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells transfected with genes encoding immune-stimulating cytokines. Examples of tumor vaccines that can be used include, but are not limited to, peptides of melanoma antigens (such as peptides of gp100, MAGE antigens, Trp-2, MARTI, and / or tyrosinase), or tumor cells transfected to express the cytokine GM-CSF.

[0268] The therapeutic methods described herein may be combined with vaccination protocols to treat cancer. In some embodiments, tumor cells are transduced to express GM-CSF. In some embodiments, tumor vaccines include proteins derived from viruses implicated in human cancers, such as human papillomavirus (HPV), hepatitis viruses (HBV and HCV), and Kaposi's herpes sarcoma virus (KHSV). In some embodiments, the therapeutic methods and regimens disclosed herein may be combined with tumor-specific antigens, such as heat shock proteins isolated from the tumor tissue itself. In some embodiments, the therapeutic methods described herein may be combined with dendritic cell immunization to activate a strong anti-tumor response.

[0269] The therapeutic methods and regimens of the present disclosure may be combined with bispecific macrocyclic peptides that target tumor cells to Fe alpha receptor-expressing effector cells or Fe gamma receptor-expressing effector cells. The therapeutic methods and regimens of the present disclosure may also be combined with macrocyclic peptides that activate host immune responsiveness.

[0270] In some alternative embodiments, the therapeutic methods of the present disclosure are combined with the administration of other therapeutic agents to the patient before, during, and / or after bone marrow or stem cell transplantation. The therapeutic methods and regimens of the present disclosure may be combined with bone marrow transplantation for the treatment of various tumors of hematopoietic origin.

[0271] When multiple pharmaceutical agents are administered to a patient, they may be administered simultaneously, separately, sequentially, or in combination (e.g., in the case of more than two agents) as discussed in any of the above embodiments.

[0272] For most of these chemotherapeutic agents, methods for their safe and effective administration are known to those skilled in the art. Moreover, their administration is described in standard references. For example, many of the chemotherapeutic agents are described for their administration in the "Physicians' Desk Reference" (PDR, e.g., 1996 edition, Medical Economics Company, Montvale, NJ), the disclosure of which is incorporated herein by reference as if set forth in its entirety.

[0273] In some embodiments, the compounds described herein may be used in combination with immune checkpoint inhibitors. Examples of immune checkpoint inhibitors include inhibitors against immune checkpoint molecules, such as CD27, CD28, CD40, CD122, CD96, CD73, CD47, OX40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, CD137 (also known as 4-1BB), ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3 (e.g., INCAGN2385), TIM3 (e.g., INCB2390), VISTA, PD-1, PD-L1, and PD-L2. In some embodiments, the immune checkpoint molecule is a stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS, OX40 (e.g., INCAGN1949), GITR (e.g., INCAGN1876), and CD137. In some embodiments, the immune checkpoint molecule is an inhibitory checkpoint molecule selected from A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, and VISTA. In some embodiments, the compounds provided herein may be used in combination with one or more agents selected from a KIR inhibitor, a TIGIT inhibitor, a LAIR1 inhibitor, a CD160 inhibitor, a 2B4 inhibitor, and a TGFR beta inhibitor.

[0274] In some embodiments, the inhibitor of an immune checkpoint molecule is a small molecule PD-L1 inhibitor. In some embodiments, the IC50 of the small molecule PD-L1 inhibitor is less than 1 μM, less than 100 nM, less than 10 nM, or less than 1 nM in the PD-L1 assay described in U.S. Patent Publication Nos. US20170107216, US20170145025, US20170174671, US20170174679, US20170320875, US20170342060, US20170362253, and US20180016260, each of which is incorporated by reference in its entirety for all purposes.

[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, 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 anticancer drugs (multiple drugs) include antibody drugs (those against 4-1BB (e.g., urelumab, utomirumab) and the like).

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

[0277] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1 (e.g., an anti-PD-L1 monoclonal antibody). In some embodiments, the anti-PD-L1 monoclonal antibody is 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 (e.g., 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 the immune checkpoint molecule is an inhibitor of LAG3 (e.g., an anti-LAG3 antibody). In some embodiments, the anti-LAG3 antibody is BMS-986016, LAG525, or INCAGN2385.

[0280] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of TIM3 (e.g., an anti-TIM3 antibody). In some embodiments, the anti-TIM3 antibody is INCAGN2390, MBG453, or TSR-022.

[0281] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of GITR (e.g., 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 agonist of OX40 (e.g., 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] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CD19 (e.g., an anti-CD19 antibody). In some embodiments, the anti-CD19 antibody is tafasitamab.

[0285] The compounds of the present disclosure may be used in combination with bispecific antibodies. In some embodiments, one of the domains of the bispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3, CD137, ICOS, CD3, or TGFβ receptors.

[0286] 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.

[0287] The compounds of the present disclosure may be combined with one or more immune checkpoint inhibitors to treat diseases, such as cancer or infectious diseases. Examples of immune checkpoint inhibitors include inhibitors against immune checkpoint molecules, such as CBL-B, CD20, CD28, CD40, CD70, CD122, CD96, CD73, CD47, CDK2, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, HPK1, CD137 (also known as 4-1BB), ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, TLR (TLR7 / 8), TIGIT, CD112R, VISTA, PD-1, PD-L1, and PD-L2. In some embodiments, the immune checkpoint molecule is a stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS, OX40, GITR, and CD137. In some embodiments, the immune checkpoint molecule is an inhibitory checkpoint molecule selected from A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, TIGIT, and VISTA. In some embodiments, the compounds provided herein may be used in combination with one or more agents selected from a KIR inhibitor, a TIGIT inhibitor, a LAIR1 inhibitor, a CD160 inhibitor, a 2B4 inhibitor, and a TGFR beta inhibitor.

[0288] In some embodiments, the compounds provided herein may be used in combination with one or more agonists of immune checkpoint molecules, such as OX40, CD27, GITR, and CD137 (also known as 4-1BB).

[0289] In some embodiments, the inhibitor of an immune checkpoint molecule is an anti-PD1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

[0290] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1 or PD-L1 (e.g., an anti-PD-1 monoclonal antibody or an anti-PD-L1 monoclonal antibody). In some embodiments, the anti-PD-1 antibody or anti-PD-L1 antibody is selected from the group consisting of nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, cemiplimab, atezolizumab, avelumab, tislelizumab, spartalizumab (PDR001), cetrelimab (JNJ-63723283), toripalimab (JS001), camrelizumab (SHR-1210), sintilimab (IBI308), AB122 (GLS-010), AMP-224, AMP-514 / MEDI -0680, BMS936559, JTX-4014, BGB-108, SHR-1210, MEDI4736, FAZ053, BCD-100, KN035, CS1001, BAT1306, LZM009, AK105, HLX10, SHR-1316, CBT-502(TQB2450), A167(KL-A167), STI-A101(ZKAB001), CK-301, BGB-A333, MSB-2311, HLX20, TSR-042, or LY3300054.In some embodiments, the PD-1 or PD-L1 inhibitor is a compound described in U.S. Pat. Nos. 7,488,802, 7,943,743, 8,008,449, 8,168,757, 8,217,149, or 10,308,644; U.S. Publication Nos. 2017 / 0145025, 2017 / 0174671, 2017 / 0174679; Same No. 2017 / 0320875, No. 2017 / 0342060, No. 2017 / 0362253, No. 2018 / 0016260, No. 2018 / 0057486, No. 20 No. 18 / 0177784, No. 2018 / 0177870, No. 2018 / 0179179, No. 2018 / 0179201, No. 2018 / 0179202, No. 2018 / 02 Nos. 2019 / 0073519, 2019 / 0040082, 2019 / 0062345, 2019 / 0071439, 2019 / 0127467, 2019 / 0144439, 2019 / 0202824, 2019 / 0225601, 2019 / 0300524, or 2019 / 0345170, or PCT Publication No. WO0 3042402, WO2008156712, WO2010089411, WO2010036959, WO2011066342, WO2011159877, WO2011082400, or WO2011161699, each of which is incorporated by reference in its entirety. In some embodiments, the inhibitor of PD-L1 is INCB086550.

[0291] In some embodiments, the antibody is an anti-PD-1 antibody (e.g., an anti-PD-1 monoclonal antibody). In some embodiments, the anti-PD-1 antibody is nivolumab, pembrolizumab, cemiplimab, spartalizumab, camrelizumab, cetrelimab, toripalimab, sintilimab, AB122, AMP-224, JTX-4014, BGB-108, BCD-100, BAT1306, LZM009, AK105, HLX10, or TSR-042. In some embodiments, the anti-PD-1 antibody is nivolumab, pembrolizumab, cemiplimab, spartalizumab, camrelizumab, cetrelimab, toripalimab, or sintilimab. In some embodiments, the anti-PD-1 antibody is pembrolizumab. In some embodiments, the anti-PD-1 antibody is nivolumab. In some embodiments, the anti-PD-1 antibody is cemiplimab. In some embodiments, the anti-PD-1 antibody is spartalizumab. In some embodiments, the anti-PD-1 antibody is camrelizumab. In some embodiments, the anti-PD-1 antibody is cetrelimab. In some embodiments, the anti-PD-1 antibody is toripalimab. In some embodiments, the anti-PD-1 antibody is sintilimab. In some embodiments, the anti-PD-1 antibody is AB122. In some embodiments, the anti-PD-1 antibody is AMP-224. In some embodiments, the anti-PD-1 antibody is JTX-4014. In some embodiments, the anti-PD-1 antibody is BGB-108. In some embodiments, the anti-PD-1 antibody is BCD-100. In some embodiments, the anti-PD-1 antibody is BAT1306. In some embodiments, the anti-PD-1 antibody is LZM009. In some embodiments, the anti-PD-1 antibody is AK105. In some embodiments, the anti-PD-1 antibody is HLX10. In some embodiments, the anti-PD-1 antibody is TSR-042. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab or pembrolizumab. In some embodiments, the anti-PD1 antibody is SHR-1210. Other anti-cancer drug(s) include antibody drugs (such as those against 4-1BB (e.g., urelumab, utomirumab)).In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1 (e.g., an anti-PD-L1 monoclonal antibody). In some embodiments, the anti-PD-L1 monoclonal antibody is atezolizumab, avelumab, durvalumab, tislelizumab, BMS-935559, MEDI4736, atezolizumab (also known as MPDL3280A; RG7446), avelumab (MSB0010718C), FAZ053, KN035, CS1001, SHR-1316, CBT-502, A167, STI-A101, CK-301, BGB-A333, MSB-2311, HLX20, or LY3300054. In some embodiments, the anti-PD-L1 antibody is atezolizumab, avelumab, durvalumab, or tislelizumab. In some embodiments, the anti-PD-L1 antibody is atezolizumab. In some embodiments, the anti-PD-L1 antibody is avelumab. In some embodiments, the anti-PD-L1 antibody is durvalumab. In some embodiments, the anti-PD-L1 antibody is tislelizumab. In some embodiments, the anti-PD-L1 antibody is BMS-935559. In some embodiments, the anti-PD-L1 antibody is MEDI4736. In some embodiments, the anti-PD-L1 antibody is FAZ053. In some embodiments, the anti-PD-L1 antibody is KN035. In some embodiments, the anti-PD-L1 antibody is CS1001. In some embodiments, the anti-PD-L1 antibody is SHR-1316. In some embodiments, the anti-PD-L1 antibody is CBT-502. In some embodiments, the anti-PD-L1 antibody is A167. In some embodiments, the anti-PD-L1 antibody is STI-A101. In some embodiments, the anti-PD-L1 antibody is CK-301. In some embodiments, the anti-PD-L1 antibody is BGB-A333. In some embodiments, the anti-PD-L1 antibody is MSB-2311. In some embodiments, the anti-PD-L1 antibody is HLX20. In some embodiments, the anti-PD-L1 antibody is LY3300054.

[0292] In some embodiments, the inhibitor of an immune checkpoint molecule is a small molecule that binds to PD-L1 or a pharma- ceutically acceptable salt thereof. In some embodiments, the inhibitor of an immune checkpoint molecule is a small molecule that binds to and internalizes PD-L1 or a pharma- ceutically acceptable salt thereof. In some embodiments, the inhibitor of an immune checkpoint molecule is a compound or a pharma- ceutically acceptable salt thereof selected from those described in US2018 / 0179201, US2018 / 0179197, US2018 / 0179179, US2018 / 0179202, US2018 / 0177784, US2018 / 0177870, US16 / 369,654 (filed March 29, 2019), and US62 / 688,164, each of which is incorporated herein by reference in its entirety.

[0293] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of KIR, TIGIT, LAIR1, CD160, 2B4, and TGFRbeta.

[0294] In some embodiments, the inhibitor is MCLA-145.

[0295] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CTLA-4 (e.g., an anti-CTLA-4 antibody). In some embodiments, the anti-CTLA-4 antibody is ipilimumab, tremelimumab, AGEN1884, or CP-675,206.

[0296] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of LAG3 (e.g., an anti-LAG3 antibody). In some embodiments, the anti-LAG3 antibody is BMS-986016, LAG525, INCAGN2385, or eftiragimodo alpha (IMP321).

[0297] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CD73. In some embodiments, the inhibitor of CD73 is oleculab.

[0298] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of TIGIT. In some embodiments, the inhibitor of TIGIT is OMP-31M32.

[0299] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of VISTA. In some embodiments, the inhibitor of VISTA is JNJ-61610588 or CA-170.

[0300] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of B7-H3. In some embodiments, the inhibitor of B7-H3 is enoblituzumab, MGD009, or 8H9.

[0301] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of KIR. In some embodiments, the inhibitor of KIR is lirilumab or IPH4102.

[0302] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of A2aR. In some embodiments, the inhibitor of A2aR is CPI-444.

[0303] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of TGF-beta. In some embodiments, the inhibitor of TGF-beta is travedersen, galusertinib, or M7824.

[0304] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PI3K-gamma. In some embodiments, the inhibitor of PI3K-gamma is IPI-549.

[0305] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CD47. In some embodiments, the inhibitor of CD47 is Hu5F9-G4 or TTI-621.

[0306] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CD73. In some embodiments, the inhibitor of CD73 is MEDI9447.

[0307] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CD70. In some embodiments, the inhibitor of CD70 is cusatuzumab or BMS-936561.

[0308] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of TIM3 (e.g., an anti-TIM3 antibody). In some embodiments, the anti-TIM3 antibody is INCAGN2390, MBG453, or TSR-022.

[0309] 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.

[0310] In some embodiments, the agonist of an immune checkpoint molecule is an agonist of OX40, CD27, CD28, GITR, ICOS, CD40, TLR7 / 8, and CD137 (also known as 4-1BB).

[0311] In some embodiments, the agonist of CD137 is urelumab. In some embodiments, the agonist of CD137 is utomirumab.

[0312] In some embodiments, the agonist of the immune checkpoint molecule is an inhibitor of GITR. In some embodiments, the agonist of GITR is TRX518, MK-4166, INCAGN1876, MK-1248, AMG228, BMS-986156, GWN323, MEDI1873, or MEDI6469. In some embodiments, the agonist of the immune checkpoint molecule is an agonist of OX40 (e.g., an OX40 agonist antibody or an OX40L fusion protein). In some embodiments, the anti-OX40 antibody is INCAGN01949, MEDI0562 (tavolimab), MOXR-0916, PF-04518600, GSK3174998, BMS-986178, or 9B12. In some embodiments, the OX40L fusion protein is MEDI6383.

[0313] In some embodiments, the agonist of the immune checkpoint molecule is an agonist of CD40. In some embodiments, the agonist of CD40 is CP-870893, ADC-1013, CDX-1140, SEA-CD40, RO7009789, JNJ-64457107, APX-005M, or Chi Lob7 / 4.

[0314] In some embodiments, the agonist of the immune checkpoint molecule is an agonist of ICOS. In some embodiments, the agonist of ICOS is GSK-3359609, JTX-2011, or MEDI-570.

[0315] In some embodiments, the agonist of the immune checkpoint molecule is an agonist of CD28. In some embodiments, the agonist of CD28 is celalizumab.

[0316] In some embodiments, the agonist of the immune checkpoint molecule is an agonist of CD27. In some embodiments, the agonist of CD27 is valilumab.

[0317] In some embodiments, the agonist of the immune checkpoint molecule is an agonist of TLR7 / 8. In some embodiments, the agonist of TLR7 / 8 is MEDI9197.

[0318] The compounds of the present disclosure may be used in combination with bispecific antibodies. In some embodiments, one of the domains of the bispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3, CD137, ICOS, CD3, or TGFβ receptor. In some embodiments, the bispecific antibody binds to PD-1 and PD-L1. In some embodiments, the bispecific antibody that binds to PD-1 and PD-L1 is MCLA-136. In some embodiments, the bispecific antibody binds to PD-L1 and CTLA-4. In some embodiments, the bispecific antibody that binds to PD-L1 and CTLA-4 is AK104.

[0319] In some embodiments, the compounds of the present disclosure may be used in combination with one or more metabolic enzyme inhibitors. In some embodiments, the metabolic enzyme inhibitor is an inhibitor of IDO1, TDO, or arginase. Examples of IDO1 inhibitors include epacadostat, NLG919, BMS-986205, PF-06840003, IOM2983, RG-70099, and LY338196. Inhibitors of arginase inhibitors include INCB1158.

[0320] The additional compounds, inhibitors, agents, etc. provided throughout may be combined with the compounds of the present disclosure in a single dosage form or sequential dosage forms, or such may be administered simultaneously or sequentially as separate dosage forms.

[0321] In some embodiments, the compounds described herein may be combined with one or more agents for treating a disease (such as cancer). In some embodiments, the agent is an alkylating agent, a proteasome inhibitor, a corticosteroid, or an immunomodulatory agent. Examples of alkylating agents include cyclophosphamide (CY), melphalan (MEL), and bendamustine. In some embodiments, the proteasome inhibitor is carfilzomib. In some embodiments, the corticosteroid is dexamethasone (DEX). In some embodiments, the immunomodulatory agent is lenalidomide (LEN) or pomalidomide (POM).

[0322] 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, as well as other antiviral agents.

[0323] 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 known as beta-L-D4C, which has the name beta-L-2',3'-dicreoxy-5-fluoro-cytidine), 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-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione), and (+)-calanolide A (NSC-675451) and B. Exemplary suitable protease inhibitors include saquinavir ( Ro31-8959), ritonavir (ABT-538), indinavir (MK-639), nelfinavir (AG-1343), amprenavir (141W94), lasinavir (BMS-234475), DMP-450, BMS-2322623, ABT-378, and AG-1549. Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside, and Yissum Project No. 11607.

[0324] Suitable agents for use in combination with the compounds described herein for the treatment of cancer include chemotherapeutic agents, targeted cancer therapy, immunotherapy, or radiation therapy. The compounds described herein may be effective in combination with antihormonal agents for the treatment of breast cancer and other tumors. Suitable examples are antiestrogens (including but not limited to tamoxifen and toremifene), aromatase inhibitors (including but not limited to letrozole, anastrozole, and exemestane), corticosteroids (e.g., prednisone), progestins (e.g., megastrol acetate), and estrogen receptor antagonists (e.g., fulvestrant). Suitable antihormonal agents used in the treatment of prostate cancer and other cancers may also be used in combination with the compounds described herein. Such antihormonal agents 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 suppress androgen production (e.g., abiraterone).

[0325] The compounds described herein may be used in combination or sequentially with other agents against membrane receptor kinases, particularly for patients with initial or acquired resistance to targeted therapy. Such agents include inhibitors or antibodies against EGFR, Her2, VEGFR, c-Met, Ret, IGFR1, or Flt-3, as well as inhibitors or antibodies against cancer-related fusion protein kinases (such as Bcr-Abl and EML4-Alk). Inhibitors against EGFR include gefitinib and erlotinib, and inhibitors against EGFR / Her2 include, but are not limited to, dacomitinib, afatinib, lapitinib, and neratinib. Antibodies against EGFR include, but are not limited to, cetuximab, panitumumab, and necitumumab. Inhibitors of c-Met may be used in combination with FGFR inhibitors. Such c-Met inhibitors include onartumzumab, tivantinib, and INC-280. Agents against Abl (or Bcr-Abl) include imatinib, dasatinib, nilotinib, and ponatinib, and agents against Alk (or EML4-ALK) include crizotinib.

[0326] Angiogenesis inhibitors may be effective in some tumors when combined with FGFR inhibitors. Such angiogenesis inhibitors include antibodies against VEGF or VEGFR, or kinase inhibitors of VEGFR. Antibodies against VEGF or other therapeutic proteins include bevacizumab and aflibercept. Inhibitors of VEGFR kinase and other antiangiogenesis inhibitors include, but are not limited to, sunitinib, sorafenib, axitinib, cediranib, pazopanib, regorafenib, brivanib, and vandetanib.

[0327] Intracellular signaling pathways are frequently activated in cancer, and drugs that target components of these pathways can be used in combination with drugs that target receptors to increase efficacy and reduce resistance. Examples of drugs that can be used in combination 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.

[0328] Drugs against PI3 kinase include, but are not limited to, topilaralisib, idelalisib, and buparisib. Inhibitors of mTOR (such as rapamycin, sirolimus, temsirolimus, and everolimus) can be used in combination with FGFR inhibitors. Other suitable examples include, but are not limited to, vemurafenib and dabrafenib (Raf inhibitors), as well as trametinib, selumetinib, and GDC-0973 (MEK inhibitors). One or more JAK inhibitors (e.g., ruxolitinib, baricitinib, tofacitinib), Hsp90 inhibitors (e.g., tanespimycin), cyclin-dependent kinase inhibitors (e.g., palbociclib), HDAC inhibitors (e.g., panobinostat), PARP inhibitors (e.g., olaparib), and proteasome inhibitors (e.g., bortezomib, carfilzomib) may also be used in combination with the compounds described herein. In some embodiments, the JAK inhibitor is selective for JAK1 over JAK2 and JAK3.

[0329] Other agents suitable for combination with the compounds described herein include combination chemotherapy used in lung cancer and other solid tumors, such as platinum-based doublet combinations (cisplatin or carboplatin + gemcitabine, cisplatin or carboplatin + docetaxel, cisplatin or carboplatin + paclitaxel, cisplatin or carboplatin + pemetrexed), or gemcitabine + paclitaxel conjugated particles (Abraxane®).

[0330] Suitable chemotherapeutic or other anti-cancer agents include, for example, alkylating agents (including but not limited to, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas, and triazenes), such as uracil mustard, chlormethine, cyclophosphamide (Cytoxan™), ifosfamide, melphalan, chlorambucil, pipobroman, triethylene-melamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

[0331] Suitable agents for use in combination with the compounds described herein include steroids, including 17alpha-ethynyl estradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide, and medroxyprogesterone acetate.

[0332] Suitable agents for use in combination with the compounds described herein include dacarbazine (DTIC), optionally in combination 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 can also be used in combination with immunotherapeutic agents, including cytokines such as interferon alpha, interleukin 2, and tumor necrosis factor (TNF).

[0333] Suitable chemotherapeutic or other anti-cancer agents include, for example, antimetabolites (including but not limited to, folate antagonists, pyrimidine analogs, purine analogs, and adenosine deaminase inhibitors), such as methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, and gemcitabine.

[0334] 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-a), etoposide, and teniposide.

[0335] Other cytotoxic agents include navelbene, CPT-11, anastrazole, letrazole, capecitabine, reloxafine, cyclophosphamide, ifosamide, and droloxafine.

[0336] Also suitable are cytotoxic agents (such as epidophyllotoxin), antineoplastic enzymes, topoisomerase inhibitors, procarbazine, mitoxantrone, platinum coordination complexes (such as cisplatin and carboplatin), biological response modifiers, growth inhibitors, anti-hormonal therapies, leucovorin, tegafur, and hematopoietic growth factors.

[0337] Other anti-cancer drug(s) include antibody drugs such as trastuzumab (Herceptin), antibodies against costimulatory molecules (such as CTLA-4 antibody, 4-1BB antibody, PD-L1 antibody, and PD-1 antibody), or antibodies against cytokines (such as IL-10, TGF-β, etc.).

[0338] Other anti-cancer drugs include those that block immune cell migration, such as antagonists to chemokine receptors, including CCR2 and CCR4.

[0339] Other anti-cancer drugs include those that boost the immune system (such as adjuvants or adoptive T-cell transfer).

[0340] 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 cancers, such as human papillomavirus (HPV), hepatitis viruses (HBV and HCV), and Kaposi's herpes sarcoma virus (KHSV). Examples of tumor vaccines that can be used include, but are not limited to, peptides of melanoma antigens, such as peptides of gp100, MAGE antigens, Trp-2, MARTI, and / or tyrosinase, or tumor cells transfected to express the cytokine GM-CSF.

[0341] The compounds of the present disclosure may be used in combination with bone marrow transplantation for the treatment of various tumors of hematopoietic origin.

[0342] For most of these chemotherapeutic agents, methods for their safe and effective administration are known to those skilled in the art. Moreover, their administration is described in standard references. For example, many of the chemotherapeutic agents are described for their administration in the "Physicians' Desk Reference" (PDR, e.g., 1996 edition, Medical Economics Company, Montvale, NJ), the disclosure of which is incorporated herein by reference as if set forth in its entirety.

[0343] The additional compounds, inhibitors, agents, etc. provided throughout may be combined with the compounds of the present disclosure in a single dosage form or sequential dosage forms, or such may be administered simultaneously or sequentially as separate dosage forms.

[0344] Pharmaceutical Preparations and Dosage Forms When utilized as pharmaceuticals, the compounds described herein may be administered in the form of pharmaceutical compositions (referring to a combination of one or more of the compounds described herein with at least one pharma- ceutically acceptable carrier or excipient). Such compositions may be prepared in a manner well known in the pharmaceutical arts and may be administered by a variety of routes, depending on whether the desired treatment is local or systemic, and on the area to be treated. Administration may be topical (including ocular administration, and administration to mucous membranes (including intranasal, intravaginal, and intrarectal delivery)), pulmonary (e.g., administration by inhalation or insufflation of powders or aerosols (including by nebulizers), intratracheal, intranasal, subcutaneous, and transdermal), ophthalmic, oral, or parenteral. Methods for ocular delivery may include topical administration (ocular drops), subconjunctival, periocular, or intravitreal injection, or introduction by balloon catheters or intraocular inserts surgically placed in the conjunctival sac. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion, or intracranial (e.g., intrathecal or intraventricular) administration. Parenteral administration can be in the form of a single bolus dose, or by, for example, a continuous infusion pump. Pharmaceutical compositions and formulations for topical administration can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous, powder, or oily bases, thickeners, and the like, may be necessary or desirable.

[0345] The present disclosure also includes pharmaceutical compositions that contain one or more of the compounds described herein as active ingredients in combination with one or more pharma- ceutically acceptable carriers or excipients. In preparing the compositions described herein, the active ingredient is typically mixed with or diluted by an excipient, or enclosed within such a carrier, for example, in the form of a capsule, sachet, paper, or other container. When an excipient serves as a diluent, it can be a solid, semi-solid, or liquid substance that serves as a vehicle, carrier, or medium for the active ingredient. Thus, the composition can take the form of a tablet, pill, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or in a liquid medium), ointment (e.g., 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 composition is suitable for topical administration.

[0346] In preparing the formulation, active compound can be milled to suitable particle size and then mixed with other components.If active compound is substantially insoluble, such active compound can be milled to particle size of less than 200 mesh.If active compound is substantially water-soluble, it can be milled to adjust particle size (for example, about 40 mesh) to ensure substantially uniform distribution in the formulation.

[0347] The compounds of the invention can be milled using known milling procedures (such as wet milling) to a particle size suitable for tablet formation and other formulation types. Finely divided (nanoparticulate) preparations of the compounds of the invention can be prepared by processes known in the art, see, for example, WO2002 / 000196.

[0348] Some examples of suitable pharmaceutical excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginic acid, tragacanth, gelatin, calcium silicate, crystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose.The formulation may additionally include lubricants (such as talc, magnesium stearate, and mineral oil), wetting agents, emulsifying and suspending agents, preservatives (such as methyl and propyl hydroxybenzoates), sweeteners, and flavoring agents.The compositions described herein may be formulated to provide quick, sustained, or delayed release of active ingredient after administration to a patient by using procedures known in the art.

[0349] In some embodiments, the pharmaceutical composition comprises silicified microcrystalline cellulose (SMCC) and at least one of the compounds described herein or a pharma- ceutical acceptable salt thereof.In some embodiments, the silicified microcrystalline cellulose comprises about 98% (w / w) microcrystalline cellulose and about 2% (w / w) silicon dioxide.

[0350] In some embodiments, the composition is a sustained release composition comprising at least one of the compounds described herein or a pharma- ceutically acceptable salt thereof and at least one pharma- ceutically acceptable carrier or excipient. In some embodiments, the composition comprises at least one of the compounds described herein or a pharma- ceutically 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 of the compounds described herein or a pharma- ceutically acceptable salt thereof and microcrystalline cellulose, lactose monohydrate, and hydroxypropyl methylcellulose. In some embodiments, the composition comprises at least one of the compounds described herein or a pharma- ceutically 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™).

[0351] In some embodiments, the composition is produced using a wet granulation process. In some embodiments, the composition is produced using a dry granulation process.

[0352] The composition can be formulated in a unit dosage form, with each dose 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 dose contains about 10 mg of active ingredient. In some embodiments, each dose contains about 50 mg of active ingredient. In some embodiments, each dose contains about 25 mg of active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce a desired therapeutic effect in association with suitable pharmaceutical excipients.

[0353] The components used to formulate the pharmaceutical composition are of high purity and substantially free of potentially harmful contaminants (e.g., at least national food grade, generally at least analytical grade, more typically at least pharmaceutical grade). In particular for human consumption, the composition is preferably manufactured or formulated under good manufacturing practice as defined in applicable regulations of the U.S. Food and Drug Administration. For example, suitable formulations may be sterile and / or substantially isotonic and / or in full compliance with the U.S. Food and Drug Administration's Good Manufacturing Practice regulations.

[0354] Active compound can be effective over a wide range of doses and is generally administered in a medicamentously effective amount.However, it will be understood that the amount of compound actually administered will usually be determined by a physician according to the relevant circumstances, including the condition to be treated, the route of administration selected, the compound actually administered, the age, weight and response of individual patient, the severity of the patient's symptoms, and the like.

[0355] The therapeutic dose of the compounds of the invention may vary depending, for example, on the particular application for which the treatment is made, the manner in which the compound is administered, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of the compound of the invention in a pharmaceutical composition may vary depending on several factors, including dosage, chemical characteristics (e.g., hydrophobicity), and route of administration. For example, the compounds of the invention may be provided in a physiologically buffered aqueous solution containing about 0.1 to about 10% w / v of the compound for parenteral administration. Some typical dose ranges are about 1 g / kg body weight / day to about 1 g / kg body weight / day. In some embodiments, the dose range is about 0.01 mg / kg body weight / day to about 100 mg / kg body weight / day. The dose may depend on such variables as the type and progression of the disease or disorder, the general health of the particular patient, the relative biological potency of the compound selected, the formulation of excipients, and its route of administration. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0356] For the preparation of solid compositions (such as tablets), the main active ingredient is mixed with excipients to form a solid preformulation composition containing a homogeneous mixture of one or more of the compounds described herein. When such preformulation compositions are referred to as homogeneous, the active ingredient is typically evenly distributed throughout the composition so that subdivision of the composition into equally effective unit dosage forms (such as tablets, pills, and capsules) can be easily achieved. This preformulation solid is then subdivided into unit dosage forms of the types described above (e.g., containing 0.1 to about 500 mg of the active ingredient of the present disclosure).

[0357] The tablets or pills of the present disclosure may be coated or otherwise treated to provide the dosage form with the advantage of extended action. For example, the tablets or pills may include an inner dosage component and an outer dosage component, the outer dosage component being in the form of an outer coating that encases the inner dosage component. These two components may be separated by an enteric layer that serves to resist disintegration in the stomach and allows the inner component to reach the duodenum intact or to delay the release of the inner component. Such enteric layers or coatings may use a variety of materials, including some polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0358] Liquid forms into which the compounds or compositions described herein may be incorporated for oral or injectable administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and emulsions flavored with edible oils (such as cottonseed oil, sesame oil, coconut oil, or peanut oil), as well as elixirs and similar pharmaceutical vehicles.

[0359] Compositions for inhalation or insufflation include solutions and suspensions in pharma- ceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharma- ceutically acceptable excipients as described above. In some embodiments, the compositions are administered by oral or nasal respiratory routes to obtain local or systemic effects. The compositions may be nebulized by using inert gases. Nebulized solutions may be directly inhaled from the nebulizing device, or the nebulizing device may be attached to a face mask tent or intermittent positive pressure respirator. Solution, suspension, or powder compositions may be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0360] Topical formulations may include one or more conventional carriers. In some embodiments, ointments may include water and one or more hydrophobic carriers (e.g., selected from liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white petrolatum, and the like). Cream carrier compositions may be based on water in combination with glycerol and one or more other ingredients (e.g., glyceryl monostearate, PEG-glyceryl monostearate, and cetylstearyl alcohol). Gels may be formulated using a suitable combination of isopropyl alcohol and water with other ingredients (e.g., glycerol, hydroxyethylcellulose, and the like). In some embodiments, topical formulations include at least about 0.1 wt%, at least about 0.25 wt%, at least about 0.5 wt%, at least about 1 wt%, at least about 2 wt%, or at least about 5 wt% of the compound of the present invention. Topical formulations may be suitably packaged in tubes (eg, 100 g, optionally accompanied by instructions for treatment of a selected indication (eg, psoriasis or other skin condition)).

[0361] 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 mode of administration, and the like. In therapeutic applications, the compositions may be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of such disease and its complications. The effective dose will depend on the condition being treated and the judgment of the attending physician depending on factors such as the severity of the disease, the age, weight, and general condition of the patient, and the like.

[0362] The composition administered to a patient may take the form of a pharmaceutical composition as described above. Such compositions may be sterilized by conventional sterilization techniques or may be sterile filtered. Aqueous solutions may be packaged for immediate use or lyophilized, and the lyophilized preparations are mixed with a sterile aqueous carrier prior to administration. The pH of the compound preparations is typically 3-11, more preferably 5-9, and most preferably 7-8. It will be appreciated that the use of the aforementioned pharmaceutical additives, carriers, or stabilizers will result in the formation of pharmaceutical salts.

[0363] The therapeutic dosage of the compounds of the present disclosure may vary depending, for example, on the particular application for which the treatment is made, the manner in which the compound is administered, 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 may vary depending on several factors, including the dosage, chemical characteristics (e.g., hydrophobicity), and route of administration. For example, the compounds of the present disclosure may be provided in a physiologically buffered aqueous 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 body weight / day to about 1 g / kg body weight / day. In some embodiments, the dosage range is about 0.01 mg / kg body weight / day to about 100 mg / kg body weight / day. The dosage may depend on such variables as the type and progression of the disease or disorder, the general health of the particular patient, the relative biological potency of the compound selected, the formulation of excipients, and its route of administration. Effective dosages may be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0364] The compounds described herein may also be formulated in combination with one or more additional active ingredients, which may include any pharmaceutical agent, such as an antiviral agent, a vaccine, an antibody, an immunostimulant, an immunosuppressant, an anti-inflammatory agent, and the like.

[0365] Labeled Compounds and Assay Methods Another aspect of the present invention relates to the labeled compounds (radiolabeled, fluorescently labeled, etc.) of the present disclosure, which are expected to be useful not only in imaging procedures, but also in assays (both in vitro and in vivo) for localizing and quantifying FGFR3 protein in tissue samples, including humans, and identifying FGFR3 ligands by binding inhibition of the labeled compounds. Substituting one or more atoms of the compounds of the present disclosure may also be useful in distinguishing ADME (absorption, distribution, metabolism, and excretion). Thus, the present invention includes FGFR binding assays that include such labeled or substituted compounds.

[0366] The present disclosure further includes isotopically labeled compounds of the present disclosure. An "isotopically labeled" compound or "radiolabeled" compound is a compound of the present disclosure in which one or more atoms have been replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring). Suitable radionuclides that can be incorporated into the 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 may be replaced by a deuterium atom (e.g., C of formula (I)). 1-6 One or more hydrogen atoms of an alkyl group can be optionally replaced by a deuterium atom (-CH 3 Instead of -CD 3In some embodiments, the alkyl groups in formula (I) can be fully deuterated.

[0367] One or more constituent atoms of the compounds described herein may be replaced or substituted by isotopes of such atoms in natural or non-natural abundance ratios. 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 1-2, 1-3, 1-4, 1-5, or 1-6 deuterium atoms. In some embodiments, all of the hydrogen atoms in the compounds may be replaced or substituted by deuterium atoms.

[0368] Synthetic methods for incorporating isotopes into organic compounds are known in the art (Deuterium Labeling in Organic Chemistry by Alan F. Thomas (New York, NY, Appleton-Century-Crofts, 1971; The Renaissance of H / D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistry of Isotopic Labelling by James R. Hanson, Royal Society of Chemistry, 2011). Isotopically labeled compounds can be used for a variety of studies, such as NMR spectroscopy, metabolic experiments, and / or assays.

[0369] Substitution with heavy isotopes (such as deuterium) may provide certain therapeutic advantages due to increased metabolic stability (e.g., increased in vivo half-life) or reduced dosage requirements, and therefore may be preferred in some circumstances (see, e.g., A. Kerekes et.al. J. Med. Chem. 2011, 54, 201-210; R. Xu et.al. J. Label Compd. Radiopharm. 2015, 58, 308-312). In particular, substitution at one or more metabolic sites may provide one or more therapeutic advantages.

[0370] The radionuclide incorporated in the radiolabeled compounds of the present disclosure 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 It may be useful to incorporate S into the compound. For radiation imaging applications, 11 C. 18 F, 125 I, 123 I, 124 I, 131 I, 75 Br, 76 Br, or 77 Br may be useful.

[0371] It is understood that a "radiolabeled compound" or "labeled compound" is a compound into which at least one radionuclide has been incorporated. In some embodiments, the radionuclide is 3 H, 14 C. 125 I, 35 S, and 82 Br.

[0372] The present disclosure may 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 that are applicable to the disclosed compounds.

[0373] The labeled compounds of the present invention can be used in screening assays to identify and / or evaluate compounds. For example, a newly synthesized or identified compound (i.e., a test compound) can be labeled and evaluated for its ability to bind to FGFR3 protein by tracking the labeling and monitoring its concentration change upon contact with FGFR3. For example, a test compound (labeled) can be evaluated for its ability to reduce the binding of another compound (i.e., a standard compound) that is known to bind to FGFR3 protein. Thus, the ability of a test compound to compete with a standard compound for binding to FGFR3 protein directly correlates with its binding affinity. Conversely, in some other screening assays, the standard compound is labeled and the test compound is not labeled. Thus, the relative binding affinity of a test compound can be ascertained by monitoring the concentration of a labeled standard compound to evaluate the competition between the standard compound and the test compound.

[0374] kit The present invention also includes pharmaceutical kits, which are useful, for example, for treating or preventing diseases or disorders associated with FGFR (such as cancer and other diseases mentioned herein), and which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present disclosure. If desired, such kits may further include one or more of a variety of conventional pharmaceutical kit components (e.g., a container with one or more pharma-ceutically acceptable carriers, additional containers, etc.), which will be readily apparent to those skilled in the art. Instructions, either as inserts or labels, indicating the amounts of components to be administered, administration guidelines, and / or mixing guidelines for components may also be included in the kit.

[0375] The present invention will be described in more detail by examples. The following examples are provided for illustrative purposes and are not intended to limit the present invention in any manner. Those skilled in the art will recognize various non-critical parameters that can be changed or modified to obtain essentially the same results. The compounds of the examples have been found to be inhibitors of FGFR3 as described below. EXAMPLES

[0376] The following describes the experimental procedure for the compounds of the present invention. The preparative LC-MS purification of some of the compounds prepared is carried out on Waters mass specific fractionation system. The basic instrument settings, protocols and control software for operating such systems are described in detail in the literature. See, e.g., "Two-Pump At Column Dilution Configuration for Preparative LC-MS", K. Blom, J. Combi. Chem., 4, 295 (2002), "Optimizing Preparative LC-MS Configurations and Methods for Parallel Synthesis Purification", K. Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi. Chem., 5, 670 (2003), and "Preparative LC-MS Purification: Improved Compound Specific Method Optimization", K. Blom, B. Glass, R. Sparks, A. Combs, J. Combi. Chem., 6, 874-883 (2004). The separated compounds were 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 185 μm, 2.1×50 mm, buffer: mobile phase A: water containing 0.025% TFA and mobile phase B: acetonitrile; gradient from 2% to 80% B in 3 min (flow rate 2.0 mL / min).

[0377] Some of the prepared compounds were also separated on a preparative scale by reversed-phase high performance liquid chromatography (RP-HPLC) coupled with MS detection or flash chromatography (silica gel) as shown in the examples. Typical preparative reversed-phase high performance liquid chromatography (RP-HPLC) column conditions are as follows:

[0378] Purification at pH=2: Waters Sunfire™ C 18 A 5 μm, 19×100 mm column, elution mobile phase A: water containing 0.1% TFA (trifluoroacetic acid) and elution mobile phase B: acetonitrile; flow rate was 30 mL / min, and the separation gradient was optimized for each compound using the 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, a 30×100 mm column was used with a flow rate of 60 mL / min.

[0379] Purification at pH=10: Waters XBridge C 18 5μm, 19×100mm column, elution mobile phase A: NH 4Water containing 0.15% OH and elution mobile phase B: acetonitrile; flow rate was 30 mL / min, and separation gradient was optimized for each compound using the 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 was 60 mL / min using a 30 x 100 mm column.

[0380] Intermediate 1. 9-Bromo-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] Step 1. 3-Bromo-5-chloro-1,6-naphthyridine [ka] A flask containing a mixture of phosphoryl chloride (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 h. The reaction mixture was cooled to room temperature and the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by elution with saturated NaHCO 3 The mixture was extracted with EtOAc. The organic phase was washed with brine and MgSO 4 After drying at 40° C. and filtering, the solvent was evaporated under reduced pressure. The crude product obtained was used in the next step without further purification. 8 H 5 BrClN 2 (M+H) + Calculated: m / z = 242.9 / 244.9; Found: 243.0 / 244.9.

[0381] Step 2. 3-Bromo-1,6-naphthyridin-5-amine [ka] A sealed microwave vessel containing 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 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 under reduced pressure. The resulting crude product was used in the next step without further purification. C by LCMS: 8 H 7 BrN 3 (M+H) + Calculated: m / z = 224.0 / 226.0; Found: 224.2 / 226.2.

[0382] Step 3. 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 (1.32 g, 5.89 mmol), sodium bicarbonate (742 mg, 8.84 mmol), 2-bromo-1-(2,6-dichlorophenyl)ethan-1-one (1.9 g, 7.07 mmol), and tert-butanol (8 mL) was irradiated at 150 °C for 9 h using a Biotage Initator+ microwave synthesizer. After cooling to room temperature, the solid was filtered and purified by HPLC. 2 Cl 2 After washing with 500 ml of ethyl acetate, the filtrate was concentrated under reduced pressure. The resulting residue was purified by Biotage Isolera to give the desired product as an orange solid. 16 H 9 BrCl 2 N 3 (M+H) + Calculated: m / z = 391.9 / 393.9 / 395.9; found 392.1 / 394.1 / 396.1.

[0383] Step 4. 9-Bromo-2-(2,6-dichlorophenyl)-3-iodoimidazo[2,1-f][1,6]naphthyridine [ka] A vial containing 9-bromo-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine (200 mg, 0.509 mmol), NIS (114 mg, 0.509 mmol) in acetonitrile (2 mL) was stirred at 60 °C for 4 h. The solution was then cooled to room temperature and concentrated under reduced pressure before being purified by Biotage Isolera to give the desired product as a brown solid. C by LCMS 16 H 8 BrCl 2 IN 3 (M+H) + Calculated: m / z = 517.8 / 519.8; found 517.9 / 519.7.

[0384] Step 5. Methyl 9-bromo-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxylate [ka] A mixture of 9-bromo-2-(2,6-dichlorophenyl)-3-iodoimidazo[2,1-f][1,6]naphthyridine (1.20 g, 2.31 mmol), triethylamine (967 μL, 6.94 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.267 g, 0.231 mmol) was suspended in DMF (4.6 mL) and MeOH (4.6 mL). The vial was purged with CO gas for 5 min, after which the vial was heated to 60 °C under a CO atmosphere for 2 h. Upon cooling to room temperature, the solution was diluted with saturated NaHCO 3 The mixture was quenched with aqueous hexanes and extracted with diethyl ether. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by Biotage Isolera to give the desired product as a brown solid. C by LCMS 18 H11 BrCl 2 N 3 O 2 (M+H) + Calculated: m / z = 449.9 / 451.9; Found: 449.9 / 451.9.

[0385] Step 6. 9-Bromo-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxylic acid [ka] To a vial containing methyl 9-bromo-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxylate (300 mg, 0.665 mmol) as a suspension in MeOH (1.3 mL) was added 2 M aqueous sodium hydroxide (665 μL, 1.33 mmol). The reaction was heated to 50° C. for 1 h. After cooling to room temperature, saturated NH 4 The pH of the mixture was adjusted to about 5 with aqueous Cl and acetic acid, then extracted with EtOAc. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by Biotage Isolera to give the desired product as a yellow solid. C by LCMS 17 H 9 BrCl 2 N 3 O 2 (M+H) + Calculated: m / z = 435.9 / 437.9; Found: 435.9 / 437.9.

[0386] Step 7. 9-Bromo-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide A vial containing 9-bromo-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxylic acid (1.0 g, 2.29 mmol) as a suspension in THF (5 mL) was charged with SOCl 2(1.0 mL, 13.7 mmol) was added. The vial was heated to 45° C. for 4 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in THF (5 mL), cooled to 0° C., and ammonium hydroxide solution (800 μL) was added dropwise with stirring. After 10 min, the solution was rehydrated with saturated NaHCO 3 The mixture was quenched with aqueous hexanes and extracted with EtOAc. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by Biotage Isolera to give the desired product as a yellow solid. C by LCMS 17 H 10 BrCl 2 N 4 O (M+H) + Calculated: m / z = 434.9 / 436.9; Found: 434.9 / 436.9.

[0387] Example 1. 2-(2,6-dichlorophenyl)-9-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] A vial containing 9-bromo-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide (Intermediate 1, 90 mg, 0.206 mmol), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-ol (59 mg, 0.248 mmol), tripotassium phosphate (88 mg, 0.413 mmol), and (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) dichloromethane adduct (17 mg, 0.021 mmol) was evacuated and backfilled with nitrogen three times before adding 1,4-dioxane (1.9 mL) and water (190 μL) to the vial. The vial was sealed and heated to 80° C. for 1 h. After cooling to room temperature, the mixture was filtered through a SiliaPrep SPE thiol cartridge (SPE-R51030B-06P) and washed with acetonitrile. The mixture was then diluted with acetonitrile and purified by preparative LCMS (XBridge C18 column, gradient elution with acetonitrile / water containing 0.1% TFA, flow rate 60 mL / min) to give the title compound as the TFA salt. C by LCMS 22 H 17 Cl 2 N 6 O 2 (M+H) + Calculated: m / z = 467.1 / 469.1; Found: 467.1 / 469.1. 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.34 (d, J = 2.3 Hz, 1H), 9.25 (d, J = 7.7 Hz, 1H), 8.99 (d, J = 2.2 Hz, 1H), 8.61 (s, 1H), 8.27 (d, J = 0.8 Hz, 1H), 7.72 - 7.67 (m, 2H), 7.60 (dd, J = 8.9, 7.3 Hz, 1H), 7.55 (dd, J = 7.7, 0.7 Hz, 1H), 4.20 (t, J = 5.6 Hz, 2H), 3.81 (t, J = 5.6 Hz, 2H).

[0388] Example 2. 2-(2,6-dichlorophenyl)-9-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] This compound was prepared according to the procedure described in Example 1 using 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol instead of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-ol, which gave the title compound as the TFA salt. C by LCMS 24 H 21 Cl 2 N 6 O 2 (M+H) + Calculated: m / z = 495.1 / 497.1; Found: 495.1 / 497.1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.35 (d, J = 2.3 Hz, 1H), 9.25 (d, J = 7.7 Hz, 1H), 8.99 (d, J = 2.2 Hz, 1H), 8.54 (s, 1H), 8.27 (s, 1H), 7.73 - 7.65 (m, 2H), 7.60 (dd, J = 9.0, 7.1 Hz, 1H), 7.55 (d, J = 7.7 Hz, 1H), 4.07 (s, 2H), 1.12 (s, 6H).

[0389] Example 3. 9-(1-(1-amino-2-methyl-1-oxopropan-2-yl)-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] This compound was prepared according to the procedure described in Example 1 using 2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanamide instead of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-ol, which gave the title compound as the TFA salt. C by LCMS 24 H 20 Cl 2 N 7 O 2 (M+H) + Calculated: m / z = 508.1 / 510.1; Found: 508.1 / 510.1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.41 (d, J = 2.3 Hz, 1H), 9.25 (d, J = 7.6 Hz, 1H), 9.08 (d, J = 2.2 Hz, 1H), 8.81 (s, 1H), 8.33 (s, 1H), 7.73 - 7.66 (m, 2H), 7.60 (dd, J = 9.0, 7.1 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H), 1.77 (s, 6H).

[0390] Example 4. 2-(2,6-dichlorophenyl)-9-(4-(morpholine-4-carbonyl)phenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] This compound was prepared according to the procedure described in Example 1 using morpholino(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone instead of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-ol, which gave the title compound as the TFA salt. C by LCMS 28 H 22 Cl 2 N 5O 3 (M+H) + Calculated: m / z = 546.1 / 548.1; Found: 546.0 / 548.0.

[0391] Example 5. 2-(2,6-dichlorophenyl)-9-(1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] A flask containing 9-bromo-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide (Intermediate 1, 70 mg, 0.16 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (63 mg, 0.19 mmol), tripotassium phosphate (102 mg, 0.48 mmol), and (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (12 mg, 0.016 mmol) was evacuated and backfilled with nitrogen three times before adding 1,4-dioxane (1 mL) and water (100 μL). The vial was sealed and heated to 80° C. for 30 min. After cooling to room temperature, the mixture was filtered through Celite and 2 Cl 2 After washing with ethyl acetate, the filtrate was concentrated under reduced pressure. The crude product was then 2 Cl 2 (1 mL) and TFA (1 mL) and stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, then redissolved in MeOH (1 mL) and saturated NaHCO 3 To a stirred solution of water (5 mL) was added. The resulting precipitate was filtered, collected, and dried under reduced pressure. A small amount of the resulting solid (10 mg) was further diluted with acetonitrile and purified by preparative LCMS (XBridge C18 column, gradient elution with acetonitrile / water containing 0.1% TFA, flow rate 60 mL / min) to give the title compound as the TFA salt. 20 H 13 Cl 2 N6 O (M+H) + Calculated: m / z = 423.1 / 425.1; Found: 423.3 / 425.3. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.38 (d, J = 2.3 Hz, 1H), 9.25 (d, J = 7.7 Hz, 1H), 9.02 (d, J = 2.3 Hz, 1H), 8.48 (s, 2H), 7.70 (d, J = 1.3 Hz, 1H), 7.68 (s, 1H), 7.60 (dd, J = 9.1, 7.1 Hz, 1H), 7.55 (d, J = 7.7 Hz, 1H).

[0392] Example 6. 9-(1-(1-cyanopropan-2-yl)-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] To a vial containing a mixture of 2-(2,6-dichlorophenyl)-9-(1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide (Example 5, 15 mg, 0.035 mmol) and cesium carbonate (35 mg, 0.106 mmol) as a solution in DMF (500 μL) was added 3-bromobutanenitrile (6 mg, 0.035 mmol). The vial was sealed and heated to 80° C. for 5 h. After cooling to room temperature, the mixture was diluted with acetonitrile and purified by preparative LCMS (XBridge C18 column, gradient elution with acetonitrile / water containing 0.1% TFA, flow rate 60 mL / min) to give the title compound as the TFA salt. C by LCMS 24 H 18 Cl 2 N 7 O (M+H) + Calculated: m / z = 490.1 / 492.1; Found: 490.1 / 492.0.

[0393] Example 7. 2-(2,6-dichlorophenyl)-9-(1-(2-hydroxybutyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] This compound was prepared according to the procedure described in Example 6, using 1-bromobutan-2-ol instead of 3-bromobutanenitrile, which gave the title compound as the TFA salt. 24 H 21 Cl 2 N 6 O 2 (M+H) + Calculated: m / z = 495.1 / 497.1; Found: 495.1 / 497.0. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.34 (d, J = 2.3 Hz, 1H), 9.24 (d, J = 7.7 Hz, 1H), 8.98 (d, J = 2.3 Hz, 1H), 8.58 (s, 1H), 8.26 (s, 1H), 7.70 (d, J = 1.3 Hz, 1H), 7.68 (s, 1H), 7.60 (dd, J = 9.0, 7.1 Hz, 1H), 7.55 (d, J = 7.7 Hz, 1H), 4.23 - 3.96 (m, 2H), 3.86 - 3.74 (m, 1H), 1.60 - 1.22 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H).

[0394] Example 8. 2-(2,6-dichlorophenyl)-9-(1-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] This compound was prepared according to the procedure described in Example 6, using 4-(bromomethyl)-4-fluorotetrahydro-2H-pyran instead of 3-bromobutanenitrile, which gave the title compound as the TFA salt. 26 H 22 Cl 2 FN 6 O 2 (M+H) + Calculated: m / z = 539.1 / 541.1; Found: 539.2 / 541.2.

[0395] Example 9. 9-(1-((5-cyanopyridin-3-yl)methyl)-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] To a vial containing a mixture of 2-(2,6-dichlorophenyl)-9-(1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide (10 mg, 0.024 mmol) and cesium carbonate (23 mg, 0.071 mmol) in DMF (500 μL) was added 5-(bromomethyl)nicotinonitrile (7 mg, 0.035 mmol). The reaction mixture was stirred at room temperature for 1 h. The mixture was then diluted with TFA and acetonitrile and purified by preparative LCMS (XBridge C18 column, gradient elution with acetonitrile / water containing 0.1% TFA, flow rate 60 mL / min) to give the title compound as the TFA salt. C by LCMS 27 H 17 Cl 2 N 8 O (M+H) + Calculated: m / z = 539.1 / 541.1; Found: 539.0 / 541.0.

[0396] Example 10. 9-(1-((2-cyanopyridin-4-yl)methyl)-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] This compound was prepared according to the procedure described in Example 9, using 4-(bromomethyl)picolinonitrile instead of 5-(bromomethyl)nicotinonitrile, which afforded the title compound as the TFA salt. 27 H 17 Cl 2 N 8 O (M+H) + Calculated: m / z = 539.1 / 541.1; Found: 539.0 / 541.0.

[0397] Example 11. 2-(2,6-dichlorophenyl)-9-(1-(pyrimidin-4-ylmethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] To a vial containing a mixture of 2-(2,6-dichlorophenyl)-9-(1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide (10 mg, 0.024 mmol) and cesium carbonate (23 mg, 0.071 mmol) as a solution in acetonitrile (500 μL) was added 4-(bromomethyl)pyrimidine hydrobromide (9 mg, 0.035 mmol). The vial was sealed and heated to 50° C. for 2 h. After cooling to room temperature, the mixture was diluted with acetonitrile and purified by preparative LCMS (XBridge C18 column, gradient elution with acetonitrile / water containing 0.1% TFA, flow rate 60 mL / min) to give the title compound as the TFA salt. C by LCMS 25 H 17 Cl 2 N 8 O (M+H) +Calculated: m / z = 515.1 / 517.1; Found: 515.0 / 517.0.

[0398] Example 12. 9-(1-(1-(2-cyanopyridin-4-yl)ethyl)-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] Step 1. 4-(1-hydroxyethyl)picolinonitrile [ka] Sodium borohydride (78 mg, 2.07 mmol) was added in one portion to a vial containing 4-acetylpicolinonitrile (151 mg, 1.03 mmol) as a solution in methanol (6.5 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 30 min. The reaction was then quenched by dropwise addition of water (2 mL) and stirred with CH 2 Cl 2 The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product obtained was used in the next step without further purification. 8 H 9 N 2 O (M+H) + Calculated: m / z = 149.1; Found: 149.0.

[0399] Step 2. 1-(2-Cyanopyridin-4-yl)ethyl methanesulfonate [ka] 4-(1-Hydroxyethyl)picolinonitrile (110 mg, 0.74 mmol) was dissolved in CH 2 Cl 2To the vial containing triethylamine (310 μL, 2.23 mmol) as a solution in 10 mL of ethyl acetate (7.4 mL) was added followed by stirring for 1 min and then addition of methanesulfonyl chloride (75 μL, 0.965 mmol). The reaction mixture was stirred at room temperature for 1 h, after which all volatiles were concentrated under reduced pressure. The resulting crude residue was purified by HPLC using HCl. 2 Cl 2 (3 mL) and saturated NaHCO 3 After dilution with aqueous solution (3 mL), 2 Cl 2 The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product obtained was used in the next step without further purification. 9 H 11 N 2 O 3 S (M+H) + Calculated: m / z = 227.0; Found: 227.1.

[0400] Step 3. 9-(1-(1-(2-cyanopyridin-4-yl)ethyl)-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide This compound was prepared according to the procedure described in Example 9, using 1-(2-cyanopyridin-4-yl)ethyl methanesulfonate instead of 5-(bromomethyl)nicotinonitrile, which afforded the title compound as the TFA salt. 28 H 19 Cl 2 N 8 O (M+H) + Calculated: m / z = 553.1 / 555.1; Found: 553.0 / 555.0.

[0401] Example 13. 2-(2,6-dichlorophenyl)-9-(4-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)phenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] Step 1. 4-(4-bromophenyl)-3,6-dihydro-2H-thiopyran [ka] A vial containing 1-bromo-4-iodobenzene (1.0 g, 3.53 mmol), 2-(3,6-dihydro-2H-thiopyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (839 mg, 3.71 mmol), potassium carbonate (1.47 g, 10.6 mmol), and (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (289 mg, 0.353 mmol) was evacuated and backfilled with nitrogen three times, and then 1,4-dioxane (10.6 mL) and water (5.3 mL) were added to the vial. The vial was sealed and heated to 80 °C for 1 h. After cooling to room temperature, the mixture was filtered through Celite and purified by HPLC. 2 Cl 2 After washing with hexanes, the filtrate was concentrated under reduced pressure. The resulting residue was purified by Biotage Isolera to give the desired product. 11 H 12 Calculated for BrOS: m / z = 271.0 / 273.0; Found: 270.9 / 273.0.

[0402] Step 2. 4-(4-Bromophenyl)-3,6-dihydro-2H-thiopyran 1,1-dioxide [ka] 4-(4-Bromophenyl)-3,6-dihydro-2H-thiopyran (580 mg, 2.27 mmol) was dissolved in CH 2 Cl 2 To a vial containing a solution in CH 2 Cl 2 (3.5 mL) was added at 0° C. The reaction mixture was stirred for 30 min, then saturated NaHCO 3 Quench with aqueous solution (5 mL) and CH 2 Cl2 (3x). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by Biotage Isolera to give the desired product. The corresponding hydrate C by LCMS was 11 H 11 Bro 2 S H 2 Calculated for O: m / z = 304.0 / 306.0; Found: 304.0 / 306.0.

[0403] Step 3. 4-(4-Bromophenyl)tetrahydro-2H-thiopyran 1,1-dioxide [ka] To a Parr vessel containing 4-(4-bromophenyl)-3,6-dihydro-2H-thiopyran 1,1-dioxide (346 mg, 1.20 mmol) as a suspension in EtOAc (12 mL) was added platinum(IV) oxide (27 mg, 0.12 mmol). The vessel was fitted to a Parr apparatus and the vessel was then evacuated and backfilled with nitrogen three times, then evacuated one more time and pressurized to 45 psi with hydrogen. The Parr vessel was then shaken at room temperature for 16 h. Upon completion, the reaction mixture was filtered through Celite, washed with MeOH and concentrated under reduced pressure. The resulting crude product was used in the next step without further purification. The corresponding hydrate C by LCMS was 11 H 13 Bro 2 S H 2 Calculated for O: m / z = 306.0 / 308.0; Found: 306.0 / 308.0.

[0404] Step 4. 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydro-2H-thiopyran 1,1-dioxide [ka] A vial containing 4-(4-bromophenyl)tetrahydro-2H-thiopyran 1,1-dioxide (50 mg, 0.173 mmol), bis(pinacolato)diboron (66 mg, 0.259 mmol), potassium acetate (34 mg, 0.346 mmol), and (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) dichloromethane adduct (14 mg, 0.017 mmol) was evacuated and backfilled with nitrogen three times, and then 1,4-dioxane (1.1 mL) was added to the vial. The vial was sealed and heated to 80° C. for 16 h. After cooling to room temperature, the mixture was filtered through Celite, washed with THF (5 mL), and the filtrate was concentrated under reduced pressure. The resulting crude product was used in the next step without further purification. The corresponding hydrate C by LCMS was 17 H 25 BO 4 S H 2 Calculated for O: m / z = 354.2; Found: 354.2.

[0405] Step 5. 2-(2,6-dichlorophenyl)-9-(4-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)phenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide A vial containing 9-bromo-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide (10 mg, 0.023 mmol), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydro-2H-thiopyran 1,1-dioxide (12 mg, 0.034 mmol), tripotassium phosphate (15 mg, 0.069 mmol), and (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (3 mg, 3.44 μmol) was evacuated and backfilled with nitrogen three times, and then 1,4-dioxane (1 mL) and water (250 μL) were added to the vial. The vial was sealed and heated to 80° C. for 30 min. After cooling to room temperature, the mixture was filtered through Celite and 2 Cl 2After washing with ethyl acetate, the filtrate was concentrated under reduced pressure. The residue was then dissolved in acetonitrile and purified by preparative LCMS (XBridge C18 column, gradient elution with acetonitrile / water containing 0.1% TFA, flow rate 60 mL / min) to give the title compound as a TFA salt. 28 H 23 Cl 2 N 4 O 3 S (M+H) + Calculated: m / z = 565.1 / 567.1; Found: 565.2 / 567.2.

[0406] Example 14. 2-(2,6-dichlorophenyl)-9-(4-(1,1-dioxidothiomorpholino)phenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] This compound was prepared following the procedure described in Example 13 (starting from step 4) using 4-(4-bromophenyl)tetrahydro-2H-thiopyran 1,1-dioxide instead of 4-(4-bromophenyl)thiomorpholine 1,1-dioxide, which afforded the title compound as the TFA salt. 27 H 22 Cl 2 N 5 O 3 S (M+H) + Calculated: m / z = 566.1 / 568.1; Found: 566.2 / 568.2.

[0407] Example 15. 2-(2,6-dichlorophenyl)-9-(1-(pyrimidin-2-ylmethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] This compound was prepared according to the procedure described in Example 9, using 2-(chloromethyl)pyrimidine instead of 5-(bromomethyl)nicotinonitrile, which afforded the title compound as the TFA salt. 25 H 17 Cl 2 N 8 O (M+H) + Calculated: m / z = 515.1 / 517.1; Found: 515.2 / 517.2.

[0408] Example 16. 9-(1-((6-cyanopyridin-2-yl)methyl)-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] This compound was prepared according to the procedure described in Example 9, using 6-(bromomethyl)picolinonitrile instead of 5-(bromomethyl)nicotinonitrile, which afforded the title compound as the TFA salt. 27 H 17 Cl 2 N 8 O (M+H) + Calculated: m / z = 539.1 / 541.1; Found: 539.2 / 541.2. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.36 (d, J = 2.2 Hz, 1H), 9.25 (d, J = 7.7 Hz, 1H), 9.03 (d, J = 2.3 Hz, 1H), 8.80 (s, 1H), 8.38 (s, 1H), 8.08 (t, J = 7.8 Hz, 1H), 8.01 (dd, J = 7.7, 1.1 Hz, 1H), 7.72 - 7.66 (m, 2H), 7.60 (dd, J = 9.1, 7.1 Hz, 1H), 7.56 (d, J = 7.7 Hz, 1H), 7.53 (dd, J = 8.0, 1.1 Hz, 1H), 5.58 (s, 2H).

[0409] Example 17. 9-(4-(4-acetylpiperazin-1-yl)phenyl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] Step 1. 2-(2,6-dichlorophenyl)-9-(4-(piperazin-1-yl)phenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] A flask containing 9-bromo-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide (Intermediate 1, 40 mg, 0.092 mmol), tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate (39 mg, 0.10 mmol), tripotassium phosphate (58 mg, 0.27 mmol), and (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (7 mg, 9.2 μmol) was evacuated and backfilled with nitrogen three times before adding 1,4-dioxane (1 mL) and water (250 μL). The vial was sealed and heated to 80° C. for 30 min. After cooling to room temperature, the mixture was filtered through Celite and 2 Cl 2 After washing with ethyl acetate, the filtrate was concentrated under reduced pressure. The crude product was then 2 Cl 2 (1 mL) and TFA (1 mL) and stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, then redissolved in MeOH (1 mL) and saturated NaHCO 3 A stirred solution of water (5 mL) was added. The resulting precipitate was filtered, collected, and dried under reduced pressure. The crude product was used in the next step without further purification. C by LCMS 27 H 23 Cl 2 N 6 O (M+H) +Calculated: m / z = 517.1 / 519.1; Found: 517.3 / 519.3.

[0410] Step 2. 9-(4-(4-acetylpiperazin-1-yl)phenyl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide To a vial containing 2-(2,6-dichlorophenyl)-9-(4-(piperazin-1-yl)phenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide (12 mg, 0.023 mmol) as a solution in DMF (500 μL) was added DIPEA (8 μL, 0.045 mmol) and acetic acid (2 μL, 0.035 mmol), followed by HATU (13 mg, 0.035 mmol). The reaction mixture was stirred at room temperature for 1 h, upon completion water was added and the resulting solid was collected by filtration and washed with water. The solid was then dissolved in TFA and purified by preparative LCMS (XBridge C18 column, gradient elution with acetonitrile / water containing 0.1% TFA, flow rate 60 mL / min) to give the title compound as the TFA salt. C by LCMS: 29 H 25 Cl 2 N 6 O 2 (M+H) + Calculated: m / z = 559.1 / 561.1; Found: 559.1 / 561.3.

[0411] Example 18. 2-(2,6-dichlorophenyl)-9-(4-(4-(2-hydroxyacetyl)piperazin-1-yl)phenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] This compound was prepared according to the procedure described in Example 17, substituting 2-hydroxyacetic acid for acetic acid in step 2, which afforded the title compound as the TFA salt. 29 H 25 Cl 2 N 6 O3 (M+H) + Calculated: m / z = 575.1 / 577.1; Found: 575.0 / 577.0.

[0412] Example 19. 9-(4-((4-acetylpiperazin-1-yl)methyl)phenyl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] Step 1. 2-(2,6-dichlorophenyl)-9-(4-(piperazin-1-ylmethyl)phenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] A vial containing 9-bromo-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide (Intermediate 1, 20 mg, 0.046 mmol), tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazine-1-carboxylate (20 mg, 0.05 mmol), tripotassium phosphate (29 mg, 0.14 mmol), and (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (4 mg, 4.6 μmol) was evacuated and backfilled with nitrogen three times, and then 1,4-dioxane (1 mL) and water (250 μL) were added to the vial. The vial was sealed and heated to 80° C. for 30 min. After cooling to room temperature, the mixture was filtered through Celite and 2 Cl 2 After washing with ethyl acetate, the filtrate was concentrated under reduced pressure. The crude product was then 2 Cl 2 (1 mL) and TFA (1 mL) and stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, then redissolved in MeOH (1 mL) and saturated NaHCO 3A stirred solution of water (5 mL) was added. The resulting precipitate was filtered, collected, and dried under reduced pressure. The crude product was used in the next step without further purification. C by LCMS 28 H 25 Cl 2 N 6 O (M+H) + Calculated: m / z = 531.1 / 533.1; Found: 531.3 / 533.3.

[0413] Step 2. 9-(4-((4-acetylpiperazin-1-yl)methyl)phenyl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide To a vial containing 2-(2,6-dichlorophenyl)-9-(4-(piperazin-1-ylmethyl)phenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide (12 mg, 0.023 mmol) as a solution in DMF (500 μL) was added DIPEA (8 μL, 0.045 mmol) and acetic acid (2 μL, 0.035 mmol), followed by HATU (13 mg, 0.035 mmol). The reaction mixture was stirred at room temperature for 1 h, upon completion water was added and the resulting solid was collected by filtration and washed with water. The solid was then dissolved in TFA and purified by preparative LCMS (XBridge C18 column, gradient elution with acetonitrile / water containing 0.1% TFA, flow rate 60 mL / min) to give the title compound as the TFA salt. C by LCMS: 30 H 27 Cl 2 N 6 O 2 (M+H) + Calculated: m / z = 573.2 / 575.2; Found: 573.1 / 575.1.

[0414] Example 20. 2-(2,6-dichlorophenyl)-9-(4-((4-(2-hydroxyacetyl)piperazin-1-yl)methyl)phenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] This compound was prepared according to the procedure described in Example 19, substituting 2-hydroxyacetic acid for acetic acid in step 2, which afforded the title compound as the TFA salt. 30 H 27 Cl 2 N 6 O 3 (M+H) + Calculated: m / z = 589.2 / 591.1; Found: 589.1 / 591.0.

[0415] Example 21. 2-(2,6-dichlorophenyl)-9-(4-(4-methylpiperazin-1-yl)phenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] 2-(2,6-dichlorophenyl)-9-(4-(piperazin-1-yl)phenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide (12 mg, 0.023 mmol) was dissolved in CH 2 Cl 2 To a vial containing the solution in 1 mL was added acetic acid (4 μL, 0.07 mmol) and aqueous formaldehyde (37 wt%, 17 μL, 0.23 mmol), followed by sodium triacetoxyborohydride (10 mg, 0.046 mmol) and stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and the crude residue was dissolved in acetonitrile and purified by preparative LCMS (XBridge C18 column, gradient elution with acetonitrile / water containing 0.1% TFA, flow rate 60 mL / min) to give the title compound as the TFA salt. C by LCMS 28 H 25 Cl 2 N 6 O (M+H) + Calculated: m / z = 531.2 / 533.1; Found: 531.0 / 533.0. 1 H NMR (400 MHz, DMSO-d 6) δ 9.38 (d, J = 2.4 Hz, 1H), 9.29 (d, J = 7.7 Hz, 1H), 8.98 (d, J = 2.4 Hz, 1H), 7.92 (d, J = 8.8 Hz, 2H), 7.73 - 7.66 (m, 2H), 7.65 - 7.51 (m, 2H), 7.18 (d, J = 8.9 Hz, 2H), 4.02 (d, J = 13.2 Hz, 2H), 3.55 (d, J = 12.0 Hz, 2H), 3.25 - 3.12 (m, 2H), 3.06 (t, J = 12.5 Hz, 2H), 2.89 (s, 3H).

[0416] Example 22. 9-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl)phenyl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] Step 1. 4-(3-Carbamoyl-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)benzoic acid [ka] A vial containing 9-bromo-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide (Intermediate 1, 20 mg, 0.046 mmol), (4-(tert-butoxycarbonyl)phenyl)boronic acid (11 mg, 0.05 mmol), tripotassium phosphate (29 mg, 0.138 mmol), and (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (4 mg, 4.6 μmol) was evacuated and backfilled with nitrogen three times, and then 1,4-dioxane (1 mL) and water (250 μL) were added to the vial. The vial was sealed and heated to 80° C. for 30 min. After cooling to room temperature, the mixture was filtered through Celite and purified by HPLC. 2 Cl 2After washing with ethyl acetate, the filtrate was concentrated under reduced pressure. The crude residue was then purified by 2 Cl 2 (1 mL) and TFA (1 mL) and stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, then dissolved in MeOH (1 mL) and saturated NaHCO 3 A stirred solution of water (10 mL) was added. The resulting precipitate was filtered, collected, and dried under reduced pressure. The crude product obtained was used in the next step without further purification. C by LCMS 24 H 15 Cl 2 N 4 O 3 (M+H) + Calculated: m / z = 477.1 / 479.0; Found: 477.2 / 479.2.

[0417] Step 2. 9-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl)phenyl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide HATU (18 mg, 0.047 mmol) was added to a vial containing 4-(3-carbamoyl-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridin-9-yl)benzoic acid (15 mg, 0.031 mmol), (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (6 mg, 0.047 mmol), DMF (500 μL), and DIPEA (22 μL, 0.126 mmol). The reaction mixture was stirred at room temperature for 1 h, upon completion water was added, and the resulting solid was collected by filtration and washed with water. The solid was then dissolved in TFA and purified by preparative LCMS (XBridge C18 column, gradient elution with acetonitrile / water containing 0.1% TFA, flow rate 60 mL / min) to give the title compound as a TFA salt. C by LCMS 29 H 22 Cl 2 N 5 O 3 (M+H) + Calculated: m / z = 558.1 / 560.1; Found: 558.3 / 560.3.

[0418] Example 23. 9-(1-(cyanomethyl)-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] This compound was prepared according to the procedure described in Example 1 using 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetonitrile instead of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-ol, which gave the title compound as the TFA salt. C by LCMS 22 H 14 Cl 2 N 7 O (M+H) + Calculated: m / z = 462.1 / 464.1; Found: 462.1 / 464.1.

[0419] Example 24. 2-(2,6-dichlorophenyl)-9-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] This compound was prepared according to the procedure described in Example 1 using 1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole instead of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-yl)ethan-1-ol, which gave the title compound as the TFA salt. 25 H 21 Cl 2 N 6 O 2 (M+H) +Calculated: m / z = 507.1 / 509.1; Found: 507.1 / 509.1.

[0420] Example 25. 9-(1-benzyl-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] This compound was prepared according to the procedure described in Example 1 using 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole instead of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-yl)ethan-1-ol, which gave the title compound as the TFA salt. 27 H 19 Cl 2 N 6 O (M+H) + Calculated: m / z = 513.1 / 515.1; Found: 513.2 / 515.1.

[0421] Example 26. 2-(2,6-dichlorophenyl)-9-(1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] This compound was prepared according to the procedure described in Example 1 using 1-(2-(methylsulfonyl)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole instead of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-yl)ethan-1-ol, which gave the title compound as the TFA salt. 23 H 19 Cl 2 N 6 O 3 S (M+H)+ Calculated: m / z = 529.1 / 531.1; Found: 529.1 / 531.1.

[0422] Example 27. 9-(1-(1-cyanoethyl)-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] This compound was prepared according to the procedure described in Example 1 using 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanenitrile instead of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-ol, which gave the title compound as the TFA salt. C by LCMS 23 H 16 Cl 2 N 7 O (M+H) + Calculated: m / z = 476.1 / 478.1; Found: 476.0 / 478.0.

[0423] Example 28. 2-(2,6-dichlorophenyl)-9-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] This compound was prepared according to the procedure described in Example 1 using 1-(2,2-difluoroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole instead of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-yl)ethan-1-ol, which gave the title compound as the TFA salt. 22 H 15 Cl 2 F 2N 6 O (M+H) + Calculated: m / z = 487.1 / 489.1; Found: 487.0 / 489.0.

[0424] Example 29. 2-(2,6-dichlorophenyl)-9-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] This compound was prepared according to the procedure described in Example 1 using 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine instead of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-ol, which gave the title compound as the TFA salt. C by LCMS 26 H 24 Cl 2 N 7 O (M+H) + Calculated: m / z = 520.1 / 522.1; Found: 520.1 / 522.1.

[0425] Example 30. 2-(2,6-dichlorophenyl)-9-(1-(1-hydroxy-2-methylpropan-2-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] This compound was prepared according to the procedure described in Example 1 using 2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-1-ol instead of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-ol, which gave the title compound as the TFA salt. C by LCMS24 H 21 Cl 2 N 6 O 2 (M+H) + Calculated: m / z = 495.1 / 497.1; Found: 495.1 / 497.1.

[0426] Example 31. 9-(1-(2-cyanopropan-2-yl)-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] This compound was prepared according to the procedure described in Example 1 using 2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanenitrile instead of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-ol, which gave the title compound as the TFA salt. C by LCMS 24 H 18 Cl 2 N 7 O (M+H) + Calculated: m / z = 490.1 / 492.1; Found: 490.1 / 492.1.

[0427] Example 32. 9-(1-Cyclopropyl-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] This compound was prepared according to the procedure described in Example 1 using 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole instead of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-yl)ethan-1-ol, which gave the title compound as the TFA salt. 23 H 17 Cl 2 N 6 O (M+H) + Calculated: m / z = 463.1 / 465.1; Found: 463.2 / 465.2.

[0428] Example 33. 2-(2,6-dichlorophenyl)-9-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] This compound was prepared according to the procedure described in Example 1 using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole instead of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-ol, which gave the title compound as the TFA salt. 22 H 14 Cl 2 F 3 N 6 O (M+H) + Calculated: m / z = 505.1 / 507.1; Found: 505.2 / 507.2.

[0429] Example 34. 2-(2,6-dichlorophenyl)-9-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] This compound was prepared according to the procedure described in Example 1 using N,N-dimethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-amine instead of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-ol, which gave the title compound as the TFA salt. C by LCMS 24 H 22 Cl 2 N 7 O (M+H) + Calculated: m / z = 494.1 / 496.1; Found: 494.0 / 496.0.

[0430] Example 35. 2-(2,6-dichlorophenyl)-9-(1-(1-methoxy-2-methylpropan-2-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] This compound was prepared according to the procedure described in Example 1 using 1-(1-methoxy-2-methylpropan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole instead of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-yl)ethan-1-ol, which gave the title compound as the TFA salt. 25 H 23 Cl 2 N 6 O 2 (M+H) + Calculated: m / z = 509.1 / 511.1; Found: 509.1 / 511.1.

[0431] Example 36. 2-(2,6-dichlorophenyl)-9-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] This compound was prepared according to the procedure described in Example 1 using 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol instead of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-ol, which gave the title compound as the TFA salt. 23 H 19 Cl 2 N 6 O 2 (M+H) + Calculated: m / z = 481.1 / 483.1; Found: 481.1 / 483.1.

[0432] Example 37. 2-(2,6-dichlorophenyl)-9-(1-(3-(dimethylamino)propyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] This compound was prepared according to the procedure described in Example 1 using N,N-dimethyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-1-amine instead of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-ol, which gave the title compound as the TFA salt. C by LCMS 25 H 24 Cl 2 N 7 O (M+H) +Calculated: m / z = 508.1 / 510.1; Found: 508.1 / 510.1.

[0433] Example 38. 2-(2,6-dichlorophenyl)-9-(1-methyl-1H-imidazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] This compound was prepared according to the procedure described in Example 1 using 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazole instead of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-ol, which gave the title compound as the TFA salt. 21 H 15 Cl 2 N 6 O (M+H) + Calculated: m / z = 437.1 / 439.1; Found: 436.9 / 438.9.

[0434] Example 39. 2-(2,6-dichlorophenyl)-9-(6-oxo-1,6-dihydropyridin-3-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] This compound was prepared according to the procedure described in Example 1 using 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one instead of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-ol, which gave the title compound as the TFA salt. 22 H 14 Cl 2 N 5 O 2 (M+H) +Calculated: m / z = 450.1 / 452.0; Found: 450.0 / 452.0.

[0435] Example 40. 2-(2,6-dichlorophenyl)-9-(5-isopropyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] This compound was prepared according to the procedure described in Example 1 using 5-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole instead of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-yl)ethan-1-ol, which gave the title compound as the TFA salt. 23 H 19 Cl 2 N 6 O (M+H) + Calculated: m / z = 465.1 / 467.1; Found: 465.1 / 467.1.

[0436] Example 41. 2-(2,6-dichlorophenyl)-9-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] This compound was prepared according to the procedure described in Example 1 using 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole instead of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-ol, which gave the title compound as the TFA salt. 23 H 17 Cl 2 N 6 O (M+H) +Calculated: m / z = 463.1 / 465.1; Found: 463.1 / 465.1.

[0437] Example 42. 2-(2,6-dichlorophenyl)-9-(5-(2-hydroxypropan-2-yl)pyridin-3-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] This compound was prepared according to the procedure described in Example 1 using 2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)propan-2-ol instead of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-ol, which gave the title compound as the TFA salt. C by LCMS 25 H 20 Cl 2 N 5 O 2 (M+H) + Calculated: m / z = 492.1 / 494.1; Found: 492.1 / 494.1.

[0438] Example 43. 2-(2,6-dichlorophenyl)-9-(2-(methylamino)pyrimidin-5-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] This compound was prepared according to the procedure described in Example 1 using N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine instead of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-ol, which gave the title compound as the TFA salt. 22 H 16 Cl 2 N 7 O (M+H) +Calculated: m / z = 464.1 / 466.1; Found: 464.1 / 466.1.

[0439] Example 44. 2-(2,6-dichlorophenyl)-9-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] This compound was prepared according to the procedure described in Example 1 using 1-(tetrahydrofuran-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole instead of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-yl)ethan-1-ol, which gave the title compound as the TFA salt. 24 H 19 Cl 2 N 6 O 2 (M+H) + Calculated: m / z = 493.1 / 495.1; Found: 493.0 / 495.0.

[0440] Example 45. 2-(2,6-dichlorophenyl)-9-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] This compound was prepared according to the procedure described in Example 1 using 4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)morpholine instead of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-ol, which gave the title compound as the TFA salt. C by LCMS 26 H 24 Cl 2 N7 O 2 (M+H) + Calculated: m / z = 536.1 / 538.1; Found: 536.0 / 538.0.

[0441] Example 46. 2-(2,6-dichlorophenyl)-9-(1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] This compound was prepared according to the procedure described in Example 1 using 1-methyl-4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)piperazine instead of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-ol, which gave the title compound as the TFA salt. C by LCMS 27 H 27 Cl 2 N 8 O (M+H) + Calculated: m / z = 549.2 / 551.2; Found: 549.1 / 551.1.

[0442] Example 47. 2-(2,6-dichlorophenyl)-9-(1-(3-hydroxypropyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] This compound was prepared according to the procedure described in Example 1 using 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-1-ol instead of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-ol, which gave the title compound as the TFA salt. C by LCMS 23 H 19 Cl 2 N 6 O 2 (M+H) + Calculated: m / z = 481.1 / 483.1; Found: 481.1 / 483.1.

[0443] Example 48. 9-(1-(2-cyanoethyl)-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] This compound was prepared according to the procedure described in Example 1 using 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanenitrile instead of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-ol, which gave the title compound as the TFA salt. C by LCMS 23 H 16 Cl 2 N 7 O (M+H) + Calculated: m / z = 476.1 / 478.1; Found: 476.1 / 478.1.

[0444] Example 49. 9-(1-(2-amino-2-oxoethyl)-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] This compound was prepared according to the procedure described in Example 1 using 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetamide instead of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-ol, which gave the title compound as the TFA salt. C by LCMS 22 H 16 Cl 2 N 7 O 2 (M+H) + Calculated: m / z = 480.1 / 482.1; Found: 480.1 / 482.1.

[0445] Example 50. 2-(2,6-dichlorophenyl)-9-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] This compound was prepared according to the procedure described in Example 1 using 2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)propan-2-ol instead of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-ol, which gave the title compound as the TFA salt. C by LCMS 25 H 20 Cl 2 N 5 O 2 (M+H) + Calculated: m / z = 492.1 / 494.1; Found: 492.1 / 494.1.

[0446] Example 51. 2-(2,6-dichlorophenyl)-9-(6-(2,2,2-trifluoroethyl)pyridin-3-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] This compound was prepared according to the procedure described in Example 1 using 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethyl)pyridine instead of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-ol, which gave the title compound as the TFA salt. 24 H 15 Cl 2 F 3 N 5 O (M+H) + Calculated: m / z = 516.1 / 518.1; Found: 516.0 / 518.0.

[0447] Example 52. 2-(2,6-dichlorophenyl)-9-(6-(methylcarbamoyl)pyridin-3-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] This compound was prepared according to the procedure described in Example 1 using N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide instead of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-ol, which gave the title compound as the TFA salt. 24 H 17 Cl 2 N 6 O 2 (M+H) + Calculated: m / z = 491.1 / 493.1; Found: 491.0 / 493.0.

[0448] Example 53. 2-(2,6-dichlorophenyl)-9-(4-hydroxycyclohex-1-en-1-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] This compound was prepared according to the procedure described in Example 1, using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-ol instead of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-ol, which gave the title compound as the TFA salt. 23 H 19 Cl 2 N 4 O 2 (M+H) + Calculated: m / z = 453.1 / 455.1; Found: 453.1 / 455.0.

[0449] Example 54. 2-(2,6-dichlorophenyl)-9-(5-hydroxypent-1-yn-1-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] A vial containing 9-bromo-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide (Intermediate 1, 8 mg, 0.018 mmol), copper(I) iodide (0.2 mg, 1 μmol), and bis(triphenylphosphine)palladium(II) dichloride (1 mg, 1.8 μmol) was evacuated and backfilled with nitrogen three times, and then THF (183 μL), triethylamine (13 μL, 0.092 mmol), and pent-4-yn-1-ol (5 μL, 0.055 mmol) were added to the vial. The vial was sealed and heated to 55° C. for 2 h. After cooling to room temperature, the mixture was filtered through a SiliaPrep SPE thiol cartridge (SPE-R51030B-06P) and washed with acetonitrile. The mixture was then diluted with acetonitrile and purified by preparative LCMS (XBridge C18 column, gradient elution with acetonitrile / water containing 0.1% TFA, flow rate 60 mL / min) to give the title compound as a TFA salt. 22 H 17 Cl 2 N 4 O 2 (M+H) + Calculated: m / z = 439.1 / 441.1; Found: 439.1 / 441.1.

[0450] Example 55. 2-(2,6-dichlorophenyl)-9-(2-hydroxypropan-2-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] To a vial containing 9-bromo-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide (16 mg, 0.037 mmol) as a solution in THF (370 μL) was added tert-butyllithium (1.7 M in pentane, 43 μL, 0.073 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 5 min, then quenched with acetone (100 μL), then diluted with water and extracted with EtOAc (3×). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was dissolved in acetonitrile and purified by preparative LCMS (XBridge C18 column, gradient elution with acetonitrile / water containing 0.1% TFA, flow rate 60 mL / min) to give the title compound as the TFA salt. C by LCMS: 20 H 17 Cl 2 N 4 O 2 (M+H) + Calculated: m / z = 415.1 / 417.1; Found: 415.1 / 417.1.

[0451] Example 56. 2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] To a vial containing 9-bromo-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide (16 mg, 0.037 mmol) as a solution in THF (370 μL) was added tert-butyllithium (1.7 M in pentane, 43 μL, 0.073 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 5 min, then saturated NH 4The mixture was quenched with aqueous Cl (100 μL) and extracted with EtOAc (3×). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was dissolved in acetonitrile and purified by preparative LCMS (XBridge C18 column, gradient elution with acetonitrile / water containing 0.1% TFA, flow rate 60 mL / min) to give the title compound as the TFA salt. 17 H 11 Cl 2 N 4 O (M+H) + Calculated: m / z = 357.0 / 359.0; Found: 357.0 / 359.1.

[0452] Example 57. 2-Methyl-9-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide [ka] Step 1. 9-Bromo-2-chloroimidazo[2,1-f][1,6]naphthyridine [ka] A solution of 3-bromo-1,6-naphthyridin-5-amine (Intermediate 1, Step 2, 300 mg, 1.34 mmol) in ethyl bromoacetate (3 mL, 27.1 mmol) was stirred at 60 °C for 3 h. The solution was then cooled to room temperature and the resulting solid was filtered and separated by HCl. 2 Cl 2 The solid was then dissolved in phosphoryl chloride (3 mL, 32.2 mmol) and heated to 100° C. for 3 h. Upon completion, the volatiles were removed under reduced pressure and the crude residue was purified by HCl. 2 Cl 2 Dissolved in saturated NaHCO 3 The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was used in the next step without further purification. 10 H 6 BrClN 3(M+H) + Calculated: m / z = 281.9 / 283.9; Found: 282.1 / 284.0.

[0453] Step 2. 9-Bromo-2-chloro-3-iodoimidazo[2,1-f][1,6]naphthyridine [ka] NIS (382 mg, 1.7 mmol) was added to a vial containing 9-bromo-2-chloroimidazo[2,1-f][1,6]naphthyridine (400 mg, 1.42 mmol) as a solution in acetonitrile (3 mL) and then warmed to 50° C. for 30 min. Upon completion, the reaction mixture was cooled to 0° C. and water (1 mL) was added. The resulting solid was collected by filtration, washed with hexanes, dried under reduced pressure and used directly in the next step without further purification. C by LCMS 10 H 5 BrClIN 3 (M+H) + Calculated: m / z = 407.8 / 409.8; Found: 407.7 / 409.8.

[0454] Step 3. Methyl 9-bromo-2-chloroimidazo[2,1-f][1,6]naphthyridine-3-carboxylate [ka] A vial containing 9-bromo-2-chloro-3-iodoimidazo[2,1-f][1,6]naphthyridine (200 mg, 0.490 mmol) and 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) (18 mg, 0.024 mmol) was evacuated and backfilled with a balloon of CO, and to the vial was added DMF (1 mL), MeOH (1 mL), and triethylamine (205 μL, 1.47 mmol). The reaction mixture was heated to 70° C. under atmospheric pressure of CO for 3 h. Upon completion, the reaction mixture was cooled to 0° C. and water (1 mL) was added. The resulting solid was collected by filtration, washed w...

Claims

1. Formula I: 【Chemical 1】 a compound of formula I or a pharmaceutically acceptable salt thereof, wherein R １ is H, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, C ３－１０ cycloalkyl-C １－３ alkylene, 4- to 10-membered heterocycloalkyl-alkylene, C １－３ alkylene, C ６－１０ aryl-C １－３ alkylene, 5- to 10-membered heteroaryl-alkylene, C １－３ alkylene, halo, D, CN, NO ２ , OR ａ１ , SR ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , OC(O)R ｂ１ , OC(O)NR ｃ１ R ｄ１ , NR ｃ１ R ｄ１ , NR ｃ１ C(O)R ｂ１ , NR ｃ１ C(O)OR ａ１ , NR ｃ１ C(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ )R ｂ１ , C(=NOR ａ１ )R ｂ１ , C(=NR ｅ１ ), NR ｃ１ R ｄ１ , NR ｃ１ C(=NR ｅ１ ), NR ｃ１ R ｄ１ , NR ｃ１ S(O)R ｂ１ , NR ｃ１ S(O) ２ R ｂ１ , NR ｃ１ S(O) ２ NR ｃ１ R ｄ１ , S(O)R ｂ１ , SONR ｃ１ R ｄ１ , S(O) ２ R ｂ１ , and S(O) ２ NR ｃ１ R ｄ１ is selected from, and said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, C ３－１０ cycloalkyl-C １－３ alkylene, 4- to 10-membered heterocycloalkyl-C １－３ alkylene, C ６－１０ aryl-C １－３ alkylene, and 5- to 10-membered heteroaryl-C １－３ alkylene are each optionally substituted by one, two, three, or four substituents independently selected from R １０ , and R ２ is H, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, C ３－１０ cycloalkyl-C １－３ alkylene, 4- to 10-membered heterocycloalkyl-alkylene, C １－３ alkylene, C ６－１０ aryl-C １－３ alkylene, 5- to 10-membered heteroaryl-alkylene, C １－３ alkylene, halo, D, CN, NO ２ , OR ａ２ , SR 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 , NR ｃ２ R ｄ２ , NR ｃ２ C(O)R ｂ２ , NR ｃ２ C(O)OR ａ２ , NR ｃ２ C(O)NR ｃ２ R ｄ２ , C(=NR ｅ２ ), R ｂ２ , C(=NOR ａ２ ), R ｂ２ , C(=NR ｅ２ ), NR ｃ２ R ｄ２ , NR ｃ２ C(=NR ｅ２ ), NR ｃ２ R ｄ２ , NR ｃ２ S(O)R ｂ２ , NR ｃ２ S(O) ２ R ｂ２ , NR ｃ２ S(O) ２ NR ｃ２ R ｄ２ , S(O)R ｂ２ , SONR ｃ２ R ｄ２ , S(O) ２ R ｂ２ , and S(O) ２ NR ｃ２ R ｄ２ is selected from, and said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, C ３－１０ cycloalkyl-C １－３ alkylene, 4- to 10-membered heterocycloalkyl-C １－３ alkylene, C ６－１０ aryl-C １－３ alkylene, and 5- to 10-membered heteroaryl-C １－３ alkylene are each optionally substituted by one, two, three, or four substituents independently selected from R ２０ , respectively. R ３ is H, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, C ３－１０ cycloalkyl-C １－３ alkylene, 4- to 10-membered heterocycloalkyl-alkylene, C １－３ alkylene, C ６－１０ aryl-C １－３ alkylene, 5- to 10-membered heteroaryl-alkylene, C １－３ alkylene, halo, D, CN, NO ２ , OR ａ３ , SR ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , OC(O)R ｂ３ , OC(O)NR ｃ３ R ｄ３ , NR ｃ３ R ｄ３ , NR ｃ３ C(O)R ｂ３ , NR ｃ３ C(O)OR ａ３ , NR ｃ３ C(O)NR ｃ３ R ｄ３ , C(=NR ｅ３ ), R ｂ３ , C(=NOR ａ３ ), R ｂ３ , C(=NR ｅ３ , NR ｃ３ R ｄ３ , NR ｃ３ , C(=NR ｅ３ , NR ｃ３ R ｄ３ , NR ｃ３ , SR(O) ｂ３ , NR ｃ３ , SR(O) ２ R ｂ３ , NR ｃ３ , SR(O) ２ , NR ｃ３ R ｄ３ , SR(O) ｂ３ , SONR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , and S(O) ２ NR ｃ３ R ｄ３ is selected from, and said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, C ３－１０ cycloalkyl-C １－３ alkylene, 4- to 10-membered heterocycloalkyl-C １－３ alkylene, C ６－１０ aryl-C １－３ alkylene, and 5- to 10-membered heteroaryl-C １－３ alkylene are each optionally substituted by one, two, three, or four substituents independently selected from R ３０ , and R ４ is H, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, C ３－１０ cycloalkyl-C １－３ alkylene, 4- to 10-membered heterocycloalkyl-alkylene, C １－３ alkylene, C ６－１０ aryl-C １－３ alkylene, 5- to 10-membered heteroaryl-alkylene, C １－３ alkylene, halo, D, CN, NO ２ , OR ａ４ , SR ａ４ , C(O)R ｂ４ , C(O)NR ｃ４ R ｄ４ , C(O)OR ａ４ , OC(O)R ｂ４ , OC(O)NR ｃ４ R ｄ４ , NR ｃ４ R ｄ４ , NR ｃ４ C(O)R ｂ４ , NR ｃ４ C(O)OR ａ４ , NR ｃ４ C(O)NR ｃ４ R ｄ４ , C(=NR ｅ４ )R ｂ４ , C(=NOR ａ４ )R ｂ４ , C(=NR ｅ４ ), NR ｃ４ R ｄ４ , NR ｃ４ C(=NR ｅ４ ), NR ｃ４ R ｄ４ , NR ｃ４ S(O)R ｂ４ , NR ｃ４ S(O) ２ R ｂ４ , NR ｃ４ S(O) ２ , NR ｃ４ R ｄ４ , S(O)R ｂ４ , SONR ｃ４ R ｄ４ , S(O) ２ R ｂ４ , and S(O) ２ NR ｃ４ R ｄ４ is selected from, and the C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, C ３－１０ cycloalkyl-C １－３ alkylene, 4- to 10-membered heterocycloalkyl-C １－３ alkylene, C ６－１０ aryl-C １－３ alkylene, and 5- to 10-membered heteroaryl-C １－３ alkylene are each optionally substituted by one, two, three, or four substituents independently selected from R ４０ , R ５ is H, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, C ３－１０ cycloalkyl-C １－３ alkylene, 4- to 10-membered heterocycloalkyl-alkylene, C １－３ alkylene, C ６－１０ aryl-C １－３ alkylene, 5- to 10-membered heteroaryl-alkylene, C １－３ alkylene, halo, D, CN, NO ２ , OR ａ５ , SR ａ５ , C(O)R ｂ５ , C(O)NR ｃ５ R ｄ５ , C(O)OR ａ５ , OC(O)R ｂ５ , OC(O)NR ｃ５ R ｄ５ , NR ｃ５ R ｄ５ , NR ｃ５ C(O)R ｂ５ , NR ｃ５ C(O)OR ａ５ , NR ｃ５ C(O)NR ｃ５ R ｄ５ , C(=NR ｅ５ ), R ｂ５ , C(=NOR ａ５ ), R ｂ５ , C(=NR ｅ５ ), NR ｃ５ R ｄ５ , NR ｃ５ , C(=NR ｅ５ ), NR ｃ５ R ｄ５ , NR ｃ５ , S(O)R ｂ５ , NR ｃ５ , S(O) ２ R ｂ５ , NR ｃ５ , S(O) ２ , NR ｃ５ R ｄ５ , S(O)R ｂ５ , SONR ｃ５ R ｄ５ , S(O) ２ R ｂ５ , and S(O) ２ NR ｃ５ R ｄ５ is selected from, and the C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, C ３－１０ cycloalkyl-C １－３ alkylene, 4- to 10-membered heterocycloalkyl-C １－３ alkylene, C ６－１０ aryl-C １－３ alkylene, and 5- to 10-membered heteroaryl-C １－３ alkylene are each optionally substituted by one, two, three, or four substituents independently selected from R ５０ , and Z is N or CR ６ and R ６ is H, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, C ３－１０ cycloalkyl-C １－３ alkylene, 4- to 10-membered heterocycloalkyl-alkylene, C １－３ alkylene, C ６－１０ aryl-C １－３ alkylene, 5- to 10-membered heteroaryl-alkylene, C １－３ alkylene, halo, D, CN, NO ２ , OR ａ６ , SR ａ６ , C(O)R ｂ６ , C(O)NR ｃ６ R ｄ６ , C(O)OR ａ６ , OC(O)R ｂ６ , OC(O)NR ｃ６ R ｄ６ , NR ｃ６ R ｄ６ , NR ｃ６ C(O)R ｂ６ , NR ｃ６ C(O)OR ａ６ , NR ｃ６ C(O)NR ｃ６ R ｄ６ , C(=NR ｅ６ ), R ｂ６ , C(=NOR ａ６ ), R ｂ６ , C(=NR ｅ６ ), NR ｃ６ R ｄ６ , NR ｃ６ , C(=NR ｅ６ ), NR ｃ６ R ｄ６ , NR ｃ６ , S(O)R ｂ６ , NR ｃ６ , S(O) ２ R ｂ６ , NR ｃ６ , S(O) ２ , NR ｃ６ R ｄ６ , S(O)R ｂ６ , SONR ｃ６ R ｄ６ , S(O) ２ R ｂ６ , and S(O) ２ NR ｃ６ R ｄ６ is selected from, and said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, C ３－１０ cycloalkyl-C １－３ alkylene, 4- to 10-membered heterocycloalkyl-C １－３ alkylene, C ６－１０ aryl-C １－３ alkylene, and 5- to 10-membered heteroaryl-C １－３ alkylene are each optionally substituted by one, two, three, or four substituents independently selected from R ６０ , Each R １０ is C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, C ３－１０ cycloalkyl-C １－３ alkylene, 4- to 10-membered heterocycloalkyl-C １－３ alkylene, C ６－１０ aryl-C １－３ alkylene, 5- to 10-membered heteroaryl-C １－３ alkylene, halo, D, CN, NO ２ , OR ａ１０ , SR ａ１０ , C(O)R ｂ１０ , C(O)NR ｃ１０ R ｄ１０ , C(O)OR ａ１０ , OC(O)R ｂ１０ , OC(O)NR ｃ１０ R ｄ１０ , NR ｃ１０ R ｄ１０ , NR ｃ１０ C(O)R ｂ１０ , NR ｃ１０ C(O)OR ａ１０ , NR ｃ１０ C(O)NR ｃ１０ R ｄ１０ , C(=NR ｅ１０ )R ｂ１０ , C(=NOR ａ１０ )R ｂ１０ , C(=NR ｅ１０ ), NR ｃ１０ R ｄ１０ , NR ｃ１０ C(=NR ｅ１０ ), NR ｃ１０ R ｄ１０ , NR ｃ１０ S(O)R ｂ１０ , NR ｃ１０ S(O) ２ R ｂ１０ , NR ｃ１０ S(O) ２ NR ｃ１０ R ｄ１０ , S(O)R ｂ１０ , S(O)NR ｃ１０ R ｄ１０ 、 S(O) ２ R ｂ１０ 、 and S(O) ２ NR ｃ１０ R ｄ１０ is independently selected from, said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, C ３－１０ cycloalkyl-C １－３ alkylene, 4- to 10-membered heterocycloalkyl-C １－３ alkylene, C ６－１０ aryl-C １－３ alkylene, and 5- to 10-membered heteroaryl-C １－３ alkylene are each optionally substituted by one, two, three, or four substituents independently selected from R １１ ; Each R １１ is C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, C ３－１０ cycloalkyl-C １－３ alkylene, 4- to 10-membered heterocycloalkyl-C １－３ alkylene, C ６－１０ aryl-C １－３ alkylene, 5- to 10-membered heteroaryl-C １－３ alkylene, halo, D, CN, OR ａ１１ , SR ａ１１ , C(O)R ｂ１１ , C(O)NR ｃ１１ R ｄ１１ , C(O)OR ａ１１ , NR ｃ１１ R ｄ１１ , NR ｃ１１ C(O)R ｂ１１ , NR ｃ１１ C(O)OR ａ１１ , NR ｃ１１ C(O)NR ｃ１１ R ｄ１１ , NR ｃ１１ S(O)R ｂ１１ , NR ｃ１１ S(O) ２ R ｂ１１ , NR ｃ１１ S(O) ２ NR ｃ１１ R ｄ１１ , S(O)R ｂ１１ , S(O)NR ｃ１１ R ｄ１１ , S(O) ２ R ｂ１１ , and S(O) ２ NR ｃ１１ R ｄ１１ is independently selected from, said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－３ alkylene, 4- to 10-membered heterocycloalkyl-C １－３ alkylene, C ６－１０ aryl-C １－３ alkylene, and 5- to 10-membered heteroaryl-C １－３ each alkylene is optionally substituted by one, two, three, or four substituents independently selected from R １２ and is optionally substituted by one, two, three, or four substituents independently selected from R Each R １２ is 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- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, halo, D, CN, OR ａ１２ , SR ａ１２ , C(O)R ｂ１２ , C(O)NR ｃ１２ R ｄ１２ , C(O)OR ａ１２ , NR ｃ１２ R ｄ１２ , NR ｃ１２ C(O)R ｂ１２ , NR ｃ１２ C(O)OR ａ１２ , NR ｃ１２ C(O)NR ｃ１２ R ｄ１２ , NR ｃ１２ , S(O)R ｂ１２ , NR ｃ１２ , S(O) ２ R ｂ１２ , NR ｃ１２ , S(O) ２ , NR ｃ１２ R ｄ１２ , S(O)R ｂ１２ , S(O)NR ｃ１２ R ｄ１２ , S(O) ２ R ｂ１２ , and S(O) ２ , NR ｃ１２ R ｄ１２ is independently selected from, and each of the C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－６ cycloalkyl, C ６－１０ aryl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl is optionally substituted with one, two, three, or four substituents independently selected from R ｇ , Each R ２０ is C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, C ３－１０ cycloalkyl-C １－３ alkylene, 4- to 10-membered heterocycloalkyl-C １－３ alkylene, C ６－１０ aryl-C １－３ alkylene, 5- to 10-membered heteroaryl-C １－３ alkylene, halo, D, CN, NO ２ , OR ａ２０ , SR ａ２０ , C(O)R ｂ２０ , C(O)NR ｃ２０ R ｄ２０ , C(O)OR ａ２０ , OC(O)R ｂ２０ , OC(O)NR ｃ２０ R ｄ２０ , NR ｃ２０ R ｄ２０ , NR ｃ２０ C(O)R ｂ２０ , NR ｃ２０ C(O)OR ａ２０ , NR ｃ２０ C(O)NR ｃ２０ R ｄ２０ , C(=NR ｅ２０ )R ｂ２０ , C(=NOR ａ２０ )R ｂ２０ , C(=NR ｅ２０ )NR ｃ２０ R ｄ２０ , NR ｃ２０ C(=NR ｅ２０ )NR ｃ２０ R ｄ２０ , NR ｃ２０ S(O)R ｂ２０ , NR ｃ２０ S(O) ２ R ｂ２０ , NR ｃ２０ S(O) ２ NR ｃ２０ R ｄ２０ , S(O)R ｂ２０ , S(O)NR ｃ２０ R ｄ２０ 、 S(O) ２ R ｂ２０ 、 and S(O) ２ NR ｃ２０ R ｄ２０ is independently selected from, said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, C ３－１０ cycloalkyl-C １－３ alkylene, 4- to 10-membered heterocycloalkyl-C １－３ alkylene, C ６－１０ aryl-C １－３ alkylene, and 5- to 10-membered heteroaryl-C １－３ alkylene are each optionally substituted by one, two, three, or four substituents independently selected from R ２１ and, Each R ２１ is C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, C ３－１０ cycloalkyl-C １－３ alkylene, 4- to 10-membered heterocycloalkyl-C １－３ alkylene, C ６－１０ aryl-C １－３ alkylene, 5- to 10-membered heteroaryl-C １－３ alkylene, halo, D, CN, OR ａ２１ , SR ａ２１ , C(O)R ｂ２１ , C(O)NR ｃ２１ R ｄ２１ , C(O)OR ａ２１ , NR ｃ２１ R ｄ２１ , NR ｃ２１ C(O)R ｂ２１ , NR ｃ２１ C(O)OR ａ２１ , NR ｃ２１ C(O)NR ｃ２１ R ｄ２１ , NR ｃ２１ S(O)R ｂ２１ , NR ｃ２１ S(O) ２ R ｂ２１ , NR ｃ２１ S(O) ２ NR ｃ２１ R ｄ２１ , S(O)R ｂ２１ , S(O)NR ｃ２１ R ｄ２１ , S(O) ２ R ｂ２１ , and S(O) ２ NR ｃ２１ R ｄ２１ is independently selected from, said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－３ alkylene, 4- to 10-membered heterocycloalkyl-C １－３ alkylene, C ６－１０ aryl-C １－３ alkylene, and 5- to 10-membered heteroaryl-C １－３ each alkylene is optionally substituted by one, two, three, or four substituents independently selected from R ２２ and is optionally substituted by one, two, three, or four substituents independently selected from R Each R ２２ is C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ３－６ cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, halo, D, CN, OR ａ２２ , SR ａ２２ , C(O)R ｂ２２ , C(O)NR ｃ２２ R ｄ２２ , C(O)OR ａ２２ , NR ｃ２２ R ｄ２２ , NR ｃ２２ C(O)R ｂ２２ , NR ｃ２２ C(O)OR ａ２２ , NR ｃ２２ C(O)NR ｃ２２ R ｄ２２ , NR ｃ２２ S(O)R ｂ２２ , NR ｃ２２ S(O) ２ R ｂ２２ , NR ｃ２２ S(O) ２ NR ｃ２２ R ｄ２２ , S(O)R ｂ２２ , S(O)NR ｃ２２ R ｄ２２ , S(O) ２ R ｂ２２ , and S(O) ２ NR ｃ２２ R ｄ２２ is independently selected from, and each of said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－６ cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl is optionally substituted with one, two, three, or four substituents independently selected from R ｇ . Each R ３０ is C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, C ３－１０ cycloalkyl-C １－３ alkylene, 4- to 10-membered heterocycloalkyl-C １－３ alkylene, C ６－１０ aryl-C １－３ alkylene, 5- to 10-membered heteroaryl-C １－３ alkylene, halo, D, CN, NO ２ , OR ａ３０ , SR ａ３０ , C(O)R ｂ３０ , C(O)NR ｃ３０ R ｄ３０ , C(O)OR ａ３０ , OC(O)R ｂ３０ , OC(O)NR ｃ３０ R ｄ３０ , NR ｃ３０ R ｄ３０ , NR ｃ３０ C(O)R ｂ３０ , NR ｃ３０ C(O)OR ａ３０ , NR ｃ３０ C(O)NR ｃ３０ R ｄ３０ , C(=NR ｅ３０ )R ｂ３０ , C(=NOR ａ３０ )R ｂ３０ , C(=NR ｅ３０ )NR ｃ３０ R ｄ３０ , NR ｃ３０ C(=NR ｅ３０ )NR ｃ３０ R ｄ３０ , NR ｃ３０ S(O)R ｂ３０ , NR ｃ３０ S(O) ２ R ｂ３０ , NR ｃ３０ S(O) ２ NR ｃ３０ R ｄ３０ , S(O)R ｂ３０ , S(O)NR ｃ３０ R ｄ３０ 、 S(O) ２ R ｂ３０ 、 and S(O) ２ NR ｃ３０ R ｄ３０ is independently selected from, said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, C ３－１０ cycloalkyl-C １－３ alkylene, 4- to 10-membered heterocycloalkyl-C １－３ alkylene, C ６－１０ aryl-C １－３ alkylene, and 5- to 10-membered heteroaryl-C １－３ alkylene are each optionally substituted by one, two, three, or four substituents independently selected from R ３１ and, Each R ３１ is C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, C ３－１０ cycloalkyl-C １－３ alkylene, 4- to 10-membered heterocycloalkyl-C １－３ alkylene, C ６－１０ aryl-C １－３ alkylene, 5- to 10-membered heteroaryl-C １－３ alkylene, halo, D, CN, OR ａ３１ , SR ａ３１ , C(O)R ｂ３１ , C(O)NR ｃ３１ R ｄ３１ , C(O)OR ａ３１ , NR ｃ３１ R ｄ３１ , NR ｃ３１ C(O)R ｂ３１ , NR ｃ３１ C(O)OR ａ３１ , NR ｃ３１ C(O)NR ｃ３１ R ｄ３１ , NR ｃ３１ S(O)R ｂ３１ , NR ｃ３１ S(O) ２ R ｂ３１ , NR ｃ３１ S(O) ２ , NR ｃ３１ R ｄ３１ , S(O)R ｂ３１ , S(O)NR ｃ３１ R ｄ３１ , S(O) ２ R ｂ３１ , and S(O) ２ , NR ｃ３１ R ｄ３１ is independently selected from, said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－３ alkylene, 4- to 10-membered heterocycloalkyl-C １－３ alkylene, C ６－１０ aryl-C １－３ alkylene, and 5- to 10-membered heteroaryl-C １－３ each alkylene is optionally substituted by one, two, three, or four substituents independently selected from R ３２ and is optionally substituted by one, two, three, or four substituents independently selected from R Each R ３２ is 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- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, halo, D, CN, OR ａ３２ , SR ａ３２ , C(O)R ｂ３２ , C(O)NR ｃ３２ R ｄ３２ , C(O)OR ａ３２ , NR ｃ３２ R ｄ３２ , NR ｃ３２ C(O)R ｂ３２ , NR ｃ３２ C(O)OR ａ３２ , NR ｃ３２ C(O)NR ｃ３２ R ｄ３２ , NR ｃ３２ , S(O)R ｂ３２ , NR ｃ３２ , S(O) ２ R ｂ３２ , NR ｃ３２ , S(O) ２ , NR ｃ３２ R ｄ３２ , S(O)R ｂ３２ , S(O)NR ｃ３２ R ｄ３２ , S(O) ２ R ｂ３２ , and S(O) ２ , NR ｃ３２ R ｄ３２ is independently selected from, and each of the C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－６ cycloalkyl, C ６－１０ aryl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl is optionally substituted with one, two, three, or four substituents independently selected from R ｇ , Each R ４０ is C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, C ３－１０ cycloalkyl-C １－３ alkylene, 4- to 10-membered heterocycloalkyl-C １－３ alkylene, C ６－１０ aryl-C １－３ alkylene, 5- to 10-membered heteroaryl-C １－３ alkylene, halo, D, CN, NO ２ , OR ａ４０ , SR ａ４０ , C(O)R ｂ４０ , C(O)NR ｃ４０ R ｄ４０ , C(O)OR ａ４０ , OC(O)R ｂ４０ , OC(O)NR ｃ４０ R ｄ４０ , NR ｃ４０ R ｄ４０ , NR ｃ４０ C(O)R ｂ４０ , NR ｃ４０ C(O)OR ａ４０ , NR ｃ４０ C(O)NR ｃ４０ R ｄ４０ , C(=NR ｅ４０ )R ｂ４０ , C(=NOR ａ４０ )R ｂ４０ , C(=NR ｅ４０ ), NR ｃ４０ R ｄ４０ , NR ｃ４０ C(=NR ｅ４０ ), NR ｃ４０ R ｄ４０ , NR ｃ４０ S(O)R ｂ４０ , NR ｃ４０ S(O) ２ R ｂ４０ , NR ｃ４０ S(O) ２ NR ｃ４０ R ｄ４０ , S(O)R ｂ４０ , S(O)NR ｃ４０ R ｄ４０ 、 S(O) ２ R ｂ４０ 、 and S(O) ２ NR ｃ４０ R ｄ４０ is independently selected from, said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, C ３－１０ cycloalkyl-C １－３ alkylene, 4- to 10-membered heterocycloalkyl-C １－３ alkylene, C ６－１０ aryl-C １－３ alkylene, and 5- to 10-membered heteroaryl-C １－３ alkylene are each optionally substituted by one, two, three, or four substituents independently selected from R ４１ ; Each R ４１ is C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, C ３－１０ cycloalkyl-C １－３ alkylene, 4- to 10-membered heterocycloalkyl-C １－３ alkylene, C ６－１０ aryl-C １－３ alkylene, 5- to 10-membered heteroaryl-C １－３ alkylene, halo, D, CN, OR ａ４１ , SR ａ４１ , C(O)R ｂ４１ , C(O)NR ｃ４１ R ｄ４１ , C(O)OR ａ４１ , NR ｃ４１ R ｄ４１ , NR ｃ４１ C(O)R ｂ４１ , NR ｃ４１ C(O)OR ａ４１ , NR ｃ４１ C(O)NR ｃ４１ R ｄ４１ , NR ｃ４１ S(O)R ｂ４１ , NR ｃ４１ S(O) ２ R ｂ４１ , NR ｃ４１ S(O) ２ NR ｃ４１ R ｄ４１ , S(O)R ｂ４１ , S(O)NR ｃ４１ R ｄ４１ , S(O) ２ R ｂ４１ , and S(O) ２ NR ｃ４１ R ｄ４１ is independently selected from, said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－３ alkylene, 4- to 10-membered heterocycloalkyl-C １－３ alkylene, C ６－１０ aryl-C １－３ alkylene, and 5- to 10-membered heteroaryl-C １－３ Each alkylene is optionally substituted by one, two, three, or four substituents independently selected from R ４２ and is optionally substituted by one, two, three, or four substituents independently selected from R Each R ４２ is 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- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, halo, D, CN, OR ａ４２ , SR ａ４２ , C(O)R ｂ４２ , C(O)NR ｃ４２ R ｄ４２ , C(O)OR ａ４２ , NR ｃ４２ R ｄ４２ , NR ｃ４２ C(O)R ｂ４２ , NR ｃ４２ C(O)OR ａ４２ , NR ｃ４２ C(O)NR ｃ４２ R ｄ４２ , NR ｃ４２ , S(O)R ｂ４２ , NR ｃ４２ , S(O) ２ R ｂ４２ , NR ｃ４２ , S(O) ２ , NR ｃ４２ R ｄ４２ , S(O)R ｂ４２ , S(O)NR ｃ４２ R ｄ４２ , S(O) ２ R ｂ４２ , and S(O) ２ , NR ｃ４２ R ｄ４２ is independently selected from, and each of said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－６ cycloalkyl, C ６－１０ aryl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl is optionally substituted with one, two, three, or four substituents independently selected from R ｇ . Each R ５０ is C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, C ３－１０ cycloalkyl-C １－３ alkylene, 4- to 10-membered heterocycloalkyl-C １－３ alkylene, C ６－１０ aryl-C １－３ alkylene, 5- to 10-membered heteroaryl-C １－３ alkylene, halo, D, CN, NO ２ , OR ａ５０ , SR ａ５０ , C(O)R ｂ５０ , C(O)NR ｃ５０ R ｄ５０ , C(O)OR ａ５０ , OC(O)R ｂ５０ , OC(O)NR ｃ５０ R ｄ５０ , NR ｃ５０ R ｄ５０ , NR ｃ５０ C(O)R ｂ５０ , NR ｃ５０ C(O)OR ａ５０ , NR ｃ５０ C(O)NR ｃ５０ R ｄ５０ , C(=NR ｅ５０ ), R ｂ５０ , C(=NOR ａ５０ ), R ｂ５０ , C(=NR ｅ５０ ), NR ｃ５０ R ｄ５０ , NR ｃ５０ C(=NR ｅ５０ ), NR ｃ５０ R ｄ５０ , NR ｃ５０ S(O)R ｂ５０ , NR ｃ５０ S(O) ２ R ｂ５０ , NR ｃ５０ S(O) ２ NR ｃ５０ R ｄ５０ , S(O)R ｂ５０ , S(O)NR ｃ５０ R ｄ５０ 、 S(O) ２ R ｂ５０ 、 and S(O) ２ NR ｃ５０ R ｄ５０ is independently selected from, said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, C ３－１０ cycloalkyl-C １－３ alkylene, 4- to 10-membered heterocycloalkyl-C １－３ alkylene, C ６－１０ aryl-C １－３ alkylene, and 5- to 10-membered heteroaryl-C １－３ alkylene are each optionally substituted by one, two, three, or four substituents independently selected from R ５１ and, Each R ５１ is C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, C ３－１０ cycloalkyl-C １－３ alkylene, 4- to 10-membered heterocycloalkyl-C １－３ alkylene, C ６－１０ aryl-C １－３ alkylene, 5- to 10-membered heteroaryl-C １－３ alkylene, halo, D, CN, OR ａ５１ , SR ａ５１ , C(O)R ｂ５１ , C(O)NR ｃ５１ R ｄ５１ , C(O)OR ａ５１ , NR ｃ５１ R ｄ５１ , NR ｃ５１ C(O)R ｂ５１ , NR ｃ５１ C(O)OR ａ５１ , NR ｃ５１ C(O)NR ｃ５１ R ｄ５１ , NR ｃ５１ S(O)R ｂ５１ , NR ｃ５１ S(O) ２ R ｂ５１ , NR ｃ５１ S(O) ２ NR ｃ５１ R ｄ５１ , S(O)R ｂ５１ , S(O)NR ｃ５１ R ｄ５１ , S(O) ２ R ｂ５１ , and S(O) ２ NR ｃ５１ R ｄ５１ is independently selected from, said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－３ alkylene, 4- to 10-membered heterocycloalkyl-C １－３ alkylene, C ６－１０ aryl-C １－３ alkylene, and 5- to 10-membered heteroaryl-C １－３ each alkylene is optionally substituted by one, two, three, or four substituents independently selected from R ５２ and is optionally substituted by one, two, three, or four substituents independently selected from R Each R ５２ is 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- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, halo, D, CN, OR ａ５２ , SR ａ５２ , C(O)R ｂ５２ , C(O)NR ｃ５２ R ｄ５２ , C(O)OR ａ５２ , NR ｃ５２ R ｄ５２ , NR ｃ５２ C(O)R ｂ５２ , NR ｃ５２ C(O)OR ａ５２ , NR ｃ５２ C(O)NR ｃ５２ R ｄ５２ , NR ｃ５２ S(O)R ｂ５２ , NR ｃ５２ , S(O) ２ R ｂ５２ , NR ｃ５２ , S(O) ２ , NR ｃ５２ R ｄ５２ , S(O)R ｂ５２ , S(O)NR ｃ５２ R ｄ５２ , S(O) ２ R ｂ５２ , and S(O) ２ , NR ｃ５２ R ｄ５２ is independently selected from, and each of the C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－６ cycloalkyl, C ６－１０ aryl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl is optionally substituted with one, two, three, or four substituents independently selected from R ｇ . Each R ６０ is C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, C ３－１０ cycloalkyl-C １－３ alkylene, 4- to 10-membered heterocycloalkyl-C １－３ alkylene, C ６－１０ aryl-C １－３ alkylene, 5- to 10-membered heteroaryl-C １－３ alkylene, halo, D, CN, NO ２ , OR ａ６０ , SR ａ６０ , C(O)R ｂ６０ , C(O)NR ｃ６０ R ｄ６０ , C(O)OR ａ６０ , OC(O)R ｂ６０ , OC(O)NR ｃ６０ R ｄ６０ , NR ｃ６０ R ｄ６０ , NR ｃ６０ C(O)R ｂ６０ , NR ｃ６０ C(O)OR ａ６０ , NR ｃ６０ C(O)NR ｃ６０ R ｄ６０ , C(=NR ｅ６０ )R ｂ６０ , C(=NOR ａ６０ )R ｂ６０ , C(=NR ｅ６０ )NR ｃ６０ R ｄ６０ , NR ｃ６０ C(=NR ｅ６０ )NR ｃ６０ R ｄ６０ , NR ｃ６０ S(O)R ｂ６０ , NR ｃ６０ S(O) ２ R ｂ６０ , NR ｃ６０ S(O) ２ NR ｃ６０ R ｄ６０ , S(O)R ｂ６０ , S(O)NR ｃ６０ R ｄ６０ 、 S(O) ２ R ｂ６０ 、 and S(O) ２ NR ｃ６０ R ｄ６０ is independently selected from, said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, C ３－１０ cycloalkyl-C １－３ alkylene, 4- to 10-membered heterocycloalkyl-C １－３ alkylene, C ６－１０ aryl-C １－３ alkylene, and 5- to 10-membered heteroaryl-C １－３ alkylene are each optionally substituted by one, two, three, or four substituents independently selected from R ６１ ; Each R ６１ is C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, C ３－１０ cycloalkyl-C １－３ alkylene, 4- to 10-membered heterocycloalkyl-C １－３ alkylene, C ６－１０ aryl-C １－３ alkylene, 5- to 10-membered heteroaryl-C １－３ alkylene, halo, D, CN, OR ａ６１ , SR ａ６１ , C(O)R ｂ６１ , C(O)NR ｃ６１ R ｄ６１ , C(O)OR ａ６１ , NR ｃ６１ R ｄ６１ , NR ｃ６１ C(O)R ｂ６１ , NR ｃ６１ C(O)OR ａ６１ , NR ｃ６１ C(O)NR ｃ６１ R ｄ６１ , NR ｃ６１ S(O)R ｂ６１ , NR ｃ６１ S(O) ２ R ｂ６１ , NR ｃ６１ S(O) ２ NR ｃ６１ R ｄ６１ , S(O)R ｂ６１ , S(O)NR ｃ６１ R ｄ６１ , S(O) ２ R ｂ６１ , and S(O) ２ NR ｃ６１ R ｄ６１ is independently selected from, said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－３ alkylene, 4- to 10-membered heterocycloalkyl-C １－３ alkylene, C ６－１０ aryl-C １－３ alkylene, and 5- to 10-membered heteroaryl-C １－３ each alkylene is optionally substituted by one, two, three, or four substituents independently selected from R ６２ and Each R ６２ is 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- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, halo, D, CN, OR ａ６２ , SR ａ６２ , C(O)R ｂ６２ , C(O)NR ｃ６２ R ｄ６２ , C(O)OR ａ６２ , NR ｃ６２ R ｄ６２ , NR ｃ６２ C(O)R ｂ６２ , NR ｃ６２ C(O)OR ａ６２ , NR ｃ６２ C(O)NR ｃ６２ R ｄ６２ , NR ｃ６２ S(O)R ｂ６２ , NR ｃ６２ S(O) ２ R ｂ６２ , NR ｃ６２ S(O) ２ NR ｃ６２ R ｄ６２ , S(O)R ｂ６２ , S(O)NR ｃ６２ R ｄ６２ , S(O) ２ R ｂ６２ , and S(O) ２ NR ｃ６２ R ｄ６２ is independently selected from, and each of said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－６ cycloalkyl, C ６－１０ aryl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl is optionally substituted with one, two, three, or four substituents independently selected from R ｇ . Each R ａ１ 、R ｂ１ 、R ｃ１ 、and R ｄ１ is independently selected from H, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl, and said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl are each optionally substituted by one, two, three, or four substituents independently selected from R １０ and or any R attached to the same N atom ｃ１ and R ｄ１ are, together with the N atom to which they are attached, optionally substituted by one, two, three, or four substituents independently selected from １０ form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by substituents Each R ｅ１ is independently selected from H, CN, C １－６ alkyl, C １－６ haloalkyl, C １－６ alkylthio, C １－６ alkylsulfonyl, C １－６ alkylcarbonyl, C １－６ alkylaminosulfonyl, carbamyl, C １－６ alkylcarbamyl, di(C １－６ alkyl)carbamyl, aminosulfonyl, C １－６ alkylaminosulfonyl, and di(C １－６ alkyl)aminosulfonyl, Each R ａ２ 、R ｂ２ 、R ｃ２ 、and R ｄ２ is independently selected from H, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl, and said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl are each optionally substituted by one, two, three, or four substituents independently selected from R ２０ , or any R attached to the same N atom ｃ２ and R ｄ２ are, together with the N atom to which they are attached, optionally substituted by one, two, or three substituents independently selected from ２０ a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by substituents Each R ｅ２ is independently selected from H, CN, C １－６ alkyl, C １－６ haloalkyl, C １－６ alkylthio, C １－６ alkylsulfonyl, C １－６ alkylcarbonyl, C １－６ alkylaminosulfonyl, carbamyl, C １－６ alkylcarbamyl, di(C １－６ alkyl)carbamyl, aminosulfonyl, C １－６ alkylaminosulfonyl, and di(C １－６ alkyl)aminosulfonyl, Each R ａ３ and R ｂ３ and R ｃ３ and R ｄ３ are independently selected from H, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl, and said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl are each optionally substituted by one, two, three, or four substituents independently selected from R ３０ ; or any R attached to the same N atom ｃ３ and R ｄ３ are, together with the N atom to which they are attached, optionally substituted by one, two, three, or four substituents independently selected from ３０ form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by substituents Each R ｅ３ is independently selected from H, CN, C １－６ alkyl, C １－６ haloalkyl, C １－６ alkylthio, C １－６ alkylsulfonyl, C １－６ alkylcarbonyl, C １－６ alkylaminosulfonyl, carbamyl, C １－６ alkylcarbamyl, di(C １－６ alkyl)carbamyl, aminosulfonyl, C １－６ alkylaminosulfonyl, and di(C １－６ alkyl)aminosulfonyl, Each R ａ４ 、R ｂ４ 、R ｃ４ 、and R ｄ４ is independently selected from H, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl, and said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl are each optionally substituted by one, two, three, or four substituents independently selected from R ４０ ; or any R attached to the same N atom ｃ４ and R ｄ４ are, together with the N atom to which they are attached, optionally substituted by one, two, three, or four substituents independently selected from ４０ form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by substituents Each R ｅ４ is independently selected from H, CN, C １－６ alkyl, C １－６ haloalkyl, C １－６ alkylthio, C １－６ alkylsulfonyl, C １－６ alkylcarbonyl, C １－６ alkylaminosulfonyl, carbamyl, C １－６ alkylcarbamyl, di(C １－６ alkyl)carbamyl, aminosulfonyl, C １－６ alkylaminosulfonyl, and di(C １－６ alkyl)aminosulfonyl, Each R ａ５ 、R ｂ５ 、R ｃ５ 、and R ｄ５ is independently selected from H, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl, and said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl are each optionally substituted by one, two, three, or four substituents independently selected from R ５０ ; or any R attached to the same N atom ｃ５ and R ｄ５ are, together with the N atom to which they are attached, optionally substituted by one, two, three, or four substituents independently selected from ５０ a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by Each R ｅ５ is independently selected from H, CN, C １－６ alkyl, C １－６ haloalkyl, C １－６ alkylthio, C １－６ alkylsulfonyl, C １－６ alkylcarbonyl, C １－６ alkylaminosulfonyl, carbamyl, C １－６ alkylcarbamyl, di(C １－６ alkyl)carbamyl, aminosulfonyl, C １－６ alkylaminosulfonyl, and di(C １－６ alkyl)aminosulfonyl, Each R ａ６ and R ｂ６ and R ｃ６ and R ｄ６ are each independently selected from H, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl, and said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl are each optionally substituted by one, two, three, or four substituents independently selected from R ６０ ; or any R attached to the same N atom ｃ６ and R ｄ６ are, together with the N atom to which they are attached, optionally substituted by one, two, three, or four substituents independently selected from ６０ form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by substituents Each R ｅ６ is independently selected from H, CN, C １－６ alkyl, C １－６ haloalkyl, C １－６ alkylthio, C １－６ alkylsulfonyl, C １－６ alkylcarbonyl, C １－６ alkylaminosulfonyl, carbamyl, C １－６ alkylcarbamyl, di(C １－６ alkyl)carbamyl, aminosulfonyl, C １－６ alkylaminosulfonyl, and di(C １－６ alkyl)aminosulfonyl Each R ａ１０ , R ｂ１０ , R ｃ１０ , and R ｄ１０ is independently selected from H, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl, and said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl are each optionally substituted by one, two, three, or four substituents independently selected from R １１ . or any R attached to the same N atom ｃ１０ and R ｄ１０ are, together with the N atom to which they are attached, optionally substituted by one, two, three, or four substituents independently selected from １１ form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by substituents Each R ｅ１０ is independently selected from H, CN, C １－６ alkyl, C １－６ haloalkyl, C １－６ alkylthio, C １－６ alkylsulfonyl, C １－６ alkylcarbonyl, C １－６ alkylaminosulfonyl, carbamyl, C １－６ alkylcarbamyl, di(C １－６ alkyl)carbamyl, aminosulfonyl, C １－６ alkylaminosulfonyl, and di(C １－６ alkyl)aminosulfonyl, Each R ａ１１ , R ｂ１１ , R ｃ１１ , and R ｄ１１ is independently selected from 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, and said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－６ cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each optionally substituted by one, two, three, or four substituents independently selected from R １２ . or any R attached to the same N atom ｃ１１ and R ｄ１１ are, together with the N atom to which they are attached, optionally substituted by one, two, or three substituents independently selected from １２ form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by substituents Each R ａ１２ , R ｂ１２ , R ｃ１２ , and R ｄ１２ is independently selected from H, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, and C １－６ haloalkyl, and said C １－６ alkyl, C ２－６ alkenyl, and C ２－６ alkynyl are each optionally substituted by one, two, three, or four substituents independently selected from R ｇ , Each R ａ２０ 、R ｂ２０ 、R ｃ２０ 、and R ｄ２０ is independently selected from H, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl, and said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl are each optionally substituted by one, two, three, or four substituents independently selected from R ２１ ; or any R attached to the same N atom ｃ２０ and R ｄ２０ are, together with the N atom to which they are attached, optionally substituted by one, two, three, or four substituents independently selected from ２１ form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by substituents Each R ｅ２０ is independently selected from H, CN, C １－６ alkyl, C １－６ haloalkyl, C １－６ alkylthio, C １－６ alkylsulfonyl, C １－６ alkylcarbonyl, C １－６ alkylaminosulfonyl, carbamyl, C １－６ alkylcarbamyl, di(C １－６ alkyl)carbamyl, aminosulfonyl, C １－６ alkylaminosulfonyl, and di(C １－６ alkyl)aminosulfonyl, Each R ａ２１ , R ｂ２１ , R ｃ２１ , and R ｄ２１ is independently selected from 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, and said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－６ cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each optionally substituted by one, two, three, or four substituents independently selected from R ２２ . or any R attached to the same N atom ｃ２１ and R ｄ２１ are, together with the N atom to which they are attached, optionally substituted by one, two, or three substituents independently selected from ２２ a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by one, two, or three substituents independently selected from R Each R ａ２２ , R ｂ２２ , R ｃ２２ , and R ｄ２２ is independently selected from H, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, and C １－６ haloalkyl, and said C １－６ alkyl, C ２－６ alkenyl, and C ２－６ alkynyl are each optionally substituted by one, two, three, or four substituents independently selected from R ｇ , Each R ａ３０ , R ｂ３０ , R ｃ３０ , and R ｄ３０ is independently selected from H, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl, and said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl are each optionally substituted by one, two, three, or four substituents independently selected from R ３１ , or any R attached to the same N atom ｃ３０ and R ｄ３０ are, together with the N atom to which they are attached, optionally substituted by one, two, three, or four substituents independently selected from ３１ form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by substituents Each R ｅ３０ is independently selected from H, CN, C １－６ alkyl, C １－６ haloalkyl, C １－６ alkylthio, C １－６ alkylsulfonyl, C １－６ alkylcarbonyl, C １－６ alkylaminosulfonyl, carbamyl, C １－６ alkylcarbamyl, di(C １－６ alkyl)carbamyl, aminosulfonyl, C １－６ alkylaminosulfonyl, and di(C １－６ alkyl)aminosulfonyl, Each R ａ３１ , R ｂ３１ , R ｃ３１ , and R ｄ３１ is independently selected from 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, and said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－６ cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each optionally substituted by one, two, three, or four substituents independently selected from R ３２ . or any R attached to the same N atom ｃ３１ and R ｄ３１ are, together with the N atom to which they are attached, optionally substituted by one, two, or three substituents independently selected from ３２ form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by substituents Each R ａ３２ 、R ｂ３２ 、R ｃ３２ 、and R ｄ３２ is independently selected from H, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, and C １－６ haloalkyl, and said C １－６ alkyl, C ２－６ alkenyl, and C ２－６ alkynyl are each optionally substituted by one, two, three, or four substituents independently selected from R ｇ , and Each R ａ４０ 、R ｂ４０ 、R ｃ４０ 、and R ｄ４０ are each independently selected from H, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl, and said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl are each optionally substituted by one, two, three, or four substituents independently selected from R ４１ ; or any R attached to the same N atom ｃ４０ and R ｄ４０ are, together with the N atom to which they are attached, optionally substituted by one, two, three, or four substituents independently selected from ４１ form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by substituents Each R ｅ４０ is independently selected from H, CN, C １－６ alkyl, C １－６ haloalkyl, C １－６ alkylthio, C １－６ alkylsulfonyl, C １－６ alkylcarbonyl, C １－６ alkylaminosulfonyl, carbamyl, C １－６ alkylcarbamyl, di(C １－６ alkyl)carbamyl, aminosulfonyl, C １－６ alkylaminosulfonyl, and di(C １－６ alkyl)aminosulfonyl, Each R ａ４１ , R ｂ４１ , R ｃ４１ , and R ｄ４１ is independently selected from 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, and said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－６ cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each optionally substituted by one, two, three, or four substituents independently selected from R ４２ , or any R attached to the same N atom ｃ４１ and R ｄ４１ are, together with the N atom to which they are attached, optionally substituted by one, two, or three substituents independently selected from ４２ 4-, 5-, 6-, or 7-membered heterocycloalkyl groups optionally substituted by substituents, forming Each R ａ４２ 、R ｂ４２ 、R ｃ４２ 、and R ｄ４２ is independently selected from H, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, and C １－６ haloalkyl, and said C １－６ alkyl, C ２－６ alkenyl, and C ２－６ alkynyl are each optionally substituted by one, two, three, or four substituents independently selected from R ｇ and are optionally substituted by one, two, three, or four substituents independently selected from R Each R ａ５０ 、R ｂ５０ 、R ｃ５０ 、and R ｄ５０ is independently selected from H, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl, and said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl are each optionally substituted by one, two, three, or four substituents independently selected from R ５１ ; or any R attached to the same N atom ｃ５０ and R ｄ５０ are, together with the N atom to which they are attached, optionally substituted by one, two, three, or four substituents independently selected from ５１ a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by substituents to form Each R ｅ５０ is independently selected from H, CN, C １－６ alkyl, C １－６ haloalkyl, C １－６ alkylthio, C １－６ alkylsulfonyl, C １－６ alkylcarbonyl, C １－６ alkylaminosulfonyl, carbamyl, C １－６ alkylcarbamyl, di(C １－６ alkyl)carbamyl, aminosulfonyl, C １－６ alkylaminosulfonyl, and di(C １－６ alkyl)aminosulfonyl, Each R ａ５１ 、R ｂ５１ 、R ｃ５１ 、and R ｄ５１ is independently selected from 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, and said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－６ cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each optionally substituted by one, two, three, or four substituents independently selected from R ５２ . or any R attached to the same N atom ｃ５１ and R ｄ５１ are, together with the N atom to which they are attached, optionally substituted by one, two, or three substituents independently selected from ５２ form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by substituents Each R ａ５２ 、R ｂ５２ 、R ｃ５２ 、and R ｄ５２ is independently selected from H, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, and C １－６ haloalkyl, and said C １－６ alkyl, C ２－６ alkenyl, and C ２－６ alkynyl are each optionally substituted by one, two, three, or four substituents independently selected from R ｇ and Each R ａ６０ 、R ｂ６０ 、R ｃ６０ 、and R ｄ６０ is independently selected from H, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl, and said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl are each optionally substituted by one, two, three, or four substituents independently selected from R ６１ , or any R attached to the same N atom ｃ６０ and R ｄ６０ are, together with the N atom to which they are attached, optionally substituted by one, two, three, or four substituents independently selected from ６１ form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by substituents Each R ｅ６０ is independently selected from H, CN, C １－６ alkyl, C １－６ haloalkyl, C １－６ alkylthio, C １－６ alkylsulfonyl, C １－６ alkylcarbonyl, C １－６ alkylaminosulfonyl, carbamyl, C １－６ alkylcarbamyl, di(C １－６ alkyl)carbamyl, aminosulfonyl, C １－６ alkylaminosulfonyl, and di(C １－６ alkyl)aminosulfonyl, Each R ａ６１ , R ｂ６１ , R ｃ６１ , and R ｄ６１ is independently selected from 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, and said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－６ cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each optionally substituted by one, two, three, or four substituents independently selected from R ６２ . or any R attached to the same N atom ｃ６１ and R ｄ６１ are, together with the N atom to which they are attached, optionally substituted by one, two, or three substituents independently selected from ６２ a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by one, two, or three substituents independently selected from R Each R ａ６２ 、R ｂ６２ 、R ｃ６２ 、and R ｄ６２ are independently selected from H, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, and C １－６ haloalkyl, and said C １－６ alkyl, C ２－６ alkenyl, and C ２－６ alkynyl are each optionally substituted by one, two, three, or four substituents independently selected from R ｇ , Each R ｇ is D, OH, NO ２ , 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, H ２ N-C １－３ alkyl, amino, C １－６ alkylamino, di(C １－６ alkyl)amino, thio, C １－６ alkylthio, C １－６ alkylsulfinyl, C １－６ alkylsulfonyl, carbamyl, C １－６ alkylcarbamyl, di(C １－６ alkyl)carbamyl, carboxy, C １－６ alkylcarbonyl, C １－６ alkoxycarbonyl, C １－６ alkylcarbonylamino, C １－６ alkoxycarbonylamino, C １－６ alkylcarbonyloxy, aminocarbonyloxy, C １－６ alkylaminocarbonyloxy, di(C １－６ alkyl)aminocarbonyloxy, C １－６ alkylsulfonylamino, aminosulfonyl, C １－６ alkylaminosulfonyl, di(C １－６ alkyl)aminosulfonyl, aminosulfonylamino, C １－６ alkylaminosulfonylamino, di(C １－６ alkyl)aminosulfonylamino, aminocarbonylamino, C １－６ Alkylaminocarbonylamino, and di(C １－６ alkyl)aminocarbonylamino, the compound or a pharmaceutically acceptable salt thereof.

2. Z is CR ６ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Z is CR

3. R １ is H, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, halo, D, CN, NO ２ , OR ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , OC(O)R ｂ１ , NR ｃ１ R ｄ１ , NR ｃ１ C(O)R ｂ１ , S(O) ２ R ｂ１ , and S(O) ２ , NR ｃ１ R ｄ１ selected from, said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl are each optionally substituted by one, two, three, or four substituents independently selected from R １０ , the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

4. R １ is selected from H, C １－６ alkyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl, and the C １－６ alkyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl are each optionally substituted by one, two, three, or four substituents independently selected from R １０ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is optionally substituted by

5. R １ is C ３－６ selected from cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl, wherein said C ３－６ cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each optionally substituted by one or two substituents independently selected from R １０ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is optionally substituted by one or two substituents independently selected from

6. R １ is selected from pyrazol-4-yl, imidazol-4-yl, 6-oxo-1,6-dihydropyridin-3-yl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl, pyridin-3-yl, and pyrimidin-5-yl, each of which is optionally substituted by one or two substituents independently selected from １０ R of claim 1, or a pharmaceutically acceptable salt thereof.

7. R １ wherein R １０ is pyrazolyl optionally substituted by one or two substituents independently selected from R, according to claim 1, the compound or a pharmaceutically acceptable salt thereof.

8. R １ is phenyl optionally substituted by one or two substituents independently selected from １０ R, according to claim 1, the compound or a pharmaceutically acceptable salt thereof.

9. R １ is H, 1-(2-hydroxyethyl)-1H-pyrazol-4-yl, 1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl, 1-(1-amino-2-methyl-1-oxopropan-2-yl)-1H-pyrazol-4-yl, 4-(morpholine-4-carbonyl)phenyl, 1H-pyrazol-4-yl, 1-(1-cyanopropan-2-yl)-1H-pyrazol-4-yl, 1-(2-hydroxybutyl)-1H-pyrazol-4-yl, 1-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-yl, 1-(((5-cyanopyridin-3-yl)methyl)-1H-pyrazol-4-yl, 1-(((2-cyanopyridin-4-yl)methyl)-1H-pyrazol-4-yl, 1-(pyrimidin-4-ylmethyl)-1H-pyrazol-4-yl, 1-(1-(2-cyanopyridin-4-yl)ethyl)-1H-pyrazol-4-yl, 4-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)phenyl, 4-(1,1-dioxidothiomorpholino)phenyl, 1-(pyrimidin-2-ylmethyl)-1H-pyrazol-4-yl, 1-(((6-cyanopyridin-2-yl)methyl)-1H-pyrazol-4-yl, 4-(4-acetylpiperazin-1-yl)phenyl, 4-(4-(2-hydroxyacetyl)piperazin-1-yl)phenyl, 4-(((4-acetylpiperazin-1-yl)methyl)phenyl, 4-(((4-(2-hydroxyacetyl)piperazin-1-yl)methyl)phenyl, 4-(4-methylpiperazin-1-yl)phenyl, 4-(((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl)phenyl, 1-(cyanomethyl)-1H-pyrazol-4-yl, 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl, 1-benzyl-1H-pyrazol-4-yl, 1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-4-yl, 1-(1-cyanoethyl)-1H-pyrazol-4-yl, 1-(2,2-(Difluoroethyl)-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-cyanopropan-2-yl)-1H-pyrazol-4-yl, 1-cyclopropyl-1H-pyrazol-4-yl, 1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl, 1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl, 1-(1-methoxy-2-methylpropan-2-yl)-1H-pyrazol-4-yl, 9-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl, 1-(3-(dimethylamino)propyl)-1H-pyrazol-4-yl, 1-methyl-1H-imidazol-4-yl, 6-oxo-1,6-dihydropyridin-3-yl, 5-isopropyl-1H-pyrazol-4-yl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl, 5-(2-hydroxypropan-2-yl)pyridin-3-yl, 2-(methylamino)pyrimidin-5-yl, 1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl, 1-(2-morpholinoethyl)-1H-pyrazol-4-yl, 1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-pyrazol-4-yl, 1-(3-hydroxypropyl)-1H-pyrazol-4-yl, 1-(2-cyanoethyl)-1H-pyrazol-4-yl, 1-(2-amino-2-oxoethyl)-1H-pyrazol-4-yl, 6-(2-hydroxypropan-2-yl)pyridin-3-yl, 6-(2,2,2-trifluoroethyl)pyridin-3-yl, 6-(methylcarbamoyl)pyridin-3-yl, 4-hydroxycyclohex-1-en-1-yl, 5-hydroxypent-1-in-1-yl, and 2-hydroxypropan-2-yl, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.,

10. Each R １０ is C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, halo, D, CN, NO ２ , OR ａ１０ , C(O)R ｂ１０ , C(O)NR ｃ１０ R ｄ１０ , C(O)OR ａ１０ , OC(O)R ｂ１０ , NR ｃ１０ R ｄ１０ , NR ｃ１０ C(O)R ｂ１０ , S(O) ２ R ｂ１０ , and S(O) ２ NR ｃ１０ R ｄ１０ and is independently selected from, wherein said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl are each optionally substituted by one, two, three, or four substituents independently selected from R １１ , the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

11. Each R １０ is independently selected from C １－６ alkyl, C １－６ haloalkyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, OR ａ１０ , C(O)NR ｃ１０ R ｄ１０ , and NR ｃ１０ R ｄ１０ , and wherein said C １－６ alkyl, C ３－１０ cycloalkyl, and 4- to 10-membered heterocycloalkyl are each optionally substituted by one, two, three, or four substituents independently selected from R １１ , the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

12. Each R １０ is C １－６ alkyl, C １－６ haloalkyl, OR ａ１０ , C(O)NR ｃ１０ R ｄ１０ , NR ｃ１０ R ｄ１０ , 1,1-dioxidotetrahydro-2H-thiopyranyl, 1,1-dioxidothiomorpholino, piperazinyl, tetrahydro-2H-pyranyl, piperidinyl, cyclopropyl, tetrahydrofuran-3-yl, and cyclohexenyl, each independently selected therefrom, and each optionally substituted with one, two, three, or four substituents independently selected from R １１ , the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

13. Each R １１ is independently selected from C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, halo, D, CN, OR ａ１１ , C(O)R ｂ１１ , C(O)NR ｃ１１ R ｄ１１ , C(O)OR ａ１１ , NR ｃ１１ R ｄ１１ , S(O)NR ｃ１１ R ｄ１１ , S(O) ２ R ｂ１１ , and S(O) ２ NR ｃ１１ R ｄ１１ and the C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl are each optionally substituted by one, two, three, or four substituents independently selected from R １２ The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

14. Each R １１ is independently selected from C １－６ alkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, CN, OR ａ１１ , C(O)R ｂ１１ , C(O)NR ｃ１１ R ｄ１１ , NR ｃ１１ R ｄ１１ , and S(O) ２ R ｂ１１ , and the C １－６ alkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl are each optionally substituted with one, two, three, or four substituents independently selected from R １２ , the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

15. Each R １２ is independently selected from C １－６ alkyl, halo, CN, OR ａ１２ , and C(O)R ｂ１２ , and said C １－６ alkyl is optionally substituted by one or two substituents independently selected from R ｇ , the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

16. R ２ wherein R is H, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, halo, D, CN, NO ２ , OR ａ２ , C(O)R ｂ２ , C(O)NR ｃ２ R ｄ２ , C(O)OR ａ２ , NR ｃ２ R ｄ２ , S(O) ２ R ｂ２ , and S(O) ２ NR ｃ２ R ｄ２ and is selected from the group consisting of the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

17. R ２ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is H.

18. R ３ wherein R is H, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, halo, D, CN, NO ２ , OR ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , and S(O) ２ NR ｃ３ R ｄ３ and is selected from the group consisting of the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

19. R ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is H.

20. R ４ is H, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, halo, D, CN, NO ２ , OR ａ４ , C(O)R ｂ４ , C(O)NR ｃ４ R ｄ４ , C(O)OR ａ４ , NR ｃ４ R ｄ４ , S(O) ２ R ｂ４ , and S(O) ２ NR ｃ４ R ｄ４ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from

21. R ４ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R is H.

22. R ５ is H, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, halo, D, CN, NO ２ , OR ａ５ , C(O)R ｂ５ , C(O)NR ｃ５ R ｄ５ , C(O)OR ａ５ , NR ｃ５ R ｄ５ , S(O) ２ R ｂ５ , and S(O) ２ NR ｃ５ R ｄ５ selected from, wherein said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl are each optionally substituted by one, two, three, or four substituents independently selected from R ５０ The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

23. R ５ is H, C １－６ alkyl, and C ６－１０ aryl, and the C １－６ alkyl and C ６－１０ aryl are each optionally substituted by one, two, three, or four substituents independently selected from R ５０ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is optionally substituted by one, two, three, or four substituents independently selected from R

24. R ５ is selected from C １－６ alkyl and phenyl, and said C １－６ alkyl and phenyl are each optionally substituted by one, two, three, or four substituents independently selected from R ５０ The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

25. R ５ wherein R ５０ is phenyl optionally substituted by one, two, three or four substituents independently selected from R, according to claim 1, the compound or a pharmaceutically acceptable salt thereof.

26. R ５ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R is H, methyl, or 2,6-dichlorophenyl.

27. Each R ５０ is C １－６ alkyl, C １－６ haloalkyl, halo, D, CN, OR ａ５０ , C(O)R ｂ５０ , C(O)NR ｃ５０ R ｄ５０ , C(O)OR ａ５０ , NR ｃ５０ R ｄ５０ , NR ｃ５０ C(O)R ｂ５０ , S(O) ２ R ｂ５０ , and S(O) ２ NR ｃ５０ R ｄ５０ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is independently selected from

28. Each R ５０ is independently selected from halo, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

29. Each R ５０ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is Cl.

30. the compound has the formula II: 【Chemical 2】 The compound or a pharmaceutically acceptable salt thereof according to claim 1, which has the formula II.

31. the compound has the formula IIIa or formula IIIb: [Chemical 3] The compound or a pharmaceutically acceptable salt thereof according to claim 1, which has the formula IIIa or formula IIIb.

32. the compound has the formula IVa or formula IVb: [Chemical Formula 4] The compound or a pharmaceutically acceptable salt thereof according to claim 1, which has the formula IVa or formula IVb.

33. R １ is H, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, halo, D, CN, NO ２ , OR ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , OC(O)R ｂ１ , NR ｃ１ R ｄ１ , NR ｃ１ C(O)R ｂ１ , S(O) ２ R ｂ１ , and S(O) ２ , NR ｃ１ R ｄ１ selected from, said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl are each optionally substituted by one, two, three, or four substituents independently selected from R １０ , respectively, and R ２ is H, and R ３ is H, and R ４ is H, and R ５ is H, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, halo, D, CN, NO ２ , OR ａ５ , C(O)R ｂ５ , C(O)NR ｃ５ R ｄ５ , C(O)OR ａ５ , NR ｃ５ R ｄ５ , S(O) ２ R ｂ５ , and S(O) ２ NR ｃ５ R ｄ５ is selected from, wherein said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl are each optionally substituted by one, two, three, or four substituents independently selected from R ５０ and are optionally substituted by one, two, three, or four substituents independently selected from R Z is CR ６ and R ６ is H, and Each R １０ is C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, halo, D, CN, NO ２ , OR ａ１０ , C(O)R ｂ１０ , C(O)NR ｃ１０ R ｄ１０ , C(O)OR ａ１０ , OC(O)R ｂ１０ , NR ｃ１０ R ｄ１０ , NR ｃ１０ C(O)R ｂ１０ , S(O) ２ R ｂ１０ , and S(O) ２ NR ｃ１０ R ｄ１０ is independently selected from, and said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl are each optionally substituted by one, two, three, or four substituents independently selected from R １１ , Each R １１ is C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, halo, D, CN, OR ａ１１ , C(O)R ｂ１１ , C(O)NR ｃ１１ R ｄ１１ , C(O)OR ａ１１ , NR ｃ１１ R ｄ１１ , S(O)NR ｃ１１ R ｄ１１ , S(O) ２ R ｂ１１ , and S(O) ２ NR ｃ１１ R ｄ１１ is independently selected from, and said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl are each optionally substituted by one, two, three, or four substituents independently selected from R １２ ; Each R １２ is 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- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, halo, D, CN, OR ａ１２ , C(O)R ｂ１２ , C(O)NR ｃ１２ R ｄ１２ , C(O)OR ａ１２ , NR ｃ１２ R ｄ１２ , NR ｃ１２ C(O)R ｂ１２ , S(O)NR ｃ１２ R ｄ１２ , S(O) ２ R ｂ１２ , and S(O) ２ NR ｃ１２ R ｄ１２ is independently selected from, and each of said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－６ cycloalkyl, C ６－１０ aryl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl is optionally substituted by one, two, three, or four substituents independently selected from R ｇ . Each R ５０ is C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, halo, D, CN, NO ２ , OR ａ５０ , C(O)R ｂ５０ , C(O)NR ｃ５０ R ｄ５０ , C(O)OR ａ５０ , OC(O)R ｂ５０ , NR ｃ５０ R ｄ５０ , NR ｃ５０ C(O)R ｂ５０ , S(O) ２ R ｂ５０ , and S(O) ２ , NR ｃ５０ R ｄ５０ is independently selected from, and each of said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl is optionally substituted with one, two, three, or four substituents independently selected from R ５１ , Each R ５１ is C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, halo, D, CN, OR ａ５１ , C(O)R ｂ５１ , C(O)NR ｃ５１ R ｄ５１ , C(O)OR ａ５１ , NR ｃ５１ R ｄ５１ , NR ｃ５１ C(O)R ｂ５１ , S(O) ２ R ｂ５１ , and S(O) ２ , NR ｃ５１ R ｄ５１ is independently selected from, and each of said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl is optionally substituted by one, two, three, or four substituents independently selected from R ５２ , Each R ５２ is 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- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, halo, D, CN, OR ａ５２ , C(O)R ｂ５２ , C(O)NR ｃ５２ R ｄ５２ , C(O)OR ａ５２ , NR ｃ５２ R ｄ５２ , NR ｃ５２ C(O)R ｂ５２ , S(O) ２ R ｂ５２ , and S(O) ２ NR ｃ５２ R ｄ５２ is independently selected from, said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－６ cycloalkyl, C ６－１０ aryl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each optionally substituted by one, two, three, or four substituents independently selected from R ｇ , Each R ａ１ 、R ｂ１ 、R ｃ１ 、and R ｄ１ is independently selected from H, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl, and said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl are each optionally substituted by one, two, three, or four substituents independently selected from R １０ . or any R attached to the same N atom ｃ１ and R ｄ１ are, together with the N atom to which they are attached, optionally substituted by one, two, three, or four substituents independently selected from １０ a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by substituents Each R ａ５ , R ｂ５ , R ｃ５ , and R ｄ５ are independently selected from H, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl, and said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl are each optionally substituted by one, two, three, or four substituents independently selected from R ５０ , or any R attached to the same N atom ｃ５ and R ｄ５ are, together with the N atom to which they are attached, optionally substituted by one, two, three, or four substituents independently selected from ５０ a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by substituents to form Each R ａ１０ 、R ｂ１０ 、R ｃ１０ 、and R ｄ１０ is independently selected from H, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl, and said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl are each optionally substituted by one, two, three, or four substituents independently selected from R １１ . or any R attached to the same N atom ｃ１０ and R ｄ１０ are, together with the N atom to which they are attached, optionally substituted by one, two, three, or four substituents independently selected from １１ a 4-membered, 5-membered, 6-membered, or 7-membered heterocycloalkyl group optionally substituted by substituents Each R ａ１１ 、R ｂ１１ 、R ｃ１１ 、and R ｄ１１ is independently selected from 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, and said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－６ cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each optionally substituted with one, two, three, or four substituents independently selected from R １２ ; or any R attached to the same N atom ｃ１１ and R ｄ１１ are, together with the N atom to which they are attached, optionally substituted by one, two, or three substituents independently selected from １２ 4-, 5-, 6-, or 7-membered heterocycloalkyl groups optionally substituted by substituents, forming Each R ａ１２ , R ｂ１２ , R ｃ１２ , and R ｄ１２ is independently selected from H, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, and C １－６ haloalkyl, and said C １－６ alkyl, C ２－６ alkenyl, and C ２－６ alkynyl are each optionally substituted by one, two, three, or four substituents independently selected from R ｇ , and Each R ａ５０ 、R ｂ５０ 、R ｃ５０ 、and R ｄ５０ is independently selected from H, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl, and said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl are each optionally substituted by one, two, three, or four substituents independently selected from R ５１ ; or any R attached to the same N atom ｃ５０ and R ｄ５０ are, together with the N atom to which they are attached, optionally substituted by one, two, three, or four substituents independently selected from ５１ form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by substituents Each R ａ５１ , R ｂ５１ , R ｃ５１ , and R ｄ５１ is independently selected from 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, and said C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－６ cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each optionally substituted by one, two, three, or four substituents independently selected from R ５２ . or any R attached to the same N atom ｃ５１ and R ｄ５１ are, together with the N atom to which they are attached, optionally substituted by one, two, or three substituents independently selected from ５２ 4-, 5-, 6-, or 7-membered heterocycloalkyl groups optionally substituted by substituents, forming Each R ａ５２ 、R ｂ５２ 、R ｃ５２ 、and R ｄ５２ is independently selected from H, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, and C １－６ haloalkyl, and said C １－６ alkyl, C ２－６ alkenyl, and C ２－６ alkynyl are each optionally substituted by one, two, three, or four substituents independently selected from R ｇ , and Each R ｇ is independently selected from D, OH, CN, halo, C １－６ alkyl, and C １－６ haloalkyl, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

34. R １ is selected from H, C １－６ alkyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl, and the C １－６ alkyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl are each optionally substituted by one, two, three, or four substituents independently selected from R １０ and optionally substituted by one, two, three, or four substituents independently selected from R R ２ is H, and R ３ is H, and R ４ is H, and R ５ is selected from H, C １－６ alkyl, and C ６－１０ aryl, and said C １－６ alkyl and C ６－１０ aryl are each optionally substituted by one, two, three, or four substituents independently selected from R ５０ and Z is CR ６ and R ６ is H, and Each R １０ is C １－６ alkyl, C １－６ haloalkyl, C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, OR ａ１０ , C(O)NR ｃ１０ R ｄ１０ , and NR ｃ１０ R ｄ１０ is independently selected from, and the C １－６ alkyl, C ３－１０ cycloalkyl, and 4- to 10-membered heterocycloalkyl are each optionally substituted by one, two, three, or four substituents independently selected from R １１ , Each R １１ is selected independently from C １－６ alkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, CN, OR ａ１１ , C(O)R ｂ１１ , C(O)NR ｃ１１ R ｄ１１ , NR ｃ１１ R ｄ１１ , and S(O) ２ R ｂ１１ and is optionally substituted by one, two, three, or four substituents independently selected from R １－６ wherein the C ６－１０ alkyl, 4- to 10-membered heterocycloalkyl, C １２ aryl, and 5- to 10-membered heteroaryl are each optionally substituted by one, two, three, or four substituents independently selected from R and Each R １２ is independently selected from C １－６ alkyl, halo, CN, OR ａ１２ , and C(O)R ｂ１２ , and said C １－６ alkyl is optionally substituted by one or two substituents independently selected from R ｇ , and is optionally substituted by one or two substituents independently selected from R Each R ５０ is independently selected from the halo and Each R ａ１０ , R ｃ１０ , and R ｄ１０ is independently selected from H and C １－６ alkyl, and said C １－６ alkyl is optionally substituted by one, two, three, or four substituents independently selected from R １１ , or any R attached to the same N atom ｃ１０ and R ｄ１０ are, together with the N atom to which they are attached, optionally substituted by one, two, three, or four substituents independently selected from １１ form a 6- or 7-membered heterocycloalkyl group optionally substituted by substituents Each R ａ１１ , R ｂ１１ , R ｃ１１ , and R ｄ１１ is independently selected from H and C １－６ alkyl, and said C １－６ alkyl is optionally substituted by one, two, three, or four substituents independently selected from R １２ . Each R ａ１２ and R ｂ１２ are each independently selected from H and C １－６ alkyl, and said C １－６ alkyl is optionally substituted by R ｇ . R ｇ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R is OH.

35. the compound is 2-(2,6-dichlorophenyl)-9-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, 2-(2,6-dichlorophenyl)-9-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, 9-(1-(1-amino-2-methyl-1-oxopropan-2-yl)-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, 2-(2,6-dichlorophenyl)-9-(4-(morpholine-4-carbonyl)phenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, 2-(2,6-dichlorophenyl)-9-(1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, 9-(1-(1-cyanopropan-2-yl)-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, 2-(2,6-dichlorophenyl)-9-(1-(2-hydroxybutyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, 2-(2,6-Dichlorophenyl)-9-(1-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, 9-(1-(((5-cyanopyridin-3-yl)methyl)-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, 9-(1-(((2-cyanopyridin-4-yl)methyl)-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, 2-(2,6-Dichlorophenyl)-9-(1-(pyrimidin-4-ylmethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, 9-(1-(1-(2-cyanopyridin-4-yl)ethyl)-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, 2-(2,6-Dichlorophenyl)-9-(4-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)phenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, 2-(2,6-Dichlorophenyl)-9-(4-(1,1-dioxidothiomorpholino)phenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, 2-(2,6-Dichlorophenyl)-9-(1-(pyrimidin-2-ylmethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, 9-(1-(((6-cyanopyridin-2-yl)methyl)-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, 9-(4-(4-acetylpiperazin-1-yl)phenyl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, 2-(2,6-Dichlorophenyl)-9-(4-(4-(2-hydroxyacetyl)piperazin-1-yl)phenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, 9-(4-((4-acetylpiperazin-1-yl)methyl)phenyl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, 2-(2,6-dichlorophenyl)-9-(4-((4-(2-hydroxyacetyl)piperazin-1-yl)methyl)phenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, 2-(2,6-dichlorophenyl)-9-(4-(4-methylpiperazin-1-yl)phenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, 9-(4-(((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl)phenyl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, 9-(1-(cyanomethyl)-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, 2-(2,6-dichlorophenyl)-9-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, 9-(1-benzyl-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, 2-(2,6-dichlorophenyl)-9-(1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, 9-(1-(1-cyanoethyl)-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, 2-(2,6-dichlorophenyl)-9-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, 2-(2,6-dichlorophenyl)-9-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, 2-(2,6-Dichlorophenyl)-9-(1-(1-hydroxy-2-methylpropan-2-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, 9-(1-(2-Cyanopropan-2-yl)-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, 9-(1-Cyclopropyl-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, 2-(2,6-Dichlorophenyl)-9-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, 2-(2,6-Dichlorophenyl)-9-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, 2-(2,6-Dichlorophenyl)-9-(1-(1-methoxy-2-methylpropan-2-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, 2-(2,6-Dichlorophenyl)-9-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, 2-(2,6-Dichlorophenyl)-9-(1-(3-(dimethylamino)propyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, 2-(2,6-Dichlorophenyl)-9-(1-methyl-1H-imidazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, 2-(2,6-Dichlorophenyl)-9-(6-oxo-1,6-dihydropyridin-3-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, 2-(2,6-Dichlorophenyl)-9-(5-isopropyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, 2-(2,6-Dichlorophenyl)-9-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, 2-(2,6-Dichlorophenyl)-9-(5-(2-hydroxypropan-2-yl)pyridin-3-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, 2-(2,6-Dichlorophenyl)-9-(2-(methylamino)pyrimidin-5-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, 2-(2,6-Dichlorophenyl)-9-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, 2-(2,6-Dichlorophenyl)-9-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, 2-(2,6-Dichlorophenyl)-9-(1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, 2-(2,6-Dichlorophenyl)-9-(1-(3-hydroxypropyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, 9-(1-(2-Cyanoethyl)-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, 9-(1-(2-Amino-2-oxoethyl)-1H-pyrazol-4-yl)-2-(2,6-dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, 2-(2,6-Dichlorophenyl)-9-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, 2-(2,6-Dichlorophenyl)-9-(6-(2,2,2-trifluoroethyl)pyridin-3-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, 2-(2,6-Dichlorophenyl)-9-(6-(methylcarbamoyl)pyridin-3-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, 2-(2,6-Dichlorophenyl)-9-(4-hydroxycyclohex-1-en-1-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, 2-(2,6-Dichlorophenyl)-9-(5-hydroxypent-1-en-1-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, 2-(2,6-Dichlorophenyl)-9-(2-hydroxypropan-2-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, 2-(2,6-Dichlorophenyl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, 2-Methyl-9-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide, and 9-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,6]naphthyridine-3-carboxamide The compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from:

36. A pharmaceutical composition comprising the compound according to any one of claims 1 to 35 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or pharmaceutical additive.

37. An FGFR3 enzyme inhibitor comprising the compound according to any one of claims 1 to 35 or a pharmaceutically acceptable salt thereof.

38. A medicament for treating cancer in a patient, comprising the compound according to any one of claims 1 to 35 or a pharmaceutically acceptable salt thereof.

39. A medicament for treating cancer in a patient, comprising the compound according to any one of claims 1 to 35 or a pharmaceutically acceptable salt thereof, wherein the medicament is administered to the patient in combination with another treatment method or therapeutic agent.

40. The medicament according to claim 38, wherein the cancer is selected from adenocarcinoma, bladder cancer, breast cancer, cervical cancer, cholangiocarcinoma, colorectal cancer, endometrial cancer, esophageal cancer, gallbladder cancer, gastric cancer, glioma, head and neck cancer, hepatocellular carcinoma, kidney cancer, liver cancer, lung cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, rhabdomyosarcoma, skin cancer, thyroid cancer, leukemia, multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, B-cell lymphoma, acute myeloid leukemia, Hodgkin lymphoma or non-Hodgkin lymphoma, Waldenström macroglobulinemia, hairy cell lymphoma, and Burkitt lymphoma.

41. The medicament according to claim 38, wherein the cancer is selected from adenocarcinoma, bladder cancer, breast cancer, cervical cancer, cholangiocarcinoma, endometrial cancer, gastric cancer, glioma, head and neck cancer, lung cancer, ovarian cancer, leukemia, and multiple myeloma.

42. A medicament for treating skeletal disorders or chondrocyte disorders in a patient, comprising the compound according to any one of claims 1 to 35 or a pharmaceutically acceptable salt thereof.

43. The medicament according to claim 42, wherein the skeletal disorder or the chondrocyte disorder is selected from achondrogenesis, hypochondrogenesis, pituitary dwarfism, thanatophoric dysplasia (TD), Apert syndrome, Crouzon syndrome, Jackson-Weiss syndrome, Beare-Stevenson cutis gyrata syndrome, Pfeiffer syndrome, and craniosynostosis syndrome.

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