Substituted tricyclic compounds as FGFR inhibitors

Abstract

To provide compounds, and pharmaceutical compositions of the same, that are inhibitors of FGFR enzymes and are useful in the treatment of FGFR-associated diseases such as cancer.SOLUTION: The present invention provides tricyclic compounds of formula I, and pharmaceutical compositions of the same.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to tricyclic compounds and pharmaceutical compositions thereof, which are inhibitors of one or more FGFR enzymes and are useful for the treatment of FGFR-related diseases such as cancer.

Background Art

[0002] Fibroblast growth factor receptor (FGFR) is a receptor tyrosine kinase that binds to fibroblast growth factor (FGF) ligands. There are four FGFR proteins (FGFR1-4) that can bind to ligands and are involved in the regulation of many biological processes, including tissue growth, angiogenesis, wound healing, and metabolic regulation. Upon ligand binding, the receptor undergoes dimerization and phosphorylation reactions, leading to stimulation of protein kinase activity and recruitment of many intracellular docking proteins. These interactions promote the activation of a series of intracellular signaling pathways, including Ras-MAPK, AKT-PI3K, and phospholipase C, which are important for cell growth, proliferation, and survival (Non-Patent Document 1). Aberrant activation of this pathway, either by overexpression of FGF ligand or FGFR or activation of mutations in FGFR, may lead to tumor growth, progression, and resistance to conventional cancer therapies. In human cancers, genetic changes have been described, including gene amplification, chromosomal translocations, and somatic mutations that result in activation of ligand-independent receptors. Large-scale DNA sequencing of thousands of tumor samples has revealed that components of the FGFR pathway are among the most frequently mutated in human cancers. Many of these activating mutations are identical to germline mutations that cause skeletal dysplasia syndromes. Mechanisms that result in abnormal ligand-dependent signaling in human diseases include overexpression of FGF, which results in receptors with more irregular ligand-binding capabilities, and changes in FGFR splicing (Non-Patent Documents 2 and 3). Therefore, the development of inhibitors targeting FGFR may be useful in the clinical treatment of diseases that increase FGF or FGFR activity.

[0003] Cancer types in which FGF / FGFR is involved include, but are not limited to, epithelial malignancies (e.g., bladder, breast, cervical, colorectal, endometrial, gastric, head and neck, kidney, liver, lung, ovary, prostate), hematopoietic malignancies (e.g., multiple myeloma, chronic lymphocytic leukemia, adult T-cell leukemia, acute myeloid leukemia, non-Hodgkin lymphoma, myeloproliferative neoplasms, and Waldenström macroglobulinemia), and other tumors (e.g., glioblastoma, melanoma, and rhabdomyosarcoma). In addition to its role in tumor-forming tumors, FGFR activation is also thought to be involved in skeletal or chondrocyte disorders including, but not limited to, achondroplasia and craniosynostosis syndrome.

Prior Art Documents

Non-Patent Documents

[0004]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Summary of the Invention

Problems to be Solved by the Invention

[0005] There is a continuing need for the development of new drugs for the treatment of cancer and other diseases, and the FGFR inhibitors described herein serve to address this need.

Means for Solving the Problems

[0006] The present invention relates to formula I: [Chemistry] The present invention relates to a compound of formula or a pharmaceutically acceptable salt thereof, wherein the constituent variables are defined below in the specification.

[0007] The present invention relates to a compound of formula II, III, or IV: [Chemistry] The present invention relates to a compound of formula or a pharmaceutically acceptable salt thereof, wherein the constituent variables are defined below in the specification.

[0008] The present invention relates to a compound of formula V: [Chemistry] The present invention relates to a compound of formula or a pharmaceutically acceptable salt thereof, wherein the constituent variables are defined below in the specification.

[0009] The present invention further relates to a pharmaceutical composition comprising a compound of any one of formulas I, II, III, IV, and V, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0010] The present invention further relates to a method for treating cancer in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of any one of formulas I, II, III, IV, and V, or a pharmaceutically acceptable salt thereof.

[0011] The present invention further relates to a method for treating a myeloproliferative disease in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of any one of formulas I, II, III, IV, and V, or a pharmaceutically acceptable salt thereof.

[0012] The present invention further relates to a method for treating skeletal or chondrocyte disorders in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of any one of Formulas I, II, III, IV, and V, or a pharmaceutically acceptable salt thereof.

[0013] The present invention further relates to the use of a compound of any one of Formulas I, II, III, IV, and V, or a pharmaceutically acceptable salt thereof, in therapy.

[0014] The present invention further relates to the use of a compound of any one of Formulas I, II, III, IV, and V, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for use in therapy.

DETAILED DESCRIPTION OF THE INVENTION

[0015] The present invention relates to an FGFR inhibitor which is a compound of Formula I:

CHEMICAL

CHEMICAL

Chemical formula

[0016] In some embodiments, the present invention relates to a compound of formula I:

Chemical formula

Chemical formula

[0017] In some embodiments, R 4 、R 5 、R 6 、R 7 、And R 8 Are each independently selected from H, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, CN, OR a1 、SR a1 、C(O)R b1 、C(O)NR c1 R d1 、C(O)ORa1 , 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(=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 , S(O)NR c1 R d1 , 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 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each optionally, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)Rb1 、 OC(O)NR c1 R d1 、 C(=NR e1 )NR c1 R d1 、 NR c1 C(=NR e1 )NR c1 R d1 、 NR c1 R d1 、 NR c1 C(O)R b1 、 NR c1 C(O)OR a1 、 NR c1 C(O)NR c1 R d1 、 NR c1 S(O)R b1 、 NR c1 S(O) 2 R b1 、 NR 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 is substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 9 is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-10 cycloalkyl-C 1-4 alkyl, (5- to 10-membered heteroaryl)-C 1-4 alkyl, or (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl, and the C 1-6 alkyl, C 2-6 alkenyl, C 2-6Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, (5- to 10-membered heteroaryl)-C 1-4 Alkyl, and (4- to 10-membered heterocycloalkyl)-C 1-4 Each alkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 9a and each R 9a is independently Cy 1 halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, 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 , C(=NR e2 )NR c2 R d2 , NR c2 C(=NR e2 )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 , NR c2 S(O)R b2 , NR c2 S(O) 2 R b2 , NR c2 S(O) 2 NR c2 Rd2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 selected from, and the C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally, Cy 1 , halo, 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 , C(=NR e2 )NR c2 R d2 , NR c2 C(=NR e2 )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 , 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 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 , NR c2 R d2 substituted with 1, 2, or 3 substituents independently selected from R 10 、R 11 、R 12 、R 13 、R 12a 、R 13a 、R 14 、およびR 15 are each independently H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, 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(=NR e3 )NR c3 R d3 、NR c3 C(=NR e3 )NR c3 R d3 、NR c3 S(O)R b3 、NR c3 S(O) 2 R b3 、NR 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 is selected from, and the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 10a ; each R 10a is independently Cy 2 , halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, 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 , C(=NR e3 )NR c3 R d3 , NR c3 C(=NR e3 )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 , NR c3 S(O)R b3 , NR c3 S(O) 2 R b3 , NR c3 S(O) 2 NR c3 R d3 , S(O)R b3 , S(O)NRc3 R d3 、 S(O) 2 R b3 、 and S(O) 2 NR c3 R d3 selected from, and the C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally, Cy 2 , halo, 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 , C(=NR e3 )NR c3 R d3 , NR c3 C(=NR e3 )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 , NR c3 S(O)R b3 , NR c3 S(O) 2 R b3 , NR 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 substituted with 1, 2, or 3 substituents independently selected from, or alternatively, R 12 and R 13together with the carbon atom to which they are attached, form a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group, or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, each optionally Cy 2 , C 1-6 alkyl, C 1-6 haloalkyl, halo, CN, 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)NR c3 R d3 , NR c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , NR c3 C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , NR c3 S(O) 2 R b3 , NR c3 S(O) 2 NR c3 R d3 , and S(O) 2 NR c3 R d3 is substituted with 1, 2, or 3 substituents independently selected from 1-6 alkyl is optionally Cy 2 , halo, CN, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)Rb3 、 OC(O)NR c3 R d3 、 NR c3 R d3 、 NR c3 C(O)R b3 、 NR c3 C(O)NR c3 R d3 、 NR c3 C(O)OR a3 、 C(=NR e3 )NR c3 R d3 、 NR c3 C(=NR e3 )NR c3 R d3 、 S(O)R b3 、 S(O)NR c3 R d3 、 S(O) 2 R b3 、 NR c3 S(O) 2 R b3 、 NR c3 S(O) 2 NR c3 R d3 、 and S(O) 2 NR c3 R d3 is substituted by one, two, or three substituents independently selected from or, R 12a and R 13a together with the carbon atom to which they are attached form a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group, or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, each optionally, Cy 2 、 C 1-6 alkyl, C 1-6 haloalkyl, halo, CN, 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)NR c3 R d3 , NR c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , NR c3 , C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , NR c3 , NR 2 S(O) b3 , NR c3 , S(O) 2 NR c3 R d3 , and S(O) 2 NR c3 R d3 is substituted with 1, 2, or 3 substituents independently selected from 1-6 the C 2 alkyl is optionally Cy a3 , halo, CN, OR a3 , SR b3 , C(O)R c3 , C(O)NR 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)NR c3 R d3 , NR c3 , C(O)OR a3 , C(=NR e3 )NR c3 R d3 , NR c3 , C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2 R b3 、 NR c3 S(O) 2 R b3 、 NR c3 S(O) 2 NR c3 R d3 、および S(O) 2 NR c3 R d3 is substituted by 1, 2, or 3 substituents independently selected from R 16 and R 16a are each independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-10 cycloalkyl-C 1-4 alkyl, (5- to 10-membered heteroaryl)-C 1-4 alkyl, and (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl, and said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-10 cycloalkyl-C 1-4 alkyl, (5- to 10-membered heteroaryl)-C 1-4 alkyl, and (4- to 10-membered heterocycloalkyl)-C 1-4 aryl is each optionally Cy 3 、 halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO 2 、 OR a4 、 SRa4 、 C(O)R b4 、 C(O)NR c4 R d4 、 C(O)OR a4 、 OC(O)R b4 、 OC(O)NR c4 R d4 、 C(=NR e4 )NR c4 R d4 、 NR c4 C(=NR e4 )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 、 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 、 S(O)NR c4 R d4 、 S(O) 2 R b4 、 and S(O) 2 NR c4 R d4 is substituted with 1, 2, 3, 4, or 5 substituents independently selected from, and said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally, Cy 3 、 halo, 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 、 C(=NR e4)NR c4 R d4 、NR c4 C(=NR e4 )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 、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 、S(O)NR c4 R d4 、S(O) 2 R b4 、およびS(O) 2 NR c4 R d4 is substituted with 1, 2, or 3 substituents independently selected from R A and R B are each independently H, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-10 cycloalkyl-C 1-4 alkyl, (5- to 10-membered heteroaryl)-C 1-4 alkyl, or (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl, and the C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 6-10 aryl, C3-10 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, (5- to 10-membered heteroaryl)-C 1-4 Alkyl, and (4- to 10-membered heterocycloalkyl)-C 1-4 Alkyl is optionally substituted with one, two, or three substituents independently selected from OH, CN, amino, halo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, di(C 1-4 Alkyl)amino, C 1-4 Haloalkyl, and C 1-4 Haloalkoxy; and Cy 1 , Cy 2 , and Cy 3 are each independently C 6-10 Aryl, C 3-10 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, optionally substituted with halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, 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(=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 , S(O)NR c5 R d5 , S(O) 2 R b5 , and S(O) 2 NR c5 R d5 is substituted by 1, 2, 3, 4, or 5 substituents independently selected from 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl, each optionally, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, 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 , C(=NR e5 )NR c5 R d5 , NR c5 C(=NR e5)NR c5 R d5 、 NR c5 R d5 、 NR c5 C(O)R b5 、 NR c5 C(O)OR a5 、 NR c5 C(O)NR c5 R d5 、 NR c5 S(O)R b5 、 NR c5 S(O) 2 R b5 、 NR 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 is substituted with 1, 2, 3, 4, or 5 substituents independently selected from each R a 、 R b 、 R c 、 R d 、 R a1 、 R b1 、 R c1 、 R d1 、 R a2 、 R b2 、 R c2 、 R d2 、 R a3 、 R b3 、 R c3 、 R d3 、 R a4 、 R b4 、 R c4 、 and R d4 、 R a5 、 R b5 、 R c5 、 and R d5 is independently H, C 1-6 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, (5-10 membered heteroaryl)-C 1-4 Alkyl, or (4-10 membered heterocycloalkyl)-C 1-4 alkyl, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, (5-10 membered heteroaryl)-C 1-4 Alkyl, and (4-10 membered heterocycloalkyl)-C 1-4 Alkyl is optionally C 1-4 Alkyl, C 1-4 Haloalkyl, Halo, CN, 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)NR c6 R d6 , N.R. c6 C(O)OR a6 , C(=NR e6 )NR c6 R d6 , N.R. c6 C(=NR e6 )NR c6 R d6 , S(O)R b6 , S(O)NR c6 Rd6 、 S(O) 2 R b6 、 NR c6 S(O) 2 R b6 、 NR c6 S(O) 2 NR c6 R d6 、 and S(O) 2 NR c6 R d6 substituted with 1, 2, 3, 4, or 5 substituents independently selected from, or, any R c and R d together with the N atom to which they are attached, C 1-6 alkyl, C 3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, C 6-10 aryl, 5- to 6-membered heteroaryl, C 1-6 haloalkyl, halo, CN, 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)NR c6 R d6 、 NR c6 C(O)OR a6 、 C(=NR e6 )NR c6 R d6 、 NR c6 C(=NR e6 )NR c6 R d6 、 S(O)R b6 、 S(O)NR c6 R d6 、 S(O) 2 R b6 、 NR c6 S(O) 2 R b6 、 NR c6 S(O)2 NR c6 R d6 、 and S(O) 2 NR c6 R d6 forms a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from 1-6 alkyl, C 3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, C 6-10 aryl, and 5- to 6-membered heteroaryl, which are optionally substituted with halo, CN, 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)NR c6 R d6 , NR c6 C(O)OR a6 , C(=NR e6 )NR c6 R d6 , NR c6 C(=NR e6 )NR c6 R d6 , S(O)R b6 , S(O)NR c6 R d6 , S(O) 2 R b6 , NR c6 S(O) 2 R b6 , NR c6 S(O) 2 NR c6 R d6 , and S(O) 2 NR c6 R d6 substituted by 1, 2, or 3 substituents independently selected from, or alternatively, any R c1 and Rd1 together with the N atom to which they are attached, C 1-6 alkyl, C 3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, C 6-10 aryl, 5- to 6-membered heteroaryl, C 1-6 haloalkyl, halo, CN, 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)NR c6 R d6 , NR c6 C(O)OR a6 , C(=NR e6 )NR c6 R d6 , NR c6 C(=NR e6 )NR c6 R d6 , S(O)R b6 , S(O)NR c6 R d6 , S(O) 2 R b6 , NR c6 S(O) 2 R b6 , NR c6 S(O) 2 NR c6 R d6 , and S(O) 2 NR c6 R d6 forms a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from 1-6 alkyl, C 3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, C 6-10 aryl, and 5- to 6-membered heteroaryl are optionally, halo, CN, OR a6 , SRa6 , 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)NR c6 R d6 , NR c6 C(O)OR a6 , C(=NR e6 )NR c6 R d6 , NR c6 C(=NR e6 )NR c6 R d6 , S(O)R b6 , S(O)NR c6 R d6 , S(O) 2 R b6 , NR c6 S(O) 2 R b6 , NR c6 S(O) 2 NR c6 R d6 , and S(O) 2 NR c6 R d6 is substituted by one, two, or three substituents independently selected from or, any R c2 and R d2 together with the N atom to which they are attached, C 1-6 alkyl, C 3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, C 6-10 aryl, 5- to 6-membered heteroaryl, C 1-6 haloalkyl, halo, CN, OR a6 , SR a6 , C(O)R b6 , C(O)NR c6 R d6 , C(O)OR a6 , OC(O)R b6 , OC(O)NRc6 R d6 、 NR c6 R d6 、 NR c6 C(O)R b6 、 NR c6 C(O)NR c6 R d6 、 NR c6 C(O)OR a6 、 C(=NR e6 )NR c6 R d6 、 NR c6 C(=NR e6 )NR c6 R d6 、 S(O)R b6 、 S(O)NR c6 R d6 、 S(O) 2 R b6 、 NR c6 S(O) 2 R b6 、 NR c6 S(O) 2 NR c6 R d6 、 and S(O) 2 NR c6 R d6 is optionally substituted with one, two, or three substituents independently selected from R 1-6 alkyl, C 3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, C 6-10 aryl, and 5- to 6-membered heteroaryl, which are optionally substituted with halo, CN, 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)NR c6 R d6 、 NR c6 C(O)OR a6, C(=NR e6 )NR c6 R d6 , NR c6 C(=NR e6 )NR c6 R d6 , S(O)R b6 , S(O)NR c6 R d6 , S(O) 2 R b6 , NR c6 S(O) 2 R b6 , NR c6 S(O) 2 , NR c6 R d6 , and S(O) 2 , NR c6 R d6 is substituted by 1, 2, or 3 substituents independently selected from or, any R c3 and R d3 together with the N atom to which they are attached, form C 1-6 alkyl, C 3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, C 6-10 aryl, 5- to 6-membered heteroaryl, C 1-6 haloalkyl, halo, CN, 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)NR c6 R d6 , NR c6 C(O)OR a6 , C(=NR e6 )NR c6 R d6 , NR c6 C(=NR e6 )NR c6 R d6, S(O)R b6 , S(O)NR c6 R d6 , S(O) 2 R b6 , NR c6 S(O) 2 R b6 , NR c6 S(O) 2 NR c6 R d6 , and S(O) 2 NR c6 R d6 A 4-, 5-, 6-, or 7-membered heterocycloalkyl group, optionally substituted with 1, 2, or 3 substituents independently selected from 1-6 C alkyl, C 3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, C 6-10 aryl, and 5- to 6-membered heteroaryl, which are optionally substituted with halo, CN, 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)NR c6 R d6 , NR c6 C(O)OR a6 , C(=NR e6 )NR c6 R d6 , NR c6 C(=NR e6 )NR c6 R d6 , S(O)R b6 , S(O)NR c6 R d6 , S(O) 2 R b6 , NR c6 S(O) 2 R b6 , NR c6 S(O) 2 NRc6 R d6 and S(O) 2 NR c6 R d6 and is substituted with 1, 2, or 3 substituents independently selected from, alternatively, any R c4 and R d4 together with the N atom to which they are attached, form a C 1-6 alkyl, C 3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, C 6-10 aryl, 5- to 6-membered heteroaryl, C 1-6 haloalkyl, halo, CN, 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)NR c6 R d6 NR c6 C(O)OR a6 C(=NR e6 )NR c6 R d6 NR c6 C(=NR e6 )NR c6 R d6 S(O)R b6 S(O)NR c6 R d6 S(O) 2 R b6 NR c6 S(O) 2 R b6 NR c6 S(O) 2 NR c6 R d6 and S(O) 2 NR c6 R d6forms a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected therefrom, and said C 1-6 alkyl, C 3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, C 6-10 aryl, and 5- to 6-membered heteroaryl are optionally substituted with halo, CN, 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 , NR c6 R d6 , NR c6 , C(O)OR a6 , C(=NR e6 )NR c6 R d6 , NR c6 , C(=NR e6 )NR c6 R d6 , S(O)R b6 , S(O)NR c6 R d6 , S(O) 2 R b6 , NR c6 , S(O) 2 R b6 , NR c6 , S(O) 2 , NR c6 R d6 , and S(O) 2 , NR c6 R d6 is substituted by 1, 2, or 3 substituents independently selected therefrom, or alternatively, any R c5 and R d5 together with the N atom to which they are attached form a C 1-6 alkyl, C 3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, C6-10 Aryl, 5- or 6-membered heteroaryl, C 1-6 Haloalkyl, halo, CN, 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)NR c6 R d6 , NR c6 C(O)OR a6 , C(=NR e6 )NR c6 R d6 , NR c6 C(=NR e6 )NR c6 R d6 , S(O)R b6 , S(O)NR c6 R d6 , S(O) 2 R b6 , NR c6 S(O) 2 R b6 , NR c6 S(O) 2 NR c6 R d6 , and S(O) 2 NR c6 R d6 optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of 4-, 5-, 6-, or 7-membered heterocycloalkyl groups, and said C 1-6 alkyl, C 3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, C 6-10 aryl, and 5- or 6-membered heteroaryl are optionally substituted with halo, CN, OR a6 , SR a6 , C(O)R b6 , C(O)NR c6 R d6 , C(O)OR a6 , OC(O)Rb6 、 OC(O)NR c6 R d6 、 NR c6 R d6 、 NR c6 C(O)R b6 、 NR c6 C(O)NR c6 R d6 、 NR c6 C(O)OR a6 、 C(=NR e6 )NR c6 R d6 、 NR c6 C(=NR e6 )NR c6 R d6 、 S(O)R b6 、 S(O)NR c6 R d6 、 S(O) 2 R b6 、 NR c6 S(O) 2 R b6 、 NR c6 S(O) 2 NR c6 R d6 、 and S(O) 2 NR c6 R d6 is substituted by 1, 2, or 3 substituents independently selected from each R e1 、 R e2 、 R e3 、 R e4 、 and R e5 is independently H, C 1-4 alkyl, CN, OR a6 、 SR b6 、 S(O) 2 R b6 、 C(O)R b6 、 S(O) 2 NR c6 R d6 、 and C(O)NR c6 R d6 selected from, each R a6 、 R b6 、 R c6 、 and R d6 is independently H, C 1-4 alkyl, C 1-4Haloalkyl, C 2-4 Alkenyl, and C 2-4 Alkynyl selected therefrom, said C 1-4 Alkyl, C 2-4 Alkenyl, and C 2-4 Alkynyl is optionally substituted with one, two, or three substituents independently selected from OH, CN, amino, halo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, di(C 1-4 Alkyl)amino, C 1-4 Haloalkyl, and C 1-4 Haloalkoxy, or is optionally substituted with one, two, or three substituents independently selected from OH, CN, amino, halo, C Alternatively, any R c6 And R d6 Together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with one, two, or three substituents independently selected from OH, CN, amino, halo, C 1-6 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, di(C 1-4 Alkyl)amino, C 1-4 Haloalkyl, and C 1-4 Haloalkoxy, and each R Is independently selected from H, C e6 Alkyl, and CN. 1-4

[0018] In some embodiments, W is NR 9 Or O.

[0019] In some embodiments, W is O.

[0020] In some embodiments, W is NR 9 Or CR 17 CR 18

[0021] In some embodiments, W is CR 17CR 18 is as follows.

[0022] In some embodiments, W is NR 9 is as follows.

[0023] In some embodiments, R 9 is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-10 cycloalkyl-C 1-4 alkyl, (5- to 10-membered heteroaryl)-C 1-4 alkyl, or (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl, and the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-10 cycloalkyl-C 1-4 alkyl, (5- to 10-membered heteroaryl)-C 1-4 alkyl, and (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 9a .

[0024] In some embodiments, R 9 is H, C 1-6 alkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C3-10 Cycloalkyl-C 1-4 Alkyl, (5- to 10-membered heteroaryl)-C 1-4 Alkyl, or (4- to 10-membered heterocycloalkyl)-C 1-4 is alkyl, and the C 1-6 Alkyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, (5- to 10-membered heteroaryl)-C 1-4 Alkyl, and (4- to 10-membered heterocycloalkyl)-C 1-4 Each alkyl is optionally substituted with 1, 2, or 3 R 9a groups.

[0025] In some embodiments, R 9 is H, C 1-6 Alkyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, (5- to 10-membered heteroaryl)-C 1-4 Alkyl, or (4- to 10-membered heterocycloalkyl)-C 1-4 is alkyl, and the C 1-6 Alkyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, (5- to 10-membered heteroaryl)-C 1-4 Alkyl, and (4- to 10-membered heterocycloalkyl)-C 1-4 Each alkyl is optionally substituted with R 9a groups.

[0026] In some embodiments, R 9 is H, C 1-6 alkyl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl, C 3-10 cycloalkyl-C 1-4 alkyl, or (5- to 10-membered heteroaryl)-C 1-4 alkyl, and each is optionally substituted with 1, 2, or 3 substituents independently selected from R 9a therefrom.

[0027] In some embodiments, R 9 is H, C 1-6 alkyl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl, or C 3-10 cycloalkyl-C 1-4 alkyl, and each is optionally substituted with 1, 2, or 3 substituents independently selected from R 9a therefrom.

[0028] In some embodiments, R 9 is H, C 1-6 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl, or C 3-10 cycloalkyl-C 1-4 alkyl, and each is optionally substituted with 1, 2, or 3 substituents independently selected from R 9a therefrom.

[0029] In some embodiments, R 9is C optionally substituted by H, OH 1-6 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, or C 3-10 cycloalkyl-C 1-4 alkyl.

[0030] In some embodiments, R 9 is C optionally substituted by H, OH 1-6 alkyl, C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, or C 3-10 cycloalkyl-C 1-4 alkyl.

[0031] In some embodiments, R 9 is H, C 1-6 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, or C 3-10 cycloalkyl-C 1-4 alkyl.

[0032] In some embodiments, R 9 is H, C 1-6 alkyl, C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, or C 3-10 cycloalkyl-C 1-4 alkyl.

[0033] In some embodiments, R 9 is C 1-6 alkyl.

[0034] In some embodiments, R 9 is methyl.

[0035] In some embodiments, R 9 is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from R 9a .

[0036] In some embodiments, R 9 is 5- to 10-membered heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected from R 9a .

[0037] In some embodiments, R 9 is pyridyl optionally substituted with 1, 2, or 3 substituents independently selected from R 9a .

[0038] In some embodiments, R 9 is pyridyl.

[0039] In some embodiments, R 17 and R 18 are each independently H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, 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 c3R d3 、 C(=NR e3 )R b3 、 C(=NR e3 )NR c3 R d3 、 NR c3 C(=NR e3 )NR c3 R d3 、 NR c3 S(O)R b3 、 NR c3 S(O) 2 R b3 、 NR 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 is selected from, and the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 10a .

[0040] In some embodiments, R 17 and R 18 are each independently H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, and CN, and the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10Cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 10a and are unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from R

[0041] In some embodiments, R 17 and R 18 are each independently H, halo, 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, C 2-6 alkynyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 10a and are unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from R

[0042] In some embodiments, R 17 and R 18 are each independently selected from H and C 1-6 alkyl.

[0043] In some embodiments, R 17 is H.

[0044] In some embodiments, R 18 is H.

[0045] In some embodiments, R 17 and R 18 are both H.

[0046] In some embodiments, R 17 and R 18 are both C 1-6 alkyl.

[0047] In some embodiments, R 17 and R 18 together with the carbon atom to which they are attached form a C 3-7Forms a cycloalkyl.

[0048] In some embodiments, R 2 and R 3 are each independently H, CN, C(O)NR c R d , and C 1-7 alkyl, and the C 1-7 alkyl is optionally substituted by one, two, or three substituents independently selected from halo, OR a , CN, NR c R d , and C(O)NR c R d is substituted.

[0049] In some embodiments, R 2 and R 3 are both H.

[0050] In some embodiments, each of R 1 , R 2 , and R 3 is H.

[0051] In some embodiments, each of R 1 , R 2 , R 3 , R 12 , and R 13 is H.

[0052] In some embodiments, each of R 4 , R 5 , R 6 , R 7 , and R 8 is independently H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, CN, OR a1 , SR a1 , C(O)Rb1 、 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(=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 、 S(O)NR c1 R d1 、 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 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each optionally, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO 2 、 OR a1 、 SR a1 、 C(O)R b1 、 C(O)NRc1 R d1 、 C(O)OR a1 、 OC(O)R b1 、 OC(O)NR c1 R d1 、 C(=NR e1 )NR c1 R d1 、 NR c1 C(=NR e1 )NR c1 R d1 、 NR c1 R d1 、 NR c1 C(O)R b1 、 NR c1 C(O)OR a1 、 NR c1 C(O)NR c1 R d1 、 NR c1 S(O)R b1 、 NR c1 S(O) 2 R b1 、 NR 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 is substituted with 1, 2, 3, 4, or 5 substituents independently selected from

[0053] In some embodiments, at least one of R 4 、 R 5 、 R 6 、 R 7 、 and R 8 is other than H.

[0054] In some embodiments, at least two of R 4 、 R 5 、 R 6 、 R 7 、 and R 8 are other than H.

[0055] In some embodiments, R 4 , R 5 , R 6 , R 7 , and R 8 are each independently selected from H, halo, C 1-6 alkyl, C 1-6 haloalkyl, CN, and OR a1 .

[0056] In some embodiments, R 4 , R 5 , R 6 , R 7 , and R 8 are each independently selected from H, halo, and methoxy.

[0057] In some embodiments, R 5 and R 7 are both methoxy, and R 4 , R 6 , and R 8 are each independently selected from H and halo.

[0058] In some embodiments, R 4 is halo, R 5 is methoxy, R 6 is H, R 7 is methoxy, and R 8 is halo.

[0059] In some embodiments, R 10 , R 11 , R 12 , R 13 , R 12a , R 13a , R 14 , and R 15 are each independently selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, 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(=NR e3 )NR c3 R d3 , NR c3 C(=NR e3 )NR c3 R d3 , NR c3 , S(O)R b3 , NR c3 , S(O) 2 R b3 , NR 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 selected from, and the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 10a .

[0060] In some embodiments, R 12 and R 13 are each independently H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl, 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(=NR e3 )NR c3 R d3 , NR c3 C(=NR e3 )NR c3 R d3 , NR c3 S(O)R b3 , NR c3 S(O) 2 R b3 , NR 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 is selected from, and the C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 10a .

[0061] In some embodiments, R 12 and R 13 are each independently H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, 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(=NR e3 )NR c3 R d3 , NR c3 , C(=NR e3 )NR c3 R d3 , NR c3 , S(O)R b3 , NR c3 , S(O) 2 R b3 , NRc3 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 selected from, and the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 10a .

[0062] Alternatively, R 12 and R 13 , together with the carbon atom to which they are attached, form Cy 2 , C 1-6 alkyl, C 1-6 haloalkyl, halo, CN, 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)NR c3 R d3 , NR c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , NR c3 C(=NR e3 )NR c3 R d3 、 S(O)R b3 、 S(O)NRc3 R d3 、 S(O) 2 R b3 、 NR c3 S(O) 2 R b3 、 NR c3 S(O) 2 NR c3 R d3 、 and S(O) 2 NR c3 R d3 to form a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from 1-6 alkyl is optionally Cy 2 、 halo, CN, 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)NR c3 R d3 、 NR c3 C(O)OR a3 、 C(=NR e3 )NR c3 R d3 、 NR c3 C(=NR e3 )NR c3 R d3 、 S(O)R b3 、 S(O)NR c3 R d3 、 S(O) 2 R b3 、 NR c3 S(O) 2 R b3 、 NR c3 S(O) 2 NR c3 R d3 、 and S(O) 2 NR c3 R d3is substituted with 1, 2, or 3 substituents independently selected therefrom. In some embodiments, R 12 and R 13 together with the carbon atom to which they are attached form a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group.

[0063] In some embodiments, the compound has Formula II, III, or IV.

Chemical formula

[0064] In some embodiments, the compound has Formula II.

[0065] In some embodiments where the compound has Formula II, W is NR 9 or CR 17 R 18 is.

[0066] In some embodiments where the compound has Formula II, W is NR 9 is.

[0067] In some embodiments where the compound has Formula II, W is CR 17 R 18 is.

[0068] In some embodiments where the compound has Formula II, X is CR 15 is.

[0069] In some embodiments where the compound has Formula II, X is CH.

[0070] In some embodiments, R 15 is H or a 5- to 10-membered heteroaryl optionally substituted with C 1-6 alkyl.

[0071] In some embodiments, R 10is H, C 1-6 alkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, CN, or C(O)NR c3 R d3 wherein said C 1-6 alkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each optionally Cy 2 , halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, 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 , C(=NR e3 )NR c3 R d3 , NR c3 C(=NR e3 )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 , NR c3 S(O)R b3 , NR c3 S(O) 2 R b3 , NR c3 S(O) 2 NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 Rb3 and S(O) 2 NR c3 R d3 is substituted with 1, 2, 3, 4, or 5 substituents independently selected from 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with Cy 2 , halo, 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 , C(=NR e3 )NR c3 R d3 , NR c3 C(=NR e3 )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 , NR c3 S(O)R b3 , NR c3 S(O) 2 R b3 , NR 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 is substituted with 1, 2, or 3 substituents independently selected from

[0072] In some embodiments, R10 is H, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, CN, or C(O)NR c3 R d3 wherein said C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each optionally Cy 2 , halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, 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 , C(=NR e3 )NR c3 R d3 , NR c3 C(=NR e3 )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 , NR c3 S(O)R b3 , NR c3 S(O) 2 R b3 , NR 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) 2NR c3 R d3 is substituted with 1, 2, 3, 4, or 5 substituents independently selected from, and the C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally, Cy 2 , halo, 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 , C(=NR e3 )NR c3 R d3 , NR c3 C(=NR e3 )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 , NR c3 S(O)R b3 , NR c3 S(O) 2 R b3 , NR 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 is substituted with 1, 2, or 3 substituents independently selected from.

[0073] In some embodiments where the compound has formula II, R 10 is H, C 6-10Aryl, C 3-10 Cycloalkyl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl, CN, or C(O)NR c3 R d3 wherein said C 6-10 Aryl, C 3-10 Cycloalkyl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 10a In some embodiments where the compound has Formula II, R

[0074] is H, C 10 Aryl, C 6-10 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, CN, or C(O)NR 3-10 R c3 wherein said C d3 Aryl, C 6-10 Cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 3-10 In some embodiments where the compound has Formula II, R 10a is H, methyl, ethyl, phenyl, pyrazolyl, piperidinyl, tetrahydropyridinyl, CN, or C(O)NR

[0075] wherein said methyl, ethyl, phenyl, pyrazolyl, piperidinyl, and tetrahydropyridinyl are each optionally substituted with 1, 2, or 3 substituents independently selected from Cy 10 is H, methyl, ethyl, phenyl, pyrazolyl, piperidinyl, tetrahydropyridinyl, CN, or C(O)NR c3 R d3 wherein said methyl, ethyl, phenyl, pyrazolyl, piperidinyl, and tetrahydropyridinyl are each optionally substituted with 1, 2, or 3 substituents independently selected from Cy 2 , NR c3 R d3 , and OR a3 substituted C 1-6 alkyl. In some embodiments where the compound has Formula II, R

[0076] is H, methyl, ethyl, phenyl, pyrazolyl, piperidinyl, tetrahydropyridinyl, CN, or C(O)NR 10is H, phenyl, pyrazolyl, piperidinyl, tetrahydropyridinyl, CN, or C(O)NR c3 R d3 wherein said phenyl, pyrazolyl, piperidinyl, and tetrahydropyridinyl are each optionally, Cy 2 , and OR a3 and are each independently selected from 1, 2, or 3 substituents that are optionally substituted with C 1-6 alkyl.

[0077] In some embodiments where the compound has Formula II, R 10 is H, (4-methylpiperazin-1-yl)phenyl, 1-methyl-1H-pyrazolyl, 1-(2-hydroxyethyl)-1H-pyrazolyl, methylaminocarbonyl, cyano, 1-methyl-1,2,3,6-tetrahydropyridinyl, 1-methylpiperidin-4-yl, dimethylaminocarbonyl, (3-hydroxyazetidin-1-yl)carbonyl, (3-hydroxypyrrolidin-1-yl)carbonyl, (4-methylpiperazin-1-yl)carbonyl, cyclopropylaminocarbonyl, (3-cyanopyrrolidin-1-yl)carbonyl, (3-hydroxypiperidin-1-yl)carbonyl, tetrahydro-2H-pyran-4-yl, (4-methylpiperazin-1-yl)carbonyl, morpholin-4-ylcarbonyl, or (4,4-difluoropiperidin-1-yl)carbonyl.

[0078] In some embodiments where the compound has Formula II, R 10is H, (4-methylpiperazin-1-yl)phenyl, 1-methyl-1H-pyrazolyl, 1-(2-hydroxyethyl)-1H-pyrazolyl, methylaminocarbonyl, cyano, 1-methyl-1,2,3,6-tetrahydropyridinyl, 1-methylpiperidin-4-yl, dimethylaminocarbonyl, (3-hydroxyazetidin-1-yl)carbonyl, (3-hydroxypyrrolidin-1-yl)carbonyl, (4-methylpiperazin-1-yl)carbonyl, cyclopropylaminocarbonyl, (3-cyanopyrrolidin-1-yl)carbonyl, or (3-hydroxypiperidin-1-yl)carbonyl.

[0079] In some embodiments where the compound has Formula II, R 10is H, (4-methylpiperazin-1-yl)phenyl, 1-methyl-1H-pyrazolyl, 1-(2-hydroxyethyl)-1H-pyrazolyl, methylaminocarbonyl, cyano, 1-methyl-1,2,3,6-tetrahydropyridinyl, 1-methylpiperidin-4-yl, dimethylaminocarbonyl, (3-hydroxyazetidin-1-yl)carbonyl, (3-hydroxypyrrolidin-1-yl)carbonyl, (4-methylpiperazin-1-yl)carbonyl, cyclopropylaminocarbonyl, (3-cyanopyrrolidin-1-yl)carbonyl, (3-hydroxypiperidin-1-yl)carbonyl, morpholin-4-ylmethyl, (4-methylpiperazin-1-yl)methyl, 4-ethylpiperazin-1-yl)methyl, 4-(2-hydroxyethyl)piperazin-1-yl]methyl, cyanoethylpiperazinylmethyl, cyanopiperidinylmethyl, cyanopyrrolidinylmethyl, (1-methylpiperidin-4-yl)aminomethyl, (tetrahydrofuran-3-ylamino)methyl, 1H-imidazol-1-ylmethyl, 1H-pyrazol-1-ylmethyl, (1-methyl-1H-pyrazol-4-yl)methyl, 2-pyridin-2-ylethyl, 2-morpholin-4-ylethyl, 2-(diethylamino)ethyl, 2-(3-fluoroazetidin-1-yl)ethyl, 2-(3-methoxyazetidin-1-yl)ethyl, (4-ethylpiperazin-1-yl)methyl, 3-(dimethylamino)pyrrolidin-1-yl]methyl, 2-(4-ethylpiperazin-1-yl)ethyl, 2-(4-methylpiperazin-1-yl)ethyl, (pyridin-3-yloxy)methyl, (2-oxopyridin-1(2H)-yl)methyl, (3-cyanoazetidin-1-yl)methyl, (3-fluoroazetidin-1-yl)methyl, or (3-hydroxyazetidin-1-yl)methyl.

[0080] In some embodiments where the compound has formula II, R 10is morpholin-4-ylmethyl, (4-methylpiperazin-1-yl)methyl, 4-ethylpiperazin-1-yl)methyl, (4-methylpiperazin-1-yl)methyl, 4-(2-hydroxyethyl)piperazin-1-yl]methyl, cyanoethylpiperazinylmethyl, cyanopiperidinylmethyl, cyanopyrrolidinylmethyl, (1-methylpiperidin-4-yl)aminomethyl, (tetrahydrofuran-3-ylamino)methyl, 1H-imidazol-1-ylmethyl, 1H-pyrazol-1-ylmethyl, (1-methyl-1H-pyrazol-4-yl)methyl, 2-pyridin-2-ylethyl, 2-morpholin-4-ylethyl, 2-(diethylamino)ethyl, 2-(3-fluoroazetidin-1-yl)ethyl, 2-(3-methoxyazetidin-1-yl)ethyl, (4-ethylpiperazin-1-yl)methyl, 3-(dimethylamino)pyrrolidin-1-yl]methyl, or 2-(4-ethylpiperazin-1-yl)ethyl, 2-(4-methylpiperazin-1-yl)ethyl.

[0081] In some embodiments where the compound has formula II, R 10 is morpholin-4-ylmethyl, (4-methylpiperazin-1-yl)methyl, 4-ethylpiperazin-1-yl)methyl, (4-methylpiperazin-1-yl)methyl, 4-(2-hydroxyethyl)piperazin-1-yl]methyl, cyanoethylpiperazinylmethyl, cyanopiperidinylmethyl, cyanopyrrolidinylmethyl, 1H-imidazol-1-ylmethyl, 1H-pyrazol-1-ylmethyl, (1-methyl-1H-pyrazol-4-yl)methyl, (4-ethylpiperazin-1-yl)methyl, or 3-(dimethylamino)pyrrolidin-1-yl]methyl.

[0082] In some embodiments where the compound has formula II, R 10is 2-pyridin-2-ylethyl, 2-morpholin-4-ylethyl, 2-(diethylamino)ethyl, 2-(3-fluoroazetidin-1-yl)ethyl, 2-(3-methoxyazetidin-1-yl)ethyl, 2-(4-ethylpiperazin-1-yl)ethyl, or 2-(4-methylpiperazin-1-yl)ethyl.

[0083] In some embodiments, R 10 is Cy 2 , NR c3 R d3 , and OR a3 and is independently selected from 1, 2, or 3 substituents that are optionally substituted with C 1-6 alkyl that is optionally substituted with C 1-6 alkyl.

[0084] In some embodiments, R 10 is C 1-6 alkyl optionally substituted with 4- to 7-membered heterocycloalkyl, where the 4- to 7-membered heterocycloalkyl is optionally halo, C 1-6 alkyl, C 1-6 haloalkyl, CN, OR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , OC(O)R b5 , NR c5 R d5 , and NR c5 C(O)R b5 and is substituted with 1, 2, or 3 substituents independently selected from

[0085] In some embodiments where the compound has Formula II, R 10 is C 1-6 alkyl optionally substituted with 4- to 7-membered heterocycloalkyl, where the 4- to 7-membered heterocycloalkyl is selected from morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, and azetidinyl, and the 4- to 7-membered heterocycloalkyl is optionally halo, C 1-6Alkyl, C 1-6 Haloalkyl, CN, OR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , OC(O)R b5 , NR c5 R d5 , and NR c5 C(O)R b5 is substituted with 1, 2, or 3 substituents independently selected from

[0086] In some embodiments, R c3 and R d3 together with the nitrogen atom to which they are attached form a 4, 5, 6, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from 1-6 alkyl, C 1-6 haloalkyl, halo, CN, OR a6 , and NR c6 R d6

[0087] In some embodiments, Cy 2 is halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, 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 , NR c5 R d5 , C(=NR e5 )R​b5 , C(=NR e5 )NR c5 R d5 , NR c5 C(=NR e5 )NR c5 R d5 , NR c5 S(O)R b5 , NR c5 S(O) 2 R b5 , NR 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 is selected from 4- to 7-membered heterocycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from

[0088] In some embodiments where the compound has Formula II, R 10 is H.

[0089] In some embodiments where the compound has Formula II, R 10 is other than H.

[0090] In some embodiments where the compound has Formula II, R 17 and R 18 are each independently H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, CN, NO 2 , OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)ORa3 , 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(=NR e3 )NR c3 R d3 , NR c3 , C(=NR e3 )NR c3 R d3 , NR c3 , S(O)R b3 , NR c3 , S(O) 2 R b3 , NR 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 is selected from, and the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 10a .

[0091] In some embodiments where the compound has formula II, R 17 and R 18 are each independently H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, and CN, and the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 10a to

[0092] In some embodiments where the compound has Formula II, R 17 and R 18 are each independently selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl, and the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 10a to

[0093] In some embodiments where the compound has Formula II, R 17 and R 18 are both C 1-6 alkyl.

[0094] In some embodiments where the compound has Formula II, R 17 and R 18 are both methyl.

[0095] In some embodiments where the compound has Formula II, R 17 and R 18 are each independently selected from H and halo.

[0096] In some embodiments where the compound has Formula II, R 17 is H.

[0097] In some embodiments where the compound has Formula II, R 18 is H.

[0098] In some embodiments where the compound has Formula II, R 17 and R 18 are both H.

[0099] In some embodiments, R 17 and R 18 , together with the carbon atom to which they are attached, form a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, each optionally, Cy 2 , C 1-6 alkyl, C 1-6 haloalkyl, halo, CN, 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)NR c3 R d3 , NR c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , NR c3 C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , NR c3 S(O)2 R b3 、 NR c3 S(O) 2 NR c3 R d3 、および S(O) 2 NR c3 R d3 is substituted with 1, 2, or 3 substituents independently selected from 1-6 the C 2 alkyl is optionally Cy a3 、 halo, CN, OR a3 、 SR b3 、 C(O)R c3 、 C(O)NR d3 R a3 、 C(O)OR b3 、 OC(O)R c3 、 OC(O)NR d3 R c3 、 NR d3 R c3 、 NR b3 C(O)R c3 、 NR c3 C(O)NR d3 R c3 、 NR a3 C(O)OR e3 、 C(=NR c3 )NR d3 R c3 、 NR e3 C(=NR c3 )NR d3 R b3 、 S(O)R c3 、 S(O)NR d3 R 2 、 S(O) b3 R c3 、 NR 2 S(O) b3 R c3 、 NR 2 S(O) c3 NR d3 R 2 、および S(O) c3 NR d3 R

[0100] In some embodiments, R 17 and R 18Together with the carbon atom to which they are attached, they form a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group.

[0101] In some embodiments, R 17 and R 18 together with the carbon atom to which they are attached form a cyclobutyl group or a cyclopentyl group.

[0102] In some embodiments, R 17 and R 18 together with the carbon atom to which they are attached are Cy 2 , C 1-6 alkyl, C 1-6 haloalkyl, halo, CN, 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)NR c3 R d3 , NR c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , NR c3 C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , NR c3 S(O) 2 R b3 , NR c3 S(O) 2 , NR c3 R d3 , and S(O) 2 , NR c3 R d3forms a 4-, 5-, 6-, or 7-membered heterocycloalkyl group substituted with 1, 2, or 3 substituents independently selected therefrom, and said C 1-6 Alkyl is optionally Cy 2 , halo, CN, 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)NR c3 R d3 , NR c3 , C(O)OR a3 , C(=NR e3 ), NR c3 R d3 , NR c3 , C(=NR e3 ), NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , NR c3 , S(O) 2 R b3 , NR c3 , S(O) 2 , NR c3 R d3 , and S(O) 2 , NR c3 R d3 is substituted with 1, 2, or 3 substituents independently selected therefrom.

[0103] In some embodiments, R 17 and R 18 together with the carbon atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with C 1-6 alkyl.

[0104] In some embodiments, R 17 and R 18 together with the carbon atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group.

[0105] In some embodiments, R 17 and R 18 together with the carbon atom to which they are attached form a tetrahydropyran ring or an N-methylpiperidine ring.

[0106] In some embodiments, the compound has Formula IIa.

Chemical formula

[0107] In some embodiments, the compound has Formula IIb.

Chemical formula

[0108] In some embodiments, the compound has Formula III.

[0109] In some embodiments where the compound has Formula III, Z is CH.

[0110] In some embodiments where the compound has Formula III, Y is S.

[0111] In some embodiments where the compound has Formula III, R 11 is H.

[0112] In some embodiments, the compound has Formula IIIa.

Chemical formula

[0113] In some embodiments, the compound has Formula IIIb. [Chem.]

[0114] In some embodiments, the compound has Formula IV.

[0115] In some embodiments, R 14 is selected from H, C 1-6 alkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, and CN, wherein the C 1-6 alkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R 10a .

[0116] In some embodiments where the compound has Formula IV, R 14 is H, C 1-6 alkyl, 3- to 10-membered heterocycloalkyl, or CN, wherein the C 1-6 alkyl and 3- to 10-membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 10a .

[0117] In some embodiments where the compound has Formula IV, R 14 is H, C 1-6 alkyl, 4- to 10-membered heterocycloalkyl, or CN, wherein the C 1-6 alkyl and 4- to 10-membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 10a .

[0118] In some embodiments where the compound has Formula IV, R 14is H, methyl, 1-methylpiperidinyl, CN, cyanomethyl, or 2-hydroxyethyl.

[0119] In some embodiments where the compound has formula IV, R 14 is H.

[0120] In some embodiments where the compound has formula IV, R 14 is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from R 10a .

[0121] In some embodiments, R 14 is phenyl optionally substituted with R 10a .

[0122] In some embodiments, R 14 is (4-ethylpiperazin-1-yl)phenyl.

[0123] In some embodiments, the compound has formula IVa.

Chemical formula

[0124] In some embodiments, the compound has formula IVb.

Chemical formula

[0125] In some embodiments, the compound has formula V.

Chemical formula

[0126] In some embodiments where the compound has formula V, W is NR 9 .

[0127] In some embodiments where the compound has formula V, R 9 is H, C 1-6 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl, or C 3-10 cycloalkyl-C 1-4 alkyl, each optionally substituted with 1, 2, or 3 substituents independently selected from R 9a and is substituted with 1, 2, or 3 substituents independently selected from R

[0128] In some embodiments where the compound has formula V, R 9 is H, C 1-6 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, or C 3-10 cycloalkyl-C 1-4 alkyl.

[0129] In some embodiments where the compound has formula V, R 9 is C 9a aryl-C 6-10 alkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 1-4 and is substituted with 1, 2, 3, 4, or 5 substituents independently selected from R

[0130] In some embodiments where the compound has formula V, R 9 is benzyl optionally substituted with 1, 2, or 3 substituents independently selected from R 9a and is substituted with 1, 2, or 3 substituents independently selected from R

[0131] In some embodiments where the compound has formula V, R 9 is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from R 9a and is substituted with 1, 2, or 3 substituents independently selected from R

[0132] In some embodiments where the compound has formula V, R 9is H, C 1-6 alkyl, C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, or C 3-10 cycloalkyl-C 1-4 is alkyl.

[0133] In some embodiments where the compound has formula V, R 9 is C 3-10 is cycloalkyl.

[0134] In some embodiments where the compound has formula V, R 9 is cyclobutyl.

[0135] In some embodiments where the compound has formula V, R 9 is C 1-6 is alkyl.

[0136] In some embodiments, R 9 is methyl, ethyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, 3-fluorophenylmethyl, or 4-chloro-2-fluorophenyl.

[0137] In some embodiments where the compound has formula V, R 9 is methyl, ethyl, cyclopropyl, or cyclopropylmethyl.

[0138] In some embodiments where the compound has formula V, R 9 is methyl.

[0139] In some embodiments where the compound has formula V, R 2 and R 3 are each independently selected from H, CN, C(O)NR c R d and C 1-7 alkyl, where the C 1-7 alkyl is optionally halo, OR a CN, NRc R d 、 and C(O)NR c R d is substituted by 1, 2, or 3 substituents independently selected from

[0140] In some embodiments where the compound has formula V, R 2 and R 3 are each H.

[0141] In some embodiments where the compound has formula V, R 2 and R 3 are each H.

[0142] In some embodiments where the compound has formula V, R 1 , R 2 , and R 3 are each H.

[0143] In some embodiments where the compound has formula V, R 4 , R 5 , R 6 , R 7 , and R 8 are each independently H, halo, C 1-6 alkyl, C 1-6 haloalkyl, CN, and OR a1 selected from.

[0144] In some embodiments where the compound has formula V, R 4 , R 5 , R 6 , R 7 , and R 8 are each independently selected from H, halo, and methoxy.

[0145] In some embodiments where the compound has formula V, R 5 and R 7 are both methoxy, and R 4 , R 6 , and R 8 are each independently selected from H and halo.

[0146] In some embodiments where the compound has formula V, R 4 is halo, R 5 is methoxy, R 6 is H, R 7 is methoxy, R 8 is halo.

[0147] In some embodiments where the compound has formula V, Q is absent.

[0148] In some embodiments where the compound has formula V, Q is O, NR 16a , or CR 12a R 13a .

[0149] In some embodiments where the compound has formula V, R 12 and R 13 are each independently H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl, 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(=NR e3 )NRc3 R d3 、 NR c3 C(=NR e3 )NR c3 R d3 、 NR c3 S(O)R b3 、 NR c3 S(O) 2 R b3 、 NR 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 is selected from, and said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 10a .

[0150] In some embodiments where the compound has formula V, R 12 and R 13 are each independently H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, 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 Rd3 、 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(=NR e3 )NR c3 R d3 、 NR c3 C(=NR e3 )NR c3 R d3 、 NR c3 S(O)R b3 、 NR c3 S(O) 2 R b3 、 NR 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 selected from, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 10a therefrom.

[0151] In some embodiments where the compound has formula V, R 12 and R 13 together with the carbon atom to which they are attached form a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, each optionally 2 Cy 1-6 alkyl, C1-6 Haloalkyl, halo, CN, 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)NR c3 R d3 , NR c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , NR c3 C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , NR c3 , NR 2 S(O) b3 , NR c3 , NR 2 S(O) c3 R d3 , and S(O) 2 , NR c3 R d3 is substituted with 1, 2, or 3 substituents independently selected from 1-6 alkyl is optionally, Cy 2 , halo, CN, 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 , NRc3 C(O)NR c3 R d3 、NR c3 C(O)OR a3 、C(=NR e3 )NR c3 R d3 、NR c3 C(=NR e3 )NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O) 2 R b3 、NR c3 S(O) 2 R b3 、NR c3 S(O) 2 NR c3 R d3 、およびS(O) 2 NR c3 R d3 is substituted with 1, 2, or 3 substituents independently selected from

[0152] In some embodiments where the compound has formula V, R 12 and R 13 together with the carbon atom to which they are attached form a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group.

[0153] In some embodiments where the compound has formula V, R 12 and R 13 are each H.

[0154] In some embodiments where the compound has formula V, R 2 , R 3 , R 12 and R 13 are each H.

[0155] In some embodiments where the compound has formula V, n is 1.

[0156] In some embodiments where the compound has formula V, n is 1 and Q is absent.

[0157] In some embodiments where the compound has formula V, n is 0.

[0158] In some embodiments, the compound has formula Va. [Chemical formula]

[0159] In some embodiments, the compound has formula Vb. [Chemical formula]

[0160] It is further understood that certain features of the invention, which are described in the context of separate embodiments for clarity, may also be provided in combination with a single embodiment. Conversely, various features of the invention that are described in the context of a single embodiment for brevity may also be provided separately or in any suitable partial combination.

[0161] At various places in this specification, the substituents of the compounds of the invention are disclosed in groups or ranges. The invention is specifically intended to include any and every individual partial combination of the members of such groups and ranges. For example, the term "C 1-6 alkyl" is specifically intended to individually disclose methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.

[0162] At various places in this specification, various aryl, heteroaryl, cycloalkyl, and heterocycloalkyl rings are described. Unless otherwise indicated, these rings can be attached to the rest of the molecule at any ring member, when permitted by valence. For example, the term "pyridine ring" can refer to a pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl ring.

[0163] When the term "n-membered" is used where n is an integer, it typically 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.

[0164] For compounds of the invention where a variable appears more than once, each variable can be a different moiety independently selected from the group defining that variable. For example, when the structure is described as having two R groups that are present simultaneously on the same compound, the two R groups can represent different moieties independently selected from the group defined for R.

[0165] As used herein, the expression "optionally substituted" means unsubstituted or substituted.

[0166] As used herein, the term "substituted" means that a hydrogen atom is replaced by a non-hydrogen group. It should be understood that substitution at a given atom is limited by valence.

[0167] As used herein, when i and j are integers, the term "C i-j " used in combination with a chemical group denotes the number of carbon atoms in various ranges in the chemical group using i - j to define the range. For example, C 1-6Alkyl refers to an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms.

[0168] As used herein, the term "alkyl," used alone or in combination with other terms, refers to a saturated hydrocarbon group that can be straight-chain or branched-chain. In some embodiments, the alkyl group contains 1-7, 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, n-heptyl, etc. In some embodiments, the alkyl group is methyl, ethyl, or propyl.

[0169] As used herein, the term "alkenyl," used alone or in combination with other terms, refers to an alkyl group having one or more carbon-carbon double bonds. In some embodiments, the alkenyl moiety contains 2-6 or 2-4 carbon atoms. Exemplary alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, etc.

[0170] As used herein, the term "alkynyl," used alone or in combination with other terms, refers to an alkyl group having one or more carbon-carbon triple bonds. Exemplary alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, etc. In some embodiments, the alkynyl moiety contains 2-6 or 2-4 carbon atoms.

[0171] As used herein, the term "halo" or "halogen," used alone or in combination with other terms, includes fluoro, chloro, bromo, and iodo. In some embodiments, halo is F or Cl.

[0172] As used herein, the term "haloalkyl", used alone or in combination with other terms, refers to an alkyl group having substituents of halogen atoms of the maximum total valence number which may be the same or different. In some embodiments, the halogen atom is a fluoro atom. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. Exemplary 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", used alone or in combination with other terms, refers to a group of the formula -O-alkyl. Exemplary alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy and the like. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

[0174] As used herein, the term "haloalkoxy", used alone or in combination with other terms, refers to a group of the formula -O-(haloalkyl). In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. An exemplary haloalkoxy group is -OCF 3 .

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

[0176] As used herein, the term "alkylamino," used alone or in combination with other terms, refers to a group of the formula -NH(alkyl). In some embodiments, the alkylamino group has 1 to 6 or 1 to 4 carbon atoms. Exemplary alkylamino groups include methylamino, ethylamino, propylamino (e.g., n-propylamino and isopropylamino), and the like.

[0177] As used herein, the term "dialkylamino," used alone or in combination with other terms, refers to a group of the formula -N(alkyl) 2 In some embodiments, each alkyl group independently has 1 to 6 or 1 to 4 carbon atoms. Exemplary dialkylamino groups include dimethylamino, diethylamino, dipropylamino (e.g., di(n-propyl)amino and di(isopropyl)amino), and the like.

[0178] As used herein, the term "alkylthio," used 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.

[0179] As used herein, the term "cycloalkyl", used alone or in combination with other terms, refers to non-aromatic cyclic hydrocarbons including cycloalkyl and alkenyl groups. The cycloalkyl group can include a monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings, bridged rings, or spiro rings) ring system. Also included within the definition of cycloalkyl are moieties having one or more aromatic rings fused (i.e., having a common bond) to the cycloalkyl ring, such as, for example, benzo derivatives of cyclopentane, cyclohexene, cyclohexane, or pyrido derivatives of cyclopentane or cyclohexane. The carbon atoms forming the ring of the cycloalkyl group can optionally be substituted by oxo. The cycloalkyl group also includes cycloalkylidene. Also, the term "cycloalkyl" includes bridged cycloalkyl groups (e.g., non-aromatic cyclic hydrocarbon moieties containing at least one bridgehead carbon such as adamantan-1-yl) and spirocycloalkyl groups (e.g., non-aromatic hydrocarbon moieties containing at least two rings fused at a single carbon atom such as spiro[2.5]octane). In some embodiments, the cycloalkyl group has 3 to 10 ring members, or 3 to 7 ring members. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is C 3-7 a monocyclic cycloalkyl group. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, tetrahydronaphthalenyl, octahydronaphthalenyl, indanyl, and the like. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0180] As used herein, the term "cycloalkylalkyl", used alone or in combination with other terms, refers to a group of the formula cycloalkyl-alkyl-. In some embodiments, the alkyl moiety has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atom(s). In some embodiments, the alkyl moiety is methylene. In some embodiments, the cycloalkyl moiety has 3 to 10 or 3 to 7 ring members. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl moiety is monocyclic. In some embodiments, the cycloalkyl moiety is C 3-7 a monocyclic cycloalkyl group.

[0181] As used herein, the term "heterocycloalkyl," used alone or in combination with other terms, refers to a non-aromatic ring or ring system, which optionally may contain one or more alkenylene or alkynylene groups as part of the ring structure and has at least one heteroatom ring member independently selected from nitrogen, sulfur, oxygen, and phosphorus. The heterocycloalkyl group can include a monocyclic or bicyclic (e.g., having 2, 3, or 4 fused, bridged, or spiro rings) ring system. 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 is a moiety having one or more aromatic rings (e.g., aryl or heteroaryl rings) fused to (i.e., having a common bond with) a non-aromatic heterocycloalkyl ring such as, for example, 1,2,3,4-tetrahydro-quinoline. The heterocycloalkyl group can also include a bridgehead heterocycloalkyl group (e.g., a heterocycloalkyl moiety containing at least one bridgehead atom such as azadamantan-1-yl) and a spiroheterocycloalkyl group (e.g., a heterocycloalkyl moiety containing at least two rings fused at a single atom such as [1,4-dioxa-8-aza-spiro[4.5]decan-N-yl]). In some embodiments, the heterocycloalkyl group has 3 to 10 ring-forming atoms, 4 to 10 ring-forming atoms, or about 3 to 8 ring-forming atoms. In some embodiments, the heterocycloalkyl group has 2 to 20 carbon atoms, 2 to 15 carbon atoms, 2 to 10 carbon atoms, or about 2 to 8 carbon atoms. In some embodiments, the heterocycloalkyl group has 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 to 2 heteroatoms. The carbon atoms or heteroatoms in the ring(s) of the heterocycloalkyl group can be oxidized to form a carbonyl, N-oxide, or sulfonyl group (or other oxidized bond), or a nitrogen atom can be quaternized. In some embodiments, the heterocycloalkyl moiety is C 2-7It is a monocyclic heterocycloalkyl group. In some embodiments, the heterocycloalkyl group is a morpholine ring, a pyrrolidine ring, a piperazine ring, a piperidine ring, a tetrahydropyran ring, a tetrahydropyridine, an azetidine ring, or a tetrahydrofuran ring.

[0182] As used herein, the term "heterocycloalkylalkyl," used alone or in combination with other terms, refers to a group of the formula heterocycloalkyl-alkyl-. In some embodiments, the alkyl moiety has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atom(s). In some embodiments, the alkyl moiety is methylene. In some embodiments, the heterocycloalkyl moiety has 3 to 10 ring members, 4 to 10 ring members, or 3 to 7 ring members. In some embodiments, the heterocycloalkyl group is monocyclic or bicyclic. In some embodiments, the heterocycloalkyl moiety is monocyclic. In some embodiments, the heterocycloalkyl moiety is C 2-7 It is a monocyclic heterocycloalkyl group.

[0183] As used herein, the term "aryl," used alone or in combination with other terms, refers to a monocyclic or polycyclic (e.g., having two fused rings) aromatic hydrocarbon moiety such as, but not limited to, phenyl, 1-naphthyl, 2-naphthyl, etc. In some embodiments, the aryl group has 6 to 10 carbon atoms or 6 carbon atoms. In some embodiments, the aryl group is a monocyclic or bicyclic group. In some embodiments, the aryl group is phenyl or naphthyl.

[0184] As used herein, the term "arylalkyl," used alone or in combination with other terms, refers to a group of the formula aryl-alkyl-. In some embodiments, the alkyl moiety has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atom(s). In some embodiments, the alkyl moiety is methylene. In some embodiments, the aryl moiety is phenyl. In some embodiments, the aryl group is a monocyclic or bicyclic group. In some embodiments, the arylalkyl group is benzyl.

[0185] As used herein, the term "heteroaryl", used alone or in combination with other terms, refers to a monocyclic or polycyclic (e.g., having two or three fused rings) aromatic hydrocarbon moiety having one or more heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl group is a monocyclic or bicyclic group having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. Exemplary heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, pyrrolyl, azolyl, quinolinyl, isoquinolinyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl, and the like. The carbon or heteroatoms in the ring(s) of the heteroaryl group can be oxidized to form a carbonyl, N-oxide, or sulfonyl group (or other oxidized bond), or the nitrogen atom can be quaternized, provided that the aromatic nature of the ring is preserved. In some embodiments, the heteroaryl group has 3 to 10 carbon atoms, 3 to 8 carbon atoms, 3 to 5 carbon atoms, 1 to 5 carbon atoms, or 5 to 10 carbon atoms. In some embodiments, the heteroaryl group contains 3 to 14, 4 to 12, 4 to 8, 9 to 10, or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to 4, 1 to 3, or 1 to 2 carbon atoms.

[0186] As used herein, the term "heteroarylalkyl," used alone or in combination with other terms, refers to a group of the formula heteroaryl-alkyl-. In some embodiments, the alkyl moiety has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atom(s). In some embodiments, the alkyl moiety is methylene. In some embodiments, the heteroaryl moiety is a monocyclic or bicyclic group having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl moiety has 5 to 10 carbon atoms.

[0187] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). Unless otherwise specified, all stereoisomers such as enantiomers and diastereomers are contemplated. Compounds of the invention containing an asymmetrically substituted carbon atom can be isolated as an optically active form or as a racemate. Methods for how to prepare optically active forms from optically inactive starting materials are known in the art and include, for example, by resolution of a racemic mixture or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, etc. can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. The cis and trans geometric isomers of the compounds of the invention are described and can be isolated as a mixture of isomers or as a separated isomeric form.

[0188] The resolution of a racemic mixture of a compound can be carried out by any of a number of methods known in the art. Exemplary methods include fractional recrystallization using a chiral resolving acid, which is an optically active salt-forming organic acid. Resolving agents suitable for the fractional recrystallization method are, for example, optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, D- and L-lactic acid, or various optically active camphorsulfonic acids. Other resolving agents suitable for the fractional crystallization method include stereoisomerically pure forms of methylbenzylamine (e.g., S- and R-forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like. The resolution of the racemic mixture can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent compositions can be determined by those skilled in the art.

[0189] The compounds of the present invention also include tautomers. Tautomers result from the exchange of a single bond with an adjacent double bond, along with the accompanying movement of a proton. Tautomers include prototropic tautomers, which are isomeric protonation states having the same empirical formula and total charge. Exemplary prototropic tautomers include keto-enol pairs, amide-imido acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms where a proton can occupy two or more positions in a heterocyclic system, such as 1H- and 3H-imidazole, 1H-, 2H-, and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomers can be in an equilibrium state or can be stereochemically fixed into one form by appropriate substitution.

[0190] The compounds of the present invention also include all isotopes of atoms that occur in the intermediates or final compounds. Isotopes include atoms that have the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0191] As used herein, the term "compound" is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures shown.

[0192] All compounds, and their pharmaceutically acceptable salts, may be found together with, or isolated from, other substances such as water and solvents (e.g., in the form of hydrates and solvates).

[0193] In some embodiments, the compounds of the present invention, or salts thereof, are substantially isolated. "Substantially isolated" means that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched in the compound of the present invention. Substantial separation can include a composition containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compound of the present invention, or a salt thereof. Methods for isolating compounds and their salts are conventional in the art.

[0194] The expression "pharmaceutically acceptable" as used herein refers to compounds, substances, compositions, and / or dosage forms that are suitable for use in contact with human and animal tissues within the scope of sound medical judgment, without excessive toxicity, irritation, allergic reaction, or other problems or complications, and commensurate with a reasonable benefit / risk ratio.

[0195] In addition, the present invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds in which the parent compound is modified by converting an existing acidic or basic moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, and alkali or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts of the present invention include, for example, non-toxic salts of the parent compounds formed from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water, in an organic solvent, or in a mixture of the two, and generally, non-aqueous media such as ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol), or acetonitrile (ACN) are preferred. A list of suitable salts can be found in Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is hereby incorporated by reference in its entirety.

[0196] Synthesis The compounds of the present invention, including their salts, can be prepared using known organic synthesis techniques and can be synthesized according to any of a number of possible synthetic routes.

[0197] The reactions for preparing the compounds of the present invention can be carried out in a suitable solvent that can be readily selected by an expert in the field of organic synthesis. A suitable solvent can be substantially non-reactive with the starting materials (reactants), intermediates, or products, at a temperature at which the reaction is carried out, for example, a temperature that can range from the freezing temperature of the solvent to the boiling temperature of the solvent. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, a solvent suitable for the particular reaction step can be selected by one skilled in the art.

[0198] The preparation of the compounds of the present invention can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, as well as the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemical nature of protecting groups can be found, for example, in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., Wiley & Sons, Inc., New York (1999), which is hereby incorporated by reference in its entirety.

[0199] The reaction can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., ultraviolet-visible), mass spectrometry, etc., or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC).

[0200] As used herein, the expressions "ambient temperature", "room temperature", and "r.t." are understood in the art and generally refer to the temperature, for example, the reaction temperature, approximately the temperature of the room in which the reaction is being carried out, for example, a temperature of about 20 °C to about 30 °C.

[0201] The compounds of the present invention can be prepared according to a number of preparation routes known in the literature. An exemplary synthetic method for preparing the compounds of the present invention is provided in the following scheme.

[0202] A series of urea derivatives of formula 5 can be prepared by the method outlined in Scheme 1. Compound 2 can be prepared by treating a suitable amine R 9 NH 2 with aldehyde 1, followed by reductive amination with aniline 3 to obtain diamino compound 4. Cyclization of diamino compound 4 with an equivalent such as triphosgene, or carbonyldiimidazole (CDI), phosgene, diphosgene, etc., but not limited thereto, can give a urea derivative of formula 5.

Chemical formula

[0203] Similarly, a series of urea derivatives of formula 9 can be prepared by the method outlined in Scheme 2. Ketone 6 can be obtained by reaction of aldehyde 1 with a suitable Grignard reagent R 2 MgX or alkyllithium R 2 Li, followed by oxidation. Conversion of ketone 6 to the corresponding aminoketone 7 can be achieved by replacement of chlorine with a suitable amine R 9 NH 2 Diamino derivative 8 can be obtained by reductive amination of ketone 7 with aniline 3 using a suitable reducing agent such as sodium cyanoborohydride, or sodium borohydride, etc., but not limited thereto. Cyclization of diamino compound 8 with triphosgene or carbonyldiimidazole (CDI), phosgene, diphosgene, etc., can give a urea derivative of formula 9.

Chemical formula

[0204] A series of aniline derivatives 14 can be prepared according to the procedure outlined in Scheme 3. Replacement of the fluorine in compound 10 with benzylamine (BnNH 2 ) gives aniline 11, which can be reacted with a suitable sodium alkoxide (NaOR, where R is, for example, methyl, alkyl, or R a1 ), and then converted to a bis-ether by saponification to give acid 12. Compound 13 can be obtained by decarboxylation of benzoic acid 12, and then the protecting group can be removed by hydrogenation to give aniline 14.

Chemical Structure

[0205] A series of aniline derivatives 18 can be prepared according to the procedure outlined in Scheme 4. Treatment of aniline 15 (where R = methyl or alkyl) with acetic anhydride or acetyl chloride at low temperature gives compound 16. Treatment of compound 16 with sulfuryl chloride gives compound 17, which can be converted to aniline derivative 18 by removal of the acetyl group under basic conditions.

Chemical Structure

[0206] A series of aniline derivatives 21 can be prepared according to the procedure outlined in Scheme 5. Treatment of compound 16 with Selectfluor® gives the desired monofluoride 19, which can be converted to compound 20 by treatment with sulfuryl chloride. The acetyl group of 20 can be removed under basic conditions to give aniline derivative 21.

Chemical Structure

[0207] A series of 1H-pyrrolo[2,3-b]pyridine urea derivatives 26 can be prepared according to the procedure outlined in Scheme 6. Under basic conditions, protection of 1H-pyrrolo[2,3-b]pyridine urea 22, which can be prepared according to the procedure described in Scheme 1 using a suitable protecting reagent such as PhSO 2 Cl, etc., gives the corresponding protected urea 23. Urea halide 24 (L = halo) can be prepared by treating urea 23 at low temperature with a strong base such as LDA, LiHMDS, NaHMDS, or butyllithium, etc., in an inert solvent such as THF, ether, or HMPA, etc., but not limited to these, to obtain a metallated intermediate, followed by treatment with a halogen reagent such as iodine, bromine, 1,2-dibromo-1,1,2,2-tetrachloroethane, NBS, or NIS, etc. Deprotection of urea halide 24 gives the corresponding deprotected product 25, which can be further converted to the desired urea derivative 26 by Suzuki coupling using an appropriate boronic acid or ester R 10 B(OR”) 2 (R” = H or alkyl). [Chemical Structure]

[0208] Alternatively, a series of 1H-pyrrolo[2,3-b]pyridine urea derivatives 30 can be prepared according to the procedure outlined in Scheme 7. Compound 27 can be prepared using the procedure described in Scheme 6. Chlorination of compound 27 with sulfuryl chloride gives dichloride 28 (X 1 =X 2 =Cl). Treatment of compound 27 with Selectfluor® gives a fluoro-substituted compound 28 (X 1 =X 2 =F). Removal of the protecting group from compound 28, followed by treatment with the above-mentioned appropriate boronic acid or ester R 10 B(OR’’) 2The Suzuki coupling of compound 29 using (R’’ = H or alkyl) can afford the 1H-pyrrolo[2,3-b]pyridine urea derivative 30. [Chemical formula]

[0209] A series of amide derivatives 33 can be prepared according to the method outlined in Scheme 8. Treatment of protected urea 23 with a strong base such as LDA, LiHMDS, NaHMDS, or butyllithium, etc. in an inert solvent such as THF, ether, or HMPA, etc. (but not limited to these), followed by addition of dry ice to the reaction mixture can afford carboxylic acid 31. Deprotection of carboxylic acid 31 gives the corresponding acid 32, which can be converted to amide 33 by coupling with a suitable amine (e.g., NHR c3 R d3 ) in the presence of a suitable amide coupling reagent such as HATU, HBTU, BOP, EDCI / HOBT, EDCI / HOAT, or CDI, etc. (but not limited to these). Alternatively, treatment with oxalyl chloride or thionyl chloride, followed by reaction with a suitable amine, can afford amide 33 by conversion of acid 32 to the corresponding chloride. [Chemical formula]

[0210] A series of urea derivatives 37 can be prepared according to the procedure outlined in Scheme 9. Protection of 1H-pyrrolo[2,3-b]pyridine urea 34 can be achieved by reacting with a suitable protecting reagent (PG) under basic conditions to afford urea 35. Alkylation of urea 35 with an alkyl halide (e.g., R 9 halide) under basic conditions gives the corresponding substituted urea 36, and subsequent removal of the protecting group PG under standard conditions in the art can afford the final compound 37. [Chemical formula]

[0211] A series of urea derivatives 41 can be prepared according to the procedure outlined in Scheme 10. Urea 38 can be treated with pyridinium tribromide or pyridinium bromide to obtain dibromo and / or monobromo intermediates 39 and 40 respectively, which can be subjected to Zn / acetic acid mediated reduction to obtain urea derivative 41.

Chemical formula

[0212] A series of 3H-imidazo[4,5-b]pyridine urea derivatives 50 can be prepared according to the procedure outlined in Scheme 11. H 3 PO 4 Or an appropriate acid R at high temperature under acidic conditions such as polyphosphoric acid (PPA) 10 COOH is used for the condensation of pyridyldiamine 42 (CAS number 1131604-99-3) to obtain 3H-imidazo[4,5-b]pyridine 43. The free NH functional group of compound 43 can be protected by treatment with PG-Cl such as MeOCH 2 Cl or SEMCl etc. (but not limited to these). By palladium-catalyzed coupling of compound 44 using tributyl(vinyl)stannane, compound 45 can be obtained, which can be subjected to ozonolysis to obtain the corresponding aldehyde 46. The chlorine in compound 46 can be replaced with an appropriate amine R 9 NH 2 to obtain the corresponding aminoaldehyde 47. Using a suitable reducing agent such as sodium cyanoborohydride or sodium borohydride etc. (but not limited to these), by reductive amination of aminoaldehyde 47 with aniline 3, diamino derivative 48 can be obtained. By cyclization of diamino compound 48 using triphosgene, urea derivative 49 can be obtained. By removing the protecting group PG in 49, urea derivative 50 can be obtained. [Chemical]

[0213] A series of urea derivatives 51 can be prepared according to the procedure outlined in Scheme 12. The free NH functional group of compound 52 (R 14 =H, CAS number 1034769-88-4) can be protected with a suitable protecting group to obtain the protected product 53. By palladium-catalyzed coupling of compound 53 with tributyl(vinyl)stannane, compound 54 can be obtained, which is subjected to ozonolysis to obtain the corresponding aldehyde 55. The chlorine group of 55 can be replaced with a suitable amine R 9 NH 2 to obtain the corresponding aminoaldehyde 56. Using a suitable reducing agent such as sodium cyanoborohydride, sodium borohydride, etc., but not limited to these, by reductive amination of aminoaldehyde 56 with aniline 3, diamino derivative 57 can be obtained. By cyclization of diamino compound 57 using triphosgene or an equivalent, urea derivative 58 can be obtained. By removing the protecting group of 58, urea derivative 51 can be obtained.

[0214] Also, the compounds of the present invention having a thieno[3,2-b]pyridine core can be prepared according to Scheme 12 starting from 6-bromo-7-chlorothieno[3,2-b]pyridine (CAS number 875340-63-9) instead of 52. [Chemical]

[0215] A series of urea derivatives of formula 5 can alternatively be prepared by the procedure outlined in Scheme 13. Reduction amination of aldehyde derivative 1 using aniline 3 can produce chloro compound 59. By palladium-catalyzed amination of compound 59, diamino compound 4 can be obtained. Urea derivative 5 can be obtained by intramolecular cyclization of compound 4 using triphosgene or an equivalent.

Chem.

[0216] A series of azaoxyindole derivatives 62 can be prepared according to the procedure outlined in Scheme 14. By alkylation of compound 60, which can be prepared from compound 36 using conditions similar to those described in Scheme 10, compound 61 can be produced under base conditions such as, but not limited to, Cs 2 CO 3 , NaH, etc. Removal of the protecting group can afford azaoxyindole derivative 62.

Chem.

[0217] A series of lactam derivatives 64 can be prepared according to the procedure outlined in Scheme 15. Palladium-catalyzed coupling of chloro compound 59 using potassium ethyl malonate or an equivalent, followed by in-situ intramolecular cyclization, can produce lactam 63, which can be alkylated to afford lactam derivative 64.

Chem.

[0218] A series of cyclic carbamate derivatives 67 can be prepared according to the procedure outlined in Scheme 16. Replacement of the chlorine in compound 59 with an alkoxide under basic conditions can form compound 65, which can be reacted with a chloroformate ester or equivalent to obtain a carbamate compound 66. Removal of the protecting group, followed by in-situ cyclization of compound 66, can yield the cyclic carbamate derivative 67.

Chem.

[0219] A series of pyrazolo[3,4-b]pyridine urea derivatives 51 can be prepared according to the procedure outlined in Scheme 17. Halogenation of compound 68, which can be generated using a suitable reagent such as, but not limited to, NCS, NBS, or NIS, according to the procedure described in Scheme 12 or Scheme 13, can afford the corresponding halide 69 (L = Cl, Br, or I). Compound 51 can be obtained by coupling of halide 69 using a standard Suzuki, Stille, or Negishi coupling condition, where M is a boronic acid, boronic ester, or appropriately substituted metal reagent (e.g., M is B(OR 2 , SnBu 3 , or ZnBr) R 14 -M.

Chem.

[0220] A series of tricyclic amino derivatives 74 can be prepared according to the procedure outlined in Scheme 18. A suitable protecting reagent under basic conditions, e.g., PhSO 2By protecting the 1H-pyrrolo[2,3-b]pyridine derivative 70 using Cl etc., the corresponding protected compound 71 can be obtained. In an inert solvent such as THF, for example, by treating compound 71 at low temperature with a strong base such as lithium diisopropylamide (LDA), butyllithium, or lithium bis(trimethylsilyl)amide (LiHMDS), a metallated intermediate can be obtained, and this is quenched with a suitable formyl reagent such as dimethylformamide (DMF) etc. to obtain the aldehyde derivative 72. The amino derivative 74 is obtained by reductive amination of aldehyde 72 using a suitable amine (e.g., NHR c3 R d3 ), and then, for example, in the presence of a suitable base such as K 2 CO 3 , KOH, KO t Bu, or tetra-n-butylammonium fluoride (TBAF), it can be prepared by removal of the PhSO 2 -protecting group.

Chemical Structure

[0221] Alternatively, compound 74 can be prepared according to the procedure outlined in Scheme 19. For example, in the presence of a suitable base such as K 2 CO 3 , KOH, KO t Bu, or tetra-n-butylammonium fluoride (TBAF), removal of the PhSO 2 -protecting group in compound 72 can generate compound 75. Compound 74 can be obtained by reductive amination of aldehyde 75 using a suitable amine (e.g., NHR c3 R d3 ).

Chemical Structure

[0222] A series of tricyclic amino derivatives 80 can be prepared according to the procedure outlined in Scheme 20. A vinyl ether derivative 77 can be obtained by Suzuki coupling of compound 76 (L = halogen), which can be prepared using a procedure similar to that described in Scheme 6 using an appropriate boronic acid or ester, and this can be hydrolyzed under aqueous acidic conditions to obtain an aldehyde derivative 78. Compound 79 can be obtained by reductive amination of aldehyde 78 using an appropriate amine (e.g., NHR c3 R d3 ), and subsequently, the amino derivative 80 can be obtained by removal of the PhSO 2 -protecting group in the presence of a suitable base such as K 2 CO 3 , KOH, KO t Bu, or tetra-n-butylammonium fluoride (TBAF). [Chemical Structure]

[0223] Method of Use The compounds of the present invention can inhibit the activity of one or more FGFR enzymes. For example, the compounds of the present invention can be used by administering to a cell, an individual, or a patient an amount of the compound of the present invention that inhibits the activity of the FGFR enzyme in a cell, an individual, or a patient that requires inhibition of the enzyme. In some embodiments, the compounds of the present invention are inhibitors of one or more of FGFR1, FGFR2, FGFR3, and FGFR4. In some embodiments, the compounds of the present invention inhibit each of FGFR1, FGFR2, and FGFR3. In some embodiments, the compounds of the present invention are selective for one or more FGFR enzymes. In some embodiments, the compounds of the present invention are selective for one or more FGFR enzymes over VEGFR2. In some embodiments, this selectivity is 2-fold or greater, 3-fold or greater, 5-fold or greater, 10-fold or greater, 50-fold or greater, or 100-fold or greater.

[0224] As an FGFR inhibitor, the compound of the present invention is useful for the treatment of various diseases associated with abnormal expression or activity of FGFR enzymes or FGFR ligands.

[0225] For example, the compounds of the present invention are useful for the treatment of cancer. Examples of cancers include bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer (e.g., adenocarcinoma, small cell lung cancer, and non-small cell lung cancer), ovarian cancer, prostate cancer, esophageal cancer, gallbladder cancer, pancreatic cancer (e.g., extrapancreatic cancer), gastric cancer, thyroid cancer, skin cancer (e.g., squamous cell carcinoma).

[0226] Further examples of cancers include hematopoietic malignancies, such as leukemia, multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, B-cell lymphoma, acute myeloid leukemia, Hodgkin or non-Hodgkin lymphoma, myeloproliferative tumors (e.g., polycythemia vera, essential thrombocythemia, and primary myelofibrosis), Waldenström macroglobulinemia, hairy cell lymphoma, Burkitt lymphoma.

[0227] Other cancers treatable with the compounds of the present invention include glioblastoma, melanoma, and rhabdomyosarcoma.

[0228] Other cancers treatable with the compounds of the present invention include gastrointestinal stromal tumors.

[0229] In addition to neoplastic tumors, the compounds of the present invention may be useful in the treatment of skeletal or chondrocyte disorders including, but not limited to, achrondroplasia, hypochondroplasia, pituitary dwarfism, lethal osteogenesis imperfecta (TD) (clinical types TD I and TD II), Apert syndrome, Crouzon syndrome, Jackson-Weiss syndrome, Beare-Stevenson cutis gyrate syndrome, Pfeiffer syndrome, and craniosynostosis syndromes.

[0230] The compounds of the present invention may further be useful in the treatment of fibrosis, such as when the condition or disorder is characterized by fibrosis. Exemplary fibroses include cirrhosis, glomerulonephritis, pulmonary fibrosis, systemic fibrosis, rheumatoid arthritis, and wound healing.

[0231] In some embodiments, the compounds of the present invention can be used in the treatment of hypophosphatemic disorders, such as X-linked hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, and autosomal dominant hypophosphatemic rickets, or tumor-induced osteomalacia.

[0232] As used herein, the term "cell" is meant to refer to cells in vitro, ex vivo, or in vivo. In some embodiments, ex vivo cells can be part of a tissue sample excised from an organism such as a mammal. In some embodiments, in vitro cells can be cells in cell culture. In some embodiments, in vivo cells are cells living in an organism such as a mammal.

[0233] As used herein, the term "contacting" refers to bringing together the designated moieties in an in vitro or in vivo system. For example, "contacting" an FGFR enzyme with a compound of the present invention includes administering the compound of the present invention having an FGFR to an individual or patient such as a human, and also introducing, for example, the compound of the present invention into a sample containing a cell preparation or a purified preparation containing the FGFR enzyme.

[0234] As used herein, the terms "individual" or "patient" used interchangeably refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, and most preferably humans.

[0235] As used herein, the term "therapeutically effective amount" refers to an amount of an active compound or pharmaceutical agent that elicits a biological or drug response that is sought by a researcher, veterinarian, physician, or other clinician in a tissue, system, animal, individual, or human.

[0236] As used herein, the terms "treating" or "treatment" refer to: 1) preventing a disease, e.g., preventing a disease, condition, or disorder in an individual who may be predisposed to the disease, condition, or disorder but has not yet experienced or displayed the symptoms or manifestations of the disease; 2) inhibiting a disease, e.g., inhibiting a disease, condition, or disorder in an individual who is experiencing or displaying the symptoms or manifestations of the disease (i.e., arresting further progression of the symptoms and / or manifestations), or 3) alleviating a disease, e.g., alleviating a disease, condition, or disorder in an individual who is experiencing or displaying the symptoms or manifestations of the disease (i.e., reversing the symptoms and / or manifestations).

[0237] Combination therapy One or more additional pharmaceutical agents or therapies, e.g., chemotherapeutic agents, or other anti-cancer agents, immunostimulants, immunosuppressants, immunotherapies, radiation, anti-tumor and anti-viral vaccines, cytokine therapies (e.g., IL2, GM-CSF, etc.), and / or kinases (tyrosine, or serine / threonine), epigenetic or signal transduction inhibitors, etc., can be used in combination with the compounds of the invention for the treatment of diseases, disorders, or conditions associated with the activation of an FGF ligand, receptor, or pathway. The agents can be used in combination with the compound in a single dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms.

[0238] Suitable agents for use in combination with the compounds of the present invention for the treatment of cancer include chemotherapeutic agents, targeted cancer therapies, immunotherapies, or radiation therapies. The compounds of the present invention may be effective in combination with antihormonal agents for the treatment of breast cancer and other tumors. Suitable examples include, but are not limited to, antiestrogen agents such as tamoxifen and toremifene, aromatase inhibitors such as letrozole, anastrozole, and exemestane, corticosteroids (e.g., prednisone), progestins (e.g., megestrol acetate), and estrogen receptor antagonists (e.g., fulvestrant). Suitable antihormonal agents used in the treatment of prostate and other cancers may also be combined with the compounds of the present invention. These include, but are not limited to, antiandrogens such as flutamide, bicalutamide, and nilutamide, luteinizing hormone-releasing hormone (LHRH) analogs including leuprolide, goserelin, triptorelin, and histrelin, LHRH antagonists (e.g., degarelix), androgen receptor blockers (e.g., enzalutamide), and agents that inhibit androgen production (e.g., abiraterone).

[0239] The compounds of the present invention may, in particular, be combined with or used in sequence with other agents against membrane receptor kinases, even for patients who have developed primary or acquired resistance to targeted therapies. These therapeutic 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, lapatinib, and neratinib. Antibodies against EGFR include, but are not limited to, cetuximab, panitumumab, and necitumumab. Inhibitors of c-Met can be used in combination with FGFR inhibitors. These include (onartumzumab, tivantnib, INC-280). Agents against Abl (or Bcr-Abl) include imatinib, dasatinib, nilotinib, and ponatinib, and those against Alk (or EML4-ALK) include crizotinib.

[0240] Angiogenesis inhibitors may be effective in some tumors when combined with FGFR inhibitors. These 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 anti-angiogenesis inhibitors include, but are not limited to, sunitinib, sorafenib, axitinib, cediranib, pazopanib, regorafenib, brivanib, and vandetanib.

[0241] Activation of intracellular signaling pathways is frequent in cancer, and drugs targeting the components of these pathways are combined with drugs targeting receptors to enhance efficacy and reduce resistance. Examples of drugs that can be combined with the compounds of the present invention include inhibitors of the PI3K-AKT-mTOR pathway, inhibitors of the Raf-MAPK pathway, inhibitors of the JAK-STAT pathway, as well as chaperone proteins and inhibitors of cell cycle progression.

[0242] Drugs for PI3 kinase include, but are not limited to, topilaralisib, idelalisib, and buparlisib. Inhibitors of mTOR such as rapamycin, sirolimus, temsirolimus, and everolimus may be combined with FGFR inhibitors. Other suitable examples include, but are not limited to, vemurafenib and dabrafenib (Raf inhibitors) and trametinib, selumetinib, and GDC-0973 (MEK inhibitors). Inhibitors of JAK (ruxolitinib), Hsp90 (tanespimycin), cyclin-dependent kinase (palbociclib), HDAC (panobinostat), PARP (olaparib), and proteasome (bortezomib, carfilzomib) can also be combined with the compounds of the present invention.

[0243] Suitable chemotherapeutic agents or other anti-cancer agents include, for example, alkylating agents such as uracil mustard, chloromethine, cyclophosphamide (Cytoxan (trademark)), ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramide, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide (including, but not limited to, nitrogen mustard, ethyleneimine derivatives, alkyl sulfonates, nitrosoureas, and triazenes).

[0244] Other suitable agents for use in combination with the compounds of the present invention include platinum doublets used in lung cancer (cisplatin or carboplatin + gemcitabine, cisplatin or carboplatin + docetaxel, cisplatin or carboplatin + paclitaxel, cisplatin or carboplatin + pemetrexed) or combination chemotherapy such as gemcitabine + paclitaxel conjugate particles (Abraxane).

[0245] Suitable chemotherapy or other anti-cancer agents include, for example, antimetabolites such as methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, and gemcitabine (including, but not limited to, folic acid antagonists, pyrimidine analogs, purine analogs, and adenosine deaminase inhibitors).

[0246] Suitable chemotherapy or other anti-cancer agents further include, for example, certain natural products and their derivatives such as vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel (TAXOL (trademark)), mitomycin, deoxycholformycin, mitomycin-C, L-asparaginase, interferon (especially IFN-a), etoposide, and teniposide (e.g., vinca alkaloids, antitumor antibiotics, enzymes, lymphokines, and epipodophyllotoxins).

[0247] Other cytotoxic agents include navelbine, CPT-11, capecitabine, lefloxafine, cyclophosphamide, ifosfamide, and droloxafine.

[0248] Also suitable are cytotoxic agents such as epipodophyllotoxins, antitumor enzymes, topoisomerase inhibitors, procarbazine, mitoxantrone, platinum coordination complexes such as cisplatin and carboplatin, biological response modifiers, growth inhibitors, leucovorin, tegafur, and hematopoietic growth factors.

[0249] The compounds according to the present invention may also be combined with immunotherapeutic agents including cytokines such as interferon alpha, interleukin 2, and tumor necrosis factor (TNF).

[0250] Other anti-cancer agents (including plural ones) include co-stimulatory factors, for example, antibody therapies against CTLA-4, 4-1BB, and PD-1, etc., or antibodies against cytokines (IL-10, TGF-β, etc.).

[0251] Also, other anti-cancer agents include those that block immune cell migration, such as antagonists against chemokine receptors including CCR2 and CCR4.

[0252] Other anti-cancer agents include those that reinforce the immune system, such as adjuvants or adoptive T cell transfer.

[0253] Anti-cancer vaccines include dendritic cells, synthetic peptides, DNA vaccines, and recombinant viruses.

[0254] Methods for safely and effectively administering most of these chemotherapeutic agents are known to those skilled in the art. Furthermore, their administration is described in standard literature. For example, the administration of many chemotherapeutic agents is described in the "Physicians’ Desk Reference" (PDR, for example, the 1996 edition, Medical Economics Company, Montvale, NJ), and its disclosure is incorporated herein by reference as if the whole thereof were set forth.

[0255] Pharmaceutical formulations and dosage forms When used as a medicament, the compounds of the present invention can be administered in the form of a pharmaceutical composition, which refers to a combination of the compounds of the present invention, or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable carrier. These compositions can be prepared in manners well known in the pharmaceutical art and can be administered by various routes depending on whether local or systemic treatment is desired and on the area to be treated. Administration can be local (including ophthalmic, and transmucosal including, for example, intranasal, intravaginal, and rectal delivery), pulmonary (e.g., inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal, and transdermal), ocular, oral, or parenteral. Methods of ocular delivery can include topical administration (eye drops), subconjunctival, periocular or intravitreal injection, or introduction by a balloon catheter or ophthalmic insert surgically placed in the conjunctival sac. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion, or intracranial, e.g., intrathecal or intraventricular administration. Parenteral administration can be in the form of a single bolus dose or, for example, by means of a continuous infusion pump. Pharmaceutical compositions and formulations for local administration can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous, powder, or oily bases, thickening agents, etc. may be necessary or desirable.

[0256] The present invention also includes pharmaceutical compositions containing, as an active ingredient, one or more of the compounds of the present invention as defined above in combination with one or more pharmaceutically acceptable carriers. When preparing the compositions of the present invention, the active ingredient is typically admixed with, diluted by, or enclosed within such a carrier in the form of, for example, capsules, sachets, paper, or other containers. When the excipient functions as a diluent, it can be a solid, semi-solid, or liquid substance that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, troches, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0257] When preparing the formulations, the active compound can be comminuted to provide an appropriate particle size before being mixed with the other ingredients. If the active compound is substantially insoluble, it can be comminuted to a particle size of less than 200 mesh. If the active compound is substantially water-soluble, the particle size can be adjusted by comminution to provide a substantially uniform distribution, for example, in a formulation of about 40 mesh.

[0258] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginic acid, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. The formulations can further include lubricants such as talc, magnesium stearate, and mineral oil, wetting agents, emulsifying agents and suspending agents, preservatives such as methyl benzoate and propyl hydroxybenzoate, sweetening agents, and flavoring agents. The compositions of the present invention can be formulated to provide rapid release, sustained release, or delayed release of the active ingredient after administration to a patient using procedures known in the art.

[0259] The composition can be formulated into unit dosage forms, and each dosage contains from about 5 to about 100 mg, more usually from about 10 to about 30 mg of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit being associated with a suitable pharmaceutical excipient and containing a predetermined quantity of the active substance calculated to produce the desired therapeutic effect.

[0260] The active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. However, it will be understood that the actual amount of the compound administered will usually be determined by the physician according to the relevant circumstances, including the condition to be treated, the selected route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, etc.

[0261] To prepare solid compositions such as tablets, the major active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of the compounds of the present invention. When these preformulation compositions are referred to as homogeneous, the active ingredient is typically uniformly dispersed throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules. The solid preformulation is then subdivided into unit dosage forms of the above type containing, for example, from about 0.1 to about 500 mg of the active ingredient of the present invention.

[0262] The tablets or pills of the present invention can be coated or formulated in other ways to provide a dosage form with the advantage of sustained action. For example, the tablets or pills may contain internal and external dosing components, and the latter takes the form of a coating for the former. The two components can be separated by an enteric layer that functions to withstand disintegration in the stomach and allow the internal component to enter the duodenum intact or to delay release. A variety of substances can be used for such enteric layers or coatings, and such substances include some polymeric acids, as well as mixtures of polymeric acids with substances such as shellac, cetyl alcohol, and cellulose acetate.

[0263] Liquid forms in which the compounds and compositions of the present invention can be incorporated for oral or injectable administration include aqueous solutions, preferably 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.

[0264] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. The liquid or solid compositions may contain the suitable pharmaceutically acceptable excipients described above. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effects. The compositions can be nebulized by the use of an inert gas. The nebulized solution can be inhaled directly from the nebulizer or the nebulizer can be attached to a face mask tent or an intermittent positive pressure breathing apparatus. The solution, suspension, or powder composition can be administered orally or nasally from a device that delivers the formulation in a suitable manner.

[0265] The amount of the compound or composition to be administered to a patient will vary depending on what is being administered, the purpose of administration such as prevention or treatment, the condition of the patient, the mode of administration, etc. In therapeutic applications, the composition can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. The effective dosage will vary according to the medical condition being treated, as well as factors such as the severity of the disease, the age, weight, and general condition of the patient, at the discretion of the attending physician.

[0266] The composition to be administered to a patient can be in the form of the pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques or can be filter-sterilized. Aqueous solutions can be packaged for use as such or can be lyophilized, and the lyophilized preparation is combined with a sterile aqueous carrier prior to administration. The pH of the compound preparation is typically from 3 to 11, more preferably from 5 to 9, and most preferably from 7 to 8. It will be understood that the use of some of the excipients, carriers, or stabilizers described above can result in the formation of pharmaceutical salts.

[0267] The therapeutic dosage of the compounds of the present invention can vary, for example, depending on the particular use for which the treatment is carried out, the mode of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of the compound of the present invention in the pharmaceutical composition can vary depending on several factors, including the dosage, chemical properties (e.g., hydrophobicity), and route of administration. For example, the compounds of the present invention can be provided in a physiologically buffered aqueous solution containing from about 0.1 to about 10 w / v% of the compound for parenteral administration. Some typical dosage ranges are from about 1 μg / kg body weight to about 1 g / kg body weight per day. In some embodiments, the dosage range is from about 0.01 mg / kg body weight to about 100 mg / kg body weight per day. The dosage is likely to depend on variable factors such as the type and degree of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficiency of the selected compound, the formulation of the excipient, and the route of its administration. The effective dosage can be extrapolated from the dose-response curve obtained from in vitro or animal model test systems.

[0268] The compounds of the present invention can also be formulated in combination with one or more additional active ingredients, which may include any agents such as antiviral agents, vaccines, antibodies, immunostimulants, immunosuppressants, anti-inflammatory agents, and the like.

[0269] Labeled Compounds and Assay Methods Another aspect of the present invention relates to fluorescent stains, spin labels, heavy metals or radiolabeled compounds of the present invention, which are useful not only in imaging techniques but also in both in vitro and in vivo assays for localizing and quantifying FGFR enzymes in tissue samples, including human tissue, and for identifying FGFR enzyme ligands by inhibitory binding of the labeled compounds. Accordingly, the present invention includes FGFR enzyme assays containing such labeled compounds.

[0270] The present invention further includes isotopically labeled compounds of the present invention. "Isotopically" or "radioactively labeled" compounds are compounds of the present invention in which one or more atoms are replaced or substituted by atoms 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 invention include 2 H (also denoted as D of deuterium), 3 H (also denoted as T of 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 I, but are not limited thereto. The radionuclide incorporated into the radiolabeled compound of the present invention will depend on the specific use of the radiolabeled compound. For example, for in vitro FGFR enzyme labeling and competitive assays, 3 H, 14 C, 82 Br, 125 I, 131 I, or 35 S incorporated compounds will generally be the most useful. For radiography applications, 11 C, 18 F, 125 I, 123 I, 124 I, 131 I, 75 Br, 76 Br, or 77 Br will generally be the most useful.

[0271] It should be understood that a "radioactive label" or "labeling compound" is a compound incorporating at least one radionuclide. In some embodiments, the radionuclide is 3 H, 14 C, 125 I, 35 S, and 82 selected from the group consisting of Br. Synthetic methods for incorporating radioisotopes into organic compounds are applicable to the compounds of the present invention and are well known in the art.

[0272] The radiolabeled compounds of the present invention can be used in screening assays to identify / evaluate compounds. Generally, newly synthesized or identified compounds (i.e., test compounds) can be evaluated for their ability to reduce the binding of the radiolabeled compounds of the present invention to the FGFR enzyme. Thus, the ability of a test compound to compete with the radiolabeled compound for binding to the FGFR enzyme is directly correlated with its binding affinity.

[0273] Kit The present invention also includes, for example, pharmaceutical kits useful in the treatment or prevention of FGFR-related diseases or disorders, obesity, diabetes and other diseases mentioned herein, which contain a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention, and include one or more containers. As will be readily apparent to those skilled in the art, such kits can further include one or more of various conventional pharmaceutical kit components, such as, for example, containers having one or more pharmaceutically acceptable carriers, additional containers, etc. Instructions for use, either as an insert or as a label, indicating the amount of the components to be administered, guidelines for administration, and / or guidelines for mixing the components can also be included in the kit.

[0274] The present invention will be described in further detail by way of specific examples. The following examples are provided for illustrative purposes and are not intended to limit the present invention in any way. Those skilled in the art will readily recognize various non-essential parameters that can be changed or modified to obtain essentially the same results. The compounds of the examples were found to be inhibitors of one or more of the FGFRs described below.

Examples

[0275] Experimental procedures for the compounds of the present invention are provided below. Preparative LC-MS purification of some of the prepared compounds was performed on a Waters mass-based fractionation system. The basic instrument settings, protocols, and control software for the operation of these systems are detailed in the literature. See, for example, “Two-Pump At Column Dilution Configuration for Preparative LC-MS”, K. Blom, J. Combi. Chem., 4, 295 (2002), “Optimizing Preparative LC-MS Configurations and Methods for Parallel Synthesis Purification”, K. Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi. Chem., 5, 670 (2003), and “Preparative LC-MS Purification: Improved Compound Specific Method Optimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Combi. Chem., 6, 874 - 883 (2004). The isolated compounds were typically subjected to analytical liquid chromatography mass spectrometry (LCMS) for purity confirmation under the following conditions: instrument, Agilent 1100 series, LC / MSD, column: Waters Sunfire (trademark) C 185 μm, 2.1×5.0 mm, buffer: mobile phase A: 0.025% TFA in water and mobile phase B: 0.025% TFA in acetonitrile, gradient 2% - 80% of B at a flow rate of 1.5 mL / min for 3 minutes.

[0276] Some of the prepared compounds were also separated on a preparative scale by reverse-phase high-performance liquid chromatography (RP-HPLC) equipped with an MS detector or flash chromatography (silica gel) as shown in the examples. Typical preparative reverse-phase high-performance liquid chromatography (RP-HPLC) column conditions are as follows:

[0277] pH = 2 purification: Waters Sunfire™ C 18 5 μm, 19×100 mm column, eluted with mobile phase A: 0.1% TFA (trifluoroacetic acid) in water and mobile phase B: 0.1% TFA in acetonitrile; the 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, the flow rate used with a 30×100 mm column was 60 mL / min.

[0278] pH = 10 purification: Waters XBridge C 18 5 μm, 19×100 mm column, mobile phase A: 0.15% NH 4 OH in water and mobile phase B: 0.15% NH 4Eluted with OH; the 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, the flow rate used with a 30×100 mm column was 60 mL / min.

[0279] Example 1 3-(3,5-Dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one

Chem.

Chem.

[0280] Step 2: 5-{[(3,5-Dimethoxyphenyl)amino]methyl}-N-methyl-1H-pyrrolo[2,3-b]pyridin-4-amine

Chemical formula

[0281] Step 3: 3-(3,5-Dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one A stirred solution of 5-{[(3,5-dimethoxyphenyl)amino]methyl}-N-methyl-1H-pyrrolo[2,3-b]pyridin-4-amine (16 mg, 0.05 mmol) and triethylamine (21 μL, 0.15 mmol) in tetrahydrofuran (1.5 mL) was added with triphosgene (18 mg, 0.06 mmol) in tetrahydrofuran (0.5 mL) at 0 °C. The resulting yellow suspension was stirred at 0 °C for 30 minutes, and then NaOH solution (1 N, 1 mL) was added. All the precipitate was dissolved to obtain a two-layer solution, and the reaction mixture was stirred at 0 °C for an additional 30 minutes. The organic layer containing the desired product was purified by RP-HPLC (pH = 2) to obtain the desired product as a white solid. LC-MS C 18 H 19 N 4 O 3 [M+H] + Calculated for m / z: 339.1, Found: 339.1.

[0282] Example 2 3-(3,5-Dimethoxyphenyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one

Chemical formula

[0283] Example 3 3-(3,5-Dimethoxyphenyl)-1-ethyl-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one

Chemical formula

[0284] Example 4 1-Cyclopropyl-3-(3,5-dimethoxyphenyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one

Chemical Structure

[0285] Example 5 1-(Cyclopropylmethyl)-3-(3,5-dimethoxyphenyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one [Chemical Structure] This compound was prepared by using the same procedure as described in Example 1, replacing methylamine with cyclopropylmethylamine in Step 1 and raising the reaction temperature to 130 °C. LC-MS C 21 H 23 N 4 O 3 [M+H] + Calculated value for m / z: 379.2, Measured value: 379.1.

[0286] Example 6 1-Benzyl-3-(3,5-dimethoxyphenyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one [Chemical Structure] This compound was prepared by using the same procedure as described in Example 1, replacing methylamine with benzylamine in Step 1 and raising the reaction temperature to 130 °C. LC-MS C 24 H 23 N 4 O 3 [M+H] + Calculated value for m / z: 415.2, Measured value: 415.2.

[0287] Example 7 3-(2-Chloro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one [Chemical Structure] Step 1: 3-(3,5-Dimethoxyphenyl)-1-methyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one

Chem.

[0288] To a stirred solution of 5-{[(3,5-dimethoxyphenyl)amino]methyl}-N-methyl-1H-pyrrolo[2,3-b]pyridin-4-amine (Example 1, Step 2: 2.33 g, 7.46 mmol) and triethylamine (3.1 mL, 22 mmol) in tetrahydrofuran (50 mL) was added triphosgene (2.66 g, 8.95 mmol) in tetrahydrofuran (20 mL) at 0 °C. The resulting yellow suspension was stirred at 0 °C for 30 minutes, then NaOH solution (1 N, 20 mL) was added. All the precipitate dissolved to give a two-layer solution, and the reaction mixture was stirred at 0 °C for an additional 30 minutes. The mixture was extracted with ethyl acetate (EtOAc). The combined organic layers were washed with water, brine, and then dried over Na 2 SO 4 The solvent was removed under reduced pressure. The residue was dissolved in tetrahydrofuran (50 mL), cooled to 0 °C, and then sodium hydroxide (60 wt% dispersion in mineral oil, 600 mg, 15 mmol) was added in three portions. The resulting brown solution was stirred at 0 °C for 30 minutes, then benzenesulfonyl chloride (1.4 mL, 11 mmol) was added dropwise. After stirring at 0 °C for 30 minutes, the reaction was quenched with water and the mixture was extracted with EtOAc. The combined organic layers were washed with water, brine, and then dried over Na 2 SO 4 The solvent was removed under reduced pressure and the residue was purified by column (Biotage®): 40 g silica gel column eluting with 20 - 50% EtOAc / hexane to give a pale yellow solid, which was triturated with diethyl ether to give the pure product (2.75 g, 77%) as a white solid. LC-MS C 24 H 23 N 4 O 5 S [M+1]+ Calculated value for m / z: 479.1, measured value: 479.1.

[0289] Step 2: 3-(2-Chloro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one To a stirred solution of 3-(3,5-dimethoxyphenyl)-1-methyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one (29 mg, 0.06 mmol) in acetonitrile (3 mL, 60 mmol) was added sulfuryl chloride (7.36 μL, 0.09 mmol) in dichloromethane (0.2 mL) dropwise at 0 °C over 5 minutes. The resulting pale yellow solution was stirred at 0 °C for 10 minutes, at which point LC-MS indicated complete consumption of the starting material. The reaction was quenched with saturated NaHCO 3 solution at 0 °C and then extracted with EtOAc. The organic layer was washed with water, brine, and dried over Na 2 SO 4 . The solvent was removed under reduced pressure. The residue and potassium carbonate (50 mg, 0.36 mmol) were dissolved in methanol (9.5 mL) and water (0.5 mL). The resulting solution was heated to 65 °C and stirred for 2 hours. The mixture was purified by RP-HPLC (pH = 2) to afford the desired product as a white solid. LC-MS C 18 H 18 ClN 4 O 3 [M+H] + Calculated value for m / z: 373.1, measured value: 373.2. 1 H NMR (500 MHz, DMSO) δ 12.05 (s, 1H), 8.07 (s, 1H), 7.53 - 7.48 (m, 1H), 6.85 (d, J = 2.1 Hz, 1H), 6.79 (d, J = 2.7 Hz, 1H), 6.73 (d, J = 2.7 Hz, 1H), 4.89 (d, J = 13.4 Hz, 1H), 4.66 (d, J = 13.4 Hz, 1H), 3.87 (s, 3H), 3.80 (s, 3H), 3.66 (s, 3H).

[0290] Example 8 3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one

Chemical Structure

[0291] Example 9 3-(2,4-Dichloro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one

Chemical Structure

[0292] Example 10 3-(3,5-Dimethoxyphenyl)-1-methyl-8-[4-(4-methylpiperazin-1-yl)phenyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one

Chemical Structure

[0293] Step 2: 8-Bromo-3-(3,5-dimethoxyphenyl)-1-methyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one

Chemical Structure

[0294] Step 3: 3-(3,5-Dimethoxyphenyl)-1-methyl-8-[4-(4-methylpiperazin-1-yl)phenyl]-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one

Chemical formula

[0295] Step 4: 3-(3,5-Dimethoxyphenyl)-1-methyl-8-[4-(4-methylpiperazin-1-yl)phenyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one To a stirred solution of 3-(3,5-dimethoxyphenyl)-1-methyl-8-[4-(4-methylpiperazin-1-yl)phenyl]-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one (12 mg, 0.02 mmol) in tetrahydrofuran (2 mL) was added potassium t-butoxide (1 M in THF, 0.2 mL). The resulting yellow solution was stirred at room temperature for 15 minutes, then diluted with methanol and purified by RP-HPLC (pH = 2) to afford the desired product as a yellow solid. LC-MS C 29 H 33 N 6 O 3 [M+H] + Calculated for [M+H]: 513.3, found: 513.3. 1 H NMR (500 MHz, DMSO) δ 12.27 (s, 1H), 8.00 (s, 1H), 7.89 (d, J = 8.8 Hz, 2H), 7.15 (s, 1H), 7.11 (d, J = 8.9 Hz, 2H), 6.55 (d, J = 2.1 Hz, 2H), 6.40 (t, J = 2.1 Hz, 1H), 4.83 (s, 2H), 3.98 (br, 2H), 3.75 (s, 6H), 3.70 (s, 3H), 3.54 (br, 2H), 3.18 (br, 2H), 3.05 (br, 2H), 2.88 (s, 3H).

[0296] Example 11 3-(3,5-Dimethoxyphenyl)-1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one

Chemical formula

[0297] Example 12 3-(3,5-Dimethoxyphenyl)-N,1-dimethyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidine-8-carboxamide

Chemical formula

Chemical formula

[0298] Step 2: 3-(3,5-Dimethoxyphenyl)-N,1-dimethyl-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidine-8-carboxamide

Chemical Structure

[0299] Step 3: 3-(3,5-Dimethoxyphenyl)-N,1-dimethyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidine-8-carboxamide To a stirred solution of 3-(3,5-dimethoxyphenyl)-N,1-dimethyl-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidine-8-carboxamide (21 mg, 0.039 mmol) in tetrahydrofuran (3 mL) was added potassium tert-butoxide (1 M in THF, 0.4 mL, 0.4 mmol). The resulting yellow solution was stirred at room temperature for 15 minutes, then diluted with MeOH and purified by RP-HPLC (pH = 2) to afford the desired product as a white solid. LC-MS C 20 H 22 N 5 O 4 [M+H] + Calculated for [M+H]: 396.2, found: 396.2.

[0300] Example 13 3-(2-Chloro-3,5-dimethoxyphenyl)-1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one

Chemical formula

Chemical formula

[0301] Step 2: 3-(2-Chloro-3,5-dimethoxyphenyl)-1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one 8-Bromo-3-(2-chloro-3,5-dimethoxyphenyl)-1-methyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one (15 mg, 0.025 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (10 mg, 0.051 mmol), a complex of [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane (1:1) (2 mg, 0.002 mmol), and potassium carbonate (10. mg, 0.076 mmol) were dissolved in 1,4-dioxane (3 mL, 40 mmol), and then water (0.3 mL, 20 mmol) was added. The mixture was degassed and then backfilled three times with nitrogen. The resulting red solution was heated to 90 °C and stirred for 30 minutes, at which point LC-MS indicated that the reaction was complete. The reaction mixture was cooled to room temperature, diluted with EtOAc, and then washed with water and brine. The organic layer was dried over Na 2 SO 4 and the solvent was removed under reduced pressure. The residue was dissolved in tetrahydrofuran (3 mL), and then potassium tert-butoxide (1 M in THF, 0.2 mL, 0.2 mmol) was added. The resulting yellow solution was stirred at room temperature for 30 minutes and then diluted with MeOH and purified by RP-HPLC (pH = 2) to afford the desired product as a white solid. Calculated value for LC-MS C 22 H 22 ClN 6 O 3 [M+H] + m / z: 453.1, found: 453.1. 1 H NMR (500 MHz, DMSO) δ 12.25 (s, 1H), 8.20 (s, 1H), 8.00 (s, 1H), 7.96 (s, 1H), 7.00 (d, J = 1.8 Hz, 1H), 6.78 (d, J = 2.7 Hz, 1H), 6.73 (d, J = 2.7 Hz, 1H), 4.87 (d, J = 13.4 Hz, 1H), 4.64 (d, J = 13.4 Hz, 1H), 3.90 (s, 3H), 3.87 (s, 3H), 3.80 (s, 3H), 3.67 (s, 3H).

[0302] Example 14 3-(2-Chloro-3,5-dimethoxyphenyl)-8-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one

Chemical Structure

Chemical Structure

[0303] Step 2: 3-(2-Chloro-3,5-dimethoxyphenyl)-8-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one The mixture of the crude product from Step 1, 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]ethanol (12 mg, 0.051 mmol), the complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane (1:1) (2 mg, 0.002 mmol), and potassium carbonate (10 mg, 0.076 mmol) was dissolved in 1,4-dioxane (3 mL) and water (0.3 mL). The reaction mixture was degassed and then backfilled three times with nitrogen. The resulting solution was heated to 90 °C. After stirring for 7 hours, the reaction mixture was cooled to room temperature, diluted with MeOH, then filtered and purified by RP-HPLC (pH = 10) to obtain the product as a yellow solid. LC-MS C 23 H 24 ClN 6 O 4 [M+H] + Calculated for [M+H]: 483.2, Found: 483.2.

[0304] Example 15 3-(2-Chloro-3,5-dimethoxyphenyl)-1-methyl-8-(1-methyl-1H-pyrazol-5-yl)-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one

Chemical formula

[0305] Example 16 3-(2-Chloro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidine-8-carbonitrile

Chemical Structure

Chemical Structure

[0306] Step 2: 3-(2-Chloro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidine-8-carbonitrile The phenylsulfonyl protecting group was removed using the same conditions as described in Step 4 of Example 10. The product was purified by RP-HPLC (pH = 10) to obtain a white solid. LC-MS C19 H 17 ClN 5 O 3 [M+H] + Calculated value for m / z: 398.1, measured value: 398.0.

[0307] Example 17 3-(3,5-Dimethoxyphenyl)-1-methyl-8-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one

Chemical formula

[0308] Example 18 3-(3,5-Dimethoxyphenyl)-1-methyl-8-(1-methylpiperidin-4-yl)-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one

Chemical formula

[0309] Example 19 3-(3,5-Dimethoxyphenyl)-N,N,1-trimethyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidine-8-carboxamide

Chem.

Chem.

[0310] Step 2: 3-(3,5-Dimethoxyphenyl)-N,N,1-trimethyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidine-8-carboxamide To a solution of 3-(3,5-dimethoxyphenyl)-1-methyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidine-8-carboxylic acid (13 mg, 0.034 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (16 mg, 0.037 mmol) in N,N-dimethylformamide (4 mL) was added triethylamine (50 μL, 0.3 mmol) and dimethylamine (2 M in THF, 80 μL, 0.2 mmol). The mixture was stirred at room temperature for 30 minutes, at which point LC-MS indicated that the reaction was complete. The mixture was diluted with MeOH and purified by RP-HPLC (pH = 2) to afford the desired product as a white solid. LC-MS C 21 H 24 N 5 O4 [M+H] + Calculated value for m / z: 410.2, measured value: 410.2.

[0311] Example 20 3-(3,5-Dimethoxyphenyl)-8-[(3-hydroxyazetidin-1-yl)carbonyl]-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one

Chemical formula

[0312] Example 21 3-(3,5-Dimethoxyphenyl)-8-[(3-hydroxypyrrolidin-1-yl)carbonyl]-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one

Chemical formula

[0313] Example 22 3-(3,5-Dimethoxyphenyl)-1-methyl-8-[(4-methylpiperazin-1-yl)carbonyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one

Chem.

[0314] Example 23 3-(2-Chloro-3,5-dimethoxyphenyl)-N,1-dimethyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidine-8-carboxamide

Chem.

Chem.

[0315] Step 2: 3-(2-Chloro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidine-8-carboxylic acid

Chemical Structure

[0316] Step 3: 3-(2-Chloro-3,5-dimethoxyphenyl)-N,1-dimethyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidine-8-carboxamide To a solution of the crude product from Step 2 and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (17 mg, 0.039 mmol) in N,N-dimethylformamide (4 mL) were added triethylamine (25 μL, 0.18 mmol) and methylamine (2 M in THF, 54 μL, 0.11 mmol). The mixture was stirred at room temperature for 30 minutes, at which point LC-MS indicated completion of the reaction. The mixture was diluted with MeOH and purified by RP-HPLC (pH = 10) to afford the desired product as a white solid. LC-MS C 20 H 21 ClN 5 O 4 [M+H] + Calculated for m / z: 430.1, found: 430.1. 11H NMR (500 MHz, DMSO) δ 12.11 (s, 1H), 8.46 (d, J = 4.6 Hz, 1H), 8.06 (s, 1H), 7.46 (s, 1H), 6.78 (d, J = 2.7 Hz, 1H), 6.72 (d, J = 2.7 Hz, 1H), 4.86 (d, J = 13.4 Hz, 1H), 4.64 (d, J = 13.4 Hz, 1H), 3.87 (s, 3H), 3.80 (s, 3H), 3.66 (s, 3H), 2.83 (d, J = 4.6 Hz, 3H).

[0317] Example 24 3-(2-Chloro-3,5-dimethoxyphenyl)-N,N,1-trimethyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidine-8-carboxamide

Chemical Structure

[0318] Example 25 3-(2-Chloro-3,5-dimethoxyphenyl)-8-[(3-hydroxyazetidin-1-yl)carbonyl]-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one

Chemical Structure

[0319] Example 26 3-(2-Chloro-3,5-dimethoxyphenyl)-1-methyl-8-[(4-methylpiperazin-1-yl)carbonyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one

Chemical Structure

[0320] Example 27 N-Cyclopropyl-3-(2-fluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidine-8-carboxamide

Chemical Structure

Chem.

[0321] Step 2: N-Cyclopropyl-3-(2-fluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidine-8-carboxamide To a solution of 3-(2-fluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidine-8-carboxylic acid (6 mg, 0.015 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (8 mg, 0.018 mmol) in N,N-dimethylformamide (2.5 mL) were added triethylamine (20 μL, 0.1 mmol) and cyclopropylamine (5.2 μL, 0.075 mmol). The resulting yellow solution was stirred at room temperature for 30 minutes, at which point LC-MS indicated that the reaction was complete. The mixture was diluted with MeOH and purified by RP-HPLC (pH = 2) to afford the desired product as a white solid. LC-MS C 22 H 23 FN 5 O 4 [M+H] + Calculated for [M+H]: 440.2, Found: 440.1.

[0322] Example 28 3-(2-Fluoro-3,5-dimethoxyphenyl)-8-[(3-hydroxyazetidin-1-yl)carbonyl]-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one

Chemical Structure

[0323] Example 29 1-{(3-(2-Fluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-8-yl)carbonyl}pyrrolidine-3-carbonitrile

Chem.

[0324] Example 30 3-(2-Fluoro-3,5-dimethoxyphenyl)-1-methyl-8-[(4-methylpiperazin-1-yl)carbonyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one

Chem.

[0325] Example 31 3-(2-Fluoro-3,5-dimethoxyphenyl)-8-[(3-hydroxypiperidin-1-yl)carbonyl]-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one

Chemical formula

[0326] Example 32 3-(2-Fluoro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one

Chemical formula

Chemical formula

[0327] Step 2: 3-(2-Fluoro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one

Chemical Structure

[0328] Example 33 3-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one [Chemical formula] This compound was formed in the same reaction as described in Example 32. LC-MS C 18 H 17 F 2 N 4 O 3 [M + H] + Calculated value for m / z: 375.1, measured value: 375.2. 1 1H NMR (500 MHz, DMSO) δ 11.98 (s, 1H), 8.03 (s, 1H), 7.52 - 7.46 (m, 1H), 7.04 (t, J = 8.1 Hz, 1H), 6.82 (d, J = 2.0 Hz, 1H), 4.78 (s, 2H), 3.89 (s, 6H), 3.65 (s, 3H).

[0329] Example 34 3-(2-Fluoro-3,5-dimethoxyphenyl)-N,N,1-trimethyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidine-8-carboxamide [Chemical formula] Step 1: 3-(2-Fluoro-3,5-dimethoxyphenyl)-N,N,1-trimethyl-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidine-8-carboxamide

Chemical Structure

[0330] To a solution of 3-(2-fluoro-3,5-dimethoxyphenyl)-1-methyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one (75.0 mg, 0.151 mmol) (mixed with 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one, Example 32, Step 1) in tetrahydrofuran (1.0 mL) was added dropwise the prepared LDA solution at -78 °C. The resulting yellow suspension was stirred at -78 °C for 50 minutes, then a solution of N,N-dimethylcarbamoyl chloride (70 μL, 0.76 mmol) in tetrahydrofuran (1.0 mL) was added dropwise. The reaction mixture was stirred at -20 °C for 1 hour, then quenched with saturated NH 4 Cl solution and then extracted twice with AcOEt. The combined organic phases were washed with brine and dried over MgSO 4 , and the solvent was removed under reduced pressure to obtain the desired compound, which was used in the next step without further purification. LC-MS C 27 H 27 FN 5 O 6 S [M+H] +Calculated value for m / z: 568.2, measured value: 568.2.

[0331] Step 2: 3-(2-Fluoro-3,5-dimethoxyphenyl)-N,N,1-trimethyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidine-8-carboxamide To the solution of the above residue prepared in Step 1 in THF (2 mL), 1.0 M potassium tert-butoxide in THF (450 μL, 0.45 mmol) was added. The solution was stirred at room temperature for 30 minutes and then concentrated to remove the solvent. The residue was dissolved in MeOH and purified by RP-HPLC (pH = 2) to obtain the desired product. LC-MS of C 21 H 23 FN 5 O 4 [M+H] + Calculated value for m / z: 428.2, measured value: 428.2. 1 1H NMR (500 MHz, DMSO) δ 12.27 (s, 1H), 8.10 (s, 1H), 7.07 (s, 1H), 6.72 - 6.66 (m, 1H), 6.64 - 6.60 (m, 1H), 4.81 (s, 2H), 3.84 (s, 3H), 3.76 (s, 3H), 3.64 (s, 3H), 3.35 - 2.95 (m, 6H).

[0332] Example 35 3-(2,6-Difluoro-3,5-dimethoxyphenyl)-N,N,1-trimethyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidine-8-carboxamide

Chemical Structure

[0333] Example 36 3-(2-Chloro-6-fluoro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one

Chemical Structure

Chemical Structure

[0334] Step 2: 3-(2-Chloro-6-fluoro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one To a solution of the above residue formed in Step 2 in THF (3 mL) was added 1.0 M potassium tert-butoxide in THF (1.8 mL, 1.8 mmol). The solution was stirred at room temperature for 30 minutes and then concentrated to remove the solvent. The residue was dissolved in MeOH and purified by RP-HPLC (pH = 2) to obtain the desired product. LC-MS C 18 H 17 ClFN 4 O 3 [M+H] + Calculated for m / z: 391.1, Found: 391.1. 1 H NMR (500 MHz, DMSO) δ 12.10 (s, 1H), 8.07 (s, 1H), 7.52 (s, 1H), 7.03 (d, J = 7.7 Hz, 1H), 6.86 (d, J = 3.2 Hz, 1H), 4.79 - 4.71 (m, 2H), 3.94 (s, 3H), 3.91 (s, 3H), 3.66 (s, 3H).

[0335] Example 37 3-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-methyl-3,4,7,9-tetrahydro-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidine-2,8-dione

Chemical Structure

Chemical Structure

[0336] Step 2: 3-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-methyl-3,4,7,9-tetrahydro-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidine-2,8-dione Zinc (10 mg, 0.2 mmol) was added to a mixture of 9-bromo-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-3,4,7,9-tetrahydro-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidine-2,8-dione (10.0 mg, 0.0213 mmol) and 9,9-dibromo-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-3,4,7,9-tetrahydro-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidine-2,8-dione (10.0 mg, 0.0182 mmol) in methanol (0.3 mL) / acetic acid (0.3 mL), and then the mixture was stirred at room temperature for 3 h. The reaction mixture was filtered, and then the product was purified by RP-HPLC (pH = 2). LC-MS C 18 H 17 F 2 N 4 O 4 [M+H] + Calculated for m / z: 391.1, found: 391.1. 11H NMR (500 MHz, DMSO) δ 10.99 (s, 1H), 7.82 (s, 1H), 7.03 (t, J = 8.1 Hz, 1H), 4.60 (s, 2H), 4.00 (s, 2H), 3.88 (s, 6H), 3.39 (s, 3H).

[0337] Example 38 3-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-methyl-3,4-dihydrothieno[2’,3’:5,6]pyrido[4,3-d]pyrimidin-2(1H)-one [Chemical Structure] Step 1: 7-Chlorothieno[3,2-b]pyridine-6-carbaldehyde [Chemical Structure] To a solution of ethyl 7-chlorothieno[3,2-b]pyridine-6-carboxylate (409 mg, 1.69 mmol, purchased from Synthonix, Inc, catalog number E4282, CAS number 90690-94-1) in tetrahydrofuran (5.0 mL), diisobutylaluminum hydride (1.0 M in hexane, 5.1 mL, 5.1 mmol) was added at 0 °C. The resulting mixture was stirred at this temperature for 2 hours, then quenched with MeOH (5 mL) and NaHCO 3 solution (10 mL). The aqueous phase was extracted with EtOAc (3 × 10 mL), dried over Na 2 SO 4 and concentrated in vacuo. The crude alcohol was used without further purification. LC-MS calculated value for C 8 H 7 ONSCl [M+H] + Calculated: 200.1, Found: 200.1.

[0338] To a solution of the alcohol obtained above in methylene chloride (5.0 mL), sodium bicarbonate (710 mg, 8.5 mmol) and Dess-Martin periodinane (860 mg, 2.0 mmol) were added. The resulting mixture was stirred for 1 hour, then filtered through Na 2 S2 O 3 Solution (5 mL) and NaHCO 3 The reaction was quenched with solution (5 mL). The aqueous phase was extracted with methylene chloride (3 × 10 mL), and Na 2 SO 4 dried over and concentrated under vacuum. The crude mixture was purified by flash column (MeOH / DCM, 3% - 20%) to give the aldehyde (237 mg, 72% in 2 steps) as a white solid. LC-MS C 8 H 5 ONSCl [M + H] + Calculated for m / z: 198.1, found 198.1.

[0339] Step 2: 7-(Methylamino)thieno[3,2-b]pyridine-6-carbaldehyde

Chemical formula

[0340] Step 3: 6-{[(3,5-Dimethoxyphenyl)amino]methyl}-N-methylthieno[3,2-b]pyridin-7-amine

Chemical formula

[0341] Step 4: 3-(3,5-Dimethoxyphenyl)-1-methyl-3,4-dihydrothieno[2’,3’:5,6]pyrido[4,3-d]pyrimidin-2(1H)-one

Chemical Structure

[0342] Step 5: 3-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-methyl-3,4-dihydrothieno[2’,3’:5,6]pyrido[4,3-d]pyrimidin-2(1H)-one CH 3 To a solution of 3-(3,5-dimethoxyphenyl)-1-methyl-3,4-dihydrothieno[2’,3’:5,6]pyrido[4,3-d]pyrimidin-2(1H)-one (10.0 mg, 0.0281 mmol) in CN (1.0 mL) was added 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane ditetrafluoroborate (Selectfluor®) (24.9 mg, 0.0703 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 hours and then diluted with MeOH (9 mL). The compound was purified by RF-HPLC (pH = 10) to give 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-3,4-dihydrothieno[2’,3’:5,6]pyrido[4,3-d]pyrimidin-2(1H) (3.0 mg, 27%) as a white solid. LC-MS C 18 H 16 F 2 N 3 O 3 S [M+H] + Calculated value for m / z: 392.1, measured value 392.1. 1 H NMR (500 MHz, DMSO) δ 8.40 (s, 1H), 8.15 (d, J = 5.6 Hz, 1H), 7.55 (d, J = 5.6 Hz, 1H), 7.05 (t, J = 8.2 Hz, 1H), 4.85 (s, 2H), 3.89 (s, 6H), 3.71 (s, 3H).

[0343] Example 39 3-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-methyl-8-(tetrahydro-2H-pyran-4-yl)-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one [Chemistry] Step 1: 5-{(E)-[(2,6-Difluoro-3,5-dimethoxyphenyl)imino]methyl}-N-methyl-1H-pyrrolo[2,3-b]pyridin-4-amine [Chemistry] A mixture of 4-(methylamino)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (1.98 g, 11.3 mmol, prepared as described in Example 1, Step 1), 2,6-difluoro-3,5-dimethoxyaniline (2.6 g, 14 mmol), and D-(+)-10-camphorsulfonic acid (Aldrich, catalog number 21360: 0.72 g, 3.1 mmol) in toluene (200 mL) was heated to reflux and water was removed azeotropically for 48 h using a Dean - stark tube. The reaction mixture was concentrated and the residue was used in the next step without further purification. LC - MS C 17 H 17 F 2 N 4 O 2 [M + H] + Calculated for m / z: 347.1, found 347.1.

[0344] Step 2: 5-{[(2,6-Difluoro-3,5-dimethoxyphenyl)amino]methyl}-N-methyl-1H-pyrrolo[2,3-b]pyridin-4-amine [Chemistry] The crude product from Step 1 was dissolved in tetrahydrofuran (200 mL), cooled to 0 °C, and then LiAlH 4(0.86 g, 23 mmol) was added. The reaction mixture was warmed to 50 °C and stirred overnight. The reaction was quenched by adding the minimum amount of water at 0 °C, filtered through celite, and washed with THF. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with 0 - 5% methanol in dichloromethane to afford the desired product (2.00, 51%) as a yellow solid. LC-MS C 17 H 19 F 2 N 4 O 2 [M + H] + Calculated for [M + H]: 349.1, found 349.1.

[0345] Step 3: 3-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one

Chemical Structure

[0346] Step 4: 3-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-methyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one

Chem.

[0347] Step 5: 8-Bromo-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one

Chem.

[0348] (2) To a stirred solution of 3 - (2,6 - difluoro - 3,5 - dimethoxyphenyl) - 1 - methyl - 7 - (phenylsulfonyl) - 1,3,4,7 - tetrahydro - 2H - pyrrolo[3’,2’:5,6]pyrido[4,3 - d]pyrimidin - 2 - one (1.60 g, 3.11 mmol) in tetrahydrofuran (100 mL), the freshly prepared LDA solution was added dropwise at - 78 °C. After 30 minutes, a solution of 1,2 - dibromo - 1,1,2,2 - tetrachloroethane (1.06 g, 3.26 mmol) in tetrahydrofuran (6 mL) was added dropwise. The resulting clear yellow solution was stirred at - 78 °C for 1 hour. The reaction mixture was quenched with saturated NH 4 Cl aqueous solution and extracted with ethyl acetate (3×40 mL). The combined organic layers were washed with brine, dried over MgSO 4 4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using EtOAc in DCM (0 - 10%) to give the desired product (1.50 g, 81.3%). The calculated value for LC - MS C 24 H 20 BrF 2 N 4 O 5 S[M + H] + m / z: calculated value: 593.0, measured value 592.9.

[0349] Step 6: 8 - Bromo - 3 - (2,6 - difluoro - 3,5 - dimethoxyphenyl) - 1 - methyl - 1,3,4,7 - tetrahydro - 2H - pyrrolo[3’,2’:5,6]pyrido[4,3 - d]pyrimidin - 2 - one

Chemical formula

[0350] Step 7: 3-(2,6-Difluoro-3,5-dimethoxyphenyl)-8-(3,6-dihydro-2H-pyran-4-yl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one

Chemical Structure

[0351] Step 8: 3-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-methyl-8-(tetrahydro-2H-pyran-4-yl)-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one Palladium on activated carbon (10 wt%, 10 mg) was added to a solution of the product from Step 7 in methanol (5 mL), and the reaction mixture was stirred at room temperature for 2 h under a H 2 balloon. The mixture was filtered and purified by RP-HPLC (pH = 2) to give the desired product. LC-MS C 23 H 25 F 2 N 4 O 4 [M+H] + Calculated for [M+H]: 459.2, found 459.1.

[0352] Example 40 3-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-methyl-8-[(4-methylpiperazin-1-yl)carbonyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one

Chem.

Chem.

[0353] Step 2: 3-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidine-8-carboxylic acid [Chemical Structure] To a solution of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidine-8-carboxylic acid (762 mg, 1.36 mmol) in tetrahydrofuran (23 mL) was added 1.0 M potassium tert-butoxide in THF (6.0 mL, 6.0 mmol). The resulting pale yellow suspension was stirred at room temperature for 30 minutes, at which point LC-MS indicated that the reaction to the desired product was complete. The reaction was quenched with water and then extracted with EtOAc. The aqueous layer was acidified with 1 N HCl, and the white precipitate was collected by filtration and dried to give the pure product (528 mg, 93%) as a white solid. LC-MS C 19 H 17 F 2 N 4 O 5 [M+H] + Calculated for m / z: 419.1, found 419.1.

[0354] Step 3: 3-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-methyl-8-[(4-methylpiperazin-1-yl)carbonyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one A stirred solution of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidine-8-carboxylic acid (207 mg, 0.495 mmol) in N,N-dimethylformamide (15 mL) was treated with triethylamine (210 μL, 1.5 mmol), followed by addition of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (230 mg, 0.52 mmol). The mixture was stirred at room temperature for 5 minutes, then 1-methylpiperazine (160 μL, 1.5 mmol) was added. After stirring at room temperature for 30 minutes, the reaction mixture was diluted with MeOH and then purified by RP-HPLC (pH = 2) to afford the desired product (200 mg, 81%) as a white solid. LC-MS C 24 H 27 F 2 N 6 O 4 [M+H] + Calculated for [M+H]: 501.2, found 501.1.

[0355] Example 41 3-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-methyl-8-(morpholine-4-carbonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one

Chemical Structure

[0356] Example 42 3-(2,6-Difluoro-3,5-dimethoxyphenyl)-8-[(4,4-difluoropiperidin-1-yl)carbonyl]-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one

Chem.

[0357] Example 43 3-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-methyl-9-(1-methyl-1H-pyrazol-4-yl)-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one

Chem.

Chem.

[0358] Step 2: tert-Butyl 9-bromo-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-1,2,3,4-tetrahydro-7H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidine-7-carboxylate

Chemical Structure

[0359] Step 3: 3-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-methyl-9-(1-methyl-1H-pyrazol-4-yl)-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one A mixture of tert-butyl 9-bromo-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-1,2,3,4-tetrahydro-7H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidine-7-carboxylate (35.0 mg, 0.063 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (26 mg, 0.13 mmol), bis(tri-t-butylphosphine)palladium (6 mg, 0.01 mmol), and N,N-diisopropylethylamine (33 μL, 0.19 mmol) in 1,4-dioxane (1.7 mL) and water (0.2 mL) was degassed and then filled with nitrogen. After stirring at 120 °C for 2 h, the reaction mixture was filtered and concentrated to dryness. The residue was dissolved in TFA / CH 2 Cl 2 (1:1, 1 mL) and stirred at room temperature for 1 h. The reaction mixture was concentrated and the residue was dissolved in MeOH and purified by RP-HPLC (pH = 2) to give the desired product. LC-MS C 22 H 21 F 2 N 6 O 3 [M+H] + Calculated for m / z: 455.2, Found: 455.1.

[0360] Example 44 3-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-(2-hydroxyethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one

Chemical formula

Chemical formula

[0361] Step 2: 1-Allyl-3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one

Chemical formula

[0362] Step 3. [3-(2,6-Difluoro-3,5-dimethoxyphenyl)-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-1-yl]acetaldehyde

Chemical Structure

[0363] Step 4.3 - (2,6 - Difluoro - 3,5 - dimethoxyphenyl) - 1 - (2 - hydroxyethyl) - 7 - (phenylsulfonyl) - 1,3,4,7 - tetrahydro - 2H - pyrrolo[3’,2’:5,6]pyrido[4,3 - d]pyrimidin - 2 - one

Chemical formula

[0364] Step 5.3 - (2,6 - Difluoro - 3,5 - dimethoxyphenyl)-1-(2 - hydroxyethyl)-1,3,4,7 - tetrahydro - 2H - pyrrolo[3’,2’:5,6]pyrido[4,3 - d]pyrimidin - 2 - one 6.0 M potassium hydroxide in water (0.1 mL, 0.6 mmol) was added to a solution of 3-(2,6 - difluoro - 3,5 - dimethoxyphenyl)-1-(2 - hydroxyethyl)-7-(phenylsulfonyl)-1,3,4,7 - tetrahydro - 2H - pyrrolo[3’,2’:5,6]pyrido[4,3 - d]pyrimidin - 2 - one (30.0 mg, 0.0551 mmol) in THF (0.6 mL), and then the mixture was stirred at 70 °C overnight. The product was purified by RP - HPLC (pH = 2) to give the desired product as a white solid. LC - MS of C 19 H 19 F 2 N 4 O 4 [M+H] + Calculated value for m / z: 405.1, measured value: 405.2. 1 H NMR (400 MHz, DMSO) δ 12.03 (s, 1H), 8.03 (s, 1H), 7.54 (s, 1H), 7.04 (t, J = 8.0 Hz, 3H), 6.73 (s, 1H), 4.78 (s, 2H), 4.23 (t, J = 6.8 Hz, 2H), 3.89 (s, 6H), 3.70 (t, J = 6.8 Hz, 2H).

[0365] Example 45 1 - Cyclopropyl - 3-(2,6 - difluoro - 3,5 - dimethoxyphenyl)-1,3,4,7 - tetrahydro - 2H - pyrrolo[3’,2’:5,6]pyrido[4,3 - d]pyrimidin - 2 - one

Chemical Structure

[0366] Step 2: N-[(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl]-2,6-difluoro-3,5-dimethoxyaniline [Chemical formula] The crude product from Step 1 was dissolved in tetrahydrofuran (300 mL), cooled to 0 °C, and then LiAlH4 (3.6 g, 96 mmol) was added. The reaction mixture was warmed to 50 °C and stirred overnight. The reaction was then quenched with a minimal amount of water and diluted with ethyl acetate. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with methanol in dichloromethane (0 - 5%) to give the desired product (7.00 g, 71.5%). LC-MS C 16 H 15 ClF 2 N 3 O 2 [M + H] + Calculated for m / z: 354.1, found 354.0.

[0367] Step 3: N-Cyclopropyl-5-{[(2,6-difluoro-3,5-dimethoxyphenyl)amino]methyl}-1H-pyrrolo[2,3-b]pyridin-4-amine

Chemical formula

[0368] Step 4: 1-Cyclopropyl-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one Triphosgene (0.20 g, 0.6 mmol) was added to a solution of N-cyclopropyl-5-{[(2,6-difluoro-3,5-dimethoxyphenyl)amino]methyl}-1H-pyrrolo[2,3-b]pyridin-4-amine (0.17 g, 0.44 mmol) and triethylamine (590 μL, 4.2 mmol) in tetrahydrofuran (5 mL) at 0 °C. The reaction mixture was stirred at room temperature for 30 minutes, then 2N NaOH (2.0 mL) was added. After stirring at room temperature for 1 hour, the reaction mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with MeOH in DCM (0 - 5%) to afford the desired product. LC-MS C 20 H 19 F 2 N 4 O 3 [M+H] + Calculated for m / z: 401.1, Found 401.1. 1 H NMR (400 MHz, DMSO) δ 11.97 (s, 1H), 8.04 (s, 1H), 7.52 - 7.46 (m, 1H), 7.03 (t, J = 8.2 Hz, 1H), 6.97 - 6.93 (m, 1H), 4.66 (s, 2H), 3.88 (s, 6H), 3.38 - 3.28 (m, 1H), 1.13 - 1.03 (m, 2H), 0.70 - 0.62 (m, 2H).

[0369] Example 46 3-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-(tetrahydro-2H-pyran-4-yl)-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one

Chemical Structure

[0370] Example 47 3-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-phenyl-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one

Chemical Structure

[0371] Example 48 1-Cyclopropyl-3-(2,6-difluoro-3,5-dimethoxyphenyl)-3,4,7,9-tetrahydro-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidine-2,8-dione

Chemical Structure

[0372] Example 49 3-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-ethyl-3,4,7,9-tetrahydro-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidine-2,8-dione

Chemical Structure

[0373] Step 2: 5-{[(2,6-Difluoro-3,5-dimethoxyphenyl)amino]methyl}-N-ethyl-1H-pyrrolo[2,3-b]pyridin-4-amine [Chemical formula] A mixture of 4-(ethylamino)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (7.0 g, 37 mmol), 2,6-difluoro-3,5-dimethoxyaniline (9.1 g, 48 mmol), and [(1S)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonic acid (Aldrich, catalog number 21360: 2 g, 7 mmol) in xylene (250 mL) was heated to reflux and water was removed azeotropically using Dean-Stark for 2 days. At this point, LC-MS indicated that the reaction was complete. The mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was dissolved in tetrahydrofuran (500 mL), and then 2.0 M lithium tetrahydroaluminate in THF (37 mL, 74 mmol) was slowly added. The resulting mixture was stirred at 50 °C for 3 hours and then cooled to room temperature. The reaction was quenched by adding water, 15% aqueous NaOH, and water. The mixture was filtered and washed with THF. The filtrate was concentrated and the residue was washed with CH 2 Cl 2 and then filtered to give the pure product (11 g, 82%). LC-MS C 18 H 21 F 2 N 4 O 2 [M+H] + Calculated for m / z: 363.2, found: 363.1.

[0374] Step 3: 3-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-ethyl-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one

Chemical formula

[0375] Step 4: 3-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-ethyl-3,4,7,9-tetrahydro-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidine-2,8-dione A mixture of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one (3.0 g, 7.7 mmol) in isopropyl alcohol (70 mL, 900 mmol) / water (7 mL, 400 mmol) was added pyridinium tribromide (11 g, 31 mmol). The reaction mixture was then stirred at 40 °C for 3 h. The mixture was cooled to room temperature and then acetic acid (10 mL, 200 mmol) and zinc (5.05 g, 77.2 mmol) were added. The resulting mixture was stirred at room temperature overnight and then filtered. The filtrate was concentrated and the residue was triturated with water (100 mL) / AcCN (10 mL) and stirred for 30 min. The solid was collected by filtration and then dried. The solid was then stirred with CH 2 Cl 2 / MeOH (100 mL / 10 mL) for 30 min, then filtered to give the pure desired product. The filtrate was concentrated and the residue was stirred with AcCN / water (40 mL / 5 mL) at 40 °C for 10 min, then filtered and dried to give another batch of pure product. LC-MS C 19 H 19 F 2 N 4 O 4 [M+H] + Calculated for m / z: 405.1, found: 405.2. 1 H NMR (500 MHz, DMSO-d 6 ): δ 1.19 (t, 3H), 3.86 (m, 2H), 3.88 (s, 6H), 3.90 (m, 2H), 4.61 (s, 2H), 7.03 (m, 1H), 7.83 (s, 1H), 11.01 (s, 1H) ppm.

[0376] Example 50 1-(Cyclopropylmethyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-3,4,7,9-tetrahydro-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidine-2,8-dione

Chemical Structure

[0377] Example 51 3-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrazolo[4’,3’:5,6]pyrido[4,3-d]pyrimidin-2-one

Chemical Structure

Chemical Structure

[0378] Step 2: 3-(2,6-Difluoro-3,5-dimethoxyphenyl)-7-(4-methoxybenzyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrazolo[4’,3’:5,6]pyrido[4,3-d]pyrimidin-2-one

Chemical Structure

[0379] This compound was prepared using the same procedure as in Example 39, Step 3. The product was purified by flash column (EtOAc / hexane, 30% - 80%) to obtain urea as a white solid. LC-MS C 25 H 24 F 2 N 5 O 4 [M+H] + Calculated for [M+H]: 496.2, Found 496.1.

[0380] Step 3: 3-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrazolo[4’,3’:5,6]pyrido[4,3-d]pyrimidin-2-one A solution of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(4-methoxybenzyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrazolo[4’,3’:5,6]pyrido[4,3-d]pyrimidin-2-one (300 mg, 0.6 mmol) in TFA (4.0 mL) was heated to 70 °C for 2 hours. The solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by RP-HPLC (pH 2) to give the desired product as a white solid. LC-MS C 17 H 16 O 3 N 5 F 2 [M+H] + Calculated for [M+H]: 376.1, Found 376.1. 1 H NMR (300 MHz, DMSO) δ 13.67 (s, 1H), 8.41 (s, 1H), 8.24 (s, 1H), 7.06 (t, J = 8.2 Hz, 1H), 4.83 (s, 2H), 3.89 (s, 6H), 3.66 (s, 3H).

[0381] Example 52 3-(2,6-Difluoro-3,5-dimethoxyphenyl)-1,9-dimethyl-1,3,4,7-tetrahydro-2H-pyrazolo[4’,3’:5,6]pyrido[4,3-d]pyrimidin-2-one

Chemical formula

[0382] Step 1: 9-Bromo-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrazolo[4’,3’:5,6]pyrido[4,3-d]pyrimidin-2-one

Chemical formula

[0383] Step 2: 3-(2,6-Difluoro-3,5-dimethoxyphenyl)-1,9-dimethyl-1,3,4,7-tetrahydro-2H-pyrazolo[4’,3’:5,6]pyrido[4,3-d]pyrimidin-2-one To a solution of 9-bromo-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrazolo[4’,3’:5,6]pyrido[4,3-d]pyrimidin-2-one (80.0 mg, 0.176 mmol) in 1,4-dioxane (2.0 mL) was added a complex of [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane (20.0 mg, 0.0245 mmol). To this solution was added ZnMe 2 (0.50 mL, 2.0 M solution in toluene, 1.0 mmol). The resulting mixture was heated to 100 °C for 1 h, then diluted with MeOH and purified by RP-HPLC (pH 2). LC-MS C 18 H 18 O 3 N 5 F 2 [M+H] + Calculated for m / z: 390.1, found 390.1. 11H NMR (300 MHz, DMSO) δ 8.22 (s, 1H), 7.03 (t, J = 9.0 Hz, 1H), 4.78 (s, 2H), 3.88 (s, 6H), 3.55 (s, 3H), 2.67 ppm (s, 3H).

[0384] Example 53 3-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrazolo[4’,3’:5,6]pyrido[4,3-d]pyrimidine-9-carbonitrile

Chem.

[0385] Example 54 [3-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrazolo[4’,3’:5,6]pyrido[4,3-d]pyrimidin-9-yl]acetonitrile

Chem.

[0386] Example 55 3-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-methyl-9-(1-methylpiperidin-4-yl)-1,3,4,7-tetrahydro-2H-pyrazolo[4’,3’:5,6]pyrido[4,3-d]pyrimidin-2-one

Chemical Structure

[0387] Example 56 3-(2,6-Difluoro-3,5-dimethoxyphenyl)-9-(2-hydroxyethyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrazolo[4’,3’:5,6]pyrido[4,3-d]pyrimidin-2-one

Chemical Structure

[0388] To a solution of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-9-vinyl-1,3,4,7-tetrahydro-2H-pyrazolo[4’,3’:5,6]pyrido[4,3-d]pyrimidin-2-one (17.0 mg, 0.036 mmol) in THF (1.0 mL) was added BH 3 -THF (0.40 mmol). The resulting mixture was stirred at room temperature for 12 hours, and then quenched with NaOH (2N, 0.2 mL) and H 2 O 2 (0.2 mL). The mixture was diluted with MeOH and purified by RP-HPLC (pH 2) to give the product as a white solid. LC-MS C 19 H 20 F 2 N 5 O 4 [M + H] + Calculated for m / z: 420.1, Found 420.1.

[0389] Example 57 3-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-ethyl-1,3,4,7-tetrahydro-2H-pyrazolo[4’,3’:5,6]pyrido[4,3-d]pyrimidin-2-one

Chemical Structure

[0390] Example 58 3-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-(2-hydroxyethyl)-1,3,4,7-tetrahydro-2H-pyrazolo[4’,3’:5,6]pyrido[4,3-d]pyrimidin-2-one

Chemical formula

[0391] Example 59 3’-(2,6-Difluoro-3,5-dimethoxyphenyl)-1’-methyl-4’,7’-dihydrospiro[cyclopropane-1,9’-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidine]-2’,8’(1’H,3’H)-dione

Chemical formula

Chemical formula

[0392] Step 2. 3-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-methyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,9-tetrahydro-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidine-2,8-dione

Chemical Structure

[0393] Step 3. 3’-(2,6-Difluoro-3,5-dimethoxyphenyl)-1’-methyl-4’,7’-dihydros piro[cyclopropane-1,9’-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidine]-2’,8’(1’H,3’H)-dione Bubble nitrogen through a solution of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,9-tetrahydro-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidine-2,8-dione (100.0 mg, 0.192 mmol) in DMF (2.0 mL) for 20 minutes, then add cesium carbonate (190 mg, 0.58 mmol) and 1-bromo-2-chloroethane (48 μL, 0.58 mmol) under nitrogen. After stirring overnight at room temperature, the mixture was filtered and then the solvent was removed under reduced pressure. The residue was dissolved in CH 2 Cl 2 (0.5 mL), then add TFA (0.8 mL) and stir the reaction mixture for 1 hour. Remove the solvent, dissolve the residue in methanol (2 mL), then add ethylenediamine (0.15 mL) and stir the mixture for 2 hours at room temperature. The product was purified by preparative HPLC (pH 2). LC-MS C 20 H 19 F 2 N 4 O 4 (M+H) + Calculated for: 417.1, Found: 417.1. 1 H NMR (500 MHz, DMSO) δ 11.31 (s, 1H), 7.90 (s, 1H), 7.01 (t, J = 8.1 Hz, 1H), 4.59 (s, 2H), 3.87 (s, 6H), 3.14 (s, 3H), 1.92 - 1.87 (m, 2H), 1.49 - 1.43 (m, 2H).

[0394] Example 60 7-(2,6-Difluoro-3,5-dimethoxyphenyl)-3,6,7,9-tetrahydro-8H-pyrrolo[2,3-c]-2,7-naphthyridin-8-one

Chemical Structure

[0395] Step 2. 7-(2,6-Difluoro-3,5-dimethoxyphenyl)-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,6,7,9-tetrahydro-8H-pyrrolo[2,3-c]-2,7-naphthyridin-8-one [Chemical formula] Preparation of Potassium Ethyl Malonate: A 100 mL two-necked round-bottom flask was charged with diethyl malonate (22.0 mmol), water (20.5 mmol), and ethanol (20 mL), and then the reaction mixture was stirred at 40 °C. A solution of potassium tert-butoxide (2.24 g, 20.0 mmol) in ethanol (20 mL) was added dropwise over 30 minutes. After the addition was complete, the reaction mixture was stirred at 40 °C until the starting materials were consumed. The reaction mixture was concentrated and then diethyl ether (20 mL) was added. The resulting solid was collected by filtration and washed successively with a 1:1 mixture of diethyl ether and ethanol and then with diethyl ether. The solid was dried to obtain the potassium salt.

[0396] A mixture of N-[(4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl]-2,6-difluoro-3,5-dimethoxyaniline (200.0 mg, 0.4132 mmol), potassium ethyl malonate (140 mg, 0.83 mmol), dicyclohexyl(2’,6’-diisopropoxybiphenyl-2-yl)phosphine (5.8 mg, 0.012 mmol), and π-allylpalladium chloride dimer (14 mg, 0.037 mmol) in mesitylene (2.0 mL) was evacuated and refilled with nitrogen three times. The reaction mixture was stirred at 160 °C overnight. The mixture was cooled to room temperature, filtered, and then washed with ethyl acetate. The filtrate was concentrated. The residue was purified by chromatography eluting with 0 - 40% EtOAc / CH 2 Cl 2 and purified by chromatography eluting with 0 - 40% EtOAc / CH 24 H 30 F 2 N 3 O 4 Si(M + H) + Calculated for C

[0397] Step 3. 7-(2,6-Difluoro-3,5-dimethoxyphenyl)-3,6,7,9-tetrahydro-8H-pyrrolo[2,3-c]-2,7-naphthyridin-8-one Trifluoroacetic acid (1.0 mL) was added to a solution of 7-(2,6-difluoro-3,5-dimethoxyphenyl)-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,6,7,9-tetrahydro-8H-pyrrolo[2,3-c]-2,7-naphthyridin-8-one (60.0 mg, 0.122 mmol) in methylene chloride (1.0 mL). The mixture was stirred at room temperature for 2 h and then concentrated. The residue was dissolved in methanol (1.0 mL), and then ethylenediamine (0.2 mL) was added. The mixture was stirred at room temperature overnight. The product was purified by preparative HPLC (pH 2). LC-MS C 18 H 16 F 2 N 3 O 3 (M+H) + Calculated for: 360.1, found: 360.2. 1 H NMR (500 MHz, DMSO) δ 11.77 (s, 1H), 8.17 (s, 1H), 7.53 - 7.48 (m, 1H), 7.05 (t, J = 8.2 Hz, 1H), 6.64 - 6.60 (m, 1H), 4.90 (s, 2H), 4.06 (s, 2H), 3.89 (s, 6H).

[0398] Example 61 7-(2,6-Difluoro-3,5-dimethoxyphenyl)-9-methyl-3,6,7,9-tetrahydro-8H-imidazo[4’,5’:5,6]pyrido[4,3-d]pyrimidin-8-one

Chemical formula

Chemical formula

[0399] Step 2: 7-Chloro-3-{[2-(trimethylsilyl)ethoxy]methyl}-6-vinyl-3H-imidazo[4,5-b]pyridine

Chemical formula

[0400] Step 3: 7-Chloro-3-{[2-(trimethylsilyl)ethoxy]methyl}-3H-imidazo[4,5-b]pyridine-6-carbaldehyde

Chemical formula

[0401] Step 4: 7-(methylamino)-3H-imidazo[4,5-b]pyridine-6-carbaldehyde

Chemical Structure

[0402] Step 5: 6-{[(2,6-Difluoro-3,5-dimethoxyphenyl)amino]methyl}-N-methyl-3H-imidazo[4,5-b]pyridin-7-amine

Chemical Structure

[0403] Step 6: 7-(2,6-Difluoro-3,5-dimethoxyphenyl)-9-methyl-3,6,7,9-tetrahydro-8H-imidazo[4’,5’:5,6]pyrido[4,3-d]pyrimidin-8-one A solution of 6-{[(2,6-difluoro-3,5-dimethoxyphenyl)amino]methyl}-N-methyl-3H-imidazo[4,5-b]pyridin-7-amine (155 mg, 0.44 mmol) in tetrahydrofuran (5 mL, 60 mmol) was added with triethylamine (0.31 mL, 2.2 mmol), followed by addition of triphosgene (140 mg, 0.49 mmol). The resulting yellow suspension was stirred at room temperature for 1 hour, then 5 mL of 1N aqueous NaOH solution was added. After stirring at room temperature for 30 minutes, the mixture was diluted with EtOAc. The organic layer was washed with water, brine, then dried over Na 2 SO 4 and concentrated. The residue was dissolved in MeOH and purified by preparative HPLC (pH 2, ACN / water) to obtain the desired product as a white solid. Calculated value for LC-MS C 17 H 16 F 2 N 5 O 3 [M+H] + m / z: calculated value 376.1, measured value 376.1. 1 H NMR (500 MHz, DMSO) δ 8.41 (s, 1H), 8.10 (s, 1H), 7.05 (t, J = 8.2 Hz, 1H), 4.83 (s, 2H), 3.89 (s, 6H), 3.85 (s, 3H).

[0404] Example 62 3-(2,6-Difluoro-3,5-dimethoxyphenyl)-4,7-dihydropyrazolo[4’,3’:5,6]pyrido[3,4-e][1,3]oxazin-2(3H)-one

Chemical Structure

Chemical Structure

[0405] Step 2: N-{[4-chloro-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-difluoro-3,5-dimethoxyaniline

Chemical Structure

[0406] Step 3: N-{[4-(allyloxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-difluoro-3,5-dimethoxyaniline

Chem.

[0407] Step 4: {[4-(allyloxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}(2,6-difluoro-3,5-dimethoxyphenyl)carbamic acid chloride

Chem.

[0408] Step 5: 3-(2,6-Difluoro-3,5-dimethoxyphenyl)-4,7-dihydropyrazolo[4’,3’:5,6]pyrido[3,4-e][1,3]oxazin-2(3H)-one To a stirred solution of crude {[4-(allyloxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}(2,6-difluoro-3,5-dimethoxyphenyl)carbamic acid chloride (0.16 g, 0.287 mmol) in THF (0.5 mL) / 1-propanol (3 mL, 40 mmol) was added rhodium(III) chloride trihydrate (7.95 mg, 0.0302 mmol). The mixture was then heated to 90 °C. After 2 h, the reaction was quenched with saturated NH 4 Cl aqueous solution and then extracted with methylene chloride. The combined organic layers were dried over MgSO 4It was dried and then concentrated. The residue was dissolved in trifluoroacetic acid (2 mL, 20 mmol) and heated at 75 °C for 1 hour. Then, the volatile substances were removed under reduced pressure, and the residue was purified on RP-HPLC (XBridge C18 column eluting with a gradient of acetonitrile / water containing 0.05% TFA at a flow rate of 60 mL / min) to obtain the desired product (50 mg, 46%) as its TFA salt. LC-MS C 16 H 13 F 2 N 4 O 4 (M+H) + : Calculated value for m / z = 363.1, measured value: 363.1; 1 H NMR (500 MHz, DMSO-d 6 ): δ 8.41 (s, 1H), 8.26 (s, 1H), 7.14 (t, J = 10.0 Hz, 1H), 4.99 (s, 2H), 3.92 (s, 6H) ppm.

[0409] Example 63 3-(2-Chloro-6-fluoro-3,5-dimethoxyphenyl)-1-ethyl-3,4,7,9-tetrahydro-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidine-2,8-dione

Chemical Structure

Chemical Structure

[0410] Step 2: N-(2-Chloro-6-fluoro-3,5-dimethoxyphenyl)acetamide

Chemical formula

[0411] Step 3: 2-Chloro-6-fluoro-3,5-dimethoxyaniline

Chemical formula

[0412] Step 4: 5-{[(2-chloro-6-fluoro-3,5-dimethoxyphenyl)amino]methyl}-N-ethyl-1H-pyrrolo[2,3-b]pyridin-4-amine

Chemical formula

[0413] Step 5: 3-(2 - Chloro - 6 - fluoro - 3,5 - dimethoxyphenyl)-1 - ethyl - 1,3,4,7 - tetrahydro - 2H - pyrrolo[3’,2’:5,6]pyrido[4,3 - d]pyrimidin - 2 - one

Chemical Structure

[0414] Step 6: 3-(2-Chloro-6-fluoro-3,5-dimethoxyphenyl)-1-ethyl-3,4,7,9-tetrahydro-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidine-2,8-dione To a mixture of 3-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)-1-ethyl-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one (1.14 g, 2.82 mmol) in isopropyl alcohol (10 mL, 100 mmol) and water (0.8 mL, 40 mmol) was added pyridinium tribromide (3.5 g, 9.8 mmol). The resulting mixture was stirred at 30 °C overnight, then cooled to room temperature, and acetic acid (10 mL, 200 mmol) and zinc (1.84 g, 28.2 mmol) were added. After stirring at room temperature for 2 h, the mixture was filtered and the filtrate was concentrated. The residue was triturated with water, and the precipitate was collected by filtration and then washed with water. The solid was purified by chromatography eluting with 0 - 5% MeOH in CH 2 Cl 2 to give the desired product. LC-MS C 19 H 19 ClFN 4 O 4 (M + H) + Calculated for: 421.1, Found: 421.0. 1 H NMR (500 MHz, DMSO) δ 11.02 (s, 1H), 7.83 (s, 1H), 7.01 (d, J = 7.7 Hz, 1H), 4.56 (s, 2H), 3.94 - 3.85 (m, 10H), 1.19 (t, J = 7.0 Hz, 3H).

[0415] Example 64 1-Cyclobutyl-3-(2,6-difluoro-3,5-dimethoxyphenyl)-3,4,7,9-tetrahydro-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidine-2,8-dione

Chemical Structure

[0416] Step 1: 1-Cyclobutyl-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one

Chemical Structure

[0417] Step 2: 1-Cyclobutyl-3-(2,6-difluoro-3,5-dimethoxyphenyl)-3,4,7,9-tetrahydro-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidine-2,8-dione This compound was prepared by replacing 3-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)-1-ethyl-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one with 1-cyclobutyl-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one using the same procedure as in Step 6 of Example 63. LC-MS C 21 H 21 F 2 N 4 O 4 (M+H) + Calculated value for m / z: 431.2, Measured value: 431.1. 11H NMR (500 MHz, DMSO) δ 11.00 (s, 1H), 7.86 (s, 1H), 7.02 (t, J = 8.2 Hz, 1H), 4.53 (s, 2H), 4.51 - 4.42 (m, 1H), 3.88 (s, 6H), 3.80 (s, 2H), 2.64 - 2.53 (m, 2H), 2.32 - 2.22 (m, 2H), 1.77 - 1.64 (m, 2H).

[0418] Example 65 3-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-(3-fluorobenzyl)-3,4,7,9-tetrahydro-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidine-2,8-dione [Chemical formula] Step 1: 3-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-(3-fluorobenzyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one [Chemical formula] This compound was prepared by replacing cyclopropylamine with 1-(3-fluorophenyl) using the same procedure as in Example 45. LC-MS C 24 H 20 F 3 N 4 O 3 (M + H) + Calculated value for m / z: 469.1, Measured value: 469.1.

[0419] Step 2: 3-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-(3-fluorobenzyl)-3,4,7,9-tetrahydro-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidine-2,8-dione This compound was prepared by replacing 3-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)-1-ethyl-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one with 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(3-fluorobenzyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-2-one using a procedure similar to that in Example 63, Step 6. LC-MS C 24 H 20 F 3 N 4 O 4 (M+H) + Calculated for m / z: 485.1, Found: 485.0. 1 H NMR (500 MHz, DMSO) δ 10.99 (s, 1H), 7.89 (s, 1H), 7.44 - 7.37 (m, 1H), 7.12 - 6.96 (m, 4H), 5.18 (s, 2H), 4.77 (s, 2H), 3.88 (s, 6H), 3.41 (s, 2H).

[0420] Example 66 7’-(2,6-Difluoro-3,5-dimethoxyphenyl)-6’,7’-dihydrospir...

Claims

1. Formula I: 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, wherein W is NR ９ , O, or CR １７ R １８ and Ring A is 【Chemistry 2】 and X is CR １５ or N, Y is NR １６ , O, or S; Z is N or CH; Q is absent, O, NR １６ａ , or C.R. １２ａ R １３ａ and n is 0 or 1, and when n is 0, Q is not absent; R １ But H, NR Ａ R Ｂ , Halo, and C １－３ is alkyl, R ２ and R ３ are each independently H, CN, C(O)NR ｃ R ｄ , and C １－７ alkyl, １－７ Alkyl is optionally halo, OR ａ , C.N., N.R. ｃ R ｄ , and C(O)NR ｃ R ｄ or substituted by 1, 2, or 3 substituents independently selected from Or, R ２ and R ３ together with the carbon atom to which they are attached form a 3- to 7-membered cycloalkyl ring or a 4- to 7-membered heterocycloalkyl ring, each of which is optionally selected from halo, C １－６ Alkyl, C １－６ Haloalkyl, CN, OR ａ , S.R. ａ , C(O)R ｂ , C(O)NR ｃ R ｄ , C(O)OR ａ , O.C.(O)R ｂ , O.C.(O)NR ｃ R ｄ , N.R. ｃ R ｄ , N.R. ｃ C(O)R ｂ , and N.R. ｃ C(O)OR ａ and is substituted by 1, 2, or 3 substituents independently selected from R ４ , R ５ , R ６ , R ７ , and R ８ are H, halo, and C, respectively. １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl, C ３－１０ Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, 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(=NR ｅ１ ) N.R. ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ ) N.R. ｃ１ R ｄ１ , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S (O) ２ R ｂ１ , N.R. ｃ１ S (O) ２ N.R. ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ , and S(O) ２ N.R. ｃ１ R ｄ１ Independently selected from the group consisting of C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ６－１０ Aryl, C ３－１０ Cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each optionally selected from halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, 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 , C(=NR ｅ１ ) N.R. ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ ) N.R. 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 , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S (O) ２ R ｂ１ , N.R. ｃ１ S (O) ２ N.R. ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ , and S(O) ２ N.R. ｃ１ R ｄ１ and is substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ９ But, H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ６－１０ Aryl, C ３－１０ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－１０ Cycloalkyl-C １－４ Alkyl, (5-10 membered heteroaryl)-C １－４ alkyl, or (4-10 membered heterocycloalkyl)-C １－４ alkyl, １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ６－１０ Aryl, C ３－１０ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－１０ Cycloalkyl-C １－４ Alkyl, (5-10 membered heteroaryl)-C １－４ alkyl, and (4-10 membered heterocycloalkyl)-C １－４ Each alkyl is optionally ９ａ and is substituted with 1, 2, 3, 4, or 5 substituents independently selected from Each R ９ａ is independent, Cy １ , Haro, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, 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 , C(=NR ｅ２ ) N.R. ｃ２ R ｄ２ , N.R. ｃ２ C (=NR ｅ２ ) N.R. 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 , N.R. ｃ２ S(O)R ｂ２ , N.R. ｃ２ S (O) ２ R ｂ２ , N.R. ｃ２ S (O) ２ N.R. ｃ２ R ｄ２ , S(O)R ｂ２ , S(O)NR ｃ２ R ｄ２ , S(O) ２ R ｂ２ , and S(O) ２ N.R. ｃ２ R ｄ２ and C is selected from １－６ Alkyl, C ２－６ Alkenyl, and C ２－６ Each alkynyl is optionally １ , Haro, 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 , C(=NR ｅ２ ) N.R. ｃ２ R ｄ２ , N.R. ｃ２ C (=NR ｅ２ ) N.R. 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 , N.R. ｃ２ S(O)R ｂ２ , N.R. ｃ２ S (O) ２ R ｂ２ , N.R. ｃ２ S (O) ２ N.R. ｃ２ R ｄ２ , S(O)R ｂ２ , S(O)NR ｃ２ R ｄ２ , S(O) ２ R ｂ２ , and S(O) ２ N.R. ｃ２ R ｄ２ and is substituted with 1, 2, or 3 substituents independently selected from R １０ , R １１ , R １２ , R １３ , R １２ａ , R １３ａ , R １４ , R １５ , R １７ , and R １８ each independently represents H, halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl, C ３－１０ Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, 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(=NR ｅ３ ) N.R. ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) N.R. ｃ３ R ｄ３ , N.R. ｃ３ S(O)R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ N.R. ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , and S(O) ２ N.R. ｃ３ R ｄ３ and C is selected from １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ６－１０ Aryl, C ３－１０ Cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each optionally represented by R １０ａ and is substituted with 1, 2, 3, 4, or 5 substituents independently selected from Each R １０ａ is independent, Cy ２ , Haro, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, 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 , C(=NR ｅ３ ) N.R. ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) N.R. 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 , N.R. ｃ３ S(O)R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ N.R. ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , and S(O) ２ N.R. ｃ３ R ｄ３ and C is selected from １－６ Alkyl, C ２－６ Alkenyl, and C ２－６ Each alkynyl is optionally ２ , Haro, 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 , C(=NR ｅ３ ) N.R. ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) N.R. 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 , N.R. ｃ３ S(O)R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ N.R. ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , and S(O) ２ N.R. ｃ３ R ｄ３ or substituted with 1, 2, or 3 substituents independently selected from Or, R １２ and R １３ together with the carbon atom to which they are attached form a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group, or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, each optionally being selected from the group consisting of Cy ２ , C １－６ Alkyl, C １－６ Haloalkyl, Halo, CN, 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)NR ｃ３ R ｄ３ , N.R. ｃ３ C(O)OR ａ３ , C(=NR ｅ３ ) N.R. ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) N.R. ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ N.R. ｃ３ R ｄ３ , and S(O) ２ N.R. ｃ３ R ｄ３ and wherein the C is substituted with 1, 2, or 3 substituents independently selected from １－６ Alkyl is optionally Cy ２ , Haro, CN, 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)NR ｃ３ R ｄ３ , N.R. ｃ３ C(O)OR ａ３ , C(=NR ｅ３ ) N.R. ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) N.R. ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ N.R. ｃ３ R ｄ３ , and S(O) ２ N.R. ｃ３ R ｄ３ or substituted by 1, 2, or 3 substituents independently selected from Or, R １２ａ and R １３ａ together with the carbon atom to which they are attached form a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group, or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, each optionally being selected from the group consisting of Cy ２ , C １－６ Alkyl, C １－６ Haloalkyl, Halo, CN, 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)NR ｃ３ R ｄ３ , N.R. ｃ３ C(O)OR ａ３ , C(=NR ｅ３ ) N.R. ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) N.R. ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ N.R. ｃ３ R ｄ３ , and S(O) ２ N.R. ｃ３ R ｄ３ and wherein the C is substituted with 1, 2, or 3 substituents independently selected from １－６ Alkyl is optionally Cy ２ , Haro, CN, 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)NR ｃ３ R ｄ３ , N.R. ｃ３ C(O)OR ａ３ , C(=NR ｅ３ ) N.R. ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) N.R. ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ N.R. ｃ３ R ｄ３ , and S(O) ２ N.R. ｃ３ R ｄ３ or substituted by 1, 2, or 3 substituents independently selected from Or, R １７ and R １８ together with the carbon atom to which they are attached form a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group, or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, each optionally being selected from the group consisting of Cy ２ , C １－６ Alkyl, C １－６ Haloalkyl, Halo, CN, 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)NR ｃ３ R ｄ３ , N.R. ｃ３ C(O)OR ａ３ , C(=NR ｅ３ ) N.R. ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) N.R. ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ N.R. ｃ３ R ｄ３ , and S(O) ２ N.R. ｃ３ R ｄ３ and wherein the C is substituted with 1, 2, or 3 substituents independently selected from １－６ Alkyl is optionally Cy ２ , Haro, CN, 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)NR ｃ３ R ｄ３ , N.R. ｃ３ C(O)OR ａ３ , C(=NR ｅ３ ) N.R. ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) N.R. ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ N.R. ｃ３ R ｄ３ , and S(O) ２ N.R. ｃ３ R ｄ３ and is substituted by 1, 2, or 3 substituents independently selected from R １６ and R １６ａ each independently represents H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ６－１０ Aryl, C ３－１０ Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, aryl-C １－４ Alkyl, cycloalkyl-C １－４ Alkyl, (5-10 membered heteroaryl)-C １－４ alkyl, and (4-10 membered heterocycloalkyl)-C １－４ alkyl, １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ６－１０ Aryl, C ３－１０ Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, aryl-C １－４ Alkyl, cycloalkyl-C １－４ Alkyl, (5-10 membered heteroaryl)-C １－４ alkyl, and (4-10 membered heterocycloalkyl)-C １－４ Each aryl is optionally selected from Cy ３ , Haro, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, 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 , C(=NR ｅ４ ) N.R. ｃ４ R ｄ４ , N.R. ｃ４ C (=NR ｅ４ ) N.R. 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 , N.R. ｃ４ S(O)R ｂ４ , N.R. ｃ４ S (O) ２ R ｂ４ , N.R. ｃ４ S (O) ２ N.R. ｃ４ R ｄ４ , S(O)R ｂ４ , S(O)NR ｃ４ R ｄ４ , S(O) ２ R ｂ４ , and S(O) ２ N.R. ｃ４ R ｄ４ and wherein said C is substituted with 1, 2, 3, 4, or 5 substituents independently selected from １－６ Alkyl, C ２－６ Alkenyl, and C ２－６ Each alkynyl is optionally ３ , Haro, 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 , C(=NR ｅ４ ) N.R. ｃ４ R ｄ４ , N.R. ｃ４ C (=NR ｅ４ ) N.R. 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 , N.R. ｃ４ S(O)R ｂ４ , N.R. ｃ４ S (O) ２ R ｂ４ , N.R. ｃ４ S (O) ２ N.R. ｃ４ R ｄ４ , S(O)R ｂ４ , S(O)NR ｃ４ R ｄ４ , S(O) ２ R ｂ４ , and S(O) ２ N.R. ｃ４ R ｄ４ and is substituted with 1, 2, or 3 substituents independently selected from R Ａ and R Ｂ are each independently H, C １－４ Alkyl, C １－４ Haloalkyl, C ２－４ Alkenyl, C ２－４ Alkynyl, C ６－１０ Aryl, C ３－１０ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－１０ Cycloalkyl-C １－４ Alkyl, (5-10 membered heteroaryl)-C １－４ alkyl, or (4-10 membered heterocycloalkyl)-C １－４ alkyl, １－４ Alkyl, C ２－４ Alkenyl, C ２－４ Alkynyl, C ６－１０ Aryl, C ３－１０ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－１０ Cycloalkyl-C １－４ Alkyl, (5-10 membered heteroaryl)-C １－４ alkyl, and (4-10 membered heterocycloalkyl)-C １－４ Alkyl is optionally OH, CN, amino, halo, C １－４ Alkyl, C １－４ Alkoxy, C １－４ Alkylthio, C １－４ Alkylamino, di(C １－４ Alkyl)amino, C １－４ Haloalkyl, and C １－４ substituted with 1, 2, or 3 substituents independently selected from haloalkoxy; Cy １ , Cy ２ , and Cy ３ Each independently represents C ６－１０ Aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl, each of which is optionally selected from halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl, C ３－１０ Cycloalkyl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl, CN, NO ２ , 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(=NR ｅ５ ) N.R. ｃ５ R ｄ５ , N.R. ｃ５ C (=NR ｅ５ ) N.R. ｃ５ R ｄ５ , N.R. ｃ５ S(O)R ｂ５ , N.R. ｃ５ S (O) ２ R ｂ５ , N.R. ｃ５ S (O) ２ N.R. ｃ５ R ｄ５ , S(O)R ｂ５ , S(O)NR ｃ５ R ｄ５ , S(O) ２ R ｂ５ , and S(O) ２ N.R. ｃ５ R ｄ５ and wherein said C is substituted by 1, 2, 3, 4, or 5 substituents independently selected from １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ６－１０ Aryl, C ３－１０ Cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each optionally selected from halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, CN, NO ２ , 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 , C(=NR ｅ５ ) N.R. ｃ５ R ｄ５ , N.R. ｃ５ C (=NR ｅ５ ) N.R. 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 , N.R. ｃ５ S(O)R ｂ５ , N.R. ｃ５ S (O) ２ R ｂ５ , N.R. ｃ５ S (O) ２ N.R. ｃ５ R ｄ５ , S(O)R ｂ５ , S(O)NR ｃ５ R ｄ５ , S(O) ２ R ｂ５ , and S(O) ２ N.R. ｃ５ R ｄ５ and is substituted with 1, 2, 3, 4, or 5 substituents independently selected from Each R ａ , R ｂ , R ｃ , R ｄ , R ａ１ , R ｂ１ , R ｃ１ , R ｄ１ , R ａ２ , R ｂ２ , R ｃ２ , R ｄ２ , R ａ３ , R ｂ３ , R ｃ３ , R ｄ３ , R ａ４ , R ｂ４ , R ｃ４ , and R ｄ４ , R ａ５ , R ｂ５ , R ｃ５ , and R ｄ５ are independent, H, C １－６ Alkyl, C １－４ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ６－１０ Aryl, C ３－１０ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－１０ Cycloalkyl-C １－４ Alkyl, (5-10 membered heteroaryl)-C １－４ alkyl, or (4-10 membered heterocycloalkyl)-C １－４ alkyl, １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ６－１０ Aryl, C ３－１０ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－１０ Cycloalkyl-C １－４ Alkyl, (5-10 membered heteroaryl)-C １－４ alkyl, and (4-10 membered heterocycloalkyl)-C １－４ Alkyl is optionally C １－４ Alkyl, C １－４ Haloalkyl, Halo, CN, 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)NR ｃ６ R ｄ６ , N.R. ｃ６ C(O)OR ａ６ , C(=NR ｅ６ ) N.R. ｃ６ R ｄ６ , N.R. ｃ６ C (=NR ｅ６ ) N.R. ｃ６ R ｄ６ , S(O)R ｂ６ , S(O)NR ｃ６ R ｄ６ , S(O) ２ R ｂ６ , N.R. ｃ６ S (O) ２ R ｂ６ , N.R. ｃ６ S (O) ２ N.R. ｃ６ R ｄ６ , and S(O) ２ N.R. ｃ６ R ｄ６ or substituted with 1, 2, 3, 4, or 5 substituents independently selected from Or, any R ｃ and R ｄ together with the N atom to which they are attached, C １－６ Alkyl, C ３－７ Cycloalkyl, 4-7 membered heterocycloalkyl, C ６－１０ Aryl, 5-6 membered heteroaryl, C １－６ Haloalkyl, Halo, CN, 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)NR ｃ６ R ｄ６ , N.R. ｃ６ C(O)OR ａ６ , C(=NR ｅ６ ) N.R. ｃ６ R ｄ６ , N.R. ｃ６ C (=NR ｅ６ ) N.R. ｃ６ R ｄ６ , S(O)R ｂ６ , S(O)NR ｃ６ R ｄ６ , S(O) ２ R ｂ６ , N.R. ｃ６ S (O) ２ R ｂ６ , N.R. ｃ６ S (O) ２ N.R. ｃ６ R ｄ６ , and S(O) ２ N.R. ｃ６ R ｄ６ and forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from １－６ Alkyl, C ３－７ Cycloalkyl, 4-7 membered heterocycloalkyl, C ６－１０ Aryl and 5-6 membered heteroaryl are optionally selected from halo, CN, 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)NR ｃ６ R ｄ６ , N.R. ｃ６ C(O)OR ａ６ , C(=NR ｅ６ ) N.R. ｃ６ R ｄ６ , N.R. ｃ６ C (=NR ｅ６ ) N.R. ｃ６ R ｄ６ , S(O)R ｂ６ , S(O)NR ｃ６ R ｄ６ , S(O) ２ R ｂ６ , N.R. ｃ６ S (O) ２ R ｂ６ , N.R. ｃ６ S (O) ２ N.R. ｃ６ R ｄ６ , and S(O) ２ N.R. ｃ６ R ｄ６ or substituted by 1, 2, or 3 substituents independently selected from Or, any R ｃ１ and R ｄ１ together with the N atom to which they are attached, C １－６ Alkyl, C ３－７ Cycloalkyl, 4-7 membered heterocycloalkyl, C ６－１０ Aryl, 5-6 membered heteroaryl, C １－６ Haloalkyl, Halo, CN, 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)NR ｃ６ R ｄ６ , N.R. ｃ６ C(O)OR ａ６ , C(=NR ｅ６ ) N.R. ｃ６ R ｄ６ , N.R. ｃ６ C (=NR ｅ６ ) N.R. ｃ６ R ｄ６ , S(O)R ｂ６ , S(O)NR ｃ６ R ｄ６ , S(O) ２ R ｂ６ , N.R. ｃ６ S (O) ２ R ｂ６ , N.R. ｃ６ S (O) ２ N.R. ｃ６ R ｄ６ , and S(O) ２ N.R. ｃ６ R ｄ６ and forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from １－６ Alkyl, C ３－７ Cycloalkyl, 4-7 membered heterocycloalkyl, C ６－１０ Aryl and 5-6 membered heteroaryl are optionally selected from halo, CN, 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)NR ｃ６ R ｄ６ , N.R. ｃ６ C(O)OR ａ６ , C(=NR ｅ６ ) N.R. ｃ６ R ｄ６ , N.R. ｃ６ C (=NR ｅ６ ) N.R. ｃ６ R ｄ６ , S(O)R ｂ６ , S(O)NR ｃ６ R ｄ６ , S(O) ２ R ｂ６ , N.R. ｃ６ S (O) ２ R ｂ６ , N.R. ｃ６ S (O) ２ N.R. ｃ６ R ｄ６ , and S(O) ２ N.R. ｃ６ R ｄ６ or substituted by 1, 2, or 3 substituents independently selected from Or, any R ｃ２ and R ｄ２ together with the N atom to which they are attached, C １－６ Alkyl, C ３－７ Cycloalkyl, 4-7 membered heterocycloalkyl, C ６－１０ Aryl, 5-6 membered heteroaryl, C １－６ Haloalkyl, Halo, CN, 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)NR ｃ６ R ｄ６ , N.R. ｃ６ C(O)OR ａ６ , C(=NR ｅ６ ) N.R. ｃ６ R ｄ６ , N.R. ｃ６ C (=NR ｅ６ ) N.R. ｃ６ R ｄ６ , S(O)R ｂ６ , S(O)NR ｃ６ R ｄ６ , S(O) ２ R ｂ６ , N.R. ｃ６ S (O) ２ R ｂ６ , N.R. ｃ６ S (O) ２ N.R. ｃ６ R ｄ６ , and S(O) ２ N.R. ｃ６ R ｄ６ and forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from １－６ Alkyl, C ３－７ Cycloalkyl, 4-7 membered heterocycloalkyl, C ６－１０ Aryl and 5-6 membered heteroaryl are optionally selected from halo, CN, 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)NR ｃ６ R ｄ６ , N.R. ｃ６ C(O)OR ａ６ , C(=NR ｅ６ ) N.R. ｃ６ R ｄ６ , N.R. ｃ６ C (=NR ｅ６ ) N.R. ｃ６ R ｄ６ , S(O)R ｂ６ , S(O)NR ｃ６ R ｄ６ , S(O) ２ R ｂ６ , N.R. ｃ６ S (O) ２ R ｂ６ , N.R. ｃ６ S (O) ２ N.R. ｃ６ R ｄ６ , and S(O) ２ N.R. ｃ６ R ｄ６ or substituted by 1, 2, or 3 substituents independently selected from Or, any R ｃ３ and R ｄ３ together with the N atom to which they are attached, C １－６ Alkyl, C ３－７ Cycloalkyl, 4-7 membered heterocycloalkyl, C ６－１０ Aryl, 5-6 membered heteroaryl, C １－６ Haloalkyl, Halo, CN, 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)NR ｃ６ R ｄ６ , N.R. ｃ６ C(O)OR ａ６ , C(=NR ｅ６ ) N.R. ｃ６ R ｄ６ , N.R. ｃ６ C (=NR ｅ６ ) N.R. ｃ６ R ｄ６ , S(O)R ｂ６ , S(O)NR ｃ６ R ｄ６ , S(O) ２ R ｂ６ , N.R. ｃ６ S (O) ２ R ｂ６ , N.R. ｃ６ S (O) ２ N.R. ｃ６ R ｄ６ , and S(O) ２ N.R. ｃ６ R ｄ６ and forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from １－６ Alkyl, C ３－７ Cycloalkyl, 4-7 membered heterocycloalkyl, C ６－１０ Aryl and 5-6 membered heteroaryl are optionally selected from halo, CN, 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)NR ｃ６ R ｄ６ , N.R. ｃ６ C(O)OR ａ６ , C(=NR ｅ６ ) N.R. ｃ６ R ｄ６ , N.R. ｃ６ C (=NR ｅ６ ) N.R. ｃ６ R ｄ６ , S(O)R ｂ６ , S(O)NR ｃ６ R ｄ６ , S(O) ２ R ｂ６ , N.R. ｃ６ S (O) ２ R ｂ６ , N.R. ｃ６ S (O) ２ N.R. ｃ６ R ｄ６ , and S(O) ２ N.R. ｃ６ R ｄ６ or substituted by 1, 2, or 3 substituents independently selected from Or, any R ｃ４ and R ｄ４ together with the N atom to which they are attached, C １－６ Alkyl, C ３－７ Cycloalkyl, 4-7 membered heterocycloalkyl, C ６－１０ Aryl, 5-6 membered heteroaryl, C １－６ Haloalkyl, Halo, CN, 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)NR ｃ６ R ｄ６ , N.R. ｃ６ C(O)OR ａ６ , C(=NR ｅ６ ) N.R. ｃ６ R ｄ６ , N.R. ｃ６ C (=NR ｅ６ ) N.R. ｃ６ R ｄ６ , S(O)R ｂ６ , S(O)NR ｃ６ R ｄ６ , S(O) ２ R ｂ６ , N.R. ｃ６ S (O) ２ R ｂ６ , N.R. ｃ６ S (O) ２ N.R. ｃ６ R ｄ６ , and S(O) ２ N.R. ｃ６ R ｄ６ and forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from １－６ Alkyl, C ３－７ Cycloalkyl, 4-7 membered heterocycloalkyl, C ６－１０ Aryl and 5-6 membered heteroaryl are optionally selected from halo, CN, 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)NR ｃ６ R ｄ６ , N.R. ｃ６ C(O)OR ａ６ , C(=NR ｅ６ ) N.R. ｃ６ R ｄ６ , N.R. ｃ６ C (=NR ｅ６ ) N.R. ｃ６ R ｄ６ , S(O)R ｂ６ , S(O)NR ｃ６ R ｄ６ , S(O) ２ R ｂ６ , N.R. ｃ６ S (O) ２ R ｂ６ , N.R. ｃ６ S (O) ２ N.R. ｃ６ R ｄ６ , and S(O) ２ N.R. ｃ６ R ｄ６ or substituted by 1, 2, or 3 substituents independently selected from Or, any R ｃ５ and R ｄ５ together with the N atom to which they are attached, C １－６ Alkyl, C ３－７ Cycloalkyl, 4-7 membered heterocycloalkyl, C ６－１０ Aryl, 5-6 membered heteroaryl, C １－６ Haloalkyl, Halo, CN, 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)NR ｃ６ R ｄ６ , N.R. ｃ６ C(O)OR ａ６ , C(=NR ｅ６ ) N.R. ｃ６ R ｄ６ , N.R. ｃ６ C (=NR ｅ６ ) N.R. ｃ６ R ｄ６ , S(O)R ｂ６ , S(O)NR ｃ６ R ｄ６ , S(O) ２ R ｂ６ , N.R. ｃ６ S (O) ２ R ｂ６ , N.R. ｃ６ S (O) ２ N.R. ｃ６ R ｄ６ , and S(O) ２ N.R. ｃ６ R ｄ６ and forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from １－６ Alkyl, C ３－７ Cycloalkyl, 4-7 membered heterocycloalkyl, C ６－１０ Aryl and 5-6 membered heteroaryl are optionally selected from halo, CN, 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)NR ｃ６ R ｄ６ , N.R. ｃ６ C(O)OR ａ６ , C(=NR ｅ６ ) N.R. ｃ６ R ｄ６ , N.R. ｃ６ C (=NR ｅ６ ) N.R. ｃ６ R ｄ６ , S(O)R ｂ６ , S(O)NR ｃ６ R ｄ６ , S(O) ２ R ｂ６ , N.R. ｃ６ S (O) ２ R ｂ６ , N.R. ｃ６ S (O) ２ N.R. ｃ６ R ｄ６ , and S(O) ２ N.R. ｃ６ R ｄ６ and is substituted by 1, 2, or 3 substituents independently selected from Each R ｅ１ , R ｅ２ , R ｅ３ , R ｅ４ , and R ｅ５ are independent, H, C １－４ Alkyl, CN, OR ａ６ , S.R. ｂ６ , S(O) ２ R ｂ６ , C(O)R ｂ６ , S(O) ２ N.R. ｃ６ R ｄ６ , and C(O)NR ｃ６ R ｄ６ is selected from Each R ａ６ , R ｂ６ , R ｃ６ , and R ｄ６ are independent, H, C １－４ Alkyl, C １－４ Haloalkyl, C ２－４ Alkenyl, and C ２－４ alkynyl, １－４ Alkyl, C ２－４ Alkenyl, and C ２－４ Alkynyl is optionally OH, CN, amino, halo, C １－４ Alkyl, C １－４ Alkoxy, C １－４ Alkylthio, C １－４ Alkylamino, di(C １－４ Alkyl)amino, C １－４ Haloalkyl, and C １－４ substituted with 1, 2, or 3 substituents independently selected from haloalkoxy; Or, any R ｃ６ and R ｄ６ together with the N atom to which they are attached, OH, CN, amino, halo, C １－６ Alkyl, C １－４ Alkoxy, C １－４ Alkylthio, C １－４ Alkylamino, di(C １－４ alkyl)amino, C １－４ Haloalkyl, and C １－４ forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from haloalkoxy; Each R ｅ６ are independent, H, C １－４ alkyl, and CN; However, ring A is 【Chemistry 3】 When W is NR ９ and R １ , R ２ , R ３ are each H, R ９ C １－６ is alkyl, R ４ , R ５ , R ６ , R ７ , and R ８ or a pharma- ceutically acceptable salt thereof, wherein at least four of are other than H.

2. Formula II, III, or IV: 【Chemistry 4】 2. The compound of claim 1 having the formula:

3. 3. The compound of claim 1 or 2, wherein W is O, or a pharma- ceutically acceptable salt thereof.

4. W is NR ９ 3. The compound of claim 1 or 2, which is: or a pharma- ceutically acceptable salt thereof.

5. R ９ But, H, C １－６ Alkyl, C ６－１０ Aryl, C ３－１０ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－１０ Cycloalkyl-C １－４ Alkyl, (5-10 membered heteroaryl)-C １－４ alkyl, or (4-10 membered heterocycloalkyl)-C １－４ alkyl, １－６ Alkyl, C ６－１０ Aryl, C ３－１０ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－１０ Cycloalkyl-C １－４ Alkyl, (5-10 membered heteroaryl)-C １－４ alkyl, and (4-10 membered heterocycloalkyl)-C １－４ Each alkyl is optionally ９ａ 5. The compound of claim 1, 2, or 4, or a pharma- ceutically acceptable salt thereof, substituted with:

6. R ９ But, H, C １－６ Alkyl, C ３－１０ Cycloalkyl, 4-10 membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, or C ３－１０ Cycloalkyl-C １－４ 5. The compound of any one of claims 1, 2, and 4, or a pharma- ceutically acceptable salt thereof, wherein: R is an alkyl group;

7. R ９ C １－６ 5. The compound of any one of claims 1, 2, and 4, or a pharma- ceutically acceptable salt thereof, wherein: R is an alkyl group;

8. R ９ 5. The compound of claim 1, 2, or 4, or a pharma- ceutically acceptable salt thereof, wherein is methyl.

9. W is CR １７ R １８ 3. The compound of claim 1 or 2, which is: or a pharma- ceutically acceptable salt thereof.

10. R １７ and R １８ each independently represents H, halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, and CN; １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ６－１０ Aryl, C ３－１０ Cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each optionally represented by R １０ａ 10. The compound of claim 1, 2, or 9, or a pharma- ceutically acceptable salt thereof, substituted with 1, 2, 3, 4, or 5 substituents independently selected from:

11. R １７ and R １８ each independently represents H, halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, and C １－６ haloalkyl; １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Each alkynyl is optionally １０ａ 10. The compound of claim 1, 2, or 9, or a pharma- ceutically acceptable salt thereof, substituted with 1, 2, 3, 4, or 5 substituents independently selected from:

12. R １７ and R １８ are each independently H and C １－６ 10. The compound of any one of claims 1, 2, and 9, or a pharma- ceutically acceptable salt thereof, wherein: R is selected from the group consisting of aryl, ...

13. R １７ and R １８ together with the carbon atom to which they are attached, C ３－７ 10. The compound according to any one of claims 1, 2, and 9, or a pharma- ceutically acceptable salt thereof, which forms a cycloalkyl.

14. R １ , R ２ , and R ３ Each of the following is H: or a pharma- ceutically acceptable salt thereof.

15. R ４ , R ５ , R ６ , R ７ , and R ８ each independently represents H, halo, C １－６ Alkyl, C １－６ Haloalkyl, CN, and OR ａ１ 15. The compound according to any one of claims 1 to 14, or a pharma- ceutically acceptable salt thereof, selected from:

16. R ４ , R ５ , R ６ , R ７ , and R ８ 15. The compound of any one of claims 1 to 14, or a pharma- ceutically acceptable salt thereof, wherein each is independently selected from H, halo, and methoxy.

17. R ５ and R ７ are both methoxy, and R ４ , R ６ , and R ８ 15. The compound of any one of claims 1 to 14, or a pharma- ceutically acceptable salt thereof, wherein each is independently selected from H and halo.

18. R ４ is halo, R ５ is methoxy, R ６ is H, and R ７ is methoxy, R ８ The compound of any one of claims 1 to 14, or a pharma- ceutically acceptable salt thereof, wherein is halo.

19. 15. The compound of any one of claims 1 to 14, having formula II, or a pharma- ceutically acceptable salt thereof.

20. X is CR １５ 20. The compound according to any one of claims 1 to 19, which is: or a pharma- ceutically acceptable salt thereof.

21. 20. The compound of any one of claims 1 to 19, or a pharma- ceutically acceptable salt thereof, wherein X is CH.

22. R １５ is H or C １－６ 22. The compound of any one of claims 1 to 21, which is 5-10 membered heteroaryl optionally substituted with alkyl, or a pharma- ceutically acceptable salt thereof.

23. R １０ But, H, C １－６ Alkyl, C ６－１０ Aryl, C ３－１０ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, or C(O)NR ｃ３ R ｄ３ and said C １－６ Alkyl, C ６－１０ Aryl, C ３－１０ Cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each optionally selected from Cy ２ , Haro, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, 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 , C(=NR ｅ３ ) N.R. ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) N.R. 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 , N.R. ｃ３ S(O)R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ N.R. ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , and S(O) ２ N.R. ｃ３ R ｄ３ and wherein said C is substituted with 1, 2, 3, 4, or 5 substituents independently selected from １－６ Alkyl, C ２－６ Alkenyl, and C ２－６ Each alkynyl is optionally ２ , Haro, 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 , C(=NR ｅ３ ) N.R. ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) N.R. 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 , N.R. ｃ３ S(O)R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ N.R. ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , and S(O) ２ N.R. ｃ３ R ｄ３ 23. The compound of any one of claims 1 to 22, or a pharma- ceutically acceptable salt thereof, substituted with 1, 2, or 3 substituents independently selected from:

24. R １０ is H, methyl, ethyl, phenyl, pyrazolyl, piperidinyl, tetrahydropyridinyl, CN, or C(O)NR ｃ３ R ｄ３ wherein the methyl, ethyl, phenyl, pyrazolyl, piperidinyl, and tetrahydropyridinyl are each optionally selected from the group consisting of Cy ２ , N.R. ｃ３ R ｄ３ , and OR ａ３ C optionally substituted with １－６ 23. The compound of any one of claims 1 to 22, or a pharma- ceutically acceptable salt thereof, substituted with 1, 2, or 3 substituents independently selected from alkyl.

25. R １０ H, (4-methylpiperazin-1-yl)phenyl, 1-methyl-1H-pyrazolyl, 1-(2-hydroxyethyl)-1H-pyrazolyl, methylaminocarbonyl, cyano, 1-methyl-1,2,3,6-tetrahydropyridinyl, 1-methylpiperidin-4-yl, dimethylaminocarbonyl, (3-hydroxyazetidin-1-yl)carbonyl, (3-hydroxypyrrolidin-1-yl)carbonyl, (4-methylpiperazin-1-yl) 23. The compound according to any one of claims 1 to 22, which is (3-cyanopyrrolidin-1-yl)carbonyl, (3-hydroxypiperidin-1-yl)carbonyl, tetrahydro-2H-pyran-4-yl, (4-methylpiperazin-1-yl)carbonyl, morpholin-4-ylcarbonyl, or (4,4-difluoropiperidin-1-yl)carbonyl, or a pharma- ceutically acceptable salt thereof.

26. R １０ is optionally substituted with 4- to 7-membered heterocycloalkyl; １－６ alkyl, said 4 to 7 membered heterocycloalkyl being selected from morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, and azetidinyl, said 4 to 7 membered heterocycloalkyl being optionally selected from halo, C １－６ Alkyl, C １－６ Haloalkyl, CN, OR ａ５ , C(O)R ｂ５ , C(O)NR ｃ５ R ｄ５ , C(O)OR ａ５ , O.C.(O)R ｂ５ , N.R. ｃ５ R ｄ５ , and N.R. ｃ５ C(O)R ｂ５ 23. The compound of any one of claims 1 to 22, or a pharma- ceutically acceptable salt thereof, substituted by 1, 2, or 3 substituents independently selected from:

27. R １０ H, (4-methylpiperazin-1-yl)phenyl, 1-methyl-1H-pyrazolyl, 1-(2-hydroxyethyl)-1H-pyrazolyl, methylaminocarbonyl, cyano, 1-methyl-1,2,3,6-tetrahydropyridinyl, 1-methylpiperidin-4-yl, dimethylaminocarbonyl, (3-hydroxyazetidin-1-yl)carbonyl, (3-hydroxypyrrolidin-1-yl)carbonyl, (4-methylpiperazin-1-yl)carbonyl, cyclohexyl, propylaminocarbonyl, (3-cyanopyrrolidin-1-yl)carbonyl, (3-hydroxypiperidin-1-yl)carbonyl, morpholin-4-ylmethyl, (4-methylpiperazin-1-yl)methyl, 4-ethylpiperazin-1-yl)methyl, 4-(2-hydroxyethyl)piperazin-1-yl]methyl, cyanoethylpiperazinylmethyl, cyanopiperidinylmethyl, cyanopyrrolidinylmethyl, (1-methylpiperidin-4-yl)aminomethyl , (tetrahydrofuran-3-ylamino)methyl, 1H-imidazol-1-ylmethyl, 1H-pyrazol-1-ylmethyl, (1-methyl-1H-pyrazol-4-yl)methyl, 2-pyridin-2-ylethyl, 2-morpholin-4-ylethyl, 2-(diethylamino)ethyl, 2-(3-fluoroazetidin-1-yl)ethyl, 2-(3-methoxyazetidin-1-yl)ethyl, (4-ethylpiperazin-1-yl)methyl, 3-(dimethylamino)pyridine 23. The compound according to any one of claims 1 to 22, which is 2-(4-methylpiperazin-1-yl)ethyl, 2-(4-ethylpiperazin-1-yl)ethyl, (pyridin-3-yloxy)methyl, (2-oxopyridin-1(2H)-yl)methyl, (3-cyanoazetidin-1-yl)methyl, (3-fluoroazetidin-1-yl)methyl, or (3-hydroxyazetidin-1-yl)methyl, or a pharma- ceutically acceptable salt thereof.

28. R １０ The compound according to any one of claims 1 to 22, or a pharma- ceutically acceptable salt thereof, wherein

29. 19. The compound of any one of claims 1 to 18, having formula III, or a pharma- ceutically acceptable salt thereof.

30. 30. The compound of any one of claims 1 to 18 and 29, or a pharma- ceutically acceptable salt thereof, wherein Z is CH.

31. 31. The compound of any one of claims 1 to 13, 29, and 30, or a pharma- ceutically acceptable salt thereof, wherein Y is S.

32. R １１ The compound according to any one of claims 1 to 13 and 29 to 31, or a pharma- ceutically acceptable salt thereof, wherein:

33. 19. The compound of any one of claims 1 to 18, having formula IV, or a pharma- ceutically acceptable salt thereof.

34. R １４ But, H, C １－６ alkyl, 4- to 10-membered heterocycloalkyl, or CN, １－６ alkyl and 4- to 10-membered heterocycloalkyl are each optionally １０ａ 34. The compound of any one of claims 1 to 18 and 33, or a pharma- ceutically acceptable salt thereof, substituted with 1, 2, 3, 4, or 5 substituents independently selected from:

35. R １４ 34. The compound of any one of claims 1 to 18 and 33, wherein is H, methyl, 1-methylpiperidinyl, CN, cyanomethyl, or 2-hydroxyethyl, or a pharma- ceutically acceptable salt thereof.

36. R １４ But, R １０ａ 34. The compound of any one of claims 1 to 18 and 33, wherein R is phenyl optionally substituted with R, or a pharma- ceutically acceptable salt thereof.

37. R １４ 34. The compound of any one of claims 1 to 18 and 33, wherein is (4-ethylpiperazin-1-yl)phenyl, or a pharma- ceutically acceptable salt thereof.

38. Formula IIa: 【Chemistry 5】 2. The compound of claim 1 having the formula:

39. R ４ is halo, R ５ is methoxy, R ６ is H, and R ７ is methoxy, R ８ 40. The compound of claim 38, or a pharma- ceutically acceptable salt thereof, wherein is halo.

40. R ９ C １－６ 40. The compound of claim 38 or 39, or a pharma- ceutically acceptable salt thereof, wherein: R is an alkyl group;

41. R １０ But, H, C １－６ Alkyl, C ６－１０ Aryl, C ３－１０ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, or C(O)NR ｃ３ R ｄ３ and said C １－６ Alkyl, C ６－１０ Aryl, C ３－１０ Cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each optionally represented by Cy. ２ , Haro, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, 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 , C(=NR ｅ３ ) N.R. ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) N.R. 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 , N.R. ｃ３ S(O)R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ N.R. ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , and S(O) ２ N.R. ｃ３ R ｄ３ and wherein said C is substituted with 1, 2, 3, 4, or 5 substituents independently selected from １－６ Alkyl, C ２－６ Alkenyl, and C ２－６ Each alkynyl is optionally ２ , Haro, 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 , C(=NR ｅ３ ) N.R. ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) N.R. 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 , N.R. ｃ３ S(O)R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ N.R. ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , and S(O) ２ N.R. ｃ３ R ｄ３ 41. The compound of any one of claims 38 to 40, or a pharma- ceutically acceptable salt thereof, substituted with 1, 2, or 3 substituents independently selected from:

42. R １０ is optionally substituted with 4- to 7-membered heterocycloalkyl; １－６ alkyl, said 4 to 7 membered heterocycloalkyl being selected from morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, and azetidinyl, said 4 to 7 membered heterocycloalkyl being optionally selected from halo, C １－６ Alkyl, C １－６ Haloalkyl, CN, OR ａ５ , C(O)R ｂ５ , C(O)NR ｃ５ R ｄ５ , C(O)OR ａ５ , O.C.(O)R ｂ５ , N.R. ｃ５ R ｄ５ , and N.R. ｃ５ C(O)R ｂ５ 41. The compound of any one of claims 38 to 40, or a pharma- ceutically acceptable salt thereof, substituted by 1, 2, or 3 substituents independently selected from:

43. Formula IIb: 【Chemistry 6】 2. The compound of claim 1 having the formula:

44. R ４ is halo, R ５ is methoxy, R ６ is H, and R ７ is methoxy, R ８ 44. The compound of claim 43, or a pharma- ceutically acceptable salt thereof, wherein is halo.

45. R １７ and R １８ each independently represents H, halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, and C １－６ haloalkyl; １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Each alkynyl is optionally １０ａ 45. The compound of claim 43 or 44, or a pharma- ceutically acceptable salt thereof, substituted with 1, 2, 3, 4, or 5 substituents independently selected from:

46. R １７ and R １８ Both are C １－６ 45. The compound of claim 43 or 44, or a pharma- ceutically acceptable salt thereof, wherein: R is an alkyl group;

47. R １０ But, H, C １－６ Alkyl, C ６－１０ Aryl, C ３－１０ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, or C(O)NR ｃ３ R ｄ３ and said C １－６ Alkyl, C ６－１０ Aryl, C ３－１０ Cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each optionally represented by Cy. ２ , Haro, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, 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 , C(=NR ｅ３ ) N.R. ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) N.R. 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 , N.R. ｃ３ S(O)R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ N.R. ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , and S(O) ２ N.R. ｃ３ R ｄ３ and wherein said C is substituted with 1, 2, 3, 4, or 5 substituents independently selected from １－６ Alkyl, C ２－６ Alkenyl, and C ２－６ Each alkynyl is optionally ２ , Haro, 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 , C(=NR ｅ３ ) N.R. ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) N.R. 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 , N.R. ｃ３ S(O)R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ N.R. ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , and S(O) ２ N.R. ｃ３ R ｄ３ 47. The compound of any one of claims 43 to 46, or a pharma- ceutically acceptable salt thereof, substituted with 1, 2, or 3 substituents independently selected from:

48. Formula IVa: 【Chemistry 7】 2. The compound of claim 1 having the formula:

49. R ４ is halo, R ５ is methoxy, R ６ is H, and R ７ is methoxy, R ８ 49. The compound of claim 48, or a pharma- ceutically acceptable salt thereof, wherein is halo.

50. R ９ But, H, C １－６ Alkyl, C ６－１０ Aryl, C ３－１０ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－１０ Cycloalkyl-C １－４ Alkyl, (5-10 membered heteroaryl)-C １－４ alkyl, or (4-10 membered heterocycloalkyl)-C １－４ alkyl, １－６ Alkyl, C ６－１０ Aryl, C ３－１０ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－１０ Cycloalkyl-C １－４ Alkyl, (5-10 membered heteroaryl)-C １－４ alkyl, and (4-10 membered heterocycloalkyl)-C １－４ Each alkyl is optionally ９ａ 50. The compound of claim 48 or 49, or a pharma- ceutically acceptable salt thereof, substituted with 1, 2, or 3 substituents independently selected from:

51. R １４ But, H, C １－６ Alkyl, C ６－１０ Aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, and CN; １－６ Alkyl, C ６－１０ Aryl, C ３－１０ Cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each optionally represented by R １０ａ 50. The compound of any one of claims 47 to 49, or a pharma- ceutically acceptable salt thereof, substituted with 1, 2, or 3 substituents independently selected from:

52. Formula V: 【Chemistry 8】 2. The compound of claim 1 having the formula:

53. W is NR ９ or CR １７ R １８ 53. The compound of any one of claims 1 and 52, wherein:

54. W is NR ９ 54. The compound of any one of claims 1, 52, and 53, which is: or a pharma- ceutically acceptable salt thereof.

55. R ９ But, H, C １－６ Alkyl, C ３－１０ Cycloalkyl, 3-10 membered heterocycloalkyl, C ６－１０ Aryl, C ６－１０ Aryl-C １－４ Alkyl, or C ３－１０ Cycloalkyl-C １－４ alkyl, each optionally being R ９ａ 55. The compound of any one of claims 1 and 52-54, or a pharma- ceutically acceptable salt thereof, substituted with 1, 2, or 3 substituents independently selected from:

56. R ９ C １－６ 55. The compound of any one of claims 1 and 52-54, or a pharma- ceutically acceptable salt thereof, wherein: R is an alkyl group;

57. R ９ 55. The compound of any one of claims 1 and 52-54, wherein is methyl, ethyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, 3-fluorophenylmethyl, or 4-chloro-2-fluorophenyl, or a pharma- ceutically acceptable salt thereof.

58. R ９ 55. The compound of any one of claims 1 and 52-54, or a pharma- ceutically acceptable salt thereof, wherein is methyl.

59. W is CR １７ R １８ 53. The compound of claims 1 and 52, which is: or a pharma- ceutically acceptable salt thereof.

60. R １ , R ２ , and R ３ or a pharma- ceutically acceptable salt thereof.

60. The compound of any one of claims 1 and 52-59, wherein each of

61. R ４ , R ５ , R ６ , R ７ , and R ８ each independently represents H, halo, C １－６ Alkyl, C １－６ Haloalkyl, CN, and OR ａ１ 61. The compound of any one of claims 1 and 52-60, or a pharma- ceutically acceptable salt thereof, selected from:

62. R ４ , R ５ , R ６ , R ７ , and R ８ 61. The compound of any one of claims 1 and 52-60, or a pharma- ceutically acceptable salt thereof, wherein each is independently selected from H, halo, and methoxy.

63. R ５ and R ７ are both methoxy, and R ４ , R ６ , and R ８ 61. The compound of any one of claims 1 and 52-60, or a pharma- ceutically acceptable salt thereof, wherein each is independently selected from H and halo.

64. R ４ is halo, R ５ is methoxy, R ６ is H, and R ７ is methoxy, R ８ 61. The compound of any one of claims 1 and 52-60, or a pharma- ceutically acceptable salt thereof, wherein: is halo.

65. 65. The compound of any one of claims 1 and 52-64, or a pharma- ceutically acceptable salt thereof, wherein Q is absent.

66. Q is O, NR １６ａ , or C.R. １２ａ R １３ａ 65. The compound of any one of claims 1 and 52 to 64, which is: or a pharma- ceutically acceptable salt thereof.

67. R １２ and R １３ 67. The compound of any one of claims 1 and 52-66, wherein each is H, or a pharma- ceutically acceptable salt thereof.

68. R １２ and R １３ together with the carbon atom to which they are attached, C ３－７ 67. The compound of any one of claims 1 and 52-66, or a pharma- ceutically acceptable salt thereof, which forms a cycloalkyl.

69. 70. The compound of any one of claims 1, 52, and 65-68, or a pharma- ceutically acceptable salt thereof, wherein n is 1 and Q is absent.

70. Formula Va: 【Chemistry 9】 53. The compound of claim 1 or 52, having the formula: or a pharma- ceutically acceptable salt thereof.

71. R ４ is halo, R ５ is methoxy, R ６ is H, and R ７ is methoxy, R ８ 71. The compound of claim 70, or a pharma- ceutically acceptable salt thereof, wherein is halo.

72. R ９ But, H, C １－６ Alkyl, C ３－１０ Cycloalkyl, 3-10 membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, or C ３－１０ Cycloalkyl-C １－４ 72. The compound of claim 70 or 71, or a pharma- ceutically acceptable salt thereof, which is alkyl.

73. 3-(3,5-dimethoxyphenyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 1-cyclopropyl-3-(3,5-dimethoxyphenyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 1-(cyclopropylmethyl)-3-(3,5-dimethoxyphenyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 1-benzyl-3-(3,5-dimethoxyphenyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,4-dichloro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(3,5-dimethoxyphenyl)-1-methyl-8-[4-(4-methylpiperazin-1-yl)phenyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(3,5-dimethoxyphenyl)-1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(3,5-dimethoxyphenyl)-N,1-dimethyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-8-carboxamide, 3-(2-chloro-3,5-dimethoxyphenyl)-1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2-chloro-3,5-dimethoxyphenyl)-8-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2-chloro-3,5-dimethoxyphenyl)-1-methyl-8-(1-methyl-1H-pyrazol-5-yl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2-chloro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-8-carbonitrile, 3-(3,5-dimethoxyphenyl)-1-methyl-8-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(3,5-dimethoxyphenyl)-1-methyl-8-(1-methylpiperidin-4-yl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(3,5-dimethoxyphenyl)-N,N,1-trimethyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-8-carboxamide, 3-(3,5-dimethoxyphenyl)-8-[(3-hydroxyazetidin-1-yl)carbonyl]-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(3,5-dimethoxyphenyl)-8-[(3-hydroxypyrrolidin-1-yl)carbonyl]-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(3,5-dimethoxyphenyl)-1-methyl-8-[(4-methylpiperazin-1-yl)carbonyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2-chloro-3,5-dimethoxyphenyl)-N,1-dimethyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-8-carboxamide, 3-(2-chloro-3,5-dimethoxyphenyl)-N,N,1-trimethyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-8-carboxamide, 3-(2-chloro-3,5-dimethoxyphenyl)-8-[(3-hydroxyazetidin-1-yl)carbonyl]-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2-chloro-3,5-dimethoxyphenyl)-1-methyl-8-[(4-methylpiperazin-1-yl)carbonyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, N-cyclopropyl-3-(2-fluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-8-carboxamide, 3-(2-fluoro-3,5-dimethoxyphenyl)-8-[(3-hydroxyazetidin-1-yl)carbonyl]-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 1-{[3-(2-fluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-8-yl]carbonyl}pyrrolidine-3-carbonitrile, 3-(2-fluoro-3,5-dimethoxyphenyl)-1-methyl-8-[(4-methylpiperazin-1-yl)carbonyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2-fluoro-3,5-dimethoxyphenyl)-8-[(3-hydroxypiperidin-1-yl)carbonyl]-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2-fluoro-3,5-dimethoxyphenyl)-N,N,1-trimethyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-8-carboxamide, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-N,N,1-trimethyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-8-carboxamide, 3-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-3,4-dihydrothieno[2',3':5,6]pyrido[4,3-d]pyrimidin-2(1H)-one 2. The compound of claim 1 selected from: or a pharma- ceutically acceptable salt of any of the foregoing.

74. 3-(3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(3,5-dimethoxyphenyl)-1-ethyl-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, and 3-(2-chloro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one or a pharma- ceutically acceptable salt of any of the foregoing.

75. The compound according to claim 1, which is 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-3,4,7,9-tetrahydro-1H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2,8-dione, or a pharma- ceutically acceptable salt thereof.

76. 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-8-(tetrahydro-2H-pyran-4-yl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-8-[(4-methylpiperazin-1-yl)carbonyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-8-(morpholin-4-ylcarbonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-[(4,4-difluoropiperidin-1-yl)carbonyl]-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-9-(1-methyl-1H-pyrazol-4-yl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2-hydroxyethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 1-cyclopropyl-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(tetrahydro-2H-pyran-4-yl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-phenyl-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1,9-dimethyl-1,3,4,7-tetrahydro-2H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidine-9-carbonitrile, [3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-9-yl]acetonitrile, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-9-(1-methylpiperidin-4-yl)-1,3,4,7-tetrahydro-2H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-9-(2-hydroxyethyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-1,3,4,7-tetrahydro-2H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-2-one, and 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2-hydroxyethyl)-1,3,4,7-tetrahydro-2H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-2-one 2. The compound of claim 1 selected from:

77. 1-cyclopropyl-3-(2,6-difluoro-3,5-dimethoxyphenyl)-3,4,7,9-tetrahydro-1H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2,8-dione, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-3,4,7,9-tetrahydro-1H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2,8-dione, and 1-(cyclopropylmethyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-3,4,7,9-tetrahydro-1H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2,8-dione 2. The compound of claim 1 selected from:

78. 3'-(2,6-difluoro-3,5-dimethoxyphenyl)-1'-methyl-4',7'-dihydrospiro[cyclopropane-1,9'-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine]-2',8'(1'H,3'H)-dione, 7-(2,6-difluoro-3,5-dimethoxyphenyl)-3,6,7,9-tetrahydro-8H-pyrrolo[2,3-c]-2,7-naphthyridin-8-one, 7-(2,6-difluoro-3,5-dimethoxyphenyl)-9-methyl-3,6,7,9-tetrahydro-8H-imidazo[4',5':5,6]pyrido[4,3-d]pyrimidin-8-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-4,7-dihydropyrazolo[4',3':5,6]pyrido[3,4-e][1,3]oxazin-2(3H)-one, 7'-(2,6-difluoro-3,5-dimethoxyphenyl)-6',7'-dihydrospiro[cyclopropane-1,9'-pyrrolo[2,3-c][2,7]naphthyridin]-8'(3'H)-one, 7-(2,6-difluoro-3,5-dimethoxyphenyl)-9,9-dimethyl-3,6,7,9-tetrahydro-8H-pyrrolo[2,3-c]-2,7-naphthyridin-8-one, and 3-(2,6-difluoro-3,5-dimethoxyphenyl)-9-[4-(4-ethylpiperazin-1-yl)phenyl]-1-methyl-1,3,4,7-tetrahydro-2H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-2-one 2. The compound of claim 1 selected from:

79. 3'-(2,6-difluoro-3,5-dimethoxyphenyl)-1'-methyl-4',7'-dihydrospiro[cyclopropane-1,9'-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine]-2',8'(1'H,3'H)-dione, 3-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)-1-ethyl-3,4,7,9-tetrahydro-1H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2,8-dione, 1-cyclobutyl-3-(2,6-difluoro-3,5-dimethoxyphenyl)-3,4,7,9-tetrahydro-1H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2,8-dione, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(3-fluorobenzyl)-3,4,7,9-tetrahydro-1H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2,8-dione, and 1-(4-chloro-2-fluorophenyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-3,4,7,9-tetrahydro-1H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2,8-dione 2. The compound of claim 1 selected from:

80. 3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-[(4-ethylpiperazin-1-yl)methyl]-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-[2-(4-ethylpiperazin-1-yl)ethyl]-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-[3-(4-ethylpiperazin-1-yl)propyl]-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-[(1-ethylpiperidin-4-yl)methyl]-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-[(1R,2R)-2-hydroxycyclopentyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-[(1R,2R)-2-hydroxycyclopentyl]-3,4,7,9-tetrahydro-1H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2,8-dione, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2,3-difluorophenyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2,3-difluorophenyl)-3,4,7,9-tetrahydro-1H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2,8-dione, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(pyridin-2-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(pyridin-2-ylmethyl)-3,4,7,9-tetrahydro-1H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2,8-dione, 1-(4-chlorophenyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-3,4,7,9-tetrahydro-1H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2,8-dione, 1-(5-chloropyridin-2-yl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-3,4,7,9-tetrahydro-1H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2,8-dione, 3-[3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-1-yl]benzonitrile, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-pyridin-3-yl-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 1-(3-chloro-2-fluorophenyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(1-methyl-1H-pyrazol-4-yl)-1,3,4,7-tetrahydro-2H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(pyridin-2-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-2-one, 1-cyclopropyl-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1,3,4,7-tetrahydro-2H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-[(3S)-tetrahydro-2H-pyran-3-yl]-1,3,4,7-tetrahydro-2H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-[(3S)-tetrahydrofuran-3-yl]-1,3,4,7-tetrahydro-2H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-[(3R)-tetrahydrofuran-3-yl]-1,3,4,7-tetrahydro-2H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-isopropyl-1,3,4,7-tetrahydro-2H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-[2-(trifluoromethoxy)phenyl]-1,3,4,7-tetrahydro-2H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-[3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-2,3,4,7-tetrahydro-1H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-1-yl]benzonitrile, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-pyridin-3-yl-1,3,4,7-tetrahydro-2H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2-methyl-2H-tetrazol-5-yl)-1,3,4,7-tetrahydro-2H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-quinolin-8-yl-1,3,4,7-tetrahydro-2H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-2-one, 1-cyclopropyl-3-(2,6-difluoro-3,5-dimethoxyphenyl)-9-methyl-1,3,4,7-tetrahydro-2H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-9-methyl-1,3,4,7-tetrahydro-2H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1,3,4,7-tetrahydro-2H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-9-(2-morpholin-4-ylethyl)-1,3,4,7-tetrahydro-2H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)-1-cyclopropyl-1,3,4,7-tetrahydro-2H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)-1-cyclobutyl-1,3,4,7-tetrahydro-2H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1,9-dimethyl-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, [3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-9-yl]acetonitrile, 3-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)-1-cyclobutyl-3,4,7,9-tetrahydro-1H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2,8-dione, 3-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)-1-(1-methyl-1H-pyrazol-4-yl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)-1-pyridin-3-yl-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-pyridazin-3-yl-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-[(4-hydroxypiperidin-1-yl)methyl]-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-[(4,4-difluoropiperidin-1-yl)methyl]-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-[(3,3-difluoropiperidin-1-yl)methyl]-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-8-(2-morpholin-4-ylethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 8-(2-azetidin-1-ylethyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-8-(2-pyrrolidin-1-ylethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-8-(3-morpholin-4-ylpropyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 8-[3-(4-cyclopropylpiperazin-1-yl)propyl]-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-[(4-ethylpiperazin-1-yl)carbonyl]-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-{[(3R,5S)-3,5-dimethylpiperazin-1-yl]carbonyl}-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 4-[3-(2,6-difluoro-3,5-dimethoxyphenyl)-2,8-dioxo-2,3,4,7,8,9-hexahydro-1H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-1-yl]benzonitrile, 3-{[3-(2,6-difluoro-3,5-dimethoxyphenyl)-2,8-dioxo-2,3,4,7,8,9-hexahydro-1H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-1-yl]methyl}benzonitrile, 3-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)-1-(2,3-difluorophenyl)-3,4,7,9-tetrahydro-1H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2,8-dione, and 4-[3-(2,6-difluoro-3,5-dimethoxyphenyl)-2,8-dioxo-2,3,4,7,8,9-hexahydro-1H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-1-yl]-3-fluorobenzonitrile 2. The compound of claim 1 selected from:

81. 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-[(4-methylpiperazin-1-yl)methyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-[(4-ethylpiperazin-1-yl)methyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-8-[(4-methylpiperazin-1-yl)methyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-{[4-(2-hydroxyethyl)piperazin-1-yl]methyl}-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(4-{[3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-8-yl]methyl}piperazin-1-yl)propanenitrile, 1-{[3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-8-yl]methyl}piperidine-4-carbonitrile, (3S)-1-{[3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-8-yl]methyl}pyrrolidine-3-carbonitrile, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-8-{[(1-methylpiperidin-4-yl)amino]methyl}-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-8-{[(3S)-tetrahydrofuran-3-ylamino]methyl}-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-8-{[(3R)-tetrahydrofuran-3-ylamino]methyl}-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-(1H-imidazol-1-ylmethyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-8-(1H-pyrazol-1-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-8-[(1-methyl-1H-pyrazol-4-yl)methyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-8-(2-pyridin-2-ylethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 8-[2-(diethylamino)ethyl]-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-[2-(3-fluoroazetidin-1-yl)ethyl]-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-[2-(3-methoxyazetidin-1-yl)ethyl]-1-methyl-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)-1-(1-methyl-1H-pyrazol-4-yl)-1,3,4,7-tetrahydro-2H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2-hydroxyethyl)-8-(2-morpholin-4-ylethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 1-(3-chloropyridin-2-yl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-3,4,7,9-tetrahydro-1H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2,8-dione, 7'-(2,6-difluoro-3,5-dimethoxyphenyl)-6',7'-dihydrospiro[cyclobutane-1,9'-pyrrolo[2,3-c][2,7]naphthyridin]-8'(3'H)-one, 7'-(2,6-difluoro-3,5-dimethoxyphenyl)-6',7'-dihydrospiro[cyclopentane-1,9'-pyrrolo[2,3-c][2,7]naphthyridin]-8'(3'H)-one, 7'-(2,6-difluoro-3,5-dimethoxyphenyl)-2,3,5,6,6',7'-hexahydrospiro[pyran-4,9'-pyrrolo[2,3-c][2,7]naphthyridin]-8'(3'H)-one, 7'-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-6',7'-dihydrospiro[piperidine-4,9'-pyrrolo[2,3-c][2,7]naphthyridin]-8'(3'H)-one, 7-(2,6-difluoro-3,5-dimethoxyphenyl)-9,9-dimethyl-2-(morpholin-4-ylmethyl)-3,6,7,9-tetrahydro-8H-pyrrolo[2,3-c]-2,7-naphthyridin-8-one, 7-(2,6-difluoro-3,5-dimethoxyphenyl)-9,9-dimethyl-2-[(4-methylpiperazin-1-yl)methyl]-3,6,7,9-tetrahydro-8H-pyrrolo[2,3-c]-2,7-naphthyridin-8-one, 7-(2,6-difluoro-3,5-dimethoxyphenyl)-2-[(4-ethylpiperazin-1-yl)methyl]-9,9-dimethyl-3,6,7,9-tetrahydro-8H-pyrrolo[2,3-c]-2,7-naphthyridin-8-one, 1-{[7-(2,6-difluoro-3,5-dimethoxyphenyl)-9,9-dimethyl-8-oxo-6,7,8,9-tetrahydro-3H-pyrrolo[2,3-c]-2,7-naphthyridin-2-yl]methyl}piperidine-4-carbonitrile, 7-(2,6-difluoro-3,5-dimethoxyphenyl)-2-{[(3S)-3-(dimethylamino)pyrrolidin-1-yl]methyl}-9,9-dimethyl-3,6,7,9-tetrahydro-8H-pyrrolo[2,3-c]-2,7-naphthyridin-8-one, 7-(2,6-difluoro-3,5-dimethoxyphenyl)-2-{[(3R)-3-(dimethylamino)pyrrolidin-1-yl]methyl}-9,9-dimethyl-3,6,7,9-tetrahydro-8H-pyrrolo[2,3-c]-2,7-naphthyridin-8-one, 7-(2,6-difluoro-3,5-dimethoxyphenyl)-9,9-dimethyl-2-(2-morpholin-4-ylethyl)-3,6,7,9-tetrahydro-8H-pyrrolo[2,3-c]-2,7-naphthyridin-8-one, 7-(2,6-difluoro-3,5-dimethoxyphenyl)-2-[2-(4-ethylpiperazin-1-yl)ethyl]-9,9-dimethyl-3,6,7,9-tetrahydro-8H-pyrrolo[2,3-c]-2,7-naphthyridin-8-one, 7-(2,6-difluoro-3,5-dimethoxyphenyl)-9,9-dimethyl-2-[2-(4-methylpiperazin-1-yl)ethyl]-3,6,7,9-tetrahydro-8H-pyrrolo[2,3-c]-2,7-naphthyridin-8-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(1,3-oxazol-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(isoxazol-3-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(1,3-thiazol-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-[2-(difluoromethoxy)phenyl]-1,3,4,7-tetrahydro-2H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-[2-(1H-pyrazol-1-yl)ethyl]-1,3,4,7-tetrahydro-2H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3,4,7-tetrahydro-2H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-[(2S)-tetrahydrofuran-2-ylmethyl]-1,3,4,7-tetrahydro-2H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2-pyrazin-2-ylethyl)-1,3,4,7-tetrahydro-2H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2-pyridin-2-ylethyl)-1,3,4,7-tetrahydro-2H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2-pyridin-3-ylethyl)-1,3,4,7-tetrahydro-2H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2-pyridin-4-ylethyl)-1,3,4,7-tetrahydro-2H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(1-ethyl-1H-pyrazol-4-yl)-1,3,4,7-tetrahydro-2H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-1,3,4,7-tetrahydro-2H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-1,3,4,7-tetrahydro-2H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-[1-(2,2-difluoroethyl)-1H-pyrazol-4-yl]-1,3,4,7-tetrahydro-2H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-[(6-methoxypyridin-2-yl)methyl]-1,3,4,7-tetrahydro-2H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-[(2-methoxypyridin-4-yl)methyl]-1,3,4,7-tetrahydro-2H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-[(3R)-tetrahydrofuran-3-ylmethyl]-1,3,4,7-tetrahydro-2H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-[(3S)-tetrahydrofuran-3-ylmethyl]-1,3,4,7-tetrahydro-2H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2-fluorophenyl)-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-[(4-ethylpiperazin-1-yl)methyl]-1-(2-fluorophenyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 1-cyclobutyl-3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 1-cyclobutyl-3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-(2-morpholin-4-ylethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-(morpholin-4-ylmethyl)-1-propyl-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(2-morpholin-4-ylethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 1-cyclopropyl-3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 1-cyclopropyl-3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-[(4-methylpiperazin-1-yl)methyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 1-cyclopropyl-3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-[(4-ethylpiperazin-1-yl)methyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(4-fluorophenyl)-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(4-fluorophenyl)-8-[(4-methylpiperazin-1-yl)methyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(4-fluorophenyl)-8-[(4-ethylpiperazin-1-yl)methyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2,3-difluorophenyl)-8-[(4-methylpiperazin-1-yl)methyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2,3-difluorophenyl)-8-[(4-ethylpiperazin-1-yl)methyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-(morpholin-4-ylmethyl)-1-pyridin-4-yl-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-[(4-methylpiperazin-1-yl)methyl]-1-pyridin-4-yl-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2-fluorophenyl)-8-(2-morpholin-4-ylethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2-fluorophenyl)-8-[2-(4-methylpiperazin-1-yl)ethyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2-fluorophenyl)-8-[2-(4-ethylpiperazin-1-yl)ethyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-[3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-2,3,4,7-tetrahydro-1H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-1-yl]-2-fluoro-N-isopropylbenzamide, N-cyclopropyl-3-[3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-2,3,4,7-tetrahydro-1H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-1-yl]-2-fluorobenzamide, 3-[3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-2,3,4,7-tetrahydro-1H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-1-yl]-N-ethyl-2-fluorobenzamide, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-[(2-methoxypyridin-4-yl)methyl]-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(1-methyl-1H-pyrazol-4-yl)-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-[(4-methylpiperazin-1-yl)methyl]-1-(1-methyl-1H-pyrazol-4-yl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-[(4-ethylpiperazin-1-yl)methyl]-1-(1-methyl-1H-pyrazol-4-yl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 7-(2,6-difluoro-3,5-dimethoxyphenyl)-2-[(3-hydroxyazetidin-1-yl)methyl]-9,9-dimethyl-3,6,7,9-tetrahydro-8H-pyrrolo[2,3-c]-2,7-naphthyridin-8-one, 7-(2,6-difluoro-3,5-dimethoxyphenyl)-2-[(3-fluoroazetidin-1-yl)methyl]-9,9-dimethyl-3,6,7,9-tetrahydro-8H-pyrrolo[2,3-c]-2,7-naphthyridin-8-one, 1-{[3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-8-yl]methyl}azetidine-3-carbonitrile, (3R)-1-{[3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-8-yl]methyl}pyrrolidine-3-carbonitrile, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-8-[2-(3-fluoroazetidin-1-yl)ethyl]-1-(2-hydroxyethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2,3-difluorophenyl)-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(3-fluorophenyl)-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(3-fluorophenyl)-8-[(4-methylpiperazin-1-yl)methyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(3-fluorophenyl)-8-[(4-ethylpiperazin-1-yl)methyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-9-(1-methyl-1H-pyrazol-4-yl)-1,3,4,7-tetrahydro-2H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-[(6-fluoropyridin-2-yl)methyl]-1,3,4,7-tetrahydro-2H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-[(6-methylpyridin-2-yl)methyl]-1,3,4,7-tetrahydro-2H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(3-fluoropyridin-2-yl)-1,3,4,7-tetrahydro-2H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-[(2-oxopyridin-1(2H)-yl)methyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-[(pyridin-3-yloxy)methyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2-hydroxyethyl)-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2,3-difluorophenyl)-8-(2-morpholin-4-ylethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2,3-difluorophenyl)-8-[2-(4-methylpiperazin-1-yl)ethyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2,3-difluorophenyl)-8-[2-(4-ethylpiperazin-1-yl)ethyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(4-fluorophenyl)-8-(2-morpholin-4-ylethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(4-fluorophenyl)-8-[2-(4-methylpiperazin-1-yl)ethyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(3-fluorophenyl)-8-(2-morpholin-4-ylethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(3-fluorophenyl)-8-[2-(4-methylpiperazin-1-yl)ethyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(3-fluorophenyl)-8-[2-(4-ethylpiperazin-1-yl)ethyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 1-{2-[3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-8-yl]ethyl}azetidine-3-carbonitrile, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-[2-(3-fluoroazetidin-1-yl)ethyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2-fluoroethyl)-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, and 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2-fluoroethyl)-8-[(4-methylpiperazin-1-yl)methyl]-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one 2. The compound of claim 1 selected from:

82. 82. A pharmaceutical composition comprising a compound according to any one of claims 1 to 81, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable carrier.

83. 82. A method of inhibiting an FGFR enzyme comprising contacting said enzyme with a compound according to any one of claims 1 to 81, or a pharma- ceutically acceptable salt thereof.

84. 82. A method of treating cancer in a patient, comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 81, or a pharma- ceutically acceptable salt thereof.

85. 85. The method of claim 84, wherein the cancer is selected from bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer, esophageal cancer, gallbladder cancer, pancreatic cancer, thyroid cancer, skin cancer, leukemia, multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, B-cell lymphoma, acute myeloid leukemia, Hodgkin's or non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, hairy cell lymphoma, Burkitt's lymphoma, glioblastoma, melanoma, and rhabdomyosarcoma.

86. 82. A method of treating a myeloproliferative disorder in a patient, comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 81, or a pharma- ceutically acceptable salt thereof.

87. 87. The method of claim 86, wherein the myeloproliferative disorder is selected from polycythemia vera, essential thrombocythemia, and primary myelofibrosis.

88. 82. A method of treating a skeletal or chondrocyte disorder in a patient, comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 81, or a pharma- ceutically acceptable salt thereof.

89. 89. The method of claim 88, wherein the skeletal or chondrocyte disorder is selected from achondroplasia, hypochondroplasia, dwarfism, tothoracic dysplasia (TD), Apert syndrome, Crouzon syndrome, Jackson-Weiss syndrome, Beare-Stevenson cutis gyrate syndrome, Pfeiffer syndrome, and craniosynostosis syndrome.

90. 82. A method of treating a hypophosphatemic disorder in a patient, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1-81, or a pharma- ceutically acceptable salt thereof.

91. 91. The method of claim 90, wherein the hypophosphatemic disorder is X-linked hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, and autosomal dominant hypophosphatemic rickets, or tumor-induced osteomalacia.

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