Kinase inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-12129263-B2
Application number	US-202117511193-A
Country	US
Kind code	B2
Filing date	Oct 26, 2021
Priority date	May 17, 2017
Publication date	Oct 29, 2024
Grant date	Oct 29, 2024

Abstract

The present disclosure relates generally to compounds and compositions, intermediates, processes for their preparation, and their use as kinase inhibitors.

First claim

What is claimed is:

1. A compound according to Formula I:

or a pharmaceutically acceptable salt, isotopic analog, or isomer thereof, wherein
W 1 , W 3 , and W 4 are CR 7 ;
W 2 is CR 7 ;
provided that when W 2 is CR 7 , then either
a) W 4 is C—CN or
b) R 1a is not hydrogen and R 1b and R 1c together form a piperidin-4-yl ring substituted by (R 5 ) n and n is 1-9;

R 1a , R 1b , and R 1c are independently hydrogen, halogen, —CN, —N 3 , —NO 2 , —OH, —SF 5 , —SCF 3 , C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 heteroalkyl, C 3-8 cycloalkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, 4- to 12-membered heterocyclyl, C 6-10 aryl, 5- to 12-membered heteroaryl, —N(R 1d ) 2 , —C(O)R 1e , —C(O)OR 1d , —C(O)N(R 1d ) 2 , —NR 1d C(O)R 1e , —NR 1d C(O)N(R 1d ) 2 , —NR 1d C(O)OR 1d , —OC(O)N(R 1d ) 2 , —OC(O)OR 1d , —SR 1d , —S(O)R 1e , —S(O) 2 R 1e , —S(O) 3 R 1d , —S(O)N(R 1d ) 2 , —S(O) 2 N(R 1d ) 2 , —NR 1d S(O)R 1e , —NR 1d S(O) 2 R 1e , —NR 1d S(O)N(R 1d ) 2 , or —NR 1d S(O) 2 N(R 1d ) 2 , wherein each of R 1a , R 1b , and R 1c is optionally and independently substituted with one to eight R 5 and at least one of R 1a , R 1b , and R 1c is other than hydrogen; or
R 1b and R 1c are optionally taken together to form C 3-10 cycloalkyl or 4- to 12-membered heterocyclyl, each of which is optionally substituted with one to eight R 5 ; or
R 1a , R 1b , and R 1c are optionally taken together to form C 5-10 cycloalkyl or 6- to 8-membered heterocyclyl, each of which is optionally substituted with one to eight R 5 ; or
R 1a is absent and R 1b and R 1c are taken together to form C 6-10 aryl or 5- to 12-membered heteroaryl, each of which is optionally substituted with one to eight R 5 ;
each R 1d is independently hydrogen, C 1-8 alkyl, C 1-8 haloalkyl, C 3-10 cycloalkyl, or 4- to 12-membered heterocyclyl, or
two R 1d on the same atom are optionally taken together to form a 4- to 8-membered heterocyclyl optionally substituted by oxo, halo, or C 1-6 alkyl, wherein said alkyl is optionally substituted with one to eight R 5 ;
each R 1e is independently C 1-8 alkyl, C 1-8 haloalkyl, C 3-10 cycloalkyl, or 4- to 12-membered heterocyclyl;
R 2a and R 2b are independently hydrogen, halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 2-8 alkenyl, or C 2-8 alkynyl, or
R 2a and R 2b are optionally taken together to form C 3-6 cycloalkyl or 4- to 6-membered heterocyclyl, each of which is optionally substituted with one to eight R 6 ;
R 3a and R 3b are independently hydrogen, halogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 3-6 cycloalkyl, or 4- to 6-membered heterocyclyl, wherein said cycloalkyl and said heterocyclyl are optionally substituted with one to eight R 6 , or
R 3a and R 3b are optionally taken together to form oxo, C 3-6 cycloalkyl, or 4- to 6-membered heterocyclyl, wherein said cycloalkyl and said heterocyclyl are optionally substituted with one to eight R 6 ;
Y is CR 4a R 4b ;
R 4a and R 4b are independently hydrogen, halogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 3-6 cycloalkyl, or 4- to 6-membered heterocyclyl, wherein said cycloalkyl and said heterocyclyl are optionally substituted with one to eight R 6 , or
R 4a and R 4b are optionally taken together to form C 3-6 cycloalkyl or 4- to 6-membered heterocyclyl, wherein said cycloalkyl and said heterocyclyl are optionally substituted with one to eight R 6 , or
R 4a and R 1b are optionally taken together to form 4- to 12-membered heterocyclyl, which is optionally substituted with one to eight R 6 , or
R 4a and R 3a are optionally taken together to form C 3-8 cycloalkyl or 4- to 12-membered heterocyclyl, each of which is optionally substituted with one to eight R 6 , or
each R 5 is independently halogen, —CN, —OH, —SF 5 , —SCF 3 , C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 heteroalkyl, C 3-8 cycloalkyl, C 1-8 alkoxy, 4- to 12-membered heterocyclyl, C 6-10 aryl, 5- to 12-membered heteroaryl, (4- to 12-membered heterocyclyl)(C 1-8 heteroalkyl), (C 6-10 aryl)(C 1-8 heteroalkyl), (5- to 12-membered heteroaryl)(C 1-8 heteroalkyl), —N(R 5a ) 2 , —C(O)R 5b , —C(O)OR 5a , —C(O)N(R 5a ) 2 , —NR 5a C(O)R 5b , —NR 5a C(O)N(R 5a ) 2 , —NR 5a C(O)OR 5a , —OC(O)N(R 5a ) 2 , —OC(O)OR 5a , —SR 5a , —S(O)R 5b , —S(O) 2 R 5b , —S(O) 3 R 5a , —S(O)N(R 5a ) 2 , —S(O) 2 N(R 5a ) 2 , —NR 5 ªS(O)R 5b , —NR 5 ªS(O) 2 R 5b , —NR 5 ªS(O)N(R 5a ) 2 , or —NR 5a S(O) 2 N(R 5a ) 2 , each of which is optionally substituted with one to eight R 5c , or
two R 5 are optionally taken together to form oxo;
each R 5a is independently hydrogen, C 1-8 alkyl, C 1-8 haloalkyl, C 3-10 cycloalkyl, or 4- to 12-membered heterocyclyl, and
each R 5b is independently C 1-8 alkyl, C 1-8 haloalkyl, C 3-10 cycloalkyl, 4- to 12-membered heterocyclyl, or 5- to 12-membered heteroaryl;
each R 5c is independently halogen, cyano, C 1-8 haloalkyl, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, (C 1-8 alkoxy)(C 1-8 alkoxy), hydroxyl, SR 5d , N(R 5d ) 2 , N(R 5d ) 2 (C 1-8 alkoxy), C 3-10 cycloalkyl, or 4- to 12-membered heterocyclyl, or
two R 5c are optionally taken together to form oxo;
each R 5d is independently hydrogen, C 1-8 alkyl, or C 1-8 haloalkyl;
each R 6 is halogen, —CN, —OH, C 1-8 alkyl, C 1-8 heteroalkyl, C 3-8 cycloalkyl, C 1-8 haloalkyl, C 1-8 alkoxy, 4- to 12-membered heterocyclyl, C 6-10 aryl, 5- to 12-membered heteroaryl, —N(R 6a ) 2 , —C(O)R 6b , —C(O)N(R 6a ) 2 , or —C(O)OR 6a , or
two R 6 are taken together to form oxo;
each R 6a is independently hydrogen, C 1-8 alkyl, or C 1-8 haloalkyl, or
two R 6a on the same atom are optionally taken together to form 4- to 6-membered heterocyclyl;
each R 6b is independently C 1-8 alkyl or C 1-8 haloalkyl;
each R 7 is independently hydrogen, halogen, —CN, —N 3 , —NO 2 , —SF 5 , —SCF 3 , C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 heteroalkyl, C 3-8 cycloalkyl, C 1-8 haloalkyl, 4- to 12-membered heterocyclyl, C 6-10 aryl, 5- to 12-membered heteroaryl, —OR 7a , —C(O)R 7b , —N(R 7a ) 2 , —C(O)OR 7a , —C(O)N(R 7a ) 2 , —NR 7a C(O)R 7b , —NR 7a C(O)N(R 7a ) 2 , —NR 7a C(O)OR 7a , —OC(O)N(R 7a ) 2 , —OC(O)OR 7a , —SR 7a , —S(O)R 7b , —S(O) 2 R 7b , —S(O) 3 R 7a , —S(O)N(R 72 ) 2 , —S(O) 2 N(R 7a ) 2 , —NR 7a S(O)R 7b , —NR 7a S(O) 2 R 7b , —NR 7a S(O)N(R 7a ) 2 , or —NR 7a S(O) 2 N(R 7a ) 2 , each of which is optionally and independently substituted with one to eight R 8 ;
each R 7a is independently hydrogen, C 1-8 alkyl, C 1-8 haloalkyl, C 3-10 cycloalkyl, or 4- to 12-membered heterocyclyl, or
two R 7a on the same atom are optionally taken together to form a 4- to 8-membered heterocyclyl optionally substituted by oxo, halo, or C 1-6 alkyl, wherein said alkyl is optionally substituted with one to eight R 8 ;
each R 7b is independently C 1-8 alkyl, C 1-8 haloalkyl, C 3-10 cycloalkyl, or 4- to 12-membered heterocyclyl;
each R 8 is halogen, —CN, —OH, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 heteroalkyl, C 3-8 cycloalkyl, C 1-8 haloalkyl, C 1-8 alkoxy, 4- to 12-membered heterocyclyl, C 6-10 aryl, 5- to 12-membered heteroaryl, —N(R 8a ) 2 , —C(O)R 8b , or —C(O)OR 8a , or
two R 8 are optionally taken together to form oxo;
each R 8 ª is independently hydrogen, C 1-8 alkyl, or C 1-8 haloalkyl;
each R 8b is independently C 1-8 alkyl or C 1-8 haloalkyl; and
Z is O.

2. A compound of clai

Assignees

• Denali Therapeutics Inc

Inventors

• De Vicente Fidalgo Javier
• Estrada Anthony A
• Feng Jianwen A
• Fox Brian
• Francini Cinzia Maria
• Hale Christopher R H
• Hu Cheng
• Leslie Colin Philip
• Osipov Maksim
• Serra Elena
• Sweeney Zachary K
• Thottumkara Arun

Classifications

• C07D223/16

  Benzazepines; Hydrogenated benzazepines · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D267/04

  having the hetero atoms in positions 1 and 2 · CPC title

• C07D498/04 Primary

  Ortho-condensed systems · CPC title

• C07D267/14 Primary

  condensed with one six-membered ring · CPC title