Inhibiting agents for bruton's tyrosine kinase

Patent metadata

Field	Value
Publication number	US-10227341-B2
Application number	US-201815952505-A
Country	US
Kind code	B2
Filing date	Apr 13, 2018
Priority date	Apr 14, 2017
Publication date	Mar 12, 2019
Grant date	Mar 12, 2019

Abstract

Provided are compounds of Formula (I), or pharmaceutically acceptable salts thereof, and methods for their use and production.

First claim

What is claimed is:

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
Ring A is 5-membered monocyclic heteroaryl containing 3 heteroatoms independently selected from N, O and S, wherein said 5-membered monocyclic heteroaryl is optionally substituted with one or more R 1 ;
Q 1 , Q 2 , and Q 3 are each, independently, selected from O, N(R 2 ), and CH—R 3 , wherein at least two of Q 1 , Q 2 , and Q 3 are C—R 3 ;
W is selected from CH and N;
Y is selected from CH and N;
R 1 in each occurrence is independently selected from C 1-6 alkyl and 3- to 5-membered carbocyclyl, wherein said C 1-6 alkyl and 3- to 5-membered carbocyclyl are optionally substituted with one or more R 10 ;
R 10 in each occurrence is independently selected from halo, —CN, C 1-6 alkyl, and 3- to 5-membered carbocyclyl;
R 2 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 4- to 6-membered monocyclic carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, —CN, —C(O)R 2a , —C(O) 2 R 2a , —C(O)N(R 2a ) 2 , —S(O) 2 R 2a , and —S(O) 2 N(R 2a ) 2 , wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl are optionally substituted with one or more R 20 ;
R 2a in each occurrence is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl in each occurrence are optionally and independently substituted with one or more R 20 ;
R 20 in each occurrence is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 4- to 6-membered monocyclic carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, halo, —CN, —C(O)R 20a , —C(O) 2 R 20a , —C(O)N(R 20a ) 2 , —N(R 20a ) 2 , —N(R 20a )C(O)R 20a , —N(R 20a )C(O) 2 R 20a , —N(R 20a )C(O)N(R 20a ) 2 , —N(R 20a )S(O) 2 R 20a , —OR 20a , —OC(O)R 20a , —OC(O)N(R 20a ) 2 , —SR 20a , —S(O)R 20a , —S(O) 2 R 20a , —S(O)N(R 20a ) 2 , and —S(O) 2 N(R 20a ) 2 ;
R 20a in each occurrence is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl;
R 3 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 4- to 6-membered monocyclic carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, halo, —CN, —C(O)R 3a , —C(O) 2 R 3a , —C(O)N(R 3a ) 2 , —N(R 3a ) 2 , —N(R 3a )C(O)R 3a , —N(R 3a )C(O) 2 R 3a , —N(R 3a )C(O)N(R 3a ) 2 , —N(R 3a )S(O) 2 R 3a , —OR 3a , —OC(O)R 3a , —OC(O)N(R 3a ) 2 , —SR 3a , —S(O)R 3a , —S(O) 2 R 3a , —S(O)N(R 3a ) 2 , and —S(O) 2 N(R 3a ) 2 , wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl are optionally substituted with one or more R 30 ;
R 3a in each occurrence is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl in each occurrence are optionally and independently substituted with one or more R 30 ;
R 30 in each occurrence is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 4- to 6-membered monocyclic carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, halo, —CN, —C(O)R 30a , —C(O) 2 R 30a , —C(O)N(R 30a ) 2 , —N(R 30a ) 2 , —N(R 30a )C(O)R 30a , —N(R 30a )C(O) 2 R 30a , —N(R 30a )C(O)N(R 30a ) 2 , —N(R 30a )S(O) 2 R 30a , —OR 30a , —OC(O)R 30a , —OC(O)N(R 30a ) 2 , —SR 30a , —S(O)R 30a , —S(O) 2 R 30a , —S(O)N(R 30a ) 2 , and —S(O) 2 N(R 30a ) 2 ;
R 30a in each occurrence is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl;
R 4 is selected from H and C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with one or more halo;
R 5 is selected from H and C 1-6 alkyl wherein said C 1-6 alkyl is optionally substituted with one or more halo;
R 6 is selected from H and C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with one or more halo;
or R 5 and R 6 , together with the atoms to which they are attached, form a ring containing one or two heteroatoms selected from O, N, and S, wherein the ring is optionally substituted with one or more R 50 ; and
R 50 is a C 1-6 alkyl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein (i) Q 1 , Q 2 and Q 3 are each independently CH—R 3 ; (ii) Q 2 is N(R 2 ) and Q 1 and Q 3 are each independently CH—R 3 ; (iii) Q 3 is N(R 2 ) and Q 1 and Q 2 are each independently CH—R 3 ; or (iv) Q 1 is 0 and Q 2 and Q 3 are each independently CH—R 3 .

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein W is CH.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is N.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is represented by one of following formulas:

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein ring A is selected from 1,2,3-oxadiazole, 1,3,4-oxadiazole, 1,2,4-oxadizole, 1,2,3-thiadiazole, 1,3,4-thiadiazole, 1,2,4-thiadiazole, 1,2,3-triazole, and 1,2,4-triazole, each of which is optionally substituted with one or two R 1 .

7. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein ring A is represented by one of the following formula:

8. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 in each occurrence is independently C 1-6 alkyl or C 3-5 cycloalkyl; wherein said C 1-6 alkyl and C 3-5 cycloalkyl are optionally substituted with one to three R 10 ; and
R 10 in each occurrence is independently selected from halo, —CN and C 1-6 alkyl.

9. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 1 in each occurrence is independently selected from C(CH 3 ) 3 , —CH(CH 3 ) 2 , —C(CH 3 ) 2 CHF 2 , —C(CH 3 ) 2 CF 3 , —C(CH 3 ) 2 CH 2 F, —C(CH 3 ) 2 CN, 1-methylcyclopropyl, cyclobutyl, and 3,3-difluorocyclobutyl.

10. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein:
R 2 is selected from H, C 1-6 alkyl, C 4-6 cycloalkyl, saturated 4- to 6-membered monocyclic heterocyclyl, —C(O)R 2a , —C(O) 2 R 2a , and —S(O) 2 R 2a , wherein said C 1-6 alkyl, C 4-6 cycloalkyl, and saturated 4- to 6-membered monocyclic heterocyclyl are optionally substituted with one to three R 20 ;
R 2a in each occurrence is independently selected from H, C 1-6 alkyl, C 4-6 alkyl, and saturated 4- to 6-membered monocyclic heterocyclyl, wherein said C 1-6 alkyl, 4- to 6-membered monocyclic carbocyclyl, and saturated 4- to 6-membered monocyclic heterocyclyl in each occurrence are optionally and

Assignees

• Biogen Ma Inc

Inventors

• Hopkins Brian T
• Ma Bin
• Prince Robin
• Marx Isaac
• Lyssikatos Joseph P

Classifications

• A61P1/16 Primary

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D417/14 Primary

  containing three or more hetero rings · CPC title

• C07D413/14 Primary

  containing three or more hetero rings · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title