IP Library › Granted Patent US 9,862,722
Granted Patent B2
US 9,862,722 · App. 14/811,541 · Granted Jan 9, 2018

Inhibitors of Bruton's tyrosine kinase

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Quick Facts
Patent No.
US 9,862,722
App. No.
14/811,541
Granted
Jan 9, 2018
Kind
B2
Abstract

Described herein are kinase inhibitor compounds, methods for synthesizing such inhibitors, and methods for using such inhibitors in the treatment of diseases. Further described herein are methods, assays and systems for determining an appropriate inhibitor of a protein, including a kinase.

Claims (42)

1. A compound having the structure of Formula (VIII)

wherein:

L is CR a R a , O, S, NR b , N—OR b , C═O, C═S, C═N—R b or C═N—OR b ;

W is a bond or optionally substituted C 1 -C 3 alkyl;

Z is NR c C═O, SO 2 or SO;

R 1 and R 2 are each independently H or C 1 -C 3 alkyl, wherein R 1 and R 2 have a cis or trans relationship; or R 1 and R 2 join together to form a bond;

p is an integer from 0 to 3;

R 3 is H, substituted or unsubstituted C 1 -C 3 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 2 -C 6 heterocycloalkyl, substituted or unsubstituted C 6 -C 12 aryl, or substituted or unsubstituted C 5 -C 11 heteroaryl;

R 4 is substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 6 heterocycloalkyl, substituted or unsubstituted C 6 -C 12 aryl, or substituted or unsubstituted C 5 -C 11 heteroaryl;

R 5 is H, OH, OR b , NR b R b , halogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl or C 2 -C 6 heterocycloalkyl;

R a is each independently H, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, halogen, OR b , or NR b R b ;

R b is each independently H, C 1 -C 6 alkyl, C 2 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl or C 2 -C 6 heterocycloalkyl;

R c is H or C 1 -C 6 alkyl;

or a pharmaceutically acceptable salt, solvate, or N-oxide thereof.

2. A compound having the structure of Formula (X)

wherein:

L is CR a R a , O, S, NR b , N—OR b , C═O, C═S, C═N—R b or C═N—OR b ;

W is a bond or optionally substituted C 1 -C 3 alkyl;

Z is C═O, SO 2 or SO;

R 1 and R 2 are each independently H or C 1 -C 3 alkyl, wherein R 1 and R 2 have a cis or trans relationship; or R 1 and R 2 join together to form a bond;

n and p are each independently an integer from 0 to 3;

m is an integer from 1 to 3;

R 3 is H, substituted or unsubstituted C 1 -C 3 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 2 -C 6 heterocycloalkyl, substituted or unsubstituted C 6 -C 12 aryl, or substituted or unsubstituted C 5 -C 11 heteroaryl;

R 4 is methyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 6 heterocycloalkyl, substituted or unsubstituted C 6 -C 12 aryl, or substituted or unsubstituted C 5 -C 11 heteroaryl;

R 5 is H, OH, OR b , NR b R b , halogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl or C 2 -C 6 heterocycloalkyl;

R a is each independently H, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, halogen, OR b , or NR b R b ;

R b is each independently H, C 1 -C 6 alkyl, C 2 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl or C 2 -C 6 heterocycloalkyl;

or a pharmaceutically acceptable salt, solvate, or N-oxide thereof.

3. A pharmaceutical composition comprising a compound of any one of claims 1 or 2 or a pharmaceutically acceptable salt, solvate, or N-oxide thereof; and a pharmaceutically acceptable excipient, binder or carrier.

4. A compound of claim 2 , selected from:

or a pharmaceutically acceptable salt, solvate, or N-oxide thereof.

5. The compound according to either of claim 1 or 2 , wherein L is O.

6. The compound according to either of claim 1 or 2 , wherein W is a bond.

7. The compound according to either of claim 1 or 2 , wherein R 1 is H and R 2 is H.

8. The compound according to claim 1 , wherein Z is NR c C═O; and R c is H or methyl.

9. The compound according to claim 2 , wherein Z is C═O.

10. The compound according to either of claim 1 or 2 , wherein R 3 is H, methyl, ethyl, or isopropyl.

11. The compound according to either of claim 1 or 2 , wherein R 4 is substituted or unsubstituted C 3 -C 6 cycloalkyl.

12. The compound according to claim 11 , wherein R 4 is cyclopropyl or cyclobutyl.

13. The compound according to claim 2 , wherein R 4 is methyl.

14. The compound according to either of claim 1 or 2 , wherein R 5 is H.

15. The compound according to claim 2 , wherein m is 1; and n is 2 or 3.