Inhibitors of Bruton's tyrosine kinase

Patent metadata

Field	Value
Publication number	US-9656988-B2
Application number	US-201615173182-A
Country	US
Kind code	B2
Filing date	Jun 3, 2016
Priority date	Dec 5, 2013
Publication date	May 23, 2017
Grant date	May 23, 2017

Abstract

Disclosed herein are reversible and irreversible inhibitors of Bruton's tyrosine kinase (Btk). Also disclosed are pharmaceutical compositions that include the compounds. Methods of using the Btk inhibitors are described, alone or in combination with other therapeutic agents, for the treatment of autoimmune diseases or conditions, heteroimmune diseases or conditions, cancer, including lymphoma, and inflammatory diseases or conditions.

First claim

What is claimed is:

1. A compound of Formula (IA) having the structure:

wherein:
ring A is substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 7 heterocycloalkyl, substituted or unsubstituted C 6 -C 12 aryl, or substituted or unsubstituted C 1 -C 12 heteroaryl;
W is —C(R 2 )—; and X is —C(R 2 )— or —N—; or
W is —N—; and X is —C(H)— or —N—;
Y is optionally present and when present is —CH 2 O—, —OCH 2 —, —OCH 2 CH 2 O—, —O—, —N(R 3 )—, —C(O)—, —N(R 3 )C(O)—, —C(O)N(R 3 )—, —N(R 3 )C(O)N(R 3 )—, —S(O)—, —S(O) 2 —, —N(R 3 )S(O) 2 —, —S(O) 2 N(R 3 )—, —C(═NH)—, —C(═NH)N(R 3 )—, —C(═NH)N(R 3 )—, or substituted or unsubstituted C 1 -C 4 alkylene;
Z is optionally present and when present is substituted or unsubstituted C 1 -C 3 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 7 heterocycloalkyl, substituted or unsubstituted C 6 -C 12 aryl, or substituted or unsubstituted C 1 -C 12 heteroaryl;
G is

R 1 ′ is —C(O)R 9 , —C(O)C(O)R 9 , —C(O)OR 4 , —C(O)N(R 3 )(R 4 ), or —S(O) 2 R 9 ;
each R 2 is independently H, substituted or unsubstituted C 1 -C 4 alkyl, —CN, or halogen;
each R 3 is independently is H, or substituted or unsubstituted C 1 -C 4 alkyl;
each R 4 is independently H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 7 heterocycloalkyl, substituted or unsubstituted C 6 -C 12 aryl, or substituted or unsubstituted C 1 -C 12 heteroaryl;
R 5 is H, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 7 heterocycloalkyl, substituted or unsubstituted C 6 -C 12 aryl, or substituted or unsubstituted C 1 -C 12 heteroaryl;
each R 6 is independently halogen, —CN, —OH, —NH 2 , substituted or unsubstituted C 1 -C 4 alkoxy, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 6 heterocycloalkyl, or —N(R 3 ) 2 ; or R 1 and R 6 are combined to form a substituted or unsubstituted C 2 -C 9 heterocycloalkyl ring;
each R 7 is independently halogen, —CN, —OH, —NH 2 , substituted or unsubstituted C 1 -C 4 alkoxy, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 6 heterocycloalkyl, or —N(R 3 ) 2 ;
R 9 is —R 4 , or

R 10 is H, halogen, —CN, or -L 1 -L 2;
R 11 and R 12 are independently H, halogen, —CN, or -L 1 -L 2 ; or R 11 and R 12 taken together form a bond;
each L 1 is optionally present and when present each L 1 is independently substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 2 -C 7 heterocycloalkyl, substituted or unsubstituted C 6 -C 12 aryl, substituted or unsubstituted C 1 -C 12 heteroaryl, —C(═O)—, —O—, or —S—;
each L 2 is independently H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 2 -C 7 heterocycloalkyl, substituted or unsubstituted C 6 -C 12 aryl, substituted or unsubstituted C 1 -C 12 heteroaryl or —N(R 13 ) 2 ;
each R 13 is independently H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 heteroalkyl, C 2 -C 7 heterocycloalkyl, C 6 -C 12 aryl, or C 1 -C 12 heteroaryl;
n is 0-3;
p is 0-3; and
q is 0-3;
or a pharmaceutically acceptable solvate, or pharmaceutically acceptable salt thereof;
provided that
i) when W is N, and X is CH; then R 1 ′ is other than —C(O)Me, or t-Boc; and
ii) when n is 0; then each of p and q is independently 0, 1, or 2.

2. The compound of claim 1 , wherein R6 is Me.

3. The compound of claim 1 , wherein ring A is phenyl.

4. The compound of claim 1 , wherein Y is absent, —CH 2 O—, —OCH 2 —, —O—, —N(R 3 )—, —C(O)—, —N(R 3 )C(O)—, —C(O)N(R 3 )—, or substituted or unsubstituted C 1 -C 4 alkylene.

5. The compound of claim 1 , wherein Z is substituted or unsubstituted C 2 -C 7 heterocycloalkyl, substituted or unsubstituted C 6 -C 12 aryl, or substituted or unsubstituted C 1 -C 12 heteroaryl.

6. The compound of claim 1 , wherein R 1 ′ is —C(O)R 9 .

7. The compound of claim 6 , wherein R 9 is —R 4 , and R 4 is substituted or unsubstituted C 6 -C 12 aryl, or substituted or unsubstituted C 1 -C 12 heteroaryl.

8. The compound of claim 1 , wherein ring A is substituted or unsubstituted C 1 -C 12 heteroaryl.

9. The compound of claim 8 , wherein ring A is pyridyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, or isoxazolyl.

10. The compound of claim 1 , wherein X is —C(H)—.

11. The compound of claim 1 , wherein X is —N—.

12. The compound of claim 1 , wherein W is —C(H)—.

13. The compound of claim 1 , wherein W is —N—.

14. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , and a pharmaceutically acceptable excipient.

15. A method for treating rheumatoid arthritis comprising administering to a patient in need a therapeutically effective amount of a compound of claim 1 .

16. The compound of claim 6 , wherein R 9 is —R 4 , and R 4 is substituted or unsubstituted C 2 -C 7 heterocycloalkyl.

17. The compound of claim 6 , wherein R 9 is

18. The compound of claim 17 , wherein each of R 10 , R 11 , and R 12 is H; or R 11 and R 12 form a bond and R 10 is H or C 1 -C 4 alkyl; or each of R 10 and R 12 is H, and R 11 is —CH 2 —N(Me) 2 or —CH 2 —N(Me)-cyclopropyl.

19. A compound selected from the group consisting of
(R)-3-(1-(4-tert-butylbenzoyl)piperidin-3-ylamino)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide;
(R)-5-(4-(morpholine-4-carbonyl)phenylamino)-3-(1-propionylpiperidin-3-ylamino)-1,2,4-triazine-6-carboxamide;
(R)-3-(1-(cyclopropanecarbonyl)piperidin-3-ylamino)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide;
(R)-3-(1-acryloylpiperidin-3-ylamino)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide;
(R,E)-3-(1-(4-(dimethylamino)but-2-enoyl)piperidin-3-ylamino)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide;
(R,E)-3-(1-(4-(cyclopropyl(methyl)amino)but-2-enoyl)piperidin-3-ylamino)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide;
(R)-3-(1-acryloylpyrrolidin-3-ylamino)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide;
(R,E)-3-(1-(4-(cyclopropyl(methyl)amino)but-2-enoyl)pyrrolidin-3-ylamino)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide;
(R)-3-(1-acryloylpyrrolidin-3-ylamino)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide;
(R)-5((1-acryloylpiperidin-3-yl)(methyl)amino)-3-(4-(morpholine-4-carbonyl)phenylamino)pyrazine-2-carboxamide;
(R,E)-5-((1-(4-(dimethylamino)but-2-enoyl)piperidin-3-yl)(methyl)amino)-3-(4-(morpholine-4-carbonyl

Assignees

• Pharmacyclics Llc

Inventors

• Chen Wei
• Jia Zhaozhong J
• Thomas William D

Classifications

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/00

  Antineoplastic agents · CPC title