Inhibitors of Bruton's tyrosine kinase

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)phenylamino)pyrazine-2-carboxamide;

(R,E)-3-(1-(4-(dimethylamino)but-2-enoyl)piperidin-3-ylamino)-5-(4-(methylsulfonyl)phenylamino)-1,2,4-triazine-6-carboxamide;

(R,E)-3-(1-(4-(cyclopropyl(methyl)amino)but-2-enoyl)piperidin-3-ylamino)-5-(4-(methylsulfonyl)phenylamino)-1,2,4-triazine-6-carboxamide;

(R,E)-5((1-(4-(cyclopropyl(methyl)amino)but-2-enoyl)piperidin-3-yl)(methyl)amino)-3-(4-(morpholine-4-carbonyl)phenylamino)pyrazine-2-carboxamide;

(R)-5((1-but-2-ynoylpiperidin-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-phenoxyphenylamino)pyrazine-2-carboxamide; and

(R)-3-(5-carbamoyl-6-(3-methyli sothiazol-5-ylamino)pyrazin-2-ylamino)-N,N-dimethylazepane-1-carboxamide;

or a pharmaceutically acceptable solvate, or pharmaceutically acceptable salt thereof.