Inhibitors of Bruton's tyrosine kinase

1. A method for treating a lymphoma in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (A):

wherein

A is N;

R 1 is phenyl-O-aryl or phenyl-S-aryl;

R 2 and R 3 are independently selected from H, lower alkyl and substituted lower alkyl;

R 4 is L 3 -X-L 4 -G, wherein,

L 3 is optional, and when present is a bond, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted alkynyl;

X is optional, and when present is a bond, O, —C(═O), S, —S(═O), —S(═O) 2 , —NH, —NR 9 , —NHC(O), —C(O)NH, —NR 9 C(O), —C(O)NR 9 , —S(═O) 2 NH, —NHS(═O) 2 , —S(═O) 2 NR 9 —, —NR 9 S(═O) 2 , —OC(O)NH—, —NHC(O)O—, —OC(O)NR 9 —, —NR 9 C(O)O—, —CH═NO—, —ON═CH—, —NR 10 C(O)NR 10 —, heteroaryl, aryl, —NR 10 C(═NR 11 )NR 10 —, —NR 10 C(═NR 11 )—, —C(═NR 11 )NR 10 —, —OC(═NR 11 )—, or —C(═NR 11 )O—;

L 4 is optional, and when present is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle;

or L 3 , X and L 4 taken together form a nitrogen containing heterocyclic ring;

G is

 wherein, R 6 , R 7 and R 8 are each independently H;

each R 9 is independently selected from among H, substituted or unsubstituted lower alkyl, and substituted or unsubstituted lower cycloalkyl;

each R 10 is independently H, substituted or unsubstituted lower alkyl, or substituted or unsubstituted lower cycloalkyl; or

two R 10 groups can together form a 5-, 6-, 7-, or 8-membered heterocyclic ring; or

R 9 and R 10 can together form a 5-, 6-, 7-, or 8-membered heterocyclic ring; or

each R 11 is independently selected from H, —S(═O) 2 R 8 , —S(═O) 2 NH 2 , —C(O)R 8 , —CN, —NO 2 , heteroaryl, or heteroalkyl; or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 , wherein the compound of Formula (A) is administered orally.

3. The method of claim 1 , wherein the compound of Formula (A) bonds to a Bruton's tyrosine kinase (Btk) irreversibly.

4. The method of claim 1 , wherein the compound of Formula (A) forms a covalent bond to Bruton's tyrosine kinase (Btk).

5. The method of claim 3 , wherein the compound of Formula (A) bonds to the cysteine residue of the Bruton's tyrosine kinase.

6. The method of claim 1 , wherein the compound of Formula (A) has the structure of Formula (D) or a pharmaceutically acceptable salt thereof:

wherein:

L a is O or S;

Ar is an unsubstituted phenyl;

Y is a 4-, 5-, 6-, or 7-membered cycloalkyl ring, or

Y is azetidinyl, pyrrolidinyl, piperidinyl, or azepanyl;

Z is C(═O), OC(═O), NHC(═O), S(═O) x , or NHS(═O) x , where x is 2;

R 6, R 7 , and R 8 are each independently H; or

R 7 and R 8 taken together form a bond and R 6 is H.

7. The method of claim 6 , wherein L a is O.

8. The method of claim 6 , wherein Z is C(═O), NHC(═O), or S(═O) 2 .

9. The method of claim 6 , wherein R 6 , R 7 , and R 8 are each independently H.

10. The method of claim 1 , wherein the compound of Formula (A) has a structure:

or a pharmaceutically acceptable salt thereof.

11. A method for treating a lymphoma in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the structure