Inhibitors of Bruton's tyrosine kinase

1. A method of treating pancreatic cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the structure of Formula (A):

wherein:

A is independently selected from N or CR 5 ;

R 1 is H, L 2 -(substituted or unsubstituted alkyl), L 2 -(substituted or unsubstituted cycloalkyl), L 2 -(substituted or unsubstituted alkenyl), L 2 -(substituted or unsubstituted cycloalkenyl), L 2 -(substituted or unsubstituted heterocycle), L 2 -(substituted or unsubstituted heteroaryl), or L 2 -(substituted or unsubstituted aryl), where L 2 is a bond, O, S, —S(═O), —S(═O) 2 , C(═O), -(substituted or unsubstituted C 1 -C 6 alkyl), or -(substituted or unsubstituted C 2 -C 6 alkenyl);

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 independently selected from among H, lower alkyl or substituted lower alkyl, lower heteroalkyl or substituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, and substituted or unsubstituted lower heterocycloalkyl;

R 5 is H, halogen, -L 6 -(substituted or unsubstituted C 1 -C 3 alkyl), -L 6 -(substituted or unsubstituted C 2 -C 4 alkenyl), -L 6 -(substituted or unsubstituted heteroaryl), or -L 6 -(substituted or unsubstituted aryl), wherein L 6 is a bond, O, S, —S(═O), S(═O) 2 , NH, C(O), —NHC(O)O, —OC(O)NH, —NHC(O), or —C(O)NH;

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 10 and R 11 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 has the structure:

3. The method of claim 1 , wherein A is N; R 1 is L 2 -substituted aryl; and L 2 is a bond.

4. The method of claim 1 , wherein R 2 and R 3 are independently H.

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

wherein:

Y is alkyl or substituted alkyl, or a 4-, 5-, or 6-membered cycloalkyl ring;

each R a is independently H, halogen, —CF 3 , —CN, —NO 2 , OH, NH 2 , -L a -(substituted or unsubstituted alkyl), -L a -(substituted or unsubstituted alkenyl), -L a -(substituted or unsubstituted heteroaryl), or -L a -(substituted or unsubstituted aryl), wherein L a is a bond, O, S, —S(═O), —S(═O) 2 , NH, C(O), CH 2 , —NHC(O)O, —NHC(O), or —C(O)NH;

G is

wherein,

R 6 , R 7 and R 8 are independently selected from among H, lower alkyl or substituted lower alkyl, lower heteroalkyl or substituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, and substituted or unsubstituted lower heterocycloalkyl;

R 12 is H or lower alkyl; or

Y and R 12 taken together form a 4-, 5-, or 6-membered heterocyclic ring; or a pharmaceutically acceptable salt thereof.

6. The method of claim 5 , wherein Y and R 12 taken together form a 6-membered heterocyclic ring.

7. The method of claim 5 , wherein the compound of Formula (B) has the structure of Formula (C):

Y is alkyl or substituted alkyl, or a 4-, 5-, or 6-membered cycloalkyl ring;

R 12 is H or lower alkyl; or

Y and R 12 taken together form a 4-, 5-, or 6-membered heterocyclic ring;

G is

wherein,

R 6 , R 7 and R 8 are independently selected from among H, lower alkyl or substituted lower alkyl, lower heteroalkyl or substituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, and substituted or unsubstituted lower heterocycloalkyl; or a pharmaceutically acceptable salt thereof.

8. The method of claim 7 , wherein Y and R 12 taken together form a 4-, 5-, or 6-membered heterocyclic ring.

9. The compound of claim 7 , wherein G is

10. The compound of claim 7 , wherein R 6 , R 7 , and R 8 are independently H.

11. A method of treating pancreatic cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the structure of Formula (D):

wherein

L a is CH 2 , O, NH or S;

Ar is an optionally substituted aromatic carbocycle or an aromatic heterocycle;

Y is an optionally substituted alkyl, heteroalkyl, carbocycle, heterocycle, or combination thereof;

Z is C(O), OC(O), NHC(O), C(S), S(O) x , OS(O) x , NHS(O) x , where x is 1 or 2; and

R 6 , R 7 , and R 8 are independently selected from H, alkyl, heteroalkyl, carbocycle, heterocycle, or combinations thereof.

12. The method of claim 11 , wherein La is O, Ar is an aromatic carbocycle, Y is heterocycle, Z is C(O), and R 6 , R 7 , and R 8 are independently H.