Benzothiazole kinase inhibitors and methods of use

1. A compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein:

M 1 is benzothiazolyl substituted with —(W 2 ) k —R 2 ;

k is 1;

R 1 is -H, -L-alkyl, -L-cycloalkyl, -L-alkyl-cycloalkyl, -L- aryl, -L-heteroaryl, -L-alkylaryl, -L-alkylheterocyclyl, or -L-heterocyclyl, each of which is unsubstituted or substituted by one or more independent R 3 substituents;

L is a bond, C═O, —C(═O)O—, —C(═O)NR 31 —, —S—, —S(O)—, —S(O) 2 —, —S(O) 2 NR 31 —, or —NR 31 —;

X 1 is N and X 2 is N;

E 2 is —(W 1 ) j —R 4 ;

j, in each instance, is 0 or 1;

W 1 is —O—, —NR 6 —, —S(O) 0-2 —, —C(O)—, —C(O)N(R 6 )—, —N(R 6 )C(O)—, —N(R 6 )S(O)—, —N(R 6 )S(O) 2 —, —C(O)O—, —CH(R 6 )N(C(O)OR 7 )—, —CH(R 7 )N(C(O)R 7 )—, —CH(R 6 )N(SO 2 R 7 )—, —CH(R 6 )N(R 7 )—, —CH(R 6 )C(O)N(R 7 )—, —CH(R 6 )N(R 7 )C(O)—, —CH(R 6 )N(R 7 )S(O)—, or —CH(R 6 )N(R 7 )S(O) 2 —;

W 2 is —O—, —NR 6 —, —S(O) 0-2 —, —C(O)—, —C(O)N(R 6 )—, —N(R 6 )C(O)—, —N(R 6 )S(O)—, —N(R 6 )S(O) 2 —, —C(O)O—, —CH(R 6 )N(C(O)OR 7 )—, —CH(R 7 )N(C(O)R 7 )—, —CH(R 6 )N(SO 2 R 7 )—, —(R 6 )N(R 7 )—, —CH(R 6 )C(O)N(R 7 )—, —CH(R 6 )N(R 7 )C(O)—, —CH(R 6 )N(R 7 )S(O)—, or —CH(R 6 )N(R 7 )S(O) 2 —;

R 3 and R 4 are independently hydrogen, halogen, —OH, —R 31 , —CF 3 , —OCF 3 , —OR 31 , —NR 31 R 32 , —NR 34 R 35 , —C(O)R 31 , —CO—, —C(═O)NR 31 R 32 , —C(═O)NNR 34 R 35 , —NO 2 , —CN, —S(O) 0-2 R 31 , —SO 2 NR 31 R 32 , —SO 2 NR 34 R 35 , —NR 31 C(═O)R 32 , —NR 31 C(═O)OR 32 , —NR 31 C(═O)NR 32 R 33 , —NR 31 S(O) 0-2 R 32 , —C(═S)OR 31 , —C(═O)SR 31 , —NR 31 C(═NR 32 )NR 33 R 32 , —NR 31 C(═NR 32 )OR 33 , —NR 31 C(═NR 32 )SR 33 , —OC(═O)OR 33 , —OC(═O)NR 31 R 32 , —OC(═O)SR 31 , —SC(═O)OR 31 , —P(0)0R 31 OR 32 , or-SC(═O)NR 31 R 32 ;

R 2 is hydrogen, bicyclic aryl, substituted monocyclic aryl, hetaryl, alkyl, cycloalkyl, -alkyl-cycloalkyl, -alkyl-monocyclic aryl, -alkylbicycloaryl, -alkylhetaryl, -alkylheterocyclyl, alkenyl, or alkynyl;

R 6 and R 7 are each independently hydrogen, alkyl, alkenyl, aryl, heteroaryl, heterocyclyl or cycloalkyl, wherein each alkyl, alkenyl, aryl, heteroaryl, heterocyclyl or cycloalkyl is unsubstituted or substituted by one or more independent R 8 substituents; and

R 8 is halo, —OR 31 , —SH, NH 2 , —NR 34 R 35 , —NR 31 R 32 , —CO 2 R 31 , —CO 2 aryl —C(═O)NR 31 R 32 , C(═O) NR 34 R 35 , —NO 2 , —CN, —S(O) 0-2 alkyl, —S(O) 0-2 aryl, —SO 2 NR 34 R 35 , —SO 2 NR 31 R 32 , alkyl, alkenyl, or alkynyl;

R 31 , R 32 , and R 33 , in each instance, are independently H or alkyl; and

R 34 and R 35 are taken together with the nitrogen atom to which they are attached to form a 3-10 membered ring.

2. The compound or pharmaceutically acceptable salt of claim 1 , wherein E 2 is —H.

3. The compound or pharmaceutically acceptable salt of claim 2 , wherein L is —N(R 31 )C(O)—.

4. The compound or pharmaceutically acceptable salt of claim 1 , wherein M 1 is 5-benzothiazolyl substituted at the 2-position with —(W 2 ) k —R 2 —.

5. The compound or pharmaceutically acceptable salt of claim 1 , wherein —(W 2 ) k — is —NR 6 —.

6. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 2 is —H, alkyl, cycloalkyl, or -alkyl-cycloalkyl.

7. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 1 is alkyl, cycloalkyl or heterocyclyl.

8. The compound of claim 1 , wherein the compound is of Formula X

or a pharmaceutically acceptable salt thereof.

9. The compound or pharmaceutically acceptable salt of claim 8 wherein —(W 2 ) k — is —NR 6 —.

10. The compound or pharmaceutically acceptable salt of claim 8 wherein R 2 is —H, alkyl, cycloalkyl, or -alkyl-cycloalkyl.

11. The compound or pharmaceutically acceptable salt of claim 8 , wherein R 1 is alkyl, cycloalkyl or heterocyclyl.

12. The compound or pharmaceutically acceptable salt of claim 1 or claim 8 wherein the compound inhibits a protein kinase.

13. The compound or pharmaceutically acceptable salt of claim 1 or claim 8 wherein the compound inhibits a lipid kinase.

14. The compound or pharmaceutically acceptable salt of claim 1 or claim 8 wherein the compound inhibits a protein kinase and a lipid kinase.

15. The compound or pharmaceutically acceptable salt of claim 1 or claim 8 wherein the compound inhibits mTorC1 and/or mTorC2.

16. A pharmaceutical composition comprising a compound of claim 1 or claim 8 and a pharmaceutically acceptable carrier.

17. The compound or pharmaceutically acceptable salt of claim 1 , wherein the compound is

18. The compound or pharmaceutically acceptable salt of claim 1 , wherein the compound is

19. The compound or pharmaceutically acceptable salt of claim 1 , wherein the compound is