Vinylogous thioester compounds and methods of use

1. A method for treating a disorder associated with Ras deregulation or dysregulation comprising administering to a subject in need of treatment an effective amount of a compound having the structure of Formula (I):

or a pharmaceutically acceptable salt thereof;

wherein:

A is selected from the group consisting of phenyl, pyridyl, and pyrimidinyl; wherein A is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, cyano, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, and C 1 -C 6 thioalkyl;

B is selected from H, halo and C 1 -C 6 alkyl;

C is selected from H, halo and C 1 -C 6 alkyl;

D is a heteroaryl moiety;

wherein D is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, hydroxy, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkyl-C(O)NH 2 , C 1 -C 6 alkyl-C(O)N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl-S(O) x (C 1 -C 6 alkyl), C 1 -C 6 alkyl-C 3 -C 6 heterocycloalkyl, C 1 -C 6 alkyl-heteroaryl, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy-C 1 -C 6 alkyl, C 1 -C 6 thioalkyl, aryl and heteroaryl;

wherein x is 0, 1 or 2; and

represents a double bond having E or Z stereochemistry.

2. The method of claim 1 , wherein said disorder associated with Ras deregulation or dysregulation comprises a disease state that results from a mutation or loss of function in a neurofibromin 1 gene.

3. The method of claim 1 , wherein said disorder associated with Ras deregulation or dysregulation is Neurofibromatosis Type 1.

4. The method according to claim 1 , wherein said disorder associated with Ras deregulation or dysregulation is neuroblastoma, lung adenocarcinoma, squamous cell carcinoma, glioblastoma, pancreatic cancer, ovarian cancer, colon cancer, lung cancer, neurofibromas, malignant peripheral nerve sheath tumor, optic glioma, Schwannoma, glioma, leukemia, pheochromocytoma or pancreatic adenocarcinoma.

5. A method for inhibiting autophagy in a cell, comprising contacting the cell with a compound having the structure of Formula (I):

or a pharmaceutically acceptable salt thereof;

wherein:

A is selected from the group consisting of phenyl, pyridyl, and pyrimidinyl; wherein A is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, cyano, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, and C 1 -C 6 thioalkyl;

B is selected from H, halo and C 1 -C 6 alkyl;

C is selected from H, halo and C 1 -C 6 alkyl;

D is a heteroaryl moiety;

wherein D is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, hydroxy, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkyl-C(O)NH 2 , C 1 -C 6 alkyl-C(O)N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl-S(O) x (C 1 -C 6 alkyl), C 1 -C 6 alkyl-C 3 -C 6 heterocycloalkyl, C 1 -C 6 alkyl-heteroaryl, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy-C 1 -C 6 alkyl, C 1 -C 6 thioalkyl, aryl and heteroaryl;

wherein x is 0, 1 or 2; and

represents a double bond having E or Z stereochemistry.

6. The method of claim 1 , wherein B and C are both H.

7. The method of claim 1 , wherein represents a double bond having E stereochemistry.

8. The method of claim 1 , wherein A is unsubstituted or is substituted with 1-3 substituents selected from the group consisting of —Cl, —F, —CN, —CH 3 , —CHF 2 , —CF 3 , —OCH 3 , —SCH 3 , —OCHF 2 , —OCF 3 , —SCHF 2 , and —SCF 3 .

9. The method of claim 1 , wherein A is phenyl.

10. The method of claim 1 , provided that:

i. when A is unsubstituted phenyl, D is not 3-methylthio-1,2,4-thiadiazol-5-yl, 1-methyl-tetrazol-5-yl, 1-phenyl-tetrazol-5-yl, 4-cyano-5-methyl-isothiazol-3-yl, or 4-phenyl-thiazol-2-yl, and D does not comprise a moiety selected from the group consisting of 1,2,4-triazolyl, pyridinyl, pyrimidinyl, benzimidazol-2-yl, benzoxazol-2-yl, benzothiazol-2-yl and purinyl;

ii. when A is 4-fluorophenyl, D is not 1-methylimidazol-2-yl, 1-phenyl-tetrazol-5-yl, 4-phenyl-thiazol-2-yl, or 4-methyl-1,2,4-triazol-3-yl, and D does not comprise a moiety selected from pyridinyl, pyrimidinyl, benzimidazol-2-yl, benzoxazol-2-yl, benzothiazol-2-yl; and

iii. when A is 4-chlorophenyl, D is not 1H-1,2,4-triazol-5-yl, 1-methylimidazol-2-yl, 1-methyl-tetrazol-5-yl, 1-phenyl-tetrazol-5-yl, 3-methylthio-1,2,4-thiadiazol-5-yl, 4-phenyl-thiazol-2-yl, and D does not comprise a moiety selected from pyridinyl, pyrimidinyl, benzimidazol-2-yl, benzoxazol-2-yl, benzothiazol-2-yl.

11. The method of claim 1 , wherein the compound of Formula (I) has the structure of Formula (la), or a pharmaceutically acceptable salt thereof:

12. The method of claim 1 , wherein the compound of Formula (I) has the structure of Formula (Ib), or a pharmaceutically acceptable salt thereof:

13. The method of claim 1 , wherein the compound of Formula (I) has the structure of Formula (Ic), or a pharmaceutically acceptable salt thereof:

14. The method of claim 1 , wherein the compound of Formula (I) has the structure of Formula (Id), or a pharmaceutically acceptable salt thereof:

15. The method of claim 1 , wherein the compound of Formula (I) has the structure of Formula (Ie), or a pharmaceutically acceptable salt thereof:

16. The method of claim 1 , wherein the compound of Formula (I) has the structure of Formula (If), or a pharmaceutically acceptable salt thereof:

17. The method of claim 1 , wherein the compound of Formula (I) has the structure of Formula (Ig), or a pharmaceutically acceptable salt thereof:

wherein n is 1 or 2.

18. The method of claim 1 , wherein D is selected from

provided that:

i. when A is unsubstituted phenyl, 4-methylphenyl, 4-methoxyphenyl, or 4-chlorophenyl, D is not

and

ii. when A is 4-fluorophenyl, D is not

19. The method of claim 1 , wherein the compound of Formula (I) is selected from compounds

and pharmaceutically acceptable salts thereof.