Vinylogous thioester compounds and methods of use

Patent metadata

Field	Value
Publication number	US-9873705-B2
Application number	US-201615282644-A
Country	US
Kind code	B2
Filing date	Sep 30, 2016
Priority date	Oct 2, 2015
Publication date	Jan 23, 2018
Grant date	Jan 23, 2018

Abstract

Provided herein are vinylogous thioester compounds and methods for using the compounds.

First claim

The invention claimed is:

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

Assignees

• Dartmouth College

Inventors

• Sanchez Yolanda
• Allaway Robert
• Bouley Stephanie
• Wood Matthew

Classifications

• C07D285/08

  1,2,4-Thiadiazoles; Hydrogenated 1,2,4-thiadiazoles · CPC title

• C07D271/113

  with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical · CPC title

• C07D401/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D409/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title