Thieno[3,2-d]pyrimidine-6-carboxamides and analogues as sirtuin modulators

Patent metadata

Field	Value
Publication number	US-2016002273-A1
Application number	US-201414771334-A
Country	US
Kind code	A1
Filing date	Mar 7, 2014
Priority date	Mar 7, 2013
Publication date	Jan 7, 2016
Grant date	—

Abstract

Provided herein are novel substituted thieno[3,2-d]pyrimidine-6-carboxamide sirtuin inhibitors and methods of use thereof. The sirtuin inhibitors may be used for inhibiting a sirtuin-mediated biological process, and, e.g. for treating and/or preventing diseases and disorders including, but not limited to cancer, neurodegenerative disease and inflammation. Also provided herein are pharmaceutical compositions comprising these sirtuin inhibitors and compositions comprising a sirtuin inhibitor in combination with another therapeutic agent.

First claim

We claim:

1 . A compound of the formula (I):

or a salt thereof wherein:
each of Z 1 and Z 2 is independently selected from N and CR 1 , wherein:
at least one of Z 1 and Z 2 is N;
each R 1 is independently selected from hydrogen, halo, C 1 -C 4 straight chain or branched alkyl, halo substituted C 1 -C 4 straight chain or branched alkyl, —O—C 1 -C 4 straight chain or branched alkyl, —O-halo-substituted C 1 -C 4 straight chain or branched alkyl, C 1 -C 4 alkoxy-substituted C 1 -C 4 straight chain or branched alkyl, and hydroxy-substituted C 1 -C 4 straight chain or branched alkyl;
W is selected from S and O;
X is selected from —C(═O)—NH 2 , —S(═O) 2 —NH 2 , —C(═NH)—NH 2 , —C(═O)NHOH, —C(═S)—NH 2 , —S(═O)—NH 2 and —SO 3 H;
Y is selected from CHR 2 , CR 2 —(C 1 -C 4 straight chain or branched alkyl)-NR 3 R 3 , CH—(C 1 -C 4 straight chain or branched alkyl)-R 2 , CH—(C 1 -C 4 straight chain or branched alkyl)-NR 3 R 3 , CH—(C 1 -C 4 straight chain or branched alkyl)-NH—C(═O)—R 2 , CH—(C 1 -C 4 straight chain or branched alkyl)-NH—C(═S)—R 2 , CH—(C 1 -C 4 straight chain or branched alkyl)-C(═O)—NR 3 R 3 , N—(C 1 -C 4 straight chain or branched alkyl)-NH—C(═O)—R 2 , N—(C 1 -C 4 straight chain or branched alkyl)-NH—C(═S)—R 2 , N—(C 1 -C 4 straight chain or branched alkyl)-NR 3 R 3 , N—(C 1 -C 4 straight chain or branched alkyl)-R 2 , and C-linked 5-6 membered saturated heterocycle;
R 2 is selected from 5- to 6-membered saturated or unsaturated carbocycle or heterocycle, —OH, —O—(C 1 -C 4 straight chain or branched alkyl), —C 1 -C 4 straight chain or branched alkyl, —S(═O) 2 —CH 3 , —C(═O)—O—(C 1 -C 4 straight chain or branched alkyl), —C(═O)—(C 1 -C 4 straight chain or branched alkyl), and when R 2 is a 5- to 6-membered saturated or unsaturated carbocycle or heterocycle, R 2 is also optionally substituted with one or more substituents independently selected from halo, —C 1 -C 4 straight chain or branched alkyl, —C(═O)—NH—(C 1 -C 4 straight chain or branched alkyl), —C(═O)—O—(C 1 -C 4 straight chain or branched alkyl), —C(═O)—O—(C 1 -C 4 straight chain or branched alkyl), —C(═O)—OH, —O—PO 3 H 2 and —C(═O)—NH—(C 1 -C 4 straight chain or branched alkyl)-NH 2 ; and
R 3 is independently selected from hydrogen, —C 1 -C 4 straight chain or branched alkyl, —C(═O)-(5- to 6-membered saturated carbocycle or heterocycle) and —S(═O) 2 —CH 3 ; or
two R 3 bound to the same nitrogen are taken together with the nitrogen atom to form a 5- to 6-membered saturated heterocycle optionally comprising one or two additional heteroatoms selected from N, S, S(═O), S(═O) 2 , and O, wherein the heterocycle is optionally substituted at any carbon atom with one or more of —OH, ═O, halo, —C 1 -C 4 straight chain or branched alkyl, fluoro-substituted C 1 -C 4 straight chain or branched alkyl, hydroxy-substituted C 1 -C 4 straight chain or branched alkyl, alkoxy-substituted C 1 -C 4 straight chain or branched alkyl, —C(═O)—C 1 -C 4 straight chain or branched alkyl, and optionally substituted at any substitutable nitrogen atom with —C 1 -C 4 straight chain or branched alkyl, —C(═O)—C 1 -C 4 straight chain or branched alkyl,hydroxy-substituted C 1 -C 4 straight chain or branched alkyl, alkoxy-substituted C 1 -C 4 straight chain or branched alkyl, or halo-substituted C 1 -C 4 straight chain or branched alkyl; wherein
when Y is a C-linked 5- to 6-membered heterocycle, it is further optionally substituted at any carbon atom with one or more of —C(═O)—R 2 , —OH, ═O, halo, —C 1 -C 4 straight chain or branched alkyl, fluoro-substituted C 1 -C 4 straight chain or branched alkyl, hydroxy-substituted C 1 -C 4 straight chain or branched alkyl, alkoxy-substituted C 1 -C 4 straight chain or branched alkyl, and optionally substituted at any substitutable nitrogen atom with —C 1 -C 4 straight chain or branched alkyl, —C(═O)—R 2 , hydroxy-substituted C 1 -C 4 straight chain or branched alkyl, alkoxy-substituted C 1 -C 4 straight chain or branched alkyl, or halo-substituted C 1 -C 4 straight chain or branched alkyl.

2 . The compound or salt of claim 1 , having the formula:

3 . The compound or salt of claim 1 , selected from:

4 . The compound or salt of claim 1 , wherein W is S.

5 . The compound or salt of claim 1 , wherein X is —C(═O)—NH 2 .

6 . The compound or salt of claim 1 , wherein Y is selected from CH—(C 1 -C 4 straight chain or branched alkyl)-NH—C(═O)—R 2 , CH—(C 1 -C 4 straight chain or branched alkyl)-NR 3 R 3 , N—(C 1 -C 4 straight chain or branched alkyl)-NH—C(═O)—R 2 , N—(C 1 -C 4 straight chain or branched alkyl)-NR 3 R 3 , CH—(C 1 -C 4 straight chain or branched alkyl)-R 2 , and CH—(C 1 -C 4 straight chain or branched alkyl)-NH—C(═S)—R 2 .

7 . The compound or salt of claim 6 , wherein Y is CH—(C 1 -C 4 straight chain or branched alkyl)-NH—C(═O)—R 2 , and wherein the compound or salt is selected from any one of:

8 . The compound or salt of claim 6 , wherein Y is CH—(C 1 -C 4 straight chain or branched alkyl)-NR 3 R 3 , and wherein the compound or salt is selected from any one of:

9 . The compound or salt of claim 6 , wherein Y is N—(C 1 -C 4 straight chain or branched alkyl)-NH—C(═O)—R 2 , and wherein the compound or salt is selected from any one of:

10 . The compound or salt of claim 6 , wherein Y is N—(C 1 -C 4 straight chain or branched alkyl)-NR 3 R 3 , and wherein the compound or salt is:

11 . The compound or salt of claim 6 , wherein Y is CH—(C 1 -C 4 straight chain or branched alkyl)-R 2 , and wherein the compound or salt is selected from any one of:

12 . The compound or salt of claim 6 , wherein Y is CH—(C 1 -C 4 straight chain or branched alkyl)-NH—C(═S)—R 2 , and wherein the compound or salt is:

13 . The compound or salt of claim 1 , wherein Y is CHR 2 , and wherein the compound or salt is:

14 . The compound or salt of claim 1 , wherein Y is a C-linked heterocycle, and wherein the compound or salt is selected from any one of:

15 . The compound or salt of claim 1 , wherein R 2 is selected from a 5- to 6-membered saturated or unsaturated carbocycle or heterocycle, —C 1 -C 4 straight chain or branched alkyl, —O—(C 1 -C 4 straight chain or branched alkyl), and —OH.

16 . The compound or salt of claim 1 , wherein R 3 is selected from —C 1 -C 4 straight chain or branched alkyl and —S(═O) 2 —CH 3 .

17 . The compou

Assignees

• Glaxosmithkline Llc

Inventors

• Blum Charles A
• Disch Jeremy S
• Evindar Ghotas
• Perni Robert B

Classifications

• C07D495/04 Primary

  Ortho-condensed systems · CPC title

• C07F9/65616 Primary

  containing the ring system [IMAGE cpc-sch-C07F-1006.gif] having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D491/048

  the oxygen-containing ring being five-membered · CPC title

• C12Q1/34

  involving hydrolase · CPC title