Benzimidazole derivatives as rlk and itk inhibitors

Patent metadata

Field	Value
Publication number	US-2016368908-A1
Application number	US-201515121605-A
Country	US
Kind code	A1
Filing date	Feb 23, 2015
Priority date	Mar 3, 2014
Publication date	Dec 22, 2016
Grant date	—

Abstract

The present disclosure is directed to certain inhibitors of RLK and ITK of formula (I), pharmaceutical compositions comprising such compounds, and method of treating diseases mediated by inhibition of RLK and ITK.

First claim

We claim:

1 . A compound of Formula (I):

wherein:
Z 1 , Z 2 , and Z 3 are CH (or C if substituted with R 1 or R 2 ) or Z 1 , Z 2 , and Z 3 are independently N or CH (or C if substituted with R 1 or R 2 ) provided that only one of Z 1 , Z 2 , and Z 3 is N;
R 1 is hydrogen, hydroxyalkyl, alkoxyalkyl, heterocyclyl, heterocyclylalkyl (wherein the heterocyclyl ring in heterocyclyl and heterocyclylalkyl is optionally substituted with one, two, or three substituents independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, or alkoxyalkyl), —NR 3 COR 4 , —CONR 3 R 5 , -(alkylene)-NR 3 R 5 (where each R 3 is hydrogen, alkyl, or cycloalkyl, R 4 is alkyl, haloalkyl, cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl, and each R 5 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, acyl, cycloalkyl, cycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, heterocyclyl, or heterocyclylalkyl (wherein the heterocyclyl ring in heterocyclyl and heterocyclylalkyl is optionally substituted with one, two, or three substituents independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, or alkoxyalkyl); or R 3 and R 5 together with the nitrogen atom to which they are attached form heterocycloamino or spiroheterocycloamino wherein the heterocycloamino ring is optionally substituted with one, two, or three substituents independently selected from alkyl, halo, hydroxyl, alkoxy, hydroxyalkyl, or alkoxyalkyl), —NR 6 R 7 (where R 6 is hydrogen or alkyl and R 7 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or acyl, or R 6 and R 7 together with the nitrogen atom to which they are attached form heterocycloamino optionally substituted with one, two, or three substituents independently selected from alkyl, halo, hydroxyl, hydroxyalkyl, or alkoxyalkyl), —OR 8 (where R 8 is alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, or heterocyclylalkyl wherein the heterocyclyl ring in heterocyclylalkyl is optionally substituted with one, two, or three substituents independently selected from alkyl, halo, hydroxyalkyl, or alkoxyalkyl), or -(alkylene)-OR 9 where R 9 is alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, or heterocyclylalkyl wherein the heterocyclyl ring in heterocyclylalkyl is optionally substituted with one, two, or three substituents independently selected from alkyl, halo, hydroxyalkyl, or alkoxyalkyl);
R 2 is hydrogen, alkyl, cyano, alkoxy, hydroxy, halo, haloalkyl, or haloalkoxy;
Ar is phenyl or 5-membered heteroaryl optionally substituted with one or two substituents independently selected from alkyl, alkoxy, hydroxy, cyano, alkylthio, halo, haloalkyl, haloalkoxy, or cycloalkyl;
Ar 1 is 5- or 6-membered optionally substituted heteroaryl;
X is a moiety of formula II (where Z is bond or alkylene, and ring A is heterocycloamino optionally substituted with one or two substituents independently selected from alkyl, hydroxy, or fluoro), -cycloalkylene-NR a -, or -(alkylene)-NR a — (where each R a is hydrogen, alkyl or cycloalkyl and alkylene in -(alkylene)-NR a — is optionally substituted with hydroxy or alkoxy);

Y is —CO— or —SO 2 —;
R b is hydrogen, halo, or cyano;
R c is hydrogen, alkyl, alkyl substituted with alkoxy or hydroxy, cycloalkyl optionally substituted with alkyl, or 3 to 6 membered saturated monocyclic heterocyclyl containing one or two heteroatoms selected from N, O, or S and optionally substituted with one, two, or three substituents independently selected from hydroxy, alkyl, alkoxy, oxetan-3-yl, or fluoro; and
R d is hydrogen, alkyl, or alkyl or alkyl substituted with amino, alkylamino, or dialkylamino; or R b and R d together form a bond;

and/or a pharmaceutically acceptable salt thereof;
provided, however, (i) —Ar—Ar 1 is not 5-(pyrazol-4-yl)-thien-2-yl and (ii) when R b is cyano, then R d is hydrogen but R c is not hydrogen.

2 . The compound or a pharmaceutically acceptable salt thereof according to claim 1 wherein:
Ar is thiophenylene;
Ar 1 is 5- or 6-membered heteroaryl optionally substituted with one or two substituents independently selected from alkyl, alkoxy, hydroxy, cyano, alkylthio, halo, haloalkyl, haloalkoxy, or cycloalkyl;
X is moiety of formula II (where Z is bond or alkylene, and ring A is heterocycloamino), -cycloalkylene-NR a -, or -(alkylene)-NR a — (where each R a is hydrogen, alkyl or cycloalkyl and alkylene in -(alkylene)-NR a — is optionally substituted with hydroxy or alkoxy)

3 . The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2 wherein:
Ar is 2,5-thiophenylene.
Ar 1 is 5- or 6-membered heteroaryl optionally substituted with one or two substituents independently selected from alkyl, alkoxy, hydroxy, cyano, alkylthio, halo, haloalkyl, haloalkoxy, or cycloalkyl;
X is moiety of formula II (where Z is bond or alkylene, and ring A is heterocycloamino), -cycloalkylene-NR a -, or -(alkylene)-NR a — (where each R a is hydrogen, alkyl or cycloalkyl and alkylene in -(alkylene)-NR a — is optionally substituted with hydroxy or alkoxy)

4 . The compound or a pharmaceutically acceptable salt thereof according to any of claims 1 to 3 wherein the compound of Formula (I) has the structure (Ia):

5 . The compound or a pharmaceutically acceptable salt thereof according to any of claims 1 to 4 wherein the compound of Formula (I) has the structure (Ib)

6 . The compound or a pharmaceutically acceptable salt thereof of any of any one of claims 1 to 5 wherein R b and R c are hydrogen.

7 . The compound or a pharmaceutically acceptable salt thereof of claim 6 wherein R d is hydrogen.

8 . The compound or pharmaceutically acceptable a salt thereof of any of claims 1 to 5 wherein R b is cyano and R c is alkyl, alkyl substituted with alkoxy or hydroxy, cyclolalkyl substituted with alkyl, or 3 to 6 membered saturated monocyclic heterocyclyl containing one or two heteroatoms selected from N, O, or S and optionally substituted with one, two, or three substituents independently selected from hydroxy, alkyl, alkoxy, oxetan-3-yl, or fluoro.

9 . The compound or a pharmaceutically acceptable salt thereof of claim 8 wherein R c is alkyl.

10 . The compound or a pharmaceutically acceptable salt thereof of claim 9 wherein R c is isopropyl or tert-butyl.

11 . The compound or a pharmaceutically acceptable salt thereof of claim 8 wherein R c is cycloalkyl.

12 . The compound or a pharmaceutically acceptable salt thereof of claim 11 wherein R c is cyclopropyl.

13 . The compound or a pharmaceutically acceptable salt thereof of claim 11 wherein R c is 1-methylcyclopropanyl.

14 . The compound or a pharmaceutically acceptable salt thereof of any of claims 1 to 13 wherein Z 1 , Z 2 and Z 3 are CH (or C if substituted with R 2 ).

15 . The compound or a pharmaceutically acceptable salt thereof of any of claims 1 to 14 whe

Assignees

• Principia Biopharma Inc

Inventors

• Owens Timothy
• Hill Ronald J

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D413/14 Primary

  containing three or more hetero rings · CPC title

• C07D419/14

  containing three or more hetero rings · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title