Quinolone derivatives as fgfr inhibitors

Patent metadata

Field	Value
Publication number	US-2018155340-A1
Application number	US-201615575448-A
Country	US
Kind code	A1
Filing date	May 18, 2016
Priority date	May 22, 2015
Publication date	Jun 7, 2018
Grant date	—

Abstract

Compounds that are Fibroblast Growth Factor Inhibitors (FGFR) and are therefore useful for the treatment of diseases treatable by inhibition of FGFR are disclosed. Also disclosed are pharmaceutical compositions containing such compounds and processes for preparing such compounds.

First claim

What is claimed is:

1 . a compound of Formula (I):

wherein:
J is N or CH;
J′ is N or CR 1 where R 1 is hydrogen, halo, alkyl, or cycloalkyl;
Ar is phenyl or heteroaryl, each ring optionally substituted with one, two, three, or four substituents independently selected from alkyl, cycloalkyl, hydroxy, alkoxy, halo, haloalkyl, alkylsulfonyl, haloalkoxy, and cyano;
R 2 is hydrogen, alkyl, alkynyl, acyl, alkoxycarbonyl, haloalkyl, cycloalkyl optionally substituted with amino, alkylamino, dialkylamino, or hydroxy, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, alkoxyalkyloxyalkyl, aminoalkyl, heterocyclyl (wherein heterocyclyl is optionally substituted with one, two, or three substituents independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, alkoxyalkyloxy, aminoalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl), heterocyclylalkyl (wherein the heterocyclyl ring in heterocyclylalkyl is optionally substituted with one, two, or three substituents independently selected from alkyl, halo, acyl, hydroxy, alkoxy, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl), aralkyl, heteroaralkyl, phenyl, or heteroaryl (where phenyl, phenyl ring in aralkyl, heteroaryl ring in heteroaralkyl and heteroaryl are optionally substituted with one, two, or three substituents where two of the optional substituents are independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, and cyano and one of the optional substituents is alkyl, cycloalkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxyalkyl, alkoxyalkyl, aminoalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl); and
(i) Q is alkylene and X is —NR b —Y—C(CN)═CHR c ; or
(ii) Q is alkylene, substituted alkylene, heteroalkylene, substituted heteroalkylene, or alkylene-cycloalkylene-alkylene; and
X is a group of formula (a), (b), (c), or (d):

wherein:
T, U, and V, are independently N or CH provided that at least one of T and U is nitrogen;
ring A is heterocycloamino; bridged heterocycloamino, or spiroheterocycloamino;
rings B and C are independently azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, or imidazolidine;
ring D is azetidinyl, pyrrolidinyl, piperidinyl, bridged heterocycloamino, or spiro heterocycloamino;
ring E is 5- or 6-membered cycloalkylene, phenylene, or 5- or 6-membered heteroarylene;
R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are independently hydrogen, alkyl, hydroxy, alkoxy, or halo; and
R 11 is hydrogen, alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, or cyano;
R 12 is hydrogen, alkyl, cycloalkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, or cyano;
each Y is —CO— or —SO 2 —;
each R b is hydrogen or alkyl; and
each R c is alkyl, alkoxyalkyloxyalkyl, cycloalkyl optionally substituted with alkyl, 1-aminocycloalk-1-yl, substituted alkyl, heterocyclylalkyl, heterocyclyl (wherein the heterocyclyl in heterocyclylalkyl and heterocyclyl is optionally substituted with one, two, or three substituents where two of the optional substituents are independently selected from alkyl, alkoxy, hydroxy, halo, amino, and oxo, and one of the optional substituent is alkyl, hydroxyalkyl, alkoxyalkyl, acyl, haloalkyl, alkylsulfonyl, alkoxycarbonyl, or heterocyclyl wherein the heterocyclyl is optionally substituted with one or two substitutents independently selected from alkyl, halo, hydroxy, or alkoxy), heteroaralkyl (wherein the heteroaryl ring is optionally substituted with one or two substituents independently selected from alkyl, amino, alkylamino, or dialkylamino), bridged heterocycloaminoalkyl or spiroheterocycloaminoalkyl (wherein each of the aforementioned ring optionally substituted with one or two alkyl and further wherein the alkylene chain in bridged heterocycloaminoalkyl or spiroheterocycloaminoalkyl is attached to the nitrogen atom of the bridged heterocycloamino and spiroheterocycloamino group), or -(alkylene)-NR 13 R 14 where R 13 and R 14 together with the nitrogen atom to which they are attached form

where one or two of X 1 , X 2 and X 3 are nitrogen and the rest are carbon and the ring is optionally substituted with one or two substituents independently selected from alkyl, haloalkyl, and halo;
and/or a pharmaceutically acceptable salt thereof;
provided that: (1) when (i) ring E is 6-membered cycloalkylene, phenylene, or 6-membered heteroarylene or (ii) ring D is piperidinyl, then Q and —NR b —Y—C(CN)═CHR c are meta or para to each other; (2) when ring A is piperidinyl, then Q and —Y—C(CN)═CR c R d are meta or para to each other; (3) when ring A is piperazinyl, then Q and —Y—C(CN)═CHR c are para to each other; and (4) when rings A and D are pyrrolidinyl or azetidinyl, then Q and —NR b —Y—C(CN)═CHR c or Q and —Y—C(CN)═CHR c are (1,3) to each other.

2 . The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein J is CH.

3 . The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein J is N.

4 . The compound of any of claims 1 - 3 or a pharmaceutically acceptable salt thereof wherein J′ is —CR 1 .

5 . The compound of any of claims 1 - 4 or a pharmaceutically acceptable salt thereof wherein R 1 is hydrogen.

6 . The compound of any of claims 1 - 4 or a pharmaceutically acceptable salt thereof wherein R 1 is methyl.

7 . The compound of any of claims 1 - 4 or a pharmaceutically acceptable salt thereof wherein R 1 is chloro or fluoro.

8 . The compound of any of claims 1 - 7 or a pharmaceutically acceptable salt thereof wherein Ar is phenyl optionally substituted with one, two, three, or four substituents independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

9 . The compound of any of claims 1 - 7 or a pharmaceutically acceptable salt thereof wherein Ar is 3-methoxyphenyl, 2-halo-3-methoxyphenyl, 2-halo-5-methoxyphenyl, 2-halo-3,5-dimethoxyphenyl, 2,6-dihalo-3,5-dimethoxyphenyl, 3,5-dimethoxyphenyl, 2-halophenyl, or 2,6-dihalophenyl.

10 . The compound of any of claims 1 - 9 or a pharmaceutically acceptable salt thereof wherein X is a group of formula (a) or (b).

11 . The compound of claim 10 or a pharmaceutically acceptable salt thereof wherein Q is -alkylene.

12 . The compound of claim 11 wherein X is a group of formula (a) where,

is:

13 . The compound of claim 11 or a pharmaceutically acceptable salt thereof wherein X is a group of formula (a) where

is:

14 . The compound of claim 10 or a pharmaceutically acceptable salt thereof wherein Q is heteroalkylene, preferably —(CH 2 ) 2 O—, —(CH 2 ) 2 S—, —(CH 2 ) 2 NR where R is alkyl, hydroxyalkyl, or alkoxyalkyl.

15 .

Assignees

• Principia Biopharma Inc

Inventors

• Brameld Kenneth Albert
• Verner Erik

Classifications

• A61P19/08

  for bone diseases, e.g. rachitism, Paget's disease · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · 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

• A61P35/00

  Antineoplastic agents · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title