Quinolone derivatives as fibroblast growth factor receptor inhibitors

Patent metadata

Field	Value
Publication number	US-2018065960-A1
Application number	US-201715806525-A
Country	US
Kind code	A1
Filing date	Nov 8, 2017
Priority date	Feb 7, 2014
Publication date	Mar 8, 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:

1 . A compound of Formula (III):

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 the phenyl ring in aralkyl, the heteroaryl ring in heteroaralkyl, phenyl, 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 or substituted alkylene; and
X is a group of formula (a), (b), (c), or (h):

wherein:
ring B is aza bridged heterocycloamino or aza spiroheterocycloamino;
ring C is azetidinyl, pyrrolidinyl, piperidinyl, bridged heterocycloamino, or spiro heterocycloamino wherein the nitrogen atom in aforementioned (a), (b) and (c) rings is attached to the Q group;
rings K and L are independently azetidinyl, pyrrolidinyl, piperidinyl, or homopiperidinyl;
each R 3 is hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, or halo; and
each R 4 is hydrogen, alkyl, hydroxy, alkoxy, or halo; or

(ii) Q is heteroalkylene, substituted heteroalkylene, or aminoheteroalkylene, and
X is a group of formula (d) or (e):

wherein:
Ar 1 is 5- or 6-membered cycloalkylene, phenylene, or 5- or 6-membered heteroarylene;
ring D is heterocycloamino, bridged heterocycloamino, or spiroheterocycloamino;
R 5 is hydrogen, alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, or cyano;
R 6 is hydrogen, alkyl, cycloalkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, or cyano; and
R 7 and R 8 are independently hydrogen, alkyl, hydroxy, alkoxy, or halo; or

(iii) Q is -alkylene-cycloalkylene-alkylene-, and
X is a group of formula (f) or (g):

wherein:
Ar 2 is 5- or 6-membered cycloalkylene, phenylene, 5- or 6-membered heteroarylene, azetidinyl, pyrrolidinyl, or piperidinyl wherein the ring nitrogen atom in azetidinyl, pyrrolidinyl, or piperidinyl is attached to the Q group;
ring E is heterocycloamino, bridged heterocycloamino, or spiroheterocycloamino;
R 9 is hydrogen, alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, or cyano;
R 10 is hydrogen, alkyl, cycloalkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, or cyano; and
R 11 and R 12 are independently hydrogen, alkyl, hydroxy, alkoxy, or halo;
each Y is —CO— or —SO 2 —;
each R b is hydrogen or alkyl;
each R c is hydrogen, alkyl, or substituted alkyl; and
each R d is hydrogen or alkyl; or
each R d and the hydrogen atom on carbon attached to group Y can form a bond to give a triple bond

and/or a pharmaceutically acceptable salt thereof;
provided that: (1) when (i) Ar 1 is phenylene or 6-membered heteroarylene or (ii) Ar 2 is phenylene, 6-membered heteroarylene or piperidinyl or (iii) ring C is piperidinyl, then Q and —NR b —Y—CH═CR c R d are meta or para to each other; (2) when ring D or E is piperidinyl, then Q and —Y—CH═CR c R d are meta or para to each other; (3) when ring D or E is piperazinyl, then Q and —Y—CH═CR c R d are para to each other; and (4) when ring C, D, or E is pyrrolidinyl or azetidinyl, then Q and —NR b —Y—CH═CR c R d or Q and —Y—CH═CR c R d are (1,3) to each other.

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

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

4 . The compound of claim 3 or a pharmaceutically acceptable salt thereof wherein:
R 1 is hydrogen, halo, or alkyl;
R 2 is hydrogen, alkyl, acyl, alkoxycarbonyl, alkynyl, haloalkyl, cycloalkyl substituted with amino, alkylamino, or dialkylamino, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, alkoxyalkyloxyalkyl, aminoalkyl, heterocyclyl (wherein heterocyclyl is optionally substituted with one two, or three substituents independently selected from alkyl, hydroxy, halo, 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, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl), aralkyl, heteroaralkyl, phenyl, or heteroaryl (where phenyl in aralkyl, heteroaryl ring in heteroaralkyl, phenyl, 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 a group of formula (a), (b), or (c):

wherein:
ring B is a aza bridged heterocycloamino or aza spiroheterocycloamino;
ring C is azetidinyl, pyrrolidinyl, piperidinyl, bridged heterocycloamino, or spiro heterocycloamino wherein the nitrogen atom in aforementioned (a), (b) and (c) rings is attached to the Q group;
each R 3 is hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, or halo; and
each R 4 is hydrogen, alkyl, hydroxy, alkoxy, or halo; or

(ii) Q is heteroalkylene, and
X is a group of formula (d) or (e):

wherein:
Ar 1 is 5- or 6-membered cycloalkylene, phenylene, or 5- or 6-membered heteroarylene;
ring D is heterocycloamino, bridged heterocycloamino, or spi

Assignees

• Principia Biopharma Inc

Inventors

• Verner Erik
• Brameld Kenneth Albert

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title