Substituted pyrazolo[3,4-b]pyridin-6-carboxylic acids and method of use

Patent metadata

Field	Value
Publication number	US-9796711-B2
Application number	US-201615287922-A
Country	US
Kind code	B2
Filing date	Oct 7, 2016
Priority date	Oct 9, 2015
Publication date	Oct 24, 2017
Grant date	Oct 24, 2017

Abstract

The present invention provides for compounds of formula (I)

wherein R 1 , R 2 , R 3 , and R 4 have any of the values defined in the specification, and pharmaceutically acceptable salts thereof, that are useful as agents in the treatment of diseases and conditions mediated and modulated by CFTR, including cystic fibrosis, Sjögren's syndrome, pancreatic insufficiency, chronic obstructive lung disease, and chronic obstructive airway disease. Also provided are pharmaceutical compositions comprised of one or more compounds of formula (I).

First claim

We claim:

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof,

wherein
R 1 is G 1A , -G 1B -G 1C , -G 1B -L 1A -G 1C , C 1 -C 6 haloalkyl, C 1 -C 6 alkyl, —(C 1 -C 6 alkylenyl)-CN, —(C 1 -C 6 alkylenyl)-G 1D , or -G 1D —O-benzyl;
L 1A is —O— or —O—(C 1 -C 3 alkylenyl)-; wherein the left end of the L 1A moiety is attached to G 1B ;
G 1A is phenyl 5-6 membered monocyclic heteroaryl, 4-7 membered monocyclic heterocycle, fused bicyclic heterocycle, or C 3 -C 6 monocyclic cycloalkyl; wherein each G 1A is optionally substituted with 1, 2, 3, or 4 independently selected R 1a groups;
G 1B is phenyl or 5-6 membered monocyclic heteroaryl; wherein each G 1B is optionally substituted with 1, 2, 3, or 4 independently selected R 1b groups;
G 1C is 4-7 membered monocyclic heterocycle which is optionally substituted with 1, 2, 3, or 4 independently selected R 1c groups;
G 1D , at each occurrence, is a 4-7 membered monocyclic heterocycle, 5-6 membered monocyclic heteroaryl, or a C 3 -C 6 monocyclic cycloalkyl; wherein each G 1D is optionally substituted with 1, 2, 3, or 4 independently selected R 1d groups;
R 2 is C 2 -C 4 alkenyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OR 2xa , —(C 1 -C 6 alkylenyl)-OR 2xb , —(C 1 -C 6 alkylenyl)-N(R 2xb ) 2 , —C(O)OR 2xb , —C(O)N(R 2xb ) 2 , or -G 2A ;
R 2xa is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or G 2B ;
R 2xb , at each occurrence, is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
G 2A and G 2B are each independently 4-7 membered monocyclic heterocycle or C 3 -C 6 monocyclic cycloalkyl; wherein G 2A and G 2B are each optionally substituted with 1, 2, or 3 independently selected R 2a groups;
R 3 is halogen, G 3A , -G 3B -L 1 -G 3C , -G 3B -L 3 -G 3C -L 4 -G 3F , —(C 1 -C 6 alkylenyl)-G 3E , —OR 3a , —N(R 3a )(R 3b ), —N(R 3b )C(O)G 3D , or —C(O)G 3D ;
R 3a , at each occurrence, is independently G 3E , C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl; wherein the C 1 -C 6 haloalkyl and the C 1 -C 6 alkyl are each optionally substituted with one or two substituents independently selected from the group consisting of G 3E , —OR 3xa , —C(O)G 3D , —N(R 3xb ) 2 , and —S(O) 2 R 3xc ;
R 3xa , R 3xb , and R 3xc , at each occurrence, are each independently hydrogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl, G 3E , —(C 1 -C 6 alkylenyl)-OR 3ya , or —(C 1 -C 6 alkylenyl)-N(R 3ya ) 2 ; wherein R 3ya , at each occurrence, is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
R 3b , at each occurrence, is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
L 1 is a bond, C 1 -C 6 alkylenyl, (C 1 -C 6 alkylenyl) r -L 2 -(C 1 -C 6 alkylenyl) s , or O—(C 1 -C 6 alkylenyl)-C(O), wherein the left end of the L 1 moiety is attached to G 3B ;
L 2 is O, N(R x ), C(O), N(R x )C(O), or C(O)N(R x ); wherein each R x is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
L 3 is a bond or C 1 -C 6 alkylenyl;
L 4 is a bond, C 1 -C 6 alkylenyl, O, N(R 2x ), C(O), N(R 2x )C(O), or C(O)N(R 2x ); wherein each R 2x is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
r is 0 or 1;
s is 0 or 1;
G 3A , G 3B , and G 3C , are each independently C 3 -C 11 cycloalkyl, phenyl, 5-6 membered monocyclic heteroaryl, or 4-11 membered heterocycle, wherein G 3A , G 3B , and G 3C are each optionally substituted with 1, 2, 3, or 4 independently selected R e groups;
G 3D , at each occurrence, is 4-7 membered monocyclic heterocycle which is optionally substituted with 1, 2, 3, or 4 independently selected R e groups;
G 3E , at each occurrence, is independently C 3 -C 8 monocyclic cycloalkyl or 4-11 membered heterocycle; wherein each G 3E is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of R e and G 3F ;
G 3F , at each occurrence, is independently a 4-7 membered monocyclic heterocycle or a C 3 -C 6 monocyclic cycloalkyl; wherein each G 3F is optionally substituted with 1, 2, 3, or 4 independently selected R e groups;
R e , at each occurrence, is independently C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halogen, oxo, —CN, —N 3 , NO 2 , —OR f , —OC(O)R g , —OC(O)NR f R h , —SR f , —S(O) 2 R f , —S(O) 2 NR f R h , —C(O)R f , —C(O)OR f , —C(O)NR f R h , —C(O)N(R h )S(O) 2 R f , —N(R f ) 2 , —N(R h )C(O)R f , —N(R h )S(O) 2 R g , —N(R h )C(O)O(R g ), —N(R h )C(O)NR f R h , or —N(R h )S(O) 2 NR f R h ; wherein the C 1 -C 6 haloalkyl and the C 1 -C 6 alkyl are each optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen, —CN, NO 2 , —OR f , —OC(O)R g , —OC(O)NR f R h , —SR f , —S(O) 2 R f , —S(O) 2 NR f R h , —C(O)R, —C(O)OR, —C(O)NR f R h , —C(O)N(R h )S(O) 2 R f , —N(R f ) 2 , —N(R h )C(O)R f , —N(R h )S(O) 2 R g , —N(R h )C(O)O(R g ), —N(R h )C(O)NR f R h , and —N(R h )S(O) 2 NR f R h ;
R f , at each occurrence, is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, —(C 1 -C 6 alkylenyl)-CN, —(C 1 -C 6 alkylenyl)-OR m , —(C 1 -C 6 alkylenyl)-OC(O)R n , —(C 1 -C 6 alkylenyl)-OC(O)N(R m ) 2 , —(C 1 -C 6 alkylenyl)-SR m , —(C 1 -C 6 alkylenyl)-S(O) 2 R m , —(C 1 -C 6 alkylenyl)-S(O) 2 N(R m ) 2 , —(C 1 -C 6 alkylenyl)-C(O)R m , —(C 1 -C 6 alkylenyl)-C(O)OR m , —(C 1 -C 6 alkylenyl)-C(O)N(R m ) 2 , —(C 1 -C 6 alkylenyl)-C(O)N(R m )S(O) 2 R n , —(C 1 -C 6 alkylenyl)-N(R m ) 2 , —(C 1 -C 6 alkylenyl)-N(R m )C(O)R n , —(C 1 -C 6 alkylenyl)-N(R m )S(O) 2 R n , —(C 1 -C 6 alkylenyl)-N(R m )C(O)O(R n ), —(C 1 -C 6 alkylenyl)-N(R m )C(O)N(R m ) 2 , or —(C 1 -C 6 alkylenyl)-N(R m )S(O) 2 N(R m ) 2 ;
R g , at each occurrence, is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, —(C 1 -C 6 alkylenyl)-CN, —(C 1 -C 6 alkylenyl)-OR m , —(C 1 -C 6 alkylenyl)-OC(O)R n , —(C 1 -C 6 alkylenyl)-OC(O)N(R m ) 2 , —(C 1 -C 6 alkylenyl)-SR m , —(C 1 -C 6 alkylenyl)-S(O) 2 R m , —(C 1 -C 6 alkylenyl)-S(O) 2 N(R m ) 2 , alkylenyl)-C(O)R m , —(C 1 -C 6 alkylenyl)-C(O)OR m , —(C 1 -C 6 alkylenyl)-C(O)N(R m ) 2 , —(C 1 -C 6 alkylenyl)-C(O)N(R m )S(O) 2 R n , —(C 1 -C 6 alkylenyl)-N(R m ) 2 , —(C 1 -C 6 alkylenyl)-N(R m )C(O)R n , —(C 1 -C 6 alkylenyl)-N(R m )S(O) 2 R n , —(C 1 -C 6 alkylenyl)-N(R m )C(O)O(R″), —(C 1 -C 6 alkylenyl)-N(R m )C(O)N(R m ) 2 , or —(C 1 -C 6 alkylenyl)-N(R m )S(O) 2 N(R m ) 2 ;
R h , at each occurrence, is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or —(C 1 -C 6 alkylenyl)-OR m ;
R 1a , R 1b , R 1c , R 1d , and R 2a , at each occurrence, are each independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, C 1 -C 6 haloalkyl, oxo, —CN, NO 2 , —OR m , —OC(O)R n , —OC(O)N(R m ) 2 , —SR m , —S(O) 2 R m , —S(O) 2 N(R m ) 2 , —C(O)R m , —C(O)OR m , —C(O)N(R m ) 2 , —C(O)N(R m )S(O) 2 R n , —N(R m ) 2 , —N(R m )(alkoxyalkyl), —N(alkoxyalkyl) 2 , —N(R m )C(O)R n , —N(R m )S(O) 2 R n , —N(R m )C(O)O(R n ), —N(R m )C(O)N(R m ) 2 , —N(R m )S(O) 2 N(R m ) 2 , —(C 1 -C 6 alkylenyl)-CN, —(C 1 -C 6 alkylenyl)-OR m , —(C 1 -C 6 alkylenyl)-OC(O)R n , —(C 1 -C 6 alkylenyl)-OC(O)N(R m ) 2 , —(C 1 -C 6 alkylenyl)-SR m , —(C 1 -C 6 alkylenyl)-S(O) 2 R m , —(C 1 -C 6 alkylenyl)-S(O) 2 N(R m ) 2 , —(C 1 -C 6 alkylenyl)-C(O)R m , —(C 1 -C 6 alkylenyl)-C(O)OR m , —(C 1 -C 6 alkylenyl)-C(O)N(R m ) 2 , —(C 1 -C 6 alkylenyl)-C(O)N(R m )S(O) 2 R n , —(C 1 -C 6 alkylenyl)-N(R m ) 2 , —(C 1 -C 6 alkylenyl)-N(R m )C(O)R n , —(C 1 -C 6 alkylenyl)-N(R m )S(O) 2 R n , —(C 1 -C 6 alkylenyl)-N(R m )C(O)O(R n ), —(C 1 -C 6 alkylenyl)-N(R m )C(O)N(R n ) 2 , or —(C 1 -C 6 alkylenyl)-N(R m )S(O) 2 N(R n ) 2 ;
R m , at each occurrence, is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloal

Assignees

• Abbvie S Àr L
• Galapagos Nv
• Abbvie S Á R L

Inventors

• Akkari Rhalid
• Alvey Luke Jonathan
• Bock Xavier Marie
• Claes Pieter Isabelle Roger
• Cowart Marlon D
• De Lemos Elsa
• Desroy Nicolas
• Duthion Béranger
• Gfesser Gregory A
• Gosmini Romain Luc Marie
• Housseman Christopher Gaëtan
• Jansen Koen Karel
• Ji Jianguo
• Kym Philip R
• Lefrancois Jean-Michel
• Mammoliti Oscar
• Menet Christel Jeanne Marie
• Newsome Gregory John Robert
• Palisse Adeline Marie Elise
• Patel Sachin V
• Pizzonero Mathieu Rafaël
• Shrestha Anurupa
• Swift Elizabeth C
• Van Der Plas Steven Emiel
• Wang Xueqing

Classifications

• A61P43/00

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

• A61K31/437

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/541

  Non-condensed thiazines containing further heterocyclic rings · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title