N-sulfonylated pyrazolo[3,4-b]pyridin-6-carboxamides and method of use

Patent metadata

Field	Value
Publication number	US-9890158-B2
Application number	US-201615287911-A
Country	US
Kind code	B2
Filing date	Oct 7, 2016
Priority date	Oct 9, 2015
Publication date	Feb 13, 2018
Grant date	Feb 13, 2018

Abstract

The present invention provides for compounds of formula (I)

wherein R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 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 , 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 G 1A ;
G 1A , at each occurrence, is independently phenyl, 5-6 membered monocyclic heteroaryl, 4-7 membered monocyclic heterocycle, 5-11 membered fused bicyclic heterocycle, or C 3 -C 6 monocyclic cycloalkyl; wherein each G 1A is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of R 1a and G 1B ;
G 1B , at each occurrence, is independently 4-7 membered monocyclic heterocycle which is optionally substituted with 1, 2, 3, or 4 independently selected R 1b groups;
R 2 is hydrogen, C 2 -C 4 alkenyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OR 2xa , —N(R 2xa )(R 2xb ), or G 2A ;
R 2xa , at each occurrence, is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or G 2B ;
R 2xb is hydrogen, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl;
G 2A and G 2B are each independently a 4-7 membered monocyclic heterocycle or a 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 G 3A , -G 3B -L 1 -G 3C , -G 3B -L 3 -G 3C -G 3E , —(C 1 -C 6 alkylenyl)-G 3D , —OR 3a , or —N(R 3a )(R 3b );
R 3a , at each occurrence, is independently G 3D , 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 3D , —OR 3xa , and —N(R 3xb ) 2 ;
R 3xa and R 3xb , at each occurrence, are each independently hydrogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl, or G 3D ;
R 3b 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;
r is 0 or 1;
s is 0 or 1;
G 3A , G 3B , and G 3C and 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 independently C 3 -C 8 monocyclic cycloalkyl, 4-7 membered monocyclic heterocycle, a 5-11 membered fused bicyclic heterocycle, or a 5-11 membered spiro heterocycle; wherein each G 3D is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of R e and G 3E ;
G 3E , at each occurrence, is independently C 3 -C 8 monocyclic cycloalkyl or 4-7 membered monocyclic heterocycle; wherein each G 3E is optionally substituted with 1, 2, 3, or 4 independently selected R e groups;
R 4 is hydrogen, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl;
R 5 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, —N(R 5ax )(R 5bx ), —OR 5dx , or G 5A ; wherein the C 1 -C 6 alkyl and the C 1 -C 6 haloalkyl are each optionally substituted with one or two substituents independently selected from the group consisting of G 5A , —CN, —N 3 , —OR 5ax , —S(O) 2 R 5ax , —S(O) 2 N(R 5ax )(R 5bx ), —N(R 5ax )(R 5bx ), —N(R 5bx )S(O) 2 R 5cx , —N(R 5bx ) C(O)R 5cx , —N(R 5bx )C(O)N(R 5ax )(R 5bx ), —N(R 5bx )C(O)OR 5cx , —C(O)R 5ax , —C(O)OR 5ax , —C(O)N(R 5bx )S(O) 2 R 5cx , and —C(O)N(R 5ax )(R 5bx );
R 5ax and R 5bx , at each occurrence, are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OR 5ex , —(C 1 -C 6 alkylenyl)-OR 5ex , G 5A , or —(C 1 -C 6 alkylenyl)-G 5A ;
R 5cx , at each occurrence, is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, G 5A , or —(C 1 -C 6 alkylenyl)-G 5A ;
R 5dx is C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
R 5ex is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
G 5A , at each occurrence, is independently C 3 -C 11 cycloalkyl, phenyl, 5-6 membered monocyclic heteroaryl, or 4-11 membered heterocycle; wherein each G 5A is optionally substituted with 1, 2, 3, or 4 independently selected R 5a groups;
R 5a , at each occurrence, is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, C 1 -C 6 haloalkyl, oxo, G 5B , —CN, NO 2 , —OR b , —OC(O)R c , —OC(O)N(R d ) 2 , —SR b , —S(O) 2 R b , —S(O) 2 N(R d ) 2 , —C(O)R b , —C(O)OR b , —C(O)N(R d ) 2 , —C(O)N(R d )S(O) 2 R c , —N(R d ) 2 , —N(R d )C(O)R c , —N(R d )S(O) 2 R c , —N(R d )C(O)O(R b ), —N(R d )C(O)N(R d ) 2 , —N(R d )S(O) 2 N(R d ) 2 , —(C 1 -C 6 alkylenyl)-CN, —(C 1 -C 6 alkylenyl)-G 5B , —(C 1 -C 6 alkylenyl)-OR b , —(C 1 -C 6 alkylenyl)-OC(O)R c , —(C 1 -C 6 alkylenyl)-OC(O)N(R d ) 2 , —(C 1 -C 6 alkylenyl)-SR b , —(C 1 -C 6 alkylenyl)-S(O) 2 R b , —(C 1 -C 6 alkylenyl)-S(O) 2 N(R d ) 2 , —(C 1 -C 6 alkylenyl)-C(O)R b , —(C 1 -C 6 alkylenyl)-C(O)OR b , —(C 1 -C 6 alkylenyl)-C(O)N(R d ) 2 , —(C 1 -C 6 alkylenyl)-C(O)N(R d )S(O) 2 R c , —(C 1 -C 6 alkylenyl)-N(R d ) 2 , —(C 1 -C 6 alkylenyl)-N(R d )C(O)R c , —(C 1 -C 6 alkylenyl)-N(R d )S(O) 2 R c , —(C 1 -C 6 alkylenyl)-N(R d )C(O)O(R c ), —(C 1 -C 6 alkylenyl)-N(R d )C(O)N(R d ) 2 , or —(C 1 -C 6 alkylenyl)-N(R d )S(O) 2 N(R d ) 2 ;
R b and R d , at each occurrence, are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, alkoxyalkyl, G 5B , or —(C 1 -C 6 alkylenyl)-G 5B ;
R c , at each occurrence, is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, alkoxyalkyl, G 5B , or —(C 1 -C 6 alkylenyl)-G 5B ;
G 5B , at each occurrence, is independently C 3 -C 6 monocyclic cycloalkyl, phenyl, 5-6 membered monocyclic heteroaryl, or 4-7 membered monocyclic heterocycle; wherein each G 5B is optionally substituted with 1, 2, 3, or 4 independently selected R 5b 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 h , —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 —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 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 g , —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

Assignees

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

Inventors

• Akkari Rhalid
• Alvey Luke Jonathan
• Bock Xavier Marie
• Brown Brian S
• Claes Pieter Isabelle Roger
• Cowart Marlon D
• De Lemos Elsa
• Desroy Nicolas
• Duthion Beranger
• 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
• Merayo Nuria Merayo
• Newsome Gregory John Robert
• Palisse Adeline Marie Elise
• Patel Sachin V
• Pizzonero Matthieu Rafaël
• Shrestha Anurupa
• Swift Elizabeth C
• Van Der Plas Steven Emiel
• Wang Xueqing
• De Blieck Ann

Classifications

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P5/14

  of the thyroid hormones, e.g. T3, T4 · CPC title

• A61P43/00

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

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title