Substituted tricyclics and method of use

Patent metadata

Field	Value
Publication number	US-9840513-B2
Application number	US-201615205512-A
Country	US
Kind code	B2
Filing date	Jul 8, 2016
Priority date	Jul 16, 2015
Publication date	Dec 12, 2017
Grant date	Dec 12, 2017

Abstract

The present invention provides for compounds of formula (I)

wherein X, Y, and R 1 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 H or C 1 -C 3 alkyl;
X is formula (a) or formula (b)

wherein
R 2A , R 2B , R 2C , and R 2D , are each independently hydrogen or halogen;
R 3 , R 4 , R 6 , and R 7 , are each independently hydrogen, C 1 -C 3 alkyl, or halogen;
R 5 , at each occurrence, is independently hydrogen, C 1 -C 3 alkyl, C 2 -C 4 alkenyl, or C 1 -C 3 haloalkyl;
X 1A is O or CH 2 ;
X 1B is O or CH 2 ;
Y is -G 1 , or Y is formula (c), (d), (e), (f), or (g);

wherein
G 1 is phenyl or monocyclic heteroaryl, each of which is optionally substituted with 1, 2, or 3 independently selected R p groups; wherein each R p is independently C 1 -C 6 alkyl, halogen, C 1 -C 6 haloalkyl, G 2 , C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, —C(O)-G A , —C(O)NR A R B , or —NR A R B ; wherein
R A , at each occurrence, is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
R B , at each occurrence, is independently hydrogen, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl which is optionally substituted with 1 or 2 —OH;
G A is a C 3 -C 6 cycloalkyl or a 4-6 membered monocyclic heterocycle; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OH, C 1 -C 3 alkoxy, and C 1 -C 3 haloalkoxy; and
G 2 is phenyl, heterocycle, or monocyclic heteroaryl; each of which is optionally substituted with 1, 2, or 3 independently selected R q groups;
X 2 is O or N(R 2x ) wherein R 2x is hydrogen, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl;
X 3 is N or CH;
X 4 -X 5 is N═C, C(R 4x )═C, or C(R 4x ) 2 —C(R 5x ), wherein R 4x and R 5x , at each occurrence, are each independently hydrogen, halogen, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl;
R 8 groups are optional substituents on the benzo ring, and are each independently halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, or C 1 -C 3 haloalkoxy;
m is 0, 1, 2, 3, or 4;
G 3 is —(C 1 -C 3 alkylenyl)-OR g , —(C 1 -C 3 alkylenyl)-G B , phenyl, cycloalkyl, 4-6 membered monocyclic heterocycle, or monocyclic heteroaryl; wherein the phenyl, the cycloalkyl, the 4-6 membered monocyclic heterocycle, and the monocyclic heteroaryl are each optionally substituted with 1, 2, or 3 independently selected R s groups;
G B is phenyl, cycloalkyl, 4-6 membered monocyclic heterocycle, or monocyclic heteroaryl; each of which is optionally substituted with 1, 2, or 3 independently selected R s groups;
R 9 is C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, or phenyl; wherein the C 3 -C 6 cycloalkyl and the phenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, —OH, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, and C 1 -C 3 haloalkoxy;
n is 0, 1, 2, or 3;
R 10 is C 1 -C 6 alkyl substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, OH, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, and 2,2-dimethyl-1,3-dioxolan-4-yl; or R 10 is phenyl, C 3 -C 6 cycloalkyl, or monocyclic heteroaryl, wherein the phenyl, C 3 -C 6 cycloalkyl, and monocyclic heteroaryl are each optionally substituted with 1, 2, or 3 independently selected R v groups;
R 11 is halogen, C 1 -C 3 alkyl, or G 4 wherein G 4 is C 3 -C 6 cycloalkyl, 4-6 membered monocyclic heterocycle, monocyclic heteroaryl, or phenyl; each G 4 is optionally substituted with 1, 2, or 3 independently selected R w groups;
R 12 are optional substituents of the benzo ring, and are each independently halogen, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl;
p is 0, 1, 2, or 3;
R 13 is hydrogen or C 1 -C 6 alkyl which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of —CN, 2,2-dimethyl-1,3-dioxolan-4-yl, —OR 13 a, —O-benzyl, —N(R 13a ) 2 , —N(R 13a )S(O) 2 R 13b , and —N(R 13a )C(O)R 13b , wherein R 13a , at each occurrence, is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl, and R 13b , at each occurrence, is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl;
R 14 and R 15 are each independently C 1 -C 3 alkyl, or
R 14 and R 15 , together with the carbon atom to which they are attached, form a C 3 -C 6 cycloalkyl or a 4-6 membered monocyclic heterocycle containing one heteroatom selected from the group consisting of oxygen and nitrogen; wherein the C 3 -C 6 cycloalkyl and the 4-6 membered monocyclic heterocycle are each optionally substituted with 1 or 2 substituents independently selected from the group consisting of C 1 -C 3 alkyl, halogen, C 1 -C 3 haloalkyl, —OH, C 1 -C 3 alkoxy, and C 1 -C 3 haloalkoxy;
R 16 is —OH or C 1 -C 6 alkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of —CN, —OR j , —O-benzyl, —OC(O)R k , —OC(O)N(R j ) 2 , —SR j , —S(O) 2 R j , —S(O) 2 N(R j ) 2 , —C(O)R j , —C(O)OR j , —C(O)N(R j ) 2 , —C(O)N(R j )S(O) 2 R k , —N(R j ) 2 , —N(R j )C(O)R k , —N(R j )S(O) 2 R k , —N(R j )C(O)O(R k ), and —N(R j )C(O)N(R j ) 2 ;
R q is C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, C 1 -C 6 haloalkyl, —CN, oxo, NO 2 , —OR x , —OC(O)R y , —OC(O)N(R x ) 2 , —SR x , —S(O) 2 R x , —S(O) 2 N(R x ) 2 , —C(O)R x , —C(O)OR x , —C(O)N(R x ) 2 , —C(O)N(R x )S(O) 2 R y , —N(R x ) 2 , —N(R x )C(O)R y , —N(R x )S(O) 2 R y , —N(R x )C(O)O(R y ), —N(R x )C(O)N(R x ) 2 , G 2A , or C 1 -C 6 alkyl which is optionally substituted with 1 or 2 substituents independently selected from the group consisting of —CN, NO 2 , —OR x , —OC(O)R y , —OC(O)N(R x ) 2 , —SR x , —S(O) 2 R x , —S(O) 2 N(R x ) 2 , —C(O)R x , —C(O)OR x , —C(O)N(R x ) 2 , —C(O)N(R x )S(O) 2 R y , —N(R x ) 2 , —N(R x )C(O)R y , —N(R x )S(O) 2 R y , —N(R x )C(O)O(R y ), —N(R x )C(O)N(R x ) 2 , and G 2A ;
R x , at each occurrence, is independently hydrogen, C 1 -C 6 alkyl, G 2A , C 1 -C 6 haloalkyl, or —(C 1 -C 6 alkylenyl)-G 2A ;
R y , at each occurrence, is independently C 1 -C 6 alkyl, G 2A , C 1 -C 6 haloalkyl, or —(C 1 -C 6 alkylenyl)-G 2A ;
G 2A , at each occurrence, is independently phenyl or C 3 -C 6 cycloalkyl; each of which is optionally substituted with 1, 2, or 3 R z groups;
R s , at each occurrence, is independently C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, C 1 -C 6 haloalkyl, —CN, oxo, NO 2 , —OR j , —OR h , —OC(O)R k , —OC(O)N(R j ) 2 , —SR, —S(O) 2 R j , —S(O) 2 N(R j ) 2 , —C(O)R j , —C(O)OR j , —C(O)O(benzyl), —C(O)N(R j ) 2 , —C(O)N(R m )(R n ), —C(O)N(R j )S(O) 2 R k , —N(R j ) 2 , —N(R j )C(O)R k , —N(R j )S(O) 2 R k , —N(R j )C(O)O(R k ), G 3A , —N(R j )C(O)N(R j ) 2 , or C 1 -C 6 alkyl which is optionally substituted with 1 or 2 substituents independently selected from the group consisting of —CN, NO 2 , —OR j , —O-benzyl, —OC(O)R k , —OC(O)N(R j ) 2 , —SR, —S(O) 2 R j , —S(O) 2 N(R j ) 2 , —C(O)R j , —C(O)OR j , —C(O)N(R j ) 2 , —C(O)N(R j )S(O) 2 R k , —N(R j ) 2 , —N(R j )C(O)R k , —N(R j )S(O) 2 R k , —N(R j )C(O)O(R k ), —N(R j )C(O)N(R j ) 2 , and G 3A ;
G 3A , at each occurrence, is independently phenyl or 4-6 membered monocyclic heterocycle; each G 3A is optionally substituted with 1, 2, 3, or 4 R c groups;
R g is hydrogen or benzyl, or R g is C 2 -C 6 alkyl which is substituted with 1 or 2 —OR j ;
R h is benzyl or R h is C 2 -C 6 alkyl which is substituted with 1 or 2 —OR j ;
R m is G 3B or C 1 -C 6 alkyl which is substituted with 1 or 2 substituents independently selected

Assignees

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

Inventors

• Altenbach Robert J
• Bogdan Andrew
• Cowart Marlon D
• Esmieu William Ramesh
• Gfesser Gregory A
• Greszler Stephen N
• Koenig John R
• Kym Philip R
• Liu Bo
• Malagu Karine Fabienne
• Patel Sachin V
• Scanio Marc J
• Searle Xenia B
• Voight Eric
• Wang Xeuquing
• Yeung Ming C

Classifications

• A61P43/00

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

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• C07D493/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/443

  containing a five-membered ring with oxygen as a ring hetero atom · CPC title

• A61K31/5377

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