Substituted chromanes and method of use

Patent metadata

Field	Value
Publication number	US-9642831-B2
Application number	US-201514925649-A
Country	US
Kind code	B2
Filing date	Oct 28, 2015
Priority date	Oct 31, 2014
Publication date	May 9, 2017
Grant date	May 9, 2017

Abstract

The invention provides for compounds of formula (I)

wherein R 1 , X, Y, R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , m, and R″ 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 having formula (I) or a pharmaceutically acceptable salt thereof

wherein
X is CR 2 and Y is CR 3 ; or
X is N and Y is CR 3 ; or
X is CR 2 and Y is N;
m is 0, 1, 2, or 3;
R″ are optional substituents on the cyclopropyl ring, and at each occurrence, are each independently halogen, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl;
R 1 and R 2 , are each independently hydrogen, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl, —OR 1A , —C(O)OR 1B , —NR 1A R 2A , or —C(O)NR 1A R 2A ;
R 1A and R 2A , at each occurrence, are each independently hydrogen, C 1 -C 6 haloalkyl, G 1A , 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 —OR ZA , —SR ZA , —S(O) 2 R ZA , —C(O)R ZA , —C(O)OR ZA , —C(O)N(R ZA ) 2 , —N(R ZA ) 2 , —N(R ZA )C(O)R ZB , —N(R ZA )S(O) 2 R ZB , —N(R ZA )C(O)OR ZB , —N(R ZA )C(O)N(R ZA ) 2 , —CN, and G 1A ; or R 1A and R 2A together with the nitrogen atom to which they are attached form a 4-6 membered heterocycle wherein the 4-6 membered heterocycle 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, —OR j , and N(R j ) 2 ; wherein
R ZA , at each occurrence, is independently hydrogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl, G 1A , or (C 1 -C 6 alkylenyl)-G 1A ; and
R ZB , at each occurrence, is independently C 1 -C 6 haloalkyl, C 1 -C 6 alkyl, G 1A , or —(C 1 -C 6 alkylenyl)-G 1A ;
R 1B is hydrogen, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl;
R 3 and R 14 , are each independently hydrogen, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl, —OH, or —O—(C 1 -C 6 alkyl);
R 4 is hydrogen, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl;
R 5 is hydrogen, —C(O)R i , —C(O)OH, —C(O)O(C 1 -C 6 alkyl), —C(O)N(R h ) 2 , C 1 -C 6 haloalkyl, C 1 -C 6 alkyl, or G 2A ; 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 —OR h , —OC(O)N(R h ) 2 , —C(O)R h , —C(O)OR h , —C(O)N(R h ) 2 , —N(R h ) 2 , —N(R h )C(O)R 1 , —N(R h )S(O) 2 R i , —N(R h )C(O)O(R i ), —N(R h )C(O)N(R h ) 2 , and G 2A ; or
R 4 and R 5 , together with the carbon atom to which they are attached, form a C 3 -C 6 cycloalkyl or a 4-6 membered heterocycle; wherein the C 3 -C 6 cycloalkyl and the 4-6 membered heterocycle are each optionally substituted with 1, 2, or 3 independently selected R p groups;
G 2A , at each occurrence, is independently cycloalkyl, cycloalkenyl, heterocycle, aryl, or heteroaryl, each of which is independently unsubstituted or substituted with 1, 2, or 3 independently selected R q groups;
R p and R q , at each occurrence, are each independently C 1 -C 6 alkyl, halogen, C 1 -C 6 haloalkyl, —CN, oxo, NO 2 , —OR h , —OC(O)R i , —OC(O)N(R h ) 2 , —SR h , —S(O) 2 R h , —S(O) 2 N(R h ) 2 , —C(O)R h , —C(O)OR h , —C(O)N(R h ) 2 , —C(O)N(R h )S(O) 2 R h , —N(R h ) 2 , —N(R h )C(O)R i , —N(R h )S(O) 2 R i , —N(R h )C(O)O(R i ), —N(R h )C(O)N(R h ) 2 , or G A , 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 —OR h , —OC(O)R i , —OC(O)N(R h ) 2 , —SR h , —S(O) 2 R h , —S(O) 2 N(R h ) 2 , —C(O)R h , —C(O)OR h , —C(O)N(R h ) 2 , —C(O)N(R h )S(O) 2 R h , —N(R h ) 2 , —N(R h )C(O)R i , —N(R h )S(O) 2 R i , —N(R h )C(O)O(R i ), —N(R h )C(O)N(R h ) 2 , —CN, and G A ;
R h , at each occurrence, is independently hydrogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl, or G A , 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 —OR j , —OC(O)N(R j ) 2 , —SR j , —C(O)OR j , —C(O)N(R j ) 2 , —N(R j ) 2 , —CN, and G A ;
R i , at each occurrence, is independently C 1 -C 6 haloalkyl, C 1 -C 6 alkyl, or G A , 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 —OR j , —OC(O)N(R j ) 2 , —SR j , —C(O)OR j , —C(O)N(R j ) 2 , —N(R j ) 2 , —CN, and G A ;
R 6 is hydrogen, halogen, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl;
R 7 is hydrogen, halogen, —OR j , —N(R j ) 2 , —N(R j )C(O)R k , C 1 -C 6 haloalkyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or —(C 1 -C 6 alkylenyl)-G 3A ;
R 8 is hydrogen, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl;
R 9 , R 10 , and R 13 , are each independently hydrogen, halogen, —OR j , C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl;
R 11 and R 12 are each independently hydrogen, C 1 -C 3 alkyl, or halogen;
G 1A , G 3A , and G A , at each occurrence, are each independently cycloalkyl, cycloalkenyl, heterocycle, aryl, or heteroaryl, each of which is independently unsubstituted or substituted with 1, 2, or 3 independently selected R s groups; wherein
R s , 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, —CN, oxo, NO 2 , —OR j , —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 , —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 , —(C 1 -C 6 alkylenyl)-OR j , —(C 1 -C 6 alkylenyl)-OC(O)R k , —(C 1 -C 6 alkylenyl)-OC(O)N(R j ) 2 , —(C 1 -C 6 alkylenyl)-SR j , —(C 1 -C 6 alkylenyl)-S(O) 2 R j , —(C 1 -C 6 alkylenyl)-S(O) 2 N(R j ) 2 , —(C 1 -C 6 alkylenyl)-C(O)R j , —(C 1 -C 6 alkylenyl)-C(O)OR j , —(C 1 -C 6 alkylenyl)-C(O)N(R j ) 2 , —(C 1 -C 6 alkylenyl)-N(R j ) 2 , —(C 1 -C 6 alkylenyl)-N(R j )C(O)R k , —(C 1 -C 6 alkylenyl)-N(R j )S(O) 2 R k , —(C 1 -C 6 alkylenyl)-N(R j )C(O)O(R k ), —(C 1 -C 6 alkylenyl)-N(R j )C(O)N(R j ) 2 , or —(C 1 -C 6 alkylenyl)-CN;
R j , at each occurrence, is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; and
R k , at each occurrence, is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl.

2. The compound of claim 1 having formula (I-a) or a pharmaceutically acceptable salt thereof

wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , m, and R″, are as set forth in claim 1 .

3. The compound of claim 1 having formula (I-b) or a pharmaceutically acceptable salt thereof

wherein R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , m, and R″, are as set forth in claim 1 .

4. The compound of claim 1 having formula (I-c) or a pharmaceutically acceptable salt thereof

wherein R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , m, and R″, are as set forth in claim 1 .

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 8 is hydrogen.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof,
wherein
R 8 is hydrogen; and
m is 0.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof,
wherein
R 8 is hydrogen;

Assignees

• Abbvie S Á R L
• Galapagos Nv

Inventors

• Altenbach Robert J
• Bogdan Andrew
• Greszler Stephen N
• Koenig John R
• Kym Philip R
• Liu Bo
• Searle Xenia B
• Voight Eric
• Wang Xueqing
• Yeung Ming C

Classifications

• C07D491/052

  the oxygen-containing ring being six-membered · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D407/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• A61K31/5377

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