Substituted tetrahydropyrans and method of use

Patent metadata

Field	Value
Publication number	US-9567322-B2
Application number	US-201514926727-A
Country	US
Kind code	B2
Filing date	Oct 29, 2015
Priority date	Oct 31, 2014
Publication date	Feb 14, 2017
Grant date	Feb 14, 2017

Abstract

Compounds of formula (I)

and pharmaceutically acceptable salts or radiolabelled forms 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 and m are as defined in the specification, are useful in treating conditions or disorders prevented by or ameliorated by the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein. Methods for making the compounds are described. Also described are pharmaceutical compositions of compounds of formula (I), and methods for using such compounds and compositions.

First claim

We claim:

1. A compound having formula (I) or a pharmaceutically acceptable salt thereof, or a diastereomer thereof, or an enantiomer thereof,

wherein:
R 1 is phenyl, phenyl fused to a C 3 -C 6 cycloalkyl, or phenyl fused to a 4-6-membered heterocycle, wherein the phenyl, the phenyl of phenyl fused to a C 3 -C 6 cycloalkyl, or the phenyl of phenyl fused to a 4-6-membered heterocycle are independently optionally substituted with one, two, or three R x groups, wherein each R x group is independently selected, at each occurrence, from C 1 -C 6 alkyl, halogen, —CN, —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 i , —C(O)OR h , —C(O) N(R h ) 2 , —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 , and G A ,
wherein the C 1 -C 6 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of fluorine, —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 i , —C(O)OR h , —C (O)N(R h ) 2 , —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 , and -G B ;
wherein the C 3 -C 6 cycloalkyl of phenyl fused to a C 3 -C 6 cycloalkyl or the 4-6-membered heterocycle of phenyl fused to a 4-6-membered heterocycle are each optionally substituted with 1, 2 or 3 independently selected R s groups;
m is 0, 1, 2, or 3;
R s and R t , at each occurrence, are each independently C 1 -C 6 alkyl, halogen, —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 i , —C(O)OR h , —C(O) N(R h ) 2 , —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 C ,
wherein the C 1 -C 6 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of fluorine, —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 i , —C(O)OR h , —C (O)N(R h ) 2 , —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 , and G D ;
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 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of fluorine, —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 E ;
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 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of fluorine, —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 E ;
R 2 and R 3 are each independently hydrogen, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl;
R 4 and R 5 are each independently hydrogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl or G F , wherein the C 1 -C 6 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of fluorine, —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 i , —C(O)OR h , —C (O)N(R h ) 2 , —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 ), and —N(R h )C(O)N(R h ) 2 ; 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 t groups;
R 6 is hydrogen, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl;
R 7 is an optional substituent on the cyclopropyl ring, and at each occurrence, is independently halogen, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl;
R 8 , R 9 , and R 10 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 A , G B , G C , G D , G E , and G F 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 u groups; wherein
R u , 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 k , —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 k , —(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 or pharmaceutically acceptable salt of claim 1 , wherein R 2 , R 3 , R 4 and R 5 are each hydrogen.

3. The compound or pharmaceutically acceptable salt of claim 2 , wherein R 1 is phenyl, wherein the phenyl is optionally substituted with one, two, or three R x groups, wherein each R x group is independently selected, at each occurrence, from C 1 -C 6 alkyl, halogen, —CN, —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 i , —C(O)OR h , —C(O) N(R h ) 2 , —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 , and G A ,
wherein the C 1 -C 6 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of fluorine, —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 i , —C(O)OR h , —C (O)N(R h ) 2 , —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 , and -G B .

4. The compound or pharmaceutically acceptable salt of claim 3 , wherein R 1 is phenyl, wherein the phenyl is optionally substituted with one, two, or three R x groups, wherein each R x group is independently selected from C 1 -C 6 alkyl, halogen, —OR h , —C(O)R i , and —C(O)OR h ,
wherein the C 1 -C 6 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of fluorine and —OR h ;
R h , at each occurrence, is independently hydrogen, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl; and
R i , at each occurrence, is independently C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl.

5. The compound or pharmaceutically acceptable salt of claim 4 , wherein R 1 is phenyl, wherein the phenyl is optionally substituted with one, two, or three R x groups, wherein each R x group is independently selected from C 1 -C 6 alkyl, halogen, —OR h , —C(O)R i , and —C(O)OR h ,
wherein the C 1 -C 6 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of fluorine and —OR h ;
R h , at each occurrence, is independently hydrogen, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl;
R i , at each occurrence,

Assignees

• Abbvie S Á R L
• Galapagos Nv

Inventors

• Kym Philip R
• Liu Bo
• Searle Xenia B
• Wang Xueqing
• 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

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/357

  having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel · CPC title

• C07D407/12 Primary

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