IP Library › Granted Patent US 9,567,322

Granted Patent B2

US 9,567,322 · App. 14/926,727 · Granted Feb 14, 2017

Substituted tetrahydropyrans and method of use

Inventors: Philip R. Kym (Libertyville, IL); Bo Liu (Waukegan, IL); Xenia B. Searle (Grayslake, IL); Xueqing Wang (Northbrook, IL); Ming C. Yeung (Grayslake, IL)

Assignees: AbbVie S.á.r.l.; Galapagos NV

C07D407/12 A61K31/357 A61K45/06

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Quick Facts

Patent No.: US 9,567,322
App. No.: 14/926,727
Granted: Feb 14, 2017
Kind: B2

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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.

Claims (592)

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 ,

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 ,

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, is independently C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl

R 6 is hydrogen;

m is 0;

R 8 , R 9 , and R 10 are each hydrogen; and

R 11 and R 12 are each halogen.

6. The compound or pharmaceutically acceptable salt of claim 5 , wherein R 11 and R 12 are each fluorine.

7. The compound or pharmaceutically acceptable salt of claim 2 , wherein the compound or pharmaceutically acceptable salt is a cis diastereomer of formula (II), wherein

R 1 is phenyl or phenyl fused to a 4-6-membered heterocycle, wherein the phenyl 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 4-6-membered heterocycle of phenyl fused to a 4-6-membered heterocycle is optionally substituted with 1, 2 or 3 independently selected R 5 groups.

8. The compound or pharmaceutically acceptable salt of claim 7 , wherein, R 1 is phenyl fused to a 4-6-membered heterocycle, wherein the phenyl of phenyl fused to a 4-6-membered heterocycle 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 4-6-membered heterocycle of phenyl fused to a 4-6-membered heterocycle is optionally substituted with 1, 2 or 3 independently selected R s groups.

9. The compound or pharmaceutically acceptable salt of claim 8 , wherein R 1 is phenyl fused to a 4-6-membered heterocycle, wherein the phenyl of phenyl fused to a 4-6-membered heterocycle is optionally substituted with one, two or three IV 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 ; and

wherein the 4-6-membered heterocycle of phenyl fused to a 4-6-membered heterocycle is optionally substituted with 1, 2 or 3 independently selected R s groups;

R s , at each occurrence, is 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 , —S(O) 2 R h , —SR 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, or C 1 -C 6 alkyl;

R 6 is hydrogen;

m is 0;

R 8 , R 9 , and R 10 are each hydrogen;

R 11 and R 12 are each halogen;

G A , G C , G D and G E 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.

10. The compound or pharmaceutically acceptable salt of claim 9 , wherein R 11 and R 12 are each fluorine.

11. The compound or pharmaceutically acceptable salt of claim 1 , wherein the compound or pharmaceutically acceptable salt is an enantiomer of formula (IIa)

12. The compound or pharmaceutically acceptable salt of claim 1 , wherein the compound or pharmaceutically acceptable salt is an enantiomer of formula (IIb)

13. The compound or pharmaceutically acceptable salt of claim 7 , 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 1 , —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 .

14. The compound or pharmaceutically acceptable salt of claim 13 , 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, is independently C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl;

R 6 is hydrogen;

m is 0;

R 8 , R 9 , and R 10 , are each hydrogen; and

R 11 and R 12 are each halogen.

15. The compound or pharmaceutically acceptable salt of claim 14 , wherein R 11 and R 12 are each fluorine.

16. The compound or pharmaceutically acceptable salt of claim 15 , wherein the compound or pharmaceutically acceptable salt is an enantiomer of formula (IIc), wherein

each R x is an optional substituent 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.

17. The compound or pharmaceutically acceptable salt of claim 1 , wherein the compound or pharmaceutically acceptable salt is an enantiomer of formula (IId), wherein

each R x is an optional substituent 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.

18. The compound or pharmaceutically acceptable salt of claim 2 , wherein the compound or pharmaceutically acceptable salt is a trans diastereomer of formula (III), wherein

R 1 is phenyl or phenyl fused to a 4-6-membered heterocycle, wherein the phenyl or the phenyl of phenyl fused to a 4-6-membered heterocycle are independently optionally substituted with one, two, or three IV groups, wherein each IV 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 ,

19. The compound or pharmaceutically acceptable salt of claim 18 , wherein,

R 1 is phenyl, wherein the phenyl is optionally substituted with one, two, or three IV groups,

wherein each IV 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 1 , —N(R h )S(O) 2 R 1 , —N(R h )C(O)O(R i ), —N(R h )C(O)N(R h ) 2 , and G A ,

20. The compound or pharmaceutically acceptable salt of claim 19 , wherein

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, is independently C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl;

R 6 is hydrogen;

m is 0;

R 8 , R 9 , and R 10 are each hydrogen; and

R 11 and R 12 are each halogen.

21. The compound or pharmaceutically acceptable salt of claim 20 , wherein R 11 and R 12 are each fluorine.

22. The compound or pharmaceutically acceptable salt of claim 21 , wherein the compound or pharmaceutically acceptable salt is an enantiomer of formula (IIIa), wherein

each R x is an optional substituent 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.

23. The compound or pharmaceutically acceptable salt of claim 1 , wherein the compound or pharmaceutically acceptable salt is an enantiomer of formula (IIIb), wherein

each R x is an optional substituent 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.

24. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 2 , R 3 , and R 4 are hydrogen and R 5 is G F ; wherein,

G F is C 3 -C 7 cycloalkyl, C 5 -C 7 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 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.

25. The compound or pharmaceutically acceptable salt of claim 24 , wherein,

R 5 is C 3 -C 7 cycloalkyl or phenyl, wherein the C 3 -C 7 cycloalkyl and the phenyl are optionally unsubstituted or substituted with 1, 2, or 3 independently selected R u groups; wherein

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.

26. The compound or pharmaceutically acceptable salt of claim 25 , wherein

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, is independently C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl;

R 5 is phenyl, wherein the phenyl is optionally 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, halogen, C 1 -C 6 haloalkyl, —OR j , —C(O)R k , or —C(O)OR j ;

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.

27. The compound or pharmaceutically acceptable salt of claim 26 , wherein

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, is independently C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl;

R 5 is phenyl, wherein the phenyl is optionally 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, halogen, C 1 -C 6 haloalkyl, —OR j , —C(O)R k , or —C(O)OR j ;

R j , at each occurrence, is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

R k , at each occurrence, is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl;

R 6 is hydrogen;

m is 0;

R 8 , R 9 , and R 10 are each hydrogen; and

R 11 and R 12 are each halogen.

28. The compound or pharmaceutically acceptable salt of claim 27 , wherein R 11 and R 12 are each fluorine.

29. The compound or pharmaceutically acceptable salt of claim 24 , wherein the compound or pharmaceutically acceptable salt is a diastereomer of formula (IV), wherein

wherein the 4-6-membered heterocycle of phenyl fused to a 4-6-membered heterocycle is optionally substituted with 1, 2 or 3 independently selected R s groups;

R 5 is G F ; wherein,

G F is C 3 -C 7 cycloalkyl, aryl or heteroaryl, each of which is independently unsubstituted or substituted with 1, 2, or 3 independently selected R u groups; wherein

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.

30. The compound or pharmaceutically acceptable salt of claim 29 , wherein,

R 5 is phenyl; wherein, the phenyl is unsubstituted or substituted with 1, 2, or 3 independently selected R u groups; wherein

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.

31. The compound or pharmaceutically acceptable salt of claim 30 , wherein

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, is independently C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl;

R 5 is phenyl, wherein the phenyl is optionally 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, halogen, C 1 -C 6 haloalkyl, —OR j , —C(O)R k , or —C(O)OR j ;

R j , at each occurrence, is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

R k , at each occurrence, is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl;

R 6 is hydrogen;

m is 0;

R 8 , R 9 , and R 10 are each hydrogen; and

R 11 and R 12 are each halogen.

32. The compound or pharmaceutically acceptable salt of claim 31 , wherein R 11 and R 12 are each fluorine.

33. The compound or pharmaceutically acceptable salt of claim 32 , wherein the compound or pharmaceutically acceptable salt is an enantiomer of formula (IVa), wherein

R x is an optional substituent independently selected at each occurrence 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 is hydrogen, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl;

R i is C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl;

R u is an optional substituent independently selected at each occurrence from C 1 -C 6 alkyl, halogen, C 1 -C 6 haloalkyl, —OR j , —C(O)R k , or —C(O)OR j ;

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.

34. The compound or pharmaceutically acceptable salt of claim 1 , wherein the compound or pharmaceutically acceptable salt is an enantiomer of formula (IVb), wherein

R x is an optional substituent independently selected at each occurrence 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, is independently C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl;

R u is an optional substituent independently selected at each occurrence from C 1 -C 6 alkyl, halogen, C 1 -C 6 haloalkyl, —OR j , —C(O)R k , or —C(O)OR j ;

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.

35. The compound or pharmaceutically acceptable salt of claim 24 , wherein the compound or pharmaceutically acceptable salt is a diastereomer of formula (V), wherein

wherein the 4-6-membered heterocycle of phenyl fused to a 4-6-membered heterocycle is optionally substituted with 1, 2 or 3 independently selected R s groups;

R 5 is G F ; wherein,

G F is C 3 -C 7 cycloalkyl, aryl or heteroaryl, each of which is independently unsubstituted or substituted with 1, 2, or 3 independently selected R u groups; wherein

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.

36. The compound or pharmaceutically acceptable salt of claim 35 , wherein,

R 5 is phenyl; wherein, the phenyl is unsubstituted or substituted with 1, 2, or 3 independently selected R u groups; wherein

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.

37. The compound or pharmaceutically acceptable salt of claim 36 , 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, is independently C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl;

R 5 is phenyl, wherein the phenyl is optionally 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, halogen, C 1 -C 6 haloalkyl, —OR j , —C(O)R k , or —C(O)OR j ;

R j , at each occurrence, is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

R k , at each occurrence, is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl;

R 6 is hydrogen;

m is 0;

R 8 , R 9 , and R 10 are each hydrogen; and

R 11 and R 12 are each halogen.

38. The compound or pharmaceutically acceptable salt of claim 37 , wherein R 11 and R 12 are each fluorine.

39. The compound or pharmaceutically acceptable salt of claim 38 , wherein the compound or pharmaceutically acceptable salt is an enantiomer of formula (Va), wherein

R x is an optional substituent independently selected at each occurrence 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, is independently C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl;

R u is an optional substituent independently selected at each occurrence from C 1 -C 6 alkyl, halogen, C 1 -C 6 haloalkyl, —OR j , —C(O)R k , or —C(O)OR j ;

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.

40. The compound or pharmaceutically acceptable salt of claim 1 , wherein the compound or pharmaceutically acceptable salt is an enantiomer of formula (Vb), wherein

R x is an optional substituent independently selected at each occurrence 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, is independently C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl;

R u is an optional substituent independently selected at each occurrence from C 1 -C 6 alkyl, halogen, C 1 -C 6 haloalkyl, —OR j , —C(O)R k , and —C(O)OR j ;

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.

41. The compound or pharmaceutically acceptable salt of claim 25 , wherein

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, is independently C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl;

R 5 is cycloalkyl, wherein the cycloalkyl is optionally 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 1 -C 6 haloalkyl, —C(O)R k , or —C(O)OR j ;

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.

42. The compound or pharmaceutically acceptable salt of claim 41 , wherein

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, is independently C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl;

R 5 is cycloalkyl, wherein the cycloalkyl is optionally 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 1 -C 6 haloalkyl, —C(O)R k , or —C(O)OR j ;

R j , at each occurrence, is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

R k , at each occurrence, is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl;

R 6 is hydrogen;

m is 0;

R 8 , R 9 , and R 10 are each hydrogen; and

R 11 and R 12 are each halogen.

43. The compound or pharmaceutically acceptable salt of claim 42 , wherein R 11 and R 12 are each fluorine.

44. The compound or pharmaceutically acceptable salt of claim 29 , wherein,

R 5 is C 3 -C 7 cycloalkyl; wherein, the C 3 -C 7 cycloalkyl is 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 1 -C 6 haloalkyl, —C(O)R k , or —C(O)OR j ;

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.

45. The compound or pharmaceutically acceptable salt of claim 44 , wherein

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, is independently C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl;

R 5 is C 3 -C 7 cycloalkyl, wherein the C 3 -C 7 cycloalkyl is optionally 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 1 -C 6 haloalkyl, —C(O)R k , or —C(O)OR j ;

R j , at each occurrence, is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

R k , at each occurrence, is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl;

R 6 is hydrogen;

m is 0;

R 8 , R 9 , and R 10 are each hydrogen; and

R 11 and R 12 are each halogen.

46. The compound or pharmaceutically acceptable salt of claim 45 , wherein R 11 and R 12 are each fluorine.

47. The compound or pharmaceutically acceptable salt of claim 46 , wherein the compound or pharmaceutically acceptable salt is an enantiomer of formula (IVc), wherein

R x is an optional substituent independently selected at each occurrence 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, is independently C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl;

R u is an optional substituent independently selected at each occurrence from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —C(O)R k , and —C(O)OR j ;

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.

48. The compound or pharmaceutically acceptable salt of claim 1 , wherein the compound or pharmaceutically acceptable salt is an enantiomer of formula (IVd), wherein

R x is an optional substituent independently selected at each occurrence 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, is independently C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl;

R u is an optional substituent independently selected at each occurrence from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —C(O)R k , and —C(O)OR j ;

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.

49. The compound or pharmaceutically acceptable salt of claim 35 , 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 ;

R 5 is C 3 -C 7 cycloalkyl; wherein, the C 3 -C 7 cycloalkyl is 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 1 -C 6 haloalkyl, —C(O)R k , or —C(O)OR j ;

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.

50. The compound or pharmaceutically acceptable salt of claim 49 , wherein

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, is independently C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl;

R 5 is C 3 -C 7 cycloalkyl; wherein, the C 3 -C 7 cycloalkyl is 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 1 -C 6 haloalkyl, —C(O)R k , or —C(O)OR j ;

R j , at each occurrence, is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

R k , at each occurrence, is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl;

m is 0;

R 8 , R 9 , and R 10 are each hydrogen; and

R 11 and R 12 are each halogen.

51. The compound or pharmaceutically acceptable salt of claim 50 , wherein R 11 and R 12 are each fluorine.

52. The compound or pharmaceutically acceptable salt of claim 51 , wherein the compound or pharmaceutically acceptable salt is an enantiomer of formula (Vc), wherein

R x , at each occurrence, is an optional substituent 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, is independently C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl;

R u , at each occurrence, is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —C(O)R k , or —C(O)OR j ;

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.

53. The compound or pharmaceutically acceptable salt of claim 1 , wherein the compound or pharmaceutically acceptable salt is an enantiomer of formula (Vd), wherein

R x , at each occurrence, is an optional substituent 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, is independently C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl;

R u , at each occurrence, is an optional substituent independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —C(O)R k , and —C(O)OR j ;

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.

54. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 2 , R 3 , and R 4 are hydrogen and R 5 is C 1 -C 6 alkyl, 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 .

55. The compound or pharmaceutically acceptable salt of claim 54 , wherein,

R 5 is C 1 -C 6 alkyl, 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 ;

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 , —C(O)OR j , —C(O)N(R j ) 2 , —N(R j ) 2 , —CN, and G E ; and

56. The compound or pharmaceutically acceptable salt of claim 55 , wherein

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, is independently C 1 -C 6 haloalkyl or C 1 -C 6 alkyl; and

57. The compound or pharmaceutically acceptable salt of claim 56 , wherein

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, is independently C 1 -C 6 haloalkyl or C 1 -C 6 alkyl;

R 6 is hydrogen;

m is 0;

R 8 , R 9 , and R 10 are each hydrogen; and

R 11 and R 12 are each halogen.

58. The compound or pharmaceutically acceptable salt of claim 57 , wherein R 11 and R 12 are each fluorine.

59. The compound or pharmaceutically acceptable salt of claim 54 , wherein the compound or pharmaceutically acceptable salt is a diastereomer of formula (IV), wherein

wherein the 4-6-membered heterocycle of phenyl fused to a 4-6-membered heterocycle is optionally substituted with 1, 2 or 3 independently selected R s groups;

R h , at each occurrence, is independently hydrogen, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl;

R i , at each occurrence, is independently C 1 -C 6 haloalkyl or C 1 -C 6 alkyl; and

60. The compound or pharmaceutically acceptable salt of claim 59 , wherein,

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 , —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 ;

R h , at each occurrence, is independently hydrogen, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl;

R i , at each occurrence, is independently C 1 -C 6 haloalkyl or C 1 -C 6 alkyl; and

61. The compound or pharmaceutically acceptable salt of claim 60 , wherein

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, is independently C 1 -C 6 haloalkyl or C 1 -C 6 alkyl;

R 5 is C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is 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 ;

R 6 is hydrogen;

m is 0;

R 8 , R 9 , and R 10 are each hydrogen; and

R 11 and R 12 are each halogen.

62. The compound or pharmaceutically acceptable salt of claim 61 , wherein R 11 and R 12 are each fluorine.

63. The compound or pharmaceutically acceptable salt of claim 62 , wherein the compound or pharmaceutically acceptable salt is an enantiomer of formula (IVe), wherein

R x , at each occurrence, is an optional substituent 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.

64. The compound or pharmaceutically acceptable salt of claim 1 , wherein the compound or pharmaceutically acceptable salt is an enantiomer of formula (IVf), wherein

R x , at each occurrence, is an optional substituent 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 is C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl.

65. The compound or pharmaceutically acceptable salt of claim 54 , wherein the compound or pharmaceutically acceptable salt is a diastereomer of formula (V), wherein

wherein the 4-6-membered heterocycle of phenyl fused to a 4-6-membered heterocycle is optionally substituted with 1, 2 or 3 independently selected R s groups;

R h , at each occurrence, is independently hydrogen, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl;

R i , at each occurrence, is independently C 1 -C 6 haloalkyl or C 1 -C 6 alkyl; and

66. The compound or pharmaceutically acceptable salt of claim 65 , wherein,

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 i , —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 ;

R h , at each occurrence, is independently hydrogen, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl;

R i , at each occurrence, is independently C 1 -C 6 haloalkyl or C 1 -C 6 alkyl; and

67. The compound or pharmaceutically acceptable salt of claim 66 , wherein

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, is independently C 1 -C 6 haloalkyl or C 1 -C 6 alkyl;

R 6 is hydrogen;

m is 0;

R 8 , R 9 , and R 10 are each hydrogen; and

R 11 and R 12 are each halogen.

68. The compound or pharmaceutically acceptable salt of claim 67 , wherein R 11 and R 12 are each fluorine.

69. The compound or pharmaceutically acceptable salt of claim 68 , wherein the compound or pharmaceutically acceptable salt is an enantiomer of formula (Ve), wherein

R x , at each occurrence, is an optional substituent 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 is 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.

70. The compound or pharmaceutically acceptable salt of claim 1 , wherein the compound or pharmaceutically acceptable salt is an enantiomer of formula (Vf), wherein

R x , at each occurrence, is an optional substituent 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.

71. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 2 and R 3 are each hydrogen and R 4 and R 5 are each C 1 -C 6 alkyl.

72. The compound or pharmaceutically acceptable salt of claim 71 , wherein,

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 , —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 .

73. The compound or pharmaceutically acceptable salt of claim 72 , 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 —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.

74. The compound or pharmaceutically acceptable salt of claim 73 , wherein

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, is independently C 1 -C 6 haloalkyl or C 1 -C 6 alkyl;

R 6 is hydrogen;

m is 0;

R 8 , R 9 , and R 10 are each hydrogen; and

R 11 and R 12 are each halogen.

75. The compound or pharmaceutically acceptable salt of claim 74 , wherein R 11 and R 12 are each fluorine.

76. The compound or pharmaceutically acceptable salt of claim 71 , wherein the compound or pharmaceutically acceptable salt is a cis diastereomer of formula (VI), wherein

wherein the 4-6-membered heterocycle of phenyl fused to a 4-6-membered heterocycle is optionally substituted with 1, 2 or 3 independently selected R s groups; and

R 4 and R 5 are each C 1 -C 6 alkyl.

77. The compound or pharmaceutically acceptable salt of claim 76 , wherein,

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 , —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 .

78. The compound or pharmaceutically acceptable salt of claim 77 , 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, —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, is independently C 1 -C 6 haloalkyl or C 1 -C 6 alkyl;

R 6 is hydrogen;

m is 0;

R 8 , R 9 , and R 10 are each hydrogen; and

R 11 and R 12 are each halogen.

79. The compound or pharmaceutically acceptable salt of claim 78 , wherein R 11 and R 12 are each fluorine.

80. The compound or pharmaceutically acceptable salt of claim 79 , wherein the compound or pharmaceutically acceptable salt is an enantiomer of formula (VIa), wherein

R x , at each occurrence, is an optional substituent independently selected from C 1 -C 6 alkyl, halogen, —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, is independently C 1 -C 6 haloalkyl or C 1 -C 6 alkyl; and

R 4 and R 5 are each C 1 -C 6 alkyl.

81. The compound or pharmaceutically acceptable salt of claim 1 , wherein the compound or pharmaceutically acceptable salt is an enantiomer of formula (VIb), wherein

R x , at each occurrence, is an optional substituent independently selected from C 1 -C 6 alkyl, halogen, —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, is independently C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl; and

R 4 and R 5 are each C 1 -C 6 alkyl.

82. The compound or pharmaceutically acceptable salt of claim 71 , wherein the compound or pharmaceutically acceptable salt is a trans diastereomer of formula (VII), wherein

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 , —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 4-6-membered heterocycle of phenyl fused to a 4-6-membered heterocycle is optionally substituted with 1, 2 or 3 independently selected R s groups; and

R 4 and R 5 are each C 1 -C 6 alkyl.

83. The compound or pharmaceutically acceptable salt of claim 82 , wherein,

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 , —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 .

84. The compound or pharmaceutically acceptable salt of claim 83 , wherein

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, is independently C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl;

R 6 is hydrogen;

m is 0;

R 8 , R 9 , and R 10 are each hydrogen; and

R 11 and R 12 are each halogen.

85. The compound or pharmaceutically acceptable salt of claim 84 , wherein R 11 and R 12 are each fluorine.

86. The compound or pharmaceutically acceptable salt of claim 85 , wherein the compound or pharmaceutically acceptable salt is an enantiomer of formula (VIIa), wherein

R x , at each occurrence, is an optional substituent independently selected from C 1 -C 6 alkyl, halogen, —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, is independently C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl; and

R 4 and R 5 are each C 1 -C 6 alkyl.

87. The compound or pharmaceutically acceptable salt of claim 1 , wherein the compound or pharmaceutically acceptable salt is an enantiomer of formula (VIIb), wherein

R x , at each occurrence, is an optional substituent independently selected from C 1 -C 6 alkyl, halogen, —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 ; and

R h , at each occurrence, is independently hydrogen, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl;

R i , at each occurrence, is independently C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl; and

R 4 and R 5 are each C 1 -C 6 alkyl.

88. The compound or pharmaceutically acceptable salt of claim 1 , selected from:

rac-1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[(2R,4S)-2-phenyltetrahydro-2H-pyran-4-yl]cyclopropanecarboxamide;

rac-3-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]benzoic acid;

methyl rac-3-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]benzoate;

methyl rac-3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]benzoate;

rac-3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]benzoic acid;

rac-1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-{(2R,4R)-2-[3-(hydroxymethyl)phenyl]tetrahydro-2H-pyran-4-yl}cyclopropanecarboxamide;

rac-1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-{(2R,4R)-2-[3-(2-hydroxypropan-2-yl)phenyl]tetrahydro-2H-pyran-4-yl}cyclopropanecarboxamide;

rac-N-[(2R,4S)-2-(3-acetylphenyl)tetrahydro-2H-pyran-4-yl]-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarboxamide;

rac-1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-{(2R,4S)-2-[3-(hydroxymethyl)phenyl]tetrahydro-2H-pyran-4-yl]cyclopropanecarboxamide;

rac-1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-{(2R,4S)-2-[3-(2-hydroxypropan-2-yl)phenyl]tetrahydro-2H-pyran-4-yl}cyclopropanecarboxamide;

methyl rac-2-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]benzoate;

rac-2-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]benzoic acid;

methyl rac-4-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]benzoate;

rac-4-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]benzoic acid;

N-[(2S,4R)-2-(1,3-benzodioxol-5-yl)tetrahydro-2H-pyran-4-yl]-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarboxamide;

methyl 3-[(2S,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]benzoate;

methyl 3-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]benzoate;

3-[(2S,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]benzoic acid;

3-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]benzoic acid;

N-[(2R,4R)-2-(4-bromophenyl)tetrahydro-2H-pyran-4-yl]-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarboxamide;

N-[(2S,4S)-2-(4-bromophenyl)tetrahydro-2H-pyran-4-yl]-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarboxamide;

methyl rac-3-[(2R,4R,6S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-phenyltetrahydro-2H-pyran-2-yl]benzoate;

methyl rac-3-[(2R,4S,6S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-phenyltetrahydro-2H-pyran-2-yl]benzoate;

rac-3-[(2R,4S,6S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-phenyltetrahydro-2H-pyran-2-yl]benzoic acid;

rac-3-[(2R,4R,6S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-phenyltetrahydro-2H-pyran-2-yl]benzoic acid;

3-[(2S,4R,6R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-phenyltetrahydro-2H-pyran-2-yl]benzoic acid;

3-[(2R,4S,6S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-phenyltetrahydro-2H-pyran-2-yl]benzoic acid;

methyl 4-[(2S,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]benzoate;

methyl 4-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]benzoate;

4-[(2S,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]benzoic acid;

4-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]benzoic acid;

methyl rac-4-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6,6-dimethyltetrahydro-2H-pyran-2-yl]benzoate;

rac-4-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6,6-dimethyltetrahydro-2H-pyran-2-yl]benzoic acid;

methyl rac-4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6, 6-dimethyltetrahydro-2H-pyran-2-yl]benzoate

rac-4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6,6-dimethyltetrahydro-2H-pyran-2-yl]benzoic acid

methyl rac-4-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]-methylbenzoate;

rac-4-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]-methylbenzoic acid;

methyl rac-4-[(2R,6S)-6-cyclopropyl-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]benzoate;

methyl rac-4-[(2R,4S,6R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-methyltetrahydro-2H-pyran-2-yl]benzoate;

methyl rel-4-[(2S,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]-methylbenzoate;

methyl rel-4-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]-methylbenzoate;

rel-4-[(2S,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]-methylbenzoic acid;

rel-4-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]-methylbenzoic acid;

4-[6-cyclopropyl-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]benzoic acid;

rac-4-[(2R,4S,6R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-methyltetrahydro-2H-pyran-2-yl]benzoic acid;

methyl rac-4-[(2R,4R,6R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-methyltetrahydro-2H-pyran-2-yl]benzoate;

methyl rac-4-[(2R,4R,6S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-phenyltetrahydro-2H-pyran-2-yl]benzoate;

methyl rac-4-[(2R,4S,6S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-phenyltetrahydro-2H-pyran-2-yl]benzoate;

rac-4-[(2R,4R,6S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-phenyltetrahydro-2H-pyran-2-yl]benzoic acid;

rac-4-[(2R,4S,6S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-phenyltetrahydro-2H-pyran-2-yl]benzoic acid;

dimethyl rac-4,4′-[(2R,4S,6S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2,6-diyl]dibenzoate;

dimethyl rac-4,4′-[(2R,4r,6S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2,6-diyl]dibenzoate;

rel-4-[(2R,4S,6S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-phenyltetrahydro-2H-pyran-2-yl]benzoic acid;

rel-4-[(2S,4R,6R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-phenyltetrahydro-2H-pyran-2-yl]benzoic acid;

methyl rac-4-[(2R,4R,6S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-(4-methoxyphenyl)tetrahydro-2H-pyran-2-yl]benzoate;

rac-4-[(2R,4S,6S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-(4-methoxyphenyl)tetrahydro-2H-pyran-2-yl]benzoic acid;

rac-4-[(2R,4R,6S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-(4-methoxyphenyl)tetrahydro-2H-pyran-2-yl]benzoic acid;

rel-4-[(2S,4R,6S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-methyltetrahydro-2H-pyran-2-yl]benzoic acid;

rel-4-[(2R,4S,6R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-methyltetrahydro-2H-pyran-2-yl]benzoic acid;

rac-4-[(2R,4S,6S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-phenyltetrahydro-2H-pyran-2-yl]-fluorobenzoic acid;

rac-4-[(2R,4R,6S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-phenyltetrahydro-2H-pyran-2-yl]-fluorobenzoic acid;

methyl rac-4-[(2R,4S,6S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-phenyltetrahydro-2H-pyran-2-yl]-methylbenzoate;

methyl rac-4-[(2R,4S,6S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-phenyltetrahydro-2H-pyran-2-yl]-3-fluorobenzoate;

rac-4-[(2R,4R,6S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-phenyltetrahydro-2H-pyran-2-yl]-3-methylbenzoic acid;

rel-4-[(2R,4R,6S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-(4-methoxyphenyl)tetrahydro-2H-pyran-2-yl]benzoic acid;

rel-4-[(2S,4S,6R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-(4-methoxyphenyl)tetrahydro-2H-pyran-2-yl]benzoic acid;

ethyl rac-3-[(2R,4R,6S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-(3-methoxyphenyl)tetrahydro-2H-pyran-2-yl]benzoate;

rac-3-[(2R,4R,6S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-(3-methoxyphenyl)tetrahydro-2H-pyran-2-yl]benzoic acid;

rac-3-[(2R,4S,6S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-phenyltetrahydro-2H-pyran-2-yl]-4-methylbenzoic acid;

methyl rac-3-[(2R,4S,6S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-phenyltetrahydro-2H-pyran-2-yl]-4-methylbenzoate;

ethyl rac-3-[(2R,4S,6S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-phenyltetrahydro-2H-pyran-2-yl]-5-methylbenzoate;

rac-3-[(2R,4S,6S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-phenyltetrahydro-2H-pyran-2-yl]-5-methylbenzoic acid;

rel-3-[(2R,4R,6S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-(3-methoxyphenyl)tetrahydro-2H-pyran-2-yl]benzoic acid;

rel-3-[(2R,4S,6S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-phenyltetrahydro-2H-pyran-2-yl]-5-methylbenzoic acid; and

rel-3-[(2S,4R,6R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-phenyltetrahydro-2H-pyran-2-yl]-5-methylbenzoic acid.

89. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.

90. A method for alleviating cystic fibrosis in a subject comprising administering a therapeutically effective amount of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

91. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents.

92. The pharmaceutical composition of claim 91 wherein the additional therapeutic agents are selected from the group consisting of CFTR modulators and CFTR amplifiers.

93. The pharmaceutical composition of claim 92 wherein the additional therapeutic agents are CFTR modulators.

94. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, one potentiator, and one or more correctors.

95. A method for alleviating cystic fibrosis in a subject comprising administering a compound of claim 1 or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents.

96. The method of claim 95 wherein the additional therapeutic agents are selected from the group consisting of CFTR modulators and CFTR amplifiers.

97. The method of claim 95 wherein the additional therapeutic agents are CFTR modulators.

98. A method for alleviating cystic fibrosis in a subject comprising administering a compound of claim 1 or a pharmaceutically acceptable salt thereof, one potentiator, and one or more correctors.

Assignments (3)

MERGER Recorded May 13, 2020

From: ABBVIE S.Á.R.L.

To: ABBVIE OVERSEAS S.Á.R.L.

Reel/Frame 052647/0794 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 13, 2016

From: KYM, PHILIP R.; WANG, XUEQING; SEARLE, XENIA B.; LIU, BO; YEUNG, MING C.

To: ABBVIE S.Á.R.L.

Reel/Frame 039715/0617 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 1, 2016

From: ABBVIE INC.

To: ABBVIE S.Á.R.L.; GALAPAGOS NV

Reel/Frame 037863/0882 →

Continuity (2)

Provisional Application 62073586 · Oct 31, 2014

Related Publication 20160122331A1 · May 5, 2016