Patent Application

App. No. 19/052,650

Abstract

Claims (265)

1 . A compound, which compound is a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

X 1 and X 2 is independently O or CHR 6 ;

each of Y 1 , Y 2 , and Y 3 is independently N, CR 3 , or C—X 1 —R 1 , provided that only one of Y 1 , Y 2 , and Y 3 may be attached to X 1 ;

each of Z 1 , Z 2 , and Z 3 is independently N or CR 3 ;

each R 1 is independently optionally substituted C 1-6 hydrocarbyl or 2-9 membered heterocarbyl, which optional substitution is with one or more of halo, R 1A , or OR 1A ;

each R 1A is independently optionally substituted C 1-6 hydrocarbyl, which optional substitution is with one or more of halo;

each of R 2A and R 2B is independently hydrogen or C 1-6 alkyl optionally substituted with one or more halo, or R 2A and R 2B are taken together to form a C 3-5 cycloalkyl or 3-5 membered cycloheteroalkyl;

each R 3 is independently hydrogen, halo, C 1-6 alkyl optionally substituted with one or more halo;

R 4 is hydrogen or C 1-6 alkyl;

R 5 is N(R 5A ) 2 , NHR 5A , or optionally substituted C 1-8 hydrocarbyl or 2-9 membered heterocarbyl, which optional substitution is with one or more of halo, hydroxyl, nitrile, RA, OR 5A , N(R 5A ) 2 , NHR 5A , or NH 2 ;

each R 5A is independently optionally substituted C 1-8 hydrocarbyl or 2-9 membered heterocarbyl, which optional substitution is with one or more of halo, hydroxyl, nitrile, R 5B , OR 5B , N(R 5B ) 2 , NHR 5 B, or NH 2 ;

each R 5B is independently optionally substituted C 1-8 hydrocarbyl or 2-9 membered heterocarbyl, which optional substitution is with one or more of halo, hydroxyl, nitrile, R C , OR 5C , N(R 5C ) 2 , NHR C , or NH 2 ;

each R 5C is independently optionally substituted C 1-8 hydrocarbyl or 2-9 membered heterocarbyl, which optional substitution is with one or more of halo, hydroxyl, nitrile, or NH 2 ; and

each R 6 is independently H or C 1-6 alkyl.

2 . (canceled)

3 . (canceled)

4 . (canceled)

5 . The compound of claim 1 , wherein at least one of Y 1 , Y 2 , and Y 3 is N.

6 . (canceled)

7 . (canceled)

8 . (canceled)

9 . (canceled)

10 . The compound of claim 1 , wherein Z 3 is CR 3 .

11 . The compound of claim 1 , which is of formula III:

or a pharmaceutically acceptable salt thereof.

12 . (canceled)

13 . (canceled)

14 . The compound of claim 1 , which is of formula IV:

or a pharmaceutically acceptable salt thereof.

15 . The compound of claim 14 , wherein Z 3 is CR 3 .

16 . (canceled)

17 . (canceled)

18 . The compound of claim 1 , which is of formula V(a):

or a pharmaceutically acceptable salt thereof.

19 . (canceled)

20 . The compound of claim 18 , wherein Y 3 is N.

21 . The compound of claim 20 , wherein R 5 is one of:

22 . (canceled)

23 . (canceled)

24 . (canceled)

25 . (canceled)

26 . (canceled)

27 . (canceled)

28 . The compound of claim 21 , wherein R 1 is optionally substituted C 1-8 hydrocarbyl.

29 . The compound of claim 28 , wherein R 1 is cyclopropylmethyl, phenyl, or cyclopropyl.

30 . (canceled)

31 . (canceled)

32 . (canceled)

33 . (canceled)

34 . The compound of claim 29 , wherein R 2A is methyl or ethyl.

35 . The compound of claim 34 , wherein R 2B is hydrogen.

36 . (canceled)

37 . (canceled)

38 . (canceled)

39 . The compound of claim 35 , wherein at least one R 3 is fluoro.

40 . (canceled)

41 . The compound of claim 21 , wherein R 5A is optionally substituted with OR 5 B.

42 . (canceled)

43 . The compound of claim 1 , which compound is:

N-((4-(2-aminoethyl)phenyl)sulfonyl)-2,3-difluoro-4-((3-phenoxybenzyl)oxy)benzamide;

N-((2-aminoethyl)sulfonyl)-2,3-dichloro-4-(1-(3-phenoxyphenyl)ethoxy)benzamide;

rac-(R)-2,3-dichloro-N-((4-methylpiperazin-1-yl)sulfonyl)-4-(1-(3-phenoxyphenyl)ethoxy)benzamide;

rac-(R)—N-((4-(aminomethyl)phenyl)sulfonyl)-2,3-dichloro-4-(1-(3-phenoxyphenyl)ethoxy)benzamide;

rac-(R)—N-((2-aminoethyl)sulfonyl)-2,3-dichloro-4-(1-(3-phenoxyphenyl)ethoxy)benzamide;

N-((4-((dimethylamino)methyl)phenyl)sulfonyl)-2,3-difluoro-4-((3-phenoxybenzyl)oxy)benzamide;

2,3-difluoro-N-((4-((methylamino)methyl)phenyl)sulfonyl)-4-((3-phenoxybenzyl)oxy)benzamide;

N-((4-(aminomethyl)phenyl)sulfonyl)-2,3-difluoro-4-((4-phenoxybenzyl)oxy)benzamide;

N-((4-(aminomethyl)phenyl)sulfonyl)-4-(1-(3-(cyclopentyloxy)phenyl)ethoxy)-2,3-difluorobenzamide;

N-((4-(aminomethyl)phenyl)sulfonyl)-2,3-dichloro-4-((3-phenoxybenzyl)oxy)benzamide;

rac-(R)—N-((4-(aminomethyl)phenyl)sulfonyl)-3-methyl-4-(1-(3-phenoxyphenyl)ethoxy)benzamide;

N-((4-(aminomethyl)phenyl)sulfonyl)-2,3-difluoro-4-(1-(3-phenoxyphenyl)ethoxy)benzamide;

N-((4-(aminomethyl)phenyl)sulfonyl)-4-(1-(3-(thiophen-3-yloxy)phenyl)ethoxy)-3-(trifluoromethyl)benzamide;

N-((4-(aminomethyl)phenyl)sulfonyl)-4-(1-(3-(pyridin-3-yloxy)phenyl)ethoxy)-3-(trifluoromethyl)benzamide;

N-((4-(aminomethyl)phenyl)sulfonyl)-4-(2-(3-phenoxyphenyl)propoxy)-3-(trifluoromethyl)benzamide;

N-((4-(aminomethyl)phenyl)sulfonyl)-2,3-dichloro-4-(2-(3-phenoxyphenyl)propoxy)benzamide;

N-((4-(aminomethyl)phenyl)sulfonyl)-2,3-difluoro-4-(1-(3-(pyridin-3-yloxy)phenyl)ethoxy)benzamide;

N-((4-(aminomethyl)phenyl)sulfonyl)-4-(1-(3-(cyclopentyloxy)phenyl)ethoxy)-3-(trifluoromethyl)benzamide;

N-((4-(aminomethyl)phenyl)sulfonyl)-4-(1-(3-(pyrimidin-5-yloxy)phenyl)ethoxy)-3-(trifluoromethyl)benzamide;

N-((4-(aminomethyl)phenyl)sulfonyl)-4-(1-(3-(pyridin-2-yloxy)phenyl)ethoxy)-3-(trifluoromethyl)benzamide;

N-((4-(aminomethyl)phenyl)sulfonyl)-4-(1-(3-(pyrazin-2-yloxy)phenyl)ethoxy)-3-(trifluoromethyl)benzamide;

N-((4-(aminomethyl)phenyl)sulfonyl)-4-(1-(3-((1-methyl-1H-pyrazol-4-yl)oxy)phenyl)ethoxy)-3-(trifluoromethyl)benzamide;

N-((4-(aminomethyl)phenyl)sulfonyl)-4-(1-(3-((2-methylpentyl)oxy)phenyl)ethoxy)-3-(trifluoromethyl)benzamide;

N-((4-(aminomethyl)phenyl)sulfonyl)-4-(1-(3-(pentyloxy)phenyl)ethoxy)-3-(trifluoromethyl)benzamide;

N-((4-(aminomethyl)phenyl)sulfonyl)-4-(1-(3-(cyclopentylmethoxy)phenyl)ethoxy)-3-(trifluoromethyl)benzamide;

N-((4-(aminomethyl)phenyl)sulfonyl)-4-(cyclopentylmethoxy)-3-(trifluoromethyl)benzamide;

rac-(R)—N-((2-aminoethyl)sulfonyl)-4-(1-(3-phenoxyphenyl)ethoxy)-3-(trifluoromethyl)benzamide;

N-((3-morpholinopropyl)sulfonyl)-4-(1-(5-(pyridazin-3-yloxy)pyridin-2-yl)ethoxy)-3-(trifluoromethyl)benzamide;

4-(1-(5-ethoxypyridin-2-yl)propoxy)-N-((3-morpholinopropyl)sulfonyl)-3-(trifluoromethyl)benzamide;

4-(1-(5-ethoxypyridin-2-yl)propoxy)-N-((4-(2-(methylamino)ethoxy)phenyl)sulfonyl)-3-(trifluoromethyl)benzamide;

4-(1-(5-ethoxypyridin-2-yl)ethoxy)-2,3-difluoro-N-((4-methylpiperazin-1-yl)sulfonyl)benzamide;

4-(1-(5-ethoxypyridin-2-yl)ethoxy)-2,3-difluoro-N-(piperidin-4-ylsulfonyl)benzamide;

4-(1-(3-(cyclopropylmethoxy)phenyl)ethoxy)-N-((1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)sulfonyl)-2,3-difluorobenzamide;

N-((4-(2-(1H-imidazol-1-yl)ethoxy)phenyl)sulfonyl)-4-(1-(5-ethoxypyridin-2-yl)ethoxy)-2,3-difluorobenzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((4-(2-morpholinoethoxy)phenyl)sulfonyl)benzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-N-((4-(2-(dimethylamino)ethoxy)phenyl)sulfonyl)-2,3-difluorobenzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)sulfonyl)benzamide;

(R)—N-((4-(2-(1H-imidazol-1-yl)ethoxy)phenyl)sulfonyl)-2,3-difluoro-4-(1-(5-(2-methoxyethoxy)pyridin-2-yl)propoxy)benzamide;

(R)—N-((4-(2-(dimethylamino)ethoxy)phenyl)sulfonyl)-2,3-difluoro-4-(1-(5-(2-methoxyethoxy)pyridin-2-yl)propoxy)benzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)sulfonyl)benzamide;

4-((R)-1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((4-(2-((S)-3-fluoropyrrolidin-1-yl)ethoxy)phenyl)sulfonyl)benzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((4-(2-(oxetan-3-ylamino)ethoxy)phenyl)sulfonyl)benzamide;

(R)—N-((4-((1H-imidazol-4-yl)methoxy)phenyl)sulfonyl)-2,3-difluoro-4-(1-(5-(2-methoxyethoxy)pyridin-2-yl)propoxy)benzamide;

(R)—N-((4-(2-(cyclopropylamino)ethoxy)phenyl)sulfonyl)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluorobenzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((4-((1-methylpiperidin-4-yl)oxy)piperidin-1-yl)sulfonyl)benzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-N-((6-(2-(dimethylamino)ethoxy)-2-azaspiro[3,3]heptan-2-yl)sulfonyl)-2,3-difluorobenzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((6-(2-(pyrrolidin-1-yl)ethoxy)-2-azaspiro[3,3]heptan-2-yl)sulfonyl)benzamide;

4-((R)-1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((4-(((S)-1-methylpyrrolidin-3-yl)oxy)phenyl)sulfonyl)benzamide;

4-((R)-1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((4-(((R)-1-methylpyrrolidin-3-yl)oxy)phenyl)sulfonyl)benzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-N-((4-((1-ethylpiperidin-4-yl)oxy)phenyl)sulfonyl)-2,3-difluorobenzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((4-((1-methylazetidin-3-yl)oxy)phenyl)sulfonyl)benzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((6-((1-methylpiperidin-4-yl)oxy)pyridazin-3-yl)sulfonyl)benzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((6-((1-methylpiperidin-4-yl)oxy)pyridin-3-yl)sulfonyl)benzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((4-((1-(methyl-d 3 )piperidin-4-yl)oxy)phenyl)sulfonyl)benzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-N-((4-((1-(cyclopropylmethyl)piperidin-4-yl)oxy)phenyl)sulfonyl)-2,3-difluorobenzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((4-((1-(2-hydroxyethyl)piperidin-4-yl)oxy)phenyl)sulfonyl)benzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((4-((1-isopropylpiperidin-4-yl)oxy)phenyl)sulfonyl)benzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((6-((1-methylpiperidin-4-yl)amino)pyridin-3-yl)sulfonyl)benzamide;

4-((R)-1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((4-((12,2-trimethylpiperidin-4-yl)oxy)phenyl)sulfonyl)benzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((4-(piperidin-4-yloxy)phenyl)sulfonyl)benzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((4-(2-(pyrrolidin-1-yl)ethoxy)piperidin-1-yl)sulfonyl)benzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((2-((1-methylpiperidin-4-yl)oxy)pyrimidin-5-yl)sulfonyl)benzamide;

4-((R)-1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((4-(((1R 4 R 5 R)-2-methyl-2-azabicyclo[2.2.1]heptan-5-yl)oxy)phenyl)sulfonyl)benzamide;

4-((R)-1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((5-(2-(pyrrolidin-1-yl)ethoxy)-2-azabicyclo[2.2.1]heptan-2-yl)sulfonyl)benzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-N-((4-((1-(2,2-difluoroethyl)piperidin-4-yl)oxy)phenyl)sulfonyl)-2,3-difluorobenzamide;

N-((4-(((1R 4 R 5 R)-2-azabicyclo[2.2.1]heptan-5-yl)oxy)phenyl)sulfonyl)-4-((R)-1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluorobenzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((6-(2-(pyrrolidin-1-yl)ethoxy)pyridazin-3-yl)sulfonyl)benzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((6-((2-(pyrrolidin-1-yl)ethyl)amino)pyridin-3-yl)sulfonyl)benzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((4-((1-methylpiperidin-4-yl)oxy)phenyl)sulfonyl)benzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((5-((1-methylpiperidin-4-yl)oxy)pyridin-2-yl)sulfonyl)benzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((5-((1-methylpiperidin-4-yl)amino)pyridin-2-yl)sulfonyl)benzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((6-((1-isopropylpiperidin-4-yl)amino)pyridin-3-yl)sulfonyl)benzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((6-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl)sulfonyl)benzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((6-((1-methylpiperidin-4-yl)oxy)-2-azaspiro[3,3]heptan-2-yl)sulfonyl)benzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((6-((1-isopropylpiperidin-4-yl)oxy)pyridin-3-yl)sulfonyl)benzamide;

(R)—N-((4-((1-azabicyclo[2.2.1]heptan-4-yl)oxy)phenyl)sulfonyl)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluorobenzamide;

4-((R)-1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((4-(2-((R)-1-methylpiperidin-2-yl)ethoxy)phenyl)sulfonyl)benzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((4-(2-(piperidin-1-yl)ethoxy)phenyl)sulfonyl)benzamide;

(R)-2,3-difluoro-N-((4-((1-methylpiperidin-4-yl)oxy)piperidin-1-yl)sulfonyl)-4-(1-(5-(pyridin-2-yloxy)pyridin-2-yl)propoxy)benzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-N-((6-((4-ethylpiperazin-1-yl)methyl)pyridin-3-yl)sulfonyl)-2,3-difluorobenzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((4-((1-(2-methoxyethyl)piperidin-4-yl)oxy)phenyl)sulfonyl)benzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((4-((1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)oxy)phenyl)sulfonyl)benzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((4-((1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)oxy)piperidin-1-yl)sulfonyl)benzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((4-((1-(2-methoxyethyl)piperidin-4-yl)oxy)piperidin-1-yl)sulfonyl)benzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-N-((4-((1-(cyclopropylmethyl)piperidin-4-yl)oxy)piperidin-1-yl)sulfonyl)-2,3-difluorobenzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-N-((4-((4-ethylpiperazin-1-yl)methyl)piperidin-1-yl)sulfonyl)-2,3-difluorobenzamide;

(R)-2,3-difluoro-4-(1-(5-(2-methoxyethoxy)pyridin-2-yl)propoxy)-N-((4-((1-methylpiperidin-4-yl)oxy)phenyl)sulfonyl)benzamide;

(R)—N-((4-(2-(dimethylamino)ethoxy)piperidin-1-yl)sulfonyl)-2,3-difluoro-4-(1-(5-(2-methoxyethoxy)pyridin-2-yl)propoxy)benzamide;

(R)-2,3-difluoro-4-(1-(5-(2-methoxyethoxy)pyridin-2-yl)propoxy)-N-((4-((1-methylpiperidin-4-yl)oxy)piperidin-1-yl)sulfonyl)benzamide;

(R)—N-((4-(2-(dimethylamino)ethoxy)piperidin-1-yl)sulfonyl)-2,3-difluoro-4-(1-(5-(pyridin-2-yloxy)pyridin-2-yl)propoxy)benzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-N-((4-(2-(dimethylamino)ethoxy)piperidin-1-yl)sulfonyl)-2,3-difluorobenzamide;

(R)-2,3-difluoro-N-((4-methylpiperazin-1-yl)sulfonyl)-4-(1-(5-(pyridin-2-yloxy)pyridin-2-yl)propoxy)benzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((1-methylpiperidin-4-yl)sulfonyl)benzamide;

(R)-2,3-difluoro-4-(1-(5-(pyridin-2-yloxy)pyridin-2-yl)propoxy)-N-((2,2,4-trimethylpiperazin-1-yl)sulfonyl)benzamide;

(R)-2,3-difluoro-N-((1-methylpiperidin-4-yl)sulfonyl)-4-(1-(5-(pyridin-2-yloxy)pyridin-2-yl)propoxy)benzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((2,2,4-trimethylpiperazin-1-yl)sulfonyl)benzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-N-((1-(dimethylamino)-2-methylpropan-2-yl)sulfonyl)-2,3-difluorobenzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((4-methylpiperazin-1-yl)sulfonyl)benzamide;

(R)—N-((1-(dimethylamino)-2-methylpropan-2-yl)sulfonyl)-2,3-difluoro-4-(1-(5-(pyridin-2-yloxy)pyridin-2-yl)propoxy)benzamide;

(R)—N-((4-((1-methylpiperidin-4-yl)oxy)piperidin-1-yl)sulfonyl)-4-(1-(5-(pyridin-2-yloxy)pyridin-2-yl)propoxy)-3-(trifluoromethyl)benzamide;

(R)—N-((4-(2-(dimethylamino)ethoxy)phenyl)sulfonyl)-4-(1-(5-(pyridin-2-yloxy)pyridin-2-yl)propoxy)-3-(trifluoromethyl)benzamide;

(R)—N-((4-(2-(dimethylamino)ethoxy)phenyl)sulfonyl)-2,3-difluoro-4-(1-(5-(pyridin-2-yloxy)pyridin-2-yl)propoxy)benzamide;

(R)—N-((4-((1-methylpiperidin-4-yl)oxy)piperidin-1-yl)sulfonyl)-4-(1-(5-(pyridin-2-yloxy)pyridin-2-yl)ethoxy)-3-(trifluoromethyl)benzamide;

(R)—N-((4-(2-(dimethylamino)ethoxy)phenyl)sulfonyl)-4-(1-(5-(pyridin-2-yloxy)pyridin-2-yl)ethoxy)-3-(trifluoromethyl)benzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((4-isopropylpiperazin-1-yl)sulfonyl)benzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-N-((4-cyclopropylpiperazin-1-yl)sulfonyl)-2,3-difluorobenzamide;

4-((R)-1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((4-((1-methylpiperidin-3-yl)oxy)phenyl)sulfonyl)benzamide;

2,3-difluoro-N-((4-((1-methylpiperidin-3-yl)oxy)phenyl)sulfonyl)-4-((R)-1-(5-(pyridin-2-yloxy)pyridin-2-yl)propoxy)benzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((4-methyl-1,4-diazepan-1-yl)sulfonyl)benzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((3,3,4-trimethylpiperazin-1-yl)sulfonyl)benzamide;

4-((R)-1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-(((3S,5R)-3,4,5-trimethylpiperazin-1-yl)sulfonyl)benzamide;

(R)—N-((4-(2-(dimethylamino)ethoxy)phenyl)sulfonyl)-2,3-difluoro-4-(1-(5-(pyridin-2-yloxy)pyridin-2-yl)ethoxy)benzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((4-(2-methoxyethyl)piperazin-1-yl)sulfonyl)benzamide;

4-((R)-1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((6-methyl-3,6-diazabicyclo[3,1,1]heptan-3-yl)sulfonyl)benzamide;

4-((R)-1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-N—(((S)-3,4-dimethylpiperazin-1-yl)sulfonyl)-2,3-difluorobenzamide;

4-((R)-1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-N—(((R)-3,4-dimethylpiperazin-1-yl)sulfonyl)-2,3-difluorobenzamide;

(R)-2,3-difluoro-N-((4-((1-(2-methoxyethyl)piperidin-4-yl)oxy)piperidin-1-yl)sulfonyl)-4-(1-(5-(pyridin-2-yloxl)pyridin-2-yl)propoxy)benzamide;

4-((R)-1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((8-methyl-3,8-diazabicyclo[3,2,1]octan-3-yl)sulfonyl)benzamide;

N-((4-(2-(dimethylamino)ethoxy)phenyl)sulfonyl)-2,3-difluoro-4-((R)-1-(5-((1R,3R)-3-methoxycyclobutoxy)pyridin-2-yl)propoxy)benzamide;

2,3-difluoro-4-((R)-1-(5-((1R 3 R)-3-methoxycyclobutoxy)pyridin-2-yl)propoxy)-N-((4-((1-methylpiperidin-4-yl)oxy)piperidin-1-yl)sulfonyl)benzamide;

4-((R)-1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-(((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)sulfonyl)benzamide;

4-((R)-1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-(((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)sulfonyl)benzamide;

(R)—N-((4-ethylpiperazin-1-yl)sulfonyl)-2,3-difluoro-4-(1-(5-(pyridin-2-yloxy)pyridin-2-yl)propoxy)benzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-N-((4-ethylpiperazin-1-yl)sulfonyl)-2,3-difluorobenzamide;

(R)—N-((4-methylpiperazin-1-yl)sulfonyl)-4-(1-(5-(pyridin-2-yloxy)pyridin-2-yl)propoxy)-3-(trifluoromethyl)benzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-N-((4-((1-methylpiperidin-4-yl)oxy)piperidin-1-yl)sulfonyl)-3-(trifluoromethyl)benzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-N-((4-methylpiperazin-1-yl)sulfonyl)-3-(trifluoromethyl)benzamide;

(R)—N-((4-cyclopropylpiperazin-1-yl)sulfonyl)-2,3-difluoro-4-(1-(5-(pyridin-2-yloxy)pyridin-2-yl)propoxy)benzamide;

(R)—N-((4-cyclohexylpiperazin-1-yl)sulfonyl)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluorobenzamide;

(R)—N-((4-cyclohexylpiperazin-1-yl)sulfonyl)-2,3-difluoro-4-(1-(5-(pyridin-2-yloxy)pyridin-2-yl)propoxy)benzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-N-((4-(2-(dimethylamino)ethoxy)phenyl)sulfonyl)-3-(trifluoromethyl)benzamide;

(R)-4-(1-(4-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((4-((1-methylpiperidin-4-yl)oxy)piperidin-1-yl)sulfonyl)benzamide;

(R)-4-(1-(4-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-N-((4-(2-(dimethylamino)ethoxy)phenyl)sulfonyl)-2,3-difluorobenzamide;

(R)-4-(1-(4-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((4-((1-methylpiperidin-4-yl)oxy)phenyl)sulfonyl)benzamide;

(R)-2,3-difluoro-N-((4-((1-methylpiperidin-4-yl)oxy)piperidin-1-yl)sulfonyl)-4-(1-(4-(pyridin-2-yloxy)pyridin-2-yl)propoxy)benzamide;

(R)-2,3-difluoro-N-((4-methylpiperazin-1-yl)sulfonyl)-4-(1-(4-(pyridin-2-yloxy)pyridin-2-yl)propoxy)benzamide;

(R)—N-((4-cyclopropylpiperazin-1-yl)sulfonyl)-2,3-difluoro-4-(1-(4-(pyridin-2-yloxy)pyridin-2-yl)propoxy)benzamide;

(R)—N-((4-(2-(dimethylamino)ethoxy)phenyl)sulfonyl)-2,3-difluoro-4-(1-(4-(pyridin-2-yloxy)pyridin-2-yl)propoxy)benzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-N-((4-(cyclopropylmethyl)piperazin-1-yl)sulfonyl)-2,3-difluorobenzamide;

(R)—N-((4-(cyclopropylmethyl)piperazin-1-yl)sulfonyl)-2,3-difluoro-4-(1-(5-(pyridin-2-yloxy)pyridin-2-yl)propoxy)benzamide;

(R)—N-((4-cyclopentylpiperazin-1-yl)sulfonyl)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluorobenzamide;

(R)—N-((4-cyclopentylpiperazin-1-yl)sulfonyl)-2,3-difluoro-4-(1-(5-(pyridin-2-yloxy)pyridin-2-yl)propoxy)benzamide;

N-((4-(2-(dimethylamino)ethoxy)phenyl)sulfonyl)-4-((R)-1-(5-((1R3R)-3-methoxycyclobutoxy)pyridin-2-yl)propoxy)-3-(trifluoromethyl)benzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-N-((4-ethylpiperazin-1-yl)sulfonyl)-3-(trifluoromethyl)benzamide;

4-((R)-1-(5-((1R,3R)-3-methoxyvclobutoxy)pyridin-2-yl)propoxy)-N-((4-((1-methylpiperidin-4-yl)oxy)piperidin-1-yl)sulfonyl)-3-(trifluoromethyl)benzamide;

4-((R)-1-(5-((1R,3R)-3-(difluoromethoxy)cyclobutoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((4-methylpiperazin-1-yl)sulfonyl)benzamide;

(R)—N-((4-ethylpiperazin-1-yl)sulfonyl)-4-(1-(5-(pyridin-2-yloxy)pyridin-2-yl)propoxy)-3-(trifluoromethyl)benzamide;

4-((R)-1-(5-((1R,3R)-3-methoxyevclobutoxy)pyridin-2-yl)propoxy)-N-((4-methylpiperazin-1-yl)sulfonyl)-3-(trifluoromethyl)benzamide;

N-((4-cyclopropylpiperazin-1-yl)sulfonyl)-2,3-difluoro-4-((R)-1-(5-((1R,3R)-3-methoxycyclobutoxy)pyridin-2-yl)propoxy)benzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)sulfonyl)benzamide;

N—(((S)-3,4-dimethylpiperazin-1-yl)sulfonyl)-2,3-difluoro-4-((R)-1-(5-(pyridin-2-yloxy)pyridin-2-yl)propoxy)benzamide;

(R)-4-(1-(3-(cyclopropylmethoxy)phenyl)propoxy)-2,3-difluoro-N-((4-((1-methylpiperidin-4-yl)oxy)piperidin-1-yl)sulfonyl)benzamide;

2,3-difluoro-4-((R)-1-(5-((1R3R)-3-methoxycyclobutoxy)pyridin-2-yl)propoxy)-N-((4-methylpiperazin-1-yl)sulfonyl)benzamide;

(R)-2,3-difluoro-N-((4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)sulfonyl)-4-(1-(5-(pyridin-2-yloxy)pyridin-2-yl)propoxy)benzamide;

(R)-2,3-difluoro-N-((4-(2-fluoro-2-methylpropyl)piperazin-1-yl)sulfonyl)-4-(1-(5-(pyridin-2-yloxy)pyridin-2-yl)propoxy)benzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((4-(2-fluoro-2-methylpropyl)piperazin-1-yl)sulfonyl)benzamide;

(R)-4-(1-(4-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((4-methylpiperazin-1-yl)sulfonyl)benzamide;

(R)—N-((4-cyclobutylpiperazin-1-yl)sulfonyl)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluorobenzamide;

(R)—N-((4-cyclobutylpiperazin-1-yl)sulfonyl)-2,3-difluoro-4-(1-(5-(pyridin-2-yloxy)pyridin-2-yl)propoxy)benzamide;

N-((4-ethylpiperazin-1-yl)sulfonyl)-4-((R)-1-(5-((1R3R)-3-methoxycyclobutoxy)pyridin-2-yl)propoxy)-3-(trifluoromethyl)benzamide;

2,3-difluoro-4-((R)-1-(4-((1R3R)-3-methoxycyclobutoxy)pyridin-2-yl)propoxy)-N-((4-methylpiperazin-1-yl)sulfonyl)benzamide;

2,3-difluoro-4-((R)-1-(4-((1R3R)-3-methoxycyclobutoxy)pyridin-2-yl)propoxy)-N-((4-((1-methylpiperidin-4-yl)oxy)piperidin-1-yl)sulfonyl)benzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((4-((1-methylazetidin-3-yl)oxy)piperidin-1-yl)sulfonyl)benzamide;

(R)-2,3-difluoro-N-((4-((1-methylazetidin-3-yl)oxy)piperidin-1-yl)sulfonyl)-4-(1-(5-(pyridin-2-yloxy)pyridin-2-yl)propoxy)benzamide;

(R)-2,3-difluoro-N-((6-methyl-2,6-diazaspiro[3,3]heptan-2-yl)sulfonyl)-4-(1-(5-(pyridin-2-yloxy)pyridin-2-yl)propoxy)benzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((6-methyl-2,6-diazaspiro[3,3]heptan-2-yl)sulfonyl)benzamide;

23-difluoro-N-((8-methyl-3,8-diazabicyclo[3,2,1]octan-3-yl)sulfonyl)-4-((R)-1-(5-(pyridin-2-yloxy)pyridin-2-yl)propoxy)benzamide;

2,3-difluoro-N-((4-(((S)-1-methylpiperidin-3-yl)oxy)phenyl)sulfonyl)-4-((R)-1-(5-(pyridin-2-yloxy)pyridin-2-yl)propoxy)benzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((3-((1-methylpiperidin-4-yl)oxy)azetidin-1-yl)sulfonyl)benzamide;

(R)-2,3-difluoro-N-((3-((1-methylpiperidin-4-yl)oxy)azetidin-1-yl)sulfonyl)-4-(1-(5-(pyridin-2-yloxy)pyridin-2-yl)propoxy)benzamide;

N-((4-ethylpiperazin-1-yl)sulfonyl)-2,3-difluoro-4-((R)-1-(5-((1R3R)-3-methoxycyclobutoxy)pyridin-2-yl)propoxy)benzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((5-methyl-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)sulfonyl)benzamide;

2,3-difluoro-N-((4-(((R)-1-methylpiperidin-3-yl)oxy)phenyl)sulfonyl)-4-((R)-1-(5-(pyridin-2-yloxy)pyridin-2-yl)propoxy)benzamide;

(R)-2,3-difluoro-N-((5-methyl-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)sulfonyl)-4-(1-(5-(pyridin-2-yloxy)pyridin-2-yl)propoxy)benzamide;

(R)-2,3-difluoro-N-((4-(3-fluoropropyl)piperazin-1-yl)sulfonyl)-4-(1-(5-(pyridin-2-yloxy)pyridin-2-yl)propoxy)benzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((4-(3-fluoropropyl)piperazin-1-yl)sulfonyl)benzamide;

(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((4-(2-(methylamino)ethoxy)phenyl)sulfonyl)benzamide;

4-((R)-1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((4-(((S)-1-methylpiperidin-3-yl)oxy)phenyl)sulfonyl)benzamide;

4-((R)-1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-((4-(((R)-1-methylpiperidin-3-yl)oxy)phenyl)sulfonyl)benzamide; or

2,3-difluoro-N-((6-methyl-3,6-diazabicyclo[3,1,1]heptan-3-yl)sulfonyl)-4-((R)-1-(5-(pyridin-2-yloxy)pyridin-2-yl)propoxy)benzamide;

or a pharmaceutically acceptable salt thereof.

44 . A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

45 . A method of preparing a compound of formula 1h:

which comprises contacting a compound of formula if:

with a compound of formula 1g:

in mixture under conditions sufficient to provide the compound of formula 1h, wherein:

Y 3 is N or CR 3 ;

each R 1 is independently optionally substituted C 1-s hydrocarbyl or 2-9 membered heterocarbyl, which optional substitution is with one or more of halo, RA, or OR 1A ;

each R 1A is independently optionally substituted C 1-6 hydrocarbyl, which optional substitution is with one or more of halo;

R 2A is C 1-6 alkyl optionally substituted with one or more halo;

each R 3 is independently hydrogen, halo, or C 1-6 alkyl optionally substituted with one or more halo;

R 5 is N(R 5A ) 2 , NHR 5A , or optionally substituted C 1-6 hydrocarbyl or 2-9 membered heterocarbyl, which optional substitution is with one or more of halo, hydroxyl, RA, OR 5A , N(RA) 2 , NHR 5A , or NH 2 ;

each R 5A is independently optionally substituted C 1-6 hydrocarbyl or 2-9 membered heterocarbyl, which optional substitution is with one or more halo, hydroxyl, or R 5B , OR 5B , N(R 5B ) 2 , NHR 5B , or NH 2 ;

each R 5B is independently optionally substituted C 1-8 hydrocarbyl or 2-9 membered heterocarbyl, which optional substitution is with one or more of halo, hydroxyl, or R 5C , OR 5C , N(R 5C ) 2 , NHR 5C , or NH 2 ; and

each R 5C is independently optionally substituted C 1-8 hydrocarbyl or 2-9 membered heterocarbyl, which optional substitution is with one or more of halo, hydroxyl, or NH 2 .

46 . (canceled)

47 . (canceled)

48 . (canceled)

49 . (canceled)

50 . A method of inhibiting acyl-CoA synthetase 5 (ACSL5), which comprises contacting ACSL5 with a compound of claim 1 .

51 . A method of treating or managing a metabolic disease or disorder, which comprises administering to a patient in need thereof a therapeutically or prophylactically effective amount of a compound of claim 1 .

52 . (canceled)

53 . (canceled)

54 . (canceled)

55 . (canceled)

Assignments (8)