Inhibiting fatty acid synthase (FASN)

1. A compound of Formula (I)

or a pharmaceutically acceptable salt thereof, wherein:

Ring A is 6-10 membered aryl or 6-10 membered heteroaryl containing 1-2 N atoms;

R 1 is C 1-3 aliphatic, 3-4 membered cycloalkyl, 5-membered heterocyclyl containing 1 O atom, or 5-membered heteroaryl containing 1-3 heteroatoms independently selected from the group consisting of O and N,

wherein R 1 is optionally substituted with —OH or —NH 2 ;

R 2 is —CO 2 R 3 , —SO 2 NHCOR 3 , or an optionally substituted group selected from the group consisting of 3-4 membered cycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl containing 1-2 heteroatoms independently selected from the group consisting of O, N, and S, wherein an optionally substituted group of R 2 is optionally substituted with 1-6 R d ;

each R a is independently halogen;

each R b is independently C 1-3 aliphatic;

R c is hydrogen or halogen;

R c′ is hydrogen or halogen;

R c″ is hydrogen, halogen, —CO 2 H, or tetrazole;

each R d is independently halogen, —CO 2 R 3 , —OR 3 , —S(O) 2 NH 2 , —SO 2 NHCOR 3 , —P(O)R 4 OR 3 , —CH 2 CO 2 R 3 , or an optionally substituted group selected from the group consisting of C 1-3 aliphatic, 4-membered cycloalkyl, and 5-membered heteroaryl containing 1-4 N atoms;

wherein an optionally substituted group of R d is optionally substituted with halogen, oxo, OH, or C 1-3 aliphatic;

each R 3 is independently hydrogen or C 1-3 alkyl optionally substituted with fluoro;

R 4 is C 1-6 aliphatic;

m is 0-4; and

n is 0-6.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is:

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is:

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is:

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is:

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is:

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is:

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof,

wherein the compound is:

9. The compound of claim 1 , wherein the compound is selected from the group consisting of 4-{4-[(1S)-6-(1-hydroxycyclopropanecarbonyl)-6-azaspiro[2.5]octan-1-yl]phenyl}-3-methylbenzoic acid; (S)-4′-(6-(1-hydroxycyclopropane-1-carbonyl)-6-azaspiro[2.5]octan-1-yl)-6-methyl-[1,1′-biphenyl]-3-carboxylic acid; ((S)-1-(4′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)-6-azaspiro[2.5]octan-6-yl)((R)-tetrahydrofuran-2-yl)methanone; 6-methoxy-4′-((S)-6-((R)-tetrahydrofuran-2-carbonyl)-6-azaspiro[2.5]octan-1-yl)-[1,1′-biphenyl]-3-carboxylic acid; 5-chloro-6-methoxy-4′-((S)-6-((R)-tetrahydrofuran-2-carbonyl)-6-azaspiro[2.5]octan-1-yl)-[1,1′-biphenyl]-3-carboxylic acid; ((S)-1-(2′-methoxy-4′-(2H-tetrazol-5-yl)-1′,2′,3′,4′,5′,6′-hexahydro-[1,1′-biphenyl]-4-yl)-6-azaspiro[2.5]octan-6-yl)((R)-tetrahydrofuran-2-yl)methanone; and 4-[4-[(1S)-6-(1-hydroxycyclopropanecarbonyl)-6-azaspiro[2.5]octan-1-yl]phenyl]quinoline-2-carboxylic acid; or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is:

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is:

12. The compound of claim 1 , wherein R 2 is an optionally substituted group selected from the group consisting of 3-4 membered cycloalkyl, phenyl, and 5-10 membered heteroaryl containing 1-2 heteroatoms independently selected from the group consisting of O, N, and S; and wherein an optionally substituted group of R 2 is optionally substituted with 1-6 R d .

13. The compound of claim 12 , wherein each R d is independently halogen, —CO 2 R 3 , —OR 3 , —S(O) 2 NH 2 , —SO 2 NHCOR 3 , —P(O)R 4 OR 3 , or an optionally substituted group selected from the group consisting of C 1-3 aliphatic, or 5-membered heteroaryl containing 1-4 N atoms; wherein an optionally substituted group of R d is optionally substituted with halogen or C 1-3 aliphatic.

14. A compound of Formula (II)

or a pharmaceutically acceptable salt thereof, wherein:

Ring A is 6-10 membered aryl or 5-10 membered heteroaryl containing 1-2 heteroatoms independently selected from the group consisting of O, N, and S;

R 1 is C 1-6 aliphatic, 3-6 membered cycloalkyl, 4-6-membered heterocyclyl containing 1-3 heteroatoms independently selected from the group consisting of O, N, and S, or 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from the group consisting of O, N, and S; wherein R 1 is optionally substituted with halogen, oxo, —CN, —NO 2 , —OR 3 , —SR 3 , —CO 2 R 3 , —N(R 4 )(R 4′ ),—C(O)N(R 4 )(R 4′ ),—S(O) 2 N(R 4 )(R 4′ ), tetrazolyl, or C 1-3 alkyl optionally substituted with halogen or —CO 2 R 3 ;

R 2 is —CN, —NO 2 , —OR 3 , —SR 3 , —CO 2 R 3 , —N(R 4 )(R 4′ ),—C(O)N(R 4 )(R 4′ ), —S(O) 2 N(R 4 )(R 4′ ), or an optionally substituted group selected from the group consisting of 3-7 membered cycloalkyl, 6-10 membered aryl and 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S; wherein an optionally substituted group of R 2 is optionally substituted with 1-6 R d ;

each R a is independently halogen, —CN, —NO 2 , —OR 3 , —CO 2 R 3 , —N(R 4 )(R 4′ ), —SR 3 , —C(O)N(R 4 )(R 4′ ), —S(O) 2 N(R 4 )(R 4′ ), tetrazolyl, or C 1-3 aliphatic optionally substituted with halogen;

each R b is independently C 1-6 aliphatic optionally substituted with halogen;

R c is hydrogen or halogen;

R c′ is hydrogen or halogen;

each R d is independently halogen, oxo, —CN, —NO 2 , —OR 3 , —SR 3 , —CO 2 R 3 , —N(R 4 )(R 4′ )N(R 4 )(R 4′ ), —C(O)N(R 4 )(R 4′ ), —S(O) 2 N(R 4 )(R 4′ ), —COR 5 , —N(R 4 )COR 5 , —N(R 4 )SOR 5 , —N(R 4 )SO 2 R 5 , —SOR 5 , —SO 2R 5 , —N(R 4 )CO 2 R 3 , —N(R 4 )C(O)N(R 4 )(R 4′ ), or an optionally substituted group selected from the group consisting of C 1-6 aliphatic and 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S; wherein an optionally substituted group of R d is optionally substituted with halogen, —OH, —NH 2 , —CN, oxo, or C 1-3 alkyl;

each R 3 is independently hydrogen or C 1-6 aliphatic optionally substituted with halogen, —OH, —NH 2 , —CN, or oxo;

each R 4 is independently hydrogen, —OH, —CN, or C 1-6 aliphatic optionally substituted with halogen, —OH, —NH 2 , —CN, or oxo;

each R 4′ is independently hydrogen, or C 1-6 aliphatic optionally substituted with halogen, —OH, —NH 2 , —CN, or oxo;

each R 5 is independently hydrogen or C 1-6 aliphatic optionally substituted with halogen, —OH, —NH 2 , —CN, or oxo;

m is 0-4; and

n is 0-6.

15. A compound of claim 14 , wherein the compound is a compound of Formula (III):

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is C 1-3 aliphatic, 3-4 membered cycloalkyl, 5-membered heterocyclyl containing 1-3 heteroatoms independently selected from the group consisting of O, N, and S, or 5-membered heteroaryl containing 1-3 heteroatoms independently selected from the group consisting of O, N, and S;

wherein R 1 is optionally substituted with —OH or NH 2 ;

R 2 is —CO 2 H or an optionally substituted group selected from the group consisting of phenyl and 5-10 membered heteroaryl containing 1-2 heteroatoms independently selected from the group consisting of O, N, and S,

wherein an optionally substituted group of R 2 is optionally substituted with 1-6 R d ;

each R a is independently halogen;

each R d is independently halogen, —OR 3 , —CO 2 R 3 , —S(O) 2 NH 2 , or an optionally substituted group selected from the group consisting of C 1-3 aliphatic, and 5-7 membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S;

wherein an optionally substituted group of R d is optionally substituted with halogen or C 1-3 aliphatic;

each R 3 is independently hydrogen or C 1-3 alkyl; and

n is 0-4.

16. The compound of claim 15 , or a pharmaceutically acceptable salt thereof, wherein

R 1 is 3-4 membered cycloalkyl or 5-membered heterocyclyl containing 1-3 heteroatoms independently selected from the group consisting of O, N and S; wherein R 1 is optionally substituted with —OH or NH 2 ; and

R 2 is an optionally substituted group selected from the group consisting of phenyl and 5-10 membered heteroaryl containing 1-2 heteroatoms independently selected from the group consisting of O, N, and S, wherein an optionally substituted group of R 2 is optionally substituted with 1-6 R d .

17. The compound of claim 14 , wherein the compound is a compound of formula (IV)

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is C 1-3 aliphatic, 3-4 membered cycloalkyl, 5-membered heterocyclyl containing 1-3 heteroatoms independently selected from the group consisting of O, N, and S, or 5-membered heteroaryl containing 1-3 heteroatoms independently selected from the group consisting of O, N, and S; and wherein R 1 is optionally substituted with —OH or —NH 2 ;

each R a is independently halogen;

each R d is independently halogen, —CO 2 R 3 , —OR 3 , —S(O) 2 NH 2 , or an optionally substituted group selected from the group consisting of C 1-3 aliphatic and 5-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S,

wherein an optionally substituted group of R d is optionally substituted with halogen or C 1-3 aliphatic;

each R 3 is independently hydrogen or C 1-3 alkyl; and

n is 0-4.

18. The compound of claim 14 , wherein the compound is a compound of formula (VI-A)

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is 3-membered cycloalkyl optionally substituted with —OH, or 5-membered heterocyclyl containing 1-3 heteroatoms independently selected from the group consisting of O, N, and S;

each R d is independently halogen, —CO 2 H, —OR 3 , C 1-3 aliphatic, or 5-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S; and

each R 3 is independently hydrogen or C 1-3 alkyl.

19. The compound of claim 14 , wherein the compound is a compound of formula (V)

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is 3-membered cycloalkyl optionally substituted with —OH, or 5-membered heterocyclyl containing 1-3 heteroatoms independently selected from the group consisting of O, N, and S;

each R d is independently halogen, —CO 2 H, —OR 3 , C 1-3 aliphatic, or 5-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N and S; and

each R 3 is independently hydrogen or C 1-3 alkyl.

20. The compound of claim 14 , wherein m is 0 and n is 0.

21. The compound of claim 20 , wherein:

Ring A is 6-10 membered aryl;

R 2 is 6-10 membered aryl substituted with 1-5 R d ; and

each R 3 is independently hydrogen or C 1-6 aliphatic.

22. The compound of claim 21 , wherein

R 1 is 3-6 membered cycloalkyl substituted with —OR 3 ; and

each R d is independently —CO 2 R 3 or C 1-6 aliphatic.

23. The compound of claim 21 , wherein

Ring A is phenyl;

R 1 is 5-membered heterocyclyl containing 1-3 heteroatoms independently selected from the group consisting of O, N, and S;

R 2 is phenyl substituted with 1-5 R d ; and

each R d is independently —CO 2 R 3 , —OR 3 , or 5-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S.

24. The compound of claim 14 , wherein:

R 1 is 4-6 membered heterocyclyl containing 1-3 heteroatoms independently selected from the group consisting of O, N, and S; and

each R d is independently —CO 2 R 3 , —OR 3 , or 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S.

25. The compound of claim 14 , wherein R 1 is selected from the group consisting of methyl, ethyl,

26. The compound of claim 14 , wherein R 2 is —CO 2 R 3 or an optionally substituted group selected from the group consisting of phenyl,

wherein R 2 is optionally substituted with 1-6 R d .

27. The compound of claim 14 , wherein

R 1 is methyl, ethyl, tetrahydrofuranyl, oxazolyl, triazolyl, cyclobutyl, or cyclopropyl optionally substituted with —CH 2 CO 2 H, —OH, or —NH 2 ; and

each R d is fluoro, methyl, —CO 2 H, tetrazolyl, methoxy, chloro, —CF 3 , —OCF 3 , or N-methyl pyrazolyl.

28. The compound of claim 27 , wherein R 1 is selected from the group consisting of cyclopropyl,

29. The compound of claim 28 , wherein the compound is a compound of formula (VI-A)

or a pharmaceutically acceptable salt thereof.

30. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

Ring A is phenyl or naphthyl;

R 1 is methyl, ethyl, tetrahydrofuranyl, oxazolyl, triazolyl, cyclobutyl, or cyclopropyl optionally substituted with —CH 2 CO 2 H, —OH, or —NH 2 ;

R 2 is —CO 2 H, cyclobutyl, benzoxazolyl, indolyl, indazolyl, benzimidazolyl, quinolinyl, phenyl, naphthyl, pyridyl, or isoquinolinyl;

each R a is independently fluoro or chloro;

each R b is independently methyl;

R c is hydrogen or fluoro;

R c′ is hydrogen or fluoro;

R c″ is hydrogen or —CO 2 H;

m is 0-1; and

n is 0-3.