MACROCYCLIC INHIBITORS OF ATP CITRATE LYASE

1 . A compound of formula (I)

or a stereoisomer and/or a pharmaceutically acceptable salt thereof, wherein:

Ring A is phenyl, pyridinyl, or pyridonyl, wherein the nitrogen atom of the pyridonyl may optionally be substituted by C 1-6 alkyl;

Ring B is phenyl or 5-10 membered heterocyclyl;

Ring C is phenyl, 5-10 membered heterocyclyl, or 5-10 membered heteroaryl; or

Ring C is absent;

R 1 is independently, for each occurrence, selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —O—C(O)C 1-6 alkyl, —O—C(O)C 3-6 cycloalkyl, and N(R E ) 2 ;

R 2 is independently, for each occurrence, selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl, and COOH;

R 3 is selected from the group consisting of cyano, halogen, C 1-6 alkyl, and C 3-6 cycloalkyl;

X 1 is selected from the group consisting of *—S(O) 2 N(R A )—**, —C(O)—, *—C(O)N(R A )—**, *—CH 2 N(R A )—**, and *—S(O) 2 CH 2 —**, wherein * denotes the point of attachment to Ring A and ** denotes the point of attachment to Ring B;

X 2 is a bond or —O—;

X 3 is #-L 1 -L 2 -L 3 -##, wherein # denotes the point of attachment to Ring A and ##denotes the point of attachment to Ring C or to Ring B when Ring C is absent;

L 1 is selected from the group consisting of —CH 2 —, —O—, —C(O)—, —C(O)N(R B )—, —C(O)O—C 1-6 alkyl-O—, —CH 2 —C(O)O—, —CH 2 —N(R B )C(O)—, and 5-6 membered heteroaryl;

L 2 is C 1-6 alkyl or 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl may be optionally substituted with oxo; or

L 2 is absent;

L 3 is selected from the group consisting of a bond, —O—, —O—C 1-6 alkyl, C 1-6 alkyl-O—, and 4-6 membered heterocyclyl;

R A is hydrogen or C 1-6 alkyl;

R B is hydrogen or C 1-6 alkyl;

R E is independently, for each occurrence, hydrogen or C 1-6 alkyl;

n is 0, 1, or 2;

o is 1 or 2; and

p is 0 or 1.

2 . The compound of claim 1 , wherein Ring A is phenyl, pyridinyl, or 2-pyridonyl, wherein the nitrogen atom of the 2-pyridonyl may optionally be substituted by C 1-6 alkyl.

3 . The compound of claim 1 or 2 , wherein Ring A is phenyl, pyridinyl, or 2-pyridonyl, wherein the nitrogen atom of the 2-pyridonyl may optionally be substituted by CH 3 .

4 . The compound of any one of claims 1-3 , wherein Ring A is selected from the group consisting of

wherein Δ denotes the point of attachment to X 1 and AA denotes the point of attachment to X 3 .

5 . The compound of any one of claims 1-4 , wherein n is 0.

6 . The compound of any one of claims 1-4 , wherein n is 1.

7 . The compound of claim 6 , wherein R 1 is selected from the group consisting of chloro, hydroxyl, CH 3 , CHF 2 , and NH 2 .

8 . The compound of any one of claims 1-4 , wherein n is 2.

9 . The compound of claim 8 , wherein R 1 is independently, for each occurrence, selected from the group consisting of chloro, fluoro, hydroxyl, CH 3 , CHF 2 , —O—CH 3 , —O—CHF 2 , —O—C(O)CH 3 , and

10 . The compound of any one of claims 1-9 , wherein Ring B is phenyl or 9-membered heterocyclyl.

11 . The compound of any one of claims 1-10 , wherein Ring B is phenyl or

12 . The compound of any one of claims 1-10 , wherein Ring B is

wherein ● denotes the point of attachment to X 1 and ●● denotes the point of attachment to X 2 .

13 . The compound of any one of claims 1-12 , wherein o is 1.

14 . The compound of claim 13 , wherein R 2 is selected from the group consisting of fluoro, hydroxyl, cyclopropyl, CF 3 , —O—CH 3 , —O—CHF 2 , —O—CF 3 , and C(O)OH.

15 . The compound of any one of claims 1-12 , wherein o is 2.

16 . The compound of claim 15 , wherein R 2 is independently, for each occurrence, selected from the group consisting of chloro, fluoro, CH 3 , CF 3 , and —O—CH 3 .

17 . The compound of any one of claims 1-16 , wherein Ring C is absent.

18 . The compound of any one of claims 1-16 , wherein Ring C is selected from the group consisting of phenyl, pyrrolidinyl, piperidinyl, pyridinyl,

19 . The compound of any one of claims 1-16 or 18 , wherein Ring C is selected from the group consisting of

wherein □ denotes the point of attachment to X 2 and □□ denotes the point of attachment to X 3 .

20 . The compound of any one of claims 1-16, 18, and 19 , wherein p is 1.

21 . The compound of claim 20 , wherein R 3 is selected from the group consisting of bromo, chloro, fluoro, cyano, CH 3 , and cyclopropyl.

22 . The compound of any one of claims 1-16, 18, and 19 , wherein p is 0.

23 . The compound of any one of claims 1-22 , wherein X 1 is selected from the group consisting of *—S(O) 2 N(H)—**, *—S(O) 2 N(CH 3 )—**, —C(O)—, *—C(O)N(H)—**, *—CH 2 N(H)—**, and *—S(O) 2 CH 2 —**, wherein * denotes the point of attachment to Ring A and ** denotes the point of attachment to Ring B.

24 . The compound of any one of claims 1-23 , wherein X 2 is a bond.

25 . The compound of any one of claims 1-23 , wherein X 2 is —O—.

26 . The compound of any one of claims 1-25 , wherein L 1 is selected from the group consisting of —C(O)N(H)—, —C(O)N(CH 3 )—, —C(O)O—, —CH 2 —, —CH 2 —O—, —C(O)—, —CH 2 —C(O)O—, —CH 2 —N(CH 3 )C(O)—, —O—, and

27 . The compound of any one of claims 1-26 , wherein L 2 is selected from the group consisting of —CH 2 CH 2 —, —(CH 2 ) 3 —, —CH 2 —, —(CH 2 ) 4 —, —CH(CH 3 )CH 2 —, —CH 2 CH 2 C(H)(CH 3 )—,

28 . The compound of any one of claims 1-26 , wherein L 2 is absent.

29 . The compound of any one of claims 1-28 , wherein L 3 is a bond.

30 . The compound of any one of claims 1-28 , wherein L 3 is —O—, —CH 2 —O—, or

31 . The compound of any one of claims 1-25 , wherein X 3 is selected from the group consisting of

wherein # denotes the point of attachment to Ring A and ## denotes the point of attachment to Ring C.

32 . A compound of formula (Ia)

or a stereoisomer and/or a pharmaceutically acceptable salt thereof, wherein:

R 4 is selected from the group consisting of hydrogen, hydroxyl, halogen, and C 1-6 alkyl;

R 5 is selected from the group consisting of hydrogen, halogen, hydroxyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, —C(O)OC 1-6 alkyl, and —C(O)OC 1-6 cycloalkyl;

R 6 is selected from the group consisting of hydrogen, halogen, hydroxyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, and C(O)OH;

R 7 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6 alkoxy;

R 8 is hydrogen, halogen, or C 1-6 alkyl;

R 9 is selected from the group consisting of hydrogen, cyano, halogen, and C 3-6 cycloalkyl;

R 10 is hydrogen, cyano, or halogen;

X 4 is selected from the group consisting of *—S(O) 2 N(R C )—**, *—C(O)N(R C )—**, *—CH 2 N(R C )—**, and *—S(O) 2 CH 2 —**, wherein * denotes the point of attachment to

and ** denotes the point of attachment to

X 5 is #-L 4 -L 5 -L 6 -##, wherein # denotes the point of attachment to

and ## denotes the point of attachment to

L 4 is selected from the group consisting of CH 2 , C 1-6 alkyl-O—, —O—, —C(O)—, —C(O)N(R D )—, —C(O)O—, —CH 2 —C(O)O—, —CH 2 —N(R D )C(O)—, and 5-6 membered heteroaryl;

L 5 is C 1-6 alkyl or 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl may be optionally substituted with oxo;

L 6 is selected from the group consisting of a bond, —O—, C 1-6 alkyl-O—, and 4-6 membered heterocyclyl;

R C is hydrogen or C 1-6 alkyl; and

R D is hydrogen or C 1-6 alkyl.

33 . The compound of claim 32 , wherein R 4 is selected from the group consisting of hydrogen, hydroxyl, chloro, and CH 3 .

34 . The compound of claim 32 or 33 , wherein R 5 is selected from the group consisting of hydrogen, fluoro, hydroxyl, CHF 2 , —O—CH 3 , —O—CHF 2 , —O—C(O)CH 3 , and

35 . The compound of any one of claims 32-34 , wherein R 6 is selected from the group consisting of hydrogen, hydroxyl, fluoro, chloro, cyclopropyl, CF 3 , —O—CH 3 , —O—CHF 2 , —O—CF 3 , and C(O)OH.

36 . The compound of any one of claims 32-35 , wherein R 7 is selected from the group consisting of hydrogen, chloro, fluoro, —O—CH 3 , CH 3 , and CF 3 .

37 . The compound of any one of claims 32-36 , wherein R 8 is hydrogen, CH 3 , or chloro.

38 . The compound of any one of claims 32-37 , wherein R 9 is selected from the group consisting of hydrogen, cyano, chloro, bromo, fluoro, and cyclopropyl.

39 . The compound of any one of claims 32-38 , wherein R 10 is selected from the group consisting of hydrogen, cyano, chloro, and fluoro.

40 . The compound of any one of claims 32-39 , wherein X 4 is selected from the group consisting of *—S(O) 2 N(H)—**, *—S(O) 2 N(CH 3 )—**, *—C(O)N(H)—**, *—CH 2 N(H)—**, and *—S(O) 2 CH 2 —**, wherein * denotes the point of attachment to

and ** denotes the point of attachment

41 . The compound of any one of claims 32-40 , wherein L 4 is selected from the group consisting of —CH 2 —, —O—, —C(O)—, —C(O)N(H)—, —C(O)N(CH 3 )—, —C(O)O—, —CH 2 —C(O)O—, —CH 2 —N(CH 3 )C(O)—, —CH 2 —O—, and

42 . The compound of any one of claims 32-41 , wherein L 5 is selected from the group consisting of —CH 2 —, —CH 2 CH 2 —, —(CH 2 ) 3 —, —C(H)(CH 3 )CH 2 —, —CH 2 CH 2 C(H)(CH 3 )—, —(CH 2 ) 4 —,

43 . The compound of any one of claims 32-42 , wherein L 6 is a bond.

44 . The compound of any one of claims 32-42 , wherein L 6 is —O—, —CH 2 —O—, or

45 . The compound of any one of claims 32-40 , wherein X 5 is selected from the group consisting of

wherein # denotes the point of attachment to

and ## denotes the point of attachment to

46 . A compound selected from any compound set forth in Table 1, or a pharmaceutically acceptable salt thereof.

47 . A pharmaceutical composition comprising a compound of any one of claims 1-46 ; and a pharmaceutically acceptable carrier.

48 . A method of inhibiting ACLY in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-46 or a pharmaceutical composition of claim 47 .

49 . The method of claim 48 , wherein the subject has a liver condition, disease, or disorder.

50 . The method of claim 49 , wherein the liver condition, disease, or disorder is NAFLD or NASH.

51 . The method of claim 48 , wherein the subject has type-2 diabetes.

52 . The method of claim 48 , wherein the subject has inflammation.

53 . The method of claim 48 , wherein the subject has chronic kidney disease.

54 . The method of claim 48 , wherein the subject has autoimmunity.

55 . The method of claim 48 , wherein the subject has cancer.

56 . A method of treating NAFLD in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-46 or a pharmaceutical composition of claim 47 .

57 . A method of treating NASH in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-46 or a pharmaceutical composition of claim 47 .

58 . A method of treating type-2 diabetes in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-46 or a pharmaceutical composition of claim 47 .

59 . A method of treating inflammation in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-46 or a pharmaceutical composition of claim 47 .

60 . A method of treating chronic kidney disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-46 or a pharmaceutical composition of claim 47 .

61 . A method of treating autoimmunity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-46 or a pharmaceutical composition of claim 47 .

62 . A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-46 or a pharmaceutical composition of claim 47 .

63 . A method of treating a condition, disease, or disorder as described herein in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-46 or of the pharmaceutical composition of claim 47 .