ACC inhibitors and uses thereof
The present invention provides compounds useful as inhibitors of Acetyl CoA Carboxylase (ACC), compositions thereof, and methods of using the same.
1. A compound of formula II:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is C 1-4 aliphatic;
R 2 is —C(O)R, —C(O)OR, or —OC(O)R;
each R is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R 3 is —C(O)N(R) 2 or —C(O)OR;
R 4 is an optionally substituted phenyl;
each of R 5 and R 5′ is independently —R; and
each of R 7 and R 7′ is independently hydrogen, —R, or —OR.
2. A composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
3. The compound of claim 1 , wherein R 4 is phenyl optionally substituted, on any of its substitutable carbon atoms, with a substituent independently selected from halogen, —OR ∘ , —CN, and —S(O) 2 R ∘ , wherein R ∘ is independently hydrogen or C 1-6 aliphatic.
4. The compound of claim 1 , wherein R 2 is —C(O)OR, and R is C 1-6 aliphatic.
5. The compound of claim 1 , wherein R 3 is —C(O)N(R) 2 , and R is independently hydrogen or C 1-6 aliphatic.
6. The compound of claim 1 , wherein R 7 is independently hydrogen or —OR, and R is optionally substituted C 1-6 aliphatic.
7. A compound of formula III:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is C 1-4 aliphatic;
R 2 is —C(O)R, —C(O)OR, or —OC(O)R;
each R is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R 3 is —C(O)N(R) 2 or —C(O)OR;
each of R 5 and R 5′ is independently —R;
R 6 is —R, —C(O)N(R) 2 , or —C(O)R;
each R 8 is independently selected from halogen, —R, —OR, —SR, —N(R) 2 or deuterium; and
n is 0-5.
8. The compound of claim 7 , wherein R 6 is —R, and R is optionally substituted C 1-6 aliphatic.
9. A compound of formula IV:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is C 1-4 aliphatic;
R 2 is —C(O)R, —C(O)OR, or —OC(O)R;
each R is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R 3 is —C(O)N(R) 2 or —C(O)OR;
each of R 5 and R 5′ is independently —R;
R 6 is —R, —C(O)N(R) 2 , or —C(O)R;
each R 8 is independently selected from halogen, —R, —OR, —SR, —N(R) 2 or deuterium; and
n is 0-5.
10. The compound of claim 9 , wherein R 6 is —R, and R is optionally substituted C 1-6 aliphatic.
11. A method of inhibiting ACC in a patient in need thereof, comprising administering to said patient the composition according to claim 2 .
12. A method of inhibiting ACC in a biological sample, comprising contacting the biological sample with the compound according to claim 1 .
13. A method for treating a metabolic disorder in a patient in need thereof, comprising administering to said patient the composition according to claim 2 .
14. The method according to claim 13 , wherein the metabolic disorder is obesity.
15. The method according to claim 13 , wherein the metabolic disorder is dyslipidemia or hyperlipidemia.
16. The method according to claim 14 , wherein the obesity is a symptom of Prader-Willi syndrome, Bardet-Biedl syndrome, Cohen syndrome or MOMO syndrome.
17. The method according to claim 14 , wherein the obesity is a side effect of the administration of another medication selected from insulin, a sulfonylurea, a thiazolidinedione, an antipsychotic, an antidepressant, a steroid, an anticonvulsant, pizotifen, or a hormonal contraceptive.
18. A method of treating a cancer or other proliferative disorder in a patient in need thereof, comprising administering to said patient the composition according to claim 2 .
19. A method of treating a fungal, parasitic, or bacterial infection in a patient in need thereof, comprising administering to said patient the composition according to claim 2 .
20. A method of inhibiting ACC in a plant, comprising contacting the plant with the compound according to claim 1 .