ACC inhibitors and uses thereof

Inventors: Geraldine C. Harriman (Charlestown, RI); Craig E. Masse (Cambridge, MA); James Harwood (Ledyard, CT); Sathesh Bhat (West New York, NY); Jeremy Robert Greenwood (Brooklyn, NY)

Assignee: Nimbus Apollo, Inc.

C07D495/04 A61K31/519

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Quick Facts

Patent No.: US 8,969,557
App. No.: 13/673,610
Granted: Mar 3, 2015
Kind: B2

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Abstract

The present invention provides compounds useful as inhibitors of Acetyl CoA Carboxylase (ACC), compositions thereof, and methods of using the same.

Claims (36)

1. A compound of formula II:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is hydrogen or C 1-4 aliphatic, optionally substituted with one or more halogen, —OR, —SR, —N(R) 2 , —N(R)C(O)R, —C(O)N(R) 2 , —N(R)C(O)N(R) 2 , —N(R)C(O)OR, —OC(O)N(R) 2 , —N(R)SO 2 R, —SO 2 N(R) 2 , —C(O)R, —C(O)OR, —OC(O)R, —S(O)R, or —SO 2 R;

R 2 is Hy, where Hy is selected from 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 hydrogen, halogen, —CN, —OR, —SR, —N(R) 2 , —N(R)C(O)R, —C(O)N(R) 2 , —N(R)C(O)N(R) 2 , —N(R)C(O)OR, —OC(O)N(R) 2 , —N(R)SO 2 R, —SO 2 N(R) 2 , —C(O)R, —C(O)OR, —OC(O)R, —S(O)R, —SO 2 R, —B(OH) 2 , or an optionally substituted ring selected from phenyl or 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R 4 is an optionally substituted phenyl or naphthyl ring;

each of R 5 and R 5′ is independently —R, —OR, —SR, —N(R) 2 , —N(R)C(O)R, —C(O)N(R) 2 , —N(R)C(O)N(R) 2 , —N(R)C(O)OR, —OC(O)N(R) 2 , —N(R)SO 2 R, —SO 2 N(R) 2 , —C(O)R, —C(O)OR, —OC(O)R, —S(O)R, or —SO 2 R; or R 5 and R 5′ are taken together to form a cyclopropylenyl, cyclobutylenyl, or oxetanyl group;

each of R 7 and R 7′ is independently hydrogen, —R, —OR, —SR, —N(R) 2, —N(R)C(O)R, —C(O)N(R) 2 , —N(R)C(O)N(R) 2 , —N(R)C(O)OR, —OC(O)N(R) 2 , —N(R)SO 2 R, —SO 2 N(R) 2 , —C(O)R, —C(O)OR, —OC(O)R, —S(O)R, or —SO 2 R; or R 7 and R 7′ are taken together to form a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and

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.

2. The compound according to claim 1 , wherein R 1 is methyl or trifluoromethyl, or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 2 , wherein R 2 is oxazolyl, or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 2 , wherein R 3 is tetrazolyl, —C(O)OR, —C(O)N(R) 2 , or —OR, or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 wherein R 5 and R 5′ are each methyl, or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 wherein R 3 is —C(O)OR or —C(O)NR 2 , or a pharmaceutically acceptable salt thereof.

7. The compound of claim 6 wherein R 3 is —C(O)OH, or a pharmaceutically acceptable salt thereof.

8. A composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

9. A compound of formula III:

or a pharmaceutically acceptable salt thereof, wherein:

each of R 5 and R 5 ′ is independently —R, —OR, —SR, —N(R) 2 , —N(R)C(O)R, —C(O)N(R) 2 , —N(R)C(O)N(R) 2 , —N(R)C(O)OR, —OC(O)N(R) 2 , —N(R)SO 2 R, —SO 2 N(R) 2 , —C(O)R, —C(O)OR, —OC(O)R, —S(O)R, or —SO 2 R; or R 5 and R 5′ are taken together to form a cyclopropylenyl, cyclobutylenyl, or oxetanyl group;

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;

n is 0-5.

10. A compound of formula IV:

or a pharmaceutically acceptable salt thereof, wherein:

R l is hydrogen or C 1-4 aliphatic, optionally substituted with one or more halogen, —OR, —SR, —N(R) 2 , —N(R)C(O)R, —C(O)N(R) 2 , —N(R)C(O)N(R) 2 , —N(R)C(O)OR, —OC(O)N(R) 2 , —N(R)SO 2 R, —SO 2 N(R) 2 , —C(O)R, —C(O)OR, —OC(O)R, —S(O)R, or —SO 2 R;

each of R 5 and R 5 ′ is independently —R, —OR, —SR, —N(R) 2 , —N(R)C(O)R, —C(O)N(R) 2 , —N(R)C(O)N(R) 2 , —N(R)C(O)OR, —OC(O)N(R) 2 , —N(R)SO 2 R, —SO 2 N(R) 2 , —C(O)R, —C(O)OR, —OC(O)R, —S(O)R, or —SO 2 R; or R 5 and R 5′ are taken together to form a cyclopropylenyl, cyclobutylenyl, or oxetanyl group;

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;

n is 0-5.

Assignments (10)

CHANGE OF NAME Recorded Oct 3, 2016

From: GILEAD APOLLO, INC.

To: GILEAD APOLLO, LLC

Reel/Frame 040209/0033 →

MERGER AND CHANGE OF NAME Recorded Jul 27, 2016

From: NIMBUS APOLLO, INC.; GILEAD APOLLO, INC.

To: GILEAD APOLLO, INC.

Reel/Frame 039490/0648 →