GCN2 inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-12084438-B2
Application number	US-202016907622-A
Country	US
Kind code	B2
Filing date	Jun 22, 2020
Priority date	Jan 29, 2018
Publication date	Sep 10, 2024
Grant date	Sep 10, 2024

Abstract

The present invention provides compounds, compositions thereof, and methods of using the same.

First claim

We claim:

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:
Ring A is selected from a 4-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur optionally fused to a 5-6 membered aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-12 membered partially unsaturated spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-12 membered partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-12 membered partially unsaturated bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or
Het, wherein Het is a 5-8 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-12 membered saturated spirocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-12 membered saturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-12 membered saturated bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

Ring B is

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; or
two R groups are optionally taken together to form a bivalent C 2-4 alkylene chain;
two R groups are optionally taken together with their intervening atoms to form an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each R′ is independently hydrogen or a C 1-3 aliphatic group optionally substituted with halogen;
each of R 1 is independently hydrogen, halogen, —NO 2 , —C(O)R, —C(O)NRS(O) 2 R, —C(O)N═S(O)R 2 , —NR 2 , —NRC(O)R, —NRC(O)NR 2 , —NRC(O)OR, —NRS(O) 2 R, —NRS(O) 2 NR 2 , —OR, —ON(R)SO 2 R, —P(O)R 2 , —SR, —S(O)R, —S(O) 2 R, —S(O)(NH)R, —S(O) 2 N(R) 2 , —S(NH 2 ) 2 (O)OH,—N═S(O)R 2 , —CH 3 , —CH 2 OH, —CH 2 NHSO 2 CH 3 , —CD 3 , or —CD 2 NRS(O) 2 R, or
each R 1 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, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or
two R 1 groups are optionally taken together with their intervening atoms to form an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; or
two R 1 groups are optionally taken together to form —O or ═NH; or
two R 1 groups are optionally taken together to form a bivalent C 2-4 alkylene chain;

each of R 2 is independently hydrogen, halogen, —C(O)N(R′) 2 , —OR′, —N(R′) 2 , —S(O) 2 R, —S(O) 2 N(R) 2 , —O— phenyl, or an optionally substituted group selected from C 1-3 aliphatic, phenyl, 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-8 membered saturated monocyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R 3 is hydrogen, halogen, —CN, —OR′, —N(R′) 2 , or an optionally substituted group selected from C 1-3 aliphatic, or a 5 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R 4 is hydrogen, halogen, —CN, —OR, or an optionally substituted group selected from C 1-3 aliphatic, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-12 membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
m is 0, 1, 2, 3, 4 or 5;
n is 0, 1, or 2;
p is 0 or 1; and
q is 0 or 1.

2. The compound of claim 1 , wherein Ring A is Het.

3. The compound of claim 2 , wherein Het is a 5-8 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-12 membered saturated spirocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-12 membered saturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

4. The compound of claim 1 , wherein each of R 1 is independently hydrogen, halogen, —C(O)R, —C(O)NRS(O) 2 R, —C(O)N═S(O)R 2 , —NR 2 , —NRC(O)R, —NRC(O)NR 2 , —NRC(O)OR, —NRS(O) 2 R, —NRS(O) 2 NR 2 , —OR, —ON(R)SO 2 R, —P(O)R 2 , —SR, —S(O)R, —S(O) 2 R, —S(O)(NH)R, —S(O) 2 N(R) 2 , —S(NH 2 ) 2 (O)OH, —N═S(O)R 2 , —CH 3 , —CH 2 OH, —CH 2 NHSO 2 CH 3 , —CD 3 , or —CD 2 NRS(O) 2 R, or each R 1 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, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or
two R 1 groups are optionally taken together to form a bivalent C 2-4 alkylene chain; or
two R 1 groups are optionally taken together with their intervening atoms to form an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

5. The compound of claim 1 , wherein each of R 2 is independently hydrogen, halogen, —C(O)N(R′) 2 , —OR′, —N(R′) 2 , or an optionally substituted group selected from C 1-3 aliphatic, or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

6. The compound of claim 1 , wherein R 3 is hydrogen, halogen, —CN, —OR′, —N(R′) 2 , or an optionally substituted group selected from C 1-3 aliphatic, or a 5 membered monocyc

Assignees

• Merck Patent Gmbh
• Vertex Pharma

Inventors

• Bleich Matthew
• Charrier Jean-Damien
• Dong Huijun
• Durrant Steven
• Eno Meredith Suzanne
• Etxebarria I Jardi Gorka
• Everitt Simon
• Fraysse Damien
• Knegtel Ronald
• Mochalkin Igor
• North Kiri
• Porichis Filippos
• Qiu Hui
• Pullin Robert
• Storck Pierre-Henri
• Twin Heather Clare
• Xiao Yufang

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title

• A61K31/4545

  containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine · CPC title