Gcn2 inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-2025059190-A1
Application number	US-202418775203-A
Country	US
Kind code	A1
Filing date	Jul 17, 2024
Priority date	Jan 29, 2018
Publication date	Feb 20, 2025
Grant date	—

Abstract

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

First claim

1 . A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:
Ring A is selected from a 3-8 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, a 5-6 membered monocyclic heteroaromatic ring having 1-4 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 4-8 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;

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; or
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, —CN, —NO 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —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 , —CD3, —CD2NRS(O) 2 R, or R; 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, —CN, —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, phenyl, or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R 4 is hydrogen, halogen, —CN, —OR, —N═S(O)R 2 , —N(R) 2 , 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 4-8 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 . (canceled)

5 . The compound of claim 1 , wherein each of R 1 is independently hydrogen, halogen, —CN, —C(O)R, —C(O)OR, —C(O)NR 2 , —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 , —CD3, —CD2NRS(O) 2 R, or R.

6 . The compound of claim 1 , wherein each of R 2 is independently hydrogen, halogen, —CN, —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.

7 . 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 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

8 . The compound of claim 1 , wherein R 4 is hydrogen, halogen, —CN, —OR, —N(R) 2 , 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.

9 .- 16 . (canceled)

17 . The compound of claim 1 , wherein the compound is of one of formulae XII-a, XII-b, or XII-c:

or a pharmaceutically acceptable salt thereof.

18 . The compound of claim 1 , wherein the compound is of one of formulae XVI-a, XVI-b, or XVI-c:

or a pharmaceutically acceptable salt thereof.

19 . The compound of claim 1 , wherein the compound is of one of formulae XVII-a, XVII-b, or XVII-c:

or a pharmaceuticall

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

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title