US 12,084,438 B2
GCN2 inhibitors and uses thereof
Matthew Bleich, Brighton, MA (US); Jean-Damien Charrier, Wantage (GB); Huijun Dong, Arlington, MA (US); Steven Durrant, Abingdon (GB); Meredith Suzanne Eno, Brighton, MA (US); Gorka Etxebarria I Jardi, Abingdon (GB); Simon Everitt, Abingdon (GB); Damien Fraysse, Abingdon (GB); Ronald Knegtel, Abingdon (GB); Igor Mochalkin, Westford, MA (US); Kiri North, Abingdon (GB); Filippos Porichis, Melrose, MA (US); Hui Qiu, Acton, MA (US); Robert Pullin, Abingdon (GB); Pierre-Henri Storck, Abingdon (GB); Heather Clare Twin, Abingdon (GB); and Yufang Xiao, Lexington, MA (US)
Assigned to Merck Patent GmbH, Darmstadt (DE); and Vertex Pharmaceuticals Incorporated, Boston, MA (US)
Filed by Merck Patent GmbH, Darmstadt (DE); and Vertex Pharmaceuticals Incorporated, Boston, MA (US)
Filed on Jun. 22, 2020, as Appl. No. 16/907,622.
Application 16/907,622 is a continuation of application No. 16/260,019, filed on Jan. 28, 2019, granted, now 10,793,563.
Claims priority of provisional application 62/623,312, filed on Jan. 29, 2018.
Prior Publication US 2021/0040083 A1, Feb. 11, 2021
This patent is subject to a terminal disclaimer.
Int. Cl. C07D 471/04 (2006.01); C07D 519/00 (2006.01); A61P 35/00 (2006.01)
CPC C07D 471/04 (2013.01) [C07D 519/00 (2013.01); A61P 35/00 (2018.01)] 25 Claims
 
1. A compound of formula I:

OG Complex Work Unit Chemistry
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

OG Complex Work Unit Chemistry
each R is independently hydrogen or an optionally substituted group selected from C1-6 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 C2-4 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 C1-3 aliphatic group optionally substituted with halogen;
each of R1 is independently hydrogen, halogen, —NO2, —C(O)R, —C(O)NRS(O)2R, —C(O)N═S(O)R2, —NR2, —NRC(O)R, —NRC(O)NR2, —NRC(O)OR, —NRS(O)2R, —NRS(O)2NR2, —OR, —ON(R)SO2R, —P(O)R2, —SR, —S(O)R, —S(O)2R, —S(O)(NH)R, —S(O)2N(R)2, —S(NH2)2(O)OH,—N═S(O)R2, —CH3, —CH2OH, —CH2NHSO2CH3, —CD3, or —CD2NRS(O)2R, or
each R1 is independently hydrogen or an optionally substituted group selected from C1-6 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 R1 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 R1 groups are optionally taken together to form —O or ═NH; or
two R1 groups are optionally taken together to form a bivalent C2-4 alkylene chain;
each of R2 is independently hydrogen, halogen, —C(O)N(R′)2, —OR′, —N(R′)2, —S(O)2R, —S(O)2N(R)2, —O— phenyl, or an optionally substituted group selected from C1-3 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;
R3 is hydrogen, halogen, —CN, —OR′, —N(R′)2, or an optionally substituted group selected from C1-3 aliphatic, or a 5 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R4 is hydrogen, halogen, —CN, —OR, or an optionally substituted group selected from C1-3 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.