Oxer1 antagonists and uses thereof

A compound of formula I:

• or an N-oxide, or a pharmaceutically acceptable salt thereof, wherein:
• Ring A is an 8-10 membered aromatic or partially aromatic bicyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• or phenyl;
• L1 is one of the following:
• (a) a C1-5 bivalent straight or branched, saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with —O—, —C(O)—, —C(S)—, -Cy-, —C(R)2—, —CH(R)—, —CH(OR)—, —C(F)2—, —N(R)—, —S—, —S(O)—, or —S(O)2—;
• or
• (b) a covalent bond;
• each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic;
• phenyl;
• an 8-10 membered bicyclic aryl ring, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring;
• a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• and an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• or
• two R groups on the same nitrogen are optionally taken together with the nitrogen to form an optionally substituted 4-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• each -Cy- is independently an optionally substituted bivalent ring selected from a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenylenyl, a 3-7 membered saturated or partially unsaturated carbocyclylenyl, or a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• L2 is one of the following:
• (a) a C1-7 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with —O—, —C(O)—, —C(S)—, -Cy-, —C(R)2—, —CH(R)—, —CH(OR)—, —CH(F)—, —C(F)2—, —N(R)—, S—, —S(O)—, or —S(O)2—;
• or
• (b) a covalent bond;
• R1 is selected from (i) —C(O)OR, —C(O)N(R)S(O)2R, —C(O)N(R)OR, —C(O)NR2, —CN, —OH, and hydrogen;
• (ii) a 5-6 membered partially unsaturated oxo-heterocyclyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• which is substituted with n instances of R5;
• and (iii) a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• which is substituted with n instances of R5;
• R2 is one of the following:
• (a) phenyl;
• a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring;
• a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• a 5-10 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• or an 8-10 membered aromatic or partially aromatic bicyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• each of which is substituted with p instances of R6;
• or
• (b) C1-7 aliphatic, —C≡CR, —C(O)OR, or —C(O)R;
• each of which is substituted with p instances of R6;
• or
• (c) hydrogen;
• R3 is one of the following:
• (a) a C1-6 aliphatic group optionally substituted with one or more —OH or —N(R)2;
• (b) —CD3;
• (c) hydrogen;
• or
• (d) absent;
• each instance of R4 is independently hydrogen, deuterium, Rz, —C≡CR, halogen, —CN, —NO2, —OR, —OCF3, —SR, —NR2, —S(O)2R, —S(O)2NR2, —S(O)R, —S(O)NR2, —CF2R, —CF3, —CR2(CN), —CR2(OR), —CR2(NR2), —C(O)R, —C(O)OR, —C(O)NR2, —C(O)N(R)OR, —OC(O)R, —OC(O)NR2, —C(S)NR2, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR2, —N(R)C(NR)NR2, —N(R)NR2, —N(R)S(O)2NR2, —N(R)S(O)2R, —N═S(O)R2, —S(NR)(O)R, —N(R)S(O)R, —N(R)CN, —Si(OR)R2, —SiR3, —P(O)(R)NR2, —P(O)(R)OR or —P(O)R2;
• or
• two R4 groups are optionally taken together to form ═O;
• or
• two R4 groups are optionally taken together with their intervening atoms to form an optionally substituted 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur;
• each instance of R5, and R6 is independently hydrogen, deuterium, Rz, halogen, —CN, —NO2, —OR, —OCF3, —SR, —NR2, —S(O)2R, —S(O)2NR2, —S(O)R, —S(O)NR2, —CF2R, —CF3, —CR2(CN), —CR2(OR), —CR2(NR2), —C(O)R, —C(O)OR, —C(O)NR2, —C(O)N(R)OR, —OC(O)R, —OC(O)NR2, —C(S)NR2, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR2, —N(R)C(NR)NR2, —N(R)NR2, —N(R)S(O)2NR2, —N(R)S(O)2R, —N═S(O)R2, —S(NR)(O)R, —N(R)S(O)R, —N(R)CN, —Si(OR)R2, —SiR3, —P(O)(R)NR2, —P(O)(R)OR or —P(O)R2;
• or
• two R5 groups are optionally taken together to form ═O;
• two R6 groups are optionally taken together to form ═O;
• two R5 groups are optionally taken together with their intervening atoms to form an optionally substituted 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur;
• or
• two R6 groups are optionally taken together with their intervening atoms to form an optionally substituted 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur;
• each instance of Rz is independently selected from an optionally substituted group selected from C1-6 aliphatic;
• phenyl;
• a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• m is 0, 1, 2, 3, or 4;
• n is 0, 1, 2, 3, or 4;
• and
• p is 0, 1, 2, 3, or 4;
• provided that if L1-R1 is
• and ring A with its R3 and R4 substituents is
• then L2-R2 is not n-hexyl,
• and
• provided that if L1-R1 is
• and ring A with its R3 and R4 substituents is
• then L2-R2 is not n-hexyl.