Erk inhibitors and uses thereof

A compound of formula VIII:

• or a pharmaceutically acceptable salt thereof, wherein:
• Ring A is an optionally substituted group selected from phenyl, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 4-7 membered monocyclic heterocylic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or
• Ring A is selected from
• R1 is a warhead group -L-Y, wherein R1 is attached to an atom adjacent to where NH is attached, wherein:
• L is a bivalent C2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and one or two methylene units of L are optionally and independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO2—, —SO2N(R)—, —S—, —S(O)—, —OC(O)—,—C(O)O—, cyclopropylene, —O—, —N(R)—, or —C(O)—;
• or
• L is a bivalent C2-8 straight or branched, hydrocarbon chain wherein L has at least one alkylidenyl double bond and at least one methylene unit of L is replaced by —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO2—, —SO2N(R)—, —S—, —S(O)—, —SO2—, —OC(O)—, or —C(O)O—, and one additional methylene unit of L is optionally replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—;
• or
• L is a bivalent C2-8 straight or branched, hydrocarbon chain wherein one methylene unit of L is replaced by cyclopropylene and one additional methylene unit of L is replaced by —NRC(O)—, —C(O)NR—, —N(R)SO2—, —SO2N(R)—, —S—, —S(O)—, —SO2—, —OC(O)—, or —C(O)O—;
• or
• L is a bivalent C2-8 straight or branched, hydrocarbon chain wherein L has at least one triple bond and one or two methylene units of L are optionally and independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO2—, —SO2N(R)—, —S—, —S(O)—, —SO2—, —OC(O)—, or —C(O)O—;
• and
• Y is hydrogen, C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN, or a 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein said ring is substituted with 1-4 Re groups;
• or
• L is a covalent bond, —CH2—, —NH—, —C(O)—, —CH2NH—, —NHCH2—, —NHC(O)—, —NHC(O)CH2OC(O)—, —CH2NHC(O)—, —NHSO2—, —NHSO2CH2—, —NHC(O)CH2OC(O)—, or —SO2NH—, and Y is selected from:
• (i) C1-6 alkyl substituted with oxo, halogen, NO2, or CN;
• or
• (ii) C2-6 alkenyl substituted with oxo, halogen, NO2, or CN;
• or
• (iii) C2-6 alkynyl optionally substituted with oxo, halogen, NO2, or CN;
• or
• (iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 Re groups;
• or
• (v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-4 Re groups;
• or
• (vi)
• or
• (vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
• or
• (viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
• or
• (ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
• or
• (x)
• or
• (xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
• or
• (xii)
• or
• (xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 Re groups;
• or
• (xiv)
• or
• (xv) a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 Re groups;
• or
• (xvi)
• or
• (xvii) an 8-10 membered bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
• or
• L is a covalent bond, —C(O)—, —N(R)C(O)—, or a bivalent C1-8 saturated or unsaturated, straight or branched, hydrocarbon chain;
• and Y is selected from the following (i) through (xvii):
• (i) C1-6 alkyl substituted with oxo, halogen, NO2 or CN;
• (ii) C2-6 alkenyl optionally substituted with oxo, halogen, NO2, or CN;
• or
• (iii) C2-6 alkenyl optionally substituted with oxo, halogen, NO2, or CN;
• or
• (iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 Re groups;
• or
• (v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-4 Re groups;
• or
• (vi)
• wherein each R, Q, Z;
• or
• (vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
• or
• (viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
• or
• (ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
• (x)
• or
• (xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
• or
• (xii)
• or
• (xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 Re groups;
• or
• (xiv)
• wherein each Re is as defined above and described herein;
• or
• (xv) a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 Re groups;
• or
• (xvi)
• (xvii) an 8-10 membered bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
• each Re is independently selected from -Q-Z, oxo, NO2, halogen, CN, a suitable leaving group selected from alkoxy, sulphonyloxy, optionally substituted alkylsulphonyloxy, optionally substituted alkenylsulfonyloxy, optionally substituted arylsulfonyloxy, acyl, diazonium, or C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN, wherein:
• Q is a bivalent C1-6 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of Q are optionally and independently replaced by —N(R)—, —S—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —SO—, or —SO2—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO2—, or —SO2N(R)—;
• and
• each Z is independently hydrogen or C1-6 aliphatic substituted with oxo, halogen, NO2 or CN;
• each R2 is independently hydrogen, an optionally substituted C1-6 aliphatic, halogen, or —OR;
• each R3 is independently selected from —R, -Cy, halogen, —OR, —SR, —CN, —NO2, —SO2NR, —SO2R, —SOR, —C(O)R, —C(O)OR, —OC(O)R, —OC(O)N(R)2, —C(O)N(R)2, —C(O)N(R)—OR —C(O)C(O)R, —P(O)(R)2, —NRC(O)OR, —NRC(O)R, —NRC(O)N(R)2, —NRSO2R, or —N(R)2;
• or two R3 groups on the same carbon atom together form —C(O)—, —C(S)—, or —C(N—R)—;
• each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 4-7 membered heterocylic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• or
• two R groups on the same nitrogen are taken together with the nitrogen atom to which they are attached to form a 4-7 membered heterocylic ring having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 4-7 membered heteroaryl ring having 0-4 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• Cy is an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• Ry is hydrogen, optionally substituted C1 aliphatic, halogen, haloalkyl, —CN, —C(O)R1, —C(O)N(R′)2, —C(═N—R″)R′ or —N(R′)2;
• each R′ is independently hydrogen or an optionally substituted C1-6 aliphatic;
• R″ is hydrogen or —OR;
• and
• m and p are each independently 0-4.