Pyrrolopyrazines and pyrazolopyrazines useful as inhibitors of protein kinases

A compound of formula I:

• or a pharmaceutically acceptable salt thereof,
• wherein X is CH or N;
• R1 is C6-10 aryl or 5-14 membered heteroaryl independently and optionally substituted with up to five J groups;
• R2 and R3 are each independently hydrogen, halogen, —CN, —NO2, —V—R, —V—Ra, or —V—Rb
• optionally substituted with R7;
• R4 is R5, C1-4aralkyl, —COR5, —CO2R5, —CON(R5)2, —SO2R5, or —SO2N(R5)2;
• or two R4 taken together with the atom(s) to which they are attached form an optionally substituted 3-10 membered cycloaliphatic or 5-14 membered heterocyclyl;
• R5 is optionally substituted R, C6-10 aryl, C3-10 cycloaliphatic, 5-14 membered heteroaryl, or 5-14 membered heterocyclyl;
• or two R5 groups, together with the atom(s) to which they are attached, form an optionally substituted 3-7 membered monocyclic or 8-14 membered bicyclic ring;
• R is H or optionally substituted C1-6 aliphatic;
• Ra is optionally substituted C6-10 aryl, C3-10 cycloaliphatic, 5-14 membered heteroaryl, or 5-14 membered heterocyclyl;
• Rb is —OR5, —N(R5)2, or —SRS;
• V is a bond, Q, or an optionally substituted C1-6 aliphatic chain, wherein up to two methylene units of the chain are optionally and independently replaced by Q in a chemically stable arrangement;
• Q is —NRS—, —S—, —O—, —CS—, —C(O)O—, —OC(O)—, —C(O)—, —C(O)C(O)—, —C(O)NR5—, —NR5C(O)—, —NR5C(O)O—, —SO2NR5—, —NR5SO2—, —C(O)NR5NR5—, —NR5C(O)NR5—, —OC(O)NR5, —NR5NR5—, —NR5SO2NR5—, —SO—, —SO2—, —PO—, —PO2—, or —PONR5—;
• each J is independently halogen, optionally substituted C1-6aliphatic, C1-6alkoxy, —N(R5)2, —C(O)R5, —NC(O)R5, —C(O)NR5, —C(O)OR5, —SORB, —SO2R5, or —U—(R6)n wherein
• each R6 is independently H or optionally substituted C1-12 aliphatic, C3-10 cycloaliphatic, C7-12benzofused cycloaliphatic, C6-10aryl, 5-14 membered heterocyclyl, 5-14 membered heteroaryl, OR5, N(R4)2, or SR5;
• U is a bond or optionally substituted C1-6 aliphatic wherein up to two methylene units are optionally and independently replaced by Y in a chemically stable arrangement;
• Y is a group selected from —O—, —NR—, —S—, —NR5C(O)—, —N(SO2)—, —NR5C(O)NR5—, —C(O)NR5—, —C(O)—, —OC(O)NR5—, —NR5C(O)O—, —C(O)O—, or —OC(O)—;
• n is 1 or 2;
• R7 is ═O, ═NR5, ═S, —CN, —NO2, or —Z—Rc;
• Z is a bond or optionally substituted C1-6 aliphatic wherein up to two methylene units of the chain are optionally and independently replaced by —NR—, —S—, —O—, —CS—, —C(O)O—, —OC(O)—, —C(O)—, —C(O)C(O)—, —C(O)NR5—, —NR5C(O)—, —NR5C(O)O—, —SO2NR5—, —NR5SO2—, —C(O)NR5NR5—, —NR5C(O)NR5—, —OC(O)NR5—, —NR5NR5—, —NR5SO2NR5—, —SO—, —SO2—, —PO—, —PO2—, or —POR5—;
• Rc is an optionally substituted 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• provided that
• a) when R1 is unsubstituted phenyl, R2 and R3 are each independently not H, CH3, or unsubstituted phenyl;
• b) when R1 is unsubstituted phenyl, R2 is not CN and R3 is not NH2;
• c) when X is N, and R2 and R3 are H, R1 is not unsubstituted 2-naphthyl;
• d) when one of R2 or R3 is optionally substituted phenyl, the other one of R2or R3 is not
• wherein ring A is an optionally substituted heterocycyclyl;
• optional substituents on the unsaturated carbon atom of an aryl or heteroaryl group are generally selected from halogen;
• —Ro;
• —ORo;
• —SRo;
• phenyl (Ph) optionally substituted with Ro;
• —O(Ph) optionally substituted with Ro;
• —(CH2)1-2(Ph), optionally substituted with Ro;
• —CH═CH(Ph), optionally substituted with Ro;
• a 5-6 membered heteroaryl or heterocyclic ring optionally substituted with Ro;
• —NO2;
• —CN;
• —N(Ro)2;
• —NRoC(O)Ro;
• —NRoC(S)Ro;
• —NRoC(O)N(Ro)2;
• —NRoC(S)N(Ro)2;
• —NRoCO2Ro;
• —NRoNRoC(O)Ro;
• —NRoNRoC(O)N(Ro)2;
• —NRoNRoCO2Ro;
• —C(O)C(O)Ro;
• —C(O)CH2C(O)Ro;
• —CO2Ro;
• —C(O)Ro;
• —C(S)Ro;
• —C(O)N(Ro)2;
• —C(S)N(Ro)2;
• —OC(O)N(Ro)2;
• —OC(O)Ro;
• —C(O)N(ORoRo;
• —C(NORoRo;
• —S(O)2Ro;
• —S(O)3Ro;
• —SO2N(Ro)2;
• —S(O)Ro;
• —NRoSO2N(Ro)2;
• —NRoSO2Ro;
• —N(ORoRo;
• —C(═NH)—N(Ro)2;
• —P(O)2Ro;
• —PO(Ro)2;
• —OPO(Ro)2;
• or —(CH2)0-2NHC(O)Ro;
• wherein each independent occurrence of Ro is selected from hydrogen, optionally substituted C1-6 aliphatic, an unsubstituted 5-6 membered heteroaryl or heterocyclic ring, phenyl, —O(Ph), or —CH2(Ph), or, notwithstanding the definition above, two independent occurrences of Ro, on the same substituent or different substituents, taken together with the atom(s) to which each Ro group is bound, to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• optional substituents on the aliphatic group of Ro are selected from NH2, NH(C1-4aliphatic), N(C1-4aliphatic)2, halogen, C1-4aliphatic, OH, O(C1-4aliphatic), NO2, CN, CO2H, CO2(C1-4aliphatic), O(haloC1-4aliphatic), or haloC1-4aliphatic, wherein each of the foregoing C1-4aliphatic groups of Ro is unsubstituted;
• optional substituents on the saturated carbon of an aliphatic or heteroaliphatic group, or of a non-aromatic heterocyclic ring are selected from those listed above for the unsaturated carbon of an aryl or heteroaryl group and additionally include the following:
• ═O, ═S, ═NNHR*, ═NN(R*)2, ═NNHC(O)R*, ═NNHCO2(alkyl), ═NNHSO2(alkyl), or ═NR*, where each R* is independently selected from hydrogen or an optionally substituted C1-6 aliphatic group;
• optional substituents on the nitrogen of a non-aromatic heterocyclic ring are generally selected from —R+, —N(R)2, —C(O)R+, —CO2R+, —C(O)C(O)R+, —C(O)CH2C(O)R+, —SO2R+, —SO2N(R+)2, —C(═S)N(R+1)2, —C(═NH)—N(R+)2, or —NR+SO2R+;
• wherein R+ is hydrogen, an optionally substituted C1-6 aliphatic, optionally substituted phenyl, optionally substituted —O(Ph), optionally substituted —CH2(Ph), optionally substituted —(CH2)1-2(Ph);
• optionally substituted —CH═CH(Ph);
• or an unsubstituted 5-6 membered heteroaryl or heterocyclic ring having one to four heteroatoms independently selected from oxygen, nitrogen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R+, on the same substituent or different substituents, taken together with the atom(s) to which each R+ group is bound, form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• optional substituents on the aliphatic group or the phenyl ring of R+ are selected from —NH2, —NH(C1-4 aliphatic), —N(C1-4 aliphatic)2, halogen, C1-4 aliphatic, —OH, —O(C1-4 aliphatic), —NO2, —CN, —CO2H, —CO2(C1-4 aliphatic), —O(halo C1-4 aliphatic), or halo(C1-4 aliphatic), wherein each of the foregoing C1-4aliphatic groups of R+ is unsubstituted.