Fused bicyclic mTOR inhibitors

A compound represented by Formula (I):

• wherein:
• X1 and X2 are both CH;
• X3 and X5 are both N;
• X4, X6, and X7 are all C;
• R3 is C0-10alkyl, cycloC3-10alkyl, aminomethylcycloC3-10alkyl, bicycloC5-10alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclyl or heterobicycloC5-10alkyl any of which is optionally substituted by one or more independent G11 substituents;
• Q1 is -A(R1)mB(W)n or —B(G11)nA(Y)m;
• A and B are respectively, 5 membered heteroaromatic and 6 membered aromatic or heteroaromatic rings, fused together to form a 9-membered heteroaromatic system excluding 5-benzo[b]furyl and 3-indolyl;
• or Q1 is -A(R1)mA(Y)m, wherein each A is the same or different 5-membered aromatic or heteroaromatic ring, and the two are fused together to form an 8-membered heteroaromatic system;
• R1 is independently, hydrogen, —N(C0-8alkyl)(C0-8alkyl), hydroxyl, halogen, oxo, aryl(optionally substituted with 1 or more R31 groups), hetaryl(optionally substituted with 1 or more R31 groups), C1-6alkyl, —C0-8alkylC3-8cycloalkyl, —C0-8alkyl-NR311S(O)0-2R321, —C0-8alkyl-NR311S(O)0-2NR321R331, —C0-8alkyl-S(O)0-2NR311R321, —C0-8alkyl-NR311COR321, —C0-8alkyl-NR311CO2R321, —C0-8alkyl-NR311CONR321R331, —C0-8alkyl-CONR311R321, —C0-8alkyl-CON(R311)S(O)0-2R321, —C0-8alkyl-CO2R311, —C0-8alkyl-S(O)0-2R311, —C0-8alkyl-O—C1-8alkyl, —C0-8alkyl-O—C0-8alkylC3-8cycloalkyl, —C0-8alkyl-O—C0-8alkylheterocyclyl, —C0-8alkyl-O—C0-8alkylaryl, —C0-8alkylaryl, —C0-8alkylhetaryl, —C0-8alkylheterocyclyl, —C0-8alkyl-O—C0-8alkylhetaryl, —C0-8alkyl-S—C0-8alkyl, —C0-8alkyl-S—C0-8alkylC3-8cycloalkyl, —C0-8alkyl-S—C0-8alkylheterocyclyl, —C0-8alkyl-S—C0-8alkylaryl, —C0-8alkyl-S—C0-8alkylhetaryl, —C0-8alkyl-N(R311)—C0-8alkyl, —C0-8alkyl-N(R311)—C0-8alkylC3-8cycloalkyl, —C0-8alkyl-N(R311)—C0-8alkylheterocyclyl, —C0-8alkyl-N(R311)—C0-8alkylaryl, —C0-8alkyl-N(R311)—C0-8alkylhetaryl, —C0-8alkyl-NR311R321, —C2-8alkenyl, —C2-8alkynyl, NO2, CN, CF3, OCF3, OCHF2;
• W is independently, hydrogen, —N(C0-8alkyl)(C0-8alkyl), hydroxyl, halogen, oxo, aryl(optionally substituted with 1 or more R31 groups), hetaryl(optionally substituted with 1 or more R31 groups), C1-6alkyl, —C0-8alkylC3-8cycloalkyl, —C0-8alkyl-NR312S(O)0-2R322, —C0-8alkyl-NR311S(O)0-2NR321R331, —C0-8alkyl-NR311CO2R321, —C0-8alkyl-CON(R311)S(O)0-2R321, —C0-8alkyl-S(O)0-2NR312R322, —C0-8alkyl-NR312COR322, —C0-8alkyl-NR312CONR322R332, —C0-8alkyl-CONR312R322, —C0-8alkyl-CO2R312, —C0-8alkylS(O)0-2R312, —C0-8alkyl-O—C1-8alkyl, —C0-8alkyl-O—C0-8alkylcyclyl, —C0-8alkyl-O—C0-8alkylheterocycloalkyl, —C0-8alkyl-O—C0-8alkylaryl, —C0-8alkylaryl, —C0-8alkylhetaryl, —C0-8alkylheterocyclyl, -Oaryl, —C0-8alkyl-O—C0-8alkylhetaryl, —C0-8alkyl-S—C0-8alkyl, —C0-8alkyl-S—C0-8alkylC3-8cycloalkyl, —C0-8alkyl-S—C0-8alkylheterocycloalkyl, —C0-8alkyl-S—C0-8alkylaryl, —C0-8alkyl-S—C0-8alkylhetaryl, —C0-8alkyl-N(R312)—C0-8alkyl, —C0-8alkyl-N(R312)—C0-8alkylC3-8cycloalkyl, —C0-8alkyl-N(R312)—C0-8alkylheterocycloalkyl, —C0-8alkyl-N(R312)—C0-8alkylaryl, —C0-8alkyl-N(R312)—C0-8alkylhetaryl, C0-8alkyl-NR312R322, —C2-8alkenyl, —C2-8alkynyl, NO2, CN, CF3, OCF3, OCHF2;
• Y is independently, hydrogen, —N(C0-8alkyl)(C0-8alkyl), hydroxyl, halogen, oxo, aryl(optionally substituted with 1 or more R31 groups), hetaryl(optionally substituted with 1 or more R31 groups), C0-6alkyl, —C0-8alkylC3-8cycloalkyl, —C0-8alkyl-NR311S(O)0-2R321, —C0-8alkyl-NR311S(O)0-2NR321R331, —C0-8alkyl-NR311CO2R321, —C0-8alkyl-CON(R311)S(O)0-2R321, —C0-8alkyl-S(O)0-2NR311R321, —C0-8alkyl-NR311COR321, —C0-8alkyl-NR311CONR321R331, —C0-8alkyl-CONR311R321, —C0-8alkyl-CO2R311, —C0-8alkylS(O)0-2R311, —C0-8alkyl-O—C1-8alkyl, —C0-8alkyl-O—C0-8alkylC3-8cycloalkyl, —C0-8alkyl-O—C0-8alkylheterocycloalkyl, —C0-8alkyl-O—C0-8alkylaryl, —C0-8alkylaryl, —C0-8alkylhetaryl, —C0-8alkylheterocyclyl, —C0-8alkyl-O—C0-8alkylhetaryl, —C0-8alkyl-S—C0-8alkyl, —C0-8alkyl-S—C0-8alkylC3-8cycloalkyl, —C0-8alkyl-S—C0-8alkylheterocycloalkyl, —C0-8alkyl-S—C0-8alkylaryl, —C0-8alkyl-S—C0-8alkylhetaryl, —C0-8alkyl-N(R311)—C0-8alkyl, —C0-8alkyl-N(R311)—C0-8alkylC3-8cycloalkyl, —C0-8alkyl-N(R311)—C0-8alkylheterocycloalkyl, —C0-8alkyl-N(R311)—C0-8alkylaryl, —C0-8alkyl-N(R311)—C0-8alkylhetaryl, —C0-8alkyl-NR311R321, —C2-8alkenyl, —C2-8alkynyl, NO2, CN, CF3, OCF3, OCHF2;
• G11 is halo, oxo, —CF3, —OCF3, —OR312, —NR312R322, —C(O)R312, —C(O)C3-8cycloalkyl, —CO2C3-8cycloalkyl, —CO2R312, —C(═O)NR312R322, —NO2, —CN, —S(O)0-2R312, —SO2NR312R322, NR312(C═O)R322, NR312C(═O)OR322, NR312C(═O)NR322R332, NR312S(O)0-2R322, —C(═S)OR312, —C(═O)SR312, —NR312C(═NR322)NR332R341, —NR312C(═NR322)OR332, —NR312C(═NR322)SR332, —OC(═O)OR312, —OC(═O)NR312R322, —OC(═O)SR312, —SC(═O)OR312, —SC(═O)NR312R322, —P(O)OR3120R322, C1-10alkylidene, C0-10alkyl, C2-10alkenyl, C2-10alkynyl, —C1-10alkoxyC1-10alkyl, —C1-10alkoxyC2-10alkenyl, —C1-10alkoxyC2-10alkynyl, —C1-10alkylthioC1-10alkyl, —C1-10alkylthioC2-10alkenyl, —C1-10alkylthioC2-10alkynyl, cycloC3-8alkyl, cycloC3-8alkenyl, -cycloC3-8alkylC1-10alkyl, -cycloC3-8alkenylC1-10alkyl, -cycloC3-8alkylC2-10alkenyl, -cycloC3-8alkenylC2-10alkenyl, -cycloC3-8alkylC2-10alkynyl, -cycloC3-8alkenylC2-10alkynyl, -heterocyclyl-C0-10alkyl, -heterocyclyl-C2-10alkenyl, or -heterocyclyl-C2-10alkynyl, any of which is optionally substituted with one or more independent halo, oxo, —CF3, —OCF3, —OR313, —NR313R323, —C(O)R313, —CO2R313, —C(═O)NR313R323, —NO2, —CN, —S(O)0-2R313, —SO2NR313R323, —NR313C(═O)R323, —NR313C(═O)OR323, —NR313C(═O)NR323R333, —NR313S(O)0-2R323, —C(═S)OR313, —OC(═O)SR313, —NR313C(═NR323)NR333R342, —NR313C(═NR323)OR333, —NR313C(═NR323)SR333, —OC(═O)OR333, —OC(═O)NR313R323, —OC(═O)SR313, —SC(═O)OR313, —P(O)OR313OR323, or —SC(═O)NR313R323 substituents;
• or G11 is aryl-C0-10alkyl, aryl-C2-10alkenyl, aryl-C2-10alkynyl, hetaryl-C0-10alkyl, hetaryl-C2-10alkenyl, or hetaryl-C2-10alkynyl, where the attachment point is from either the left or right as written, where any of which is optionally substituted with one or more independent halo, —CF3, —OCF3, —OR313, —NR313R323, —C(O)R313, —CO2R313, —C(═O)NR313R323, —NO2, —CN, —S(O)0-2R313, —SO2NR313R323, —NR313C(═O)R323, —NR313C(═O)OR323, —NR313C(═O)NR323R333, —NR313S(O)0-2R323, —C(═S)OR313, —C(═O)SR313, —NR323C(═NR313)NR333R342, —NR313C(═NR323)OR333, —NR313C(═NR323)SR333, —C(═O)OR313, —C(═O)NR313R323, —OC(═O)SR313, —SC(═O)OR313, —P(O)OR313OR323, or —SC(═O)NR313R323 substituents;
• provided that G11 is not N—CH2CO2H when R3 is 4-piperidinyl;
• provided that Q1 is not N-methyl-2-indolyl, N-(phenylsulfonyl)-2-indolyl, 4-benzyloxy-2-indolyl, or 2-carboxy-5-benzo[b]thiophenyl;
• R31, R32, R33, R311, R321, R331, R312, R322, R332, R341, R313, R323, R333, and R342, in each instance, is independently
• C0-8alkyl optionally substituted with an aryl, heterocyclyl or hetaryl substituent, or C0-8alkyl optionally substituted with 1-6 independent halo, —CON(C0-8alkyl)(C0-8alkyl), —CO(C0-8alkyl), —OC0-8alkyl, -Oaryl, -Ohetaryl, -Oheterocyclyl, —S(O)0-2aryl, —S(O)0-2hetaryl, —S(O)0-2heterocyclyl, —S(O)0-2C0-8alkyl, —N(C0-8alkyl)(C0-8alkyl), —N(C0-8alkyl)CON(C0-8alkyl)(C0-8alkyl), —N(C0-8alkyl)CO(C1-8alkyl), —N(C0-8alkyl)CO(C3-8cycloalkyl), —N(C0-8alkyl)CO2(C1-8alkyl), S(O)1-2N(C0-8alkyl)(C0-8alkyl), —NR11S(O)1-2(C0-8alkyl), —CON(C3-8cycloalkyl)(C3-8cycloalkyl), —CON(C0-8alkyl)(C3-8cycloalkyl), —N(C3-8cycloalkyl)CON(C0-8alkyl)(C0-8alkyl), —N(C3-8cycloalkyl)CON(C3-8cycloalkyl)(C0-8alkyl), —N(C0-8alkyl)CON(C3-8cycloalkyl)(C0-8alkyl), —N(C0-8alkyl)CO2(C3-8cycloalkyl), —N(C3-8cycloalkyl)CO2(C3-8cycloalkyl), S(O)1-2N(C0-8alkyl)(C3-8cycloalkyl), —NR11S(O)1-2(C3-8cycloalkyl), C2-8alkenyl, C2-8alkynyl, CN, CF3, OH, or optionally substituted aryl substituents;
• such that each of the above aryl, heterocyclyl, hetaryl, alkyl or cycloalkyl groups may be optionally, independently substituted with —N(C0-8alkyl)(C0-8alkyl), hydroxyl, halogen, oxo, aryl, hetaryl, C0-6alkyl, —C0-8alkylcyclyl, —C0-8alkyl-N(C0-8alkyl)-S(O)0-2—(C0-8alkyl), —C0-8alkyl-S(O)0-2—N(C0-8alkyl)(C0-8alkyl), —C0-8alkyl-N(C0-8alkyl)CO(C0-8alkyl), —C0-8alkyl-N(C0-8alkyl)CO—N(C0-8alkyl)(C0-8alkyl), —C0-8alkyl-CO—N(C0-8alkyl)(C0-8alkyl), —C1-8alkyl-CO2—(C0-8alkyl), —C0-8alkylS(O)0-2—(C0-8alkyl), —C0-8alkyl-O—C1-8alkyl, —C0-8alkyl-O—C0-8alkylcyclyl, —C0-8alkyl-O—C0-8alkylheterocyclyl, —C0-8alkyl-O—C0-8alkylaryl, —C0-8alkyl-O—C0-8alkylhetaryl, —C0-8alkyl-S—C0-8alkyl, —C0-8alkyl-S—C0-8alkylcyclyl, —C0-8alkyl-S—C0-8alkylheterocyclyl, —C0-8alkyl-S—C0-8alkylaryl, —C0-8alkyl-S—C0-8alkylhetaryl, —C0-8alkyl-N(C0-8alkyl)-C0-8alkyl, —C0-8alkyl-N(C0-8alkyl)-C0-8alkylcyclyl, —C0-8alkyl-N(C0-8alkyl)-C0-8alkylheterocyclyl, —C0-8alkyl-N(C0-8alkyl)-C0-8alkylaryl, —C0-8alkyl-N(C0-8alkyl)-C0-8alkylhetaryl, —C2-8alkenyl, —C2-8alkynyl, NO2, CN, CF3, OCF3, OCHF2,
• —C0-8alkyl-C3-8cycloalkyl,
• —C0-8alkyl-O—C0-8alkyl,
• —C0-8alkyl-N(C0-8alkyl)(C0-8alkyl),
• —C0-8alkyl-S(O)0-2-C0-8alkyl, or
• heterocyclyl optionally substituted with 1-4 independent C0-8alkyl, cyclyl, or substituted cyclyl substituents;
• E1 in each instance is independently halo, —CF3, —OCF3, —OR2, —NR31R32, —C(═O)R31, —CO2R31, —CONR31R32, —NO2, —CN, —S(O)0-2R31, —S(O)0-2NR31R32, —NR31C(═O)R32, —NR31C(═O)OR32, —NR31C(═O)NR32R33, —NR31S(O)0-2R32, —C(═S)OR31, —C(═O)SR31, —NR31C(═NR32)NR33R31, —NR31C(═NR32)OR33, —NR31C(═NR31)SR31, —OC(═O)OR31, —OC(═O)NR31R32, —OC(═O)SR31, —SC(═O)OR31, —SC(═O)NR31R32, C0-10alkyl, C2-10alkenyl, C2-10alkynyl, —C1-10alkoxyC1-10alkyl, —C1-10alkoxyC2-10alkenyl, —C1-10alkoxyC2-10alkynyl, —C1-10alkylthioC1-10alkyl, —C1-10alkylthioC2-10alkenyl, —C1-10alkylthioC2-10alkynyl, cycloC3-8alkyl, cycloC3-8alkenyl, -cycloC3-8alkylC1-10alkyl, -cycloC3-8alkenylC1-10alkyl, -cycloC3-8alkylC2-10alkenyl, -cycloC3-8alkenylC2-10alkenyl, -cycloC3-8alkylC2-10alkynyl, -cycloC3-8alkenylC2-10alkynyl, -heterocyclyl-C0-10alkyl, -heterocyclyl-C2-10alkenyl, or -heterocyclyl-C2-10alkynyl, any of which is optionally substituted with one or more independent halo, oxo, —CF3, —OCF3, —OR31, —NR31R32, —C(═O)R31, —CO2R31, —C(═O)NR31R32, —NO2, —CN, —S(═O)0-2R31, —SO2NR31, —NR31C(═O)R32, —NR31C(═O)OR31, —NR31C(═O)NR32R33, —NR31S(O)0-2R31, —C(═S)OR31, —C(═O)SR31, —NR31C(═NR32)NR33R31, —NR31C(═NR32)OR33, —NR31C(═NR32)SR33, —OC(═O)OR31, —OC(═O)NR31R32, —OC(═O)SR31, —SC(═O)OR31, or —SC(═O)NR31R32 substituents;
• or E1 in each instance is independently aryl-C0-10alkyl, aryl-C2-10alkenyl, aryl-C2-10alkynyl, hetaryl-C0-10alkyl, hetaryl-C2-10alkenyl, or hetaryl-C2-10alkynyl, where the attachment point is from either the left or right as written, where any of which is optionally substituted with one or more independent halo, —CF3, —OCF3, —OR31, —NR31R32, —C(O)R31, —CO2R31, —C(═O)NR31R32, —NO2, —CN, —S(O)0-2R31, —S(O)0-2NR31R32, —NR31C(═O)R32, —NR31C(═O)OR32, —NR31C(═O)NR32R33, —NR31S(O)0-2R32, —C(═S)OR31, —C(═O)SR31, —NR31C(═NR32)NR33R31, —NR31C(═NR32)OR33, —NR31C(═NR32)SR33, —OC(═O)OR31, —OC(═O)NR31R32, —OC(═O)SR31, —SC(═O)OR31, or —SC(═O)NR31R32 substituents;
• in the cases of —NR31R32, —NR311R321, —NR312R322, —NR332R341, —NR313R323, and —NR323R333, the respective R31 and R32, R311 and R321, R312 and R322, R331 and R341, R313 and R323, and R323 and R333 are optionally taken together with the nitrogen atom to which they are attached to form a 3-10 membered saturated or unsaturated ring;
• wherein said ring in each instance independently is optionally substituted by one or more independent —N(C0-8alkyl)(C0-8alkyl), hydroxyl, halogen, oxo, aryl, hetaryl, C0-6alkyl, —C0-8alkylC3-8cycloalkyl, —C0-8alkyl-N(C0-8alkyl)S(O)0-2C0-8alkyl, —C0-8alkyl-N(C0-8alkyl)S(O)0-2N(C0-8alkyl)(C0-8alkyl), —C0-8alkyl-N(C0-8alkyl)CO2(C0-8alkyl), —C0-8alkyl-CON((C0-8alkyl))S(O)0-2(C0-8alkyl), —C0-8alkyl-S(O)0-2N(C0-8alkyl)(C0-8alkyl), —C0-8alkyl-N(C0-8alkyl)CO(C0-8alkyl), —C0-8alkyl-N(C0-8alkyl)CON(C0-8alkyl)(C0-8alkyl), —C0-8alkyl-CON(C0-8alkyl)(C0-8alkyl), —C0-8alkyl-CO2(C0-8alkyl), —C0-8alkylS(O)0-2(C0-8alkyl), —C0-8alkyl-O—C0-8alkyl, —C0-8alkyl-O—C0-8alkylcyclyl, —C0-8alkyl-O—C0-8alkylheterocycloalkyl, —C0-8alkyl-O—C0-8alkylaryl, -Oaryl, —C0-8alkyl-O—C0-8alkylhetaryl, —C0-8alkyl-S—C0-8alkyl, —C0-8alkyl-S—C0-8alkylC3-8cycloalkyl, —C0-8alkyl-S—C0-8alkylheterocycloalkyl, —C0-8alkyl-S—C0-8alkylaryl, —C0-8alkyl-S—C0-8alkylhetaryl, —C0-8alkyl-N(C0-8alkyl)-C0-8alkyl, —C0-8alkyl-N(C0-8alkyl)-C0-8alkylC3-8cycloalkyl, —C0-8alkyl-N(C0-8alkyl)—C0-8alkylheterocycloalkyl, —C0-8alkyl-N(C0-8alkyl)—C0-8alkylaryl, —C0-8alkyl-N(C0-8alkyl)—C0-8alkylhetaryl, —C0-8alkyl-N(C0-8alkyl)(C0-8alkyl), C2-8alkenyl, C2-8alkynyl, NO2, CN, CF3, OCF3, or OCHF2 substituents;
• wherein said ring in each instance independently optionally includes one or more heteroatoms other than the nitrogen;
• m is 0, 1, 2, or 3;
• n is 0, 1, 2, 3, or 4;
• and
• aa is 0 or 1;
• and provided that the compound is not
• trans-4-[8-amino-1-(7-chloro-4-hydroxy-1H-indol-2-yl)imidazo[1,5-a]pyrazin-3-yl]cyclohexanecarboxylic acid;
• cis-3-[8-amino-1-(7-chloro-1H-indol-2-yl)imidazo[1,5-a]pyrazin-3-yl]cyclobutanecarboxylic acid,
• trans-4-{8-amino-1-[7-(3-isopropyl)phenyl-1H-indol-2-yl]imidazo[1,5-a]pyrazin-3-yl}cyclohexanecarboxylic acid;
• or
• trans-4-{8-amino-1-[7-(2,5-dichloro)phenyl-1H-indol-2-yl]imidazo[1,5-a]pyrazin-3-yl}cyclohexane carboxylic acid;
• or a pharmaceutically acceptable salt thereof.