Isoquinoline compounds and uses thereof

A compound of Formula (I)

• or a pharmaceutically acceptable salt thereof, wherein:
• R1 is hydrogen, halogen, hydroxyl, C1-6 alkyl optionally substituted with halogen, C3-4 cycloalkyl, or —O(C1-6 alkyl) optionally substituted with halogen;
• R2 is (i) or (ii):
• (i) a monocyclic 5- or 6-membered heteroaryl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R10;
• or
• (ii) a polycyclic heteroaryl having the formula (a) or (b):
• wherein the wavy line represents the attachment point to the parent structure,
• Q is CR20, NR21, N, O or S;
• T is N or CR22;
• Z1 and Z2 are independently N or C, provided at least one of Z1 and Z2 is C;
• T1, T2 and T3 are independently N or CR23;
• ring A and ring B are independently a C5-8 cycloalkyl or a 5- to 8-membered heterocycle having at least 3 ring-forming carbon atoms and 1, 2 or 3 ring-forming heteroatoms independently selected from the group consisting of N, P, O and S;
• wherein the C5-8 cycloalkyl and the 5- to 8-membered heterocycle are independently optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R10;
• and wherein two substituents of the C5-8 cycloalkyl or the 5- to 8-membered heterocycle, where present, optionally taken together form a spiro, fused or bridged cycloalkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R10 or a sprio, fused or bridged heterocyclyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R10;
• R20, R21, R22 and R23 are each independently hydrogen or R10;
• R3 is hydrogen or halogen;
• cyano, C1-6 alkyl, C3-8 cycloalkyl, 3- to 14-membered heterocyclyl, or —OR7;
• wherein the C1-6 alkyl, C3-8 cycloalkyl and 3- to 14-membered heterocyclyl of R3 are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R10;
• R4 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-14 aryl, 5- to 14-membered heteroaryl, 3- to 14-membered heterocyclyl or halogen, cyano, —C(O)R6, —C(O)OR7, —C(O)NR8aR8b, —OR7, —OC(O)R6, —OC(O)NR8aR8b, —SR7, —S(O)R9, —S(O)2R9, —S(O)2NR8aR8b, —P(O)R9aR9b, —NR8aR8b, —N(R8)C(O)R6, —N(R8)C(O)OR7, —N(R8)C(O)NR8aR8b, —N(R8)S(O)2R9, or —N(R8)S(O)2NR8aR8b;
• wherein the-C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-14 aryl, 5- to 14-membered heteroaryl and 3- to 14-membered heterocyclyl of R4 are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R10;
• R5 is hydrogen, halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-14 aryl, 5- to 14-membered heteroaryl, 3- to 14-membered heterocyclyl, halogen, cyano, —C(O)R6, —C(O)OR7, —C(O)NR8aR8b, —OR7, —OC(O)R6, —OC(O)NR8aR8b, —SR7, —S(O)R9, —S(O)2R9, —S(O)2NR8aR8b, —P(O)R9aR9b, —NR8aR8b, —N(R8)C(O)R6, —N(R8)C(O)OR7, —N(R8)C(O)NR8aR8b, —N(R8)S(O)2R9, or —N(R8)S(O)2NR8aR8b;
• wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-14 aryl, 5- to 14-membered heteroaryl and 3- to 14-membered heterocyclyl of R5 are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R10;
• each R6 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 14-membered heteroaryl or 3- to 12-membered heterocyclyl;
• wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 14-membered heteroaryl and 3- to 12-membered heterocyclyl of R6 are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R10;
• each R7 is independently hydrogen, C1-6 alkyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 14-membered heteroaryl or 3- to 12-membered heterocyclyl;
• wherein the C1-6 alkyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 14-membered heteroaryl and 3- to 12-membered heterocyclyl of R7 are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R10;
• each R8 is independently hydrogen or C1-6 alkyl;
• each R8a and R8b is independently hydrogen, C1-6 alkyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 14-membered heteroaryl or 3- to 12-membered heterocyclyl;
• wherein the C1-6 alkyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 14-membered heteroaryl and 3- to 12-membered heterocyclyl of R8a and R8b are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R10;
• or R8a and R8b are taken together with the nitrogen atom to which they are attached to form a 4- to 12-membered heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R10;
• each R9 is independently C1-6 alkyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 14-membered heteroaryl or 3- to 12-membered heterocyclyl;
• wherein the C1-6 alkyl, C3_8 cycloalkyl, C6-10 aryl, 5- to 14-membered heteroaryl and 3- to 12-membered heterocyclyl of R9 are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R10;
• each R9a and R9b is independently C1-6 alkyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 14-membered heteroaryl, 3- to 12-membered heterocyclyl, or —O—C1-6 alkyl;
• wherein the C1-6 alkyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 14-membered heteroaryl and 3- to 12-membered heterocyclyl of R9a and R9b are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R10;
• or R9a and R9b are taken together with the phosphorus atom to which they are attached to form a 4- to 12-membered heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R10;
• each R10 is independently oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, halogen, cyano, —C(O)Ra, —C(O)OR, —C(O)NRcRd, —OR, —OC(O)Ra, —OC(O)NRcRd, —SRb, —S(O)R, —S(O)2Re, —S(O)(═NH)Rc, —S(O)2NRcRd, —NRcRd, —N(Rf)C(O)Ra, —N(Rf)C(O)OR, —N(Rf)C(O)NRcRd, —N(Rf)S(O)2Re, —N(Rf)S(O)2NRcRd, or —P(O)RgRh;
• wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-14 aryl, 5- to 14-membered heteroaryl and 3- to 14-membered heterocyclyl of R10 are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R11;
• each Ra is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3_8 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl or 3- to 12-membered heterocyclyl;
• wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3_8 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl and 3- to 12-membered heterocyclyl of Ra are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R11;
• each Rb is independently hydrogen, C1-6 alkyl, C3_8 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl or 3- to 12-membered heterocyclyl;
• wherein the C1-6 alkyl, C3_8 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl and 3- to 12-membered heterocyclyl of Rb are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R11;
• each Rc and Rd is independently hydrogen, C1-6 alkyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl or 3- to 12-membered heterocyclyl;
• wherein the C1-6 alkyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl and 3- to 12-membered heterocyclyl of Rc and Rd are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R11;
• or Rc and Rd are taken together with the nitrogen atom to which they are attached to form a 4- to 12-membered heterocyclyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R11;
• each Rc is independently C1-6 alkyl, C3-s cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl or 3- to 12-membered heterocyclyl;
• wherein the C1-6 alkyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl and 3- to 12-membered heterocyclyl of Rc are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R11;
• each Rf is independently hydrogen or C1-6 alkyl;
• each Rg and Rh is independently C1-6 alkyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, or —O—C1-6 alkyl;
• wherein the C1-6 alkyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl and 3- to 12-membered heterocyclyl of Rg and Rh are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R11;
• or Rg and Rh are taken together with the phosphorus atom to which they are attached to form a 4- to 12-membered heterocyclyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R11;
• each R11 is independently oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 3- to 8-membered heterocyclyl, halogen, cyano, —C(O)Ra1, —C(O)ORb1, —C(O)NRc1Rd1, —ORb1, —OC(O)Rai, —OC(O)NRc1Rd1, —SRb1, —S(O)Re1, —S(O)2Re1, —S(O)2NRc1Rd1, —NRc1Rd1, —N(Rf1)C(O)Ra1, —N(Rf1)C(O)ORf1, —N(Rf1)C(O)NRc1Rd1, —N(Rf1)S(O)2Re1, —N(Rf1)S(O)2NRc1Rd1, or —P(O)Rg1Rh1;
• wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C6-14 aryl, 5- to 14-membered heteroaryl and 3- to 14-membered heterocyclyl of R11 are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R12;
• each Ra1 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl or 3- to 8-membered heterocyclyl;
• wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl and 3- to 8-membered heterocyclyl of Ra1 are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R12;
• each Rb1 is independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl or 3- to 8-membered heterocyclyl;
• wherein the C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl and 3- to 8-membered heterocyclyl of R are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R12;
• each Rc1 and Rd1 is independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl or 3- to 8-membered heterocyclyl;
• wherein the C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl and 3- to 8-membered heterocyclyl of Rc1 and Rd1 are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R12;
• or Rc1 and Rd1 are taken together with the nitrogen atom to which they are attached to form a 4- to 8-membered heterocyclyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R12;
• each Re1 is independently C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl or 3- to 8-membered heterocyclyl;
• wherein the C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl and 3- to 8-membered heterocyclyl of Rc1 are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R12;
• each Rf1 is independently hydrogen or C1-6 alkyl;
• each Rg1 and Rh1 is independently C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 3- to 8-membered heterocyclyl, or —O—C1-6 alkyl;
• wherein the C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl and 3- to 8-membered heterocyclyl of Rg1 and Rh1 are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R12;
• or Rg1 and Rh1 are taken together with the phosphorus atom to which they are attached to form a 4- to 8-membered heterocyclyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R12;
• each R12 is independently oxo, C1-6 alkyl, C3-6 cycloalkyl, C6 aryl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocyclyl, halogen, cyano, —C(O)Ra2, —C(O)OR2, —C(O)NRc2R2, —OR2, —OC(O)Ra2, —OC(O)NRc2Rd2, —S(O)2Re2, —S(O)2NRc2Rd2, —NRc2Rd2, —N(Rf2)C(O)Ra2, —N(Rf2)C(O)ORf2, —N(Rf2)C(O)NRc2Rd2, —N(Rf2)S(O)2Re2, —N(Rf2)S(O)2NRc2Rd2, or —P(O)Rg2Rh2;
• wherein the C1-6 alkyl, C3-6 cycloalkyl, C6 aryl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl of R12 are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R13;
• each Ra2 is independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C6 aryl, 5- to 6-membered heteroaryl or 3- to 6-membered heterocyclyl;
• wherein the C1-6 alkyl, C3-6 cycloalkyl, C6 aryl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl of R2 are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R13;
• each Rb2 is independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl or 3- to 6-membered heterocyclyl;
• wherein the C1-6 alkyl, C3-6 cycloalkyl and 3- to 6-membered heterocyclyl of Rb2 are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R13;
• each Rc2 and Rd2 is independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl or 3- to 8-membered heterocyclyl;
• wherein the C1-6 alkyl, C3-6 cycloalkyl and 3- to 8-membered heterocyclyl of Rc2 and Rd2 are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R13;
• or Rc2 and Rd2 are taken together with the nitrogen atom to which they are attached to form a 4- to 6-membered heterocyclyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R13;
• each Re2 is independently C1-6 alkyl, C3-6 cycloalkyl, C6 aryl, 5- to 6-membered heteroaryl or 3- to 6-membered heterocyclyl;
• wherein the C1-6 alkyl, C3-6 cycloalkyl, C6 aryl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl of Re2 are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R13;
• each Rf2 is independently hydrogen or C1-6 alkyl;
• each Rg2 and Rh2 is independently C1-6 alkyl, C3-6 cycloalkyl, 3- to 8-membered heterocyclyl, or —O—C1-6 alkyl;
• wherein the C1-6 alkyl, C3-6 cycloalkyl, and 3- to 8-membered heterocyclyl of Rg2 and Rh2 are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R13;
• or Rg2 and Rh2 are taken together with the phosphorus atom to which they are attached to form a 4- to 6-membered heterocyclyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R13;
• and
• each R13 is independently oxo, halogen, hydroxyl, —O(C1-6 alkyl), cyano, C1-6 alkyl or C1-6 haloalkyl;
• provided that the compound is other than
• 1H-Pyrazole-1-ethanol, 4-[3-[[2-methoxy-6-(4-morpholinyl)-3-pyridinyl]amino]-6-isoquinolinyl]-α,α-dimethyl-;
• 1H-Pyrazole-1-ethanol, 4-[3-[[5-(1,2-dimethyl-1H-imidazol-5-yl)-3-methoxy-2-pyridinyl]amino]-6-isoquinolinyl]-α,α-dimethyl-;
• 1H-Pyrazole-1-ethanol, 4-[3-[[6-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxy-3-pyridinyl]amino]-6-isoquinolinyl]-α,α-dimethyl-;
• and
• 3-Isoquinolinamine, 6-(1H-pyrazol-4-yl)-N-[4-(1-pyrrolidinylmethyl)-2-pyridinyl]-;
• and
• salts thereof.