US 12,473,301 B2
Isoquinoline compounds for the treatment of cancer
Jun Liang, South San Francisco, CA (US); Rohan V. Mendonca, South San Francisco, CA (US); Michael Siu, South San Francisco, CA (US); John Tellis, South San Francisco, CA (US); Weiru Wang, South San Francisco, CA (US); BinQing Wei, South San Francisco, CA (US); Bryan Chan, South San Francisco, CA (US); Edna F. Choo, South San Francisco, CA (US); Joy Drobnick, South San Francisco, CA (US); Lewis J. Gazzard, South San Francisco, CA (US); and Timothy Heffron, South San Francisco, CA (US)
Assigned to Genentech, Inc., South San Francisco, CA (US)
Filed by Genentech, Inc., South San Francisco, CA (US)
Filed on Apr. 1, 2021, as Appl. No. 17/220,307.
Application 17/220,307 is a continuation of application No. PCT/US2019/054272, filed on Oct. 2, 2019.
Claims priority of provisional application 62/740,269, filed on Oct. 2, 2018.
Prior Publication US 2021/0332064 A1, Oct. 28, 2021
Int. Cl. C07D 498/04 (2006.01); C07D 401/04 (2006.01); C07D 401/14 (2006.01); C07D 519/00 (2006.01)
CPC C07D 498/04 (2013.01) [C07D 401/04 (2013.01); C07D 401/14 (2013.01); C07D 519/00 (2013.01)] 18 Claims
 
1. A compound of Formula (I)

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt thereof, wherein
R1 is hydrogen, halogen, hydroxyl, C1-6 alkyl, C1-6 haloalkyl, C3-4 cycloalkyl, —O(C1-6 alkyl), or —O(C1-6 haloalkyl);
R15 is —OR16, —SR16, —NR17R18, or D;
each R16 is independently C1-6 alkyl, C3-10 cycloalkyl, or 3- to 14-membered heterocyclyl; wherein the C1-6 alkyl, C3-10 cycloalkyl and 3- to 14-membered heterocyclyl of R16 are each independently optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R10;
R17 is hydrogen or C1-6 alkyl;
R18 is 3- to 14-membered heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R10; C3-10 cycloalkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R10; or C1-6 alkyl substituted with 1, 2, 3, 4 or 5 substituents independently selected from R10;
or R17 and R18 are taken together with the nitrogen atom to which they are attached to form a saturated 4- to 12-membered heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R10;
D is

OG Complex Work Unit Chemistry
 wherein the wavy line represents the attachment point to the parent structure;
R30, R31, R32, R33 and R34 are independently hydrogen or R10; or,
optionally two of R30, R31, R32, R33 and R34 taken together with the carbon atoms to which they are attached form a C3-8 cycloalkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R10 or 3- to 10-membered heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R10; provided that at least one of R30, R31, R32, R33 and R34 is other than hydrogen;
R3 is hydrogen, 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 selected from the group consisting of:

OG Complex Work Unit Chemistry
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 saturated 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)ORb, —C(O)NRcRd, —ORb, —OC(O)Ra, —OC(O)NRcRd, —SRb, —S(O)Re, —S(O)2Re, —S(O)(═NH)Re, —S(O)2NRcRd, —NRcRd, —N(Rf)C(O)Ra, —N(Rf)C(O)ORb, —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, C6-10 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 saturated 4- to 12-membered heterocyclyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R11;
each Re is independently 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 Re 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)Ra1, —OC(O)NRc1Rd1, —SRb1, —S(O)Re1, —S(O)2Re1, —S(O)2NRc1Rd1, —NRc1Rd1, —N(Rf1)C(O)Ra1, —N(Rf1)C(O)ORb1, —N(Rf1)C(O)NRc1Rd1, —N(Rf1)S(O)2Rel, —N(Rf1)S(O)2NRc1Rd1, or —P(O)Rg1Rh1; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C6-10 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 Ral 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 Rb1 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 saturated 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 Rel 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)ORb2, —C(O)NRc2Rd2, —ORb2, —OC(O)Ra2, —OC(O)NRc2Rd2, —S(O)2Re2, —S(O)2NRc2Rd2, —NRc2Rd2, —N(Rf2)C(O)Ra2, —N(Rf2)C(O)ORb2, —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 Ra2 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 saturated 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.