	US 11,999,733 B2
	Diacylglycerol kinase modulating compounds
Julian A. Codelli, Mountlake Terrace, WA (US); and Jonathan William Medley, San Bruno, CA (US)
Assigned to Gilead Sciences, Inc., Foster City, CA (US)
Filed by Gilead Sciences, Inc., Foster City, CA (US)
Filed on Jun. 21, 2022, as Appl. No. 17/844,921.
Claims priority of provisional application 63/213,884, filed on Jun. 23, 2021.
Prior Publication US 2023/0046340 A1, Feb. 16, 2023
Int. Cl. C07D 471/14 (2006.01); A61P 31/18 (2006.01); A61P 31/20 (2006.01); A61P 35/00 (2006.01); A61P 35/04 (2006.01); C07D 471/04 (2006.01); C07D 519/00 (2006.01)

CPC C07D 471/14 (2013.01) [C07D 471/04 (2013.01); C07D 519/00 (2013.01)]

19 Claims

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein

Z¹is N or CR¹;

Z²is N or CR²;

R¹is hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, halogen, C_1-6haloalkyl, C_1-6haloalkoxy, or —CN;

R²is hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6hydroxyalkyl, C_1-6aminoalkyl, C_1-6alkoxy, C_2-6alkoxyalkyl, halogen, C_1-6haloalkyl, C_1-6haloalkoxy, —CN, —NO, —NO₂, —C(O)R^2a, —C(O)OR^2a, —OC(O)R^2a, —C(O)N(R^2a)(R^2b), —N(R^2a)C(O)R^2b, —OC(O)N(R^2a)(R^2b), —N(R^2a)C(O)OR^2b, —C(═NR^2a)N(R^2b)(R^2c), —N(R^2a)(R^2b), —N(R^2a)N(R^2b)(R^2c), —N(R^2a)N═C(R^2b)(OR²c), —OR^2a, —SR^2a, —S(O)R^2a, —S(O)(NR^2a)(R^2b), —S(NR^2a)(NR^2b)(R^2c), —S(O)₂R^2a, —S(O)₂N(R^2a)(R^2b), —N(R^2a)S(O)₂(R^2b), —P(R^2a)(R^2b), —P(O)(R^2a)(R^2b), —P(O)(OR^2a)(R^2b), —P(O)(OR^2a)(OR^2b), C_3-10cycloalkyl, C_1-6alkyl-C_3-10cycloalkyl, C_6-12aryl, C_1-6alkyl-C_6-12aryl, heterocycloalkyl, C_1-6alkyl-(heterocycloalkyl), heteroaryl, or C_1-6alkyl-(heteroaryl), wherein each alkyl, alkenyl or alkynyl is independently optionally substituted with 1 to 3 R^2dgroups which can be the same or different, each cycloalkyl is optionally substituted with 1 to 3 R^2egroups which can be the same or different, each aryl is optionally substituted with 1 to 3 R^2fgroups which can be the same or different, each heterocycloalkyl is optionally substituted with 1 to 3 R^2ggroups which can be the same or different, and each heteroaryl is optionally substituted with 1 to 3 R^2hgroups which can be the same or different;

each R^2a, R^2b, and R^2cis independently hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6hydroxyalkyl, C_1-6aminoalkyl, C_2-6alkoxyalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, C_1-6alkyl-C_3-10cycloalkyl, C_6-12aryl, C_1-6alkyl-C_6-12aryl, heterocycloalkyl, C_1-6alkyl-(heterocycloalkyl), heteroaryl, or C_1-6alkyl-(heteroaryl), wherein the aryl or heteroaryl is optionally substituted with 1 to 3 R^2jwhich can be the same or different;

alternatively, R^2a, R^2b, and R^2cwhen attached to the same atom can be combined with the atom to which they are attached to form a heterocycloalkyl;

each R^2dis independently —CN, —C(O)R^2d1, —C(O)OR^2d1, —OC(O)R^2d1, —C(O)N(R^2d1)(R^2d2), —N(R^2d1)C(O)R^2d2, —OC(O)N(R^2d1)(R^2d2), —N(R^2d1)C(O)OR^2d2, —N(R^2d1)(R^2d2), ═O, —OR^2d1, —SR^2d1, —S(O)R^2d1, —S(O)(NR^2d1)(R^2d2), —S(O)₂R^2d1, —S(O)N(R^2d1)(R^2d2), —N(R^2d1)S(O)₂R^2d2, C_3-10cycloalkyl, C_1-6alkyl-C_3-10cycloalkyl, C_6-12aryl, C_1-6alkyl-C_6-12aryl, heterocycloalkyl, C_1-6alkyl-(heterocycloalkyl), heteroaryl, or C_1-6alkyl-(heteroaryl);

each R^2d1and R^2d2is independently hydrogen, C_1-6alkyl, C_1-6hydroxyalkyl, C_1-6aminoalkyl, C_2-6alkoxyalkyl, or C_1-6haloalkyl;

each R^2e, R^2f, R^2g, and R^2his independently hydrogen, C_1-6alkyl, C_1-6hydroxyalkyl, C_1-6aminoalkyl, C_1-6alkoxy, C_2-6alkoxyalkyl, halogen, C_1-6haloalkyl, C_1-6haloalkoxy, —CN, or —OH;

each R^2jis independently C_1-6alkyl, C_1-6hydroxyalkyl, C_1-6aminoalkyl, C_1-6alkoxy, C_2-6alkoxyalkyl, halogen, C_1-6haloalkyl, or C_1-6haloalkoxy;

R³is hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6hydroxyalkyl, C_1-6aminoalkyl, C_1-6alkoxy, C_2-6alkoxyalkyl, halogen, C_1-6haloalkyl, C_1-6haloalkoxy, —CN, —NO, —NO₂, —C(O)R^3a, —C(O)OR³a, —OC(O)R^3a, —C(O)N(R^3a)(R^3b), —N(R^3a)C(O)R^3b, —OC(O)N(R^3a)(R^3b), —N(R^3a)C(O)OR³b, —C(═NR³a)N(R^3b)(R^3c), —N(R^3a)(R^3b), —N(R^3a)N(R^3b)(R^3c), —N(R^3a)N═C(R^3b)(OR³c), —OR³a, —SR³a, —S(O)R^3a, —S(O)(NR³a)(R^3b), —S(NR³a)(NR³b)(R^3c), —S(O)₂R^3a, —S(O)₂N(R^3a)(R^3b), —N(R^3a)S(O)₂(R^3b), —P(R^3a)(R^3b), —P(O)(R^3a)(R^3b), —P(O)(OR³a)(R^3b), —P(O)(OR^3a)(OR^3b), C_3-10cycloalkyl, C_1-6alkyl-C_3-10cycloalkyl, C_6-12aryl, C_1-6alkyl-C_6-12aryl, heterocycloalkyl, C_1-6alkyl-(heterocycloalkyl), heteroaryl, or C_1-6alkyl-(heteroaryl), wherein each alkenyl or alkynyl is independently optionally substituted with 1 to 3 R^3dgroups, each cycloalkyl is optionally substituted with 1 to 3 R^3egroups which can be the same or different, each aryl is optionally substituted with 1 to 3 R^3fgroups which can be the same or different, each heterocycloalkyl is optionally substituted with 1 to 3 R^3ggroups which can be the same or different, and each heteroaryl is optionally substituted with 1 to 3 R^3hgroups which can be the same or different;

each R^3a, R^3b, and R^3cis independently hydrogen, C_1-6alkyl, C_1-6hydroxyalkyl, C_2-6alkoxyalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, C_1-6alkyl-C_3-10cycloalkyl, C_6-12aryl, C_1-6alkyl-C_6-12aryl, heterocycloalkyl, or heteroaryl;

alternatively, R^3a, R^3b, and R^3cwhen attached to the same atom can be combined with the atom to which they are attached to form a heterocycloalkyl;

each R^3dis independently —N(R^3d1)(R^3d2), —OR^3d1, C_3-10cycloalkyl, C_1-6alkyl-C_3-10cycloalkyl, C_6-12aryl, C_1-6alkyl-C_6-12aryl, heterocycloalkyl, or heteroaryl;

each R^3d1and R^3d2is independently hydrogen, C_1-6alkyl, or —C(O)O—(C_1-6alkyl);

each R^3e, R³, R³⁹, and R^3his independently hydrogen, C_1-6alkyl, C_1-6alkoxy, halogen, C_1-6haloalkyl or C_1-6haloalkoxy;

R⁴is hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, halogen, C_1-6haloalkyl, C_1-6haloalkoxy, or —CN;

R⁵is hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6hydroxyalkyl, C_2-6alkoxyalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, C_1-6alkyl-C_3-10cycloalkyl, C_6-12aryl, C_1-6alkyl-C_6-12aryl, heterocycloalkyl, C_1-6alkyl-(heterocycloalkyl), heteroaryl, or C_1-6alkyl-(heteroaryl), wherein the alkyl is optionally substituted with R^5a;

R^5ais —OSi(R^5a1a(R^5a2)(R^5a3);

R^5a1, R^5a2, and R^5a3are each independently C_1-6alkyl; and

R⁶is C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_6-12aryl, or heteroaryl, wherein the aryl or heteroaryl are each optionally substituted with 1 to 3 R^6awhich can be the same or different;

each R^6ais independently C_1-6alkyl, C_2-6alkenyl, C_2-8alkynyl, C_1-6hydroxyalkyl, C_1-6aminoalkyl, C_1-6alkoxy, C_2-6alkoxyalkyl, halogen, C_1-6haloalkyl, C_1-6haloalkoxy, —CN, —NO₂, —C(O)R^6b, —C(O)OR^6b, —OC(O)R^6b, —C(O)N(R^6b)(R^6c), —N(R⁶b)C(O)R^6c, —C(═NR⁶b)N(R^6c)(R^6d), —N(R^6b)(R^6c), —OR⁶b, —SR⁶b, —S(O)R^6b, —S(O)₂R^6b, —S(NR⁶b)(NR⁶c)R^6d, —S(O)(NR⁶b)(R^6c), —S(O)₂N(R^6b)(R^6c), —N(R⁶b)S(O)₂(R^6c), —P(R^6b)(R^6c), —P(O)(R^6b)(R^6c), —P(O)(OR⁶b)(R^6c), —P(O)(OR^6b)(OR^6c), C_3-10cycloalkyl, C_1-6alkyl-C_3-10cycloalkyl, C_6-12aryl, C_1-6alkyl-C_6-12aryl, heterocycloalkyl, C_1-6alkyl-(heterocycloalkyl), heteroaryl, or C_1-6alkyl-(heteroaryl), wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is each optionally substituted with 1 to 3 R^6ewhich can be the same or different, the alkyl is optionally substituted with R^6f, and the alkynyl is optionally substituted with 1 to 4 R^6jwhich can be the same or different;

each R^6b, R^6cand R^6dis independently hydrogen, C_1-6alkyl, C_1-6hydroxyalkyl, C_1-6aminoalkyl, C_2-6alkoxyalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, C_1-6alkyl-C_3-10cycloalkyl, C_6-12aryl, C_1-6alkyl-C_6-12aryl, heterocycloalkyl, C_1-6alkyl-(heterocycloalkyl), heteroaryl, or C_1-6alkyl-(heteroaryl), wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted by 1 to 3 R^6kwhich can be the same or different;

each R^6kis independently C_1-6alkyl, C_1-6hydroxyalkyl, C_1-6aminoalkyl, C_1-6alkoxy, C_2-6alkoxyalkyl, C_1-6haloalkyl, C_1-6haloalkoxy, C_3-10cycloalkyl, C_1-6alkyl-C_3-10cycloalkyl, heterocycloalkyl, or C_1-6alkyl-(heterocycloalkyl);

each R^6eis independently C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6hydroxyalkyl, C_1-6aminoalkyl, C_1-6alkoxy, C_2-6alkoxyalkyl, halogen, C_1-6haloalkyl, C_1-6haloalkoxy, —CN, —NO₂, —C(O)R^6e1, —C(O)OR^6e1, —OC(O)R^6e1, —C(O)N(R^6e1)(R^6e2), —N(R^6e1)C(O)R^6e2, —OC(O)N(R^6e1)(R^6e2), —N(R^6e1)C(O)OR^6e2, —C(═NR^6e1)N(R^6e2)(R^6e3), —N(R^6e1)(R^6e2), ═O, —OR^6e1, —SR^6e1—S(O)R^6e1, —S(NR^6e1)(NR^6e2), —S(O)(NR^6e1)(R^6e2), —S(O)₂R^6e1, —S(O)₂N(R^6e1)(R^6e2), —SF₅, —N(R^6e1)S(O)₂(R^6e2), —P(R^6e1)(R^6e2), —P(O)(R^6e1)(R^6e2), —P(O)(OR^6e1)(R^6e2), —P(O)(OR^6e1)(OR^6e2), —Si(R^6e1)(R^6e2)(R^6e3), C_3-10cycloalkyl, C_1-6alkyl-C_3-10cycloalkyl, C_6-12aryl, C_1-6alkyl-C_6-12aryl, heterocycloalkyl, C_1-6alkyl-heterocycloalkyl, heteroaryl, or C_1-6alkyl-heteroaryl, wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is each optionally substituted with 1 to 3 R^6hwhich can be the same or different, and the alkyl is optionally substituted with 1 to 3 R^6mwhich can be the same or different;

each R^6e1, R^6e2, and R^6e3is independently hydrogen, C_1-6alkyl, C_1-6hydroxyalkyl, C_1-6aminoalkyl, C_1-6alkoxyalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, C_1-6alkyl-C_3-10cycloalkyl, C_6-10aryl, C_1-6alkyl-C_6-10aryl, heterocycloalkyl, C_1-6alkyl-(heterocycloalkyl), heteroaryl, or C_1-6alkyl-(heteroaryl), wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with 1 to 3 R⁶ⁿwhich can be the same or different;

each R⁶ⁿis C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6hydroxyalkyl, C_1-6aminoalkyl, C_1-6alkoxy, C_2-6alkoxyalkyl, halogen, C_1-6haloalkyl, C_1-6haloalkoxy, —CN, —C(O)R⁶ⁿ¹, —C(O)OR⁶ⁿ¹, —OC(O)R⁶ⁿ¹, —C(O)N(R⁶ⁿ¹)(R⁶ⁿ²), —N(R⁶ⁿ¹)C(O)R⁶ⁿ², —OC(O)N(R⁶ⁿ¹)(R⁶ⁿ²), —N(R⁶ⁿ¹)C(O)OR⁶ⁿ², —C(═NR⁶ⁿ¹)N(R⁶ⁿ²)(R⁶ⁿ³), —N(R⁶ⁿ¹)(R⁶ⁿ²), ═O, —OH, —SR⁶ⁿ¹, —S(O)R⁶ⁿ¹, —S(NR⁶ⁿ¹)(NR⁶ⁿ²)R⁶ⁿ³, —S(O)(NR⁶ⁿ¹)(R⁶ⁿ²), —S(O)₂R⁶ⁿ¹, —S(O)₂N(R⁶ⁿ¹)(R⁶ⁿ²), or —N(R⁶ⁿ¹)S(O)₂(R⁶ⁿ²);

each R⁶ⁿ¹, R⁶ⁿ²and R⁶ⁿ³is independently hydrogen, C_1-6alkyl, C_1-6hydroxyalkyl, C_1-6aminoalkyl, C_2-6alkoxyalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, C_1-6alkyl-C_3-10cycloalkyl, C_6-10aryl, C_1-6alkyl-C_6-10aryl, heterocycloalkyl, C_1-6alkyl-(heterocycloalkyl), heteroaryl, or C_1-6alkyl-(heteroaryl);

each R^6his independently C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6hydroxyalkyl, C_1-6aminoalkyl, C_1-6alkoxy, C_2-6alkoxyalkyl, halogen, C_1-6haloalkyl, C_1-6haloalkoxy, —CN, —C(O)R^6h1, —C(O)OR^6h1, —OC(O)R^6h1, —C(O)N(R^6h1)(R^6h2), —N(R^6h1)C(O)R^6h2, —OC(O)N(R^6h1)(R^6h2), —N(R^6h1)C(O)OR^6h2, —C(═NR^6h1)N(R^6h2)(R^6h3), —N(R^6h1)(R^6h2), ═O, —OH, —SR^6h1, —S(O)R^6h1, —S(NR^6h1)(NR^6h2)R^6h3, —S(O)(NR^6h1)(R^6h2), —S(O)₂R^6h1, —S(O)₂N(R^6h1)(R^6h2), —N(R^6h1)S(O)₂(R^6h2), C_3-10cycloalkyl, C_1-6alkyl-C_3-10cycloalkyl, heterocycloalkyl, or C_1-6alkyl-(heterocycloalkyl);

each R^6h1, R^6h2, and R^6h3is independently hydrogen, C_1-6alkyl, C_1-6hydroxyalkyl, C_1-6aminoalkyl, C_2-6alkoxyalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, C_1-6alkyl-C_3-10cycloalkyl, C_6-10aryl, C_1-6alkyl-C_6-10aryl, heterocycloalkyl, C_1-6alkyl-(heterocycloalkyl), heteroaryl, or C_1-6alkyl-(heteroaryl);

each R^6mis independently halogen, C_1-6haloalkyl, C_1-6haloalkoxy, —CN, —C(O)R^6m1, —C(O)OR^6m1, —OC(O)R^6m1, —C(O)N(R^6m1)(R^6m2), —N(R^6m3)C(O)R^6m2, —OC(O)N(R^6m1)(R^6m2), —N(R^6m1)C(O)OR^6m2, —C(═NR^6m3)N(R^6m1)(R^6m2), —N(R^6m1)(R^6m2), ═O, —OH, —SR^6m1, —S(O)R^6m1, —S(NR^6m1)(NR^6m2)R^6m3, —S(O)(NR^6m1)(R^6m2), —S(O)₂R^6m1, —S(O)₂N(R^6m1)(R^6m2), or —N(R^6m3)S(O)₂(R^6m2);

each R^6m1, R^6m2, and R^6m3is independently hydrogen, C_1-6alkyl, C_1-6hydroxyalkyl, C_1-6aminoalkyl, C_2-6alkoxyalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, C_1-6alkyl-C_3-10cycloalkyl, C_6-10aryl, C_1-6alkyl-C_6-10aryl, heterocycloalkyl, C_1-6alkyl-(heterocycloalkyl), heteroaryl, or C_1-6alkyl-(heteroaryl);

R^6fis —OSi(R^6f1)(R^6f2)(R^6f3);

R^6f1, R^6f2, and R^6f3are each independently C_1-6alkyl;

each R^6jis independently C_2-6alkoxyalkyl, halogen, C_1-6haloalkyl, C_1-6haloalkoxy, —CN, —C(O)R^6j1, —C(O)OR^6j1, —OC(O)R^6j1, —C(O)N(R^6j1)(R^6j2), —N(R^6j3)C(O)R^6j2, —OC(O)N(R^6j1)(R^6j2), —N(R^6j1)C(O)OR^6j2, —C(═NR^6j3)N(R^6j1)(R^6j2), —N(R^6j1)(R^6j2), ═O, —OR^6j1, —SR^6j1, —S(O)R^6j1, —S(NR^6j1)(NR^6j2), —S(NR^6j1)(NR^6j2)R^6j3, —S(O)(NR^6j1)(R^6j2), —S(O)₂R^6j1, —S(O)₂N(R^6j1)(R^6j2), —N(R^6j1)S(O)₂(R^6j2), —Si(R^6j1)(R^6j2)(R^6j3), C_3-10cycloalkyl, C_6-12aryl, heterocycloalkyl, or heteroaryl, wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with 1 to 3 R^6pwhich can be the same or different;

each R^6j1, R^6j2, and R^6j3is independently hydrogen, C_1-6alkyl, C_1-6hydroxyalkyl, C_1-6aminoalkyl, C_2-6alkoxyalkyl, C_1-6haloalkyl, C_3-10cycloalkyl optionally substituted with C_1-6haloalkyl, C_1-6alkyl-C_3-10cycloalkyl, C_6-10aryl, C_1-6alkyl-C_6-10aryl, heterocycloalkyl, C_1-6alkyl-(heterocycloalkyl), heteroaryl, or C_1-6alkyl-(heteroaryl);

each R^6pis independently C_1-6alkyl, C_1-6hydroxyalkyl, C_1-6aminoalkyl, C_1-6alkoxy, C_2-6alkoxyalkyl, halogen, C_1-6haloalkyl, C_1-6haloalkoxy, —CN, —C(O)R^6p1, —C(O)OR^6p1, —OC(O)R^6p1, —C(O)N(R^6p1)(R^6p2), —N(R^6p1)C(O)R^6p2, —OC(O)N(R^6p1)(R^6p2), —N(R^6p1)C(O)OR^6p2, —C(═NR^6p3)N(R^6p1)(R^6p2), —N(R^6p1)(R^6p2), ═O, —OH, —SR^6p1, —S(O)R^6p1, —S(NR^6p1)(NR^6p2)R^6p3, —S(O)(NR^6p1)(R^6p2), —S(O)₂R^6p1, —S(O)₂N(R^6p1)(R^6p2), or —N(R^6p1)S(O)₂(R^6p2);

each R^6p1, R^6p2, and R^6p3is independently hydrogen, C_1-6alkyl, C_1-6hydroxyalkyl, C_1-6aminoalkyl, C_2-6alkoxyalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, C_1-6alkyl-C_3-10cycloalkyl, C_6-10aryl, C_1-6alkyl-C_6-10aryl, heterocycloalkyl, C_1-6alkyl-(heterocycloalkyl), heteroaryl, or C_1-6alkyl-(heteroaryl);

or R⁵and one R^6atogether with the atoms to which they are attached form a heterocycloalkyl, optionally substituted with 1 to 3 R^6gwhich can be the same or different;

each R^6gis independently C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6hydroxyalkyl, C_1-6aminoalkyl, C_2-6alkoxyalkyl, halogen, C_1-6haloalkyl, C_1-6haloalkoxy, or —CN;

R⁷is hydrogen, C_1-6alkyl, C_1-6hydroxyalkyl, C_1-6aminoalkyl, C_2-6alkoxyalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, C_1-6alkyl-C_3-10cycloalkyl, heterocycloalkyl, or C_1-6alkyl-(heterocycloalkyl);

each heterocycloalkyl is a 3 to 20 membered ring having 1 to 4 heteroatoms each independently N, O or S; and

each heteroaryl is a 5 to 18 membered ring having 1 to 4 heteroatoms each independently N, O or S.