US 12,138,263 B2
Pyrazolo[3,4-b]pyrazine SHP2 phosphatase inhibitors and methods of use thereof
Alexander M. Taylor, Cambridge, MA (US); Fabrizio Giordanetto, New York, NY (US); Jack Benjamin Greisman, New York, NY (US); Paul Maragakis, New York, NY (US); and Heike Schoenherr, Ann Arbor, MI (US)
Assigned to Relay Therapeutics, Inc., Cambridge, MA (US); and D.E. Shaw Research, LLC, New York, NY (US)
Appl. No. 16/982,395
Filed by Relay Therapeutics, Inc., Cambridge, MA (US); and D. E. Shaw Research, LLC, New York, NY (US)
PCT Filed Mar. 21, 2019, PCT No. PCT/US2019/023386
§ 371(c)(1), (2) Date Sep. 18, 2020,
PCT Pub. No. WO2019/183364, PCT Pub. Date Sep. 26, 2019.
Claims priority of provisional application 62/661,906, filed on Apr. 24, 2018.
Claims priority of provisional application 62/649,834, filed on Mar. 29, 2018.
Claims priority of provisional application 62/646,086, filed on Mar. 21, 2018.
Claims priority of provisional application 62/646,080, filed on Mar. 21, 2018.
Claims priority of provisional application 62/646,099, filed on Mar. 21, 2018.
Claims priority of provisional application 62/646,104, filed on Mar. 21, 2018.
Prior Publication US 2021/0069188 A1, Mar. 11, 2021
Int. Cl. A61K 31/4985 (2006.01); A61K 38/46 (2006.01); A61K 45/06 (2006.01); A61K 47/64 (2017.01); C07D 487/04 (2006.01); C07D 519/00 (2006.01)
CPC A61K 31/4985 (2013.01) [A61K 38/465 (2013.01); A61K 45/06 (2013.01); A61K 47/64 (2017.08); C07D 487/04 (2013.01); C07D 519/00 (2013.01)] 16 Claims
 
1. A compound having Formula i, ii, iii, or iv, or a pharmaceutically acceptable salt or stereoisomer thereof:

OG Complex Work Unit Chemistry
wherein:
Z1is N or CH;
Z is N or CH;
X is selected from the group consisting of a bond, —O—, —NRX1—, and —S(O)w—;
w is 0, 1 or 2;
RX1 is selected from the group consisting of hydrogen, —(C1-C6)alkyl and phenyl;
R1 is a ring moiety selected from the group consisting of a 8-12 membered bicyclic heteroaryl, a 11-15 membered tricyclic heteroaryl, phenyl, a 5-7 membered monocyclic heteroaryl, and a 4-7 membered heterocyclyl, wherein the ring moiety is substituted with —O—S(O)2-F or —S(O)2-F, and wherein the ring moiety may additionally and optionally be further substituted with one, two or more substituents each independently selected from the group consisting of R10, —OR10, —S(O)wR10, —C1-6alkyl-S(O)w—C1-3alkyl, —N(R10)2, —N(CO)R10, —N—S(O)w—R10, —OS(O)w—R10, —S(O)w—N(R10)2, —S(O)(NH)R10, —N(H)—SO2—C1-3alkyl, —N(SO2—C1-3alkyl)2, P(O)(R10)2, —C(O)R10, —C(O)OR10, —C(O)N(R10)2, oxo, halogen, hydroxyl, cyano, nitro, —C(═N—ORa)—C1-3alkyl, —C(═N—ORa)—H, —S(O)(NRa)—C1-3alkyl, phenyl (optionally substituted with one, two or three halogen, —O-phenyl, C1-3alkyl or C1-3haloalkyl), C1-3alkyl, C2-6alkynyl, C1-3haloalkyl, C3-6cycloalkyl, heterocyclyl (optionally substituted with one, two or three halogen, oxo, C1-3alkyl or C1-3haloalkyl), and heteroaryl (optionally substituted with one, two or three halogen, —C(O)N(R10)2, C1-3alkyl, C1-3alkyl-O—C1-3alkyl, C1-3alkyl-OH, or C1-3haloalkyl);
R10 is independently selected from the group consisting of hydrogen, C1-6alkyl, C2-6 alkenyl, C2-6alkynyl, C3-6cycloalkyl, C5-6cycloalkenyl, C2-6heteroalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C5-6cycloalkenyl, C2-6 heteroalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted by one, two, three or more substituents each independently selected from the group consisting of halogen, hydroxyl, —NRaC(O)—R20, —C(O)—R20, —C(NRa)—Rb, —NRaRb, C1-6alkyl, C1-6haloalkyl and C1-6alkoxy;
R20 is selected from the group consisting of hydrogen, hydroxyl, halogen, —NRaRb, C1-6alkyl and C1-6alkoxy;
Ra and Rb are each independently selected from the group consisting of hydrogen and C1-3alkyl;
R6 is independently for each occurrence selected from the group consisting of H, —(C1-6)alkyl, —C(O)OC1-4alkyl, and phenyl;
q is 0 or 1;
RY is selected from the group consisting of hydrogen and —(C1-C6)alkyl;
Y is selected from the group consisting of a 3-7 membered saturated carbocycle, a 4-7 membered saturated heterocycle, phenyl, and a 5-6 membered monocyclic heteroaryl; wherein Y is optionally substituted with one or more substituents each independently selected from the group consisting of (C1-C6)alkyl, —C(O)N(R6)2, —N(R6)2, halogen, and cyano, wherein said —(C1-C6)alkyl is optionally substituted with one or more substituents selected from the group consisting of —OH, —N(R6)2, oxo, and halogen;
R55 is selected from the group consisting of —C1-4 alkyl-N(R6)2, —N(R6)2, and heteroaryl (optionally substituted by one, two, or three substituent each independently selected from halogen, hydroxyl, cyano, —(C1-C6)alkyl, and —O(C1-C6) alkyl, —C(O)N(R6)2, —N(R6)2, and —(C1-C6)alkyl-N(R6)2);
R54 is selected from the group consisting of H, and C1-2alkyl, or
R54 and R55 taken together with the carbon to which they are attached form a ring selected from the group consisting of C3-6cycloalkyl and heterocyclyl, wherein the ring is optionally substituted on a carbon by one, two or three substituents each independently selected from the group consisting of R4 and R5 and on a nitrogen if present by R6;
RC is selected from the group consisting of H, OH, —(C1-C6)alkyl, —C(O)—O—C1-6(alkyl), —C(O)—C1-6(alkyl), and heterocyclyl, wherein C1-6(alkyl) is optionally substituted by one two or three substituents each selected from the group consisting of halogen, hydroxyl and N(R6)2; or
wherein RC is absent and R54 and R55 taken together with the carbon to which they are attached form a ring selected from C5-6cyclalkenyl and phenyl; wherein the ring is optionally substituted on a carbon by one, two or three substituents each independently selected from the group consisting of R4 and R5;
R56 is N(R6)2 or heterocycle (optionally substituted by one, two or three substituents each independently selected from halogen, hydroxyl, N(R6)2, —(C1-C6)alkyl, —C(O)—O—C1-6(alkyl), —C(O)—C1-6(alkyl), wherein C1-6(alkyl) is optionally substituted by one two or three substituents each selected from the group consisting of: halogen, hydroxyl or N(R6)2);
R4 and R5 are each independently selected from the group consisting of H, —OH, —(C1-C6)alkyl, —O(C1-C6)alkyl, —(C1-C6)alkyl-O—R6, —C(O)N(R6)2, —N(R6)2, halogen, —(C1-C6)alkyl-N(R6)2, and cyano, wherein said —(C1-C6)alkyl, —O(C1-C6)alkyl, —(C1-C6)alkyl-O—R6, or —(C1-C6)alkyl-N(R6)2 is optionally substituted with one or more substituents selected from the group consisting of —OH, —NH2, oxo, and halogen;
or R4 and R5, taken together with the carbon to which they are attached, form a 4-6 membered carbocyclic heterocylic ring B; which ring B is optionally substituted with one or or two substitutes each independently selected from the group consisting of (C1-C6)alkyl, —O(C1-C6)alkyl, —N(R6)2, —C(O)N(R6)2, halogen, oxo, and cyano.