US 11,701,354 B2
Pyrazolo[3,4-b]pyrazine derivatives as SHP2 phosphatase inhibitors
Alexander M. Taylor, Cambridge, MA (US); W. Patrick Walters, Westborough, MA (US); Mark Andrew Murcko, Holliston, MA (US); Fabrizio Giordanetto, New York, NY (US); Eric Therrien, Bronx, NY (US); Sathesh Bhat, Jersey City, NJ (US); and Markus Kristofer Dahlgren, Shelton, CT (US)
Assigned to D. E. Shaw Research, LLC, New York, NY (US); and Relay Therapeutics, Inc., Cambridge, MA (US)
Appl. No. 16/651,733
Filed by Relay Therapeutics, Inc., Cambridge, MA (US); and D. E. Shaw Research, LLC, New York, NY (US)
PCT Filed Sep. 28, 2018, PCT No. PCT/US2018/053322
§ 371(c)(1), (2) Date Mar. 27, 2020,
PCT Pub. No. WO2019/067843, PCT Pub. Date Apr. 4, 2019.
Claims priority of provisional application 62/565,599, filed on Sep. 29, 2017.
Prior Publication US 2020/0253969 A1, Aug. 13, 2020
Int. Cl. A61K 31/4985 (2006.01); C07D 487/04 (2006.01); A61K 45/06 (2006.01); C07D 519/00 (2006.01)
CPC A61K 31/4985 (2013.01) [A61K 45/06 (2013.01); C07D 487/04 (2013.01); C07D 519/00 (2013.01)] 40 Claims
 
1. A compound of Formula (I):

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein:
A is a 4-7 membered heterocyclyl, a monocyclic or bicyclic 6-10 membered aryl, a monocyclic 5-7 membered heteroaryl, or a bicyclic 8-10 membered heteroaryl, wherein the monocyclic 5-7 membered heteroaryl or the bicyclic 8-10 membered heteroaryl has 1 or more heteroatoms independently selected from the group consisting of N, O, and S, and further wherein A is optionally substituted by one or more substituents independently selected from the group consisting of halogen, cyano, C(O)R10, C(O)N(R10)2, N(R10)2, NR10C(O)R10, NR10S(O)wR10, OR10, ═O, OS(O)wR10, P(O)(R10)2, S(O)wR10, S(O)wN(R10)2, and R10;
X is a bond, —CRX2RX3—, —CRX4RX5NRX1—, —CRX4RX5O—, —CRX6═CRX7—, —C≡C—, —C(O)—, —C(O)NRX11—, —NRX1—, —NRX1CRX4RX5, —O—, —OCRX4RX5—, —S(O)w—, or cyclopropyl;
RX1 is H, C1-6 alkyl, or phenyl; or
RX1 and A, together with the nitrogen atom to which they are attached, form a saturated or partially unsaturated 8-10 membered bicyclic heterocyclyl, wherein the saturated or partially unsaturated 8-10 membered bicyclic heterocyclyl optionally has 1 or more additional heteroatoms independently selected from the group consisting of N, O, and S, and further wherein the saturated or partially unsaturated 8-10 membered bicyclic heterocyclyl is optionally substituted by one or more substituents independently selected from the group consisting of halogen, cyano, C(O)R10, C(O)N(R10)2, N(R10)2, OR10, ═O, OS(O)wR10, P(O)(R10), S(O)wR10, S(O)wN(R10)2, and R10;
RX2 is H, halogen, C1-6 alkyl, C(O)NRaRb, NaRb, OH, or OC1-6 alkyl, wherein the C1-6 alkyl or OC1-6 alkyl is optionally substituted by one or more independently selected RP substituents;
RX3 is H, halogen, C1-6 alkyl, C(O)NRaRb, NaRb, OH, or OC1-6 alkyl, wherein the C1-6 alkyl or OC1-6 alkyl is optionally substituted by one or more independently selected RP substituents; or
RX2 and RX3, together with the carbon atom to which they are attached, form a 3-6 membered carbocyclyl, wherein the 3-6 membered carbocyclyl is optionally substituted by one or more substituents independently selected from the group consisting of halogen, C1-6 alkyl, C(O)NRaRb, NRaRb, OC1-6 alkyl, and ═O;
RX4 is H or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted by one or more independently selected RP substituents;
RX5 is H or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted by one or more independently selected RP substituents;
RX6 is H, halogen, CN, C1-6 alkyl, or C(O)NRaRb, wherein the C1-6 alkyl is optionally substituted by one or more independently selected RP substituents;
RX7 is H, halogen, CN, C1-6 alkyl, or C(O)NRaRb, wherein the C1-6 alkyl is optionally substituted by one or more independently selected RP substituents;
RX11 is H, C1-6 alkyl, or phenyl; or
RX11 and A, together with the nitrogen atom to which they are attached, form a saturated or partially unsaturated 8-10 membered bicyclic heterocyclyl, wherein the saturated or partially unsaturated 8-10 membered bicyclic heterocyclyl optionally has 1 or more additional heteroatoms independently selected from the group consisting of N, O, and S, and further wherein the saturated or partially unsaturated 8-10 membered bicyclic heterocyclyl is optionally substituted by one or more substituents independently selected from the group consisting of halogen, cyano, C(O)R10, C(O)N(R10)2, N(R10)2, OR10, ═O, OS(O)wR10, P(O)(R10)2, S(O)wR10, S(O)wN(R10)2, S(O)NHR10, and R10;
each R10 is independently H, C1-6 alkyl, C2-6 heteroalkyl, C3-6 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each C1-6 alkyl, C2-6 heteroalkyl, C3-6 cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted by one or more substituents independently selected from the group consisting of halogen, C1-6 alkyl, C1-6 haloalkyl, C(NRa)Rb, C(O)R20, NaRb, OH, and OC1-6 alkyl;
each R20 is independently H, halogen, C1-6 alkyl, NRaRb, OH, or OC1-6 alkyl;
Y is —C1-3 alkylene-NRY—, —NRY—, or —NRY—C1-3 alkylene-;
RY is H, C1-6 alkyl, or phenyl;
B is a saturated 3-7 membered carbocyclyl or a saturated 4-7 membered heterocyclyl, wherein the saturated 4-7 membered heterocyclyl has 1 or 2 heteroatoms or heteroatomic groups independently selected from the group consisting of NRb, O, and S(O)w, and further wherein the saturated 3-7 membered carbocyclyl or the saturated 4-7 membered heterocyclyl is optionally substituted on one or more available carbons by one or more substituents independently selected from the group consisting of halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C(O)C1-6 alkyl, C(O)NRaRb, C(O)OH, C(O)OC1-6 alkyl, NRaRb, NRaC(O)C1-6 alkyl, NRaC(O)OC1-6 alkyl, NRaS(O)2C1-6 alkyl, OH, OC1-6 alkyl, OC3-6 alkenyl, OC3-6 alkynyl, ═O, S(O)wC1-6 alkyl, S(O)2NRaRb, C3-6 cycloalkyl, C3-6 cycloalkoxy, aryl, and heteroaryl, wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C(O)C1-6 alkyl, C(O)OC1-6 alkyl, NRaC(O)C1-6 alkyl, NRaC(O)OC1-6 alkyl, NRaS(O)2C1-6 alkyl, OC1-6 alkyl, OC3-6 alkenyl, OC3-6 alkynyl, S(O)C1-6 alkyl, C3-6 cycloalkyl, and C3-6 cycloalkoxy is optionally and independently substituted by one or more independently selected RP substituents, and further wherein each aryl and heteroaryl is optionally and independently substituted by one or more independently selected Rf substituents;
each Rf is independently RP, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C(O)C1-6 alkyl, C(O)OC1-6 alkyl, NRaC(O)C1-6 alkyl, NRaC(O)OC1-6 alkyl, OC1-6 alkyl, S(O)wC1-6 alkyl, or C3-6 cycloalkyl, wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C(O)C1-6 alkyl, C(O)OC1-6 alkyl, NRaC(O)C1-6 alkyl, NRaC(O)OC1-6 alkyl, OC1-6 alkyl, S(O)wC1-6 alkyl, and C3-6 cycloalkyl is optionally and independently substituted by one or more independently selected RP substituents;
each Rh is independently H, C1-6 alkyl, C3-6 alkenyl, C3-6 alkynyl, C(O)C1-6 alkyl, C(O)NRaRb, C(O)OC1-6 alkyl, S(O)2C1-6 alkyl, S(O)2NRaRb, or C3-6 cycloalkyl, wherein each C1-6 alkyl, C3-6 alkenyl, C3-6 alkynyl, C(O)C1-6 alkyl, C(O)OC1-6 alkyl, S(O)2C1-6 alkyl, and C3-6 cycloalkyl is optionally and independently substituted by one or more independently selected RP substituents;
each RP is independently halogen, cyano, C(O)NRaRb, NaRb, NRaC(O)NRaRb, OH, OC1-6 alkyl, or SO2NRaRb;
Ra is H or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted by one or more substituents independently selected from the group consisting of halogen, cyano, OH, and ═O;
Rb is H or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted by one or more substituents independently selected from the group consisting of halogen, cyano, OH, and ═O; or
Ra and Rb, together with the nitrogen atom to which they are attached, form a monocyclic 4-6 membered heterocyclyl, wherein the monocyclic 4-6 membered heterocyclyl optionally has an additional heteroatom selected from the group consisting of N, O, and S, and further wherein the monocyclic 4-6 membered heterocyclyl is optionally substituted by one or more substituents independently selected from the group consisting of halogen, cyano, OH, and ═O;
R3 is H, C1-6 alkyl, or phenyl; and
each w is independently 0, 1, or 2.
 
21. A compound of Formula (III):

OG Complex Work Unit Chemistry
wherein:
A is a 4-7 membered heterocyclyl, phenyl, or a monocyclic 5-7 membered heteroaryl, wherein the monocyclic 5-7 membered heteroaryl has 1 or more heteroatoms independently selected from the group consisting of N, O, and S, and further wherein A is optionally substituted by one or more substituents independently selected from the group consisting of halogen, cyano, C(O)N(R10)2, N(R10)2, OR10, ═O, and R10;
X is a bond, —CRX2RX3—, —C(O)—, —NRX1—, —O—, or —S(O)w—;
RX1 is H, C1-6 alkyl, or phenyl; or
RX1 and A, together with the nitrogen atom to which they are attached, form a saturated or partially unsaturated 8-10 membered bicyclic heterocyclyl, wherein the saturated or partially unsaturated 8-10 membered bicyclic heterocyclyl optionally has 1 or more additional heteroatoms independently selected from the group consisting of N, O, and S, and further wherein the saturated or partially unsaturated 8-10 membered bicyclic heterocyclyl is optionally substituted by one or more substituents independently selected from the group consisting of halogen, cyano, C(O)N(R10)2, N(R10)2, ═O, and R10;
RX2 is H, halogen, C1-6 alkyl, C(O)NRaRb, NRaRb, OH, or OC1-6 alkyl;
RX3 is H, halogen, C1-6 alkyl, C(O)NRaRb, NRaRb, OH, or OC1-6 alkyl; or
RX2 and RX3, together with the carbon atom to which they are attached, form a 3-6 membered carbocyclyl, wherein the 3-6 membered carbocyclyl is optionally substituted by one or more substituents independently selected from the group consisting of halogen, C1-6 alkyl, C(O)NRaRb, NRaRb, OC1-6 alkyl, and ═O;
each R10 is independently H, C1-6 alkyl, C3-6 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each C1-6 alkyl, C3-6 cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted by one or more substituents independently selected from the group consisting of halogen, C1-6 alkyl, C1-6 haloalkyl, and C(O)R20;
each R20 is independently halogen, C1-6 alkyl, or OH;
RY is H, C1-6 alkyl, or phenyl;
R4 is H, halogen, cyano, C1-6 alkyl, C(O)NRaRb, or RaRb, wherein the C1-6 alkyl is optionally substituted by one or more substituents independently selected from the group consisting of halogen, NRaRb, OH, and ═O;
R5 is H, halogen, cyano, C1-6 alkyl, C(O)NRaRb, or RaRb, wherein the C1-6 alkyl is optionally substituted by one or more substituents independently selected from the group consisting of halogen, NRaRb, OH, and ═O;
T is —CH2—, —NRh—, —O—, or —S(O)w—;
each Rh is independently H, C1-6 alkyl, C(O)C1-6 alkyl, C(O)NRaRb, C(O)OC1-6 alkyl, S(O)2C1-6 alkyl, or S(O)2NRaRb, wherein each C1-6 alkyl, C(O)C1-6 alkyl, C(O)OC1-6 alkyl, and S(O)2C1-6 alkyl is optionally and independently substituted by one or more substituents independently selected from the group consisting of halogen and OH;
Ra is H or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted by one or more substituents independently selected from the group consisting of halogen, cyano, OH, and ═O;
Rb is H or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted by one or more substituents independently selected from the group consisting of halogen, cyano, OH, and ═O;
R3 is H, C1-6 alkyl, or phenyl;
m is 0, 1, or 2; and
each w is independently 0, 1, or 2.