US 12,331,056 B2
SHP2 phosphatase inhibitors and methods of use thereof
Alexander M. Taylor, Cambridge, MA (US); André Lescarbeau, Somerville, MA (US); Elizabeth H. Kelley, Cambridge, MA (US); Kelley C. Shortsleeves, Maynard, MA (US); W. Patrick Walters, Westborough, MA (US); Mark Andrew Murcko, Holliston, MA (US); Thomas H. McLean, West Roxbury, MA (US); Hakan Gunaydin, Somerville, MA (US); Fabrizio Giordanetto, New York, NY (US); and Eric Therrien, Bronx, NY (US)
Assigned to Relay Therapeutics, Inc., Cambridge, MA (US); and D.E Shaw Research, LLC., New York, NY (US)
Filed by Relay Therapeutics, Inc., Cambridge, MA (US); and D. E. Shaw Research, LLC, New York, NY (US)
Filed on Dec. 15, 2022, as Appl. No. 18/066,551.
Application 18/066,551 is a continuation of application No. 16/982,401, abandoned, previously published as PCT/US2019/023389, filed on Mar. 21, 2019.
Claims priority of provisional application 62/737,819, filed on Sep. 27, 2018.
Claims priority of provisional application 62/661,902, filed on Apr. 24, 2018.
Claims priority of provisional application 62/649,834, filed on Mar. 29, 2018.
Claims priority of provisional application 62/646,099, filed on Mar. 21, 2018.
Claims priority of provisional application 62/646,083, filed on Mar. 21, 2018.
Prior Publication US 2023/0234958 A1, Jul. 27, 2023
This patent is subject to a terminal disclaimer.
Int. Cl. C07D 487/04 (2006.01); C07D 221/20 (2006.01); C07D 401/04 (2006.01); C07D 401/12 (2006.01); C07D 401/14 (2006.01); C07D 417/04 (2006.01); C07D 417/14 (2006.01); C07D 491/107 (2006.01); C07D 513/04 (2006.01); C07D 519/00 (2006.01)
CPC C07D 487/04 (2013.01) [C07D 221/20 (2013.01); C07D 401/04 (2013.01); C07D 401/12 (2013.01); C07D 401/14 (2013.01); C07D 417/04 (2013.01); C07D 417/14 (2013.01); C07D 491/107 (2013.01); C07D 513/04 (2013.01); C07D 519/00 (2013.01)] 21 Claims
 
1. A compound of Formula X:

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt thereof, wherein:
X is —CH2—, —CH(RX)—, —C(RX)2—, —C(O)—, —NH—, —N(RX)—, or —O—;
Y is C, CH, C(RY), or N;
custom character is a single bond when Y is CH, C(RY), or N; or custom character is a double bond when Y is C;
R1 is L1-CyB-L2-R2;
CyB is a bicyclic 8-10 membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein CyB is substituted by m instances of R3;
CyC is benzo; 5-6 membered heteroarylo having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3-7 membered saturated or partially unsaturated cycloaliphatic-fused; or 3-7 membered saturated or partially unsaturated heterocyclo having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein when CyC is heterocyclo or heteroarylo, said heteroatoms may occur at any position within CyC; and wherein in each case CyC is substituted by n instances of R4;
L1 is a covalent bond or —C(O)—;
L2 is a covalent bond, or a C1-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by —CH(RL)—, —C(RL)2—, C3-5 cycloalkylene, —N(R)—, —N(R)C(O)—, —C(O)N(R)—, —N(R)S(O)2—, —S(O)2N(R)—, —O—, —C(O)—, —OC (O)—, —C(O)O—, —S—, —S(O)—, or —S(O)2—;
R2 is hydrogen, RA, or RB, and when R2 is RB, R2 is substituted by q instances of RC;
each instance of R3, R4, RX, RY, and RL is independently RA or RB, and is substituted by r instances of RC;
each instance of R5 is independently RA or RB, and is substituted by r instances of RC; or two instances of R5 are taken together with their intervening atoms to form a 3-6 membered carbocyclic fused ring or a 3-6 membered heterocyclic fused ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each instance of RA is independently oxo, halogen, —CN, —NO2, —OR, —SR, —NR2, —S(O)2R, —S(O)2NR2, —S(O)R, —S(O)NR2, —C(O)R, —C(O)OR, —C(O)NR2, —C(O)N(R)OR, —OC(O)R, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR2, —N(R)C(NR)NR2, —N(R)S(O)2NR2, or —N(R)S(O)2R;
each instance of RB is independently C1-6 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each instance of RC is independently oxo, halogen, —CN, —NO2, —OR, —SR, —NR2, —S(O)2R, —S(O)2NR2, —S(O)R, —S(O)NR2, —OS(O)2F, —C(O)R, —C(O)OR, —C(O)NR2, —C(O)N(R)OR, —OC(O)R, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR2, —N(R)C(NR)NR2, —N(R)S(O)2NR2, —N(R)S(O)2R, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur;
each of b and c is independently 0 or 1; and
each of a, m, n, q, and r is independently 0, 1, 2, 3, or 4.