US 12,459,951 B2
Compounds that interact with RAS superfamily proteins for treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease
Yaron R. Hadari, Harrison, NY (US); Michael Schmertzler, St. Petersburg, FL (US); Theresa M. Williams, Harleysville, PA (US); Carolina Bigarella, Pleasantville, NY (US); Luca Carta, Scarsdale, NY (US); Rebecca Hutcheson, Stamford, CT (US); Sufang Zhang, Briarcliff Manor, NY (US); and Charles H Reynolds, Austin, TX (US)
Assigned to SHY Therapeutics, LLC, Harrison, NY (US)
Filed by SHY Therapeutics, LLC, Harrison, NY (US)
Filed on Apr. 4, 2024, as Appl. No. 18/626,740.
Application 18/626,740 is a continuation of application No. PCT/US2023/065530, filed on Apr. 7, 2023.
Claims priority of provisional application 63/384,905, filed on Nov. 23, 2022.
Claims priority of provisional application 63/329,141, filed on Apr. 8, 2022.
Prior Publication US 2024/0360141 A1, Oct. 31, 2024
Int. Cl. C07D 487/04 (2006.01); A61K 31/53 (2006.01); A61P 35/00 (2006.01)
CPC C07D 487/04 (2013.01) [A61K 31/53 (2013.01); A61P 35/00 (2018.01)] 46 Claims
 
1. A compound of Formula II:

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, and/or polymorph thereof, wherein:
X is —NR1AR2A or —OR2A,
R1A is hydrogen or C1-6 alkyl;
R2A is hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 heteroalkyl, —S(O)2R15A, —P(O)R16AR17A, or 5-6 membered heteroaryl, wherein the C1-6 alkyl, C3-6 cycloalkyl, C1-6 heteroalkyl, and 5-6 membered heteroaryl are each independently optionally substituted with 1-3 R8A substituents, optionally wherein 2 independent R8A substituents are combined to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl including the atom or atoms to which each are attached; or R1A and R2A are combined to form a 3-6 membered heterocycloalkyl including the nitrogen atom to which they are both attached, optionally wherein the 3-6 membered heterocycloalkyl formed by R1A and R2A is fused to a 5-6 membered heteroaryl;
R3A is C1-6 alkyl, C3-6 cycloalkyl, C1-6 heteroalkyl, phenyl, 5-10 membered heteroaryl, —(CO)R11A, or —C(O)NR12AR13A, wherein the C1-6 alkyl, C3-6 cycloalkyl, C1-6 heteroalkyl, phenyl, and 5-10 membered heteroaryl are each independently optionally substituted with 1-3 R9A substituents;
R4A is phenyl or 5-10 membered heteroaryl, wherein the phenyl and 5-10 membered heteroaryl are each independently optionally substituted with 1-3 R10A substituents, optionally wherein 2 independent R10A substituents are combined to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl including the atom or atoms to which each are attached;
R5A is hydrogen;
R6A and R7A are each independently C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, or C1-6 heteroalkyl, wherein the C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, and C1-6 heteroalkyl, are each independently optionally substituted with 1-3 R8A substituents;
R8A and R9A are each independently selected from the group consisting of halo, CN, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 heteroalkyl, 3-6 membered heterocycloalkyl, —NR12AR13A, —(CO)R11A, oxo, —OH, C1-6 alkoxy, C3-6 cycloalkoxy, C1-6 haloalkoxy, 5-6 membered heteroaryl, biotinamide, or a biotinylated substituent;
R10A is independently selected from the group consisting of halo, CN, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 heteroalkyl, 3-6 membered heterocycloalkyl, —OH, C1-6 alkoxy, C3-6 cycloalkoxy, C1-6 haloalkoxy, —NR12AR13A, or 5-6 membered heteroaryl, wherein the C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 heteroalkyl, 3-6 membered heterocycloalkyl, C1-6 alkoxy, C3-6 cycloalkoxy, C1-6 haloalkoxy, or 5-6 membered heteroaryl are each independently optionally substituted with 1-3 R8A substituents;
R11A is C1-6 alkyl, C3-6 cycloalkyl, or C1-6 heteroalkyl, wherein the C1-6 alkyl, C3-6 cycloalkyl, and C1-6 heteroalkyl, are each independently optionally substituted with 1-3 R8A substituents;
R12A and R13A are each independently selected from the group consisting of hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 heteroalkyl, —OH, C1-6 alkoxy, or C1-6 haloalkoxy, or R12A and R13A are combined to form a 3-6 membered heterocycloalkyl including the nitrogen atom to which they are both attached;
R15A is C1-6 alkyl, C3-6 cycloalkyl, or C1-6 heteroalkyl, wherein the C1-6 alkyl, C3-6 cycloalkyl, and C1-6 heteroalkyl, are each independently optionally substituted with 1-3 R8A substituents;
R16Aand R17Aare each independently selected from the group consisting C1-6 alkyl, C1-6 alkoxy, or C1-6 heteroalkyl, wherein the C1-6 alkyl, C1-6 alkoxy, and C1-6 heteroalkyl, are each independently optionally substituted with 1-3 R8A substituents, or R16Aand R17Aare combined to form a 3-7 membered heterocycloalkyl including the phorphorus atom to which they are both attached;
m is 0, 1 or 2; and
wherein, when X is OH or

OG Complex Work Unit Chemistry
Y is N-methyl imidazoyl, and R5A is H, at least one of R3A and R4A is not unsubstituted phenyl.