US 2026/0234112 A1 · COMPOUNDS, COMPOSITIONS, AND METHODS OF USE THEREOF

Abstract

The present disclosure provides, in part, compounds of formula: (I) and pharmaceutically acceptable salts thereof, and compositions comprising said compounds or salts thereof and a pharmaceutically acceptable excipient. In some embodiments, the compounds or salts thereof and compositions disclosed herein are effective at inhibiting CDK2 activity. In some embodiments, the compounds or salts thereof and compositions disclosed herein are selective at inhibiting CDK2 over other CDKs. Thus, also provided herein are uses of the compounds or salts thereof and compositions in methods of treating, preventing, or reducing the risk or severity of certain diseases or disorders mediated by CDK2, such as cancer.

A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:
A2 is phenyl, 2,3-naphthyl, or 5 or 6-membered heteroaryl;
A4 is aryl, heteroaryl, C3-12 carbocyclyl, or 4-12 membered heterocyclyl;
L1 is —O—, —S—, —NH—, —S(═O)1-2—, —S(═O)(═NR5)—, —C(R6)2—, or —C(═O)—;
L2 is —NR7SO2—, —C(R8)2SO2—, —NR7SO2—C(R8)2—, —C(R8)2C(═O)—, —C(═O)C(R8)2—, —C(═O)O—, —OC(═O)—, —C(R8)2O—, —OC(R8)2—, —C(═O)NR7—, —NR7C(═O)—, —C(R8)2NR7—, —NR7C(R8)2—, —C(R8)2S(═O)0-2—, —S(═O)0-2C(R8)2—, —C(R8)2S(═O)NR7—, S(═O)NR7C(R8)2—, or —C(R8)2C(R8)2—;
R1 is C3-12 carbocyclyl, 4-12 membered heterocyclyl, phenyl, 5-12 membered heteroaryl, —(C7-6 alkylene)-(C3-10 carbocyclyl), —(C1-6 alkylene)-(4-12 membered heterocyclyl), —(C1-6alkylene)-(phenyl), —(C1-6alkylene)-(5-12 membered heteroaryl), —(C1-6alkylene)-OR9, or —(C1-6alkylene)-NR7R10, wherein R1 is optionally substituted by 0-5 R11;
R2 is each independently H, halogen, cyano, nitro, hydroxy, —NR7R10, —NHCOR9, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C2-6 alkenoxy, C2-6 alkynoxy, COR9, CON(R9)2, CF3, CF2H, CF3CF2, CF3CH2, C1-6 haloalkyl, CF3O, CF2HO, CF3CF2O, CF3CH2O, C1-6 haloalkoxy, C3-8 cycloalkyl, C3-8 cycloalkenyl, C1-6 alkylthio, C2-6 alkenylthio, C1-6 alkylsulfonyl, aryl, or heteroaryl, wherein R2 is each independently optionally substituted by 0-4 R11;
R3 is each independently H, halogen, cyano, nitro, hydroxy, —NR7R10, —NHCOR9, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C2-6 alkenoxy, C2-6 alkynoxy, COR9, CON(R9)2, CF3, CF2H, CF3CF2, CF3CH2, C1-6 haloalkyl, CF3O, CF2HO, CF3CF2O, CF3CH2O, C1-6 haloalkoxy, C3-8 cycloalkyl, C3-8 cycloalkenyl, C1-6 alkylthio, C2-6 alkenylthio, or C1-6 alkylsulfonyl, wherein R3 is each independently optionally substituted by 0-4 R11;
R4 is each independently H, halogen, cyano, nitro, hydroxy, NR7R10, NHCOR9, NR7CONR7, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, COR9, CO2R9, CONR7R10, C1-6 alkoxy, C2-6 alkenoxy, C2-6 alkynoxy, CF3, CF2H, CF3CF2, CF3CH2, C1-6 haloalkyl, CF3O, CF2HO, CF3CF2O, CF3CH2O, C1-6 haloalkoxy, C3-8 cycloalkyl, C3-8 cycloalkenyl, C1-6 alkylthio, C2-6 alkenylthio, C1-6 alkylsulfonyl, SO2N(R7)2, or phenyl, or any two occurrences of R4 on contiguous atoms, taken together with the contiguous atoms to which the two occurrences of R4 are attached, form a saturated or unsaturated 5-7 membered ring comprising 0-2 heteroatoms each independently selected from O, S(═O)0-2, P(═O)R12, N, and NR10, wherein R4 is each independently optionally substituted by 0-4 R11;
R5 is each independently H or C1-4 alkyl;
R6 is each independently H, F, OH, cyano, or C1-6 alkyl;
R7 is each independently H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C4-6 heterocycloalkyl, aryl, 5-10 membered heteroaryl, C1-3 alkylene-C3-6 cycloalkyl, or C1-3 alkylene-C4-6 heterocycloalkyl, or two R7s along with the N atom to which they are attached form a 4-7 membered ring comprising an additional 0-1 heteroatoms selected from NR5, O and S(═O)0-2;
R8 is each independently H, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C2-6 cycloalkyl, C4-6heterocycloalkyl, C1-3 alkylene-C3-6 cycloalkyl, C1-3 alkylene-C4-6 heterocycloalkyl, or two R8s taken together with the C atom to which they are attached form a 4-7 membered ring comprising 0-1 heteroatom selected from O, S(═O)0-2, P(═O)R12, and NR5, wherein R8 is optionally substituted by 1-3 R11;
each R9 is H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C4-10 heterocycloalkyl, C1-3 alkylene-C3-6 cycloalkyl, C1-3 alkylene-C4-6 heterocycloalkyl, C1-6 acyl, phenyl, or 5-12 membered heteroaryl, wherein R9 is optionally substituted by 1-3 R11;
each R10 is independently H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C4-10 heterocycloalkyl, C1-3 alkylene-C3-6 cycloalkyl, C1-3 alkylene-C4-6heterocycloalkyl, C1-6 acyl, C1-6 alkylsulfonyl, phenyl, or 5-12 membered heteroaryl, wherein R10 is optionally substituted by 1-3 R11;
or R7 and R10 on the same N atom may be taken together with the N atom to which they are attached form a 4-7 membered ring comprising an additional 0-1 heteroatoms selected from NR5, O, S(═O)0-2, P(═O)R12, and NR13;
R11 is each independently R6, oxo, nitro, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6hydroxyalkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, 4-6 membered heterocycloalkyl, C1-3 alkylene-C3-6 cycloalkyl, C1-3 alkylene-C4-6 heterocycloalkyl, C6-10 aryl, C5-10 heteroaryl, SO2R7, S(═O)NR5, SO2N(R7)2, CON(R7)2, or N(R7)2;
R12 is each independently H, OH, C1-6 alkyl, C1-6 alkoxy, or —N(R7)2;
R13 is each independently H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C2-6 cycloalkyl, C4-6 heterocycloalkyl, C1-3 alkylene-C3-6 cycloalkyl, or C1-3 alkylene-C4-6 heterocycloalkyl, C1-6 acyl, aroyl, or heteroaroyl;
m is an integer 0, 1 or 2;
n is an integer 0, 1, 2, or 3;
and
p is an integer 0, 1, 2, or 3,
provided that
the A1 ring and the L1 linker are on contiguous C atoms of A2, whereas L1 and L2 are not situated on contiguous atoms of the A3 ring;
and when A2 is
L1 is not —O—, wherein * is the site covalently linked to the A1 ring, and *** is the site covalently linked to L1.

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Compounds, compositions, and methods of use thereof

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Compounds, compositions, and methods of use thereof

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Abstract

Claims83