Fused pyridine, pyrimidine and triazine compounds as cell cycle inhibitors

摘要

Compounds, pharmaceutical compositions and methods are provided that are useful in the treatment of CDK4-mediated disorders, such as cancer. The subject compounds are fused pyridine, pyrimide and triazine derivatives.

主权项

1. A compound of Formula I enantiomers, diastereomers, and salts thereof wherein W is CH; X is N; A1 and A2 together with ring carbon atoms to which they are attached combine to form benzene, cyclopentadiene, pyridine, pyridone, pyrimidine, pyrazine, pyridazine, 2H-pyran, pyrrole, imidazole, pyrazole, triazole, furan, oxazole, isoxazole, oxadiazole, thiophene, thiazole, isothiazole or thiadiazole any of which may be optionally partially saturated, and any of which may be optionally independently substituted with one or more Rx groups as allowed by valance; R1 is —Y-(alkylene)m-Ra; Y is cycylopentyl, cyclohexyl, piperazinyl, phenyl, pyridinyl, pyrmidinyl, cyclopentadienyl, pyrrolyl, imidazolyl, oxazolyl, or thiazolyl, any of which may be optionally substituted with one or more Rx as allowed by valence; Ra is heterocyclo, heteroaryl, —NR3R4, —C(═O)NR3R4; —O—R5, —S(O)n-R5, or —S(O)n-NR3R4 any of which may be optionally independently substituted with one or more Rx groups as allowed by valance, and wherein two groups bound to the same or adjacent atom may optionally combine to form a ring; R2 is alkyl, cycloalkyl, heterocyclo, aryl, —S(O)nR5, —C(═O)R5, —C(═S)R5, —C(═O)OR5, —C(═S)OR5, —C(═O)NR3R4, —C(═S)NR3R4, or —SO2NR3R4, any of which may be optionally independently substituted with one or more Rx groups as allowed by valance; R3 and R4 at each occurance are independently
(i) hydrogen or(ii) alkyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl any of which may be optionally independently substituted with one or more Rx groups as allowed by valance, and wherein two Rx groups bound to the same or adjacent atom may optionally combine to form a ring; or R3 and R4 together with the nitrogen atom to which they are attached may combine to form a heterocyclo ring optionally independently substituted with one or more Rx groups as allowed by valance, and wherein two Rx groups bound to the same or adjacent atom may optionally combine to form a ring; R3* and R4* at each occurrence are independently
(i) hydrogen or(ii) alkyl, alkenyl, alkynyl cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl any of which may be optionally independently substituted with one or more Rx groups as allowed by valance; or R3* and R4* together with the nitrogen atom to which they are attached may combine to form a heterocyclo ring optionally independently substituted with one or more Rx groups as allowed by valance; R5 and R5* at each occurrence is
(i) hydrogen or(ii) alkyl, alkenyl, alkynyl cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl any of which may be optionally independently substituted with one or more Rx groups as allowed by valance; Rx at each occurrence is independently, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, -(alkylene)m-OR5, -(alkylene)m-S(O)nR5, -(alkylene)m-NR3R4, -(alkylene)m-C(═O)R5, -(alkylene)m-C(═S)R5, -(alkylene)m-C(═O)OR5, -(alkylene)m-OC(═O)R5, -(alkylene)m-C(═S)OR5, -(alkylene)m-C(═O)NR3R4, -(alkylene)m-C(═S)NR3R4, -(alkylene)m-N(R3)C(═O)NR3R4, -(alkylene)m-N(R3)C(═S)NR3R4, -(alkylene)m-N(R3)C(═O)R5, -(alkylene)m-N(R3)C(═S)R5, -(alkylene)m-OC(═O)NR3R4, -(alkylene)m-OC(═S)NR3R4, -(alkylene)m-SO2NR3R4, -(alkylene)m-N(R3)SO2R5, -(alkylene)m-N(R3)SO2NR3R4, -(alkylene)m-N(R3)C(═O)OR5, -(alkylene)m-N(R3)C(═S)OR5, or -(alkylene)m-N(R3)SO2R5; wherein said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups may be further independently substituted with one or more -(alkylene)m-CN, -(alkylene)m-OR5*, -(alkylene)m-S(O)nR5*, -(alkylene)m-NR3*R4*, -(alkylene), -C(═O)R5*, -(alkylene)m-C(═S)R5*, -(alkylene)m-C(═O)O R5*, -(alkylene)m-OC(═O)R5*, -(alkylene)m-C(═S)OR5*, -(alkylene)m-C(═O)NR3*R4*, -(alkylene)m-C(═S)NR3*R4*, -(alkylene)m-N(R3*)C(═O)NR3*R4*, -(alkylene)m-N(R3*)C(═S)NR3*R4*, -(alkylene)m-N(R3*)C(═O)R5*, -(alkylene)m-N(R3*)C(═S)R5*, -(alkylene)m-OC(═O)NR3*R4*, -(alkylene)m-OC(═S)NR3*R4*, -(alkylene)m-SO2NR3*R4*, -(alkylene)m-N(R3*)SO2R5*, -(alkylene)m-N(R3*)SO2NR3*R4*, -(alkylene)m-N(R3*)C(═O)OR5*, -(alkylene)m-N(R3*)C(═S)OR5*, or -(alkylene)m-N(R3*)SO2R5*; n is independently 0, 1 or 2; and m is independently 0 or 1.