Acylsemicarbazides as cyclin dependent kinase inhibitors useful as anti-cancer and anti-proliferative agents

A compound according to formula (I):

• 37
• or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein:
• X is selected from the group:
• O, S, and NR;
• R is selected from the group:
• H, C1-4 alkyl, and NR5R5a;
• R1 is selected from the group:
• H, C1-10 alkyl substituted with 0-3 Rc, C2-10 alkenyl substituted with 0-3 Rc, C2-10 alkynyl substituted with 0-3 Rc, C1-10 alkoxy, —NHR4, C3-10 carbocycle substituted with 0-5 Ra, and 3-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 Rb;
• R2 is selected from the group:
• H, C1-10 alkyl substituted with 0-3 Rc, C2-10 alkenyl substituted with 0-3 Rc, C2-10 alkynyl substituted with 0-3 Rc, —(CF2)mCF3, C3-10 carbocycle substituted with 0-5 Ra, and 3-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 Rb;
• R3 is selected from the group:
• H, halo, —CN, NO2, C1-4 haloalkyl, NR5R5a, NR5NR5R5a, NR5C(O)OR5, NR5C(O)R5, ═O, OR5, COR5, CO2R5, CONR5R5a, NHC (O)NR5R5a, NHC(S)NR5R5a, SO2NR5R5a, SO2R5b, C1-4 alkyl, phenyl, benzyl, C1-4 alkyl substituted with 1-3 Rc, C5-10 alkyl substituted with C2-10 alkenyl optionally substituted with 0-3 R6, C2-10 alkynyl substituted with 0-3 R6, —(CF2)mCF3, C3-10 carbocycle substituted with 0-5 R6, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R6;
• and
• provided that if R3 is phenyl, it is substituted with 1-5 Ra;
• R4 is independently at each occurrence selected from the group:
• H, —CN, C1-4 alkyl, C1-4 haloalkyl, NR3R3a, NR3C(O)OR3, NR3C(O)R3, OR3, COR3, CO2R3, CONR3R3a, NHC(O)NR3R3a, NHC(S)NR3R3a, SO2NR3R3a, SO2R3b, C3-10 carbocycle substituted with 0-5 Ra, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R3;
• provided that at least one R3 is present and that this R3 is selected from the group:
• C1-4 alkyl substituted with 1-3 R6, C5-10 alkyl substituted with C2-10 alkenyl optionally substituted with 0-3 R6, C2-10 alkynyl substituted with 0-3 R6, —(CF2)mCF3, C3-10 carbocycle substituted with 0-5 R6, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R6;
• Ra is independently at each occurrence selected from the group:
• halo, —CN , N3, NO2, C1-4 alkyl, C1-4 haloalkyl, NR3R3a, ═O, OR3, COR3, CO2R3, CONR3R3a, NHC(O)NR3R3a, NHC(S)NR3R3a, NR3C(O)OR3, NR3C(O)R3, SO2NR3R3a, SO2R3b, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S;
• alternatively, when two Ra's are present on adjacent carbon atoms they combine to form —OCH2O— or —OCH2CH2O—;
• Rb is independently at each occurrence selected from the group:
• halo, —CN, NO2, C1-4 alkyl, C1-4 haloalkyl, NR3R3a, NR3C(O)OR3, NR3C(O)R3, OR3, COR3, CO2R3, CONR3R3a, NHC(O)NR3R3a, NHC(S)NR3R3a, SO2NR3R3a, and SO2R3b;
• Rc is independently at each occurrence selected from the group:
• halo, —CN, NO2, C1-4 alkyl, C1-4 haloalkyl, NR3R3a, NR5NR5R5a, NR3C(O)OR3, NR3C(O)R3, ═O OR3, COR3, CO2R3, CONR3R3a, NHC(O)NR3R3a, NHC(S)NR3R3a, SO2NR3R3a, SO2R3b, C3-10 carbocycle substituted with 0-5 Ra, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R3;
• R3a is selected from the group:
• H, C1-4 alkyl, phenyl, and benzyl;
• alternatively, R3 and R3a, together with the nitrogen atom to which they are attached, form a heterocycle having 4-8 atoms in the ring containing an additional 0-1 N, S, or O atom and substituted with 0-3 R3c;
• R3b is selected from the group:
• H, C1-4 alkyl, phenyl, and benzyl;
• R3c is independently at each occurrence selected from the group:
• halo, —CN , N3, NO2, C1-4 alkyl, C1-4 haloalkyl, NR3R3b, ═O, OR3, COR3, CO2R3, CONR3R3b, NHC(O)NR3R3b, NHC(S)NR3R3b, NR3C(O)OR3, NR3C(O)R3, SO2NR3R3b, SO2R3b, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S;
• R5 is independently selected from the group:
• H, C1-4 alkyl, phenyl and benzyl;
• R5a is independently selected from the group:
• H, C1-4 alkyl, phenyl and benzyl;
• R5b is independently selected from the group:
• H, C1-4 alkyl, phenyl and benzyl;
• R6 is independently at each occurrence selected from the group:
• halo, —CN, NO2, C1-4 alkyl, C1-4 haloalkyl, NR5R5, NR5NR5R5a, NR5C(O)OR5, NR5C(O)R5, ═O, OR5, COR5, CO2R5, CONR5R5a, NHC(O)NR5R5a, NHC(S)NR5R5a, SO2NR5R5a, SO2R5b, C3-10 carbocycle substituted with 0-5 R5, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R5;
• and
• m is selected from 0, 1, 2, and 3.