Pyrimidinone derivatives as CDC7 inhibitors

A method of treating a cancer in which Cdc7 activity is implicated in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound of Formula I:

• or a salt or solvate thereof wherein,
• X is chosen from halogen, haloC1-C6alkyl, NO2, OCN, SCN, —C(═O)NR5R6, —NHS(O)2R6, and CN;
• R2 is a group A-B-C wherein,
• A is a bond or is C1-C10alkyl;
• B is absent or is chosen from S(O)p, NR3, O, C2-C10alkenyl, and C2-C10alkynyl;
• and
• C is a 3 to 15 membered heterocycloalkyl group or a 4 to 11 membered cycloalkyl group either of which is optionally substituted with one or more R5 groups;
• R1 is a heteroaryl group of Formula A
• wherein
• Z1 is selected from C and N,
• Z2 is selected from CRa, NRb, N, O and S,
• Z3 is selected is N and NRc,
• Z4 and Z5 are independently selected from O, N, S, NRd and CRe;
• Ra is selected from hydrogen, hydroxyl, halogen, COOR3, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C0-C6alkylaryl, C0-C6alkylcycloalkyl, C0-C6alkylheterocycloalkyl, C0-C6alkylheteroaryl, C0-C6alkylCN, C0-C6alkylC(═O)C0-C6alkylR3, C0-C6alkylC(═O)C0-C6alkylOR3, C0-C6alkylC(═O)C0-C6alkylNR3R4, haloC1-C6alkyl, NO2, C0-C6alkylNR3R4, C0-C6alkylNR3C0-C6alkylOR4, C0-C6alkylOS(═O)R4, —C0-C6alkylOS(═O)2R4, —C0-C6alkylS(═O)pR4, —OCN, and —SCN, wherein any of the foregoing is optionally substituted with one or more R5 groups;
• and
• Rb and Rc are independently selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl;
• or
• Ra and Rc are taken together to form a fused 6-membered ring optionally substituted with one or more R5 groups;
• Rd is selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl;
• Re is selected from hydrogen, hydroxyl, halogen, OR3, COOR3, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C0-C6alkylaryl, C0-C6alkylcycloalkyl, C0-C6alkylheterocycloalkyl, C0-C6alkylheteroaryl, C0-C6alkylCN, C0-C6alkylC(═O)C0-C6alkylR3, C0-C6alkylC(═O)C0-C6alkylOR3, C0-C6alkylC(═O)C0-C6alkylNR3R4, haloC1-C6alkyl, NO2, C0-C6alkylNR3R4, C0-C6alkylNR3C0-C6alkylOR4, C0-C6alkylOS(═O)R4, —C0-C6alkylOS(═O)2R4, —C0-C6alkylS(═O)pR4, —OCN, and —SCN;
• or
• two adjacent Rc groups, adjacent Rc and Re or adjacent Rc and Rd groups are taken together to form a fused 6-membered ring optionally substituted with one or more R5 groups;
• each R3 and R4 are each independently chosen from H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, haloC1-C6alkyl, C0-C6alkylaryl, C0-C6alkylcycloalkyl, C0-C6alkylheteroaryl, and C0-C6alkylheterocycloalkyl, wherein any of the foregoing, except for H, is optionally substituted with one or more R5;
• or
• R3 and R4 are taken together to form a 3 to 7 membered carbocyclic or heterocyclic ring system, wherein said ring system is optionally substituted with one or more R5;
• each R5 is independently chosen from halogen, hydroxyl, OR6, C1-C10alkyl, C2-C10alkenyl, C2-C10alkynyl, C0-C6alkylaryl, C0-C6alkylcycloalkyl, C0-C6alkylheterocycloalkyl, C0-C6alkylheteroaryl, —C0-C6alkylCN, —C0-C6alkylC(═O)C0-C6alkylR6, —C0-C6alkylC(═O)C0-C6alkylOR6, —C0-C6alkylC(═O)C0-C6alkylNR6R6, —C0-C6alkylC(═O)C0-C6alkylNR6C(═O)OR6, haloC1-C6alkyl, NO2, —C0-C6alkylNR6R6, —C0-C6alkylNR6C0-C6alkylOR6, —C0-C6alkylNR6C0-C6alkylC(═O)R6, —C0-C6alkylOR6, (═O), —C0-C6alkylOC(═O)C0-C6alkylR6, —C0-C6alkylOC(═O)C0-C6alkylNR6R6, —C0-C6alkylOC(═O)C0-C6alkylOR6, —C0-C6alkylOS(═O)R6, —C0-C6alkylOS(═O)2R6, —C0-C6alkylOS(═O)2C0-C6alkylOR6, —C0-C6alkylOS(═O)2C0-C6alkylNR6R6, —C0-C6alkylS(═O)pR6, —C0-C6alkyl S(═O)2C0-C6alkylNR6R6, and —C0-C6alkyl S(═O)C0-C6alkylNR6R6, wherein each of the foregoing is optionally substituted with R7, or
• together with carbon atoms to which they are attached, two R5 groups are linked to form a fused aryl, heteroaryl, 3 to 6 membered heterocycloalkyl or a 3 to 6 membered cycloalkyl;
• each R6 is independently chosen from H, C2-C10alkenyl, C2-C10alkynyl, haloC1-C6alkyl, C0-C6alkylaryl, C0-C6alkylcycloalkyl, C0-C6alkylheteroaryl, and C0-C6alkylheterocycloalkyl, wherein each of the foregoing is optionally substituted with R7;
• or
• two R6 are taken together to form a 3 to 15 membered carbocyclic or heterocyclic ring system, wherein said ring system is optionally substituted with one or more R7;
• each R7 is independently chosen from halogen, hydroxyl, C1-C6alkyl, OC1-C6alkyl, and haloC1-C6alkyl;
• and
• each p is independently 0, 1 or 2;
• with the proviso that the compound of Formula I is not one of the following compounds:
• 6-cyclopentyl-5-iodo-2-(5-thiazolyl)-4(3H)-pyrimidinone;
• 6-cyclopentyl-2-(1-ethyl-1H-pyrazol-4-yl)-5-iodo-4(3H)-pyrimidinone;
• 6-cyclopentyl-5-iodo-2-(1-propyl-1H-pyrazol-4-yl)-4(3H)-pyrimidinone;
• 5-bromo-6-cyclopentyl-2(1-ethyl-1H-pyrazol-4-yl)-4(3H)-pyrimidinone;
• 5-bromo-6-cyclopentyl-2(1-propyl-1H-pyrazol-4-yl)-4(3H)-pyrimidinone;
• 5-bromo-6-cyclopentyl-2(1-isopropyl-1H-pyrazol-4-yl)-4(3H)-pyrimidinone;
• 6-cyclopentyl-5-iodo-2(1-isopropyl-1H-pyrazol-4-yl)-4(3H)-pyrimidinone;
• 5-bromo-6-cyclopentyl-2(5-thiazolyl)-4(3H)-pyrimidinone;
• 5-bromo-6-cyclopentyl-2(3,5-dimethyl-4-isoxazolyl)-4(3H)-pyrimidinone;
• 5-bromo-6-cyclopentyl-2(1-propyl-1H-imidazol-5-yl)-4(3H)-pyrimidinone;
• 6-cyclopentyl-5-iodo-2-(1methyl-1H-pyrazol-3-yl)-4(3H)-pyrimidinone;
• 5-bromo-6-cyclopentyl-2(1-cyclopropyl-1H-imidazol-5-yl)-4(3H)-pyrimidinone;
• 5-bromo-6-cyclopentyl-2(1-methyl-1H-pyrazol-3-yl)-4(3H)-Pyrimidinone;
• 5-bromo-6-cyclopentyl-2(1,5-dimethyl-1H-pyrazol-4-yl)-4(3H)-pyrimidinone;
• 6-cyclopentyl-5-iodo-2(1,3,5-trimethyl-1H-pyrazol-4-yl)-4(3H)-pyrimidinone;
• 6-cyclopentyl-5-iodo-2-[1(1-methylethyl)-1H-imidazol-5-yl]-4(3H)-pyrimidinone;
• 6-cyclopentyl-5-iodo-2-(1-propyl-1H-imidazol-5-yl)-4(3H)-pyrimidinone;
• 6-cyclopentyl-2-(1-ethyl 1H-imidazol-5-yl)-5-iodo-4(3H)-pyrimidinone;
• 5-bromo-6-cyclopentyl-2(1-methyl-1H-pyrazol-4-yl)-4(3H)-pyrimidinone;
• 5-bromo-6-cyclopentyl-2(1-methyl-1H-imidazol-5-yl)-4(3H)-pyrimidinone;
• 6-cyclopentyl-5-iodo-2-(1methyl-1H-pyrazol-4-yl)-4(3H)-pyrimidinone;
• 5-bromo-6-cyclopentyl-2(1,3-dimethyl-1H-pyrazol-4-yl)-4(3H)-pyrimidinone;
• 6-cyclopentyl-2-(1,3-dimethyl-1H-pyrazol-4-yl)-5-iodo-4(3H)-pyrimidinone;
• 6-cyclopentyl-2-(3,5-dimethyl-4-isoxazolyl)-5-iodo-4(3H)-pyrimidinone;
• 6-cyclopentyl-5-iodo-2-(1-methyl-1H-imidazol-5-yl)-4(3H)-pyrimidinone;
• 5-bromo-6-cyclopentyl-2-[1(1-methylethyl)-1H-imidazol-5-yl]-4(3H)-pyrimidinone;
• 5-bromo-6-cyclopentyl-2(3-ethyl-1-methyl-1H-pyrazol-4-yl)-4(3H)-pyrimidinone;
• 5-bromo-6-cyclopentyl-2(1,3,5-trimethyl-1H-pyrazol-4-yl)-4(3H)-pyrimidinone;
• 6-cyclopentyl-2-(1,5-dimethyl-1H-pyrazol-4-yl)-5-iodo-4(3H)-pyrimidinone;
• 5-bromo-6-cyclopentyl-2(1-ethyl-1H-imidazol-5-yl)-4(3H)-Pyrimidinone;
• 6-cyclopentyl-2-(1-cyclopropyl-1H-imidazol-5-yl)-5-iodo-4(3H)-pyrimidinone;
• 5-bromo-6-cyclopentyl-2(1H-1,2,4-triazol-5-yl)-4(3H)-pyrimidinone;
• 6-cyclopentyl-2-(3-ethyl-1-methyl-1H-pyrazol-4-yl)-5-iodo-4(3H)-pyrimidinone;
• 6-cyclopentyl-5-iodo-2-(1H-1,2,3-triazol-5-yl)-4(3H)-pyrimidinone;
• 6-cyclopentyl-5-iodo-2-(1H-1,2,4-triazol-5-yl)-4(3H)-pyrimidinone;
• 5-bromo-6-cyclopentyl-2(1H-1,2,3-triazol-5-yl)-4(3H)-pyrimidinone;
• 6-cyclopentyl-5-iodo-2-(1-propyl-1H-pyrazol-5-yl)-4(3H)-pyrimidinone;
• 5-bromo-6-cyclopentyl-2(1-propyl-1H-pyrazol-5-yl)-4(3H)-pyrimidinone;
• 5-bromo-6-cyclopentyl-2(1-methyl-1H-pyrazol-5-yl)-4(3H)-pyrimidinone;
• 6-cyclopentyl-5-iodo-2-(1-methyl-1H-pyrazol-5-yl)-4(3H)-pyrimidinone;
• 5-bromo-6-cyclopentyl-2(1-ethyl-1H-pyrazol-5-yl)-4(3H)-pyrimidinone;
• and
• 6-cyclopentyl-2-(1-ethyl-1H-pyrazol-5-yl)-5-iodo-4(3H)-pyrimidinone.