Inhibitors of cyclin-dependent kinases and their use

A compound of the general formula (Id), or a stereoisomer, optical isomer, pharmaceutically acceptable salt, or pharmaceutically acceptable solvate thereof

• 40
• wherein
• R1 is phenyl, which is unsubstituted or substituted by 1, 2, or 3 identical or different substituents selected from:
• halogen, C1-C4-alkyl, C1-C4-alkoxy, nitro, NR9R10, SR11, trifluoromethyl, hydroxyl, cyano, carboxy, C1-C4alkoxycarbonyl and —C1-C4-alkylenehydroxyl, or is a heterocycle, which is a saturated, partially unsaturated or aromatic ring containing 5 or 6 ring atoms of which 1, 2 or 3 are identical or different heteroatoms selected from:
• nitrogen, oxygen, sulfur, and phosphorus, and where the heterocycle is unsubstituted or substituted by 1, 2, or 3 identical or different substituents selected from:
• halogen, C1-C4-alkyl, C1-C4-alkoxy, nitro, NR9R10, SR11, trifluoromethyl, hydroxyl, cyano, carboxy, C1-C4alkoxycarbonyl and —C1-C4-alkylenehydroxyl;
• R2 is hydrogen, C1-C6-alkyl, phenyl, which is unsubstituted or substituted by 1, 2, or 3 identical or different substituents selected from:
• halogen, C1-C4-alkyl, C1-C4-alkoxy, nitro, NR9R10, SR11 trifluoromethyl, hydroxyl, cyano, carboxy, C1-C4 alkoxycarbonyl and —C1-C4-alkylenehydroxyl, OR11, halogen, cyano, nitro, NR9R10 or SR11;
• R3, R4 and R5 are each independently selected from:
• hydrogen, C1-C4-alkyl, C1-C4 alkoxyl, halogen, OR11, C1-C4-alkylcarbonyloxy, NR9R10, SO2NR9R10, carboxy, cyano and nitro;
• A is a 5- or 6-membered ring;
• wherein:
• (I) the 5-membered ring is saturated or unsaturated and represented by any one of the general structures (i) to (iv);
• 41
• wherein X1 is either a carbon atom or a heteroatom selected from:
• oxygen, sulfur, and nitrogen, except that in structures (ii) and (iv) X1 is either a carbon atom or a nitrogen atom, and wherein R13 is selected from:
• hydrogen, unsubstituted C1-C6-alkyl, or C1-C6-alkyl substituted by halogen, hydroxyl or carboxyl, C2-C6-alkenyl, hydroxyl, C1-C6-alkoxy, C1-C4-alkylcarbonyl, toluenesulfonyl , cyano, SO2R10 and —CO(CH2)mR14, phenyl, which is unsubstituted or substituted by 1, 2, or 3 identical or different substituents selected from:
• halogen, C1-C4-alkyl, C1-C4-alkoxy, nitro, NR9R10, SR11, trifluoromethyl, hydroxyl, cyano, carboxy, C1-C4-alkoxycarbonyl and —C1-C4-alkylenehydroxyl;
• R6 is —C1-C4-alkyleneOR11;
• (II) the 6-membered ring is saturated and represented by the general structure (vi):
• 42
• wherein R13 is selected from:
• hydrogen, unsubstituted C1-C6-alkyl, or C1-C6-alkyl substituted by halogen, hydroxyl, or carboxyl, C2-C6-alkenyl, hydroxyl, C1-C6-alkoxy, C1-C4-alkylcarbonyl, toluenesulfonyl, cyano, SO2R10, —CO(CH2)mR14, and phenyl, which is unsubstituted or substituted by 1, 2, or 3 identical or different substituents selected from:
• halogen, C1-C4-alkyl, C1-C4-alkoxy, nitro, NR9R10, SR11, trifluoromethyl, hydroxyl, cyano, carboxy, C1-C4-alkoxycarbonyl and —C1-C4-alkylenehydroxyl;
• R6 is —C1-C4-alkyleneOR11;
• R9 and R10 are each independently selected from:
• hydrogen, C1-C4-alkyl, C1-C4 alkanoyl, C1-C4-alkoxycarbonyl, C1-C4-alkylcarbonyl, carboxamide and sulfonamide;
• or
• R9 and R10, together with the nitrogen atom to which they are bonded, form a 3-, 4-, 5- or 6-membered heterocyclic ring which can have at least one further heteroatom selected from:
• nitrogen, oxygen and sulfur, which ring is saturated, partially unsaturated or aromatic and either unsubstituted or substituted by at least one substituent selected from:
• halogen, C1-C4-alkyl, C1-C4-alkoxy, C2-C6-alkenyl, C3-C6-alkynyl, C2-C4-alkanoyl, nitro, NR9R10, SR11, trifluoromethyl, hydroxyl, cyano, carboxy, C1-C4-alkoxycarbonyl and —C1-C4-alkylenehydroxyl;
• R11 is hydrogen, C1-C4-alkyl, C1-C4-alkanoyl, or C1-C4-alkoxycarbonyl;
• R14 is hydrogen, C1-C4-alkyl, hydroxyl, —NR9R10, halogen, —SH, or —S—C1-C4-alkyl;
• and
• m is an integer of 0 to 6.

A compound of the general formula (Ie), or a stereoisomer, optical isomer, pharmaceutically acceptable salt, or pharmaceutically acceptable solvate thereof

• 43
• wherein
• R1 is phenyl, which is unsubstituted or substituted by 1, 2, or 3 identical or different substituents selected from:
• halogen, C1-C4-alkyl, C1-C4-alkoxy, nitro, NR9R10, SR11, trifluoromethyl, hydroxyl, cyano, carboxy, C1-C4-alkoxycarbonyl and —C1-C4-alkylenehydroxyl, or is a heterocycle, which is a saturated, partially unsaturated or aromatic ring containing 6 ring atoms of which 1, 2 or 3 are identical or different heteroatoms selected from:
• nitrogen, oxygen and sulfur, and where the heterocycle is unsubstituted or substituted by 1, 2, or 3 identical or different substituents selected from:
• halogen, C1-C4-alkyl, C1-C4-alkoxy, nitro, NR9R10, SR11, trifluoromethyl, hydroxyl, cyano, carboxy, C1-C4alkoxycarbonyl and —C1-C4-alkylenehydroxyl;
• R2 and R4 are hydrogen;
• R3 and R5 are each independently selected from:
• hydroxyl, C1-C4-alkoxyl and C1-C4alkylcarbonyloxy;
• A is a 5- or 6- membered ring;
• wherein:
• (I) the 5-membered ring is saturated or unsaturated and represented by any one of the general structures (i) to (iv);
• 44
• wherein X1 is either a carbon atom or a heteroatom selected from:
• oxygen, sulfur, and nitrogen, except that in structures (ii) and (iv) X1 is either a carbon atom or a nitrogen atom, and wherein R13 is selected from:
• hydrogen, unsubstituted C1-C6-alkyl, or C1-C6-alkyl substituted by halogen, hydroxyl, or carboxyl, C2-C6-alkenyl, hydroxyl, C1-C6-alkoxy, C1-C4-alkylcarbonyl, toluenesulfonyl, cyano, SO2R10,—CO(CH2)mR14 and phenyl, which is unsubstituted or substituted by 1, 2, or 3 identical or different substituents selected from:
• halogen, C1-C4-alkyl, C1-C4-alkoxy, nitro, NR9R10, SR11, trifluoromethyl, hydroxyl, cyano, carboxy, C1-C4-alkoxycarbonyl and —C1-C4-alkylenehydroxyl;
• R6 is —C1-C4-alkyleneOR11;
• (II) the 6-membered ring is saturated and of the general structure (vi):
• 45
• wherein R13 is selected from:
• hydrogen, unsubstituted C1-C6-alkyl, or C1-C6-alkyl substituted by halogen, hydroxyl, or carboxyl, C2-C6-alkenyl, hydroxyl, C1-C6-alkoxy, C1-C4-alkylcarbonyl, toluenesulfonyl, cyano, SO2R10,—CO(CH2)mR14, and phenyl, which is unsubstituted or substituted by 1, 2, or 3 identical or different substituents selected from:
• halogen, C1-C4-alkyl, C1-C4-alkoxy, nitro, NR9R10, SR11, trifluoromethyl, hydroxyl, cyano, carboxy, C1-C4-alkoxycarbonyl and —C1-C4-alkylenehydroxyl;
• R6 is —C1-C4-alkyleneOR11;
• R9 and R10 are each independently selected from:
• hydrogen, C1-C4-alkyl, C1-C4-alkanoyl, C1-C4alkoxycarbonyl, C1-C4-alkylcarbonyl, carboxamide and sulfonamide;
• or
• R9 and R10, together with the nitrogen atom to which they are bonded, form a 3-, 4-, 5- or 6-membered heterocyclic ring which can have at least one further heteroatom selected from:
• nitrogen, oxygen and sulfur, which ring is saturated, partially unsaturated or aromatic and either unsubstituted or substituted by at least one substituent selected from:
• halogen, C1-C4-alkyl, C1-C4-alkoxy, C2-C6-alkenyl, C3-C6-alkynyl, C2-C4-alkanoyl, nitro, NR9R10, SR11, trifluoromethyl, hydroxyl, cyano, carboxy, C1-C4-alkoxycarbonyl and —C1-C4-alkylenehydroxyl;
• R11, is hydrogen, C1-C4-alkyl, C1-C4-alkanoyl, or C1-C4-alkoxycarbonyl;
• R14 is hydrogen, C1-C4-alkyl, hydroxyl, —NR9R10, halogen, —SH, or —S—C1-C4-alkyl;
• and
• m is an integer of 0 to 6.

A compound of the general formula (If), or a stereoisomer, optical isomer, pharmaceutically acceptable salt, or pharmaceutically acceptable solvate thereof

• 46
• wherein
• R1 is phenyl, which is unsubstituted or substituted by 1, 2, or 3 identical or different substituents selected from:
• halogen, C1-C4-alkyl, C1-C4-alkoxy, nitro, NR9R10, SR11, trifluoromethyl, hydroxyl, cyano, carboxy, C1-C4alkoxycarbonyl and —C1-C4-alkylenehydroxyl, or is a heterocycle, which is a saturated, partially unsaturated or aromatic ring containing 6 ring atoms of which 1, 2 or 3 are identical or different heteroatoms selected from:
• nitrogen, oxygen and sulfur, and where the heterocycle is unsubstituted or substituted by 1, 2, or 3 identical or different substituents selected from:
• halogen, C1-C4-alkyl, C1-C4-alkoxy, nitro, NR9R10, SR11, trifluoromethyl, hydroxyl, cyano, carboxy, C1-C4alkoxycarbonyl and —C1-C4-alkylenehydroxyl;
• R2 and R4 are hydrogen;
• R3 and R5 are each independently selected from:
• hydroxyl, C1-C4-alkoxyl and C1-C4-alkylcarbonyloxy;
• R6 is —C1-C4-alkylenehydroxyl;
• R9 and R10 are each independently selected from:
• hydrogen, C1-C4-alkyl, C1-C4 alkanoyl, C1-C4-alkoxycarbonyl, C1-C4-alkylcarbonyl, carboxamide and sulfonamide;
• or
• R9 and R10, together with the nitrogen atom to which they are bonded, are a 3-, 4-, 5- or 6-membered heterocyclic ring which can have at least one further heteroatom selected from:
• nitrogen, oxygen and sulfur, which ring is saturated, partially unsaturated or unsaturated and either unsubstituted or substituted by at least one substituent selected from:
• halogen, C1-C4-alkyl, C1-C4-alkoxy, C2-C6-alkenyl, C3-C6-alkynyl, C2-C4-alkanoyl, nitro, NR9R10, SR11, trifluoromethyl, hydroxyl, cyano, carboxy, C1-C4-alkoxycarbonyl and —C1-C4-alkylenehydroxyl;
• R11 is hydrogen, C1-C4-alkyl, C1-C4-alkanoyl, or C1-C4-alkoxycarbonyl;
• and
• R13 is hydrogen or C1-C4-alkyl.

A compound of the general formula (Ig), or a stereoisomer, optical isomer, pharmaceutically acceptable salt, or pharmaceutically acceptable solvate thereof

• 47
• wherein
• R1 is phenyl, which is unsubstituted or substituted by 1, 2, or 3 identical or different substituents selected from halogen, C1-C4-alkyl, C1-C4-alkoxy, nitro, NR9R10, SR11, trifluoromethyl, hydroxyl, cyano, carboxy, C1-C4alkoxycarbonyl and —C1-C4-alkylenehydroxyl, or is a heterocycle, which is a saturated, partially unsaturated or aromatic ring containing 5 or 6 ring atoms of which 1, 2 or 3 are identical or different heteroatoms selected from:
• nitrogen, oxygen, sulfur and phosphorus, and where the heterocycle is unsubstituted or substituted by 1, 2, or 3 identical or different substituents selected from:
• halogen, C1-C4-alkyl, C1-C4-alkoxy, nitro, NR9R10, SR11, trifluoromethyl, hydroxyl, cyano, carboxy, C1-C4alkoxycarbonyl and —C1-C4-alkylenehydroxyl;
• R2 is hydrogen, C1-C6-alkyl, phenyl, which is unsubstituted or substituted by 1, 2, or 3 identical or different substituents selected from:
• halogen, C1-C4-alkyl, C1-C4-alkoxy, nitro, NR9R10, SR11, trifluoromethyl, hydroxyl, cyano, carboxy, C1-C4alkoxycarbonyl and —C1-C4-alkylenehydroxyl, OR11, halogen, cyano, nitro, NR9R10 or SR11;
• R3, R4 and R5 are each independently selected from:
• hydrogen, C1-C4-alkyl, C1-C4-alkoxyl, halogen, OR11, C1-C4-alkylcarbonyloxy, NR9R10, SO2NR9R10, carboxyl, cyano and nitro;
• Z is O or S;
• A is a 5-membered saturated ring represented by any one of the general structures (i) to (v);
• 48
• wherein X1 and X2 are each independently selected from:
• a carbon atom and a heteroatom selected from:
• oxygen, sulfur, and nitrogen, provided that at least one of X1 and X2 is a heteroatom, and wherein the nitrogen atom is at least monosubstituted by R13, wherein R13 is selected from:
• hydrogen, unsubstituted C1-C6-alkyl, or C1-C6-alkyl substituted by halogen, hydroxyl, or carboxyl, C2-C6-alkenyl, hydroxyl, C1-C6-alkoxy, C1-C4-alkylcarbonyl, toluenesulfonyl, SO2R10, —CO(CH2)mR14, cyano, phenyl, which is unsubstituted or substituted by 1, 2, or 3 identical or different substituents selected from:
• halogen, C1-C4-alkyl, C1-C4-alkoxy, nitro, NR9R10, SR11, trifluoromethyl, hydroxyl, cyano, carboxy, C1-C4-alkoxycarbonyl and —C1-C4-alkylenehydroxyl;
• R6 is hydrogen, C1-C4-alkyl, —C1-C4.alkanoyl, hydroxyl, C1-C4-alkoxyl, —C1-C4 alkoxycarbonyl, —C1-C4-alkyleneOR11, —C1-C4-alkylenehalo, —C1-C4-alkyleneNR9R10, —C1-C4-alkyleneC(O)OR9, phenoxy, —NR9R10 SR12, S(O)nR12, —C(O)R12 or —C(S)R12;
• R9 and R10 are each independently selected from:
• hydrogen, C1-C4-alkyl, C1-C4 alkanoyl, C1-C4-alkoxycarbonyl, C1-C4-alkylcarbonyl, carboxamide and sulfonamide;
• or
• R9 and R10, together with the nitrogen atom to which they are bonded, form a 3-, 4-, 5- or 6-membered heterocyclic ring which can have at least one further heteroatom selected from:
• nitrogen, oxygen and sulfur, which ring is saturated, partially unsaturated or aromatic and either unsubstituted or substituted by at least one substituent selected from:
• halogen, C1-C4-alkyl, C1-C4-alkoxy, C2-C6-alkenyl, C3-C6-alkynyl, C2-C4-alkanoyl, nitro, NR9R10, SR11, trifluoromethyl, hydroxyl, cyano, carboxy, C1-C4-alkoxycarbonyl and —C1-C4-alkylenehydroxyl;
• R11 is hydrogen, C1-C4-alkyl, C1-C4-alkanoyl, or C1-C4-alkoxycarbonyl;
• R12 is hydrogen, halogen, C1-C4-alkyl, —NR9R10 or OR9;
• R14 is hydrogen, C1-C4-alkyl, hydroxyl, —NR9R10, halogen, —SH, or —S—C1-C4-alkyl;
• m is an integer of 0 to 6;
• and
• n is an integer of 1 or 2.

A compound of general formula (Ih), or a stereoisomer, optical isomer, pharmaceutically acceptable salt, or pharmaceutically acceptable solvate thereof

• 49
• wherein
• R1 is phenyl, which is unsubstituted or substituted by 1, 2, or 3 identical or different substituents selected from:
• halogen, C1-C4-alkyl, C1-C4-alkoxy, nitro, NR9R10, SR11, trifluoromethyl, hydroxyl, cyano, carboxy, C1-C4alkoxycarbonyl and —C1-C4-alkylenehydroxyl, or is a heterocycle, which is a saturated, partially unsaturated or aromatic ring containing 6 ring atoms of which 1, 2 or 3 are identical or different heteroatoms selected from:
• nitrogen, oxygen and sulfur, and where the heterocycle is unsubstituted or substituted by 1, 2, or 3 identical or different substituents selected from:
• halogen, C1-C4-alkyl, C1-C4-alkoxy, nitro, NR9R10, SR11, trifluoromethyl, hydroxyl, cyano, carboxy, C1-C4alkoxycarbonyl and —C1-C4-alkylenehydroxyl;
• R2 and R4 are hydrogen;
• R3 and R5 are each independently selected from:
• hydroxyl, C1-C4-alkoxyl and C1-C4-alkylcarbonyloxy;
• A is a 5-membered saturated ring represented by any one of the general structures (i) to (v);
• 50
• wherein X1 and X2 are each independently selected from:
• a carbon atom and a heteroatom selected from:
• oxygen, sulfur, and nitrogen, provided that at least one of X1 and X2 is a heteroatom, and wherein the nitrogen atom is at least monosubstituted by R13, wherein R13 is selected from:
• hydrogen, unsubstituted C1-C6-alkyl, or C1-C6-alkyl substituted by halogen, hydroxyl, or carboxyl, C2-C6-alkenyl, hydroxyl, C1-C6-alkoxy, C1-C4-alkylcarbonyl, toluenesulfonyl, cyano, SO2R10 —CO(CH2)mR14 and phenyl, which is unsubstituted or substituted by 1, 2, or 3 identical or different substituents selected from:
• halogen, C1-C4-alkyl, C1-C4-alkoxy, nitro, NR9R10, SR11, trifluoromethyl, hydroxyl, cyano, carboxy, C1-C4alkoxycarbonyl and —C1-C4-alkylenehydroxyl;
• R6 is hydrogen, C1-C4-alkyl, —C1-C4-alkanoyl, hydroxyl, C1-C4-alkoxyl, —C1-C4 alkoxycarbonyl, —C1-C4-alkyleneOR11, —C1-C4-alkylenehalo, —C1-C4-alkyleneNR9R10, —C1-C4-alkyleneC(O)OR9, phenoxy, —NR9R10, SR12, S(O)nR12, —C(O)R12 or —C(S) R12;
• R9 and R10 are each independently selected from:
• hydrogen, C1-C4-alkyl, C1-C4 alkanoyl, C1-C4-alkoxycarbonyl, C1-C4-alkylcarbonyl, carboxamide and sulfonamide;
• or
• R9 and R10, together with the nitrogen atom to which they are bonded, form a 3-, 4-, 5- or 6-membered heterocyclic ring which can have at least one further heteroatom selected from:
• nitrogen, oxygen and sulfur, which ring is saturated, partially unsaturated or aromatic, and either unsubstituted or substituted by at least one substituent selected from:
• halogen, C1-C4-alkyl, C1-C4-alkoxy, C2-C6-alkenyl, C3-C6-alkynyl, C2-C4-alkanoyl, nitro, NR9R10, SR11, trifluoromethyl, hydroxyl, cyano, carboxy, C1-C4-alkoxycarbonyl and —C1-C4-alkylenehydroxyl;
• R11 is hydrogen, C1-C4-alkyl, C1-C4-alkanoyl or C1-C4-alkoxycarbonyl;
• R12 is hydrogen, halogen, C1-C4-alkyl, —NR9R10, or OR9;
• R14 is hydrogen C1-C4-alkyl, hydroxyl, —NR9R10, halogen, —SH, or —S—C1-C4-alkyl;
• m is an integer of 0 to 6;
• and
• n is an integer of 1 or 2.

A compound of general formula (Ii), or a stereoisomer, optical isomer, pharmaceutically acceptable salt, or pharmaceutically acceptable solvate thereof

• 51
• wherein
• R1 is phenyl, which is unsubstituted or substituted by 1, 2, or 3 identical or different substituents selected from:
• halogen, C1-C4-alkyl, C1-C4-alkoxy, nitro, NR9R10, SR11, trifluoromethyl, hydroxyl, cyano, carboxy, C1-C4alkoxycarbonyl and —C1-C4-alkylenehydroxyl, or is a heterocycle, which is a saturated, partially unsaturated or aromatic ring containing 6 ring atoms of which 1, 2 or 3 are identical or different heteroatoms selected from:
• nitrogen, oxygen and sulfur, and where the heterocycle is unsubstituted or substituted by 1, 2, or 3 identical or different substituents selected from:
• halogen, C1-C4-alkyl, C1-C4-alkoxy, nitro, NR9R10, SR11, trifluoromethyl, hydroxyl, cyano, carboxy, C1-C4alkoxycarbonyl and —C1-C4-alkylenehydroxyl;
• R2 and R4 are hydrogen;
• R3 and R5 are each independently selected from:
• hydroxyl, C1-C4-alkoxyl and C1-C4-alkylcarbonyloxy;
• A is a 5-membered saturated ring represented by any one of the general structures (i) to (iv);
• 52
• wherein X1 is either a carbon atom or a heteroatom selected from:
• oxygen, sulphur, and nitrogen, except that in structures (ii) and (iv) X1 is either a carbon atom or a nitrogen atom, and wherein R13 is selected from:
• hydrogen, unsubstituted C1-C6-alkyl, or C1-C6-alkyl substituted by halogen, hydroxyl, or carboxyl, C2-C6-alkenyl, hydroxyl, C1-C6-alkoxy, C1-C4-alkylcarbonyl, toluenesulfonyl, cyano, SO2R10, —CO(CH2)mR14 and phenyl, which is unsubstituted or substituted by 1, 2, or 3 identical or different substituents selected from:
• halogen, C1-C4-alkyl, C1-C4-alkoxy, nitro, NR9R10, SR11, trifluoromethyl, hydroxyl, cyano, carboxy, C1-C4-alkoxycarbonyl and —C1-C4-alkylenehydroxyl;
• R6 is hydrogen, C1-C4-alkyl, —C1-C4-alkanoyl, hydroxyl, C1-C4-alkoxyl, —C-C4-alkoxycarbonyl, —C1-C4-alkyleneOR11, —C1-C4-alkylenehalo, —C1-C4-alkyleneNR9R10, —C1-C4-alkyleneC(O)OR9, phenoxy —NR9R10, SR12, S(O)nR12, —C(O)R12 or —C(S)R12;
• R9 and R10 are each independently selected from:
• hydrogen, C1-C4-alkyl, C1-C4-alkanoyl, C1-C4-alkoxycarbonyl, C1-C4-alkylcarbonyl, carboxamide and sulfonamide;
• or
• R9 and R10, together with the nitrogen atom to which they are bonded, form a 3-, 4-, 5- or 6-membered heterocyclic ring which can have at least one further heteroatom selected from:
• nitrogen, oxygen and sulfur, which ring is saturated, partially unsaturated or aromatic and either unsubstituted or substituted by at least one substituent selected from:
• halogen, C1-C4-alkyl, C1-C4-alkoxy, C2-C6-alkenyl, C3-C6-alkynyl, C2-C4-alkanoyl, nitro, NR9R10, SR11, trifluoromethyl, hydroxyl, cyano, carboxy, C1-C4-alkoxycarbonyl and —C1-C4-alkylenehydroxyl;
• R11 is hydrogen, C1-C4-alkyl, C1-C4-alkanoyl, or C1-C4-alkoxycarbonyl;
• R12 is hydrogen, halogen, C1-C4-alkyl, —NR9R10, or OR9;
• R14 is hydrogen, C1-C4-alkyl, hydroxyl, —NR9R10, halogen, —SH, or —S—C1-C4-alkyl;
• m is an integer of 0 to 6;
• and
• n is an integer of 1 or 2.