Novel triazinedione derivatives as gabab receptor modulators

A compound of Formula I

• or a stereoisomeric form, mixture of stereoisomeric forms, pharmaceutically acceptable salt, hydrate or solvate thereof,
• wherein:
• B is selected from C6-C10 aryl optionally substituted with one to 5 Y, C5-C10 cycloalkenyl optionally substituted with one to 7 Y, 5 to 14 membered heteroaryl group optionally substituted by one to 8 Y, wherein said heteroaryl group comprises one, two or three heteroatoms selected from N, O, S;
• Y is 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, —OCF3, —NO2, —CN, —CF3, an optionally substituted —(C1-C6)alkyl, —(C3-C6)cycloalkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, halo-(C1-C6)alkyl, —(C0-C6)alkylOR1, —(C0-C6)alkylNR2R3, —(C0-C6)alkyl-C(═NR4)NR2R3, —(C0-C6)alkylSR2, —(C0-C6)alkylNR2C(═O)R3, —(C0-C6)alkylNR2C(═O)2R3, —(C0-C6)alkylNR2S(═O)2R3, —(C0-C6)alkylNR4C(═O)NR2R3, —(C0-C6)alkylS(═O)R2, —(C0-C6)alkylS(═O)2R2, —(C0-C6)alkylS(═O)2NR2R3, —(C0-C6)alkyl C(═O)R2, —(C0-C6)alkylC(═O)OR1, —(C0-C6)alkylC(═O)NR2R3, —(C0-C6)alkylC(═NR2)R3, or —(C0-C6)alkylC(═NOR1)R3, heteroaryl, heteroarylalkyl, arylalkyl, aryl alkylaryl, alkylheteroaryl, heterocycloalkyl;
• wherein optionally two substituents are combined to the intervening atoms to form a bicyclic heterocycloalkyl, aryl or heteroaryl ring;
• wherein each ring is optionally further substituted with 1-5 independent halogen, —CN, —(C1-C6)alkyl, —O(C0-C6)alkyl, —O(C3-C7)cycloalkyl, —O(aryl), —O(aryl)-(C0-C3)alkyl, —O(heteroaryl), —O(heteroaryl)-(C0-C3)alkyl, —O(C1-C3)alkylaryl, —O(C1-C3)alkylheteroaryl, —N((C0-C6)alkyl)2, —N((C0-C6)alkyl))((C0-C3)alkylaryl)) or —N((C0-C6)alkyl)((C0-C3)alkylheteroaryl)) groups;
• R1 at each occurrence is selected from hydrogen, —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C3-C7)cycloalkyl, 3 to 7 membered heterocycloalkyl, —(C6-C10)aryl, 5 or 6 membered heteroaryl, —(C7-C10)arylalkyl, —C(═O)R5;
• R5 are selected from —(C1-C6)alkyl, and —(C6-C10)aryl;
• R2, R3 and R4 each independently is hydrogen, —(C1-C6)alkyl, —(C3-C6)cycloalkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C1-C6)alkylhalo, heterocycloalkyl, heteroaryl, heteroarylalkyl, arylalkyl or aryl;
• any of which is optionally substituted with 1 to 5 independent halogen, —CN, —(C1-C6)alkyl, —O(C0-C6)alkyl, —O(C3-C7)cycloalkylalkyl, —O(aryl), —O(heteroaryl), —N((C0-C6)alkyl)2, —N((C0-C6)alkyl)((C3-C7)cycloalkyl) or —N((C0-C6)alkyl)(aryl) substituents;
• wherein optionally R2, R3, R4 substituents are combined to the intervening atoms to form a bicyclic heterocycloalkyl;
• X1, X2, X3, X4 and X5 are each independently selected from the group consisting of —CR6═, —N═;
• R6 is 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, —OCF3, —CN, —CF3, —NO2, an optionally substituted —(C1-C6)alkyl, —(C3-C6)cycloalkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, halo-(C1-C6)alkyl, —(C0-C6)alkylOR7, —(C0-C6)alkylNR8R9, —(C0-C6)alkyl-C(═NR13)NR8R9, —(C0-C6)alkylSR8, —(C0-C6)alkylNR8C(═O)R9, —(C0-C6)alkylNR8C(═O)2R9, —(C0-C6)alkylNR8S(═O)2R9, —(C0-C6)alkylNR13C(═O)NR8R9, —(C0-C6)alkylS(═O)R8, —(C0-C6)alkylS(═O)2R8, —(C0-C6)alkylS(═O)2NR8R9, —(C0-C6)alkyl C(═O)R8, —(C0-C6)alkylC(═O)OR7, —(C1-C6)alkylC(═O)NR8R9, —(C0-C6)alkylC(═NR8)R9, or —(C0-C6)alkylC(═NOR7)R9, heteroaryl, heteroarylalkyl, arylalkyl, aryl, a 3 to 6 heterocycloalkyl;
• wherein optionally two substituents are combined to the intervening atoms to form a bicyclic heterocycloalkyl, aryl or heteroaryl ring;
• wherein each ring is optionally further substituted with 1 to 5 independent halogen, —CN, —(C1-C6)alkyl, —O(C0-C6)alkyl, —O(C3-C7)cycloalkyl, —O(aryl), —O(aryl)-(C0-C3)alkyl, —O(heteroaryl), —O(heteroaryl)-(C0-C3)alkyl, —O(C1-C3)alkylaryl, —O(C1-C3)alkylheteroaryl, —N((C0-C6)alkyl)2, —N((C0-C6)alkyl))((C0-C3)alkylaryl)) or —N((C0-C6)alkyl)((C0-C3)alkylheteroaryl)) groups;
• R7 at each occurrence is selected from hydrogen, —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C3-C7)cycloalkyl, 3 to 7 membered heterocycloalkyl, —(C6-C10)aryl, 5 or 6 membered heteroaryl, —(C7-C10)arylalkyl, —C(═O)R11;
• R11 are selected from —(C1-C6)alkyl, —(C3-C7)cycloalkyl and —(C6-C10)aryl;
• R8, R9 and R10 each independently is hydrogen, —(C1-C6)alkyl, —(C3-C6)cycloalkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C1-C6)alkylhalo, heterocycloalkyl, heteroaryl, heteroarylalkyl, arylalkyl or aryl;
• any of which is optionally substituted with 1 to 5 independent halogen, —CN, —(C1-C6)alkyl, —O(C0-C6)alkyl, —O(C3-C7)cycloalkylalkyl, —O(aryl), —O(aryl)-(C0-C3)alkyl, —O(heteroaryl), —O(heteroaryl)-(C0-C3)alkyl, —N((C0-C6)alkyl)2, —N((C0-C6)alkyl)((C3-C7)cycloalkyl) or —N((C0-C6)alkyl)(aryl) substituents;
• E is selected from the group consisting of hydrogen, halogen, —OCF3, —NO2, —CN, —CF3, —(C1-C6)alkyl, —(C3-C6)cycloalkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, halo-(C1-C6)alkyl, —(C0-C6)alkylOR12, —(C0-C6)alkylNR13R14, —(C0-C6)alkyl-C(═NR16)NR13R14, —(C0-C6)alkylSR12, —(C0-C6)alkylNR13C(═O)R14, —(C0-C6)alkylNR13C(═O)2R14, —(C0-C6)alkylNR13S(═O)2R14, —(C0-C6)alkylNR16C(═O)NR13R14, —(C0-C6)alkylS(═O)R13, —(C0-C6)alkylS(═O)2R13, —(C0-C6)alkylS(═O)2NR13R14, —(C0-C6)alkylC(═O)R13, —(C0-C6)alkylC(═O)OR13, —(C0-C6)alkylC(═O)NR13R14, —(C0-C6)alkyl C(═NR13)R14, or —(C0-C6)alkylC(═NOR13)R14;
• wherein optionally two substituents are combined to the intervening atoms to form a bicyclic heterocycloalkyl, aryl or heteroaryl ring;
• wherein each ring is optionally further substituted with 1 to 5 independent halogen, —CN, an optionally substituted —(C1-C6)alkyl, —O(C0-C6)alkyl, —O(C3-C7)cycloalkyl, —O(aryl), —O(aryl)-(C0-C3)alkyl, —O(heteroaryl), —O(heteroaryl)-(C0-C3)alkyl, —O(C1-C3)alkylaryl, —O(C1-C3)alkylheteroaryl, —N((C0-C6)alkyl)2, —N((C0-C6)alkyl))((C0-C3)alkylaryl)) or —N((C0-C6)alkyl)((C0-C3)alkylheteroaryl)) groups;
• R12 at each occurrence is selected from hydrogen, —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C3-C7)cycloalkyl, —C(═O)R16;
• R16 are selected from hydrogen, —(C1-C6)alkyl, —(C3-C7)cycloalkyl and —(C6-C10)aryl;
• R13, R14 and R15 each independently is hydrogen, —(C1-C6)alkyl, —(C3-C6)cycloalkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C1-C6)alkyl halo, heterocycloalkyl, heteroaryl, heteroarylalkyl, alkylheteroaryl, arylalkyl, alkylaryl or aryl;
• any of which is optionally substituted with 1 to 5 independent halogen, —CN, —(C1-C6)alkyl, —O(C0-C6)alkyl, —O(C3-C7)cycloalkylalkyl, —O(aryl), —O(aryl)-(C0-C3)alkyl, —O(heteroaryl), —O(heteroaryl)-(C0-C3)alkyl, —N((C0-C6)alkyl)2, —N((C0-C6)alkyl)((C3-C7)cycloalkyl) or —N((C0-C6)alkyl)(aryl) substituents;
• When E is —H the compounds for which X3 is not CH═ or —CF═ are excluded from the invention;
• When E is —CN the compounds of the following list are excluded from the invention:
• 4-(4-(trifluoromethyl)benzyl)-2-(4-fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile,
• 4-(4-nitrobenzyl)-2-(4-fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile,
• 4-(4-chlorobenzyl)-2-(4-fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile,
• 4-(4-chlorobenzyl)-2-(2,6-difluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile,
• 4-(4-chlorobenzyl)-3,5-dioxo-2-phenyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile,
• 4-(3-cyanobenzyl)-3,5-dioxo-2-phenyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile,
• 4-benzyl-3,5-dioxo-2-phenyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile,
• 4-(2,4-dichlorobenzyl)-3,5-dioxo-2-phenyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile,
• 4-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)methyl)-2-(4-fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile;
• W1 and W3 are each independently selected from —N═ or —C(═O);
• W2 and W4 are each independently selected from —C═ or —N—;
• L is independently selected from a —((C1-C5)alkyl-Qm)— substituted with 1-6 T;
• m is 0 or 1;
• T is 1 to 6 substituents independently selected from the group consisting of hydrogen, fluorine, —OCF3, —NO2, —CN, —CF3, —(C1-C6)alkyl, —(C3-C6)cycloalkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, halo-(C1-C6)alkyl, —(C0-C6)alkylOR17—(C0-C6)alkylNR18R19, —(C0-C6)alkyl-C(═NR20)NR18R19, —(C0-C6)alkylSR18, —(C0-C6)alkylNR18C(═O)R19, —(C0-C6)alkylNR18C(═O)2R19, —(C0-C6)alkylNR18S(═O)2R19, —(C0-C6)alkylNR20C(═O)NR18R19, —(C0-C6)alkylS(═O)R18, —(C0-C6)alkylS(═O)2R18, —(C0-C6)alkylS(═O)2NR18R19, —(C0-C6)alkylC(═O)R18, —(C0-C6)alkylC(═O)OR17, —(C0-C6)alkylC(═O)NR18R19, —(C0-C6)alkylC(═NR18)R19, or —(C0-C6)alkylC(═NOR17)R19, heteroaryl, heteroarylalkyl, arylalkyl, alkylaryl, alkylheteroaryl, aryl;
• wherein optionally two substituents are combined to the intervening atoms to form a bicyclic heterocycloalkyl, aryl or heteroaryl ring;
• wherein each ring is optionally further substituted with 1 to 5 independent halogen, —CN, —(C1-C6)alkyl, —O(C0-C6)alkyl, —O(C3-C7)cycloalkyl, —O(aryl), —O(aryl)-(C0-C3)alkyl, —O(heteroaryl), —O(heteroaryl)-(C0-C3)alkyl, —O(C1-C3)alkylaryl, —O(C1-C3)alkylheteroaryl, —N((C0-C6)alkyl))((C0-C3)alkylaryl)) or —N((C0-C6)alkyl)((C0-C3)alkylheteroaryl)) groups;
• R17 at each occurrence is selected from hydrogen, —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C3-C7)cycloalkyl, 3 to 7 membered heterocycloalkyl, —(C6-C10)aryl, 5 or 6 membered heteroaryl, —(C7-C10)arylalkyl, —C(═O)R21;
• R21 is selected from hydrogen, —(C1-C6)alkyl, —(C3-C7)cycloalkyl, and —(C6-C10)aryl;
• R18, R19 and R20 each independently is hydrogen, —(C1-C6)alkyl, —(C3-C6)cycloalkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C1-C6)alkylhalo, heterocycloalkyl, heteroaryl, heteroarylalkyl, arylalkyl alkylaryl, alkylheteroaryl, aryl;
• any of which is optionally substituted with 1 to 5 independent halogen, —CN, —(C1-C6)alkyl, —O(C0-C6)alkyl, —O(C3-C7)cycloalkylalkyl, —O(aryl), —O(aryl)-(C0-C3)alkyl, —O(heteroaryl), —O(heteroaryl)-(C0-C3)alkyl, —N((C0-C6)alkyl)2, —N((C0-C6)alkyl)((C3-C7)cycloalkyl) or —N((C0-C6)alkyl)(aryl) substituents;
• Q is —C(═O)—, —C(═O)O—, —C(═O)NR22—, —OC(═O)—, —OC(═O)NR22—, —NR22—, —NR22C(═O)—, —NR22C(═O)2—, —NR22C(═S)—, —S—, —S(═O)—, or S(═O)2—;
• R22 is selected from —(C1-C6)alkyl, and —(C6-C10)aryl;
• and
• Any N may be an N-oxide.