Nociceptin analogs

A compound of the formula (IA):

• 38
• wherein
• n is an integer from 0 to 3;
• Z is selected from the group consisting of a bond, —CH2, —NH—, —CH2O—, —CH2CH2—, 13 CH2NH—, —CH2N(CH3)—, —NHCH2—, —CH2CONH—, —NHCH2CO—, —CH2CO—, —COCH2—, —CH2COCH2—, —CH(CH3)—, —CH═, and —HC═CH—, wherein the carbon and/or nitrogen atoms are unsubstituted or substituted with a lower alkyl, halogen, hydroxy or alkoxy group;
• R1 is selected from the group consisting of hydrogen, C1-10alkyl, C3-12cycloalkyl, C2-10alkenyl, amino, C1-10alkylamino, C3-12cycloalkylamino, benzyl, C3-12 cycloalkenyl, a monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, a hetero-monocyclic ring, a hetero-bicyclic ring system, and a spiro ring system of the formula (V):
• 39
• wherein X1 and X2 are independently selected from the group consisting of NH, O, S and CH2;
• wherein said alkyl, cycloalkyl, alkenyl, C1-10alkylamino, C3-12cycloalkylamino, or benzyl is optionally substituted with 1-3 substituents selected from the group consisting of halogen, C1-10 alkyl, C1-10 alkoxy, nitro, trifluoromethyl, cyano, phenyl, benzyl, benzyloxy, said phenyl, benzyl, and benzyloxy optionally being substituted with 1-3 substituents selected from the group consisting of halogen, C1-10 alkyl, C1-10 alkoxy, and cyano;
• wherein said C3-12 cycloalkyl, C3-12 cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, hetero-monocyclic ring, hetero-bicyclic ring system, and spiro ring system of the formula (V) are optionally substituted with 1-3 substituents selected from the group consisting of halogen, C1-10 alkyl, C1-10 alkoxy, nitro, trifluoromethyl, phenyl, benzyl, phenyloxy and benzyloxy, wherein said phenyl, benzyl, phenyloxy and benzyloxy are optionally substituted with 1-3 substituents selected from the group consisting of halogen, C1-10 alkyl, C1-10 alkoxy, and cyano,
• R2 is selected from the group consisting of hydrogen, C1-10 alkyl C3-12 cycloalkyl and halogen, said alkyl optionally substituted with an oxo group;
• or a pharmaceutically acceptable salt thereof.

A compound selected from the group consisting of:

• 3-[1-(naphth-2-yl-methyl)-4-piperidinyl]-2H-benzoxazol-2-one;
• 3-[1-(naphth-1-yl-methyl)-4-piperidinyl]-2H-benzoxazol-2-one;
• 3-[1-(p-phenylbenzyl)-4-piperidinyl]-2H-benzoxazol-2-one;
• 3-[1-(p-benzyloxybenzyl)-4-piperidinyl]-2H-benzoxazol-2-one,
• 3-[1-(p-cyanobenzyl)-4-piperidinyl]-2H-benzoxazol-2-one;
• 3-[1-(3,3-diphenylpropyl)-4-piperidinyl]-2H-benzoxazol-2-one;
• 3-[1-[4,4-Bis-(4-fluorophenyl)butyl]-4-piperidinyl]-2H-benzoxazol-2-one;
• 3-[1-(2-phenylethyl)-4-piperidinyl]-2H-benzoxazol-2-one;
• 3-[1-(cyclooctylmethyl)-4-piperidinyl]-2H-benzoxazol-2-one;
• 3-[1-(1,2,3,4-tetrahydro-2-naphthyl)-4-piperidinyl]-2H-benzoxazol-2-one;
• 3-[1-(5-methylhex-2-yl)-4-piperidinyl]-2H-benzoxazol-2-one;
• 3-[1-(10,11-Dihydro-5H-dibenzo[a,d]-cyclohepten-5-yl)-4-piperidinyl]-2H-benzoxazol-2-one;
• 3-[1-(4-propyl-cyclohexyl)-4-piperidinyl]-2H-benzoxazol-2-one;
• 3-[1-(norbornan-2-yl)-4-piperidinyl]-2H-benzoxazol-2-one;
• 3-[1-(decahydro-2-naphthyl)-4-piperidinyl]-2H-benzoxazol-2-one;
• 3-[1-(3,3-dimethyl-1,5-dioxaspiro[5,5]undeca-9-yl)-4-piperidinyl]-2H-benzoxazol-2-one;
• 3-[1-[4-(1-methylethyl)-cyclohexyl]-4-piperidinyl]-2H-benzoxazol-2-one;
• 3-[1-(1,3-dihydroinden-2-yl)-4-piperidinyl]-2H-benzoxazol-2-one;
• 3-[1-(cyclooctyl)-4-piperidinyl]-2H-benzoxazol-2-one;
• and
• pharmaceutically acceptable salts thereof.

A compound of the formula (IA):

• 40
• wherein
• R2 is selected from the group consisting of hydrogen, C1-10 alkyl, C3-12 cycloalkyl and halogen, said alkyl optionally substituted with an oxo group;
• n is an integer from 0 to 3;
• ZR1 is the following
• 41
• wherein
• Y1 is R3—(C1-C12)alkyl, R4-aryl, R5-heteroaryl, R6—(C3-C12) cyclo-alkyl, R7—(C3-C7)heterocycloalkyl, —CO2(C1-C6)alkyl, CN or —C(O)NR8R9;
• Y2 is hydrogen or Y1;
• Y3 is hydrogen or (C1-C6)alkyl;
• or Y1, Y2 and Y3, together with the carbon to which they are attached, form one of the following structures:
• 42
• wherein r is 0 to 3;
• w and u are each 0-3, provided that the sum of w and u is 1-3;
• c and d are independently 1 or 2;
• s is 1 to 5;
• and ring E is a fused R4-phenyl or R5-heteroaryl ring;
• R10 is 1 to 3 substituents independently selected from the group consisting of H, (C1-C6)alkyl, —OR8, —(C1-C6)alkyl-OR8, —NR8R9 and —(C1-C6)alkyl-NR8R9;
• R11 is 1 to 3 substituents independently selected from the group consisting of R10, —CF3, —OCF3, NO2 and halo, or R11 substituents on adjacent ring carbon atoms may together form a methylenedioxy or ethylenedioxy ring;
• R8 and R9 are independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C3-C12)cycloalkyl, aryl and aryl(C1-C6)alkyl;
• R3 is 1 to 3 substituents independently selected from the group consisting of H, R4-aryl, R6—(C3-C12)cycloalkyl, R5-heteroaryl, R7—(C3-C7)heterocycloalkyl, —NR8 R9, —OR12 and —S(O)0-2R12;
• R6 is 1 to 3 substituents independently selected from the group consisting of H, (C1-C6)alkyl, R4-aryl, —NR8R9, —OR12 and —SR12;
• R4 is 1 to 3 substituents independently selected from the group consisting of hydrogen, halo, (C1-C6)alkyl, R13-aryl, (C3-C12)cycloalkyl, —CN, —CF3, —OR8, —(C1-C6)alkyl-OR8, —OCF3, —NR8R9, —(C1-C6)alkyl-NR8R9, —NHSO2R8, —SO2N(R14)2, —SO2R8, —SOR8, —SR8, —NO2, —CONR8R9, —NR9COR8, —COR8, —COCF3, —OCOR8, —OCO2R8, —COOR8, —(C1-C6)alkyl-NHCOOC(CH3)3, —(C1-C6)alkyl-NHCOCF3, —(C1-C6)alkyl-NHSO2—(C1-C6)alkyl-(C1-C6)alkyl-NHCONH—(C1-C6)-alkyl and
• 43
• wherein f is 0 to 6;
• or R4 substituents on adjacent ring carbon atoms may together form a methylenedioxy or ethylenedioxy ring;
• R5 is 1 to 3 substituents independently selected from the group consisting of hydrogen, halo, (C1-C6)alkyl, R13-aryl, (C3-C12)cycloalkyl, —CN, —CF3, —OR8, —(C1-C6)alkyl-OR8, —OCF3, —NR8R9, —(C1-C6)alkyl-NR8R9, —NHSO2R8, —SO2N(R14)2, —NO2, —CONR8R9, —NR9COR8, —COR8, —OCOR8, —OCO2R8 and —COOR8;
• R7 is H, (C1-C6)alkyl, —OR8, —(C1-C6)alkyl-OR8, —NR8R9 or —(C1-C6)alkyl-NR8R9;
• R12 is H, (C1-C6)alkyl, R4-aryl, —(C1-C6)alkyl-OR8, —(C1-C6)alkyl-NR8R9, —(C1-C6)alkyl-SR8, or aryl (C1-C6)alkyl;
• R13 is 1-3 substituents independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkoxy and halo;
• R14 is independently,selected from the group consisting of H, (C1-C6)alkyl and R13—C6H4—CH2—;
• or a pharmaceutically acceptable salt thereof.

A compound of the formula (II):

• 44
• wherein
• the dotted line represents an optional double bond;
• R is hydrogen, C1-10 alkyl, C3-12 cycloalkyl, C3-12 cycloalkyl, C1-4alkyl-, C1-10 alkoxy, C3-12 cycloalkoxy-, C1-10 alkenyl, C1-10 alkylidene, oxo C1-10 alkyl substituted with 1-3 halogen, C3-12 cycloalkyl substituted with 1-3 halogen, C3-12 cycloalkylC1-4alkyl- substituted with 1-3 halogen, C1-10 alkoxy substituted with 1-3 halogen, C3-12 cycloalkoxy- substituted with 1-3 halogen, —COOV1, —C1-4COOV1, —CH2OH, —SO2N(V1)2, hydroxyC1-10alkyl, hydroxyC3-10cycloalkyl-, cyanoC1-10alkyl-, cyanoC3-10cycloalkyl-, —CON (V1)2, NH2SO2C1-4alkyl-, NH2SOC1-4alkyl-, sulfonylaminoC1-10alkyl, diaminoalkyl-, -sulfonylC1-4alkyl, a 6-membered heterocyclic ring, a 6-membered heteroaromatic ring, a 6-membered heterocyclicC1-4alkyl-, a 6-membered heteroaromaticC1-4alkyl-, a 6-membered aromatic ring, a 6-membered aromaticC1-4alkyl-, a 5-membered heterocyclic ring optionally substituted with an oxo or thio, a 5-membered heteroaromatic ring, a 5-membered heterocyclicC1-4alkyl- optionally substituted with an oxo or thio, a 5-membered heteroaromaticC1-4alkyl-, —C1-5(═O)W1, —C1-5(═NH)W1, —C1-5NHC(O)W1, —C1-5NHS(═O)2W1, —C1-5NHS(═O)W1, wherein W1 is hydrogen, C1-10 alkyl, C3-12 cycloakyl, C1-10 alkoxy, C3-12 cycloalkoxy, —CH2OH, amino, C1-4alkylamino-, diC1-4alkylamino-, or a 5-membered heteroaromatic ring optionally substituted with 1-3 lower alkyl;
• wherein each V1 is independently selected from H, C1-6 alkyl, C3-6 cycloalkyl, benzyl and phenyl;
• n is an integer from 0 to 3;
• D is a 5-8 membered cycloalkyl, 5-8 membered heterocyclic or a 6 membered aromatic or heteroaromatic group;
• n is an integer from 0 to 3;
• A, B and Q are independently hydrogen, C1-10 alkyl, C3-12 cycloalkyl, C1-10 alkoxy, C3-12 cycloalkoxy, C1-10 alkenyl, C1-10 alkylidene, oxo, —CH2OH, —NHSO2, hydroxyC1-10alkyl-, aminocarbonyl-, C1-4alkylaminocarbonyl-, diC1-4alkylaminocarbonyl-, acylamino-, acylaminoalkyl-, amide, sulfonylaminoC1-10alkyl-, or A-B can together form a C2-6 bridge, or B-Q can together form a C3-7 bridge, or A-Q can together form a C1-5 bridge;
• Z is selected from the group consisting of a bond, straight or branched C1-6 alkylene, —NH—, —CH2O—, —CH2NH—, —CH2N(CH3)—, —NHCH2—, —CH2CONH—, —NHCH2CO—, —CH2CO—, —COCH2—, —CH2COCH2, —CH(CH3)—, —CH═, —O—, and —HC═CH—, wherein the carbon and/or nitrogen atoms are unsubstituted or substituted with one or more lower alkyl, hydroxy, halo or alkoxy group;
• R1 is selected from the group consisting of hydrogen, C1-10 alkyl, C3-12cycloalkyl, C2-10alkenyl, amino, C1-10alkylamino-, C3-12cycloalkylamino-, —COOV1, —C1-4COOV1, cyano, cyanoC1-10alkyl-, cyanoC3-10cycloalkyl-, NH2SO2—, NH2SO2C1-4alkyl-, NH2SOC1-4alkyl-, aminocarbonyl-, C1-4alkylaminocarbonyl-, diC1-4alkylaminocarbonyl-, benzyl, C3-12 cycloalkenyl-, a monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, a hetero-monocyclic ring, a hetero-bicyclic ring system, and a spiro ring system of the formula (V):
• 45
• wherein X1 and X2 are independently selected from the group consisting of NH, O, S and CH2;
• and wherein said alkyl, cycloalkyl, alkenyl, C1-10alkylamino-, C3-12cycloalkylamino-, or benzyl of R1 is optionally substituted with 1-3 substituents selected from the group consisting of halogen, hydroxy, C1-10 alkyl, C1-10 alkoxy, nitro, trifluoromethyl-, cyano, —COOV1, —C1-4COOV1, cyanoC1-10alkyl-, —C1-5(═O)2W1, —C1-5NHS(═O)W1, —C1-5NHS(═O)W1, a 5-membered heteroaromaticC0-4alkyl-, phenyl, benzyl, benzyloxy, said phenyl, benzyl, and benzyloxy optionally being substituted with 1-3 substituents selected from the group consisting of halogen, C1-10 alkyl-, C1-10 alkoxy-, and cyano;
• and wherein said C3-12 cycloalkyl, C3-12 cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, hetero-monocyclic ring, hetero-bicyclic ring system, or spiro ring system of the formula (V) is optionally substituted with 1-3 substituents selected from the group consisting of halogen, C1-10 alkyl, C1-10alkoxy, nitro, trifluoromethyl-, phenyl, benzyl, phenyloxy and benzyloxy, wherein said phenyl, benzyl, phenyloxy or benzyloxy is optionally substituted with 1-3 substituents selected from the group consisting of halogen, C1-10 alkyl, C1-10 alkoxy, and cyano;
• R2 is selected from the group consisting of hydrogen, C1-10 alkyl, C3-12 cycloalkyl-and halogen, said alkyl or cycloalkyl optionally substituted with an oxo, amino, alkylamino or dialkylamino group,
• or a pharmaceutically acceptable salt thereof or solvate thereof.

A compound of the formula (IIA):

• 46
• wherein
• the dotted line represents an optional double bond;
• Z is selected from the group consisting of a bond, —CH2—, —NH—, —CH2O—, —CH2CH2—, —CH2NH—, —CH2N(CH3)—, —NHCH2—, —CH2CONH—, —NHCH2CO—, —CH2CO—, —COCH2—, —CH2COCH2—, —CH(CH3)—, —CH═, and —HC═CH—, wherein the carbon and/or nitrogen atoms are unsubstituted or substituted with a lower alkyl, halogen, hydroxy or alkoxy group;
• R and Q are the same or different and are each selected from the group consisting of hydrogen, halogen, C1-10 alkyl, C1-10 alkenyl, C1-10 alkylidene, C3-12 cycloalkyl, C1-10 alkoxy, and oxo;
• R1 is selected from the group consisting of hydrogen, C1-10alkyl, C3-12cycloalkyl, C2-10alkenyl, amino, C1-10alkylamino, C3-12cycloalkylamino, benzyl, C3-12 cycloalkenyl, a monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, a heteromonocyclic ring, a bicyclic ring system, and a Spiro ring system of the formula (V):
• 47
• wherein X1 and X2 are independently selected from the group consisting of NH, O, S and CH2;
• wherein said alkyl, cycloalkyl, alkenyl, C1-10alkylamino, C3-12cycloalkylamino, or benzyl is optionally substituted with 1-3 substituents selected from the group consisting of halogen, C1-10 alkyl, C1-10 alkoxy, nitro, trifluoromethyl, cyano, phenyl, benzyl, benzyloxy, said phenyl, benzyl, and benzyloxy optionally being substituted with 1-3 substituents selected from the group consisting of halogen, C1-10 alkyl, C1-10 alkoxy, and cyano;
• wherein said C3-12 cycloalkyl, C3-12 cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, heteromonocyclic ring, heterobicyclic ring system, and spiro ring system of the formula (V) are optionally substituted with 1-3 substituents selected from the group consisting of halogen, C1-10 alkyl, C1-10 alkoxy, nitro, trifluoromethyl, phenyl, benzyl, phenyloxy and benzyloxy, wherein said phenyl, benzyl, phenyloxy and benzyloxy are optionally substituted with 1-3 substituents selected from the group consisting of halogen, C1-10 alkyl C1-10 alkoxy, and cyano;
• R2 is selected from the group consisting of hydrogen, C1-10 alkyl C3-12 cycloalkyl and halogen, said alkyl optionally substituted with an oxo group;
• or a pharmaceutically acceptable salt thereof.

A compound selected from the group consisting of:

• 3-ethylidene-1-[1-(5-methylhex-2-yl)-4-piperidinyl]-1,3 -dihydro-2H-indole-2-one;
• 3-ethylidene-1-[1-(4-propylcyclohexyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;
• 3-ethylidene-1-[1-(1,2,3,4-tetrahydro-2-naphthyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;
• 3-ethylidene-1-[1-(1,3-dihydroinden-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;
• 3-ethylidene-1-[1(naphth-2-yl-methyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;
• 3-ethylidene-1-[1-(p-benzyloxybenzyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;
• 3-ethylidene-1-[1-(benzyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;
• 3-ethylidene-1-[1-(cyclooctylmethyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;
• 3-ethylidene-1-[1-(norbornan-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;
• 3-ethylidene-1-[1-(3,3-diphenylpropyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;
• 3-ethylidene-1-[1-(p-cyanobenzyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one,
• 3-ethyl-1-[1-(5-methylhex-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;
• 3-ethyl-1-[1-[4-(1-methylethyl)-cyclohexyl]-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;
• 3-ethyl-1-[1-(4-propylcyclohexyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;
• 3-ethyl-1-[1-(1,2,3,4-tetrahydro-2-naphthyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2one;
• 3-ethyl-1-[1-(decahydro-2-naphthyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;
• 3-ethyl-1-[1-(1,3-dihydroinden-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;
• 3-ethyl-1-[1-(cyclooctylmethyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;
• 3-ethyl-1-[1-(norbornan-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;
• 1-[1-(naphth-1-yl-methyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one,
• 1-[1-(naphth-2-yl-methyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;
• 1-[1-p-phenylbenzyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;
• 1-[1-(3,3-Bis(phenyl)propyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;
• 1-[1-(p-cyanobenzyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;
• 1-[1-p-benzyloxybenzyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;
• 1-[1-(1,2,3,4-tetrahydronaphth-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;
• 1-[1-(5-methylhex-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;
• 1-[1-(norbornan-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;
• 1-[1-(1,3-dihydroinden-2-yl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;
• 1-[1-(cycooctylmethyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;
• 1-[1-(benzyl)-3-(methyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;
• 1-[1-(4-propyl-cyclohexyl)-3-(methyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;
• 1-[1-(5-methylhex-2-yl)-3-(methyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;
• 1-[1-(decahydro-2-naphthyl)-3-(methyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;
• 1-[1-(4-(1-methylethyl)-cyclohexyl)-3-(methyl)-4-piperidinyl-1,3-dihydro-2H-indole-2-one;
• 1-[1-(cyclooctylmethyl)-3-(methyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;
• 1-[1-(3,3-Bis(phenyl)propyl)-3-(methyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;
• 3-ethyl-1-[1-(3,3-Bis(phenyl)propyl)-3-(methyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;
• 3-ethyl-1-[1-(4-propylcyclohexyl)-3-(methyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;
• 3-ethyl-1-[1-(5-methylhex-2-yl)-3-(methyl)-4-piperidinyl]-1,3-dihydro-2-indole-2-one;
• 3-ethyl-1-[1-[4-(1-methylethyl)cyclohexyl]-3-methyl-4-piperidinyl]-1,3-dihydro-2H-indole-2-one;
• 3-ethyl-1-[1-(decahydro-2-naphthyl)-3-(methyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one,
• and pharmaceutically acceptable salts thereof.

A compound of the formula (IIA):

• 48
• wherein
• the dotted line represents an optional double bond;
• R and Q are the same or different and are each selected from the group consisting of hydrogen, halogen, C1-10 alkyl, C1-10 alkenyl, C1-10 alkylidene, C3-12 cycloalkyl, C1-10 alkoxy, and oxo;
• R2 is selected from the consisting of hydrogen, C1-10 alkyl, C3-12 cycloalkyl and halogen, said alkyl optionally substituted with an oxo group;
• ZR1 is the following
• 49
• wherein
• Y1 is R3—(C1-C12)alkyl, R4-aryl, R5-heteroaryl, R6—(C3-C12)cyclo-alkyl, R7—(C3-C7)heterocycloalkyl, —CO2(C1-C6)alkyl, CN or —C(O)NR8R9;
• Y2 is hydrogen or Y1;
• Y3 is hydrogen or (C1-C6)alkyl;
• or Y1, Y2 and Y3, together with the carbon to which they are attached, form one of the following structures:
• 50
• wherein r is 0 to 3;
• w and u are each 0-3, provided that the sum of w and u is 1-3;
• c and d are independently 1 or 2;
• s is 1 to 5;
• and ring E is a fused R4-phenyl or R5-heteroaryl ring;
• R10 is 1 to 3 substituents independently selected from the group consisting of H, (C1-C6)alkyl, —OR8, —(C1-C6)alkyl-OR8, —NR8R9 and —(C1-C6)alkyl-NR8R9;
• R11 is 1 to 3 substituents independently selected from the group consisting of R10, —CF3, —OCF3, NO2 and halo, or R11 substituents on adjacent ring carbon atoms may together form a methylenedioxy or ethylenedioxy ring;
• R8 and R9 are independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C3-C12)cycloalkyl, aryl and aryl(C1-C6)alkyl;
• R3 is 1 to 3 substituents independently selected from the group consisting of H, R4-aryl, R6-(C3-C12)cycloalkyl, R5-heteroaryl, R7—(C3-C7)heterocycloalkyl, —NR8R9, —OR12 and —S(O)0-2R12;
• R6 is 1 to 3 substituents independently selected from the group consisting of H, (C1-C6)alkyl, R4-aryl, —NR8 R9, —OR12 and —SR12;
• R4 is 1 to 3 substituents independently selected from the group consisting of hydrogen, halo, (C1-C6)alkyl, R13-aryl, (C3-C12)cycloalkyl, —CN, —CF3, —OR8, —(C1-C6)alkyl-OR8, —OCF3, —NR8R9, —(C1-C6)alkyl —NR8R9, —NHSO2R8, —SO2N(R14)2, —SO2R8, —SOR8, —SR8, —NO2, —CONR8R9, —NR9COR8, —COR8, —COCF3, —OCOR8, —OCO2R8, —COOR8, —(C1-C6)alkyl-NHCOOC(CH3)3, —(C1-C6)alkyl-NHCOCF3, —(C1-C6)alkyl-NHSO2, —(C1-C6)alkyl, —(C1-C6)alkyl-NHCONH—(C1-C6)-alkyl and
• 51
• wherein f is 0 to 6;
• or R4 substituents on adjacent ring carbon atoms may together form a methylenedioxy or ethylenedioxy ring;
• R5 is 1 to 3 substituents independently selected from the group consisting of hydrogen, halo, (C1-C6)alkyl, R13-aryl, (C3-C12)cycloalkyl, —CN, —CF3, —OR8, —(C1-C6)alkyl-OR8, —OCF3, —NR8R9, —(C1-C6)alkyl-NR8R9, —NHSO2R8, —SO2N(R14)2, —NO2, —CONR8R9, —NR9COR8, —COR8, —OCOR8, —OCO2R8 and —COOR8;
• R7 is H, (C1-C6)alkyl, —OR8, —(C1-C6)alkyl-OR8, —NR8R9 or —(C1-C6)alkyl-NR8R9;
• R12 is H, (C1-C6)alkyl, R4-aryl, —(C1-C6)alkyl-OR8, —(C1-C6)alkyl-NR8R9, —(C1-C6)alkyl-SR8, or aryl (C1-C6)alkyl;
• R13 is 1-3 substituents independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkoxy and halo;
• R14 is independently selected from the group consisting of H, (C1-C6)alkyl and R13—C6H4—CH2—;
• or a pharmaceutically acceptable salt thereof.

A compound of the (III):

• 52
• wherein R is hydrogen, C1-10 alkyl, C3-12 cycloalkyl, C3-12 cycloalkylC1-4alkyl-, C1-10 alkoxy, C3-12 cycloalkoxy-, C1-10 alkyl substituted with 1-3 halogen, C3-12 cycloalkyl substituted with 1-3 halogen, C3-12cycloalkylC1-4alkyl- substituted with 1-3 halogen, C1-10 alkoxy substituted with 1-3 halogen, C3-12 cycloalkoxy- substituted with 1-3 halogen, —COOV1, —C1-4COOV1, —CH2OH, —SO2N(V1)2, hydroxyC1-10alkyl-, hydroxyC3-10cycloalkyl-, cyanoC1-10alkyl, cyanoC3-10cycloalkyl-, —CON(V1)2, NH2SO2C1-4alkyl-, NH2SOC1-4alkyl-, sulfonylaminoC1-10alkyl-, diaminoalkyl-, -sulfonylC1-4alkyl, a 6-membered heterocyclic ring, a 6-membered heteroaromatic ring, a 6-membered heteroC1-4alkyl-, a 6-membered heteroaromaticC1-4alkyl a 6-membered aromatic ring, a 6-membered aromaticC1-4 alkyl.-, a 5-membered heterocyclic ring optionally substituted with an oxo or thio, a 5-membered heteroaromatic ring, a 5-membered heterocyclicC1-4alkyl- optionally substituted with an oxo or thio, a 5-membered heteroaromaticC1-4alkyl-, —C1-5(═O)W1, —C1-5(═NH)W1, —C1-5NHC(═O)W1, —C1-5NHS(═O)2W1, —C1-5NHS(═O)W1, wherein W1 is hydrogen, C1-10 alkyl, C3-12 cycloalkyl, C1-10 alkoxy, C3-12 cycloalkoxy, —CH2OH, amino, C1-4alkylamino-, diC1-4alkylamino-, or a 5-membered heteroaromatic ring optionally substituted with 1-3 lower alkyl;
• wherein each V1 is independently selected from H, C1-6 alkyl, C3-6 cycloalkyl, benzyl and phenyl;
• n is an integer from 0to 3;
• D is a 5-8 membered cycloalkyl, 5-8 membered heterocyclic or a 6 membered aromatic or heteroaromatic group;
• Z is selected from the group consisting of a bond, straight or branched C1-6 alkylene, —NH—, —CH2O—, —CH2NH—, —CH2N(CH3)—, —NHCH2—, —CH2CONH—, —NHCH2CO—, —CH2CO—, —COCH2—, —CH2COCH2—, —CH(CH3)—, —CH═, —O— and —HC═CH—, wherein:
• the carbon and/or nitrogen atoms are unsubstituted or substituted with one or more lower alkyl, hydroxy, halo or alkoxy group;
• or Z is a cycloalkylamino system of the formula (VI):
• 53
• wherein A, B and Q are independently hydrogen, C1-10 alkyl, C3-12 cycloalkyl, C1-10 alkoxy, C3-12 cycloalkoxy, —CH2OH, —NHSO2, hydroxyC1-10alkyl-, aminocarbonyl-, C1-4alkylaminocarbonyl-, diC1-4alkylaminocarbonyl-, acylamino-, acylaminoalkyl-, amide, sulfonylaminoC1-10alkyl-, or A-B can together form a C2-6 bridge, or B-Q can together form a C3-7 bridge, or A-Q can together form a C, bridge;
• R1 is selected from the group consisting of hydrogen, C1-10 alkyl, C3-12cycloalkyl, C2-10alkenyl, amino, C1-10alkylamino-, C3-12cycloalkylamino-, —COOV1, —C1-4COOV1, cyano, cyanoC1-10alkyl-, cyanoC3-10cycloalkyl-, NH2 SO2—, NH2SO2C1-4alkyl-, NH2SOC1-4alkyl-, aminocarbonyl-, C1-4alkylaminocarbonyl-, diC1-4alkylaminocarbonyl-, benzyl, C3-12 cycloalkenyl-, a monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, a heteromonocyclic ring, a hetero-bicyclic ring system, and a spiro ring system of the formula (V):
• 54
• wherein X1 and X2 are independently selected from the group consisting of NH, O, S and CH2;
• and wherein said alkyl, cycloalkyl, alkenyl, C1-10alkylamino-, C3-12cycloalkylamino-, or benzyl of R1 is optionally substituted with 1-3 substituents selected from the group consisting of halogen, hydroxy, C1-10 alkyl, C1-10 alkoxy, nitro, trifluoromethyl-, cyano, —COOV1, —C1-4COOV1, cyanoC1-10alkyl-, —C1-5(═O)W1, —C1-5NHS(═O)2W1, —C1-5NHS(═O)W1, a 5-membered heteroaromaticC0-4alkyl-, phenyl, benzyl, benzyloxy, said phenyl, benzyl, and benzyloxy optionally being substituted with 1-3 substituents selected from the group consisting of halogen, C1-10 alkyl-, C1-10 alkoxy-, and cyano;
• and wherein said C3-12 cycloalkyl, C3-12 cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, hetero-monocyclic ring, hetero-bicyclic ring system, or spiro ring system of the formula (V) is optionally substituted with 1-3 substituents selected from the group consisting of halogen, C1-10 alkyl, C1-10alkoxy, nitro, trifluoromethyl-, phenyl, benzyl, phenyloxy and benzyloxy, wherein said phenyl, benzyl, phenyloxy or benzyloxy is optionally substituted with 1-3 substituents selected from the group consisting of halogen, C1-10 alkyl, C1-10 alkoxy, and cyano;
• R2 is selected from the group consisting of hydrogen, C1-10 alkyl, C3-12 cycloalkyl-and halogen, said alkyl or cycloalkyl optionally substituted with an oxo, amino, alkylamino or dialkylamino group;
• or a pharmaceutically acceptable salt thereof or solvate thereof.

A compound of formula (IIIA):

• 55
• wherein
• n is an integer from 0 to3;
• Z is selected from the group consisting of a bond, —CH2—, —NH—, —CH2O—, —CH2CH2—, —CH2NH—, —CH2N(CH3)—, —NHCH2—, —CH2CONH—, —NHCH2CO—, —CH2CO—, —COCH2—, —CH2COCH2—, —CH(CH3)—, —CH═, —HC═CH—, and a cycloalkylamino system of the formula (VI):
• 56
• wherein the carbon and/or nitrogen atoms are unsubstituted or substituted with a lower alkyl halogen, hydroxy, phenyl, benzyl, or alkoxy group;
• R is selected from the group consisting of hydrogen, C1-10 alkyl, C1-10 alkoxy, and C3-12cycloalkyl;
• R1 is selected from the group consisting of hydrogen, C1-10alkyl, C3-12cycloalkyl, C2-10alkenyl, amino, C1-10alkylamino, C3-12cycloalkylamino, benzyl, C3-12 cycloalkenyl, a monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, a heteromonocyclic ring, a heterobicyclic ring system, and a spiro ring system of the formula (V):
• 57
• wherein X1 and X2 are independently selected from the group consisting of NH, O, S and CH2;
• wherein said alkyl, cycloalkyl, alkenyl, C1-10alkylamino, C3-12cycloalkylamino, or benzyl is optionally substituted with 1-3 substituents selected from the group consisting of halogen, C1-10 alkyl, C1-10 alkoxy, nitro, trifluoromethyl, cyano, phenyl, benzyl, benzyloxy, said phenyl, benzyl, and benzyloxy optionally being substituted with 1-3 substituents selected from the group consisting of halogen, C1-10 alkyl, C1-10 alkoxy, and cyano;
• wherein said C3-12 cycloalkyl, C3-12 cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, heteromonocyclic ring, heterobicyclic ring system, and spiro ring system of the formula (V) are optionally substituted with 1-3 substituents selected from the group consisting of halogen, C1-10 alkyl, C1-10 alkoxy, nitro, trifluoromethyl, phenyl, benzyl, phenyloxy and benzyloxy, wherein said phenyl, benzyl, phenyloxy and benzyloxy are optionally substituted with 1-3 substituents selected from the group consisting of halogen, C1-10 alkyl, C1-10 alkoxy, and cyano;
• R2 is selected from the group consisting of hydrogen, C1-10 alkyl, C3-12 cycloalkyl and halogen, said alkyl optionally substituted with an oxo group;
• or a pharmaceutically acceptable salt thereof.

A compound of claim selected from the group consisting of

• 3-ethyl-1-(p-phenylbenzyl)-1,3-dihydro-2H-benzimidazol-2-one;
• 3-ethyl-1-(5-methylhex-2-yl)-1,3-dihydro-2H-benzimidazol-2-one;
• 3-ethyl-1-(4-propylcyclohexyl)-1,3-dihydro-2H-benzimidazol-2-one;
• 3-ethyl-1-(decahydro-2-naphthyl)-1,3-dihydro-2H-benzimidazol-2-one;
• 3-ethyl-1-(naphth-2-yl-methyl)-1,3-dihydro-2H-benzimidazol-2-one;
• 1-(p-benzyloxybenzyl)-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one;
• 1-benzyl-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one;
• 1-[4-(benzylamino)-cyclohexyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one;
• 3-ethyl-1-(naphthylmethyl)-1,3-dihydro-2H-benzimidazol-2-one;
• 3-ethyl-1-[5-(3-fluorophenyl)-5-(4-fluorophenyl)-hexyl]-1,3-dihydro-2H-benzimidazol-2-one;
• 1-[4-[(naphth-2-yl-methyl)ethylamino]-cyclohexyl]-1,3-dihydro-2H-benzimidazol-2-one;
• 1-[4-(norbornan-2-ylamino)-cyclohexyl]-1,3-dihydro-2H-benzimidazol-2-one;
• 1-[4-[[4-(1-methylethyl)-cyclohexyl]amino]-cyclohexyl]-1,3-dihydro-2H-benzimidazol-2-one;
• 1-[4-[(decahydro-2-naphthyl)amino]-cyclohexyl]-1,3-dihydro-2H-benzimidazol-2-one;
• 1-[4-(ethylamino)-cyclohexyl]-1,3-dihydro-2H-benzimidazol-2-one;
• 1-[4-(benzylamino)-cyclohexyl]-1,3-dihydro-2H-benzimidazol-2-one;
• 1-[4-[(indan-2-yl)benzylamino]-cyclohexyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one;
• 1-[4-[(cyclooctylmethyl)amino]-cyclohexyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one;
• 1-[4-[(naphth-2-yl)amino]-cyclohexyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one;
• 1-[4-[(p-benzyloxybenzyl)amino]-cyclohexyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one;
• 1-[4-[(cyclooctylmethyl)amino]-cyclohexyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one;
• 1-[4-[(decahydro-2-naphthyl)amino]-cyclohexyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one;
• 1-[4-(benzylamino)-cyclohexyl]-5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one;
• 1-[4-(dibenzylamino)-cyclohexyl]-5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one;
• 1-[4-[(p-phenylbenzyl)amino]-cyclohexyl]-5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one;
• 1-[4-[(1,2,3,4-tetrahydronaphthyl)amino]-cyclohexyl]-5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one;
• 1-[4-[(4-propyl-cyclohexyl)amino]-cyclohexyl]-5-carbamoyl- 1,3 -dihydro-2H-benzimidazol-2one;
• 1-[4-[(5-methylhex-2-yl)amino]-cyclohexyl]-5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one;
• 1-[4-[(decahydro-2-naphthyl)amino]-cyclohexyl]-5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one;
• 1-[4-(cyclooctylamino)-cyclohexyl]-5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one;
• 1-[4-[(indan-2-yl)amino]-cyclohexyl]-5-carbamoyl- 1,3-dihydro-2H-benzimidazol-2-one;
• 1-[4-[(4-phenyl-cyclohexyl)amino]-cyclohexyl]-5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one;
• 1-[4-[(5-methylhex-2-yl)amino]-cyclohexyl]-7-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one;
• and
• pharmaceutically acceptable salts thereof.

A compound of claim (IIIA):

• 58
• wherein
• n is an integer from 0 to 3;
• R is selected from the group consisting of hydrogen, C1-10 alkyl, C1-10 alkoxy, and C3-12cycloalkyl;
• R2 is selected from the group consisting of hydrogen, C1-10 alkyl, C3-12 cycloalkyl and halogen,said alkyl optionally substituted with an oxo group;
• ZR1 is the following
• 59
• wherein
• Y1 is R3—(C1-C12)alkyl, R4-aryl, R5-heteroaryl, R6—(C3-C12)cyclo-alkyl, R7—(C3-C7)heterocycloalkyl, —CO2(C1-C6)alkyl, CN or —C(O)NR8R9;
• Y2 is hydrogen or Y1;
• Y3 is hydrogen or (C1-C6)alkyl;
• or Y1, Y2 and Y3, together with the carbon to which they are attached, form one of the following structures:
• 60
• wherein r is 0 to 3;
• w and u are each 0-3, provided that the sum of w and u is 1-3;
• c and d are independently 1 or 2;
• s is 1 to 5;
• and ring E is a fused R4-phenyl or R5-heteroaryl ring;
• R10 is 1 to 3 substituents independently selected from the group consisting of H, (C1-C6)alkyl, —OR8, —(C1-C6)alkyl-OR8, —NR8R9 and —(C1-C6)alkyl-NR8R9;
• R11 is 1 to 3 substituents independently selected from the group consisting of R10, —CF3, —OCF3, NO2 and halo, or R11 substituents on adjacent ring carbon atoms may together form a methylenedioxy or ethylenedioxy ring;
• R8 and R9 are independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C3-C12)cycloalkyl, aryl and aryl(C1-C6)alkyl;
• R3 is 1 to 3 substituents independently selected from the group consisting of H, R4-aryl, R6—(C3-C12)cycloalkyl, R5-heteroaryl, R7—(C3-C7)heterocycloalkyl, —NR8 R9, —OR12 and —S(O)0-2R12;
• R6 is 1 to 3 substituents independently selected from the group consisting of H, (C1-C6)alkyl, R4-aryl, —NR8R9, —OR12 and —SR12;
• R4 is 1 to 3 substituents independently selected from the group consisting of hydrogen, halo, (C1-C6)alkyl, R3-aryl, (C3-C12)cycloalkyl, —CN, —CF3, —OR8, —(C1-C6)alkyl-OR8, —OCF3, —NR8R9, —(C1-C6)alkyl -NR8R9, —NHSO2R8, —SO2N(R14)2, —SO2R8, —SOR8, —SR8, —NO2, —CONR8R9, —NR9COR8, —COR8, —COCF3, —OCOR8, —OCO2R8, —COOR8, —(C1-C6)alkyl-NHCOOC(CH3)3, —(C1-C6)alkyl-NHCOCF3, —(C1-C6)alkyl—NHSO2-(C1-C6)alkyl, —(C1-C6)alkyl-NHCONH—(C1-C6)-alkyl and
• 61
• wherein f is 0 to 6;
• or R4 substituents on adjacent ring carbon atoms may together form a methylenedioxy or ethylenedioxy ring;
• R5 is 1 to 3 substituents independently selected from the group consisting of hydrogen, halo, (C1-C6)alkyl, R13-aryl, (C3-C12)cycloalkyl, —CN, —CF3, —OR8, —(C1-C6)alkyl-OR9, OCF3,—NR8R9, —(C1-C6)alkyl-NR8R9, —NHSO2R8, —SO2N(R14)2, —NO2, —CONR8R9, —NR9COR8, —COR8, —OCOR8, —OCO2R8 and —COOR8;
• R7 is H, (C1-C6)alkyl, —OR8, —(C1-C6)alkyl-OR8, —NR8R9 or —(C1-C6)alkyl-NR8R9;
• R12 is H, (C1-C6)alkyl, R4-aryl, —(C1-C6)alkyl-OR8, —(C1-C6)alkyl-NR8R9, —(C1-C6)alkyl-SR8, or aryl (C1-C6)alkyl;
• R13 is 1-3 substituents independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkoxy and halo;
• R14 is independently selected from the group consisting of H, (C1-C6)alkyl and R13—C6H4—CH2—;
• or a pharmaceutically acceptable salt thereof.

A compound of formula (IV):

• 62
• wherein R is hydrogen, C1-10 alkyl, C3-12 cycloalkyl, C3-12 cycloalkylC1-4alkyl-, C1-10 alkoxy, C3-12 cycloalkoxy-, C1-10 alkyl substituted with 1-3 halogen, C3-12 cycloalkyl substitute with 1-3 halogen, C3-12 cycloalkylC1-4alkyl- substituted with 1-3 halogen, C1-10 alkoxy substituted with 1-3 halogen, C3-12 cycloalkoxy- substituted with 1-3 halogen, —COOV1, —C1-4COOV1, —CH2OH, —SO2N(V1)2, hydroxyC1-10alkyl, hydroxyC3-10cycloalkyl, cyanoC1-10alkyl, cyanoC3-10cycloalkyl-, —CON(V1)2, NH2SO2C1-4alkyl-, NH2SOC1-4alkyl-, sulfonylaminoC1-10alkyl-, diaminoalkyl-, -sulfonylC1-4alkyl, a 6-membered heterocyclic ring, a 6-membered heteroaromatic ring, a 6-membered heterocyclicC1-4alkyl-, a 6-membered heteroaromaticC1-4alkyl-, a 6-membered aromatic ring, a 6-membered aromaticC1-4 alkyl-, a 5-membered heterocyclic ring optionally substituted with an oxo or thio, a 5-membered heteroaromatic ring, a 5-membered heterocyclicC1-4alkyl- optionally substituted with an oxo or thio, a 5-membered heteroaromaticC1-4alkyl-, —C1-5(═O)W1, —C1-5(═NH)W1, —C1-5NHC(═O)W1, —C1-5NHS(═O)2W1, —C1-5NHS(═O)W1, wherein W1 is hydrogen, C1-10 alkyl, C3-12 cycloalkyl, C1-10 alkoxy, C3-12 cycloalkoxy, —CH2OH, amino, C1-4alkylamino-, diC1-4alkylamino-, or a 5-membered heteroaromatic ring optionally substituted with 1-3 lower alkyl;
• wherein each V1 is independently selected from H, C1-6 alkyl, C3-6 cycloalkyl, benzyl and phenyl;
• D is a 5-8 membered cycloalkyl, 5-8 membered heterocyclic or a 6 membered aromatic or heteroaromatic group;
• n is an integer from 0 to 3;
• A, B and Q are independently hydrogen, C1-10 alkyl, C3-12 cycloalkyl, C1-10 alkoxy, C3-12 cycloalkoxy, —CH2OH, —NHSO2, hydroxyC1-10alkyl-, aminocarbonyl-, C1-4alkylaminocarbonyl-, diC1-4alkylaminocarbonyl-, acylamino-, acylaminoalkyl-, amide, sulfonylaminoC1-10alkyl-, or A-B can together form a C2-6 bridge, or B-Q can together form a C3-7 bridge, or A-Q can together form a C1-5 bridge;
• Z is selected from the group consisting of a bond, straight or branched C1-6 alkylene, —NH—, —CH2O—, —CH2NH—, —CH2N(CH3)—, —NHCH2—, —CH2CONH—, —NHCH2CO—, —CH2CO—, —COCH2—, —CH2COCH2—, —CH(CH3)—, —CH═, —O— and —HC═CH—, wherein the carbon and/or nitrogen atoms are unsubstituted or substituted with one or more lower alkyl, hydroxy, halo or alkoxy group;
• R1 is selected from the group consisting of hydrogen, C1-10 alkyl, C3-12cycloalkyl, C2-10alkenyl, amino, C1-10alkylamino-, C3-12cycloalkylamino-, —COOV1, —C1-4COOV1, cyano, cyanoC1-10alkyl-, cyanoC3-10cycloalkyl-, NH2SO2—, NH2SO2C1-4alkyl-, NH2SOC1-4alkyl-, aminocarbonyl-, C1-4alkylaminocarbonyl-, diC1-4alkylaminocarbonyl-, benzyl, C3-12 cycloalkenyl-, a monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, a hetero-monocyclic ring, a hetero-bicyclic ring system, and a spiro ring system of the formula (V):
• 63
• wherein X1 and X2 are independently selected from the group consisting of NH, O, S and CH2;
• and wherein said alkyl, cycloalkyl, alkenyl, C1-10alkylamino-, C3-12cycloalkylamino-, or benzyl of R1 is optionally substituted with 1-3 substituents selected from the group consisting of halogen, hydroxy, C1-10 alkyl, C1-10 alkoxy, nitro, trifluoromethyl-, cyano, —COOV1, —C1-3COOV1, cyanoC1-10alkyl-, —C1-5(═O)W1, —C1-5NHS(═O)2W1, —C1-5NHS(═O)W1, a 5-membered heteroaromaticC0-4alkyl-, phenyl, benzyl, benzyloxy, said phenyl, benzyl, and benzyloxy optionally being substituted with 1-3 substituents selected from the group consisting of halogen, C1-4alkyl-, C1-10 alkoxy-, and cyano;,and wherein said C3-12 cycloalkyl, C3-12 cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, hetero-monocyclic ring, hetero-bicyclic ring system, or spiro ring system of the formula (II) is optionally substituted with 1-3 substituents selected from the group consisting of halogen, C1-10 alkyl, C1-10alkoxy, nitro, trifluoromethyl-, phenyl, benzyl, phenyloxy aid benzyloxy, wherein said phenyl, benzyl, phenyloxy or benzyloxy is optionally substituted with 1-3 substituents selected from the group consisting of halogen, C1-10 alkyl, C1-10 alkoxy, and cyano;
• R2 is selected from the group consisting of hydrogen, C1-10 alkyl C3-12 cycloalkyl-and halogen, said alkyl or cycloalkyl optionally substituted with an oxo, amino, alkylamino or dialkylamino group;
• or a pharmaceutically acceptable salt thereof or solvate thereof.

A compound of the formula (IVA):

• 64
• wherein
• n is an integer from 0 to 3,
• Z is selected from the group consisting of a bond, —CH2—, —NH—, —CH2O—, —CH2CH —, —CH2NH—, —CH2N(CH3)—, —NHCH2—, —CH2CONH—, —NHCH2CO—, —CH2CO—, —COCH2—, —CH2COCH2—, —CH(CH3)—, —CH═, and —HC═CH—, wherein the carbon and/or nitrogen atoms are unsubstituted or substituted with a lower alkyl, halogen, hydroxy or alkoxy group;
• R is selected from the group consisting of hydrogen, C1-10 alkyl, C1-10 alkoxy, and C3-12 cycloalkyl;
• R is selected from the group consisting of hydrogen C1-10alkyl, C3-12cycloalkyl, C2-10alkenyl, amino, C1-10alkylamino, C3-12cycloalkylamino, benzyl, C3-12 cycloalkenyl, a monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, a heteromonocyclic ring, a heterobicyclic ring system, and a spiro ring system of the formula (V):
• 65
• wherein X1 and X2 are independently selected from the group consisting of NH, O, S and CH2;
• wherein said alkyl, cycloalkyl, alkenyl, C1-10alkylamino, C3-12cycloalkylamino, or benzyl is optionally substituted with 1-3 substituents selected from the group consisting of halogen, C1-10 alkyl, C1-10 alkoxy, nitro, trifluoromethyl, cyano, phenyl, benzyl, benzyloxy, said phenyl, benzyl, and benzyloxy optionally being substituted with 1-3 substituents selected from the group consisting of halogen, C1-10 alkyl, C1-10 alkoxy, and cyano;
• wherein said C3-12 cycloalkyl, C3-12 cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, heteromonocyclic ring, heterobicyclic ring system, and spiro ring system of the formula (V) are optionally substituted with 1-3 substituents selected from the group consisting of halogen, C1-10 alkyl, C1-10 alkoxy, nitro, trifluoromethyl, phenyl, benzyl, phenyloxy and benzyloxy, wherein said phenyl, benzyl, phenyloxy and benzyloxy are optionally substituted with 1-3 substituents selected from the group consisting of halogen, C1-10 alkyl, C1-10 alkoxy, and cyano;
• R2 is selected from the group consisting of hydrogen, C1-10 alkyl, C3-12 cycloalkyl and halogen, said alkyl optionally substituted with an oxo group;
• or a pharmaceutically acceptable salt thereof.

A compound selected from the group consisting of

• 2-cyanoimino-3-ethyl-1-[1-(p-phenylbenzyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole;
• 2-cyanoimino-3-ethyl-1-[1-(p-benzyloxybenzyl)-4-piperidinyl]1,3-dihydro-2H-benzimidazole;
• 2-cyanoimino-3-ethyl-1-[1-(naphth-2-yl-methyl)-4-piperidinyl]1,3-dihydro-2H-benzimidazole;
• 2-cyanoimino-3-ethyl-1-[1-(4-propylcyclohexyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole;
• 2-cyanoimino-3-ethyl-1-[1-[4-(2-propyl)-cyclohexyl]-4-piperidinyl]-1,3-dihydro-2H-benzimidazole;
• 2-cyanoimino-3-ethyl-1-[1-(decahydro-2-naphthyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole;
• 2-cyanoimino-3-ethyl-1-[1-(cyclooctyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole;
• 2-cyanoimino-3-ethyl1-[1-(10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5-yl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole;
• 2-cyanoimino-3-ethyl-1-[1-(3,3-Bis(phenyl)propyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole;
• 2-cyanoimino-3-ethyl-1-[1-(1,2,3,4-tetrahydronaphthyl)4-piperidinyl]-1,3-dihydro-2H-benzimidazole;
• 2-cyanoimino-3-ethyl-1-[1-(5methylhex-2-yl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole;
• 2-cyanoimino-3-ethyl-1-[1-(norbornan-2-yl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole;
• 2-cyanoimino-3-ethyl-1-[1-(1,3-dihydroinden2-yl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole;
• 2-cyanoimino-3-ethyl-1-[1-(cyclooctylmethyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole;
• and
• pharmaceutically acceptable salts thereof.

A compound selected from the group consisting of

• 2-cyanoimino-3-(2-hydroxy)ethyl-1-[1-(cyclooetyl)-4-piperidinyl]-1,3 dihydro-2H-benzimidazole;
• 2-cyanoimino-3-methoxycarbonylmethyl-1-[1(cyclooctyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole;
• 2-cyanoimino-3-cyanomethyl-1-[1-(cyclooctyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole;
• 2-cyanoimino-3-butyl-1-[1-(cyclooctyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole;
• 2-cyanoimino-3-(2-methanesulfonamido)ethyl-1-[1-(cyclooctyl)-4-piperidinyl]1,3-dihydro-2H-benzimidazole;
• 2-cyanoimino-3-acetomido-1-[1-(cyclooctyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole;
• 2-cyanoimino-3-carboxymethyl-1-[1-(cyclooctyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole;
• 2-cyanoimino-3-(2-dimethylamino)ethyl-1-[1-(cyclooctyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole;
• 2-cyanoimino-1-[1-(cyclooctyl)-3-hydroxymethyl-4-piperidinyl]-1,3-dihydro-2H-benzimidazole;
• 2-cyanoimino-1-[1-(cyclooctyl)-4-piperidinyl]-1,3-dihydro-2H-7-azabenzimidazole;
• 2-cyanoimino-1-[1-(cyclooctyl)-2,6-ethano-4-one-4-piperidinyl]-1,3-dihydro-2H-benzimidazole;
• and
• pharmaceutically acceptable salts thereof and solvates thereof.

A compound of the formula( IVA):

• 66
• wherein
• n is an integer from 0 to 3;
• R is selected from the group consisting of hydrogen, C1-10 alkyl, C1-10 alkoxy, and C3-12cycloalkyl;
• R2 is selected from the group consisting of hydrogen, C1-10 alkyl C3-12 cycloalkyl and halogen, said alkyl optionally substituted with an oxo group;
• ZR1 is the following
• 67
• wherein
• Y1 is R3—(C1-C12)alkyl, R4-aryl, R5-heteroaryl, R6—(C3-C12)cyclo-alkyl, R7—(C3-C7)heterocycloalkyl, —CO2(C1-C6)alkyl, CN or —C(O)NR8R9;
• Y2 is hydrogen or Y1;Y3 is hydrogen or (C1-C6)alkyl;
• or Y1, Y2 and Y3l together with carbon to which they are attached, form one of the following structures:
• 68
• wherein r is 0 to 3;
• wand u are each 0-3, provided that the sum of w and u is 1-3;
• c and d are independently 1 or 2;
• s is 1 to 5;
• and ring E is a fused R4-phenyl or R5-heteroaryl ring,
• R10 is 1 to 3 substituents independently selected from the group consisting of H, (C1-C6)alkyl, —OR8, (C1-C6)alkyl-OR8, —NR8R9 and —(C1-C6)alkyl-NR8R9;
• R11 is 1 to 3 substituents independently selected from the group consisting of R10, —CF3, —OCF3, NO2 and halo, or R11 substituents on adjacent ring carbon atoms may together form a methylenedioxy or ethylenedioxy ring;
• R8and R9are independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C3-C12)cycloalkyl, aryl and aryl(C1-C6)alkyl;
• R3 is 1to 3 substituents independently selected from the group consisting of H, R4-aryl, R6—(C3-C12)cycloalkyl, R5-heteroaryl, R7—(C3-C7)heterocycloalkyl, —NR8 R9, —OR12 and —S(O)0-2R12;
• R6 is 1 to 3 substituents independently selected from the group consisting of H, (C1-C6)alkyl, R4-aryl, —NR8R9, —OR12 and —SR12;
• R4 is 1 to 3 substituents independently selected from the group consisting of hydrogen, halo, (C1-C6)alkyl, R13 -aryl, (C3- C12)cycloalkyl, —CN, —CF3, —OR8, —(C1-C6)alkyl-OR8, —OCF3, —NR8R9, —(C1-C6)alkyl -NR8R9, —NHSO2R8, —SO2N(R14)2, —SO2R8, —SOR8, —SR8,—NO2, —CONR8R9, —NR9COR8, —COR8, —COCF3, —OCOR8, —OCO2R8, —COOR8, —(C1-C6)alkyl-NHCOOC(CH3)3, —(C1-C6)alkyl-NHCOCF3, —(C1-C6)alkyl-NHSO2—(C1-C6)alkyl, —(C1-C6)alkyl-NHCONH—(C1-C6)-alkyl and
• 69
• wherein f is 0 to 6;
• or R4 substituents on adjacent ring carbon atoms may together form a methylenedioxy or ethylenedioxy ring;
• R5 is 1 to 3 substituents independently selected from the group consisting of hydrogen, halo, (C1-C6)alkyl, R13-aryl, (C3-C12)cycloalkyl, —CN, —CF3, —OR8, —(C1-C6)alkyl-OR8, —OCF3,—NR8R9, —(C1-C6)alkyl-NR8R9, —NHSO2R8, —SO2N(R14)2, —NO2, —CONR8R9, —NR9COR8, —COR8, —OCOR8, —OCO2R8 and —COOR8;
• R7 is H, (C1-C6)alkyl, —OR8, —(C1-C6)alkyl-OR8, —NR8R9 or —(C1C6)alkyl-NR8R9;
• R12 is H, (C1-C6)alkyl, R4-aryl, —(C1-C6)alkyl-OR8, —(C1-C6)alkyl-NR8R9, —(C1-C6)alkyl-SR8, or aryl (C1-C6)alkyl;
• R13 is 1-3 substituents independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkoxy and halo;
• R14 is independently selected from the group consisting of H, (C1-C6)alkyl and R13—C6H4—CH2—.
• and a pharmaceutically acceptable salt thereof.