4,5 dihydro-(1H)-pyrazole derivatives as cannabinoid CB1 receptor modulators

A medicament comprising a compound of formula (I):

• or a tautomer, stereoisomer, N-oxide, isotopically-labelled analogue, or pharmacologically acceptable salt of any of the foregoing, wherein:
• R is selected from the group consisting of:
• C3-10 linear alkyl, C4-10 branched alkyl, C4-10 alkynyl, C3-10-heteroalkyl, and C5-8-cycloalkyl-C1-5-alkyl, which are optionally substituted with 1-3 fluorine atoms,
• aryl-C1-3-alkyl and heteroaryl-C1-3-alkyl, optionally substituted with 1-3 substituents Y, wherein Y is the same or different, and is selected from the group consisting of methyl, ethyl, methoxy, ethoxy, halogen, trifluoromethyl, trifluoromethoxy and cyano,
• cyclopropyl, optionally substituted with C1-5-alkyl, benzyl, aryl, and heteroaryl, which are optionally substituted with 1-3 substituents Y, wherein Y is the same or different, and is selected from the group consisting of methyl, ethyl, methoxy, ethoxy, halogen, trifluoromethyl, trifluoromethoxy and cyano;
• R2 is selected from the group consisting of aryl and heteroaryl, which are optionally substituted with 1-5 substituents Y, wherein Y is the same or different, and is selected from the group consisting of methyl, ethyl, methoxy, ethoxy, halogen, trifluoromethyl, trifluoromethoxy and cyano;
• n is 0 or 1;
• R3 is selected from the group consisting of:
• linear and branched C3-10 alkyl, C3-8 cycloalkyl, C5-10 bicycloalkyl, C6-10 tricycloalkyl and C8-11 tetracycloalkyl, which are optionally substituted with 1-5 substituents selected from the group consisting of methyl, ethyl, hydroxy, amino, and fluoro,
• C3-8 cycloalkyl substituted with aryl and heteroaryl, wherein the aryl and heteroaryl are optionally substituted with 1-5 substituents Y, wherein Y is the same or different, and is selected from the group consisting of methyl, ethyl, methoxy, ethoxy, halogen, trifluoromethyl, trifluoromethoxy and cyano,
• C5-8 heterocycloalkyl, C6-10 bicycloheteroalkyl, and C7-10 tricycloheteroalkyl, which are optionally substituted with 1-5 substituents selected from the group consisting of methyl, ethyl, hydroxy, amino, and fluoro,
• C3-8 cycloalkyl-C1-3-alkyl, C5-10-bicycloalkyl-C1-3-alkyl, and C6-10-tricycloalkyl-C1-3-alkyl, which are optionally substituted with 1-5 substituents selected from the group consisting of methyl, ethyl, hydroxy, amino, and fluoro,
• branched and linear C3-8 heterocycloalkyl-C1-3-alkyl, C5-10 bicycloheteroalkyl-C1-3-alkyl, and C6-10 tricycloheteroalkyl-C1-3-alkyl, which groups optionally substituted with 1-5 substituents selected from the group consisting of methyl, ethyl, hydroxy, amino, and fluoro,
• aryl and heteroaryl, optionally substituted with 1-5 substituents Y, wherein Y is the same or different, and is selected from the group consisting of methyl, ethyl, methoxy, ethoxy, halogen, trifluoromethyl, trifluoromethoxy and cyano,
• aryl-C1-5-alkyl, heteroaryl-C1-5-alkyl and di(hetero)aryl-C1-5-alkyl, wherein the phenyl and heteroaromatic rings are optionally substituted with 1-5 substituents Y, wherein Y is the same or different, and is selected from the group consisting of methyl, ethyl, methoxy, ethoxy, halogen, trifluoromethyl, trifluoromethoxy and cyano,
• linear and branched C4-8 alkenyl, and C4-8 alkynyl, which are optionally substituted with 1-3 fluorine atoms, with the proviso that when n=1, R3 is selected from the group consisting of branched and linear C2-10 heteroalkyl, comprising 1-2 heteroatoms selected from the group consisting of N, O, and S;
• R5 is selected from the group consisting of hydrogen and C1-2 alkyl, which is optionally substituted with 1-3 fluorine atoms;
• and
• R6 is C1-2 alkyl, which is optionally substituted with 1-3 fluorine atoms.

A method of treating at least one condition selected from the group consisting of multiple sclerosis, traumatic brain injury, pain, appetite disorders, epilepsy, Alzheimer's disease, Tourette's syndrome, cerebral ischaemia, osteoporosis, emesis, and nausea, the method comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of formula (I):

• or a tautomer, stereoisomer, N-oxide, isotopically-labelled analogue, or pharmacologically acceptable salt of any of the foregoing, wherein:
• R is selected from the group consisting of:
• C3-10 linear alkyl, C4-10 branched alkyl, C4-10 alkynyl, C3-10-heteroalkyl, and C5-8-cycloalkyl-C1-5-alkyl, which are optionally substituted with 1-3 fluorine atoms,
• aryl-C1-3-alkyl and heteroaryl-C1-3-alkyl, optionally substituted with 1-3 substituents Y, wherein Y is the same or different, and is selected from the group consisting of methyl, ethyl, methoxy, ethoxy, halogen, trifluoromethyl, trifluoromethoxy and cyano,
• cyclopropyl, optionally substituted with C1-5-alkyl, benzyl, aryl, and heteroaryl, which are optionally substituted with 1-3 substituents Y, wherein Y is the same or different, and is selected from the group consisting of methyl, ethyl, methoxy, ethoxy, halogen, trifluoromethyl, trifluoromethoxy and cyano;
• R2 is selected from the group consisting of aryl and heteroaryl, which are optionally substituted with 1-5 substituents Y, wherein Y is the same or different, and is selected from the group consisting of methyl, ethyl, methoxy, ethoxy, halogen, trifluoromethyl, trifluoromethoxy and cyano;
• n is 0 or 1;
• R3 is selected from the group consisting of:
• linear and branched C3-10 alkyl, C3-8 cycloalkyl, C5-10 bicycloalkyl, C6-10 tricycloalkyl and C8-11 tetracycloalkyl, which are optionally substituted with 1-5 substituents selected from the group consisting of methyl, ethyl, hydroxy, amino, and fluoro,
• C3-8 cycloalkyl substituted with aryl and heteroaryl, wherein the aryl and heteroaryl are optionally substituted with 1-5 substituents Y, wherein Y is the same or different, and is selected from the group consisting of methyl, ethyl, methoxy, ethoxy, halogen, trifluoromethyl, trifluoromethoxy and cyano,
• C5-8 heterocycloalkyl, C6-10 bicycloheteroalkyl, and C7-10 tricycloheteroalkyl, which are optionally substituted with 1-5 substituents selected from the group consisting of methyl, ethyl, hydroxy, amino, and fluoro,
• C3-8 cycloalkyl-C1-3-alkyl, C5-10-bicycloalkyl-C1-3-alkyl, and C6-10-tricycloalkyl-C1-3-alkyl, which are optionally substituted with 1-5 substituents selected from the group consisting of methyl, ethyl, hydroxy, amino, and fluoro,
• branched and linear C3-8 heterocycloalkyl-C1-3-alkyl, C5-10 bicycloheteroalkyl-C1-3-alkyl, and C6-10 tricycloheteroalkyl-C1-3-alkyl, which groups optionally substituted with 1-5 substituents selected from the group consisting of methyl, ethyl, hydroxy, amino, and fluoro,
• aryl and heteroaryl, optionally substituted with 1-5 substituents Y, wherein Y is the same or different, and is selected from the group consisting of methyl, ethyl, methoxy, ethoxy, halogen, trifluoromethyl, trifluoromethoxy and cyano,
• aryl-C1-5-alkyl, heteroaryl-C1-5-alkyl and di(hetero)aryl-C1-5-alkyl, wherein the phenyl and heteroaromatic rings are optionally substituted with 1-5 substituents Y, wherein Y is the same or different, and is selected from the group consisting of methyl, ethyl, methoxy, ethoxy, halogen, trifluoromethyl, trifluoromethoxy and cyano,
• linear and branched C4-8 alkenyl, and C4-8 alkynyl, which are optionally substituted with 1-3 fluorine atoms, with the proviso that when n=1, R3 is selected from the group consisting of branched and linear C2-10 heteroalkyl, comprising 1-2 heteroatoms selected from the group consisting of N, O, and S;
• R5 is selected from the group consisting of hydrogen and C1-2 alkyl, which is optionally substituted with 1-3 fluorine atoms;
• and
• R6 is C1-2 alkyl, which is optionally substituted with 1-3 fluorine atoms.

A pharmaceutical composition comprising, at least one pharmaceutically acceptable carrier, and a therapeutically effective amount of at least one compound of formula (I):

• or a tautomer, stereoisomer, N-oxide, isotopically-labelled analogue, or pharmacologically acceptable salt of any of the foregoing, wherein:
• R is selected from the group consisting of:
• C3-10 linear alkyl, C4-10 branched alkyl, C4-10 alkynyl, C3-10-heteroalkyl, and C5-8-cycloalkyl-C1-5-alkyl, which are optionally substituted with 1-3 fluorine atoms,
• aryl-C1-3-alkyl and heteroaryl-C1-3-alkyl, optionally substituted with 1-3 substituents Y, wherein Y is the same or different, and is selected from the group consisting of methyl, ethyl, methoxy, ethoxy, halogen, trifluoromethyl, trifluoromethoxy and cyano,
• cyclopropyl, optionally substituted with C1-5-alkyl, benzyl, aryl, and heteroaryl, which are optionally substituted with 1-3 substituents Y, wherein Y is the same or different, and is selected from the group consisting of methyl, ethyl, methoxy, ethoxy, halogen, trifluoromethyl, trifluoromethoxy and cyano;
• R2 is selected from the group consisting of aryl and heteroaryl, which are optionally substituted with 1-5 substituents Y, wherein Y is the same or different, and is selected from the group consisting of methyl, ethyl, methoxy, ethoxy, halogen, trifluoromethyl, trifluoromethoxy and cyano;
• n is 0 or 1;
• R3 is selected from the group consisting of:
• linear and branched C3-10 alkyl, C3-8 cycloalkyl, C5-10 bicycloalkyl, C6-10 tricycloalkyl and C8-11 tetracycloalkyl, which are optionally substituted with 1-5 substituents selected from the group consisting of methyl, ethyl, hydroxy, amino, and fluoro,
• C3-8 cycloalkyl substituted with aryl and heteroaryl, wherein the aryl and heteroaryl are optionally substituted with 1-5 substituents Y, wherein Y is the same or different, and is selected from the group consisting of methyl, ethyl, methoxy, ethoxy, halogen, trifluoromethyl, trifluoromethoxy and cyano,
• C5-8 heterocycloalkyl, C6-10 bicycloheteroalkyl, and C7-10 tricycloheteroalkyl, which are optionally substituted with 1-5 substituents selected from the group consisting of methyl, ethyl, hydroxy, amino, and fluoro,
• C3-8 cycloalkyl-C1-3-alkyl, C5-10-bicycloalkyl-C1-3-alkyl, and C6-10-tricycloalkyl-C1-3-alkyl, which are optionally substituted with 1-5 substituents selected from the group consisting of methyl, ethyl, hydroxy, amino, and fluoro,
• branched and linear C3-8 heterocycloalkyl-C1-3-alkyl, C6-10 bicycloheteroalkyl-C1-3-alkyl, and C6-10 tricycloheteroalkyl-C1-3-alkyl, which groups optionally substituted with 1-5 substituents selected from the group consisting of methyl, ethyl, hydroxy, amino, and fluoro,
• aryl and heteroaryl, optionally substituted with 1-5 substituents Y, wherein Y is the same or different, and is selected from the group consisting of methyl, ethyl, methoxy, ethoxy, halogen, trifluoromethyl, trifluoromethoxy and cyano,
• aryl-C1-5-alkyl, heteroaryl-C1-5-alkyl and di(hetero)aryl-C1-5-alkyl, wherein the phenyl and heteroaromatic rings are optionally substituted with 1-5 substituents Y, wherein Y is the same or different, and is selected from the group consisting of methyl, ethyl, methoxy, ethoxy, halogen, trifluoromethyl, trifluoromethoxy and cyano,
• linear and branched C4-8 alkenyl, and C4-8 alkynyl, which are optionally substituted with 1-3 fluorine atoms, with the proviso that when n=1, R3 is selected from the group consisting of branched and linear C2-10 heteroalkyl, comprising 1-2 heteroatoms selected from the group consisting of N, O, and S;
• R5 is selected from the group consisting of hydrogen and C1-2 alkyl, which is optionally substituted with 1-3 fluorine atoms;
• and
• R6 is C1-2 alkyl, which is optionally substituted with 1-3 fluorine atoms.

A method of treating at least one condition selected from the group consisting of multiple sclerosis, traumatic brain injury, pain, appetite disorders, epilepsy, Alzheimer's disease, Tourette's syndrome, cerebral ischaemia, osteoporosis, emesis, abd nausea, the method comprising administering a pharmaceutical composition to a mammal in need thereof, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier, and a therapeutically effective amount of at least one compound of formula (I):

• or a tautomer, stereoisomer, N-oxide, isotopically-labelled analogue, or pharmacologically acceptable salt of any of the foregoing, wherein:
• R is selected from the group consisting of:
• C3-10 linear alkyl, C4-10 branched alkyl, C4-10 alkynyl, C3-10-heteroalkyl, and C5-8-cycloalkyl-C1-5-alkyl, which are optionally substituted with 1-3 fluorine atoms,
• aryl-C1-3-alkyl and heteroaryl-C1-3-alkyl, optionally substituted with 1-3 substituents Y, wherein Y is the same or different, and is selected from the group consisting of methyl, ethyl, methoxy, ethoxy, halogen, trifluoromethyl, trifluoromethoxy and cyano,
• cyclopropyl, optionally substituted with C1-5-alkyl, benzyl, aryl, and heteroaryl, which are optionally substituted with 1-3 substituents Y, wherein Y is the same or different, and is selected from the group consisting of methyl, ethyl, methoxy, ethoxy, halogen, trifluoromethyl, trifluoromethoxy and cyano;
• R2 is selected from the group consisting of aryl and heteroaryl, which are optionally substituted with 1-5 substituents Y, wherein Y is the same or different, and is selected from the group consisting of methyl, ethyl, methoxy, ethoxy, halogen, trifluoromethyl, trifluoromethoxy and cyano;
• n is 0 or 1;
• R3 is selected from the group consisting of:
• linear and branched C3-10 alkyl, C3-8 cycloalkyl, C5-10 bicycloalkyl, C6-10 tricycloalkyl and C8-11 tetracycloalkyl, which are optionally substituted with 1-5 substituents selected from the group consisting of methyl, ethyl, hydroxy, amino, and fluoro,
• C3-8 cycloalkyl substituted with aryl and heteroaryl, wherein the aryl and heteroaryl are optionally substituted with 1-5 substituents Y, wherein Y is the same or different, and is selected from the group consisting of methyl, ethyl, methoxy, ethoxy, halogen, trifluoromethyl, trifluoromethoxy and cyano,
• C5-8 heterocycloalkyl, C6-10 bicycloheteroalkyl, and C7-10 tricycloheteroalkyl, which are optionally substituted with 1-5 substituents selected from the group consisting of methyl, ethyl, hydroxy, amino, and fluoro,
• C3-8 cycloalkyl-C1-3-alkyl, C5-10-bicycloalkyl-C1-3-alkyl, and C6-10-tricycloalkyl-C1-3-alkyl, which are optionally substituted with 1-5 substituents selected from the group consisting of methyl, ethyl, hydroxy, amino, and fluoro,
• branched and linear C3-8 heterocycloalkyl-C1-3-alkyl, C5-10 bicycloheteroalkyl-C1-3-alkyl, and C6-10 tricycloheteroalkyl-C1-3-alkyl, which groups optionally substituted with 1-5 substituents selected from the group consisting of methyl, ethyl, hydroxy, amino, and fluoro,
• aryl and heteroaryl, optionally substituted with 1-5 substituents Y, wherein Y is the same or different, and is selected from the group consisting of methyl, ethyl, methoxy, ethoxy, halogen, trifluoromethyl, trifluoromethoxy and cyano,
• aryl-C1-5-alkyl, heteroaryl-C1-5-alkyl and di(hetero)aryl-C1-5-alkyl, wherein the phenyl and heteroaromatic rings are optionally substituted with 1-5 substituents Y, wherein Y is the same or different, and is selected from the group consisting of methyl, ethyl, methoxy, ethoxy, halogen, trifluoromethyl, trifluoromethoxy and cyano,
• linear and branched C4-8 alkenyl, and C4-8 alkynyl, which are optionally substituted with 1-3 fluorine atoms, with the proviso that when n=1, R3 is selected from the group consisting of branched and linear C2-10 heteroalkyl, comprising 1-2 heteroatoms selected from the group consisting of N, O, and S;
• R5 is selected from the group consisting of hydrogen and C1-2 alkyl, which is optionally substituted with 1-3 fluorine atoms;
• and
• R6 is C1-2 alkyl, which is optionally substituted with 1-3 fluorine atoms.