Dopamine D4 ligands for the treatment of novelty-seeking disorders

A method of treating or preventing a novelty-seeking disorder in a subject comprising administering to the subject:

• (b) an amount of a compound of the formula
• 13
• wherein X1, X2 and X3 are independently selected from carbon and nitrogen;
• R0, R1 and R2 are independently selected from hydrogen, halo (e.g., chloro, fluoro, bromo or iodo), (C1-C6)alkyl optionally substituted with from one to three fluorine atoms and (C1-C6)alkoxy optionally substituted with from one to three fluorine atoms;
• R3 is hydrogen, (C1-C6)alkyl or benzyl, wherein the phenyl moiety of said benzyl group may optionally be substituted with from one or more substituents, independently selected from halo, cyano, (C1-C6)alkyl optionally substituted with from one to three fluorine atoms, (C1-C6)alkoxy optionally substituted with from one to three fluorine atoms, (C1-C6)alkylsulfonyl, (C1-C6)alkylamino, amino, di-(C1-C6)alkylamino and (C1-C6)carboxamido;
• R4, R5 and R6 are independently selected from hydrogen, halo (e.g., chloro, fluoro, bromo and iodo), cyano, (C1-C6)alkyl optionally substituted with from one to three fluorine atoms, (C1-C6)alkoxy optionally substituted with from one to three fluorine atoms, (C1-C6)alkylsulfonyl, (C1-C6)acylamino, (phenyl)[(C1-C6)acyl]amino, amino, (C1-C6)alkylamino and di-(C1-C6)alkylamino;
• with the proviso that when X3 is nitrogen, R2 is absent;
• or a pharmaceutically acceptable salt thereof;
• (c) an amount of a compound of the formula
• 14
• wherein each of the dotted lines represents an optional double bond;
• X is carbon or nitrogen;
• R1 is benzyl, aryl selected from phenyl, indanyl and naphthyl, or heteroaryl selected from pyridyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, quinolyl and imidazolyl, wherein each of the foregoing aryl, heteroaryl and (C1-C4)alkyl groups, and the phenyl moiety of the benzyl group, may optionally be substituted with one or more substituents, preferably with from zero to two substituents, independently selected from halo (e.g., chloro, fluoro, bromo or iodo), (C1-C6)alkyl optionally substituted with from one to three fluorine atoms, (C1-C6)alkoxy optionally substituted with from one to three fluorine atoms, cyano, —C(═O)R8, aryl and heteroaryl, wherein said aryl is selected from phenyl, indanyl and naphthyl and said heteroaryl is selected from pyridyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, quinolyl and imidazolyl;
• R2 and R3 are independently selected from hydrogen, hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, cyano, —CONH2 and —NHC(═O)R9, or R2 and R3 together form an oxo group;
• R4 is hydrogen, sulfur, oxygen, (C1-C6)alkyl, amino, —NHR10, —SR10, OR10 or hydroxy;
• R5, R6 and R7 are independently selected from hydrogen, halo (e.g., chloro, fluoro, bromo or iodo), cyano, (C1-C6)alkyl optionally substituted with from one to three fluorine atoms, (C1-C6)alkoxy optionally substituted with from one to three fluorine atoms, (C1-C6)alkylsulfonyl, (C1-C6)acylamino, (phenyl)[(C1-C6)acyl]amino, amino, (C1-C6)alkylamino, di-(C1-C6)alkylamino, aryl and heteroaryl, wherein said aryl is selected from phenyl, naphthyl and indanyl, and said heteroaryl is selected from pyridyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, quinolyl and imidazolyl;
• R8, R9 and R10 are independently selected from hydrogen and (C1-C6)alkyl;
• and
• R11 is hydrogen, (C1-C6)alkyl or benzyl, wherein the phenyl moiety of said benzyl may optionally be substituted with one or more substituents, preferably with from zero to two substituents, independently selected from halo (e.g., fluoro, chloro, bromo, or iodo), (C1-C6)alkyl optionally substituted with from one to three fluorine atoms, (C1-C6)alkoxy optionally substituted with from one to three fluorine atoms, amino, cyano, (C1-C6)alkylamino and di-(C1-C6)alkylamino;
• with the proviso that:
• (a) R4 can not be either oxygen or hydroxy when both R2 and R3 are hydrogen;
• (b) when the five membered ring of formula I contains a double bond, R11 is absent;
• (c) when R4 is sulfur or oxygen, R4 is double bonded to the carbon to which is attached and such carbon is single bonded to both adjacent ring nitrogen atoms;
• and (d) when X is nitrogen and is double bonded to an adjacent carbon, R1 is absent.
• or a pharmaceutically acceptable salt thereof.
• (d) an amount of a compound of the formula
• 15
• or a pharmaceutically acceptable salt or solvate thereof wherein:
• the dashed line in the above formula represents an optional double bond where X2 is not O;
• X1 and X2 are each independently selected from O and —(CH2)j— wherein j is 1 or 2;
• X3 is —CH(R5)N(R8)CH(R6)—, —CH(R5)C(R8)(R9)CH(R6)—, —C(R5)═C(R8)CH(R6)—, or —CH(R5)C(R8)═C(R6)—;
• R1 and R2 are each independently H, hydroxy, or C1-C6 alkyl;
• or R1 and R2 are taken together as a bond;
• each R3 is independently selected from —S(O)jR7 wherein j is an integer ranging from 0 to 2, —C(O)R7, —OR7, —NC(O)R7, —NR7R12, and the substituents provided in the definition of R7 other than H;
• R4 is absent where the dashed line in the above formula 1 represents a double bond or R4 is selected from H and the substituents provided in the definition of R3;
• or R3 and R4 are taken together with the carbon atom to which each is attached to form a 5-10 membered mono-cyclic or bicyclic group wherein said cyclic group may be carbocyclic or heterocyclic with 1 to 3 heteroatoms selected from O, S, and —N(R11)— with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other;
• said cyclic group is saturated or partially unsaturated;
• aromatic or non-aromatic;
• 1 or 2 of the carbon atoms in said cyclic group optionally may be replaced by an oxo —C(O)— moiety;
• and said cyclic group is optionally substituted by 1 to 3 R10 groups;
• R5 and R6 are each independently selected from H and C1-C4 alkyl;
• or R5 and R6 are taken together as —(CH2)q— wherein q is 2 or 3;
• or R5 or R6 is taken together with R8 as defined below;
• each R7 is independently selected from H, —(CH2)t(C6-C10 aryl) and —(CH2)t(4-10 membered heterocyclic), wherein t is an integer ranging from 0 to 5;
• 1 or 2 of the carbon atoms of said heterocyclic group optionally may be replaced with an oxo —C(O)— group;
• said aryl and heterocyclic R7 groups are optionally fused to a benzene ring, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group;
• the —(CH2)t— moieties of the foregoing R7 groups optionally include a carbon-carbon double or triple bond where t is an integer between 2 and 5;
• and the foregoing R7 groups, except H, are optionally substituted by 1 to 5 R10 groups;
• R8 is selected from the substituents provided in the definition of R7 other than H;
• R9 is selected from the substituents provided in the definition of R7;
• or R8 and R9 are taken together with the carbon to which each is attached to form a 5-10 membered mono-cyclic or bicyclic group wherein said cyclic group is carbocyclic or heterocyclic with 1 to 3 heteroatoms selected from O, S, and —N(R11)— with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other;
• saturated or partially unsaturated;
• aromatic or non-aromatic;
• 1 or 2 of the carbon atoms in said cyclic group optionally may be replaced by an oxo —C(O)— moiety;
• and said cyclic group is optionally substituted by 1 to 3 R10 groups;
• or R8 taken together with either R5 or R6 and the separate carbon atoms to which each is attached to form a fused 5-10 membered mono-cyclic or bicyclic group wherein said cyclic group may be carbocyclic or heterocyclic with 1 to 3 heteroatoms selected from O, S, and —N(R11)— with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other;
• saturated or partially unsaturated;
• aromatic or non-aromatic;
• 1 or 2 of the carbon atoms in said cyclic group optionally may be replaced by an oxo —C(O)— moiety;
• and said cyclic group is optionally substituted by 1 to 3 R10 groups;
• each R10 is independently selected from C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —OR11, —C(O)R11, —C(O)OR11, —NR12C(O)OR11, —OC(O)R11, —NR12SO2R11, —SO2NR11R12, —NR12C(O)R11, —C(O)NR11R12, —NR11R12, —S(O)j(C1-C6 alkyl) wherein j is an integer ranging from 0 to 2, —(CH2)m(C6-C10 aryl), —SO2(CH2)m(C6-C10 aryl), —S(CH2)m(C6-C10 aryl), —O(CH2)m(C6-C10 aryl) and —(CH2)m(4-10 membered heterocyclic), wherein m is an integer ranging from 0 to 4;
• said C1-C10 alkyl group optionally contains 1 or 2 hetero moieties selected from O, S and —N(R12)— with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other;
• said aryl and heterocyclic R10 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group;
• and said alkyl, aryl and heterocyclic R10 groups are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —NR12SO2R11, —SO2NR11R12, —C(O)R11, —C(O)OR11, —OC(O)R11, —NR12C(O)R11, —C(O)NR11R12, —NR11R12, C1-C6 alkyl, —OR11 and the substituents listed in the definition of R11;
• each R11 is independently selected from H, C1-C10 alkyl, —(CH2)m(C6-C10 aryl), and —(CH2)m(4-10 membered heterocyclic), wherein m is an integer ranging from 0 to 4;
• said alkyl group optionally includes 1 or 2 hetero moieties selected from O, S and —N(R12)—, with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other;
• said aryl and heterocyclic R11 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group;
• and the foregoing R11 substituents, except H, are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —C(O)R12, —C(O)OR12, —CO(O)R12, —NR12C(O)R13, —C(O)NR12R13, —NR12R13, hydroxy, C1-C6alkyl, and C1-C6 alkoxy;
• and, each R12 and R13 is independently H or C1-C6 alkyl;
• (e) an amount of a compound of the formula
• 16
• or the pharmaceutically acceptable salt thereof, wherein the broken line represents an optional double bond;
• a is 0 or 1, wherein when a is 0, X may form an optional double bond with the carbon adjacent to V;
• V is CHR10 wherein R10 is hydrogen or (C1-C6)alkyl;
• T is nitrogen or CH;
• X is nitrogen or CR11 wherein R11 is hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy or cyano;
• Y and Z are each independently nitrogen or CR12 wherein R12 is hydrogen, chloro, bromo, trifluoromethyl, trifluoromethoxy, cyano, (C1-C6)alkoxy or (C1-C6)alkyl;
• R1 is hydrogen, fluoro, chloro, bromo, trifluoromethyl, trifluoromethoxy, cyano or (C1-C6)alkyl;
• R2, R6, R7, R8 and R9 are each independently selected from hydrogen, fluoro, chloro, bromo, trifluoromethyl, trifluoromethoxy, cyano, (C1-C6)alkoxy and (C1-C6)alkyl;
• R3 and R4 are each independently hydrogen or (C1-C6)alkyl;
• and
• R5 is hydrogen, (C1-C6)alkoxy, trifluoromethyl, cyano, (C1-C6)alkyl or R13CO— wherein R13 is amino, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino, (C1-C6)alkyl, (C6-C10)aryl;
• or when a is 1, R1 and R10 may be taken together with the carbons to which they are attached to form a compound of the formula
• 17
• wherein the broken lines represent optional bonds;
• T, X, Y, Z, R2, R3, R4, R5, R6, R7, R8 and R9 are defined as above;
• b is 0 or 1;
• and
• A and B are each independently CH, CH2, oxygen, sulfur, NH or nitrogen;
• with the proviso that when X is nitrogen, the optional double bond between X and V does not exist;
• with the proviso that when b is 0, the optional double bond between A and B does not exist;
• and
• with the proviso that when b is 1, A and B cannot both be oxygen or sulfur;
• or (f) an amount of a compound of the formula
• 18
• wherein a is oxygen, CH2, C(CH3)2, NR10, sulfur, SO or SO2;
• b is oxygen, CH2, C═O, C═NR11, C═NOH, SO2, Sulfur, SO, C═NO(C1-C5)alkyl or CR7R8;
• each of R1 through R8 is selected, independently, from hydrogen, halo (e.g., chloro, fluoro, bromo or iodo), trifluoromethyl, cyano and hydroxy, or R7 and R8 together can be C(═O)NH2 or C(═O)N(C1-C4)alkyl, with the proviso that neither R7 nor R8 can be halo when a is oxygen, NR11, sulfur, SO or SO2;
• and
• each of R10 and R11 is selected, independently, from hydrogen, benzyl and (C1-C6)alkyl;
• and the pharmaceutically acceptable salts of such compounds
• or a pharmaceutically acceptable salt thereof effective to treat or prevent novelty-seeking disorder in the subject.