| 主权项 |
1. A method of treating cancer or a precancerous condition comprising administering to a subject diagnosed with cancer a therapeutically effective amount of a PDE10A inhibitor selected from the group consisting of:
a) a compound of formula Awherein z isand wherein R1 is each independently selected from a group consisting of hydrogen, halogen, hydroxyl, cyano, C1 to C8 alkyl, C2 to C8 alkenyl, C2 to C8 alkynyl, C1 to C8 alkoxy, C1 to C8 haloalkyl, C3 to C8 cycloalkyl, C3 to C8 cycloalkyl-C1 to C8 alkyl, 4 to 7 membered heterocycloalkyl, C1 to C8 alkylthio, —NR3R3, —O—CF3, —S(O) n-R3, C(O)—NR3R3, and C1 to C8 alkyl substituted with a heteroatom wherein the heteroatom is selected from a group consisting of nitrogen, oxygen and sulfur and wherein the heteroatom may be further substituted with a substituent selected from a group consisting of hydrogen, C1 to C8 alkyl, C3 to C8 cycloalkyl, C2 to C8 alkenyl, C2 to C8 alkynyl, and C1 to C8 haloalkyl;
each R3 is independently selected from a group consisting of hydrogen, C1 to C8 alkyl, C2 to C8 alkenyl, C2 to C8 alkynyl, C1 to C8 haloalkyl, C3 to C8 cycloalkyl; R2 is selected from the group consisting of hydrogen, C1 to C8 alkyl, C3 to C8 cycloalkyl-C, to C8 alkyl, C2 to C8 alkenyl, C2 to C8 alkynyl, C1 to C8 haloalkyl and C3 to C8 cycloalkyl; HET1 is selected from a group consisting of a monocyclic heteroaryl and a bicyclic heteroaryl, wherein the monocyclic and bicyclic heteroaryl may be optionally substituted with at least one R4 and; R4 is selected from a group consisting of halogen, hydroxyl, cyano, C1 to C8 alkyl, C2 to C8 alkenyl, C2 to C8 alkynyl, C1 to C8 alkoxy, C3 to C8 cycloalkyl, C3 to C8 cycloalkyl-C, to C8 alkyl, C1 to C8 alkylthio, and C1 to C8 alkyl substituted with a substituent is selected from the group consisting of —OR8, —NR8R8, and —SR8, wherein R8 is independently selected from the group consisting of hydrogen and C1 to C8 alkyl HET2 is a monocyclic or bicyclic heteroaryl, wherein the monocyclic and bicyclic heteroaryl optionally substituted with at least one R5, with the proviso that HET2 is not tetrazole; R5 is independently selected from a group consisting of halogen, hydroxyl, cyano, C′ to C8 alkyl, C2 to C8 alkenyl, C2 to C8 alkynyl, C1 to C8 alkoxy, C3 to C8 cycloalkyl, C3 to C8 cycloalkyl-C, to C8 alkyl, C1 to C8 alkylthio, —NR7R7 and C1 to C8 haloalkyl; B1 and B2 are adjacent atoms in Het1 which are independently selected from a group consisting of carbon and nitrogen; bond j is a covalent bond between Z and B2; bond k is a covalent bond in Het' between B1 and B2; X and X1 are each independently selected from the group consisting of oxygen, sulfur, C(R2)2 and NR2; provided that at least one of X or X1 is carbon; Y is selected from a group consisting of carbon and nitrogen, provided that when Y is carbon it is substituted with R6; wherein each R6 is independently selected from a group consisting of hydrogen, halogen, hydroxyl, cyano, C1 to C8 alkyl, C2 to C8 alkenyl, C2 to C8 alkynyl, C1 to C8 alkoxy, C1 to C8 cycloalkyl, C3 to C8 cycloalkyl-C, to C8 alkyl, C1 to C8 alkylthio, C1 to C8 haloalkyl, —NR7R7, —O—CF3, —S(O)m-R7, and C(O)—NR7R7, C1 to C8 alkyl substituted with a heteroatom wherein the heteroatom is selected from a group consisting of nitrogen, oxygen and sulfur and wherein the heteroatom may be further substituted with a substituent selected from the group consisting of hydrogen, C1 to C8 alkyl, C3 to C8 cycloalkyl, C2 to C8 alkenyl, C2 to C8 alkynyl and C1 to C8 haloalkyl; wherein each R7 is independently selected from the group consisting of hydrogen and C1-C8 alkyl; p is 1, 2 or 3; n is 0, 1 or 2; and m is 0, 1 or 2; b) a compound of formula B wherein X, Y and Z are each independently CH or N with the proviso that at least one or two of X, Y and Z are N, but not all three, and with the proviso that Y and Z are not both N; wherein R1, R2 and R5 are independently H, halogen, CN, —COOH, —COOR3, —CON R3R4, COR3, —NR3R4, —NHCOR3, —OH, (C6-C10)aryl, 5 to 7 membered heteroaryl, (C1-C6)alkyl, (C1-C6)haloalkyl (C2-C6) alkenyl, (C2-C6) alkynyl, —O—(C1-C6)alkyl, —O—(C2-C6)alkenyl or (C3-C8) cycloalkyl; or, when R1, R2 and R5 are independently —O—(C1C6)alkyl, —O—(C2-C6)alkenyl, (C1-C6) alkyl, (C2-C6) alkenyl or (C2-C6)alkynyl, R1 and R2 or R1 and R5 may optionally be connected to form a 5 to 8 membered ring; wherein R3 and R4 are independently H, (C1-C6)alkyl or (C6-C10)aryl said aryl optionally substituted with one or more (C1-C6)alkyl groups; wherein R6 and R7 are each independently H, halogen, —COOR3, —CONR3R4, —COR4, NR3R4, —NHCOR3, —OH, —(C1-C6)alkylene-OH, —HNCOOR3, —CN, —HNCONHR4, (C1-C6)alkyl, (C2-C6)alkoxy, C6- C10 aryl orwherein n is 0 or 1;
W is carbon, oxygen or NR8, wherein R8 is hydrogen or (C1C6)alkyl, and when W is carbon, it may be optionally substituted by halogen, —C≡N, —COOH, —COOR3, —CONR3R4, —NR3R4, —NHCOR3, —OH, (C6-C10) aryl, 5 to 7 membered heteroaryl, (C1-C6)alkyl, (C1-C6) haloalkyl (C2-C6) alkenyl, (C2-C6) alkynyl, —O—(C1-C6)alkyl, —O—(C2-C6)alkenyl or (C3-C8) cycloalkyl; wherein R9 and R10 are independently hydrogen or (C1-C8)alkyl; or R9 and R10 may optionally combine to form a cyclic ring; wherein Ar is phenyl, naphthyl, or a 5- to 6-membered heteroaryl ring, which heteroaryl is optionally fused to a benzo group, and which heteroaryl contains from one to four heteroatoms selected from oxygen, nitrogen and sulfur, with the proviso that said heteroaryl ring cannot contain two adjacent oxygen atoms or two adjacent sulfur atoms, and wherein each of the foregoing phenyl, naphthyl, heteroaryl, or benzo-fused heteroaryl rings may optionally be substituted with from one to three substituents independently selected from (C1-C8)alkyl, chloro-, bromo-, iodo, fluoro-, (C1-C8) hydroxyalkyl-, (C1-C8) alkoxy- (C1-C8) alkyl-, (C3-C8)hydroxycycloalkyl-, (C3-C8)cycloalkyl, (C3-C8)cycloalkoxy-, (C1-C8)alkoxy-(C3-C8)cycloalkyl-, (3-8 membered) heterocycloalkyl, hydroxyl(3-8 membered) heterocycloalkyl, and (C1-C8)alkoxy(3-8 membered)heterocycloalkyl, wherein said alkyl, alkoxy and cycloalkyl may be optionally substituted with 1 to 3 halos and wherein each (C3-C8)cycloalkyl or heterocycloalkyl moiety may be independently substituted with from one to three (C1-C8)alkyl or benzyl groups; or wherein Ar is a 5- to 6-membered heteroaryl ring, which heteroaryl is fused to an imidazo, pyrido, pyrimido, pyrazo, pyridazo, or pyrrolo group, and which heteroaryl contains from one to four heteroatoms selected from oxygen, nitrogen and sulfur, with the proviso that said heteroaryl ring cannot contain two adjacent oxygen atoms or two adjacent sulfur atoms, and wherein each of the foregoing fused heteroaryl rings may optionally be substituted with from one to three substituents indepe.ndently selected from (C1-C8)alkyl, chloro-, bromo-, iodo, fluoro-, halo(C1-C8)alkyl, (C1- C8)hydroxyalkyl-, (C1-C8)alkoxy-(C1-C8)alkyl-, —O—(C1-C8)alkyl-halo, (C3-C8)hydroxycycloalkyl-, (C3-C8)cycloalkyl, (C3-C8)cycloalkoxy-, (C1-C8)alkoxy-(C3-C8)cycloalkyl-, (3-8 membered) heterocycloalkyl, hydroxyl(3-8 membered) heterocycloalkyl, and (C1-C8)alkoxy-(3-8 membered)heterocycloalkyl, wherein each (C3-C8)cycloalkyl or heterocycloalkyl moiety may be independently substituted with from one to three (C1-C6)alkyl or benzyl groups; or when Ar is phenyl, naphthyl, or heteroaryl ring, each ring may be optionally substituted with one to three substituents independently selected from (a) lactone formed from —(CH2)tH with an ortho —COOH, wherein t is one, two or three; (b) —CONR14R15, wherein R14 and R15 are independently selected from (C1-C8)alkyl and benzyl, or R14 and R15 together with the nitrogen to which they are attached form a 5- to 7-membered heteroalkyl ring that may contain from zero to three heteroatoms selected from nitrogen, sulfur and oxygen in addition to the nitrogen of the —CONR14R15 group, wherein when any of said heteroatoms is nitrogen it may be optionally substituted with (C1-C8)alkyl or benzyl, with the proviso that said ring cannot contain two adjacent oxygen atoms or two adjacent sulfur atoms; or (c) —(CH2)vNCOR14R15 wherein v is zero, one, two or three and —COR14R15 taken together with the nitrogen to which they are attached form a 4- to 6-membered lactam ring; c) a compound of formula Cwherein R1 is C1-6 alkyl, C1-6 haloalkyl, —(CH2)nO(CH2)mCH3 or —(CH2)nN(CH3)2; R2 is substituted or unsubstituted heterocyclyl, substituted phenyl, or substituted or unsubstituted naphthyl; R3 is substituted or unsubstituted heterocyclyl, or substituted or unsubstituted aryl; and R4 and R5 are the same or different and independently hydrogen, C1-6 alkyl or C1-6 haloalkyl; n is 1, 2, 3, 4, 5 or 6; and m is 0, 1, 2, 3, 4, 5 or 6; or
d) a compound of Formula Dwherein R1-R4 are selected from the group consisting of H; C1-C6 alkyl such as methyl; halogen such as chlorine and bromine; cyano; halo(C1-C6)alkyl such as trifluoromethyl; aryl such as phenyl; alkoxy, such as methoxy, dimethoxy, ethoxy, methoxy-ethoxy and ethoxy-methoxy; and C1-C6 hydroxyalkyl such as CH2CH2OH; and
wherein het is cyano (—C≡N—) or is selected from the group consisting ofwherein denotes the attachment point; and wherein R5 and R6 are selected from the group consisting of H; C1-C6 alkyl such as methyl, ethyl, 1-propyl, 2-propyl, isobutyl, n-butyl, sec-butyl or tert-butyl; C1-C6 alkyl(C3-C8)cycloalkyl such as cyclopropylmethyl; C1-C6 hydroxyalkyl such as hydroxyethyl; CH2CN; CH2C(O)NH2; C1-C6 arylalkyl such as benzyl and 4-chlorobenzyl; and C1-05 alkyl-heterocycloalkyl such as tetrahydropyran-4-yl-methyl and 2-morpholin-4-yl-ethyl; and wherein R7-R11 are selected from the group consisting of H; C1-C6 alkoxy such as methoxy; and halogen such as chlorine or fluorine; andwherein further L is a linker selected from the group consisting of —S—CH2—, —CH2—S—, and —CH2—CH2—; and
wherein Y is selected from the group consisting of CH , N or C—CN. |
