Amino substituted pyrazolo[1,5,-a]-1,5-pyrimidines and pyrazolo[1,5-a]-1,3,5-triazines

A compound of the formula

• or a pharmaceutically acceptable salt or an acylated derivative wherein a free hydroxyl or amino group has been acylated to form a compound capable of acting as a prodrug thereof, wherein the compound exhibits a Ki of 5 micromolar or less in a NPY1 receptor binding assay as determined by displacement of radiolabeled [125 I] NPY from the NPY1 receptor coded for by SEQ ID NO.:
• 1 in which said radiolabeled [125 I] NPY was bound to, and
• X is CR14;
• R1 is selected from H, C1-C6 alkyl, C3-C10 cycloalkyl, (C3-C10 cycloalkyl) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cyano, halo, C1-C6 haloalkyl, OR7, C1-C6 alkyl-OR7, C1-C6 cyanoalkyl, NR8R9, and C1-C6 alkyl-NR8R9;
• R2 is
• H,
• C1-C6 alkyl which optionally forms a C3-C6 aminocarbocycle or a C2-C5 aminoheterocycle with A or B, each of which is optionally substituted with R7,
• C3-C10 cycloalkyl, or
• (C3-C10 cycloalkyl) C1-C6 alkyl;
• or
• R2 and R6 jointly form with the 2 nitrogen atoms to which they are bound a C2-C5 aminoheterocycle optionally substituted with R7;
• A is (CH2)m where m is 1,2 or 3 and is optionally mono- or di-substituted at each carbon atom with C1-C6 alkyl, C3-C10 cycloalkyl, (C3-C10 cycloalkyl) C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, cyano, halogen, C1-C6 haloalkyl, OR7, C1-C6 alkyl-OR7;
• C1-C6 cyanoalkyl, NR8R9, or C1-C6 alkyl-NR8R9, or
• A and B jointly form a C3-C6 carbocycle, which is optionally substituted at each carbon atom with R7, or
• A and R2 jointly form a C3-C6 aminocarbocycle, which is optionally substituted at each carbon atom with R7;
• B is (CH2)n where n is 0, 1, 2, or 3 and is optionally substituted at each carbon atom with C1-C6 alkyl, C3-C10 cycloalkyl, (C3-C10 cycloalkyl) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cyano, halogen, C1-C6 haloalkyl, OR7, C1-C6 alkyl-OR7;
• C1-C6 cyanoalkyl, NR8, R9, or C1∝C6 alkyl-NR8R9, or
• B and R2 jointly form a C3-C6 aminocarbocycle, which is optionally substituted at each carbon atom with R7, or
• B and R6 jointly form a C3-C6 aminocarbocycle, which is optionally substituted at each carbon atom with R7;
• R3 is selected from H, C1-C6 alkyl, C3-C10 cycloalkyl, (C3-C10 cycloalkyl) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cyano, halo, C1-C6 haloalkyl, OR7, C1-C6 alkyl-OR7, C1-C6 cyanoalkyl, NR8R9, and C1-C6 alkyl-NR8R9;
• R4 is selected from aryl or heteroaryl, each optionally substituted with 1 to 5 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C10 cycloalkyl, C3-C10 cycloalkenyl, (C3-C10 cycloalkyl) C1-C6 alkyl, C1-C6 alkenyl, halogen, C1-C6 haloalkyl, trifluromethylsulfonyl, OR7, C1-C6 alkyl-OR7, NR8R9, C1-C6 alkyl-NR8R9, CONR8R9, C1-C6 alkyl-CONR8R9, COOR7, C1-C6 alkyl-COOR7, CN, C1-C6 alkyl-CN, SO2NR8R9, SO2R7, aryl, heteroaryl, heterocycloalkyl, and 3-, 4-, or 5-(2-oxo-1,3-oxazolidinyl), with the proviso that at least one of the positions ortho or para to the point of attachment of the aryl or heteroaryl ring to the pyrazole is substituted;
• R5 is H;
• R6 and C3-C10 cycloalkyl, (C3-C10 cycloalkyl) C1-C6 alkyl;
• R7 is H, C1-C6 alkyl, C3-C10 cycloalkyl, C3-C10 cycloalkenyl, (C3-C10 cycloalkyl) C1-C6 alkyl, C1-C3 haloalkyl, or heterocycloalkyl, C1-C8 alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, C1-C8 alkanoyl, aroyl, heteroaroyl, aryl, heteroaryl, C1-C6 arylalkyl or C1-C6 heteroarylalkyl each of which is optionally substituted with 1 to 5 substituents independently selected at each occurrence from halogen, C1-C6 haloalkyl, OR13, NR8R9, C1-C6 alkyl-OR13, C1-C6 alkyl-NR8R9, CONR8R9, COOR13, CN, SO2NR8R9, SO2R13, with the proviso that for SO2R7, R7 cannot be H;
• R8 and R9 are independently selected at each occurrence from H, C1-C6 alkyl, C3-C10 cycloalkyl, C2-C6 alkenyl, C3-C10 cycloalkenyl, C2-C6 alkynyl, heterocycloalkyl, C1-C8 alkanoyl, aroyl, heteroaroyl, aryl, heteroaryl, C1-C6 arylalkyl or C1-C6 heteroarylalkyl, or R8 and R9, taken together, can form a C3-C6 aminocarbocycle or a C2-C5 aminoheterocycle each optionally substituted at each occurrence with R7;
• R11 is selected from H, C1-C6 alkyl, C3-C10 cycloalkyl, (C3-C10 cycloalkyl) C1-C6 alkyl;
• R12 is selected from H, aryl, heteroaryl, C1-C6 alkyl, C3-C10 cycloalkyl, (C3-C10 cycloalkyl) C1-C6 alkyl, optionally substituted with OR7, NR8R9, C3-C6 aminocarbocycle, or C2-C5 aminoheterocycle;
• R13 is independently selected at each occurrence from H, C1-C6 alkyl, C3-C10 cycloalkyl, (C3-C10 cycloalkyl) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, with the proviso that for SO2R13, R13 cannot be H;
• and
• R14 is H, C1-C6 alkyl, C3-C10 cycloalkyl, (C3-C10 cycloalkyl) C1-C6 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, halo, or CN.

A compound of the formula

• or a pharmaceutically acceptable salt or an acylated derivative wherein a free hydroxyl or amino group has been acylated to form a compound capable of acting as a prodrug thereof, wherein the compound exhibits a Ki of 5 micromolar or less in a NPY1 receptor binding assay as determined by displacement of radiolabeled [125 I] NPY from the NPY1 receptor coded for by SEQ ID NO.:
• 1 in which said radiolabeled [125 I] NPY was bound to, and
• X is CR14;
• R1 is selected from H, C1-C6 alkyl, C3-C10 cycloalkyl, (C3-C10 cycloalkyl) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cyano, halo, C1-C6 haloalkyl, OR7, C1-C6 alkyl-OR7, C1-C6 cyanoalkyl, NR8R9, and C1-C6 alkyl-NR8R9;
• R2 is
• H,
• C1-C6 alkyl which optionally forms a C3-C6 aminocarbocycle or a C2-C5 aminoheterocycle with A or B, each of which is optionally substituted with R7,
• C3-C10 cycloalkyl, or
• (C3-C10 cycloalkyl) C1-C6 alkyl;
• or
• R2 and R6 jointly form with the 2 nitrogen atoms to which they are bound a C2-C5 aminoheterocycle optionally substituted with R7;
• A is (CH2)m where m is 1,2 or 3 and is optionally mono- or di-substituted at each carbon atom with C1-C6 alkyl, C3-C10 cycloalkyl, (C3-C10 cycloalkyl) C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, cyano, halogen, C1-C6 haloalkyl, OR7, C1-C6 alkyl-OR7;
• C1-C6 cyanoalkyl, NR8R9, or C1-C6 alkyl-NR8R9, or
• A and B jointly form a C3-C6 carbocycle, which is optionally substituted at each carbon atom with R7, or
• A and R2 jointly form a C3-C6 aminocarbocycle, which is optionally substituted at each carbon atom with R7;
• B is (CH2)n where n is 0, 1, 2, or 3 and is optionally substituted at each carbon atom with C1-C6 alkyl, C3-C10 cycloalkyl, (C3-C10 cycloalkyl) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cyano, halogen, C1-C6 haloalkyl, OR7, C1-C6 alkyl-OR7;
• C1-C6 cyanoalkyl, NR8R9, or C1-C6 alkyl-NR8R9, or
• B and R2 jointly form a C3-C6 aminocarbocycle, which is optionally substituted at each carbon atom with R7, or
• B and R6 jointly form a C3-C6 aminocarbocycle, which is optionally substituted at each carbon atom with R7;
• R3 is selected from H, C1-C6 alkyl, C3-C10 cycloalkyl, (C3-C10 cycloalkyl) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cyano, halo, C1-C6 haloalkyl, OR7, C1-C6 alkyl-OR7, C1-C6 cyanoalkyl, NR8R9, and C1-C6 alkyl-NR8R9;
• R4 is selected from aryl or heteroaryl, each optionally substituted with 1 to 5 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C10 cycloalkyl, halogen, C1-C6 haloalkyl, CN, alkylsulfonyl, OR7, NR8R9, CONR8R9, COOR7, SO2NR8R9, COR7, SO2R7;
• R5 and R6 are independently selected from H, C1-C6 alkyl, C3-C10 cycloalkyl, (C3-C10 cycloalkyl) C1-C6 alkyl;
• R7 is H, C1-C6 alkyl, C3-C10 cycloalkyl, C3-C10 cycloalkenyl, (C3-C10 cycloalkyl) C1-C6 alkyl, C1-C3 haloalkyl, or heterocycloalkyl, C1-C8 alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, C1-C8 alkanoyl, aroyl, heteroaroyl, aryl, heteroaryl, C1-C6 arylalkyl or C1-C6 heteroarylalkyl each of which is optionally substituted with 1 to 5 substituents independently selected at each occurrence from halogen, C1-C6 haloalkyl, OR13, NR8R9, C1-C6 alkyl-OR13, C1-C6 alkyl-NR8R9, CONR8R9, COOR13, CN, SO2NR8R9, SO2R13, with the proviso that for SO2R7, R7 cannot be H;
• R8 and R9 are independently selected at each occurrence from H, C1-C6 alkyl, C3-C10 cycloalkyl, C2-C6 alkenyl;
• C3-C10 cycloalkenyl, C2-C6 alkynyl, heterocycloalkyl, C1-C8 alkanoyl, aroyl, heteroaroyl, aryl, heteroaryl, C1-C6 arylalkyl or C1-C6 heteroarylalkyl, or R8 and R9, taken together, can form a C3-C6 aminocarbocycle or a C2-C5 aminoheterocycle each optionally substituted at each occurrence with C1-C6 alkyl, C3-C10 cycloalkyl, C3-C10 cycloalkenyl, (C3-C10 cycloalkyl) C1-C6 alkyl, C1-C3 haloalkyl, or heterocycloalkyl, C1-C8 alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, C1-C8 alkanoyl, aroyl, heteroaroyl, aryl, heteroaryl, C1-C6 arylalkyl or C1-C6 heteroarylalkyl;
• R11 is selected from H, C1-C6 alkyl, C3-C10 cycloalkyl, (C3-C10 cycloalkyl) C1-C6 alkyl;
• R12 is selected from H, aryl, heteroaryl, C1-C6 alkyl, C3-C10 cycloalkyl, (C3-C10 cycloalkyl) C1-C6 alkyl, optionally substituted with OR7, NR8R9, C3-C6 aminocarbocycle, or C2-C5 aminoheterocycle;
• R13 is independently selected at each occurrence from H, C1-C6 alkyl, C3-C10 cycloalkyl, (C3-C10 cycloalkyl) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, with the proviso that for SO2R13, R13 cannot be H;
• and
• R14 is H, C1-C6 alkyl, C3-C10 cycloalkyl, (C3-C10 cycloalkyl) C1-C6 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, halo, or CN.

A compound of the formula

• or a pharmaceutically acceptable salt or an acylated derivative wherein a free hydroxyl or amino group has been acylated to form a compound capable of acting as a prodrug thereof, wherein:
• X is CR14;
• R1 is selected from H, C1-C6 alkyl, C3-C10 cycloalkyl, (C3-C10 cycloalkyl) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cyano, halo, C1-C6 haloalkyl, OR7, C1-C6 alkyl-OR7, C1-C6 cyanoalkyl, NR8R9, and C1-C6 alkyl-NR8R9;
• R2 is
• H,
• C1-C6 alkyl which optionally forms a C3-C6 aminocarbocycle or a C2-C5 aminoheterocycle with A or B, each of which is optionally substituted with R7,
• C3-C10 cycloalkyl, or
• (C3-C10 cycloalkyl) C1-C6 alkyl;
• or
• R2 and R6 jointly form with the 2 nitrogen atoms to which they are bound a C2-C5 aminoheterocycle optionally substituted with R7;
• A is (CH2)m where m is 1,2 or 3 and is optionally mono- or di-substituted at each carbon atom with C1-C6 alkyl, C3-C10 cycloalkyl, (C3-C10 cycloalkyl) C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, cyano, halogen, C1-C6 haloalkyl, OR7, C1-C6 alkyl-OR7;
• C1-C6 cyanoalkyl, NR8R9, or C1-C6 alkyl-NR8R9, or
• A and B jointly form a C3-C6 carbocycle, which is optionally substituted at each carbon atom with R7, or
• A and R2 jointly form a C3-C6 aminocarbocycle, which is optionally substituted at each carbon atom with R7;
• B is (CH2)n where n is 0, 1, 2, or 3 and is optionally substituted at each carbon atom with C1-C6 alkyl, C3-C10 cycloalkyl, (C3-C10 cycloalkyl) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cyano, halogen, C1-C6 haloalkyl, OR7, C1-C6 alkyl-OR7;
• C1-C6 cyanoalkyl, NR8R9, or C1-C6 alkyl-NR8R9, or
• B and R2 jointly form a C3-C6 aminocarbocycle, which is optionally substituted at each carbon atom with R7, or
• B and R6 jointly form a C3-C6 aminocarbocycle, which is optionally substituted at each carbon atom with R7;
• R3 is selected from H, C1-C6 alkyl, C3-C10 cycloalkyl, (C3-C10 cycloalkyl) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cyano, halo, C1-C6 haloalkyl, OR7, C1-C6 alkyl-OR7, C1-C6 cyanoalkyl, NR8R9, and C1-C6 alkyl-NR8R9;
• R4 is selected from aryl or heteroaryl, each substituted with aryl, heteroaryl, heterocycloalkyl, and 3-, 4-, or (5-(2-oxo-1,3-oxazolidinyl), heterocycloalkyl, cyclopentenyl, cyclohexenyl, C1-C6 alkenyl, C1-C6 alkynyl, (C3-C10 cycloalkyl)C1-C6 alkyl, trifluoromethylsulfonyl, C1-C6 alkyl-NR8R9, C1-C6 alkyl-CN, C1-C6 alkyl-CONR8R9, C1-C6 alkyl-OR7, C1-C6 alkyl-COOR7 and optionally substituted with 1 to 4 substituents independently selected at each occurrence from C1-C6 alkyl, (C3-C10 cycloalkyl) C1-C6 alkyl, halogen, C1-C6 haloalkyl, trifluoromethylsulfonyl, OR7, C1-C6 alkyl-OR7, NR8R9, C1-C6alkyl-NR8R9, CONR8R9, C1-C6 alkyl-CONR8R9, COOR7, C1-C6 alkyl-COOR7, CN, C1-C6 alkyl-CN, SO2NR8R9, SO2R7;
• R5 and R6 are independently selected from H, C1-C6 alkyl, C3-C10 cycloalkyl, (C3-C10 cycloalkyl) C1-C6 alkyl;
• R7 is H, C1-C6 alkyl, C3-C10 cycloalkyl, C3-C10 cycloalkenyl, (C3-C10 cycloalkyl) C1-C6 alkyl, C1-C3 haloalkyl, or heterocycloalkyl, C1-C8 alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, C1-C8 alkanoyl, aroyl, heteroaroyl, aryl, heteroaryl, C1-C6 arylalkyl or C1-C6 heteroarylalkyl each of which is optionally substituted with 1 to 5 substituents independently selected at each occurrence from halogen, C1-C6 haloalkyl, OR13, NR8R9, C1-C6 alkyl-OR13, C1-C6 alkyl-NR8R9, CONR8R9, COOR13, CN, SO2NR8R9, SO2R13, with the proviso that when R7 is SO2R13, R13 cannot be H;
• R8 and R9 are independently selected at each occurrence from H, C1-C6 alkyl, C3-C10 cycloalkyl, C2-C6 alkenyl, C3-C10 cycloalkenyl, C2-C6 alkynyl, heterocycloalkyl, C1-C8 alkanoyl, aroyl, heteroaroyl, aryl, heteroaryl, C1-C6 arylalkyl or C1-C6 heteroarylalkyl, or R8 and R9, taken together, can form a C3-C6 aminocarbocycle or a C2-C5 aminoheterocycle each optionally substituted at each occurrence with C1-C6 alkyl, C3-C10 cycloalkyl, C3-C10 cycloalkenyl, (C3-C10 cycloalkyl) C1-C6 alkyl, C1-C3 haloalkyl, or heterocycloalkyl, C1-C8 alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, C1-C8 alkanoyl, aroyl, heteroaroyl, aryl, heteroaryl, C1-C6 arylalkyl or C1-C6 heteroarylalkyl;
• R11 is selected from H, C1-C6 alkyl, C3-C10 cycloalkyl, (C3-C10 cycloalkyl) C1-C6 alkyl;
• R12 is selected from H, aryl, heteroaryl, C1-C6 alkyl, C3-C10 cycloalkyl, (C3-C10 cycloalkyl) C1-C6 alkyl, optionally substituted with OR7, NR8R9, C3-C6 aminocarbocycle, or C2-C5 aminoheterocycle;
• R13 is independently selected at each occurrence from H, C1-C6 alkyl, C3-C10 cycloalkyl, (C3-C10 cycloalkyl) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, with the proviso that for SO2R13, R13 cannot be H;
• and
• R14 is H, C1-C6 alkyl, C3-C10 cycloalkyl, (C3-C10 cycloalkyl) C1-C6 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, halo, or CN.