Compounds with activity on muscarinic receptors

A compound of formula (IIa):

• wherein
• R1 is alkoxy;
• R2 is amino, hydroxyl, chloro, bromo, or straight or branched-chain C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 heteroalkyl, C1-6 aminoalkyl, C1-6 haloalkyl, C1-6 alkoxycarbonyl, —CN, —CF3, —OR3, —COR3, NO2, —NHR3, —NHC(O)R3, —C(O)NR3R4, —NR3R4, —NR3C(O)NR4R5, —OC(O)R3, or —(CH2)qNR3R4;
• where R3, R4 and R5 are the same or different, each independently being selected from H, C1-6 alkyl;
• C5-6 aryl optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with halo or C1-6 alkyl;
• C3-6 cycloalkyl;
• or R3 and R4 together with the N atom, when present, form a cyclic ring structure comprising 5-6 atoms selected from C, N, S and O;
• and q is an integer from 1 to 6;
• p is 0 or an integer from 1 to 5;
• Y is —NHC(O)— or —C(O)—;
• or
• a pharmaceutically acceptable salt, ester or prodrug thereof.

A compound of formula (IIb):

• wherein
• R1 is alkoxy;
• R2 is amino, hydroxyl, chloro, bromo, or straight or branched-chain C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 heteroalkyl, C1-6 aminoalkyl, C1-6haloalkyl, C1-6 alkoxycarbonyl, —CN, —CF3, —OR3, —COR3, NO2, —NHR3, —NHC(O)R3, —C(O)NR3R4, —NR3R4, —NR3C(O)NR4R5, —OC(O)R3, or —(CH2)qNR3R4;
• where R3, R4 and R5 are the same or different, each independently being selected from H, C1-6 alkyl;
• C5-6aryl optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with halo or C1-6 alkyl;
• C3-6 cycloalkyl;
• or R3 and R4 together with the N atom, when present, form a cyclic ring structure comprising 5-6 atoms selected from C, N, S and O;
• and q is an integer from 1 to 6;
• p is 0 or an integer from 1 to 5;
• Y is —NHC(O)— or —C(O)—;
• or
• a pharmaceutically acceptable salt, ester or prodrug thereof.

A compound of formula (I):

• wherein
• R1 is straight or branched-chain C2-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 alkylidene, C1-8 alkoxy, C1-8 heteroalkyl, C1-8 aminoalkyl, C1-8 haloalkyl, C1-8 alkoxycarbonyl, C1-8 hydroxyalkoxy, C1-8 hydroxyalkyl, —SH, C1-8 thioalkyl, or —O—CH2—C5-6 aryl;
• A is C5-7 cycloalkyl, phenyl, naphthyl or C5-12 heteroaryl, wherein said heteroaryl contains one heteroatom selected from O, N or S;
• when A is C5-7 cycloalkyl, naphthyl or C5-12 heteroaryl as defined above,
• R2 is H, amino, hydroxyl, halo, or straight or branched-chain C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 heteroalkyl, C1-6 aminoalkyl, C1-6 haloalkyl, C1-6 alkoxycarbonyl, —CN, —CF3, —OR3, —COR3, NO2, —NHR3, —NHC(O)R3, —C(O)NR3R4, —NR3R4, —NR3C(O)NR4R5, —OC(O)R3, or —(CH2)qNR3R4;
• where R3, R4 and R5 are the same or different, each independently being selected from H, C1-6 alkyl;
• C5-6 aryl optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with halo or C1-6 alkyl;
• C3-6 cycloalkyl;
• or R3 and R4 together with the N atom, when present, form a cyclic ring structure comprising 5-6 atoms selected from C, N, S and O;
• and q is an integer from 1 to 6;
• or
• when A is phenyl,
• R2 is amino, hydroxyl, chloro, bromo, or straight or branched-chain C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 heteroalkyl, C1-6 aminoalkyl, C1-6 haloalkyl, C1-6 alkoxycarbonyl, —CN, —CF3, —OR3, —COR3, NO2, —NHR3, —NHC(O)R3, —C(O)NR3R4, —NR3R4, —NR3C(O)NR4R5, —OC(O)R3, or —(CH2)qNR3R4;
• where R3, R4 and R5 are the same or different, each independently being selected from H, C1-6 alkyl;
• C5-6 aryl optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with halo or C1-6 alkyl;
• C3-6 cycloalkyl;
• or R3 and R4 together with the N atom, when present, form a cyclic ring structure comprising 5-6 atoms selected from C, N, S and O;
• and q is an integer from 1 to 6;
• n is 1, 2, 3 or 4, the groups R2, when n>1, being the same or different;
• p is 2;
• Y is —NHC(O)—;
• and
• Z is a bond;
• or
• a pharmaceutically acceptable salt, ester or prodrug thereof.

A compound of formula (I):

• wherein
• R1 is straight or branched-chain C2-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 alkylidene, C1-8 alkoxy, C1-8 aminoalkyl, C1-8 haloalkyl, C1-8 alkoxycarbonyl;
• n is 1, 2 or 3, the groups R2, when n>1, being the same or different;
• A is thienyl;
• and
• R2 is H, halo, straight or branched-chain C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 heteroalkyl;
• C1-6 aminoalkyl, C1-6 haloalkyl, C1-6 alkoxycarbonyl, —CN, —CF3, —COR3, —NHR3, —NHC(O)R3, —C(O)NR3R4, —NR3R4, —NR3C(O)NR5, —OC(O)R3, or —O(CH2)qNR3;
• where R3, R4 and R5 are the same or different, each independently being selected from H, C1-6 alkyl;
• C5-6 aryl optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with halo or C1-6 alkyl;
• C3-6 cycloalkyl;
• or R3 and R4 together with the N atom, when present, form a cyclic ring structure comprising 5-6 atoms selected from C, N, S and O;
• and q is an integer from 1 to 6;
• or R4 together with the N atom, when present, form a cyclic ring structure comprising 5-6 atoms selected from C, N, S and O;
• and q is an integer from 1 to 6;
• p is 0 or an integer from 1 to 5;
• Y is —NHC(O)— or —C(O)—;
• and
• Z is a bond or CR8R9 wherein R8 and R9 are independently selected from H, and straight or branched chain C1-8 alkyl;
• or
• a pharmaceutically acceptable salt, ester or prodrug thereof.

A pharmaceutical composition comprising an effective amount of a compound of formula (I):

• wherein
• R1 is straight or branched-chain C2-8alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 alkylidene, C1-8 alkoxy, C1-8 heteroalkyl, C1-8 aminoalkyl, C1-8 haloalkyl, C1-8 alkoxycarbonyl, C1-8 hydroxyalkoxy, C1-8 hydroxyalkyl, —SH, C1-8 thioalkyl, —O—CH2—C5-6 aryl, —C(O)—C5-6 aryl substituted with C1-3 alkyl or halo;
• C5-6 aryl or C5-6 cycloalkyl optionally comprising 1 or more heteroatoms selected from N, S and O;
• A is C5-7 cycloalkyl, phenyl, naphthyl or C5-12 heteroaryl, wherein said heteroaryl contains one heteroatom selected from O, N or S;
• when A is C5-7 cycloalkyl, naphthyl or C5-12 heteroaryl as defined above,
• R2 is H, amino, hydroxyl, halo, or straight or branched-chain C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 heteroalkyl, C1-6 aminoalkyl, C1-6haloalkyl, C1-6 alkoxycarbonyl, —CN, —CF3, —OR3, —COR3, NO2, —NHR3, —NHC(O)R3, —C(O)NR3R4, —NR3R4, —NR3C(O)NR4R5, —OC(O)R3, or —(CH2)qNR3R4;
• where R3, R4 and R5 are the same or different, each independently being selected from H, C1-6 alkyl;
• C5-6 aryl optionally comprising I or more heteroatoms selected from N, O and S, and optionally substituted with halo or C1-6 alkyl;
• C3-6 cycloalkyl;
• or R3 and R4 together with the N atom, when present, form a cyclic ring structure comprising 5-6 atoms selected from C, N, S and O;
• and q is an integer from 1 to 6;
• or when A is phenyl,
• R2 is amino, hydroxyl, chloro, bromo, or straight or branched-chain C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 heteroalkyl, C1-6 aminoalkyl, C1-6 haloalkyl, C1-6 alkoxycarbonyl, —CN, —CF3, —OR3, —COR3, NO2, —NHR3, —NHC(O)R3, —C(O)NR3R4, —NR3R4, —NR3C(O)NR4R5, —OC(O)R3, or —(CH2)qNR3R4;
• where R3, R4 and R5 are the same or different, each independently being selected from H, C1-6 alkyl;
• C5-6 aryl optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with halo or C1-6 alkyl;
• C3-6 cycloalkyl;
• or R3 and R4 together with the N atom, when present, form a cyclic ring structure comprising 5-6 atoms selected from C, N, S and O;
• and q is an integer from 1 to 6;
• n is 1, 2, 3 or 4, the groups R2, when n>1, being the same or different;
• p is 0 or an integer from 1 to 5;
• Y is —NHC(O)— or —C(O)—;
• and
• Z is a bond or CR8R9 wherein R8 and R9 are independently selected from H, and straight or branched chain C1-8 alkyl;
• provided where —(CH2)p—Y— is —(CH2)3—C(O)—, that —A—(R2)n and R1 are not together:
• o-methyl-phenyl and n-butyl, respectively;
• or
• a pharmaceutically acceptable salt, ester or prodrug thereof;
• and
• a pharmaceutically acceptable carrier.

A pharmaceutical composition comprising an effective amount of a compound of formula II:

• wherein
• R1 is alkoxy;
• R2 is amino, hydroxyl, chloro, bromo, or straight or branched-chain C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6alkoxy, C1-6 heteroalkyl, C1-6 aminoalkyl, C1-6 haloalkyl, C1-6 alkoxycarbonyl, —CN, —CF3, —OR3, —COR3, NO2, —NHR3, —NHC(O)R3, —C(O)NR3R4, —NR3R4, —NR3C(O)NR4R5, —OC(O)R3, or —(CH2)qNR3R4;
• where R3, R4 and R5 are the same or different, each independently being selected from H, C1-6 alkyl;
• C5-6 aryl optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with halo or C1-6 alkyl;
• C3-6 cycloalkyl;
• or R3 and R4 together with the N atom, when present, form a cyclic ring structure comprising 5-6 atoms selected from C, N, S and O;
• and q is an integer from 1 to 6;
• n is 1, 2, 3 or 4, the groups R2, when n>1, being the same or different;
• p is 0 or an integer from 1 to 5;
• Y is —NHC(O)— or —C(O)—;
• or.
• a pharmaceutically acceptable salt, ester or prodrug thereof;
• and
• a pharmaceutically acceptable carrier.

A method of agonizing a muscarinic receptor comprising contacting said receptor with an effective amount of a compound of formula (I):

• wherein
• R1 is straight or branched-chain C2-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 alkylidene, C1-8 alkoxy, C1-8 heteroalkyl, C1-8 aminoalkyl, C1-8 haloalkyl, C1-8 alkoxycarbonyl, C1-8 hydroxyalkoxy, C1-8 hydroxyalkyl, —SH, C1-8 thioalkyl, —O—CH2—C5-6 aryl, —C(O)—C5-6 aryl substituted with C1-3 alkyl or halo;
• C5-6 aryl or C5-6 cycloalkyl optionally comprising 1 or more heteroatoms selected from N, S and O;
• A is C5-7 cycloalkyl, phenyl, naphthyl or C5-12 heteroaryl, wherein said heteroaryl contains one heteroatom selected from O, N or S;
• when A is C5-7 cycloalkyl, naphtyl or C5-12 heteroaryl as defined above,
• R2 is H, amino, hydroxyl, halo, or straight or branched-chain C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 heteroalkyl, C1-6 aminoalkyl, C1-6 haloalkyl, C1-6 alkoxycarbonyl, —CN, —CF3, —OR3, —COR3, NO2, —NHR3, —NHC(O)R3, —C(O)NR3R4, —NR3R4, —NR3C(O)NR4R5, —OC(O)R3, or —(CH2)qNR3R4;
• where R3, R4 and R5 are the same or different, each independently being selected from H, C1-6 alkyl;
• C5-6 aryl optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with halo or C1-6 alkyl;
• C3-6 cycloalkyl;
• or R3 and R4 together with the N atom, when present, form a cyclic ring structure comprising 5-6 atoms selected from C, N, S and O;
• and q is an integer from 1 to 6;
• or
• when A is phenyl,
• R2 is amino, hydroxyl, chloro, bromo, or straight or branched-chain C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 heteroalkyl, C1-6 aminoalkyl, C1-6 haloalkyl, C1-6 alkoxycarbonyl, —CN, —CF3, —OR3, —COR3, NO2, —NHR3, —NHC(O)R3, —C(O)NR3R4, —NR3R4, —NR3C(O)NR4R5, —OC(O)R3, —C(O)R3R4, —O(CH2)qNR3, —CNR3R4 or —(CH2)qNR3R4;
• where R3, R4 and R5 are the same or different, each independently being selected from H, C1-6 alkyl;
• C5-6 aryl optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with halo or C1-6 alkyl;
• C3-6 cycloalkyl;
• or R3 and R4 together with the N atom, when present, form a cyclic ring structure comprising 5-6 atoms selected from C, N, S and O;
• and q is an integer from 1 to 6;
• n is 1, 2, 3 or 4, the groups R2, when n>1, being the same or different;
• p is 0 or an integer from 1 to 5;
• Y is —NHC(O)— or —C(O)—;
• and
• Z is a bond or CR8R9 wherein R8 and R9 are independently selected from H, and straight or branched chain C1-8 alkyl;
• provided where —(CH2)p—Y— is —(CH2)3—C(O)—, that —A—(R2)n and R1 are not together:
• o-methyl-phenyl and n-butyl, respectively;
• or
• a pharmaceutically acceptable salt, ester or prodrug thereof.

A method of agonizing a muscarinic receptor comprising contacting said receptor with an effective amount of a compound of formula (II):

• wherein
• R1 is alkoxy;
• R2 is amino, hydroxyl, chloro, bromo, or straight or branched-chain C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 heteroalkyl, C1-6 aminoalkyl, C1-6 haloalkyl, C1-6 alkoxycarbonyl, —CN, —CF3, —OR3, —COR3, NO2, —NHR3, —NHC(O)R3, —C(O)NR3R4, —NR3R4, —NR3C(O)NR4R5, —OC(O)R3, —C(O)R3R4, —O(CH2)qNR3, —CNR3R4 or —(CH2)qNR3R4;
• where R3, R4 and R5 are the same or different, each independently being selected from H, C1-6 alkyl;
• C5-6 aryl optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with halo or C1-6 alkyl;
• C3-6 cycloalkyl;
• or R3 and R4 together with the N atom, when present, form a cyclic ring structure comprising 5-6 atoms selected from C, N, S and O;
• and q is an integer from 1 to 6;
• n is 1, 2, 3 or 4, the groups R2, when n>1, being the same or different;
• p is 0 or an integer from 1 to 5;
• Y is —NHC(O)— or —C(O)—;
• or
• a pharmaceutically acceptable salt, ester or prodrug thereof.