Azacyclylbenzamide derivatives as histamine-3 antagonists

A compound having the formula:

• wherein
• X is (CH2)m;
• m is 0 or 1;
• n is 1 or 2;
• R1 is C1-C6 alkyl or C3-C6 cycloalkyl each group optionally substituted;
• R2 is C1-C6 alkyl;
• and
• R3 and R4 are taken together with the atom to which they are attached to form an optionally substituted monocyclic 5-membered aromatic ring system optionally containing one or two additional heteroatoms selected from N, O or S or an optionally substituted fused bicyclic aromatic ring system optionally containing one to three additional heteroatoms selected from N, O or S;
• or
• a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

A method for the treatment of a cognitive disorder related to or affected by the Histamine-3 (H3) receptor in a patient in need thereof which comprises providing to said patient a therapeutically effective amount of a compound of formula I

• wherein
• X is (CR7R8)m, CO or SO2;
• m is 0 or 1;
• n is 1, 2 or 3;
• R1 is C1-C6 alkyl, C1-C6 haloalkyl, C3-C10 cycloalkyl or a 3-10 membered cycloheteroalkyl each group optionally substituted;
• R2 is H or C1-C6 alkyl or C3-C10 cycloalkyl each group optionally substituted;
• R3 and R4 are taken together with the atom to which they are attached to form an optionally substituted monocyclic 5-membered aromatic ring system optionally containing one or two additional heteroatoms selected from N, O or S or an optionally substituted fused bicyclic or tricyclic 9- to 15-membered aromatic ring system optionally containing one to three additional heteroatoms selected from N, O or S;
• and
• R5 and R6 are each independently H, halogen or C1-C6 alkyl or C3-C10 cycloalkyl each optionally substituted;
• or R5 and R6 are taken together with the atoms to which they are attached to form an optionally substituted phenyl ring;
• R7 and R8 are each independently H, halogen or C1-C6 alkyl or C3-C10 cycloalkyl each group optionally substituted;
• or
• a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

A method for the inhibition of an H3 receptor comprising contacting said receptor with an effective amount of a compound of formula I

• wherein
• X is (CR7R8)m, CO or SO2;
• m is 0 or 1;
• n is 1, 2 or 3;
• R1 is H, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl or cycloheteroalkyl each group optionally substituted;
• R2 is H or C1-C6 alkyl or cycloalkyl group each group optionally substituted;
• R3 and R4 are taken together with the atom to which they are attached to form an optionally substituted monocyclic 5-membered aromatic ring system optionally containing one or two additional heteroatoms selected from N, O or S or an optionally substituted fused bicyclic or tricyclic 9- to 15-membered aromatic ring system optionally containing one to three additional heteroatoms selected from N, O or S;
• and
• R5 and R6 are each independently H, halogen or a C1-C6 alkyl C1-C6 alkoxy or C3-C6 cycloalkyl group each optionally substituted;
• or R5 and R6 are taken together with the atom to which they are attached to form an optionally substituted phenyl ring;
• R7 and R6 are each independently H, halogen or an alkyl or cycloalkyl group each group optionally substituted;
• or
• a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and an effective amount of a compound of formula I:

• wherein
• X is (CR7R8)m, CO or SO2;
• m is 0 or 1;
• n is 1, 2 or 3;
• R1 is H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C10 cycloalkyl or a 3-10 membered cycloheteroalkyl each group optionally substituted;
• R2 is H or C1-C6 alkyl or C3-C10 cycloalkyl each group optionally substituted;
• R3 and R4 are taken together with the atom to which they are attached to form an optionally substituted monocyclic 5-membered aromatic ring system optionally containing one or two additional heteroatoms selected from N, O or S or an optionally substituted fused bicyclic or tricyclic 9- to 15-membered aromatic ring system optionally containing one to three additional heteroatoms selected from N, O or S;
• and
• R5 and R6 are each independently H, halogen or C1-C6 alkyl, C1-C6 alkoxy or C3-C10 cycloalkyl each optionally substituted;
• or R5 and R6 are taken together with the atoms to which they are attached to form an optionally substituted phenyl ring;
• R7 and R8 are each independently H, halogen or C1-C6 alkyl or C3-C10 cycloalkyl each group optionally substituted;
• or
• a stereoisomer, tautomer or pharmaceutically acceptable salt thereof;
• provided that if R2 is H or R3 and R4 are taken together to form a tricyclic aromatic ring system, then n is not 2.

A process for the preparation of a compound of formula I

• wherein
• X is (CR7R8)m, CO or SO2;
• m is 0 or 1;
• n is 1, 2 or 3;
• R1 is H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C10 cycloalkyl or a 3-10 membered cycloheteroalkyl each group optionally substituted;
• R2 is H or C1-C6 alkyl or C3-C10 cycloalkyl each group optionally substituted;
• R3 and R4 are taken together with the atom to which they are attached to form an optionally substituted monocyclic 5-membered aromatic ring system optionally containing one or two additional heteroatoms selected from N, O or S or an optionally substituted fused bicyclic or tricyclic 9- to 15-membered aromatic ring system optionally containing one to three additional heteroatoms selected from N, O or S;
• and
• R5 and R6 are each independently H, halogen, C1-C6 alkyl, C1-C6 alkoxy or C3-C10 cycloalkyl each optionally substituted;
• or R5 and R6 are taken together with the atoms to which they are attached to form an optionally substituted phenyl ring;
• R7 and R8 are each independently H, halogen or C1-C6 alkyl or C3-C10 cycloalkyl each group optionally substituted;
• or
• a stereoisomer, tautomer or pharmaceutically acceptable salt thereof;
• which process comprises reacting a compound of formula II
• wherein X, R3, R4, R5 and R6 are as described hereinabove for formula I with an azacyclylamine of formula III
• in the presence of a coupling agent and optionally in the presence of a solvent to form a compound of formula IIIa:
• wherein,
• RX is R1 or a protecting group;
• RY is H or C1-C6 alkyl or C3-C10 cycloalkyl each group optionally substituted;
• wherein, if RY is H and R2 in the compound of formula I is other than H, than the process further comprises:
• reacting activated-R2 with the compound of formula IIIa, to form a compound of formula IIIb:
• wherein if RX is R1, then the compound of formula I is formed;
• or
• if RX is a protecting group, then the process further comprises:
• deprotecting the compound of formula IIIb to form a deprotected compound;
• and
• if R1 in the compound of formula I is H, then the compound of formula I is formed;
• or
• if R1 in the compound of formula I is other than H, then the process further comprises reacting the deprotected compound with activated-R1;
• wherein the compound of formula I is formed.