Aminoalkylazole derivatives as histamine-3 antagonists

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 NR13 or (CH2)p;
• Y is NR14, O or S;
• m is an integer of 1, 2 or 3;
• n is 0 or an integer of 1, 2 or 3;
• p is 0 or an integer of 1 or 2;
• R is —(CR3R4)mNR1R2 and R′ is H, halogen or an optionally substituted C1-C6 alkyl group;
• or
• R′ is —(CR3R4)mNR1R2 and R is H, halogen or an optionally substituted C1-C6 alkyl group;
• R1 and R2 are each independently H or an optionally substituted C1-C6 alkyl group or R1 and R2 may be taken together with the atom to which they are attached to form an optionally substituted 5-14 membered cycloheteroalkyl;
• R3, R4, R7 and R8 are each independently H, or an C1-C6 alkyl, C3-C10 cycloalkyl, or C6-C10 aryl group each optionally substituted;
• R5 and R6 are each independently H, halogen, OR10 or an C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 5-14 membered cycloheteroalkyl, C6-C10 aryl or 5-14 membered heteroaryl group each optionally substituted;
• R9 is NR11R12 or C6-C10 aryl or 5-14 membered heteroaryl group each group optionally substituted, provided that if n is 0 then R9 is NR11R12 or optionally substituted benzimidazolyl;
• R10 is H or an optionally substituted C1-C6 alkyl group;
• R11 and R12 are taken together with the atom to which they are attached to form an optionally substituted fused bicyclic 9- to 11-membered ring system optionally containing one to three additional heteroatoms selected from N, O or S;
• and
• R13 and R14 are each independently H or an optionally substituted C1-C6 alkyl group;
• or
• a stereoisomer or a pharmaceutically acceptable salt thereof.

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

• wherein
• X is NR13 or (CH2)p;
• Y is NR14, O or S;
• m is an integer of 1, 2 or 3;
• n is 0 or an integer of 1, 2 or 3;
• p is 0 or an integer of 1 or 2;
• R is —(CR3R4)mNR1R2 and R′ is H, halogen or an optionally substituted C1-C6 alkyl group;
• or
• R′ is —(CR3R4)mNR1R2 and R is H, halogen or an optionally substituted C1-C6 alkyl group;
• R1 and R2 are each independently H or an optionally substituted C1-C6 alkyl group or R1 and R2 may be taken together with the atom to which they are attached to form an optionally substituted 5-14 membered cycloheteroalkyl;
• R3, R4, R7 and R8 are each independently H, or an C1-C6 alkyl, C3-C10 cycloalkyl, or C6-C10 aryl group each optionally substituted;
• R5 and R6 are each independently H, halogen, OR10 or an C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 5-14 membered cycloheteroalkyl, C6-C10 aryl or 5-14 membered heteroaryl group each optionally substituted;
• R9 is NR11R12 or C6-C10 aryl or 5-14 membered heteroaryl group each group optionally substituted, provided that if n is 0 then R9 is NR11R12 or optionally substituted benzimidazolyl;
• R10 is H or an optionally substituted C1-C6 alkyl group;
• R11 and R12 are taken together with the atom to which they are attached to form an optionally substituted fused bicyclic 9- to 11-membered ring system optionally containing one to three additional heteroatoms selected from N, O or S;
• and
• R13 and R14 are each independently H or an optionally substituted C1-C6 alkyl group;
• or
• a stereoisomer or a pharmaceutically acceptable salt thereof.

A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and a compound of formula I

• wherein
• X is NR13 or (CH2)p;
• Y is NR14, O or S;
• m is an integer of 1, 2 or 3;
• n is 0 or an integer of 1, 2 or 3;
• p is 0 or an integer of 1 or 2;
• R is —(CR3R4)mNR1R2 and R′ is H, halogen or an optionally substituted C1-C6 alkyl group;
• or
• R′ is —(CR3R4)mNR1R2 and R is H, halogen or an optionally substituted C1-C6 alkyl group;
• R1 and R2 are each independently H or an optionally substituted C1-C6 alkyl group or R1 and R2 may be taken together with the atom to which they are attached to form an optionally substituted 5-14 membered cycloheteroalkyl;
• R3, R4, R7 and R8 are each independently H, or an C1-C6 alkyl, C3-C10 cycloalkyl, or C6-C10 aryl group each optionally substituted;
• R5 and R6 are each independently H, halogen, OR10 or an C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 5-14 membered cycloheteroalkyl, C6-C10 aryl or 5-14 membered heteroaryl group each optionally substituted;
• R9 is NR11R12 or C6-C10 aryl or 5-14 membered heteroaryl group each group optionally substituted, provided that if n is 0 then R9 is NR11R12 or optionally substituted benzimidazolyl;
• R10 is H or an optionally substituted C1-C6 alkyl group;
• R11 and R12 are taken together with the atom to which they are attached to form an optionally substituted fused bicyclic 9- to 11-membered ring system optionally containing one to three additional heteroatoms selected from N, O or S;
• and
• R13 and R14 are each independently H or an optionally substituted C1-C6 alkyl group;
• or
• a stereoisomer or a pharmaceutically acceptable salt thereof.

A process for the preparation of a compound of formula I

• wherein
• X is NR13 or (CH2)p;
• Y is NR14, O or S;
• m is an integer of 1, 2 or 3;
• n is 0 or an integer of 1, 2 or 3;
• p is 0 or an integer of 1 or 2;
• R is —(CR3R4)mNR1R2 and R′ is H, halogen or an optionally substituted C1-C6 alkyl group;
• or
• R′ is —(CR3R4)mNR1R2 and R is H, halogen or an optionally substituted C1-C6 alkyl group;
• R1 and R2 are each independently H or an optionally substituted C1-C6 alkyl group or R1 and R2 may be taken together with the atom to which they are attached to form an optionally substituted 5-14 membered cycloheteroalkyl;
• R3, R4, R7 and R8 are each independently H, or an C1-C6 alkyl, C3-C10 cycloalkyl, or C6-C10 aryl group each optionally substituted;
• R5 and R6 are each independently H, halogen, OR10 or an C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 5-14 membered cycloheteroalkyl, C6-C10 aryl or 5-14 membered heteroaryl group each optionally substituted;
• R9 is NR11R12 or C6-C10 aryl or 5-14 membered heteroaryl group each group optionally substituted, provided that if n is 0 then R9 is NR11R12 or optionally substituted benzimidazolyl;
• R10 is H or an optionally substituted C1-C6 alkyl group;
• R11 and R12 are taken together with the atom to which they are attached to form an optionally substituted fused bicyclic 9- to 11-membered ring system optionally containing one to three additional heteroatoms selected from N, O or S;
• and
• R13 and R14 are each independently H or an optionally substituted C1-C6 alkyl group;
• or
• a stereoisomer or a pharmaceutically acceptable salt thereof;
• which process comprises reacting a compound of formula II:
• wherein,
• Ry is H, halogen or an optionally substituted C1-C6 alkyl group;
• Hal represents Cl, Br or l;
• and
• X, Y, m, n, R3, R4, R5, R6, R7, R8 and R9 are as described for formula I;
• with an amine of formula III
• wherein R1 and R2 are as described for formula I optionally in the presence of a solvent.