Compounds specific for the human alpha1d adrenergic receptor and uses thereof

A method of inhibiting activation of a human α1d adrenergic receptor which comprises contacting the receptor with a compound so as to inhibit activation of the receptor, wherein the compound has the structure:

• 42
• wherein m is an integer from 0 to 2;
• wherein n is an integer from 0 to 2;
• wherein Y is
• 43
• wherein Z is
• 44
• wherein R1 and R2 (i) are independently H, branched or unbranched C1-C6 alkyl or alkoxy, branched or unbranched C2-C6 alkenyl or alkynyl, branched or unbranched C1-C6 hydroxyalkyl, hydroxy, substituted or unsubstituted aryl or aryl-(C1-C6)-alkyl, or substituted or unsubstituted heteroaryl or heteroaryl-(C1-C6)-alkyl, wherein the substituent if present is a halogen, CN, nitro, hydroxy, branched or unbranched C1-C6 alkyl or alkoxy group, or branched or unbranched C2-C6 alkenyl or alkynyl group;
• or (ii) taken together form a substituted or unsubstituted cycloalkyl ring containing 3-10 carbons, wherein the substituent if present is a branched or unbranched C1-C6 alkyl group or branched or unbranched C2-C6 alkenyl or alkynyl group;
• wherein R3 is H, branched or unbranched C1-C6 alkyl, branched or unbranched C2-C6 alkenyl or alkynyl, C3-C7 cycloalkyl, C3-C7 cycloalkylalkyl, aryl, heteroaryl, aryl-(C1-C6)-alkyl, heteroaryl-(C1-C6)-alkyl, substituted C1-C6 alkyl, substituted C3-C7 cycloalkyl, substituted aryl, substituted heteroaryl, substituted aryl-(C1-C6)-alkyl, or substituted heteroaryl-(C1-C6)-alkyl, wherein the substituent if present is a halogen, CN, nitro, C1-C6 alkyl, OR14, SR14, N(R14)2, SO2N(R14)2, CO2R14, SO3R14, N(R14)COR14, CON(R14)2, or N(R14)CON(R14)2;
• wherein R4 is H or CH3;
• wherein R5 is H, branched or unbranched C1-C6 alkyl, branched or unbranched C2-C6 alkenyl or alkynyl, C3-C7 cycloalkyl, C3-C7 cycloalkylalkyl, aryl, heteroaryl, aryl-(C1-C6)-alkyl, heteroaryl-(C1-C6)-alkyl, substituted C1-C6 alkyl, substituted C3-C7 cycloalkyl, substituted aryl, substituted heteroaryl, substituted aryl-(C1-C6)-alkyl, or substituted heteroaryl-(C1-C6)-alkyl, wherein the substituent if present is a halogen, CN, nitro, C1-C6 alkyl, OR14, SR14, N(R14)2, SO2N(R14)2, CO2R14, SO3R14, N(R14)COR14, CON(R14)2, or N(R14)CON(R14)2;
• wherein R6 is H, branched or unbranched C1-C6 alkyl, branched or unbranched C2-C6 alkenyl or alkynyl, C3-C7 cycloalkyl, C3-C7 cycloalkylalkyl, aryl, heteroaryl, aryl-(C1-C6)-alkyl, heteroaryl-(C1-C6)-alkyl, substituted C1-C6 alkyl, substituted C3-C7 cycloalkyl, substituted aryl, substituted heteroaryl, substituted aryl-(C1-C6)-alkyl, or substituted heteroaryl-(C1-C6)-alkyl, wherein the substituent if present is a halogen, CN, nitro, C1-C6 alkyl, OR14, SR14, N(R14)2, SO2N(R14)2, CO2R14, SO3R14, N(R14)COR14, CON(R14)2, or N(R14)CON(R14)2;
• wherein R7 is H, branched or unbranched C1-C6 alkyl, branched or unbranched C2-C6 alkenyl or alkynyl, C3-C7 cycloalkyl, aryl, aryl-(C1-C6)-alkyl, CO2R14, CON(R14)2, substituted C2-C6 alkyl, substituted aryl, wherein the substituent is N(R14)2, halogen, OR14 or SR14;
• wherein R8 is H or CH3;
• wherein R9 is H, F, Cl, Br, branched or unbranched C1-C6 alkyl or alkoxy, CN;
• wherein R10 is H or F;
• wherein R11 is H, F, Cl, Br, I, CN, branched or unbranched C1-C6 alkyl or alkoxy;
• wherein R12 is H, F, Cl, CN, branched or unbranched C1-C6 alkyl or alkoxy;
• wherein R13 is H or F;
• wherein X is N or CH;
• with the proviso that when R11 and R12 are each H, then R9 is F;
• and wherein R14 is independently H or branched or unbranched C1-C6 alkyl.

A compound having the structure:

• 52
• wherein n is an integer from 0 to 2;
• wherein m is an integer from 0 to 2;
• wherein Y is
• 53
• wherein Z is
• 54
• wherein R1 and R2 (i) are independently H, branched or unbranched C1-C6 alkyl or alkoxy, branched or unbranched C2-C6 alkenyl or alkynyl, branched or unbranched C1-C6 hydroxyalkyl, hydroxy, substituted or unsubstituted aryl or aryl-(C1-C6)-alkyl, or substituted or unsubstituted heteroaryl or heteroaryl-(C1-C6)-alkyl, wherein the substituent if present is a halogen, CN, nitro, hydroxy, branched or unbranched C1-C6 alkyl or alkoxy group, or branched or unbranched C2-C6 alkenyl or alkynyl group;
• or (ii) taken together form a substituted or unsubstituted cycloalkyl ring containing 3-10 carbons, wherein the substituent if present is a branched or unbranched C1-C6 alkyl group or branched or unbranched C2-C6 alkenyl or alkynyl group;
• wherein R3 is H, branched or unbranched C1-C6 alkyl, branched or unbranched C2-C6 alkenyl or alkynyl, C3-C7 cycloalkyl, C3-C7 cycloalkylalkyl, aryl, heteroaryl, aryl-(C1-C6)-alkyl, heteroaryl-(C2-C6)-alkyl, substituted C1-C6 alkyl, substituted C3-C7 cycloalkyl, substituted aryl, substituted heteroaryl, substituted aryl-(C1-C6)-alkyl, or substituted heteroaryl-(C1-C6)-alkyl, wherein the substituent if present is a halogen, CN, nitro, C1-C6 alkyl, OR14, SR14, N(R14)2, SO2N(R14)2, CO2R14, SO3R14, N(R14)COR14, CON(R14)2, or N(R14)CON(R14)2;
• wherein R4 is H or CH3;
• wherein R5 is H, branched or unbranched C1-C6 alkyl, branched or unbranched C2-C6 alkenyl or alkynyl, C3-C7 cycloalkyl, C3-C7 cycloalkylalkyl, aryl, heteroaryl, aryl-(C1-C6)-alkyl, heteroaryl-(C1-C6)-alkyl, substituted C1-C6 alkyl, substituted C3-C7 cycloalkyl, substituted aryl, substituted heteroaryl, substituted aryl-(C1-C6)-alkyl, or substituted heteroaryl-(C1-C6)-alkyl, wherein the substituent if present is a halogen, CN, nitro, C1-C6 alkyl, OR14, SR14, N(R14)2, SO2N(R14)2, CO2R14, SO3R14, N(R14)COR14, CON(R14)2, or N(R14)CON(R14)2;
• wherein R6 is H, branched or unbranched C1-C6 alkyl, branched or unbranched C2-C6 alkenyl or alkynyl, C3-C7 cycloalkyl, C3-C7 cycloalkylalkyl, aryl, heteroaryl, aryl-(C1-C6)-alkyl, heteroaryl-(C1-C6)-alkyl, substituted C1-C6 alkyl, substituted C3-C7 cycloalkyl, substituted aryl, substituted heteroaryl, substituted aryl-(C1-C6)-alkyl, or substituted heteroaryl-(C1-C6)-alkyl, wherein the substituent if present is a halogen, CN, nitro, C1-C6 alkyl, OR14, SR14, N(R14)2, SO2N(R14)2, CO2R14, SO3R14, N(R14)COR14, CON(R14)2, or N(R14)CON(R14)2;
• wherein R7 is H, branched or unbranched C1-C6 alkyl, branched or unbranched C2-C6 alkenyl or alkynyl, C3-C7 cycloalkyl, aryl, aryl-(C1-C6)-alkyl, CO2R14, CON(R14)2, substituted C1-C6 alkyl, substituted aryl, wherein the substituent is N(R14)2, halogen, OR14 or SR14;
• wherein R8 is H or CH3;
• wherein R10 is H or F;
• wherein R11 is H, F, Cl, Br, I, CN, branched or unbranched C1-C6 alkyl or alkoxy;
• wherein R12 is H, F, Cl, CN, branched or unbranched C1-C6 alkyl or alkoxy;
• wherein R13 is H or F;
• wherein X is N or CH;
• and wherein R14 is independently H or branched or unbranched C1-C6 alkyl.

A process of making a compound with structure:

• 61
• which comprises reacting a compound with structure:
• 62
• with a compound
• 63
• to form the compound,
• wherein Y is
• 64
• wherein Z is
• 65
• wherein R1 and R2 (i) are independently H, branched or unbranched C1-C6 alkyl or alkoxy, branched or unbranched C2-C6 alkenyl or alkynyl, branched or unbranched C1-C6 hydroxyalkyl, hydroxy, substituted or unsubstituted aryl or aryl-(C1-C6)-alkyl, or substituted or unsubstituted heteroaryl or heteroaryl-(C1-C6)-alkyl, wherein the substituent if present is a halogen, CN, nitro, hydroxy, branched or unbranched C1-C6 alkyl or alkoxy group, or branched or unbranched C2-C6 alkenyl or alkynyl group;
• or (ii) taken together form a substituted or unsubstituted cycloalkyl ring containing 3-10 carbons, wherein the substituent if present is a branched or unbranched C1-C6 alkyl group or branched or unbranched C2-C6 alkenyl or alkynyl group;
• wherein R3 is H, branched or unbranched C1-C6 alkyl, branched or unbranched C2-C6 alkenyl or alkynyl, C3-C7 cycloalkyl, C3-C7 cycloalkylalkyl, aryl, heteroaryl, aryl-(C1-C6)-alkyl, heteroaryl-(C1-C6)-alkyl, substituted C1-C6 alkyl, substituted C3-C7 cycloalkyl, substituted aryl, substituted heteroaryl, substituted aryl-(C1-C6)-alkyl, or substituted heteroaryl-(C1-C6)-alkyl, wherein the substituent if present is a halogen, CN, nitro, C1-C6 alkyl, OR14, SR14, N(R14)2, SO2N(R14)2, CO2R14, SO3R14, N(R14)COR14, CON(R14)2, or N(R14)CON(R14)2;
• wherein R4 is H or CH3;
• wherein R5 is H, branched or unbranched C1-C6 alkyl, branched or unbranched C2-C6 alkenyl or alkynyl, C3-C7 cycloalkyl, C3-C7 cycloalkylalkyl, aryl, heteroaryl, aryl-(C1-C6)-alkyl, heteroaryl-(C1-C6)-alkyl, substituted C1-C6 alkyl, substituted C3-C7 cycloalkyl, substituted aryl, substituted heteroaryl, substituted aryl-(C1-C6)-alkyl, or substituted heteroaryl-(C1-C6)-alkyl, wherein the substituent if present is a halogen, CN, nitro, C1-C6 alkyl, OR14, SR14, N(R14)2SO2N(R14)2, CO2R14, SO3R14, N(R14)COR14, CON(R14)2, or N(R14)CON(R14)2;
• wherein R6 is H, branched or unbranched C1-C6 alkyl, branched or unbranched C2-C6 alkenyl or alkynyl, C3-C7 cycloalkyl, C3-C7 cycloalkylalkyl, aryl, heteroaryl, aryl-(C1-C6)-alkyl, heteroaryl-(C1-C6)-alkyl, substituted C1-C6 alkyl, substituted C3-C7 cycloalkyl, substituted aryl, substituted heteroaryl, substituted aryl-(C1-C6)-alkyl, or substituted heteroaryl-(C1-C6)-alkyl, wherein the substituent if present is a halogen, CN, nitro, C6-C6 alkyl, OR14, SR14, N(R14)2, SO2N(R14)2, CO2R14, SO3R14, N(R14)COR14, CON(R14)2, or N(R14)CON(R14)2;
• and wherein R14 is independently H or branched or unbranched C1-C6 alkyl.