Aminopyrrolidines as chemokine receptor antagonists

A method of treating a CCR2 dependent disease or condition comprising administering a therapeutically effective amount of a compound of formula I

• pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, stereoisomers thereof or pro-drugs thereof, wherein
• X is —N(R2)—Y-Z;
• or
• X is
• optionally substituted with one or more substituents selected from the group consisting of (C1-C5)alkyl, —O(C1-C3)alkyl, CN, Cl, F, CF3 and OH;
• Y is a bond or C(O) or is selected from the optionally substituted group consisting of (C1-C6)alkyl, (C1-C4)alkyl-heterocyclyl, (C1-C4)alkyl-heteroaryl, heterocyclyl, heteroaryl, aryl, (C1-C4)alkyl-C(O), (C1-C4)alkyl-C(O)N(R2) and (C1-C4)alkyl-N(R2)C(O);
• wherein when Y is (C1-C4)alkyl-heterocyclyl, (C1-C4)alkyl-C(O)N(R2) or (C1-C4)alkyl-N(R2)C(O) it is the alkyl portion of the moiety that is attached to the nitrogen;
• Z is H or Z is selected from the optionally substituted group consisting of —(C1-C5)alkyl, —(C1-C3)alkyl-aryl, —(C1-C3)alkyl-heteroaryl, —(C1-C3)alkyl-diphenyl, —(C3-C6)cycloalkyl, heterocyclyl, —(C1-C4)alkyl-heterocyclyl, —O—(C1-C5)alkyl, aryl and heteroaryl;
• D is O, N, S(O)y, C(O) or C(R5)2;
• E is O, N, S(O)y, C(O) or C(R5)2;
• W is C(R4) or N;
• M is a bond, O or C(O);
• or
• M is selected from the optionally substituted group consisting of —(C1-C4)alkyl, —C(O)N(R2), —N(R2)C(O), —N(R2), -aryl, -heterocyclyl and -heteroaryl;
• or
• M is selected from the optionally substituted group consisting of —(C1-C4)alkyl-heterocyclyl, —(C1-C4)alkyl-C(O), —(C1-C4)alkyl-C(O)N(R2), —(C1-C4)alkyl-C(O)O, —(C1-C4)alkyl-N(R2)C(O)O, —(C1-C4))alkyl-N(R2)C(O) and —CH2—NH—C(O) wherein the alkyl portion of the moiety is connected to W;
• T is H or NH2 or T is selected from the optionally substituted group consisting of (C1-C5)alkyl, (C1-C5)alkoxy, —(C1-C3)alkyl-aryl, —(C1-C3)alkyl-heteroaryl, —(C1-C3)alkyl-diphenyl, heterocyclyl, —(C1-C4)alkyl-heterocyclyl, aryl and heteroaryl;
• A is selected from the group consisting of a bond, O and optionally substituted (C1-C5)alkyl;
• G is selected from the group consisting of a bond, N(R2), C(O), —C(O)—N(R2)—(C1-C4)alkyl, —(C1-C4)alkyl-N(R2)—C(O), —(C1-C4)alkyl-N(R2), N(R2)—(C1-C4)alkyl, N(R2)—CH(R2)—C(O), C(O)—CH(R4)—N(R2), optionally substituted —(C1-C4)alkyl, (C2)alkenyl, —(C1-C4)alkyl-N(R2)S(O)x—, —S(O)xN(R2)—(C1-C4)alkyl, —N(R2)S(O)X, —S(O)xN(R2), —N(R2)CON(R2), —N(R2)C(O), C(O)N(R2), —NH-optionally substituted heteroaryl, optionally substituted heteroaryl and optionally substituted phenyl;
• Q is H or is selected from the optionally substituted group consisting of (C1-C5)alkyl, (C3-C7)cycloalkyl, —O—(C1-C4)alkyl, —O—(C3-C7)cycloalkyl and —(C1-C3)alkyl-O—(C1-C3)alkyl;
• R1 is selected from the optionally substituted group consisting of amino, aryl, adamantanyl, diphenyl(C1-C2)alkyl, heteroaryl, heterocyclyl, (C1-C6)alkyl, —O—(C1-C4)alkyl, —O—CH2-phenyl, and (C3-C6)cycloalkyl;
• R2 is independently selected from the optionally substituted group consisting of H, (C1-C4)alkyl and (C3-C5)cycloalkyl;
• R3 is independently H, OH, CN, F, CF3, C(O)N(R2)2, N(R2)2, and oxo or R3 is independently selected from the optionally substituted group consisting of (C1-C3)alkyl, (C3-C7)cycloalkyl, —O—(C1-C3)alkyl, (C1-C3)alkyl —O—(C1-C3)alkyl, —(C1-C3)alkyl-C(O)—O—(C1-C3)alkyl, aryl, —O-aryl, heteroaryl, heterocyclyl, —(C1-C3)alkyl-aryl, —N(R2)aryl, —O-aryl, —C(O)—O—(C1-C3)alkyl, —NH-phenyl and phenyl;
• R5 is H or OH or R5 is independently selected from the optionally substituted group consisting of (C1-C4)alkyl, (C3-C5)cycloalkyl, —O—(C1-C4)alkyl and —O—(C3-C7)cycloalkyl;
• R4 is H, OH, CN or F or R4 is selected from the optionally substituted group consisting of —O—(C1-C3)alkyl, —O—(C3-C7)cycloalkyl, aryl and heteroaryl;
• m and n are independently 0, 1, or 2;
• and
• p is 1 or 2;
• x is 1 or 2;
• and
• y is 0, 1 or 2;
• provided that D and E are not O or N at the same time;
• and
• provided that when W is N, D is not N or O and E is not N or O.

A pharmaceutical composition comprising a compound of formula I

• pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, stereoisomers thereof or pro-drugs thereof, wherein
• X is —N(R2)—Y-Z;
• or
• X is
• optionally substituted with one or more substituents selected from the group consisting of (C1-C5)alkyl, —O(C1-C3)alkyl, CN, Cl, F, CF3 and OH;
• Y is a bond or C(O) or is selected from the optionally substituted group consisting of (C1-C6)alkyl, (C1-C4)alkyl-heterocyclyl, (C1-C4)alkyl-heteroaryl, heterocyclyl, heteroaryl, aryl, (C1-C4)alkyl-C(O), (C1-C4)alkyl-C(O)N(R2) and (C1-C4)alkyl-N(R2)C(O);
• wherein when Y is (C1-C4)alkyl-heterocyclyl, (C1-C4)alkyl-C(O)N(R2) or (C1-C4)alkyl-N(R2)C(O) it is the alkyl portion of the moiety that is attached to the nitrogen;
• Z is H or Z is selected from the optionally substituted group consisting of —(C1-C5)alkyl, —(C1-C3)alkyl-aryl, —(C1-C3)alkyl-heteroaryl, —(C1-C3)alkyl-diphenyl, —(C3-C6)cycloalkyl, heterocyclyl, —(C1-C4)alkyl-heterocyclyl, —O—(C1-C5)alkyl, aryl and heteroaryl;
• D is O, N, S(O)y, C(O) or C(R5)2;
• E is O, N, S(O)y, C(O) or C(R5)2;
• W is C(R4) or N;
• M is a bond, O or C(O);
• or
• M is selected from the optionally substituted group consisting of —(C1-C4)alkyl, —C(O)N(R2), —N(R2)C(O), —N(R2), -aryl, -heterocyclyl and -heteroaryl;
• or
• M is selected from the optionally substituted group consisting of —(C1-C4)alkyl-heterocyclyl, —(C1-C4)alkyl-C(O), —(C1-C4)alkyl-C(O)N(R2), —(C1-C4)alkyl-C(O)O, —(C1-C4)alkyl-N(R2)C(O)O, —(C1-C4))alkyl-N(R2)C(O) and —CH2—NH—C(O) wherein the alkyl portion of the moiety is connected to W;
• T is H or NH2 or T is selected from the optionally substituted group consisting of (C1-C5)alkyl, (C1-C5)alkoxy, —(C1-C3)alkyl-aryl, —(C1-C3)alkyl-heteroaryl, —(C1-C3)alkyl-diphenyl, heterocyclyl, —(C1-C4)alkyl-heterocyclyl, aryl and heteroaryl;
• A is selected from the group consisting of a bond, O and optionally substituted (C1-C5)alkyl;
• G is selected from the group consisting of a bond, N(R2), C(O), —C(O)—N(R2)—(C1-C4)alkyl, —(C1-C4)alkyl-N(R2)—C(O), —(C1-C4)alkyl-N(R2), N(R2)—(C1-C4)alkyl, N(R2)—CH(R2)—C(O), C(O)—CH(R4)—N(R2), optionally substituted —(C1-C4)alkyl, (C2)alkenyl, —(C1-C4)alkyl-N(R2)S(O)x—, —S(O)xN(R2)—(C1-C4)alkyl, —N(R2)S(O)x—, —S(O), N(R2), —N(R2)CON(R2), —N(R2)C(O), C(O)N(R2), —NH-optionally substituted heteroaryl, optionally substituted heteroaryl and optionally substituted phenyl;
• Q is H or is selected from the optionally substituted group consisting of (C1-C5)alkyl, (C3-C7)cycloalkyl, —O—(C1-C4)alkyl, —O—(C3-C7)cycloalkyl and —(C1-C3)alkyl-O—(C1-C3)alkyl;
• R1 is selected from the optionally substituted group consisting of amino, aryl, adamantanyl, diphenyl(C1-C2)alkyl, heteroaryl, heterocyclyl, (C1-C6)alkyl, —O—(C1-C4)alkyl, —O—CH2-phenyl, and (C3-C6)cycloalkyl;
• R2 is independently selected from the optionally substituted group consisting of H, (C1-C4)alkyl and (C3-C5)cycloalkyl;
• R3 is independently H, OH, CN, F, CF3, C(O)N(R2)2, N(R2)2, and oxo or R3 is independently selected from the optionally substituted group consisting of (C1-C3)alkyl, (C3-C7)cycloalkyl, —O—(C1-C3)alkyl, (C1-C3)alkyl-O—(C1-C3)alkyl, —(C1-C3)alkyl-C(O)—O—(C1-C3)alkyl, aryl, —O-aryl, heteroaryl, heterocyclyl, —(C1-C3)alkyl-aryl, —N(R2)aryl, —O-aryl, —C(O)—O—(C1-C3)alkyl, —NH-phenyl and phenyl;
• R5 is H or OH or R5 is independently selected from the optionally substituted group consisting of (C1-C4)alkyl, (C3-C5)cycloalkyl, —O—(C1-C4)alkyl and —O—(C3-C7)cycloalkyl;
• R4 is H, OH, CN or F or R4 is selected from the optionally substituted group consisting of —O—(C1-C3)alkyl, —O—(C3-C7)cycloalkyl, aryl and heteroaryl;
• m and n are independently 0, 1, or 2;
• and
• p is 1 or 2;
• x is 1 or 2;
• and
• y is 0, 1 or 2;
• provided that D and E are not O or N at the same time;
• and
• provided that when W is N, D is not N or O and E is not N or O.
• and a pharmaceutically acceptable carrier or excipient.