3-cycloalkylaminopyrrolidine derivatives as modulators of chemokine receptors

A method of treating inflammation, rheumatoid arthritis, atherosclerosis, neuropathic pain, lupus, systemic lupus erythematosus, restenosis, immune disorders, and transplant rejection in a mammal in need thereof comprising administering to such mammal a therapeutically effective amount of a compound of the formula 1:

• or pharmaceutically acceptable salt thereof, wherein:
• X and Y together are selected from the group consisting of:
• a) —CH2—NH—(C=O)—:
• b) —CH2—O—CH2—:
• Z is a phenyl, pyridyl or pyrimidinyl group that is substituted with a CF3 group;
• R1 is phenyl, pyridyl,thiazole, pyrimidine or pyrazine, wherein said R1 is substituted with 0-3 R1a, wherein R1a is independently selected from the group consisting of:
• CH2—OMe, alkyl amides, pyrollidinyl amides, morpholinyl, alkyl, alkoxy, CH2—NMe2, pyridyl, carboxylate, phenyl bearing a CH2—OH group, pyrimidine, thiazole, oxazole and pyrazine;
• R2 is OH;
• R3 and R4 are H
• R5 is independently selected from the group consisting of hydrogen, alkyl, and formyl;
• R6 and R7 are each independently selected from the group consisting of H, C12, C10 alkyl, OH, CH2—OMe and hydroxyalkyl;
• and
• r=1.

A method of modulating chemokine receptor activity in a mammal comprising administering an effective amount of a compound of the formula 1:

• or pharmaceutically acceptable salt thereof, wherein:
• X and Y together are selected from the group consisting of:
• a) —CH2—NH—(C═O)—;
• b) —CH2—O—CH2—;
• Z is a phenyl, pyridyl or pyrimidinyl group that is substituted with a CF3 group;
• R1 is phenyl, pyridyl,thiazole, pyrimidine or pyrazine, wherein said R1 is substituted with 0-3 R1a, wherein R1a is independently selected from the group consisting of:
• CH2—OMe, alkyl amides, pyrollidinyl amides, morpholinyl, alkyl, alkoxy, CH2—NMe2, pyridyl, carboxylate, phenyl bearing a CH2—OH group, pyrimidine, thiazole, oxazole and pyrazine;
• R2 is OH;
• R3 and R4 are H
• R5 is independently selected from the group consisting of hydrogen, alkyl, and formyl;
• R6 and R7 are each independently selected from the group consisting of H, C12, C10 alkyl, OH, CH2—OMe and hydroxyalkyl;
• and
• r=1.

A method of treating a CCR2-mediated condition or disease in a subject, said method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of the formula I:

• or pharmaceutically acceptable salt thereof, wherein:
• X and Y together are selected from the group consisting of:
• a) —CH2—NH—(C═O)—;
• b) —CH2—O—CH2—;
• Z is a phenyl, pyridyl or pyrimidinyl group that is substituted with a CF3 group;
• R1 is phenyl, pyridyl,thiazole, pyrimidine or pyrazine, wherein said R1 is substituted with 0-3 R1a, wherein R1a is independently selected from the group consisting of:
• CH2—OMe, alkyl amides, pyrollidinyl amides, morpholinyl, alkyl, alkoxy, CH2—NMe2, pyridyl, carboxylate, phenyl bearing a CH2—OH group, pyrimidine, thiazole, oxazole and pyrazine;
• R2 is OH;
• R3 and R4 are H
• R5 is independently selected from the group consisting of hydrogen, alkyl, and formyl;
• R6 and R7 are each independently selected from the group consisting of H, C12, C10 alkyl, OH, CH2—OMe and hydroxyalkyl;
• and
• r=1.

A method of treating a CCR5-mediated condition or disease in a subject, said method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of the formula I:

• or pharmaceutically acceptable salt thereof, wherein:
• X and Y together are selected from the group consisting of:
• a) —CH2—NH—(C═O)—;
• b) —CH2—O—CH2—;
• Z is a phenyl, pyridyl or pyrimidinyl group that is substituted with a CF3 group;
• R1 is phenyl, pyridyl,thiazole, pyrimidine or pyrazine, wherein said R1 is substituted with 0-3 R1a, wherein R1a is independently selected from the group consisting of:
• CH2—OMe, alkyl amides, pyrollidinyl amides, morpholinyl, alkyl, alkoxy, CH2—NMe2, pyridyl, carboxylate, phenyl bearing a CH2—OH group, pyrimidine, thiazole, oxazole and pyrazine;
• R2 is OH;
• R3 and R4 are H
• R5 is independently selected from the group consisting of hydrogen, alkyl, and formyl;
• R6 and R7 are each independently selected from the group consisting of H, C12, C10 alkyl, OH, CH2—OMe and hydroxyalkyl;
• and
• r=1.

A method of modulating activity of a chemokine receptor comprising contacting said chemokine receptor with a compound of the formula I:

• or pharmaceutically acceptable salt thereof, wherein:
• X and Y together are selected from the group consisting of:
• a) —CH2—NH—(C═O)—;
• b) —CH2—O—CH2—;
• Z is a phenyl, pyridyl or pyrimidinyl group that is substituted with a CF3 group;
• R1 is phenyl, pyridyl,thiazole, pyrimidine or pyrazine, wherein said R1 is substituted with 0-3 R1a, wherein R1a is independently selected from the group consisting of:
• CH2—OMe, alkyl amides, pyrollidinyl amides, morpholinyl, alkyl, alkoxy, CH2—NMe2, pyridyl, carboxylate, phenyl bearing a CH2—OH group, pyrimidine, thiazole, oxazole and pyrazine;
• R2 is OH;
• R3 and R4 are H
• R5 is independently selected from the group consisting of hydrogen, alkyl, and formyl;
• R6 and R7 are each independently selected from the group consisting of H, C12, C10 alkyl, OH, CH2—OMe and hydroxyalkyl;
• and
• r=1.

A method of treating a disease associated with expression or activity of a chemokine receptor in a patient comprising administering to said patient a therapeutically effective amount of a compound of the formula I:

• or pharmaceutically acceptable salt thereof, wherein:
• X and Y together are selected from the group consisting of:
• a) —CH2—NH—(C═O)—;
• b) —CH2—O—CH2—;
• Z is a phenyl, pyridyl or pyrimidinyl group that is substituted with a CF3 group;
• R1 is phenyl, pyridyl,thiazole, pyrimidine or pyrazine, wherein said R1 is substituted with 0-3 R1a, wherein R1a is independently selected from the group consisting of:
• CH2—OMe, alkyl amides, pyrollidinyl amides, morpholinyl, alkyl, alkoxy, CH2—NMe2, pyridyl, carboxylate, phenyl bearing a CH2—OH group, pyrimidine, thiazole, oxazole and pyrazine;
• R2 is OH;
• R3 and R4 are H
• R5 is independently selected from the group consisting of hydrogen, alkyl, and formyl;
• R6 and R7 are each independently selected from the group consisting of H, C12, C10 alkyl, OH, CH2—OMe and hydroxyalkyl;
• and
• r=1.

A method of treating HIV infection in a patient comprising administering to said patient a therapeutically effective amount of a compound of the formula I:

• or pharmaceutically acceptable salt thereof, wherein:
• X and Y together are selected from the group consisting of:
• a) —CH2—NH—(C═O)—;
• b) —CH2—O—CH2—;
• Z is a phenyl, pyridyl or pyrimidinyl group that is substituted with a CF3 group;
• R1 is phenyl, pyridyl,thiazole, pyrimidine or pyrazine, wherein said R1 is substituted with 0-3 R1a, wherein R1a is independently selected from the group consisting of:
• CH2—OMe, alkyl amides, pyrollidinyl amides, morpholinyl, alkyl, alkoxy, CH2—NMe2, pyridyl, carboxylate, phenyl bearing a CH2—OH group, pyrimidine, thiazole, oxazole and pyrazine;
• R2 is OH;
• R3 and R4 are H
• R5 is independently selected from the group consisting of hydrogen, alkyl, and formyl;
• R6 and R7 are each independently selected from the group consisting of H, C12, C10 alkyl, OH, CH2—OMe and hydroxyalkyl;
• and
• r=1.

A method of treating cancer in a patient comprising administering to Said patient a therapeutically effective amount of a compound of the formula I:

• or pharmaceutically acceptable salt thereof, wherein:
• X and Y together are selected from the group consisting of:
• a) —CH2—NH—(C═O)—;
• b) —CH2—O—CH2—;
• Z is a phenyl, pyridyl or pyrimidinyl group that is substituted with a CF3 group;
• R1 is phenyl, pyridyl,thiazole, pyrimidine or pyrazine, wherein said R1 is substituted with 0-3 R1a, wherein R1a is independently selected from the group consisting of:
• CH2—OMe, alkyl amides, pyrollidinyl amides, morpholinyl, alkyl, alkoxy, CH2—NMe2, pyridyl, carboxylate, phenyl bearing a CH2—OH group, pyrimidine, thiazole, oxazole and pyrazine;
• R2 is OH;
• R3 and R4 are H
• R5 is independently selected from the group consisting of hydrogen, alkyl, and formyl;
• R6 and R7 are each independently selected from the group consisting of H, C12, C10 alkyl, OH, CH2—OMe and hydroxyalkyl;
• and
• r=1.