Diazole amides
AssigneeChemoCentryx, Inc.
InventorsXi Chen, Dean R. Dragoli, Pingchen Fan, Juan C. Jaen, Yandong Li, Jay P. Powers, Viengkham Malathong, Sreenivas Punna, Hiroko Tanaka, Penglie Zhang
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Abstract
Compounds are provided that act as potent antagonists of the CCR1 receptor, and have in vivo anti-inflammatory activity. The compounds are diazole lactam derivatives and are useful in pharmaceutical compositions, methods for the treatment of CCR1-mediated disease, and as controls in assays for the identification of competitive CCR1 antagonists.
Claims23
A method of treating CCR1-mediated diseases or conditions, wherein said CCR1-mediated diseases or conditions are selected from the group consisting of transplant rejection, dermatitis, inflammatory bowel disease, asthma, Alzheimer's disease, psoriasis, encephalomyelitis, rheumatoid arthritis, multiple sclerosis, multiple myeloma, osteoporosis, and leukemia comprising administering to a subject in need thereof a therapeutically effective amount of the compound represented by the structure:
- wherein
- each A is independently selected from the group consisting of N and CH;
- A1 is N or C(R5);
- A2 is N or C(R7);
- Z is phenyl and is optionally substituted with 1-3 Ra;
- R3 is a member selected from the group consisting of halogen, C1-8alkyl, C3-8 cycloalkyl, C1-8 haloalkyl, —ORa, —NRaRb, and phenyl, and wherein the alkyl, cycloalkyl, and phenyl portions of R3 are optionally further substituted with 1-3 R3;
- R4 is a member selected from the group consisting of H and C1-8 alkyl;
- R5, R6, R7 and R8 are each independently selected from the group consisting of H, halogen, C1-8 alkyl, and C1-8 haloalkyl optionally further substituted with 1-3 Ra;
- and optionally, R4 and R5, are connected to form an additional 5- or 6-membered ring which is saturated, unsaturated or aromatic having carbon atom ring vertices;
- each Ra and Rb is independently selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, C1-8 alkyl, C1-8 alkoxy, C1-8 haloalkyl, C3-6 cycloalkyl, C3-6 cycloalkylalkyl, amino, C1-8 alkylamino, di C1-8 alkylamino, carboxamide, carboxy C1-4 alkyl ester, carboxylic acid, and —SO2—C1-8 alkyl;
- or a pharmaceutically acceptable salt thereof.
A method of treating CCR1-mediated diseases or conditions, wherein said CCR1-mediated diseases or conditions are selected from the group consisting of transplant rejection, dermatitis, inflammatory bowel disease, asthma, Alzheimer's disease, psoriasis, encephalomyelitis, rheumatoid arthritis, multiple sclerosis, multiple myeloma, osteoporosis, and leukemia comprising administering to a subject in need thereof a therapeutically effective amount of a compound selected from the group consisting of:
- or a pharmaceutically acceptable salt thereof.
A method of modulating CCR1 function comprising administering to a subject in need thereof a therapeutically effective amount of the compound represented by the structure:
- wherein
- each A is independently selected from the group consisting of N and CH;
- A1 is N or C(R5);
- A2 is N or C(R7);
- Z is phenyl and is optionally substituted with 1-3 Ra;
- R3 is a member selected from the group consisting of halogen, C1-8 alkyl, C3-8 cycloalkyl, C1-8 haloalkyl, —ORa, —NRaRb, and phenyl, and wherein the alkyl, cycloalkyl, and phenyl portions of R3 are optionally further substituted with 1-3 Ra;
- R4 is a member selected from the group consisting of H and C1-8 alkyl;
- R5, R6, R7 and R8 are each independently selected from the group consisting of H, halogen, C1-8 alkyl, and C1-8 haloalkyl optionally further substituted with 1-3 Ra;
- and optionally, R4 and R5, are connected to form an additional 5- or 6-membered ring which is saturated, unsaturated or aromatic having carbon atom ring vertices;
- each Ra and Rb is independently selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, C1-8 alkyl, C1-8 alkoxy, C1-8 haloalkyl, C3-6 cycloalkyl, C3-6 cycloalkylalkyl, amino, C1-8 alkylamino, di C1-8 alkylamino, carboxamide, carboxy C1-4 alkyl ester, carboxylic acid, and —SO2—C1-8 alkyl;
- or a pharmaceutically acceptable salt thereof.
Dependencies are inferred from the claim text.