# US 2014/0155377 A1 · 3-cycloalkylaminopyrrolidine derivatives as modulators of chemokine receptors

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- Number: US 2014/0155377 A1
- Document ID: US20140155377A1
- Status: Published application
- Kind: A1
- Application number: 14/174,300
- Filed: 2014-02-06
- Published: 2014-06-05
- Earliest claimed: 2003-12-18
- Assignees: Incyte Corporation
- Inventors: Chu-Biao Xue; Brian W. Metcalf; Amy Qi Han; Darius J. Robinson; Changsheng Zheng; Anlai Wang; Yingxin Zhang
- Web page: https://patentgrep.com/patent/US20140155377A1

## CPC

- C07D 277/24: Radicals substituted by oxygen atoms
- A61K 31/40: having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K 31/4025: not condensed and containing further heterocyclic rings, e.g. cromakalim
- A61K 31/427: not condensed and containing further heterocyclic rings
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/454: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
- A61K 31/497: containing further heterocyclic rings
- A61K 31/501: not condensed and containing further heterocyclic rings
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/08: Vasodilators for multiple indications
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 17/00: Drugs for dermatological disorders
- A61P 19/00: Drugs for skeletal disorders
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/12: Antivirals
- A61P 31/18: for HIV
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 207/14: Nitrogen atoms not forming part of a nitro radical
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 413/14: containing three or more hetero rings
- C07D 417/04: directly linked by a ring-member-to-ring-member bond
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D 417/14: containing three or more hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to 3-cycloalkylaminopyrrolidine derivatives of the formula I: (wherein R1, R2, R3, R4, R5, R6, R7, Y and Z are as defined herein) which are useful as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of chemokine receptors and more specifically as modulators of the CCR2 and/or CCR5 receptor. The compounds and compositions of the invention may bind to chemokine receptors, e.g., the CCR2 and/or CCR5 chemokine receptors, and are useful for treating diseases associated with chemokine, e.g., CCR2 and/or CCR5, activity, such as atherosclerosis, restenosis, lupus, organ transplant rejection and rheumatoid arthritis.

## Claims

### Claim at position 1

1-38. (canceled)

### Claim 39

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.

### Claim 40

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.

### Claim 41

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.

### Claim 42

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.

### Claim 43

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.

### Claim 44 (depends on 43)

The method of claim 43 wherein said chemokine receptor is CCR2 or CCR5.

### Claim 45 (depends on 43)

The method of claim 43 wherein said modulating is inhibiting.

### Claim 46

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.

### Claim 47 (depends on 46)

The method of claim 46 wherein said chemokine receptor is CCR2 or CCR5.

### Claim 48 (depends on 46)

The method of claim 46 wherein said disease is an inflammatory disease.

### Claim 49 (depends on 46)

The method of claim 46 wherein said disease is an immune disorder.

### Claim 50 (depends on 46)

The method of claim 46 wherein said disease is rheumatoid arthritis, atherosclerosis, lupus, multiple sclerosis, neuropathic pain, transplant rejection, diabetes, or obesity.

### Claim 51 (depends on 46)

The method of claim 46 wherein said disease is cancer.

### Claim 52 (depends on 51)

The method of claim 51 wherein said cancer is characterized by tumor associated macrophages. ovarian cancer or multiple myeloma.

### Claim 53 (depends on 51)

The method of claim 51 wherein said cancer is breast cancer, ovarian cancer or multiple myeloma.

### Claim 54 (depends on 46)

The method of claim 46 wherein said disease or condition is a viral infection.

### Claim 55 (depends on 54)

The method of claim 54 wherein said viral infection is HIV infection.

### Claim 56

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.

### Claim 57 (depends on 56)

The method of claim 56 further comprising simultaneously or sequentially administering at least one anti-viral agent.

### Claim 58

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.

### Claim 59 (depends on 58)

The method of claim 58, wherein the cancer is characterized by infiltration of macrophages into tumors or diseased tissue.

### Claim 60 (depends on 39)

The method of claim 39, wherein said compound is administered with a pharmaceutically acceptable carrier.