# US 9,750,722 B2 · Diazole amides

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- Number: US 9,750,722 B2
- Document ID: US9750722B2
- Status: Granted
- Kind: B2
- Application number: 14/878,784
- Filed: 2015-10-08
- Published: 2016-07-07
- Granted: 2017-09-05
- Earliest claimed: 2012-12-21
- Assignees: ChemoCentryx, Inc.
- Applicants: ChemoCentryx, Inc.
- Inventors: Xi Chen; Dean R. Dragoli; Pingchen Fan; Juan C. Jaen; Yandong Li; Jay P. Powers; Viengkham Malathong; Sreenivas Punna; Hiroko Tanaka; Penglie Zhang
- Web page: https://patentgrep.com/patent/US9750722B2

## CPC

- A61K 31/4155: non condensed and containing further heterocyclic rings
- A61K 31/4178: not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
- A61K 31/4192: 1,2,3-Triazoles
- A61K 31/4196: 1,2,4-Triazoles
- A61K 31/437: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- 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 9/14: Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
- A61P 11/06: Antiasthmatics
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 17/04: Antipruritics
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/10: for osteoporosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- 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 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- C07D 231/40: Acylated on said nitrogen atom
- C07D 233/88: Nitrogen atoms, e.g. allantoin
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 471/04: Ortho-condensed systems
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## 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.

## Claims

### Claim 1

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.

### Claim 2 (depends on 1)

A method in accordance with claim 1, wherein said CCR1-mediated disease or condition is selected from the group consisting of transplant rejection, dermatitis, inflammatory bowel disease, asthma, Alzheimer's disease, psoriasis, and encephalomyelitis.

### Claim 3 (depends on 1)

A method in accordance with claim 1, wherein said CCR1-mediated disease or condition is selected from the group consisting of rheumatoid arthritis, multiple sclerosis, multiple myeloma and osteoporosis.

### Claim 4 (depends on 1)

A method in accordance with claim 1, wherein said administering is oral, parenteral, rectal, transdermal, sublingual, nasal or topical.

### Claim 5 (depends on 1)

A method in accordance with claim 1, wherein said compound is administered in combination with an anti-inflammatory agent, analgesic agent, an anti-proliferative agent, a metabolic inhibitor, a leukocyte migration inhibitor or an immuno modulator.

### Claim 6 (depends on 1)

A method in accordance with claim 1, wherein said CCR1-mediated disease or condition is rheumatoid arthritis.

### Claim 7 (depends on 1)

A method in accordance with claim 1, wherein said CCR1-mediated disease or condition is selected from the group consisting of multiple myeloma and leukemia.

### Claim 8

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.

### Claim 9 (depends on 8)

A method in accordance with claim 8 wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 8)

A method in accordance with claim 8 wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 11 (depends on 8)

A method in accordance with claim 8, wherein said CCR1-mediated disease or condition is selected from the group consisting of transplant rejection, dermatitis, inflammatory bowel disease, asthma, Alzheimer's disease, psoriasis, encephalomyelitis, rheumatoid arthritis, multiple sclerosis, multiple myeloma and osteoporosis.

### Claim 12 (depends on 8)

A method in accordance with claim 8, wherein said CCR1-mediated disease or condition is rheumatoid arthritis.

### Claim 13 (depends on 11)

A method in accordance with claim 11, wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.

### Claim 14 (depends on 12)

A method in accordance with claim 12, wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.

### Claim 15 (depends on 8)

A method in accordance with claim 8, wherein said administering is oral, parenteral, rectal, transdermal, sublingual, nasal or topical.

### Claim 16 (depends on 8)

A method in accordance with claim 8, wherein said compound is administered in combination with an anti-inflammatory agent, an analgesic agent, an anti-proliferative agent, a metabolic inhibitor, a leukocyte migration inhibitor or an immuno modulator.

### Claim 17

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.

### Claim 18 (depends on 17)

A method in accordance with claim 17 wherein said subject has an inflammatory condition or an immunoregulatory disorder.

### Claim 19 (depends on 17)

A method in accordance with claim 17, wherein said subject has a disease or condition selected from the group consisting of transplant rejection, dermatitis, inflammatory bowel disease, asthma, Alzheimer's disease, psoriasis, rheumatoid arthritis, multiple sclerosis, multiple myeloma and osteoporosis.

### Claim 20 (depends on 17)

A method in accordance with claim 17, wherein said subject has rheumatoid arthritis.

### Claim 21 (depends on 18)

A method in accordance with claim 18, wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.

### Claim 22 (depends on 19)

A method in accordance with claim 19, wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.

### Claim 23 (depends on 20)

A method in accordance with claim 20, wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.