Azaindazole amide compounds as CCR1 receptor antagonists

• US 8,871,786 B2
• Filed: 04/26/2011
• Issued: 10/28/2014
• Est. Priority Date: 04/30/2010
• Status: Active Grant

• Current Assignee: Boehringer Ingelheim International GmbH (C.H. Boehringer Sohn AG & Co. KG)
• Original Assignee: Boehringer Ingelheim International GmbH (C.H. Boehringer Sohn AG & Co. KG)
• Inventors: Huber, John D.
• Primary Examiner(s): Kifle, Bruck
• Application Number:
  US13/643,325
• Publication Number:
  US 20130203803A1
• Time in Patent Office: 1,281 Days
• Field of Search: 546/120, 514/303
• US Class Current: 514/303
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: 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
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 29/02 without antiinflammatory effect
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

Disclosed are CCR1 inhibitor compounds of the formula (I): which are useful in the treatment of autoimmune and other diseases. Also disclosed a pharmaceutical compositions containing the same, and methods of making and using same.

Claims

1. A compound of the formula (I):

2. The compound according to claim 1 and wherein

Ar is phenyl, naphthyl, or heteroaryl chosen from aziridinyl, thienyl, furanyl, thiazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazolyl, thiadiazolyl, tetrazolyl, pyrrolyl, imidazolyl, pyrimidinyl, pyridinyl, pyrazinyl, pyridazinyl, pyranyl, benzofuranyl, indolyl, quinoxalinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzothienyl, quinolinyl, quinazolinyl, naphthyridinyl, indazolyl, triazolyl and purinyl each bearing from 0-3 substituents chosen from halogen, C_1-4 alkyl, C_3-7 cycloalkyl, C_1-4 haloalkyl, nitro, —

SR, —

OR, cyano, —

SO₂R, —

SO₂NRR¹, —

CO₂—

R, —

NRR¹, —

NR²C(O)—

R, —

C(O)NRR¹, phenyl and heteroaryl as defined herein above in this paragraph, each ring optionally substituted with 1 or 2 substituents chosen from halogen and C_1-4 alkyl;

R, R¹, and, R² are each independently hydrogen or C_1-4 alkyl;

X is fluorine;

or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 2 and wherein

Ar is phenyl, pyrazolyl, isoxazolyl, pyridinyl, indolyl, each bearing from 0-3 substituents chosen from halogen, C_1-4 alkyl, C_3-7 cycloalkyl, C_1-4 haloalkyl, nitro, —

SR, —

OR, cyano, —

SO₂R, —

SO₂NRR¹, —

CO₂—

R, —

NRR¹, —

NR²C(O)—

R, —

C(O)NRR¹, phenyl and pyrazolyl, oxadiazolyl, each ring optionally substituted with 1 or 2 substituents chosen from halogen and C_1-4 alkyl;

X is fluorine and is attached in the -para position on the phenyl ring

or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 3 and wherein

Ar is phenyl, pyrazolyl, isoxazolyl, pyridinyl, indolyl, each bearing from 0-3 substituents chosen from halogen, C_1-2 alkyl, —

CF₃, —

SO₂CH₃, —

SO₂NRR¹, —

CO₂—

R, —

NR²C(O)—

R, —

C(O)NRR¹, phenyl and pyrazolyl, oxadiazolyl, each ring optionally substituted with 1 or 2 substituents chosen from halogen and C_1-2 alkyl;

R, R¹, and, R² are each independently hydrogen or C_1-2 alkyl;

or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 4 and wherein

Ar is chosen from

7. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound according to claim 1 and one or more pharmaceutically carriers and/or adjuvants.

8. A method of treating rheumatoid arthritis or multiple sclerosis comprising administering to a patient a pharmaceutically effective amount of a compound according to claim 1.

9. The method according to claim 8 wherein the treatment is for rheumatoid arthritis.

10. The method according to claim 8 wherein the treatment is for multiple sclerosis.

6. A compound chosen from