Heterocyclic compounds as CCR1 receptor antagonists

• US 8,927,550 B2
• Filed: 10/21/2010
• Issued: 01/06/2015
• Est. Priority Date: 10/27/2009
• 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: Cook, Brian Nicholas, Kuzmich, Daniel
• Primary Examiner(s): McCormick, Melenie
• Assistant Examiner(s): MATOS NEGRON, TAINA DEL MAR
• Application Number:
  US13/502,377
• Publication Number:
  US 20120270879A1
• Time in Patent Office: 1,538 Days
• Field of Search: None
• US Class Current: 514/248
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 209/42 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems

Abstract

Disclosed are CCR1 receptor antagonists of the formula (I) wherein Ar1, Ar2, R1-R3, X and L are disclosed herein. Also disclosed are compositions, methods of making and using compounds of the formula (I).

Claims

1. A compound of the formula (I)

2. The compound according to claim 1, and wherein

X is N or C-A;

A is selected from hydrogen, methyl, trifluoromethyl, hydroxyl, cyano and C₁-C₅ alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone;

Ar₁ is phenyl, cyclohexyl or tetrahydropyranyl each optionally substituted by one to three R_a;

Ar₂ is phenyl, pyridinyl, pyrimidinyl, thiophenyl, thiazolyl, oxazolyl, pyrazolyl, imidazolyl, cyclohexyl, piperidinyl, morpholinyl or piperazinyl, each optionally substituted by one to three R_b;

R₁ is hydrogen;

R₂, R₃ are each independently hydrogen or C_1-6 alkyl, wherein the C_1-6 alkyl is optionally partially or fully halogenated or substituted with one to three groups independently selected from cyano, C_1-6 alkoxy and hydroxyl;

or

R₂ and R₃ together with the carbon atom they are commonly attached to form a C_3-4 cycloalkyl ring;

R_a is C_1-6 alkyl, hydroxyl, halogen, cyano or nitro;

R_b is hydroxyl, carboxyl, halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6alkylC(O)—

, R₄—

S(O)_m(CH₂)_0-1—

, R₄—

S(O)_m—

NR_e—

or R₄—

NR_e—

S(O)_m(CH₂)_0-1—

, each R_b where possible is optionally halogenated or substituted with 1 to 3C_1-6 alkyl, hydroxyl, C_1-6 acyl, C_1-6 alkoxycarbonyl, C_1-6 alkyl-S(O)_m—

or carboxyl;

each R_e is hydrogen, C_1-6 alkyl, C_3-10 cycloalkyl, C_1-6 alkoxy, C_1-6 alkoxyC_1-6alkyl, mono- or diC_1-6alkylaminoC_1-6alkyl, hydroxyC_1-6 alkyl or C_1-6 acyl;

R₄ is hydrogen, C_1-6 alkyl, C_3-6cycloalkyl, piperidinyl, morpholinyl, tetrahydropyranyl, pyrrolidinyl, mono- or di-C_1-6 alkylamino, mono- or di-_1-6alkylamino(CH₂)_2-3N(R_e)—

, aryl or heteroaryl each optionally substituted with 1 to 3C_1-6 alkyl, C_3-6cycloalkyl, carboxyl;

or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 2, and wherein

X is N or C-A;

A is selected from hydrogen and cyano;

Ar₁ is phenyl is substituted by one to two R_a;

Ar₂ is phenyl, pyridinyl, or thiazolyl, each optionally substituted by one to two R_b;

R₂, R₃ are each independently hydrogen or C_1-3 alkyl;

or

R₂ and R₃ together with the carbon atom they are commonly attached to form a C₃ cycloalkyl ring;

R_a is C_1-6 alkyl, halogen or cyano;

R_b is halogen, C_1-3 alkyl, R₄—

S(O)_m(CH₂)_0-1—

, R₄—

S(O)_m—

NR_e—

, or R₄—

NR_e—

S(O)_m(CH₂)_0-1—

, each R_b where possible is optionally halogenated;

each R_e is hydrogen;

R₄ is C_1-6 alkyl or piperidinyl each optionally substituted with 1 to 3C_1-3 alkyl;

each m is 2;

or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 3, and wherein

R_a is —

F;

R_b is R₄—

S(O)₂(CH₂)_0-1—

, R₄—

S(O)₂—

NR_e—

, or R₄—

NR_e—

S(O)₂(CH₂)_0-1—

, CF₃ or Br;

R₄ is C_1-3 alkyl or piperidinyl each optionally substituted with —

CH₃;

or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 4, and wherein L is selected from

6. The compound according to claim 5, and wherein Ar₂ is

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

7. A compound chosen from