Indazole and pyrazolopyridine compounds as CCR1 receptor antagonists

• US 9,056,858 B2
• Filed: 10/19/2010
• Issued: 06/16/2015
• Est. Priority Date: 10/21/2009
• 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, Mao, Can, Razavi, Hossein
• Primary Examiner(s): Kim, Jennifer M
• Application Number:
  US13/499,939
• Publication Number:
  US 20120270870A1
• Time in Patent Office: 1,701 Days
• Field of Search: 546/120, 546/275.7, 514/234.2, 514/303, 514/338, 544/127
• US Class Current: 1/1
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• 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 31/04 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 37/06 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 213/62 : Oxygen or sulfur atoms
• 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, X and G 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 nitrogen;

Ar₁ is carbocycle optionally substituted by one to three R_a;

Ar₂ is carbocycle or heteroaryl, each optionally substituted by one to three R_b;

R₁ is hydrogen;

R_a is C_1-3alkyl, C_1-3 alkoxy, di-C_1-6 alkylamino, methylsulfonyl, halogen, or cyano;

R_b is hydroxyl, carboxyl, halogen, —

(CH₂)_n—

CN, —

(CH₂)_n—

CO₂C_1-6alkyl, nitro, —

SO₃H, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10cycloalkyl, C_1-6alkoxy, C_1-6alkylC(O)—

, —

(CH₂)_n—

NR_cR_d, R₃—

S(O)_m(CH₂)_0-1—

, R₃—

S(O)_m—

NR_e—

, R₃—

NR_e—

S(O)_m(CH₂)_0-1—

, —

NR_f—

C(O)—

R_e, —

(CH₂)_y—

C(O)—

(CH₂)_n—

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

, aryl or carboxyl;

R₃ is hydrogen, C_1-6 alkyl, C_3-6cycloalkyl, heterocyclyl(CH₂)_0-1, mono- or di-C_1-6 alkylamino, mono-or di-_1-6alkylamino(CH₂)_2-3N(C_1-6alkyl)-, aryl or heteroaryl each optionally substituted with 1 to 2 C_1-6 alkyl, C_3-6cycloalkyl, C_1-6alkoxy, halogen, hydroxyl, oxo, carboxyl, —

C(O)NR_eR_f, amino, mono- or di-C_1-6 alkylamino, C_1-6 alkoxycarbonyl or C_1-6 acylamino

or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 2, and wherein

Ar₁ is phenyl is substituted by one to two R_a;

Ar₂ is phenyl, thiadiazolyl, oxadiazolyl, pyrimidinyl, furanyl, thiazolyl or pyridyl, each optionally substituted by one to two R_b;

R_a is halogen;

R_b is hydroxyl, carboxyl, halogen, —

CF₃, —

CN, —

SO₃H, C_1-3 alkyl, C_3-6 cycloalkyl C_1-3 alkoxy, —

(CH₂)_n—

CO₂C_1-3alkyl, —

(CH₂)_n—

NR_cR_d, R₃—

S(O)_m(CH₂)_0-1—

, R₃—

S(O)₂—

NR_e—

, R₃—

NR_e—

S(O)₂(CH₂)_0-1—

, —

NR_f—

C(o)—

R_e, —

(CH₂)_y—

C(o)—

NR_cR_d, or morpholinyl;

each R_e, R_f are independently hydrogen, C_1-3 alkyl, C_1-3 acyl, cyano-C_1-3 alkyl, C_1-3 alkoxycarbonylC_0-3alkyl, C_1-3 alkoxycarbonylC_3-6cycloalkyl, or —

(CH₂)_n—

C(O)—

NR_eR_f;

each R_e, R_f are independently hydrogen or C_1-3 alkyl;

R₃ is hydrogen or C_1-6alkyl, each optionally substituted with one to two C_1-6alkoxy, or oxo

or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 3, and wherein

Cyclic G is cyclopropyl;

R_a is —

F or —

Cl;

R_b is —

CH₃, carboxyl, —

F, —

Cl, —

Br, —

I, —

CF₃, cyclopropyl, —

OCH₃, —

CO₂Me, —

NR_cR_d, —

CH₂—

NR_cR_d, R₃—

S(O)_m—

, R₃—

S(O)₂—

NR_e—

, R₃—

NR_e—

S(O)₂—

, —

NR_f—

C(O)—

R_e, —

C(O)NR_cR_d or morpholinyl;

each R_c, R_d are independently hydrogen, —

CH₃, —

C(O)CH₃, —

CH₂CN, C_1-4 alkoxycarbonyl, methoxycarbonyl-C_1-2alkyl-, methoxycarbonyl-C₃cycloalkyl-or —

(CH₂)—

C(O)—

NR_eR_f;

each R_e, R_f are independently hydrogen or —

CH₃;

R₃ is hydrogen or C_1-4alkyl each optionally substituted with one to two —

OCH₃ or oxo

or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 4, and wherein

X is C—

R₂;

Ar₁ is carbocycle optionally substituted by one to three R_a;

Ar₂ is carbocycle or heteroaryl, each optionally substituted by one to three R_b;

R₁ is hydrogen;

R₂ is hydrogen or R_a;

R_a is C_1-3alkyl, C_1-3 alkoxy, di-C_1-6 alkylamino, methylsulfonyl, halogen, or cyano;

R_b is hydroxyl, carboxyl, halogen, —

(CH₂)_n—

CN, —

(CH₂)_n—

CO₂C_1-6alkyl, nitro, —

SO₃H, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10cyclo alkyl, C_1-6alkoxy, C_1-6alkylC(O)—

, —

(CH₂)_n—

NR_cR_d, R₃—

S(O)_m(CH₂)_0-1—

, R₃—

S(O)_mNR_e—

, R₃—

NR_e—

S(O)_m(CH₂)_0-1—

, —

NR_f—

C(O)—

R_e, —

(CH₂)_y—

C(O)—

(CH₂)_n—

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

, aryl or carboxyl;

each R_c, R_d are independently hydrogen, C_1-6 alkyl, C_1-6 acyl, C_3-10 cycloalkyl, C_1-6 alkoxy, hydroxyC_1-6 alkyl, cyanoC_1-6 alkyl, C_1-6 alkylC_1-6 alkoxy, C_1-6 alkylsulfonyl, C_1-6alkoxycarbonylC_0-3alkyl, C_1-6 alkoxycarbonylC_3-10cycloalkyl, —

(CH₂)_n—

C(O)—

NR_eR_f or —

(CH₂)_n—

NR_eR_f;

each R_e, R_f are independently 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;

R₃ is hydrogen, C_1-6 alkyl, C_3-6cycloalkyl, heterocyclyl(CH₂)_0-1, mono- or di-C_1-6 alkylamino, mono- or di-_1-6alkylamino(CH₂)_2-3N(C_1-6alkyl)-, aryl or heteroaryl each optionally substituted with 1 to 2 C_1-6 alkyl, C_3-6cycloalkyl, C_1-6alkoxy, halogen, hydroxyl, oxo, carboxyl, —

C(O)NR_eR_f, amino, mono- or di-C_1-6 alkylamino, C_1-6 alkoxycarbonyl or C_1-6 acylamino

or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 5, and wherein

Ar₁ is phenyl is substituted by one to two R_a;

Ar₂ is phenyl, thiadiazolyl, oxadiazolyl, pyrimidinyl, furanyl, thiazolyl or pyridyl, each optionally substituted by one to two R_b;

R_a is C_1-3alkyl, methylsulfonyl, halogen, or cyano;

R_b is hydroxyl, carboxyl, halogen, —

CF₃, —

CN, —

SO₃H, C_1-3 alkyl, C_3-6 cycloalkyl C_1-3 alkoxy, —

(CH₂)_n—

CO₂C_1-3alkyl, (CH₂)_n—

NR_cR_d, R₃—

S(O)_m(CH₂)_0-1—

, R₃—

S(O)₂—

NR_e—

, R₃—

NR_e—

S(O)₂(CH₂)_0-1—

, —

NR_f—

C(O)—

R_e, —

(CH₂)_y—

C(O)—

NR_cR_d, or morpholinyl;

each R_e, R_d are independently hydrogen, C_1-3 alkyl, C_1-3 acyl, cyano-C_1-3 alkyl, C_1-3 alkoxycarbonylC_0-3alkyl, C_1-3 alkoxycarbonylC_3-6cycloalkyl, or —

(CH₂)_n—

C(O)—

NR_eR_f;

each R_e, R_f are independently hydrogen or C_1-3 alkyl;

R₃ is hydrogen or C_1-6alkyl, each optionally substituted with one to two C_1-6alkoxy, or oxo

or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 6, and wherein

R_a is —

F or —

Cl, methyl, methylsulfonyl or cyano;

R_b is —

CH₃, carboxyl, —

F, —

Cl, —

Br, —

I, —

CF₃, cyclopropyl, —

OCH₃, —

CO₂Me, —

NR_cR_d, —

(CH₂)—

NR_cR_d, R₃—

S(O)_m—

, R₃—

S(O)₂—

NR_e—

, R₃—

NR_e—

S(O)₂—

, —

NR_f—

C(O)—

R_e, —

C(O)NR_cR_d or morpholinyl;

each R_c, R_d are independently hydrogen, —

CH₃, —

C(O)CH₃, —

CH₂CN, C_1-4 alkoxycarbonyl, methoxycarbonyl-C_1-2alkyl-, methoxycarbonyl-C₃cycloalkyl- or —

(CH₂)—

C(O)—

NR_eR_f;

each R_e, R_f are independently hydrogen or —

CH₃;

R₃ is hydrogen or C_1-4alkyl each optionally substituted with one to two —

OCH₃ or oxo

or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 7, and wherein

R_c, is hydrogen or C_1-6 alkyl, and R_d is C_1-6 acyl, cyano-C_1-6alkyl-, C_1-6alkoxycarbonyl-C_0-3alkyl-, C_1-6 alkoxycarbonylC_3-10cycloalkyl, or —

(CH₂)_n—

C(O)—

NR_eR_f;

each R_e, R_f are independently hydrogen, C_1-6 alkyl

or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 8, and wherein

Ar₂ is phenyl, pyrimidinyl, furanyl, thiazolyl or pyridyl, each optionally substituted by one or two R_b;

R_b is —

SO₂Me, —

I, —

Br, —

Cl, —

CF₃, —

OMe, —

NMe, —

CONHMe, —

SO₂NH₂

or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 9, and wherein Ar₂ is

11. The compound according to claim 10, and wherein

R_g is

i) C_1-2 alkyl, —

CF₃, C₂ alkenyl, phenyl, C_1-4 alkoxy, carbocyclylCH₂O—

, carbocyclylCH₂—

—

CH₂OH, hydroxyl, —

CO₂C_1-4 alkyl or oxo;

or

ii) is methyl, vinyl, —

CF₃, phenyl, —

CH₂OH, or hydroxyl

or a pharmaceutically acceptable salt thereof.

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

14. A method of treating chronic inflammation, allergies, contact dermatitis, psoriasis, rheumatoid arthritis, multiple sclerosis, type 1 diabetes, inflammatory bowel disease, Guillain-Barre syndrome, Crohn'"'"'s disease, ulcerative colitis, graft versus host disease, Alzheimer'"'"'s disease, asthma, chronic kidney disease, sepsis, autoimmune myocarditis and systemic lupus erythematosus, comprising administering to a patient in need thereof a pharmaceutically effective amount of a compound according to claim 1.

15. The method according to claim 14 wherein the treatment is for rheumatoid arthritis and multiple sclerosis.

16. The method according to claim 14 wherein the treatment is for rheumatoid arthritis.

17. The method according to claim 14 wherein the treatment is for multiple sclerosis.

12. A compound chosen from