Heteroaryl sulfonamides and CCR2

• US 20060173019A1
• Filed: 01/13/2006
• Published: 08/03/2006
• Est. Priority Date: 01/14/2005
• Status: Abandoned Application

• Current Assignee: ChemoCentryx, Inc. (Amgen Inc.)
• Original Assignee: ChemoCentryx, Inc. (Amgen Inc.)
• Inventors: Zang, Yibin, Wei, Zheng, Punna, Sreenivas, Ungashe, Solomon, Jin, Jeff, Basak, Arindrajit, Hansen, Derek, Charvat, Trevor T., Dairaghi, Daniel, Wright, John J., Moore, Jimmie, Pennell, Andrew M.K.
• Application Number:
  US11/332,786
• Publication Number:
  US 20060173019A1
• Time in Patent Office: Days
• US Class Current: 514/253.10
• 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 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/12 of the kidneys
• 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 25/04 Centrally acting analgesics, e.g. opioids
• 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 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07C 311/21 having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07D 213/48 Aldehydo radicals
• CPC Class Codes: C07D 213/61 Halogen atoms or nitro radicals
• CPC Class Codes: C07D 213/643 2-Phenoxypyridines; Derivatives thereof
• CPC Class Codes: C07D 213/70 Sulfur atoms
• CPC Class Codes: C07D 213/73 Unsubstituted amino or imino radicals
• CPC Class Codes: C07D 213/76 to which a second hetero atom is attached nitro radicals C07D213/61
• CPC Class Codes: C07D 213/79 : Acids; Esters
• CPC Class Codes: C07D 213/81 : Amides; Imides
• CPC Class Codes: C07D 213/89 : with hetero atoms directly attached to the ring nitrogen atom
• CPC Class Codes: C07D 241/22 : Benzenesulfonamido pyrazines
• CPC Class Codes: C07D 263/32 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 413/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems

Abstract

Compounds are provided that act as potent antagonists of the CCR2 receptor. Animal testing demonstrates that these compounds are useful for treating inflammation, a hallmark disease for CCR2. The compounds are generally aryl sulfonamide derivatives and are useful in pharmaceutical compositions, methods for the treatment of CCR2-mediated diseases, and as controls in assays for the identification of CCR2 antagonists.

Claims

1. A compound of the formula (I), or a salt thereof:

where

Ar is selected from the group consisting of substituted or unsubstituted C_6-10 aryl and substituted or unsubstituted 5- to 10-membered heteroaryl;

R¹ is selected from the group consisting of hydrogen, unsubstituted C₁ alkyl, substituted or unsubstituted C_3-8 alkyl, substituted or unsubstituted C_2-6 alkenyl, substituted or unsubstituted C_2-6 alkynyl, and substituted or unsubstituted 3- to 10-membered heterocyclyl;

Y¹ is selected from the group consisting of —

CR^2a—

, —

N—

, and —

N⁺(O)⁻

—

;

Y² is selected from the group consisting of —

CR^2b—

, —

N—

, and —

N⁺(O)⁻

—

;

Y³ is selected from the group consisting of —

CR^2c—

, —

N—

, and —

N⁺(O)⁻

—

;

R^2a, R^2b, and R^2c are each independently selected from the group consisting of hydrogen, halogen, —

CN, —

C(O)R³, —

CO₂R³, —

C(O)NR³R⁴, —

OR³, —

OC(O)R³, —

OC(O)NR³R⁴, —

SR³, —

S(O)R³, —

S(O)₂R³, —

S(O)₂NR³R⁴, —

NO₂, —

NR³R⁴, —

NR³C(O)R⁴, —

NR³C(O)OR⁴, —

NR³S(O)₂R⁴, —

NR³C(O)NR⁴R⁵, substituted or unsubstituted C_1-8 alkyl, substituted or unsubstituted C_2-8 alkenyl, substituted or unsubstituted C_2-8 alkynyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C_6-10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl;

R³, R⁴, and R⁵ are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-8 alkyl, substituted or unsubstituted C_2-8 alkenyl, substituted or unsubstituted C_2-8 alkynyl, substituted or unsubstituted C_6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl;

R³ and R⁴, R⁴ and R⁵ or R³ and R⁵ may, together with the atoms to which they are attached, form a substituted or unsubstituted 5-, 6-, or 7-membered ring;

Y⁴ is selected from the group consisting of —

N— and

—

N⁺(O)⁻

—

;

L is selected from the group consisting of a bond, —

O—

, —

S—

, —

S(O)—

, S(O)₂—

, —

CR⁶R⁷—

, —

NR⁸—

, —

C(O)— and

—

NR⁸C(O)—

;

R⁶ and R⁷ are each independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_1-8 alkyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C_2-6 alkenyl, substituted or unsubstituted C_2-6 alkynyl, —

CN, —

OR⁹, —

NR¹⁰R¹¹, —

S(O)R⁹, and —

S(O)₂R⁹;

R⁶ and R⁷ may, together with the carbon atom to which they are attached, form substituted or unsubstituted C_3-8 cycloalkyl or substituted or unsubstituted 3- to 10-membered heterocyclic ring;

R⁹ is selected from the group consisting of hydrogen, substituted or unsubstituted C_1-8 alkyl, substituted or unsubstituted C_2-8 alkenyl, substituted or unsubstituted C_2-8 alkynyl, substituted or unsubstituted C_6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl;

R¹⁰ and R¹¹ are each independently selected from the group consisting of substituted or unsubstituted C_1-8 alkyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C_6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted C_2-8 alkenyl, and substituted or unsubstituted C_2-8 alkynyl;

R¹⁰ and R¹¹ of —

NR¹⁰R¹¹ may, together with the nitrogen, form a substituted or unsubstituted C_3-8 cycloalkyl or substituted or unsubstituted 3- to 10-membered heterocyclyl;

R⁸ is selected from the group consisting of hydrogen, C(O)R¹², S(O)₂R¹², CO₂R¹², substituted or unsubstituted C_1-8 alkyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C_2-6 alkenyl, and substituted or unsubstituted C_2-6 alkynyl;

R¹² is selected from the group consisting of substituted or unsubstituted C_1-8 alkyl, substituted or unsubstituted C_2-6 alkenyl, substituted or unsubstituted C_2-6 alkynyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C_6-10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl;

Z¹ is selected from the group consisting of substituted or unsubstituted C_6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted 3- to 10-membered heterocyclyl, and —

NR³R⁴;

R¹³ and R¹⁴ are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-8 alkyl, substituted or unsubstituted C_2-8 alkenyl, substituted or unsubstituted C_2-8 alkynyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C_6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted (C_1-4 alkyl)-(C_6-10 aryl), and substituted or unsubstituted (C_1-4 alkyl)-(5- to 10-membered heteroaryl);

R¹³ and R¹⁴ may, together with the nitrogen, form a substituted or unsubstituted 4-, 5-, 6-, or 7-membered heterocyclyl with the proviso that compounds of formula CC are excluded;

where

X¹⁴ is selected from the group consisting of —

Cl, —

NO₂, —

OCH₃, —

CH₃, —

NHC(O)CH₃, and —

CH₂CH₂—

(phenyl);

R⁶⁵ is selected from the group consisting of hydrogen, substituted or unsubstituted C_1-4 alkyl, and substituted or unsubstituted —

SO₂(phenyl); and

R⁶⁰ is selected from the group consisting of —

NR⁶¹CH₂CH₂OR⁶², —

NR⁶¹CH₂CH₂NR⁶³R⁶⁴, —

NR⁶¹CH₂CH₂SR⁶²,

where R⁶¹ is selected from the group consisting of hydrogen and substituted or unsubstituted phenyl;

R⁶² is selected from the group consisting of substituted or unsubstituted phenyl, and substituted or unsubstituted C_1-4 alkyl; and

R⁶³ and R⁶⁴ are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-8 alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted —

SO₂(phenyl), —

C(O)CH₃, —

C(O)C(O)OH, and —

C(O)₂C(CH₃)₃.

2. The compound of claim 1, which is represented by formula (II) or a salt thereof:

Y⁵, Y⁶ and Y⁷ are each independently selected from the group consisting of hydrogen, halogen, —

CN, —

C(O)R¹⁵, —

CO₂R¹⁵, —

C(O)NR¹⁵R¹⁶, —

OR¹⁵, —

OC(O)R¹⁵—

OC(O)NR¹⁵R¹⁶, —

SR¹⁵, —

S(O)R¹⁵, —

S(O)₂R¹⁵, —

S(O)₂NR¹⁵R¹⁶, —

NO₂, —

NR¹⁵R¹⁶, —

NR¹⁵C(O)R¹⁶, —

NR¹⁵C(O)OR¹⁶, —

NR¹⁵S(O)₂R¹⁶, —

NR¹⁵C(O)NR¹⁶R¹⁷, substituted or unsubstituted C_1-8 alkyl, substituted or unsubstituted C_2-8 alkenyl, substituted or unsubstituted C_2-8 alkynyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C_6-10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl;

R¹⁵, R¹⁶ and R¹⁷ are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-8 alkyl, substituted or unsubstituted C_2-8 alkenyl, substituted or unsubstituted C_2-8 alkynyl, substituted or unsubstituted C_6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl;

R¹⁵ and R¹⁶, R¹⁶ and R¹⁷ or R¹⁵ and R¹⁷ may, together with the atoms to which they are attached, form a substituted or unsubstituted 5-, 6-, or 7-membered ring.

3. The compound of claim 1, which is represented by formula (CLI) or a salt thereof:

where

X^b is selected from the group consisting of —

OR^24a, and substituted or unsubstituted C_1-8 alkyl;

R^24a is selected from the group consisting of hydrogen, substituted or unsubstituted C_1-8 alkyl, substituted or unsubstituted C_2-8 alkenyl, substituted or unsubstituted C_2-8 alkynyl, substituted or unsubstituted C_6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl; and

Y^b is selected from the group consisting of hydrogen, halogen, —

CN, —

C(O)R²⁷, —

CO₂R^27a, —

C(O)NR^27aR^28a, —

OR^27a, —

OC(O)R^27a, —

OC(O)NR^27aR^28a, —

SR^27a, —

S(O)R^27a, —

S(O)₂R^27a, —

S(O)₂NR^27aR^28a, —

NO₂, —

NR^27aR^28a, —

NR^27aC(O)R^28a, —

NR^27aC(O)₂R^28a, —

NR^27aS(O)₂R^28a, —

NR^27aC(O)NR^28aR^29a, substituted or unsubstituted C_1-8 alkyl, substituted or unsubstituted C_2-8 alkenyl, substituted or unsubstituted C_2-8 alkynyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C_6-10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl;

R^27a, R^28a and R^29a are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-8 alkyl, substituted or unsubstituted C_2-8 alkenyl, substituted or unsubstituted C_2-8 alkynyl, substituted or unsubstituted C_6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl; and

R^27a and R^28a, R^28a and R^29a or R^27a and R^29a may, together with the atoms to which they are attached, form a substituted or unsubstituted 5-, 6-, or 7-membered ring.

Z^b is selected from the group consisting of substituted or unsubstituted C_1-8 alkyl.

4. The compound of claim 1, which is represented by formula (CLII) or a salt thereof:

where

X^b is selected from the group consisting of —

OR^24a, and substituted or unsubstituted C_1-8 alkyl;

R^24a is selected from the group consisting of hydrogen, substituted or unsubstituted C_1-8 alkyl, substituted or unsubstituted C_2-8 alkenyl, substituted or unsubstituted C_2-8 alkynyl, substituted or unsubstituted C_6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl; and

Z^b is OR^30a;

R^30a is selected from the group consisting of hydrogen and substituted or unsubstituted C_1-8 alkyl.

5. The compound of claim 1, which is represented by formula (CLIII) or a salt thereof:

where

X^b is selected from the group consisting of —

OR²⁴, and substituted or unsubstituted C_1-8 alkyl;

R^24a is selected from the group consisting of hydrogen, substituted or unsubstituted C_1-8 alkyl, substituted or unsubstituted C_2-8 alkenyl, substituted or unsubstituted C_2-8 alkynyl, substituted or unsubstituted C_6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl; and

Z^b is halogen.

6. A composition comprising a pharmaceutically acceptable carrier and a compound of claim 1.

18. A method of modulating CCR2 function in a cell, comprising contacting the cell with a CCR2 modulating amount of the compound of claim 1.

19. A method of modulating CCR9 function in a cell, comprising contacting the cell with a CCR9 modulating amount of the compound of claim 1.

20. A method for treating a CCR9-mediated condition or disease comprising administering to a subject an effective amount of the compound of claim 1.

7. A method for treating a CCR2-mediated condition or disease comprising administering to a subject an effective amount of a compound of formula (I), or a salt thereof:

where

Ar is selected from the group consisting of substituted or unsubstituted C_6-10 aryl and substituted or unsubstituted 5- to 10-membered heteroaryl;

R¹ is selected from the group consisting of hydrogen, substituted or unsubstituted C_1-8 alkyl, substituted or unsubstituted C_2-6 alkenyl, substituted or unsubstituted C_2-6 alkynyl, and substituted or unsubstituted 3- to 10-membered heterocyclyl;

Y¹ is selected from the group consisting of —

CR^2a—

, —

N—

, and —

N⁺(O)⁻

—

;

Y² is selected from the group consisting of —

CR^2b—

, —

N—

, and —

N⁺(O)⁻

—

;

Y³ is selected from the group consisting of —

CR^2c—

, —

N—

, and —

N⁺(O)⁻

—

;

R^2a, R^2b, and R^2c are each independently selected from the group consisting of hydrogen, halogen, —

CN, —

C(O)R³, —

CO₂R³, —

C(O)NR³R⁴, —

OR³, —

OC(O)R³, —

OC(O)NR³R⁴—

SR³, —

S(O)R³, —

S(O)₂R³, —

S(O)₂NR³R⁴, —

NO₂, —

NR³R⁴, —

NR³C(O)R⁴, —

NR³C(O)OR⁴, —

NR³S(O)₂R⁴, —

NR³C(O)NR⁴R⁵, substituted or unsubstituted C_1-8 alkyl, substituted or unsubstituted C_2-8 alkenyl, substituted or unsubstituted C_2-8 alkynyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C_6-10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl;

R³, R⁴, and R⁵ are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-8 alkyl, substituted or unsubstituted C_2-8 alkenyl, substituted or unsubstituted C_2-8 alkynyl, substituted or unsubstituted C_6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl;

R³ and R⁴, R⁴ and R⁵ or R³ and R⁵ may, together with the atoms to which they are attached, form a substituted or unsubstituted 5-, 6-, or 7-membered ring;

Y⁴ is selected from the group consisting of —

N— and

—

N⁺(O)⁻

—

;

L is selected from the group consisting of a bond, —

O—

, —

S—

, —

S(O)—

, S(O)₂—

, —

CR⁶R⁷—

NR⁸—

, —

C(O)— and

—

NR⁸C(O)—

;

R⁶ and R⁷ are each independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_1-8 alkyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C_2-6 alkenyl, substituted or unsubstituted C_2-6 alkynyl, —

CN, —

OR⁹, —

NR¹⁰R¹¹, —

S(O)R⁹, and —

S(O)₂R⁹;

R⁶ and R⁷ may, together with the carbon atom to which they are attached, form substituted or unsubstituted C_3-8 cycloalkyl or substituted or unsubstituted 3- to 10-membered heterocyclic ring;

R⁹ is selected from the group consisting of hydrogen, substituted or unsubstituted C_1-8 alkyl, substituted or unsubstituted C_2-8 alkenyl, substituted or unsubstituted C_2-8 alkynyl, substituted or unsubstituted C_6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl;

R¹⁰ and R¹¹ are each independently selected from the group consisting of substituted or unsubstituted C_1-8 alkyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C_6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted C_2-8 alkenyl, and substituted or unsubstituted C_2-8 alkynyl;

R¹⁰ and R¹¹ of —

NR¹⁰OR¹¹ may, together with the nitrogen, form a substituted or unsubstituted C_3-8 cycloalkyl or substituted or unsubstituted 3- to 10-membered heterocyclyl;

R⁸ is selected from the group consisting of hydrogen, C(O)R¹², S(O)₂R², CO₂R¹², substituted or unsubstituted C_1-8 alkyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C_2-6 alkenyl, and substituted or unsubstituted C_2-6 alkynyl;

R¹² is selected from the group consisting of substituted or unsubstituted C_1-8 alkyl, substituted or unsubstituted C_2-6 alkenyl, substituted or unsubstituted C_2-6 alkynyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C_6-10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl;

Z¹ is selected from the group consisting of substituted or unsubstituted C_6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted 3- to 10-membered heterocyclyl, and —

NR¹³R¹⁴;

R¹³ and R¹⁴ are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-8 alkyl, substituted or unsubstituted C_2-8 alkenyl, substituted or unsubstituted C_2-8 alkynyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C_6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted (C_1-4 alkyl)-(C_6-10 aryl), and substituted or unsubstituted (C_1-4 alkyl)-(5- to 10-membered heteroaryl);

R¹³ and R¹⁴ may, together with the nitrogen, form a substituted or unsubstituted 4-, 5-, 6-, or 7-membered heterocyclyl.

8. The method of claim 7, where the CCR2-mediated disease or condition is atherosclerosis.

9. The method of claim 7, where the CCR2-mediated disease or condition is restenosis.

10. The method of claim 7, where the CCR2-mediated condition or disease is multiple sclerosis.

11. The method of claim 7, where the CCR2-mediated condition or disease is selected from the group consisting of inflammatory bowel disease, renal fibrosis, rheumatoid arthritis, obesity and diabetes.

12. The method of claim 7, where the CCR2-mediated condition or disease is selected from the group consisting of chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis and idiopathic pneumonia syndrome.

13. The method of claim 7, where the CCR2-mediated condition or disease is selected from the group consisting of pulmonary fibrosis, transplantation rejection, graft-versus-host disease and cancer.

14. The method of claim 7, where the CCR2-mediated condition or disease is neuropathic pain.

15. The method of claim 7, where the administering is oral, parenteral, rectal, transdermal, sublingual, nasal or topical.

16. The method of claim 7, where the compound is administered in combination with an anti-inflammatory or analgesic agent.

17. The method of claim 7, further comprising administering an anti-inflammatory or analgesic agent.