Piperidinyl-alpha-aminoamide modulators of chemokine receptor activity

• US 20050250814A1
• Filed: 10/24/2003
• Published: 11/10/2005
• Est. Priority Date: 10/30/2002
• Status: Abandoned Application

• Current Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Original Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Inventors: Zhou, Cangyou, Yang, Lihu
• Application Number:
  US10/528,293
• Publication Number:
  US 20050250814A1
• Time in Patent Office: Days
• US Class Current: 514/323
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• 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 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 205/04 having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 207/04 having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 209/44 Iso-indoles; Hydrogenated iso-indoles
• CPC Class Codes: C07D 211/08 with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
• CPC Class Codes: C07D 215/48 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 223/04 with only hydrogen atoms, halogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 295/13 to an acyclic saturated chain
• CPC Class Codes: C07D 307/52 Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 333/10 Thiophene
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links

Abstract

The present invention is directed to compounds of the formula I: (wherein R₁, R₂, R₃, R₄, R₅, R₆, W, X, Z, m and n are defined herein) which are useful as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of the chemokine receptor CCR-2.

Claims

1. A compound of the formula I:

2. The compound of claim 1 of the formula Ia:

3. The compound of claim 1 of the formula Ib:

4. The compound of claim 3 of the formula Id:

5. The compound of claim 3 of the formula Ie:

6. The compound of claim 3 of the formula If:

7. The compound of claim 1 of the formula II:

8. The compound of claim 1 of the formula IIa:

9. The compound of claim 1 of the formula IIb:

10. The compound of claim 1 of the formula IIc:

11. The compound of claim 1 of the formula:

12. The compound of claim 1 of the formula:

13. The compound of claim 1 wherein W is hydrogen or —

CH₂—

.

14. The compound of claim 1 wherein X is —

CONH—

, phenyl or heterocycle.

15. The compound of claim 1 wherein Z is —

C—

or —

N—

.

16. The compound of claim 1 wherein n is 0 and 1.

17. The compound of claim 1 wherein m is 1.

18. The compound of claim 1 wherein heterocycle is selected from:

furanyl, imidazolyl, oxadiazolyl, oxazolyl, pyrazolyl, pyrazinyl, pyridyl, pyridazinyl, pyrimidyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, and triazolyl, and N-oxides thereof.

19. The compound of claim 1 wherein —

C_1-6alkyl, —

C_0-6alkyl-O—

C_1-6alkyl-, —

C_0-6alkyl-S—

C_1-6alkyl-, and —

(C_0-6allyl)-(C_3-7cycloalkyl)-(C_0-6alkyl),

where the alkyl and the cycloalkyl are unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from;

(a) halo,

(b) hydroxy,

(c) —

O—

C_1-3alkyl,

(d) trifluoromethyl,

(f) C_1-3alkyl,

(g) —

O—

C_1-3alkyl,

(h) —

CO₂R⁹, wherein R⁹ is independently selected from;

hydrogen, C_1-6 alkyl, C_5-6 cycloalkyl, benzyl or phenyl, which is unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from;

halo, C_1-3alkyl, C_1-3alkoxy and trifluoromethyl,

(i) —

CN,

(j) —

NR⁹R¹⁰, and

(k) —

CONR⁹R¹⁰.

20. The compound of claim 1 wherein R¹ is selected from:

(1) —

C_1-6alkyl, which is unsubstituted or substituted with 1-6 substituents where the substituents are independently selected from;

(a) halo,

(b) hydroxy,

(c) —

O—

C_1-3alkyl, and

(d) trifluoromethyl,

(2) —

C_0-6alkyl-O—

C_1-6alkyl-, which is unsubstituted or substituted with 1-6 substituents where the substituents are independently selected from;

(a) halo, and

(b) trifluoromethyl,

(3) —

C_0-6alkyl-S—

C_1-6alkyl-, which is unsubstituted or substituted with 1-6 substituents where the substituents are independently selected from;

(a) halo, and

(b) trifluoromethyl,

(4) —

(C3 5cycloalkyl)-(C_0-6alkyl), which is unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from;

(a) halo,

(b) hydroxy,

(c) —

O—

C_1-3alkyl, and

(d) trifluoromethyl.

21. The compound of claim 1 wherein R¹ is selected from:

(1) —

CH₃,

(2) —

CH₂CH₃,

(3) —

CH(CH₃)₂,

(4) —

CH₂CH₂CH₃,

(5) —

CH₂CH(CH₃)₂,

(6) -cyclopropyl,

(7) -cyclobutyl,

(8) -cyclopentyl,

(9) —

CH₂-cyclopropyl,

(10) —

CH₂-cyclobutyl,

(11) —

CH₂-cyclopentyl,

(12) —

CH₂OH,

(13) —

C(CH₃)2(OH),

(14) —

C(CH₂OH)(CH₃)₂,

(15) —

(OH)cyclobutyl,

(16) —

(OH)cyclopentyl,

(17) —

C(CH₃)₂(NHCOCH₃),

(18) —

C(CO₂H)(CH₃)₂,

(19) —

O—

CH₃,

(20) —

O—

cyclopentyl,

(21) —

O—

CH(CH₃)₂,

(22) —

S—

CH₃,

(23) —

S—

CF₃,

(24) —

SO₂—

CH₃,

(25) —

S—

CH(CH₃)₂,

(26) —

SO₂—

CH(CH₃)₂, and

(27) —

NH—

SO₂—

CH₃.

22. The compound of claim 1 wherein R² is selected from —

(C_0-4alkyl)-phenyl and —

(C_0-4alkyl)-heterocycle,

where heterocycle is selected from;

furanyl, imidazolyl, oxadiazolyl, oxazolyl, pyrazolyl, pyrazinyl, pyridyl, pyridazinyl, pyrimidyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, and triazolyl and N-oxides thereof,

where the alkyl is unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from;

(a) halo,

(b) hydroxy,

(c) —

O—

C_1-3alkyl and

(d) trifluoromethyl,

and where the phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from;

(a) halo,

(b) trifluoromethyl,

(c) trifluoromethoxy,

(d) hydroxy,

(e) C_1-3alkyl,

(f) —

O—

C_1-3alkyl

(g) —

CO₂R⁹,

(h) —

S—

C_1-3alkyl

(i) —

SO₂—

C_1-3alkyl,

(j) —

SCF₃,

(k) —

CO₂R⁹,

(l) —

NR⁹R¹⁰,

(m) —

NR⁹—

SO₂R¹⁰,

(n) —

SO₂—

NR⁹R¹⁰, and

(o) —

CONR⁹R¹⁰.

23. The compound of claim 1 wherein R² is selected from —

(C_0-4alkyl)-phenyl and —

(C_0-4alkyl)-heterocycle,

where heterocycle is selected from;

pyridyl, pyridazinyl, and N-oxides thereof,

where the alkyl is unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from;

(a) halo,

(b) hydroxy,

(c) —

O—

C_1-3alkyl, and

(d) trifluoromethyl,

and where the phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from;

(a) halo,

(b) trifluoromethyl,

(c) trifluoromethoxy,

(d) hydroxy,

(e) C_1-3alkyl,

(f) —

O—

C_1-3alkyl,

(g) —

CO₂—

C_1-3alkyl,

(h) —

CO₂H,

(i) —

SC_1-3alkyl,

(j) —

SO₂—

C_1-3alkyl,

(k) —

SCF₃,

(l) —

NH₂,

(m) —

NH-SO₂-C_1-3alkyl, and

(n) —

SO₂—

NH₂.

24. The compound of claim 1 wherein R² is selected from —

CH₂-phenyl and —

CH₂-heterocycle,

where heterocycle is selected from;

pyridyl, pyridazinyl, and N-oxides thereof,

and where the phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from;

(a) halo,

(b) trifluoromethyl,

(c) trifluoromethoxy,

(d) hydroxy,

(e) C_1-3alkyl

(f) —

O—

C_1-3alkyl,

(g) —

CO₂-C_1-3alkyl,

(h) —

CO₂H,

(i) —

S—

C_1-3alkyl,

(j) —

SO₂—

C_1-3alkyl,

(k) —

SCF₃,

(l) —

NH₂,

(m) —

NH—

SO₂—

C_1-3alkyl and

(n) —

SO₂—

NH₂.

25. The compound of claim 1 wherein R² is selected from:

(1) —

CH₂-(phenyl),

(2) —

CH₂-(4-bromophenyl),

(3) —

CH₂-(3-chlorophenyl),

(4) —

CH₂-(3,5-difluorophenyl),

(5) —

CH₂-((2-trifluoromethyl)phenyl),

(6) —

CH₂-((3-trifluoromethyl)phenyl),

(7) —

CH₂-((4trifluoromethyl)phenyl),

(8) —

CH₂-((3-trifluoromethoxy)phenyl),

(9) —

CH₂-((3-trifluoromethylthio)phenyl),

(10) —

CH₂-((3-trifluoromethoxy-5-thiomethyl)phenyl),

(11) —

CH₂-((3-trifluoromethoxy-5-methoxy)phenyl),

(12) —

CH₂-((3-trifluoromethoxy-5-methanesulfonyl)phenyl),

(13) —

CH₂-((3-trifluoromethoxy-5-amino)phenyl),

(14) —

CH₂-((3-trifluoromethoxy-5-aminomethanesulfonyl)phenyl),

(15) —

CH₂-((3-trifluoromethoxy-5-sulfonylamino)phenyl),

(16) —

CH₂-((3,5-bis-trifluoromethyl)phenyl),

(17) —

CH₂-((3-fluoro-5-trifluoromethyl)phenyl),

(18) —

CH(CH₃)-((3,5-bis-trifluoromethyl)phenyl),

(19) —

C(CH₃)₂-((3,5-bis-trifluoromethyl)phenyl),

(20) —

CH₂-(4-(2-trifluoromethylpyridyl),

(21) —

CH₂-(5-(3-trifluoromethyl)pyridyl),

(22) —

CH₂-(5-(3-tifluoromethyl)pyridazinyl),

(23) —

CH₂-(4-(2-trifluoromethylpyridyl-N-oxide), and

(24) —

CH₂-(S-(3-trifluoromethyl)pyridyl-N-oxide).

26. The compound of claim 1 wherein R³ is hydrogen and phenyl

where the phenyl is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from:

(a) halo,

(b) trifluoromethyl,

(c) hydroxy,

(d) C_1-3alkyl,

(e) —

O—

C_1-3alkyl,

(f) —

CO₂R⁹,

(g) —

CN,

(h) —

NR⁹R¹⁰, and

(i) —

CONR⁹R¹⁰.

28. The compound of claim 1 wherein R³ is phenyl, or para-fluorophenyl.

29. The compound of claim 1 wherein R⁴ is selected from:

(a) hydrogen,

(b) hydroxy,

(c) —

CO₂H,

(d) —

CO₂C_1-6alkyl, and

(e) —

CN.

30. The compound of claim 1 wherein R⁵ and R⁶ are independently selected from:

(a) hydrogen,

(b) hydroxy,

(c) —

CH₃,

(d) —

O—

CH₃, and

(e) oxo.

32. A pharmaceutical composition which comprises an inert carrier and a compound of claim 1.

33. A method for modulation of chemokine receptor activity in a mammal in need thereof which comprises the administration of an effective amount of the compound of claim 1.

34. A method for treating, ameliorating or controlling an inflammatory or immunoregulatory disorder or disease which comprises administering to a patient in need thereof an effective amount of the compound of claim 1.

35. A method for reducing the risk of an inflammatory or immunoregulatory disorder or disease which comprises administering to a patient in need thereof an effective amount of the compound of claim 1.

36. A method for treating, ameliorating or controlling rheumatoid arthritis which comprises administering to a patient in need thereof an effective amount of the compound of claim 1.

27. The compound of claim I wherein R³ is hydrogen and phenyl, where the phenyl is unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from:

(a) halo,

(c) hydroxy,

(d) C_1-3alkyl,

(e) —

O—

C_1-3alkyl, and

(f) —

CO₂R⁹.

31. A compound which is selected from the group consisting of the title compounds of the Examples, and pharmaceutically acceptable salts and individual diastereomers thereof.