Phospholipase C inhibitors for use in treating inflammatory disorders

• US 20040242639A1
• Filed: 03/31/2004
• Published: 12/02/2004
• Est. Priority Date: 03/31/2003
• Status: Abandoned Application

• Current Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Original Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Inventors: Lagu, Bharat, Wachter, Michael, Rupert, Kenneth
• Application Number:
  US10/814,070
• Publication Number:
  US 20040242639A1
• Time in Patent Office: Days
• US Class Current: 514/326
• CPC Class Codes: C07D 211/14 with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
• CPC Class Codes: C07D 211/18 with substituted hydrocarbon radicals attached to ring carbon atoms
• CPC Class Codes: C07D 401/10 linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links

Abstract

This invention is directed to heterocyclyl-substituted anilino phospholipase C inhibitor compounds useful in treating or ameliorating an inflammatory disorders and/or restenosis of the general formula (I):

and enantiomers, diastereomers and pharmaceutically acceptable salts thereof. The present invention is further directed to pharmaceutical compositions comprising the compounds of the present invention and to methods for treating conditions affected by phospholipase modulation.

Claims

1. A compound of formula (I):

2. The compound of claim 1, wherein X is selected from the group consisting of

(i) amino substituted with one R_1a substituent and one R_1b substituent;

(ii) a heterocyclyl ring optionally substituted with one or two R₂ substituents, said heterocyclyl ring having at least one nitrogen atom member, wherein the nitrogen atom member forms the point of attachment for said heterocyclyl ring on the —

C(O)—

portion of the X—

C(O)—

moiety; and

,

(iii) a heteroaryl ring optionally substituted with one or two R₂ substituents, said heteroaryl ring having at least one secondary amine member as a point of attachment for said heteroaryl ring on the —

C(O)—

portion of the X—

C(O)—

moiety;

R_1a and R_1b are independently selected from the group consisting of

(i) hydrogen;

(ii) C_1-8alkyl optionally substituted with one or two substituents independently selected from the group consisting of C_1-8alkoxy, amino, mono(C_1-8)alkylamino, di(C_1-8)alkylamino, cyano, halogen, hydroxy, nitro, carboxyl, C_3-8cycloalkyl, heterocyclyl, aryl and heteroaryl,

wherein said C_3-8cycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of C_1-8alkyl, C_1-8alkoxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy and nitro;

wherein said heterocyclyl is optionally substituted on a nitrogen atom with C_1-8alkyl, and optionally and independently substituted on one or two carbon atoms with a substituent independently selected from the group consisting of C_1-8alkyl, C_1-8alkoxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy, nitro and oxo;

wherein said aryl is optionally substituted with one or two substituents independently selected from the group consisting of C_1-8alkyl, C_1-8alkoxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy and nitro; and

,

wherein said heteroaryl is optionally substituted on a secondary amine atom with C_1-8alkyl, and optionally and independently substituted on one or two carbon atoms with a substituent independently selected from the group consisting of C_1-8alkyl, C_1-8alkoxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy and nitro; and

,

(iii) aryl optionally substituted with one or two substituents independently selected from the group consisting of amino, mono(C_1-8)alkylamino, di(C_1-8)alkylamino, cyano, halogen, hydroxy, nitro and carboxyl;

R₂ is selected from the group consisting of hydrogen and C_1-8alkyl, wherein C_1-8alkyl is optionally substituted with one or two substituents independently selected from the group consisting of amino, mono(C_1-8)alkylamino, di(C_1-8)alkylamino, cyano, halogen, hydroxy, nitro and carboxyl;

R₄ is selected from the group consisting of

(a) C_3-8cycloalkyl optionally substituted with one or two substituents independently selected from the group consisting of C_1-8alkyl, C_1-8alkoxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy and nitro;

(b) benzofused dioxolyl;

(c) benzofused dioxinyl; and

,

(d) aryl optionally substituted with one or two substituents independently selected from the group consisting of C_1-8alkyl, C_1-8alkoxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy and nitro;

R₅ is selected from the group consisting of

(i) one substituent selected from the group consisting of paragraphs (e) and (f) when L is a double bond; and

,

(ii) one or two independently selected substituents selected from the group consisting of paragraphs (e), (f) and (g) when L is a single bond or other than a direct bond,

(e) C_1-8alkyl optionally substituted with one or two substituents independently selected from the group consisting of amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy, nitro, C_3-8cycloalkyl, aryl and heteroaryl,

wherein said C_3-8cycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of C_1-8alkyl, C_1-8alkoxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy and nitro;

wherein said aryl is optionally substituted with one or two substituents independently selected from the group consisting of C_1-8alkyl, C_1-8alkoxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy and nitro; and

wherein said heteroaryl is optionally substituted on a secondary amine atom with C_1-8alkyl, and optionally and independently substituted on one or two carbon atoms with a substituent selected from the group consisting of C_1-8alkyl, C_1-8alkoxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy and nitro;

(f) C_3-8cycloalkyl optionally substituted with one or two substituents independently selected from the group consisting of C_1-8alkyl, C_1-8alkoxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy and nitro; and

,

(g) aryl optionally substituted with one or two substituents independently selected from the group consisting of C_1-8alkyl, C_1-8alkoxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy and nitro; and

,

Y is one or two optionally present C_1-8alkyl substituents optionally substituted with one or two substituents independently selected from the group consisting of amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy, nitro, C_3-8cycloalkyl, aryl and heteroaryl, wherein said C_3-8cycloalkyl, aryl and heteroaryl are optionally further substituted.

3. The compound of claim 1, wherein R_1a and R_1b are independently selected from the group consisting of

(i) hydrogen;

(ii) C_1-8alkyl optionally substituted with one or two substituents independently selected from the group consisting of C_1-8alkoxy, amino, mono(C_1-8)alkylamino, di(C_1-8)alkylamino, cyano, halogen, hydroxy, nitro, heterocyclyl and aryl

wherein said heterocyclyl is optionally substituted on a nitrogen atom with C_1-8alkyl, and optionally and independently substituted on one or two carbon atoms with a substituent independently selected from the group consisting of C_1-8alkyl, C_1-8alkoxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy, nitro and oxo; and

,

wherein said aryl is optionally substituted with one or two substituents independently selected from the group consisting of C_1-8alkyl, C_1-8alkoxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy and nitro; and

,

(iii) aryl optionally substituted with one or two substituents independently selected from the group consisting of amino, mono(C_1-8)alkylamino, di(C_1-8)alkylamino, cyano, halogen, hydroxy, nitro and carboxyl;

R₂ is selected from the group consisting of hydrogen and C_1-8alkyl;

R₅ is selected from the group consisting of

(i) one substituent selected from the group consisting of paragraphs (e) and (f) when L is a double bond; and

,

(ii) one or two independently selected substituents selected from the group consisting of paragraphs (e), (f) and (g) when L is a single bond or other than a direct bond,

(e) C_1-8alkyl optionally substituted with one or two substituents independently selected from the group consisting of amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy, nitro and aryl, wherein said aryl is optionally substituted with one or two substituents independently selected from the group consisting of C_1-8alkyl, C_1-8alkoxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy and nitro;

(f) C_3-8cycloalkyl optionally substituted with one or two substituents independently selected from the group consisting of C_1-8alkyl, C_1-8alkoxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy and nitro; and

,

(g) aryl optionally substituted with one or two substituents independently selected from the group consisting of C_1-8alkyl, C_1-8alkoxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy and nitro;

Y is absent;

m is an integer from 3 to 4 which represents the carbon atom number corresponding to the point of attachment for the X—

C(O)—

substituent moiety on the anilino ring of formula (I); and

, n is 1.

4. The compound of claim 1, wherein R_1a and R_1b are independently selected from the group consisting of

(i) hydrogen;

(ii) C_1-8alkyl optionally substituted with one or two substituents independently selected from the group consisting of C_1-8alkoxy, amino, mono(C_1-8)alkylamino, di(C_1-8)alkylamino, cyano, halogen, hydroxy, nitro, heterocyclyl and aryl, wherein said heterocyclyl is optionally substituted on a nitrogen atom with C_1-8alkyl, and optionally and independently substituted on one or two carbon atoms with a substituent independently selected from the group consisting of C_1-8alkyl, C_1-8alkoxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy, nitro and oxo; and

,

(iii) aryl;

R₂ is selected from the group consisting of hydrogen and C_1-8alkyl;

R₄ is selected from the group consisting of

(a) C_3-8cycloalkyl optionally substituted with one or two substituents independently selected from the group consisting of C_1-8alkyl, C_1-8alkoxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy and nitro;

(b) benzofused dioxolyl; and

,

(d) aryl optionally substituted with one or two substituents independently selected from the group consisting of C_1-8alkyl, C_1-8alkoxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy and nitro; and

,

R₅ is selected from the group consisting of

(i) one substituent selected from the group consisting of paragraphs (e) and (f) when L is a double bond; and

,

(ii) one or two independently selected substituents selected from the group consisting of paragraphs (e), (f) and (g) when L is a single bond or other than a direct bond,

(e) C_1-8alkyl optionally substituted with one or two substituents independently selected from the group consisting of amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy, nitro and aryl,

(f) C_3-8cycloalkyl optionally substituted with one or two substituents independently selected from the group consisting of C_1-8alkyl, C_1-8alkoxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy and nitro; and

,

(g) aryl optionally substituted with one or two substituents independently selected from the group consisting of C_1-8alkyl, C_1-8alkoxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy and nitro.

5. The compound of claim 1, wherein X is selected from the group consisting of

(i) amino substituted with one R_1a substituent and one R_1b substituent;

(ii) a heterocyclyl ring, said heterocyclyl ring having at least one nitrogen atom member, wherein the nitrogen atom member forms the point of attachment for said heterocyclyl ring on the —

C(O)—

portion of the X—

C(O)—

moiety; and

, (iii) a heteroaryl ring, said heteroaryl ring having at least one secondary amine member as a point of attachment for said heteroaryl ring on the —

C(O)—

portion of the X—

C(O)—

moiety;

R_1a and R_1b are independently selected from the group consisting of

(i) hydrogen;

(ii) C_1-8alkyl optionally substituted with one or two substituents independently selected from the group consisting of amino, mono(C_1-8)alkylamino, di(C_1-8)alkylamino, hydroxy, carboxyl, C_3-8cycloalkyl, heterocyclyl and aryl,

wherein said heterocyclyl is optionally substituted on a nitrogen atom with C_1-8alkyl, and optionally and independently substituted on one or two carbon atoms with an oxo substituent; and

,

(iii) aryl;

R₂ is hydrogen;

R₄ is selected from the group consisting of

(a) C_3-8cycloalkyl;

(b) benzofused dioxolyl; and

,

(d) aryl;

L is a direct (single or double) bond; and

,

R₅ is selected from the group consisting of

(i) one paragraph (e) substituent when L is a double bond; and

,

(ii) one or two independently selected substituents selected from the group consisting of paragraphs (e) and (g) when L is a single bond or other than a direct bond,

(e) C_1-8alkyl optionally substituted with one or two aryl substituents; and

,

(g) aryl.

6. The compound of claim 1, wherein X is selected from the group consisting of

(i) amino substituted with one R_1a substituent and one R_1b substituent;

(ii) a heterocyclyl ring selected from the group consisting of piperazinyl, morpholinyl, 1,3,4-trihydro-isoquinolinyl and pyrrolidinyl, said heterocyclyl ring having at least one nitrogen atom member, wherein the nitrogen atom member forms the point of attachment for said heterocyclyl ring on the —

C(O)—

portion of the X—

C(O)—

moiety; and

,

(iii) a heteroaryl ring, said heteroaryl ring having at least one secondary amine member as a point of attachment for said heteroaryl ring on the —

C(O)—

portion of the X—

C(O)—

moiety;

wherein said heteroaryl ring is imidazolyl;

R_1a and R_1b are independently selected from the group consisting of

(i) hydrogen;

(ii) C_1-8alkyl optionally substituted with one or two substituents independently selected from the group consisting of di(C_1-8)alkylamino, hydroxy, morpholinyl, 1,3-dihydro-2H-isoindolyl and phenyl, wherein said 1,3-dihydro-2H-isoindolyl is optionally and independently substituted on one or two carbon atoms with an oxo substituent; and

,

(iii) phenyl;

R₂ is hydrogen;

R₄ is selected from the group consisting of

(a) cyclohexyl;

(b) 1,3-benzodioxolyl; and

,

(d) phenyl; and

,

R₅ is selected from the group consisting of

(i) one paragraph (e) substituent when L is a double bond; and

,

(ii) one or two independently selected substituents selected from the group consisting of paragraphs (e) and (g) when L is a single bond or other than a direct bond,

(e) C_1-8alkyl optionally substituted with one or two phenyl substituents; and

,

(g) phenyl.

7. The compound of claim 1, wherein R_1a and R_1b are independently selected from the group consisting of

(i) hydrogen;

(iii) C_1-8alkyl optionally substituted with one or more substituents independently selected from the group consisting of C_1-8alkoxy, amino, mono(C_1-8)alkylamino, di(C_1-8)alkylamino, cyano, halogen, hydroxy, nitro, carboxyl, C_3-8cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said heterocyclyl is optionally substituted on a nitrogen atom with C_1-8alkyl, and optionally and independently substituted on one or more carbon atoms with a substituent independently selected from the group consisting of C ₁₈alkyl, C_1-8alkoxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy, nitro and oxo; and

,

(iii) aryl optionally substituted with one or more substituents independently selected from the group consisting of amino, mono(C_1-8)alkylamino, di(C_1-8)alkylamino, cyano, halogen, hydroxy, nitro and carboxyl.

8. The compound of claim 1, wherein R_1a and R_1b are independently selected from the group consisting of

(i) hydrogen;

(ii) C_1-8alkyl optionally substituted with one or more substituents independently selected from the group consisting of amino, mono(C_1-8)alkylamino, di(C_1-8)alkylamino, hydroxy, carboxyl, C_3-8cycloalkyl, heterocyclyl and aryl, wherein said heterocyclyl is optionally substituted on a nitrogen atom with C_1-8alkyl, and optionally and independently substituted on one or more carbon atoms with an oxo substituent; and

,

(iii) aryl.

9. The compound of claim 1, wherein R_1a and R_1b are independently selected from the group consisting of

(i) hydrogen;

(ii) C_1-8alkyl optionally substituted with one or more substituents independently selected from the group consisting of di(C_1-8)alkylamino, hydroxy, morpholinyl, 1,3-dihydro-2H-isoindolyl and phenyl, wherein said 1,3-dihydro-2H-isoindolyl is optionally and independently substituted on one or more carbon atoms with an oxo substituent; and

,

(iii) phenyl.

10. The compound of claim 1, wherein R₂ is selected from the group consisting of hydrogen and C_1-8alkyl.

11. The compound of claim 1, wherein R₄ is selected from the group consisting of

(a) C_3-8cycloalkyl optionally substituted with one or more substituents independently selected from the group consisting of C_1-8alkyl, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, halogen, and hydroxy;

(b) benzofused dioxolyl;

(c) benzoftised dioxinyl; and

,

(d) aryl optionally substituted with one or more substituents independently selected from the group consisting of C_1-8alkyl, C_1-8alkoxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy and nitro.

12. The compound of claim 1, wherein R₄ is selected from the group consisting of

(a) C_3-8cycloalkyl;

(b) benzofused dioxolyl;

(c) benzofused dioxinyl; and

,

(d) aryl.

13. The compound of claim 1, wherein R₄ is selected from the group consisting of

(a) C_3-8cycloalkyl;

(b) benzofused dioxolyl; and

,

(d) aryl.

14. The compound of claim 1, wherein R₄ is selected from the group consisting of

(a) cyclohexyl;

(b) 1,3-benzodioxolyl; and

,

(d) phenyl.

15. The compound of claim 1, wherein L is a direct (single or double) bond.

16. The compound of claim 1, wherein when L is a double bond, R₅ is one substituent selected from the group consisting of paragraphs (e) and (f);

and, when L is a single bond or other than a direct bond, R₅ is one or more independently selected substituents selected from the group consisting of paragraphs (e), (f) and (g);

(e) C_1-8alkyl optionally substituted with one or more substituents independently selected from the group consisting of amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy, nitro, C_3-8cycloalkyl, aryl and heteroaryl, wherein said aryl is optionally substituted with one or more substituents independently selected from the group consisting of C_1-8alkyl, C_1-8alkoxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy and nitro;

(f) C_3-8cycloalkyl optionally substituted with one or more substituents independently selected from the group consisting of C_1-8alkyl, C_1-8alkoxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy and nitro; and

,

(g) aryl optionally substituted with one or more substituents independently selected from the group consisting of C_1-8alkyl, C_1-8alkoxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy and nitro.

17. The compound of claim 1, wherein when L is a double bond, R₅ is one substituent selected from the group consisting of paragraphs (e) and (f);

and, when L is a single bond or other than a direct bond, R₅ is one or more independently selected substituents selected from the group consisting of paragraphs (e), (f) and (g);

(e) C_1-8alkyl optionally substituted with one or more substituents independently selected from the group consisting of amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy, nitro, C_3-8cycloalkyl, aryl and heteroaryl;

(f) C_3-8cycloalkyl optionally substituted with one or more substituents independently selected from the group consisting of C_1-8alkyl, C_1-8alkoxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy and nitro; and

,

(g) aryl optionally substituted with one or more substituents independently selected from the group consisting of C_1-8alkyl, C_1-8alkoxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy and nitro.

18. The compound of claim 1, wherein when L is a double bond, R₅ is one substituent selected from the group consisting of paragraphs (e) and (f);

and, when L is a single bond or other than a direct bond, R₅ is one or more independently selected substituents selected from the group consisting of paragraphs (e), (f) and (g);

(e) C_1-8alkyl optionally substituted with one or more aryl substituents;

(f) C_3-8cycloalkyl; and

,

(g) aryl.

19. The compound of claim 1, wherein when L is a double bond, R₅ is one substituent selected from the group consisting of paragraphs (e) and (f);

and, when L is a single bond or other than a direct bond, R₅ is one or more independently selected substituents selected from the group consisting of paragraphs (e), (f) and (g);

(e) C_1-8alkyl optionally substituted with one or more phenyl substituents;

(f) C_3-8cycloalkyl; and

,

(g) phenyl.

20. The compound of claim 1, wherein Y is one or two optionally present C_1-8alkyl substituents optionally substituted with one or two substituents independently selected from the group consisting of amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy, nitro, C_3-8cycloalkyl, aryl and heteroaryl, wherein said C_3-8cycloalkyl, aryl and heteroaryl are optionally further substituted.

21. The compound of claim 1, wherein Y is one or two optionally present C_1-4alkyl substituents optionally substituted with one or two substituents independently selected from the group consisting of amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy, nitro, C_3-8cycloalkyl, aryl and heteroaryl, wherein said C_3-8cycloalkyl, aryl and heteroaryl are optionally further substituted.

22. The compound of claim 1, wherein Y is one or two optionally present C_1-4alkyl substituents optionally substituted with one or two substituents independently selected from the group consisting of amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy and nitro.

23. The compound of claim 1, wherein the compound of formula (I) is a selected from a compound of formula (Ia):

24. The compound of claim 23, wherein

R_1a and R_1b are independently selected from the group consisting of

(i) hydrogen;

(ii) C_1-8alkyl optionally substituted with one or two substituents independently selected from the group consisting of C_1-8alkoxy, amino, mono(C_1-8)alkylamino, di(C_1-8)alkylamino, cyano, halogen, hydroxy, nitro, carboxyl, C_3-8cycloalkyl, heterocyclyl, aryl and heteroaryl,

wherein said C_3-8cycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of C_1-8alkyl, C_1-8alkoxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy and nitro;

wherein said heterocyclyl is optionally substituted on a nitrogen atom with C_1-8alkyl, and optionally and independently substituted on one or two carbon atoms with a substituent independently selected from the group consisting of C_1-8alkyl, C_1-8alkoxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy, nitro and oxo;

wherein said aryl is optionally substituted with one or two substituents independently selected from the group consisting of C_1-8alkyl, C_1-8alkoxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy and nitro; and

wherein said heteroaryl is optionally substituted on a secondary amine atom with C_1-8alkyl, and optionally and independently substituted on one or two carbon atoms with a substituent independently selected from the group consisting of C_1-8alkyl, C_1-8alkoxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy and nitro; and

,

(iii) aryl optionally substituted with one or two substituents independently selected from the group consisting of amino, mono(C_1-8)alkylamino, di(C_1-8)alkylamino, cyano, halogen, hydroxy, nitro and carboxyl;

R₄ is selected from the group consisting of

(a) C_3-8cycloalkyl optionally substituted with one or two substituents independently selected from the group consisting of C_1-8alkyl, C_1-8alkoxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy and nitro;

(b) benzofused dioxolyl;

(c) benzofused dioxinyl;

or

(d) aryl optionally substituted with one or two substituents independently selected from the group consisting of C_1-8alkyl, C_1-8alkoxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy and nitro;

R₅ is selected from the group consisting of

(i) one substituent selected from the group consisting of paragraphs (e) and (f) when L is a double bond; and

,

(ii) one or two independently selected substituents selected from the group consisting of paragraphs (e), (f) and (g) when L is a single bond or other than a direct bond,

(e) C_1-8alkyl optionally substituted with one or two substituents independently selected from the group consisting of amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy, nitro, C_3-8cycloalkyl, aryl and heteroaryl,

wherein said C_3-8cycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of C_1-8alkyl, C_1-8alkoxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy and nitro;

wherein said aryl is optionally substituted with one or two substituents independently selected from the group consisting of C_1-8alkyl, C_1-8alkoxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy and nitro; and

wherein said heteroaryl is optionally substituted on a secondary amine atom with C_1-8alkyl, and optionally and independently substituted on one or two carbon atoms with a substituent selected from the group consisting of C_1-8alkyl, C_1-8alkoxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy and nitro;

(f) C_3-8cycloalkyl optionally substituted with one or two substituents independently selected from the group consisting of C_1-8alkyl, C_1-8alkoxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy and nitro; and

,

(g) aryl optionally substituted with one or two substituents independently selected from the group consisting of C_1-8alkyl, C_1-8alkoxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy and nitro; and

,

Y is one or two optionally present C_1-8alkyl substituents optionally substituted with one or two substituents independently selected from the group consisting of amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy, nitro, C_3-8cycloalkyl, aryl and heteroaryl, wherein said C_3-8cycloalkyl, aryl and heteroaryl are optionally further substituted.

25. The compound of claim 1, wherein the compound of formula (I) is a selected from a compound of formula (Ib):

26. The compound of claim 25, wherein

R₂ is selected from the group consisting of hydrogen and C_1-8alkyl, wherein C_1-8alkyl is optionally substituted with one or two substituents independently selected from the group consisting of amino, mono(C_1-8)alkylamino, di(C_1-8)alkylamino, cyano, halogen, hydroxy, nitro and carboxyl;

R₄ is selected from the group consisting of

(a) C_3-8cycloalkyl optionally substituted with one or two substituents independently selected from the group consisting of C_1-8alkyl, C_1-8alkoxy, amino, mono(C ₄)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy and nitro;

(b) benzofused dioxolyl;

(c) benzofused dioxinyl;

or

(d) aryl optionally substituted with one or two substituents independently selected from the group consisting of C_1-8alkyl, C_1-8alkoxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy and nitro;

R₅ is selected from the group consisting of

(i) one substituent selected from the group consisting of paragraphs (e) and (f) when L is a double bond; and

,

(ii) one or two independently selected substituents selected from the group consisting of paragraphs (e), (f) and (g) when L is a single bond or other than a direct bond,

(e) C_1-8alkyl optionally substituted with one or two substituents independently selected from the group consisting of amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy, nitro, C_3-8cycloalkyl, aryl and heteroaryl,

wherein said C_3-8cycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of C_1-8alkyl, C_1-8alkoxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy and nitro;

wherein said aryl is optionally substituted with one or two substituents independently selected from the group consisting of C_1-8alkyl, C_1-8alkoxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy and nitro; and

wherein said heteroaryl is optionally substituted on a secondary amine atom with C_1-8alkyl, and optionally and independently substituted on one or two carbon atoms with a substituent selected from the group consisting of C_1-8alkyl, C_1-8alkoxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy and nitro;

(f) C_3-8cycloalkyl optionally substituted with one or two substituents independently selected from the group consisting of C_1-8alkyl, C_1-8alkoxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy and nitro; and

,

(g) aryl optionally substituted with one or two substituents independently selected from the group consisting of C_1-8alkyl, C_1-8alkoxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy and nitro; and

,

Y is one or two optionally present Clgalkyl substituents optionally substituted with one or two substituents independently selected from the group consisting of amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy, nitro, C_3-8cycloalkyl, aryl and heteroaryl, wherein said C_3-8cycloalkyl, aryl and heteroaryl are optionally further substituted.

27. The compound of claim 1, wherein the compound of formula (I) is a selected from a compound of formula (Ic):

28. The compound of claim 27, wherein X is selected from the group consisting of (i) amino substituted with one R_1a substituent and one R_1b substituent;

(ii) heterocyclyl ring optionally substituted with one or two R₂ substituents, said heterocyclyl ring having at least one nitrogen atom member, wherein the nitrogen atom member forms the point of attachment for said heterocyclyl ring on the —

C(O)—

portion of the X—

C(O)—

moiety; and

, (iii) a heteroaryl ring optionally substituted with one or two R₂ substituents, said heteroaryl ring having at least one secondary amine member as a point of attachment for said heteroaryl ring on the —

C(O)—

portion of the X—

C(O)—

moiety;

R_1a and R_1b are independently selected from the group consisting of

(i) hydrogen;

(ii) C ₁₈alkyl optionally substituted with one or two substituents independently selected from the group consisting of C_1-8alkoxy, amino, mono(C_1-8)alkylamino, di(C_1-8)alkylamino, cyano, halogen, hydroxy, nitro, carboxyl, C_3-8cycloalkyl, heterocyclyl, aryl and heteroaryl,

wherein said C_3-8cycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of C_1-8alkyl, C_1-8alkoxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy and nitro;

wherein said heterocyclyl is optionally substituted on a nitrogen atom with C_1-8alkyl, and optionally and independently substituted on one or two carbon atoms with a substituent independently selected from the group consisting of C_1-8alkyl, C_1-8alkoxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy, nitro and oxo;

wherein said aryl is optionally substituted with one or two substituents independently selected from the group consisting of C_1-8alkyl, C_1-8alkoxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy and nitro; and

wherein said heteroaryl is optionally substituted on a secondary amine atom with C_1-8alkyl, and optionally and independently substituted on one or two carbon atoms with a substituent independently selected from the group consisting of C_1-8alkyl, C_1-8alkoxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy and nitro; and

,

(iii) aryl optionally substituted with one or two substituents independently selected from the group consisting of amino, mono(C_1-8)alkylamino, di(C_1-8)alkylamino, cyano, halogen, hydroxy, nitro and carboxyl;

R₂ is selected from the group consisting of hydrogen and C_1-8alkyl, wherein C_1-8alkyl is optionally substituted with one or two substituents independently selected from the group consisting of amino, mono(C_1-8)alkylamino, di(C_1-8)alkylamino, cyano, halogen, hydroxy, nitro and carboxyl;

R₄ is selected from the group consisting of

(a) C_3-8cycloalkyl optionally substituted with one or two substituents independently selected from the group consisting of C_1-8alkyl, C_1-8alkoxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy and nitro;

(b) benzofused dioxolyl;

(c) benzofused dioxinyl; and

,

(d) aryl optionally substituted with one or two substituents independently selected from the group consisting of C_1-8alkyl, C_1-8alkoxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy and nitro;

L is a direct (single or double) bond, or a linking group selected from the group consisting of C_1-8alkyldiyl, C_3-8cycloalkyldiyl and aryldiyl; and

,

R₅ is selected from the group consisting of

(i) one substituent selected from the group consisting of paragraphs (e) and (f) when L is a double bond; and

,

(ii) one or two independently selected substituents selected from the group consisting of paragraphs (e), (f) and (g) when L is a single bond or other than a direct bond,

(e) C_1-8alkyl optionally substituted with one or two substituents independently selected from the group consisting of amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy, nitro, C_3-8cycloalkyl, aryl and heteroaryl,

wherein said C_3-8cycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of C_1-8alkyl, C_1-8alkoxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy and nitro;

wherein said aryl is optionally substituted with one or two substituents independently selected from the group consisting of C_1-8alkyl, C_1-8alkoxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy and nitro; and

,

wherein said heteroaryl is optionally substituted on a secondary amine atom with C_1-8alkyl, and optionally and independently substituted on one or two carbon atoms with a substituent selected from the group consisting of C_1-8alkyl, C_1-8alkoxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy and nitro;

(f) C_3-8cycloalkyl optionally substituted with one or two substituents independently selected from the group consisting of C_1-8alkyl, C_1-8alkoxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy and nitro; and

,

(g) aryl optionally substituted with one or two substituents independently selected from the group consisting of C_1-8alkyl, C_1-8alkoxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, cyano, halogen, hydroxy and nitro; and

,

m is an integer from 2 to 5 which represents the carbon atom number corresponding to the point of attachment for the X—

C(O)—

substituent moiety on the anilino ring of formula (Ic).

31. A composition comprising a pharmaceutically acceptable carrier, excipient, tableting ingredient or diluent and the compound of claim 1.

32. A method of treating or preventing a disease or condition in a subject which disease or condition is affected by phospholipase modulation, which method comprises administering to the subject in need of such treatment or prevention a therapeutically effective amount of the compound of claim 1.

33. The method of claim 32, wherein the method further comprises administering to the subject in need of such treatment or prevention a therapeutically effective amount of the composition of claim 31.

34. A method of treating or ameliorating an inflammatory disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound of claim 1.

35. The method of claim 34, wherein the method further comprises administering to the subject a therapeutically effective amount of the composition of claim 31.

36. A method of treating or ameliorating restenosis in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound of claim 1 by impregnating the therapeutically effective amount of said compound on the surface of a medical device and administering the medical device to the subject.

37. The method of claim 36, wherein the method further comprises a therapeutically effective amount of the composition of claim 31 impregnated on the surface of said medical device.

29. A compound selected from the group consisting of:

3-[[(phenylamino)carbonyl]amino]-4-[4-(phenylmethyl)-1-piperidinyl]-benzamide;

3-[[(phenylamino)carbonyl]amino]-4-(4-phenyl-1-piperidinyl)-benzamide;

3-[[(1,3-benzodioxol-5-ylamino)carbonyl]amino]-4-(4-phenyl-1-piperidinyl)-benzamide;

N-[2-(4,4-diphenyl-1-piperidinyl)-5-(1-piperazinylcarbonyl)phenyl]-N′

-phenyl-urea;

N-[5-(aminocarbonyl)-2-[4-(phenylmethyl)- 1 -piperidinyl]phenyl]hydrazine-carboxamide;

4-[4-(diphenylmethyl)-1-piperidinyl]-3-[[(phenylamino)carbonyl]amino]-benzamide;

4-[4-(diphenylmethylene)-1-piperidinyl]-3-[[(phenylamino)carbonyl]amino]-benzamide;

N-[2-[4-(diphenylmethyl)-1-piperidinyl]-4-( 1 -piperazinylcarbonyl)phenyl]-N′

-phenyl-urea; and

,

N-cyclohexyl-N-[2-[4-(diphenylmethyl)-1-piperidinyl]-4-(1-piperazinylcarbonyl) phenyl]-urea.

30. A compound selected from the group consisting of: