Pyridinedione carboxamide inhibitors of endothelial lipase

• US 8,933,235 B2
• Filed: 09/24/2012
• Issued: 01/13/2015
• Est. Priority Date: 09/30/2011
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Pi, Zulan, Lloyd, John, Qiao, Jennifer X., Wang, Tammy C., Tora, George O.
• Primary Examiner(s): REESE, HEIDI L
• Application Number:
  US14/347,662
• Publication Number:
  US 20140235673A1
• Time in Patent Office: 841 Days
• Field of Search: None
• US Class Current: 546/298
• CPC Class Codes: C07D 213/34 to which a second hetero atom is attached
• 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 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond

Abstract

The present invention provides compounds of Formula (I) as defined in the specification and compositions comprising any of such novel compounds. These compounds are endothelial lipase inhibitors which may be used as medicaments.

Claims

1. A compound of Formula (I):

2. A compound according to claim 1, wherein:

R¹ is independently selected from the group consisting of;

C_1-6 alkyl substituted with 0-2 R^a, C_2-6 alkenyl substituted with 0-2 R^a, and —

(CH₂)_n—

W—

R^1a;

W is independently selected from the group consisting of;

a bond, NH, N(C_1-4 alkyl), CO, CONH, CON(C_1-4 alkyl), SO₂, NHCO₂, and CHR^f;

R^1a is independently selected from the group consisting of;

C_3-6 cycloalkyl substituted with 0-3 R^c, phenyl substituted with 0-3 R^b, naphthyl substituted with 0-2 R^b, tetrahydronaphthyl substituted with 0-2 R^b, dihydroindenyl substituted with 0-2 R^c, and a 5- to 10-membered heterocycle comprising;

carbon atoms and 1-4 heteroatoms selected from N, NR^e, O, and S(O)_p; and

wherein said heterocycle is substituted with 0-3 R^c;

R² is independently selected from the group consisting of;

H, halogen, CF₃, OCF₃, C_1-6 alkyl substituted with 0-2 R^a, C_2-6 alkenyl substituted with 0-2 R^a, —

CO₂(C_1-4 alkyl), —

SO₂(phenyl), —

(CH₂)_n—

(C_3-6 cycloalkyl substituted with 0-3 R^c), —

(CH₂)_n-(phenyl substituted with 0-3 R^b), —

(CH₂)_n-(naphthyl substituted with 0-3 R^b), and —

(CH₂)_n-(5- to 10 membered heterocycle comprising;

carbon atoms and 1-4 heteroatoms selected from N, NR^e, O, and S(O)_p), wherein said heterocycle is substituted with 0-3 R^c;

R³ is independently selected from the group consisting of;

H, halogen, CF₃, OCF₃, C_1-6 alkyl substituted with 0-2 R^a, and phenyl substituted with 0-2 R^b;

R⁴ is independently selected from the group consisting of;

C_5-6 cycloalkyl, phenyl, naphthyl, tetrahydronaphthyl, dihydroindenyl, and a 5- to 10-membered heterocycle comprising;

carbon atoms and 1-4 heteroatoms selected from N, NR^e, O, and S(O)_p; and

wherein each moiety is substituted with 0-3 R^d;

R⁵ is independently selected from the group consisting of;

OH, O(C_1-4 alkyl substituted with 0-1 CO₂H), CN, and NR⁷R⁸; and

L is independently a hydrocarbon or hydrocarbon-heteroatom linker optionally substituted with 0-1 R^g;

wherein said hydrocarbon linker has one to six carbon atoms and may be straight or branched, saturated or unsaturated; and

said hydrocarbon-heteroatom linker has one to five carbon atoms and one group selected from O, —

CO—

, S, —

SO—

, —

SO₂—

, NH, and N(C_1-4 alkyl);

provided that;

(i) when R¹ is methyl, R² and R³ are H, R⁵ is OH, and L is —

(CH₂)₃—

, then R⁴ is other than unsubstituted phenyl;

(ii) when L is CH₂, then R⁴ is other than halogen mono-substituted phenyl or methoxy bi-substituted phenyl;

or

(iii) when R¹ is methyl, R² and R³ are H, R⁵ is OH, and L is —

(CH₂)₂—

, then R⁴ is other than methoxy mono-substituted indolyl.

3. A compound according to claim 2, wherein:

R¹ is independently selected from the group consisting of;

C_1-6 alkyl substituted with 0-2 R^a, C_2-6 alkenyl substituted with 0-2 R^a, and —

(CH₂)_n—

W—

R^1a;

W is independently selected from the group consisting of;

a bond, CO, CONH, CON(C_1-4 alkyl), SO₂, and CHR^f;

R^1a is independently selected from the group consisting of;

C_3-6 cycloalkyl substituted with 0-3 R^c, phenyl substituted with 0-3 R^b, and a 5- to 6-membered heterocycle comprising;

carbon atoms and 1-4 heteroatoms selected from N, NR^e, O, and S(O)_p; and

wherein said heterocycle is substituted with 0-3 R^c;

R⁵ is independently selected from the group consisting of;

OH and C_1-6 alkoxy; and

provided that;

(i) when R¹ is methyl, R² and R³ are H, R⁵ is OH, and L is —

(CH₂)₃—

, then R⁴ is other than unsubstituted phenyl;

(ii) when L is CH₂, then R⁴ is other than halogen mono-substituted phenyl or methoxy bi-substituted phenyl;

or

(iii) when R¹ is methyl, R² and R³ are H, R⁵ is OH, and L is —

(CH₂)₂—

, then R⁴ is other than methoxy mono-substituted indolyl.

4. A compound according to claim 3, wherein:

R¹ is independently selected from the group consisting of;

H, C_1-4 alkyl substituted with 0-1 R^a, —

CH₂CO₂(C_1-4 alkyl), cyclopropyl, cyclopropylmethyl, phenyl, 4-CF₃-phenyl, 3-halo-4-CO₂(C_1-4 alkyl)-phenyl, 2-(C_1-4 alkoxy)-5-halo-phenyl, benzyl, 2-halo-benzyl, 3-CF₃-benzyl, 4-CO₂H-benzyl, 4-CO₂(C_1-4 alkyl)-benzyl, 4-SO₂(C_1-4 alkyl)-benzyl, 2-halo-phenethyl, 4-halo-phenethyl, 2-OH-phenethyl, —

SO₂(phenyl), and pyrid-4-yl;

R² is independently selected from the group consisting of;

H, halogen, CF₃, OCF₃, C_1-4 alkyl, C_2-4 alkenyl, —

SO₂(phenyl), phenyl substituted with 0-2 R^b, naphthyl substituted with 0-2 R^b, and a heterocycle selected from;

thienyl, oxadiazolyl, pyridyl, indolyl, quinolinyl, and isoquinolinyl;

wherein said heterocycle is substituted with 0-2 R^c;

R³ is independently selected from the group consisting of;

H, C_1-4 alkyl and phenyl substituted with 0-2 R^b;

R⁴ is independently selected from the group consisting of;

phenyl substituted with 0-3R^d, naphthyl, tetrahydronaphthyl, pyrrolidinyl, morpholinyl,

5. A compound according to claim 4, wherein the compound is of Formula (II):

6. A compound according to claim 5, wherein:

R¹ is independently selected from the group consisting of;

H, methyl, ethyl, isopropyl, isobutyl, CH₂CF₃, CH₂CH₂CF₃, —

CH₂CO₂Et, cyclopropyl, cyclopropylmethyl, phenyl, 4-CF₃-phenyl, 3-F-4-CO₂Me-phenyl, benzyl, 2-F-benzyl, 3-CF₃-benzyl, 4-CO₂H-benzyl, 4-CO₂Me-benzyl, 4-SO₂Me-benzyl, 2-F-phenethyl, 4-F-phenethyl, 2-OH-phenethyl, and pyrid-4-yl;

R² is independently selected from the group consisting of;

H, Br, ethyl, isopropyl, ethenyl, CF₃, phenyl, 3-F-phenyl, 4-F-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 3-Et-phenyl, 3-(i-Pr)-phenyl, 3-CF₃-phenyl, 4-CF₃-phenyl, 3-OCF₃-phenyl, 4-OCF₃-phenyl, 4-OH-phenyl, 4-CN-phenyl, 3-NH₂-phenyl, 3-N(Me)-2-phenyl, 3-CO₂H-phenyl, 3-CONH₂-phenyl, 4-CONH₂-phenyl, 3-CON(Me)-2-phenyl, 4-CON(Me)-2-phenyl, 3-NHSO₂Me-phenyl, 4-NHSO₂Me-phenyl, 3-SO₂Me-phenyl, 4-SO₂Me-phenyl, 3-SO₂NH₂-phenyl, 3-biphenyl, 4-biphenyl, 3,4-diF-phenyl, 3,5-diF-phenyl, 3-CH₃-4-F-phenyl, 3-CF₃-5-F-phenyl, 3-CF₃-4-Cl-phenyl, 3-C_1-4—

CF₃-phenyl, 3-CF₃-4-OH-phenyl, 3,5-diCF₃-phenyl, 3-OCF₂CHF₂-5-F-phenyl, 1-naphthyl, 2-naphthyl, thien-2-yl, thien-3-yl, 5-Me-1,2,4-oxadiazol-3-yl, pyrid-4-yl, 1-Me-indol-5-yl, 3-quinolinyl, 5-quinolinyl, 6-quinolinyl, and 5-isoquinolinyl;

R³ is independently selected from the group consisting of;

H, methyl, 3-F-5-F-phenyl, and 3-CF₃-5-F-phenyl;

R⁴ is independently selected from the group consisting of;

phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 2-OMe-phenyl, 3-OMe-phenyl, 4-OMe-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-CF₃-phenyl, 3-CF₃-phenyl, 4-CF₃-phenyl, 3-OCF₃-phenyl, 4-OCF₃-phenyl, 3-CO₂Me-phenyl, 4-CO₂Me-phenyl, 2-NO₂-phenyl, 3-NO₂-phenyl, 4-NO₂-phenyl, 3,5-diF-phenyl, 2,4-diCl-phenyl, 3,4-diCl-phenyl, 2,6-diCl-phenyl, 1-naphthyl, 2-naphthyl, and

7. A compound according to claim 6, wherein:

R¹ is independently selected from the group consisting of;

H, methyl, ethyl, isopropyl, isobutyl, CH₂CF₃, —

CH₂CO₂Et, cyclopropyl, cyclopropylmethyl, phenyl, 4-CF₃-phenyl, 3-F-4-CO₂Me-phenyl, benzyl, 2-F-benzyl, 4-CO₂H-benzyl, 4-CO₂Me-benzyl, 4-SO₂Me-benzyl, 4-F-phenethyl, 2-OH-phenethyl, and pyrid-4-yl;

R² is independently selected from the group consisting of;

H, Br, ethyl, isopropyl, ethenyl, CF₃, phenyl, 3-F-phenyl, 4-F-phenyl, 4-Cl-phenyl, 3-Et-phenyl, 3-(i-Pr)-phenyl, 3-CF₃-phenyl, 4-CF₃-phenyl, 3-OCF₃-phenyl, 4-OCF₃-phenyl, 4-OH-phenyl, 4-CN-phenyl, 3-NH₂-phenyl, 3-N(Me)-2-phenyl, 4-CONH₂-phenyl, 3-CON(Me)-2-phenyl, 4-CON(Me)-2-phenyl, 3-NHSO₂Me-phenyl, 4-SO₂Me-phenyl, 3-SO₂NH₂-phenyl, 3-biphenyl, 4-biphenyl, 3,4-diF-phenyl, 3,5-diF-phenyl, 3-CH₃-4-F-phenyl, 3-CF₃-5-F-phenyl, 3-CF₃-4-Cl-phenyl, 3-Cl-4—

CF₃-phenyl, 3-CF₃-4-OH-phenyl, 3,5-diCF₃-phenyl, 3-OCF₂CHF₂-5-F-phenyl, 1-naphthyl, thien-2-yl, thien-3-yl, pyrid-4-yl, 1-Me-indol-5-yl, 3-quinolinyl, 5-quinolinyl, 6-quinolinyl, and 5-isoquinolinyl;

R³ is independently selected from the group consisting of;

H, methyl, 3-F-5-F-phenyl, and 3-CF₃-5-F-phenyl;

R⁴ is independently selected from the group consisting of;

phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 3-OMe-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-CF₃-phenyl, 3-CF₃-phenyl, 4-CF₃-phenyl, 3-OCF₃-phenyl, 3-CO₂Me-phenyl, 4-CO₂Me-phenyl, 2-NO₂-phenyl, 3-NO₂-phenyl, 3,5-diF-phenyl, 2,4-diCl-phenyl, 3,4-diCl-phenyl, 2,6-diCl-phenyl, 1-naphthyl, 2-naphthyl, and

8. A compound according to claim 7, wherein:

R¹ is independently selected from the group consisting of;

methyl, ethyl, isopropyl, isobutyl, CH₂CF₃, cyclopropyl, cyclopropylmethyl, phenyl, 4-CF₃-phenyl, 3-F-4-CO₂Me-phenyl, benzyl, 2-F-benzyl, 4-CO₂Me-benzyl, 4-SO₂Me-benzyl, 4-F-phenethyl, and pyrid-4-yl;

R² is independently selected from the group consisting of;

H, Br, ethyl, isopropyl, ethenyl, CF₃, phenyl, 3-F-phenyl, 4-F-phenyl, 3-Et-phenyl, 3-(i-Pr)-phenyl, 3-CF₃-phenyl, 4-CF₃-phenyl, 3-OCF₃-phenyl, 4-OCF₃-phenyl, 4-OH-phenyl, 4-CN-phenyl, 3-CON(Me)-2-phenyl, 3-biphenyl, 4-biphenyl, 3,4-diF-phenyl, 3,5-diF-phenyl, 3-CF₃-5-F-phenyl, 3-CF₃-4-Cl-phenyl, 3-C_1-4—

CF₃-phenyl, 3-CF₃-4-OH-phenyl, 3,5-diCF₃-phenyl, 3-OCF₂CHF₂-5-F-phenyl, 1-naphthyl, thien-2-yl, thien-3-yl, 3-quinolinyl, and 6-quinolinyl;

R³ is independently selected from the group consisting of;

H, methyl, 3-F-5-F-phenyl, and 3-CF₃-5-F-phenyl;

R⁴ is independently selected from the group consisting of;

phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 3-OMe-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2-CF₃-phenyl, 3-CF₃-phenyl, 4-CF₃-phenyl, 3-CO₂Me-phenyl, 4-CO₂Me-phenyl, 2-NO₂-phenyl, 3-NO₂-phenyl, 3,4-diCl-phenyl, 2,6-diCl-phenyl, 1-naphthyl, and 2-naphthyl; and

L is independently selected from the group consisting of;

—

(CH₂)₂—

, —

(CH₂)₃—

, —

(CH₂)₄—

, —

(CH₂)₂CH(CH₃)—

, —

O(CH₂)₃—

, —

O(CH₂)₄—

, —

O(CH₂)₂CH(CH₃)—

, and —

S(CH₂)₃—

;

provided that when R¹ is methyl, R² is H, and L is —

(CH₂)₃—

, then R⁴ is other than phenyl.

9. A compound according to claim 8, wherein the compound is of Formula (III):

11. A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier and a compound of claim 1.

12. A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier and a compound of claim 5.

13. A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier and a compound of claim 9.

14. A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier and a compound of claim 2.

15. A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier and a compound of claim 3.

16. A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier and a compound of claim 4.

17. A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier and a compound of claim 6.

18. A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier and a compound of claim 7.

19. A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier and a compound of claim 8.

10. A compound selected from:

20. A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier and a compound of claim 10.