Uracil derivatives as inhibitors of TNF-α converting enzyme (TACE) and matrix metalloproteinases

• US 7,101,883 B2
• Filed: 03/14/2003
• Issued: 09/05/2006
• Est. Priority Date: 03/18/2002
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Maduskuie, Thomas P.
• Primary Examiner(s): Wilson, James O.
• Assistant Examiner(s): Ward, Paul V.
• Application Number:
  US10/389,529
• Publication Number:
  US 20030229081A1
• Time in Patent Office: 1,271 Days
• Field of Search: 514/247, 544/224, 544/242
• US Class Current: 514/247
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: C07D 239/545 with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
• CPC Class Codes: C07D 239/69 Benzenesulfonamido-pyrimidines
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links

Abstract

The present application describes novel uracil derivatives of formula I:
A-W-U-X-Y-Z-U^a-X^a-Y^a-Z^aI

or pharmaceutically acceptable salt or prodrug forms thereof, wherein A, W, U, X, Y, Z, U^a, X^a, Y^a, and Z^a are defined in the present specification, which are useful as inhibitors of TNF-α converting enzyme (TACE), matrix metalloproteinases (MMP), aggrecanase or a combination thereof.

Claims

1. A compound of formula I:

A-W-U-X-Y-Z-U^a-X^a-Y^a-Z^a 

 

I

or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein;

A is selected from the group;

2. A compound according to claim 1, wherein;

W is (CHR^a)_m;

U is absent or is selected from;

C(O)NR^a1, NR^a1C(O), NR^a1C(O)O, OS(O)₂, S(O)₂O, S(O)₂, S(O)_pNR^a1, and NR^a1S(O)_p;

X is absent or is C_1-3 alkylene;

Y is absent;

U^a is absent or is selected from;

O, NR^a1, C(O), CR^a(OH), C(O)O, OC(O), C(O)NR^a1, NR^a1C(O), OC(O)O, OC(O)NR^a1, NR^a1C (O)O, NR^a1C (O)NR^a1, S(O)_p, S(O)_pNR_a1, NR^a1S(O)_p, and NR^a1SO₂NR^a1;

X^a is absent or is selected from C_1-4 alkylene, C_2-4 alkenylene, and C_2-4 alkynylene;

Y^a is absent or is selected from O and NR^a1;

Z^a is selected from a C_3-13 carbocycle substituted with 0–

5 R^c, and a 5–

14 membered heterocycle comprising carbon atoms and 1–

4 heteroatoms selected from the group consisting of N, O, and S(O)_p, and substituted with 0–

5 R^c;

provided that U, Y, Z, U^a, Y^a, and Z^a do not combine to form a N—

N, N—

O, O—

N, O—

O, S(O)_p—

O, O—

S(O)_p or S(O)_p—

S(O)_p group;

R¹, at each occurrence, is independently selected from H, CF₃, C_1-6 alkyl substituted with 0–

1 R^b, C_2-6 alkenyl substituted with 0–

1 R^b, C_2-6 alkynyl substituted with 0–

1 R^b, (CR^aR^a1)_sOR^a1, (CR^aR^a1)_rNR^aR^a1, (CR^aR^a1)_rC(O)NR^aR^a1, (CR^aR^a1)_r—

C_3-10 carbocycle substituted with 0–

3 R^d, and (CR^aR^a1)_r-5–

10 membered heterocycle comprising carbon atoms and 1–

4 heteroatoms selected from the group consisting of N, O, and S(O)_p, and substituted with 0–

3 R^d;

R², at each occurrence, is independently selected from H, C_1-6 alkyl, C_2-6 alkenyl, and C_2-6 alkynyl;

R³, at each occurrence, is independently selected from H, C_1-6 alkyl, C_2-6 alkenyl, and C_2-6 alkynyl;

R^a, at each occurrence, is independently selected from H, C_1-6 alkyl, phenyl, and benzyl;

R^a1, at each occurrence, is independently selected from H, C_1-6 alkyl, phenyl, and benzyl;

R^a3, at each occurrence, is independently selected from H, C_1-4 alkyl, phenyl, and benzyl; and

R^c, at each occurrence, is independently selected from H, OR^a, Cl, F, Br, ═

O, —

CN, NO₂, NR^aR^a1, CF₃, (CR^aR^a1)_rC(O)R^a1, (CR^aR^a1)_rC(O)OR^a1, (CR^aR^a1)_rC(O)NR^aR^a1, (CR^aR^a1)_rNR^aC(O)R^a1, (CR^aR^a1)_rS(O)_pR^a3, (CR^aR^a1)_rSO₂NR^aR^a1, (CR^aR^a1)_rNR^aSO₂R^a3;

C_1-6 alkyl substituted with 0–

1 R^c1;

C_2-6 alkenyl substituted with 0–

1 R^c1;

C_2-6 alkynyl substituted with 0–

1 R^c1;

(CH₂)_r—

C_3-6 carbocycle substituted with 0–

2 R^c1; and

(CH₂)_r-5–

6 membered heterocycle comprising carbon atoms and 1–

4 heteroatoms selected from the group consisting of N, O, and S(O)_p, and substituted with 0–

2 R^c1.

3. A compound according to claim 2, wherein;

W is absent or is CH₂;

U is selected from;

C(O)NH, NHC(O), OS(O)₂, S(O)₂O, S(O)₂, S(O)₂NH, and NHS(O)₂;

X is absent;

Y is absent;

Z is selected from;

phenylene substituted with 0–

5 R^b;

naphthylene substituted with 0–

5 R^b; and

a 5–

14 membered heterocycle comprising carbon atoms and 1–

4 heteroatoms selected from the group consisting of N, O, and S(O)_p, and substituted with 0–

5 R^b;

U^a is absent or is selected from;

O, NR^a1, and CR^a(OH);

X^a is absent or is selected from C_1-4 alkylene, C_2-4 alkenylene, and C_2-4 alkynylene;

Y^a is absent or is selected from O and NR^a1;

Z^a is selected from a C_5-10 carbocycle substituted with 0–

5 R^c, and a 5–

14 membered heterocycle comprising carbon atoms and 1–

4 heteroatoms selected from the group consisting of N, O, and S(O)_p, and substituted with 0–

5 R^c;

provided that U, Y, Z, U^a, Y^a, and Z^a do not combine to form a N—

N, N—

O, O—

N, O—

O, S(O)_p—

O, O—

S(O)_p or S(O)_p—

S(O)_p group;

R¹, at each occurrence, is independently selected from H, CF₃, C_1-6 alkyl substituted with 0–

1 R^b, C_2-6 alkenyl substituted with 0–

1 R^b, and C_2-6 alkynyl substituted with 0–

1 R^b, (CH₂)_nOR^a1, and (CH₂)_rNR^aR^a1;

R², at each occurrence, is independently selected from H and C_1-4 alkyl;

R³, at each occurrence, is independently selected from H and C_1-4 alkyl;

R^a, at each occurrence, is independently selected from H and C_1-6 alkyl;

R^a1, at each occurrence, is independently selected from H and C_1-6 alkyl;

R^a3, at each occurrence, is independently selected from H, C_1-4 alkyl, phenyl, and benzyl; and

R^c, at each occurrence, is independently selected from H, OR^a, Cl, F, Br, ═

O, —

CN, NO₂, NR^aR^a1, CF₃, (CR^aR^a1)_rC(O)R^a1, (CR^aR^a1)_rC(O)OR^a1, (CR^aR^a1)_rC(O)NR^aR^a1, (CR^aR^a1)_rNR^aC(O)R^a1, (CR^aR^a1)_rS(O)_pR^a3, (CR^aR^a1)_rSO₂NR^aR^a1, (CR^aR^a1)_rNR^aSO₂R^a3;

C_1-6 alkyl substituted with 0–

1 R^c1;

C_2-6 alkenyl substituted with 0–

1 R^c1;

C_2-6 alkynyl substituted with 0–

1 R^c1;

(CH₂)_r—

C_3-6 carbocycle substituted with 0–

2 R^c1; and

(CH₂)_r-5–

6 membered heterocycle comprising carbon atoms and 1–

4 heteroatoms selected from the group consisting of N, O, and S(O)_p, and substituted with 0–

2 R^c1.

4. A compound according to claim 3, wherein;

W is absent or is CH₂;

U is selected from;

NHC(O), OS(O)₂, S(O)₂, and NHS(O)₂;

X is absent;

Y is absent;

Z is selected from;

phenylene substituted with 0–

5 R^b; and

naphthylene substituted with 0–

5 R^b;

U^a is absent or is O;

X^a is absent or is CH₂ or CH₂CH₂;

Y^a is absent or is O;

Z^a is a 5–

10 membered heterocycle substituted with 0–

3 R^c and selected from the group;

pyridyl, quinolinyl, imidazolyl, benzimidazolyl, indolyl, 1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl, 1,1-dioxido-3,4-dihydro-2H-1-benzothiopyran-4-yl, 3,4-dihydro-2H-chromen-4-yl, 2H-chromen-4-yl, and pyrazolyl;

provided that U, Y, Z, U^a, Y^a, and Z^a do not combine to form a N—

N, N—

O, O—

N, O—

O, S(O)_p—

O, O—

S(O)_p or S(O)_p—

S(O)_p group;

R¹, at each occurrence, is independently selected from H, CF₃, C_1-6 alkyl substituted with 0–

1 R^b, C_2-6 alkenyl substituted with 0–

1 R^b, and C_2-6 alkynyl substituted with 0–

1 R^b, (CH₂)_sOR^a1, and (CH₂)_rNR^aR^a1; and

R^c, at each occurrence, is independently selected from H, OR^a, Cl, F, Br, ═

O, —

CN, NO₂, NR^aR^a1, CF₃, (CH₂)_rC(O)R^a1, (CH₂)_rC(O)OR^a1, (CH₂)_rC(O)NR^aR^a1, (CH₂)_rNR^aC(O)R^a1, (CH₂)_rS(O)_pR^a3, (CH₂)_rSO₂NR^aR^a1, (CH₂)_rNR^aSO₂R^a3;

C_1-6 alkyl substituted with 0–

1 R^c1;

C_2-6 alkenyl substituted with 0–

1 R^c1;

C_2-6 alkynyl substituted with 0–

1 R^c1;

(CH₂)_r—

C_3-6 carbocycle substituted with 0–

2 R^c1; and

(CH₂)_r-5–

6 membered heterocycle comprising carbon atoms and 1–

4 heteroatoms selected from the group consisting of N, O, and S(O)_p, and substituted with 0–

2 R^c1.

5. A compound according to claim 1, wherein the compound is of formula Ia:

6. A compound according to claim 5, wherein;

U^a is absent or is selected from;

O, NR^a1, and CR^a(OH);

X^a is absent or is selected from C_1-4 alkylene, C_2-4 alkenylene, and C_2-4 alkynylene;

Y^a is absent or is selected from O and NR^a1;

Z^a is selected from a C_3-13 carbocycle substituted with 0–

5 R^c, and a 5–

14 membered heterocycle comprising carbon atoms and 1–

4 heteroatoms selected from the group consisting of N, O, and S(O)_p, and substituted with 0–

5 R^c;

provided that U^a, Y^a, and Z^a do not combine to form a N—

N, N—

O, O—

N, O—

O, S(O)_p—

O, O—

S(O)_p or S(O)_p—

S(O)_p group;

R¹, at each occurrence, is independently selected from H, CF₃, C_1-6 alkyl substituted with 0–

1 R^b, C_2-6 alkenyl substituted with 0–

1 R^b, C_2-6 alkynyl substituted with 0–

1 R^b, (CR^aR^a1)_sOR^a1, (CR^aR^a1)_rNR^aR^a1, (CR^aR^a1)_rC(O)NR^aR^a1, (CR^aR^a1)_r—

C_3-10 carbocycle substituted with 0–

3 R^d, and (CR^aR^a1)_r-5–

10 membered heterocycle comprising carbon atoms and 1–

4 heteroatoms selected from the group consisting of N, O, and S(O)_p, and substituted with 0–

3 R^d;

R^a, at each occurrence, is independently selected from H, C_1-6 alkyl, phenyl, and benzyl;

R^a1, at each occurrence, is independently selected from H, C_1-6 alkyl, phenyl, and benzyl;

R^a3, at each occurrence, is independently selected from H, C_1-4 alkyl, phenyl, and benzyl;

R^c, at each occurrence, is independently selected from H, OR^a, Cl, F, Br, ═

O, —

CN, NO₂, NR^aR^a1, CF₃, (CR^aR^a1)C(O) R^a1, (CR^aR^a1)_rC(O)OR^a1, (CR^aR^a1)_rC(O)NR^aR^a1, (CR^aR^a1)_rNR^aC(O)R^a1, (CR^aR^a1)_rS(O)_pR^a3, (CR^aR^a1)_rSO₂NR^aR^a1, (CR^aR^a1)_rNR^aSO₂R^a3; and

C_1-6 alkyl substituted with 0–

1 R^c1;

C_2-6 alkenyl substituted with 0–

1 R^c1;

C_2-6 alkynyl substituted with 0–

1 R^c1;

(CH₂)_r—

C_3-6 carbocycle substituted with 0–

2 R^c1; and

(CH₂)_r-5–

6 membered heterocycle comprising carbon atoms and 1–

4 heteroatoms selected from the group consisting of N, O, and S(O)_p, and substituted with 0–

2 R^c1.

7. A compound according to claim 6, wherein;

Z is selected from;

phenylene substituted with 0–

5 R^b;

naphthylene substituted with 0–

5 R^b; and

a 5–

14 membered heterocycle comprising carbon atoms and 1–

4 heteroatoms selected from the group consisting of N, O and S(O)_p, and substituted with 0–

5 R^b;

U^a is absent or is selected from;

O, NR^a1, and CR^a(OH);

X^a is absent or is selected from C_1-4 alkylene, C_2-4 alkenylene, and C_2-4 alkynylene;

Y^a is absent or is selected from O and NR^a1;

Z^a is selected from a C_5-10 carbocycle substituted with 0–

5 R^c, and a 5–

14 membered heterocycle comprising carbon atoms and 1–

4 heteroatoms selected from the group consisting of N, O, and S(O)_p, and substituted with 0–

5 R^c;

provided that U, Y, Z, U^a, Y^a, and Z^a do not combine to form a N—

N, N—

O, O—

N, O—

O, S(O)_p—

O, O—

S(O)_p or S(O)_p—

S(O)_p group;

R¹, at each occurrence, is independently selected from H, CF₃′

, C_1-6 alkyl substituted with 0–

1 R^b, C_2-6 alkenyl substituted with 0–

1 R^b, and C_2-6 alkynyl substituted with 0–

1 R^b, (CH₂)_sOR^a1, and (CH₂)_rNR^aR^a1;

R^a, at each occurrence, is independently selected from H and C_1-6 alkyl;

R^a1, at each occurrence, is independently selected from H and C_1-6 alkyl;

R^a3, at each occurrence, is independently selected from H, C_1-4 alkyl, phenyl, and benzyl; and

R^c, at each occurrence, is independently selected from H, OR^a, Cl, F, Br, ═

O, —

CN, NO₂, NR^aR^a1, CF₃, (CR^aR^a1)_rC(O)R^a1, (CR^aR^a1)_rC(O)OR^a1, (CR^aR^a1)_rC(O)NR^aR^a1, (CR^aR^a1)_rNR^aC(O)R^a1, (CR^aR^a1)_rS(O)_pR^a3, (CR^aR^a1)_rSO₂NR^aR^a1, (CR^aR^a1)_rNR^aSO₂R^a3;

C_1-6 alkyl substituted with 0–

1 R^c1;

C_2-6 alkenyl substituted with 0–

1 R^c1;

C_2-6 alkynyl substituted with 0–

1 R^c1;

(CH₂)_r—

C_3-6 carbocycle substituted with 0–

2 R^c1; and

(CH₂)_r-5–

6 membered heterocycle comprising carbon atoms and 1–

4 heteroatoms selected from the group consisting of N, O, and S(O)_p, and substituted with 0–

2 R^c1.

8. A compound according to claim 7, wherein;

Z is selected from;

phenylene substituted with 0–

3 R^b; and

naphthylene substituted with 0–

3 R^b;

U^a is absent or is O;

X^a is absent or is CH₂ or CH₂CH₂;

Y^a is absent or is O;

Z^a is a 5–

10 membered heterocycle substituted with 0–

3 R^c and selected from the group;

pyridyl, quinolinyl, imidazolyl, benzimidazolyl, indolyl, 1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl, 1,1-dioxido-3,4-dihydro-2H-1-benzothiopyran-4-yl, 3,4-dihydro-2H-chromen-4-yl, 2H-chromen-4-yl, and pyrazolyl;

provided that U^a, Y^a, and Z^a do not combine to form a N—

N, N—

O, O—

N, O—

O, S(O)_p—

O, O—

S(O)_p or S(O)_p—

S(O)_p group;

R¹, at each occurrence, is independently selected from H, CF₃, C_1-6 alkyl substituted with 0–

1 R^b, C_2-6 alkenyl substituted with 0–

1 R^b, and C_2-6 alkynyl substituted with 0–

1 R^b, (CH₂)_sOR^a1, and (CH₂)_rNR^aR^a1; and

R^c, at each occurrence, is independently selected from H, OR^a, Cl, F, Br, ═

O, —

CN, NO₂, NR^aR^a1, CF₃, (CH₂)_rC(O)R^a1, (CH₂)_rC(O)OR^a1, (CH₂)_rC(O)NR^aR^a1, (CH₂)_rNR^aC(O)R^a1, (CH₂)_rS(O)_pR^a3, (CH₂)_rSO₂NR^aR^a1, (CH₂)_rNR^aSO₂R^a3;

C_1-6 alkyl substituted with 0–

1 R^c1;

C_2-6 alkenyl substituted with 0–

1 R^c1;

C_2-6 alkynyl substituted with 0–

1 R^c1;

(CH₂)_r—

C_3-6 carbocycle substituted with 0–

2 R^c1; and

(CH₂)_r-5–

6 membered heterocycle comprising carbon atoms and 1–

4 heteroatoms selected from the group consisting of N, O, and S(O)_p, and substituted with 0–

2 R^c1.

9. A compound according to claim 1, wherein the compound is selected from the group:

N-(2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)-4-[(2-methyl-4-quinolinyl)methoxy]benzenesulfonamide;

N-(2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)-6-[(2-methyl-4-quinolinyl)methoxy]-2-naphthalenesulfonamide;

N-(6-amino-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)-4-[(2-methyl-4-quinolinyl)methoxy]benzenesulfonamide;

2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl 4-[(2-methyl-4-quinolinyl)methoxy]benzenesulfonate;

N-(2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)-4-[(2-methyl-4-quinolinyl)methoxy]benzamide;

N-(2,4-dioxohexahydro-5-pyrimidinyl)-4-[(2-methyl-4-quinolinyl)methoxy]benzenesulfonamide;

N-(2,4-dioxohexahydro-5-pyrimidinyl)-4-[(2-methyl-4-quinolinyl)methoxy]benzamide;

N-[(2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)methyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzenesulfonamide;

6-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}thio)-2,4(1H,3H)-pyrimidinedione;

N-(2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)-4-phenoxybenzenesulfonamide;

or a pharmaceutically acceptable salt form thereof.

10. A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt form thereof.

11. A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 2 or a pharmaceutically acceptable salt form thereof.

12. A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 3 or a pharmaceutically acceptable salt form thereof.

13. A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 4 or a pharmaceutically acceptable salt form thereof.

14. A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 5 or a pharmaceutically acceptable salt form thereof.

15. A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 6 or a pharmaceutically acceptable salt form thereof.

16. A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 7 or a pharmaceutically acceptable salt form thereof.

17. A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 8 or a pharmaceutically acceptable salt form thereof.

18. A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 9 or a pharmaceutically acceptable salt form thereof.