Heteroaryl-phenyl substituted factor Xa inhibitors

• US 20020103202A1
• Filed: 06/22/2001
• Published: 08/01/2002
• Est. Priority Date: 06/23/2000
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Pharma Company (Bristol-Myers Squibb Company)
• Original Assignee: Bristol-Myers Squibb Pharma Company (Bristol-Myers Squibb Company)
• Inventors: Quan, Mimi L., Pinto, Donald J.P., Woerner, Francis J.
• Granted Patent: US 6,599,926 B2
• Time in Patent Office: Days
• US Class Current: 514/247
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: C07D 401/10 linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 403/10 linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/10 linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/14 containing three or more hetero rings

Abstract

The present application describes heteroaryl-phenyl substituted compounds and derivatives thereof, or pharmaceutically acceptable salt or prodrug forms thereof, which are useful as inhibitors of factor Xa.

Claims

1. A compound of formula Ia, Ib, or Ic:

2. A compound according to claim 1, wherein the compound is of formula Ia₁-Ic₁, wherein:

3. A compound according to claim 2, wherein the compound is of formula Ib₁ or Ic₁, wherein:

ring D₂ is a 5-membered heteroaromatic ring system comprising E, carbon atoms, and 0-2 N atoms, wherein E is selected from O, S, and N—

R^c and ring D₂ is substituted with 1 R^a and 0-1 R^b;

R is selected from H, Cl, F, Br, I, OH, C_1-3 alkoxy, NH₂, NH(C_1-3 alkyl), N(C_1-3 alkyl)₂, CH₂NH₂, CH₂NH(C_1-3 alkyl), and CH₂N(C_1-3 alkyl)₂;

R^a is selected from H, OH, SH, NH₂, NH(C_1-3 alkyl), N(C_1-3 alkyl)₂, CH₂NH₂, CH₂NH(C_1-3 alkyl), and CH₂N(C_1-3 alkyl)₂,

R^b is selected from H, C_1-4 alkyl, Cl, F, Br, I, OH, C_1-3 alkoxy, NH₂, NH(C_1-3 alkyl), N(C_1-3 alkyl)₂, CH₂NH₂, CH₂NH(C_1-3 alkyl), and CH₂N(C_1-3 alkyl)₂;

R^c is selected from H, C_1-4 alkyl, C_1-3 alkoxy, NH₂, NH(C_1-3 alkyl), N(C_1-3 alkyl)₂, CH₂NH₂, CH₂NH(C_1-3 alkyl), and CH₂N(C_1-3 alkyl)₂;

M is selected from the group;

Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R^4a;

phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazole, thiadiazole, triazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, benzofuran, benzothiofuran, indole, benzimidazole, benzimidazolone, benzoxazole, benzthiazole, indazole, benzisoxazole, benzisothiazole, and isoindazole;

Z is selected from a bond, CH₂O, OCH₂, NH, CH₂NH, NHCH₂, CH₂C(O), C(O)CH₂, C(O)NH, NHC(O), CH₂S(O)₂, S(O)₂(CH₂), SO₂NH, and NHSO₂, provided that Z does not form a N—

N, N—

O, N—

S, NCH₂N, NCH₂O, or NCH₂S bond with either group to which it is attached;

R⁴, at each occurrence, is selected from H, ═

O, (CH₂)_rOR², F, Cl, Br, I, C_1-4 alkyl, CN, NO₂, (CH₂)_rNR²R^2a, C(O)R^2c, NR²C(O) R^2b, C(O)NR²R^2a, NR²C(O)NR²R^2a, C(═

NR²)NR²R^2a, SO₂NR²R^2a, NR²SO₂NR²R^2a, NR²SO₂—

C_1-4 alkyl, NR²SO₂R⁵, S(O)_pR⁵, CF₃, 5-6 membered carbocycle substituted with 0-1 R⁵₁ and 5-6 membered heterocycle consisting of;

carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)_p substituted with 0-1 R⁵; and

,

R^4a, at each occurrence, is selected from H, ═

O, (CH₂)_rOR², CF₃, F, Br, Cl, C_1-4 alkyl, CN, NO₂, (CH₂)_rNR²R^2a, (CH₂)_rC(O)R^2c, NR²C(O)R^2b, C(O)NR²R^2a, NR²C(O)NR²R^2a, C(═

NR²)NR²R^2a, SO₂NR²R^2a, C(O)NHSO₂—

C_1-4 alkyl, S(O)_pR⁵, 5-6 membered carbocycle substituted with 0-1 R⁵, and 5-6 membered heterocycle consisting of;

carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)_p substituted with 0-1 R⁵.

4. A compound according to claim 3, wherein the compound is of formula Ib₂:

5. A compound according to claim 4, wherein the compound is selected from one of the formulas:

6. A compound according to claim 5, wherein:

A is selected from the group;

phenyl, piperidinyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-Cl-phenyl, 3-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 2-methylphenyl, 2-aminophenyl, and 2-methoxyphenyl; and

,

B is selected from the group;

2-(aminosulfonyl)phenyl, 2-(methylaminosulfonyl)phenyl, 1-pyrrolidinocarbonyl, 2-(methylsulfonyl)phenyl, 2-(N,N-dimethylaminomethyl)phenyl, 2-(N-methylaminomethyl)phenyl, 2-(N-ethyl-N-methylaminomethyl)phenyl, 2-(N-pyrrolidinylmethyl)phenyl, 1-methyl-2-imidazolyl, 2-methyl-1-imidazolyl, 2-(dimethylaminomethyl)-1-imidazolyl, 2-(methylaminomethyl)-1-imidazolyl, 2-(N-(cyclopropylmethyl)aminomethyl)phenyl, 2-(N-(cyclobutyl)aminomethyl)phenyl, 2-(N-(cyclopentyl)aminomethyl)phenyl, 2-(N-(4-hydroxypiperidinyl)methyl)phenyl, and 2-(N-(3-hydroxypyrrolidinyl)methyl)phenyl.

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

1-[3-(1′

,3′

,4′

-Triazol-2′

-on-5′

-yl)phenyl]-3-trifluoromethyl-5-[(2′

-N,N-dimethylaminomethyl-[1,1′

]-biphen-4-yl)aminocarbonyl]pyrazole;

1-[3-(1′

,3′

,4′

-Triazol-2′

-on-5′

-yl)phenyl]-3-trifluoromethyl-5-[(2′

-N-pyrrolidinylmethyl-[1,1′

]-biphen-4-yl)aminocarbonyl]pyrazole;

1-[3-(1′

,3′

,4′

-Triazol-2′

-on-5′

-yl)phenyl]-3-trifluoromethyl-5-[(3-fluoro-2′

-N,N-dimethylaminomethyl-[1,1′

]-biphen-4-yl)aminocarbonyl]pyrazole;

1-[3-(1′

,3′

,4′

-Triazol-2′

-on-5′

-yl)phenyl]-3-trifluoromethyl-5-[(3-fluoro-2′

-N-pyrrolidinylmethyl-[1,1′

]-biphen-4-yl)aminocarbonyl]pyrazole;

1-[3-(1′

,3′

,4′

-Triazol-2′

-on-5′

-yl)phenyl]-3-trifluoromethyl-5-[(2′

-sulfonylmethyl-[1,1′

]-biphen-4-yl)aminocarbonyl]pyrazole;

1-[3-(1′

,3′

,4′

-Triazol-2′

-on-5′

-yl)phenyl]-3-trifluoromethyl-5-[(3-fluoro-2′

-sulfonylmethyl-[1,1′

]-biphen-4-yl)aminocarbonyl]pyrazole;

1-[3-(2′

-Amino-1′

,3′

,4′

-triazol-5′

-yl)phenyl]-3-trifluoromethyl-5-[(3-fluoro-2′

-sulfonylmethyl-[1,1′

]-biphen-4-yl)aminocarbonyl]pyrazole;

1-[3-(2′

-Amino-1′

,3′

,4′

-triazol-5′

-yl)phenyl]-3-trifluoromethyl-5-[(3-fluoro-2′

-N,N-dimethylaminomethyl-[1,1′

]-biphen-4-yl)aminocarbonyl]pyrazole;

1-[3-(2′

-Amino-1′

,3′

,4′

-triazol-5′

-yl)phenyl]-3-trifluoromethyl-5-[(3-fluoro-2′

-N-pyrrolidinylmethyl-[1,1′

]-biphen-4-yl)aminocarbonyl]pyrazole;

1-[3-(2′

-Amino-3′

,4′

-thiadiazol-5′

-yl)phenyl]-3-trifluoromethyl-5-[(3-fluoro-2′

-sulfonylmethyl-[1,1′

]-biphen-4-yl)aminocarbonyl]pyrazole;

1-[3-(2′

-Amino-3′

,4′

-thiadiazol-5′

-yl)phenyl]-3-trifluoromethyl-5-[(3-fluoro-2′

-N,N-dimethylaminomethyl-[1,1′

]-biphen-4-yl)aminocarbonyl]pyrazole;

1-[3-(2′

-Amino-3′

,4′

-thiadiazol-5′

-yl)phenyl]-3-trifluoromethyl-5-[(3-fluoro-2′

-N-pyrrolidinylmethyl-[1,1′

]-biphen-4-yl)aminocarbonyl]pyrazole;

1-[3-(1′

,3′

,4′

-Triazol-2′

-on-5′

-yl)phenyl]-3-trifluoromethyl-5-[4-(2′

-(N,N-dimethylamino)methylimidazol-1′

-yl)-2-fluorophenyl)aminocarbonyl]pyrazole;

1-[3-(1′

,3′

,4′

-Triazol-2′

-on-5′

-yl)phenyl]-3-trifluoromethyl-5-[4-(2′

-methylimidazol-1′

-yl)-2-fluorophenyl)aminocarbonyl]pyrazole;

1-[3-(Pyrid-3′

-yl)phenyl]-3-trifluoromethyl-5-[(3-fluoro-2′

-sulfonylmethyl-[1,1′

]-biphen-4-yl)aminocarbonyl]pyrazole;

1-[3-(Pyrid-3′

-yl)phenyl]-3-trifluoromethyl-5-[(3-fluoro-2′

-N,N-dimethylaminomethyl-[1,1′

]-biphen-4-yl)aminocarbonyl]pyrazole;

1-[3-(Pyrid-3′

-yl)phenyl]-3-trifluoromethyl-5-[(3-fluoro-2′

-N-pyrrolidinylmethyl-[1,1′

]-biphen-4-yl) aminocarbonyl]pyrazole;

1-[3-(Pyrid-4′

-yl)phenyl]-3-trifluoromethyl-5-[(3-fluoro-2′

-N,N-dimethylaminomethyl-[1,1′

]-biphen-4-yl)aminocarbonyl]pyrazole;

1-[3-(Pyrid-4′

-yl)phenyl]-3-trifluoromethyl-5-[(3-fluoro-2′

-N-pyrrolidinylmethyl-[1,1]-biphen-4-yl)aminocarbonyl]pyrazole;

1-[3-(Pyrid-4′

-yl)phenyl]-3-trifluoromethyl-5-[(3-fluoro-2′

-sulfonylmethyl-[1,1′

]-biphen-4-yl)aminocarbonyl]pyrazole;

1-[3-(5-Amino-1,3,4-oxadiazol-2-yl)phenyl]-N-{2′

-[(dimethylamino)methyl]-3-fluoro-1,1′

-biphenyl-4-yl}-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;

1-[3-(5-Amino-1,3,4-oxadiazol-2-yl)phenyl]-N-(3-fluoro-2′

-{[(3S)-3-hydroxy-1-pyrrolidinyl]methyl}-1,1′

-biphenyl-4-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide; and

,

1-[3-(5-Amino-1,3,4-oxadiazol-2-yl)phenyl]-N-(3-fluoro-2′

-{[(3S)-3-hydroxy-1-pyrrolidinyl]methyl}-1,1′

-biphenyl-4-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxamide;

or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition, comprising:

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

9. A method for treating or preventing a thromboembolic disorder, comprising:

administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt form thereof.