Nitrogen containing heteroaromatics with ortho-substituted P1's as factor Xa inhibitors

• US 6,548,525 B2
• Filed: 04/12/2001
• Issued: 04/15/2003
• Est. Priority Date: 12/22/1997
• Status: Expired due to Term

• Current Assignee: Bristol-Myers Squibb Pharma Company (Bristol-Myers Squibb Company)
• Original Assignee: Bristol-Myers Squibb Pharma Company (Bristol-Myers Squibb Company)
• Inventors: Pinto, Donald J. P., Rossi, Karen A., Galemmo, Robert A. Jr., Bostrom, Lori L.
• Primary Examiner(s): Raymond, Richard L.
• Application Number:
  US09/833,302
• Publication Number:
  US 20020016326A1
• Time in Patent Office: 733 Days
• Field of Search: 548/260, 548/261, 548/266.8, 548/269.2, 514/359.383
• US Class Current: 514/359
• CPC Class Codes: C07D 231/14 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 231/22 with aryl radicals attached to ring nitrogen atoms
• CPC Class Codes: C07D 231/24 having sulfone or sulfonic acid radicals in the molecule
• CPC Class Codes: C07D 249/04 1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
• CPC Class Codes: C07D 257/04 Five-membered rings
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links

Abstract

The present application describes nitrogen containing heteroaromatics with ortho-substituted P1'"'"'s and derivatives thereof of formula I:

or pharmaceutically acceptable salt or prodrug forms thereof, wherein J is N or NH and D is substituted ortho to G on E and may be CH₂NH₂, which are useful as inhibitors of factor Xa.

Claims

1. A compound of formula I:

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;

ring M contains, in addition to J, 2 N atoms and R^1b is not present;

J is N or NH;

D is selected from CN, C(═

NR⁸)NR⁷R⁹, NHC(═

NR⁸)NR⁷R⁹, NR⁸CH(═

NR⁷), C(O)NR⁷R⁸, and (CR⁸R⁹)_tNR⁷R⁸, provided that D is substituted ortho to G on E;

E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, and piperidinyl substituted with 1-2 R;

R is selected from H, Cl, F, Br, I, (CH₂)_tOR³, C_1-4 alkyl, OCF₃, CF₃, C(O)NR⁷R⁸, and (CR⁸R⁹)_tNR⁷R⁸;

G is absent or is selected from NHCH₂, OCH₂, and SCH₂, provided that when s is 0, then G is attached to a carbon atom on ring M;

Z is selected from a C_1-4 alkylene, (CH₂)_rO(CH₂)_r, (CH₂)_rNR³(CH₂)_r, (CH₂)_rC(O)(CH₂)_r, (CH₂)_rC(O)O(CH₂)_r, (CH₂)_rOC(O)(CH₂)_r, (CH₂)_rC(O)NR³(CH₂)_r, (CH₂)_rNR³C(O)(CH₂)_r, (CH₂)_rOC(O)O(CH₂)_r, (CH₂)_rOC(O)NR³(CH₂)_r, (CH₂)_rNR³C(O)O(CH₂)_r, (CH₂)_rNR³C(O)NR³(CH₂)_r, (CH₂)_rS(O)_p(CH₂)_r, (CH₂)_rSO₂NR³(CH₂)_r, (CH₂)_rNR³SO₂(CH₂)_r, and (CH₂)_rNR³SO₂NR³(CH₂)_r, provided that Z does not form a N—

N, N—

O, N—

S, NCH₂N, NCH₂O, or NCH₂S bond with ring M or group A;

R^1a and R^1b are independently absent or selected from —

(CH₂)<sub>r—

R</sub>^1′

, —

CH═

CH—

R^1′

, NCH₂R^1″

, OCH₂R^1″

, SCH₂R^1″

, NH(CH₂)₂(CH₂)_tR^1′

, O(CH₂)₂(CH₂)_tR^1′

, and S(CH₂)₂(CH₂)_tR^1′

;

alternatively, R^1a and R^1b, when attached to adjacent carbon atoms, together with the atoms to which they are attached form a 5-8 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R⁴ and which contains from 0-2 heteroatoms selected from the group consisting of N, O, and S;

R^1′

is selected from H, C_1-3 alkyl, F, Cl, Br, I, —

CN, —

CHO, (CF₂)_rCF₃, (CH₂)_rOR², NR²R^2a, C(O)R^2c, OC(O)R², (CF₂)_rCO₂R^2c, S(O)_pR^2b, NR²(CH₂)_rOR², C(═

NR^2c)NR²R^2a, NR²C(O)R^2b, NR²C(O)NHR^2b, NR²C(O)₂R^2a, OC(O)NR^2aR^2b, C(O)NR²R^2a, C(O)NR²(CH₂)_rOR², SO₂NR²R^2a, NR²SO₂R^2b, C_3-6 carbocyclic residue substituted with 0-2 R⁴, and 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R⁴;

R^1″

is selected from H, CH(CH₂OR²)₂, C(O)R^2c, C(O)NR²R^2a, S(O)R^2b, S(O)₂R^2b, and SO₂NR²R^2a;

R², at each occurrence, is selected from H, CF₃, C_1-6 alkyl, benzyl, C_3-6 carbocyclic residue substituted with 0-2 R^4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R^4b;

R^2a, at each occurrence, is selected from H, CF₃, C_1-6 alkyl, benzyl, C_3-6 carbocyclic residue substituted with 0-2 R^4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R^4b;

R^2b, at each occurrence, is selected from CF₃, C_1-4 alkoxy, C_1-6 alkyl, benzyl, C_3-6 carbocyclic residue substituted with 0-2 R^4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R^4b;

R^2c, at each occurrence, is selected from CF₃, OH, C_1-4 alkoxy, C_1-6 alkyl, benzyl, C_3-6 carbocyclic residue substituted with 0-2 R^4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R^4b;

alternatively, R² and R^2a combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R^4b which contains from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;

alternatively, R² and R^2a, together with the atom to which they are attached, combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R^4b and containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;

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

R^3a, at each occurrence, is selected from H, C_1-4 alkyl, and phenyl;

R^3c, at each occurrence, is selected from C_1-4 alkyl, and phenyl;

A is selected from;

C_3-10 carbocyclic residue substituted with 0-2 R⁴, and

5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R⁴;

B is selected from;

Y, X—

Y, NR²R^2a, C(═

NR²)NR²R^2a, NR²C(═

NR²)NR²R^2a,

C_3-10 carbocyclic residue substituted with 0-2 R^4a, and

5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R^4a;

X is selected from C_1-4 alkylene, —

CR²(CR²R^2b) (CH₂)_t—

, —

C(O)—

, —

C(═

NR^1″

)—

, —

CR²(NR^1″

R²)—

, —

CR²(OR²)—

, —

CR²(SR²)—

, —

C(O)CR²R^2a—

, —

CR²R^2aC(O), —

S(O)_p—

, —

S(O)_pCR²R^2a—

, —

CR²R^2aS(O)_p—

, —

S(O)₂NR²—

, —

NR²S (O)₂—

, —

NR²S(O)₂CR²R^2a—

, —

CR²R^2aS(O)₂NR²—

, —

NR²S(O)₂NR²—

, —

C(O)NR²—

, —

NR²C(O)—

, —

C(O)NR²CR²R^2a—

, —

NR²C(O)CR²R^2a—

, —

CR²R^2aC(O)NR²—

, —

CR²R^2aNR²C(O)—

, —

NR²C(O)O—

, —

OC(O)NR²—

, —

NR²C(O)NR²—

, —

NR²—

, —

NR²CR²R^2a—

, —

CR²R^2aNR²—

, O, —

CR²R^2aO—

, and —

OCR²R^2a—

;

Y is selected from;

(CH₂)_rNR²R^2a, provided that X—

Y do not form a N—

N, O—

N, or S—

N bond,

C_3-10 carbocyclic residue substituted with 0-2 R^4a, and

5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R^4a;

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

O, (CH₂)_rOR², F, Cl, Br, I, 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, C(═

NS(O)₂R⁵)NR²R^2a, NHC(═

NR²)NR²R^2a, C(O)NHC(═

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

C_1-4 alkyl, NR²SO₂R⁵, S(O)_pR⁵, (CF₂)_rCF₃, NCH₂R^1″

, OCH₂R^1″

, SCH₂R^1″

, N(CH₂)₂(CH₂)_tR^1′

, O(CH₂)₂(CH₂)_tR^1′

, and S(CH₂)₂(CH₂)_tR^1′

,

alternatively, one R⁴ is a 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;

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

O, (CH₂)_rOR², (CH₂)_r—

F, (CH₂)_r—

Br, (CH₂)_r—

Cl, Cl, Br, F, I, C_1-4 alkyl, —

CN, NO₂, (CH₂)_rNR²R^2a, (CH₂)_rC(O)R^2c, NR²C(O)R^2b, C(O)NR²R^2a, C(O)NH(CH₂)₂NR²R^2a, NR²C(O)NR²R^2a, C(═

NR²)NR²R^2a, NHC(═

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

C_1-4 alkyl, C(O)NHSO₂—

C_1-4 alkyl, NR²SO₂R⁵, S(O)_pR⁵, and (CF₂)_rCF₃;

alternatively, one R^4a is a 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-1 R⁵;

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

O, (CH₂)_rOR³, F, Cl, Br, I, C_1-4 alkyl, —

CN, NO₂, (CH₂)_rNR³R^3a, (CH₂)_rC(O)R³, (CH₂)_rC(O)OR^3c, NR³C(O)R^3a, C(O)NR³R^3a, NR³C(O)NR³R^3a, C(═

NR³)NR³R^3a, NR³C(═

NR³)NR³R^3a, SO₂NR³R^3a, NR³SO₂NR³R^3a, NR³SO₂—

C_1-4 alkyl, NR³SO₂CF₃, NR³SO₂-phenyl, S(O)_pCF₃, S(O)_p—

C_1-4 alkyl, S(O)_p-phenyl, and (CF₂)_rCF₃;

R⁵, at each occurrence, is selected from CF₃, C_1-6 alkyl, phenyl substituted with 0-2 R⁶, and benzyl substituted with 0-2 R⁶;

R⁶, at each occurrence, is selected from H, OH, (CH₂)_rOR², halo, C_1-4 alkyl, CN, NO₂, (CH₂)_rNR²R^2a, (CH₂)_rC(O)R^2b, NR²C(O)R^2b, NR²C(O)NR²R^2a, C(═

NH)NH₂, NHC(═

NH)NH₂, SO₂NR²R^2a, NR²SO₂NR²R^2a, and NR²SO₂C_1-4 alkyl;

R⁷, at each occurrence, is selected from H, OH, C_1-6 alkyl, C_1-6 alkylcarbonyl, C_1-6 alkoxy, C_1-4 alkoxycarbonyl, (CH₂)n-phenyl, C_6-10 aryloxy, C_6-10 aryloxycarbonyl, C_6-10 arylmethylcarbonyl, C_1-4 alkylcarbonyloxy C_1-4 alkoxycarbonyl, C_6-10 arylcarbonyloxy C_1-4 alkoxycarbonyl, C_1-6 alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C_1-4 alkoxycarbonyl;

R⁸, at each occurrence, is selected from H, C_1-6 alkyl and (CH₂)n-phenyl;

alternatively, R⁷ and R⁸ combine to form a 5 or 6 membered saturated, ring which contains from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;

R⁹, at each occurrence, is selected from H, C_1-6 alkyl and (CH₂)n-phenyl;

n, at each occurrence, is selected from 0, 1, 2, and 3;

p, at each occurrence, is selected from 0, 1, and 2;

r, at each occurrence, is selected from 0, 1, 2, and 3;

s, at each occurrence, is selected from 0, 1, and 2; and

,

t, at each occurrence, is selected from 0, 1, 2, and 3;

provided that D—

E—

G—

(CH₂)_s— and

—

Z—

A—

B are not both benzamidines.

2. A compound according to claim 1, wherein the compound is of formulae Id-If:

wherein, groups D—

E— and

—

Z—

A—

B are attached to adjacent atoms on the ring;

R is selected from H, Cl, F, Br, I, (CH₂)_tOR³, C_1-4 alkyl, OCF₃, CF₃, C(O)NR⁷R⁸, and (CR⁸R⁹)_tNR⁷R⁸;

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

N, N—

O, NCH₂N, or NCH₂O bond with ring M or group A;

A is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R⁴;

phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, and isoindazolyl;

B is selected from;

Y, X—

Y, NR²R^2a, C(═

NR²)NR²R^2a, and NR²C (═

NR²)NR²R^2a;

X is selected from C_1-4 alkylene, —

C(O)—

, —

C(═

NR)—

, —

CR²(NR²R^2a)—

, —

C(O)CR²R^2a—

, —

CR²R^2aC(O), —

C(O)NR²—

, —

NR²C(O)—

, —

C(O)NR²CR²R^2a—

, —

NR²C(O)CR²R^2a—

, —

CR²R^2aC(O)NR²—

, —

CR²R^2aNR²C(O)—

, —

NR²C(O)NR²—

, —

NR²—

, —

NR²CR²R^2a—

, —

CR²R^2aNR²—

, O, —

CR²R^2aO—

, and —

CR²R^2a—

;

Y is NR²R^2a, provided that X—

Y do not form a N—

N or O—

N bond;

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

cylcopropyl, cyclopentyl, cyclohexyl, phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, and isoindazolyl;

alternatively, Y is selected from the following bicyclic heteroaryl ring systems;

K is selected from O, S, NH, and N.

3. A compound according to claim 2, wherein the compound is of formulae IIb-IIc:

wherein;

Z is selected from a C(O), CH₂C(O), C(O)CH₂, NHC(O), C(O)NH, C(O)N(CH₃), CH₂S(O)₂, S(O)₂(CH₂), SO₂NH, and NHSO₂, provided that Z does not form a N—

N or NCH₂N bond with ring M or group A.

4. A compound according to claim 3, wherein;

E is phenyl substituted with R or 2-pyridyl substituted with R;

D is selected from NH₂, NHCH₃, CH₂NH₂, CH₂NHCH₃, CH(CH₃)NH₂, and C(CH₃)₂NH₂, provided that D is substituted ortho to ring M on E; and

,

R is selected from H, OCH₃, Cl, and F.

5. A compound according to claim 4, wherein;

D—

E is selected from 2-aminophenyl, 2-methylaminophenyl, 2-aminomethylphenyl, 4-methoxy-2-aminophenyl, 4-methoxy-2-(methylamino)phenyl, 4-methoxy-2-aminomethylphenyl, 4-methoxy-2-(methylaminomethyl)phenyl, 4-methoxy-2-(1-aminoethyl)phenyl, 4-methoxy-2-(2-amino-2-propyl)phenyl, 4-Cl-2-aminophenyl, 4-Cl-2-(methylamino)phenyl, 4-Cl-2-aminomethylphenyl, 4-Cl-2-(methylaminomethyl)phenyl, 4-Cl-2-(1-aminoethyl)phenyl, 4-Cl-2-(2-amino-2-propyl)phenyl, 4-F-2-aminophenyl, 4-F-2-(methylamino)phenyl, 4-F-2-aminomethylphenyl, 4-F-2-(methylaminomethyl)phenyl, 4-F-2-(1-aminoethyl)phenyl, and 4-F-2-(2-amino-2-propyl)phenyl.

6. A compound according to claim 3, wherein;

Z is C(O)CH₂ and CONH, provided that Z does not form a N—

N bond with group A;

A is selected from phenyl, pyridyl, and pyrimidyl, and is substituted with 0-2 R⁴;

B is selected from X—

Y, phenyl, pyrrolidino, morpholino, 1,2,3-triazolyl, and imidazolyl, and is substituted with 0-1 R^4a;

R⁴, at each occurrence, is selected from OH, (CH₂)_rOR², halo, C_1-4 alkyl, (CH₂)_rNR²R^2a, and (CF₂)_rCF₃;

R^4a is selected from C_1-4 alkyl, CF₃, S(O)_pR⁵, (CH₂)_rNR²R^2a, SO₂NR²R^2a, and 1-CF₃-tetrazol-2-yl;

R⁵, at each occurrence, is selected from CF₃, C_1-6 alkyl, phenyl, and benzyl;

X is CH₂ or C(O); and

,

Y is selected from pyrrolidino and morpholino.

7. A compound according to claim 6, wherein;

A is selected from the group;

phenyl, 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-CF₃-phenyl, 2-(aminosulfonyl)phenyl, 2-(methylaminosulfonyl)phenyl, 2-(dimethylaminosulfonyl)phenyl, 1-pyrrolidinocarbonyl, 2-(methylsulfonyl)phenyl, 4-morpholino, 2-(1′

-CF₃-tetrazol-2-yl)phenyl, 4-morpholinocarbonyl, 2-methyl-1-imidazolyl, 5-methyl-1-imidazolyl, 2-methylsulfonyl-1-imidazolyl and, 5-methyl-1,2,3-triazolyl.

8. A compound according to claim 3, wherein;

E is phenyl substituted with R or 2-pyridyl substituted with R;

D is selected from NH₂, NHCH₃, CH₂NH₂, CH₂NHCH₃, CH(CH₃)NH₂, and C(CH₃)₂NH₂, provided that D is substituted ortho to ring M on E;

R is selected from H, OCH₃, Cl, and F;

Z is C(O)CH₂ or CONH, provided that Z does not form a N—

N bond with group A;

A is selected from phenyl, pyridyl, and pyrimidyl, and is substituted with 0-2 R⁴; and

,

B is selected from X—

Y, phenyl, pyrrolidino, morpholino, 1,2,3-triazolyl, and imidazolyl, and is substituted with 0-1 R^4a;

R⁴, at each occurrence, is selected from OH, (CH₂)_rOR², halo, C_1-4 alkyl, (CH₂)_rNR²R^2a, and (CF₂)_rCF₃;

R^4a is selected from C_1-4 alkyl, CF₃, S(O)_pR⁵, (CH₂)_rNR²R^2a, SO₂NR²R^2a, and 1-CF₃-tetrazol-2-yl;

R⁵, at each occurrence, is selected from CF₃, C_1-6 alkyl, phenyl, and benzyl;

X is CH₂ or C(O); and

,

Y is selected from pyrrolidino and morpholino.

9. A compound according to claim 8, wherein;

D—

E is selected from 2-aminophenyl, 2-methylaminophenyl, 2-aminomethylphenyl, 4-methoxy-2-aminophenyl, 4-methoxy-2-(methylamino)phenyl, 4-methoxy-2-aminomethylphenyl, 4-methoxy-2-(methylaminomethyl)phenyl, 4-methoxy-2-(1-aminoethyl)phenyl, 4-methoxy-2-(2-amino-2-propyl)phenyl, 4-Cl-2-aminophenyl, 4-Cl-2-(methylamino)phenyl, 4-Cl-2-aminomethylphenyl, 4-Cl-2-(methylaminomethyl)phenyl, 4-Cl-2-(1-aminoethyl)phenyl, 4-Cl-2-(2-amino-2-propyl)phenyl, 4-F-2-aminophenyl, 4-F-2-(methylamino)phenyl, 4-F-2-aminomethylphenyl, 4-F-2-(methylaminomethyl)phenyl, 4-F-2-(1-aminoethyl)phenyl, and 4-F-2-(2-amino-2-propyl)phenyl;

A is selected from the group;

phenyl, 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-CF₃-phenyl, 2-(aminosulfonyl)phenyl, 2-(methylaminosulfonyl)phenyl, 2-(dimethylaminosulfonyl)phenyl, 1-pyrrolidinocarbonyl, 2-(methylsulfonyl)phenyl, 4-morpholino, 2-(1′

-CF₃-tetrazol-2-yl)phenyl, 4-morpholinocarbonyl, 2-methyl-1-imidazolyl, 5-methyl-1-imidazolyl, 2-methylsulfonyl-1-imidazolyl and, 5-methyl-1,2,3-triazolyl.

10. A compound according to claim 9, wherein the compound is of formula IIb.

11. A compound according to claim 9, wherein the compound is of formula IIb.

12. A compound according to claim 3, wherein;

D is selected from —

CN, C(═

NR⁸)NR⁷R⁹, C(O)NR⁷R⁸, NR⁷R⁸, and CH₂NR⁷R⁸, provided that D is substituted ortho to ring M on E;

E is phenyl substituted with R or pyridyl substituted with R;

R is selected from H, Cl, F, OR³, CH₃, CH₂CH₃, OCF₃, CF₃, NR⁷R⁸, and CH₂NR⁷R⁸;

Z is selected from C(O), CH₂C(O), C(O)CH₂, NHC(O), and C(O)NH, provided that Z does not form a N—

N bond with ring M or group A;

R^1a and R^1b are independently absent or selected from —

(CH₂)_r—

R^1′

, NCH₂R^1″

, OCH₂R^1″

, SCH₂R^1″

, N(CH₂)₂(CH₂)_tR^1′

, O(CH₂)₂(CH₂)_tR^1′

, and S(CH₂)₂(CH₂)_tR^1′

, or combine to form a 5-8 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R⁴ and which contains from 0-2 heteroatoms selected from the group consisting of N, O, and S;

R^1′

, at each occurrence, is selected from H, C_1-3 alkyl, halo, (CF₂)_rCF₃, OR², NR²R^2a, C(O)R^2c, (CF₂)_rCO₂R^2c, S(O)_pR^2b, NR²(CH₂)_rOR², NR²C(O)R^2b, NR²C(O)₂R^2b, C(O)NR²R^2a, SO₂NR²R^2a, and NR²SO₂R^2b;

A is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R⁴;

phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, and imidazolyl;

B is selected from;

Y, X—

Y, NR²R^2a, C(═

NR²)NR²R^2a, and NR²C(═

NR²)NR²R^2a;

X is selected from CH₂, —

CR²(CR²R^2b) (CH₂)_t—

, —

C(O)—

, —

C(═

NR)—

, —

CH(NR²R^2a)—

, —

C(O)NR²—

, —

NR²C(O)—

, —

NR²C(O)NR²—

, —

NR²—

, and O;

Y is NR²R^2a, provided that X—

Y do not form a N—

N or O—

N bond;

alternatively, 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, isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, and 1,3,4-triazolyl;

R⁴, at each occurrence, is selected from ═

O, OH, Cl, F, C_1-4 alkyl, (CH₂)_rNR²R^2a, (CH₂)_rC(O)R^2b, NR²C(O)R^2b, C(O)NR²R^2a, C(═

NH)NH₂, NHC(═

NH)NH₂, SO₂NR²R^2a, NR²SO₂—

C_1-4 alkyl, NR²SO₂R⁵, S(O)_pR⁵, and (CF₂)_rCF₃;

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

O, OH, Cl, F, C_1-4 alkyl, (CH₂)_rNR²R^2a, (CH₂)_rC(O)R^2b, NR²C(O)R^2b, C(O)NR²R^2a, C(═

NH)NH₂, NHC(═

NH)NH₂, SO₂NR²R^2a, NR²SO₂—

C_1-4 alkyl, NR²SO₂R⁵, S(O)_pR⁵, (CF₂)_rCF₃, and 1—

CF₃-tetrazol-2-yl;

R⁵, at each occurrence, is selected from CF₃, C_1-6 alkyl, phenyl substituted with 0-2 R⁶, and benzyl substituted with 0-2 R⁶;

R⁶, at each occurrence, is selected from H, ═

O, OH, OR², Cl, F, CH₃, CN, NO₂, (CH₂)_rNR²R^2a, (CH₂)_rC(O)R^2b, NR²C(O)R^2b, C(═

NH)NH₂, NHC(═

NH)NH₂, and SO₂NR²R^2a;

R⁷, at each occurrence, is selected from H, OH, C_1-6 alkyl, C_1-6 alkylcarbonyl, C_1-6 alkoxy, C_1-4 alkoxycarbonyl, benzyl, C_6-10 aryloxy, C_6-10 aryloxycarbonyl, C_6-10 arylmethylcarbonyl, C_1-4 alkylcarbonyloxy C_1-4 alkoxycarbonyl, C_6-10 arylcarbonyloxy C_1-4 alkoxycarbonyl, C_1-6 alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C_1-4 alkoxycarbonyl;

R⁸, at each occurrence, is selected from H, C_1-6 alkyl and benzyl;

alternatively, R⁷ and R⁸ combine to form a morpholino group; and

,

R⁹, at each occurrence, is selected from H, C_1-6 alkyl and benzyl.

13. A compound according to claim 12, wherein;

E is phenyl substituted with R or 2-pyridyl substituted with R;

R is selected from H, Cl, F, OCH₃, CH₃, OCF₃, CF₃, NH₂, and CH₂NH₂;

z is selected from C(O)CH₂ and C(O)NH, provided that Z does not form a N—

N bond with group A;

R^1a is selected from H, CH₃, CH₂CH₃, Cl, F, CF₃, OCH₃, NR²R^2a, S(O)_pR^2b, CH₂S(O)_pR^2b, CH₂NR²S(O)_pR^2b, C(O)R^2c, CH₂C(O)R^2c, C(O)NR²R^2a, and SO₂NR²R^2a;

R^1b is selected from H, CH₃, CH₂CH₃, Cl, F, CF₃, OCH₃, NR²R^2a, S(O)_pR^2b, CH₂S(O)_pR^2b, CH₂NR²S(O)_pR^2b, C(O)R^2c, CH₂C(O)R^2c, C(O)NR²R^2a, and SO₂NR²R^2a;

A is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R⁴;

phenyl, pyridyl, pyrimidyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, and imidazolyl;

B is selected from;

Y and X—

Y;

X is selected from CH₂, —

CR²(CR²R^2b)—

, —

C(═

NR)—

, —

C(═

NR)—

, —

CH(NR²R^2a)—

, —

C(O)NR²—

, —

NR²C(O)—

, —

NR²C(O)NR²—

, —

NR²—

, and O;

Y is NR²R^2a, provided that X—

Y do not form a N—

N or O—

N bond;

alternatively, 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, isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, and 1,3,4-triazolyl;

R², at each occurrence, is selected from H, CF₃, CH₃, benzyl, and phenyl;

R^2a, at each occurrence, is selected from H, CF₃, CH₃, benzyl, and phenyl;

R^2b, at each occurrence, is selected from CF₃, OCH₃, CH₃, benzyl, and phenyl;

R^2c, at each occurrence, is selected from CF₃, OH, OCH₃, CH₃, benzyl, and phenyl;

alternatively, R² and R^2a combine to form a 5 or 6 membered saturated, partially unsaturated, or unsaturated ring which contains from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;

R³, at each occurrence, is selected from H, CH₃, CH₂CH₃, and phenyl;

R^3a, at each occurrence, is selected from H, CH₃, CH₂CH₃, and phenyl;

R⁴, at each occurrence, is selected from OH, Cl, F, CH₃, CH₂CH₃, NR²R^2a, CH₂NR²R^2a, C(O)R^2b, NR²C(O)R^2b, C(O)NR²R^2a, and CF₃;

R^4a, at each occurrence, is selected from OH, Cl, F, CH₃, CH₂CH₃, NR²R^2a, CH₂NR²R^2a, C(O)R^2b, C(O)NR²R^2a, SO₂NR²R^2a, S(O)_pR⁵, CF₃, and 1-CF₃-tetrazol-2-yl;

R⁵, at each occurrence, is selected from CF₃, C_1-6 alkyl, phenyl substituted with 0-2 R⁶, and benzyl substituted with 1 R⁶;

R⁶, at each occurrence, is selected from H, OH, OCH₃, Cl, F, CH₃, CN, NO₂, NR²R^2a, CH₂NR²R^2a, and SO₂NR²R^2a;

R⁷, at each occurrence, is selected from H and C_1-3 alkyl;

R⁸, at each occurrence, is selected from H, CH₃, and benzyl;

R⁹, at each occurrence, is selected from H, CH₃, and benzyl; and

,

t, at each occurrence, is selected from 0 and 1.

14. A compound according to claim 13, wherein;

D is selected from NR⁷R⁸ and CH₂NR⁷R⁸, provided that D is substituted ortho to ring M on E;

R^1a is absent or is selected from H, CH₃, CH₂CH₃, Cl, F, CF₃, OCH₃, NR²R^2a, S(O)_pR^2b, C(O)NR²R^2a, CH₂S(O)_pR^2a, CH₂NR²S(O)_pR^2b, C(O)R^2c, CH₂C(O)R^2c, and SO₂NR²R^2a;

R^1b is absent or is selected from H, CH₃, CH₂CH₃, Cl, F, CF₃, OCH₃, NR²R^2a, S(O)_pR^2b, C(O)NR²R^2a, CH₂S(O)_pR^2b, CH₂NR²S(O)_pR^2b, C(O)R^2b, CH₂C(O)R^2b, and SO₂NR²R^2a;

A is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R⁴;

phenyl, pyridyl, and pyrimidyl;

B is selected from;

Y and X—

Y;

X is selected from —

C(O)— and

O;

Y is NR²R^2a, provided that X—

Y do not form a O—

N bond;

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

phenyl, piperazinyl, pyridyl, pyrimidyl, morpholinyl, pyrrolidinyl, imidazolyl, and 1,2,3-triazolyl;

R², at each occurrence, is selected from H, CF₃, CH₃, benzyl, and phenyl;

R^2a, at each occurrence, is selected from H, CF₃, CH₃, benzyl, and phenyl;

R^2b, at each occurrence, is selected from CF₃, OCH₃, CH₃, benzyl, and phenyl;

R^2c, at each occurrence, is selected from CF₃, OH, OCH₃, CH₃, benzyl, and phenyl;

alternatively, R² and R^2a combine to form a ring system selected from pyrrolidinyl, piperazinyl and morpholino;

R⁴, at each occurrence, is selected from Cl, F, CH₃, NR²R^2a, and CF₃;

R^4a, at each occurrence, is selected from Cl, F, CH₃, CH₂NR²R^2a, SO₂NR²R^2a, S(O)_pR⁵, and CF₃;

R⁵, at each occurrence, is selected from CF₃ and CH₃;

R⁷, at each occurrence, is selected from H, CH₃, and CH₂CH₃; and

,

R⁸, at each occurrence, is selected from H and CH₃.

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

1-(2′

-Aminomethylphenyl)-5-[[(2′

-methylsulfonyl)-3-fluoro-[1,1′

]-biphen-4-yl]aminocarbonyl]-tetrazole;

1-(2′

-Aminomethylphenyl)-5-[(2′

-aminosulfonyl-[1,1′

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

1-[2-(Aminomethyl)phenyl]-5-[(2-fluoro)-(2′

-methylsulfonyl-[1,1′

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

and pharmaceutically acceptable salts thereof.

16. 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 thereof.

17. A method for treating 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 thereof.