Claims for Patent: 6,413,980

Summary for Patent: 6,413,980

Title:	Nitrogen containing heterobicycles as factor Xa inhibitors
Abstract:	The present application describes nitrogen containing heterobicyclics and derivatives thereof, or pharmaceutically acceptable salt forms thereof, which are useful as inhibitors of factor Xa.
Inventor(s):	John M. Fevig, Joseph Cacciola, Charles G. Clark, Qi Han, Patrick Yuk Sun Lam, Donald J.P. Pinto, James R. Pruitt, Mimi L. Quan, Karen A. Rossi
Assignee:	Bristol Myers Squibb Co
Application Number:	US09/470,326
Patent Claims:	1. A compound selected from the group: or a stereoisomer or pharmaceutically acceptable salt thereof, wherein compounds of the above formulas are substituted with 0-2 R3; G is a group of formula I or II: ring D is selected from —(CH2)3—,—(CH2)4—,—CH2N=CH—, —CH2CH2N=CH—, and a 5-6 membered aromatic system, containing from 0-2 heteroatoms selected from the group N, O, and S, provided that from 0-1 O and S atoms are present; ring D, when present, is substituted with 0-2 R; E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and pyridazinyl, substituted with 0-1 R; R is selected from Cl, F, Br, I, OH, C1-3 alkoxy, NH2, NH(C1-3 alkyl), N(C1-3 alkyl)2, CH2NH2, CH2NH (C1-3 alkyl), CH2N(C1-3 alkyl)2, CH2CH2NH2, CH2CH2NH(C1-3 alkyl), and CH2CH2N(C1-3 alkyl)2; alternatively, ring D is absent; when ring D is absent, ring E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and pyridazinyl, and ring E is substituted with R″ and R′; R″ is selected from F, Cl, Br, I, OH, C1-3 alkoxy, CN, C(=NR8)NR7R9, NHC(=NR8)NR7R9, NR8CH(=NR7), C(O)NR7R8, (CR8R9)tNR7R8, SH, C1-3 alkyl-S, S(O)R3b, S(O)2R3a, S(O)2NR2R2a, and OCF3; R′ is selected from H, F, Cl, Br, I, SR3, CO2R3, NO2, (CH2)tOR3, C1-4 alkyl, OCF3, CF3, C(O)NR7R8, and (CR8R9)tNR7R8; alternatively, R″ and R′ combine to form methylenedioxy or ethylenedioxy; Z is N or CR1a; Z1 is S, O, or NR3; Z2 is selected from H, C1-4 alkyl, phenyl, benzyl, C(O)R3, and S(O)pR3c; R1a is selected from H, —(CH2)r—R1′, —CH =CH—R1′, NCH2R1″, OCH2R1″, SCH2R1″, NH(CH2)2(CH2)tR1′, O(CH2)2(CH2)tR1′, and S(CH2)2(CH2)tR1′; R1′ is selected from H, C1-3 alkyl, F, Cl, Br, I, —CN, —CHO, (CF2)rCF3, (CH2)rOR2, NR2R2a, C(O)R2c, OC(O)R2, (CF2)rCO2R2c, S(O)pR2b, NR2(CH2)rOR2, C(=NR 2c)NR2R2a, NR2C(O)R2b, NR2C(O)R3, NR2C(O)NHR2b, NR2C(O)2R2a, OC(O)NR2aR2b, C(O)NR2R2a, C(O)NR2(CH2)rOR2, SO2NR2R2a, NR2SO2R2b, C3-6 carbocyclic residue substituted with 0-2 R4a, 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 R4a; R1″ is selected from H, CH(CH2OR2)2, C(O)R2c, C(O)NR2R2a, S(O)R2b, S(O)2R2b, and SO2NR2R2a; R2, at each occurrence, is selected from H, CF3, C1-6 alkyl, benzyl, C3-6 carbocyclic residue substituted with 0-2 R4b, a C3-6 carbocyclic—CH2— residue substituted with 0-2 R4b, 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 R4b; R2a, at each occurrence, is selected from H, CF3, C1-6 alkyl, benzyl, C3-6 carbocyclic residue substituted with 0-2 R4b, 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 R4b; R2b, at each occurrence, is selected from CF3, C1-4 alkoxy, C1-6 alkyl, benzyl, C3-6 carbocyclic residue substituted with 0-2 R4b, 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b; R2c, at each occurrence , is selected from CF3, OH, C1-4 alkoxy, C1-6 alkyl, benzyl, C3-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 014 3 R4b; alternatively, R2 and R2a, 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 R4b 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, C1-4 alkyl, and phenyl; R3a, at each occurrence, is selected from H, C1-4 alkyl, and phenyl; R3b, at each occurrence, is selected from H, C1-4 alkyl, and phenyl; R3c, at each occurrence, is selected from C1-4 alkyl, and phenyl; A is selected from: C3-10 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, C(=NR2)NR 2R2a, and NR2C(=NR2)NR2R2a, provided that B is other than a cycloalkoxy group; X is selected from C1-4 alkylene, —CR2(CR2R2b)(CH2)t—, —C(O)—, —C(=NR1″)—, —CR2(NR1″R 2)—, —CR2(OR2)-, —CR2(SR2)—, —C(O)CR2R2a—, —CR2R2aC(O), —S(O)p—, —S(O)pCR2R2a—, —CR2R2aS(O)p—, —S(O)2NR2—, —NR2S(O)2—, —NR2S(O)2CR2R2a—, —CR2R2aS(O)2NR2—, —NR2S(O)2NR2—, —C(O)NR2—, —NR2C(O)—, —C(O)NR2CR2R2a—,—NR2C(O)CR2R2a—, —CR2R2aC(O)NR2—, —CR2R2aNR2C(O)—, —NR2C(O)O—, —OC(O)NR2—, —NR2C(O)NR2—, —NR2—, —NR2CR2R2a—, —CR2R2aNR2—, O, —CR2R2aO—, and —OCR2R2a—; Y is selected from: CH2NR2R2a; CH2CH2NR2R2a; C3-10 carbocyclic residue substituted with 0-2 R4a, 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 R4a; R4, at each occurrence, is selected from H, =O, (CH2)rOR2, F, Cl, Br, I, C1-4 alkyl, —CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2c, NR2C(O)R2b, C(O)NR2R2a, NR2C(O)NR2R2a, C(=NR2)NR2R2a, C(=NS(O)2R5)NR2R2a, NHC(=NR2)NR2R2a, C(O)NHC(=NR2)NR2R2a, SO2NR2R2a, NR2SO2NR2R2a, NR2SO2—C1-4 alkyl, NR2SO2R5, S(O)pR5, (CF2)rCF3, NCH2R1″, OCH2R″, SCH2R1″, N(CH2)2(CH2)tR1′, O(CH2)2(CH2)tR1′, and S(CH2)2(CH2 tR1′; 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; R4a, at each occurrence, is selected from H, =O, (CH2)rOR2, (CH2)r—F, (CH2)r—Br, (CH2)r—Cl, Cl, Br, F, I, C1-4 alkyl, —CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2c, NR2C(O)R2b, C(O)NR2R2a, (CH2)rN=CHOR3, C(O)NH(CH2)2NR2R2a, NR2C(O)NR2R2a, C(=NR2)NR2R2a, NHC(=NR2)NR2R2a, SO2NR2R2a, NR2SO2NR2R2a, NR2SO2—C1-4 alkyl, C(O)NHSO2—C1-4 alkyl, NR2SO2R5, S(O)pR5, and (CF2)rCF3; alternatively, one R4a 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; R4b, at each occurrence, is selected from H, =O, (CH2)rOR3, F, Cl, Br, I, C1-4 alkyl, —CN, NO2, (CH2)rNR3R3a, (CH2)rC(O)R3, (CH2)rC(O)OR3c, NR3C(O)R3a, C(O)NR3R3a, NR3C(O)NR3R3a, C(=NR3NR3R3a, NR3C(=NR3)NR3R3a, SO2NR3R3a, NR3SO2NR3R3a, NR3SO2—C1-4 alkyl, NR3SO2CF3, NR3SO2—phenyl, S(O)pCF3, S(O)p—C1-4 alkyl, S(O)p—phenyl, and (CF2)rCF3; R5, at each occurrence, is selected from CF3, C1-6 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, C1-4 alkyl, CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2b, NR2C(O)R2b, NR2C(O)NR2R2a, C(=NH)NH2, NHC(=NH)NH2, SO2NR2R2a, NR2SO2NR2R2a, and NR2SO2C1-4 alkyl; R7, at each occurrence, is selected from H, OH, C1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxy, C1-4 alkoxycarbonyl, (CH2)n—phenyl, C6-10 aryloxy, C6-10 aryloxycarbonyl, C6-10 arylmethylcarbonyl, C1-4 alkylcarbonyloxy C1-4 alkoxycarbonyl, C6-10 arylcarbonyloxy C1-4 alkoxycarbonyl, C1-6 alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C1-4 alkoxycarbonyl; R8, at each occurrence, is selected from H, C1-6 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, C1-6 alkyl and (CH2)n—phenyl; n, at each occurrence, is selected from 0, 1, 2, and 3; m, at each occurrence, is selected from 0, 1, and 2; 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; t, at each occurrence, is selected from 0, 1, 2, and 3; and, provided that when the compound is a 1, 4, 5, 6—tetrahydropyrazolo—[3, 4—c]—pyridin—7—one and Y is a nitrogen—containing non-aromatic heterocycle attached via a nitrogen atom, then either (a) B is X—Y or (b) Y is substituted with at least one R4a that is other than H and alkyl. 2. A compound of claim 1, wherein the compound is selected from the group: wherein compounds of the above formulas are substituted with 0-2 R3; G is selected from the group: 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 and X—Y, provided that B is other than a cycloalkoxy group; X is selected from C1-4 alkylene, —C(O)—, —C(=NR1″)—, —CR2(NR1″R2)—, —C(O)CR2R2a—, —CR2R2aC(O), —C(O)NR2—, —NR2C(O)—, —C(O)NR2CR2R2a—, —NR2C(O)CR2R2a—, —CR2R2aC(O)NR2—, —CR2R2aNR2C(O)—, —NR2C(O)NR2—, —NR2—, —NR2CR2R2a—, —CR2R2aNR2—, O, —CR2R2aO—, and —OCR2R2a—; Y is CH2NR2R2a or CH2CH2NR2R2a; alternatively, Y is selected from one of the following carbocyclic and heterocyclic systems that are substituted with 0-2 R4a; cyclopropyl, 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; s is 0; and, provided that when the compound is a 1, 4, 5, 6—tetrahydropyrazolo—[3, 4—c]—pyridin —7—one and Y is a nitrogen—containing non—aromatic heterocycle attached via a nitrogen atom, then either (a) B is X—Y or (b) Y is substituted with at least one R4a that is other than H and alkyl. 3. A compound of claim 2, wherein the compound is selected from the group: wherein compounds of the above formulas are substituted with 0-2 R3; G is selected from the group: 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 R4a; R2, at each occurrence, is selected from H, CH3, CH2CH3, cyclopropylmethyl, cyclobutyl, and cyclopentyl; R2a, at each occurrence, is H, or CH3; alternatively, R2 and R2a, together with the atom to which they are attached, combine to form pyrrolidine substituted with 0-2 R4b; R4, at each occurrence, is selected from OH, (CH2)rOR2, halo, C1-4 alkyl, (CH2)rNR2R2a, and (CF2)rCF3; R4a is selected from C1-4 alkyl, CF3, (CH2)rOR2, (CH2)rNR2R2a, S(O)pR5, SO2NR2R2a, and 1—CF3—tetrazol—2—yl; R4b, at each occurrence, is selected from H, CH3, and OH; R5, at each occurrence, is selected from CF3, C1-6 alkyl, phenyl, and benzyl; X is CH2 or C(O); Y is selected from pyrrolidino and morpholino; and, r, at each occurrence, is selected from 0, 1, and 2; provided that when the compound is a 1, 4, 5, 6—tetrahydropyrazolo—[3, 4—c]—pyridin—7—one and Y is a nitrogen—containing non—aromatic heterocycle attached via a nitrogen atom, then either (a) B is X—Y or (b) Y is substituted with at least one R4a that is other than H and alkyl. 4. A compound of claim 3, wherein: G is selected from: 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—(aminosulfonyl)phenyl, 2—(methylaminosulfonyl)phenyl, 1—pyrrolidinocarbonyl, 2—(methylsulfonyl)phenyl, 2—(N,N—dimethylaminomethyl)phenyl, 2—(N—pyrrolidinylmethyl)phenyl, 1—methyl—2—imidaolyl, 2—methyl—1—imidazolyl, 2—(dimethylaminomethyl)—1—imidazolyl, 2—(N—(cyclopropylmethyl)aminomethyl)phenyl, 2—(N—(cyclobutyl)aminomethyl)phenyl, 2—(N—(cyclopentyl)aminomethyl)phenyl, and 2—(N—(3—hydroxypyrrolidinyl)methyl)phenyl. 5. A compound of claim 2, wherein the compound is selected from the group: wherein compounds of the above formulas are substituted with 0-2 R3; G is selected from the group: 6. A compound of claim 2, wherein the compound is selected from the group: wherein compounds of the above formulas are substituted with 0-2 R3. 7. A compound of claim 2, wherein: G is selected from the group: 8. A compound of claim 7, wherein: G is selected from: 9. A compound of claim 4, wherein: 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 R4a; R2, at each occurrence, is selected from H, CH3, CH2CH3, cyclopropylmethyl, cyclobutyl, and cyclopentyl; R2a, at each occurrence, is H or CH3; alternatively, R2 and R2a, together with the atom to which they are attached, combine to form pyrrolidine substituted with 0-2 R4b; R4, at each occurrence, is selected from OH, (CH2)rOR2, halo, C1-4 alkyl, (CH2)rNR2R2a, and (CF2)rCF3; R4a is selected from C1-4 alkyl, CF3, (CH2)rOR2, (CH2)rNR2R2a, S(O)pR5, SO2NR2R2a, and 1—CF3—tetrazol—2—yl; R4b, at each occurrence, is selected from H, CH3, and OH; R5, at each occurrence, is selected from CF3, C1-6 alkyl, phenyl, and benzyl; X is CH2 or C(O); Y is selected from pyrrolidino and morpholino; and, r, at each occurrence, is selected from 0, 1, and 2; provided that the compound is a 1, 4, 5, 6,—tetrahydropyrazolo—[3, 4—c]—pyridin—7—one and Y is a nitrogen—containing non—aromatic heterocycle attached via a nitrogen atom, then either (a) B is X—Y or (b) Y is substituted with at least one R4a that is other than H and alkyl. 10. A compound of claim 2, wherein: A is selected from phenyl, pyridyl, and pyrimidyl, and is substituted with 0-2 R4. 11. A compound of claim 2, wherein: B is selected from X-Y, phenyl, pyrrolidino, morpholino, 1, 2, 3—triazolyl, and imidazolyl, and is substituted with 0-1 R4a. 12. A compound of claim 2, wherein: X is CH2 or C(O); and, Y is selected from pyrrolidino and morpholine. 13. A compound of claim 2, wherein: R4, at each occurrence, is selected from OH, (CH2)rOR2, halo, C1-4 alkyl, (CH2)rNR2R2a, and (CF2)rCF3. 14. A compound of claim 2, wherein: R4a is selected from C1-4 alkyl, CF3, (CH2)rOR2, (CH2)rNR2R2a, S(O)pR5, SO2NR2R2a, and 1—CF3—tetrazol—2—yl. 15. A compound of claim 9, 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—pheny, 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—pyrrolidinylmethyl)phenyl, 1—methyl—2—imidazolyl, 2—methyl—1—imidazolyl, 2—(dimethylaminomethyl)—1—imidazolyl, 2—(N—(cyclopropylmethyl)aminomethyl)phenyl, 2—(N—(cyclobutyl)aminomethyl)phenyl, 2—(N—(cyclopentyl)aminomethyl)phenyl, and 2—(N—(3—hydroxypyrrolidinyl)methyl)phenyl. 16. A compound of claim 10, wherein: A is selected from the group: phenyl, 2—pyridyl, 3—pyridyl, 2—pyrimidyl, 2—Cl—phenyl, 2—F—phenyl, 3—F—phenyl, 2—methyphenyl, 2—aminophenyl, and 2—methoxyphenyl. 17. A compound of claim 11, wherein: B is selected from the group: 2—(aminosulfonyl)phenyl, 2—(methylaminosulfonyl)phenyl, 1—pyrrolidinocarbonyl, 2—(methylsulfonyl)phenyl, 2—(N,N—dimethylaminomethyl)phenyl, 2—(N—pyrrolidinymethyl)phenyl, 1—methyl—2—imidazolyl, 2—methyl—1—imidazolyl, 2—(dimethylaminomethyl)—1—imidazolyl, 2—(N-(cyclopropylmethyl)aminomethyl)phenyl, 2—(N—(cyclobutyl)aminomethyl)phenyl, 2—(N—(cyclopentyl)aminomethyl)phenyl, and 2—(N—(3—hydroxypyrrolidinyl)methyl)phenyl. 18. A compound selected from: 1—[3—Aminoiminomethylphenyl]—3—methyl—6—[2′—aminosulfonyl—[1, 1′]—biphen—4—yl]—1, 4, 5, 6—tetrahydropyrazolo—[3, 4—c]—pyridin—7—one; 1—[2—Aminomethylphenyl]—3—methyl—6—[2′—aminosulfonyl—[1, 1′—biphen—4—yl]—1, 4, 5, 6—tetrahydropyrazolo—[3, 4—c]—pyridin—7—one; 1—[3—Aminobenzisoxazol—5′—yl]—3—methyl—6—[2′—aminsulfonyl—[1, 1′]—biphen —4—yl]—1, 4, 5, 6—tetrahydropyrazolo—[3, 4—c]—pyridin —7—one; 1—[3—Aminbenzisoxazol—5′—yl]—3—methyl—6—[’′—N—pyrrolidinylmethyl—[1, 1′]—biphen—4—yl]—1, 4, 5, 6—tetrahydrol—7H—pyrazolo—[3, 4—c]—pyridin—7—one; 1—[3—Aminobenzisoxazol—5′—ul]—3—methyl—6—[2′—(3—(S)—hydroxy—N—pyrrolidinyl)methyl—[1, 1′]—biphen—4—yl]—1, 4, 5, 6—tetrahydro—7H—pyrazolo—[3, 4—c]—pyridin—7—one; 1—[3—Aminbenzisoxazol—5′—yl]—3—methyl—6—[2′—N—isopropylaminomethyl—[1, 1′]—biphen—4—yl]—1, 4, 5, 6—tetrahydro—7H—pyrazolo—[3, 4—c]—pyridin—7—one; 1—[3—Aminobenzisoxazol—5′—yl]—3—methyl—6—[2′—N,N—dimethylamiinomethyl—[1, 1′]—biphen—4—yl]—1, 4, 5, 6—tetrahydro—7H—pyrazolo—[3, 4—c]—pyridin—7—one; 1—[3—Aminobenzisoxazol—5′—yl]—3—methyl—6—[2′—methylsulfonyl—[1, 1′]—biphen—4—yl]—1, 4, 5, 6—tetrahydro—7H—pyrazolo—[3, 4—c]—pyridin—7—one; 1—[3—Aminobenzisoxazol—5′—methylsulfonyl—3—fluoro—[1, 1′]—biphen—4—yl]—1, 4, 5, 6—tetrahydro—7H—pyrazolo—[3, 4—c]—pyridin—7—one; 1—[2—Aminomethyphenyl]—3—trifluoromethyl—6—[2′—methylsulfonyl—3—fluoro—[1, 1′]—biphen—4—yl]—1, 4, 5, 6—tetrahydropyrazolo—[3, 4—c]—pyridin—7—one; 1—[2—Aminomethylphenyl]—3—trifluoromethyl—6—[2′—aminosulfonyl—3—fluoro—[1, 1′]—biphen—4—yl]—1, 4, 5, 6—tetahyfropyrazolo—[3, 4—c]—pyridin—7—one; 1—[2—Aminomethylphenyl]—3—trifluoromethyl—6—[2′—methysulfonnyl—[1, 1]—biphen—4—yl]—1, 4, 5, 6—tetrahydropyrazolo—[3, 4—c]—pyridin—7—one; 1—[2—Aminomethylphenyl]—3—trifluoromethyl—6—[2′—N,N—dimethylaminomethyl—3—fluoro—[1, 1′]—biphen—4—yl]—1, 4, 5, 6—tetrahydropyrazolo—[3, 4—c]—pyridin—7—one; 1—[2—Aminomethylphenyl]—3—trigluoromethyl—6—[2′—(3—(R)—hydroxy—N—pyrrolidinyl)methyl—3—fluoro—[1, 1′]—biphen—4—yl]—1, 4, 5, 6—tetrahydropyrazolo—[3, 4—c]—pyridin—7—one; 1—[3—Aminovenzisoxazol—5′—yl]—3—trifluoromethyl—6—[2′—dimethylaminomethyl—3—fluoro—[1, 1′]—biphen—4—yl]—1, 4, 5, 6—tetrahydropyrazolo—[3, 4—c]—pyridin—7—one; 1—[3—Aminobenzisoxazol—5′—yl]—3—trifluoromethyl—6—[2′—(3—(R)—hydroxy—N—pyrrolidinylmethyl—3—fluoro—[1, 1′]—biphen—4—yl]—1, 4, 5, 6—tetrahydropyrazolo—[3, 4—c]—ppyridin—7— one; 1—[—Aminobenzisoxazol—5′—yl]—3—trifluoromethyl—6—[2′—(3—(R)—hydroxy—N—pyrrolidinyl)methyl—[1, 1′]—biphen—4—1, 4, 4, 6—tetrahdropyraolo—[3, 4—c]—pyridin—7—one; 1—[3—Aminobenzisoxazol—5′—yl]—3—trifluoromethyl—6—[2′—isopropylaminomethyl—3—fluoro—[1, 1′]—biphen —4—yl]—1, 4, 5, 6—tetrahydropyrazolo—[3, 4—c]—pyridin—7—one; 1—[3—Aminobenzisoxazol—5′—yl]—3—trifluoromethyl—6—[2′—N—(2—methylimidazol—1—yl)methyl—3—fluoro—[1, 1′]—biphen—4—yl]—1, 4, 5, 6—tetrahydropyrazolo—[3, 4—c[—pyridin—7—one; 1—[3—Aminobenzisoxazol—5′—yl]—3—trifluoromethyl—6—[2′—N—pyrrolidinomethyl—3—fluoro—[1, 1′]—biphen—4—yl]—1, 4, 5, 6—tetrahydropyrazolo—[3, 4—c]—pyridin—7—one; 1—[3—Aminobenzisoxazol—5′—yl—3—trifluoromethyl—6—[2′—oximinomethyl—3—fluoro—[1, 1′]—biphen—4—yl]—1, 4, 5, 6—tetrahydropyrazolo—[3, 4—c]—pyridin—7—one; 1—[4—Methoxyphenyl]—3—trifluoromethyl—6—[2′—(3—(R)—hydroxy—N—pyrrolidinyl)methyl—3—fluoro—[1, 1′]—biphen—4—yl]—1, 4, 5, 6—tetrahydropyrazolo—[3, 4—c]—pyridin—7—one; 1—[3—Aminomethylphenyl]—3—trifluoromethyl—6—[2′—methylsulfonyl—3—fluoro—[1, 1′]—biphen—4—yl]—1, 4, 5, 6—tetrahydropyrazolo—[3, 4—c]—pyridin—7—one; 1—[3—Aminobenzisoxazol—5′—yl]—3—trifluoromethyl—6—[2′—(3—(S)—hydroxy—N—pyrrolidinyl)methyl—[1, 1′]—biphen—4—yl]—1, 4, 5, 6—tetrahydropyrazolo—[3, 4—c]—pyridin—7—one; 1—[3—Aminobenzisoxazol—5′—yl]—3—trifuoromethyl—6—[2′—N—(pyrrolindinyl)methyl—[1, 1′]—biphen—4—yl]—1, 4, 5, 6—tetrahydropyrazolo—[3, 4—c]—pyridin—7—one; 1—[3—Aminobenzisoxazol—5′—yl]—3—trifluoromethyl—6—[2′—N—(morpholino)methyl—[1, 1′]—biphen—4—yl]—1, 4, 5, 6—tetrahydropyrazolo—[3, 4—c]—pyridin—7—one; 1—[3—Aminobenzisoxazol—5′—yl]—3—trifluoromethyl—6—[2′—N,N—dimethylaminomethyl—[1, ′]—biphen—4—yl]—1, 4, 5, 6—tetrahydropyrazolo—[3, 4—c]—pyridin—7—one; 1[4—Meethoxyphenyl]—3—trifluoromethyl—6—[(4—aminomethyl)phenyl]—1, 4, 5, 6—tetrahydropyrazolo—[3, 4—c]pyridin—7—one; 1—[3—Aminomethylphenyl]—3—methyl—6—[(2′—N—((3—(S)—hydroxy)pyrrolidinyl)methyl—[1, 1′]—biphen—4—yl)]—1, 4, 5, 6—tetrahydro—7H—pyrazolo—[3, 4—c]—pyridin—7—one; 1—[3—Aminomethylphenyl]—3—methyl—6—[(2′—methylsulfonyl—[1, 1′]—biphen—4—yl)]—1, 4, 5, 6—tetrahydro—7H—pyrazolo[3, 4—c]pyridin—7—one; 1—[3—Aminobenzisoxazol—5′—yl]—3—methyl—6—[(3—fluoro—2′—N—(3(S)—hydroxy)pyrrolidinylmethyl—[1, 1′]—biphen—4—yl)[—1, 4, 5, 6—tetrahydro—7H—pyrazolo[3, 4—c pyridin—7—one; 1—[3—Aminobenisoxazol—5′—yl]—3—methyl—6—[(3—fluoro—2′—N—pyrrolidinylmethyl—[1, 1′]—biphen—4—yl)]—1, 4, 5, 6—tetrahydro—7H—pyrazolo[3, 4—c]pyridin—7—one; 1—[1—Aminoisoquinolin—7′—yl]—3—trifluoromethyl—6—[4—(2—methylimidazol—1′—yl)phenyl]—1, 4, 5, 6—tetrahydroprazolo—[3, 4—c]—pyridin—7—one; and, 1—[3—Aminovenzisoxazol—5′—yl]—3—methyl—6—[4—(2—(dimethylaminomethyl)imidazol1′—yl)—2—flurohphenyl]—1, 4, 5, 6—tetrahydropyrazolo—[3, 4—c]—pyridin—7—one; or a pharmaceuticlly acceptable salt form thereof. 19. A compound according to claim 18, wherein the compound is selected from the group: 1—[3—aminobenisoxazol—5′—yl]—3—methyl—6—[2′—aminosulfonyl—[1, 1′]—biphen—4—yl]—1, 4, 5, 6—tetrahydropyrazolo—[3, 4—c]—pyridin—7—one; 1—[3—aminobenzisoxazol—5′—yl]—3—trifluoromenthyl—6—[2′—(3—(R)—hydroxy—N—pyrrolidinyl)methyl—[1, 1′]—biphen—4—yl]—1, 4, 5, 6—tetrahydropyrazolo—[3, 4—c ]—pyridin—7—one; 1—[3—aminobenzisoxazol—5′—yl]—3—trufluoromethyl—6—[′—N,N—dimethylaminomethyl—[1, 1′]—biphen—4—yl]—1, 4, 5, 6—tetrahydropyrazolo—[3, 4—c]—pyridin—7—one; 1—[2—Aminomethylphenyl]—3—trifluoromethyl—6—[2′—methylsulfonyl—[1, 1]—biphen—4—yl]—1, 4, 5, 6—tetrahydropyrazolo—[3, 4—c]—pyridin—7—one; 1—[3—aminobenzisoxazol—5′—yl]—3—trifluoromethyl—6—[2′—dimethylaminomethyl—3—fluoro—[1, 1′]—biphen—4—yl]—1, 4, 5, 6—tetrahydropyrazolo—[3, 4—c]—pyridin—7—one; 1—[3—aminobenzisoxazol—5′—yl]—3—trifluoromethyl—6—[2′—(3—(R)—hydroxy—N—pyrrolidinyl)methyl—3—fluoro—[1, 1′]—biphen—4—yl]—1, 4, 5, 6—tetrahydropyrazolo—[3, 4—c]—pyridin—7—one; and, 1—[1—aminoisoquinolin—7′—yl]—3—trifluoromethyl—6—[4—(2—methylimidazol—1′—yl)phenyl]—1, 4, 5, 6—tetrahydropyrazolo—[3, 4—c]—pyridin—7—one; 20. A compound according to claim 19, wherein the compound is: 1—[3—aminobenzisoxazol—5′—yl]—3—methyl—6—[2′—aminosulfonyl—[1, 1′]—biphen—4—yl]—1, 4, 5, 6—tetrahydropyrazolo—[3, 4—c]—pyridin—7—one or a pharmaceutically acceptable salt form thereof. 21. A compound according to claim 19, wherein the compound is: 1—[3—aminobenzisoxazol—5′—yl]—3—trifluoromethyl—6—[2′—(3—(R)—hydroxy—N—pyrrolidinyl)methyl—[1, 1′]—biphen—4—yl]—1, 4, 5, 6—tetrahydropyrazolo—[3, 4—c]—pyridin—7—one or a pharmaceutically acceptable salt form thereof. 22. A compound according to claim 19, wherein the compound is: 1—[3—aminobenzisoxazol—5′—yl]—3—trifluoromethyl—6—[2′—N,N—dimethylaminomethyl—[1, 1′]—biphen—4—yl]—1, 4, 5, 6—tetrahydropyrazolo—[3, 4—c]—pyridin—7—one or a pharmaceutically acceptable salt form thereof. 23. A compound according to claim 19, wherein the compound is: 1—[2—aminomethylphenyl]—3—trifluoromethyl—6—[2′—methylsulfonyl—[1, 1]—biphen—4—yl]—1, 4, 5, 6—tetrahydropyrazolo—[3, 4—c]—pyridin—7—one or a pharmaceutically acceptable salt form thereof. 24. A compound according to claim 19, wherein the compound is: 1—[3—aminobenzisoxazol—5′—yl]—3—trifluoromethyl—6—[2 ′—dimethylaminomethyl—3—fluoro—[1, 1′]—biphen—4—yl]—1, 4, 5, 6—tetrahydropyrazolo—[3, 4—c]—pyridin—7—one or a pharmaceutically acceptable salt form thereof. 25. A compound according to claim 19, wherein the compound is: 1—[—aminobenzisoxazol—5′—yl]—3—trifluoromethyl—6—[2′—(3—(R)—hydroxy—N—pyrrolidinyl)methyl—3—fluoro—[1, 1′]—biphen—4—yl]—1, 4, 5, 6—tetrahydropyrazolo—[3, 4—c]—pyridin—7—one or a pharmaceutically acceptable salt form thereof. 26. A compound according to claim 19, wherein the compound is: 1—[1—aminoisoquinolin—7′—yl]—3—trifluoromethyl—6—[4—(2—methylimidazol—1′—yl)phenyl]—1, 4, 5, 6—tetrahydropyrazolo—[3, 4—c]—pyridin—7—one or a pharmaceutically acceptable salt form thereof. 27. 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. 28. 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. 29. 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. 30. 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. 31. 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. 32. 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. 33. 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. 34. 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. 35. 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. 36. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 10 or a pharmaceutically acceptable salt form thereof. 37. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 11 or a pharmaceutically acceptable salt form thereof. 38. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 12 or a pharmaceutically acceptable salt form thereof. 39. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 13 or a pharmaceutically acceptable salt form thereof. 40. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 14 or a pharmaceutically acceptable salt form thereof. 41. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 15 or a pharmaceutically acceptable salt form thereof. 42. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 16 or a pharmaceutically acceptable salt form thereof. 43. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 17 or a pharmaceutically acceptable salt form thereof. 44. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 18 or a pharmaceutically acceptable salt form thereof. 45. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 19 or a pharmaceutically acceptable salt form thereof. 46. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 20 or a pharmaceutically acceptable salt form thereof. 47. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 21 or a pharmaceutically acceptable salt form thereof. 48. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 22, or a pharmaceutically acceptable salt form thereof. 49. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 23 or a pharmaceutically acceptable salt form thereof. 50. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 24 or a pharmaceutically acceptable salt form thereof. 51. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 25 or a pharmaceutically acceptable salt form thereof. 52. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 26 or a pharmaceutically acceptable salt form thereof. 53. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable acceptable salt form thereof. 54. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of claim 2 or a pharmaceutically acceptable salt form thereof. 55. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of claim 3 or a pharmaceutically acceptable salt form thereof. 56. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of claim 4 or a pharmaceutically acceptable salt form thereof. 57. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of claim 5 or a pharmaceutically acceptable salt form thereof. 58. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of claim 6 or a pharmaceutically acceptable salt form thereof. 59. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of claim 7 or pharmaceutically acceptable salt form thereof. 60. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of claim 8 or a pharmaceutically acceptable salt form thereof. 61. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of claim 9 or a pharmaceutically acceptable salt form thereof. 62. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of claim 10 or a pharmaceutically acceptable salt form thereof. 63. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of claim 11 or a pharmaceutically acceptable salt form thereof. 64. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of claim 12 or a pharmaceutically acceptable salt form thereof. 65. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of claim 13 or a pharmaceutically acceptable salt form thereof. 66. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of claim 14 or a pharmaceutically acceptable salt form thereof. 67. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of claim 15 or a pharmaceutically acceptable salt form thereof. 68. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of claim 16 or a pharmaceutically acceptable salt form thereof. 69. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of claim 17 or a pharmaceutically acceptable salt form thereof. 70. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of claim 18 or a pharmaceutically acceptable salt form thereof. 71. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of claim 19 or a pharmaceutically acceptable salt form thereof. 72. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of claim 20 or a pharmaceutically acceptable salt form thereof. 73. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of claim 21 or pharmaceutically acceptable salt form thereof. 74. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of claim 22 or pharmaceutically acceptable salt form thereof. 75. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of claim 23 or a pharmaceutically acceptable salt form thereof. 76. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of claim 24 or a pharmaceutically acceptable salt form thereof. 77. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of claim 25 or a pharmaceutically acceptable salt form thereof. 78. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of claim 26 or a pharmaceutically acceptable salt form thereof.