WO1998057934A1 - (AMIDINO)6-MEMBERED AROMATICS AS FACTOR Xa INHIBITORS - Google Patents
(AMIDINO)6-MEMBERED AROMATICS AS FACTOR Xa INHIBITORS Download PDFInfo
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- WO1998057934A1 WO1998057934A1 PCT/US1998/012682 US9812682W WO9857934A1 WO 1998057934 A1 WO1998057934 A1 WO 1998057934A1 US 9812682 W US9812682 W US 9812682W WO 9857934 A1 WO9857934 A1 WO 9857934A1
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- pyridyl
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- 0 *c1c(*)c(NC2CC=CCC2)nc(Nc2ccccc2)c1* Chemical compound *c1c(*)c(NC2CC=CCC2)nc(Nc2ccccc2)c1* 0.000 description 33
- GIMFJGXYUHBIDD-NXORTQHQSA-N C/C(/C(C)=N)=C/N=C(\C)/F Chemical compound C/C(/C(C)=N)=C/N=C(\C)/F GIMFJGXYUHBIDD-NXORTQHQSA-N 0.000 description 1
- DMEPLKAPGJWNET-UHFFFAOYSA-N Cc(c(C)nnn1)c1I Chemical compound Cc(c(C)nnn1)c1I DMEPLKAPGJWNET-UHFFFAOYSA-N 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Oc1ccccc1 Chemical compound Oc1ccccc1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
Definitions
- This invention relates generally to novel 6-membered aromatics which are inhibitors of trypsin-like serine protease enzymes, especially factor Xa, pharmaceutical compositions containing the same, and methods of using the same as anticoagulant agents for treatment and prevention of thromboembolic disorders.
- Z 1 and Z 2 are O, N(R) , S or OCH 2 and the central ring may be phenyl or a variety of heterocycles .
- the presently claimed compounds do not contain the Z 1 linker or the substitution pattern of the above compounds.
- WO 95/18111 addresses fibrinogen receptor antagonists, containing basic and acidic termini, of the formula:
- R 1 represents the basic termini
- U is an alkylene or heteroatom linker
- V may be a heterocycle
- the right hand portion of the molecule represents the acidic termini .
- the presently claimed compounds do not contain the acidic termini of WO 95/18111.
- Activated factor Xa whose major practical role is the generation of thrombin by the limited proteolysis of prothrombin, holds a central position that links the intrinsic and extrinsic activation mechanisms in the final common pathway of blood coagulation.
- thrombin the final serine protease in the pathway to generate a fibrin clot, from its precursor is amplified by formation of prothrombinase complex (factor Xa, factor V, Ca 2+ and phospholipid) . Since it is calculated that one molecule of factor Xa can generate 138 molecules of thrombin (Elodi, S., Varadi, K. : Optimization of condi tions for the catalytic effect of the factor IXa- factor VIII Complex: Probable role of the complex in the amplification of blood coagulation . Thromb. Res . 1979, 15, 617-629), inhibition of factor Xa may be more efficient than inactivation of thrombin in interrupting the blood coagulation system.
- one object of the present invention is to provide novel 6-membered aromatics which are useful as factor Xa inhibitors or pharmaceutically acceptable salts or prodrugs thereof .
- I or pharmaceutically acceptable salt or prodrug forms thereof wherein A, B, D, E, M, R la , R lb , and Z are defined below, are effective factor Xa inhibitors.
- the present invention provides novel compounds of formula I :
- ring M contains from 0-4 N atoms
- E is selected from phenyl, 2-pyridyl, 4-pyridyl, pyrimidyl, and piperidinyl substituted with 1 R;
- R is selected from H, F, Cl, Br, I, OR 3 , SR 3 , CO 2 R 3 , NO 2 , and CH 2 OR 3 , and (CR 8 R 9 ) t NR 8 R 9 ;
- E and R combine to form methylenedioxy or ethylenedioxy;
- Z is selected from a bond, C ⁇ _ 4 alkylene, (CH 2 ) r O (CH 2 ) r ( CH 2 ) rNR 3( CH 2 )r, ( CH 2 ) r C ( 0 ) (CH 2 ) r , ( CH 2 ) r C ( 0 ) 0 ( CH 2 ) r , (CH 2 ) r 0C(0) (CH 2 )r/ (CH 2 ) r C (0) NR 3 (CH 2 ) r , (CH 2 ) r NR 3 C(0) (CH 2 ) r , (CH 2 ) r 0C (0) 0 (CH 2 ) r , (CH 2 )rOC(0)NR 3 (CH 2 )r, (CH 2 ) r NR 3 C (0) 0 ( CH 2 ) r , ( CH 2 )rNR 3 C(0)NR 3 (CH 2
- R la and R lb 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 R 4 and which contains from 0-2 heteroatoms selected from the group consisting of N, 0, and S;
- R la is a C(0) which replaces the amide hydrogen of Z to form a cyclic imide
- R 1 " is selected from H, CH(CH 2 OR 2 ) , C(0)R 2c , C(0)NR 2 R 2a , S(0)R 2b , S(0) R 2b , and S0NR 2 R 2a ;
- R 2 at each occurrence, is selected from H, CF 3 , C ⁇ _ 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, 0, and S substituted with ⁇ -2 R 4b ;
- R 2a is selected from H, CF 3 , C ⁇ _ 6 alkyl, benzyl, phenethyl, C 3 - 6 carbocyclic residue substituted with 0-2 R b , and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-2 R b ;
- R 2b is selected from CF , C 1 -. 4 alkoxy, C ⁇ - 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 c at each occurrence, is selected from CF 3 , OH, C 1 - 4 alkoxy, C ⁇ _ 6 alkyl, benzyl, C 3 _ 6 carbocyclic residue substituted with 0-2 R b , and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-2 R b ;
- R 2 and R a 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 b and containing from 0-1 additional heteroatoms selected from the group consisting of N, 0, and S;
- R 3 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 3b at each occurrence, is selected from H, C ⁇ _ 4 alkyl, and phenyl ;
- R 3c at each occurrence, is selected from C 1 - 4 alkyl, and phenyl ,-
- A is selected from:
- B is selected from: H, Y, and X-Y;
- Y is selected from:
- one R 4 is a 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, 0, and S;
- one R a is a 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, 0, and S and substituted with 0-1 R 5 ;
- R 5 at each occurrence, is selected from CF 3 , C ⁇ _ 6 alkyl, phenyl substituted with 0-2 R 6 , and benzyl substituted with 0-2 R 6 ;
- R 7 is selected from H, OH, C ⁇ - ⁇ alkyl, C ⁇ - 6 alkylcarbonyl , C 1 - 6 alkoxy, C ⁇ _ 4 alkoxycarbonyl , (CH 2 ) n -phenyl, C 6 - ⁇ o aryloxy, C 6 - ⁇ o aryloxycarbonyl, C 6 - ⁇ o aryl ethylcarbonyl , C ⁇ _ 4 alkylcarbonyloxy C _ 4 alkoxycarbonyl , C ⁇ -io arylcarbonyloxy C 1 - 4 alkoxycarbonyl , C ⁇ - 6 alkylaminocarbonyl , phenylaminocarbonyl , and phenyl-C ⁇ - 4 alkoxycarbonyl;
- R 8 at each occurrence, is selected from H, C ⁇ _ 6 alkyl and (CH 2 ) n-pheny1 ;
- R 7 and R 8 combine to form a 5 or 6 membered saturated, ring which contains from 0-1 additional heteroatoms selected from the group consisting of N, 0, and S;
- R 9 at each occurrence, is selected from H, C 1 - 6 alkyl and (CH 2 ) n -phenyl;
- n is selected from 0, 1, 2, and 3;
- n 0, 1, and 2;
- p is selected from 0, 1, and 2 ,-
- r is selected from 0, 1, 2, and 3;
- s is selected from 0, 1, and 2;
- t is selected from 0 and 1.
- Z is selected from a bond, CH 2 0, OCH 2 , CH 2 NH, NHCH 2 , CH 2 C(0) ,
- B is selected from: Y, X-Y, and NR 2 R 2a ;
- 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
- Y may also be selected from the following bicyclic heteroaryl ring systems :
- K is selected from 0, S, NH, and N.
- R is selected from H, F, Cl, OR 3 , CH 2 OR 3 , CH 2 NH 2 ;
- A is selected from: piperidinyl , piperazinyl, 5 - 6 carbocyclic residue substituted with 0-2 R 4 , and
- 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, benzimidazolyl, oxadiazole, thiadiazole, triazole, 1, 2 , 3 -oxadiazole, 1, 2 , 4-oxadiazole, 1, 2 , 5-oxadiazole, 1 , 3 , 4-oxadiazole, 1, 2 , 3 -thiadiazole
- the present invention provides novel compounds wherein:
- E is phenyl
- R is selected from H, F, Cl, and Br;
- A is selected from:
- C 5 _ 6 carbocyclic residue substituted with 0-2 R 4 , and 5-6 membered heteroaryl containing from 1-3 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-2 R 4 ;
- Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R a ; phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, benzimidazolyl, 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,
- R at each occurrence, is selected from H, CF 3 , C ⁇ _ 6 alkyl, benzyl, C 5 - 6 carbocyclic residue substituted with 0-2
- R b and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-2 R 4b ;
- R 2a is selected from H, CF 3 , C ⁇ _ 6 alkyl, benzyl, phenethyl, C 5 - 6 carbocyclic residue substituted with 0-2 R b , 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 b ;
- R 2b at each occurrence, is selected from CF 3 , C _ 4 alkoxy,
- R 2c is selected from CF 3 , OH, C ⁇ _ 4 alkoxy, C ⁇ _ 6 alkyl, benzyl, Cs_ 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, 0, and S substituted with 0-2 R b ;
- R 2 and R 2a together with the atom to which they are attached, combine to form a ring selected from imidazolyl, morpholino, piperazinyl, pyridyl, and pyrrolidinyl, substituted with 0-2 R 4b ;
- the present invention provides novel compounds selected from:
- the present invention provides novel pharmaceutical compositions, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof .
- the present invention provides a novel method for treating or preventing a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof .
- the compounds herein described may have asymmetric centers.
- substituted means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
- 2 hydrogens on the atom are replaced.
- Keto substituents are not present on aromatic moieties.
- the present invention is intended to include all isotopes of atoms occurring in the present compounds.
- Isotopes include those atoms having the same atomic number but different mass numbers.
- isotopes of hydrogen include tritium and deuterium.
- Isotopes of carbon include C-13 and C-14.
- substituents and/or variables are permissible only if such combinations result in stable compounds.
- a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring.
- a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent.
- Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds .
- alkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms .
- alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl.
- haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl .
- Alkoxy represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge.
- alkoxy examples include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy.
- Cycloalkyl is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl.
- Alkenyl is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl and the like.
- Alkynyl is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl and the like.
- Halo or "halogen” as used herein refers to fluoro, chloro, bromo, and iodo; and "counterion” is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.
- carbocycle or “carbocyclic residue” is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7- to 13 -membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic.
- carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3. OJbicyclooctane, [4.3.0]bicyclononane, [4.4.
- OJbicyclodecane [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl .
- heterocycle or “heterocyclic system” is intended to mean a stable 5-to 7-membered monocyclic or bicyclic or 7-to 10-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic) , and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, 0 and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
- the nitrogen and sulfur heteroatoms may optionally be oxidized.
- the heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure.
- heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and 0 atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and 0 atoms in the heterocycle is not more than 1.
- aromatic heterocyclic system is intended to mean a stable 5-to 7- membered monocyclic or bicyclic or 7-to 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 4 heterotams independently selected from the group consisting of N, 0 and S. It is preferred that the total number of S and 0 atoms in the aromatic heterocycle is not more than 1.
- heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl , benzothiophenyl, benzoxazolyl , benzthiazolyl, benztriazolyl, benztetrazolyl , benzisoxazolyl, benzisothiazolyl, benzimidazolinyl , carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-1 , 5 , 2-dithiazinyl , dihydrofuro [2 , 3 -b] tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl , imidazolyl, lJ-indazolyl,
- Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl, imidazolyl, indolyl, benzimidazolyl, lH-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, or isatinoyl . Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
- phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
- pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
- pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
- the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
- such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
- inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like
- organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic,
- the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
- such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
- Lists of suitable salts are found in Remington ' s Pharmaceutical Sciences, 17th ed. , Mack Publishing Company, Easton, PA, 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
- Prodrugs are intended to include any covalently bonded carriers which release the active parent drug according to formula (I) in vivo when such prodrug is administered to a mammalian subject.
- Prodrugs of a compound of formula (I) are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound.
- Prodrugs include compounds of formula (I) wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug or compound of formula (I) is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively.
- prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formula (I), and the like.
- “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent .
- “Substituted” is intended to indicate that one or more hydrogens on the atom indicated in the expression using “substituted” is replaced with a selection from the indicated group (s), provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
- “Therapeutically effective amount” is intended to include an amount of a compound of the present invention or an amount of the combination of compounds claimed effective to inhibit HIV infection or treat the symptoms of HIV infection in a host.
- the combination of compounds is preferably a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv. Enzyme Regul . 22:27-55 (1984), occurs when the effect (in this case, inhibition of HIV replication) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased antiviral effect, or some other beneficial effect of the combination compared with the individual components .
- the compounds of the present invention can be prepared in a number of ways known to one skilled in the art of organic synthesis .
- the compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below.
- the reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformations being effected. It will sometimes require a judgment to modify the order of synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention.
- W is defined as a suitable protected nitrogen, such as N0 2 or NHBOC; a protected sulfur, such as S-tBu or SMOM; or a methyl ester.
- a suitable protected nitrogen such as N0 2 or NHBOC
- a protected sulfur such as S-tBu or SMOM
- a methyl ester e.g., a protected boronic acid, B-B(OH) 2 .
- the W-A-Br subunit may be already linked to ring M before the Suzuki coupling reaction. Deprotection provides the complete subunit.
- Scheme 2 describes a typical example of how the A-B subunit is prepared for attachment to ring M.
- 4-Bromoaniline is protected as Boc-derivative and the coupled to 2-(t- butylamino) sulfonylphenylboronic acid under Suzuki conditions.
- 2- (t-Butylamino) sulfonylphenylboronic acid is prepared by the method described by Rivero (Bioorg. Med. Chem . Lett . 1994, 189) .
- Deprotection with TFA can provide the aminobiphenyl compound.
- the aminobiphenyl is then coupled to the core ring structures as described below.
- A-C(0)C1 a secondary NH as A-C(0)-Y part of a ring or chain
- the chemistry of Table A can be carried out in aprotic solvents such as a chlorocarbon, pyridine, benzene or toluene, at temperatures ranging from -20°C to the reflux point of the solvent and with or without a trialkylamine base.
- aprotic solvents such as a chlorocarbon, pyridine, benzene or toluene
- the coupling chemistry of table B can be carried out by a variety of methods.
- the Grignard reagent required for Y is prepared from a halogen analog of Y in dry ether, dimethoxyethane or tetrahydrofuran at 0°C to the reflux point of the solvent. This Grignard reagent can reacted directly under very controlled conditions, that is low temperature (-20°C or lower) and with a large excess of acid chloride or with catalytic or stoichiometric copper bromide*dimethyl sulfide complex in dimethyl sulfide as a solvent or with a variant thereof.
- the ether and thioether linkages of Table C can be prepared by reacting the two components in a polar aprotic solvent such as acetone, dimethylformamide or dimethylsulfoxide in the presence of a base such as potassium carbonate, sodium hydride or potassium t-butoxide at a temperature ranging from ambient to the reflux point of the solvent used.
- a polar aprotic solvent such as acetone, dimethylformamide or dimethylsulfoxide
- a base such as potassium carbonate, sodium hydride or potassium t-butoxide
- Table D Preparation of -SO- and -S0- linkages from thioether of Table C.
- Alumina/Oxone to chloroperbenzoic acid give: to give :
- the thioethers of Table C serve as a convenient starting material for the preparation of the sulfoxide and sulfone analogs of Table D.
- a combination of wet alumina and Oxone can provide a reliable reagents for the oxidation of the thioether to the sulfoxide as shown by Greenhalgh ( Syn . Lett . 1992, 235) .
- the sulfone can be prepared according to the method of Satoh ( Chem . Lett . 1992, 381) using m- chloroperbenzoic acid.
- Scheme 3 describes the synthesis of compounds wherein M is a benzene ring and Q is a protected precursor of group D of Formula I and V is a nitro, protected sulfonamide or ester group and precursor of group Z of Formula I.
- the V group is placed on an appropriately substituted phenol either via nitration as shown by Poirier et al . ( Tetrahedron 1989, 45 (5) , 1415) , sulfonylation as shown by Kuznetsov (Akad. Nauk SSSR Ser . Khim 1990, 8, 1888) or carboxylation by Sartori et al . (Synthesis 1988, 10, 763) . Bromination with triphenylphosphine and bromine (J " . Am . Chem . Soc . 1964, 86, 964) gives the desired bromide. Suzuki coupling with the appropriate boronic acid provides the desired substituted pyridine .
- Schemes 4, 5, 6, and 7 describe the synthesis of compounds wherein M is pyridine and Q is a protected precursor of group D of Formula I. Each scheme represents a different substitution pattern for the pyridine ring.
- a suitably protected aldehyde is subjected to base-catalyzed condensation with an activated ester to give after deprotection the desired aldehyde.
- Refluxing with ammonium chloride as shown by Dornow and Ische Chem . Ber. 1956, 89, 876) provides the pyridinol which is brominated with POBr 3 (Tjeenk et al . Rec . Trav. Chi . 1948, 67, 380) to give the desired 2-bromopyridine.
- Suzuki coupling with the appropriate boronic acid provides the desired substituted pyridine.
- Scheme 6 describes a synthesis of a third substitution pattern on a pyridine ring.
- the appropriate tricarbonyl compound which can be prepared by methods described in Scheme 4 is treated with ammonium chloride to form the pyridinol which is subsequently brominated. Palladium-catalyzed coupling provides the desired substituted pyridine.
- Scheme 7 takes a suitably substituted dicarbonyl compound and by chemistry illustrated in Schemes 4 and 6, reacts it with ammonium chloride. Bromination gives the 3 -bromopyridine which upon palladium-catalyzed coupling provides the desired substituted pyridine.
- Schemes 8, 9, and 10 describe the synthesis of compounds wherein M is pyridazine and Q is a protected precursor of group D of Formula I. Each scheme represents a different substitution pattern for the pyridine ring.
- an activated ester is reacted with an appropriately substituted ⁇ -keto aldehyde and hydrazine as shown by Schmidt and Druey (Helv. Chim. Acta 1954, 37, 134 and 1467) .
- Conversion of the pyridazinone to the bromide using POBr 3 and palladium- catalyzed coupling provides the desired substituted pyridazine.
- glyoxal can react under basic conditions with an activated ketone and subsequently brominated/dehydro- brominated to give the desired ketoaldehyde .
- a protected ketone can react with an activated aldehyde, undergo bromination/dehydrobromination, be deprotected and oxidized to give the regioisomeric ketoaldehyde.
- Cyclization as shown by Sprio and Madonia (Ann. Chim . 1958, 48, 1316) with hydrazine followed by palladium-catalyzed coupling provides the desired substituted pyridazine.
- a aldehyde can be reacted with an activated ketone, brominated, de ydro- brominated and deprotected to give the desired diketone.
- a regioisomeric ketone can be placed through the same reaction sequence to produce an isomeric keto aldehyde. Reaction with hydrazine followed by palladium- catalyzed coupling provides the desired substituted pyridazine .
- Schemes 11, and 12 describe the synthesis of compounds wherein M is pyrimidine and Q is a protected precursor of group D of Formula I. Each scheme represents a different substitution pattern for the pyrimidine ring.
- a condensation with an appropriately substituted acid chloride and an activated ester followed by conjugate reduction by tin hydride gives the desired 1,4 dicarbonyl compound.
- Cyclization with formamidine or a substituted amidine followed by bromination gives the desired regioisomeric pyrimidine.
- Palladium-catalyzed coupling provides the desired substituted pyrimidine.
- Scheme 12 shows how an amidine can be condensed with a 1, 3-dicarbonyl compound and subsequently brominated in the 5-position (J " . Het. Chem . 1973, 10, 153) to give a specific regioisomeric bromopyrimidine .
- Palladium-catalyzed coupling provides the desired substituted pyrimidine.
- Schemes 14 and 15 describe the synthesis of compounds wherein M is a 1, 2 , 3-triazine and Q is a protected precursor of group D of Formula I.
- a vinyl bromide is palladium coupled to a molecule containing the substituent R . Allylic bromination followed by azide displacement provide the cyclization precursor.
- Triphenylphosphine- mediated cyclization J. Org. Chem . 1990, 55, 4724
- Lead tetraacetate mediated rearrangement as shown by Neunhoeffer et al . (Ann . 1985, 1732) provides the desired regioisomeric 1, 2 , 3-triazine.
- Palladium-catalyzed coupling provides the substituted triazine.
- Schemes 16 and 17 describe the synthesis of compounds wherein M is a 1, 2 , 4-triazine and Q is a protected precursor of group D of Formula I.
- a nitrile is converted using hydrazine to give the amidrazone which is condensed with a ⁇ -ketoester to give the triazinone as shown by Paudler and Lee ( M Org. Chem . 1971, 36, 3921) .
- Bromination as shown by Rykowski and van der Plas ( J. Org. Chem . 1987, 52, 71) followed by palladium-catalyzed coupling provides the desired 1, 2, 4-triazine.
- Scheme 18 describes the synthesis of compounds wherein M is a 1, 2 , 3 , 4-tetrazine and Q is a protected precursor of group D of Formula I.
- Lithiation of a vinyl bromide, transmetallation with tin, palladium catalyzed carbonylation and hydrazone formation provides a diene for a subsequent Diels-Alder reaction as shown by Carboni and Lindsey ( J. Am. Chem. Soc . 1959, 81 , 4342) .
- Reaction with dibenzyl azodicarboxylate followed by catalytic hydrogenation to debenzylate and decarboxylate should give after bromination the desired 1, 2 , 3 , 4-tetrazine .
- Palladium-catalyzed coupling provides the desired substitution.
- Potassium permanganate (18.4 g, 116 mmol) was dissolved in water (400 mL) and added to 2-bromo-3-methylpyridine (10.0 g, 58 mmol) and refluxed for 16 hours. After cooling to room temperature, the slurry was filtered through a celite plug and rinsed with water and chloroform. The entire filtrate was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted again with CHC1 3 and acidified with 6N HCl to pH 1. A white solid was obtained on standing (2.08 g of product) . The pH of the remaining aqueous was adjusted to pH 4 with 2M NaOH and 2M HCl, then concentrated to ⁇ 100mL.
- Methyl 2-bromonicotinate (2.0 g, 9.3 mmol) and 3- cyanophenylboronic acid (2.7 g, 18.4 mmol) were combined in 190 mL benzene.
- bis (triphenylphosphine) palladium (II) chloride 325 mg, 0.5 mmol
- Methyl 2- (3 ' -cyanophenyl) nicotinate (300 mg, 1.3 mmol) was combined with of 4-amino-2 ' -t-butylaminosulfonyl- [1 , 1 ' ] biphenyl (383 mg, 1.3 mmol) in 12 mL dry CH 2 C1 2 .
- a solution of trimethylaluminum (3.8 mL, 2.0 M in heptane) was added, and an exothermic reaction immediately occurred and the mixture darkened.
- the resulting solution was stirred at room temperature under argon for 3 days and then quenched carefully with a few drops of 1 M HCl. An emulsion was obtained on dilution with EtOAc and water.
- Methyl 2- (3 ' -cyanophenyl) nicotinate (1.21 g, 5.1 mmol) was partially dissolved in MeOH (40 mL) , and lithium hydroxide monohydrate (234 mg dissolved in 6 mL H0, 5.6 mmol) was added. After 20 hours, the resulting solution was diluted with water and extracted with CHC1 3 . The aqueous was acidified to pK 4 with 1 M HCl and extracted several times with CHC1 3 . Solid sodium chloride was added to the aqueous solution and the solution was extracted with 5-10% MeOH/CHCl 3 .
- N- [5- (2-t-butylaminosulfonyl)phenylpyrid-2-yl] -2- (3 ' - cyanophenyl) nicotinamide (410 mg, 1.03) was dissolved in a mixture of dry MeOH (5mL) and dry CHC1 3 (15mL) and cooled to 0°C .
- HCl(g) was generated by the addition of concentrated H 2 S0 4 (45 mL) to NaCl (220 g) over 55 min and was bubbled into the reaction mixture. The HCl generator and ice bath were removed, and the reaction was stirred under argon for 16 hours and evaporated.
- the following table contains representative examples of the present invention. Each entry in the table is intended to be paired with each formulae at the start of the table. For example, example 1 in Table 2 is intended to be paired with each of formulae ⁇ ss 4 .
Abstract
The present application describes 6-membered aromatics of formula (I) or pharmaceutically acceptable salt forms thereof, wherein D may be CH2NH2 or C(=NH)NH2, which are useful as inhibitors of factor Xa.
Description
TITLE (AMIDIN0)6-MEMBERED AROMATICS AS FACTOR Xa INHIBITORS
FIELD OF THE INVENTION
This invention relates generally to novel 6-membered aromatics which are inhibitors of trypsin-like serine protease enzymes, especially factor Xa, pharmaceutical compositions containing the same, and methods of using the same as anticoagulant agents for treatment and prevention of thromboembolic disorders.
BACKGROUND OF THE INVENTION WO 96/28427 describes benzamidine anticoagulants of the formula:
WO 95/18111 addresses fibrinogen receptor antagonists, containing basic and acidic termini, of the formula:
wherein R1 represents the basic termini, U is an alkylene or heteroatom linker, V may be a heterocycle, and the right hand portion of the molecule represents the acidic termini . The presently claimed compounds do not contain the acidic termini of WO 95/18111.
Activated factor Xa, whose major practical role is the generation of thrombin by the limited proteolysis of prothrombin, holds a central position that links the intrinsic and extrinsic activation mechanisms in the final common pathway of blood coagulation. The generation of thrombin, the final serine protease in the pathway to generate a fibrin clot, from its precursor is amplified by formation of prothrombinase complex (factor Xa, factor V, Ca2+ and phospholipid) . Since it is calculated that one molecule of factor Xa can generate 138 molecules of thrombin (Elodi, S., Varadi, K. : Optimization of condi tions for the catalytic effect of the factor IXa- factor VIII Complex: Probable role of the complex in the amplification of blood coagulation . Thromb. Res . 1979, 15, 617-629), inhibition of factor Xa may be more efficient than inactivation of thrombin in interrupting the blood coagulation system.
Therefore, efficacious and specific inhibitors of factor Xa are needed as potentially valuable therapeutic agents for the treatment of thromboembolic disorders . It is thus desirable to discover new factor Xa inhibitors.
SUMMARY OF THE INVENTION Accordingly, one object of the present invention is to provide novel 6-membered aromatics which are useful as factor Xa inhibitors or pharmaceutically acceptable salts or prodrugs thereof .
It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof .
It is another object of the present invention to provide a method for treating thromboembolic disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof .
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that compounds of formula (I):
I or pharmaceutically acceptable salt or prodrug forms thereof, wherein A, B, D, E, M, Rla, Rlb, and Z are defined below, are effective factor Xa inhibitors.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS [1] Thus, in a first embodiment, the present invention provides novel compounds of formula I :
I or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein;
ring M contains from 0-4 N atoms;
D is selected from CN, C (=NR7 ) NR8R9 , NHC (=NR7 ) R8R9 , NR8CH(=NR7), C(0)NR8R9, and (CR8R9) tNR8R9 ;
E is selected from phenyl, 2-pyridyl, 4-pyridyl, pyrimidyl, and piperidinyl substituted with 1 R;
R is selected from H, F, Cl, Br, I, OR3, SR3 , CO2R3 , NO2, and CH2OR3, and (CR8R9)tNR8R9;
alternatively, E and R combine to form methylenedioxy or ethylenedioxy;
Z is selected from a bond, Cι_4 alkylene, (CH2) rO (CH2 ) r (CH2 )rNR3(CH2)r, (CH2 ) rC (0) (CH2 ) r , (CH2 ) rC (0) 0 (CH2 ) r , (CH2)r0C(0) (CH2)r/ (CH2) rC (0) NR3 (CH2 ) r , (CH2)rNR3C(0) (CH2)r, (CH2 ) r0C (0) 0 (CH2 ) r , (CH2)rOC(0)NR3(CH2)r, (CH2 ) rNR3C (0) 0 (CH2 ) r , (CH2)rNR3C(0)NR3(CH2)r, (CH2 ) rS (O) p (CH2 ) r , (CH2)rS02NR3(CH2)r, (CH2 ) rNR3S02 (CH2 ) r . and (CH2)rNR3S02NR3 (CH2)r/ provided that Z does not form a N- N, N-O, N-S, NCH2N, NCH20, or NCH2S bond with ring M or group A;
Rla and Rlb are independently absent or selected from -(CH2)r-R1'/ -CH=CH-R1#, NCH2R1", OCH2R1" , SCH2R1", NH(CH2)2(CH2)tR1', 0(CH2)2(CH2)tR1', and S (CH2 ) 2 (CH2 ) tR1 ' ;
alternatively, Rla and Rlb, 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, 0, and S;
alternatively, when Z is C(0)NH and Rla is attached to a ring carbon adjacent to Z, then Rla is a C(0) which replaces the amide hydrogen of Z to form a cyclic imide;
R1' is selected from H, C1-3 alkyl, F, Cl, Br, I, -CN, -CHO, (CF2)rCF3, (CH2)rOR2, NR2R2a, C(0)R2c, 0C(0)R2, (CF2)rCθ2R2c, S(0)pR2b, NR2 (CH2 ) r0R2 , CH (=NR2c)NR2R2a, NR2C(0)R2b, NR2C(0)NHR2b, NR2C(0)2R2a, OC (0)NR2 R2b,
C(0)NR2R2a, C(0)NR2(CH2)rOR2, S02NR2R2a, NR2S02R2b, C3_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, 0, and S substituted with C-2 R4;
R1" is selected from H, CH(CH2OR2) , C(0)R2c, C(0)NR2R2a, S(0)R2b, S(0) R2b, and S0NR2R2a;
R2 , at each occurrence, is selected from H, CF3, Cι_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, 0, and S substituted with ϋ-2 R4b;
R2a, at each occurrence, is selected from H, CF3 , Cχ_6 alkyl, benzyl, phenethyl, C3-6 carbocyclic residue substituted with 0-2 Rb, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-2 Rb;
R2b, at each occurrence, is selected from CF , C1-.4 alkoxy, Cι-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;
Rc, at each occurrence, is selected from CF3 , OH, C1-4 alkoxy, Cχ_6 alkyl, benzyl, C3_6 carbocyclic residue substituted with 0-2 Rb, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-2 Rb;
alternatively, R2 and Ra, 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 Rb and containing from 0-1 additional heteroatoms selected from the group consisting of N, 0, 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, Cι_4 alkyl, and phenyl ;
R3c, at each occurrence, is selected from C1-4 alkyl, and phenyl ,-
A is selected from:
C3_ιo carbocyclic residue substituted with 0-2 R , and 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-2 R4;
B is selected from: H, Y, and X-Y;
X is selected from Cι_ alkylene, -CR2 (CR2R2b) (CH2) t~ , -C(O)-, -C(=NR1")-, -CR2(NR1"R2)-, -CR2(OR2)-, -CR2(SR2)-, -C(0)CR2R2a-, -CR2R2aC(0), -S(0)p-, -S (0) pCR2R2a- , -CR2R2aS(0)p-, -S(0)2NR2-, -NR2S(0}2-, -NR2S (0) 2CR2R2a- , -CR2R2aS(0)2NR2-, -NR2S(0)2NR2-, -C(0)NR2-, -NR2C(0)-, -C(0)NR2CR2R2a-, -NR2C (0) CR2R2a- , -CR2R2aC (O)NR2- ,
-CR2R2aNR2C(0)-, -NR2C(0)0-, -0C(0)NR2-, -NR2C (0) NR2- , -NR2-, -NR2CR2R2a-, -CR2R2aNR2-, 0, -CR2R2aO-, and -OCR2R2a-;
Y is selected from:
(CH2)rNR2R2a, provided that X-Y do not form a N-N, O-N, or S-N bond,
C3_ιo carbocyclic residue substituted with 0-2 Ra, and 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-2 Ra;
R4, at each occurrence, is selected from H, =0, (CH2)rOR2 F, Cl, Br, I, Cι_4 alkyl, -CN, N02 , (CH2) rNR2R2a, (CH2)rC(0)R2c, NR2C(0)R2b, C(0)NR2R2a, NR2C (0) NR2R2 , CH(=NR2)NR2R2a, CH(=NS(0)2R5)NR2R2a, NHC (=NR2) NR2R2a, C(0)NHC(=NR2)NR2R2a, S02NR2R2a, NR2S02NR2R2a, NR2S02-Ci- alkyl, NR2S02R5, S(0)pR5, (CF2)rCF3, NCH2R1", OCH2R1",
SCH2R1 " , N ( CH2 ) 2 ( CH2 ) tR1 \ 0 ( 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, 0, and S;
Ra, at each occurrence, is selected from H, =0, (CH2)rOR2, (CH2)r-F, (CH2)r-Br, (CH2)r-Cl, I, Cι_4 alkyl, -CN, N02 , (CH2)rNR2R2a, (CH2)rNR2R2b, (CH2 ) rC (0) R2c , NR2C(0)R2b, C(0)NR2R2a, C(0)NH(CH2)2NR2R2a, NR2C (0) NR2R2a, CH(=NR2)NR2R2a, NHC(=NR2)NR2R2a, S02NR2R2a, NR2S02NR2R2a, NR2S02-Cι_4 alkyl, C (0)NHS02-Cι_4 alkyl, NR2S02R5, S(0)pR5, and (CF2)rCF3;
alternatively, one Ra is a 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, 0, and S and substituted with 0-1 R5;
R4b, at each occurrence, is selected from H, =0, (CH2)rOR3, F, Cl, Br, I, Ci-4 alkyl, -CN, N02 , (CH2) rNR3R3a, (CH2)rC(0)R3, (CH2)rC(0)0R3c, NR3C(0)R3a, C(0)NR3R3a, NR3C(0)NRR3a, CH(=NR3)NR3R3a, NH3C (=NR3 ) NR3R3a, S02NR3R3a, NR3S02NR3R3a, NR3S02-Cι_4 alkyl, NR3S02CF3, NR3S02-phenyl , S(0)pCF3, S(0)p-Cι_4 alkyl, S (0) p-phenyl , and (CF2)rCF3;
R5 , at each occurrence, is selected from CF3 , Cι_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 F» Cl, Br, I, Ci-4 alkyl, CN, N02 , (CH2) rNR2R2a, (CH2)rC(0)R2b, NR2C(0)R2b, NR2C (0)NR2R2a, CH(=NH)NH2- NHC(=NH)NH2, S0NR2R2a, NR2S02NR2R2a, and NR2S02Ci- alkyl;
R7, at each occurrence, is selected from H, OH, C±-β alkyl, Cι-6 alkylcarbonyl , C1-6 alkoxy, Cι_4 alkoxycarbonyl , (CH2)n-phenyl, C6-ιo aryloxy, C6-ιo aryloxycarbonyl, C6-ιo
aryl ethylcarbonyl , Cι_4 alkylcarbonyloxy C _4 alkoxycarbonyl , Cβ-io arylcarbonyloxy C1-4 alkoxycarbonyl , Cι-6 alkylaminocarbonyl , phenylaminocarbonyl , and phenyl-Cι-4 alkoxycarbonyl;
R8 , at each occurrence, is selected from H, Cι_6 alkyl and (CH2 ) n-pheny1 ;
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, 0, and S;
R9 , at each occurrence, is selected from H, C1-6 alkyl and (CH2)n-phenyl;
n is selected from 0, 1, 2, and 3;
m is selected from 0, 1, and 2;
p is selected from 0, 1, and 2 ,-
r is selected from 0, 1, 2, and 3;
s is selected from 0, 1, and 2; and,
t is selected from 0 and 1.
[2] In a preferred embodiment, the present invention provides novel compounds of formulae Ia-Io:
wherein .-
Z is selected from a bond, CH20, OCH2 , CH2NH, NHCH2 , CH2C(0) ,
C(0)CH2, C(0)NH, C(0)NH, CH2S(0)2, S(0)2(CH2) , S02NH, and S02NH;
B is selected from: Y, X-Y, and NR2R2a;
Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R4a; 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, benzoxazole, benzthiazole, indazole, benzisoxazole, benzisothiazole, and isoindazole;
Y may also be selected from the following bicyclic heteroaryl ring systems :
K is selected from 0, S, NH, and N.
[3] In a more preferred embodiment, the present invention provides novel compounds of formulae:
wherein:
D is selected from C(=NR7)NR8R9 and (CR8R9) tNR8R9;
R is selected from H, F, Cl, OR3, CH2OR3 , CH2NH2 ;
A is selected from: piperidinyl , piperazinyl, 5-6 carbocyclic residue substituted with 0-2 R4, and
5-6 membered heteroaryl containing from 1-4 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-2 R4;
Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R4a; phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl , oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, benzimidazolyl, 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, and 1, 3 , 4-triazole.
[4] In an even more preferred embodiment, the present invention provides novel compounds wherein:
E is phenyl;
D is selected from C(=NH)NH2 and CH2NH2
R is selected from H, F, Cl, and Br;
A is selected from:
C5_6 carbocyclic residue substituted with 0-2 R4, and 5-6 membered heteroaryl containing from 1-3 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-2 R4;
Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 Ra; phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, benzimidazolyl, 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, and 1, 3 , 4-triazole;
R , at each occurrence, is selected from H, CF3 , Cι_6 alkyl, benzyl, C5-6 carbocyclic residue substituted with 0-2
Rb, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-2 R4b;
R2a, at each occurrence, is selected from H, CF3 , Cι_6 alkyl, benzyl, phenethyl, C5-6 carbocyclic residue substituted with 0-2 Rb, 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 Rb;
R2b, at each occurrence, is selected from CF3 , C _4 alkoxy,
Cι-6 alkyl, benzyl, Cs_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, 0, and S substituted with 0-2 R4b;
R2c, at each occurrence, is selected from CF3 , OH, Cι_4 alkoxy, Cι_6 alkyl, benzyl, Cs_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, 0, and S substituted with 0-2 Rb;
alternatively, R2 and R2a, together with the atom to which they are attached, combine to form a ring selected from imidazolyl, morpholino, piperazinyl, pyridyl, and pyrrolidinyl, substituted with 0-2 R4b;
R4, at each occurrence, is selected from H, =0, OR2, CH2OR2 ,
F, Cl, Ci-4 alkyl, NR2R2a, CH2NR2R2 , C(0)R2c, CH2C(0)R2c, C(0)NR2R2a, CH(=NR2)NR2R2a, CH (=NS (0) 2R5) NR2R2a, S02NR2R2a, NR2S02-Cι_4 alkyl, S(0)2R5, and CF3
provided that if B is H, then R4 is other than tetrazole, C(0)-alkoxy, and C(0)NR2R2a;
Ra, at each occurrence, is selected from H, =0, (CH2)rOR2, F, Cl, Ci-4 alkyl, NR2R2a, CH2NR2R2a, NR2R2b, CH2NR2R2b,
(CH2)rC(0)R2c, NR2C(0)R2b, C(0)NR2R2a, C (0) NH (CH2 ) 2NR2Ra, NR2C(0)NR2R2a, S02NR2R2a, S(0)2R5, and CF3 ; and,
Rb, at each occurrence, is selected from H, =0, (CH2)rOR3, F, Cl, Ci-4 alkyl, NR3R3a, CH2NR3R3a, C(0)R3, CH2C(0)R3, C(0)0R3c, C(0)NR3R3a, CH(=NR3)NR3R3a, S02NR3R3a, NR3S0 -Cι_4 alkyl, NR3S02CF3, NR3S02-phenyl , S(0)2CF3, S(0)2-Ci_4 alkyl, S (0) 2-phenyl , and CF3.
[5] In a further preferred embodiment, the present invention provides novel compounds selected from:
N-(2'-Aminosulfonyl-[l,l' ]biphen-4-yl) -2- (3'- amidinophenyl) nicotinamide;
N- [5- (2-aminosulfonyl)phenylpyrid-2-yl] -2- (3 ' - amidinophenyl ) nicotinamide;
N- [5- (2-t-butylaminosulfonyl)phenylpyrid-2-yl] -2- (3 ' - amidinophenyl) nicotinamide; and,
N- [5- (2-aminosulfonyl)phenylpyrid-2-yl] -2- (3 ' - carboxamidophenyl) nicotinamide;
or a pharmaceutically acceptable salt thereof.
In a second embodiment, the present invention provides novel pharmaceutical compositions, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof .
In a third embodiment, the present invention provides a novel method for treating or preventing a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof .
DEFINITIONS The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, C=N double bonds , and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.
The term "substituted, " as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substitent is keto (i.e., =0), then 2 hydrogens on the atom are replaced. Keto substituents are not present on aromatic moieties.
The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.
When any variable (e.g., R^) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R6 , then said group may optionally be substituted with up to two R6 groups and R6 at each occurrence is selected independently from the definition of R6. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds .
As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms . Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl. "Haloalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example -CVFW where v = 1 to 3 and w = 1 to (2v+l) ) . Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl . "Alkoxy" represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. "Cycloalkyl" is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl. Alkenyl" is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated
carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl and the like. "Alkynyl" is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl and the like.
"Halo" or "halogen" as used herein refers to fluoro, chloro, bromo, and iodo; and "counterion" is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.
As used herein, "carbocycle" or "carbocyclic residue" is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7- to 13 -membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3. OJbicyclooctane, [4.3.0]bicyclononane, [4.4. OJbicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl .
As used herein, the term "heterocycle" or "heterocyclic system" is intended to mean a stable 5-to 7-membered monocyclic or bicyclic or 7-to 10-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic) , and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, 0 and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and 0 atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred
that the total number of S and 0 atoms in the heterocycle is not more than 1. As used herein, the term "aromatic heterocyclic system" is intended to mean a stable 5-to 7- membered monocyclic or bicyclic or 7-to 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 4 heterotams independently selected from the group consisting of N, 0 and S. It is preferred that the total number of S and 0 atoms in the aromatic heterocycle is not more than 1. Examples of heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl , benzothiophenyl, benzoxazolyl , benzthiazolyl, benztriazolyl, benztetrazolyl , benzisoxazolyl, benzisothiazolyl, benzimidazolinyl , carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-1 , 5 , 2-dithiazinyl , dihydrofuro [2 , 3 -b] tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl , imidazolyl, lJ-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl , octahydroisoquinolinyl, oxadiazolyl, 1, 2 , 3-oxadiazolyl, 1, 2 , 4-oxadiazolyl, 1,2,5- oxadiazolyl, 1, 3 , 4-oxadiazolyl, oxazolidinyl , oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl , phenanthroliny1 , phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl , purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl , tetrahydroisoquinolinyl , tetrahydroquinolinyl, 6H-1, 2 , 5-thiadiazinyl, 1,2,3- thiadiazolyl, 1, 2 , 4-thiadiazolyl, 1, 2 , 5-thiadiazolyl, 1,3,4- thiadiazolyl, thianthrenyl , thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1, 2 , 3-triazolyl, 1, 2 , 4-triazolyl, 1, 2 , 5-triazolyl,
1, 3 , 4-triazolyl, and xanthenyl . Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl, imidazolyl, indolyl, benzimidazolyl, lH-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, or isatinoyl . Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical
methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington ' s Pharmaceutical Sciences, 17th ed. , Mack Publishing Company, Easton, PA, 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
"Prodrugs" are intended to include any covalently bonded carriers which release the active parent drug according to formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of formula (I) are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of formula (I) wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug or compound of formula (I) is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formula (I), and the like. Preferred prodrugs are amidine prodrugs wherein D is C(=NR7)NH and R7 is selected from OH, C1-4 alkoxy, C6-10 aryloxy, Cι_4 alkoxycarbonyl, Cg-io aryloxycarbonyl, Cβ-io arylmethylcarbonyl , Cι_4 alkylcarbonyloxy Cι_4 alkoxycarbonyl, and C6_ιo arylcarbonyloxy C1-4 alkoxycarbonyl. More preferred prodrugs are where R7 is OH, methoxy, ethoxy, benzyloxycarbonyl, methoxycarbonyl , and methylcarbonyloxymethoxycarbonyl .
"Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent .
"Substituted" is intended to indicate that one or more hydrogens on the atom indicated in the expression using "substituted" is replaced with a selection from the indicated group (s), provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., =0) group, then 2 hydrogens on the atom are replaced.
"Therapeutically effective amount" is intended to include an amount of a compound of the present invention or an amount of the combination of compounds claimed effective to inhibit HIV infection or treat the symptoms of HIV infection in a host. The combination of compounds is preferably a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv. Enzyme Regul . 22:27-55 (1984), occurs when the effect (in this case, inhibition of HIV replication) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased antiviral effect, or some other beneficial effect of the combination compared with the individual components .
SYNTHESIS The compounds of the present invention can be prepared in a number of ways known to one skilled in the art of organic synthesis . The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformations being effected. It will sometimes require a judgment to modify the order of synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention. It will also be recognized that another major
consideration in the planning of any synthetic route in this field is the judicious choice of the protecting group used for the protection of the reactive functional groups present in the compounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Greene and Wuts ( Protective Groups in Organic Chemistry, Wiley and Sons, 1991) . All references cited herein are hereby incorporated in their entirety herein by reference. Compounds of this invention where B is either a carbocyclic or heterocyclic residue as defined in Formula 1 are coupled to A as shown generically and by specific example in Schemes 1 and 2, respectively. Either or both of A and B may be substituted with 0-2 R . W is defined as a suitable protected nitrogen, such as N02 or NHBOC; a protected sulfur, such as S-tBu or SMOM; or a methyl ester. Halogen-metal exchange of the bromine in bromo-B with n-butyl lithium, quenching with triisopropyl borate and acidic hydrolysis gives the required boronic acid, B-B(OH)2. The W-A-Br subunit may be already linked to ring M before the Suzuki coupling reaction. Deprotection provides the complete subunit.
Scheme 1
B—Br
1) n-BuLi 2) (iPrO)3B 3) HCl
B-B(0H)2
I A - W-A— B
I Br Pd(0)
Scheme 2 describes a typical example of how the A-B subunit is prepared for attachment to ring M. 4-Bromoaniline is protected as Boc-derivative and the coupled to 2-(t- butylamino) sulfonylphenylboronic acid under Suzuki conditions. 2- (t-Butylamino) sulfonylphenylboronic acid is prepared by the method described by Rivero (Bioorg. Med. Chem . Lett . 1994, 189) . Deprotection with TFA can provide the aminobiphenyl
compound. The aminobiphenyl is then coupled to the core ring structures as described below.
Scheme 2
When B is defined as X-Y, the following description applies. Groups A and B are available either through commercial sources, known in the literature or readily synthesized by the adaptation of standard procedures known to practitioners skilled in the art of organic synthesis . the required reactive functional groups appended to analogs of A and B are also available either through commercial sources, known in the literature or readily synthesized by the adaptation of standard procedures known to practitioners skilled in the art of synthesis . In the tables that follow the chemistry required to effect the coupling of A to B is outlined.
Table A: Preparation of Amide Ester, Urea, Sulfonamide and Sulfamide Linkages Between A and B.
If A contains: then the reactive to give the following substituent of Y is: product A-X-Y:
A-NHR as a C1C(0)-Y A-NR2-C(0)-Y substituent a secondary NH C1C(0)-Y A-C(0)-Y as part of a ring or chain
A-OH as a C1C(0)-Y A-0-C(0)-Y substituent A-NHR2 as a ClC(0)-CR2R2a- •Y A-NR2-C (0) -CR2Ra-Y substituent
a secondary NH C1C(0) -CR2R2a-Y A-C(0)-CR2R2a- as part of a ring or chain
A-OH as a C1C (0)-CR2R2a-Y A-O-C(O) -CR2R2a-Y substituent
A-NHR2 as a C1C(0)-CNR -Y A-NR -C(0) -CNR -Y substituent a secondary NH C1C(0)-CNR -Y A-C(0)-CNR -Y as part of a ring or chain
A-OH as a C1C(0)-CNR -Y A-0-C(0)-CNR -Y substituent
A-NHR2 as a ClSO -Y A-NR -SO,-Y substituent a secondary NH C1S02-Y A-S02-Y as part of a ring or chain
A-NHR2 as a ClS0,-CR2R2a-Y A-NR -SO, -CR2R2a- substituent a secondary NH ClS0,-CR2R2a-Y A-S02-CR2Ra-Y as part of a ring or chain
A-NHR2 as a CISO2- R -Y A-NR2-S02-NR2-Y substituent a secondary NH CISO2-NR -Y A-SO2-NR -Y as part of a ring or chain
A-C(0)C1 HO-Y as a substituent A-C(0)-0-Y
A-C(0)C1 NHR2-Y as a A-C(0)-NR2-Y substituent
A-C(0)C1 a secondary NH as A-C(0)-Y part of a ring or chain
A-CR2R2aC(0)Cl HO-Y as a substituent A-CR2R2aC(0)-0-Y A-CR2R2aC(0)Cl NHR2-Y as a A-CR2R2aC(0)-NR2-Y substituent
A-CR2R aC (0) Cl a secondary NH as A-CR2R2aC (O) -Y part of a ring or chain A-S02C1 NHR2-Y as a A-S02-NR2-Y substituent A-S02C1 secondary NH as A-S02-Y part of a ring or chain A-CR2R2aS02Cl NHR2-Y as a A-CR2R2aS02-NR2-Y substituent A-CR2R2aS02Cl a secondary NH as A-CR2R2aS02-Y part of a ring or chain
The chemistry of Table A can be carried out in aprotic solvents such as a chlorocarbon, pyridine, benzene or toluene, at temperatures ranging from -20°C to the reflux point of the solvent and with or without a trialkylamine base.
Table B: Preparation of Ketone Linkages between A and B.
If A contains: then the reactive to give the following substituent of Y is: product A-X-Y:
A-C(0)C1 BrMg-Y A-C(0)-Y
A-CR2R2aC (0) Cl BrMg-Y A-CR2R2aC (0) -Y
A-C(0)C1 BrMgCR2R2a-Y A-C (0) CR2R2a-Y
A-CR2R2aC (0) Cl BrMgCR2R2a-Y A-CR2R2aC (0) CR2R2a-Y
The coupling chemistry of table B can be carried out by a variety of methods. The Grignard reagent required for Y is prepared from a halogen analog of Y in dry ether, dimethoxyethane or tetrahydrofuran at 0°C to the reflux point of the solvent. This Grignard reagent can reacted directly under very controlled conditions, that is low temperature (-20°C or lower) and with a large excess of acid chloride or with catalytic or stoichiometric copper bromide*dimethyl sulfide complex in dimethyl sulfide as a solvent or with a variant thereof. Other methods available include transforming
the Grignard reagent to the cadmium reagent and coupling according to the procedure of Carson and Prout (Org. Syn. Col Vol. 3 (1955) 601) or a coupling mediated by Fe(acac)3 according to Fiandanese et al.(Tetr. Lett . 1984, 4805), or a coupling mediated by manganese (II) catalysis (Cahiez and aboue, Tetr . Lett . 1992, 33 (31 ) , 4437).
Table C: Preparation of Ether and Thioether linkages between
A and B.
If A contains: then the reactive to give the following substituent of Y is: product A-X-Y:
A-OH Br-Y A-O-Y A-CR2R2a-0H Br-Y A-CR2R2a0-Y
A-OH Br-CR2R2a-Y A-0CR2R2a-Y
A-SH Br-Y A-S-Y A-CR2R2a-SH Br-Y A-CR2R2aS-Y
A-SH Br-CR2R2a-Y A-SCR2R2a-Y
The ether and thioether linkages of Table C can be prepared by reacting the two components in a polar aprotic solvent such as acetone, dimethylformamide or dimethylsulfoxide in the presence of a base such as potassium carbonate, sodium hydride or potassium t-butoxide at a temperature ranging from ambient to the reflux point of the solvent used.
Table D: Preparation of -SO- and -S0- linkages from thioether of Table C.
If the starting then it is oxidized then it is oxidized material is : with wet with m-
Alumina/Oxone to chloroperbenzoic acid give: to give :
A-S-Y A-S(0)-Y A-S02-Y A-CR2R2aS-Y A-CR2R2aS(0)-Y A-CR2R2aS02-Y A-SCR2R2a-Y A-S(0)CR2R2a-Y A-S02CR2R2a-Y
The thioethers of Table C serve as a convenient starting material for the preparation of the sulfoxide and sulfone
analogs of Table D. A combination of wet alumina and Oxone can provide a reliable reagents for the oxidation of the thioether to the sulfoxide as shown by Greenhalgh ( Syn . Lett . 1992, 235) . The sulfone can be prepared according to the method of Satoh ( Chem . Lett . 1992, 381) using m- chloroperbenzoic acid.
Scheme 3 describes the synthesis of compounds wherein M is a benzene ring and Q is a protected precursor of group D of Formula I and V is a nitro, protected sulfonamide or ester group and precursor of group Z of Formula I. The V group is placed on an appropriately substituted phenol either via nitration as shown by Poirier et al . ( Tetrahedron 1989, 45 (5) , 1415) , sulfonylation as shown by Kuznetsov (Akad. Nauk SSSR Ser . Khim 1990, 8, 1888) or carboxylation by Sartori et al . (Synthesis 1988, 10, 763) . Bromination with triphenylphosphine and bromine (J". Am . Chem . Soc . 1964, 86, 964) gives the desired bromide. Suzuki coupling with the appropriate boronic acid provides the desired substituted pyridine .
Scheme 3
Schemes 4, 5, 6, and 7 describe the synthesis of compounds wherein M is pyridine and Q is a protected precursor of group D of Formula I. Each scheme represents a different substitution pattern for the pyridine ring. In Scheme 4, a suitably protected aldehyde is subjected to base-catalyzed condensation with an activated ester to give after deprotection the desired aldehyde. Refluxing with ammonium chloride as shown by Dornow and Ische ( Chem . Ber. 1956, 89, 876) provides the pyridinol which is brominated with POBr3 (Tjeenk et al . Rec . Trav. Chi . 1948, 67, 380) to give the desired 2-bromopyridine. Suzuki coupling with the appropriate boronic acid provides the desired substituted pyridine.
Scheme 4
Treatment of an appropriately substituted 5-ethoxyoxazole with an alkene as shown by Kondrat ' eva et al . Dokl . Akad. Nauk SSSR 1965, 164 , 816) provides a pyridine with the V substituent at the para position. Bromination at the 3- position as shown by van der Does and Hertog (Rec . Trav. Khim . Pays-Bas 1965, 84 , 951) followed by palladium-catalyzed boronic acid coupling provides the desired substituted pyridine .
Scheme 5
Scheme 6 describes a synthesis of a third substitution pattern on a pyridine ring. The appropriate tricarbonyl compound which can be prepared by methods described in Scheme
4 is treated with ammonium chloride to form the pyridinol which is subsequently brominated. Palladium-catalyzed coupling provides the desired substituted pyridine.
Scheme 6
Scheme 7 takes a suitably substituted dicarbonyl compound and by chemistry illustrated in Schemes 4 and 6, reacts it with ammonium chloride. Bromination gives the 3 -bromopyridine which upon palladium-catalyzed coupling provides the desired substituted pyridine.
Scheme 7
Schemes 8, 9, and 10 describe the synthesis of compounds wherein M is pyridazine and Q is a protected precursor of group D of Formula I. Each scheme represents a different substitution pattern for the pyridine ring. In Scheme 8 an activated ester is reacted with an appropriately substituted α-keto aldehyde and hydrazine as shown by Schmidt and Druey (Helv. Chim. Acta 1954, 37, 134 and 1467) . Conversion of the pyridazinone to the bromide using POBr3 and palladium-
catalyzed coupling provides the desired substituted pyridazine.
Scheme 8
In Scheme 9, glyoxal can react under basic conditions with an activated ketone and subsequently brominated/dehydro- brominated to give the desired ketoaldehyde . Alternatively, a protected ketone can react with an activated aldehyde, undergo bromination/dehydrobromination, be deprotected and oxidized to give the regioisomeric ketoaldehyde. Cyclization as shown by Sprio and Madonia (Ann. Chim . 1958, 48, 1316) with hydrazine followed by palladium-catalyzed coupling provides the desired substituted pyridazine.
Scheme 9
By analogy to Scheme 9, in Scheme 10 a aldehyde can be reacted with an activated ketone, brominated, de ydro- brominated and deprotected to give the desired diketone. Alternatively, a regioisomeric ketone can be placed through the same reaction sequence to produce an isomeric keto aldehyde. Reaction with hydrazine followed by palladium-
catalyzed coupling provides the desired substituted pyridazine .
Scheme 10
Schemes 11, and 12 describe the synthesis of compounds wherein M is pyrimidine and Q is a protected precursor of group D of Formula I. Each scheme represents a different substitution pattern for the pyrimidine ring. In Scheme 11, a condensation with an appropriately substituted acid chloride and an activated ester followed by conjugate reduction by tin hydride (Moriya et al . J. Org. Chem. 1986, 51 , 4708) gives the desired 1,4 dicarbonyl compound. Cyclization with formamidine or a substituted amidine followed by bromination gives the desired regioisomeric pyrimidine. Palladium-catalyzed coupling provides the desired substituted pyrimidine.
Scheme 11
Using similar chemistry, Scheme 12 shows how an amidine can be condensed with a 1, 3-dicarbonyl compound and subsequently brominated in the 5-position (J". Het. Chem . 1973, 10, 153) to give a specific regioisomeric bromopyrimidine . Palladium-catalyzed coupling provides the desired substituted pyrimidine.
Scheme 12
Using the same ketoaldehyde from Scheme 12, cyclization with an appropriately substituted 1,2-diamine ( Chimia 1967, 21 , 510) followed by aromatization (Helv. Chim. Acta 1967, 50, 1754) provides a regioisomeric mixture of pyrazines as illustrated in Scheme 13. Bromination of the hydrobromide salt (U.S. Patent No. 2,403,710) yields the intermediate for
the palladium-catalyzed coupling step which occurs as shown above .
Scheme 13
OH
Schemes 14 and 15 describe the synthesis of compounds wherein M is a 1, 2 , 3-triazine and Q is a protected precursor of group D of Formula I. In Scheme 14, a vinyl bromide is palladium coupled to a molecule containing the substituent R . Allylic bromination followed by azide displacement provide the cyclization precursor. Triphenylphosphine- mediated cyclization (J. Org. Chem . 1990, 55, 4724) give the 1-aminopyrazole which is subsequently brominated with N- bromosuccimide. Lead tetraacetate mediated rearrangement as shown by Neunhoeffer et al . (Ann . 1985, 1732) provides the desired regioisomeric 1, 2 , 3-triazine. Palladium-catalyzed coupling provides the substituted triazine.
Scheme 14
1) RlbCH2Br
In Scheme 15, an alkene is allylically brominated and the bromide is displaced to give a regioisomer of the azide in Scheme 14. Following the same reaction sequence as shown above, cyclization provides the 1-aminopyrazole. Bromination followed by lead tetraacetate mediated rearrangement give the
1 , 2 , 3 -triazine . Palladium-catalyzed coupling provides the other desired triazine .
Scheme 15
Schemes 16 and 17 describe the synthesis of compounds wherein M is a 1, 2 , 4-triazine and Q is a protected precursor of group D of Formula I. In Scheme 16, a nitrile is converted using hydrazine to give the amidrazone which is condensed with a α-ketoester to give the triazinone as shown by Paudler and Lee ( M Org. Chem . 1971, 36, 3921) . Bromination as shown by Rykowski and van der Plas ( J. Org. Chem . 1987, 52, 71) followed by palladium-catalyzed coupling provides the desired 1, 2, 4-triazine.
Scheme 16
Rιbc
In Scheme 16, to achieve the opposite regioisomer the reaction scheme shown above is modify by the substituting a protect α-ketoester. This allows the most nucleophilic nitrogen to attack the ester functionality setting up the opposite regiochemistry. Deprotection and thermal cyclization gives the triazinone which is brominated as shown above.
Palladium-catalyzed coupling provides the other desired 1,2,4- triazine.
Scheme 17
b
RlbCN
4 ) POBr3
Scheme 18 describes the synthesis of compounds wherein M is a 1, 2 , 3 , 4-tetrazine and Q is a protected precursor of group D of Formula I. Lithiation of a vinyl bromide, transmetallation with tin, palladium catalyzed carbonylation and hydrazone formation provides a diene for a subsequent Diels-Alder reaction as shown by Carboni and Lindsey ( J. Am. Chem. Soc . 1959, 81 , 4342) . Reaction with dibenzyl azodicarboxylate followed by catalytic hydrogenation to debenzylate and decarboxylate should give after bromination the desired 1, 2 , 3 , 4-tetrazine . Palladium-catalyzed coupling provides the desired substitution.
Scheme 18
C02Bn 1 ) nBuLi i ) ^
Br 2) (nBu)3SnCl Bn ^^
=<
V 3) Pd(0), CO \ 2) H2, Pd
4) BnNHNH2 v 3) NBS
Other features of the invention will become apparent in the course of the following descriptions of exemplary
embodiments which are given for illustration fo the invention and are not intended to be limiting thereof.
EXAMPLES
Example 1
N- (2 ' -Aminosulfonyl- [1, 1' ]biphen-4-yi) -2- (3 ' - amidinophenyl) nicotinamide, trifluoroacetic acid salt
Part A. Preparation of 2-bromonicotinic acid.
Potassium permanganate (18.4 g, 116 mmol) was dissolved in water (400 mL) and added to 2-bromo-3-methylpyridine (10.0 g, 58 mmol) and refluxed for 16 hours. After cooling to room temperature, the slurry was filtered through a celite plug and rinsed with water and chloroform. The entire filtrate was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted again with CHC13 and acidified with 6N HCl to pH 1. A white solid was obtained on standing (2.08 g of product) . The pH of the remaining aqueous was adjusted to pH 4 with 2M NaOH and 2M HCl, then concentrated to <100mL. A white precipitate was filtered. The pH was adjusted to 4 and the mixture filtered again, combining the isolated solids for a total of 3.88 g of product. The filtrate was concentrated again to <100mL and adjusted to pH 1.5 and an additional quanitity of white solid was obtained (1.80 g) , for a combined yield of 3 crops, (8.76 g, 66%). hi NMR (DMSO-d6) : δ 13.76 (bs, IH) , 8.46 (m, IH) ,
8.09 (dd, IH, J = 7.7, J' = 2.2), 7.51 (m, IH) .
Part B. Preparation of methyl 2-bromonicotinate.
2-Bromonicotinic acid (7.33 g, 36 mmol) was suspended in dry Et20 (40 L) , and MeOH (2.3 mL) and diethyl azodicarboxylate (5.8 mL, 37 mmol) were added. Triphenylphosphine (9.61 g in 40mL Et20, 37 mmol) was added dropwise over 2.5 hours . After stirring an additional two hours, the reaction was filtered and evaporated. The resulting clear liquid was chromatographed on silica gel (10-
40% EtOAc/ exanes) to yield a clear oil (8.63 g, 100%). 1H NMR (CDC13) : δ 8.49 (dd, IH, J = 4.8, J' = 2.2), 8.09 (dd,
IH, J = 7.7, J' = 1.8), 7.36 (m, IH) , 3.97 (s, 3H) .
Part C. Preparation of 3-cyanophenylboronic acid.
3-Bromobenzonitrile (10.0 g, 55 mmol) was dissolved in dry THF (100 mL) and cooled to -100°C (Et20/N2) . n- Butyllithium (24.2 mL, 2.5 M in hexane) was added over 30 minutes, maintaining the internal temp under -90°. After 20 minutes, triisopropylborate (18.0 mL) was added over 15 minutes, again maintaining the internal temperature. After the addition was complete, the reaction was allowed to warm slowly to room temperature over 1.5 hours. The reaction was stirred at room temp for 16 hours, then cooled to 15°C, after which 6 M HCl (25 mL) was added. After stirring vigorously for 3.5 hours, the reaction was partitioned between water and EtOAc . After extracting a second time with EtOAc, the combined organics were washed with 2 M NaOH. The aqueous extract was neutralized with 6 M HCl. The white precipitate was filtered, yielding the desired product (4.80 g, 60%). 1H NMR (DMSO-d6) : δ 8.37 (s, 2H) , 8.10 (s, IH) , 8.03 (dt, IH, J
= 7.3, J' = 1.1), 7.83 (dt, IH, J = 7.6, J' = 1.4), 7.53 (t, IH, J = 7.7) .
Part D. Preparation of methyl 2- (3 ' -cyanophenyl) nicotinate .
Methyl 2-bromonicotinate (2.0 g, 9.3 mmol) and 3- cyanophenylboronic acid (2.7 g, 18.4 mmol) were combined in 190 mL benzene. Sodium carbonate (19 mL of a 2 M aqueous solution), tetrabutylammonium bromide (152 mg, 0.5 mmol), and bis (triphenylphosphine) palladium (II) chloride (325 mg, 0.5 mmol) were added. The entire mixture was evacuated to remove dissolved gasses, then placed under argon. The reaction was refluxed for 14 hours, diluted with water and EtOAc, separated, dried over Na2S04, filtered, and evaporated. The resulting yellow solid was chromatographed on silica gel (30% EtOAc/hexanes) to yield a light yellow solid (1.70 g, 77%).
XH NMR (CDCI3) : δ 8.81 (dd, IH, J = 4.8, J' = 1.8) , 8.23 (dd, IH, J = 8.0, J' =1.9) , 7.85 (s, IH) , 7.73 (m, 2H) , 7.55 (t, IH, J = 7.7) , 7.43 (m, IH) , 3.76 (s, 3H) .
Part E. Preparation of 2- ( t-butylaminosulfonyl ) phenylboronic acid.
To a solution of 206.5 g (0.968 mol) of benzene- (N-t- butyl) sulfonamide in 2500 mL of THF under N2 was added 790 mL (1.98 mol) of 2.5M n-butyllithium in hexane over 35 minutes, keeping the temperature between 0-5°C. The reaction mixture was allowed to warm to 10°C, at which time a thick precipitate formed. Triisopropylborate (305 mL, 1.32 mol) was added keeping the temperature below 35°C. After 1 hour, the reaction mixture was cooled, IN HCl (1570 mL) was added, and the mixture was stirred overnight. The mixture was extracted with 400 mL of ether three times, and the combined organic extracts were extracted with 500 mL of IN NaOH three times. The aqueous extracts were acidified to pH 1 with 6N HCl, and then extracted with 500 mL ether three times. The combined ether extracts were dried over MgS04, and the solvents evaporated in vacuo until the volume was 700 mL. Hexane (150 mL) was added and overnight, a white precipitate formed. The solid was collected and washed with 10% ether/hexane (250 mL) , then dried in vacuo to give 216.3 g (87%) of the desired compound as white crystals. m.p. 118-119°C; XH NMR (CDC13): δ
8.00 (d, IH) ; 7.82 (d, IH) ; 7.53 (m, 2H) ; 6.29 (br s, 2H) ; 5.13 (s, IH) ; 1.18 (s, 9H) .
Part F. Preparation of 4-amino-2 ' -t-butylaminosulfonyl- [1,1'] biphenyl .
A mixture of 3.44 g (20 mmol) of 4-bromoaniline and 5.14 g (20 mmol) of 2- (t-butylaminosulfonyl) phenylboronic acid, 1.16 g of tetrakis ( triphenylphosphine) palladium(O) (1 mmol), 0.32 g of tetrabutylammonium bromide (1 mmol) and 20 mL of 2M aqueous sodium carbonate were refluxed with 180 mL of benzene under N2 for 5.5 hours. After cooling, the mixture was
diluted with methylene chloride and water. The two phases were separated and the organic phase was washed with water, dried with MgS04 and concentrated in vacuo . The resulting thick oil was chromatographed on silica with 30% EtOAc/hexane to afford 2.52 g (41%) of the aniline. XH NMR (CDC13): δ 8.14
(d, IH) ; 7.53 (t, IH) ; 7.43 (t, IH) ; 7.33 (d, 2H) ; 7.27 (d, IH) ; 6.76 (d, 2H) ; 3.7 (br s, IH) ; 0.99 (s, 9H) .
Part G. Preparation of N- (2 ' -t-butylaminosulfonyl- [1,1' ]biphen-4-yl) -2- (3 ' -cyanophenyl) nicotinamide.
Methyl 2- (3 ' -cyanophenyl) nicotinate (300 mg, 1.3 mmol) was combined with of 4-amino-2 ' -t-butylaminosulfonyl- [1 , 1 ' ] biphenyl (383 mg, 1.3 mmol) in 12 mL dry CH2C12. A solution of trimethylaluminum (3.8 mL, 2.0 M in heptane) was added, and an exothermic reaction immediately occurred and the mixture darkened. The resulting solution was stirred at room temperature under argon for 3 days and then quenched carefully with a few drops of 1 M HCl. An emulsion was obtained on dilution with EtOAc and water. The layers were separated, and the organic was extracted again with water and brine, dried over Na2S0 , filtered, and evaporated. A small amount of additional material was obtained from the aqueous extract by adjusting the pH to 8 with sat. NaHC03 and extracting with EtOAc. This material was dried over Na2S04, filtered, evaporated, and combined with the previous extract for chromatography on silica gel (50-60% EtOAc/hexanes) to yield the desired product (190 mg, 30%). XH NMR (CDC13): δ 8.86
(dd, IH, J = 4.7, J' = 1.9), 8.14 (m, 3H) , 8.00 (d, IH, J = 7.7), 7.73 (d, IH, J = 8.1), 7.50 (m, 9H) , 7.29 (dd, IH, J = 7.4, J' = 1.1), 3.60 (s, IH) , 1.02 (s, 9H) .
Part H. Preparation of N- (2 ' -aminosulfonyl- [1, 1' ]biphen-4- yl) -2- (3 ' -amidinophenyl) nicotinamide, trifluoroacetic acid salt.
N- (2 ' -t-butylaminosulfonyl- [1, 1 ' ]biphen-4-yl) -2- (3 ' - cyanophenyl) nicotinamide (190 mg, 0.37 mmol) was dissolved in
dry MeOH (10 mL) and cooled to 0°C. HCl (g) was generated by the addition of concentrated H2S04 (60 mL) to NaCl (240 g) over 40 minutes and was bubbled into the reaction mixture. The gas was permitted to continue bubbling through the reaction for 3 hours after the H2S04 addition was complete. At this point, the HCl generator and ice bath were removed, and the reaction stirred under argon for 19 hours. This solution was then evaporated, placed under high vacuum, and redissolved in dry MeOH (10 mL) . Ammonium carbonate (200 mg) was added, stirred for 24 hours under argon, and evaporated.
The product was purified by preparative HPLC on a C-18 reverse phase column (10-70% MeCN/H2O/0.05% TFA), yielding a white powder (140 mg, 54%). XH NMR (DMSO-d6) : δ 10.65 (s, IH) , 9.38
(s, 2H) , 8.92 (s, 2H) , 8.81 (dd, IH, J = 4.4, J' = 1.4), 8.10 (m, 2H) , 7.97 (m, 2H) , 7.76 (m, IH) , 7.67 (t, IH, J = 8.0),
7.57 ( , 5H) , 7.29 (m, 5H) . HRMS calc . for C25H22N503S: m/z 472.1443; found, 472.1457.
Examples 2, 3 and 4 N- [5- (2- minosulfonyl) henylpyrid-2-yl] -2- (3 ' - amidinophenyl)nicotinamide, trifluoroacetic acid salt (Exastple
2) , N- [5- (2-t-butylaminosulfonyl)phenylpyrid-2-yl] -2- (3'- amidinophenyl) nicotinamide, trifluoroacetic acid salt (Example 3), and N- [5- (2-aminosulfonyl)phenylpyrid-2-yl] -2- (3'- carboxamidophenyl)nicotinamide, trifluoroacetic acid salt
(Example 4)
Part A. Preparation of 2- (3 ' -cyanophenyl) nicotinic acid.
Methyl 2- (3 ' -cyanophenyl) nicotinate (1.21 g, 5.1 mmol) was partially dissolved in MeOH (40 mL) , and lithium hydroxide monohydrate (234 mg dissolved in 6 mL H0, 5.6 mmol) was added. After 20 hours, the resulting solution was diluted with water and extracted with CHC13. The aqueous was acidified to pK 4 with 1 M HCl and extracted several times with CHC13. Solid sodium chloride was added to the aqueous solution and the solution was extracted with 5-10% MeOH/CHCl3. The organic extracts were combined, dried over Na2S0 ,
filtered, and evaporated to yield a white solid (1.06 g, 93%) . XH NMR (CDC13) : δ 8.85 (dd, IH, J = 5.1, J' = 1.5) , 8.35 (dd,
IH, J = 7.6, J' = 1.4), 7.84 (s, IH) , 7.75 (m, 2H) , 7.55 (t, IH, J = 7.7) , 7.47 (m, IH) .
Part B. Preparation of 2-amino-5- (2-t-butylamino- sulfonyl) phenylpyridine .
A mixture of 1.55 g (9.0 mmol) of 2-amino-5-bromopyridine and 2.3 g (9.0 mmol) of 2- (t-butylaminosulfonyl) phenylboronic acid, 0.52 g of tetrakis ( triphenylphosphine) palladium(O) (0.45 mmol), 0.15 g of tetrabutylammonium bromide (0.45 mmol) and 9 mL of 2M aqueous sodium carbonate were refluxed with 80 mL of benzene under Ar for 5 hours. After cooling, the mixture was diluted with 25 mL of methylene chloride and 25 mL of water. The two phases were separated and the organic phase was washed with water, dried with MgS04 and concentrated in vacuo . The resulting thick oil was chromatographed on silica with 50% EtOAc/hexane to afford 1.34 g (49%) of the aniline. 1H NMR (CDCI3): δ 8.18 (d, IH) ; 8.07 (m, IH) ; 7.70 (dd, IH) ;
7.58 (dt, IH) ; 7.48 (dt, IH) ; 7.28 (d, IH) ; 6.56 (d, IH) ; 4.62 (br s, 2H) ; 3.88 (br s, IH) ; 1.06 (s, 9H) .
Part C. Preparation of N-[5-(2-t- butylaminosulfonyl)phenylpyrid-2-yl] -2- (3 ' - cyanophenyl ) nicotinamide .
2- (3 ' -cyanophenyl) nicotinic acid (300 mg, 1.3 mmol) was suspended in 5 mL dry CH2C12 , and oxalyl chloride (175 μl, 2.0 mmol) was added, followed by 2 drops of dry DMF. The reaction stirred at room temperature under argon for 2 hours and then evaporated. This solid was redissolved in 8 mL dry CH2C12, and dimethylaminopyridine (490 mg, 4.0 mmol) was added, followed by 2-amino-5- (2-t-butylaminosulfonyl)phenylpyridine (410 mg, 1.3 mmol) . The reaction was stirred 3 days at room temperature, diluted with CH2C12, extracted with saturated NaHC03, dried over Na2S04, filtered, and evaporated. The resulting material was chromatographed on silica gel (50-75%
EtOAc / hexanes) to yield the desired product (423 mg, 62%) . XH NMR (CDC13) : δ 8.83 (dd, IH, J = 4.8, J' = 1.5) , 8.40 (bs,
IH) , 8.29 (bd, IH, J = 8.4), 8.17 (dd, IH) , J = 8.0, J' =
1.1), 8.09 (m, 3H) , 7.97 (d, IH, J = 7.7), 7.79 (d, IH, J = 8.4), 7.69 (d, IH, J = 7.7), 7.54 (m, 4H) , 7.25 (m, IH) , 4.19 (bs, IH) , 1.08 (s, 9H) .
Part D. Preparation of N- [5- (2-aminosulfonyl)phenylpyrid-2- yl] -2- (3 ' -amidinophenyl) nicotinamide, trifluoroacetic acid salt (Example 2), N- [5- (2-t-butylaminosulfonyl) phenylpyrid-2- yl] -2- (3 ' -amidinophenyl) nicotinamide, trifluoroacetic acid salt (Example 3), and N- [5- (2-aminosulfonyl) phenylpyrid-2-yl] - 2- (3 ' -carboxamidophenyl) nicotinamide, trifluoroacetic acid salt (Example 4) .
N- [5- (2-t-butylaminosulfonyl)phenylpyrid-2-yl] -2- (3 ' - cyanophenyl) nicotinamide (410 mg, 1.03) was dissolved in a mixture of dry MeOH (5mL) and dry CHC13 (15mL) and cooled to 0°C . HCl(g) was generated by the addition of concentrated H2S04 (45 mL) to NaCl (220 g) over 55 min and was bubbled into the reaction mixture. The HCl generator and ice bath were removed, and the reaction was stirred under argon for 16 hours and evaporated. The resulting solid was redissolved in dry MeOH (15 mL) , and ammonium carbonate (385 mg) was added. The reaction was stirred 19 hours at room temperature under argon and evaporated. The resulting solid was purified by preparative HPLC on a C-18 reverse phase column (5-70% MeCN / H20 / 0.05% TFA) to yield N- [5- (2-aminosulfonyl) phenylpyrid-2- yl] -2- (3 ' -amidinophenyl) nicotinamide, trifluoroacetic acid salt (Example 2), (250 mg, 45%). XH NMR (DMS0-d6) : δ 11.27
(s, IH) , 9.43 (s, 2H) , 8.98 (s, 2H) , 8.83 (dd, IH, J = 4.8, J' = 1.9), 8.32 (s, IH) , 8.13 (m, 2H) , 8.05 (m, 2H) , 7.96 (d, IH, J = 7.3), 7.81 (d, 2H, J = 8.4), 7.65 (m, 4H) , 7.47 (s, 2H) , 7.37 (m, IH) . HRMS calc . for C24H21N603S: m/z 473.1396; found, 473.1397. A second product, N- [5- (2-t-butylaminosulfonyl) - phenylpyrid-2-yl] -2- (3 ' -amidinophenyl) nicotinamide, trifluoroacetic acid salt (Example 3), was also obtained (58 mg, 10%). λK NMR (DMSO-d6) : δ 9.7 (s, IH) , 9.41 (s, 2H) , 8.95
(s, 2H) , 8.82 (m, IH) , 8.28 (s, IH) , 8.09 (m, 4H) , 7.95 (d, IH, J = 7.7), 7.79 (m, 2H) , 7.63 (m, 4H) , 7.34 (d, IH, J = 7.7), 7.18 (s, IH) , 1.04 (s, 9H) . HRMS calc . for C28H29N603S: 529.2022; found, 529.2050. A third product, N-[5-(2- aminosulfonyl) phenylpyrid-2-yl] -2- (3 ' - carboxamidophenyl) nicotinamide, trifluoroacetic acid sale (Example 4) was isolated and chromatographed on silica gel (10-20% MeOH/CHCl3) to yield a white solid (77 mg, 20%) . XH NMR (DMSO-d6) : δ 11.13 (s, IH) , 8.75 (dd, IH, J = 4.8, J' = 1.9), 8.26 (m, 2H) , 8.02 (m, 4H) , 7.84 (d, IH, J = 7.7), 7.74 (m, 2H) , 7.59 (m, 2H) , 7.47 (m, 2H) , 7.36 (m, 4H) .
Table 1
The following table contains representative examples of the present invention. Each entry in the table is intended to be paired with each formulae at the start of the table. For example, example 1 in Table 2 is intended to be paired with each of formulae ~ss4.
Table 2
U R=F, D=NH2 ^ R=F, D=NH2 h R=F, D=NH2 J2 R=H, D=NH2 k2 R=H, D=NH2 12 R=H, D=NH2 j3 R=F, D=CH2NH2 k3 R=F, D=CH2NH2 13 R=F, D=CH2NH2 j4 R=H, D=CH2NH2 l^ R=H, D=CH2NH2 14 R=H, D=CH2NH2 j5 R=F, D=C(=NH)NH2 k5 R=F, D=C(=NH)NH2 15 R=F, D=C(=NH)NH2 J6 R=H, D=C(=NH)NH2 k6 R=H, D=C(=NH)NH2 16 R=H, D=C(=NH)NH2 j7 R=F, D=C(0)NH2 k7 R=F, D=C(0)NH2 17 R=F, D=C(0)NH2 j8 R=H, D=C(Q)NH2 k8 R=H, D=C(0)NH2 18 R=H, D=C(0)NH2
P! R=F, D=NH2 qi R=F, D=NH2 R=F, D=NH2 p2 R=CI, D=NH2 q2 R=CI, D=NH2 R=CI, D=NH2 p3 R=OMe, D=NH2 q3 R=OMe, D=NH2 R=OMe, D=NH2 p4 R=F, D=CH2NH2 q4 R=F, D=CH2NH2 R=F, D=CH2NH2 p5 R=CI, D=CH2NH2 q5 R=CI, D=CH2NH2 R=CI, D=CH2NH2 p6 R=OMe, D=CH2NH2 q6 R=OMe, D=CH2NH2 R=OMe, D=CH2NH2 p7 R=F, D=C(=NH)NH2 q7 R=F, D=C(=NH)NH2 R=F, D=C(=NH)NH2 p8 R=CI, D=C(=NH)NH2 q8 R=CI, D=C(=NH)NH2 8 R=CI, D=C(=NH)NH2 P9 R=OMe, D=C(=NH)NH2 q9 R=OMe, D=C(=NH)NH2 9 R=OMe, D=C(=NH)NH2 P10 R=F, D=C(0)NH2 q10 R=F, D=C(0)NH2 10 R=F, D=C(0)NH2 Pn R=CI, D=C(0)NH2 qn R=CI, D=C(0)NH2 n R=CI, D=C(0)NH2 p12 R=OMe, D=C(0)NH2 q12 R=OMe, D=C(0)NH2 12 R=OMe, D=C(0)NH2
Si s2 s3 s4 s5 s6 s s8 s s1 S Sι
Ex # Rlb
1 H phenyl 2- (aminosulfonyl) phenyl
2 H phenyl 2- (methylaminosulfonyl) phenyl
3 H phenyl 1-pyrrolidinocarbonyl
4 H phenyl 2- (me hylsulfonyl) phenyl
5 H phenyl 4-morpholino
6 H phenyl 2- (1' -CF3-tetrazol-2-yl) phenyl
7 H phenyl 4-morpholinocarbonyl
8 H 2-pyridyl 2- (aminosulfonyl) phenyl
9 H 2-pyridyl 2- (methylaminosulfonyl) phenyl
10 H 2-pyridyl 1-pyrro1idinocarbony1
11 H 2-pyridyl 2- (me hylsulfonyl)phenyl
12 H 2-pyridyl 4-morpholino
13 H 2-pyridyl 2- ( 1 ' -CF3-tetrazol-2-yl) phenyl
H 2-pyridyl 4-morpholinocarbonyl
H 3 -pyridyl 2- ( aminosulfonyl ) phenyl
H 3 -pyridyl 2- (methylaminosulfonyl) phenyl
H 3-pyridyl 1-pyrrolidinocarbonyl
H 3-pyridyl 2- (methylsulfonyl) phenyl
H 3-pyridyl 4-morpholino
H 3-pyridyl 2- (1' -CF3-tetrazol-2-yl) phenyl
H 3-pyridyl 4-morpholinocarbonyl
H 2-pyrimidyl 2- (aminosulfonyl) phenyl
H 2-pyrimidyl 2- (methylaminosulfonyl) phenyl
H 2-pyrimidyl 1-pyrrolidinocarbonyl
H 2-pyrimidyl 2- (methylsulfonyl) phenyl
H 2-pyrimidyl 4-morpholino
H 2-pyrimidyl 2-(l'-CF3-tetrazol-2-yl)phenyl
H 2-pyrimidyl 4-morpholinocarbony1
H 5-pyrimidyl 2- (aminosulfonyl) phenyl
H 5-pyrimidyl 2- (methylaminosulfonyl) phenyl
H 5-pyrimidyl 1-pyrro1idinocarbony1
H 5-pyrimidyl 2- (methylsulfonyl) phenyl
H 5-pyrimidyl 4-morpholino
H 5-pyrimidyl 2- (1 ' -CF3-tetrazol-2-yl) phenyl
H 5-pyrimidyl 4-morpholinocarbonyl
H 2-Cl-phenyl 2- (aminosulfonyl ) phenyl
H 2-Cl-phenyl 2- (methylaminosulfonyl) phenyl
H 2-C1-phenyl 1-pyrrolidinocarbonyl
H 2-Cl-phenyl 2- (methylsulfonyl) phenyl
H 2-Cl-phenyl 4-morpholino
H 2-C1-phenyl 2- (1' -CF3-tetrazol-2-yl)phenyl
H 2-Cl-phenyl 4-morpholinocarbonyl
H 2-F-phenyl 2- (aminosulfonyl) phenyl
H 2-F-phenyl 2- (methylaminosulfonyl) phenyl
H 2-F-phenyl 1-pyrro1idinocarbony1
H 2-F-phenyl 2- (methylsulfonyl) phenyl
H 2-F-phenyl 4-morpholino
H 2-F-phenyl 2- (1' -CF3-tetrazol-2-yl) phenyl
H 2-F-phenyl 4-morpholinocarbonyl
H 2 , 5-diF-phenyl 2- (aminosulfonyl) phenyl
H 2, 5-diF-phenyl 2- (methylaminosulfonyl) phenyl
H 2, 5-diF-phenyl 1-pyrrolidinocarbony1
H 2, 5-diF-phenyl 2- (methylsulfonyl) phenyl
H 2, 5-diF-phenyl 4-morpholino
H 2, 5-diF-phenyl 2- ( 1 ' -CF3 -tetrazol-2-yl ) phenyl
H 2, 5-diF-phenyl 4-morpholinocarbonyl
H phenyl 2- (N-pyrrolidinyl-methyl)phenyl
H phenyl 2- (N-piperidinyl-methyl ) phenyl
H phenyl 2- (N-morpholino-methyl) phenyl
H phenyl 2- (N,N' -methylmorpholinium- methyl) phenyl
H phenyl 2- (N-pyridinium-methyl) phenyl
H phenyl 2-(N-4- (N, N' -dimethylamino)- pyridinium-methyl ) phenyl
H phenyl 2- (N-azatanyl-methyl) phenyl
H phenyl 2- (N-azetidinyl-methyl) phenyl
H phenyl 2- (N-piperazinyl-methyl) phenyl
H phenyl 2- (N,N' -BOC-piperazinyl- methyl) phenyl
H phenyl 2- (N-imidazolyl-methyl) phenyl
H phenyl 2- (N-methoxy-N-methylamino- methyl ) phenyl
H phenyl 2- (N-pyridonyl-methyl ) phenyl
H phenyl 2- (N- (N' ,N' -dimethylhydrazinyl- methyl ) phenyl
H phenyl 2- (amidiny1 ) henyl
H phenyl 2- (N-guanidinyl ) phenyl
H phenyl 2- ( imidazolyl ) phenyl
H phenyl 2- (imidazolidinyl) phenyl
H phenyl 2- (2-imidazolidinyl- sulfonyl ) phenyl
H phenyl 2- (2-pyrrolidinyl) phenyl
H phenyl 2- (2-piperidinyl) phenyl
H phenyl 2- (amidinyl-methyl ) phenyl
H phenyl 2- (2-imidazolidinyl- methyl ) phenyl
H phenyl 2- (N- (2-aminoimidazolyl) - methyl ) phenyl
H phenyl 2-dimethylaminoimidazol-l-yl
H phenyl 2- (3-aminophenyl )
H phenyl 2- (3-pyrrolidinylcarbonyl)
H phenyl 2-glycinoyl
H phenyl 2- imidazol-1-ylacetyl)
H 2-pyridyl 2- N-pyrrolidinyl-methyl ) phenyl
H 2-pyridyl 2- N-piperidinyl-methyl) phenyl
H 2-pyridyl 2- N-morpholino-methyl ) phenyl
H 2-pyridyl 2- N,N' -methylmorpholinium- methyl ) phenyl
H 2-pyridyl 2- N-pyridinium-methyl) henyl
H 2-pyridyl 2- N-4- (N,N' -dimethylamino) - pyridinium-methyl) phenyl
H 2-pyridyl 2- N-azatanyl-methyl) phenyl
H 2-pyridyl 2- N-azetidinyl-methyl) phenyl
H 2-pyridyl 2- N-piperazinyl-methyl ) phenyl
H 2-pyridyl 2- N,N' -BOC-piperazinyl- methyl) phenyl
H 2-pyridyl 2- N-imidazolyl-methyl ) phenyl
H 2-pyridyl 2- N-methoxy-N-methylamino- methyl) phenyl
H 2-pyridyl 2- N-pyridonyl-methyl ) phenyl
H 2-pyridyl 2- N- (N ' , N ' -dimethylhydrazinyl- methyl) phenyl
H 2-pyridyl 2- amidinyl) phenyl
H 2-pyridyl 2- N-guanidinyl) phenyl
H 2-pyridyl 2- imidazolyl ) phenyl
H 2-pyridyl 2- imidazolidinyl) phenyl
H 2-pyridyl 2- 2-imidazolidinyl- sulfonyl) phenyl
H 2-pyridyl 2- 2-pyrrolidinyl) phenyl
H 2-pyridyl 2- 2-piperidinyl) phenyl
H 2-pyridyl 2- amidinyl-methyl) phenyl
H 2-pyridyl 2- 2-imidazolidinyl- methyl) phenyl
H 2-pyridyl 2- (N- (2-aminoimidazolyl) - methyl) phenyl
110 H 2-pyridyl 2-dimethylaminoimidazol-l-yl
111 H 2-pyridyl 2- 3-aminophenyl)
112 H 2 -pyridyl 2- 3 -pyrrolidinylcarbonyl ]
113 H 2-pyridyl 2-glycinoyl
114 H 2-pyridyl imidazol-1-ylacetyl )
115 H 3 -pyridyl (N-pyrrolidinyl-methyl ) henyl
116 H 3 -pyridyl (N-piperidinyl-methyl) phenyl
117 H 3 -pyridyl (N-morpholino-methyl ) phenyl
118 H 3 -pyridyl (N, N ' -methylmorpholinium- methyl ) phenyl
119 H 3 -pyridyl (N-pyridinium-methyl ) phenyl
120 H 3 -pyridyl (N-4- (N,N' -dimethylamino) - pyridinium-methyl ) phenyl
121 H 3 -pyridyl (N-azatanyl-methyl) phenyl
122 H 3 -pyridyl (N-azetidiny1-methyl ) phenyl
123 H 3 -pyridyl (N-piperazinyl-methyl) phenyl
124 H 3 -pyridyl (N, N ' -BOC-piperazinyl- methyl ) phenyl
125 H 3 -pyridyl (N-imidazolyl-methyl) phenyl
126 H 3 -pyridyl (N-methoxy-N-methylamino- methyl ) phenyl
127 H 3 -pyridyl (N-pyridonyl-methyl ) phenyl
128 H 3 -pyridyl (N- (N ' , N ' -dimethylhydrazinyl- methyl ) phenyl
129 H 3 -pyridyl [amidinyl ) phenyl
130 H 3 -pyridyl (N-guanidinyl ) phenyl
131 H 3 -pyridyl imidazolyl ) phenyl
132 H 3-pyridyl imidazolidinyl ) phenyl
133 H 3-pyridyl [2 -imidazolidiny1- sulfonyl ) phenyl
134 H 3-pyridyl [ 2 -pyrrolidinyl ) phenyl
135 H 3 -pyridyl [ 2 -piperidinyl ) phenyl
136 H 3-pyridyl [ amidinyl-methyl ) phenyl
137 H 3 -pyridyl [2-imidazolidinyl- methyl ) phenyl
138 H 3 -pyridyl (N- (2 -aminoimidazolyl) - methyl ) phenyl
139 H 3 -pyridyl -dimethylaminoimidazol-1-yl
140 H 3 -pyridyl 3 -aminophenyl )
141 H 3 -pyridyl [ 3 -pyrrolidinylcarbonyl )
142 H 3-pyridyl 2-glycinoyl
143 H 3 -pyridyl 2- imidazol-1-ylacetyl )
144 H 2-pyrimidyl 2- N-pyrrolidinyl-methyl ) phenyl
145 H 2-pyrimidyl 2- N-piperidinyl-methyl ) phenyl
146 H 2-pyrimidyl 2- N-morpholino-methyl ) phenyl
147 H 2-pyrimidyl 2- N, N ' -methylmorpholinium- methyl ) phenyl
148 H 2-pyrimidyl 2- N-pyridinium-methyl ) phenyl
149 H 2-pyrimidyl 2- N-4- (N,N' -dimethylamino) - pyridinium-methyl ) phenyl
150 H 2-pyrimidyl 2- N-azatanyl-methyl ) phenyl
151 H 2-pyrimidyl 2- N-azetidinyl-methyl ) phenyl
152 H 2-pyrimidyl 2- N-piperazinyl-methyl ) phenyl
153 H 2-pyrimidyl 2- N,N' -BOC-piperazinyl- methyl) phenyl
154 H 2-pyrimidyl 2- N-imidazolyl-methyl) phenyl
155 H 2-pyrimidyl 2- (N-methoxy-N-methylamino- methyl ) phenyl
156 H 2-pyrimidyl 2- (N-pyridonyl-methyl) phenyl
157 H 2-pyrimidyl 2- (N- (N' ,N' -dimethylhydrazinyl- methyl) phenyl
158 H 2-pyrimidyl 2- (amidinyl ) phenyl
159 H 2-pyrimidyl 2- (N-guanidinyl) phenyl
160 H 2-pyrimidyl 2- ( imidazolyl ) phenyl
161 H 2-pyrimidyl 2- (imidazolidinyl) phenyl
162 H 2-pyrimidyl 2- (2-imidazolidinyl- sulfonyl ) phenyl
163 H 2-pyrimidyl 2- (2-pyrrolidinyl) phenyl
164 H 2-pyrimidyl 2- ( 2-piperidinyl ) phenyl
165 H 2-pyrimidyl 2- (amidinyl-methyl ) phenyl
166 H 2-pyrimidyl 2- (2-imidazolidinyl- methyl ) phenyl
167 H 2-pyrimidyl 2- (N- (2-aminoimidazolyl) - methyl ) phenyl
168 H 2-pyrimidyl 2-dimethylaminoimidazol-1-yl
169 H 2-pyrimidyl 2- ( 3 -aminophenyl )
170 H 2-pyrimidyl 2- (3-pyrrolidinylcarbonyl)
171 H 2-pyrimidyl 2-glycinoyl
172 H 2-pyrimidyl 2- ( imidazol-1-ylacetyl)
173 H 2-Cl-phenyl 2- (N-pyrrolidinyl-methyl) phenyl
174 H 2-Cl-phenyl 2- (N-piperidinyl-methyl) phenyl
175 H 2-Cl-phenyl 2- (N-morpholino-methyl) phenyl
176 H 2-Cl-phenyl 2- (N,N' -methylmorpholinium- methyl ) phenyl
177 H 2-Cl-phenyl 2- (N-pyridinium-methyl) phenyl
178 H 2-Cl-phenyl 2- (N-4- (N, N ' -dimethylamino) - pyridinium-methyl) phenyl
179 H 2-Cl-phenyl 2- (N-azatanyl-methyl) phenyl
180 H 2-Cl-phenyl 2- (N-azetidinyl-methyl) phenyl
181 H 2-Cl-phenyl 2- (N-piperazinyl-methyl) phenyl
182 H 2-Cl-phenyl 2-(N,N' -BOC-piperazinyl- methyl ) phenyl
183 H 2-Cl-phenyl 2- (N-imidazolyl-methyl) phenyl
184 H 2-Cl-phenyl 2- (N-methoxy-N-methylamino- methyl) phenyl
185 H 2-Cl-phenyl 2- (N-pyridonyl-methyl ) phenyl
186 H 2-Cl-phenyl 2- (N- (N' ,N' -dimethylhydrazinyl- methyl ) phenyl
187 H 2-Cl-phenyl 2- (amidinyl) phenyl
188 H 2-C1-phenyl 2- (N-guanidinyl ) phenyl
189 H 2-Cl-phenyl 2- ( imidazolyl) phenyl
190 H 2-Cl-phenyl 2- (imidazolidinyl) phenyl
191 H 2-Cl-phenyl 2- (2-imidazolidinyl- sulfonyl ) phenyl
192 H 2-C1-phenyl 2- ( 2-pyrrolidinyl) phenyl
193 H 2-Cl-phenyl 2- (2-piperidinyl) phenyl
194 H 2-Cl-phenyl 2- (amidinyl-methyl ) phenyl
195 H 2-Cl-phenyl 2- (2-imidazolidinyl- methyl) phenyl
196 H 2-Cl-phenyl 2- (N- (2-aminoimidazolyl) - methyl) phenyl
197 H 2-Cl-phenyl 2-dimethylaminoimidazol-1-yl
198 H 2-Cl-phenyl 2- 3 -aminophenyl )
199 H 2-Cl-phenyl 2- 3 -pyrrolidinylcarbonyl )
200 H 2-Cl-phenyl 2-glycinoyl
201 H 2-Cl-phenyl 2- imidazol-1-ylacetyl)
202 H 2-F-phenyl 2- N-pyrrolidinyl-methyl) phenyl
203 H 2-F-phenyl 2- N-piperidinyl-methyl ) phenyl
204 H 2-F-phenyl 2- N-morpholino-methyl) phenyl
205 H 2-F-phenyl 2- N, N ' -mathylmorpholinium- methyl) phenyl
206 H 2-F-phenyl 2- N-pyridinium-methyl ) phenyl
207 H 2-F-phenyl 2- N-4- (N,N' -dimethylamino) - pyridinium-methyl) phenyl
208 H 2-F-phenyl 2- N-azatanyl-methyl ) phenyl
209 H 2-F-phenyl 2- N-azetidinyl-methyl ) phenyl
210 H 2-F-phenyl 2- N-piperazinyl-methyl) phenyl
211 H 2-F-phenyl 2- N, N ' -BOC-piperazinyl- methyl ) phenyl
212 H 2-F-phenyl 2- N-imidazolyl-methyl) phenyl
213 H 2-F-phenyl 2- N-methoxy-N-methylamino- methyl ) henyl
214 H 2-F-phenyl 2- N-pyridonyl-methyl ) phenyl
215 H 2-F-phenyl 2- N- (N' ,N' -dimethylhydrazinyl- methyl) phenyl
216 H 2-F-phenyl 2- amidinyl) phenyl
217 H 2-F-phenyl 2- N-guanidinyl ) phenyl
218 H 2-F-phenyl 2- imidazolyl) phenyl
219 H 2-F-phenyl 2- imidazolidinyl) phenyl
220 H 2-F-phenyl 2- 2-imidazolidinyl- sulfonyl ) phenyl
221 H 2-F-phenyl 2- 2-pyrrolidiny1) phenyl
222 H 2-F-phenyl 2- 2-piperidinyl) phenyl
223 H 2-F-phenyl 2- amidinyl-methyl ) phenyl
224 H 2-F-phenyl 2- 2-imidazolidiny1- methyl ) phenyl
225 H 2-F-phenyl 2- N- (2-aminoimidazolyl) - methyl ) phenyl
226 H 2-F-phenyl 2- dimethylaminoimidazol-1-yl
227 H 2-F-phenyl 2- 3 -aminophenyl )
228 H 2-F-phenyl 2- 3-pyrrolidinylcarbonyl)
229 H 2-F-phenyl 2- glycinoyl
230 H 2-F-phenyl 2- imidazol-1-ylacetyl )
231 H 2, 5-diF-phenyl 2- N-pyrrolidinyl-methyl) phenyl
232 H 2, 5-diF-phenyl 2- N-piperidinyl-methyl) phenyl
233 H 2, 5-diF-phenyl 2- N-morpholino-methyl) phenyl
234 H 2, 5-diF-phenyl 2- N, ' -methylmorpholinium- methyl) phenyl
235 H 2, 5-diF-phenyl 2- N-pyridinium-methyl) phenyl
236 H 2, 5-diF-phenyl 2- N-4- (N,N' -dimethylamino) - pyridinium-methyl ) phenyl
237 H 2, 5-diF-phenyl 2- N-azatanyl-methyl) phenyl
238 H 2, 5-diF-phenyl 2- N-azetidinyl-methyl) phenyl
239 H 2, 5-diF-phenyl 2- N-piperazinyl-methyl) phenyl
240 H 2, 5-diF-phenyl 2- N,N' -BOC-piperazinyl- methyl) phenyl
241 H 2, 5-diF-phenyl 2- N-imidazolyl-methyl) phenyl
242 H 2, 5-diF-phenyl 2- N-methoxy-N-methylamino-
methyl ) phenyl
243 H 2, 5-diF-phenyl 2- (N-pyridonyl-methyl ) phenyl
244 H 2, 5-diF-phenyl 2- (N- (N' ,N' -dimethylhydrazinyl- methyl ) phenyl
245 H 2, 5-diF-phenyl 2- (amidinyl ) phenyl
246 H 2, 5-diF-phenyl 2- (N-guanidinyl) phenyl
247 H 2, 5-diF-phenyl 2- ( imidazolyl) phenyl
248 H 2, 5-diF-phenyl 2- (imidazolidinyl) phenyl
249 H 2, 5-diF-phenyl 2- (2-imidazolidinyl- sulfonyl ) phenyl
250 H 2, 5-diF-phenyl 2- ( 2-pyrrolidinyl) phenyl
251 H 2 , 5-diF-phenyl 2- (2-piperidinyl) phenyl
252 H 2, 5-diF-phenyl 2- (amidinyl-methyl ) phenyl
253 H 2, 5-diF-phenyl 2- (2-imidazolidinyl- methyl) phenyl
254 H 2, 5-diF-phenyl 2- (N- (2-aminoimidazolyl) - methyl ) phenyl
255 H 2 , 5-diF-phenyl 2-dimethylaminoimidazol-l-yl
256 H 2, 5-diF-phenyl 2- (3 -aminophenyl )
257 H 2, 5-diF-phenyl 2- (3-pyrrolidinylcarbonyl)
258 H 2, 5-diF-phenyl 2-glycinoyl
259 H 2, 5-diF-phenyl 2- ( imidazol-1-ylacetyl)
260 -CN phenyl 2- (aminosulfonyl) phenyl
261 -CN phenyl 2- (methylaminosulfonyl) phenyl
262 -CN phenyl 1-pyrro1idinocarbony1
263 -CN phenyl 2- (methylsulfonyl) phenyl
264 -CN phenyl 4-morpholino
265 -CN phenyl 2- (l'-CF3-tetrazol-2-yl)phenyl
266 -CN phenyl 4-morpholinocarbonyl
267 -CN 2-pyridyl 2- (aminosulfonyl ) phenyl
268 -CN 2-pyridyl 2- (methylaminosulfonyl) phenyl
269 -CN 2-pyridyl 1-pyrro1idinocarbony1
270 -CN 2-pyridyl 2- (methylsulfonyl) phenyl
271 -CN 2-pyridyl 4-morpholino
272 -CN 2-pyridyl 2- ( 1 ' -CF3 -tetrazol-2-yl ) phenyl
273 -CN 2-pyridyl 4-morpholinocarbonyl
274 -CN 3 -pyridyl 2- (aminosulfonyl) phenyl
275 -CN 3 -pyridyl 2- (methylaminosulfonyl ) phenyl
276 -CN 3-pyridyl 1-pyrrolidinocarbonyl
277 -CN 3-pyridyl 2- (methylsulfonyl) phenyl
278 -CN 3-pyridyl 4-morpholino
279 -CN 3-pyridyl 2-(l'-CF3-tetrazol-2-yl)phenyl
280 -CN 3-pyridyl 4-morpholinocarbonyl
281 -CN 2-pyrimidyl 2- (aminosulfonyl ) phenyl
282 -CN 2-pyrimidyl 2- (methylaminosulfonyl) phenyl
283 -CN 2-pyrimidyl 1-pyrrolidinocarbonyl
284 -CN 2-pyrimidyl 2- (methylsulfonyl) phenyl
285 -CN 2-pyrimidyl 4-morpholino
286 -CN 2-pyrimidyl 2- (l'-CF3-tetrazol-2-yl) phenyl
287 -CN 2-pyrimidyl 4-morpholinocarbonyl
288 -CN 5-pyrimidyl 2- (aminosulfonyl) henyl
289 -CN 5-pyrimidyl 2- (methylaminosulfonyl) phenyl
290 -CN 5-pyrimidyl 1-pyrrolidinocarbonyl
291 -CN 5-pyrimidyl 2- (methylsulfonyl) phenyl
292 -CN 5-pyrimidyl 4-morpho1ino
293 -CN 5-pyrimidyl 2- (1' -CF3-tetrazol-2-yl) phenyl
294 -CN 5-pyrimidyl 4-morpho1inocarbony1
295 -CN 2-Cl-phenyl 2- aminosulfonyl ) phenyl
296 -CN 2-Cl-phenyl 2- methylaminosulfonyl ) phenyl
297 -CN 2-Cl-phenyl 1-pyrrolidinocarbonyl
298 -CN 2-Cl-phenyl 2- methylsulfonyl ) phenyl
299 -CN 2-Cl-phenyl 4-morpholino
300 -CN 2-Cl-phenyl 2- ( 1 ' -CF3 -tetrazol-2 -yD phenyl
301 -CN 2-Cl-phenyl 4-morpholinocarbonyl
302 -CN 2-F-phenyl 2 - aminosulfonyl ) phenyl
303 -CN 2-F-phenyl 2 - methylaminosulfony1) phenyl
304 -CN 2-F-phenyl 1-pyrro1idinocarbony1
305 -CN 2-F-phenyl 2- methylsulfonyl ) phenyl
306 -CN 2-F-phenyl 4-morpholino
307 -CN 2-F-phenyl 2- 1 ' -CF3 -tetrazol-2-yl ) phenyl
308 -CN 2-F-phenyl 4-morpholinocarbonyl
309 -CN 2 , 5-diF-phenyl 2- aminosulfonyl ) henyl
310 -CN 2, 5-diF-phenyl 2- methylaminosulfonyl ) phenyl
311 -CN 2, 5-diF-phenyl 1-pyrrolidinocarbonyl
312 -CN 2, 5-diF-phenyl 2- (methylsulfonyl) phenyl
313 -CN 2 , 5-diF-phenyl 4-morpholino
314 -CN 2, 5-diF-phenyl 2- 1 ' -CF3 -tetrazol-2-yl ) phenyl
315 -CN 2 , 5-diF-phenyl 4-morpholinocarbonyl
316 -CN phenyl 2- N-pyrrolidinyl-methyl ) phenyl
317 -CN phenyl 2- N-piperidinyl-methyl ) phenyl
318 -CN phenyl 2- N-morpholino-methyl) phenyl
319 -CN phenyl 2- N, N ' -methylmorpholinium- methyl) phenyl
320 -CN phenyl 2- (N-pyridinium-methyl) phenyl
321 -CN phenyl 2- (N-4- (N,N' -dimethylamino) - pyridinium-methyl) phenyl
322 -CN phenyl 2- (N-azatanyl-methyl) phenyl
323 -CN phenyl 2- (N-azetidinyl-methyl) phenyl
324 -CN phenyl 2- (N-piperazinyl-methyl) phenyl
325 -CN phenyl 2-(N,N' -BOC-piperazinyl- methyl) phenyl
326 -CN phenyl 2- (N-imidazolyl-methyl) phenyl
327 -CN phenyl 2- (N-methoxy-N-methylamino- methyl) phenyl
328 -CN phenyl 2- (N-pyridonyl-methyl ) phenyl
329 -CN phenyl 2- (N- (N1 ,N' -dimethylhydrazinyl- methyl) phenyl
330 -CN phenyl 2- (amidinyl) phenyl
331 -CN phenyl 2- (N-guanidinyl ) phenyl
332 -CN phenyl 2- ( imidazolyl) phenyl
333 -CN phenyl 2- (imidazolidinyl) phenyl
334 -CN phenyl 2- (2-imidazolidinyl- sulfonyl ) phenyl
335 -CN phenyl 2- (2-pyrrolidinyl) phenyl
336 -CN phenyl 2- (2-piperidinyl) phenyl
337 -CN phenyl 2- (amidinyl-methyl ) phenyl
338 -CN phenyl 2- (2-imidazolidinyl- methyl) phenyl
339 -CN phenyl 2- (N- (2-aminoimidazolyl) - methyl) phenyl
340 -CN phenyl 2-dimethylaminoimidazol-1-yl
341 -CN phenyl 2- (3-aminophenyl )
342 -CN phenyl 2- (3 -pyrrolidinylcarbonyl)
343 -CN phenyl 2-glycinoyl
344 -CN phenyl 2- (imidazol-1-ylacetyl)
345 -CN 2-pyridyl 2- (N-pyrrolidinyl-methyl) phenyl
346 -CN 2-pyridyl 2- (N-piperidinyl-methyl) phenyl
347 -CN 2-pyridyl 2- (N-morpholino-methyl) phenyl
348 -CN 2-pyridyl 2- (N,NT -methylmorpholinium- methyl ) phenyl
349 -CN 2-pyridyl 2- (N-pyridinium-methyl ) phenyl
350 -CN 2-pyridyl 2- (N-4- (N,N' -dimethylamino) - pyridinium-methyl ) phenyl
351 -CN 2-pyridyl 2- (N-azatanyl-methyl) phenyl
352 -CN 2-pyridyl 2- (N-azetidinyl-methyl) phenyl
353 -CN 2-pyridyl 2 - (N-piperazinyl-methyl) phenyl
354 -CN 2-pyridyl 2-(N,N' -BOC-piperazinyl- methyl ) phenyl
355 -CN 2-pyridyl 2- (N-imidazolyl-methyl) phenyl
356 -CN 2-pyridyl 2- (N-methoxy-N-methylamino- methyl ) phenyl
357 -CN 2-pyridyl 2- (N-pyridonyl-methyl ) phenyl
358 -CN 2-pyridyl 2-(N-(N' ^'-dimethylhydrazinyl- methyl ) phenyl
359 -CN 2-pyridyl 2- (amidinyl ) phenyl
360 -CN 2-pyridyl 2- (N-guanidinyl ) phenyl
361 -CN 2-pyridyl 2- ( imidazolyl ) phenyl
362 -CN 2-pyridyl 2- (imidazolidinyl) phenyl
363 -CN 2-pyridyl 2- (2-imidazolidinyl- sulfonyl ) phenyl
364 -CN 2-pyridyl 2- (2-pyrrolidinyl) phenyl
365 -CN 2-pyridyl 2- (2-piperidinyl) phenyl
366 -CN 2-pyridyl 2- (amidinyl-methyl) henyl
367 -CN 2-pyridyl 2- (2-imidazolidinyl- methyl) phenyl
368 -CN 2-pyridyl 2- (N- (2-aminoimidazolyl) - methyl) phenyl
369 -CN 2-pyridyl 2-dimethylaminoimidazol-l-yl
370 -CN 2-pyridyl 2- (3 -aminophenyl )
371 -CN 2-pyridyl 2- (3-pyrrolidinylcarbonyl)
372 -CN 2-pyridyl 2-glycinoyl
373 -CN 2-pyridyl 2- (imidazol-1-ylacetyl)
374 -CN 3-pyridyl 2- (N-pyrrolidinyl-methyl ) phenyl
375 -CN 3-pyridyl 2- (N-piperidinyl-methyl) phenyl
376 -CN 3-pyridyl 2- (N-morpholino-methyl) phenyl
377 -CN 3-pyridyl 2- (N,N' -methylmorpholinium- methyl) phenyl
378 -CN 3-pyridyl 2- (N-pyridinium-methyl) phenyl
379 -CN 3-pyridyl 2- (N-4- (N,N' -dimethylamino) - pyridinium-methyl) phenyl
380 -CN 3-pyridyl 2- (N-azatanyl-methyl) phenyl
381 -CN 3-pyridyl 2- (N-azetidinyl-methyl) phenyl
382 -CN 3-pyridyl 2- (N-piperazinyl-methyl) phenyl
383 -CN 3-pyridyl 2-(N,N' -BOC-piperazinyl- methyl) phenyl
384 -CN 3-pyridyl 2- (N-imidazolyl-methyl) phenyl
385 -CN 3-pyridyl 2- (N-methoxy-N-methylamino- methyl) phenyl
386 -CN 3-pyridyl 2- (N-pyridonyl-methyl) phenyl
387 -CN 3 -pyridyl 2-(N-(N' ^'-dimethylhydrazinyl- methyl ) phenyl
388 -CN 3 -pyridyl 2- (amidinyl ) phenyl
389 -CN 3 -pyridyl 2- (N-guanidinyl ) phenyl
390 -CN 3 -pyridyl 2- ( imidazolyl ) phenyl
391 -CN 3 -pyridyl 2- (imidazolidinyl) phenyl
392 -CN 3 -pyridyl 2- (2 -imidazolidinyl - sulfonyl ) phenyl
393 -CN 3 -pyridyl 2- (2-pyrrolidinyl) phenyl
394 -CN 3-pyridyl 2- (2-piperidinyl ) phenyl
395 -CN 3-pyridyl 2- (amidinyl-methyl) phenyl
396 -CN 3 -pyridyl 2- (2 -imidazolidinyl- methyl ) phenyl
397 -CN 3-pyridyl 2- (N- (2-aminoimidazolyl) - methyl ) phenyl
398 -CN 3-pyridyl 2-dimethylaminoimidazol-l-yl
399 -CN 3-pyridyl 2- ( 3 -aminophenyl )
400 -CN 3-pyridyl 2- (3 -pyrrolidinylcarbonyl)
401 -CN 3-pyridyl 2-glycinoyl
402 -CN 3-pyridyl 2- (imidazol-1-ylacetyl)
403 -CN 2-pyrimidyl 2- (N-pyrrolidinyl-methyl) phenyl
404 -CN 2-pyrimidyl 2- (N-piperidinyl-methyl) phenyl
405 -CN 2-pyrimidyl 2- (N-morpholino-methyl) phenyl
406 -CN 2-pyrimidyl 2- (N,N' -methylmorpholinium- methyl) phenyl
407 -CN 2-pyrimidyl 2- (N-pyridinium-methyl) phenyl
408 -CN 2-pyrimidyl 2- (N-4- (N,N' -dimethylamino) - pyridinium-methyl ) phenyl
409 -CN 2-pyrimidyl 2- (N-azatanyl-methyl) phenyl
410 -CN 2-pyrimidyl 2- (N-azetidinyl-methyl) phenyl
411 -CN 2-pyrimidyl 2- (N-piperazinyl-methyl) phenyl
412 -CN 2-pyrimidyl 2- (N,N' -BOC-piperazinyl- methyl ) phenyl
413 -CN 2-pyrimidyl 2- (N-imidazolyl-methyl) phenyl
414 -CN 2-pyrimidyl 2- (N-methoxy-N-methylamino- methyl ) phenyl
415 -CN 2-pyrimidyl 2- (N-pyridonyl-methyl) phenyl
416 -CN 2-pyrimidyl 2- (N- (N' ,N' -dimethylhydrazinyl- methyl ) phenyl
417 -CN 2-pyrimidyl 2- (amidinyl ) phenyl
418 -CN 2-pyrimidyl 2- (N-guanidinyl) henyl
419 -CN 2-pyrimidyl 2- (imidazolyl) phenyl
420 -CN 2-pyrimidyl 2- (imidazolidinyl) phenyl
421 -CN 2-pyrimidyl 2- (2-imidazolidinyl- sulfonyl) phenyl
422 -CN 2-pyrimidyl 2- (2-pyrrolidiny1) phenyl
423 -CN 2-pyrimidyl 2- (2-piperidinyl) phenyl
424 -CN 2-pyrimidyl 2- (amidinyl-methyl)phenyl
425 -CN 2-pyrimidyl 2- (2-imidazolidinyl- methyl ) phenyl
426 -CN 2-pyrimidyl 2- (N- (2-aminoimidazolyl) - methyl) phenyl
427 -CN 2-pyrimidyl 2-dimethylaminoimidazol-1-yl
428 -CN 2-pyrimidyl 2- (3 -aminophenyl )
429 -CN 2-pyrimidyl 2- (3-pyrrolidinylcarbonyl)
430 -CN 2-pyrimidyl 2-glycinoyl
431 -CN 2-pyrimidyl 2- (imidazol-1-ylacetyl)
432 -CN 2-Cl-phenyl 2- (N-pyrrolidinyl-methyl) phenyl
433 -CN 2-Cl-phenyl 2- (N-piperidinyl-methyl) phenyl
434 -CN 2-Cl-phenyl 2- (N-morpholino-methyl) phenyl
435 -CN 2-Cl-phenyl 2- (N, N ' -methylmorpholinium- methyl ) phenyl
436 -CN 2-Cl-phenyl 2- (N-pyridinium-methyl ) phenyl
437 -CN 2-Cl-phenyl 2- (N-4- (N,N' -dimethylamino) - pyridinium-methyl) phenyl
438 -CN 2-Cl-phenyl 2- (N-azatanyl-methyl) phenyl
439 -CN 2-Cl-phenyl 2- (N-azetidinyl-methyl) phenyl
440 -CN 2-Cl-phenyl 2- (N-piperazinyl-methyl) phenyl
441 -CN 2-Cl-phenyl 2- (N,N' -BOC-piperazinyl- methyl ) phenyl
442 -CN 2-Cl-phenyl 2- (N-imidazolyl-methyl) phenyl
443 -CN 2-Cl-phenyl 2- (N-methoxy-N-methylamino- methyl) phenyl
444 -CN 2-Cl-phenyl 2- (N-pyridonyl-methyl ) phenyl
445 -CN 2-Cl-phenyl 2-(N-(N' ^'-dimethylhydrazinyl- methyl) phenyl
446 -CN 2-Cl-phenyl 2- (amidinyl ) phenyl
447 -CN 2-Cl-phenyl 2- (N-guanidinyl ) phenyl
448 -CN 2-Cl-phenyl 2- ( imidazolyl) phenyl
449 -CN 2-Cl-phenyl 2- (imidazolidinyl) phenyl
450 -CN 2-Cl-phenyl 2- (2-imidazolidinyl- sulfonyl ) phenyl
451 -CN 2-Cl-phenyl 2- (2-pyrrolidinyl) phenyl
452 -CN 2-Cl-phenyl 2- (2-piperidinyl) phenyl
453 -CN 2-Cl-phenyl 2- (amidinyl-methyl) phenyl
454 -CN 2-Cl-phenyl 2- (2-imidazolidiny1- methyl) phenyl
455 -CN 2-Cl-phenyl 2- (N- (2-aminoimidazolyl) - methyl) phenyl
456 -CN 2-Cl-phenyl 2-dimethylaminoimidazol-l-yl
457 -CN 2-Cl-phenyl 2- (3 -aminophenyl )
458 -CN 2-Cl-phenyl 2- (3 -pyrrolidinylcarbonyl)
459 -CN 2-Cl-phenyl 2-glycinoyl
460 -CN 2-Cl-phenyl 2- ( imidazol-1-ylacetyl)
461 -CN 2-F-phenyl 2- (N-pyrrolidinyl-methyl) phenyl
462 -CN 2-F-phenyl 2- (N-piperidinyl-methyl ) phenyl
463 -CN 2-F-phenyl 2- (N-morpholino-methyl ) phenyl
464 -CN 2-F-phenyl 2- (N,N' -methylmorpholinium- methyl) phenyl
465 -CN 2-F-phenyl 2- (N-pyridinium-methyl ) phenyl
466 -CN 2-F-phenyl 2- (N-4- (N,N' -dimethylamino) - pyridinium-methyl) phenyl
467 -CN 2-F-phenyl 2- (N-azatanyl-methyl) phenyl
468 -CN 2-F-phenyl 2- (N-azetidinyl-methyl) phenyl
469 -CN 2-F-phenyl 2- (N-piperazinyl-methyl) phenyl
470 -CN 2-F-phenyl 2-(N,N' -BOC-piperazinyl- methyl) phenyl
471 -CN 2-F-phenyl 2- (N-imidazolyl-methyl) phenyl
472 -CN 2-F-phenyl 2- (N-methoxy-N-methylamino- methyl) phenyl
473 -CN 2-F-phenyl 2- (N-pyridonyl-methyl ) henyl
474 -CN 2 -F-phenyl 2-(N-(N' ^'-dimethylhydrazinyl- methyl ) phenyl
475 -CN 2 -F-phenyl 2- [amidinyl ) phenyl
476 -CN 2 -F-phenyl 2- (N-guanidinyl ) phenyl
477 -CN 2 -F-phenyl 2- imidazolyl ) phenyl
478 -CN 2 -F-phenyl 2- [ imidazolidinyl) phenyl
479 -CN 2 -F-phenyl 2- 2 -imidazolidinyl- sulfonyl ) phenyl
480 -CN 2 -F-phenyl 2- ;2-pyrrolidiny1 ) phenyl
481 -CN 2 -F-phenyl 2- ;2-piperidinyl) phenyl
482 -CN 2 -F-phenyl 2- (amidinyl-methyl ) phenyl
483 -CN 2 -F-phenyl 2- [ 2-imidazolidiny1- methyl ) phenyl
484 -CN 2 -F-phenyl 2- (N- (2-aminoimidazolyl) - methyl) phenyl
485 -CN 2-F-phenyl 2 dimethylaminoimidazol-1-y1
486 -CN 2-F-phenyl 2- ;3 -aminophenyl)
487 -CN 2-F-phenyl 2- 3 -pyrrolidinylcarbonyl )
488 -CN 2-F-phenyl 2 glycinoyl
489 -CN 2-F-phenyl 2- imidazol-1-ylacetyl )
490 -CN 2, 5-diF-phenyl 2- (N-pyrrolidinyl-methyl ) phenyl
491 -CN 5-diF-phenyl 2- (N-piperidinyl-methyl ) phenyl
492 -CN 5-diF-phenyl 2- (N-morpholino-methyl) phenyl
493 -CN 5-diF-phenyl 2- (N, N ' -methylmorpholinium- methyl) phenyl
494 -CN 5-diF-phenyl 2- (N-pyridinium-methyl ) phenyl
495 -CN 5-diF-phenyl 2- (N-4- (N,N' -dimethyiamino) - pyridinium-methyl ) phenyl
496 -CN 5-diF-pheny1 2- (N-azatanyl-methyl) phenyl
497 -CN 5-diF-phenyl 2- (N-azetidinyl-methyl) phenyl
498 -CN 5-diF-phenyl 2- (N-piperazinyl-methyl) phenyl
499 -CN 5-diF-phenyl 2- (N, N ' -BOC-piperazinyl- methyl) phenyl
500 -CN 5-diF-phenyl 2- (N-imidazolyl-methyl ) phenyl
501 -CN 5-diF-phenyl 2- (N-methoxy-N-methylamino- methyl) phenyl
502 -CN 5-diF-phenyl 2- (N-pyridonyl-methyl ) phenyl
503 -CN 5-diF-phenyl 2- (N- (N' ,N' -dimethylhydrazinyl- methyl) phenyl
504 -CN 5-diF-phenyl 2- (amidinyl ) phenyl
505 -CN 5-diF-phenyl 2- (N-guanidinyl ) phenyl
506 -CN 5-diF-phenyl 2- [ imidazolyl) phenyl
507 -CN 5-diF-phenyl 2- [ imidazolidinyl ) phenyl
508 -CN 5-diF-phenyl 2- [2-imidazolidinyl- sulfonyl ) phenyl
509 -CN 5-diF-phenyl 2- [2-pyrrolidinyl ) phenyl
510 -CN 5-diF-phenyl 2- ;2-piperidinyl) phenyl
511 -CN 5-diF-phenyl 2- (amidinyl-methyl) phenyl
512 -CN 5-diF-phenyl 2- [2-imidazolidinyl- methyl) phenyl
513 -CN 5-diF-phenyl 2- (N- (2-aminoimidazolyl) - methyl) phenyl
514 -CN 5-diF-phenyl 2-dimethylaminoimidazol-1-yl
515 -CN 5-diF-phenyl 2- (3-aminophenyl )
516 -CN 5-diF-phenyl 2- (3-pyrrolidinylcarbonyl)
517 -CN 5-diF-phenyl 2-glycinoyl
518 -CN 2 , 5-diF-phenyl 2- (imidazol-1-ylacetyl)
519 CF3 phenyl 2- (aminosulfonyl ) phenyl
520 CF3 phenyl 2- (methylaminosulfonyl) phenyl
521 CF3 phenyl 1-pyrrolidinocarbonyl
522 CF3 phenyl 2- (methylsulfonyl) phenyl
523 CF3 phenyl 4-morpholino
524 CF3 phenyl 2 - ( l ' -CF3 - tetrazol-2 -yD phenyl
525 CF3 phenyl 4-morpholinocarbony1
526 CF3 2-pyridyl 2- (aminosulfonyl)phenyl
527 CF3 2-pyridyl 2- (methylaminosulfonyl) phenyl
528 CF3 2-pyridyl 1-pyrro1idinocarbony1
529 CF3 2-pyridyl 2- (methylsulfonyl) phenyl
530 CF3 2-pyridyl 4-morpholino
531 CF3 2-pyridyl 2- ( 1 ' -CF3 -tetrazol-2-yl ) phenyl
532 CF3 2-pyridyl 4-morpholinocarbonyl
533 CF3 3 -pyridyl 2- (aminosulfonyl) phenyl
534 CF3 3-pyridyl 2- (methylaminosulfonyl) phenyl
535 CF3 3-pyridyl 1-pyrrolidinocarbonyl
536 CF3 3-pyridyl 2- (methylsulfonyl) phenyl
537 CF3 3-pyridyl 4-morpholino
538 CF3 3-pyridyl 2- ( 1 ' -CF3 -tetrazol-2-yl ) phenyl
539 CF3 3 -pyridyl 4-morpholinocarbonyl
540 CF3 2-pyrimidyl 2- (aminosulfonyl) phenyl
541 CF3 2-pyrimidyl 2- (methylaminosulfonyl) phenyl
542 CF3 2-pyrimidyl 1-pyrrolidinocarbonyl
543 CF3 2-pyrimidyl 2- (methylsulfonyl) phenyl
544 CF3 2-pyrimidyl 4-morpholino
545 CF3 2-pyrimidyl 2-(l'-CF3-tetrazol-2-yl)phenyl
546 CF3 2-pyrimidyl 4-morpholinocarbonyl
547 CF3 5-pyrimidyl 2- (aminosulfonyl) phenyl
548 CF3 5-pyrimidyl 2- (methylaminosulfonyl) phenyl
549 CF3 5-pyrimidyl 1-pyrro1idinocarbony1
550 CF3 5-pyrimidyl 2- (methylsulfonyl) henyl
551 CF3 5-pyrimidyl 4-morpho1ino
552 CF3 5-pyrimidyl 2- ( 1 ' -CF3 -tetrazol-2-yl ) phenyl
553 CF3 5-pyrimidyl 4-morpholinocarbonyl
554 CF3 2-Cl-phenyl 2- (aminosulfonyl) phenyl
555 CF3 2-Cl-phenyl 2- (methylaminosulfonyl) phenyl
556 CF3 2-Cl-phenyl 1-pyrro1idinocarbony1
557 CF3 2-Cl-phenyl 2- (methylsulfonyl) phenyl
558 CF3 2-Cl-phenyl 4-morpholino
559 CF3 2-Cl-phenyl 2- ( 1 ' -CF3 -tetrazol-2-yl) phenyl
560 CF3 2-Cl-phenyl 4-morpholinocarbonyl
561 CF3 2-F-phenyl 2- (aminosulfonyl) henyl
562 CF3 2-F-phenyl 2- (methylaminosulfonyl) phenyl
563 CF3 2-F-phenyl 1-pyrro1idinocarbony1
564 CF3 2-F-phenyl 2- (methylsulfonyl) phenyl
565 CF3 2-F-phenyl 4-morpholino
566 CF3 2-F-phenyl 2- ( 1 ' -CF3 -tetrazol-2-yl ) phenyl
567 CF3 2-F-phenyl 4-morpholinocarbonyl
568 CF3 2 , 5-diF-phenyl 2- (aminosulfonyl) phenyl
569 CF3 2 , 5-diF-phenyl 2- (methylaminosulfonyl) phenyl
570 CF3 2,5-diF -phenyl 1-pyrrolidinocarbonyl
571 CF3 2,5-diF -phenyl 2- (methylsulfonyl) phenyl
572 CF3 2,5-diF'-phenyl 4-morpholino
573 CF3 2,5-diF'-phenyl 2- ( 1 ' -CF3 -tetrazol-2 -yD phenyl
574 CF3 2,5-diF -phenyl 4-morpholinocarbonyl
575 CF3 phenyl (N-pyrrolidinyl-methyl ) phenyl
576 CF3 phenyl (N-piperidinyl-methyl) phenyl
577 CF3 phenyl (N-morpholino-methyl) phenyl
578 CF3 phenyl (N,N' -methylmorpholinium- methyl ) phenyl
579 CF3 phenyl (N-pyridinium-methyl ) phenyl
580 CF3 phenyl (N-4- (N,N' -dimethylamino) - pyridinium-methyl ) phenyl
581 CF3 phenyl (N-azatanyl-methyl) phenyl
582 CF3 phenyl (N-azetidinyl-methyl ) phenyl
583 CF3 phenyl (N-piperazinyl-methyl) phenyl
584 CF3 phenyl (N,N' -BOC-piperazinyl- methyl ) phenyl
585 CF3 phenyl (N-imidazolyl-methyl ) phenyl
586 CF3 phenyl (N-methoxy-N-methylamino- methyl ) phenyl
587 CF3 phenyl (N-pyridonyl-methyl ) phenyl
588 CF3 phenyl (N- (N ' , N ' -dimethylhydrazinyl- methyl ) phenyl
589 CF3 phenyl (amidinyl ) phenyl
590 CF3 phenyl (N-guanidinyl ) phenyl
591 CF3 phenyl ( imidazolyl ) phenyl
592 CF3 phenyl (imidazolidinyl) phenyl
593 CF3 phenyl (2-imidazolidiny1- sulfonyl ) phenyl
594 CF3 phenyl (2-pyrrolidinyl) phenyl
595 CF3 phenyl (2-piperidinyl) phenyl
596 CF3 phenyl (amidinyl-methyl ) phenyl
597 CF3 phenyl - (2-imidazolidinyl- methyl ) henyl
598 CF3 phenyl - (N- (2-aminoimidazolyl) - methyl ) phenyl
599 CF3 phenyl -dimethylaminoimidazol-1-yl
600 CF3 phenyl - (3-aminophenyl )
601 CF3 phenyl - (3-pyrrolidinylcarbonyl)
602 CF3 phenyl 2-glycinoyl
603 CF3 phenyl 2- imidazol-1-ylacetyl)
604 CF3 2-pyridyl 2- N-pyrrolidinyl-methyl) phenyl
605 CF3 2-pyridyl 2- N-piperidinyl-methyl) phenyl
606 CF3 2-pyridyl 2- N-morpholino-methyl) phenyl
607 CF3 2-pyridyl 2- N, N ' -methylmorpholinium- methyl ) phenyl
608 CF3 2-pyridyl 2- N-pyridinium-methyl)phenyl
609 CF3 2-pyridyl 2- N-4- (N,N' -dimethylamino) - pyridinium-methyl) phenyl
610 CF3 2-pyridyl 2- N-azatanyl-methyl) phenyl
611 CF3 2-pyridyl 2- N-azetidinyl-methyl ) phenyl
612 CF3 2-pyridyl 2- N-piperazinyl-methyl ) phenyl
613 CF3 2-pyridyl 2- (N,N' -BOC-piperazinyl- methyl ) phenyl
614 CF3 2-pyridyl 2- (N-imidazolyl-methyl) phenyl
615 CF3 2-pyridyl 2- (N-methoxy-N-methylamino- methyl ) phenyl
616 CF3 2-pyridyl 2- (N-pyridonyl-methyl ) phenyl
617 CF3 2-pyridyl 2- (N- (N' ,N' -dimethylhydrazinyl- methyl) phenyl
618 CF3 2-pyridyl 2- (amidinyl ) phenyl
619 CF3 2-pyridyl 2- ( -guanidinyl ) phenyl
620 CF3 2-pyridyl 2- ( imidazolyl ) phenyl
621 CF3 2-pyridyl 2- (imidazolidinyl) phenyl
622 CF3 2-pyridyl 2- (2-imidazolidinyl- sulfonyl ) phenyl
623 CF3 2-pyridyl 2- (2-pyrrolidinyl ) phenyl
624 CF3 2-pyridyl 2- (2-piperidinyl) phenyl
625 CF3 2-pyridyl 2- (amidinyl-methyl ) phenyl
626 CF3 2-pyridyl 2- (2-imidazolidinyl- methyl ) phenyl
627 CF3 2-pyridyl N- (2-aminoimidazolyl) - methyl ) phenyl
628 CF3 2-pyridyl 2-dimethylaminoimidazol-l-yl
629 CF3 2-pyridyl 2- (3 -aminophenyl)
630 CF3 2-pyridyl 2- (3-pyrrolidinylcarbonyl)
631 CF3 2-pyridyl 2-glycinoyl
632 CF3 2-pyridyl 2- imidazol-1-ylacetyl)
633 CF3 3-pyridyl 2- N-pyrrolidinyl-methyl ) phenyl
634 CF3 3-pyridyl 2- N-piperidinyl-methyl ) phenyl
635 CF3 3-pyridyl 2- N-morpholino-methyl) phenyl
636 CF3 3-pyridyl 2- N, N ' -methylmorpholinium- methyl) phenyl
637 CF3 3-pyridyl 2- N-pyridinium-methyl ) phenyl
638 CF3 3-pyridyl 2- N-4- (N,N' -dimethylamino) - pyridinium-methyl) phenyl
639 CF3 3-pyridyl 2- N-azatanyl-methyl) phenyl
640 CF3 3-pyridyl 2- N-azetidinyl-methyl) phenyl
641 CF3 3-pyridyl 2- N-piperazinyl-methyl) phenyl
642 CF3 3-pyridyl 2- N,N' -BOC-piperazinyl- methyl) phenyl
643 CF3 3-pyridyl 2- N-imidazolyl-methyl) phenyl
644 CF3 3-pyridyl 2- N-methoxy-N-methylamino- methyl)phenyl
645 CF3 3-pyridyl 2- N-pyridonyl-methyl) phenyl
646 CF3 3-pyridyl 2- N- (N ' , N ' -dimethylhydrazinyl- methyl) phenyl
647 CF3 3-pyridyl 2- amidinyl) phenyl
648 CF3 3-pyridyl 2- N-guanidinyl) phenyl
649 CF3 3-pyridyl 2- imidazolyl ) phenyl
650 CF3 3-pyridyl 2- imidazolidinyl) phenyl
651 CF3 3-pyridyl 2- 2-imidazolidiny1- sulfonyl ) phenyl
652 CF3 3-pyridyl 2- 2-pyrrolidinyl) phenyl
653 CF3 3-pyridyl 2- 2-piperidinyl) phenyl
654 CF3 3-pyridyl 2- (amidinyl-methyl ) phenyl ~~
655 CF3 3 -pyridyl 2- (2-imidazolidinyl- methyl) phenyl
656 CF3 3-pyridyl 2- (N- (2-aminoimidazolyl) - methyl) phenyl
657 CF3 3-pyridyl 2-dimethylaminoimidazol-1-yl
658 CF3 3 -pyridyl (3 -aminophenyl )
659 CF3 3 -pyridyl - ( 3-pyrrolidinylcarbonyl )
660 CF3 3-pyridyl -glycinoyl
661 CF3 3-pyridyl - (imidazol-1-ylacetyl)
662 CF3 2-pyrimidyl - (N-pyrrolidinyl-methyl) phenyl
663 CF3 2-pyrimidyl (N-piperidinyl-methyl ) phenyl
664 CF3 2-pyrimidyl (N-morpholino-methyl ) henyl
665 CF3 2-pyrimidyl (N,N' -methylmorpholinium- methyl ) phenyl
666 CF3 2-pyrimidyl (N-pyridinium-methyl ) phenyl
667 CF3 2-pyrimidyl (N-4- (N,N' -dimethylamino) - pyridinium-methyl ) phenyl
668 CF3 2-pyrimidyl (N-azatanyl-methyl) phenyl
669 CF3 2-pyrimidyl (N-azetidinyl-methyl) phenyl
670 CF3 2-pyrimidyl (N-piperazinyl-methyl ) phenyl
671 CF3 2-pyrimidyl (N,N' -BOC-piperazinyl- methyl ) phenyl
672 CF3 2-pyrimidyl (N-imidazolyl-methyl ) phenyl
673 CF3 2-pyrimidyl (N-methoxy-N-methylamino- methyl) phenyl
674 CF3 2-pyrimidyl (N-pyridonyl-methyl ) phenyl
675 CF3 2-pyrimidyl (N- (N ' ,N ' -dimethylhydrazinyl- methyl) phenyl
676 CF3 2-pyrimidyl (amidinyl) phenyl
677 CF3 2-pyrimidyl (N-guanidinyl ) phenyl
678 CF3 2-pyrimidyl (imidazolyl) phenyl
679 CF3 2-pyrimidyl ( imidazolidiny1) phenyl
680 CF3 2-pyrimidyl (2-imidazolidiny1- sulfonyl ) phenyl
681 CF3 2-pyrimidyl (2-pyrrolidiny1 ) phenyl
682 CF3 2-pyrimidyl (2-piperidinyl ) phenyl
683 CF3 2-pyrimidyl (amidinyl-methyl ) phenyl
684 CF3 2-pyrimidyl (2-imidazolidinyl- methyl) phenyl
685 CF3 2-pyrimidyl 2- (N- (2-aminoimidazolyl) - methyl) phenyl
686 CF3 2-pyrimidyl 2-dimethylaminoimidazol-l-yl
687 CF3 2-pyrimidyl 2- (3-aminophenyl)
688 CF3 2-pyrimidyl 2- (3-pyrrolidinylcarbonyl)
689 CF3 2-pyrimidyl 2-glycinoyl
690 CF3 2-pyrimidyl 2- imidazol-1-ylacetyl)
691 CF3 2-Cl-phenyl 2- N-pyrrolidinyl-methyl) phenyl
692 CF3 2-Cl-phenyl 2- N-piperidinyl-methyl ) phenyl
693 CF3 2-Cl-phenyl 2- N-morpholino-methyl) phenyl
694 CF3 2-Cl-phenyl 2- N, N ' -methylmorpholinium- methyl) phenyl
695 CF3 2-Cl-phenyl (N-pyridinium-methyl) phenyl
696 CF3 2-Cl-phenyl 2- (N-4- (N,N' -dimethylamino) - pyridinium-methyl ) phenyl
697 CF3 2-Cl-phenyl 2- (N-azatanyl-methyl) phenyl
698 CF3 2-Cl-phenyl 2- (N-azetidinyl-methyl) phenyl
699 CF3 2-Cl-phenyl 2- (N-piperazinyl-methyl) phenyl
700 CF3 2-Cl-phenyl 2- (N,NT -BOC-piperazinyl- methyl ) phenyl
701 CF3 2-Cl-phenyl 2- (N-imidazolyl-methyl) phenyl
702 CF3 2-Cl-phenyl 2- (N-methoxy-N-methylamino- methyl ) phenyl
703 CF3 2-Cl-phenyl 2- (N-pyridonyl-methyl) phenyl
704 CF3 2-Cl-phenyl 2- (N- (N' ,N' -dimethylhydrazinyl- methyl) phenyl
705 CF3 2-Cl-phenyl 2- (amidinyl ) phenyl
706 CF3 2-Cl-phenyl 2- (N-guanidinyl ) phenyl
707 CF3 2-Cl-phenyl 2- ( imidazolyl) phenyl
708 CF3 2-Cl-phenyl 2- (imidazolidinyl) phenyl
709 CF3 2-Cl-phenyl 2- (2-imidazolidinyl- sulfonyl ) phenyl
710 CF3 2-Cl-phenyl 2- (2-pyrrolidinyl) phenyl
711 CF3 2-Cl-phenyl 2- ( 2-piperidinyl ) henyl
712 CF3 2-Cl-phenyl 2- (amidinyl-methyl ) phenyl
713 CF3 2-Cl-phenyl 2- (2-imidazolidinyl- methyl ) phenyl
714 CF3 2-Cl-phenyl 2- (N- (2-aminoimidazolyl) - methyl) phenyl
715 CF3 2-Cl-phenyl 2-dimethylaminoimidazol-l-yl
716 CF3 2-Cl-phenyl 2- (3-aminophenyl)
717 CF3 2-Cl-phenyl 2- ( 3-pyrrolidinylcarbonyl )
718 CF3 2-Cl-phenyl 2-glycinoyl
719 CF3 2-Cl-phenyl 2- (imidazol-1-ylacetyl)
720 CF3 2-F-phenyl 2- (N-pyrrolidinyl-methyl) phenyl
721 CF3 2-F-phenyl 2- (N-piperidinyl-methyl) phenyl
722 CF3 2-F-phenyl 2- (N-morpholino-methyl) phenyl
723 CF3 2-F-phenyl 2- (N,N' -methylmorpholinium- methyl) phenyl
724 CF3 2-F-phenyl 2- (N-pyridinium-methyl ) phenyl
725 CF3 2-F-phenyl 2- (N-4- (N,N' -dimethylamino) - pyridinium-methyl) phenyl
726 CF3 2-F-phenyl 2- (N-azatanyl-methyl) phenyl
727 CF3 2-F-phenyl 2- (N-azetidinyl-methyl) phenyl
728 CF3 2-F-phenyl 2- (N-piperazinyl-methyl) phenyl
729 CF3 2-F-phenyl 2- (N,N' -BOC-piperazinyl- methyl ) phenyl
730 CF3 2-F-phenyl 2- (N-imidazolyl-methyl) phenyl
731 CF3 2-F-phenyl 2- (N-methoxy-N-methylamino- methyl) phenyl
732 CF3 2-F-phenyl 2- (N-pyridonyl-methyl ) phenyl
733 CF3 2-F-phenyl 2- (N- (N' ,N' -dimethylhydrazinyl- methyl) phenyl
734 CF3 2-F-phenyl 2- (amidinyl) phenyl
735 CF3 2-F-phenyl 2- (N-guanidinyl ) phenyl
736 CF3 2-F-phenyl 2- ( imidazolyl) phenyl
737 CF3 2-F-phenyl 2- (imidazolidinyl) phenyl
738 CF3 2-F-phenyl 2- (2-imidazolidinyl- sulfonyl ) phenyl
739 CF3 2-F-phenyl 2- (2-pyrrolidinyl) phenyl
740 CF3 2-F-phenyl 2- (2-piperidinyl ) phenyl
741 CF3 2-F-phenyl 2- (amidinyl-methyl) phenyl
742 CF3 2-F-phenyl 2- (2-imidazolidinyl- methyl ) henyl
743 CF3 2-F-phenyl 2- (N- ( 2 -aminoimidazolyl ) - methyl ) phenyl
744 CF3 2-F-phenyl 2-dimethylaminoimidazol-l-yl
745 CF3 2-F-phenyl 2- (3 -aminophenyl )
746 CF3 2-F-phenyl 2- (3-pyrrolidinylcarbonyl)
747 CF3 2-F-phenyl 2-glycinoyl
748 CF3 2-F-phenyl 2- ( imidazol-1-ylacetyl)
749 CF3 2, 5-diF-phenyl 2- (N-pyrrolidinyl-methyl) phenyl
750 CF3 2, 5-diF-phenyl 2- (N-piperidinyl-methyl) phenyl
751 CF3 2, 5-diF-phenyl 2- (N-morpholino-methyl) phenyl
752 CF3 2, 5-diF-phenyl 2- (N,N' -methylmorpholinium- methyl ) phenyl
753 CF3 2, 5-diF-phenyl 2- (N-pyridinium-methyl) phenyl
754 CF3 2, 5-diF-phenyl 2- (N-4- (N, N' -dimethylamino) - pyridinium-methyl ) phenyl
755 CF3 2, 5-diF-phenyl 2- (N-azatanyl-methyl) phenyl
756 CF3 2, 5-diF-phenyl 2- (N-azetidinyl-methyl) phenyl
757 CF3 2, 5-diF-phenyl 2- (N-piperazinyl-methyl) phenyl
758 CF3 2, 5-diF-phenyl 2-(N,N' -BOC-piperazinyl- methyl ) phenyl
759 CF3 2, 5-diF-phenyl 2- (N-imidazolyl-methyl) phenyl
760 CF3 2, 5-diF-phenyl 2- (N-methoxy-N-methylamino- methyl) phenyl
761 CF3 2, 5-diF-phenyl 2- (N-pyridonyl-methyl) phenyl
762 CF3 2, 5-diF-phenyl 2- (N- (N' ,N' -dimethylhydrazinyl- methyl ) phenyl
763 CF3 2, 5-diF-phenyl 2- (amidinyl ) phenyl
764 CF3 2, 5-diF-phenyl 2- (N-guanidinyl ) phenyl
765 CF3 2, 5-diF-phenyl 2- (imidazolyl) phenyl
766 CF3 2, 5-diF-phenyl 2- (imidazolidinyl) phenyl
767 CF3 2, 5-diF-phenyl 2- (2-imidazolidinyl- sulfonyl ) phenyl
768 CF3 2, 5-diF-phenyl 2- (2-pyrrolidinyl) henyl
769 CF3 2, 5-diF-phenyl 2- (2-piperidinyl) phenyl
770 CF3 2, 5-diF-phenyl 2- (amidinyl-methyl ) phenyl
771 CF3 2, 5-diF-phenyl 2- (2-imidazolidinyl- methyl) phenyl
772 CF3 2, 5-diF-phenyl 2- (N- (2-aminoimidazolyl) - methyl) phenyl
773 CF3 2, 5-diF-phenyl 2-dimethylaminoimidazol-1-yl
774 CF3 2, 5-diF-phenyl 2- (3 -aminophenyl )
775 CF3 2, 5-diF-phenyl 2- (3-pyrrolidinylcarbonyl)
776 CF3 2, 5-diF-phenyl 2-glycinoyl
777 CF3 2, 5-diF-phenyl 2- ( imidazol-1-ylacetyl)
778 CONH2 phenyl 2- (aminosulfonyl) phenyl
779 CONH2 phenyl 2- (methylaminosulfonyl) phenyl
780 CONH2 phenyl 1-pyrrolidinocarbony1
781 C0NH2 phenyl 2- (methylsulfonyl) phenyl
782 CONH2 phenyl 4-morpholino
783 C0NH2 phenyl 2-(l'-CF3-tetrazol-2-yl)phenyl
784 C0NH2 phenyl 4-morpholinocarbonyl
785 C0NH2 2-pyridyl 2- (aminosulfonyl) phenyl
786 CONH2 2-pyridyl 2- (methylaminosulfonyl) phenyl
787 CONH2 2-pyridyl 1-pyrrolidinocarbonyl
788 CONH2 2-pyridyl 2- (methylsulfonyl) phenyl
789 CONH2 2-pyridyl 4-morpholino
790 C0NH2 2-pyridyl 2- ( 1 ' -CF3 -tetrazol-2 -yD phenyl
791 C0NH2 2-pyridyl 4-morpho1inocarbony1
792 CONH2 3-pyridyl 2- (aminosulfonyl) phenyl
793 CONH2 3-pyridyl 2- (methylaminosulfonyl) phenyl
794 CONH2 3-pyridyl 1-pyrrolidinocarbonyl
795 CONH2 3-pyridyl 2- (methylsulfonyl) phenyl
796 CONH2 3-pyridyl 4-morpholino
797 CONH2 3-pyridyl 2- (1 ' -CF3-tetrazol-2-yl) phenyl
798 CONH2 3-pyridyl 4-morpholinocarbonyl
799 CONH2 2-pyrimidyl 2- (aminosulfonyl ) phenyl
800 CONH2 2-pyrimidyl 2- (methylaminosulfonyl) phenyl
801 CONH2 2-pyrimidyl 1-pyrro1idinocarbony1
802 CONH2 2-pyrimidyl 2- (methylsulfonyl) phenyl
803 CONH2 2-pyrimidyl 4-morpholino
804 CONH2 2-pyrimidyl 2- (1' -CF3-tetrazol-2-yl) phenyl
805 CONH2 2-pyrimidyl 4-morpholinocarbonyl
806 CONH2 5-pyrimidyl 2- (aminosulfonyl) phenyl
807 CONH2 5-pyrimidyl 2- (methylaminosulfonyl ) phenyl
808 CONH2 5-pyrimidyl 1-pyrro1idinocarbony1
809 CONH 5-pyrimidyl 2- (methylsulfonyl) phenyl
810 CONH2 5-pyrimidyl 4-morpholino
811 C0NH2 5-pyrimidyl 2- ( 1 ' -CF3-tetrazol-2-yl ) phenyl
812 C0NH2 5-pyrimidyl 4-morpholinocarbonyl
813 CONH2 2-Cl-phenyl 2- (aminosulfonyl) phenyl
814 CONH2 2-Cl-phenyl 2- (methylaminosulfonyl) phenyl
815 C0NH2 2-Cl-phenyl 1-pyrrolidinocarbonyl
816 C0NH2 2-Cl-phenyl 2- (methylsulfonyl) phenyl
817 C0NH2 2-Cl-phenyl 4-morpholino
818 C0NH2 2-Cl-phenyl 2- (1 ' -CF3-tetrazol-2-yl)phenyl
819 C0NH2 2-Cl-phenyl 4-morpholinocarbonyl
820 C0NH2 2-F-phenyl 2- (aminosulfonyl) phenyl
821 CONH2 2-F-phenyl 2- (methylaminosulfonyl) phenyl
822 CONH2 2-F-phenyl 1-pyrro1idinocarbony1
823 C0NH2 2-F-phenyl 2- (methylsulfonyl ) phenyl
824 CONH2 2-F-phenyl 4-morpholino
825 C0NH2 2-F-phenyl 2- ( 1 ' -CF3-tetrazol-2-yl ) phenyl
826 CONH2 2-F-phenyl 4-morpho1inocarbony1
827 CONH2 2, 5-diF-phenyl 2- (aminosulfonyl) phenyl
828 C0NH2 2, 5-diF-phenyl 2- (methylaminosulfonyl) phenyl
829 C0NH2 2, 5-diF-phenyl 1-pyrro1idinocarbony1
830 C0NH2 2, 5-diF-phenyl 2- (methylsulfonyl ) phenyl
831 C0NH2 2 , 5-diF-phenyl 4-morpholino
832 C0NH2 2, 5-diF-phenyl 2- ( 1 ' -CF3 -tetrazol-2-yl ) phenyl
833 C0NH2 2, 5-diF-phenyl 4-morpholinocarbonyl
834 C0NH2 phenyl 2- (N-pyrrolidinyl-methyl) phenyl
835 C0NH2 phenyl 2- (N-piperidinyl-methyl) phenyl
836 C0NH2 phenyl 2- (N-morpholino-methyl) phenyl
837 C0NH2 phenyl 2- (N,N' -methylmorpholinium- methyl) phenyl
838 C0NH2 phenyl 2- (N-pyridinium-methyl) phenyl
839 CONH2 phenyl 2- (N-4- (N,N' -dimethylamino) - pyridinium-methyl ) phenyl
840 CONH2 phenyl 2- (N-azatanyl-methyl) phenyl
841 CONH2 phenyl 2- (N-azetidinyl-methyl) phenyl
842 CONH2 phenyl 2- (N-piperazinyl-methyl) phenyl
843 CONH2 phenyl 2-(N,N' -BOC-piperazinyl- methyl ) phenyl
844 CONH2 phenyl 2- (N-imidazolyl-methyl) phenyl
845 CONH2 phenyl 2- (N-methoxy-N-methylamino- methyl) phenyl
846 CONH2 phenyl 2- (N-pyridonyl-methyl ) phenyl
847 CONH2 phenyl 2- (N- (N' ,N' -dimethylhydrazinyl- methyl) phenyl
848 CONH2 phenyl 2- (amidinyl) phenyl
849 CONH2 phenyl 2- (N-guanidinyl ) phenyl
850 CONH2 phenyl 2- ( imidazolyl ) phenyl
851 CONH2 phenyl 2- (imidazolidinyl) phenyl
852 CONH2 phenyl 2- (2-imidazolidinyl- sulfonyl) henyl
853 CONH2 phenyl 2- (2-pyrrolidinyl) phenyl
854 CONH2 phenyl 2- (2-piperidinyl) phenyl
855 CONH2 phenyl 2- (amidinyl-methyl) phenyl
856 CONH2 phenyl 2- (2-imidazolidinyl- methyl) phenyl 8 85577 CCOONNHH22 phenyl 2- (N- (2-aminoimidazolyl) - methyl ) phenyl
858 CONH2 phenyl 2-dimethylaminoimidazol-l-yl
859 CONH2 phenyl 2- (3 -aminophenyl )
860 CONH2 phenyl 2- (3-pyrrolidinylcarbonyl)
861 CONH2 phenyl 2-glycinoyl
862 CONH2 phenyl 2- imidazol-1-ylacetyl)
863 CONH2 2-pyridyl 2- N-pyrrolidinyl-methyl) phenyl
864 CONH2 2-pyridyl 2- N-piperidinyl-methyl ) phenyl
865 CONH2 2-pyridyl 2- N-morpholino-methyl) phenyl
866 CONH2 2-pyridyl 2- N, N ' -methylmorpholinium- methyl) phenyl
867 CONH2 2-pyridyl 2- N-pyridinium-methyl) phenyl
868 CONH2 2-pyridyl 2- N-4- (N,N' -dimethylamino) - pyridinium-methyl) phenyl
869 CONH2 2-pyridyl 2- N-azatanyl-methyl) phenyl
870 CONH2 2-pyridyl 2- N-azetidinyl-methyl ) phenyl
871 CONH2 2-pyridyl 2- N-piperazinyl-methyl) phenyl
872 CONH2 2-pyridyl 2- N,N' -BOC-piperazinyl- methyl) phenyl
873 CONH2 2-pyridyl 2- N-imidazolyl-methyl) phenyl
874 CONH2 2-pyridyl 2- N-methoxy-N-methylamino- methyl) phenyl
875 CONH2 2-pyridyl 2- N-pyridonyl-methyl ) phenyl
876 CONH2 2-pyridyl 2- N- (N ' , N ' -dimethylhydrazinyl- methyl ) phenyl
877 CONH2 2-pyridyl 2- amidinyl ) phenyl
878 CONH2 2-pyridyl 2- N-guanidinyl ) phenyl
879 CONH2 2-pyridyl 2- imidazolyl) phenyl
880 CONH2 2-pyridyl 2- imidazolidinyl ) phenyl
881 CONH2 2-pyridyl 2- 2-imidazolidiny1- sulfonyl ) phenyl
882 CONH2 2-pyridyl 2- 2-pyrrolidinyl ) phenyl
883 CONH2 2-pyridyl 2- 2-piperidinyl ) phenyl
884 CONH2 2-pyridyl 2- amidinyl-methyl ) phenyl
885 CONH2 2-pyridyl 2- 2-imidazolidinyl- methyl) phenyl
886 CONH2 2-pyridyl 2 N- (2-aminoimidazolyl) - methyl ) phenyl
887 CONH2 2-pyridyl 2 dimethylaminoimidazol-1-yl
888 CONH2 2-pyridyl 2 3 -aminophenyl )
889 CONH2 2-pyridyl 2 3 -pyrrolidinylcarbonyl )
890 CONH2 2-pyridyl 2 glycinoyl
891 CONH2 2-pyridyl 2 imidazol-1-ylacetyl)
892 CONH2 3-pyridyl 2 N-pyrrolidinyl-methyl ) phenyl
893 CONH2 3-pyridyl 2 N-piperidinyl-methyl ) phenyl
894 CONH 3-pyridyl 2 N-morpholino-methyl) phenyl
895 CONH2 3-pyridyl 2 N, N ' -methylmorpholinium- methyl) phenyl
896 CONH2 3-pyridyl 2 N-pyridinium-methyl) phenyl
897 CONH2 3-pyridyl 2 N-4- (N,N' -dimethylamino) - pyridinium-methyl) phenyl
898 CONH2 3-pyridyl 2 N-azatanyl-methyl) phenyl
899 CONH2 3-pyridyl 2 N-azetidinyl-methyl) phenyl
900 CONH2 3-pyridyl 2 N-piperazinyl-methyl) phenyl
901 CONH2 3-pyridyl 2 N,N' -BOC-piperazinyl- methyl ) phenyl
902 CONH2 3-pyridyl 2 N-imidazolyl-methyl) phenyl
903 CONH2 3-pyridyl 2 N-methoxy-N-methylamino- methyl ) phenyl
904 CONH2 3-pyridyl 2 N-pyridonyl-methyl ) phenyl
905 CONH2 3-pyridyl 2 N- (N' ,N' -dimethylhydrazinyl- methyl) phenyl
906 CONH2 3-pyridyl 2 amidinyl) phenyl
907 CONH2 3-pyridyl 2 N-guanidinyl) phenyl
908 CONH2 3-pyridyl 2 imidazolyl) phenyl
909 CONH2 3-pyridyl 2 imidazolidinyl) phenyl
910 CONH2 3-pyridyl 2 2-imidazolidiny1- sulfonyl) phenyl
911 CONH2 3-pyridyl 2 2-pyrrolidinyl) phenyl
912 CONH2 3-pyridyl 2 2-piperidinyl) phenyl
913 CONH2 3-pyridyl 2 amidinyl-methyl ) phenyl
914 CONH2 3-pyridyl 2 2-imidazolidinyl-
methyl ) phenyl
915 CONH 3-pyridyl 2- (N- (2-aminoimidazolyl) - methyl) phenyl
916 CONH2 3-pyridyl 2-dimethylaminoimidazol-1- yi 917 CONH2 3 -pyridyl ; 3 -aminophenyl ) 918 CONH2 3 -pyridyl ; 3-pyrrolidinylcarbonyl ) 919 CONH2 3-pyridyl -glycinoyl 920 CONH2 3-pyridyl - (.ιmidazol-1-ylacetyl) 921 CONH2 2-pyrimidyl - (N-pyrrolidinyl-methyl ) phenyl 922 CONH2 2-pyrimidyl - (N-piperidinyl-methyl) phenyl 923 CONH2 2-pyrimidyl - (N-morpholino-methyl) phenyl 924 CONH2 2-pyrimidyl - (N, N ' -methylmorpholinium- methyl ) phenyl
925 CONH2 2-pyrimidyl - (N-pyridinium-methyl) phenyl 926 CONH2 2-pyrimidyl - (N-4- (N,N? -dimethylamino) - pyridinium-methyl ) phenyl
927 CONH2 2-pyrimidyl - (N-azatanyl-methyl) phenyl 928 CONH2 2-pyrimidyl - (N-azetidinyl-methyl) phenyl 929 CONH2 2-pyrimidyl - (N-piperazinyl-methyl ) phenyl
930 CONH2 2-pyrimidyl (N,N' -BOC-piperazinyl- methyl ) phenyl
931 CONH2 2-pyrimidyl (N-imidazolyl-methyl) phenyl 932 CONH2 2-pyrimidyl (N-methoxy-N-methylamino- methyl ) phenyl
933 CONH2 2-pyrimidyl (N-pyridonyl-methyl ) phenyl 934 CONH2 2-pyrimidyl (N- (N ' , N ' -dimethylhydrazinyl- methyl) phenyl
935 CONH2 2-pyrimidyl (amidinyl ) phenyl 936 CONH2 2-pyrimidyl (N-guanidinyl ) phenyl 937 CONH2 2-pyrimidyl ( imidazolyl) phenyl 938 CONH2 2-pyrimidyl ( imidazolidinyl) phenyl 939 CONH2 2-pyrimidyl (2-imidazolidinyl- sulfonyl ) phenyl
940 CONH2 2-pyrimidyl (2-pyrrolidinyl) phenyl 941 CONH2 2-pyrimidyl (2-piperidinyl) phenyl 942 CONH2 2-pyrimidyl (amidinyl-methyl) phenyl 943 CONH2 2-pyrimidyl (2-imidazolidinyl- methyl ) phenyl
944 CONH2 2-pyrimidyl 2- (N- (2-aminoimidazolyl) - methyl ) phenyl
945 CONH2 2-pyrimidyl 2-dimethylaminoimidazol-l-yl 946 CONH2 2-pyrimidyl 2- (3-aminophenyl) 947 CONH2 2-pyrimidyl 2- (3-pyrrolidinylcarbonyl) 948 CONH2 2-pyrimidyl 2-glycinoyl 949 CONH2 2-pyrimidyl 2- imidazol-1-ylacetyl) 950 CONH2 2-Cl-phenyl 2- N-pyrrolidinyl-methyl ) phenyl 951 CONH2 2-Cl-phenyl 2- N-piperidinyl-methyl) phenyl 952 CONH2 2-Cl-phenyl 2- N-morpholino-methyl) phenyl 953 CONH2 2-Cl-phenyl 2- N,N' -methylmorpholinium- methyl) phenyl
954 CONH2 2-Cl-phenyl 2- N-pyridinium-methyl) phenyl 955 CONH2 2-Cl-phenyl 2- N-4- (N,N' -dimethylamino) - pyridinium-methyl) henyl
956 CONH2 2-Cl-phenyl 2 (N-azatanyl-methyl) phenyl
957 CONH2 2-Cl-phenyl 2 (N-azetidinyl-methyl) phenyl
958 CONH2 2-Cl-phenyl 2 (N-piperazinyl-methyl) phenyl
959 CONH2 2-Cl-phenyl 2 (N,N' -BOC-piperazinyl- methyl ) phenyl
960 CONH2 2-Cl-phenyl 2 (N-imidazolyl-methyl) phenyl
961 CONH2 2-Cl-phenyl 2 (N-methoxy-N-methylamino- methyl) phenyl
962 CONH2 2-Cl-phenyl 2 (N-pyridonyl-methyl ) phenyl
963 CONH2 2-Cl-phenyl 2 (N- (N' ,N' -dimethylhydrazinyl- methyl ) phenyl
964 CONH2 2-Cl-phenyl 2 (amidinyl) phenyl
965 CONH2 2-Cl-phenyl 2 (N-guanidinyl ) phenyl
966 CONH2 2-Cl-phenyl 2 ( imidazolyl ) phenyl
967 CONH2 2-Cl-phenyl 2 ( imidazolidinyl ) phenyl
968 CONH2 2-Cl-phenyl 2 (2-imidazolidinyl- sulfonyl ) phenyl
969 CONH2 2-Cl-phenyl 2 ( 2-pyrrolidinyl ) phenyl
970 CONH2 2-Cl-phenyl 2 (2-piperidinyl) phenyl
971 CONH2 2-Cl-phenyl 2 (amidinyl-methyl ) phenyl
972 CONH2 2-Cl-phenyl 2 (2-imidazolidinyl- methyl) phenyl
973 CONH2 2-Cl-phenyl (N- (2-aminoimidazolyl) - methyl) phenyl
974 CONH2 2-Cl-phenyl 2 dimethylaminoimidazol-1-yl
975 CONH2 2-Cl-phenyl 2 (3-aminophenyl )
976 CONH2 2-Cl-phenyl 2 ( 3-pyrrolidinylcarbonyl)
977 CONH2 2-Cl-phenyl 2 glycinoyl
978 CONH2 2-Cl-phenyl 2 (imidazol-1-ylacetyl)
979 CONH2 2-F-phenyl 2 (N-pyrrolidinyl-methyl)phenyl
980 CONH2 2-F-phenyl 2 (N-piperidinyl-methyl) phenyl
981 CONH2 2-F-phenyl 2 (N-morpho1ino-methyl) phenyl
982 CONH2 2-F-phenyl 2 (N, N ' -methylmorpholinium- methyl) phenyl
983 CONH2 2-F-phenyl 2 (N-pyridinium-methyl) phenyl
984 CONH2 2-F-phenyl 2 (N-4- (N,N' -dimethylamino) - pyridinium-methyl) henyl
985 CONH2 2-F-phenyl 2 (N-azatanyl-methyl) phenyl
986 CONH2 2-F-phenyl 2 (N-azetidinyl-methyl ) phenyl
987 CONH2 2-F-phenyl 2 (N-piperazinyl-methyl) phenyl
988 CONH2 2-F-phenyl 2 (N,N' -BOC-piperazinyl- methyl) phenyl
989 C0NH2 2-F-phenyl 2 (N-imidazolyl-methyl ) phenyl
990 CONH2 2-F-phenyl 2 (N-methoxy-N-methy1amino- methyl) phenyl
991 CONH2 2-F-phenyl 2- (N-pyridonyl-methyl ) phenyl
992 CONH2 2-F-phenyl 2- (N- (N' ,N' -dimethylhydrazinyl- methyl) phenyl
993 CONH2 2-F-phenyl 2- (amidinyl) phenyl 994 CONH2 2-F-phenyl 2- (N-guanidinyl ) phenyl
995 CONH2 2-F-phenyl 2- (imidazolyl ) phenyl
996 CONH2 2-F-phenyl 2- ( imidazolidinyl) phenyl
997 CONH2 2-F-phenyl 2- (2-imidazolidinyl-
sulfonyl ) phenyl
998 CONH2 2-F-phenyl 2- 2-pyrrolidinyl ) phenyl
999 CONH2 2-F-phenyl 2- 2-piperidinyl ) phenyl
1000 CONH2 2-F-phenyl 2- amidinyl-methyl ) phenyl
1001 CONH2 2-F-phenyl 2- 2-imidazolidinyl- methyl) phenyl
1002 CONH2 2-F-phenyl N- (2-aminoimidazolyl) - methyl ) phenyl
1003 CONH2 2-F-phenyl 2- dimethylaminoimidazol-1-yl 1004 CONH2 2-F-phenyl 2- 3-aminophenyl ) 1005 CONH2 2-F-phenyl 2- 3 -pyrrolidinylcarbonyl) 1006 CONH2 2-F-phenyl 2-glycinoyl 1007 CONH2 2-F-phenyl (imidazol-1-ylacetyl) 1008 CONH2 2, 5-diF-phenyl (N-pyrrolidinyl-methyl) phenyl 1009 CONH2 2 5-diF-phenyl (N-piperidinyl-methyl) henyl 1010 CONH2 2 5-diF-phenyl (N-morpholino-methyl ) phenyl 1011 CONH2 2 5-diF-phenyl (N, N ' -methylmorpholinium- methyl) phenyl
1012 CONH2 5-diF-phenyl (N-pyridinium-methyl ) phenyl 1013 CONH2 5-diF-phenyl (N-4- (N,N' -dimethylamino) - pyridinium-methyl ) phenyl
1014 CONH2 5-diF-phenyl (N-azatanyl-methyl) phenyl 1015 CONH2 5-diF-phenyl (N-azetidinyl-methyl) phenyl 1016 CONH2 5-diF-phenyl (N-piperazinyl-methyl) phenyl 1017 CONH2 5-diF-phenyl (N,N' -BOC-piperazinyl- ethyl)phenyl
1018 CONH2 5-diF-phenyl (N-imidazolyl-methyl ) phenyl 1019 CONH2 5-diF-phenyl (N-methoxy-N-methylamino- methyl) phenyl
1020 CONH2 5-diF-phenyl (N-pyridonyl-methyl ) phenyl 1021 CONH2 5-diF-phenyl (N- (N' ,N' -dimethylhydrazinyl- methyl) phenyl
1022 CONH2 5-diF-phenyl (amidinyl ) phenyl 1023 CONH2 5-diF-phenyl (N-guanidinyl ) phenyl 1024 CONH2 5-diF-phenyl (imidazolyl ) phenyl 1025 C0NH2 5-diF-phenyl (imidazolidinyl) phenyl 1026 CONH2 5-diF-phenyl (2-imidazolidinyl- sulfonyl ) phenyl
1027 CONH2 5-diF-phenyl (2-pyrrolidinyl) phenyl 1028 CONH2 5-diF-phenyl (2-piperidinyl) phenyl 1029 CONH2 5-diF-phenyl (amidinyl-methyl) phenyl 1030 CONH2 5-diF-phenyl (2-imidazolidinyl- methyl) phenyl
1031 CONH2 5-diF-phenyl 2 N- (2-aminoimidazolyl) - methyl) phenyl
1032 CONH2 5-diF- ■phenyl 2-dimethylaminoimidazol-l-yl 1033 CONH2 5-diF-■phenyl 2- (3-aminophenyl) 1034 CONH2 5-diF-•phenyl 2- (3-pyrrolidinylcarbonyl) 1035 CONH2 5-diF-•phenyl 2-glycinoyl 1036 CONH2 5-diF-•phenyl 2- imidazol-1-ylacetyl ) 1037 SCH3 phenyl 2- aminosulfonyl)phenyl 1038 SCH3 phenyl 2- methylaminosulfonyl) phenyl 1039 SCH3 phenyl 1-pyrrolidinocarbonyl
1040 SCH3 phenyl 2- (methylsulfonyl) phenyl
1041 SCH3 phenyl 4-morpholino
1042 SCH3 phenyl 2- (l'-CF3-tetrazol-2-yl) phenyl
1043 SCH3 phenyl 4-morpholinocarbonyl
1044 SCH3 2-pyridyl 2- (aminosulfony1) phenyl
1045 SCH3 2-pyridyl 2- (methylaminosulfonyl) phenyl
1046 SCH3 2-pyridyl 1-pyrro1idinocarbony1
1047 SCH3 2-pyridyl 2- (methylsulfonyl) phenyl
1048 ΞCH3 2-pyridyl 4-morpholino
1049 SCH3 2-pyridyl 2- (1' -CF3-tetrazol-2-yl) phenyl
1050 SCH3 2-pyridyl 4-morpholinocarbonyl
1051 SCH3 3-pyridyl 2- (aminosulfonyl ) phenyl
1052 SCH3 3-pyridyl 2- (methylaminosulfonyl ) phenyl
1053 SCH3 3-pyridyl 1-pyrro1idinocarbonyl
1054 SCH3 3-pyridyl 2- (methylsulfonyl) phenyl
1055 SCH3 3-pyridyl 4-morpholino
1056 SCH3 3 -pyridyl 2- ( 1 ' -CF3-tetrazol-2-yl) phenyl
1057 SCH3 3-pyridyl 4-morpholinocarbonyl
1058 SCH3 2-pyrimidyl 2- (aminosulfonyl) phenyl
1059 SCH3 2-pyrimidyl 2- (methylaminosulfonyl) phenyl
1060 SCH3 2-pyrimidyl 1-pyrro1idinocarbonyl
1061 SCH3 2-pyrimidyl 2- (methylsulfonyl) phenyl
1062 SCH3 2-pyrimidyl 4-morpholino
1063 SCH3 2-pyrimidyl 2- ( 1 ' -CF3-tetrazol-2-yl ) phenyl
1064 SCH3 2-pyrimidyl 4-morpholinocarbonyl
1065 SCH3 5-pyrimidyl 2- (aminosulfonyl ) phenyl
1066 SCH3 5-pyrimidyl 2- (methylaminosulfonyl ) phenyl
1067 SCH3 5-pyrimidyl 1-pyrro1idinocarbony1
1068 SCH3 5-pyrimidyl 2- (methylsulfonyl) phenyl
1069 SCH3 5-pyrimidyl 4-morpholino
1070 SCH3 5-pyrimidyl 2- (l'-CF3-tetrazol-2-yl)phenyl
1071 SCH3 5-pyrimidyl 4-morpholinocarbonyl
1072 SCH3 2-Cl-phenyl 2- (aminosulfonyl) phenyl
1073 SCH3 2-Cl-phenyl 2- (methylaminosulfonyl) phenyl
1074 SCH3 2-Cl-phenyl 1-pyrrolidinocarbonyl
1075 SCH3 2-Cl-phenyl 2- (methylsulfonyl ) phenyl
1076 SCH3 2-Cl-phenyl 4-morpholino
1077 SCH3 2-Cl-phenyl 2- ( 1 ' -CF3 -tetrazol-2-yl) phenyl
1078 SCH 2-Cl-phenyl 4-morpholinocarbonyl
1079 SCH3 2-F-phenyl 2- (aminosulfonyl) phenyl
1080 SCH3 2-F-phenyl 2- (methylaminosulfonyl) phenyl
1081 SCH3 2-F-phenyl 1-pyrrolidinocarbonyl
1082 SCH3 2-F-phenyl 2- (methylsulfonyl) phenyl
1083 SCH3 2-F-phenyl 4-morpholino
1084 SCH3 2-F-phenyl 2- ( 1 ' -CF3-tetrazol-2-yl) phenyl
1085 SCH3 2-F-phenyl 4-morpholinocarbonyl
1086 SCH3 2, 5-diF-phenyl 2- (aminosulfonyl) phenyl
1087 SCH3 2, 5-diF-phenyl 2- (methylaminosulfonyl) henyl
1088 SCH3 2, 5-diF-phenyl 1-pyrrolidinocarbonyl
1089 SCH3 2, 5-diF-phenyl 2- (methylsulfonyl) phenyl
1090 SCH3 2, 5-diF-phenyl 4-morpholino
1091 SCH3 2, 5-diF-phenyl 2- ( 1 ' -CF3-tetrazol-2-yl) phenyl
1092 SCH3 2, 5-diF-phenyl -morpholinocarbonyl
1093 SCH3 phenyl - (N-pyrrolidinyl-methyl ) phenyl
1094 SCH3 phenyl - (N-piperidinyl-methyl) phenyl
1095 SCH3 phenyl - (N-morpholino-methyl) phenyl
1096 SCH3 phenyl - (N, ' -methylmorpholinium- methyl) phenyl
1097 SCH3 phenyl - (N-pyridinium-methyl) phenyl
1098 SCH3 phenyl - (N-4- (N,N' -dimethylamino) - pyridinium-methyl) phenyl
1099 SCH3 phenyl - (N-azatanyl-methyl) phenyl
1100 SCH3 phenyl - (N-azetidinyl-methyl) phenyl
1101 SCH3 phenyl - (N-piperazinyl-methyl) phenyl
1102 SCH3 phenyl (N,N' -BOC-piperazinyl- methyl) henyl
1103 SCH3 phenyl (N-imidazolyl-methyl) phenyl
1104 SCH3 phenyl (N-methoxy-N-methylamino- methyl ) phenyl
1105 SCH3 phenyl (N-pyridonyl-methyl ) phenyl
1106 SCH3 phenyl (N- (N' ,N' -dimethylhydrazinyl- methyl) phenyl
1107 SCH3 phenyl (amidinyl ) phenyl
1108 SCH3 phenyl • (N-guanidinyl ) phenyl
1109 SCH3 phenyl • ( imidazolyl ) phenyl
1110 SCH3 phenyl ( imidazolidinyl ) phenyl
1111 SCH3 phenyl (2-imidazolidinyl- sulfonyl ) phenyl
1112 SCH3 phenyl (2-pyrrolidinyl) phenyl
1113 SCH3 phenyl (2-piperidinyl ) phenyl
1114 SCH3 phenyl (amidinyl-methyl) phenyl
1115 SCH3 phenyl (2-imidazolidinyl- methyl ) phenyl
1116 SCH phenyl N- (2-aminoimidazolyl) - methyl ) phenyl
1117 SCH3 phenyl 2-dimethylaminoimidazol-l-yl 1118 SCH3 phenyl 2- ( 3 -aminophenyl ) 1119 SCH3 phenyl 2- (3-pyrrolidinylcarbonyl) 1120 SCH3 phenyl 2-glycinoyl 1121 SCH3 phenyl 2- imidazol-1-ylacetyl) 1122 SCH3 2-pyridyl 2- N-pyrrolidinyl-methyl) phenyl 1123 SCH3 2-pyridyl 2- N-piperidinyl-methyl) phenyl 1124 SCH3 2-pyridyl 2- N-morpholino-methyl) phenyl 1125 SCH3 2-pyridyl 2- N,N' -methylmorpholinium- methyl) phenyl
1126 SCH3 2-pyridyl 2- N-pyridinium-methyl) phenyl
1127 SCH3 2-pyridyl 2- N-4- (N,N' -dimethylamino) - pyridinium-methyl) phenyl
1128 SCH3 2-pyridyl 2- N-azatanyl-methyl) phenyl
1129 SCH3 2-pyridyl 2- N-azetidinyl-methyl) phenyl
1130 SCH3 2-pyridyl 2- N-piperazinyl-methyl) phenyl
1131 SCH3 2-pyridyl 2- N,N' -BOC-piperazinyl- methyl)phenyl
1132 SCH3 2-pyridyl 2- N-imidazolyl-methyl)phenyl
1133 SCH3 2-pyridyl 2- N-methoxy-N-methylamino-
methyl ) phenyl
1134 SCH3 2-pyridyl 2- (N-pyridonyl-methyl) phenyl
1135 SCH3 2-pyridyl 2- (N- (N' ,N' -dimethylhydrazinyl- methyl) phenyl
1136 SCH3 2-pyridyl 2- (amidinyl) phenyl
1137 SCH3 2-pyridyl 2- (N-guanidinyl ) phenyl
1138 SCH3 2-pyridyl 2- ( imidazolyl) phenyl
1139 SCH3 2-pyridyl 2- ( imidazolidiny1 ) phenyl
1140 SCH3 2-pyridyl 2- (2-imidazolidinyl- sulfonyl ) phenyl
1141 SCH3 2-pyridyl 2- (2-pyrrolidinyl) phenyl
1142 SCH3 2-pyridyl 2- (2-piperidinyl) phenyl
1143 SCH3 2-pyridyl 2- (amidinyl-methyl ) phenyl
1144 SCH3 2-pyridyl 2- (2-imidazolidinyl- methyl ) phenyl
1145 SCH3 2-pyridyl 2- (N- (2-aminoimidazolyl ) - methyl) phenyl
1146 SCH3 2-pyridyl 2-dimethylaminoimidazol-1-yl
1147 SCH3 2-pyridyl 2- (3 -aminophenyl )
1148 SCH3 2-pyridyl 2- (3-pyrrolidinylcarbonyl)
1149 SCH3 2-pyridyl 2-glycinoyl
1150 SCH3 2-pyridyl 2- (imidazol-1-ylacetyl)
1151 SCH3 3-pyridyl 2- (N-pyrrolidinyl-methyl ) phenyl
1152 SCH3 3-pyridyl 2- (N-piperidinyl-methyl ) phenyl
1153 SCH3 3 -pyridyl 2- (N-morpholino-methyl) phenyl
1154 SCH3 3-pyridyl 2- (N,N' -methylmorpholinium- methyl) phenyl
1155 SCH3 3-pyridyl 2- (N-pyridinium-methyl) phenyl
1156 SCH3 3-pyridyl 2- (N-4- (N,N' -dimethylamino) - pyridinium-methyl) phenyl
1157 SCH3 3-pyridyl 2- (N-azatanyl-methyl) phenyl
1158 SCH3 3-pyridyl 2- (N-azetidinyl-methyl) phenyl
1159 SCH3 3-pyridyl 2- (N-piperazinyl-methyl) phenyl
1160 SCH3 3-pyridyl 2-(N,N' -BOC-piperazinyl- methyl) phenyl
1161 SCH3 3-pyridyl 2- (N-imidazolyl-methyl) phenyl
1162 SCH3 3-pyridyl 2- (N-methoxy-N-methylamino- methyl) phenyl
1163 SCH3 3-pyridyl 2- (N-pyridonyl-methyl ) phenyl
1164 SCH3 3-pyridyl 2- (N- (N' ,N' -dimethylhydrazinyl- methyl) phenyl
1165 SCH3 3-pyridyl 2- (amidinyl)phenyl
1166 SCH3 3-pyridyl 2- (N-guanidinyl) phenyl
1167 SCH3 3-pyridyl 2- ( imidazolyl) phenyl
1168 SCH3 3-pyridyl 2- ( imidazolidinyl) phenyl
1169 SCH3 3-pyridyl 2- (2-imidazolidinyl- sulfonyl) phenyl
1170 SCH3 3-pyridyl 2- (2-pyrrolidinyl) phenyl
1171 SCH3 3-pyridyl 2- (2-piperidin 1) phenyl
1172 SCH3 3-pyridyl 2- (amidinyl-methyl) phenyl
1173 SCH3 3-pyridyl 2- (2-imidazolidinyl- methyl) phenyl
1174 SCH3 3-pyridyl 2- (N- (2-aminoimidazolyl ) -
methyl ) phenyl
1175 SCH3 3 -pyridyl 2-dimethylaminoimidazol-l-yl
1176 SCH3 3 -pyridyl 2- 3 -aminophenyl )
1177 SCH3 3 -pyridyl 2- 3 -pyrrolidinylcarbonyl )
1178 SCH3 3-pyridyl 2-glycinoyl
1179 SCH3 3-pyridyl 2- (imidazol-1-ylacetyl)
1180 SCH3 2-pyrimidyl 2- (N-pyrrolidiny1 -methyl ) phenyl
1181 SCH3 2-pyrimidyl 2- (N-piperidinyl-methyl) phenyl
1182 SCH3 2-pyrimidyl 2- (N-morpholino-methyl) phenyl
1183 SCH3 2-pyrimidyl 2- (N,N' -methylmorpholinium- methyl ) phenyl
1184 SCH3 2-pyrimidyl 2- (N-pyridinium-methyl) phenyl
1185 SCH3 2-pyrimidyl 2- (N-4- (N,N' -dimethylamino) - pyridinium-methyl) phenyl
1186 SCH3 2-pyrimidyl 2- (N-azatanyl-methyl) phenyl
1187 SCH3 2-pyrimidyl 2- (N-azetidinyl-methyl) phenyl
1188 SCH3 2-pyrimidyl 2- (N-piperaziny1-methyl ) phenyl
1189 SCH3 2-pyrimidyl 2- (N,N' -BOC-piperazinyl- methyl ) phenyl
1190 SCH3 2-pyrimidyl 2- (N-imidazolyl-methyl) phenyl
1191 SCH3 2-pyrimidyl 2- (N-methoxy-N-methylamino- rnethyl ) phenyl
1192 SCH3 2-pyrimidyl 2- (N-pyridonyl-methyl) phenyl
1193 SCH3 2-pyrimidyl 2- (N- (N' ,N' -dimethylhydrazinyl- methyl) henyl
1 1119944 S SCCHH33 2-pyrimidyl 2- (amidinyl) phenyl 1 1119955 S SCCHH33 2-pyrimidyl 2- (N-guanidinyl) phenyl 1 1119966 S SCCHH33 2-pyrimidyl 2- (imidazolyl) phenyl 1 1119977 S SCCHH33 2-pyrimidyl 2- (imidazolidinyl) phenyl 1 1119988 S SCCHH33 2-pyrimidyl 2- (2-imidazolidinyl- sulfonyl) phenyl
1199 SCH3 2-pyrimidyl 2- (2-pyrrolidinyl) phenyl
1200 SCH3 2-pyrimidyl 2- (2-piperidinyl ) phenyl
1201 SCH3 2-pyrimidyl 2- (amidinyl-methyl) phenyl
1202 SCH3 2-pyrimidyl 2- (2-imidazolidinyl- methyl) phenyl 1 1220033 SSCCHH33 2-pyrimidyl 2- (N- (2-aminoimidazolyl) - methyl) phenyl
1204 SCH3 2-pyrimidyl 2-dimethylaminoimidazol-l-yl
1205 SCH3 2-pyrimidyl 2- (3-aminophenyl )
1206 SCH3 2-pyrimidyl 2- (3-pyrrolidinylcarbonyl)
1207 SCH3 2-pyrimidyl 2-glycinoyl
1208 SCH3 2-pyrimidyl 2- imidazol-1-ylacetyl)
1209 SCH3 2-Cl-phenyl 2- N-pyrrolidinyl-methyl)phenyl
1210 SCH3 2-Cl-phenyl 2- N-piperidinyl-methyl) phenyl
1211 SCH3 2-Cl-phenyl 2- N-morpholino-methyl) phenyl
1212 SCH3 2-Cl-phenyl 2- N, N ' -methylmorpholinium- methyl) phenyl
1213 SCH3 2-Cl-phenyl 2- N-pyridinium-methyl) phenyl
1214 SCH3 2-Cl-phenyl 2- N-4- (N,N' -dimethylamino) - pyridinium-methyl) phenyl
1215 SCH3 2-Cl-phenyl 2- N-azatanyl-methyl) phenyl
1216 SCH3 2-Cl-phenyl 2- N-azetidinyl-methyl) phenyl
1217 SCH3 2-Cl-phenyl 2- (N-piperazinyl-methyl) phenyl
1218 SCH3 2-Cl-phenyl 2-(N,N' -BOC-piperazinyl- methyl ) phenyl
1219 SCH3 2-Cl-phenyl 2- (N-imidazolyl-methyl) phenyl
1220 SCH3 2-Cl-phenyl 2- (N-methoxy-N-methylamino- ethyl) phenyl
1221 SCH3 2-Cl-phenyl 2- (N-pyridonyl-methyl) phenyl
1222 SCH3 2-Cl-phenyl 2- (N- (N' ,N' -dimethylhydrazinyl- methyl ) phenyl
1223 SCH3 2-Cl-phenyl 2- (amidinyl) phenyl
1224 SCH3 2-Cl-phenyl 2- (N-guanidinyl ) phenyl
1225 SCH3 2-Cl-phenyl 2- (imidazolyl)phenyl
1226 SCH3 2-Cl-phenyl 2- ( imidazolidinyl ) phenyl
1227 SCH3 2-Cl-phenyl 2- (2-imidazolidinyl- sulfonyl ) phenyl
1228 SCH3 2-Cl-phenyl 2- (2-pyrrolidinyl) phenyl
1229 SCH3 2-Cl-phenyl 2- (2-piperidinyl ) phenyl 1230 SCH3 2-Cl-phenyl 2- (amidinyl-methyl ) phenyl
1231 SCH3 2-Cl-phenyl 2- (2-imidazolidinyl- methyl) phenyl
1232 SCH3 2-Cl-phenyl N- (2-aminoimidazolyl) - methyl) phenyl
1233 SCH3 2-Cl-phenyl 2-dimethylaminoimidazol-l-yl 1234 SCH3 2-Cl-phenyl 2- (3-aminophenyl ) 1235 SCH3 2-Cl-phenyl 2- (3-pyrrolidinylcarbonyl) 1236 SCH3 2-Cl-phenyl 2-glycinoyl 1237 SCH3 2-Cl-phenyl 2- imidazol-1-ylacetyl) 1238 SCH3 2-F-phenyl 2- N-pyrrolidinyl-methyl ) phenyl 1239 SCH3 2-F-phenyl 2- N-piperidinyl-methyl) phenyl 1240 SCH3 2-F-phenyl 2- N-morpholino-methyl) phenyl 1241 SCH3 2-F-phenyl 2- N,N' -methylmorpholinium- methyl) phenyl
1242 SCH3 2-F-phenyl 2- N-pyridinium-methyl) phenyl 1243 SCH3 2-F-phenyl 2- N-4- (N,N' -dimethylamino) - pyridinium-methyl) phenyl
1244 SCH3 2-F-phenyl 2- N-azatanyl-methyl ) phenyl 1245 SCK3 2-F-phenyl 2- N-azetidinyl-methyl) phenyl 1246 SCH3 2-F-phenyl 2- N-piperazinyl-methyl) phenyl 1247 SCH3 2-F-phenyl 2- N, N ' -BOC-piperazinyl- methyl) phenyl
1248 SCH3 2-F-phenyl 2- N-imidazolyl-methyl) phenyl 1249 SCH3 2-F-phenyl 2- N-methoxy-N-methylamino- methyl) phenyl
1250 SCH3 2-F-phenyl 2- N-pyridonyl-methyl) phenyl 1251 SCH3 2-F-phenyl 2- N- (N ' , N ' -dimethylhydrazinyl- methyl)phenyl
1252 SCH3 2-F-phenyl 2- amidinyl) phenyl 1253 SCH3 2-F-phenyl 2- N-guanidinyl) phenyl 1254 SCH3 2-F-phenyl 2- imidazolyl)phenyl 1255 SCH 2-F-phenyl 2- imidazolidinyl) phenyl 1256 SCH3 2-F-phenyl 2- 2-imidazolidinyl- sulfonyl ) phenyl
1257 SCH3 2-F-phenyl (2-pyrrolidinyl) phenyl
1258 SCH3 2-F-phenyl 2- (2-piperidinyl ) phenyl
1259 SCH3 2-F-phenyl 2- (amidinyl-methyl ) phenyl
1260 SCH3 2-F-phenyl 2- (2-imidazolidinyl- me hyl) henyl
1261 SCH3 2-F-phenyl 2- (N- (2-aminoimidazolyl) - methyl ) henyl
1262 SCH3 2-F-phenyl 2-dimethylaminoimidazol-1-yl
1263 SCH3 2-F-phenyi 2- (3-aminophenyl)
1264 SCH3 2-F-phenyl 2- (3-pyrrolidinylcarbonyl)
1265 SCH3 2-F-phenyl 2-glycinoyl
1266 SCH3 2-F-phenyl 2- (imidazol-1-ylacetyl)
1267 SCH3 2, 5-diF-phenyl 2- (N-pyrrolidinyl-methyl) phenyl
1268 SCH3 2, 5-diF-phenyl 2- (N-piperidinyl-methyl) phenyl
1269 SCH3 2, 5-diF-phenyl 2- (N-morpholino-methyl) phenyl
1270 SCH3 2, 5-diF-phenyl 2- (N,N' -methylmorpholinium- methyl ) phenyl
1271 SCH3 2, 5-diF-phenyl 2- (N-pyridinium-methyl) phenyl
1272 SCH3 2, 5-diF-phenyl 2- (N-4- (N, N' -dimethylamino)- pyridinium-methyl) phenyl
1273 SCH3 2, 5-diF-phenyl 2- (N-azatanyl-methyl) phenyl
1274 SCH3 2, 5-diF-phenyl 2- (N-azetidinyl-methyl) phenyl
1275 SCH3 2, 5-diF-phenyl 2- (N-piperazinyl-methyl) phenyl
1276 SCH3 2 , 5-diF-phenyl 2-(N,N' -BOC-piperazinyl- methyl ) phenyl
1277 SCH3 2, 5-diF-phenyl 2- (N-imidazolyl-methyl) phenyl
1278 SCH3 2 , 5-diF-phenyl 2- (N-methoxy-N-methylamino- methyl ) phenyl
1279 SCH3 2 , 5-diF-phenyl 2- (N-pyridonyl-methyl)phenyl
1280 SCH3 2, 5-diF-phenyl 2- (N- (N1 ,N' -dimethylhydrazinyl- methyl) henyl
1281 SCH3 2, 5-diF-phenyl 2- (amidinyl) henyl
1282 SCH3 2, 5-diF-phenyl 2- (N-guanidinyl ) phenyl
1283 SCH3 2, 5-diF-phenyl 2- ( imidazolyl ) phenyl
1284 SCH3 2, 5-diF-phenyl 2- (imidazolidinyl) phenyl
1285 SCH3 2, 5-diF-phenyl 2- (2-imidazolidinyl- sulfonyl ) phenyl
1286 SCH3 2, 5-diF-phenyl 2- (2-pyrrolidinyl) phenyl
1287 SCH3 2, 5-diF-phenyl 2- (2-piperidinyl ) phenyl
1288 SCH3 2, 5-diF-phenyl 2- (amidinyl-methyl ) phenyl
1289 SCH3 2, 5-diF-phenyl 2- (2-imidazolidinyl- methyl) phenyl
1290 SCH3 2, 5-diF-phenyl 2- (N- (2-aminoimidazolyl) - methyl) henyl
1291 SCH3 2, 5-diF-phenyl 2-dimethylaminoimidazol-l-yl
1292 SCH3 2, 5-diF-phenyl 2- (3-aminophenyl)
1293 SCH3 2, 5-diF-phenyl 2- (3-pyrrolidinylcarbonyl)
1294 SCH3 2, 5-diF-phenyl 2-glycinoyl
1295 SCH3 2, 5-diF-phenyl 2- (imidazol-1-ylacetyl)
1296 S02CH3 phenyl 2- (aminosulfonyl) phenyl
1297 Sθ2CH3 phenyl 2- (methylaminosulfonyl) phenyl
1298 S02CH3 phenyl 1-pyrro1idinocarbonyl
1299 S02CH3 phenyl 2- (methylsulfonyl) henyl
1300 S02CH3 phenyl 4-morpholino
1301 S02CH3 phenyl 2- ( 1 ' -CF3 -tetrazol-2-yl ) phenyl
1302 S02CH3 phenyl 4-morpholinocarbonyl
1303 S0CH3 2-pyridyl 2- (aminosulfonyl ) phenyl
1304 S02CH3 2-pyridyl 2- (methylaminosulfonyl) phenyl
1305 S02CH3 2-pyridyl 1-pyrrolidinocarbonyl
1306 S02CH3 2-pyridyl 2- (methylsulfonyl) phenyl
1307 S0CH3 2-pyridyl 4-morpholino
1308 S02CH3 2-pyridyl 2- ( 1 ' -CF3 -tetrazol-2-yl ) phenyl
1309 S02CH3 2-pyridyl 4-morpholinocarbonyl
1310 S02CH3 3-pyridyl 2- (aminosulfonyl) phenyl
1311 S02CH3 3-pyridyl 2- (methylaminosulfonyl) phenyl
1312 S02CH3 3-pyridyl 1-pyrro1idinocarbonyl
1313 S02CH3 3-pyridyl 2- (methylsulfonyl) phenyl
1314 S02CH3 3-pyridyl 4-morpholino
1315 S02CH3 3-pyridyl 2-(l'-CF3-tetrazol-2-yl)phenyl
1316 S02CH3 3-pyridyl 4-morpholinocarbonyl
1317 S02CH3 2-pyrimidyl 2- (aminosulfonyl) henyl
1318 S02CH3 2-pyrimidyl 2- (methylaminosulfonyl) phenyl
1319 S02CH3 2-pyrimidyl 1-pyrro1idinocarbonyl
1320 S02CH3 2-pyrimidyl 2- (methylsulfonyl) phenyl
1321 S02CH3 2-pyrimidyl 4-morpholino
1322 S0CH3 2-pyrimidyl 2- ( 1 ' -CF3-tetrazol-2-yl ) phenyl
1323 S02CH3 2-pyrimidyl 4-morpholinocarbonyl
1324 S02CH3 5-pyrimidyl 2- (aminosulfonyl ) phenyl
1325 S02CH3 5-pyrimidyl 2- (methylaminosulfonyl) phenyl
1326 S02CH3 5-pyrimidyl 1-pyrro1idinocarbonyl
1327 S02CH3 5-pyrimidyl 2- (methylsulfonyl) phenyl
1328 S02CH3 5-pyrimidyl 4-morpholino
1329 S02CH3 5-pyrimidyl 2- (1 ' -CF3-tetrazol-2-yl)phenyl
1330 S02CH3 5-pyrimidyl 4-morpho1inocarbony1
1331 S02CH3 2-Cl-phenyl 2- (aminosulfonyl) phenyl
1332 S02CH3 2-Cl-phenyl 2- (methylaminosulfonyl) phenyl
1333 S02CH3 2-Cl-phenyl 1-pyrro1idinocarbonyl
1334 S02CH3 2-Cl-phenyl 2- (methylsulfonyl) phenyl
1335 S02CH3 2-Cl-phenyl 4-morpho1ino
1336 S02CH3 2-Cl-phenyl 2- ( 1 ' -CF3-tetrazol-2-yl ) phenyl
1337 S02CH3 2-Cl-phenyl 4-morpholinocarbonyl
1338 S02CH3 2-F-phenyl 2- (aminosulfonyl) phenyl
1339 S02CH3 2-F-phenyl 2- (methylaminosulfonyl ) phenyl
1340 S02CH3 2-F-phenyl 1-pyrrolidinocarbonyl
1341 S02CH3 2-F-phenyl 2- (methylsulfonyl) phenyl
1342 S02CH3 2-F-phenyl 4-morpholino
1343 Sθ2CH3 2-F-phenyl 2- ( 1 ' -CF3-tetrazol-2-yl ) phenyl
1344 S02CH3 2-F-phenyl 4-morpholinocarbonyl
1345 S02CH3 2,5-diF-phenyl 2- ( minosulfonyl)phenyl
1346 S02CH3 2, 5-diF-phenyl 2- (methylaminosulfonyl) phenyl
1347 S02CH3 2, 5-diF-phenyl 1-pyrrolidinocarbonyl
1348 S02CH3 2, 5-diF-phenyl 2- (methylsulfonyl) phenyl
1349 S02CH3 2,5-diF-phenyl 4-morpholino
1350 S02CH3 2, 5-diF-phenyl 2- (1 ' -CF3-tetrazol-2-yl) phenyl
1351 S02CH3 2,5-diF-phenyl 4-morpholinocarbonyl
1352 S02CH3 phenyl 2- (N-pyrrolidinyl-methyl) phenyl
1353 S02CH3 phenyl 2- (N-piperidinyl-methyl) phenyl
1354 S02CH3 phenyl 2- (N-morpholino-methyl) phenyl
1355 S02CH3 phenyl 2- (N,N' -methylmorpholinium- methyl ) phenyl
1356 S0 CH3 phenyl 2- (N-pyridinium-methyl ) phenyl
1357 S02CH3 phenyl 2- (N-4- (N,NT -dimethylamino) - pyridinium-methyl) henyl i358 S02CH3 phenyl 2- (N-azatanyl-methyl) phenyl
1359 S0 CH3 phenyl 2- (N-azetidinyl-methyl) phenyl
1360 S02CH3 phenyl 2- ( -piperazinyl-methyl ) phenyl
1361 S02CH3 phenyl 2- (N,N' -BOC-piperazinyl- methyl ) phenyl
1362 S02CH3 phenyl 2- (N-imidazolyl-methyl) phenyl
1363 S02CH3 phenyl 2- (N-methoxy-N-methylamino- methyl ) phenyl
1364 S02CH3 phenyl 2- (N-pyridonyl-methyl )phenyl
1365 S02CH3 phenyl 2- (N- (N ' , N ' -dimethylhydrazinyl- methyl ) phenyl
1366 S02CH3 phenyl 2- (amidinyl ) phenyl
1367 S02CH3 phenyl 2- (N-guanidinyl ) phenyl
1368 S02CH3 phenyl 2- ( imidazolyl ) phenyl
1369 S02CH3 phenyl 2- ( imidazolidinyl ) phenyl
1370 S02CH3 phenyl 2- (2-imidazolidinyl- sulfonyl ) phenyl
1371 S02CH3 phenyl 2- (2-pyrrolidinyl) phenyl
1372 S02CH3 phenyl 2- (2-piperidinyl) phenyl
1373 S02CH3 phenyl 2- (amidinyl-methyl ) phenyl
1374 S02CH3 phenyl 2- (2-imidazolidinyl- methyl ) phenyl
1375 S02CH3 phenyl 2- (N- (2-aminoimidazolyl) - methyl ) phenyl
1376 S02CH3 phenyl 2-dimethylaminoimidazol-l-yl
1377 S02CH3 phenyl 2- ( 3 -aminophenyl)
1378 S0 CH3 phenyl 2- ( 3 -pyrrolidinylcarbonyl)
1379 S02CH3 phenyl 2-glycinoyl
1380 S02CH3 phenyl 2- (imidazol-1-ylacetyl)
1381 S02CH3 2-pyridyl 2- (N-pyrrolidinyl-methyl) phenyl
1382 S02CH3 2-pyridyl 2- (N-piperidinyl-methyl) phenyl
1383 S02CH3 2-pyridyl 2- (N-morpholino-methyl ) phenyl
1384 S02CH3 2-pyridyl 2- (N,N' -methylmorpholinium- methyl) phenyl
1385 S02CH3 2-pyridyl 2- (N-pyridinium-methyl ) phenyl
1386 S0CH3 2-pyridyl 2- (N-4- (N,N' -dimethylamino) - pyridinium-methyl ) phenyl
1387 S02CH3 2-pyridyl 2- (N-azatanyl-methyl) phenyl
1388 S02CH3 2-pyridyl 2- (N-azetidinyl-methyl) phenyl
1389 S02CH3 2-pyridyl 2- (N-piperazinyl-methyl) phenyl
1390 S02CH3 2-pyridyl 2- (N,N' -BOC-piperazinyl- methyl)phenyl
1391 S02CH3 2-pyridyl 2- (N-imidazolyl-methyl) phenyl
1392 S02CH3 2-pyridyl 2- (N-methoxy-N-methylamino- methyl ) phenyl
1393 S02CH3 2-pyridyl 2- (N-pyridonyl-methyl ) phenyl
1394 S02CH3 2-pyridyl 2- (N- ( ' , N ' -dimethylhydrazinyl- methyl ) phenyl
1395 S02CH3 2-pyridyl 2- (amidinyl ) phenyl
1396 S02CH3 2-pyridyl 2- (N-guanidinyl) phenyl
1397 S02CH3 2-pyridyl 2- ( imidazolyl ) phenyl
1398 S02CH3 2-pyridyl 2- (imidazolidinyl) phenyl
1399 S02CH3 2-pyridyl 2- (2-imidazolidinyl- sulfonyl ) phenyl
1400 S02CH3 2-pyridyl 2- (2-pyrrolidinyl) henyl
1401 S02CH3 2-pyridyl 2- (2-piperidinyl) phenyl
1402 S02CH3 2-pyridyl 2- (amidinyl-methyl ) phenyl
1403 S02CH3 2-pyridyl 2- (2-imidazolidinyl- methyl ) phenyl
1404 S02CH3 2-pyridyl 2- (N- (2-aminoimidazolyl) - methyl) phenyl
1405 S02CH3 2-pyridyl 2-dimethylaminoimidazol-l-yl
1406 S02CH3 2-pyridyl 2- (3 -aminophenyl )
1407 S02CH3 2-pyridyl 2- (3-pyrrolidinylcarbonyl)
1408 S02CH3 2-pyridyl 2-glycinoyl
1409 S02CH3 2-pyridyl 2- ( imidazol-1-ylacetyl )
1410 S02CH3 3-pyridyl 2- (N-pyrrolidinyl-methyl) phenyl
1411 S02CH3 3-pyridyl 2- (N-piperidinyl-methyl) phenyl
1412 S0CH3 3 -pyridyl 2- (N-morpholino-methyl) phenyl
1413 S02CH3 3-pyridyl 2- (N,N' -methylmorpholinium- methyl ) phenyl
1414 S02CH3 3-pyridyl 2- (N-pyridinium-methyl) phenyl
1415 S02CH3 3-pyridyl 2- (N-4- (N,N' -dimethylamino) - pyridinium-methyl ) phenyl
1416 S02CH3 3-pyridyl 2- (N-azatanyl-methyl) phenyl
1417 S02CH3 3-pyridyl 2- (N-azetidinyl-methyl) phenyl
1418 S02CH3 3-pyridyl 2- (N-piperazinyl-methyl) phenyl
1419 S02CH3 3-pyridyl 2-(N,N' -BOC-piperazinyl- methyl) phenyl
1420 S02CH3 3-pyridyl 2- (N-imidazolyl-methyl) phenyl
1421 S02CH3 3-pyridyl 2- (N-methoxy-N-methylamino- me hyl) phenyl
1422 S02CH3 3-pyridyl 2- (N-pyridonyl-methyl ) phenyl
1423 S02CH3 3-pyridyl 2- (N- (N' ,N' -dimethylhydrazinyl- methyl)phenyl
1424 S0CH3 3-pyridyl 2- (amidinyl) phenyl
1425 S02CH3 3-pyridyl 2- (N-guanidinyl) phenyl
1426 S02CH3 3-pyridyl 2- (imidazolyl) phenyl
1427 S02CH3 3-pyridyl 2- (imidazolidinyl)phenyl
1428 S02CH3 3-pyridyl 2- (2-imidazolidinyl- sulfonyl ) phenyl
1429 S02CH3 3-pyridyl 2- (2-pyrrolidinyl) phenyl
1430 S02CH3 3-pyridyl 2- (2-piperidinyl)phenyl
1431 S02CH3 3-pyridyl 2- (amidinyl-methyl ) phenyl
1432 S02CH3 3-pyridyl 2- (2-imidazolidinyl- methyl) phenyl
1433 S0CH3 3-pyridyl 2- (N- (2-aminoimidazolyl) - methyl) phenyl
1434 S02CH3 3-pyridyl 2-dimethylaminoimidazol-1-yl
1435 S02CH3 3-pyridyl 2-(3 -aminophenyl )
1436 S02CH3 3-pyridyl 2-( 3 -pyrrolidinylcarbonyl )
1437 S02CH3 3-pyridyl 2-gglycinoyl
1438 S02CH3 3-pyridyl 2-( imidazol-1-ylacetyl)
1439 S0CH3 2-pyrimidyl 2-0N-pyrrolidinyl-methyl ) phenyl
1440 S02CH3 2-pyrimidyl 2-0N-piperidinyl-methyl ) phenyl
1441 S02CH3 2-pyrimidyl 2-0N-mcrpholino-methyl ) phenyl
1442 S02CH3 2-pyrimidyl 2-0N,N' -methylmorpholinium- methyl ) phenyl
1443 S02CH3 2-pyrimidyl 2-0N-pyridinium-methyl ) phenyl
1444 S02CH3 2-pyrimidyl 2-0N-4- (N,N' -dimethylamino) - pyridinium-methyl ) phenyl
1445 S02CH3 2-pyrimidyl 2-(lN-azatanyl-methyl) phenyl
1446 S02CH3 2-pyrimidyl 2-(N-azetidinyl-methyl) phenyl
1447 S02CH3 2-pyrimidyl 2-(N-piperazinyl-methyl ) phenyl
1448 S0CH3 2-pyrimidyl 2-(N,N' -BOC-piperazinyl- methyl ) phenyl
1449 S02CH3 2-pyrimidyl 2-(N-imidazolyl-methyl ) phenyl
1450 S0CH3 2-pyrimidyl 2-(N-methoxy-N-methylamino- methyl ) phenyl
1451 S02CH3 2-pyrimidyl 2-(N-pyridonyl-methyl ) phenyl
1452 S02CH3 2-pyrimidyl 2-(N- (N ' , N ' -dimethylhydrazinyl- methyl ) phenyl
1453 S02CH3 2-pyrimidyl 2-(amidinyl ) phenyl
1454 S02CH3 2-pyrimidyl 2- (N-guanidinyl ) phenyl
1455 S02CH3 2-pyrimidyl 2-( imidazolyl ) phenyl
1456 S02CH3 2-pyrimidyl 2-( imidazolidinyl ) phenyl
1457 S02CH3 2-pyrimidyl 2-(2 -imidazolidinyl- sulfonyl ) phenyl
1458 S02CH3 2-pyrimidyl 2-(2-pyrrolidinyl ) phenyl
1459 S02CH3 2-pyrimidyl 2-(2-piperidinyl ) phenyl
1460 S02CH3 2-pyrimidyl 2-(amidinyl-methyl ) phenyl
1461 S0CH3 2-pyrimidyl 2-(2-imidazolidinyl- methyl ) phenyl
1462 S02CH3 2-pyrimidyl 2-(N- (2-aminoimidazolyl) - methyl ) phenyl
1463 S02CH3 2-pyrimidyl 2-ddimethylaminoimidazol-1-yl
1464 S02CH3 2-pyrimidyl 2 - ( 3 -aminophenyl )
1465 S02CH3 2-pyrimidyl 2-(3 -pyrrolidinylcarbonyl)
1466 S0CH3 2-pyrimidyl 2-gglycinoyl
1467 S02CH3 2-pyrimidyl 2-( imidazol-1-ylacetyl)
1468 S02CH3 2-Cl-phenyl 2-(N-pyrrolidinyl-methyl ) phenyl
1469 S02CH3 2-Cl-phenyl 2-(N-piperidinyl-methyl ) phenyl
1470 S0CH3 2-Cl-phenyl 2-(N-morpholino-methyl ) phenyl
1471 S02CH3 2-Cl-phenyl 2-(N, N ' -methylmorpholinium- methyl ) phenyl
1472 S02CH3 2-Cl-phenyl 2-(N-pyridinium-methyl ) phenyl
1473 S02CH3 2-Cl-phenyl 2-(N-4- (N,N' -dimethylamino) - pyridinium-methyl ) phenyl
1474 S02CH3 2-Cl-phenyl 2-(N-azatanyl-methyl ) phenyl
1475 S02CH3 2-Cl-phenyl 2-(N-azetidinyl-methyl ) phenyl
1476 S02CH3 2-Cl-phenyl 2-(N-piperazinyl-methyl ) phenyl
1477 S02CH3 2-Cl-phenyl 2-(N,N' -BOC-piperazinyl-
methyl ) henyl
1478 S02CH3 2-Cl-phenyl 2- (N-imidazolyl-methyl) phenyl
1479 S0 CH3 2-Cl-phenyl 2- (N-methoxy-N-methylamino- methyl ) phenyl
1480 S02CH3 2-Cl-phenyl 2- (N-pyridonyl-methyl ) phenyl
1481 S02CH3 2-Cl-phenyl 2-(N-(N' ^'-dimethylhydrazinyl- methyl ) phenyl
1482 S02CH3 2-Cl-phenyl 2- (amidinyl ) phenyl
1483 S02CH3 2-Cl-phenyl 2- (N-guanidinyl ) phenyl
1484 S02CH3 2-Cl-phenyl 2- (imidazolyl) henyl
1485 Sθ2CH3 2-Cl-phenyl 2- (imidazolidinyl) phenyl
1486 S02CH3 2-Cl-phenyl 2- (2-imidazolidinyl- sulfonyl ) phenyl
1487 S02CH3 2-Cl-phenyl 2- (2-pyrrolidinyl) phenyl
1488 S02CH3 2-Cl-phenyl 2- ( 2-piperidinyl) phenyl
1489 S02CH3 2-Cl-phenyl 2- (amidinyl-methyl) phenyl
1490 S02CH3 2-Cl-phenyl 2- (2-imidazolidinyl- methyl) phenyl
1491 S02CH3 2-Cl-phenyl N- (2-aminoimidazolyl) - methyl ) phenyl
1492 S02CH3 2-Cl-phenyl 2-dimethylaminoimidazol-l-yl 1493 S02CH3 2-Cl-phenyl 2- (3 -aminophenyl ) 1494 S02CH3 2-Cl-phenyl 2- (3 -pyrrolidinylcarbonyl) 1495 S02CH3 2-Cl-phenyl 2-glycinoyl 1496 S02CH3 2-Cl-phenyl 2- imidazol-1-ylacetyl ) 1497 S0CH3 2-F-phenyl 2- N-pyrrolidinyl-methyl ) phenyl 1498 Sθ2CH3 2-F-phenyl 2- N-piperidinyl-methyl) henyl 1499 S02CH3 2-F-phenyl 2- N-morpholino-methyl) phenyl 1500 S02CH3 2-F-phenyl 2- N, N ' -methylmorpholinium- methyl) phenyl
1501 S02CH3 2-F-phenyl 2- N-pyridinium-methyl ) phenyl 1502 S02CH3 2-F-phenyl 2- N-4- (N,N' -dimethylamino) - pyridinium-methyl ) phenyl
1503 S02CH3 2-F-phenyl 2- N-azatanyl-methyl) phenyl 1504 S02CH3 2-F-phenyl 2- N-azetidinyl-methyl) phenyl 1505 S02CH3 2-F-phenyl 2- N-piperazinyl-methyl ) phenyl 1506 S02CH3 2-F-phenyl 2- N,N' -BOC-piperazinyl- methyl) phenyl
1507 S02CH3 2-F-phenyl 2- N-imidazolyl-methyl) phenyl 1508 S02CH3 2-F-phenyl 2- N-methoxy-N-methylamino- methyl) phenyl
1509 S02CH3 2-F-phenyl 2- N-pyridonyl-methyl ) phenyl
1510 S02CH3 2-F-phenyl 2- N- (N' , N ' -dimethylhydrazinyl- methyl) phenyl
1511 S02CH3 2-F-phenyl 2- amidinyl) phenyl 1512 S02CH3 2-F-phenyl 2- N-guanidinyl ) phenyl 1513 Sθ2CH3 2-F-phenyl 2- imidazolyl)phenyl 1514 Sθ2CH3 2-F-phenyl 2- imidazolidinyl) phenyl 1515 S02CH3 2-F-phenyl 2- 2-imidazolidinyl- sulfonyl ) phenyl
1516 S02CH3 2-F-phenyl 2- 2-pyrrolidinyl) phenyl 1517 Sθ2CH3 2-F-phenyl 2- 2-piperidinyl ) phenyl 1518 S02CH3 2-F-phenyl 2- amidinyl-methyl ) phenyl
1519 S02CH3 2-F-phenyl - (2-imidazolidinyl- methyl ) phenyl 1520 S02CH3 2-F-phenyl - (N- (2-aminoimidazolyl) - methyl ) phenyl
1521 S02CH3 2-F-phenyl -dimethylaminoimidazol-1-yl 1522 S02CH3 2-F-phenyl - ( 3 -aminophenyl ) 1523 S02CH3 2-F-phenyl - ( 3 -pyrrolidinylcarbonyl ) 1524 S02CH3 2-F-phenyl -glycinoyl 1525 S02CH3 2-F-phenyl ( imidazol-1-ylacetyl) 1526 S02CH3 2, 5-diF-phenyl (N-pyrrolidinyl-methyl ) phenyl 1527 S02CH3 5-diF-phenyl (N-piperidinyl-methyl) phenyl 1528 S02CH3 5-diF-phenyl (N-morpholino-methyl) phenyl 1529 S02CH3 5-diF-phenyl (N, N ' -methylmorpholinium- methyl ) phenyl 1530 S02CH3 5-diF-phenyl (N-pyridinium-methyl) phenyl 1531 S02CH3 5-diF-phenyl (N-4- (N,N' -dimethylamino) - pyridinium-methyl) phenyl
1532 S02CH3 5-diF-phenyl (N-azatanyl-methyl) phenyl
1533 S02CH3 5-diF-phenyl (N-azetidinyl-methyl) phenyl
1534 Sθ2CH3 5-diF-phenyl (N-piperazinyl-methyl) phenyl 1535 S02CH3 5-diF-phenyl (N,N' -BOC-piperazinyl- methyl ) phenyl
1536 S02CH3 5-diF-phenyl (N-imidazolyl-methyl ) phenyl
1537 S02CH3 5-diF-phenyl (N-methoxy-N-methylamino- methyl ) phenyl
1538 S0CH3 5-diF-phenyl (N-pyridonyl-methyl ) phenyl
1539 S02CH3 5-diF-phenyl (N- (N' ,N' -dimethylhydrazinyl- methyl ) phenyl
1540 S02CH3 5-diF-phenyl (amidinyl ) phenyl 1541 S02CH3 5-diF-phenyl (N-guanidinyl) phenyl 1542 S02CH3 5-diF-phenyl ( imidazolyl ) phenyl 1543 S02CH3 5-diF-phenyl ( imidazolidinyl) phenyl 1544 S02CH3 5-diF-phenyl (2-imidazolidinyl- sulfonyl ) phenyl
1545 S02CH3 5-diF-phenyl (2-pyrrolidinyl) phenyl 1546 S02CH3 5-diF-phenyl (2-piperidinyl) phenyl 1547 S02CH3 5-diF-phenyl (amidinyl-methyl ) phenyl 1548 S02CH3 5-diF-phenyl (2-imidazolidinyl- methyl) phenyl 1549 S02CH3 5-diF-phenyl 2- N- (2-aminoimidazolyl) - methyl) phenyl
1550 S02CH3 5-diF-phenyl 2-dimethylaminoimidazol-1-yl 1551 S02CH3 5-diF--phenyl 2- (3-aminophenyl ) 1552 S02CH3 5-diF-•phenyl 2- ( 3 -pyrrolidinylcarbonyl ) 1553 S02CH3 5-diF--phenyl 2-glycinoyl 1554 S02CH3 5-diF-•phenyl 2- imidazol-1-ylacetyl) 1555 NHS02CH3 phenyl 2- aminosulfonyl) phenyl 1556 NHS02CH3 phenyl 2- methylaminosulfonyl) phenyl 1557 NHS02CH3 phenyl -pyrrolidinocarbonyl 1558 NHS02CH3 phenyl 2- methylsulfonyl) phenyl 1559 NHS02CH3 phenyl 4-morpholino 1560 NHS02CH3 phenyl 2- 1 ' -CF3 -tetrazol-2 -yD phenyl 1561 NHS0CH3 phenyl 4-morpholinocarbonyl
1562 NHS02CH3 2-pyridyl 2- (aminosulfonyl) phenyl
1563 NHS02CH3 2-pyridyl 2- (methylaminosulfonyl) phenyl
1564 NHS02CH3 2-pyridyl 1-pyrro1idinocarbonyl
1565 NHS02CH3 2-pyridyl 2- (methylsulfonyl) phenyl
1566 NHS02CH3 2-pyridyl 4-morpholino
1567 NHS02CH3 2-pyridyl 2- ( 1 ' -CF3 -tetrazol-2-yl ) phenyl
1568 NHS02CH3 2-pyridyl 4-morpholinocarbonyl
1569 NHS02CH3 3-pyridyl 2- (aminosulfonyl ) phenyl
1570 NHS02CH3 3-pyridyl 2- (methylaminosulfonyl) phenyl
1571 NHS02CH3 3-pyridyl 1-pyrrolidinocarbonyl
1572 NHS02CH3 3 -pyridyl 2- (methylsulfonyl) phenyl
1573 NHS02CH3 3-pyridyl 4-morpholino
1574 NHS02CH3 3 -pyridyl 2- ( 1 ' -CF3 -tetrazol-2-yl) phenyl
1575 NHS02CH3 3-pyridyl 4-morpholinocarbonyl
1576 NHS02CH3 2-pyrimidyl 2- (aminosulfonyl) phenyl
1577 NHS0CH3 2-pyrimidyl 2- (methylaminosulfonyl) phenyl
1578 NHS02CH3 2-pyrimidyl 1-pyrrolidinocarbonyl
1579 NHS02CH3 2-pyrimidyl 2- (methylsulfonyl) phenyl
1580 NHS02CH3 2-pyrimidyl 4-morpholino
1581 NHS02CH3 2-pyrimidyl 2- ( 1 ' -CF3 -tetrazol-2 -yD phenyl
1582 NHS02CH3 2-pyrimidyl 4-morpholinocarbonyl
1583 NHS02CH3 5-pyrimidyl 2- (aminosulfonyl) phenyl
1584 NHS02CH3 5-pyrimidyl 2- (methylaminosulfonyl) phenyl
1585 NHS02CH3 5-pyrimidyl 1-pyrrolidinocarbonyl
1586 NHS02CH3 5-pyrimidyl 2- (methylsulfonyl) phenyl
1587 NHS02CH3 5-pyrimidyl 4-morpholino
1588 NHS02CH3 5-pyrimidyl 2- ( 1 ' -CF3 -tetrazol-2-yl) phenyl
1589 NHS0CH3 5-pyrimidyl 4-morpholinocarbonyl
1590 NHS02CH3 2-Cl-phenyl 2- (aminosulfonyl ) phenyl
1591 NHS02CH3 2-Cl-phenyl 2- (methylaminosulfonyl) phenyl
1592 NHS02CH3 2-Cl-phenyl 1-pyrro1idinocarbonyl
1593 NHS02CH3 2-Cl-phenyl 2- (methylsulfonyl) phenyl
1594 NHS02CH3 2-Cl-phenyl 4-morpholino
1595 NHS02CH3 2-Cl-phenyl 2- ( 1 ' -CF3 -tetrazol-2-yl ) phenyl
1596 NHS02CH3 2-Cl-phenyl 4-morpholinocarbonyl
1597 NHS02CH3 2-F-phenyl 2- (aminosulfonyl) phenyl
1598 NHS02CH3 2-F-phenyl 2- (methylaminosulfonyl) henyl
1599 NHS02CH3 2-F-phenyl 1-pyrrolidinocarbonyl
1600 NHS02CH3 2-F-phenyl 2- (me hylsulfonyl) phenyl
1601 NHS02CH3 2-F-phenyl 4-morpholino
1602 NHS02CH3 2-F-phenyl 2- (l'-CF3-tetrazol-2-yl) phenyl
1603 NHS02CH3 2-F-phenyl 4-morpholinocarbonyl
1604 NHS02CH3 2, 5-diF-phenyl 2- (aminosulfonyl) phenyl
1605 NHS02CH3 2,5-diF-phenyl 2- (methylaminosulfonyl) phenyl
1606 NHS02CH3 2,5-diF-phenyl 1-pyrro1idinocarbony1
1607 NHS02CH3 2, 5-diF-phenyl 2- (methylsulfonyl) phenyl
1608 NHS02CH3 2, 5-diF-phenyl 4-morpholino
1609 NHS02CH3 2,5-diF-phenyl 2-(l'-CF3-tetrazol-2-yl)phenyl
1610 NHS02CH3 2, 5-diF-phenyl 4-morpholinocarbonyl
1611 NHS02CH3 phenyl 2- (N-pyrrolidinyl-methyl) phenyl
1612 NHS02CH3 phenyl 2- (N-piperidinyl-methyl ) phenyl
1613 NHS02CH3 phenyl 2- (N-morpholino-methyl) phenyl
1614 NHS02CH3 phenyl 2- (N,N' -methylmorpholinium- methyl) phenyl
1615 NHS02CH3 phenyl 2- (N-pyridinium-methyl ) phenyl
1616 NHS02CH3 phenyl 2- (N-4- (N,N' -dimethylamino) - pyridinium-methyl ) phenyl
1617 NHS02CH3 phenyl 2- (N-azatanyl-methyl) phenyl
1618 NHS02CH3 phenyl 2- (N-azetidinyl-methyl) phenyl
1619 NHS02CH3 phenyl 2- (N-piperazinyl-methyl) pnenyl
1620 NHS02CH3 phenyl 2-(N,N' -BOC-piperazinyl- methyl ) phenyl
1621 NHS02CH3 phenyl 2- (N-imidazolyl-methyl) phenyl
1622 NHS0CH3 phenyl 2- (N-methoxy-N-methylamino- methyl) phenyl
1623 NHS02CH3 phenyl 2- (N-pyridonyl-methyl ) phenyl
1624 NHS02CH3 phenyl 2-(N-(N' ^'-dimethylhydrazinyl- methyl) phenyl
1625 NHS02CH3 phenyl 2- (amidinyl ) phenyl
1626 NHS02CH3 phenyl 2- (N-guanidinyl) phenyl
1627 NHS02CH3 phenyl 2- ( imidazolyl ) phenyl
1628 NHS02CH3 phenyl 2- ( imidazolidinyl ) phenyl
1629 NHS02CH3 phenyl 2- (2-imidazolidinyl- sulfonyl ) phenyl
1630 NHS02CH3 phenyl 2- (2-pyrrolidinyl) phenyl
1631 NHS02CH3 phenyl 2- (2-piperidinyl ) phenyl
1632 NHS02CH3 phenyl 2- (amidinyl-methy ) phenyl
1633 NHS02CH3 phenyl 2- (2-imidazolidinyl- methyl) phenyl
1634 NHS02CH3 phenyl N- (2-aminoimidazolyl) - methyl ) phenyl
1635 NHS02CH3 phenyl 2-dimethylaminoimidazol-1-yl
1636 NHS02CH3 phenyl 2- (3 -aminophenyl )
1637 NHS02CH3 phenyl 2- ( 3-pyrrolidinylcarbonyl )
1638 NHS02CH3 phenyl 2-glycinoyl
1639 NHS02CH3 phenyl 2- imidazol-1-ylacetyl)
1640 NHS02CH3 2-pyridyl 2- N-pyrrolidinyl-methyl) phenyl
1641 NHS02CH3 2-pyridyl 2- N-piperidinyl-methyl) phenyl
1642 NHS02CH3 2-pyridyl 2- N-morpholino-methyl ) phenyl
1643 NHS02CH3 2-pyridyl 2- N,N' -methylmorpholinium- methyl) phenyl
1644 NHS02CH3 2-pyridyl 2- N-pyridinium-methyl) phenyl
1645 NHS02CH3 2-pyridyl 2- N-4- (N,N' -dimethylamino) - pyridinium-methyl) phenyl
1646 NHS02CH3 2-pyridyl 2- N-azatanyl-methyl ) phenyl
1647 NHS0CH3 2-pyridyl 2- N-azetidinyl-methyl) phenyl
1648 NHS02CH3 2-pyridyl 2- N-piperazinyl-methyl) phenyl
1649 NHS02CH3 2-pyridyl 2- N,N' -BOC-piperazinyl- methyl) phenyl
1650 NHS02CH3 2-pyridyl 2- N-imidazolyl-methyl) phenyl
1651 NHSO2CH3 2-pyridyl 2- N-methoxy-N-methylamino- methyl) phenyl
1652 NHS02CH3 2-pyridyl 2- N-pyridonyl-methyl ) phenyl
1653 NHS02CH3 2-pyridyl 2- N- (N ' , N ' -dimethylhydrazinyl- methyl) phenyl
1654 NHS0CH3 2-pyridyl 2- (amidinyl) phenyl
1655 NHS0CH3 2-pyridyl 2- (N-guanidinyl) phenyl
1656 NHS02CH3 2-pyridyl 2- ( imidazolyl ) phenyl
1657 NHS02CH3 2-pyridyl 2- (imidazolidinyl) phenyl
1658 NHS02CH3 2-pyridyl 2- (2-imidazolidinyl- sulfonyl ) phenyl
1659 NHS02CH3 2-pyridyl 2- (2-pyrrolidinyl) phenyl
1660 NHS02CH3 2-pyridyl 2- (2-piperidinyl ) phenyl
1661 NHS02CH3 2-pyridyl 2- (amidinyl-methyl) phenyl
1662 NHS02CH3 2-pyridyl 2- (2-imidazolidinyl- methyl ) phenyl
1663 NHS02CH3 2-pyridyl 2- (N- (2-aminoimidazolyl) - methyl ) phenyl
1664 NHS02CH3 2-pyridyl 2-dimethylaminoimidazol-l-yl
1665 NHS02CH3 2-pyridyl 2- (3 -aminophenyl )
1666 NHS02CH3 2-pyridyl 2- (3-pyrrolidinylcarbonyl)
1667 NHS02CH3 2-pyridyl 2-glycinoyl
1668 NHS02CH3 2-pyridyl 2- (imidazol-1-ylacetyl)
1669 NHS0 CH3 3 -pyridyl 2- (N-pyrrolidinyl-methyl) phenyl
1670 NHS02CH3 3 -pyridyl 2- (N-piperidinyl-methyl) phenyl
1671 NHS02CH3 3-pyridyl 2- (N-morpholino-methyl) phenyl
1672 NHS02CH3 3-pyridyl 2- (N,N' -methylmorpholinium- methyl) phenyl
1673 NHS02CH3 3-pyridyl 2- (N-pyridinium-methyl) phenyl
1674 NHS02CH3 3 -pyridyl 2- (N-4- (N,N' -dimethylamino) - pyridinium-methyl ) phenyl
1675 NHS02CH3 3-pyridyl 2- (N-azatanyl-methyl) phenyl
1676 NHS02CH3 3-pyridyl 2- (N-azetidinyl-methyl) phenyl
1677 NHS02CH3 3-pyridyl 2- (N-piperazinyl-methyl) phenyl
1678 NHS0CH3 3-pyridyl 2- (N,N' -BOC-piperazinyl- methyl) phenyl
1679 NHS02CH3 3-pyridyl 2- (N-imidazolyl-methyl) phenyl
1680 NHS02CH3 3-pyridyl 2- (N-methoxy-N-methylamino- methyl) phenyl
1681 NHS02CH3 3-pyridyl 2- (N-pyridonyl-methyl ) phenyl
1682 NHS02CH3 3-pyridyl 2- (N- (N' ,N' -dimethylhydrazinyl- methyl) phenyl
1683 NHS02CH3 3-pyridyl 2- (amidinyl ) phenyl
1684 NHS02CH3 3-pyridyl 2- (N-guanidinyl ) phenyl
1685 NHS02CH3 3-pyridyl 2- (imidazolyl) phenyl
1686 NHS02CH3 3-pyridyl 2- ( imidazolidinyl) phenyl
1687 NHS02CH3 3-pyridyl 2- (2-imidazolidinyl- sulfonyl ) phenyl
1688 NHS02CH3 3-pyridyl 2- (2-pyrrolidinyl) phenyl
1689 NHS02CH3 3-pyridyl 2- (2-piperidinyl ) phenyl
1690 NHS02CH3 3-pyridyl 2- (amidinyl-methyl ) phenyl
1691 NHS02CH3 3-pyridyl 2- (2-imidazolidinyl- methyl)phenyl
1692 NHS02CH3 3-pyridyl 2- (N- (2-aminoimidazolyl) - methyl) phenyl
1693 NHS02CH3 3-pyridyl 2-dimethylaminoimidazol-l-yl
1694 NHS02CH3 3-pyridyl 2- (3-aminophenyl )
1695 NHS02CH3 3-pyridyl 2- (3 -pyrrolidinylcarbonyl)
1696 NHS02CH3 3-pyridyl 2-glycinoyl 1697 NHS02CH3 3-pyridyl 2- (imidazol-1-ylacetyl) 1698 NHS02CH3 2-pyrimidyl 2- (N-pyrrolidinyl-methyl) phenyl 1699 NHS02CH3 2-pyrimidyl 2- (N-piperidinyl-methyl) phenyl 1700 NHS02CH3 2-pyrimidyl 2- (N-morpholino-methyl) phenyl 1701 NHS02CH3 2-pyrimidyl 2- (N,N' -methylmorpholinium- ethyl ) phenyl
1702 NHS02CH3 2-pyrimidyl 2- (N-pyridinium-methyl) phenyl 1703 NHS02CH3 2-pyrimidyl 2- (N-4- (N,N* -dimethylamino) - pyridinium-methyl) phenyl
1704 NHS02CH3 2-pyrimidyl 2- (N-azatanyl-methyl) phenyl 1705 NHS02CH3 2-pyrimidyl 2- (N-azetidinyl-methyl) phenyl 1706 NHS02CH3 2-pyrimidyl 2- (N-piperazinyl-methyl) henyl 1707 NHS02CH3 2-pyrimidyl 2- (N,N' -BOC-piperazinyl- methyl) phenyl
1708 NHS02CH3 2-pyrimidyl 2- (N-imidazolyl-methyl) phenyl 1709 NHS02CH3 2-pyrimidyl 2- (N-methoxy-N-methylamino- methyl) phenyl
1710 NHS02CH3 2-pyrimidyl 2- (N-pyridonyl-methyl ) phenyl 1711 NHS02CH3 2-pyrimidyl 2- (N- (N' ,N' -dimethylhydrazinyl- methyl ) phenyl
1712 NHS02CH3 2-pyrimidyl 2- (amidinyl ) phenyl 1713 NHS02CH3 2-pyrimidyl 2- (N-guanidinyl ) phenyl 1714 NHS02CH3 2-pyrimidyl 2- ( imidazolyl ) phenyl 1715 NHS02CH3 2-pyrimidyl 2- (imidazolidinyl) phenyl 1716 NHS02CH3 2-pyrimidyl 2- (2-imidazolidinyl- sulfonyl ) phenyl
1717 NHS0CH3 2-pyrimidyl 2- (2-pyrrolidinyl) phenyl 1718 NHS02CH3 2-pyrimidyl 2- ( 2-piperidinyl) phenyl 1719 NHS0 CH3 2-pyrimidyl 2- (amidinyl-methyl ) phenyl 1720 NHS02CH3 2-pyrimidyl 2- (2-imidazolidinyl- methyl ) phenyl
1721 NHS0 CH3 2-pyrimidyl 2- (N- (2-aminoimidazolyl) - methyl ) phenyl
1722 NHS02CH3 2-pyrimidyl 2-dimethylaminoimidazol-l-yl 1723 NHS02CH3 2-pyrimidyl 2- (3 -aminophenyl ) 1724 NHS0 CH3 2-pyrimidyl 2- (3 -pyrrolidinylcarbonyl) 1725 NHS02CH3 2-pyrimidyl 2-glycinoyl 1726 NHS02CH3 2-pyrimidyl 2- (imidazol-1-ylacetyl) 1727 NHS02CH3 2-Cl-phenyl 2- (N-pyrrolidinyl-methyl) phenyl 1728 NHS0 CH3 2-Cl-phenyl 2- (N-piperidinyl-methyl) phenyl 1729 NHS02CH3 2-Cl-phenyl 2- (N-morpholino-methyl) phenyl 1730 NHS0 CH3 2-Cl-phenyl 2- (N,N' -methylmorpholinium- methyl) phenyl
1731 NHS0CH3 2-Cl-phenyl 2- (N-pyridinium-methyl) phenyl 1732 NHS02CH3 2-Cl-phenyl 2- (N-4- (N,N' -dimethylamino) - pyridinium-methyl) phenyl
1733 NHS02CH3 2-Cl-phenyl 2- (N-azatanyl-methyl) phenyl 1734 NHS02CH3 2-Cl-phenyl 2- (N-azetidinyl-methyl) phenyl 1735 NHS02CH3 2-Cl-phenyl 2- (N-piperazinyl-methyl) phenyl 1736 NHS02CH3 2-Cl-phenyl 2-(N,N' -BOC-piperazinyl- methyl) phenyl
1737 NHS02CH3 2-Cl-phenyl 2- (N-imidazolyl-methyl) phenyl
1738 NHSO2CH3 2-Cl-phenyl 2- (N-methoxy-N-methylamino- methyl ) phenyl
1739 NHS02CH3 2-Cl-phenyl 2- (N-pyridonyl-methyl ) phenyl 1740 NHS02CH3 2-Cl-phenyl 2- (N- (N' ,N' -dimethylhydrazinyl- methyl ) phenyl
1741 NHS02CH3 2-Cl-phenyl 2- (amidinyl ) phenyl 1742 NHS02CH3 2-Cl-phenyl 2- (N-guanidinyl ) henyl 1743 NHS02CH3 2-Cl-phenyl 2- ( imidazolyl ) phen 1 1744 NHS0CH3 2-Cl-phenyl 2- (imidazolidinyl) phenyl 1745 NHS02CH3 2-Cl-phenyl 2- (2-imidazolidinyl- sulfonyl ) phenyl
1746 NHS02CH3 2-Cl-phenyl 2- (2-pyrrolidinyl) phenyl 1747 NHS02CH3 2-Cl-phenyl 2- ( 2-piperidinyl) phenyl 1748 NHS02CH3 2-Cl-phenyl 2- (amidinyl-methyl ) phenyl 1749 NHS02CH3 2-Cl-phenyl 2- (2-imidazolidinyl- methyl ) phenyl
1750 NHS02CH3 2-Cl-phenyl 2- (N- (2-aminoimidazolyl) - methyl) phenyl
1751 NHS02CH3 2-Cl-phenyl 2-dimethylaminoimidazol-l-yl 1752 NHS02CH3 2-Cl-phenyl 2- ( 3-aminophenyl ) 1753 NHS02CH 2-Cl-phenyl 2- (3 -pyrrolidinylcarbonyl) 1754 NHS02CH3 2-Cl-phenyl 2-glycinoyl 1755 NHS02CH3 2-Cl-phenyl 2- imidazol-1-ylacetyl) 1756 NHS02CH3 2-F-phenyl 2- N-pyrrolidinyl-methyl ) phenyl 1757 NHS02CH3 2-F-phenyl 2- N-piperidinyl-methyl ) phenyl 1758 NHS02CH3 2-F-phenyl 2- N-morpholino-methyl ) phenyl 1759 NHS0 CH3 2-F-phenyl 2- N,N' -methylmorpholinium- methyl) phenyl
1760 NHS02CH3 2-F-phenyl 2- N-pyridinium-methyl) phenyl 1761 NHS02CH3 2-F-phenyl 2- N-4- (N,N' -dimethylamino) - pyridinium-methyl) phenyl
1762 NHS02CH3 2-F-phenyl 2- N-azatanyl-methyl ) phenyl 1763 NHS02CH3 2-F-phenyl 2- N-azetidinyl-methyl) phenyl 1764 NHS02CH3 2-F-phenyl 2- N-piperazinyl-methyl) phenyl 1765 NHS0 CH3 2-F-phenyl 2- N,N' -BOC-piperazinyl- methyl) phenyl
1766 NHS02CH3 2-F-phenyl 2- N-imidazolyl-methyl) phenyl 1767 NHS02CH3 2-F-phenyl 2- N-methoxy-N-methylamino- methyl) phenyl
1768 NHS02CH3 2-F-phenyl 2- N-pyridonyl-methyl ) phenyl 1769 NHS02CH3 2-F-phenyl 2- N- (N ' , N ' -dimethylhydrazinyl- methyl) phenyl
1770 NHS02CH3 2-F-phenyl 2- amidinyl ) phenyl 1771 NHS02CH3 2-F-phenyl 2- N-guanidinyl ) phenyl 1772 NHS02CH3 2-F-phenyl 2- imidazolyl) phenyl 1773 NHS02CH3 2-F-phenyl 2- imidazolidinyl) phenyl 1774 NHS02CH3 2-F-phenyl 2- 2-imidazolidinyl- sulfonyl ) phenyl
1775 NHS02CH3 2-F-phenyl 2- 2-pyrrolidinyl) phenyl 1776 NHS02CH3 2-F-phenyl 2- 2-piperidinyl) phenyl 1777 NHS02CH3 2-F-phenyl 2- amidinyl-methyl ) phenyl 1778 NHS02CH3 2-F-phenyl 2- 2-imidazolidinyl- methyl) phenyl
1779 NHS02CH3 2-F-phenyl 2- (N- (2-aminoimidazolyl) - methyl ) phenyl
1780 NHS0CH3 2-F-phenyl 2-dimethylaminoimidazol-l-yl 1781 NHS02CH3 2-F-phenyl (3 -aminophenyl ) 1782 NHS0 CH3 2-F-phenyl - (3-pyrrolidinylcarbonyl) 1783 NHS02CH3 2-F-phenyl -glycinoyl 1784 HHSO2CH3 2-F-phenyl - (imidazol-i-ylacetyl) 1785 NHSO2CH3 2 , 5-diF-phenyl - (N-pyrrolidinyl-methyl ) phenyl 1786 NHS02CH 2 , 5-diF-phenyl (N-piperidinyl-methyl) phenyl 1787 NHS02CH3 2 , 5-diF-phenyl (N-morpholino-methyl ) phenyl 1788 NHS02CH3 2, 5-diF-phenyl (N, N ' -methylmorpholinium- methyl ) phenyl
1789 NHS02CH3 5-diF-phenyl (N-pyridinium-methyl ) phenyl 1790 NHS02CH3 5-diF-phenyl (N-4- (N,N' -dimethylamino) - pyridinium-methyl) phenyl
1791 NHS02CH3 5-diF-phenyl (N-azatanyl-methyl) phenyl 1792 NHS0CH3 5-diF-phenyl (N-azetidinyl-methyl)phenyl 1793 NHS02CH3 5-diF-phenyl (N-piperazinyl-methyl) phenyl 1794 NHS02CH3 5-diF-phenyl (N,N' -BOC-piperazinyl- methyl ) phenyl
1795 NHS02CH3 5-diF-phenyl (N-imidazolyl-methyl) phenyl 1796 NHS02CH3 5-diF-phenyl (N-methoxy-N-methylamino- methyl) phenyl
1797 NHS0 CH3 5-diF-phenyl (N-pyridonyl-methyl ) phenyl 1798 NHS02CH3 5-diF-phenyl (N- (N ' , N ' -dimethylhydrazinyl- methyl ) phenyl
1799 NHS02CH3 5-diF-phenyl (amidinyl) phenyl 1800 NHS02CH3 5-diF-phenyl (N-guanidinyl ) phenyl 1801 NHS02CH3 5-diF-phenyl ( imidazolyl ) henyl 1802 NHS02CH3 5-diF-phenyl ( imidazolidinyl) phenyl 1803 NHS02CH3 5-diF-phenyl (2-imidazolidinyl- sulfonyl ) phenyl
1804 NHS02CH3 5-diF-phenyl (2-pyrrolidinyl) phenyl 1805 NHS02CH3 5-diF-phenyl (2-piperidinyl ) phenyl 1806 NHS02CH3 5-diF-phenyl (amidinyl-methyl ) phenyl 1807 NHS02CH3 5-diF-phenyl (2-imidazolidinyl- methyl) phenyl
1808 NHS02CH3 2 5-diF-phenyl 2 (N- (2-aminoimidazolyl) - methyl) phenyl
1809 NHS0 CH3 5-diF-phenyl 2-dimethylaminoimidazol-l-yl 1810 NHS02CH3 5-diF-phenyl 2- (3-aminophenyl) 1811 NHS02CH3 5-diF-phenyl 2- (3-pyrrolidinylcarbonyl) 1812 NHS02CH3 5-diF-phenyl 2-glycinoyl 1813 NHS02CH3 5-diF-phenyl 2- (imidazol-i-ylacetyl)
Table 3
J1 R=F, D=NH2 ki R=F, D=NH2 R=F, D=NH2 J2 R=H, D=NH2 k2 R=H, D=NH2 12 R=H, D=NH2 J3 R=F, D=CH2NH2 k3 R=F, D=CH NH2 13 R=F, D=CH2NH2 j R=H, D=CH2NH2 IC4 R=H, D=CH2NH2 14 R=H, D=CH2NH2 j5 R=F, D=C(=NH)NH2 k5 R=F, D=C(=NH)NH2 15 R=F, D=C(=NH)NH2 j6 R=H, D=C(=NH)NH2 ke R=H, D=C(=NH)NH2 16 R=H, D=C(=NH)NH2 j7 R=F, D=C(0)NH2 k7 R=F, D=C(0)NH2 17 R=F, D=C(0)NH2 J8 R=H, D=C(0)NH2 k8 R=H, D=C(Q)NH2 18 R=H, D=C(0)NH2
Pi R=F, D= NH2 qi R=F, D=NH2 1 R=F, D=NH2 p2 R=CI, D= NH2 q2 R=CI, D=NH2 2 R=CI, D=NH2 p3 R=OMe, D=NH2 q3 R=OMe, D=NH2 3 R=OMe, D=NH2 p4 R=F, D= CH2NH2 q4 R=F, D=CH2NH2 4 R=F, D=CH2NH2 p5 R=CI, D CH2NH2 q5 R=CI, D=CH2NH2 5 R=CI, D=CH2NH2 p6 R=OMe, D=CH2NH2 q6 R=0Me, D=CH2NH2 6 R=OMe, D=CH2NH2 p7 R=F, D= C(=NH)NH2 q7 R=F, D=C(=NH)NH2 7 R=F, D=C(=NH)NH2 p8 R=CI, D =C(=NH)NH2 q8 R=CI, D=C(=NH)NH2 8 R=CI, D=C(=NH)NH2 p9 R=OMe, D=C(=NH)NH2 q9 R=0Me, D=C(=NH)NH2 g R=OMe, D=C(=NH)NH2 P10 R=F, D =C(0)NH2 qio R=F, D=C(0)NH2 10 R=F, D=C(0)NH2 Pii R=CI, D: =C(0)NH2 qn R=CI, D=C(0)NH2 11 R=CI, D=C(0)NH2 Pi2 R=OMe , D=C(0)NH2 q1 R=0Me, D=C(0)NH2 ι2 R=OMe, D=C(0)NH2
Si R=F, D=NH2 ti R=F, D=NH2 uι R=F, D=NH2 s2 R=CI, D=NH2 t2 R=CI, D=NH2 u2 R=CI, D=NH2 s3 R=OMe, D=NH2 t3 R=OMe, D=NH2 u3 R=OMe, D=NH2 s4 R=F, D=CH2NH2 t4 R=F, D=CH2NH2 u4 R=F, D=CH2NH2 s5 R=CI, D=CH2NH2 t5 R=CI, D=CH2NH2 u5 R=CI, D=CH2NH2 s6 R=OMe, D=CH2NH2 t6 R=OMe, D=CH2NH2 u6 R=OMe, D=CH2NH2 s7 R=F, D=C(=NH)NH2 t7 R=F, D=C(=NH)NH2 u7 R=F, D=C(=NH)NH2 s8 R=CI, D=C(=NH)NH2 t8 R=CI, D=C(=NH)NH2 u8 R=CI, D=C(=NH)NH2 s9 R=OMe, D=C(=NH)NH2 t9 R=OMe, D=C(=NH)NH2 u9 R=OMe, D=C(=NH)NH2 Sιo R=F, D=C(0)NH2 tιo R=F, D=C(0)NH2 uιo R=F, D=C(0)NH2 SH R=CI, D=C(0)NH2 tn R=CI, D=C(0)NH2 uιι R=CI, D=C(0)NH2 s12 R=OMe, D=C(0)NH2 ti2 R=OMe, D=C(0)NH2 Ui2 R=OMe, D=C(0)NH2
Vi R=F, D=NH2 wι R=F, D=NH2 Xi R=F, D=NH2 v2 R=CI, D=NH2 w2 R=CI, D=NH2 2 R= Cl, D=NH2 v3 R=OMe, D=NH2 w3 R=OMe, D=NH2 X3 R= OMe, D=NH2 v4 R=F, D=CH2NH2 w4 R=F, D=CH2NH2 X4 R= F, D=CH2NH2 v5 R=CI, D=CH2NH2 w5 R=CI, D=CH2NH2 5 R= Cl, D=CH2NH2 v6 R=OMe, D=CH2NH2 w6 R=OMe, D=CH2NH2 β R= O< Me, D=CH2NH2 v7 R=F, D=C(=NH)NH2 w7 R=F, D=C(=NH)NH2 7 R= F, D=C(=NH)NH2 v8 R=CI, D=C(=NH)NH2 w8 R=CI, D=C(=NH)NH2 X8 R R==CI, D=C(=NH)NH2 v9 R=OMe, D=C(=NH)NH2 w9 R=OMe, D=C(=NH)NH2 xg
D=C(=NH)NH2 V10 R=F, D=C(0)NH2 Wιo R=F, D=C(0)NH2 χ10 C(0)NH2 ι ι R=CI, D=C(0)NH2 wι ι R=CI, D=C(0)NH2 Xi i R=CI, D=C(0)NH2 12 R=OMe, D=C(0)NH2 W12 R=OMe, D=C(0)NH2 xi 2 R=OMe, D=C(0)NH2
V4 R= F, D=CH2NH2 z4 R=F, D=CH2NH2 aa4 R=F, D=CH2NH2
Y5 R= C( l, D=CH2NH2 z5 R=CI, D=CH2NH2 aa5 R=CI, D=CH2NH2 y6 R= Oι Me, D=CH2NH2 z6 R=OMe, D=CH2NH2 aa6 R=OMe, D=CH2NH2 y7 R= F, D=C(=NH)NH2 z7 R=F, D=C(=NH)NH2 aa7 R=F, D=C(=NH)NH2 y8 R= Cι l, D=C(=NH)NH2 z8 R=CI, D=C(=NH)NH2 aa8 Rs-CI, D=C(=NH)NH2 y9 R= OMe, D=C(=NH)NH2 z9 R=OMe, D=C(=NH)NH2 aag R=OMe, D=C(=NH)NH2 Yιo R =F, D=C(0)NH2 Zιo R=F, D=C(0)NH2 aaio R=F, D=C(0)NH2 yn R Cl, D=C(0)NH2 zι ι R=CI, D=C(0)NH2 aai i R=CI, D=C(0)NH2 yi 2 R OMe, D=C(0)NH2 R=OMe, D=C(0)NH2 aai 2 R=0Me, D=C(Q)NH2
Ex# R"3 B
1 H phenyl 2 - ( (Me ) 2N-methyl ) phenyl
2 H phenyl 2 - ( (Me ) NH-methyl ) phenyl
3 H phenyl 2 - ( H2N-me thyl ) phenyl
4 H phenyl 2 -HOCH2 -phenyl
5 H 2-F-phenyl 2 - ( (Me ) 2N-methyl ) phenyl
6 H 2-F-phenyl 2 - ( (Me ) NH-methyl ) phenyl
7 H 2-F-phenyl 2- (H2N-methyl ) phenyl
8 H 2-F-phenyl 2 -HOCH2 -phenyl
9 H phenyl 2-methylimidazol-l-yl
10 H phenyl 2-ethylimidazol-l-yl
11 H phenyl 2- ( (Me) 2N-methyl ) imidazol-1-yl
12 H phenyl 2-CH3Sθ2-imidazol-l-yl
H phenyl 2-CH3OCH2-imidazol-l-yl
H 2-F-phenyl 2-methylimidazol-l-yl
H 2-F-phenyl 2-ethylimidazol-l-yl
H 2-F-phenyl 2- ( (Me) 2N-methyl) imidazol-1-yl
H 2-F-phenyl 2-CH3S02-imidazol-l-yl
H 2-F-phenyl 2-CH3OCH2-imidazol-l-yl
H 2-Cl-phenyl 2-methylimidazol-l-yl
H 2-Cl-phenyl 2-ethylimidazol-l-yl
H 2-Cl-phenyl 2- ( (Me) 2N-methyl) imidazol-1-yl
H 2-Cl-phenyl 2-CH3S0 -imidazol-l-yl
H 2-Cl-phenyl 2-CH3OCH2-imidazol-l-yl
H 2-(Me)2N-phenyl 2-methylimidazol-l-yl
H 2-(Me)2N-phenyl 2-ethylimidazol-l-yl
H 2- (Me) 2N-phenyl 2-( (Me)2N-methyl) imidazol-1-yl
H 2- (Me) 2N-phenyl 2 -CH3S02 -imidazol-l-yl
H 2- (Me) 2N-phenyl 2 -CH3OCH2-imidazol-l-yl
H phenyl N-methylimidazol-2 -yl
H phenyl 4 -methyl imidazol- 5 -yl
H phenyl 5-CF3-pyrazol-l-yl
H 2-F-phenyl N-methylimidazol-2-yl
H 2-F-phenyl 4-methylimidazol-5-yl
H 2-F-phenyl 5-CF3-pyrazol-l-yl
H phenyl guanidino
H phenyl 2-thiazolin-2-ylamine
H phenyl N-methyl-2-imidazolin-2-yl
H phenyl N-methyl-1,4,5, 6- tetrahydropyrimid-2-yl
H phenyl N-methylimidazol-2-ylthiol
H phenyl t-butoxycarbonylamine
H phenyl (N-pyrrolidino) formylimino
H phenyl (N-pyrrolidino) formyl-N-
(methanesulfamoyl) imino
H 2-F-phenyl guanidino
H 2-F-phenyl 2-thiazolin-2-ylamine
H 2-F-phenyl N-methyl-2-imidazolin-2-yl
H 2-F-phenyl N-methyl-1, 4,5,6- tetrahydropyrimid-2-yl
H 2-F-phenyl N-methylimidazol-2-ylthio
H 2-F-phenyl t-butoxycarbonylamine
H 2-F-phenyl (N-pyrrolidino) formylimino
H 2-F-phenyl (N-pyrrolidino) formyl-N-
(methanesulfamoyl) imino
H 2-CH30-phenyl (N-pyrrolidino) formylimino
H 2-CH30-phenyl (N-pyrrolidino) formyl-N-
(methanesulfamoyl) imino
-CN phenyl 2- ( (Me) 2N-methyl ) phenyl
-CN phenyl 2- ( (Me) NH-methyl) phenyl
-CN phenyl 2- (H2N-methyl) phenyl
-CN phenyl 2-HOCH2-phenyl
-CN 2-F-phenyl 2- ( (Me) 2N-methyl ) phenyl
-CN 2-F-phenyl 2- ( (Me) NH-methyl) phenyl
-CN 2-F-phenyl 2- (H2N-methyl ) phenyl
-CN 2-F-phenyl 2-HOCH2-phenyl
-CN phenyl 2-methylimidazol-l-yl
-CN phenyl 2-ethylimidazol-l-yl
-CN phenyl 2-( (Me) 2N-methyl) imidazol-1-yl
-CN phenyl 2-CH3S02-imidazol-l-yl
-CN phenyl 2-CH3OCH2-imidazol-l-yl
-CN 2-F-phenyl 2-methylimidazol-l-yl
-CN 2-F-phenyl 2-ethylimidazol-l-yl
-CN 2-F-phenyl 2- ( (Me) 2N-methyl) imidazol-1-yl
-CN 2-F-phenyl 2-CH3S02-imidazol-l-yl
-CN 2-F-phenyl -Ch3OCH2-imidazol-1-yl
-CN 2-Cl-phenyl 2-methylimidazol-l-yl
-CN 2-Cl-phenyl 2-ethylimidazol-l-yl
-CN 2-Cl-phenyl 2-( (Me) 2N-methyl) imidazol-1-yl
-CN 2-Cl-phenyl 2-CH3S02-imidazol-l-yl
-CN 2-Cl-phenyl 2-CH3OCH2-imidazol-l-yl
-CN 2- (Me) 2N-phenyl 2-methylimidazol-l-yl
-CN 2- (Me) N-phenyl 2-ethylimidazol-l-yl
-CN 2- (Me) N-phenyl 2-( (Me)2N-methyl) imidazol-1-yl
-CN 2- (Me) 2N-phenyl 2-CH3S02-imidazol-l-yl
-CN 2- (Me) 2N-phenyl 2-CH3OCH2-imidazol-l-yl
-CN phenyl N-methylimidazol-2-yl
-CN phenyl 4-methylimidazol-5-yl
-CN phenyl 5-CF -pyrazol-l-yl
-CN 2-F-phenyl N-methylimidazol-2-yl
-CN 2-F-phenyl 4-methylimidazol-5-yl
-CN . 2-F-phenyl 5-CF3-pyrazol-l-yl
-CN phenyl guanidino
-CN phenyl 2-thiazolin-2-ylamine
-CN phenyl N-methyl-2-imidazolin-2-yl
-CN phenyl N-methyl-1,4,5, 6- tetrahydropyrimid-2-yl
-CN phenyl N-methylimidazol-2-ylthiol
-CN phenyl t-butoxycarbonylamine
-CN phenyl (N-pyrrolidino) formylimino
-CN phenyl (N-pyrrolidino) formyl-N-
(methanesulfamoyl) imino
-CN 2-F-phenyl guanidino
-CN 2-F-phenyl 2-thiazolin-2-ylamine
-CN 2-F-phenyl N-methyl-2-imidazolin-2-yl
-CN 2-F-phenyl N-methyl-1,4, 5,6- tetrahydropyrimid-2-yl
-CN 2-F-phenyl N-methylimidazol-2-ylthio
-CN 2-F-phenyl t-butoxycarbonylamine
-CN 2-F-phenyl (N-pyrrolidino) formylimino
-CN 2-F-phenyl (N-pyrrolidino) formyl-N-
(methanesulfamoyl) imino
-CN 2-CH30-phenyl (N-pyrrolidino) formylimino
-CN 2-CH30-phenyl (N-pyrrolidino) formyl-N-
(methanesulfamoyl) imino
CF3 phenyl 2- ( (Me) N-methyl) phenyl
CF3 phenyl 2- ( (Me) H-methyl ) phenyl
CF3 phenyl 2- (H2N-methyl) phenyl
CF3 phenyl 2-HOCH2-phenyl
CF3 2-F-phenyl 2- ( (Me) 2N-methyl ) phenyl
CF3 2-F-phenyl 2- ( (Me) NH-methyl) phenyl
CF3 2-F-phenyl 2- (H2N-methyl ) phenyl
112 CF3 2-F-phenyl 2 -HOCH2-phenyl
113 CF3 phenyl 2-methylimidazol-l-yl
114 CF3 phenyl 2-ethylimidazol-l-yl
115 CF3 phenyl 2- ( (Me) 2N-methyl) imidazol-1-yl
116 CF3 phenyl 2-CH3S02-imidazol-1-yl
117 CF3 phenyl 2-CH3OCH2-imidazol-1-yl
113 CF3 2-F-phenyl 2 -methylimidazol-1-yl
119 CF3 2-F-phenyl 2-ethylimidazol-l-yl
120 CF3 2-F-phenyl 2- ( (Me) 2N-methyl) imidazol-1-yl
121 CF3 2-F-phenyl 2-CH3S02-imidazol-l-yl
122 CF3 2-F-phenyl 2 -CH3OCH2-imidazol-1-yl
123 CF3 2-Cl-phenyl 2-methylimidazol-l-yl
124 CF3 2-Cl-phenyl 2-ethylimidazol-l-yl
125 CF3 2-Cl-phenyl 2- ( (Me) N-methyl) imidazol-1-yl
126 CF3 2-Cl-phenyl 2-CH3S02-imidazol-l-yl
127 CF3 2-Cl-phenyl 2-CH3OCH2-imidazol-l-yl
128 CF3 2 - (Me ) 2N-phenyl 2-methylimidazol-l-yl
129 CF3 2- (Me) 2N-phenyl 2-ethylimidazol-l-yl
130 CF3 2- (Me) 2N-phenyl 2-( (Me) 2N-methyl) imidazol-1-yl
131 CF3 2- (Me)2N-phenyl 2-CH3S02-imidazol-l-yl
132 CF3 2- (Me)2N-phenyl 2-CH3OCH2-imidazol-l-yl
133 CF3 phenyl N-methylimidazol-2-yl
134 CF3 phenyl 4-methylimidazol-5-yl
135 CF3 phenyl 5-CF3-pyrazol-1-yl
136 CF3 2-F-phenyl N-methylimidazol-2-yl
137 CF3 2-F-phenyl 4-methylimidazol-5-yl
138 CF3 2-F-phenyl 5-CF3-pyrazol-1-yl
139 CF3 phenyl guanidino
140 CF3 phenyl 2-thiazolin-2-ylamine
141 CF3 phenyl N-methyl-2-imidazolin-2-yl
142 CF3 phenyl N-methyl-1,4,5, 6- tetrahydropyrimid-2 -yl
143 CF3 phenyl N-methylimidazol-2-ylthiol
144 CF3 phenyl t-butoxycarbonylamine
145 CF3 phenyl (N-pyrrolidino) formylimino
146 CF3 phenyl (N-pyrrolidino) formyl-N-
(methanesulfamoyl) imino
147 CF3 2-F-phenyl guanidino
148 CF3 2-F-phenyl 2-thiazolin-2-ylamine
149 CF3 2-F-phenyl N-methyl-2-imidazolin-2-yl
150 CF3 2-F-phenyl N-methyl-1, 4,5,6- tetrahydropyrimid-2-yl
151 CF3 2-F-phenyl N-methylimidazol-2-ylthio
152 CF3 2-F-phenyl t-butoxycarbonylamine
153 CF3 2-F-phenyl (N-pyrrolidino) formylimino
154 CF3 2-F-phenyl (N-pyrrolidino) formyl-N-
(methanesulfamoyl) imino
155 CF3 2-CH30-phenyl (N-pyrrolidino) formylimino
156 CF3 2-CH30-phenyl (N-pyrrolidino) formyl-N-
(methanesulfamoyl) imino
157 CONH2 phenyl 2- ( (Me) N-methyl ) phenyl
158 CONH2 phenyl 2 - ( (Me) NH-methyl ) phenyl
159 C0NH2 phenyl 2- (H2N-methyl ) phenyl
160 C0NH2 phenyl 2-HOCH2-phenyl
161 C0NH2 2-F-phenyl 2- ( (Me) 2N-methyl) phenyl
162 C0NH2 2-F-phenyl 2- ( (Me) NH-methyl ) phenyl
163 C0NH2 2-F-phenyl 2- (H2N-methyl) phenyl
164 C0NH2 2-F-phenyl 2-HOCH2-phenyl
165 C0NH2 phenyl 2-methylimidazol-l-yl
166 C0NH2 phenyl 2-ethylimidazol-l-yl
167 C0NH2 phenyl 2- ( (Me) 2N-methyl) imidazol-1-yl
168 C0NH2 phenyl 2-CH3S02-imidazol-l-yl
169 C0NH2 phenyl 2-CH3OCH2-imidazol-l-yl
170 C0NH2 2-F-phenyl 2-methylimidazol-l-yl
171 C0NH2 2-F-phenyl 2-ethylimidazol-l-yl
172 C0NH2 2-F-phenyl 2- ( (Me) 2N-methyl) imidazol-1-yl
173 C0NH2 2-F-phenyl 2-CH3S02-imidazol-l-yl
174 C0NH2 2-F-phenyl 2-CH3OCH2-imidazol-1-yl
175 C0NH2 2-Cl-phenyl 2-methylimidazol-l-yl
176 C0NH2 2-Cl-phenyl 2-ethylimidazol-l-yl
177 C0NH2 2-Cl-phenyl 2- ( (Me) 2N-methyl) imidazol-1-yl
178 C0NH2 2-Cl-phenyl 2-CH3S02-imidazol-1-yl
179 C0NH2 2-Cl-phenyl 2-CH3OCH2-imidazol-l-yl
180 C0NH2 2- (Me) 2N-phenyl 2-methylimidazol-l-yl
181 CONH2 2-(Me)2N-phenyl 2-ethylimidazol-l-yl
182 CONH2 2- (Me) 2N-phenyl 2-( (Me)2N-methyl)imidazol-l-yl
183 CONH2 2- (Me) 2N-phenyl 2-CH3S02-imidazol-l-yl
184 CONH2 2-(Me)2N-phenyl 2-CH3OCH2-imidazol-l-yl
185 CONH2 phenyl N-methylimidazol-2-yl
186 CONH2 phenyl 4-methylimidazol-5-yl
187 CONH2 phenyl 5-CF3-pyrazol-1-yl
188 CONH2 2-F-phenyl N-methylimidazol-2-yl
189 CONH2 2-F-phenyl 4-methylimidazol-5-yl
190 CONH2 2-F-phenyl 5-CF3-pyrazol-1-yl
191 CONH2 phenyl guanidino
192 CONH2 phenyl 2-thiazolin-2-ylamine
193 CONH2 phenyl N-methyl-2-imidazolin-2-yl
194 CONH2 phenyl N-methyl-1,4, 5, 6- tetrahydropyrimid-2-yl
195 CONH2 phenyl N-methylimidazol-2-ylthiol
196 CONH2 phenyl t-butoxycarbonylamine
197 CONH2 phenyl (N-pyrrolidino) formylimino
198 CONH2 phenyl (N-pyrrolidino) formyl-N-
(methanesulfamoyl) imino
199 CONH2 2-F-phenyl guanidino
200 CONH2 2-F-phenyl 2-thiazolin-2-ylamine
201 CONH2 2-F-phenyl N-methyl-2-imidazolin-2-yl
202 CONH2 2-F-phenyl N-methyl-1, 4,5,6- tetrahydropyrimid-2-yl
203 CONH2 2-F-phenyl N-methylimidazol-2-ylthio
204 CONH2 2-F-phenyl t-butoxycarbonylamine
205 CONH2 2-F-phenyl (N-pyrrolidino) formylimino
206 CONH2 2-F-phenyl (N-pyrrolidino) formyl-N-
(methanesulfamoyl) imino
207 CONH 2-CH30-phenyl (N-pyrrolidino) formylimino
208 CONH2 2-CH30-phenyl (N-pyrrolidino) formyl-N-
(methanesulfamoyl) imino
209 SCH3 phenyl 2- ( (Me) 2N-methyl) phenyl
210 SCH3 phenyl 2- ( (Me) H-methyl) phenyl
211 SCH3 phenyl 2- (H2N-methyl ) phenyl
212 SCH3 phenyl 2-HOCH2-phenyl
213 SCH 2-F-phenyl 2- ( (Me) 2N-methyl ) phenyl
214 SCH3 2-F-phenyl 2- ( (Me) NH-methyl) henyl
215 SCH3 2-F-phenyl 2- (H2N-methyl ) phenyl
216 SCH3 2-F-phenyl 2-HOCH2-phenyl
217 SCH3 phenyl 2-methylimidazol-l-yl
218 SCH3 phenyl 2-ethylimidazol-l-yl
219 SCH3 phenyl 2-( (Me) N-methyl) imidazol-1-yl
220 SCH3 phenyl 2-CH3S02-imidazol-l-yl
221 SCH3 phenyl 2-CH3OCH2-imidazol-l-yl
222 SCH3 2-F-phenyl 2-methylimidazol-l-yl
223 SCH3 2-F-phenyl 2-ethylimidazol-l-yl
224 SCH3 2-F-phenyl 2- ( (Me) 2N-methyl) imidazol-1-yl
225 SCH3 2-F-phenyl 2-CH3S02-imidazol-l-yl
226 SCH3 2-F-phenyl 2-CH3OCH2-imidazol-l-yl
227 SCH3 2-Cl-phenyl 2-methylimidazol-l-yl
228 SCH3 2-Cl-phenyl 2-ethylimidazol-l-yl
229 SCH3 2-Cl-phenyl 2-( (Me) 2N-methyl) imidazol-1-yl
230 SCH3 2-Cl-phenyl 2-CH3S02-imidazol-1-yl
231 SCH3 2-Cl-phenyl 2-CH3OCH -imidazol-l-yl
232 SCH3 2-(Me)2N-phenyl 2-methylimidazol-1-yl
233 SCH3 2-(Me)2N-phenyl 2-ethylimidazol-l-yl
234 SCH3 2-(Me)2N-phenyl 2-( (Me)2N-methyl) imidazol-1-yl
235 SCH3 2-(Me)2N-phenyl 2-CH3S02-imidazol-l-yl
236 SCH3 2-(Me)2N-phenyl 2-CH3OCH2-imidazol-l-yl
237 SCH3 phenyl N-methylimidazol-2-yl
238 SCH3 phenyl 4-methylimidazol-5-yl
239 SCH3 phenyl 5-CF3-pyrazol-1-yl
240 SCH3 2-F-phenyl N-methylimidazol-2-yl
241 SCH3 2-F-phenyl 4-methylimidazol-5-yl
242 SCH3 2-F-phenyl 5-CF3-pyrazol-1-yl
243 SCH3 phenyl guanidino
244 SCH3 phenyl 2-thiazolin-2-ylamine
245 SCH3 phenyl N-methyl-2-imidazolin-2-yl
246 SCH3 phenyl N-methyl-1,4,5,6- tetrahydropyrimid-2-y1
247 SCH3 phenyl N-methylimidazol-2-ylthiol
248 SCH3 phenyl t-butoxycarbonylamine
249 SCH3 phenyl (N-pyrrolidino) formylimino
250 SCH3 phenyl (N-pyrrolidino) formyl-N-
(methanesulfamoyl) imino
251 SCH3 2-F-phenyl guanidino
252 SCH3 2-F-phenyl 2-thiazolin-2-ylamine
253 SCH3 2-F-phenyl N-methyl-2-imidazolin-2-yl
254 SCH3 2-F-phenyl N-methyl-1,4,5,6- tetrahydropyrimid-2-yl
255 SCH3 2-F-phenyl N-methylimidazol-2-ylthio
256 SCH3 2-F-phenyl t-butoxycarbonylamine
257 SCH3 2-F-phenyl (N-pyrrolidino) formylimino
258 SCH3 2-F-phenyl (N-pyrrolidino) formyl-N-
(methanesulfamoyl) imino
259 SCH3 2-CH30-phenyl (N-pyrrolidino) formylimino
260 SCH3 2-CH30-phenyl (N-pyrrolidino) -For yl-N-
(methanesulfamoyl) imino
261 S02CH3 phenyl 2- ( (Me) 2N-methyl ) phenyl
262 S02CH3 phenyl 2- ( (Me) NH-methyl ) phenyl
263 S02CH3 phenyl 2- (H2N-methyl ) phenyl
264 S02CH3 phenyl 2-HOCH2-phenyl
265 S02CH3 2-F-phenyl 2- ( (Me) 2N-methyl) phenyl
266 S02CH3 2-F-phenyl 2-( (Me) NH-methyl) phenyl
267 S02CH3 2-F-phenyl 2- (H2N-methyl ) phenyl
268 S02CH3 2-F-phenyl 2-HOCH2-phenyl
269 S02CH3 phenyl 2-methylimidazol-1-yl
270 S0CH3 phenyl 2-ethylimidazol-l-yl
271 S02CH3 phenyl 2- ( (Me) 2N-methyl) imidazol-1-yl
272 S02CH3 phenyl 2-CH3S02-imidazol-1-yl
273 S0CH3 phenyl 2-CH3OCH2-imidazol-l-yl
274 S02CH3 2-F-phenyl 2-methylimidazol-l-yl
275 S02CH3 2-F-phenyl 2-ethylimidazol-l-yl
276 S0CH3 2-F-phenyl 2-( (Me) 2N-methyl) imidazol-1-yl
277 S02CH3 2-F-phenyl 2-CH3SO2-imidazol-1-yl
278 S02CH3 2-F-phenyl 2-CH3OCH2-imidazol-l-yl
279 S02CH3 2-Cl-phenyl 2-methylimidazol-l-yl
280 S02CH3 2-Cl-phenyl 2-ethylimidazol-l-yl
281 S02CH3 2-Cl-phenyl 2-( (Me)2N-methyl) imidazol-1-yl
282 S02CH3 2-Cl-phenyl 2-CH3S02-imidazol-l-yl
283 S02CH3 2-Cl-phenyl 2-CH3OCH2-imidazol-1-yl
284 S02CH3 2- (Me) 2N-phenyl 2-methylimidazol-l-yl
285 S02CH3 2- (Me) 2N-phenyl 2-ethylimidazol-1-yl
286 S02CH3 2- (Me) 2N-phenyl 2-( (Me) 2N-methyl) imidazol-1-yl
287 S02CH3 2- (Me) 2N-phenyl 2-CH3S02-imidazol-1-yl
288 S02CH3 2- (Me) 2N-phenyl 2-CH3OCH2-imidazol-l-yl
289 S02CH3 phenyl N-methylimidazol-2-yl
290 S02CH3 phenyl 4-methylimidazol-5-yl
291 S0CH3 phenyl 5-CF3-pyrazol-1-y1
292 S02CH3 2-F-phenyl N-methylimidazol-2-yl
293 S02CH3 2-F-phenyl 4-me hylimidazol-5-yl
294 S02CH3 2-F-phenyl 5-CF3-pyrazol-1-yl
295 S02CH3 phenyl guanidino
296 S02CH3 phenyl 2-thiazolin-2-ylamine
297 S02CH3 phenyl N-methyl-2-imidazolin-2-yl
298 S02CH3 phenyl N-methyl-1,4,5,6- tetrahydropyrimid-2-y1
299 S02CH3 phenyl N-methylimidazol-2-ylthiol
300 S02CH3 phenyl t-butoxycarbonylamine
301 S02CH3 phenyl (N-pyrrolidino) formylimino
302 S02CH3 phenyl (N-pyrrolidino) formyl-N-
(methanesulfamoyl) imino
303 S0CH3 2-F-phenyl guanidino
304 S02CH3 2-F-phenyl 2-thiazolin-2-ylamine
305 S02CH3 2-F-phenyl N-methyl-2-imidazolin-2-yl
306 S02CH3 2-F-phenyl N-methyl-1,4,5,6- tetrahydropyrimid-2-yl
307 S02CH3 2-F-phenyl N-methylimidazol-2-ylthio
308 S0CH3 2-F-phenyl t-butoxycarbonylamine
309 Sθ2CH3 2-F-phenyl (N-pyrrolidino) formylimino
310 S02CH3 2-F-phenyl (N-pyrrolidino) formyl-N-
(methanesulfamoyl) imino
311 Sθ2CH3 2-CH30-phenyi (N-pyrrolidino) formylimino
312 Sθ2CH3 2-CH30-phenyl (N-pyrrolidino) formyl-N-
(methanesulfamoyl) imino
313 NHS02CH3 phenyl 2- ( (Me) 2N-methyl ) phenyl
314 NHS02CH3 phenyl 2- ( (Me) NH-methyl ) phenyl
315 NHS02CH3 phenyl 2- (H2N-methyl ) phenyl
316 NHS02CH3 phenyl 2-H0CH2-phenyl
317 NHS02CH3 2-F-phenyl 2- ( (Me) 2N-methyl) phenyl
318 NHS02CH3 2-F-phenyl 2-( (Me) NH-methyl) phenyl
319 NHS02CH3 2-F-phenyl 2- (H2N-methy1 ) phenyl
320 NHS02CH3 2-F-phenyl 2-H0CH2-phenyl
321 NHS02CH3 phenyl 2-methylimidazol-l-yl
322 NHS02CH3 phenyl 2-ethylimidazol-l-yl
323 NHS02CH3 phenyl 2-( (Me) 2N-methyl) imidazol-1-yl
324 NHS02CH3 phenyl 2-CH3S02-imidazol-l-yl
325 NHS02CH3 phenyl 2-CH30CH2-imidazol-l-yl
326 NHS02CH3 2-F-phenyl 2-methylimidazol-l-yl
327 NHS02CH3 2-F-phenyl 2-ethylimidazol-l-yl
328 NHS02CH3 2-F-phenyl 2- ( (Me) N-methyl) imidazol-1-yl
329 NHS02CH3 2-F-phenyl 2-CH3S02-imidazol-l-yl
330 NHSθ2CH3 2-F-phenyl 2-CH30CH2-imidazol-l-yl
331 NHS02CH3 2-Cl-phenyl 2-methylimidazol-l-yl
332 NHS02CH3 2-Cl-phenyl 2-ethylimidazol-l-yl
333 NHS02CH3 2-Cl-phenyl 2- ( (Me) 2N-methyl) imidazol-1-yl
334 NHS02CH3 2-Cl-phenyl 2-CH3S02-imidazol-l-yl
335 NHS02CH3 2-Cl-phenyl 2-CH30CH2-imidazol-l-yl
336 NHS02CH3 2- (Me) 2N-phenyl 2-methylimidazol-l-yl
337 NHS02CH3 2- (Me) 2N-phenyl 2-ethylimidazol-l-yl
338 NHS02CH3 2- (Me) 2N-phenyl 2- ( (Me) 2N-methyl) imidazol-1-yl
339 NHS0CH3 2- (Me) 2N-phenyl 2-CH3S02-imidazol-l-yl
340 NHS02CH3 2-(Me)2N-phenyl 2-CH30CH2-imidazol-l-yl
341 NHS02CH3 phenyl N-methylimidazol-2-yl
342 NHSθ2CH3 phenyl 4-methylimidazol-5-yl
343 NHS02CH3 phenyl 5-CF3-pyrazol-l-yl
344 NHS02CH3 2-F-phenyl N-methylimidazol-2-yl
345 NHS02CH3 2-F-phenyl 4-methylimidazol-5-yl
346 NHS02CH3 2-F-phenyl 5-CF3-pyrazol-1-yl
347 NHS02CH3 phenyl guanidino
348 NHS02CH3 phenyl 2-thiazolin-2-ylamine
349 NHS02CH3 phenyl N-methyl-2-imidazolin-2-yl
350 NHS02CH3 phenyl N-methyl-1,4,5, 6- tetrahydropyrimid-2-yl
351 NHS02CH3 phenyl N-methylimidazol-2-ylthiol
352 NHS02CH3 phenyl t-butoxycarbonylamine 353 NHS02CH3 phenyl (N-pyrrolidino) formylimino
354 NHS02CH3 phenyl (N-pyrrolidino) formyl-N-
(methanesulfamoyl) imino
355 NHS02CH3 2-F-phenyl guanidino
356 NHS02CH 2-F-phenyl 2-thiazolin-2 -ylamine
357 NHS02CH3 2-F-phenyl N-methyl-2-imidazolin-2-yl
358 NHS02CH3 2-F-phenyl N-methyl-1, 4,5,6- tetrahydropyrimid-2 -yl
359 NHS02CH3 2-F-phenyl N-methylimidazol-2-ylthio
360 NHS02CH3 2-F-phenyl t-butoxycarbonylamine 361 NHS02CH3 2-F-phenyl (N-pyrrolidino) formylimino 362 NHS02CH3 2-F-phenyl (N-pyrrolidino) formyl-N-
(methanesulfamoyl) imino
363 NHS02CH3 2-CH30-phenyl (N-pyrrolidino) formylimino
364 NHS02CH3 2-CH30-phenyl (N-pyrrolidino) formyl-N-
(methanesulfamoyl) imino
Table 4
Pi R=F, D=NH2 qi R=F, D=NH2 ri R=F, D=NH2 P2 R=CI, D=NH2 q2 R=CI, D=NH2 r2 R=CI, D=NH2 p3 R=OMe, D=NH2 q3 R=OMe, D=NH2 r3 R=OMe, D=NH2 p4 R=F, D=CH2NH2 q4 R=F, D=CH2NH2 r4 R=F, D=CH2NH2 p5 R=CI, D=CH2NH2 q5 R=CI, D=CH2NH2 r5 R=CI, D=CH2NH2 p6 R=OMe, D=CH2NH2 q6 R=OMe, D=CH2NH2 r6 R=OMe, D=CH2NH2 p7 R=F, D=C(=NH)NH2 q7 R=F, D=C(=NH)NH2 r7 R=F, D=C(=NH)NH2 p8 R=CI, D=C(=NH)NH2 q8 R=CI, D=C(=NH)NH2 r8 R=CI, D=C(=NH)NH2 p9 R=OMe, D=C(=NH)NH2 q9 R=OMe, D=C(=NH)NH2 r9 R=OMe, D=C(=NH)NH2 P10 R=F, D=C(0)NH2 qio R=F, D=C(0)NH2 r10 R=F, D=C(0)NH2 P11 R=CI, D=C(0)NH2 qn R=CI, D=C(0)NH2 rn R=CI, D=C(0)NH2 P12 R=OMe, D=C(0)NH2 qi2 R=OMe, D=C(0)NH2 ri2 R=OMe, D=C(0)NH2
Si s2 s3 s4 s5 s6 s7 s8 s9 Sιo SH Sι2
D=CH2NH2 D=CH2NH2 D=CH2NH2
kki R=F, D=CH2NH2 lh R=F, D=CH2NH2 mm-i R=F, D=CH2NH2 kk2 R=CI, D=CH2NH2 112 R=CI, D=CH2NH2 mm2 R=CI, D=CH2NH2 kk3 R=OMe, D=CH2NH2 113 R=OMe, D=CH2NH2 mm3 R=OMe, D=CH2NH2 kk4 R=CH2NH2, 114 R=CH2NH2, mm4 R=CH2NH2, D=CH2NH2 D=CH2NH2 D=CH2NH2
Ex# Rlb
1 H phenyl 2 - ( aminosul f onyl ) phenyl
2 H phenyl 2- (methylaminosulfonyl ) phenyl
3 H phenyl 1-pyrrolidinocarbonyl
4 H phenyl 2- (methylsulf onyl ) phenyl
5 H phenyl 4-morpholino
6 H phenyl 2 - ( 1 ' -CF3 -tetrazol-2 -yl ) phenyl
7 H phenyl 4-morpholinocarbonyl
8 H 2-pyridyl 2- (aminosulfonyl ) phenyl
9 H 2-pyridyl 2- (methylaminosulfonyl ) phenyl
10 H 2-pyridyl 1-pyrrolidinocarbonyl
11 H 2-pyridyl 2- (methylsulf onyl ) henyl
12 H 2 -pyridyl 4 -mo rpho 1 ino
H 2-pyridyl 2- ( 1 ' -CF3 -tetrazol-2-yl ) phenyl
H 2-pyridyl 4-morpholinocarbonyl
H 3-pyridyl 2- (aminosulfonyl) phenyl
H 3-pyridyl 2- (methylaminosulfonyl) phenyl
H 3-pyridyl 1-pyrrolidinocarbonyl
H 3-pyridyl 2- (methylsulfonyl) phenyl
H 3 -pyridyl 4-morpholino
H -pyridyl 2 - (l'"-CF3-tetrazol-2-yDphenyl
H 3-pyridyl 4-morpholinocarbonyl
H 2-pyrimidyl 2- (aminosulfonyl) phenyl
H 2-pyrimidyl 2- (methylaminosulfonyl) phenyl
H 2-pyrimidyl 1-pyrrolidinocarbonyl
H 2-pyrimidyl 2- (methylsulfonyl) phenyl
H 2-pyrimidyl 4-morpho1ino
H 2-pyrimidyl 2- ( 1 ' -CF3 -tetrazol-2-yl ) phenyl
H 2-pyrimidyl 4-morpholinocarbonyl
H 5-pyrimidyl 2- (aminosulfonyl) phenyl
H 5-pyrimidyl 2- (methylaminosulfonyl) phenyl
H 5-pyrimidyl 1-pyrrolidinocarbonyl
H 5-pyrimidyl 2- (methylsulfonyl) phenyl
H 5-pyrimidyl 4-morpholino
H 5-pyrimidyl 2- ( 1 ' -CF3 -tetrazol-2-yl ) phenyl
H 5-pyrimidyl 4-morpholinocarbonyl
H 2-Cl-phenyl 2- (aminosulfonyl ) phenyl
H 2-Cl-phenyl 2- (methylaminosulfonyl) phenyl
H 2-Cl-phenyl 1-pyrro1idinocarbony1
H 2-Cl-phenyl 2- (methylsulfonyl) phenyl
H 2-Cl-phenyl 4-morpholino
H 2-Cl-phenyl 2- (1 ' -CF3-tetrazol-2-yl)phenyl
H 2-Cl-phenyl 4-morpholinocarbonyl
H 2-F-phenyl 2- (aminosulfonyl) phenyl
H 2-F-phenyl 2- (methylaminosulfonyl ) phenyl
H 2-F-phenyl 1-pyrro1idinocarbonyl
H 2-F-phenyl 2- (methylsulfonyl) phenyl
H 2-F-phenyl 4-morpholino
H 2-F-phenyl 2- (1' -CF3-tetrazol-2-yl) phenyl
H 2-F-phenyl 4-morpholinocarbonyl
H 2,5-diF-phenyl 2- (aminosulfonyl) phenyl
H 2 , 5-diF-phenyl 2- (methylaminosulfonyl) phenyl
H 2, 5-diF-phenyl 1-pyrrolidinocarbonyl
H 2 , 5-diF-phenyl 2- (methylsulfonyl) phenyl
H 2,5-diF-phenyl 4-morpholino
H 2,5-diF-phenyl 2- (1' -CF3-tetrazol-2-yDphenyl
H 2,5-diF-phenyl 4-morpholinocarbonyl
-CN phenyl 2- (aminosulfonyl) phenyl
-CN phenyl 2- (methylaminosulfonyl) phenyl
-CN phenyl 1-pyrro1idinocarbonyl
-CN phenyl 2- (methylsulfonyl) phenyl
-CN phenyl 4-morpholino
-CN phenyl 2- (1' -CF3-tetrazol-2-yl) phenyl
-CN phenyl 4-morpholinocarbonyl
-CN 2-pyridyl 2- (aminosulfonyl) phenyl
-CN 2-pyridyl 2- (methylaminosulfonyl) phenyl
-CN 2-pyridyl 1-pyrrolidinocarbonyl
-CN 2-pyridyl 2- (methylsulfonyl) phenyl
-CN 2-pyridyl 4-morpholino
-CN 2-pyridyl 2- (1' -CF3-tetrazol-2-yl) phenyl
-CN 2-pyridyl 4-morpholinocarbonyl
-CN 3-pyridyl 2- (aminosulfonyl ) phenyl
-CN 3-pyridyl 2- (methylaminosulfonyl) phenyl
-CN 3-pyridyl 1-pyrrolidinocarbonyl
-CN 3-pyridyl 2- (methylsulfonyl) phenyl
-CN 3-pyridyl 4-morpholino
-CN 3-pyridyl 2- (1 ' -CF3-tetrazol-2-yl) phenyl
-CN 3-pyridyl 4-morpholinocarbony1
-CN 2-pyrimidyl 2- (aminosulfonyl ) phenyl
-CN 2-pyrimidyl 2- (methylaminosulfonyl) phenyl
-CN 2-pyrimidyl 1-pyrrolidinocarbonyl
-CN 2-pyrimidyl 2- (methylsulfonyl) phenyl
-CN 2-pyrimidyl 4-morpholino
-CN 2-pyrimidyl 2- (1 ' -CF3-tetrazol-2-yl) phenyl
-CN 2-pyrimidyl 4-morpholinocarbonyl
-CN 5-pyrimidyl 2- (aminosulfonyl) phenyl
-CN 5-pyrimidyl 2- (methylaminosulfonyl) phenyl
-CN 5-pyrimidyl 1-pyrrolidinocarbonyl
-CN 5-pyrimidyl 2- (methylsulfonyl) phenyl
-CN 5-pyrimidyl 4-morpholino
-CN 5-pyrimidyl 2- (1' -CF3 -tetrazol-2-yDphenyl
-CN 5-pyrimidyl 4-morpholinocarbonyl
-CN 2-Cl-phenyl 2- (aminosulfonyl) phenyl
-CN 2-Cl-phenyl 2- (methylaminosulfonyl) phenyl
-CN 2-Cl-phenyl 1-pyrrolidinocarbonyl
-CN 2-Cl-phenyl 2- (methylsulfonyl) p enyl
-CN 2-Cl-phenyl 4-morpholino
-CN 2-Cl-phenyl 2- ( 1 ' -CF3 -tetrazol-2-yl) phenyl
-CN 2-Cl-phenyl 4-morpholinocarbonyl
-CN 2-F-phenyl 2- (aminosulfonyl ) phenyl
-CN 2-F-phenyl 2- (methylaminosulfonyl)phenyl
-CN 2-F-phenyl 1-pyrrolidinocarbonyl
-CN 2-F-phenyl 2- (methylsulfonyl) phenyl
-CN 2-F-phenyl 4-morpho1ino
-CN 2-F-phenyl 2- (1' -CF3-tetrazol-2-yl)phenyl
-CN 2-F-phenyl 4-morpholinocarbonyl
-CN 2,5-diF-phenyl 2- (aminosulfonyl) phenyl
-CN 2, 5-diF-phenyl 2- (methylaminosulfonyl) phenyl
-CN 2, 5-diF-phenyl 1-pyrrolidinocarbonyl
-CN 2,5-diF-phenyl 2- (methylsulfonyl) phenyl
-CN 2,5-diF-phenyl 4-morpholino
-CN 2,5-diF-phenyl 2- (1 ' -CF3 -tetrazol-2-yl ) phenyl
-CN 2,5-diF-phenyl 4-morpholinocarbony1
CF3 phenyl 2- (aminosulfonyl ) phenyl
CF3 phenyl 2- (methylaminosulfonyl) phenyl
CF3 phenyl 1-pyrrolidinocarbony1
CF3 phenyl 2- (methylsulfonyl) phenyl
CF3 phenyl 4-morpholino
CF3 phenyl 2- (1' -CF3-tetrazol-2-yl) phenyl
CF3 phenyl 4-morpholinocarbonyl
CF3 2-pyridyl 2- (aminosulfony1) phenyl
CF3 2-pyridyl 2- (methylaminosulfonyl) phenyl
CF3 2-pyridyl 1-pyrrolidinocarbonyl
CF3 2-pyridyl 2- (methylsulfonyl) phenyl
124 CF3 2-pyridyl 4-morpholino
125 CF3 2-pyridyl 2- ( 1 ' -CF3-tetrazol-2-yl ) phenyl
126 CF3 2-pyridyl 4-morpholinocarbonyl
127 CF3 3 -pyridyl 2- (aminosulfonyl) henyl
128 CF3 3 -pyridyl 2- (methylaminosulfonyl) phenyl
129 CF3 3-pyridyl 1-pyrrolidinocarbonyl
130 CF3 3 -pyridyl 2- (methylsulfonyl) phenyl
131 CF3 3 -pyridyl 4-morpholino
132 CF3 3-pyridyl 2- ( 1 ' -CF3 -tetrazol-2 -yD phenyl
133 CF3 3-pyridyl 4-morpho1inocarbony1
134 CF3 2-pyrimidyl 2- (aminosulfonyl ) henyl
135 CF3 2-pyrimidyl 2- (methylaminosulfonyl) phenyl
136 CF3 2-pyrimidyl 1-pyrro1idinocarbonyl
137 CF3 2-pyrimidyl 2- (methylsulfonyl) phenyl
138 CF3 2-pyrimidyl 4-morpholino
139 CF3 2-pyrimidyl 2- ( 1 ' -CF3 -tetrazol-2 -yD phenyl
140 CF3 2-pyrimidyl 4-morpholinocarbonyl
141 CF3 5-pyrimidyl 2- (aminosulfonyl) phenyl
142 CF3 5-pyrimidyl 2- (methylaminosulfonyl ) phenyl
143 CF3 5-pyrimidyl 1-pyrrolidinocarbonyl
144 CF3 5-pyrimidyl 2- (methylsulfonyl) phenyl
145 CF3 5-pyrimidyl 4-morpholino
146 CF3 5-pyrimidyl 2- ( 1 ' -CF3 -tetrazol-2-yl ) phenyl
147 CF3 5-pyrimidyl 4-morpholinocarbonyl
148 CF3 2-Cl-phenyl 2- (aminosulfonyl) phenyl
149 CF3 2-Cl-phenyl 2- (methylaminosulfonyl) phenyl
150 CF3 2-Cl-phenyl 1-pyrro1idinocarbonyl
151 CF3 2-Cl-phenyl 2- (methylsulfonyl) phenyl
152 CF3 2-Cl-phenyl 4-morpholino
153 CF3 2-Cl-phenyl 2- ( 1 ' -CF3-tetrazol-2-yl ) phenyl
154 CF3 2-Cl-phenyl 4-morpholinocarbonyl
155 CF3 2-F-phenyl 2- (aminosulfonyl) phenyl
156 CF3 2-F-phenyl 2- (methylaminosulfonyl) phenyl
157 CF3 2-F-phenyl 1-pyrrolidinocarbonyl
158 CF3 2-F-phenyl 2- (methylsulfonyl) phenyl
159 CF3 2-F-phenyl 4-morpholino
160 CF3 2-F-phenyl 2- ( 1 ' -CF3-tetrazol-2-yl ) phenyl
161 CF3 2-F-phenyl 4-morpholinocarbonyl
162 CF3 2, 5-diF-phenyl 2- (aminosulfonyl) phenyl
163 CF3 2, 5-diF-phenyl 2- (methylaminosulfonyl) phenyl
164 CF3 2, 5-diF-phenyl 1-pyrro1idinocarbonyl
165 CF3 2, 5-diF-phenyl 2- (methylsulfonyl ) phenyl
166 CF3 2, 5-diF-phenyl 4-morpholino
167 CF3 2, 5-diF-phenyl 2- (l'-CF3-tetrazol-2-yl) phenyl
168 CF3 2,5-diF-phenyl 4-morpho1inocarbony1
169 CONH2 phenyl 2- (aminosulfony1 ) phenyl
170 CONH2 phenyl 2- (methylaminosulfonyl ) phenyl
171 CONH2 phenyl 1-pyrrolidinocarbonyl
172 CONH2 phenyl 2- (methylsulfonyl) phenyl
173 CONH2 phenyl 4-morpholino
174 CONH2 phenyl 2- ( 1 ' -CF3 -tetrazol-2-yl) phenyl
175 CONH2 phenyl 4-morpholinocarbonyl
176 CONH2 2-pyridyl 2- (aminosulfonyl ) phenyl
177 CONH2 2-pyridyl 2- (methylaminosulfonyl) phenyl
178 CONH2 2-pyridyl 1-pyrrolidinocarbonyl
179 CONH2 2 -pyridyl 2- (methyls αlfonyl) phenyl
180 CONH2 2-pyridyl 4-morpholino
181 CONH2 2-pyridyl 2 - ( 1 ' -CF3 -tetrazol-2 -yl ) phenyl
182 CONH2 2-pyridyl 4-morpholinocarbonyl
183 CONH2 3 -pyridyl 2 - (aminosulfonyl ) phenyl
184 CONH2 3 -pyridyl 2 - (methylaminosulfonyl ) phenyl
185 CONH2 3 -pyridyl 1-pyrrolidinocarbonyl
186 CONH2 3 -pyridyl 2- (methylsulfonyl) phenyl
187 CONH2 3 -pyridyl 4-morpholino
188 CONH2 3 -pyridyl 2- (l'-CF3-tetrazol-2 -yl) phenyl
189 CONH2 3 -pyridyl 4-morpholinocarbonyl
190 CONH2 2-pyrimidyl 2 - ( aminosulfonyl ) phenyl
191 CONH2 2 -pyrimidyl 2- (methylaminosulfonyl) phenyl
192 CONH2 2 -pyrimidyl 1-pyrrolidinocarbonyl
193 CONH2 2 -pyrimidyl 2- (methylsulfonyl) phenyl
194 CONH2 2-pyrimidyl 4-morpholino
195 CONH2 2 -pyrimidyl 2-(l'-CF3-tetrazol-2-yl)phenyl
196 CONH2 2-pyrimidyl 4-morpholinocarbony1
197 CONH2 5-pyrimidyl 2- ( aminosulfonyl ) phenyl
198 CONH2 5-pyrimidyl 2- (methylaminosulfonyl) phenyl
199 CONH2 5-pyrimidyl 1-pyrrolidinocarbonyl
200 CONH2 5-pyrimidyl 2- (methylsulfonyl) phenyl
201 CONH2 5-pyrimidyl 4-morpholino
202 CONH2 5-pyrimidyl 2- ( 1 ' -CF3 -tetrazol-2-yl ) phenyl
203 CONH2 5-pyrimidyl 4-morpholinocarbonyl
204 CONH2 2-Cl-phenyl 2- (aminosulfonyl) phenyl
205 CONH2 2-Cl-phenyl 2- (methylaminosulfonyl) phenyl
206 CONH2 2-Cl-phenyl 1-pyrrolidinocarbonyl
207 CONH2 2-Cl-phenyl 2- (methylsulfonyl) phenyl
208 CONH2 2-Cl-phenyl 4-morpholino
209 CONH2 2-Cl-phenyl 2 - ( 1 ' -CF3 -tetrazol-2-yl ) phenyl
210 CONH2 2-Cl-phenyl 4-morpholinocarbonyl
211 CONH2 2-F-phenyl 2- (aminosulfonyl) phenyl
212 CONH2 2-F-phenyl 2- (methylaminosulfonyl ) phenyl
213 CONH2 2-F-phenyl 1-pyrro1idinocarbonyl
214 CONH2 2-F-phenyl 2- (methylsulfonyl) phenyl
215 CONH2 2-F-phenyl 4-morpholino
216 CONH2 2-F-phenyl 2- ( l ' -CF3 -tetrazol-2 -yD phenyl
217 CONH2 2-F-phenyl 4-morpho1inocarbony1
218 CONH2 2,5-diF-phenyl 2- (aminosulfonyl) phenyl
219 CONH2 2,5-diF-phenyl 2 - (methylaminosulfonyl ) phenyl
220 CONH2 2,5-diF-phenyl 1-pyrro1idinocarbonyl
221 CONH2 2,5-diF-phenyl 2- (methylsulfonyl) phenyl
222 CONH2 2,5-diF-phenyl 4-morpholino
223 CONH2 2, 5-diF-phenyl 2- ( 1 ' -CF3 -tetrazol-2 -yl ) phenyl
224 CONH2 2, 5-diF-phenyl 4-morpholinocarbonyl
225 SCH3 phenyl 2- (aminosulfony1 ) phenyl
226 SCH3 phenyl 2- (methylaminosulfonyl) phenyl
227 SCH3 phenyl 1-pyrro1idinocarbonyl
228 SCH3 phenyl 2- (methylsulfonyl) phenyl
229 SCH3 phenyl 4-morpho1ino
230 SCH3 phenyl 2- ( 1 ' -CF3 -tetrazol-2-yl ) phenyl
231 SCH3 phenyl 4-morpholinocarbony1
232 SCH3 2-pyridyl 2- (aminosulfonyl) phenyl
233 SCH3 2-pyridyl 2- (methylaminosulfonyl ) phenyl
234 SCH3 2-pyridyl 1-pyrro1idinocarbonyl
235 SCH3 2-pyridyl 2- (methylsulfonyl) phenyl
236 SCH3 2-pyridyl 4-morpholino
237 SCH3 2-pyridyl 2- ( 1 ' -CF3-tetrazol-2-yl) phenyl
238 SCH3 2-pyridyl 4-morpholinocarbonyl
239 SCH3 3-pyridyl 2- (aminosulfonyl) phenyl
240 SCH3 3-pyridyl 2- (methylaminosulfonyl) phenyl
241 SCH3 3-pyridyl 1-pyrrolidinocarbonyl
242 SCH3 3-pyridyl 2- (methylsulfonyl) phenyl
243 SCH3 3 -pyridyl 4-morpholino
244 SCH3 3 -pyridyl 2- ( 1 ' -CF3 -tetrazol-2-yl ) phenyl
245 SCH3 3-pyridyl 4-morpho1inocarbony1
246 SCH3 2-pyrimidyl 2- (aminosulfony1 ) henyl
247 SCH3 2-pyrimidyl 2- (methylaminosulfonyl) phenyl
248 SCH3 2-pyrimidyl 1-pyrrolidinocarbonyl
249 SCH3 2-pyrimidyl 2- (methylsulfonyl) phenyl
250 SCH3 2-pyrimidyl 4-morpho1ino
251 SCH3 2-pyrimidyl 2- ( 1 ' -CF3 -tetrazol-2-yl ) phenyl
252 SCH3 2-pyrimidyl 4-morpholinocarbonyl
253 SCH3 5-pyrimidyl 2- (aminosulfonyl) phenyl
254 SCH3 5-pyrimidyl 2- (methylaminosulfonyl) phenyl
255 SCH3 5-pyrimidyl 1-pyrrolidinocarbonyl
256 SCH3 5-pyrimidyl 2- (methylsulfonyl) phenyl
257 SCH3 5-pyrimidyl 4-morpholino
258 SCH3 5-pyrimidyl 2-(l'-CF3-tetrazol-2-yl)phenyl
259 SCH3 5-pyrimidyl 4-morpholinocarbonyl
260 SCH3 2-Cl-phenyl 2- (aminosulfonyl) phenyl
261 SCH3 2-Cl-phenyl 2- (methylaminosulfonyl) phenyl
262 SCH3 2-Cl-phenyl 1-pyrrolidinocarbonyl
263 SCH3 2-Cl-phenyl 2- (methylsulfonyl) phenyl
264 SCH3 2-Cl-phenyl 4-morpholino
265 SCH3 2-Cl-phenyl 2- (1 ' -CF3-tetrazol-2-yl) phenyl
266 SCH3 2-Cl-phenyl 4-morpholinocarbonyl
267 SCH3 2-F-phenyl 2- (aminosulfonyl) phenyl
268 SCH3 2-F-phenyl 2- (methylaminosulfonyl) phenyl
269 SCH3 2-F-phenyl 1-pyrro1idinocarbonyl
270 SCH3 2-F-phenyl 2- (methylsulfonyl) phenyl
271 SCH3 2-F-phenyl 4-morpho1ino
272 SCH3 2-F-phenyl 2- ( 1 ' -CF3-tetrazol-2-yl) phenyl
273 SCH3 2-F-phenyl 4-morpholinocarbonyl
274 SCH3 2, 5-diF-phenyl 2- (aminosulfonyl) phenyl
275 SCH3 2,5-diF-phenyl 2- (methylaminosulfonyl) phenyl
276 SCH3 2, 5-diF-phenyl 1-pyrro1idinocarbony1
277 SCH3 2, 5-diF-phenyl 2- (methylsulfonyl) phenyl
278 SCH3 2,5-diF-phenyl 4-morpho1ino
279 SCH3 2,5-diF-phenyl 2- (l'-CF3-tetrazol-2-yl) phenyl
280 SCH3 2, 5-diF-phenyl 4-morpholinocarbonyl
281 S02CH3 phenyl 2- (aminosulfonyl) phenyl
282 S02CH3 phenyl 2- (methylaminosulfonyl) phenyl
283 S02CH3 phenyl 1-pyrrolidinocarbonyl
284 S02CH3 phenyl 2- (methylsulfonyl) phenyl
285 S02CH3 phenyl 4-morpholino
286 SϋCH3 phenyl 2- ( 1 ' -CF3 -tetrazol-2-yl) phenyl
287 S02CH3 phenyl 4-morpholinocarbonyl
288 S02CH3 2-pyridyl 2- (aminosulfony1 ) phenyl
289 S02CH3 2-pyridyl 2- (methylaminosulfonyl) phenyl
290 S02CH3 2-pyridyl 1-pyrrolidinocarbonyl
291 S02CH3 2-pyridyl 2- (methylsulfonyl) phenyl
292 S02CH3 2-pyridyl 4-morpholino
293 S02CH3 2-pyridyl 2- ( 1 ' -CF3 -tetrazol-2-yl ) phenyl
294 S02CH3 2-pyridyl 4-morpholinocarbonyl
295 S02CH3 3-pyridyl 2- (aminosulfonyl)phenyl
296 S02CH3 3-pyridyl 2- (methylaminosulfonyl) phenyl
297 S02CH3 3-pyridyl 1-pyrro1idinocarbonyl
298 S0CH3 3-pyridyl 2- (methylsulfonyl) phenyl
299 S02CH3 3-pyridyl 4-morpholino
300 S02CH3 3-pyridyl 2 - ( 1 ' -CF3 -tetrazol-2 -yD phenyl
301 S02CH3 3-pyridyl 4-morpholinocarbonyl
302 S02CH3 2-pyrimidyl 2- (aminosulfonyl) phenyl
303 S0CH3 2-pyrimidyl 2- (methylaminosulfonyl) phenyl
304 S02CH3 2-pyrimidyl 1-pyrro1idinocarbonyl
305 S02CH3 2-pyrimidyl 2- (methylsulfonyl) phenyl
306 S02CH3 2-pyrimidyl 4-morpholino
307 S0CH3 2-pyrimidyl 2- (1' -CF3-tetrazol-2-yl) phenyl
308 S02CH3 2-pyrimidyl 4-morpholinocarbonyl
309 S02CH3 5-pyrimidyl 2- (aminosulfonyl)phenyl
310 S02CH3 5-pyrimidyl 2- (methylaminosulfonyl) henyl
311 S02CH3 5-pyrimidyl 1-pyrro1idinocarbonyl
312 S02CH3 5-pyrimidyl 2- (methylsulfonyl) phenyl
313 S02CH3 5-pyrimidyl 4-morpho1ino
314 S02CH3 5-pyrimidyl 2- ( 1 ' -CF3 - tetrazol-2 -yD phenyl
315 S0CH3 5-pyrimidyl 4-morpholinocarbonyl
316 S02CH3 2-Cl-phenyl 2- (aminos lfonyl) phenyl
317 S02CH 2-Cl-phenyl 2- (methylaminosulfonyl) phenyl
318 S02CH3 2-Cl-phenyl 1-pyrrolidinocarbonyl
319 S02CH3 2-Cl-phenyl 2- (methylsulfonyl) phenyl
320 S02CH3 2-Cl-phenyl 4-morpholino
321 S02CH3 2-Cl-phenyl 2- ( 1 ' -CF3 -tetrazol-2-yl ) phenyl
322 Sθ2CH3 2-Cl-phenyl 4-morpholinocarbonyl
323 S02CH3 2-F-phenyl 2- (aminosulfonyl) phenyl
324 S02CH3 2-F-phenyl 2- (methylaminosulfonyl) phenyl
325 S02CH3 2-F-phenyl 1-pyrro1idinocarbonyl
326 S02CH3 2-F-phenyl 2- (methylsulfonyl) phenyl
327 S0CH3 2-F-phenyl 4-morpho1ino
328 S02CH3 2-F-phenyl 2- (l'-CF3-tetrazol-2-yl) phenyl
329 S02CH3 2-F-phenyl 4-morpholinocarbonyl
330 S02CH3 2, 5-diF-phenyl 2- (aminosulfonyl) phenyl
331 S02CH3 2,5-diF-phenyl 2- (methylaminosulfonyl) phenyl
332 S02CH3 2, 5-diF-phenyl 1-pyrro1idinocarbonyl
333 S02CH3 2, 5-diF-phenyl 2- (methylsulfonyl) phenyl
334 S02CH3 2, 5-diF-phenyl 4-morpholino
335 S0CH3 2, 5-diF-phenyl 2- (1 ' -CF3-tetrazol-2-yl) phenyl
336 S02CH3 2, 5-diF-phenyl 4-morpholinocarbonyl
337 NHS02CH3 phenyl 2- (aminosulfonyl ) phenyl
338 NHS02CH3 phenyl 2- (methylaminosulfonyl) phenyl
339 NHS02CH3 phenyl 1-pyrrolidinocarbonyl
340 NHS02CH3 phenyl 2- (methylsulfonyl) phenyl
341 NHS0CH3 phenyl 4-morpholino
342 NHS02CH3 phenyl 2- (l'-CF3-tetrazol-2-yl) phenyl
343 NHS02CH3 phenyl 4-morpholinocarbonyl
344 NHS02CH3 2-pyridyl 2- (aminosulfonyl ) phenyl
345 NHS02CH3 2-pyridyl 2- (methylaminosulfonyl) phenyl
346 NHS02CH3 2-pyridyl 1-pyrro1idinocarbonyl
347 NHS0CH3 2-pyridyl 2- (methylsulfonyl) phenyl
348 NHS0CH3 2-pyridyl 4-morpholino
349 NHS02CH3 2-pyridyl 2- (1 ' -CF3 -tetrazol-2-yl ) phenyl
350 NHS02CH3 2-pyridyl 4-morpholinocarbonyl
351 NHS02CH3 3 -pyridyl 2- (aminosulfony1) phenyl
352 NHS02CH3 3 -pyridyl 2- (methylaminosulfonyl) phenyl
353 NHS02CH3 3 -pyridyl 1-pyrro1idinocarbonyl
354 NHS02CH3 3 -pyridyl 2- (methylsulfonyl) phenyl
355 NHS02CH3 3 -pyridyl 4-morpholino
356 NHS02CH3 3 -pyridyl 2- ( 1 ' -CF3 -tetrazol-2-yl ) phenyl
357 NHS02CH3 3-pyridyl 4-morpholinocarbonyl
358 NHS02CH3 2-pyrimidyl 2- (aminosulfony1) phenyl
359 NHS0CH3 2-pyrimidyl 2- (methylaminosulfonyl) phenyl
360 NHS02CH3 2-pyrimidyl 1-pyrrolidinocarbonyl
361 NHS02CH3 2-pyrimidyl 2- (methylsulfonyl) phenyl
362 NHS02CH3 2-pyrimidyl 4-morpholino
363 NHS02CH3 2-pyrimidyl 2-(l'-CF3-tetrazol-2-yl)phenyl
364 NHS02CH3 2-pyrimidyl 4-morpholinocarbonyl
365 NHS02CH3 5-pyrimidyl 2- (aminosulfonyl) phenyl
366 NHS02CH3 5-pyrimidyl 2- (methylaminosulfonyl) phenyl
367 NHS0CH3 5-pyrimidyl 1-pyrrolidinocarbonyl
368 NHS02CH3 5-pyrimidyl 2- (methylsulfonyl) phenyl
369 NHS02CH3 5-pyrimidyl 4-morpholino
370 NHS02CH3 5-pyrimidyl 2- ( 1 ' -CF3 -tetrazol-2 -yD phenyl
371 NHS02CH3 5-pyrimidyl 4-morpholinocarbonyl
372 NHS02CH3 2-Cl-phenyl 2- (aminosulfonyl) phenyl
373 NHS02CH3 2-Cl-phenyl 2- (methylaminosulfonyl) phenyl
374 NHS02CH3 2-Cl-phenyl 1-pyrro1idinocarbonyl
375 NHS0CH3 2-Cl-phenyl 2- (methylsulfonyl) phenyl
376 NHS02CH3 2-Cl-phenyl 4-morpholino
377 NHS0CH3 2-Cl-phenyl 2- (1' -CF3-tetrazol-2-yl) henyl
378 NHS02CH3 2-Cl-phenyl 4-morpholinocarbonyl
379 NHS02CH3 2-F-phenyl 2- (aminosulfonyl) phenyl
380 NHS02CH3 2-F-phenyl 2- (methylaminosulfonyl) phenyl
381 NHS02CH3 2-F-phenyl 1-pyrro1idinocarbony1
382 NHS02CH3 2-F-phenyl 2- (methylsulfonyl) phenyl
383 NHS02CH3 2-F-phenyl 4-morpholino
384 NHS02CH3 2--F--phenyl 2- (1' -CF3-tetrazol-2-yl) phenyl
385 NHS02CH3 2- -F- -phenyl 4-morpholinocarbonyl
386 NHS02CH3 2, ,5- -diF-phenyl 2- (aminosulfonyl) phenyl
387 NHS02CH3 2, ,5- -diF-phenyl 2- (methylaminosulfonyl) phenyl
388 NHS02CH3 2, ,5- -diF-phenyl 1-pyrro1idinocarbonyl
389 NHS02CH3 2, ,5- -diF-phenyl 2- (methylsulfonyl) phenyl
390 NHS02CH3 2, ,5- -diF-phenyl 4-morpholine
391 NHS02CH3 2, ,5- -diF-phenyl 2- ( 1 ' -CF3 -tetrazol-2-yl ) phenyl
392 NHS02CH3 2, ,5- -diF-phenyl 4-morpholinocarbonyl
Table 5
J1 R=F, D=NH2 ki R=F, D=NH2 h R=F, D=NH2 j2 R=H, D=NH2 k2 R=H, D=NH2 12 R=H, D=NH2 j3 R=F, D=CH2NH2 k3 R=F, D=CH2Nh2 13 R=F, D=CH2NH2 j4 R=H, D=CH2NH2 l< R=H, D=CH2NH2 14 R=H, D=CH2NH2 j5 R=F, D=C(=NH)NH2 k5 R=F, D=C(=NH)NH2 15 R=F, D=C(=NH)NH2 j6 R=H, D=C(=NH)NH2 k6 R=H, D=C(=NH)NH2 16 R=H, D=C(=NH)NH2 j7 R=F, D=C(0)NH2 k7 R=F, D=C(0)NH2 17 R=F, D=C(0)NH2 j8 R=H, D=C(0)NH2 k8 R=H, D=C(0)NH2 18 R=H, D=C(0)NH2
Pi R=F, D=NH2 qi R=F, D=NH2 R=F, D= NH2 p2 R=CI, D=NH2 q2 R=CI, D=NH2 R=CI, D: :NH2 p3 R=OMe, D=NH2 q3 R=OMe, D=NH2 R=OMe, D=NH2 p4 R=F, D=CH2NH2 q4 R=F, D=CH2NH2 R=F, D= CH2NH2 p5 R=CI, D=CH2NH2 q5 R=CI, D=CH2NH2 R=CI, D :CH2NH2 p6 R=OMe, D=CH2NH2 q6 R=OMe, D=CH2NH2 R=OMe, D=CH2NH2 p7 R=F, D=C(=NH)NH2 q7 R=F, D=C(=NH)NH2 R=F, D= C(=NH)NH2 p8 R=CI, D=C(=NH)NH2 q8 R=CI, D=C(=NH)NH2 R=CI, D =C(=NH)NH2 p9 R=OMe, D=C(=NH)NH2 q9 R=OMe, D=C(=NH)NH2 R=OMe, D=C(=NH)NH2 P10 R=F, D=C(0)NH2 qio R=F, D=C(0)NH2 10 R=F, D =C(0)NH2 Pii R=CI, D=C(0)NH2 qn R=CI, D=C(0)NH2 n R=CI, D >=C(0)NH2 P12 R=OMe, D=C(0)NH2 qi2 R=OMe, D=C(0)NH2 12 R=OMe , D=C(0)NH2
Si R=F, D=NH2 ti R=F, D=NH2 uι R=F, D=NH2 s2 R=CI, D=NH2 t2 R=CI, D=NH2 u2 R=CI, D=NH2 s3 R=OMe, D=NH2 t3 R=OMe, D=NH2 u3 R=OMe, D=NH2 s4 R=F, D=CH2NH2 t4 R=F, D=CH2NH2 u4 R=F, D=CH2NH2 s5 R=CI, D=CH2NH2 t5 R=CI, D=CH2NH2 u5 R=CI, D=CH2NH2 s6 R=OMe, D=CH2NH2 t6 R=OMe, D=CH2NH2 u6 R=OMe, D^H^h^ s7 R=F, D=C(=NH)NH2 t7 R=F, D=C(=NH)NH2 u7 R=F, D=C(=NH)NH2 s8 R=CI, D=C(=NH)NH2 t8 R=CI, D=C(=NH)NH2 u8 R=CI, D=C(=NH)NH2 s9 R=OMe, D=C(=NH)NH2 t9 R=OMe, D=C(=NH)NH2 ug R=OMe, D=C(=NH)NH2 Sιo R=F, D=C(0)NH2 ti0 R=F, D=C(0)NH2 Uιo R=F, D=C(0)NH2 SH R=CI, D=C(0)NH2 tn R=CI, D=C(0)NH2 Uιι R=CI, D=C(0)NH2 sι2 R=OMe, D=C(0)NH2 tι2 R=OMe, D=C(0)NH2 uι2 R=OMe, D=C(0)NH2
Ex# R"* B
1 H phenyl 2- ( (Me) 2N-methyl) phenyl
2 H phenyl 2 - ( (Me ) NH-methyl ) phenyl
3 H phenyl 2 - (H2N-methyl ) phenyl
4 H phenyl 2 -HOCH2 -phenyl
5 H 2-F-phenyl 2- ( (Me) 2N-me thyl ) phenyl
6 H 2-F-phenyl 2 - ( (Me ) NH-methyl ) phenyl
7 H 2-F-phenyl 2 - ( H2N-me thy 1 ) phenyl
8 H 2-F-phenyl 2 -HOCH2 -phenyl
9 H phenyl 2-methylimidazol-l-yl
10 H phenyl 2-ethylimidazol-l-yl
11 H phenyl 2- ( (Me) 2N-methyl ) imidazol-1-yl
12 H phenyl 2-CH3NHS02-imidazol-l-yl
H phenyl 2-CH3OCH2-imidazol-l-yl
H 2-F-phenyl 2-methylimidazol-l-yl
H 2-F-phenyl 2-ethylimidazol-l-yl
H 2-F-phenyl 2- ( (Me) N-methyl) imidazol-1-yl
H 2-F-phenyl 2-CH3S02-imidazol-l-yl
H 2-F-phenyl 2-CH3OCH2-imidazol-l-yl
H 2-Cl-phenyl 2-methylimidazol-l-yl
H 2-Cl-phenyl 2-ethylimidazol-l-yl
H 2-Cl-phenyl 2- ( (Me) 2N-methyl) imidazol-1-yl
H 2-Cl-phenyl 2-CH3S02-imidazol-l-yl
H 2-Cl-phenyl 2-CH3OCH2-imidazol-l-yl
H 2- (Me) 2 -phenyl 2-methylimidazol-l-yl
H 2- (Me)2N-phenyl 2-ethylimidazol-l-yl
H 2-(Me)2N-phenyl 2- ( (Me)2N-methyl) imidazol-1-yl
H 2- (Me)2N-phenyl 2-CH3S02-imidazol-l-yl
H 2-(Me)2N-phenyl 2-CH3OCH2-imidazol-l-yl
H phenyl N-methylimidazol-2-yl
H phenyl 4-methylimidazol-5-yl
H phenyl 5-CF3-pyrazol-1-yl
H 2-F-phenyl N-methylimidazol-2-yl
H 2-F-phenyl 4-methylimidazol-5-yl
H 2-F-phenyl 5-CF3-pyrazol-1-yl
H phenyl guanidino
H phenyl 2-thiazolin-2-ylamine
H phenyl N-methyl-2-imidazolin-2-yl
H phenyl N-methyl-1, 4,5,6- tetrahydropyrimid-2-yl
H phenyl N-methylimidazol-2-ylthiol
H phenyl t-butoxycarbonylamine
H phenyl (N-pyrrolidino) formylimino
H phenyl (N-pyrrolidino) formyl-N-
(methanesulfamoyl) imino
H 2-F-phenyl guanidino
H 2-F-phenyl 2-thiazolin-2-ylamine
H 2-F-phenyl N-methyl-2-imidazolin-2-yl
H 2-F-phenyl N-methyl-1,4,5, 6- tetrahydropyrimid-2-yl
H 2-F-phenyl N-methylimidazol-2-ylthio
H 2-F-phenyl t-butoxycarbonylamine
H 2-F-phenyl (N-pyrrolidino) formylimino
H 2-F-phenyl (N-pyrrolidino) formyl-N-
(methanesulfamoyl) imino
H 2-CH30-phenyl (N-pyrrolidino) formylimino
H 2-CH30-phenyl (N-pyrrolidino) formyl-N-
(methanesulfamoyl) imino
-CN phenyl 2- ( (Me) 2N-methyl) henyl
-CN phenyl 2- ( (Me) NH-methyl) phenyl
-CN phenyl 2- (H2N-methyl) phenyl
-CN phenyl 2-HOCH2-phenyl
-CN 2-F-phenyl 2- ( (Me) N-methyl) phenyl
-CN 2-F-phenyl 2- ( (Me) NH-methyl) phenyl
-CN 2-F-phenyl 2- (H2N-methyl) phenyl
-CN 2-F-phenyl 2-HOCH2-phenyl
-CN phenyl 2-methylimidazol-l-yl
-CN phenyl 2-ethylimidazol-l-yl
-CN pheryl 2 - ( (Me) N-methyl ) imidazol-1-yl
-CN pheryl 2-CH3S02-imidazol-l-yl
-CN phenyl 2 -CH3OCH2- imidazol -1-yl
-CN 2-F-phenyl 2-methylimidazol-l-yl
-CN 2-F-phenyl 2-ethylimidazol-l-yl
-CN 2-F-phenyl 2- ( (Me) 2N-methyl) imidazol-1-yl
-CN 2-F-phenyl 2-CH3S02-imidazol-1-yl
-CN 2-F-phenyl 2-CH3OCH2-imidazol-l-yl
-CN 2-Cl-phenyl 2-methylimidazol-l-yl
-CN 2-Cl-phenyl 2-ethylimidazol-l-yl
-CN 2-Cl-phenyl 2-( (Me)2N-methyl) imidazol-1-yl
-CN 2-Cl-phenyl 2-CH3S02-imidazol-1-yl
-CN 2-Cl-phenyl 2-CH3OCH2-imidazol-l-yl
-CN 2- (Me)2N-phenyl 2-methylimidazol-l-yl
-CN 2-(Me)2N-phenyl 2-ethylimidazol-l-yl
-CN 2-(Me)2N-phenyl 2-( (Me)2N-methyl) imidazol-1-yl
-CN 2- (Me) 2N-phenyl 2-CH3S02-imidazol-l-yl
-CN 2-(Me)2N-phenyl 2-CH3OCH2-imidazol-l-yl
-CN phenyl N-methylimidazol-2-yl
-CN phenyl 4-methylimidazol-5-yl
-CN phenyl 5-CF3-pyrazol-1-yl
-CN 2-F-phenyl N-methylimidazol-2-yl
-CN 2-F-phenyl 4-methylimidazol-5-yl
-CN 2-F-phenyl 5-CF3-pyrazol-1-yl
-CN phenyl guanidino
-CN phenyl 2-thiazolin-2-ylamine
-CN phenyl N-methyl-2-imidazolin-2-yl
-CN phenyl N-methyl-1,4, 5, 6- tetrahydropyrimid-2-yl
-CN phenyl N-methylimidazol-2-ylthiol
-CN phenyl t-butoxycarbonylamine
-CN phenyl (N-pyrrolidino) formylimino
-CN phenyl (N-pyrrolidino) formyl-N-
(methanesulfamoyl) imino
-CN 2-F-phenyl guanidino
-CN 2-F-phenyl 2-thiazolin-2-ylamine
-CN 2-F-phenyl N-methyl-2-imidazolin-2-yl
-CN 2-F-phenyl N-methyl-1,4, 5, 6- tetrahydropyrimid-2-yl
-CN 2-F-phenyl N-methylimidazol-2-ylthio
-CN 2-F-phenyl t-butoxycarbonylamine
-CN 2-F-phenyl (N-pyrrolidino) formylimino
-CN 2-F-phenyl (N-pyrrolidino) formyl-N-
(methanesulfamoyl) imino
-CN 2-CH30-phenyl (N-pyrrolidino) formylimino
-CN 2-CH30-phenyl (N-pyrrolidino) formyl-N-
(methanesulfamoyl) imino
CF3 phenyl 2- ( (Me) 2N-methyl) phenyl
CF3 phenyl 2- ( (Me) NH-methyl ) phenyl
CF3 phenyl 2- (H2N-methyl ) phenyl
CF3 phenyl 2-HOCH2-phenyl
CF3 2-F-phenyl 2- ( (Me) 2N-methyl ) phenyl
CF3 2-F-phenyl 2- ( (Me) NH-methyl) phenyl
CF3 2-F-phenyl 2- (H2N-methyl) phenyl
112 CF3 2-F-phenyl 2-HOCH2-phenyl
113 CF3 phenyl 2-methylimidazol-l-yl
114 CF3 phenyl 2-ethylimidazol-l-yl
115 CF3 phenyl 2-( (Me) 2N-methyl) imidazol-1-yl
116 CF3 phenyl 2-CH3S02-imidazol-l-yl
117 CF3 phenyl 2-CH3OCH2-imidazol-l-yl
118 CF3 2-F-phenyl 2-methylimidazol-l-yl
119 CF3 2-F-phenyl 2-ethylimidazol-l-yl
120 CF3 2-F-phenyl 2- ( (Me) 2N-methyl) imidazol-1-yl
121 CF3 2-F-phenyl 2 -CH3S02-imidazol-1-yl
122 CF3 2-F-phenyl 2-CH3OCH2-imidazol-l-yl
123 CF3 2-Cl-phenyl 2-methylimidazol-l-yl
124 CF3 2-Cl-phenyl 2-ethylimidazol-l-yl
125 CF3 2-Cl-phenyl 2- ( (Me) 2N-methyl) imidazol-1-yl
126 CF3 2-Cl-phenyl 2-CH3S0 -imidazol-l-yl
127 CF3 2-Cl-phenyl 2-CH3OCH2-imidazol-l-yl
128 CF3 2-(Me)2N-phenyl 2-methylimidazol-l-yl
129 CF3 2-(Me)2N-phenyl 2-ethylimidazol-l-yl
130 CF3 2- (Me) 2N-phenyl 2- ( (Me) 2N-methyl) imidazol-1-yl
131 CF3 2- (Me) 2N-phenyl 2-CH3S02-imidazol-l-yl
132 CF3 2- (Me) 2N-phenyl 2-CH3OCH2-imidazol-l-yl
133 CF3 phenyl N-methylimidazol-2 -yl
134 CF3 phenyl 4-methylimidazol-5-yl
135 CF3 phenyl 5-CF3-pyrazol-1-yl
136 CF3 2-F-phenyl N-methylimidazol-2-yl
137 CF3 2-F-phenyl 4-methylimidazol-5-yl
138 CF3 2-F-phenyl 5-CF3-pyrazol-1-yl
139 CF3 phenyl guanidino
140 CF3 phenyl 2-thiazolin-2-ylamine
141 CF3 phenyl N-methyl-2-imidazolin-2-yl
142 CF3 phenyl N-methyl-1,4, 5, 6- tetrahydropyrimid-2 -yl
143 CF3 phenyl N-methylimidazol-2-ylthiol
144 CF3 phenyl t-butoxycarbonylamine
145 CF3 phenyl (N-pyrrolidino) formylimino
146 CF3 phenyl (N-pyrrolidino) formyl-N-
(methanesulfamoyl) imino
147 CF3 2-F-phenyl guanidino
148 CF3 2-F-phenyl 2-thiazolin-2 -ylamine
149 CF3 2-F-phenyl N-methyl-2-imidazolin-2-yl
150 CF3 2-F-phenyl N-methyl-1,4, 5, 6- tetrahydropyrimid-2-yl
151 CF3 2-F-phenyl N-methylimidazol-2-ylthio
152 CF3 2-F-phenyl t-butoxycarbonylamine
153 CF3 2-F-phenyl (N-pyrrolidino) formylimino
154 CF3 2-F-phenyl (N-pyrrolidino) formyl-N-
(methanesulfamoyl) imino
155 CF3 2-CH30-phenyl (N-pyrrolidino) formylimino
156 CF3 2-CH30-phenyl (N-pyrrolidino) formyl-N-
(methanesulfamoyl) imino
157 CONH2 phenyl 2- ( (Me) 2N-methyl) phenyl
158 CONH2 phenyl 2- ( (Me) NH-methyl) phenyl
159 CONH2 phenyl 2- (H2N-methyl) phenyl
160 CONH2 phenyl 2-HOCH2-phenyl
161 CONH 2-F-phenyl 2- ( (Me) 2N-methyl)phenyl
162 CONH2 2-F-phenyl 2- ( (Me) NH-methyl) phenyl
163 CONH2 2-F-phenyl 2- (H2N-methyl) phenyl
164 CONH2 2-F-phenyl 2-HOCH2-phenyl
165 CONH2 phenyl 2-methylimidazol-l-yl
166 CONH2 phenyl 2-ethylimidazol-l-yl
167 CONH2 phenyl 2- ( (Me) 2N-methyl) imidazol-1-yl
168 CONH2 phenyl 2-CH3S02-imidazol-l-yl
169 CONH2 phenyl 2-CH3OCH2-imidazol-l-yl
170 CONH2 2-F-phenyl 2-methylimidazol-l-yl
171 CONH2 2-F-phenyl 2-ethylimidazol-l-yl
172 CONH2 2-F-phenyl 2-( (Me)2N-methyl) imidazol-1-yl
173 CONH2 2-F-phenyl 2-CH3S02-imidazol-1-yl
174 CONH2 2-F-phenyl 2-CH3OCH2-imidazol-1-yl
175 CONH2 2-Cl-phenyl 2-methylimidazol-l-yl
176 CONH2 2-Cl-phenyl 2-ethylimidazol-l-yl
177 CONH2 2-Cl-phenyl 2- ( (Me) N-methyl) imidazol-1-yl
178 CONH2 2-Cl-phenyl 2-CH3S0 -imidazol-l-yl
179 CONH2 2-Cl-phenyl 2-CH3OCH2-imidazol-l-yl
180 CONH 2-(Me)2N-phenyl 2-methylimidazol-l-yl
181 CONH2 2- (Me)2N-phenyl 2-ethylimidazol-l-yl
182 CONH2 2- (Me) 2N-phenyl 2- ( (Me) 2N-methyl) imidazol-1-yl
183 CONH2 2- (Me) 2N-phenyl 2-CH3S02-imidazoi-l-yl
184 CONH2 2- (Me) 2N-phenyl 2-CH3OCH2-imidazol-l-yl
185 CONH2 phenyl N-methylimidazol-2-yl
186 CONH2 phenyl 4-methylimidazol-5-yl
187 CONH2 phenyl 5-CF3-pyrazol-1-yl
188 CONH2 2-F-phenyl N-methylimidazol-2-yl
189 CONH2 2-F-phenyl 4-methylimidazol-5-yl
190 CONH2 2-F-phenyl 5-CF3-pyrazol-1-yl
191 CONH2 phenyl guanidino
192 CONH2 phenyl 2-thiazolin-2-ylamine
193 CONH2 phenyl N-methyl-2-imidazolin-2-yl
194 CONH2 phenyl N-methyl-1,4, 5, 6- tetrahydropyrimid-2-yl
195 CONH2 phenyl N-methylimidazol-2-ylthiol
196 CONH2 phenyl t-butoxycarbonylamine
197 CONH2 phenyl (N-pyrrolidino) formylimino
198 CONH2 phenyl (N-pyrrolidino) formyl-N-
(methanesulfamoyl) imino
199 CONH2 2-F-phenyl guanidino
200 CONH2 2-F-phenyl 2-thiazolin-2-ylamine
201 CONH2 2-F-phenyl N-methyl-2-imidazolin-2-yl
202 CONH2 2-F-phenyl N-methyl-1,4, 5, 6- tetrahydropyrimid-2-yl
203 CONH2 2-F-phenyl N-methylimidazol-2-ylthio
204 CONH2 2-F-phenyl t-butoxycarbonylamine
205 CONH2 2-F-phenyl (N-pyrrolidino) formylimino
206 CONH2 2-F-phenyl (N-pyrrolidino) formyl-N-
(methanesulfamoyl) imino
207 CONH2 2-CH30-phenyl (N-pyrrolidino) formylimino
208 CONH2 2-CH30-phenyl (N-pyrrolidino) formyl-N-
(methanesulfamoyl) imino
209 SCH3 phenyl 2- ( (Me) 2N-methyl ) phenyl
210 SCH3 phenyl 2- ( (Me) NH-methyl) phenyl
211 SCH3 phenyl 2- (H2N-methyl) phenyl
212 SCH3 phenyl 2-HOCH2-phenyl
213 SCH3 2-F-phenyl 2- ( (Me) 2N-methyl) phenyl
214 SCH3 2-F-phenyl 2- ( (Me) NH-methyl ) phenyl
215 SCH3 2-F-phenyl 2- (H2N-methyl ) phenyl
216 SCH3 2-F-phenyl 2-HOCH2-phenyl
217 SCH3 phenyl 2-methylimidazol-l-yl
218 SCH3 phenyl 2-ethylimidazol-l-yl
219 SCH3 phenyl 2- ( (Me) 2N-methyl) imidazol-1-yl
220 SCH3 phenyl 2-CH3S02-imidazol-l-yl
221 SCH3 phenyl 2-CH3OCH2-imidazol-l-yl
222 SCH3 2-F-phenyl 2-methylimidazol-l-yl
223 SCH3 2-F-phenyl 2-ethylimidazol-l-yl
224 SCH3 2-F-phenyl 2- ( (Me) 2N-methyl) imidazol-1-yl
225 SCH3 2-F-phenyl 2-CH3S02-imidazol-l-yl
226 SCH3 2-F-phenyl 2-CH3OCH2-imidazol-1-yl
227 SCH3 2-Cl-phenyl 2-methylimidazol-l-yl
228 SCH3 2-Cl-phenyl 2-ethylimidazol-l-yl
229 SCH3 2-Cl-phenyl 2- ( (Me) 2N-methyl) imidazol-1-yl
230 SCH3 2-Cl-phenyl 2-CH3S02-imidazol-l-yl
231 SCH3 2-Cl-phenyl 2-CH3OCH2-imidazol-l-yl
232 SCH3 2- (Me) 2N-phenyl 2-methylimidazol-l-yl
233 SCH3 2- (Me)2N-phenyl 2-ethylimidazol-l-yl
234 SCH3 2- (Me) 2N-phenyl 2- ( (Me) 2N-methyl) imidazol-1-yl
235 SCH3 2-(Me)2N-phenyl 2-CH3S02-imidazol-l-yl
236 SCH3 2- (Me)2N-phenyl 2-CH3OCH2-imidazol-l-yl
237 SCH3 phenyl N-methylimidazol-2-yl
238 SCH3 phenyl 4-methylimidazol-5-yl
239 SCH3 phenyl 5-CF3-pyrazol-1-yl
240 SCH3 2-F-phenyl N-methylimidazol-2-yl
241 SCH3 2-F-phenyl 4-methylimidazol-5-yl
242 SCH3 2-F-phenyl 5-CF3-pyrazol-1-yl
243 SCH3 phenyl guanidino
244 SCH3 phenyl 2-thiazolin-2-ylamine
245 SCH3 phenyl N-methyl-2-imidazolin-2-yl
246 SCH3 phenyl N-methyl-1,4, 5, 6- tetrahydropyrimid-2-y1
247 SCH3 phenyl N-methylimidazol-2-ylthiol
248 SCH3 phenyl t-butoxycarbonylamine
249 SCH3 phenyl (N-pyrrolidino) formylimino
250 SCH3 phenyl (N-pyrrolidino) formyl-N-
(methanesulfamoyl) imino
251 SCH3 2-F-phenyl guanidino
252 SCH3 2-F-phenyl 2-thiazolin-2 -ylamine
253 SCH3 2-F-phenyl N-methyl-2-imidazolin-2-yl
254 SCH3 2-F-phenyl N-methyl-1,4, 5, 6- tetrahydropyrimid-2-yl
255 SCH3 2-F-phenyl N-methylimidazol-2-ylthio
256 SCH3 2-F-phenyl t-butoxycarbonylamine
257 SCH3 2-F-phenyl (N-pyrrolidino) formylimino
258 SCH3 2-F-phenyl (N-pyrrolidino) formyl-N-
(methanesulfamoyl) imino
259 SCH3 2-CH30-phenyl (N-pyrrolidino) formylimino
260 SCH3 2-CH30-phenyl (N-pyrrolidino) formyl-N-
(methanesulfamoyl) imino
261 S02CH3 phenyl 2- ( (Me)2N-methyl) phenyl
262 S02CH3 phenyl 2- ( (Me) NH-methyl) phenyl
263 S02CH3 phenyl 2- (H2N-methyl) phenyl
264 S02CH3 phenyl 2-HOCH -phenyl
265 S02CH3 2-F-phenyl 2- ( (Me) 2N-methy1 ) phenyl
266 S02CH3 2-F-phenyl 2- ( (Me) NH-methyl ) phenyl
267 S02CH3 2-F-phenyl 2- (H2N-methyl) phenyl
268 S02CH3 2-F-phenyl 2-HOCH2-phenyl
269 S02CH3 phenyl 2-methylimidazol-1-yl
270 S02CH3 phenyl 2-ethylimidazol-l-yl
271 S02CH3 phenyl 2- ( (Me) 2N-methyl) imidazol-1-yl
272 S02CH3 phenyl 2-CH3S02-imidazol-l-yl
273 S02CH3 phenyl 2-CH3OCH2-imidazol-l-yl
274 S02CH3 2-F-phenyl 2-methylimidazol-l-yl
275 S02CH3 2-F-phenyl 2-ethylimidazol-l-yl
276 S02CH3 2-F-phenyl 2-( (Me) 2N-methyl) imidazol-1-yl
277 S02CH3 2-F-phenyl 2-CH3S02-imidazol-l-yl
278 S02CH3 2-F-phenyl 2-CH3OCH2-imidazol-l-yl
279 S0CH3 2-Cl-phenyl 2-methylimidazol-l-yl
280 S02CH3 2-Cl-phenyl 2-ethylimidazol-l-yl
281 S02CH3 2-Cl-phenyl 2- ( (Me) 2N-methyl) imidazol-1-yl
282 S02CH3 2-Cl-phenyl 2-CH3S02-imidazol-1-yl
283 S02CH3 2-Cl-phenyl 2-CH3OCH2-imidazol-l-yl
284 S02CH3 2- (Me) 2N-phenyl 2-methylimidazol-1-yl
285 S0CH3 2- (Me) 2N-phenyl 2-ethylimidazol-l-yl
286 S02CH3 2-(Me)2N-phenyl 2- ( (Me)2N-methyl) imidazol-1-yl
287 S02CH3 2-(Me)2N-phenyl 2-CH3S02-imidazol-l-yl
288 S02CH3 2-(Me)2N-phenyl 2-CH3OCH2-imidazol-l-yl
289 S02CH3 phenyl N-methylimidazol-2-yl
290 S02CH3 phenyl 4-methylimidazol-5-yl
291 S02CH3 phenyl 5-CF3-pyrazol-1-yl
292 S02CH3 2-F-phenyl N-methylimidazol-2-yl
293 S02CH3 2-F-phenyl 4-methylimidazol-5-yl
294 S02CH3 2-F-phenyl 5-CF3-pyrazol-1-yl
295 S02CH3 phenyl guanidino
296 S02CH3 phenyl 2-thiazolin-2-ylamine
297 S02CH3 phenyl N-methyl-2-imidazolin-2-yl
298 S02CH3 phenyl N-methyl-1,4, 5, 6- tetrahydropyrimid-2-y1
299 S02CH3 phenyl N-methylimidazol-2-ylthiol
300 S02CH3 phenyl t-butoxycarbonylamine
301 S02CH3 phenyl (N-pyrrolidino) formylimino
302 S02CH3 phenyl (N-pyrrolidino) formyl-N-
(methanesulfamoyl) imino
303 S0CH3 2-F-phenyl guanidino
304 S02CH3 2-F-phenyl 2-thiazolin-2-ylamine
305 S02CH3 2-F-phenyl N-methyl-2-imidazolin-2-yl
306 S02CH3 2-F-phenyl N-methyl-1,4, 5, 6- tetrahydropyrimid-2-yl
307 S02CH3 2-F-phenyl N-methylimidazol-2-ylthio
308 S02CH3 2-F-phenyl t-butoxycarbonylamine
309 S02CH3 2-F-phenyl (N-pyrrolidino) formylimino
310 S02CH3 2-F-phenyl (N-pyrrolidino) formyl-N-
(methanesulfamoyl) imino
311 S02CH3 2-CH30-phenyl (N-pyrrolidino) formylimino
312 S02CH3 2-CH30-phenyl (N-pyrrolidino) formyl-N-
(methanesulfamoyl) imino
313 NHSθ2CH3 phenyl 2- ( (Me) 2N-methyl) phenyl
314 NHS02CH3 phenyl 2- ( (Me)NH-methyl) henyl
315 NHS02CH3 phenyl 2- (H2N-methyl ) phenyl
316 NHS0CH3 phenyl 2-H0CH2-phenyl
317 NHS0CH3 2-F-phenyl 2- ( (Me) 2N-methyl) phenyl
318 NHS02CH3 2-F-phenyl 2- ( (Me) NH-methyl) henyl
319 NHS0CH3 2-F-phenyl 2- (H2N-methyl ) phenyl
320 NHS0CH3 2-F-phenyl 2-H0CH2-phenyl
321 NHS02CH3 phenyl 2-methylimidazol-l-yl
322 NHS02CH3 phenyl 2-ethylimidazol-l-yl
323 NHS02CH3 phenyl 2- ( (Me) 2N-methyl) imidazol-1-yl
324 NHS0CH3 phenyl 2-CH3S02-imidazol-l-yl
325 NHS0CH3 phenyl 2-CH30CH2-imidazol-1-yl
326 NHS02CH3 2-F-phenyl 2-methylimidazol-l-yl
327 NHS02CH3 2-F-phenyl 2-ethylimidazol-l-yl
328 NHS02CH3 2-F-phenyl 2- ( (Me) 2N-methyl) imidazol-1-yl
329 NHS02CH3 2-F-phenyl 2-CH3S02-imidazol-l-yl
330 NHS02CH3 2-F-phenyl 2-CH30CH2-imidazol-1-yl
331 NHS02CH3 2-Cl-phenyl 2-methylimidazol-1-yl
332 NHS02CH3 2-Cl-phenyl 2-ethylimidazol-l-yl
333 NHS02CH3 2-Cl-phenyl 2-( (Me) N-methyl) imidazol-1-yl
334 NHS02CH3 2-Cl-phenyl 2-CH3S02-imidazol-l-yl
335 NHS0CH3 2-Cl-phenyl 2-CH30CH2-imidazol-l-yl
336 NHSθ2CH3 2-(Me)2N-phenyl 2-methylimidazol-l-yl
337 NHS02CH3 2-(Me)2N-phenyl 2-ethylimidazol-l-yl
338 NHSθ2CH3 2-(Me)2N-phenyl 2- ( (Me) 2N-methyl) imidazol-1-yl
339 NHS02CH3 2- (Me) 2N-phenyl 2-CH3S02-imidazol-1-yl
340 NHS0CH3 2-(Me)2N-phenyl 2-CH30CH2-imidazol-1-yl
341 NHS02CH3 phenyl N-methylimidazol-2-yl
342 NHS02CH3 phenyl 4-methylimidazol-5-yl
343 NHS02CH3 phenyl 5-CF3-pyrazol-1-yl
344 NHS02CH3 2-F-phenyl N-methylimidazol-2-yl
345 NHS02CH3 2-F-phenyl 4-methylimidazol-5-yl
346 NHS02CH3 2-F-phenyl 5-CF3-pyrazol-1-yl
347 NHS02CH3 phenyl guanidino
348 NHS02CH3 phenyl 2-thiazolin-2-ylamine
349 NHS02CH3 phenyl N-methyl-2-imidazolin-2-yl
350 NHS02CH3 phenyl N-methyl-1,4, 5, 6- tetrahydropyrimid-2-y1
351 NHS02CH3 phenyl N-methylimidazol-2-ylthiol
352 NHS02CH3 phenyl t-butoxycarbonylamine
353 NHS02CH3 phenyl (N-pyrrolidino) formylimino
354 NHS0CH3 phenyl (N-pyrrolidino) formyl-N-
(methanesulfamoyl) imino
355 NHS02CH3 2- -F-phenyl guanidino
356 NHS02CH3 2- -F-phenyl 2-thiazolin-2-ylamine
357 NHS02CH3 2- -F-phenyl N-methyl-2-imιdazolin-2-yl
358 NHS02CH3 2- -F-phenyl N-methyl-1, 4,5,6- tetrahydropyrimid-2-yl
359 NHS02CH3 2- -F-phenyl N-methylimidazol-2-ylthio
360 NHS0CH3 2- -F-phenyl t-butoxycarbonylamine
361 NHS02CH3 2- -F-phenyl (N-pyrrolidino) formylimino
362 NHS02CH3 2- -F-phenyl (N-pyrrolidino) formyl-N-
(methanesulfamoyl) imino
363 NHS0CH3 2- -CH30-phenyl (N-pyrrolidino) formylimino
364 NHS02CH3 2- -CH30-phenyl (N-pyrrolidino) formyl-N-
(methanesulfamoyl) imino
Utility The compounds of this invention are useful as anticoagulants for the treatment or prevention of thromboembolic disorders in mammals. The term "thromboembolic disorders" as used herein includes arterial or venous cardiovascular or cerebrovascular thromboembolic disorders, including, for example, unstable angina, first or recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary and cerebral arterial thrombosis, cerebral embolism, kidney embolisms, and pulmonary embolisms. The anticoagulant effect of compounds of the present invention is believed to be due to inhibition of factor Xa or thrombin. The effectiveness of compounds of the present invention as inhibitors of factor Xa was determined using purified human factor Xa and synthetic substrate. The rate of factor Xa hydrolysis of chromogenic substrate S2222 (Kabi Pharmacia, Franklin, OH) was measured both in the absence and presence of compounds of the present invention. Hydrolysis of the substrate resulted in the release of pNA, which was monitored spectrophotometrically by measuring the increase in absorbance at 405 nM. A decrease in the rate of absorbance change at 405 nm in the presence of inhibitor is indicative of enzyme inhibition. The results of this assay are expressed as inhibitory constant, Ki .
Factor Xa determinations were made in 0.10 M sodium phosphate buffer, pH 7.5, containing 0.20 M NaCl, and 0.5 % PEG 8000. The Michaelis constant, Km, for substrate hydrolysis was determined at 25°C using the method of ineweaver and Burk. Values of Ki were determined by allowing 0.2-0.5 nM human factor Xa (Enzyme Research Laboratories, South Bend, IN) to react with the substrate (0.20 ιrιM-1 mM) in the presence of inhibitor. Reactions were allowed to go for 30 minutes and the velocities (rate of absorbance change vs time) were measured in the time frame of 25-30 minutes. The following relationship was used to calculate Ki values:
(v0-vs)/vs = I/(Ki (1 + S/Kπ )
where : v0 is the velocity of the control in the absence of inhibitor; vs is the velocity in the presence of inhibitor; I is the concentration of inhibitor;
Ki is the dissociation constant of the enzyme : inhibitor complex; S is the concentration of substrate; Km is the Michaelis constant. Using the methodology described above, a number of compounds of the present invention were found to exhibit a Ki of <.15 μM, thereby confirming the utility of the compounds of the present invention as effective Xa inhibitors.
The antithrombotic effect of compounds of the present invention can be demonstrated in a rabbit arterio-venous (AV) shunt thrombosis model. In this model, rabbits weighing 2-3 kg anesthetized with a mixture of xylazine (10 mg/kg i.m.) and ketamine (50 mg/kg i.m.) are used A saline-filled AV shunt device is connected between the femoral arterial and the femoral venous cannulae. The AV shunt device consists of a piece of 6-cm tygon tubing which contains a piece of silk thread. Blood will flow from the femoral artery via the AV- shunt into the femoral vein. The exposure of flowing blood to a silk thread will induce the formation of a significant thrombus. After forty minutes, the shunt is disconnected and the silk thread covered with thrombus is weighed. Test agents or vehicle will be given (i.v., i.p., s.c, or orally) prior to the opening of the AV shunt. The percentage inhibition of thrombus formation is determined for each treatment group. The ID50 values (dose which produces 50% inhibition of thrombus formation) are estimated by linear regression. The compounds of formula (I) may also be useful as inhibitors of serine proteases, notably human thrombin, plasma kallikrein and plasmin. Because of their inhibitory action, these compounds are indicated for use in the prevention or treatment of physiological reactions, blood coagulation and inflammation, catalyzed by the aforesaid class of enzymes. Specifically, the compounds have utility as drugs for the
treatment of diseases arising from elevated thrombin activity such as myocardial infarction, and as reagents used as anticoagulants in the processing of blood to plasma for diagnostic and other commercial purposes. Some compounds of the present invention were shown to be direct acting inhibitors of the serine protease thrombin py their ability to inhibit the cleavage of small molecule substrates by thrombin in a purified system. In vi tro inhibition constants were determined by the method described by Kettner et al . in J. Biol . Chem . 265, 18289-18297 (1990), herein incorporated by reference. In these assays, thrombin- mediated hydrolysis of the chromogenic substrate S2238 (Helena Laboratories, Beaumont, TX) was monitored spectrophotometrically. Addition of an inhibitor to the assay mixture results in decreased absorbance and is indicative of thrombin inhibition. Human thrombin (Enzyme Research Laboratories, Inc., South Bend, IN) at a concentration of 0.2 nM in 0.10 M sodium phosphate buffer, pH 7.5 , 0.20 M NaCl, and 0.5% PEG 6000, was incubated with various substrate concentrations ranging from 0.20 to 0.02 mM. After 25 to 30 minutes of incubation, thrombin activity was assayed by monitoring the rate of increase in absorbance at 405 nm which arises owing to substrate hydrolysis. Inhibition constants were derived from reciprocal plots of the reaction velocity as a function of substrate concentration using the standard method of Lineweaver and Burk. Using the methodology described above, some compounds of this invention were evaluated and found to exhibit a Ki of less than 15 μm, thereby confirming the utility of the compounds of the present invention as effective Xa inhibitors.
The compounds of the present invention can be administered alone or in combination with one or more additional therapeutic agents. These include other anticoagulant or coagulation inhibitory agents, anti-platelet or platelet inhibitory agents, thrombin inhibitors, or thrombolytic or fibrinolytic agents .
The compounds are administered to a mammal in a therapeutically effective amount. By "therapeutically
effective amount" it is meant an amount of a compound of Formula I that, when administered alone or in combination with an additional therapeutic agent to a mammal, is effective to prevent or ameliorate the thromboembolic disease condition or the progression of the, disease.
By "administered in combination" or "combination therapy" it is meant that the compound of Formula I and one or more additional therapeutic agents are administered concurrently to the mammal being treated. When administered in combination each component may be administered at the same time or sequentially in any order at different points in time. Thus, each component may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect. Other anticoagulant agents (or coagulation inhibitory agents) that may be used in combination with the compounds of this invention include warfarin and heparin, as well as other factor Xa inhibitors such as those described in the publications identified above under Background of the Invention. The term anti-platelet agents (or platelet inhibitory agents) , as used herein, denotes agents that inhibit platelet function such as by inhibiting the aggregation, adhesion or granular secretion of platelets. Such agents include, but are not limited to, the various known non-steroidal anti- inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, and piroxicam, including pharmaceutically acceptable salts or prodrugs thereof. Of the NSAIDS, aspirin (acetylsalicyclic acid or ASA) , and piroxicam are preferred. Other suitable anti-platelet agents include ticlopidine, including pharmaceutically acceptable salts or prodrugs thereof . Ticlopidine is also a preferred compound since it is known to be gentle on the gastro-intestinal tract in use. Still other suitable platelet inhibitory agents include lib/Ilia antagonists, thromboxane-A2-receptor antagonists and thromboxane-A2-synthetase inhibitors, as well as pharmaceutically acceptable salts or prodrugs thereof.
The term thrombin inhibitors (or anti-thrombin agents) , as used herein, denotes inhibitors of the serine protease thrombin. By inhibiting thrombin, various thrombin-mediated processes, such as thrombin-mediated platelet activation (that is, for example, the aggregation of platelets, and/or the granular secretion of plasminogen activator inhibitor-1 and/or serotonin) and/or fibrin formation are disrupted. A number of thrombin inhibitors are known to one of skill in the art and these inhibitors are contemplated to be used in combination with the present compounds. Such inhibitors include, but are not limited to, boroarginine derivatives, boropeptides , heparins, hirudin and argatroban, including pharmaceutically acceptable salts and prodrugs thereof . Boroarginine derivatives and boropeptides include N-acetyl and peptide derivatives of boronic acid, such as C-terminal a-aminoboronic acid derivatives of lysine, ornithine, arginine, homoarginine and corresponding isothiouronium analogs thereof . The term hirudin, as used herein, includes suitable derivatives or analogs of hirudin, referred to herein as hirulogs, such as disulfatohirudin. Boropeptide thrombin inhibitors include compounds described in Kettner et al . , U.S. Patent No. 5,187,157 and European Patent Application Publication Number 293 881 A2, the disclosures of which are hereby incorporated herein by reference. Other suitable boroarginine derivatives and boropeptide thrombin inhibitors include those disclosed in PCT Application Publication Number 92/07869 and European Patent Application Publication Number 471,651 A2 , the disclosures of which are hereby incorporated herein by reference. The term thrombolytics (or fibrinolytic) agents (or thrombolytics or fibrinolytics) , as used herein, denotes agents that lyse blood clots (thrombi) . Such agents include tissue plasminogen activator, anistreplase, urokinase or streptokinase, including pharmaceutically acceptable salts or prodrugs thereof. The term anistreplase, as used herein, refers to anisoylated plasminogen streptokinase activator complex, as described, for example, in European Patent Application No. 028,489, the disclosure of which is hereby
incorporated herein by reference herein. The term urokinase, as used herein, is intended to denote both dual and single chain urokinase, the latter also being referred to herein as prourokinase . Administration of the compounds of Formula I of the invention in combination with such additional therapeutic agent, may afford an efficacy advantage over the compounds and agents alone, and may do so while permitting the use of lower doses of each. A lower dosage minimizes the potential of side effects, thereby providing an increased margin of safety.
The compounds of the present invention are also useful as standard or reference compounds, for example as a quality standard or control, in tests or assays involving the inhibition of factor Xa. Such compounds may be provided in a commercial kit, for example, for use in pharmaceutical research involving factor Xa. For example, a compound of the present invention could be used as a reference in an assay to compare its known activity to a compound with an unknown activity. This would ensure the experimenter that the assay was being performed properly and provide a basis for comparison, especially if the test compound was a derivative of the reference compound. When developing new assays or protocols, compounds according to the present invention could be used to test their effectiveness . The compounds of the present invention may also be used in diagnostic assays involving factor Xa. For example, the presence of factor Xa in an unknown sample could be determined by addition of chromogenic substrate S2222 to a series of solutions containing test sample and optionally one of the compounds of the present invention. If production of pNA is observed in the solutions containing test sample, but no compound of the present invention, then one would conclude factor Xa was present .
Dosaσe and Formulation
The compounds of this invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations) ,
pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They may also be administered in intravenous (bolus or infusion) , intraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. They can be administered alone, but generally will be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice. The dosage regimen for the compounds of the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired. A physician or veterinarian can determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the thromboembolic disorder.
By way of general guidance, the daily oral dosage of each active ingredient, when used for the indicated effects, will range between about 0.001 to 1000 mg/kg of body weight, preferably between about 0.01 to 100 mg/kg of body weight per day, and most preferably between about 1.0 to 20 mg/kg/day. Intravenously, the most preferred doses will range from about 1 to about 10 mg/kg/minute during a constant rate infusion. Compounds of this invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.
Compounds of this invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using transdermal skin patches. When administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
The compounds are typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as pharmaceutical carriers) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices .
For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl callulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like. The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles . Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines. Compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol,
polyhydroxyethylaspartamidephenol, or polyethyleneoxide- polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans , polycyanoacylates , and crosslinked or amphipathic block copolymers of hydrogels.
Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 milligram to about 100 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition.
Gelatin capsules may contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours . Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance . In general, water, a suitable oil, saline, aqueous dextrose (glucose) , and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions . Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition,
parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol .
Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.
Representative useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows: Capsules
A large number of unit capsules can be prepared by filling standard two-piece hard gelatin capsules each with 100 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.
Soft Gelatin Capsules
A mixture of active ingredient in a digestable oil such as soybean oil, cottonseed oil or olive oil may be prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100 milligrams of the active ingredient. The capsules should be washed and dried. Tablets
Tablets may be prepared by conventional procedures so that the dosage unit is 100 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delay absorption. Inπectable
A parenteral composition suitable for administration by injection may be prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution should be made isotonic with sodium chloride and sterilized.
Suspension
An aqueous suspension can be prepared for oral administration so that each 5 mL contain 100 mg of finely divided active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S. P., and 0.025 L of vanillin.
Where the compounds of this invention are combined with other anticoagulant agents, for example, a daily dosage may be about 0.1 to 100 milligrams of the compound of Formula I and about 1 to 7.5 milligrams of the second anticoagulant, per kilogram of patient body weight. For a tablet dosage form, the compounds of this invention generally may be present in an amount of about 5 to 10 milligrams per dosage unit, and the second anti-coagulant in an amount of about 1 to 5 milligrams per dosage unit .
Where the compounds of Formula I are administered in combination with an anti-platelet agent, by way of general guidance, typically a daily dosage may be about 0.01 to 25 milligrams of the compound of Formula I and about 50 to 150 milligrams of the anti-platelet agent, preferably about 0.1 to 1 milligrams of the compound of Formula I and about 1 to 3 milligrams of antiplatelet agents, per kilogram of patient body weight .
Where the compounds of Formula I are adminstered in combination with thrombolytic agent, typically a daily dosage may be about 0.1 to 1 milligrams of the compound of Formula I, per kilogram of patient body weight and, in the case of the thrombolytic agents, the usual dosage of the thrombolyic agent when administered alone may be reduced by about 70-80% when administered with a compound of Formula I.
Where two or more of the foregoing second therapeutic agents are administered with the compound of Formula I, generally the amount of each component in a typical daily dosage and typical dosage form may be reduced relative to the usual dosage of the agent when administered alone, in view of the additive or synergistic effect of the therapeutic agents when administered in combination.
Particularly when provided as a single dosage unit, the potential exists for a chemical interaction between the combined active ingredients. For this reason, when the compound of Formula I and a second therapeutic agent are combined in a single dosage unit they are formulated such that although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized (that is, reduced). For example, one active ingredient may be enteric coated. By enteric coating one of the active ingredients, it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in the stomach but rather is released in the intestines. One of the active ingredients may also be coated with a material which effects a sustained- release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients. Furthermore, the sustained-released component can be additionally enteric coated such that the release of this component occurs only in the intestine. Still another approach would involve the formulation of a combination product in which the one component is coated with a sustained and/or enteric release polymer, and the other component is also coated with a polymer such as a lowviscosity grade of hydroxypropyl methylcellulose (HPMC) or other appropriate materials as known in the art, in order to further separate the active components . The polymer coating serves to form an additional barrier to interaction with the other component. These as well as other ways of minimizing contact between the components of combination products of the present invention, whether administered in a single dosage form or administered in separate forms but at the same time by the same manner, will be readily apparent to those skilled in the art, once armed with the present disclosure.
Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the
scope of the appended claims, the invention may be practiced otherwise that as specifically described herein.
Claims
1. A compound of formula I :
I or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein;
ring M contains from 0-4 N atoms;
D is selected from CN, C (=NR7 ) NR8R9 , NHC (=NR7)NR8R9 , NR8CH(=NR7), C(0)NR8R9, and (CR8R9) tNR8R9 ;
E is selected from phenyl, 2-pyridyl, 4-pyridyl, pyrimidyl, and piperidinyl substituted with 1 R;
R is selected from H, F, Cl, Br, I, OR3, SR3 , CO2R3 , NO2, and CH2OR3, and (CR8R9) tNR8R9 ;
alternatively, E and R combine to form methylenedioxy or ethylenedioxy;
Z is selected from a bond, C1-4 alkylene, (CH2) rO (CH2) , (CH2)rNR3(CH2)r, (CH ) rC (0) (CH2) r , (CH2) rC (O) 0 (CH2 ) r, (CH2)rOC(0) (CH2)r, (CH2 ) rC (O)NR3 (CH2) r , (CH2)r R3C(0) (CH2)r, (CH2 ) rOC (0) 0 (CH2) r, (CH2) rOC (0)NR3 (CH2 ) r, (CH2 ) rNR3C (0) 0 (CH2 ) r . (CH2)rNR3C(0)NR3(CH2)r, (CH2 ) rS (0) p (CH2 ) r, (CH2)rS02NR3(CH2)r, (CH2 ) r R3S02 (CH2 ) r and (CH2)rN 3S╬╕2NR3 (CH2)r provided that Z does not form a N- N, N-O, N-S, NCH2N, NCH0, or NCH2S bond with ring M or group A; Rla and Rlb are independently absent or selected from -(CH2)r-R1', -CH^CH-R1', NCH2R1", OCH2R1", SCH2R1". NH(CH2)2(CH2)tR1', 0(CH2)2(CH2)tR1', and S (CH2 ) 2 (CH2 ) tR1 ' ;
alternatively, Rla and Rlb, 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, 0, and S;
alternatively, when Z is C(0)NH and Rla is attached to a ring carbon adjacent to Z, then Rla is a C(0) which replaces the amide hydrogen of Z to form a cyclic imide;
R1' is selected from H, C╬╣_3 alkyl, F, Cl , Br, I, -CN, -CHO, (CF2)rCF3, (CH2)rOR2, NR2R2a, C(0)R2c, 0C(0)R2, (CF2)rC02R2c, S(0)pR2b, NR2(CH2)rOR2, CH (=NR2c) NR2R2a, NR2C(0)R2b, NR2C(0)NHR2b, NR2C(0) R2a, OC (0)NR2aR2b, C(0)NR2R2a, C(0)NR2(CH2)rOR2, S02NR2R2a, NR2S02R2b, C3_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;
R1" is selected from H, CH(CH2OR2)2, C(0)R2c, C(0)NR2R2a, S(0)R2b, S(0)2R2b, and S0NR2R2a;
R2, at each occurrence, is selected from H, CF3 , C╬╣_6 alkyl, benzyl, C3_6 carbocyclic residue substituted with 0-2
Rb, 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 Rb;
R2a, at each occurrence, is selected from H, CF , Cχ_6 alkyl, benzyl, phenethyl, 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, 0, and S substituted with 0-2 R4b;
R2b, at each occurrence, is selected from CF3 , C╬╣_4 alkoxy, C╬╣-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, 0, and S substituted with 0-2 R4b;
R2c, at each occurrence, is selected from CF3 , OH, C1-.4 alkoxy, C╬╣-6 alkyl, benzyl, C3_6 carbocyclic residue substituted with 0-2 Rb, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-2 R4b;
alternatively, R2 and Ra, 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 Rb 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, C╬╣_4 alkyl, and phenyl ;
R3b, at each occurrence, is selected from H, C1-4 alkyl, and phenyl ;
Rc, at each occurrence, is selected from C╬╣_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, 0, and S substituted with 0-2 R4;
B is selected from: H, Y, and X-Y;
X is selected from C╬╣_ alkylene, -CR2 (CR2R2b) (CH2) t-, -C(0)-, -C(=NR!")-, -CR2(NR1"R2)-, -CR2(OR2)-, -CR2(SR2)-, -C(0)CR2R2a-, -CR2R2aC(0), -S(0)p-, -S (0) pCR2R2a- , -CR2R2aS(0)p-, -S(0)2NR2-, -NR2S(0)2-, -NR2S (O) 2CR2R2a- , -CR2R2 S(0)2NR2-, -NR2S(0)2NR2-, -C(0)NR2-, -NR2C(0)-, -C(0)NR2CR2R2a-, -NR2C(0)CR2R2a-, -CR2R2aC (0) NR2- , -CR2R2aNR2C(0)-, -NR2C(0)0-, -0C(0)NR2-, -NR2C (0) NR2- , -NR2-, -NR2CR2R2a-, -CR2R2aNR2-, 0, -CR2R2a0-, and -0CR2R2a-;
Y is selected from:
(CH2)rNR2R2a, provided that X-Y do not form a N-N, 0-N, or S-N bond, C3_io carbocyclic residue substituted with 0-2 Ra, and 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-2 R4a;
R4, at each occurrence, is selected from H, =0, (CH2)rOR2, F, Cl, Br, I, C╬╣_4 alkyl, -CN, N02, (CH2) rNR2R2a, (CH2)rC(0)R2c, NR2C(0)R2b, C(0)NR2R2a, NR2C (O) NR2R2a, CH(=NR2)NR2R2a, CH(=NS(0)2R5)NR2R2a, NHC (=NR2) NR2R2a, C(0)NHC(=NR2)NR2R2a, S02NR2R2a, NR2S0NR2R2 , NR2S02-C╬╣_ alkyl, NR2S02R5, S(0)PR5, (CF2)rCF3, NCH2R1", OCH2R1", SCH2R!\ N(CH2)2(CH2)tR1', 0 (CH2 ) 2 (CH2) t 1 ' , 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, =0, (CH2)r0R2, (CH2)r-F, (CH2)r-Br, (CH2)r-Cl, I, C1-4 alkyl, -CN, N02 , (CH2)rNR2R2a, (CH2)rNR2R2b, (CH2) rC (0) R2c, NR2C(0)R2b, C(0)NR2R2a, C(0)NH(CH2)2NR2R2a, NR2C (0) NR2R2a, CH(=NR2)NR2R2a, NHC (=NR2 ) NR2R2a . S0NR2R2a, NR2S02NR2R2a,
NR2S02-C╬╣_4 alkyl, C (0)NHS02-C╬╣_4 alkyl, NR2S02R5, S(0)pR5, and (CF2)rCF3;
alternatively, one Ra is a 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, 0, and S and substituted with 0-1 R5 ;
R4b, at each occurrence, is selected from H, =0, (CH2)r0R3, F, Cl, Br, I, C╬╣_4 alkyl, -CN, N02 , (CH2) rNR3R3a, (CH2)rC(0)R3, (CH2)rC(0)0R3c, NR3C(0)R3a, C(0)NR3R3a,
NR3C(0)NR3R3a, CH(=NR3)NR3R3a, NH3C (=NR3) NR3R3a, S02NR3R3a, NR3S0NR3R3 , NR3S02-C╬╣_4 alkyl, NR3S02CF3, NR3S02-phenyl , S(0)PCF3, S(0)p-Ci-4 alkyl, S (0)p-phenyl , and (CF2)rCF3;
R5, at each occurrence, is selected from CF3 , C╬╣_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)r0R2, F, Cl, Br, I, C1-4 alkyl, CN, N02 , (CH2) rNR2R2a,
(CH2)rC(0)R2b, NR2C(0)R2b, NR2C (0)NR2R2a, CH(=NH)NH2, NHC(=NH)NH2, S02NR2R2a, NR2S02NR2R2a, and NR2S02C╬╣_4 alkyl;
R7, at each occurrence, is selected from H, OH, C╬╣_6 alkyl, C╬╣_6 alkylcarbonyl , C -╬▓ alkoxy, C╬╣_4 alkoxycarbonyl,
(CH2)n-phenyl, C6-╬╣o aryloxy, C6-╬╣o aryloxycarbonyl , C6-╬╣o arylmethylcarbonyl , C╬╣_4 alkylcarbonyloxy C1-.4 alkoxycarbonyl, C6-10 arylcarbonyloxy C╬╣_4 alkoxycarbonyl, C╬╣- alkylaminocarbonyl , phenylaminocarbonyl , and phenyl-C╬╣_4 alkoxycarbonyl;
R8, at each occurrence, is selected from H, C╬╣_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, 0, and S;
R9 , at each occurrence, is selected from H, C╬╣_6 alkyl and (CH )n-phenyl;
n is selected from 0, 1, 2, and 3;
m is selected from 0, 1, and 2 ;
p is selected from 0, 1, and 2 ;
r is selected from 0, 1, 2, and 3;
s is selected from 0, 1, and 2; and,
t is selected from 0 and 1
2. A compound according to Claim 1, wherein the compound is of formulae Ia-Io:
Z is selected from a bond, CH20, OCH2 , CH2NH, NHCH2 , CH2C(0), C(0)CH2, C(0)NH, C(0)NH, CH2S(0)2, S(0)2(CH2), S02NH, and S02NH;
B is selected from: Y, X-Y, and NR2R2a;
Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 Ra; 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, benzoxazole, benzthiazole, indazole, benzisoxazole, benzisothiazole, and isoindazole;
Y may also be selected from the following bicyclic heteroaryl ring systems
K is selected from 0, S, NH, and N.
3. A compound according to Claim 2 , wherein the compound is of formulae: 
wherein :
D is selected from C(=NR7)NR8R9 and (CR8R9) tNR8R9;
R is selected from H, F, Cl, OR3, CH20R3 , CH2NH2 ;
A is selected from: piperidinyl , piperazinyl,
C5_6 carbocyclic residue substituted with 0-2 R4, and 5-6 membered heteroaryl containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4;
Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R4a; phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, benzimidazolyl, 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, and 1, 3 , 4-triazole.
4. A compound according to Claim 3, wherein: E is phenyl ;
D is selected from C(=NH)NH and CH2NH ;
R is selected from H, F, Cl, and Br;
A is selected from:
C5_6 carbocyclic residue substituted with 0-2 R4, and 5-6 membered heteroaryl containing from 1-3 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-2 R4;
Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 Ra; phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, benzimidazolyl, 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, and 1, 3 , 4-triazole;
R2, at each occurrence, is selected from H, CF3, C╬╣_6 alkyl, benzyl, C5-6 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, 0, and S substituted with 0-2 R4b;
R2a, at each occurrence, is selected from H, CF3 , C╬╣_ alkyl, benzyl, phenethyl, Cs_6 carbocyclic residue substituted with 0-2 Rb, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-2 R4b;
R2b, at each occurrence, is selected from CF3, C1-4 alkoxy,
C╬╣_6 alkyl, benzyl, Cs_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, 0, and S substituted with 0-2 R4b;
R2c, at each occurrence, is selected from CF3 , OH, C1-4 alkoxy, C╬╣_6 alkyl, benzyl, C5-6 carbocyclic residue substituted with 0-2 Rb, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-2 Rb;
alternatively, R2 and R2a, together with the atom to which they are attached, combine to form a ring selected from imidazolyl, morpholino, piperazinyl, pyridyl, and pyrrolidinyl, substituted with 0-2 Rb;
R , at each occurrence, is selected from H, =0, OR2, CH2OR2 ,
F, Cl, C╬╣_4 alkyl, NR2R2a, CH2NR2R2 , C(0)R2c, CH2C(0)R2c, C(0)NR2R2a, CH(=NR2)NR2R2a, CH (=NS (0) 2R5 ) NR2R2a, S02NR2R a, NR2S02-Ci- alkyl, S(0)2R5, and CF3
provided that if B is H, then R4 is other than tetrazole, C(0)-alkoxy, and C (0)NR2R2 ;
Ra, at each occurrence, is selected from H, =0, (CH2)r0R2, F, Cl, C╬╣_4 alkyl, NR2R2a, CHNR2R2a, NR2R2b, CH2NR2R2b,
(CH2)rC(0)R2c, NR2C(0)R2b, C(0)NR2R2a, C (0) NH (CH2) 2NR2R2a, NR2C(0)NR2R2a, S0NR2R2a, S(0)2R5, and CF3 ; and,
Rb, at each occurrence, is selected from H, =0, (CH2)r0R3, F, Cl, C╬╣_4 alkyl, NR3R3 , CH2NR3R3a, C(0)R3, CH2C(0)R3, C(0)0R3c, C(0)NR3R3a, CH(=NR3)NR3R3a, S02NR3R3a, NR3S02-C╬╣_4 alkyl, NR S02CF3 NR3S02-phenyl, S(0)2CF3, S(0)2-C╬╣_4 alkyl, S (0) 2-phenyl, and CF3.
5. A compound according to Claim 1, wherein the compound is selected from: N- (2 '-Aminosulfonyl- [1,1' ]biphen-4-yl) -2- (3'- amidinophenyl) nicotinamide;
N- [5- (2-aminosulfonyl )phenylpyrid-2-yl] -2- (3 ' - amidinophenyl) nicotinamide;
N- [5- (2-t-butylaminosulfonyl)phenylpyrid-2-yl] -2- (3 ' - amidinophenyl ) nicotinamide; and,
N- [5- (2-aminosulfonyl) phenylpyrid-2-yl] -2- (3 ' - carboxamidophenyl) nicotinamide;
or a pharmaceutically acceptable salt thereof .
6. 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 .
7. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to Claim 2 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 3 or a pharmaceutically acceptable salt thereof .
9. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to Claim 4 or a pharmaceutically acceptable salt thereof .
10. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to Claim 5 or a pharmaceutically acceptable salt thereof.
11. A method for treating or preventing a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of <_╬╣ compound according to Claim 1 or a pharmaceutically acceptable salt thereof .
12. 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 2 or a pharmaceutically acceptable salt thereof .
13. 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 3 or a pharmaceutically acceptable salt thereof.
14. 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 4 or a pharmaceutically acceptable salt thereof .
15. 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 5 or a pharmaceutically acceptable salt thereof .
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002293824A CA2293824A1 (en) | 1997-06-19 | 1998-06-18 | (amidino)6-membered aromatics as factor xa inhibitors |
| EP98930362A EP0993448A1 (en) | 1997-06-19 | 1998-06-18 | (AMIDINO)6-MEMBERED AROMATICS AS FACTOR Xa INHIBITORS |
| AU79769/98A AU7976998A (en) | 1997-06-19 | 1998-06-18 | (amidino)6-membered aromatics as factor xa inhibitors |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US87856297A | 1997-06-19 | 1997-06-19 | |
| US08/878,562 | 1997-06-19 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1998057934A1 true WO1998057934A1 (en) | 1998-12-23 |
Family
ID=25372285
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US1998/012682 WO1998057934A1 (en) | 1997-06-19 | 1998-06-18 | (AMIDINO)6-MEMBERED AROMATICS AS FACTOR Xa INHIBITORS |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP0993448A1 (en) |
| AU (1) | AU7976998A (en) |
| CA (1) | CA2293824A1 (en) |
| WO (1) | WO1998057934A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999050255A2 (en) * | 1998-03-27 | 1999-10-07 | Du Pont Pharmaceuticals Company | Disubstituted pyrazolines and triazolines as factor xa inhibitors |
| WO2000047554A2 (en) * | 1999-02-11 | 2000-08-17 | Cor Therapeutics Inc. | INHIBITORS OF FACTOR Xa |
| WO2000071508A2 (en) * | 1999-05-24 | 2000-11-30 | Cor Therapeutics, Inc. | INHIBITORS OF FACTOR Xa |
| WO2001019798A2 (en) * | 1999-09-17 | 2001-03-22 | Cor Therapeutics Inc. | INHIBITORS OF FACTOR Xa |
| WO2001019788A2 (en) * | 1999-09-17 | 2001-03-22 | Cor Therapeutics, Inc. | BENZAMIDES AND RELATED INHIBITORS OF FACTOR Xa |
| WO2001064643A2 (en) * | 2000-02-29 | 2001-09-07 | Cor Therapeutics, Inc. | BENZAMIDES AND RELATED INHIBITORS OF FACTOR Xa |
| EP1135131A1 (en) * | 1998-12-04 | 2001-09-26 | Berlex Laboratories, Inc. | Aryl and heterocyclyl substituted pyrimidine derivatives as anti-coagulants |
| WO2002010145A1 (en) * | 2000-07-28 | 2002-02-07 | Merck Patent Gmbh | Urethane derivatives |
| US6358960B1 (en) | 1998-02-17 | 2002-03-19 | Ono Pharmaceutical Co., Ltd. | Amidino derivatives and drugs containing the same as the active ingredient |
| US6369227B1 (en) | 1998-12-23 | 2002-04-09 | Bristol-Myers Squibb Pharma Company | Thrombin or factor Xa inhibitors |
| WO2002076945A1 (en) * | 2001-03-09 | 2002-10-03 | Ortho-Mcneil Pharmaceutical, Inc. | Aminopyrrolidine sulfonamides as serine protease inhibitors |
| EP1254136A1 (en) * | 2000-01-29 | 2002-11-06 | LG Chem Investment, Ltd. | FACTOR Xa INHIBITORS WITH ARYL-AMIDINES AND DERIVATIVES, AND PRODRUGS THEREOF |
| US6506771B2 (en) | 2000-06-23 | 2003-01-14 | Bristol-Myers Squibb Pharma Company | Heteroaryl-phenyl heterobicyclic factor Xa inhibitors |
| US6599926B2 (en) | 2000-06-23 | 2003-07-29 | Bristol-Myers Squibb Company | Heteroaryl-phenyl substituted factor Xa inhibitors |
| US6632815B2 (en) | 1999-09-17 | 2003-10-14 | Millennium Pharmaceuticals, Inc. | Inhibitors of factor Xa |
| US6670362B2 (en) | 2000-09-20 | 2003-12-30 | Pfizer Inc. | Pyridazine endothelin antagonists |
| US6686368B1 (en) | 1999-09-17 | 2004-02-03 | Millennium Pahrmaceuticals, Inc. | Inhibitors of factor Xa |
| US6710061B2 (en) | 2001-03-09 | 2004-03-23 | Ortho-Mcneil Pharamceutical, Inc. | Aminopyrrolidine sulfonamides as serine protease inhibitors |
| US6716834B2 (en) | 2000-05-16 | 2004-04-06 | Astrazeneca Ab | Thiochromane derivatives and their use as thrombin inhibitors |
| US6844367B1 (en) | 1999-09-17 | 2005-01-18 | Millennium Pharmaceuticals, Inc. | Benzamides and related inhibitors of factor Xa |
| US6949550B2 (en) | 2001-12-04 | 2005-09-27 | Bristol-Myers Squibb Company | Substituted amino methyl factor Xa inhibitors |
| US6967208B2 (en) | 2001-09-21 | 2005-11-22 | Bristol-Myers Squibb Pharma Company | Lactam-containing compounds and derivatives thereof as factor Xa inhibitors |
| US7115627B2 (en) | 2001-12-04 | 2006-10-03 | Bristol-Myers Squibb Company | Glycinamides as factor Xa inhibitors |
| US7122557B2 (en) | 2003-03-18 | 2006-10-17 | Bristol-Myers Squibb Company | Sulfonyl-amidino-containing and tetrahydropyrimidino-containing compounds as factor Xa inhibitors |
| US7125898B2 (en) | 2002-02-12 | 2006-10-24 | Smithkline Beecham Corporation | Nicotinamide derivatives useful as p38 inhibitors. |
| US7151118B2 (en) | 2001-10-17 | 2006-12-19 | Glaxo Group Limited | Biphenylcarboxylic amide derivatives as p38-kinase inhibitors |
| US7166623B2 (en) | 2001-10-17 | 2007-01-23 | Glaxo Group Limited | 2′-Methyl-5′-(1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide derivatives and their use as p38 kinase inhibitors |
| US7183297B2 (en) | 2001-10-17 | 2007-02-27 | Glaxo Group Limited | Biphenyl-derivatives as p38-kinase inhibitors |
| US7208629B2 (en) | 2001-10-17 | 2007-04-24 | Glaxo Group Limited | 5′-Carbamoyl-1,1-biphenyl-4-carboxamide derivatives and their use as p38 kinase inhibitors |
| US7271289B2 (en) | 2003-04-09 | 2007-09-18 | Smithkline Beecham Corporation | Biphenylcarboxylic amide derivatives as p38 kinase inhibitors |
| US7312214B2 (en) | 2002-05-10 | 2007-12-25 | Bristol-Myers Squibb Company | 1, 1-disubstituted cycloalkyl derivatives as factor Xa inhibitors |
| US7338963B2 (en) | 2001-09-21 | 2008-03-04 | Bristol-Myers Squibb Company | Lactam-containing compounds and derivatives thereof as factor Xa inhibitors |
| US7384963B2 (en) | 2001-10-17 | 2008-06-10 | Glaxo Group Limited | 2′-Methyl-5-(1,3,4-oxadiazol-2-yl)1, 1′-biphenyl-4-carboxaide derivatives and their use as p38 kinase |
| US7396843B2 (en) | 2001-10-17 | 2008-07-08 | Glaxo Group Limited | 5′-carbamoyl-1,1′-biphenyl-4-carboxamide derivatives and their use as p38 kinase inhibitors |
| US7432289B2 (en) | 2001-10-17 | 2008-10-07 | Glaxo Group Limited | 5-Acylamino-1,1′-biphenyl-4-carboxamide derivatives and their use as P38 kinase inhibitors |
| US7615651B2 (en) | 2006-11-13 | 2009-11-10 | Pfizer Inc. | Diaryl, dipyridinyl and aryl-pyridinyl derivatives and uses thereof |
| EP2319516A1 (en) * | 2003-07-23 | 2011-05-11 | Synta Pharmaceuticals Corp. | Compounds for treating inflammatory and autoimmune disorders |
| US8202999B2 (en) | 2005-01-07 | 2012-06-19 | Synta Pharmaceuticals Corp. | Compounds for inflammation and immune-related uses |
| US8524907B2 (en) | 2006-11-02 | 2013-09-03 | Millennium Pharmaceuticals, Inc. | Methods of synthesizing pharmaceutical salts of a factor Xa inhibitor |
| EP2982668A2 (en) | 2002-12-03 | 2016-02-10 | Pharmacyclics LLC | 2-(2-hydroxybiphenyl-3-yl)-1h-benzoimidazole-5-carboxamidine derivatives as factor viia inhibitors for the treatment of thromboembolic disorders |
Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995018111A1 (en) * | 1993-12-28 | 1995-07-06 | The Du Pont Merck Pharmaceutical Company | Compounds containing basic and acidic termini useful as fibrinogen receptor antagonists |
| WO1996016940A1 (en) * | 1994-12-02 | 1996-06-06 | Yamanouchi Pharmaceutical Co., Ltd. | Novel amidinonaphthyl derivative or salt thereof |
| WO1996028427A1 (en) * | 1995-03-10 | 1996-09-19 | Berlex Laboratories, Inc. | Benzamidine derivatives their preparation and their use as anti-coagulants |
| WO1997023212A1 (en) * | 1995-12-21 | 1997-07-03 | The Du Pont Merck Pharmaceutical Company | ISOXAZOLINE, ISOTHIAZOLINE AND PYRAZOLINE FACTOR Xa INHIBITORS |
| WO1997038984A1 (en) * | 1996-04-17 | 1997-10-23 | Du Pont Pharmaceuticals Company | N-(amidinophenyl)-n'-(subst.)-3h-2,4-benzodiazepin-3-one derivatives as factor xa inhibitors |
| WO1998006694A1 (en) * | 1996-08-16 | 1998-02-19 | Du Pont Pharmaceuticals Company | Amidinophenyl-pyrrolidines, -pyrrolines, and -isoxazolidines and derivatives thereof |
| WO1998011094A1 (en) * | 1996-09-12 | 1998-03-19 | Schering Aktiengesellschaft | Benzamidine derivatives substituted by cyclic amino acid or cycl ic hydroxy acid derivatives and their use as anti-coagulants |
| WO1998028269A1 (en) * | 1996-12-23 | 1998-07-02 | Du Pont Pharmaceuticals Company | NITROGEN CONTAINING HETEROAROMATICS AS FACTOR Xa INHIBITORS |
| WO1998028282A2 (en) * | 1996-12-23 | 1998-07-02 | Du Pont Pharmaceuticals Company | OXYGEN OR SULFUR CONTAINING 5-MEMBERED HETEROAROMATICS AS FACTOR Xa INHIBITORS |
-
1998
- 1998-06-18 AU AU79769/98A patent/AU7976998A/en not_active Abandoned
- 1998-06-18 CA CA002293824A patent/CA2293824A1/en not_active Abandoned
- 1998-06-18 EP EP98930362A patent/EP0993448A1/en not_active Ceased
- 1998-06-18 WO PCT/US1998/012682 patent/WO1998057934A1/en not_active Application Discontinuation
Patent Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995018111A1 (en) * | 1993-12-28 | 1995-07-06 | The Du Pont Merck Pharmaceutical Company | Compounds containing basic and acidic termini useful as fibrinogen receptor antagonists |
| WO1996016940A1 (en) * | 1994-12-02 | 1996-06-06 | Yamanouchi Pharmaceutical Co., Ltd. | Novel amidinonaphthyl derivative or salt thereof |
| EP0798295A1 (en) * | 1994-12-02 | 1997-10-01 | Yamanouchi Pharmaceutical Co. Ltd. | Novel amidinonaphthyl derivative or salt thereof |
| WO1996028427A1 (en) * | 1995-03-10 | 1996-09-19 | Berlex Laboratories, Inc. | Benzamidine derivatives their preparation and their use as anti-coagulants |
| WO1997023212A1 (en) * | 1995-12-21 | 1997-07-03 | The Du Pont Merck Pharmaceutical Company | ISOXAZOLINE, ISOTHIAZOLINE AND PYRAZOLINE FACTOR Xa INHIBITORS |
| WO1997038984A1 (en) * | 1996-04-17 | 1997-10-23 | Du Pont Pharmaceuticals Company | N-(amidinophenyl)-n'-(subst.)-3h-2,4-benzodiazepin-3-one derivatives as factor xa inhibitors |
| WO1998006694A1 (en) * | 1996-08-16 | 1998-02-19 | Du Pont Pharmaceuticals Company | Amidinophenyl-pyrrolidines, -pyrrolines, and -isoxazolidines and derivatives thereof |
| WO1998011094A1 (en) * | 1996-09-12 | 1998-03-19 | Schering Aktiengesellschaft | Benzamidine derivatives substituted by cyclic amino acid or cycl ic hydroxy acid derivatives and their use as anti-coagulants |
| WO1998028269A1 (en) * | 1996-12-23 | 1998-07-02 | Du Pont Pharmaceuticals Company | NITROGEN CONTAINING HETEROAROMATICS AS FACTOR Xa INHIBITORS |
| WO1998028282A2 (en) * | 1996-12-23 | 1998-07-02 | Du Pont Pharmaceuticals Company | OXYGEN OR SULFUR CONTAINING 5-MEMBERED HETEROAROMATICS AS FACTOR Xa INHIBITORS |
Non-Patent Citations (5)
| Title |
|---|
| EDMUNDS J J ET AL: "THROMBIN AND FACTOR XA INHIBITION", ANNUAL REPORTS IN MEDICINAL CHEMISTRY, vol. 31, 1996, pages 51 - 60, XP000653962 * |
| KUNITADA S ET AL: "FACTOR XA INHIBITORS", CURRENT PHARMACEUTICAL DESIGN, vol. 2, no. 5, October 1996 (1996-10-01), pages 531 - 542, XP002057653 * |
| MAO S -S: "FACTOR XA INHIBITORS", PERSPECTIVES IN DRUG DISCOVERY AND DESIGN, vol. 1, no. 3, 1993, pages 423 - 430, XP000654087 * |
| STUERZEBECHER J ET AL: "SYNTHETIC INHIBITORS OF SERINE PROTEINASES XXIII. INHIBITION OF FACTOR XA BY DIAMIDINES", THROMBOSIS RESEARCH, vol. 17, no. 3/04, 1980, pages 545 - 548, XP000602215 * |
| TIDWELL R R ET AL: "STRATEGIES FOR ANTICOAGULATION WITH SYNTHETIC PROTEASE INHIBITORS XA INHIBITORS VERSUS THROMBIN INHIBITORS", THROMBOSIS RESEARCH, vol. 19, no. 3, 1 August 1980 (1980-08-01), pages 339 - 349, XP000574196 * |
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| CA2293824A1 (en) | 1998-12-23 |
| AU7976998A (en) | 1999-01-04 |
| EP0993448A1 (en) | 2000-04-19 |
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