Field of the Invention The invention relates to novel compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII) and formula (VIII) (hereinafter referred to as"formulae (I)- (VIII)"), which more particularly include sulfonylurea derivatives, sulfonylthiourea derivatives, sulfonylguanidine derivatives, sulfonylcyanoguanidine derivatives, thioacylsulfonamide derivatives, and acylsulfonamide derivatives which are effective platelet ADP receptor inhibitors. These derivatives may be used in various pharmaceutical compositions, and are particularly effective for the prevention and/or treatment of cardiovascular diseases, particularly those diseases related to thrombosis.

Description of the Related Art Thrombotic complications are a major cause of death in the industrialized world.

Examples of these complications include acute myocardial infarction, unstable angina, chronic stable angina, transient ischemic attacks, strokes, peripheral vascular disease, preeclampsia/eclampsia, deep venous thrombosis, embolism, disseminated intravascular coagulation and thrombotic cytopenic purpura. Thrombotic and restenotic complications also occur following invasive procedures, e. g. , angioplasty, carotid endarterectomy, post CABG (coronary artery bypass graft) surgery, vascular graft surgery, stent placements and insertion of endovascular devices and prostheses. It is generally thought that platelet aggregates play a critical role in these events. Blood platelets, which normally circulate freely in the vasculature, become activated and aggregate to form a thrombus with disturbed blood flow caused by ruptured atherosclerotic lesions or by invasive treatments such as angioplasty, resulting in vascular occlusion. Platelet activation can be initiated by a variety of agents, e. g. , exposed subendothelial matrix molecules such as collagen, or by thrombin which is formed in the coagulation cascade.

An important mediator of platelet activation and aggregation is ADP (adenosine 5'-diphosphate) which is released from blood platelets in the vasculature upon activation by various agents, such as collagen and thrombin, and from damaged blood cells, endothelium or tissues. Activation by ADP results in the recruitment of more platelets and stabilization of existing platelet aggregates. Platelet ADP receptors mediating aggregation are activated by ADP and some of its derivatives and antagonized by ATP (adenosine 5'-triphosphate) and some of its derivatives (Mills, D. C : B. (1996) TTzro.

He77lost. 76: 835-856). Therefore, platelet ADP receptors are members of the family of P2 receptors activated by purine and/or pyrimidine nucleotides (King, B. F. , Townsend- Nicholson, A. & Burnstock, G. (1998) Erends Phar7nacol. Sci. 19: 506-514).

Recent pharmacological data using selective antagonists suggests that ADP- dependent platelet aggregation requires activation of at least two ADP receptors (Kunapuli, S. P. (1998), Trends Pharmacol. Sci. 19 : 391-394 ; Kunapuli, S. P. & Daniel, J. L. (1998) Bioc7zenn. J 336: 513-523; Jantzen, H. M. et al. (1999) Thronlb. Hemost.

81: 111-117). One receptor appears to be identical to the cloned P2Yl receptor, mediates phospholipase C activation and intracellular calcium mobilization and is required for platelet shape change. The second platelet ADP receptor important for aggregation mediates inhibition of adenylyl cyclase. Molecular cloning of the gene or cDNA for this receptor (P2Ylz) has recently been reported (Hollopeter, G. et. al. (2001) Natzre 409: 202- 207). Based on its pharmacological and signaling properties this receptor has been previously termed P2YADP (Fredholm, B. B. et al. (1997) SIPS 18 : 79-82), P2TAc (Kunapuli, S. P. (1998), Trends Pharmacol. Sci. 19: 391-394) or P2Ycyc (Hechler, B. et al. (1998) Blood 92,152-159).

Various directly or indirectly acting synthetic inhibitors of ADP-dependent platelet aggregation with antithrombotic activity have been reported. The orally active antithrombotic thienopyridines ticlopidine and clopidogrel inhibit ADP-induced platelet aggregation, binding radiolabeled ADP receptor agonist 2-methylthioadenosine 5'- diphosphate to platelets, and other ADP-dependent events indirectly, probably via formation of an unstable and irreversible acting metabolite (Quinn, M. J. & Fitzgerald, D. J. (1999) Circulation 100 : 1667-1667). Some purine derivatives of the endogenous antagonist ATP, e. g. , AR-C (formerly FPL or ARL) 67085MX and AR-C69931MX, are selective platelet ADP receptor antagonists which inhibit ADP-dependent platelet aggregation and are effective in animal thrombosis models (Humphries et al. (1995), Trends Pharmacol. Sci. 16, 179; Ingall, A. H. et al. (1999) J. Med. Chem. 42,213-230).

Novel triazolo [4,5-d] pyrimidine compounds have been disclosed as P2T-antagonists (WO 99/05144). Tricyclic compounds as platelet ADP receptor inhibitors have also been disclosed in WO 99/36425. The target of these antithrombotic compounds appears to be the platelet ADP receptor mediating inhibition of adenylyl cyclase.

Despite these compounds, there exists a need for more effective platelet ADP receptor inhibitors. In particular, there is a need for platelet ADP receptor inhibitors having antithrombotic activity that are useful in the prevention and/or treatment of cardiovascular diseases, particularly those related to thrombosis.

Summary of the Invention The invention provides compounds of formula (I), formula (II), formula (III), fonnula (IV), formula (V), formula (VI), formula (VII) and fonnula (VIII): A is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, and alkylheteroaryl.

W is selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl.

E is selected from the group consisting of H,-C1-C8 alkyl, polyhaloalkyl,-C3 s- cycloalkyl, aryl, alkylaryl, substituted aryl, heteroaryl, and substituted heteroaryl.

D is selected from the group consisting of NR1-(C=O)-R2, -O-R1; wherein : R'is independently selected from the group consisting of : H, C1-C8 alkyl, polyhaloalkyl,-C3 8-cycloalkyl, aryl, alkylaryl, substituted aryl, heteroaryl, substituted heteroaryl,- (C=O)-Cl-Cs alkyl, -(C=O)-aryl, -(C=O)-substituted aryl, -(C=O)-heteroaryl and - (C=O)-substituted heteroaryl; R2 is independently selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, or R1 and R2 can be direct linked or can be indirectly linked through a carbon chain that is from 1 to about 8 carbon atoms in length, n is 0-4, m is 0 or 1, y is 0-4 and Q is independently C or N, with the proviso that when Q is a ring carbon atom, each ring carbon atom is independenty substituted by X.

X is in each case a member independently selected from the group consisting of : H, halogen, polyhaloalkyl,-OR3,-SR3,-CN,-NO2,-SOzR3, -C1-10-alkyl, -C3-8-cycloalkyl, aryl, aiyl-substituted by 1-4 R3 groups, amino, amino-C1-8-alkyl, C1-3-acylamino, C1-3-acylamino-C1-8-alkyl, C1-6-alkylamino, C1-6-alkylamino C1-8 alkyl, C1-6 dialkylamino, C1-6 dialkylamino C1-8 alkyl, C1-6 alkoxy, C1-6 alkoxy-C1-6-alkyl, carboxy-C1-6-alkyl, C1-3-alkoxycarbonyl, C1-3-alkoxycarbonyl-C1-6-alkyl, carboxy C1-6 alkyloxy, hydroxy, hydroxy Cl-6 allcyl, and a 5 to 10 membered fused or non-fused aromatic or nonaromatic heterocyclic ring system, having 1 to 4 heteroatoms independently selected from N, O, and S, with the proviso that the carbon and nitrogen atoms, when present in the heterocyclic ring system, are unsubstituted, mono-or di- substituted independently with 0-2 R4 groups.

R3 and R4 are each independently selected from the group consisting of : H, halogen,-CN,-NO2,-Cl-lo alkyl, C3-s-cycloalkyl, aiyl, amino, amino-C1-8-alkyl, C1-3-acylamino, C1-3-acylamino-C1-8-alkyl, C1-6- alkylamino, C1-6-alkylamino C1-8 alkyl, C1-6 dialkylamino, C1-6 dialkylamino C1-8 alkyl, C1-6 alkoxy, C1-6 alkoxy-C1-6-alkyl, carboxy-CL-6-alkyl, CI-3-alkoxycarbonyl, Cl-3-alkoxycarbonyl-Cl-6-alkyl, carboxy-Cl-6-alkyloxy, hydroxy, hydroxy-CI 6-alkyl,-thio and thio-CI 6-alkyl.

Y is selected from the group consisting of O, S, N-OR5, and NR5, wherein R is selected from the group consisting of : H, C 1-lo alkyl, C 3-8-cycloalkyl, NR2, and CN; and Z is selected from the group consisting of NR1 and O.

The invention also covers all pharmaceutically acceptable salts and prodmgs of the compounds of formulae (I)- (VIII).

In another aspect, the invention provides pharmaceutical compositions for preventing or treating thrombosis in a mammal containing a therapeutically effective amount of a compound of formulae (I)- (VIII) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The invention further provides a method for preventing or treating thrombosis in a mammal by administering a therapeutically effective amount of a compound of formulae (I)- (VIII) or a phaumaceutically acceptable salt thereof.

Detailed Description of the Invention Definitions In accordance with the present invention and as used herein, the following terms are defined with the following meanings, unless explicitly stated otherwise.

The term"alkenyl"refers to a trivalent straight chain or branched chain unsaturated aliphatic radical. The term"alkinyl" (or"alkynyl") refers to a straight or branched chain aliphatic radical that includes at least two carbons joined by a triple bond.

If no number of carbons is specified, alkenyl and alkinyl each refer to radicals having from 2-12 carbon atoms.

The tenn"allcyl"refers to saturated aliphatic groups including straight-chain, branched-chain and cyclic groups having the number of carbon atoms specified, or if no number is specified, having up to about 12 carbon atoms. The term"cycloalkyl"as used herein refers to a mono-, bi-, or tricyclic aliphatic ring having 3 to about 14 carbon atoms and preferably 3 to about 7 carbon atoms.

The term''Cl-C6 alkoxy"as used herein refers to an ether moiety whereby the oxygen is connected to a straight or branched chain of carbon atoms of the number indicated.

The term"mono-C-C6 alkylamino"as used herein refers to an amino moiety whereby the nitrogen is substituted with one H and one Cl-C6 alkyl substituent, the latter being defined as above.

The term"di-C,-C6 alkylamino"as used herein refers to an amino moiety whereby the nitrogen is substituted with two Cl-C6 alkyl substituents as defined above.

The term"monoarylamino"as used herein refers to an amino moiety whereby the nitrogen is substituted with one H and one aryl substituent, such as a phenyl, the latter being defined as above.

The tenn"diarylamino"as used herein refers to an amino moiety whereby the nitrogen is substituted with two aryl substituents, such as phenyl, the latter being defined as above.

The term"C1-C6 alkylsulfonyl"as used herein refers to a dioxosulfur moiety with the sulfur atom also connected to one Cl-ces alkyl substituent, the latter being defined as above.

The tenn"C,-C6 alkoxycarbonyl"as used herein refers to a hydroxycarbonyl moiety whereby the hydrogen is replaced by a Cl-C6 alkyl substituent, the latter being defined as above.

As used herein, the terms"carbocyclic ring structure"and"3-16 carbocyclic mono, bicyclic or tricyclic ring structure"or the like are each intended to mean stable ring structures having only carbon atoms as ring atoms wherein the ring structure is a substituted or unsubstituted member selected from the group consisting of : a stable monocyclic ring which is an aromatic ring ("aryl") having six ring atoms ("phenyl") ; a stable monocyclic non-aromatic ring having from 3 to about 7 ring atoms in the ring; a stable bicyclic ring structure having a total of from 7 to about 12 ring atoms in the two rings wherein the bicyclic ring structure is selected from the group consisting of ring structures in which both of the rings are aromatic, ring structures in which one of the rings is aromatic and ring structures in which both of the rings are non-aromatic; and a stable tricyclic ring structure having a total of from about 10 to about 16 atoms in the three rings wherein the tricyclic ring structure is selected from the group consisting of : ring structures in which three of the rings are aromatic, ring structures in which two of the rings are aromatic and ring structures in which three of the rings are non-aromatic. In each case, the non-aromatic rings when present in the monocyclic, bicyclic or tricyclic ring structure may independently be saturated, partially saturated or fully saturated.

Examples of such carbocyclic ring structures include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, cyclooctyl, [3. 3. 0] bicyclooctane, [4.3. 0] bicyclononane, [4.4. 0] bicyclodecane (decalin), 2.2. 2] bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin). Moreover, the ring structures described herein may be attached to one or more indicated pendant groups via any carbon atom which results in a stable structure. The tenn"substituted"as used in conjunction with carbocyclic ring structures means that hydrogen atoms attached to the ring carbon atoms of ring structures described herein may be substituted by one or more of the substituents indicated for that structure if such substitution (s) would result in a stable compound.

The term"aryl"which is included with the tenn"carbocyclic ring structure"refers to an unsubstituted or substituted aromatic ring, substituted with one, two or three substituents selected from lower alkoxy, lower alkyl, lower alkylamino, hydroxy, halogen, cyano, hydroxyl, mercapto, nitro, thioalkoxy, carboxaldehyde, carboxyl, carboalkoxy and carboxamide, including but not limited to carbocyclic aryl, heterocyclic aryl, and biaryl groups and the like, all of which may be optionally substituted. Preferred aryl groups include phenyl, halophenyl, loweralkylphenyl, napthyl, biphenyl, phenanthrenyl and naphthacenyl.

The term"arylalkyl"which is included with the term"carbocyclic aryl"refers to one, two, or three aryl groups having the number of carbon atoms designated, appended to an alkyl group having the number of carbon atoms designated. Suitable arylalkyl groups include, but are not limited to, benzyl, picolyl, naphthylmethyl, phenethyl, benzyhydryl, trityl, and the like, all of which may be optionally substituted.

The term"phenyl"as used herein refers to a six carbon containing aromatic ring which can be variously mono-or poly-substituted with H, Cl-C6 alkyl, hydroxyl, Cl-C6 alkoxy, amino, mono-Cl-C6 alkylamino, di-C1-C6 alkylamino, nitro, fluoro, chloro, bromo, iodo, hydroxycarbonyl, or Cl-C6 alkoxycarbonyl.

As used herein, the term"heterocyclic ring"or"heterocyclic ring system"is intended to mean a substituted or unsubstituted member selected from the group consisting of a stable monocyclic ring having from 5-7 members in the ring itself and having from 1 to 4 hetero ring atoms selected from the group consisting of N, O and S ; a stable bicyclic ring structure having a total of from 7 to 12 atoms in the two rings wherein at least one of the two rings has from 1 to 4 hetero atoms selected from N, O and S, including bicyclic ring structures wherein any of the described stable monocyclic heterocyclic rings is fused to a hexane or benzene ring; and a stable tricyclic heterocyclic ring structure having a total of from 10 to 16 atoms in the three rings wherein at least one of the three rings has from 1 to 4 hetero atoms selected from the group consisting of N, 0 and S. Any nitrogen and sulfur atoms present in a heterocyclic ring of such a heterocyclic ring structure may be oxidized. Unless indicated otherwise the terms "heterocyclic ring"or"heterocyclic ring system"include aromatic rings, as well as non- aromatic rings which can be saturated, partially saturated or fully saturated non-aromatic rings. Also, unless indicated otherwise the term"heterocyclic ring system"includes ring structures wherein all of the rings contain at least one hetero atom as well as structures having less than all of the rings in the ring structure containing at least one hetero atom, for example bicyclic ring structures wherein one ring is a benzene ring and one of the rings has one or more hetero atoms are included within the term"heterocyclic ring systems"as well as bicyclic ring structures wherein each of the two rings has at least one hetero atom. Moreover, the ring structures described herein may be attached to one or more indicated pendant groups via any hetero atom or carbon atom which results in a stable structure. Further, the term"substituted"means that one or more of the hydrogen atoms on the ring carbon atom (s) or nitrogen atom (s) of the each of the rings in the ring structures described herein may be replaced by one or more of the indicated substituents if such replacement (s) would result in a stable compound. Nitrogen atoms in a ring structure may be quaternized, but such compounds are specifically indicated or are included within the term"a pharmaceutically acceptable salt"for a particular compound.

When the total number of 0 and S atoms in a single heterocyclic ring is greater than 1, it is preferred that such atoms not be adjacent to one another. Preferably, there are no more that 1 O or S ring atoms in the same ring of a given heterocyclic ring structure.

Examples of monocylic and bicyclic heterocylic ring systems, in alphabetical order, are acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-1,5, 2- dithiazinyl, dihydrofulo [2,3-b] tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, lH-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isocluomanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), 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, phenamthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyroazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pryidooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2, 5- thiadazinyl, 1,2, 3-thiadiazolyl, 1,2, 4-thiadiazolyl, 1,2, 5-tlziadiazolyl, 1,3, 4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, tluenothiazolyl, tlaienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, 1, 2, 5-triazolyl, 1,3, 4-triazolyl and xanthenyl. Preferred heterocyclic ring structures include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl, imidazolyl, indolyl, benzimidazolyl, IH-indazolyl, oxazolinyl, or isatinoyl. Also included are fused ring and spiro compounds containing, for example, the above heterocylic ring structures.

As used herein the term"aromatic heterocyclic ring system"has essentially the same definition as for the monocyclic and bicyclic ring systems except that at least one ring of the ring system is an aromatic heterocyclic ring or the bicyclic ring has an aromatic or non-aromatic heterocyclic ring fused to an aromatic carbocyclic ring structure.

The terms"halo"or"halogen"as used herein refer to Cl, Br, F or I substituents.

The tenn"haloalkyl", and the like, refer to an aliphatic carbon radicals having at least one hydrogen atom replaced by a Cl, Br, F or I atom, including mixtures of different halo atoms. Trihaloalkyl includes trifluoromethyl and the like as preferred radicals, for example.

The term"methylene"refers to-CH2-.

The term"pharmaceutically acceptable salts"includes salts of compounds derived from the combination of a compound and an organic or inorganic acid. These compounds are useful in both free base and salt form. In practice, the use of the salt form amounts to use of the base form ; both acid and base addition salts are within the scope of the present invention.

"Pharmaceutically acceptable acid addition salt"refers to salts retaining the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cil. ami acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicyclic acid and the like.

"Phannaceutically acceptable base addition salts"include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable organic nontoxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, lzydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly preferred organic nontoxic bases are isopropylamine, diethylamine, ethanolamine, trimethamine, dicyclohexylamine, choline, and caffeine.

"Biological property"for the purposes herein means an in vivo effector or antigenic function or activity that is directly or indirectly performed by a compound of this invention that are often shown by in vitro assays. Effector functions include receptor or ligand binding, any enzyme activity or enzyme modulatory activity, any carrier binding activity, any hormonal activity, any activity in promoting or inhibiting adhesion of cells to an extracellular matrix or cell surface molecules, or any structural role.

Antigenic functions include possession of an epitope or antigenic site that is capable of reacting with antibodies raised against it.

In the compounds of this invention, carbon atoms bonded to four non-identical substituents are asymmetric. Accordingly, the compounds may exist as diastereoisomers, enantiomers or mixtures thereof The syntheses described herein may employ racemates, enantiomers or diastereomers as starting materials or intermediates. Diastereomeric products resulting from such syntheses may be separated by chromatographic or crystallization methods, or by other methods known in the art. Likewise, enantiomeric product mixtures may be separated using the same techniques or by other methods known in the art. Each of the asymmetric carbon atoms, when present in the compounds of this invention, may be in one of two configurations (R or S) and both are within the scope of the present invention.

Compound Embodiments of the Invention Compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII) and formula (VIII) below represent one embodiment of the invention: A is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, and alkylheteroaryl.

W is selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl.

E is selected from the group consisting of H, -C-C8 alkyl, polyhaloalkyl, -C3-8- cycloalkyl, aryl, alkylaiyl, substituted aryl, heteroaiyl, and substituted heteroaiyl.

D is selected from the group consisting of NR'- (C=O)-R wherein: Rl is independently selected from the group consisting of : H, Cl-C8 alkyl, polyhaloalkyl,-C3-g-cycloalkyl, aryl, alkylaryl, substituted aryl, heteroaryl, substituted heteroaryl, -(C=O)-C1-C8 alkyl,- (C=O)-aryl,- (C=O)-substituted aryl,- (C=O)-heteroaryl and - (C=O)-substituted heteroaryl ; R2 is selected from the group consisting of : aryl, substituted aryl, heteroaryl, substituted heteroaryl, or R1 and R2 can be direct linked or can be indirectly linked through a carbon chain that is from 1 to about 8 carbon atoms in length, n is 0-4, m is 0 or 1, y is 0-4 and Q is independently C or N, with the proviso that when Q is a ring carbon atom, each ring carbon atom is independently substituted by X, wherein X is in each case a member independently selected from the group consisting of : H, halogen, polyhaloalkyl,-OR3,-SR3,-CN,-NO2,-SOzR3, -C1-10-alkyl, -C3-8-cycloalkyl, aryl, aryl-substituted by 1-4 R3 groups, amino, amino-C1_g-allcyl, Ct-3-acylamino, C1-3-acylamino-C1-8-alkyl, C1-6-alkylamino, C1-6-alkylamino C1-8 alkyl, C1-6 dialkylamino, C1-6 dialkylamino C1-8 alkyl, C1-6 alkoxy, C1_6 alkoxy-CI-6-alkyl, carboxy-CI_6-alkyl, Cl-3-alkoxycarbonyl, C1-3-alkoxycarbonyl-C1-6-alkyl, carboxy C1-6 alkyloxy, hydroxy, hydroxy C1-6 alkyl, and a 5 to 10 membered fused or non-fused aromatic or nonaromatic heterocyclic ring system, having 1 to 4 heteroatoms independently selected from N, O, and S, with the proviso that the carbon and nitrogen atoms, when present in the heterocyclic ring system, are unsubstituted, mono-or di- substituted independently with 0-2 R4 groups, and wherein R3 and R4 are each independently selected from the group consisting of : H, halogen,-CN,-NO2,-C1_lo alkyl, C3-8-cycloallcyl, aryl, amino, amino-C1-8-alkyl, C1-3-acylamino, C1-3-acylamino-C1-8-alkyl, C1-6- alkylamino, C1-6-alkylamino C1-8 alkyl, C1-6 dialkylamino, C1-6 dialkylamino C1-8 alkyl, C1-6 alkoxy, C1-6 alkoxy-C1-6-alkyl, carboxy-C1-6-alkyl, C1-3-alkoxycarbonyl, CI-3-alkoxycarbonyl-CI-6-alkyl, carboxy-CI-6-alkyloxy, hydroxy, hydroxy-CI-6-alkyl,-thio and thio-CI-6-alkyl.

Y is selected from the group consisting of O, S, N-OR5, and wherein Rs is selected from the group consisting of: H, C 1-10 alkyl, C 3-8-cycloalkyl, and CN; and Z is selected from the group consisting of NRl and O.

The invention also covers all pharmaceutically acceptable salts and prodrugs of the compounds of formula I to formula VIII.

In a preferred embodiment of the invention, compounds of formulae (I)- (VIII) A is selected from the group consisting of : Y is selected from the group consisting of O, S, N-OR5 and NR5. E is selected from the group consisting of H, or C1-8 alkyl.

W is selected from the group consisting of : D is selected from the group consisting of: In a more preferred embodiment of the invention, compounds of formulae (I) to (VIII) include the compounds wherein: D is selected from the group consisting of : In another preferred embodiment of the invention, compounds of formulae (I) - (VI) include the compounds set forth below in Tables 1-4 : Table 1 Y s A --NH H-N I W I Nt R2 N n p o Formula la R2 W Y A C X tCI ci ci OYE 1/ OMe N CF3 '-0 Br Br s cri (/NCN \CI I Ci Table 1 (cont.) Y os A SNH H-N I W I R XNtR2 0 o Formula la Rz R1 W Y A H N 0 s ci Br s ci NU OMe CI OMe C NH i F S N-C-=N s/ ci ci Me N CF3 Me II 0 Ci N OH s H-yin OMe S u", Ky" N Table 2 ° Y s A CONH o y °NsSaPA N XNw-aN O H Formula Ib X W Y A 3-Br Y p S ci Br Br 3-Br"¢ NH ci N 3-Ci NH \tCt 4-O M e s p F H 4-OMe i) 0 L F N-C-N S cl ci ce 3 3, 4-diMe NH I % cF N H 3-some Me N OH s Me N ci N \e Xc.

A. Table 3 o Y s A v SN H N 0 H Formula in Y A Y A Cl ci NU 'ci zu zon N-C-N s ci NH nCF3 NH zu N OH N B. Table 4 R o ° I --NH, I R H ci Rl 0 Formula Id W Ri R2 W Bu Br mye cl ci F CL ci If NEZ N Cl Me ! N N H Me ( H (/4N Examples of specific preferred compound are listed below: CI NC-N S y i \ N N N S S'CI -NH S N N S N NH O O 0 0 Example 1 Example 2 H O-N 0 0 HO-N N NH o O J i \/. N NH 0 0 o Example 3 Example 4 CI Me0-N Exampie5-.., _. N /NH S\ I < I HN NH ZIZI p/ i 1\, j O O Example 5 Example 6 N CI Sv < _NH N H/S N'S nu S O O 0 5 'O Example 7 Example 8 0 NC-N 0 CI 0 cl CI CI --NH N NH oSO I /N NH NS \ i AN9NH S 4 {+N XNH Sv O F3C O F3C 0 0 Example 9 Example 10 0 0 0 HN CN \\ HN/CN N S 0/0 ouzo 0 % b 0 0 Example 11 Example 12 H2N H 0 0 CN 0 0 cl Example 13 / Example13 Exampfe 13 Example 14 O S\\ H S CI O p han S H s N N H O O Con Example 16 Example 15 O CI NC-N N -N s N NH NS I 1 N \/N NS\\ \ 1 CI H /ils\ : HN \ p HN O O H 0 Example 18 - S -.. Examp) e18 Exampfe17 CI Me-N H ci 0 N ci S O O O Example 20 Example 19 N) 03NH W 0 H Cl , N NH S\ N NU Example 21 ci cl H H s N N \ N N l ° MeOJC5 0 =0 MeO 0 nez 0 Me0 O Example 22 Example 23 ci ci H H H H s rr Y c ? rYY N, N N N N N \. S N JID p MeHN I nu Example 24 Example 25 cl CI N H H 0 sz 0 N N,,, Z \\O I T H2NO2S o o,) \\o N \ 0 0 O Example 26 Example 27 cl Cl N N, H H c 'Y. rT '. O 0 \/v Br p N Na zon Example 29 Cl S ci N N H H iJTo-o, rYY tS y N- N 0 0 0 0 su /% iiv /O 0 O /9N Example 30 XN /Example 31 O cl Ci H H S H H s N N,,,, N N, Me0 N/ o Me0 S O O O 0 i i ° o Example 32 Example 33 CI CI H H s H H N tq, S) O S . Gw O/il S Met N N O EtHN Example 34 Example 35 Cl Cl H H zu T zSX N N,., S s, d N N, (Me) 2N HN A III ° Example 36 1 ° Example 37 ci cl N N H H l N N. if zizi 0 Ò) wN 5/t J NH NON O Examp 38 O Examp 39 ci CI H H N N, S"d\ c. f). r if A AN Example 40 N 0 N'bon Cl ci H H s HN N) a Br 0 0 CI I p O Br p O O ion /I O HN Example 41 Example 42 Gui S ci Ci H H s s 0 s N NN p O N Han O HN O Example 43 Example 44 ci ci H H s l . ,, o s., w o o', o O O O \ N nier H N I "N O Exampfe 45 N Example 46 N (Me) Ci ci S O/N II N. S H H S N N H H s 0 s N N y""\\o 0 s IN Han N 0 0 Example 47 Exam le p 48 0 0 Cl ci H H s N nez N, N N S o o I"O \ N O N NMe Example 49 H O Example 50 CI N H N N . N N N, , aN 0 0 : 1-1 0, a 0 N N N nez C HN C s Example 52 Example 51 CI H H N NEZ / 050 H I NóZSXò 'N Non H N 0 Example 53 N O/ CI CI 0 ci ci H H-\\ N N H H 0 N \ N / H N H N J Example 54 Example 55 ZON ci cri H H s s /N Ns N N w CAN CONS2 MEON CONH 2 MeHN Y OH Example 56 CONH2 Example 57 Example 56 Cl CL S N N s N N O/ II p'SO O I ll O SO N N MeHN MeHN CN Example 58 MEHN Example 59 Cl Cl S s H H s O \ I II O'S O \ \ I II Om v0 N H H N N N N 0 y s CO2Me O NH Example 60 Example 61 N Ci cul H H N N N N, 0 y-s I p N \ O N MeHN MeHN MeHN S02Me N Example 63 Exampfe 62 CI CI N N \ //"o MeHN- MeHN O, N 54 ° NH MeHN MeHN CONH Nu NH Example 64 Example 65 N Ct cri H H ci o I HS H y c Ny N N S \ O O /"Trr" s A o c/o N 0 0 //Example 66 N Example 67 Cl ce N jus 0 s N N y//\, o /I N /p O O //Me-N I-N H Example 68 Example 69 cl cl N, H H 0 N y s N N, O I , S N N \ /O N p p O N MeHN I MOHN Example 70 MEHN Example 71 N N J Cl Cl H H S H H N \ N N \ //"o D, N SX U/NN Sot zu N Example 72 NH Example 73 CI Ci H H s H H s N N, s N N, /Q p / p O /// N Example 75 , Me Example 74 ce Cl \ \ . \ 0 Cl H MeO I_ :" Mu0 CAN Example 76 Example 77 Ci ci H H S H s 0F N Ns 0F N N, /p O O OSO N N) : : : r O MeHN Example 78 Example 79 Cl CI S F N N H H isv O F Examp) e80 Examp) e81 N H2NO2S N 0 00 -can I 0 0 Example 80 Example 81 CI CI S N N o I \ F \ N/O O O Br \ I/II O v0 zon / Example 83 Example 83 Cl cl F N \ S F /O O O O igv j F3c i o'o N G ° Example 84 o Example 85 Ci ci F N N \ F N NS Y 0 y MeO 0 0 Me02S N 0 ZIP O Example 86 Example 87 ci cl H Ho s FX t S o F N NH MeS O //\\ 0 s N / ° Example 88 EtHN 40 Example 89 ci H Hs H H s 0 F N Ns 0 F N N OSO N // Me N Example 90 ß ° Example 91 Cl Cl H H H H s N N, s 0 F N Nez N N HN N : a Example 92 ° F3c NH Example 93 ci s H ho oa O I" 0 N'S IN N 0 Example 94 Cl Cl /NNg F N N ci 0 0//\\o SO HN HNX ao 0 HN 0 H I 0 HN/ Example 95 Example 96 cl ci H H S H H HN HN ¢to "p50 0 11/\\O 0 O Example 97 Example 98 Cl ci s H H s N'N w 0 F/N N/s\ w Q I iSVO \ I II O vQ O \ I \ wN HN I HN/O O Example 99 N Me N Example 100 () Cl ci H Cl H H S \s n - H H S- F) a N N H H 0 y s 0 F N N s \ O un HAN Example 101 Example 102 C 0 0 CI CI F N N \ H H O g F/N N N N, F-Cr N N O O I p 0 O N N w u \o N/ nue H O Example 103 Example 104 Ci ci HHf-HH. H H s H H s O \ I IDl OSO O \ I I01 OSO N I \ N I/N p H N p co 0 Example 106 "-0 Example 105 CI S N N O S\ H H s HN F Ny N, Han Han 0 Example 107 e N o CI ci H H S \ N 0 0 0 0 0//'o 6 O 0 H. , /1, \\ INN O Example 108 Example 109 C) CI CI F N N / F/N\ N w 0 e % \o N 0 Zon CONH 2 MeHN CONH2 CONH Example 110 Example 111 CI s H H s H H F N N Y °° zozo y 0 0 In MEHN CN N Example 113 ci ci CL H H F N N : xy rv''' 0 F N N, s 0 Y e, \\ N meon MEON CO2Me Example 114 S Example 115 zu ci Cl ci s F N N \ F/N N Q/I 10) O SO. \ O \ 101 O SO MeHN I °°° //MeHN MeHN MEHN MEHN Example 116 Example 117 CI H H H H s O \ \ I/II O O i/II 0 v0 N I N mehl MeHN O NS Example 118 ° NH Example 119 0 O 0 Cl H o 0 0 N N N 0 0//IZIO H. j !. 0 0 0 0 Y"-T Y, S YN""S- A'0 C/0 N-<N Y xS+O 5 N<N N 5zU \\ I \ N S \ N/O O N Exampie 120 N Example 121 Cl s cri H H \ F N Nis\ F N N 1 W T o' o'r'Ys N-"0 H J N J/Q 0//\o 0 ANYN, S \ H Example 122 Example 123 ci ci H H s F N N o o 0 o t jfj 5 N NYN Sß zon MeHN"r" Mehl U Example 124 t Example 125 N ce s s N nez isv O N NNS N 0 1 0 0 N Example 126 Me0 Example 127 ci cl H S H H s 0 N s 0 N N y N, s N I \, N I \, N ci 0 Example 128 MEHN 0 Example 129 Cl H H s N N, H H O I \ ; ; S O N \ N II N iS \ CI H2N°zS /0 O O N I N Example 131 ci ci S N N' \\ H H 0 N//\4 0 N NYNs O Br p O O I \ N \ N Example 132 ° Example 133 ci s ci N nus N N \ p O O o i S\ 0 0 0 S"d Example 134 I/ O Example 135 Ci Ci H H f M f o H s H H s MeO N 0 0 0 Me02S N 0 0 MeOS O N 0 Example 136 Example 137 0 0 CI CI S Cl ci H H s s y o N MeS Sx 0 0/1 N 0 Example 138 EtHN 0 Example 139 ci ci N N N N O \ \ II \ O O O Cl Cl N N N S't N<NgN St (Me) 2N 0 Exam le Examp) e141 Cl Cl CI CI N N N N I O I/II OSO O I \ Nwll N Sv \ p O O H H H H s N N, 0 N N N, Example 142 F3CJ NH Example 143 cl H H s N NEZ 0 0 1 0 0 ZON / N N Exampfe 144 n Cl S N N H H NYN CI O N p SO N/II 0 HN 0 I O Example 145 0 Example 146 ci ci , < U o Ó ° Y óZSO wu Y//\o 147 e146 c'a O O Q p O Han O HN O Example 147 Example 148 Ci C) S O N N N \ O N O O \ I O I N /HN NN 0 O J Example 149 Example 150 N (Me) CI Ci H H s H H NYNNS O, j , % O N i I NvN. \ O w un N' Example 151 0 Example 152 N Example 152 cri ci H H s ci ci H H t H H fez O N N NS N N v N S \ \ II O O O \ I O O O N N \ N O IN) v vy N/ NMe H O Example 153 Example 154 CI CI H to N 0 0 0 N 0 (HNß Xo O O O \ N I _N H N p Exam le 156 Example 155 Example 156 Cl Cri N N S N N N HN O HN- Han ION Example 157 N 0 ci ci H H S H H S 0 NYNN s 0 N Ny N, s lol 0 0 0 0. HN HN Example 158 N Example 159 NYN ci ci H H O Ni N NS 0 N y S C) N I II g p0 O CONH CONH2 MOHN OH Example 160 CONH2 Example 161 Cl Cl s H H H H N y N N N w N N NS N Yc-b r' \ I O Or O \ O O Zon MEON MeHN I MeHN//Exam le 6 Example 162 N02 Example 163 ci ci CI CL H N N N N, 0 N Y o N I"oso I II Qo O y 0 I MEHN I MEHN C02Me Example 164 NH Example 165 N CI CI H H N N, N N N 0 N MeHN N w ,,, O p I N \ O //MeHN MeHN Example 167 SOMME Example 1 66 ci ci N N N H H H H s 0 N N N, s 0 NYNNS y//"0 ZON Meon MeHN NU NH Example 168 ° NH 0 O Cl' 0 N N H H rNX N Cl N s Ny N, F-I p'O p N g \ N I I O N S \ % O O Example 170 N Example 171 ce cl H H N N S P J nO 0 NYs </Me-N N N a, I H Example 172 Example 173 CI ci cl S N N NSX H H t N N, H H MeHN-"'" Jl" ? Zozo N MeHN I MOHN Example 174 Example 175 N \N J cl ci s Cl CI C H. N Ns \\ N N N zu , I N I N Example 176 NH Example 177 ce Cl Cl N N t O O 0 C (N N 0 O/O O I N Example 178 Example 179 Me \ ci cri Cl S CI N N \ \ Cl N N I\ N N 0 'N N/O Me0' Example 180 Example 18'I C ! C ! Cl cl H H H H ci N N s ci N N /O Example'182 MeHN O Example 183 ci cl Cl S O CI N NS \ CI N N CI I/ O O H N II \ N 2 2S N/p O O / Example 184 Example 185 ci ci Cl ci N N, H H CI N N \\ N N \\ O S C y N ci N N Y Example 186 0 Example 187 Ci Cul Cl C \ NNS H H CI N'NS /O p I/F3C N 0 Example 188 o Example 189 0 C) H H f H H f Cl Cl H H S s CI fV N \ CI N Nus iSv 0 \ ii v MeO N 0 Me02S N 00 O Example 190 Example 191 CI CI H H s s ci N N, H H 0 s ci N N, MeS o / o Example 192 EtHN Example 193 CI Ci H H H FEZ 0 NyN SZ\ 0ci NYNs 0 0//\\O 0 N (Me) 2N Example 194 HN 0 0 Example 195 Ci ci S ci H H H 0 N NN S"d\ 0ci N y/ ; \\ s /p 00 ZON HN C ! C. N N 0 Example 196 O Example 197 F3C NH CI 5 \ cri N N OSO zon ZON H 0 Example 198 ci H H S H H N NS CI CI i p O o/I II SO Br N \ O Example 199 HN Example 200 Cl H H s H H s CI/N'N CI N O \ I O O Sv0 O/I I I SVO O N HN HN VI-I 0 Example 201 Example 202 Cl Cl s H H H H ci N N ci N N 0 s 'Xr" Xr y I\ N N HO Example 203 N Example 204 N (Me) 2 ex Cl l Cl ci N N H H O I , 5 O CI/N Ns/ \ N HN o Han ION Example 205 N Example 206 10 ci ci s O CI/N N S \ CI 'oo I OS0 zon /I N . k 0 0 0 n 0 0 0 nue H C N Né H 0 Example 207 Example 208 Ct Ct ci ci Cln H s H H s tA HNXO \ N I N p HN- O Example 209 Example 210 Ci S Cl NYNs \ \ I O N HN O O N Example 211 o ci ci C ! CI S H H \ N N S \ CI/N N N \ I O INN HN 0 HN HN p HN Example 213 f ka 91 9 1 0 Example 293 N ce Cl o CI/N NS CI N N 'o' o N N 0 CONH2 MEHN Example 214 CONH2 Example 215 Ci s H H s H H ci N N cl NYNs 0 c MEON N N \ C / N cl cri Zon H N J MeH N CN NO2 Example 217 CN Examp) e217 Example 216 CI CI MEON Meon JJ' MeHN"" N I MeHN I MeHN CO2Me O NH Example 218 % Example 219 N cl ci Gui S \ CaNyN, 0 p sS\ I Sv \ I II O O \ N \ O O II'I N, I, //MeHN MEHN' S02Me Example 220 N example 221 ci ci H H H H s ci N N s ci N N, 0') a 0 0 y 0 N Nec MENU MeHN v NH O NH Example 223 Example 222 C) ci c Ng N N N H H S O I isv Cl N N 0//"o N N, I/p O O S N I \ I / Example 224 N Example 225 Cul ci S S CI NYN <N N X \ I CI N N p O s0 Me-N v Example 226 Example 227 CI Cl H H r"rN MeHN""f AJ-J' Zozo N MOHN MOHN /Example 228 t Example229 N ci ci S s ci Ny N ci Ny N i N NYN N NH Example 230 Example 231 n f H H f cl cri C H s Me N) aH H H //""0 \ N N /I/ N/ Me Example 232 Example 233 ci ci S H H s H H 0 0 N N, 'N N/0 Me0 I N'\ H Example 234 Example 235 CI ci Cul \ N 0 0 0 N 0 0 0 cul A N 0 Example 236 MEHN N H H s Cl CI S N N, H H i v O \ Cl 0 0 /O O N . H /H O Example 238 Example 239 CI ci ci H H s N N, H H o D NYN SA N y N 'N N/O Po H o Example 240 Nao 0 H Example 241 Ci N NH CI . \ S Os0 C, N N, s H H s / N 0 I N H F3C N 0 0 0 Example e242 N o H Example 243 cl ci N NH N N N N o S \/S \ MeO 0 e02S I \ N I H ° H ° H Example 244 Example 245 CI H H S H H H H H H N N N N, , so Z"y zon H0 EtHN I N' H Example 246 H Example 247 CI H H s \ H H N nua 00 I/' N (Me) 2N H4O HN HNAo O Example 248 Exqmple 249 CI ci ci H H H H C 0 N l,-, \ l I \ N I \ wN Han HN H p Example 250 H O C) H H Example 251 Cl ci H NU 0 O I"OSO 0"0 0 0 ZON H/H Example 252 CI H H S H H Su p/NS N N CI I Il Br N I O _ H O H N N 'O Example 253 Example 254 Cl Cl H H s H H s N II NS N N zu 0 ru HNN-) HN-No H Example 255 Example 256 Cl Cl ci H H s H H aN N p O _%. C. N I , H N' HN/N' H N f c, n Examp ! e258 N (Me) 2 Example 257 Example 258 Ci Cl H H /N N N H _ 0 Ns 0 N N% s N 0/\\o 7 N 0 r O Exampfe 259 Example 260 0 0 CI H H s H H s /. N N II O/ rsv O I p O 0 Zon N NU né H H H Example 261 Example 262 Cl ci cl N N 0 N N, s 0 N N, s A o c-o r' N N 0 0 0 N,, a 0 0 >Jk O ° ° 4 N H ° HNeH4o zozo Example 264 Example 263 Ci /NYN Il o O su 0 0 0 HN N H f Example 265 o Cl ci ci H H s H H s SN H4O HN H4O O - N \ N J J H 0 HN Neo H Example 266 N'1 Example 267 cil ci H H S F N'NS \ F N N ii v O S /p O 0 I/O o I'll \1 zozo Me0 MeO N AO Example 268 Example 269 CI S s F N ii O 0 I/ p p N I , N LJ-'LJ'' H Example 270 CI CI S F N y N H H L L. A CI/O O O HNs I I 0 00 y //\\ H Example 272 N Example 273 ce ci H H F N N H H 0 s F N N / O O Br II "p O I \ N \ N O /N \\O I/ H Example 274 H0 Example 275 Ci S-/C) \ N Ng H H 0 00 0 S"d ? Y T I A FN N II F :), : : : rN N / 1 O O F3C N/O Example 276 Nô Example 277 ci cl H H S H H F. F I y/S y \\ 0 \ N\O/N'\\ O Example 278 Example 279 CI Cl S H H H H S" ( H EtH N N Ao 0 0 0 0 N NO EtNN I N- H Example 280 H Example 281 CI H H H H s H N H H . N'''N '' J. i i J. 1 i o (Me) 2N HNao HN HN4O H H Example 282 Example 283 U CI H H s H H s H H/ H H o D N N F N N 0 Nao HNY, o dso "OSO, \" i o HN I HN N p v N O F3CJ Example284 NH H Example285 ci H H N N 0-110 0 /p O O H H" /N O H H Example 286 Cl Cl H H s H H s HN HNao HN H4O cl 0 o//\-o N Br 0 0 o t H j H I O H N N O I H Example 287 Example 288 Cl ci H H s H H Xr . T O \ I p p N HN-No HNN"\, ) H u Example 289 Example 290 Ci ci H H c\ H H y H H F N Sb H N Ns 0 s P O In zozo H N N I \ H H Exam le 291 E N (Me) 2 cl ce H H F/N N' N H N (Me) 2"r \ \ O O I I I ii O HN NI \ HN i N-\ O N Example 293 Example 294 0 CL CL H 0 N N, 0 F N N, y y//"\ N N o A N) a 0 0 0 w N Ao NMe H H Example 295 Example 296 CL CL H rV fA'" H H H H s 0 N 0 0 N \ O O I NI ° H O H Example 297 Example 298 CL H H s H H t F HN N, HN y//\% J L 1 HN N Ao H Example 299 N 909 CL CL S H H s H H s oso H N N H AO HN N-\\o O HNNo HNNo Example 300 Example 301 NYN u ci ci H H s H H s N\/N O N N oSO \ \ N N/O N) \\o H MeO N--\0 H n Example 302 Example 303 Ci CI H H X H H N N \ N N O I \ II OSO O I \ II OSO N, a N Cl H ° Example 304 MeHN H4O Cl Example 305 cl H H \\ H H NYN N'\\o N'\\o CI N o HNOS N /p O O 0 \ H H Exmaple 306 example 307 Cl H H/ H H N N 9 N N N N N, Y 0 y s H 0 0 Zon // H Exam le 308 NO Example 309 CI Cl H ci 0 N N N s H H y N N 0 0 0 d\ 0 N S"d\ y"//\\- N 0 00 H I/ G Example 310 Example 311 Cl Ci H H s H H s O N N NS \ N N NS I y 11 1\ MeO N 0 0 0 Me02S N 0 N Ao H N AO Example 313 Example 312 CI S H H s s N N, H H 0 N y s 0 N N N, s MeS 0 y Zon N N Ao EtH N N'o H Example 314 Cl Example 315 CI H H \ H S N nez zozo 0/1 \\O y I I (Me) zN H4O HN H4O Example 316 Cl Example 317 Cl cl S N N H H s H H X Y /O N N", a H N N Ao HN r\l A a N- Y Example 319 rsL Example 318 ci H H Pq, OO ? Xj dO N nez 0 N nua N N Ao Example 320 CI ci H H s H H. S 0 H H H. S cl 0 y//' N Br 0 0 o Br N \ O H N N 'O H N N 'O H H Example 321 Example 322 Cl ci ci H Sot N, N N 0 0 (\ N I \ wN HN H4O HN H4O ' U Example 323 Example 324 Ci Ci H H s , H S N N O N N N g O N I 5\0 y N p O N HN HN N'O H N N-1 H HN N Ao H Example 325 Example 326 N (Me) 2 Ci Cl H H H H S4, Cl 0/\0 O ou \. J II O \O O N/I N II N SO HN HNao HN NA N 0 H ° N f N H O N Example 327 N Example 328 0 0 Of CI H H H H 0 N N N, 0 N N, Y 0//S, \o y// 0 0 0 . N \ N Examp) e 329 Example 330 Cl H H H H 0 N N y N 0 N N y N s N N Ós} N v T SSX O \ I 101 O S 0 O \ I II O v0 HN H O Example 332 Example 331 Cl S N NS H H s Ny HNAo Zon yin 0 H N H 'O Example 333 N CI CRI 0 Cl Cl N H zanni H H y I pso O I O O 0"/\\ wN \ N HN HNao HN HN o N N N Example 334 N Example 335 Cl Cl S S p C N N% s\ \ o CI N 0 ci NyN- y//\\ H Meo N Ao H n Example 336 Example 337 Cl Ct C ! \ c'Y'Y c'Yr'Y O ii iS O iS i j. i i j. i 'N'N )-) t-)'- Examp) e338.-, , Example 338 H Example 339 Cl H H s HH s 0 Cl :] aN 0 Ns 0 ci NNs nos CI N 2 2 N I/O O O l I d ho Example 340 Example 341 Cl Cl H H s HH s H H CI N\/N \ N N O , S CI \ S O O O O H Br 0 0 N N N Ao-J\\0 Example 342 N Example 343 Ci C ! ci N N'S H H S Cul 0, aN N, /O O O N F3C N 0 NO H Example 344 Example 345 Cl H H H H s H H N CI) AN N, CI ZON N 0 0 0 i y Me0 I N/p O O MeOS I N'\\o N-'\\o H Example 346 Cl H Example 347 ci Cl H H S H H S CI N N \ CI N N asz O \ iS O MeS N 0 o ; 0 N'\\o EtH N N-\\o N p EtH N N 'O Example 348 Ci C ! H H S H H S Example 349 Cl H H S H H S N 0 0 0 N 0 0 0 /p O O \ N /p O O N (Me) 2N H4O HN HN4o H Example 350 Example 351 Ci CI H H H H s = C. N. ii v isv H 0 0 I/p O O HN I H N N I Example 353 Fisc" Example 352 Ci H H C'S JL JU" H H Sa O X f Sw N N4o H H Example 354 CI CI H H s H H s 0 II NS/CI N N CI I p O 0 0/"o ) H j H H N N I \ H N N' 0 Example 355 Example 356 Ci CI H H S H H Cl Cl II i, y S \ O I p O N \ 0 H N N'p H N ( N' H Example 358 Example 357 Example 358 Cl ci H H H'H ci N N ci N N 0 s p O N I 0 0 0 N HN N' H H Example 359 N N (Me) 2 Example 360 ci ci CI H Cul Cl N Ns, H H S 0 y//\-o cl N N H N \ O O \. I il O v0 ruz HN neo O N Example 361 0 Example 362 0 0 Cl ci S H H N cl N N, N N w 0 A--a 0 O 0 II r vo _N \ N N Ao N Example 363 Example 364 CI H H H H H s zu O"iS II O SO p O 0 N \ O N N 0 0 0 N 0 H Example 366 Example 365 CI HN N4o 0 N N, S / N 0 0 0 \ \ I O lYi HN N'\O H Example 367 0 0 CI ci H H s H H s o AO HN N Ao < Example 368 0 _N \ N i HN H p H Example 368 Example 369 NU N ci cl N Nits\ . zozo N 0 0 0 y N Mu0 MeO Example 370 ci ci H H c NH N N o 0 0 0 oso /O N Example 372 MeHN Example 373 cl CI S N Ns z43 H H H isv O H2NO2S I \ N 2 2 N O O Example 374 Example 375 CI Cl s cri N,-'N , \ H H <J I Sv O \ N N. S \ 0 y s N N vs F 0 0 Example 376 Example 377 Ci Cl t H s cl N F3CA X O O O 0 H H F3C 0 0 0 ZON G-- Example 379 ci cl H H f H H O v I isv MeO ICI : N 0 0 0 Me02S , a 0 0 Example 380 Example 381 CI CI S ci Ci II \. MeS y//\\ 0 N N s MeS 0 0 y N 0 0 0 //I / ETHAN Example 383 Example 382 HI CI H H S H H N N H H 0 0//\\O y i o 0 0 Zon (Me) 2N HN Example 384 Example 385 CI CI H H S H H I-N N N, I/0 S O I/ I \ N I \ wN HN 0 e \\O J' F C Example 386 NH Example 387 cl Cri N N Cl 0. o T S /O I _N N Example 388 CI H H 0/"o H H H /N N. N N 0 \\o CI O I O 0 Br ps0 N N //I// HN HN Example389 | Example 390 Cl Cl H H H N N T O \ N I \ N HN HN Example 391 Example 392 ce CI Cl Cl N N S ° N 0 y N//S, 0 0 0 0 0 0 N N H N /han HN Example 394 Example 393 N (Me) 2 Ci ci H H N'N' H H N N s, 2 H H, O O. I II I \ N \ N O N ! ' N Example 395 Example 396 0 0 CL CL H H S , H H H) H H f o N N s N N, I y 0 y O O _N \ N N NMe H Example 398 Example 397 CL CL H H, H H 4 S N N 0 Ny N, O \ I lOl iSv 0/ (II O SO O O \ O \ N I \ N o Z, J Example 400 Example 399 CL H H N N H O s0 \ I O ZON / un HN Example 401 N o CL N H S CL CL 0 0 0 0 0 0 6 cl cul H H H s 0 N N, s NYN"s Example 402 Example 403 N eN ci ci H H s s O F \ N NiS \ O F \ N N. \ F C ! Cj 0 s F N N I _N \ N/ MeO Me0 Example 405 Example 404 Ci S S F N N F NYNs 0 y 0 N 0 0 0 0 I _N I \ N MeHN Example 406 Example 407 cl CI S F N N \ H H O. I S F N NEZ CI N/O HNp2s \ / SD I I. N s ,, Example 408 Example 409 CI CL F N N \ H H p I S\ F N N S O O I i v F I N/O Br \ N/ O O i i i r Example 410 Example 41. 1 Ci S ci N ICI N H N, 0 0 0 0 /o I N Example 413 ci ci H H S H H H o F N N S F N N s Met 0 o N //I// Example 414 Example 415 Cl H H s H H s 0 F) a N y N 0 F NY Is Mes 0 0/0 MeS N/O/p O O Cl Cl EtHN Example 416 Example 417 Cl /Cl H H s H H s . Y ' O I/O OSO O I \ II OSO I \ N I \ N/O (Me) 2N H N Example 418 Example 419 cl H H C ! Ci Cul Cl H N H N HN I HN I// F C Example 420 NH Example 421 ci Cl H H 0 0 0 0 0 0 N's N N H H Example 422 ci ci H H\ s O F/N N S. / O F/N N 'o 0 ci N o 0 Br 0 o HN I HN Example 423 Example 424 cl cri H H F H ? N) N S 4 0 ANYN//\\o 0 s I \ N HO HAN Example 426 Example 425 Example 426 Ci ci H H s H H 0 F : aNYN s N NN 6 // l Han Example 427 N Example 428 N (Me) 2 CI CI F H H H H s 0 ANYN F N N-1 //Sl 0 s o " I \ N \ N \ 0 HN HN I// Example 429 N Example 430 0) C) Cl H H S \ H H 0 N N, is N N, n v O I isv y 11 , 0 y O 0 p O O ZON N N NMe H Example 431 Example 432 ci cl H H H H "fY' y I'll \\ O,! OSO ZON w u HN- Example 433 Example 434 cl HHs F/N N O iS 0 F NN, ZON A 0 0 0 H N Example 435 0 0 ci cri Cl S O F/N N5 \ F/N N F N N N N \ O I p O O N HN HN I// Example 436 Example 437 0 ci s s 0 N NN N .. 0 O N isv O N O O p O O I \ N N/ Me0 Example 438 Example 439 Cl Cl H H S H H N 0 N N NS \ ci oC O ° °, < Y N SX H H s H H CI I MeHN Example 440 Example 441 cl N N \ H H O N \ S O N \ N II N iS \ 0 N N yN, \\ 0 N Ny N-S"ld\ (\ N I \ N //// Example 442 Example 443 CI H Hs H H s N\/N 0 i \ Ogo O N N/N% S\ 00 y F \ N/O Br \ N /O I// Example 444 Example 445 Ci Cl S N N \\ S H H N N I/II O 0 O N \ II Sv H i I A NS , . '0 0 0 0 N, 0 bw H H t a 0 y 0// G-- N Example 446 Example 447 Ci ci H H H H s H N N N NYNI 0 Example 448 /Me0 S N/O Example 44S Example 449 a'a S N Ns MeS 0 0 0 0 ETHN 1) N Example 450 Example 451 EtHN Example 450 Example 451 cl N \ N N S \ H H O I O O O N NNS N O N p p O (Me) N ( HN example 452 Example 453 CI ci cri H H H O I/II OO O I \ N II NS s ils o a N 0 0 N 0 0 0 'YS 0 N'S H N H N F3CJ Example 454 NH Example 455 CI H H N N, O O N \ II iS 0 I, \\O -10 0 N H Example 456 Ci ci ci Cul O i ? 'Y ! ? T'T Br N \ O N HN HN I// Example 457 Example 458 Cl H H \ H H 0 N O N I NN S\O p O Cl Cl N Example 459 example 460 Ci Ci H H s H H NYNs 0 N NYNsi 0 0 0//\\o 1 0 0//-, \o N ial Cl Cl \ N HN ? Example 461 N Example 462 N (Me) 2 Ci Ci H H N N H H O N NS ,)/S Y Suso () v Y Sb \ 0 0 HAN HO Example 463 N Example 464 N 0 0 CL CL H H S H H O N N NS N N A CCO \ U i p O 0 N Example 466 Example 465 CL CL H H s H H s v N N NS 0 s 0 N y S t HN) J // Example 468 Example 467 CL e-. H H f 9 Sx N O O N HN Example 469 N 0 CL CL Cul H 0 N N N, 0 N N Ns o. s o yr'T" N I N HN' HN Example 470 L, example 471 NU N CI CI H H S S H. H . I \ N N g\ O CI N N is\ \ \ /p O O I/ O O N Me0 Example 472 Example 473 Ci ci S S ci N s ci 1-N N, y I/\\o Cl MeHN \ N I \ wN //// Example 474 Example 475 CI CI S H N H H 0 0 y'//\\ O O H N O 5 CI N 2 z N I/0 O O Example 476 Example 477 CI H H s cl NEZ N S \ \ CI N N II O \O O \. "OSO F N Br 0 0 0 rr"YN- o o o Example 478 Example 479 Ci Ci ci N H H CI dz r. c. iXyTA ci //F3C \ N O Example 480 Example 481 Cl Cl O Clv Y/Sx\ o Cl NN>Sl$ II O II Me0 o O O MeO2S< < ° ° ° N Exam le 483 Example 482 Example 483 CI ci H H H H s . w \ 0 ou 0 MeS I In Example 484 Example 485 CI S CI N N \ CI N N o 1 o So OSO (Me) 2N HN Me N Example 486 Example 487 Cl "d\ H H H H CI N N I/O O O I/II 0 v o Ó Ò 0 HN HN<J Example 488 NH Example 489 Cul Ci CI N N c I 0 N NIS Cl N N H Example 490 ce H H ? H H s CI/N N / Cl °'Y '' I \ N Br \ N \ O O HN HN I// Example 491 Example 492 CI ci Cul rE v Y SuSo O v Y Sb Vu \J Iso I \, N I \ wN HN HN Example 493 Example 494 Ci cl s H H s H H ci N N O CI/N II NS/O/i, II So \ p O O N ki N //f-I N HN Example 495 Example 496 ? N N (Me) 2 Ci ce H H s s CI N N' H H 0 n'S ci N N . ''"XrY" Y oleo Han HAN Example 497 N N N Example 498 0) C) ci ci S o CI/N N S CI/ N N lol r y O N Xi N NMe H --NMe Example 499 Exampfe 500 Cl Cl S Clv ? ci N N o"YY ? TT cl N N 0 5--l s O zon // Example 502 HN 4/t, N N S Example 501 Ci CI O OSO lci NN, N 0 00 HN Example 503 0 HN- /Exampfe 503 CI CI S CI/N NS \ CI/N N O v0 O I I I O SO \ O H N HNJCI HM HN-'L Example 504 Example 505 N ci ce S O H s H H S N N 0 y 'N N/0 J I Me0 NJ Example 506 Example 507 Cl H H S H H fez D N N s Ny N, oy 0//1\0 0 0 0S 0 Zon Cl Example 509 Example 509 ' CI S N N t H H t 0 y 0 N N c y CI 0 ° SJ g 0-0 N N Example 510 Example 511 CI ci ci S N N \ H H 0 s N N, 'UL / O O I iy Ber 0 0 ZON NJ Example 512 Example 513 ci Sua N N, s I I is N N /O 0 O I . OSO /O N Example 514/NJ E xampie 515 ci cl H H S H H SU D \ N S \ met 0 \\O LL N Me025 N/O I NJ I NJ Example 516 Example 517 CI Cl H H s H H s NYN \. MeS O /O Zon EtHN N J Example 518 Example 519 cl ci H H H H s N N H H 0, y'S 0, aNYN s /p O O N \ N (Me) 2N NJ HN N Example 520 Example 521 CI S ci ci H H s H H i N I/J HN N v ZON Example 522 NH Example 523 FOC H H N nez > . M i J Example 524 CI ci H H S 0, aNYN"IS) aN NN l \ 0 s Br N I O O N Br 0 0 0 Example 525 ci ci C'a N I I N S \ N N 0 0//\\o y \ p O O N H HNXNJ S \J Example 527 Example 528 Cl Cl CI s H H s H H N N p O I ° J HN i NJ HN N H N eN"j ? ? Example 529 N (Me) 2 Example 529 Example 530 CI ci H H / N H H 0 y s N N I/\11 N p0 zon HN NJ HN N N Example 531 N Example 532 0 Cl H H s s /N Ns / N 0 0 0 N zor 0 0 0 zon NMe H N Example 533 Example 534 ci cul N N H N /. S \/ 0 y"s 0 0 0//\\ N) 0 0 N N NJ HN Example 535 Exampie 536 CI Han N N nez //\10 OSO HNO O N HN N_ Esample 537 N 0 CI ci H H s H H s 0"faNyN, s 0 NYN-ls Y ° ° rY'°' O 0 N HN NJ HN I NJ Example 538 Example 539 N eN ci H H S H H F N N, H H fV ° AT S0 y/\\ J I MeO"5 Example 540 Example 541 CI Cl ci F H N ii ii y lls\4 N N Cl N MeHN NJ Example 542 Example 543 cl ci S F N N F N N O v0 O \ iSv Example 544 -- J NJ N Example 544 Example 545 ci ci H H s H H F N y N, F NYNs 0 s 0 'UL Examp) e 546 J N Example 546 Example 547 CI ci H H s N N_ F S N F3 I N z Esample 548 N Example 549 ci ci H H H H S o'rY'Ts o'YY O FX Y/S o F H H $ I-r o-,,, S,-o 0 y I, N \ N J J N Example 550 N Example 551 CI ci S F N NS \ F N N II ii O 0 F N y Ns 0 F N Nez\ I J I , EtH N N J Example 552 Example 553 H H S H H S" ( CI ci S 0 F N NEZ zu F N y N, o l i 1 oso o I oso 0 N (Me) 2N NJ HN NJ Example 554 Example 555 CI S o TrT c Y o, < °° ì v O Ó Ò I/J HN i/J HN N v N Example 556 NH Example 557 ci H H F N N, 0 0 y In J N I's N AN N H Example 558 Cl Cl H H H T H H Y s II II , SO HN N HN N ci 0 N HN I NJ Example 559 | Example 560 CI H H ? H H s F N N /F N N O \ I I I O Sv0 O/I I01 O Sv0 o 0 \ N \ N HN NJ HN N J \J Example 561 Example 562 ci ci C ! J ) aH H ! 0 F N N N N AT J o- N I I ! s J H N/N ' HN N Example 563 N Example 564 N (Me) 2 cl ci CI H H F N'N H H "°''° ' \ O O O O I) OSO I \ N \ N \ O HNJX HNX N N Example 565 0 Example 566 O 0 F N NH, F N N > 4 p H H i H H i"S ci cl S F/N lol y p y y J zon Example 567 Example 568 cl ci H F/N N O F/N NS O II Sv I II O v0 r" S \ J 00 0 0 1 N N N HN N Example 570 Example 569 CI S \ 0-, s O iso 0o o N HN N HNN Example 571 N o H H f H H f CI ci H H s H H s 0 F NYNIS N N, s 0 y//' N H 0 0 H N Example 572 N31 Example 573 Cl Cl H H S \ H H s O N iSv O N N . S onto N N Sot Y I _N \ N/ Y 0 0 N J eN) Mu0 Example 574 Example 575 Cl Cl H N H S . N N O N Sv < N o ° N N N, s N Cl N MeHN N Example 576 Example 577 CI N N, H H N N \ H H N o N y/\\ 0 N N Cl H2NO2S 0 0 0 N N Example 579 CI Cl Cl H H N y N H H 1-1'S Ny N 0//\4 0 N I \ N Br N/p O O J i N Example 580 Example 581 ci H H s CI N/N S 0 N s H fez N N s J Y C-C o"CO t N Example 583 CI H H s H s O N S\ p i S N N N N s J Example 584 ci N Example 585 Cl 0 NYNs 0 N N N s N MeS 0 ol 11\0 1 0 Ol/1\0 ZON J I EtH N N J Example 587 Ci ci Cl H H S H H 0 y//"\ , X b', s o XNN, I\ N O (Me) 2N NJ HN NJ Example 588 Example 589 CI ci ci H H s H H s .-YYS C NS 0 N S ° ° I O ° ° O O /p O O Han HN NJ Example 590 NH Example 591 ci Fisc" H H ß zu zozo , 8 0 0 0 N N H Example 592 Ci ci H H S H H zu 0 'YS 0, N / 0 1/"10 cri 0 y HN-'N HN'"N Exam le 594 Example 593 Cl Cl H H S H H S NYN O N \ O HN NJ HN N ; N-b- 0 0 Example 595 Example 596 Ci Ci s H H s H H JO 0 N'YS Cl Cl w I o o'"o w N w l o o 0 N H N eN H N &N"j 0 Example 597 N N (Me) 2 C Example 598 CI ci H H N N H H 0 N s N N I N O N HO'AN Exam I 43 Example 600 0 Ci cri H H H H H H H h I'll, I'll, O N I isv \-NMe H ZON N J N N --NMe Example 601 Example 602 Cl H H H H s H H i N N. w N i N NS O \ I II OSO O \ I 0 v0 Zon N N HN N Nw/NJ HN N Example 604 Example 603 ci Erz 0 N N N, s p O O Zon 00 ° cl H H s H H s Example 605 N o Cl Cl H H f' H H JL7 i N N. w N i N N. S H N HNeNj O HN NJ HN N N Example 606 eN Example 607 Cl cl H H S \ S N) SX, <NX O Ó Ò N MeOeN-y N J I Me0 N J Example 608 Examle 609 ci S S O CI N NS \\ OCI N NS H H H H s ci Ny N ci N N 0 0 S Example 610 Example 611 ci cl H H S N H ci N N HH C 0 0 y, s4 H2NO2S 0 0 0 I -NJ I J Example 612 Example 613 cl ci S CI) CRNYN,-H H N L p O O I _N Example 614 Example 615 Ci Cl ? HY Y A C ! N R Cl N N s oS H H $ 0 0 0 0 S"O\ O O 'O C J Exam le 616 P Exampie 697 cl cri H H S H H H MeOC>N ° ° ° Me°2SCo < ° ° ° Me0 I o'0 I"0 O L LL N Example 618 N Cl Example 619 cl S o CI N N S \ CI NEZ s MeS N/0 MeS Cl H H S- 0 J I J EtN N N Example 620 Example 621 Cl Cl H H s H H s CI N N \ CI N "I"\ O I/II OSO O I \ II OSO I \ N I \ N/O (Me) 2N NJ HN NJ Example 622 Example 623 H H S H H S CI ci S 0 ci Ny N's 0 ci N y NN s O I/II OSO O I \ II OSO J HN N v N Exmple 624 NH Example 625 Cri H H H H Si 0 0 sz 0 To I J0N N H Example 626 Cl Cl H H s H H-s CI/N/NS/C/N N 'BTA ci o 0/0 0// HN N HN N Example 627 Example 628 Cl ci H H s H H s HN NJ HN N HNN HN""N \ i N O HN NJ HN NJ Example 629 Example 630 cl Cl s H H s H H S CI N N NYNIS y //--, N O I _ 0 0/"'o N HN N 0 Example 631 0 Example 632 N N (Me) 2 ci Ci H H s w H H S ) 0 y s ci N N vs I \ wN \ N \ O 0 0 0 Example 633 N Example 634 0 CI S H H H H s N N Example 635 Example 636 o Cl N N o Cl NH NH 4 tA HNXN N N N N N N né H --NMe Example 635 Example 636 ci ci H H s H H s han N OSO \ I U \ N ( N N HN N s'\ cri Example 638 Example 637 CL Han N CI O O O O v I HN' NJ N 9 Example 639 ci cl 0-/ c ! a H H ? H H ? 0 N N, s cl NYNs Asz 0 0 0// zozo H N N HN NJ HN I NJ Example 640 Example 641 C) ci H H S \ H S O \ N II N. \ N N asz /p O O I/O O met ZON Me0 I N% \ Example 642 Example 643 Cl S S N H H s H H s I \ N I \ N 0 0 0 0 0 Cl Nzl MeHN Nzl Example 644 Example 645 ci ci Cl N H H N N \ H H 0 s 0 N N, o ry T "p s c 0 H2NO2S 0 0//\\O N 646 N Example 646 Example 647 ci ci Cl N N HH N N \ H H p S\ O N N S / O O I \ N Br N/p 00 /N' I/'''\ N Example 648 Example 649 Ci S cri \ 0 Os0, N 0 "oxo C N/O i Ni \ <J N. Example 650 Example 651 Cl Ci H H H H s N N N N y/S, aNYN N. L _N \ N N Example 652 Example 653 ci CI H Ho N N //1\ I OSO Zon // EtHN4 Example 654 Example 655 Cl ci H H s H H s N N '''N '' I \ N I \ N/O (Me) 2N NJ\ HN Na Example 656 Example 657 Cl Cl H H Y H H N N N 0 0/1 \\O y/1 \\ I \ N HI I \ N/O N H N N ; \ AN 1 ) NH Example 659 F3C Example 658 Ci H H J" ( H H 0 N N, s /tHN Nzl N N 0 0 0 AN H N N H Example 660 ci cl H H s H H s /N II N w N N w cl \ O Br \ N I p O HN N-\ HN Exam le 661 HN N ;- H H f H H ? Example 661 Example 662 ci ci Cl /N I) NS w N N y// \\O i/N I N HN N1 HN NJ\ HN Example 663 Example 664 Ci ci s H H s H H NYN 0 ouzo p 0 N 0 N HNEN' N N Example 664 Example 666 CI CI S H H s Cl N N H H s Q s-q N fYy, rN' ° ° N N 0 0 H N N Example 668 0 \-' O CL CL H H H H s N N N N 0 S'0 y 11 , y N N 0 0 0 N zor 0 \ N N H NMe H Example 669 Example 670 CL CL S H H s . Y A xy T.. Q p O O Zon N I/ I/N W/N HN Example 672 Example 671 CL H H ß 0 i5v p N N, Zon 0 0 0 A 0 0 0 HN Nzl Example 673 o CL CL / \ N H H N 0 N, s N N, H / \\ 0 0 p O 0 I \ N \ N H N HNN. HN'M-. Example 674 Example 675 Nu N CI S F N N, H H ° lfoso o 1 o N Met Example 677 Example 676 CI C) C) \ \ O F N ii H Ny N F N N, s N CI I N'\ MeHN I N_ Example 678 Example 679 Cl CI S F N N \ H H CI O I/ OSO F I \ NN% S\ \ N 2NO2S N 0 N 680 Example 681 CI ci ci H H s H H s F N N \ H H F N N o . O O I" P a c rT c YA N U Exmple 682 Example 683 Cri S \ CI F N N, H H ( i F N N 0 ou/1\0 0 Y sud N 0 0 0 NeN' F3C N example 684/N-\ Example 685 G- Ci ci H H s H H s g TYTs c YY Me0 I O O O I"O O 'N LL N Example 686 Example 687 Ci ci S 0 F N y N's 0 F N N s po N 0 0/110 Mes Example 688 Example 689 CI ci H H SU H S F N N \ o N N 0//iso O I/II OSO O I \ II OSO I \ N O (Me) 2N NJ\ HN NJ\ Example 690 Example 691 CI CI HN N N Ion N 0 0 0 N 0 0 0 o HN I i\ HN N N NH Exmple 693 FOC Example 692 Cl H H i F N N Jt N N JX . N N H Example 694 CI H H H H 0 F N N 0 F N N CI O "O /I"Sp Br N \ HN N HN N'l Example 695 Example 696 ci cl H H S H H F X XTTc N I \ fV O HN Na HN Na r Example 697 Example 698 ci Ci HNt4 ; X\4 ; \ X t5t° HN'N \ NN 52 H H 0 H H s F N N y 0 0/--o 0 0/\10 / ° HN NI \ Exam lu 699 N (Me) 2 Example 700 ci ci H H H H ? c- F) a N N 1. 6 H H s / O \ N \ N \ I O O O HN N_ \ HN I N- N Example 701 Example 702 O o a H H H H s 0/NuN. s F/N N w I % v O JJ o o o. . A o ° ° o 0 b o N) a 0 0 0 _N \ N NMe H N --NMe Example 703 Example 704 0 ci Cl S H H s F H H s O II Sv I i v p O O \ O 0 O N N HN N Example 706 Example 705 H H s F N N N 0 0 0 HN Y, 000 i\ HN N N Example 707 o CI ci H H S , H F/N N S /F/N N HNN- HN-"-N O O t,/-) Exampfe 708 j HAN N Nxy Ns Example 709 N N Cl ci H H f\\ u D S-/ n, CNTN SX O/O, SW N N H H Me0 I Ni\ Example 710 Example 711 Ci ci H H H H s \ ICN"R 0 0 0 O O /O Cl N ; \ MeHN NJ\ Example 712 Cl Example 713 CL S N N \ N H 0 N s 0 N N N 0 S\ o N N CI N / H2Np2g \"OSO . c I y N Example 715 CI Cl H H s s N Bro N\/N H H Vg H H S F \ N/O O O Br \ /101 O 0 l N N Example 716 Example 719 H \ CI N N N N N OSO N N N \ O yv zozo /N' N Gaz N Example 718 Example 719 ci ci H H 0 N N N, d\ N N O I \ N II N S O I \ II S Me0 O O O O Me02S N/O "'N-\ Exampfe 721 Example 721 H H S" H H f" ( Example720 Cl 4 Cl H N N n H s N N O I \ S\ O N \ (I O SO \ MeS 0 / I EtHN 0//\\O EtHN I NI Example 722 Example 723 Cl ci S H H O H N 0 SO \ I I /O (Me) 2N NJ\ HN Nzl\ (Me). NN HNN Example 724 Example 725 CI Cl Cl . N 0//\\O 0 0 HN I/ HN I NI \ F CJ Example 726 NH Example 727 3 Cl H H 0 0 -10 oll \\O N N 0 N NI H Example 728 cl Cl Cl 0 N i nu N S/O N s 0 Ny N H H o 0 Br 0 0// O N \ N HN N1 HN N ; \ Example 729 Example 730 Cl H H H H 1 H H 0 Ny Ns 0 N Ny N s \ HN HNeNj Exampole 732 Example 731 ci Cl H H H H Y K,. NN. ==/ p O \ N z N X ° °) T Ó +O .. JLJ T 00 N °' HN J) N HNN ! N (Me) 2 Example 733 t Example 734 CI ci ci H H H H s w H H .. CrY al 0 o 0"/\o N I/ HN N_ _ FiN I N- N N Example 735 Example 736 O Cl Cl H H H H s 0 H H N ? 1 "A ? V ! T Y O N I isv Ni- N N W N NMe H Example 737 Example 738 Ci C ! H H f M M JD o Ns o "r Y'. "" cl ci i N N. w N i N N. S/ O \ I 101 OSO O \ I II O v0 \ N I \ N teD HN Example 740 Example 739 cl H H s H H f NH NH b HN Nzl N Example 741 N CI Cl H N N, NEZ nus O \ I II O S O O \ I II HN NH H M \ mUs o O O vN HN4NJ\ HN<NJs Example 742 N Example 743 <y Example 743 ci ci /cl N\/N CI N H S C <, o o o, e, 1 o ó o /p O O I p O \O ca if 0 Me0 Example 744 Example 745 Ci cri S S ci ci H H H H s Cl MeHN Cf MeHN O Example 746 ci Example 747 Cl H H S N N \ CI H H isv O \ 0 y 0 NYNs c oxo o / O 0 0 Example 748 Example 749 cl Cl H H Cl N N ci H H P A 0 0 0 H 0 s 0 o I 0 0 Example 750 Example 751 Cl 0 cul N N 0 0 0 y Cl IN\i 751 , CI / 0 Example 752 Example 753 CI H H S --CI H H ! ? fT'Y ? fT /NN. /CI N nez CI pl O Br \ N 0 0 p I o Ni o Example 754 Example 755 Cl Cl H H S Cl O \ I II OS\O O/I II SO p O I \ N I \ wN HN HN Example 757 Example 756 Cul Ci H H S \ H H H s ci N N CI 0/N N S o I oSo \ I o O Cl N N HO Example 758 Example 759 N (Me) 2 Ci cl H H CI H H s CI zu ! !/' Examp) e761 \ I II i \ N N p O HO ? 0 N ? 0 Example 761 Example 760 '0- O CL CL 0 N C N N \ CI 9 H O vs O 0 _N \ N v v wo N NMe H 0 Example 762 Example 763 CL CL H H s cl CI O/N N \S CI 0 N N N W óò p \ N p O O N i N HN 0 Example 765 Example 764 CL \ CI N nez HN O OSO HAN HN O Example 766 N 00 CL CL H H ? y-a H H f y-Ct ? H ci H H cl N ° r""' N HN p HN Example 767 Exarple 768 N en ci ci Cl /NuN N N \ I O S o/I-. SO \ O r i CONH2 MeHN H CONH2 Exampfe 770 Example 769 Example 770 Cl Cl H H ci 0 N N, s 0 c \10 O II OSO O \ I Ii O v0 meon N I AJ MeHN"""" MeHN'¢X$ MeHN j NO ? CN Example 782 Example 781 Ci CI ci ci /N N To °°° N MeHN'< MeHNJt 0 NYNIS 0 Y C02Me ° NH Example 783 S Example 784 N ci ci S'\ n H H ? y-Ct H H ! . NN / s ci H H s ci ?) T Yo JL J 0 0 MeHN4J MeHN ; su N N, s 0 y s I MOHN MOHN S02Me N- Example 786 Example 785 CI ci S S ! ? fY'Ts" o Y' O S O I/ SO 0 _N I. \ N MeNN MeHN ° NH O\NH Example 788 Example 787' N cl s cri O \ I I H . / \O\ I N S N/pJ 0 neo N Example 789 Examp ; le 790 CI s cri N N S . \ \ CI H H N N CI ° ° ° l 'So N O </Me-N N Example 791 Example 797 Example 792 s ci cri N nus / O //"o N N 0 0 o MOHN Meon Xi Example 794 Example 793 ce H. H 6 0 "O o I"pSO /0/O N N N Example 795 NH Example 796 ci ci Me N N \ C N N O I/Ipl O Sv0 O I \ I I O Sv0 I _N (_N 0//"o N/ N nua N Example 798 H H s s F N N H H \ N N g\ F N p O 0 I/ O O _N \ N mye0 0 Example 799 Example 800 S S FS 0'YS- H H H H s Cl A to MeHN J<o oo I/00 I \ N I \ N 0 0 0 0 0 0 Example 801 Example 802 H H s s H H \ N H . 0 F \ N N g\ 0 F N NS O O N) cr H2NO2S N 0 0 0 0 Example 803 Example 804 H H s p F I N OSO F N\/N% S\ \ N/ Br N I/0 o 0 Example 805 Example 806 H H s NS I H NH NH, H H /O O I iiv C/ O O FOC N 0 ( Example 807 Example 808 H H s H H s o'Y'Y' o'YYY O ii y O I I i v MeO>< o ó ò MeO2S < ° ° ° 0 0 0 0 Example 810 H Hs s , Q, H H i MeS N f/O O O I/ 0 O I/I , N O EtH N N Example 811 Example 812 H H H H H H SU, H H, X (Me) 2N HN A I \ N (\ ZON (Me) zon O HN/O Example 813 Example 814 H H s H H F N Is 0 F N y N I s N 0 zu I 0 O HAN Han p O NU Example 815 Example 816 H H s H S Jan H Zon H ° H O Example 817 H H S H H H 19 H I is F N N, s 0 F N N c. A XT T ? YTV O I II SvO O/II, Sw N 0 Br 0 Hi O Hi/ O Example 818 Example 819 H H S H H F/N N F N N 0 N N % s, L-- 0 F Ny N y iso I \ N I \ wN HN 0 HN 0 v Example 820 Example 821 H H F N N, /N N. J HN-"- 0 w N I Han HN 0 ? Example 822 N N (Me) 2 C Example 823 H H F N N H H O S\ F/N N ? r T T o - . .. o o. 0 o-Y-y Y s Fa N Y No_ H H 0 Han 0 N N Example 824 N Example 825 O s F H H HH / YY c YYY 0 0 0 o A N N N CONH --NMe Example 826 Example 827 5 H H H H /II S O II S O \ i O O O \ O O O C y 0 A N T N I/ 0 H N 0 -0 Example 829 Example 828 F N N 0 y iso O O zon Han 0 Example 830 N Oc-) H H HH oxo nN<N 0 2, 0 N jDtN HN 0 HN 0 N NN O HN Example 831 Example 832 NsS NC Example 832 H H s H H . Xy O \ I II ONSO O/INII O \ N O CONH MeNN OH CON H Example 833 Example 834 H H H H, MeHN X MeHN F N N Is, 0 s 0 \\o J \ wN Meon CN Example 835 Example 836 H H H H F N N O I 0 p°SD O ! II O zon I I MEON MeHN-" C02Me CNH Example 837 Example 838 N \ S H H Yo"Ss L \ F, N N 0 N meon Zon N MeHN I MeHN SOME Example 840 Example 839 H H H H S F N N \ I/II O v0 I/I01 O Sv0 _N I \ wN mehr Menu 0 NH 0 NH rN Example 841 N Example 842 C) H H 9 F) a N Ns HYH H O I II Or v0 O F \ N N. S'' ° \ N/ S i/ p O <\ \ N N Example 843 Example 844 H H H s O F \ N N. S S I II v0 O F \ N NS_ /'\ N I/ p O \N l//Me_I \ N N Example 845 Example 846 H H ' S- H 846 F N N \ H H O I So F N 0 Ny N 0 0 0 b 'N Mehr MOHN meon N Example 848 N F F H N \ H S O N N NS N N '-"O O O O //S-//S- zon zu Mu0 Example 849 Example 850 F F S N N , N S ii NXN) NN Sot N N N So N N I N p MeHN 0 Cl <+r X N X N g N 5, $ H2N °25) NC N bo N 5, (S Example 851 example 854 H H s \ s N N H H 0 N So 0 '0 CI H NO S " 2 2 N O O O / o Example 853 example 854 F F S N NEZ \ N H N S N N O O N S\ F zozo Br O 0 Zon O/ Example 855 F Example 856 H H s F N 0 s H H y N, N Sb 0 0 0 0 F3C 0 0 0 zon O Example 857 Example 858 F F H H S H H s ? N N N, s N s N 0 Me02S N 0 0 O O Example 859 F example 860 F H H s H H s N N \ N N MeS N N y N's 0 Ny N s MeS /O N IN 0 EtH N Example 861 F Example 862 F H H s H H s N nez O N \ O N \ N NS 0 I _N I N (Me) 2N HN Exampfe 864 Example 863 F F S H H H H s 0 T 0 NS o oxo HN HN O O J NH F3C Example 865 Example 866 H H s F N H A, N"N S U /1 1\ K ° 'fizz H 0 Example 867 F F H H H H s N N o CII \ N O Br N I p 0 O HN 0 Example 868 Example 869 F F H H 0 H H NYN O O O HN HN O Example 871 Example 870 F F H H s \ H H H H NYNs n N H ? T Y 0 N N 0 N ; ;" p 0 \\o HAN han Han ? N (Me) 2 Example 873 Example 872 F F H H N N H H N NS 0 N s N N \ N O I/ Han H N N Example 87 N Example 875 O F F N NH 0 N N N, s 0 N N, s i i ii v p N N 0 o N 0 0 0 Nw I/I \ wN c 0 N 0 NMe H Example 876 Example 877 F F H H H f M M J/ JO-Y ' O O O \ N HNS aO N'nu HN/O O O F Example 879 D/S Y S b HN O Example 878 S 0 N N N, s ° NS N 0 0 zon Han 0 HN O Example 880 zon ' 0 0 N y s //N\ A, J"oo fr !' ° ° ° 0//, o 0 0 0 N 0 azol Ho han e 0 eN 0 4S Example 882 F F H H S \, H 0 N NNSJ N N w I o o,, o o N l o s, 0 N N \ O 0 0 o,"0 CONH2 MeHN OH CONH2 Example 883 Example 884 F S \ s H H s jTc ry ° ° p p'Q N \ O N MeHN) MeHN N ; ;' N y N 0 N ; ' y e \\ 0 0 0 0 CN Example 886 Example 885 F F H H s H H N N, o \ I p 0 zon / MEHN I MEHN CO2Me O NH NH Example 887) Example 888 N F F N nez N T N H H c N o rY JJ Aj ? Oo <N \ o i N 0 0 N MOHN MOHN SO2Me N ~ I Example 889 Example 890 F F H H S H N O N NN N N 0 N s 0 N Nq N , N mehl meon NH NH Example 891 N Example 892 N F H H s F -Zzz N N N, s H H s p I OS\O H 0 0 o s p O N N Example 894 F H H S F N N H H p i \ /O Xi // N /p O O \N //Me_N I \ N H// Example 895 Example 896 F H H s N N H H N N JX X ° ° b X o ó b \ N /J p O /u MEHN MeHN MOHN U Example897 n N Example 898 N F F H H S H'N St N NS \ N N \ N, /p p O /0 p O N I N NH NH Example 899 Example 900 F F H H S S H H s H H s Me /O I _N I N /// Me Me Example 901 Example 902 ci cl N N S \\ N N \ I/iiv O/I01 OSO Su j, N 0 0 0 Y CF3 MEHN I) \\ CH3 H Example 903 Example 904 cl C S 0 s F NYNNS I y//\\ 0 , O O II \ N N/0 MEHN N-\ H Example 905 Cl Example 906 Cl CI S ci N \ p F N N ost /p N/O N I / F MeHN MeHN H O Example 908 Exampfe 907 N Ns \ N N H H s H H s 0 N N, s 0 N N N, s I'll \\O N 0 0 N A F MEHN N MEAN 0 H Example 910 Example 909 ci s ci IN NY NS OMe H H s 0 N N J' f ! "N" N Y N 0 0 0 MeHN HN4o MeHN HO MEHN N) \\o Example 911 Example 912 ci s N N, ci H H MeHN H o Ol/\\O CL3 ZON H MEHN N H Example 913 Example 914 CI s ry o YA- ci ci H H s s N N \ CI H H O I S\ F N N CI O O I isv N F N N/p 00 MeHN NI \ F MeHN I N'\ F O Example 915 CI Example 916 CI Clx, NN WCI o Fe, NrN S, SCI iso s H H s \ N F MEHN N Ao CF3 MeHN H O MEHN N Ao H Example 917 Example 918 CI CI CI N 0 0 N N 0 0 ii /O 0 NN Q O O I _N I MeHN N4o MeHN HNao H H Example 919 Cl Example 920 S \ CI N N\/N CI OMe g p OSO N N NS \ CI 0 Y 0 I zoo zon MeHN NAo MeHN N- Example 921 H Example 922 H H s s N N H H N NS N N ,'-', ii O S /"O O /p O O CF3 I MeHN HN o MeHN H o H O Example 923 Example 924 H H s N N H H i, u p \ y 0 I \ N N/p O O MEHN N Ao F MeHN N 0 H Example 925 Example 926 . H H YY H H o Cl Vof"s"o Ft Y"S" /O OSO N I OSO F MEHN N Ao MeHN H O Example 927 Example 928 H H H H N N, N N N k N) °nÒ fiv /p O NN 0 0 O I MeHN N4o MeHN HNao H Example 929 Example 930 H H s , N N N OMe s O O N N NS N, N NS H H, N N Joy 0 0 0 0 S"Q\ MEHN N H MeHN 'N o Example 932 ce O N, , N, N N \ I/II O v0 O I/II O S O N MeHNw CF3 MeHN CH3 MeHN Example 933 Example 934 cl ci H H S H-H S Cl e v Y Sß X V Ó Ó Ò \ o I/ N MeHN F MeHN I F Example 935 Example 936 ci cul s CI N N \ p F N. \ OSO MeHN O MeHN CF3 N I CF3 //F MeHN MeHN Example 937 Example 938 Example ci H H HH MeHN MeHN 0 o o N N 0 0 0 ZON MeHN F MeHN Example 939 Example 940 Ci Cl S H H \ , N N N_S H H MeHN y 0 0 0 N y p 00 MEHN MEHN MeHN / MeHN Example 942 CI CI H H s 0 NYNI H H O I 1t S o N N S iI /O o I/II y N MeHN NJ 0 Ny N, MeHN N Example 943 Example 944 ce ci H H s N N, H H ii v . s \ /I01 O O I v 'N N/0 0 O MEHN N5 F Me H N F Example 945 Example 946 ci s H H s Cl v N N, o s s i o 0 0 N o'o I /+ J F MeHN N CF3 MeHN N Example 947 Example 948 ci ci H H \ o N N 0 N y N, 0 N NyN, s /O N O N MeHN N F MeHN N Example 949 Example 950 Cl S \ cri Example 950 Cl ) : N-) 0 0 , J<N) aN H X asz A 0 O MeHN N MeHN NJ Example 951 Example 952 CI ci S S 0 NEZ N non , $0N oX NH NsX _N \ N MeHN I N- CF3 I C H H Example 953 Example 954 cl ci Cl Nu ho p I \ NN F N\/N /O I/ F I _ F H MEHN N Ao H Example 955 Example 956 CI C) s ho CI N N \ 0 F N N 0'k N 0 O I \HN I/lol MEHN N Ao H F MeHN v N- H MeHN HO Example 957 Example 958 Cl Cl H H, $ NH N o/t N 0 N,-N 0 ° ' p 1 /p NN 0 MeH N N Wo MeH N HN Wo H Example 959 Example 960 Ci Cl N NN OMe 0 N N 0 0 I/\ N NJ O MeHN J. i i Meon neo H Example 961 Example 962 CI CI O H s 0 H s MeHN N, s N, p I \ g o I N. S \ /O O/0 0 _N \ N MeHN I NI CF3 I C O MeHN H'O Example 963 Example 964 CI 0 F N, , b O (\ OSO O F I \ N. S \ / O O MEHN N Ao F MeHN Hp MeHN N_ p Example 965 Example 966 /' /0 g-/ o'' Cl (D d ci N 0 s \ 3 MeHN H/\\ F A O H Example 967 Example 968 ci ci S O \ O N \ HN050 \ O N N NOSO N'" \\o F MEHN : IN O H Example 969 Example 970 ci g CI OMe . S fV" 0 han, 0 0 0 N s zon MEHN N Ao MeHN H -O Example 971 H Example 972 ce H H s N N H H N"N isv O NNS ''H N 0 0 0 H N 0 Example 974 Cl , \ H H . 0 N O O o'o v ó, S, ° zon s /O/N. N Example 975 H Example 976 CI S N H H s H H N N, N Nu OSO y \/O I II N"0 Example 977 Example 978 Ci ci s H H N N T N, 0 y SZ\ o H N Exam (e 979 Example Example 980 CI CI S H H O \ N, NiS \ N N. Me0 \ I/ p p I/ pS0 MeHN N O 0 0 Example 981 Example 982 CI CI H MEHN N 0 < O rrV °"° I/, N MeHN O MeO N Example 983 H Example 984 cl H H H H Cl Cl O I \ N N.. S \ O I/I01 OSO O O \ INY MeHN MeHN NO Example 985 Example 986 ce cl H H N N p NuNs \ <) N MeHN 0 s pp - I MeHN, HN Exampfe 987 o. H c s Aj (j T A N-yJ 0 ° ° MeHN' Example 988 CI S S ci ci ci N N, F N N, y//N\ 0 s T"° rA \/O Example 989 Cl Cl a ci S S n \S n' r rT H H s H H s jazz y //\\o y 0 0 0 Example 991 H Example 992 ci ci s H H 0ci N N, \ 0 1 y//\\ \/lol O O N. _ 0 Example 993 Example 994 Ci Ci S N. CI N NS ci N NN o zozo r H N 0 Example 995 Example 996 ci y S S H H \ rT ° ° rr" u N nez H O a0 O I I O S O N N 0 NI O Example 997 Example 998 Cl ci S S C H N, s F N NS 0 "I \\ 1 11 \\ 0 0 0 0 0 0 0 NN II O N Example 999 H Example 1000 ci ci s H H s H H S F N NS F ? 1) ! Y A O I \ T O SO \ I/II O v0 /O N O Example 1001 Example 1002 ci cl Cl F N N 0 s ii v 1/ O 0 0//\\O 0 0 0 F HAN 0 0 Example 1003 Example 1004 ci cri H H s H H S N"N \ O I \ Sv O \ N II N. S n O O I i v N N 0 0 N_ O Example 1005 H Example 1006 0 CL H H S H H 0 N N, s 0 N N, s O I II Sv O I II Sv 0 N 'N \ N-- 0 non O N Example 1007 H Example 1008 Cl CI S 0 N N 0 y 0 0 0 'N"--0 I/N I/N. 0 Example 1009 Example 1010 CI ci cri s H H H r\\ N N 0 s 0 s y ii OC 0 0 0 H N o Example 1011 Example 1012 Cl ci cri H H f\\ u S- or'Ys o c. .. H H H s H H s /O I/NI I/ MeHN N O Example 1013 H Example 1014 CI S H H S N N \\ N N \ O \ II Sv O I II Sv pp \/p 00 C Me0, N. N CI MeHN OT"0\ N MEHN N Cl Example 1016 Cl CI S \ H H S H H N N \ NS O \ i O O in cul I ci N Cl MeHN O MEHR Example 1017 Example 1018 Cl Cl/ s H H s N NS II "MeHN O U SO /0 \ 1 ci Mehl H NU Example 1019 Example 1020 CI Ci H His MeOX SE Ss met y /O I MeHN MeHN N O H Example 1021 Example 1022 cl S S H H 5 O N 0 N \ l. III MeHN o MeO H 0 0 0 Me0 I N-N F MeHN 0 Example 1023 Cl Example 1024 Cl Cl S N N S s N\/N O I \ T O S O \ I/II O v0 /O I /N F MeHN MEHR Example 1025 Example 1026 Cl ci Ci s \ 0 S ! Y A H H N N, N N 0 s I o o F F HN MEON 0 Example 1027 Example 1028 CI CI N Ns S \ N N \ \ MeHN'"N""0 U i p O O 0 0 0 MeHN H O H Example 1029 Example 1030 CI H N Ng W O S O I i II O O I ii zozo if Me0 H. N mehl 0 Example 1031 Example 1032 y cl Soh H H H F 0 N N MeHN v Y/5\ S"d\ y 0 NJ I 1''N Nez MEON Example 1033 Example 1034 Ci Cl H H N N 0 \ N N, 0 Y 0// I N J Q p MeHN I N / HN--° MeHN 0 0 N Example 1035 Example 1036 CI CI N N H H O I N\/NS N N \ I ii O S /O O I I I O -" N CI Example 1038 Example 1037 Example 1038 Cl Cl H H s H H s . \ p I \ g\ F N\/NS \ p O O I/p O O in - N F-N F Example 1039 Example 1040 Cl ci S N N N, 0 y s NYN 0 - NYN Example 1041 Example 1042 cl ci H H s N N H H Ny N, O NN NNS 0 N N N i, 0 N s zon 0 N 0 0 Example 9043 Example 1043 Example 1044 ci ci S N N H H O I S N N ii v /O O O I \ II OSO N N/O -'"N CI MOHN Example 1045 Example 1046 ci ci H H H F N Ns O O N _N , i - N F-'N F MeHN MeHN Example 1047 Example 1048 Ci Cl H H F H H \\ H H s H H N N, N N N, i p O O 0 0 0 i _ N. _ N MEHN MEHN Example 1049 Example 1050 a v o Ó Ò t 4 N O ° ° CI s H H s H H NYN, IN N N 0 N s lot nez N'N .-N--N MEHR MeHN Example 1052 0 ci ci O \ N (Ng \ N zu I/O O O O I \ II OSO 'N N/O '_"N i 'N CI MeHN Example 1053 MEHN Example 1054 ci CI H H S \ F N N I, qNy 0 N O I II,, S O I 0 0 O /O 0 O r - N F'"N F MeHN Example 1055 MeHN Example 1056 CI s H H s O N [' S I/ pp N. p 00 N MeHN Example 1057 MeHN Example 1058 Example 1058 Cl N N Y 0/1, \\O N Oy \\O NU"-, 0 p N i N O O - N, _. N. N MeHN Fam le 1059 MeHN P Example 1060 Preparation of Compounds of the Invention A compound of formulae (I)- (VIII) may be prepared by various methods as outlined in the following documents: J. Med. Chem., 33,23-93-2407 (1990); Biorg. & Med. Chem. Letts. , Vol. 2, No. 9, pp. 987-992 (1992); J. Med. Chem., 35,3012-3016 (1992); U. S. Patent 5,234, 955 (1993), U. S. Patent 5,354, 778 (1994); U. S. Patent 5,565, 494 (1996); U. S. 5,594, 028 (1997); U. S. Patent 5,302, 724 (1994); and WO 97/08 i 45, which are incorporated herein in their entirety by reference. Other well-known heterocyclic and carbocyclic synthetic procedures as well as modification of the procedures that are incorporated above may be utilized.

Compounds of formulae (I)- (VIII) may be isolated using typical isolation and purification teclmiques known in the art, including, for example, chromatographic and recrystallization methods.

In compounds of formula formulae (I)- (VIII) of the invention, carbon atoms to which four non-identical substituents are bonded are asymmetric. Accordingly, a compound of formulae (I)- (VIII) may exist as enantiomers, diastereomers or a mixture thereof. The enantiomers and diastereomers may be separated by chromatographic or crystallization methods, or by other methods known in the art. The asymmetric carbon atom when present in a compound of formulae (I)- (VIII) of the invention, may be in one of two configurations (R or S) and both are within the scope of the invention. The presence of small amounts of the opposing enantiomer or diastereomer in the final purified product does not affect the therapeutic or diagnostic application of such compounds.

According to the invention, compounds of formulae (I)- (VIII) may be further treated to form pharmaceutically acceptable salts. Treatment of a compound of the invention with an acid or base may form, respectively, a pharmaceutically acceptable acid addition salt and a pharmaceutically acceptable base addition salt, each as defined above.

Various inorganic and organic acids and bases known in the art including those defined herein may be used to effect the conversion to the salt.

The invention also relates to pharmaceutically acceptable isomers, hydrates, and solvates of compounds of formulae (I)- (VIII). Compounds of formulae (I)- (VIII) may also exist in various isomeric and tautomeric forms including pharmaceutically acceptable salts, hydrates and solvates of such isomers and tautomers.

This invention also encompasses prodrug derivatives of the compounds of formulae (I)- (VIII). The term"prodrug"refers to a pharmacologically inactive derivative of a parent drug molecule that requires biotransformation, either spontaneous or enzymatic, within the organism to release the active drug. Prodnigs are variations or derivatives of the compounds of fonnulae (I)-(VIII) of this invention which have groups cleavable under metabolic conditions. Prodrugs become the compounds of the invention which are pharmaceutically active in vivo when they undergo solvolysis under physiological conditions or undergo enzymatic degradation. Prodrug compounds of this invention may be called single, double, triple, etc. , depending on the number of biotransfoimation steps required to release the active drug within the organism, and indicating the number of functionalities present in a precursor-type form. Prodrug forms often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (Bundgard, Design7 ofProdrti,-s, pp. 7-9,21-24, Elsevier, Amsterdam (1985); Silvennan, The Organic Chemistry of Drug Design and Drug Action, pp. 352-401, Academic Press, San Diego, CA (1992) ). Prodrugs commonly known in the art include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acids with a suitable alcohol, or amides prepared by reaction of the parent acid compound with an amine, or basic groups reacted to form an acylated base derivative. Moreover, the prodrug derivatives of this invention may be combined with other features herein taught to enhance bioavailability.

Example 1 Preparation of 5-chloro-2- [({[(5-chloro(2-thienyl)) sulfonyl]amino} (cyanoimino) methvll amino]-2-methylphenvl} benzo [c] azolidine-1, 3-dione A solution of N-(4-amino-2-methylphenyl)-4-chlorophthalimide (0.14 g, 0.5 mmol) and dimethyl N-cyanodithioiminocarbonate (0.13 g, 1 mmol) in pyridine (1.3 mL) was stirred at 115'C for 8 hr. The reaction mixture was then cooled and concentrated in vacuo. To a solution of this crude intermediate (56 mg, 0.11 mol) in pyridine (0.7 mL) was added DBU (33 µL, 0.22 mmol) and 5-chlorothiophene-2-sulfonamide (44 mg, 0.22 mmol). The reaction mixture was heated at 115 °C for 23 hr with addition of DMAP (10 mg) after 2 hr. Acidification and HPLC purification yielded (2Z)-2-aza-3- [ (5-chloro (2- thienyl) ) sulfonyl] amino}-3-{[4-(5-chloro-1,3-dioxobenzo [c] azolidin-2-yl)-3- methylphenyl]amino}prop-2-enenitrile (14 mg, 24%). ES-MS (M+H) += 534,536 (Cl).

H-NMR (DMSO-d6) : 8 2.03 (s, 3H), 7.06-7. 07 (d, 1H), 7.18-7. 20 (d, 1H), 7.30-7. 31 (d, 1H), 7.37 (s, 2H), 7.93-7. 94 (2H), 8.03 (d, 1H), 8.84 (s, 1H).

Example 1061 Preparation of (5-chloro (2-thienyl))-N- ( { [4- (5-chloro-1, 3-dioxobenzo [c] azolin-2-yl)-3- methylphenyl] amino} thioxomethyl) carboxamide A. Synthesis of 5-chlorothiophene-2-carbonyl chloride To a chilled solution of 5-chlorothiophene-2-carboxylic acid (0.16 g, 1.0 mmol) in EtOAc (3 mL) and DMF (1 drop) was added neat oxalyl chloride (92 pL, 1. 05 mmol).

The reaction mixture was stirred cold for 2 hr and concentrated in vacuo to give crude 5- chlorothiophene-2-carbonyl chloride.

B. Synthesis of (5-chloro (2-thienn)-N-( { [4-(5-chloro-153-dioxobenzo [c] azolin-2- yl)-3-methylphenyl] aminothioxomethyl) carboxamide To a suspension of KSCN (29 mg, 0.3 mmol) in dry acetonitrile (0.2 mL) was added a solution of the crude acid chloride (36 mg, 0.2 mmol) in CH3CN (0.2 mL). The resulting suspension was stirred at room temp for 30 min. This acylthioisocyanate in situ was added to a suspension of N-(4-amino-2-methylphenyl)-4-chlorophthalimide (58 mg, 0.2 mmol) in CH3CN. The reaction mixture was stirred at room temp for 1 hr, filtered and dried to give pure (5-chloro-(2-thienyl))-N-({[4-(5-chloro-1,3-dioxobenzo[c]azo lin- 2-yl) -3-methylphenyl] amino} thioxomethyl) carboxamide (66 mg, 70%). ES-MS (M+H) + = 490, 492 (Cl).

Example 1062 Preparation of 5-chloro-2-(4-{[5-(5-chloro(2-thienyl))(4H-1, 2,4-triazol-3-yl)] amino}-2- methylphenyl) benzo [c] azoline-1, 3-dione To a suspension of (5-chloro (2-thienyl))-N-({[4-(5-chloro-1, 3- dioxobenzo [c] azolin-2-yl)-3-methylphenyl] amino} thioxomethyl) carboxamide (15 mg, 0.030 mmol) and hydrazine dihydrochloride (4 mg, 0.038 mmol) in DMF (0.3 mL) was added EgO (7 mg, 0.032 mmol). The reaction was stirred at room temp for 17 hr, and HPLC purified to give the desired product 5-chloro-2- (4- f [5- (5-chloro (2-thienyl) ) (4H- 1, 2,4-triazol-3-yl)] amino}-2-methylphenyl) benzo [c] azoline-1, 3-dione (2 mg) (ES-MS (M+H) + = 470,472) and the aminoguanidine intermediate N- ( (lE)-2-aza-1- f [4- (5- chloro-1, 3-dioxobenzo [c] azolidin-2-yl)-3-metlzylphenyl] amino}-2-aminovinyl) (5- chloro (2-thienyl) ) carboxamide (2 mg) ES-MS (M+H) + = 488, 490 (2C1).

Example 1063 Preparation of 3- (4- { [5- (5-chloro-2-thienyl)-4H-l, 2,4-triazol-3- yl] amino} phenyl)-1, 3-dihydroquinazoline-2, 4-dione was executed using the same methodology as shown in Examples 1061 and 1062, using 3-(4-aminophenyl)-1, 3- dihydroquinazoline-2,4-dione as the aniline in step B from Example 1061. ES-MS (M+H) + = 437,439 (Cl).

Example 1064 To a solution of triphosgene (22 mg, 0.074 mmol) in CH2C12 (1 mL) was added a suspension of N-(4-amino-2-methylphenyl)-4-chlorophthalimide (57 mg, 0.2 mmol) in CH2C12 (1.5 mL) and diethylisopropylamine (70 ptL) dropwise over 10 min. The reaction mixture was stirred for 10 min, then a suspension of benzenesulfonylhydrazide (52 mg, 0.3 mmol) in CH2Cl2 (1.5 mL) and DIEA (35 µL) was added. The mixture was stirred at room temp for 17 hr, acidified and HPLC purified to give N- [4- (5-chloro-1, 3- dioxobenzo [c] azolidin-2-yl) -3-methylphenyl] [2- (phenylsulfonyl) hydrazino] -carboxamide (43 mg, 46%). ES-MS (M+H) + = 485, 487. IH-X (DMSO-d6) : 5 2.00 (s, 3H), 7.13- 7.15 (d, 1H), 7.28-7. 31 (d, 1H), 7.34 (s, 1H), 7.55-7. 67 (m, 3H), 7.82-7. 84 (m, 2H), 7.93 (s, 2H), 8.02 (s, 1H).

Example 1065 Preparation of { [ (5-chloro (2-thienyl)) methyl] amino}-N- [4- (5-chloro-l, 3- dioxobenzo [c] azolidin-2-yl)-3-methylphenyl] carboxamide A. Synthesis of 5-chloro-2-[(1,3,5,7-tetraazatricyclo[3. 3.1. 1 (3, U decyl) methylthiophene To a suspension of hexamethylenetetramine (HMTA) (3.12 g, 22.2 mmol) in CHC13 (35 mL) was added 2-chloro-5-chloromethylthiophene (1. 02 mL, 8.46 mmol).

The reaction mixture was heated at reflux for 4 hr, cooled, and filtered to give white solid 5-chloro-2- [ (1, 3,5, 7-tetraazatricyclo- [3. 3.1. 1 (3,7)] decyl) methyl] thiophene (2.28 g, 88%). ES-MS (M) += 271,273 (Cl).'H-NMR (DMSO-d6) : 8 4.27 (s, 2H), 4.39-4. 57 (ABq, 6H), 5.06 (s, 6H), 7. 21-7. 24 (ABq, 2H).

B. Synthesis of (5-chloro-2-thienylmethylamine To a solution of 5-chloro-2- [ (1, 3,5, 7-tetraazatricyclo [3.3. 1. 1 (3,7)] decyl) methyl] thiophene (2. 15 g, 7 mmol) in methanol (10 mL) and water (5 mL) was added conc. HC1 (5 mL). The reaction mixture was refluxed for 3 hr, poured onto water and washed with ethyl ether. The aqueous layer was basified with 4N NaOH and extracted into ethyl ether, washed with brine, dried and concentrated in vacuo to give (5- chloro-2-thienyl) methylamine (0.8 g, 78%).

C. Synthesis of {[(5-chloro(2-thienyl))methyl]amino}-N-[4-(5-chloro-1,3- dioxobenzo[c]azolidin-2-yl)-3-methylphenyl]carboxamide To a solution of triphosgene (22 mg, 0.074 mmol) in CH2Cl2 (1 mL) was added suspension of N- (4-amino-2-methylphenyl)-4-chlorophthalimide (57 mg, 0.2 mmol) in CH2C12 (1.5 mL) and diethylisopropylamine (70 ßL) dropwise over 10 min. The reaction mixture was stirred for 10 min, then a solution (5-chloro-2-thienyl) methylamine from step B (47 mg, 0.32 mmol) in CH2C12 (1 mL) and DIEA (35 µL) was added. The mixtu was stirred at room temp for 17 hr, acidified and HPLC purified to give { [ (5-chloro (2- thienyl) ) methyl] amino}-N- [4- (5-chloro-1, 3-dioxobenzo [c] azolidin-2-yl)-3- methylphenyl] carboxamide (18 mg, 20%). ES-MS (M+H) + = 460,462 (CI). 1H-NMR (DMSO-d6) : # 2.02 (s, 3H), 4. 34-4. 36 (d, 2H), 6.77-6. 80 (t, 1H), 6.82-6. 93 (2d, 2H), 7. 14-7. 16 (d, 1H), 7.29-7. 32 (dd, 1H), 7. 41 (d, 1H), 7.93 (ABq, 2H), 8.02 (s, 1H), 8. 77 (' 1H).

Example 1066 Preparation of 5-chloro-2- 4-[({[(5-chloro(2-thienyl))sulfonyl]amino}thioxomethyl) amino]-2-methylphenyl} benzo [c] azolidine-1, 3-dione: A. Synthesis of 4-(5-chloro-1,3-dioxobenzo[c]azolidin-2-yl)-3- methylbenzenisothiocyanate To a slurry of 150 mg (0.52 mmol) of 2- (4-amino-2-methylphenyl)-5- chlorobenzo [c] azoline-1, 3-dione in 2 mL of acetone, was added 41 uL (0.54 mmol) of thiophosgene. The yellow slurry dissolved whereupon a white precipitate formed. After 1h, this solid was collected by filtration and dried to give 127 mg (74%) of the desired product.

B. Synthesis of 5-chloro-2-{4-[({[(5-chloro(2-thienyl))sulfonyl]amino} thioxomethyl)amino]-2-methylphenyl}benzo[c]azolidine-1,3-dio ne To a slurry of 51 mg (0.156 mmol) of the isothiocyanate prepared above and 31 mg (0.156 mmol) of 5-chlorothiophenesulfonamide in 300 pL of DMSO was added 26 all of 1, 8-diazabicyclo [5.4. 0] undec-7-ene (DBU). After a few minutes the reaction mixture was diluted with 1.2 mL of water and acidified with acetic acid to pH 4 when a precipitate was formed, collected, and dried to give 77 mg (94%) of the titled compound.

ES-MS (M+H) + = 525.8 (2C1).

Example 1067 Preparation of 2- [4- ( { (IZ)-2-aza-2- [ (5-chloro (2-thienyl)) sulfonyl]-l- methylthiovinyl} amino)-2-methylpllenyl]-5-chlorobenzo [c] azolidine-1, 3-dione: To a solution of 20 mg (0.038 mmol) 5-chloro-2-{4-[({[(5-chloro (2- thienyl) ) sulfonyl amino} thioxomethyl) amino]-2-methylphenyl} benzo [c] azolidine-1, 3- dione in 780 D. L of acetone and 63 ptL of 0. 6M NaHCOs was added 5. 9 JIL of methyl iodide. After 2h, the reaction mixture was acidified with acetic acid and the precipitate was collected and dried to give 13 mg (63%) of the titled compound.

Example 1068 Preparation of 5-chloro-2- {4-[({[(5-chloro (2-thienyl) ) sulfonyl] amino} iminomethyl) amino]-2-methylphenyl} benzo [c] azolidine-1, 3-dione A 15 mg portion of the 5-chloro-2- {4-[({[(5-chloro (2- thienyl)) sulfonyl] amino} thioxomethyl)-amino]-2-metllylphenyl} benzo [c] azolidine-1, 3- dione was dissolved in 120 pL of DX containing 6.6 mg of conc. ammonium hydroxide and 6 mg of mercuric oxide was added. After stirring for 18 h, the mercuric sulfide was filtered off and the solution was purified by reversed phase HPLC to give 1 mg (7%) of a white solid. ES-MS (M+H) + = 509 (2C1).

Example 1069 Preparation of 5-chloro-2- {4-[({[(5-chloro(2-thienyl))sulfonyl]amino} (hydroxyimino) methyl) amino]-2-methylphenyl} benzo [c] azolidine-1, 3-dione The titled compound was prepared in a similar fashion as for Example 1068 with a 10% yield after purification. ES-MS. (M+H) + = 525 (2C1).

Example 1070 Preparation of 5-chloro-2- 4-[({[(5-chloro (2-thienyl) ) sulfonyl] amino} methyl) amino]-2- methylphenyl} benzo [c] azolidine-1, 3-dione A. Synthesis of 2- ((1E)-1-aza-2-ethoxyvinyl)-2-methylphenyl]-5- chlorobenzo Ll azolidine-1, 3-dione A 50 mg (0.175 mmol) portion of 2- (4-amino-2-methylphenyl)-5- chlorobenzo [c] azoline-1, 3-dione in 2 mL of triethylorthoformate was heated to reflux for lh then distilled to leave a solid, 598 mg (100%).

B Synthesis of 5-chloro-2-{4-[({[(5-chloro(2- thienyl)) )sulfonyl]amino}methyl)amino]-2-methylphenyl}benzo[c]azolidi ne-1,3- dione A 100 mg sample of2- [4- ( (lE)-l-aza-2-ethoxyvinyl)-2-methylphenyl]-5- chlorobenzo [c]-azolidine-1, 3-dione plus 58 mg (0.29 mmol) of 5- chlorothiophenesulfonamide was slurred in 1.2 mL of MeOH, heated to reflux for 2h, and the methanol was distilled off. The remaining solid was triturated with ACN/MeOH, filtered, and concentrated to afford 104 mg (87%) of the titled compound. ES-MS (M+H) + = 494.

Example 1071 Preparation of 5-chloro-2- [4- ( {l- [ (5-chloro (2-thienyl) ) sulfonyl] (1, 2,3, 4-tetraazol-5- yl)} amino)-2-methylphenyl] benzo [c] azolidine-1, 3-dione The titled compound was prepared in a similar fashion as for Example 1068 to yield, a 18% yield after RP-HPLC purification. ES-MS (M+H) + = 535 (2C1).

Example 1072 5-chloro-2- [4- ( {l- [ (5-chloro (2-thienyl) ) sulfonyl] (1, 2,3, 4-tetraazol-5-yl)} amino)-2- methylphenyl] benzo [c] azolidine-1,3-dione A. Synthesis of chlorophenylsulfoxide To 2 g (12 mmol) of sodium benzenesulfinic acid was added 5 mL of thionyl chloride and stirred at 0 °C for 4 h. The product was isolated by bulb-to-bulb distillation (180 °C @ 4 mmHg) to afford 1.25g (64%) of the liquid benzenesulfinic chloride.

B. Synthesis of benzenesulfinamide The chlorophenylsulfoxide (500 mg, 3.2 mmol) was dissolved in 5 mL of diethyl ether at 0 °C and anhydrous ammonia was bubbled through until no more precipitate is formed. The solution was filtered and concentrated to afford a solid which was reciystallized from water to afford 152 mg (35%) of benzenesulfinamide.

C. Synthesis of 5-chloro-2-[4-({1-[(5-chloro(2-thienyl))sulfonyl](1,2,3, 4-tetraazol-5- yl)] amino)-2-methylphenyl]benzo[c]azolidine-1, 3-dione A 16 mg portion of benzenesulfinamide and 47 mg of 2- (4-amino-2- methylphenyl)-5-chlorobenzo [c] azoline-l, 3-dione was dissolved in 232 uL of CAN followed by 18 pL of DBU. The reaction was stirred at 23 °C for lh and purified by RP- HPLC to give 20 mg (38%) of the desired material. ES-MS (M+H) + = 454 (2Cl).

Example 1073 Preparation of {j4- (5-chloro-1, 3-dioxobenzo [c] azolidin-2-yl)-3-methylphenyl] amino}-N- (N-t-butylphenylsulfonimidoyl) carboxamide: A. Synthesis of (tert-butyl)(phenylsulfonyl)amine In a similar fashion for the preparation of Example 1072 B, tert-butyl amine (5 equivalents) was used to prepare the named compound in 75% yield. tH-NMR (DMSO- d6): 8 7.67 (m, 2); 7.45 (m, 3) 4.83 (br s, l); 1.39 (s, 9).

B. Synthesis of (tert-butyl)(phenyliminosulfonyl)amine To a 50 mg-portion (0.25 mmol) of (tert-butyl) (phenylsulfonyl) amine in 5 mL of anhydrous THF was added 58 mg (0.26 mmol) of N-chlorosaccharin under an argon atmosphere. After a few minutes the reaction mixture was cooled to-78 °C, and anhydrous ammonia was bubbled through. After warming to 23 °C the solvent was evaporated, the residue was dissolved in water, extracted 3 times with EtOAc. The combined organic layers were washed with 5% NaHC03, dried (Na2S04), and concentrated to afford 37 mg (68%) of the titled compound. ES-MS (M+H) + = 236.

C. Synthesis of4- (5-chloro-l, 3-dioxobenzo [c] azQlidin-2-yl')-3- methylphenyl]amino}-N-(N-t-butylphenylsulfonimidoyl)carboxam ide In a similar fashion for preparation of Example 1072C, the titled compound was prepared in 2% yield after RP-HPLC purification. ES-MS (M+H) + = 525.

Example 1074 Preparation of { [4- (5-chloro-1, 3-dioxobenzo [c] azolidin-2-yl)-3-methylphenyl] amino}-N- (N-benzylphenylsulfonimidoyl) carboxamide A. Synthesis of CbenzvDCphenvlsulrbnyDamine In a similar fashion for the preparation of Example 1072 Step B, benzylamine (5 equivalents) was used to prepare the named compound in 74% yield. ES-MS (M+H) + = 232. 1. 1H-NMR (CDCl3) # 7.67 (m, 2); 7. 51 (m, 3); 7.28 (m, 5); 4.28 (ABX, 1) ; 4.23 (ABX, 1) ; 3. 89 (X, 1).

B. Synthesis of (benzyl)(phenyliminosulfonyl)amine In a similar fashion as for the preparation of Example 1072 Step C, the titled compound was prepared in quantitative yield.

C. {[4-(5-chloro-1,3-dioxobenzo[c]azolidin-2-yl)-3-methylphenyl ]amino}-N-(N- benzylphenylsulfonamidoyl)carboxamide In a similar fashion for preparation of Example 1072 Step C, the titled compound was prepared in 34% yield after RP-HPLC purification. ES-MS (M+H) + = 559.

Example 1075 Preparation of {[4-(5-chloro-1,3-dioxobenzo [c] azolidin-2-yl)-3-methylphenyl] amino}- N-(N-p-methoxybenzylphenylsulfonamidoyl)carboxamide A. Synthesis of (p-methoxybenzyl amine In a similar fashion for the preparation of Example 1072 Step B, p- methoxybenzylamine (5 equivalents) was used to prepare the named compound in 66% yield. ES-MS (M+H) + = 262. tH-mR (CDCI3) : 5 7.97 (m, 2); 7.49 (m, 3); 7. 18 (d, 2); 6.81 (d, 2); 4.20 (m, 2); 3.8 (dd, 1); 3. 74 (s, 3).

B. Synthesis of (p-methoxybenzyl)(phenyliminosulfonyl)amine In a similar fashion as for the preparation of Example 1072 Step C, the titled compound was prepared in quantitative yield. Material used in next step without purification.

C. Synthesis of {[4-(5-chloro-1,3-dioxobenzo[c]azolidin-2-yl)-3- methylpheny] amino (N-benzylphenylsulfonimidoyl) carboxamide In a similar fashion for preparation of Example 1072 Step C, the titled compound was prepared in 17% yield after RP-HPLC purification. ES-MS (M+H) + = 589.

Example 1076 Preparation of { [4- (5-chloro-1, 3-dioxobenzo [c] azolidin-2-yl)-3-methylphenyl] amino}- N- (phenylsulfonimidoyl) carboxamide To 10 mg (0.016 mmol) of {[4-(5-chloro-1,3-dioxobenzo[c] azolidin-2-yl) -3- methylphenyl]-amino}-N-(N-p-methoxybenzylphenylsulfonimidoyl ) carboxamide dissolved in 380 µL of CAN followed by 96 uL of water was added 70 mg (0. 13 mmol) of cerric ammonium nitrate. After 20 m, the reaction was complete and purified by RP- HPLC to give 1. 8 mg (23%) after lyophilization. ES-MS (M+H) + = 469 (Cl).

Example 1077 Preparation of N-{[4-(1,3-dioxobenzo[c] azolidin-2-yl) phenyl] sulfonyl (phenylamino) carboxamide: A. Synthesis of 4-(1,3-dioxobenzo[c]azolidin-2-yl)benzenesulfonamide A solution of 1.0 g (5.8 mmol) of p-aminophenylsulfonamide in 3.6 mL of pyridine was added 878 pL (6.1 mmol) of phthalic dichoride. After heating to 60 °C for 18 h, the solution was poured into IN HC1, cooled to 0 °C, the precipitate was collected by filtration, and dried under vacuum to give 1.58 g (90%) of the titled compound.

A. Synthesis of N-f [4-(1,3-dioxobenzo[c]azolidin-2-yl)phenyl]sulfonyl} (phenylamino) carboxamide To a solution of 4-(1, 3-dioxobenzo [c] azolidin-2-yl) benzenesulfonamide in 660 uL of DMSO was added 60 mg (0.40 mmol) of DBU followed by 36 al (0.33 mmol) of phenylsulfonylisocyanate. After stirring for 0.5 h, the mixture was poured into IN HC1, cooled, and the precipitate was collected by filtration and dried under vacuum to give 137 mg (100%) of the titled compound.

Example 1078 Preparation of N- [ (5-chloro (2-thienyl) ) sulfonyl]-N'- [4- (5-chloro-1, 3-dioxobenzo [c] azolidin-2-yl)-3-methylphenyl] ethane-1, 2-diamide : A 200 mg (1.0 mmol) of 5-chlorothiophenesulfonamide was slurred in 0. 5 mL of oxalyl chloride and refluxed for 6h. The solvent was removed in vacuo and 36 mg of the resulting solid was dissolved in 240 pL acetonitrile and treated with 40 mg (O. 14 nunol) 2-(4-amino-2-methylphenyl)-5-chlorobenzo[c]azoline-1, 3-dione. After stirring for Ih, the solvent was removed and the residue was purified by RP-HPLC to give 33 mg (44%) of the titled compound. ES-MS (M+H) += 538 (2C1).

Example 1079 Preparation of [4- (1, 3-dioxobenzo [c] azolidin-2-yl) phenyl]-N- [ (5-chloro (2- thienyl)) sulfonyl]-carboxamide A. Synthesis of N-[(5-chloro (2-thienvl !) sulfonyl] (4-nitrophenvl) carboxamide A 85 mg portion (0.43 mmol) of 5-chlorothiophenesulfonamide dissolved in 2 mL of acetone was treated with 11 O pL of 4N NaOH (0.43 mmol) followed by addition of 80 mg (0.43 mmol) of 4-nitrobenzoyl chloride. After stirring for 12 h, the solution was acidfied IN HCl and the precipitate was collected by filtration and dried.

Recrystallization from EtOAc/hexane afforded 120 mg (81%) of the titled compound.

ES-MS (M+H) + = 347 (Cl).

B. Synthesis of (4-aminophenyl)-N-[(5-chloro(2-thienyl))sulfonyl]carboxamide A 74 mg portion (0.21 mmol) of [4- (1, 3-dioxobenzo [c] azolidin-2-yl) phenyl]-N- [ (5- chloro (2-thienyl)) sulfonyl]-carboxamide, 192 mg (0. 84 mmol) of tin dichloride dihydrate were combined and dissolved in 1.4 mL of EtOAc. The mixture was refluxed for 4h, filtered through celite, and concentrated in vacuo to afford a solid which was purified on silica gel eluting with 10% MeOH/CH2Cl2 to give a quantitative yield of the titled compound. ES-MS (M+H) + =317 (Cl).

C. Synthesis of [4-(1,3-dioxobenzo[c]azolidin-2-yl)phenyl]-N-[(5-chloro(2- thienvll) sulfonyl]lcarboxamide A 22 mg portion (0.070) of (4-aminophenyl)-N-[(S-chloro (2- thienyl) ) sulfonyl] carboxamide was combined with 15 mg (0.10 mmol) of phthalic anhydride in 140 pL of DMF. After 18 h of heating at 110 °C, the mixture was cooled and purified by RP-HPLC, to give 20 mg (55%) of the desired compound. ES-MS (M+H) + = 447 (Cl).

Example 1080 [4-(2, 4-dioxo (1, 3-dihydroquinazolin-3-yl)) phenyl]-N- [ (5-chloro (2-thienyl) ) sulfonyl]carboxamide A 44 mg portion (0. 14) of (4-aminophenyl)-N-[ (5-chloro (2- thienyl) ) sulfonyl] carboxamide was combined with 25 mg (0.14 mmol) of methyl 2- isocyanatobenzoate in 500 uL of THF followed by the addition of 1 equivalent of TEA (24 pL) and 1 equivalent of DBU. After 18h, the mixture was purified by RP-HPLC, to give 21 mg (34%) of the desired compound. ES-MS (M+H) + = 462 (Cl).

Scheme 1 General Synthesis of Phthalimide Compounds : General Procedure for synthesizing phthalimide targets A. General Procedure for phthalic anhydride reaction A mixture of phthalic anhydride (0.96 g, 6.5 mmol) and the substituted nitroaniline (5 mmol) in DMF (10 mL) was heated to 120°C for 22 Itr. The reaction was then concentrated and chromatographed on silica gel using CH2Cl2/hexane mixtures as eluent to give pure product in 35-65% yields, depending on the substituents.

B-1. General reduction procedure 1/ A suspension of the nitrophenyl intermediate (0.75 mmol) and tin (II) chloride dihydrate (3 mmol) in ethyl acetate (4.5 mL) was heated at 70°C for 2 hr. The reaction mixture was then poured onto ice (25 mL), basified with 5% NaHCO3 (13 mL), extracted with EtOAc, washed with brine, dried and concentrated in vacuo to give pure aniline product in very good yields, typically >90%.

B-2. General reduction procedure 2 To a suspension of the nitrophenyl intermediate (0.8 mmol) in methanol (3 mL), ethyl acetate (2 mL) and 2 N HCI (0.4 mL, 0.8 mmol) was added 10% Pd/C (43 mg, 0.04 mmol) under argon. The reaction mixture was hydrogenated under 1 atm EI2 for 2 hr, filtered through Celite and concentrated in vacuo to give the aniline hydrochloride salt in very good yields.

C. General Procedure for coupling the aniline intermediate with 5- chlorothiophenesulfonamides to form sulfonvl ureas To a suspension of 5-chlorothiophene-2-sulionamide (40 mg, 0.2 mmol) and DSC (61 mg, 0. 24 mmol) in dry acetonitrile (1 mL) was added DBU (60 µL, 0.4 mmol). The resulting solution was stirred at room temp : for 16 hr. The aniline from step B (0.2 mmol) was then added as a solid with additional acetonitrile (1 mL), and the reaction was heated to 70°C and stirred for another 17 hr. Acidification and HPLC purification of the crude reaction product gave the final compounds in varying yields (20-70%).

Example 7 and Examples 1081-1093 The targets above were prepared using the procedures outlined in Scheme 1, steps A-C using a variety of substituted nitroanilines, where R = 3-C1 ; 3-CN; 3-CF3; 3-F; 3-Br; 3-OMe; 3-iPr; 2-CF3; 2-Cl, 5-Me; 2-NMe2, 5-Cl ; 2,5-diMe ; 3,5-diMe ; 3,5-diCl ; 2-OMe, 5-Me; and X = N, R = H.

Example 7 N- [4- (1, 3-dioxobenzo [c] azolidin-2-yl)-3-chlorophenyl] { [ (5-chloro (2- thienyl) ) sulfonyl] amino}-carboxamide. ES-MS (M+H) + = 496, 498 (2C1).

Example 1081 N- [4- (1, 3-dioxobenzo [c] azolidin-2-yl)-3-cyanophenyl] { [ (5-chloro (2- thienyl) ) sulfonyl] amino}-carboxamide, ES-MS (M+H) + = 487, 489 (Cl).

Example 1082 N-[4-(1,3-dioxobenzo[c]azolidin-2-yl)-3-(trifluoromethyl)phe nyl]{[(5-chloro (2- thienyl) ) sulfonyl]-amino} carboxamide. ES-MS (M+H) + = 530, 532 (Cl).

Example 1083 N- [4- (1, 3-dioxobenzo [c] azolidin-2-yl)-3-fluorophenyl] { [ (5-chloro (2- thienyl) ) sulfonyl] amino}-carboxamide. ES-MS (M+H) + = 530,532 (Cl).

Example 1084 N- [4- (1, 3-dioxobenzo [c] azolidin-2-yl)-3-bromophenyl] f [ (5-chloro (2- thienyl)) sulfonyl] amino}-carboxamide. ES-MS (M+H) += 540,542 (Cl, Br).

Example 1085 N- [4-(1, 3-dioxobenzo [c] azolidin-2-yl)-3-methoxyphenyl] { [ (5-chloro (2- thienyl) ) sulfonyl]amino}-carboxamide. ES-MS (M+H) + = 492.0 (Cl).

Example 1086 N- [4- (1, 3-dioxobenzo [c] azolidin-2-yl)-3- (methylethyl) phenyl] { [ (5-chloro (2- thienyl) ) sulfonyl] amino}-carboxamide. ES-MS (M+H) + = 490.9 (Cl).

Example 1087 N- [4- (1, 3-dioxobenzo [c] azolidin-2-yl)-2-(trifluoromethyl) phenyl] { [ (5-chloro (2- thienyl)) sulfonyl]-amino} carboxamide. ES-MS (M+H) +=463, 465 (Cl).

Example 1088 N- [4- (1, 3-dioxobenzo [c] azolidin-2-yl)-2-chloro-5-methylphenyl] { [ (5-chloro (2- thienyl) ) sulfonyl]-amino}carboxamide. ES-MS (M+H) += 510,512 (2C1).

Example 1089, N- [2- (dimethylainino)-4- (1, 3-dioxobeiizo [c] azolidin-2-yl)-5-chloropheny1] [ (5-chloro (2- thienyl))-sulfonyl]amino}carboxamide. ES-MS (M+H) + = 539,541 (2Cl).

Example 1090 N- [4- (1, 3-dioxobenzo [c] azolidin-2-yl)-2, 5-dimethylphenyl]{[(5-chloro (2- thienyl)) sulfonyl] amino}-carboxamide. ES-MS (M+H) + = 490.0 (Cl).

Example 1091 N-[4-(1,3-dioxobenzo[c]azolidin-2-yl)-3,5-dimethylphenyl]{[ (5-chloro (2- thienyl) ) sulfonyl] amino}-carboxamide. ES-MS (M+H) +=490. 0 (CI).

Example 1092 N- [4- (1, 3-dioxobenzo [c]azolidin-2-yl)-3,5-dichlorophenyl]{[(5-chloro(2- thienyl)) sulfonyl] amino}-carboxamide. ES-MS (M+H) += 529.9, 532. 0 (2Cl) Example 1093 N- [4- (1, 3-dioxobenzo [c] azolidin-2-yl)-5-methyl-2-methoxyphenyl] {[(5-chloro (2- thienyl) ) sulfonyl]-amino} carboxamide. ES-MS (M+H) += 506,507 (Cl).

Example 1094 Preparation of N- [6- (1, 3-dioxobenzo [c] azolidin-2-yl) (3-pyridyl) ] { [ (5-chloro (2- thienyl)) sulfonyl]-amino} carboxamide was accomplished using the procedures outlined in Scheme 1, steps A-C using 2-amino-5-nitropyridine. ES-MS (M+H) + = 463,465 (Cl).

Example 1095 Preparation of N- [6- (I, 3-dioxobenzo [c] azolidin-2-yl) (3-phenyl) ] {[(5-chloro (2- thienyl) ) sulfonyl]-amino} carboxamide was accomplished using the procedures outlined in Scheme 1, steps A-C. ES-MS (M+H) + = 462. 0 (Cl).

Example 1096 Preparation of N-[4-(1,3-dioxobenzo[c]azolidin-2-yl)-4-napthyl]{[(5-chloro (2- thienyl)) sulfonyl]-amino}carboxamide was accomplished using the procedures outlined in Scheme 1, steps A-C. ES-MS (M+H) + = 511.9 (Cl).

Scheme 2 Example 1097 Preparation of N- [5- (1, 3-dioxobenzo [cgazolidin-2-yl) (2-pyridyl)] {[(5-chloro (2-thienyl) )- sulfonyl] amino} carboxamide A. Synthesis of (tert-butoxy)-N-(5-nitro(2-pyridyl))carboxamide To a solution of 2-amino-5-nitropylidine (0.555 g, 4 mmol) in THF (10 mL) was added 1 M NaHMDS in THF (8 mL, 8 mmol). The resulting dark red suspension was stirred for 15 min, followed by addition of a solution of Boc anlzydride (0.87 mL, 3.8 mmol) in THF (5 mL). The reaction mixture was stirred at room temp for 21 hr, dilute with EtOAc, washed with 1 N HCl and brine, dried and concentrated in vacuo to give (tert-butoxy)-N- (5-nitro (2-pyridyl) ) carboxamide (0.63 g, 70%). ES-MS (M+H-tBu) += 184.

B. Synthesis of N-(5-amino(2-pyridinyl))(tert-butoxy)carboxamide To a suspension of (tert-butoxy)-N- (5-nitro (2-pyridyl)) carboxamide (0. 27 g, 1. 13 mmol) in methanol (2 mL), ethyl acetate (4 mL) and TEA (0.16 mL) was added 10% Pd/C (60 mg, 0. 056 mmol) under argon. The reaction mixture was hydrogenated under 1 atm Ha for 20 hr, filtered through Celite and concentrated in vacuo to give N- (5-amino (2- pyridyl) ) (tert-butoxy) carboxamide (0.226 g, 97%). IH-NMR (DMSO-d6) : 5 1.40 (s, 9H), 4.92 (br s, 2H), 6.89-6. 91 (dd, 1H), 7. 35-7.37 (d, 1H), 7.58 (d, 1H), 9.06 (s, 1H).

C. Synthesis of N-[5-(1,3-dioxobenzo[c]azolidin-2-yl)(2-pyridyl)]{[(5-chloro (2- thienyl))-sulfonyl]amino}carboxamide N- [5- (1, 3-dioxobenzo [c] azolidin-2-yl) (2-pylidyl)] { [ (5-chloro (2-thienyl) )- sulfonyl]amino}carboxamide was prepared by following the procedure in Scheme 1 step A, followed by TFA deprotection, followed by the coupling procedure outlines in Scheme 1 step C. ES-MS (M+H) + = 463, 465 (Cl).

Example 1098 Preparation of N-[2-(1, 3-dioXobenzoCc3azolidin-2-yl) pyrimidin-5-yl] {[(5-chloro (2- thienyl)) sulfonyl] amino} carboxamide.

A. Synthesis of N-(2-aminopyrimidin-5-yl)(tert-butoxy)carboxamide To a suspension of2-amino-5-nitropynmidine (0.25 g, 1.78 mmol) in methanol (4 mL) was added tert-butyl (tert-butoxycarbonyloxy) formate (0.5 mL, 2. 18 mmol) and 10% Pd/C (96 mg, 0.090 mmol) under argon. The reaction mixture was hydrogenated under 1 atm H2 for 5 hr, filtered through Celite and concentrated in vacuo to give crude N- (2-aminopyrimidin-5-yl) (tert-butoxy) carboxamide (0.435 g). ES-MS (M+H) + = 211.

B. Synthesis of (tert-butoxy)-N-[2-(1,3-dioxobenzo[c]azolidin-2-yl)pyrimidin -5- yljcarboxamide To a solution of N- (2-aminopyrimidin-5-yl) (tert-butoxy) carboxamide (0.237 g, 1.0 mmol) in pyridine (1 mL) was added phthaloyl dichloride (0.144 mL, 1.0 mmol).

The resulting suspension was stirred at 45 °C for 2 hr, diluted with EtOAc, washed with water and brine, dried and concentrated in vacuo to give crude (tert-butoxy)-N- [2- (1, 3- dioxobenzo [c] azolidin-2-yl) pyrimidin-5-yl] carboxamide (0. 31 g). ES-MS (M+H) += 341; (M+H-tBu) +=285.

C. Synthesis of N-[2-(1,3-dioxobenzo[c]azolidin-2-yl)pyrimidin-5-yl]{[(5-chl oro(2- thienyl))sulfonyl]amino}carboxamide TFA deprotection of (tert-butoxy)-N- [2- (1, 3-dioxobenzo [c] azolidin-2- yl) pyrimidin-S-yl] carboxamide and coupling with 5-chlorothiophenesulfonamide (see Scheme 1 step C) gave N-[2-(1, 3-dioxobenzo [c]azolidin-2-yl)pyrimidin-5-yl]{[(5- chloro (2-thienyl)) sulfonyl] amino}carboxamide in 27% yield. ES-MS (M+H) + = 464, 466 (Cl).

Scheme 3 Benzamide-containg Sulfonvlureas 0 NH2 R ci 0 R SnC12. 2H20 0 R i, EtOAc i \ I--R----R i N N R' PhCH3 /H /H NO2 reflux R"X cl S S"NAO-N /Cs2CO3 DMF 0 R 0 O 1 1) SnC12. 2H0 " S N-_aN02 EtOAc R N N N R'HNvNO2-> Rt U R"H H R' 2) CIThSZNHCSu 1 : R=2-Me, R'=H, R"=H 2 : R=2-Me, R'=H, R"=Me 3 : R=2-Me, R'=CI, R"=H 4 : R=2-Br, R'=H, R"=H Example 1099 Preparation ofN- [4- ( [ (5-chloro (2-thienyl)) sulfonyl] amino} carbonylamino)-2-<BR> <BR> methylphenyl]-b enzamide A. Synthesis of N-f2-methyl-4-nitropllenyl) benzamide To a suspension of 2-methyl-4-nitroaniline (0.76 g, 5 mmol) in toluene (25 mL) was added neat benzoyl chloride (0.59 mL, 5.08 mmol). The reaction mixture was refluxed for 16 hr, cooled and filtered to give N- (2-methyl-4-nitrophenyl) benzamide (1.21 g, 95%) as a beige solid. ES-MS (M+H) + = 257.

B. Synthesis of N-(4-amino-2-methylphenvl ! benzamide A suspension of N-(2-methyl-4-nitrophenyl) benzamide (0.256 g, 1.0 mmol) and tin (II) chloride dihydrate (0.89 g, 3.96 mmol) in ethyl acetate (6 mL) was heated at 70 °C for 19 hr. The reaction mixture was then chilled, poured onto 50 mL ice, basified with 5% NaHCOs (20 mL), extracted into EtOAc, washed with brine, dried and concentrated in vacuo to give N- (4-amino-2-methylphenyl)-benzamide (0.22 g, 97%). ES-MS (M+H) + = 227, (M+Na) + = 249.

C. Synthesis of N-[4-({[(5-chloro(2-thienyl))sulfonyl]amino}carbonylamino)-2 - methylphenyl] b enzamide A solution of 5-chlorothiophene-2-sulfonamide (30 mg, 0.15 mmol) and DSC (46 mg, 0.18 mmol) in CH3CN (1 mL) and DBU (45 L) was heated at 40°C for 1 hr. To this mixture was added N- (4-amino-2-methylphenyl) benzamide (34 mg, 0.15 mmol) with further heating for 3 days. Acidification and HPLC purification gave N-[4-({[(5- chloro (2-thienyl)) sulfonyl] amino} carbonyl-amino)-2-methylphenyl] benzamide (24 mg, 35%). ES-MS (M+H) + = 450,452 (Cl).

Example 1100 Preparation of N-[4-({[(5-chloro (2-thienyl) ) sulfonyl] amino} carbonylamino)-2- methylphenyl]-N-methylb enzamide A. Synthesis ofN-methyl-N- (2-metllyl-4-nitrophenyl) benzamide To a solution of N-(2-methyl-4-nitrophenyl) benzamide (Example 1099A) (0. 38 g, 1.48 mmol) in DMF (2 mL) was added cesium carbonate (1.2 g, 3.68 mmol) followed by methyl iodide (0. 12 mL, 1.9 mmol). The reaction mixture was stirred at room temp for 2 hr, extracted with EtOAc, washed with water and brine, dried and concentrated in vacuo to give N-methyl-N- (2-methyl-4-nitrophenyl)-benzamide (0.38 g, 95%). ES-MS (M+H)+=271.

B. Synthesis of n-[4-({[(5-chloro(2-thienyl))sulfonyl]amino}carbonylamino)-2 - methyIphenylj-N-methyIbenzamide N-methyl-N- (2-methyl-4-nitrophenyl) benzamide was reduced and coupled with 5-chloro-thiophenesulfonamide using the same procedure as shown in Example 1099, steps B and C to give N-[4-({[(5-chloro(2-thienyl))sulfonyl]amino}carbonylamino)-2 - methylphenyl]-N-methylbenzamide (44 mg, 31%). ES-MS (M+H) + = 464,466 (Cl).

Example 1101 Preparation of N-[4-({[(5-chloro (2-thienyl) ) sulfonyl] amino} carbonylamino) -2- methylphenyl3 (3-chlorophenyl) -carboxamide was prepared using a similar procedure as that shown in Example 1099 steps A-C, using 3-chlorobenzoyl chloride in the first step, instead of benzoyl chloride. The final product was obtained in 43% yield. ES-MS (M+H) += 484, 486 (2C1).

Example 1102 Preparation of N-[2-bromo-4-({[(5-chloro (2- thienyl)) sulfonyl] amino} carbonylamino) phenyl] benzamide was prepared using a similar procedure as that shown in Example 1099 steps A-C, using 2-bromo-4-nitro-aniline in the first step, instead of 2-metl-lyl-4-nitro aniline. The final product was obtained in 64% yield. ES-MS (M+H) + = 514, 516, 518 (Cl, Br).

Scheme 4 Example 1103 Preparation of N- (4-amino-3-methylphenyl) { [ (5-chloro (2-thienyl) ) sulfonyl] amino} carboxamide A. Synthesis of N-{4-[(tert-butoxy)carbonylamino]-3-methylphenyl} {[(5-chloro(2- thienyl))sulfonyl]amino}carboxamide A solution of 5-chlorothiopllene-2-sulfonamide (0.2 g, 1.0 mmol) and DSC (0.307 g, 1.2 mmol) in CH2C12 (5 mL) and DBU (0.3 mL) was stirred at room temp for 16 hr.

To this mixture was added N- (4-amino-2-methylphenyl) (tert-butoxy) carboxamide (0.26 g, 1 mmol), followed by heating at 40 °C for 2hr. Acidification and HPLC purification gave N-{4-[(tert-butoxy) carbonylamino]-3-methyl-phenyl} {[(5-chloro (2- thienyl)) sulfonyl] amino} carboxamide (0.28 g, 63%). ES-MS (M+Na) + = 468, (M+H- tBu) = 390,392 (Cl).

B. Synthesis of N-(4-amino-3-methylphenyl){[(5-chloro(2- thienyl))sulfonyl]amino}carboxamide To a chilled solution of N-{4-[(tert-butoxy)carbonylamino]-3-methylphenyl}{[(5- chloro (2-thienyl)) sulfonyl] amino} carboxamide (0.246 g, 0.55 mmol) in CH2C12 (5 mL) was added neat TFA (1. 1 mL). The reaction mixture was stirred cold for 1.5 hr, concentrated in vacuo, azeotroped with heptane and dried to give N- (4-amino-3- methylphenyl) {[(5-chloro(2-thienyl))sulfonyl]amino}-carboxamide (0.26 g) as the mono TFA salt. ES-MS (M+H) + = 346.

Examples 1104-1116 The compounds above were prepared according to Scheme 4 using the following general synthetic procedure: 1.1 equivalent of the benzoic acid and 1 equivalent of N- (4- amino-3-methylphenyl) { [ (5-chloro (2-thienyl) ) sulfonylgamino} carboxamide were dissolved in DMF (0.5 M) and 1.2 equivalent of PyBOP was added. After 2h, the reaction mixture was directly purified by RP-HPLC to give the targets above where R = p-CH3, p- OCH3, p-Cl, o-Cl, o-NO2, o-OBn, o-OH, m-F, m, p-diCl, o-pyr, m-pyr and p-pyr. The o- NE2 analog was obtained by reduction of o-NO ? using H2/Pt/C in methanol.

Example 1104 N-[4-({[(5-chloro(2-thienyl))sulfonyl]amino}carbonylamino)-2 -methylphenyl] (4- methylphenyl)-carboxamide. ES-MS (M+H) + = 464, 466 (Cl).

Example 1105 N-[4-({[(5-chloro (2-thienyl) ) sulfonyl] amino} carbonylamino)-2-methylphenyl] (4- methoxyphenyl) -carboxamide. ES-MS (M+H) + = 480,482 (Cl).

Example 1106 N-[4-({[(5-chloro(2-thienyl))sulfonyl]amino}carbonylamino)-2 -methylphenyl] (4- chlorophenyl) -carboxamide. ES-MS (M+H) + = 483. 9,485. 9,487. 9 (2C1).

Example 1107 N-[4-({[(5-chloro(2-thienyl))sulfonyl]amino}carbonylamino)-2 -methylphenyl] (2- chlorophenyl) -carboxamide. ES-MS (M+H) + = 484, 486 (2C1).

Example 1108 N- [4-({[ (5-chloro (2-thienyl)) sulfonyl] amino} carbonylamino)-2-metlylphenyl] (2- nitrophenyl)-carboxamide. ES-MS (M+H) + = 495,497 (Cl).

Example 1109 N-[4-({[ (5-chloro (2-thienyl)) sulfonyl] amino} carbonylamino) -2-methylphenyl] [2- (phenylmethoxy)-phenyl] carboxamide. ES-MS (M+H) +=556, 558 (Cl).

Example 1110 N- [4-({[(5-chloro (2-thienyl) ) sulfonyl]amino}carbonylamino)-2-methylphenyl] [2- hydroxyphenyl]-carboxamide. ES-MS (M+H) += 466,468 (Cl).

Example 1111 N-[4-({[(5-chloro (2-thienyl) ) sulfonyl] amino}carbonylamino)-2-methylphenyl] (3- fluorophenyl) -carboxamide. ES-MS (M+H) += 468,470 (Cl).

Example 1112 N-[4-({[(5-chloro(2-thienyl))sulfonyl]amino}carbonylamino)-2 -methylphenyl](3, 4- dichlorophenyl)-carboxamide. ES-MS (M+H) += 517.9, 519.9, 521.9 (3C1).

Example 1113 N-[4-({[(5-chloro(2-thienyl))sulfonyl]amino}carbonylamino)-2 -methylphenyl]-2- pyridylcarboxamide. ES-MS (M+H) + = 451,453 (Cl).

Example 1114 N- [4-({[(5-chloro(2-thienyl))sulfonyl]amino}carbonylamino)-2-m ethylphenyl]-3- pyridylcarboxamide. ES-MS (M+H) + = 451, 453 (Cl).

Example 1115 N-[4-({[(5-chloro(2-thienyl))sulfonyl]amino}carbonylamino)-2 -methylphenyl]-4- pyridylcarboxamide. ES-MS (M+H) + = 451, 453 (Cl).

Example 1116 <BR> <BR> <BR> <BR> N- [4- ( { [ (5-chloro (2-thi enyl)) sulfonyl] amino} carbonylamino)-2-methylphenyl] (2- aminophenyl) -carboxamide. ES-MS (M+H) + = 465,467 (Cl).

Example 1117-1120 Example1117 1.0 equivalent of N-(4-amino-3-methylphenyl){[(5-chloro(2- thienyl) ) sulfonyl amino}-carboxamide was treated with 1.0 equivalent of PhCH2COOH/PyBOP to give X = CH2, {[(5-chloro(2-thienyl)) sulfonyl] amino}-N-{3- methyl-4- [benzylamino] phenyl} carboxamide. ES-MS (M+H) + = 464,466 (Cl).

Example 1118 Alternatively (for X=S02), the compounds above were prepared according to Scheme 4 using the following general synthetic procedure: 1.0 equivalents of N- (4- amino-3-methylphenyl) { [ (5-chloro (2-tlienyl)) sulfonyl] amino}-carboxamide dissolved in DMF (0.5 M) was treated with 1.0 equivalent of PhSO2CI and 1.2 equivalents of DIEA to give, after RP-HPLC purification, X = SO2, { [ (5-chloro (2-thienyl)) sulfonyl] amino}-N- {3-methyl-4-[(phenylsulfonyl)amino]phenyl}carboxamide. ES-MS (M+H) + = 486,488 (Cl).

Example 1119 For X = C=NH: Treatment with methyl benzimidate. HCl (1. 4 eq) in DMF gave the amidine X = C=NH, S [(5-chloro(2-thienyl))sulfonyl]amino}-N-{4- [(iminophenylmethyl)amino]-3-methylphenyl}carboxamide. ES-MS (M+H) + = 449, 451 (Cl).

Example 1120 For X = NH-C=O : Treatment with phenyl isocyanate (1.07 eq) in DMF to give the urea X = NH-C=O, {[(5-chloro (2-thienyl) ) sulfonyl] amino}-N- {3-methyl-4- [ (phenylamino) carbonylamino] phenyl} carboxamide. ES-MS (M+H) + = 465, 467 (Cl).

Scheme 5 Example 1121 Preparation of { [(5-chloro (2-thienyl) ) sulfonyl]amino}-N-[4-(N-phenylcarbamoyl) phenyl] carboxamide A. Synthesis of methyl 4-({[(5-chloro-2-thienyl)sulfonyl]amino} carbonelamino ! benzoate A solution of 5-chlorothiophene-2-sulfonamide (0.2 g, 1.0 mmol) and DSC (0.307 g, 1.2 mmol) in CH2Cl2 (5 mL) and DBU (0.3 mL) was stirred at room temp overnight.

To this mixture was added methyl 4-aminobenzoate (0.15 g, 1.0 mmol). The reaction was then stirred at room temp for 17 hr, acidified and HPLC purified to give methyl 4- ( { [ (5-chloro-2-thienyl) sulfonyl] amino} carbonyl-amino) benzoate (0.23 g, 61%). ES-MS (M+H) +=375, 377 (Cl).

B. Synthesis of 4-({[(5-chloro-2-thienyl)sulfonyl]amino}carbonylamino)benzoi c acid To a suspension of methyl 4-({[(5-chloro-2- thienyl) sulfonyl] amino} carbonylamino) benzoate (56 mg, 0.15 mmol) inmethanol (1 mL) and acetonitrile (1 mL) was added IN LiOH (0.16 mL, 0.16 mmol). The resulting solution was stirred at room temp for 21 hr, then an additional 0.32 mL IN LiOH was added and the reaction was stirred at 40 °C for another 21 hr til complete. Concentration in vacuo gave crude 4-({[(5-chloro-2-thienyl) sulSonyl] amino3carbonylamino) benzOic acid (69 mg). ES-MS (M+H) +=361.

C. Synthesis of {[(5-chloro(2-thienyl))sulfonyl]amino}-N-[4-(N- phenylcarb amoyl) phenyl]-c arb oxamide To a solution of ( { [ (5-chloro-2-thienyl) sulfonyl] amino} carbonylamino) benzoic acid (69 mg) in DMF (0.7 mL) was added aniline (21 uL, 0.23 mmol), DIEA (3 eq. ) then PyBOP (85 mg, 0.16 mmol). The reaction mixture was stirred at room temp for 28 hr, acidified and HPLC purified to give {[(5-chloro(2-thienyl))sulfonyl]amino}-N-[4-(N- phenylcarbamoyl) phenyl] carboxamide (29 mg, 45%). ES-MS (M+H) + = 436, 438 (Cl). Scheme 6: General Procedure for the Synthesis of Isoquinolinone-containing Sulfonylureas R= 6, 7-diCl 7-Me 6-Me,-CF3,-CI 7, 8-diC1 7-C1 6-OMe, 6-OH, 6-OiPr, 6-OCH2CH2OMe 7-Cl, 6-OMe 7-CF3 6-NH2,-NHAc, -NHMe, -NMe2 7-F 6-NHEt,-NHPr,-NHCH2cPr,-NCH2CH2F,-NHBn 8-NHMe 7-SMe 6-NHCH2CH2OMe 8-CN 7-OMe 6-NHPh 7-SOMe 6-F 4-CO2H 7-SO2Me 6-NHNH2 4-CONH2 7-CN 6-Br,-CN General Procedure for synthesizing Isoquinolinone-containing Sulfonyl Ureas A. General Procedure for synthesis ofcinnamic acids To a solution of malonic acid (10.4 g, 0. 1 mol) and the benzaldehyde (0.05 mol) in pyridine (20 mL) was added neat piperidin (0.75 mL, 7.6 mmol). The reaction mixture was stirred at 80 °C for 17 hr, chilled, then added to 200 mL cold water. This mixture was acidified with conc. HCl (25 mL) and the white precipitate collected by filtration, washed with 5 x 1 OmL water, and dried to give pure cinnamic acid in typical yields of>95%.

B-1. General Procedure 1 for cvclization of cinnamic acids to isoquinolinones To a chilled suspension of the cinnamic acid (25 mmol) in benzene (40 mL) and DMF (5 drops) was added neat thionyl chloride (2.2 mL, 30 mmol). The reaction mixture was stirred at 60 °C for 2 hr, chilled, concentrated in vacuo and dried to give crude acid chloride. To a solution of the acid chloride in 1,2-dichlorobenzene (22 mL) was added NaN3 (2.6 g, 40 mmol). After heating at 140 °C for 6 hr, complete conversion to the isocyanate was observed, catalytic 12 was added and the reaction was heated to 180 °C for 17 hr. Reaction workups included either precipitation of product with hexane or concentration and flash chromatography using EtOAc/CH2Cl2 eluent. Yields varied widely depending on the substituent (5-80%).

B-2. General Procedure 2 for cyclization of cinnamic acids to isoquinolinones To a chilled solution of the cinnamic acid (16 mmol) in dry THF (35 mL) and triethylamine (2.9 mL, 20.8 mmol) was added neat ethyl chloroformate (1.85 mL, 19.4 mmol) dropwise over several minutes. The resulting suspension was stirred cold for 1 hr, then a solution of NaN3 (1.56 g, 24 mmol) in 10 mL water was added. The reaction was stirred at room temp. for 1 hr. Reaction workups included either collection of the reaction precipitate, or extraction of product into CH2C12, giving pure acyl azide in >90% yields. A solution of the acyl azide in 1, 2-dichlorobenzene (18 mL) was then heated to 140°C to form the isocyanate, followed by addition of cat. iodine and heating to 180 °C overnight. Workups were the same as in general procedure B-l.

C. General Procedure for alkvlation ofisoquinolinone with 1-fluoro-4-nitrobenzene To a solution of the isoquinolinone (2.5 mmol) in DMF (5 mL) was added potassium carbonate (0.7 g, 5 mmol), followed by neat fluoro-4-nitrobenzene (0.3 mL, 2.8 mmol). The reaction mixture was stirred at 90 °C for 8 hr, poured onto cold water and filtered to give pure product in typical yields of 85-95%.

D. General reduction procedure A suspension of the nitrophenyl intermediate from C (0.75 mmol) and tin (II) chloride dihydrate (0.68 g, 3 mmol) in ethanol (8 mL) was stirred at 70 °C for 4 hr. The reaction was then chilled, diluted with EtOAc, mixed with Celite, basified with 1M Na2CO3 (20 mL) then filtered. The organic layer was washed with water and brine, dried with Na2S04, concentrated in vacuo to give the product aniline in typical yields of 85- 95%.

E. General Procedure for coupling the aniline intermediate with 5- chlorothiophenesulfonamide To a suspension of 5-chlorothiophene-2-sulfonamide (40 mg, 0.2 mmol) and DSC (61 mg, 0. 24 mmol) in dry acetonitrile (1 mL) was added DBU (60 pL, 0.4 mmol). The resulting solution was stirred at room temp for 16 hr. The aniline from D (0.2 mmol) was then added as a solid with additional acetonitrile (1 mL), and the reaction was heated to 70 °C and stirred for another 17 hr. Acidification and HPLC purification of the crude reaction gave the final target in varying yields (20-70%) depending on the substituent.

Examples 371, 372, 374, 376, 379, 380 and 1122-1128 The compounds above where, for example, R= 7-CH3, 7-C1, 7-F, 7-CF3,7- OCH3, 6-CH3, 6-Cl, 6-F, 6-Br, 6-CF3,6-OCH3, and 6, 7-diCl were synthesized from commercially available benzaldehydes or cinnamic acids using the general procedure outlined in Scheme 6. The 7, 8-diCl analog was isolated as a by-product during the synthesis of the 6,7-isomer.

Example 371 {[(5-chloro(2-thienyl))sulfonyl]amino}-N-[4-(6-methoxy-1-oxo (2-2-hydroisoquinolyl))- phenyl] carboxamide. ES-MS (M+H) +=490, 492 (Cl).

Example 372 { [(5-chloro(2-thienyl))sulfonyl]amino}-N-[4-(6-chloro-1-oxo(2 -2-hydroisoquinolyl))- phenyl] carboxamide. ES-MS (M+H) + = 494,496, 498 (2Cl).

Example 374 { [ (5-chloro (2-thienyl)) sulfonyl] amino}-N-[4-(7-chloro-1-oxo (2-2- hydroisoquinolyl)) phenyl]-carboxamide. ES-MS (M+H) + = 494,496, 498 (2Cl).

Example 376 { [ (5-chloro (2-thienyl)) sulfonyl] amino}-N- [4- (7-fluoro-1-oxo (2-2- hydroisoquinolyl) ) phenyl] -carboxamide. ES-MS (M+H) + = 478.0 (Cl).

Example 379 ( [ (5-chloro (2-thienyl)) sulfonyl] ammo}-N- [4- (7-triiluoromethyl-l-oxo (2-2- hydroisoquinolyl))-phenyl] carboxamide. ES-MS (M+H) + = 528, 530 (Cl).

Example 380 { [ (5-chloro (2-thienyl) ) sulfonyl] amino}-N- [4- (7-methoxy-1-oxo (2-2-hydroisoquinolyl))- phenyl] carboxamide. ES-MS (M+H) += 490, 492 (Cl).

Example 1122 { [ (5-chloro (2-thienyl) ) sulfonyl3 amino}-N- [4- (7-methyl-1-oxo (2-2- hydroisouqinolyl)) phenyl]-carboxamide. ES-MS (M+H) + = 473.9, 475.9 (Cl).

Example 1123 { [ (5-chloro (2-thienyl) ) sulfonyl]amino}-N-[4-(6-methyl-1-oxo(2-2-hydroisoquinolyl))- phenyl] carboxamide. ES-MS (M+H) + = 474,476 (Cl).

Example 1124 {[(5-chloro(2-thienyl))sulfonyl]amino}-N-[4-(6-fluoro-1-oxo( 2-2-hydroisoquinolyl))- phenyl] carboxamide. ES-MS (M+H) + = 477.9 (Cl).

Example 1125 { [ (5-chloro (2-thienyl)) sulfonyl] amino}-N- [4- (6-bromo-1-oxo (2-2-hydroisoquinolyl))- phenyl] carboxamide. ES-MS (M+H) + = 537. 9 (Cl).

Example 1126 {[(5-chloro(2-thienyl))sulfonyl]amino}-N-[4-(6-trifluorometh yl-1-oxo (2-2- hydroisoquinolyl))-phenyl] carboxamide. ES-MS (M+H) + = 528, 530 (Cl).

Example 1127 N- [4-(6, 7-dichloro-1-oxo (2-2-hydroisoquinolyl)) phenyl] {[(5-chloro (2-thienyl) ) sulfonyl3- amino} carboxamide. ES-MS (M+H) += 528, 530,532 (3Cl).

Example 1128 N-[4-(7,8-dichloro-1-oxo(2-2-hydroisoquinolyl))phenyl] { [ (5-chloro (2-thienyl)) sulfonyl]- amino} carboxamide. ES-MS (M+H) + = 528, 530, 532 (3C1).

Example 1129 Preparation of {[(5-chloro(2-thienyl))sulfonyl]amino}-N-(4-(7-chloro-6-meth oxy-1- oxo (2-2-hydroisoquinolyl)) phenyl] carboxamide A. Synthesis of 4-chloro-3-methoxvtoluene To a solution of 2-chloro-5-methylphenol (10.7 g, 75 mmol) in DMF (40 mL) was added potassium carbonate (26 g, 188 mmol) followed by neat methyl iodide (4.9 mL, 79 mmol). The reaction mixture was stirred at room temp for 6 hr, extracted with EtOAc, washed with water and brine, dried and concentrated in vacuo to give 4-chloro-3- methoxytoluene (10.8 g, 92%). tH-NMR (DMSO-d6) : 8 2.26 (s, 3H), 3.79 (s, 3H), 6.71- 6.73 (dd, 1H), 6.94 (s, 1H), 7. 22-7.24 (d, 1H).

B. Synthesis of 4-chloro-3-methoxybenzoic acid To the crude toluene (7.8 g, 50 mmol) was added a solution KMnO4 (19.8 g, 125 mmol) in water (300 mL). The reaction mixture was stirred vigorously at reflux for 17 hr and filtered warm through Celite, washing the cake with 200 mL hot water. The clear filtrate was washed with ethyl ether (2 x 150 mL), acidified with conc. HCl (9 mL) and filtered to give pure white solid 4-chloro-3-methoxybenzoic acid (5.36 g, 58%). ES-MS (M+H) +=187.

C. Synthesis of (4-chloro-3-methoxyphenyl) methan-l-ol To a solution of 4-chloro-3-methoxybenzoic acid (4. 88 g, 26.2 mmol) in THF (50 mL) was added borane-THF complex (52 mL 1M solution in THF, 52 mmol) via addition funnel over 10 min. The reaction mixture was refluxed for 2 hr, cooled, extracted with EtOAc, washed with water, 5% Na2C03 and brine, dried and concentrated in vacuo to give (4-chloro-3-methoxyphenyl) methan-1-ol (4.5 g, 99%). ES-MS (M+H-H20) += 155, 157 (Cl).

D. Synthesis of4-chloro-3-methoxvbenzaldehyde To a solution of (4-chloro-3-methoxyphenyl) methan-1-ol (5.08 g, 29.4 mmol) in benzene (120 mL) was added Mon02 (5. 65 g, 65 mmol). The reaction mixture was refluxed for 17 hr, chilled, and filtered through Celite, washing the cake with CH2C12 (300 mL). The filtrate was concentrated in vacuo to give 4-chloro-3- methoxybenzaldehyde (4.5 g, 89%).

E. Synthesis of {[(5-chloro(2-thienyl))sulfonyl]amino}-N-[4-(7-chloro-6-meth oxy- 1-oxo (2-2-hydroisoquinolyl))phenyl]carboxamide {[(5-chloro (2-thienyl) ) sulfonyl] amino}-N-[4-(7-chloro-6-methoxy-1-oxo (2-2- hydroisoquinolyl)) phenyl] carboxamide was synthesized from the benzaldehyde using the general procedure outlined in Scheme 6, steps A-E. ES-MS (M+H) += 489,491 (Cl).

Example 1130 Preparation of N- {2- [4- ( { [ (5-chloro (2-thienyl) ) sulfonyl] amino} carbonylamino) phenyl] - 1-oxo-6-2-hydroisoquinolyl} acetamide A. Synthesis of N-(3-formylphenyl ! acetamide To a chilled suspension of 3-aminobenzyl alcohol (9. 24 g, 75 mmol) in THF (50 mL) was added neat acetic anhydride (8.1 mL, 86 mmol). The reaction mixture was stirred cold for 1 hr, diluted with EtOAc, washed with aq. NaOH and brine, and concentrated in vacuo to give N- [3- (hydroxymethyl) phenyl] acetamide (10.5 g, 85%).

A mixture of N- [3- (hydroxymethyl) phenyl] acetamide (10 g, 60.6 mmol) and Mn02 (7.8 g, 90 mmol) in toluene (250 mL) was refluxed for 29 hr, with addition of more MnO2 (0.7 g, 9 mmol) at 24 hr. The reaction was cooled, filtered through Celite and concentrated in vacuo to give N- (3-formylphenyl) acetamide (9.2 g, 75%). ES-MS (M+H) +=164.

B. Synthesis of [4-({[(5-chloro(2-thienyl))sulfonyl]amino} carbonylamino) phenyl]-l-oxo-6-2-hydroisoquinolyl} acetaniide N- {2-[4-({[ (5-chloro (2-thienyl)) sulfonyl] amino} carbonylamino) phenyl]-l-oxo-6- 2-hydroisoquinolyl} acetamide was synthesized from N- (3-formylphenyl) acetamide using the general procedure outlined in Scheme 6, steps A-E. ES-MS (M+H) + = 517, 519 (Cl).

Example 1131 Preparation of N-[4-(6-amino-1-oxo(2-2-hydroisoquinolyl)) phenyl] { [ (5-chloro (2- thienyl)) sulfonyl] amino}-carboxamide : This compound was synthesized by treating N- {2-[4-({[(5-chloro(2-thienyl))sulfonyl]amino}carbonyl-amino) phenyl]-1-oxo-6-2- hydroisoquinolyl} acetamide with 30 equiv. NaOMe in MeOH and refluxing overnight. It was also synthesized by treatment with neat hydrazine hydrate at 70 °C. ES-MS (M+H) + = 475, 477 (Cl).

Example 373 Preparation of { [ (5-chloro (2-thienyl) ) sulfonyl] amino}-N-{4-[6-(methylamino)-1-oxo (2- 2-hydroisoquinolyl)] phenyl} carboxamide A. Synthesis of N-methyl-N-[2-(4-nitrophenyl)-1-oxo(6-2- hydroisoquinolyl)]acetamide To a solution of crude N- [2- (4-nitrophenyl)-l-oxo-6-2- hydroisoquinolyl] acetamide (0.26 g, 0.8 mmol) in DMF (2 mL) was added cesium carbonate (0.645 g, 2 mmol) followed by neat methyl iodide (75 pL, 1.2 mmol). The reaction mixture was stirred at room temp for 17 hr, precipitated with addition of water and filtered to give N-methyl-N- [2- (4-nitrophenyl)-l-oxo (6-2- hydroisoquinolyl) ] acetamide (75 mg, 25%). ES-MS (M+H) += 338.

B. Synthesis of N-{2-[4-({[(5-chloro(2- thienyl)) sulibnvl] amino} carbonylamino) phenyl]-l-oxo (6-2-hydroisoquinolyl')}- N-methylacetamide The reduction and coupling steps were performed using the procedures outlined in Scheme 6, steps D and E. ES-MS (M+H) + = 531,533 (Cl).

C. Synthesis of {[(5-chloro(2-thienyl)sulfonyl]amino}-N-{4-[6-(methylamino)- 1- oxo (2-2-hvdroisoquinolyllphenvl carboxamide To a solution of N-{2-[4-({[(5-chloro(2-thienyl))sulfonyl]amino} carbonylamino) phenyl]-l-oxo (6-2-hydroisoquinolyl)}-N-methylacetamide (3 5 mg, 0.072 mmol) in methanol (1.2 mL) was added 0.5 M NaOMe (0.44 mL, 0.22 mmol) in methanol. The reaction mixture was stirred at 60 °C overnight, acidified and HPLC purified to give { [ (5-chloro (2-thienyl) ) sulfonyl] amino}-N- {4- [6- (methylamino)-l-oxo (2- 2-hydroisoquinolyl)] phenyl} carboxamide (22 mg, 63%). ES-MS (M+H) + = 489,491 (Cl).

Examples 383 and 1132-1135 The compounds above where, for example, R = Et, n-Pr, CH2-c-Pr, CH2CH2F and benzyl were synthesized using the procedure outlined in Example 373 for R = Me, varying the alkylating agent in step A.

Example 383 { [ (5-chloro (2-thienyl) ) sulfonyl]amino}-N-{4-[6-(ethylamino)-1-oxo (2-2- hydroisoquinolyl)]-phenyl} carboxamide. ES-MS (M+H) + = 503,505 (Cl).

Example 1132 {[(5-chloro(2-thienyl))sulfonyl]amino}-N-{4-[1-oxo-6-(propyl amino) (2-2- hydroisoquinolyl) J-phenyl} carboxamide. ES-MS (M+H) + = 517,519 (Cl).

Example 1133 {[ (5-chloro (2-thienyl)) sulfonylgamino}-N-(4- {6-[(cyclopropylmethyl) amino]-1-oxo (2-2- hydroisoquinolyl)} phenyl) carboxamide. ES-MS (M+H) += 529,531 (Cl).

Example 1134 {[(5-chloro (2-thienyl) ) sulfonyl]amino}-N-(4-{6-[(2-fluoroethyl)amino]-1-oxo (2-2- hydroisoquinolyl) phenyl) carboxamide. ES-MS (M+H) +=521, 523 (Cl).

Example 1135 { [ (5-chloro (2-thienyl) ) sulfonyl] amino}-N-(4-{1-oxo-6- [benzylamino] (2-2- hydroisoquinolyl)}-phenyl) carboxamide. ES-MS (M+H) + = 565,567 (CI).

Example 1136 Preparation of { [ (5-chloro (2-thienyl)) sulfonyl] amino}-N- {4- [1-oxo-6- (phenylamino) (2- 2-hydroisoquinolyl)] phenyl} carboxamide A. 2- 4-nitrophenyl)-6-phenylaminol-2-hydroisoquinolin-1-one To a dry RBF under argon was added 6-bromo-2- (4-utrophenyl)-2-llydroisoquinolin-l- one (66 mg, 0.191 mmol) (prepared as outlined in Example 1125), cesium carbonate (106 mg, 0.325 mmol), tris (dibenzylideneacetone) dipalladium (O) (3.5 mg, 0.076 mmol), 9,9- dimethyl-4,5-bis (diphenylphosphino) xanthene (12 mg, 0.0207 mmol) and neat aniline (0.026 mL, 0.285 mmol). To this flask was added dry dioxane (0.5 mL) and dry toluene (0.5 mL). The reaction was stirred at 80 °C for 5 hr, concentrated and chromatographed on silica gel to give pure 2- (4-nitrophenyl)-6- (phenylamino)-2-hydroisoquinolin-1-one (55 mg, 81%). ES-MS (M+H) += 358.

B. {[(5-chloro(2-thienyl))sulfonyl]amino}-N-{4-[1-oxo-6-(phenyl amino)(2-2- hydroisoquinolyl)]phenyl}carboxamide Preparation of the final target was accomplished using the general procedure outlined in Scheme 6, steps D-E, to give the above named sulfonyl urea. ES-MS (M+H) +=551, 553 (C1).

Example 1137 Preparation of { [ (5-chloro (2-thienyl) ) sulfonyl] amino}-N-(4-{6-[(2- methoxyethyl) amino]-1-oxo (2-2-hydroisoquinolyl)} phenyl) carboamide was accomplished using a similar Buchwald procedure as shown in Example 1136. ES-MS (M+H) += 533. 0 (Cl).

Example 1138 Preparation of { [ (5-chloro (2-thienyl) ) sulfonyl] aininol-N- [4- (6-hydrazino-l-oxo (2-2-<BR> hydroisoquinolyl)) phenylgzarboxamide A 5mg (0.011 mmol) sample of f [ (5-chloro (2-thienyl)) sulfonyl] amizo}-N- [4- (6- fluoro-1-oxo (2-2-hydroisoquinolyl))-phenyl] carboxamide was dissolved in 50 µL of neat anhydrous hydrazine and stirred for 18h. The solution was diluted with 250 uL of water and lyopholized to give 3.8 mg (74%) of the desired material. ES-MS (M+H) + = 490.0 (Cl).

Example 1139 Preparation of N- {4- [6- (dimethylamino)-l-oxo (2-2- hydroisoquinolyl)] phenyl} {[(5-chloro (2-thiellyl)) sulfonyl] amino} carboxamide : To a suspension of {[(5-chloro (2-thienyl) ) sulfonyl] amino}-N-{4-56-(methylamino)-1-oXo (2-2- hydroisoquinolyl) ] phenyl} carboxamide (17 mg, 0.035 mmol) (prepared in Example 373) in glacial acetic acid (0.7 mL) was added formaldehyde (12 pL, 0.15 mmol) followed by sodium triacetoxyborohydride (14 mg, 0.067 mmol). The reaction mixture was stirred at 45°C for 2 hr. HPLC purification yielded the final product (7 mg, 40%). ES-MS (M+H) +=503, 505 (CI).

Example 1140 Preparation of { [ (5-chloro (2-thienyl)) suIfbnyl] amino}-N-4- (6-hydroxy-l-oxo (2-2- hydroisoquinolyl)) phenyl] carboxamide : A. Synthesis of 6-hydroxy-2-(4-nitrophenyl)-2-hydroisoquinolin-1-one To a solution of 6-methOxy-2-(4-nitrophenyl)-2-hydroisoquinolin-1-one (100 mg, 0. 338 mmol) (prepared by the general procedure outline in Scheme 6) in CH2C12 (3 mL) was added a 1M BBr3 solution in CH2C12 (1. 35 mL, 1.35 mmol). The solution was refluxed for 18 h, the solvent was removed in vacuo, the residue was triturated with water, and the resulting greenish solid was collected and dried to give 6-hydroxy-2- (4- nitrophenyl)-2-hydroisoquinolin-1-one (89 mg, 93%).

B. Synthesis of 2- (4-aminoph. enyl)-6-hvdroxv-2-hydroisoquinolin-1-one 6-hydroxy-2- (4-nitrophenyl)-2-hydroisoquinolin-l-one was reduced according to the general procedure in Scheme 6 to give the corresponding aniline in 27% yield. ES- MS (M+H) + = 252.9.

C. Synthesis of {[(5-chloro(2-thienyl))sulfonyl]amino}-N-[4-(6-hydroxy-1-oxo (2-2- hydroisoquinolyl))phenyl]carboxamide 2- (4-aminophenyl)-6-hydroxy-2-hydroisoquinolin-1-one was coupled according to the general procedure outlined in Scheme 6 to give the above named sulfonyl urea.

ES-MS (M+H) + = 476 (Cl).

Example 1141 Preparation of { [(5-chloro (2-thienyl)) sulfonyI] amino}-N-{4-[6-(methylethOxy)-l-oXo (2- 2-hydroisoquinolyl) ] phenyl} carboxamide: A. Synthesis of 6-(methylethoxy)-2-(4-nitrophenyl)-2-hydroisoquinolin-1-one To a solution of 6-hydroxy-2-(4-nitrophenyl)-2-hydroisoquinolin-1-one (50 mg, 0.177 mmol) in DMF (0.38 mL) was added 2-bromopropane (0.03 mL) and cesium carbonate (86 mg, 0.267 mmol). After heating at 60 °C for 18h, water was added and the solution stirred and cooled to 0°C. The precipitate was collected and dried to give 6- (methylethoxy)-2- (4-nitrophenyl)-2-hydroisoquinolin-1-one (34 mg, 59%).

B. Synthesis of 2- 4-aminophenyl)-6- (methylethoxv)-2-hydroisoquinolin-1-one This material was reduced according to the general procedure in Scheme 6 to give the corresponding aniline in 91% yield. ES-MS (M+H) + = 295.

C. Synthesis of {[(5-chloro(2-thienyl))sulfonyl]amino}-N-{4-[6-(methylethoxy )-1- oxo (2-2-hydroisoquinolyl phenyl} carboxamide 2- (4-aminophenyl)-6- (methylethoxy)-2-hydroisoquinolin-1-one was coupled according to the general procedure outlined in Scheme 6 to give the above named sulfonyl urea. ES-MS (M+H) + = 518 (Cl) ; ES-MS (M-H) + = 516.

Example 1142 Preparation of {[(5-chloro (2-thienyl)) sulfonyl] amino}-N-{4-[6-(2- methoxyethoxy)-1-oxo (2-2-hydroisoquinolyl)] phenyl} carboxamide was accomplished according to the procedure of Example 1141 to give the desired sulfonyl urea. ES-MS (M+H) + = 534. 1 (CI).

Example 1143 Preparation of { [ (5-chloro (2-thienyl) ) sulfonyl] amino}-N- [4- (7-methylthio-I- oxo (2-2-hydroisoquinolyl)) phenyl] carboxamide was accomplished according to the procedure of Example 1145, using {[(5-chloro(2-thienyl))sulfonyl]amino}-N-[4-(7- fluoro-l-oxo (2-2-hydroisoquinolyl)) phenyl]-carboxamide as starting material, to give the desire sulfonyl urea. ES-MS (M+H) + = 506 (Cl).

Scheme 7: General Synthetic Scheme for the Preparation of Quinazolinones : ) SOCI2 GOOH FXCOOH) I NH F-v NH 2) formamide F N NH4+CO2- n f NUJeNJ J4< Nu, S _NA N WCI N H H F N zip Nu = OMe, SMe Example 1144 Preparation of { [(5-chloro (2-thienyl) ) sulfonyl] amino}-N- [4- (7-fluoro-4-oxo (3- hydroquinazolin-3-yl) ) phenyl] carboxamide A. Synthesis of ethyl 2-amino-4-fluorobenzoate To a chilled solution of 2-amino-4-fluorobenzoic acid (1. 57 g, 10. 1 mmol) in absolute ethanol (20 mL) was added neat thionyl chloride (4.4 mL, 60 mmol). The reaction mixture was refluxed for 4 days total, with addition of more SOC12 (8 mL, 110 mmol), then concentrated, diluted with EtOAc, washed with 2N NaOH, dried and concentrated in vacuo to give ethyl 2-amino-4-fluorobenzoate (1.73 g, 94%).

B. Synthesis of 7-fluoro-3-hvdroquinazolin-4-one To a suspension of ethyl 2-amino-4-fluorobenzoate (1.73 g, 9.45 mmol) in fonnamide (8 mL) was added ammonium formate (0.9 g, 14 mmol). The reaction mixture was stirred at 140 °C for 24 hr, with additional ammonium formate (0.92 g, 15 mmol) at 6 hr. The reaction was dilute with EtOAc, washed with water, back-extracted with EtOAc, dried and concentrated in vacuo to give 7-fluoro-3-hydroquinazolin-4-one (2. 82 g) which contains some formamide. ES-MS (M+H) + =165.

C. Synthesis of {[(5-chloro(2-thienyl))sulfonyl]amino}-N-[4-(7-fluoro-4-oxo( 3- hydroquinazolin-3-yl)) phenyl] carboxamide { [ (5-chloro (2-thienyl)) sulfonyl] amino}-N- [4- (7-fluoro-4-oxo (3-hydroquinazolin- 3-yl) ) phenyl] carboxamide was synthesized from the quinazolinone using the procedures for alkylation, reduction and coupling outlined in Scheme 6, steps C, D and E. The alkylation product was chromatographed on silica gel to remove folmamide carried over from the previous step to give pure intermediate in 42% yield. The reduction step was performed in EtOAc instead of EtOH. The coupling proceeded in 50% yield. ES-MS (M+H) + = 479, 481 (Cl).

Example 507 Preparationof { [ (5-chloro (2-thienyl) ) sulfonyl] amino}-N- [4- (7-methoxy-4-oxo (3- hydroquinazolin-3-yl)) phenyl] carboxamide: To a solution of { [ (5-chloro (2- thienyl) ) sulfonyl] amino}-N- [4- (7-fluoro-4-oxo (3-hydro-quinazolin-3- yl) ) phenyl] carboxamide (20 mg, 0.042 mmol) in methanol (0.75 mL) and DMF (0.3 mL) was added 0.5 M NaOMe in MeOH (0.42 mL, 0.21 mmol). The reaction mixture was stirred at 70 °C for 24 hr, acidified and HPLC purified to give pure {[(S-chIoro (2- thienyl)) sulfonyl] amino}-N- [4- (7-methoxy-4-oxo (3-hydroquinazolin-3- yl) ) pllenylgzarboxamide (7 mg, 33%). ES-MS (M+H) + = 491, 493 (Cl).

Example 1145 Preparation of { [ (5-chloro (2-thienyl)) sulfbnyl] amino}-N- [4- (7-methylthio-4- oxo (3-hydroquinazolin-3-yl)) phenyl] carboxamide : To a solution of {[(5-chloro (2- thienyl) ) sulfonyl] amino}-N- [4- (7-fluoro-4-oxo (3-hydro-quinazolin-3- yl)) phenyl] carboxamide (20 mg, 0.042 mmol) in DMF (0.21 mL) was added NaSMe (7 mg, 0.1 mmol). The reaction mixture was stirred at room temp for 3 hr, acidified and <BR> <BR> HPLC purified to give pure { [ (5-chloro (2-thienyl)) sulfonyl] amino}-N- [4- (7-methylthio- 4-oxo (3-hydroquinazolin-3-yl)) phenyl] carboxamide (17 mg, 80%). ES-MS (M+H) + = 507,509 (Cl). Scheme 8: General synthetic scheme forprepaling quinazolinedione-containing sulfonyl ureas NH2 NH2 0 R COzMe or X : I, Y y Neo N ! ! 0 NO2 NHBoc r O R p\ ArSOzNCO f \ O R 's, ArSO ? NHCOgSu X : : Y N I NH H H Ar N NH2 N-- O O R = Br : Ar= 5-CI thiophene (1) X = N : Ar = 5-CI thiophene (1) Y = N : Ar = 5-CI thiophene, Ph (2) R = H : Ar = Ph, subsituted Ph, substituted thiophenes, etc. (30) Example 1146 Preparation of N-[4-(2, 4-dioxo (1, 3-dihydroquinazolin-3-yl) )-3-bromophenyl] { [ (5- chloro (2-thienyl) ) sulfonyl] amino} carboxamide A. Synthesis of 3-(2-bromo-4-nitrophenyl) 3-dihydroquinazoline-2q4-dione To a solution of methyl 2-isocyanatobenzoate (0.266 g, 1.5 mmol) and 2-bromo- 4-nitroaniline (0.325 g, 1. 5 mmol) in DMF (2 mL) was added DIEA (0.79 mL). The reaction mixture was stirred at room temp for 24 hr, with addition of DBU (0. 22 mL) at 17 hr. The reaction mixture was extracted with EtOAc, washed with 1 N HCl and brine, dried and concentrated to give crude product, which was chromatographed on silica gel with 10% EtOAc/CH2Cl2 to give 3- (2-bromo-4-nitrophenyl)-1, 3-dihydroquinazoline-2,4- dione (0.24 g, 44%). ES-MS (M+H) + = 362, 364 (Br).

B. Synthesis of 3-(4-amino-2-bromophenyl)-1,3-dihydroquinazoline-2,4-dione A suspension of 3-(2-bromo-4-nitrophenyl)-1, 3-dihydroquinazoline-2,4-dione (0.18 g, 0.5 mmol) and tin (II) chloride dihydrate (0.45 g, 2.0 mmol) in ethyl acetate (5 mL) was heated at 70 °C for 4 hr. The reaction mixture was then cooled, mixed with Celite, made basic with 4N NaOH (3 mL), filtered through Celite, and concentrated in vacuo to give the desired compound (0.155 g, 94%). ES-MS (M+H) + = 332,334 (Br).

C. General Procedure for coupling anilines with aryl sulfonamides to form sulfonyl ureas A solution of the aryl sulfonamide (0.15 mmol) and DSC (0.18 mmol) in CH2C12 (1 mL) and DBU (45 pL, 0.3 mmol) was stirred at room temp for 16 hr. To this mixture was added the aniline intermediate (0.15 mmol) and CH3CN (1 mL) and DBU (23 pL, 0.15 mmol) (if aniline is TFA salt). The reaction was heated at 60°C for 17 hr, acidified and HPLC purified to give sulfonyl urea product in typical yields between 25-70%.

Preparation of N- [4- (2, 4-dioxo (1, 3-dihydroquinazolin-3-yl) )-3- bromophenyl] {[(5-chloro (2-thienyl) ) sulfonyl] amino} carboxamide was achieved in 25% yield. ES-MS (M+H) + = 556.9. 558.9 (Br, Cl).

Example 302 Preparation of N- [6- (2, 4-dioxo (1, 3-dihydroquinazolin-3-yl)) (3-pyridyl)] {[(5-chloro (2- thienyl) ) sulfonylgamino} carboxamide: This compound was prepared by first following step A in Example 1146, reacting 2-amino-5-nitropyridine with methyl 2-isocyanatobenzoate. The nitro group was reduced under 1 atm H2, 10% Pd/C, 1 eq. HC1, MeOH conditions for 6 hr. After filtration and concentration, the aniline was coupled with 5-chlorothiophene-2-sulfonamide using the conditions outlined in step C in Example 1146 to give N- [6- (2, 4-dioxo (1, 3- dihydroquinazolin-3-yl)) (3-pyridyl)] { [ (5-chloro (2-thienyl)) sulfbnyl] amino} carboxamide (47 mg, 33%). ES-MS (M+H) + = 478,480 (Cl).

Example 1147 Preparation of 3-(4-aminophenyl)-1, 3-dihydroquinazoline-2, 4-dione trifluoroacetate salt A. Synthesis of (tert-butoxy [4-(2,4-dioxo(1,3-dihydroquinazolin-3- all Dhenyl] carboxamìde To a solution of methyl 2-isocyanatobenzoate (0.97 g, 5.5 mmol) and Boc 1,4- phenylenediamine (1.04 g, 5 mmol) in THF (15 mL) was added DIEA (0.87 mL, 5 mmol) and DBU (0.75 mL, 5 mmol). The reaction mixture stirred at room temp for 5 hr, the off-white solid filtered and washed with ethyl ether to give desired compound (1.49 g, 85%). ES-MS (M+Na) + = 376. 1, (M-tBu+H) + = 298.0.

B. Synthesis of 3-(4-aminophenyl)-1,3-dihydroquinazoline-2,4-dione trifluoroacetate salt To a chilled suspension of (tert-butoxy)-N- [4- (2, 4-dioxo (1, 3-dihydroquinazolin- 3-yl) ) phenyl]carboxamide (0.35 g, 1 mmol) in CH2Cl2 (2 mL) was added neat TFA (2 mL). The resulting solution was stirred cold for 1 hr, concentrated in vacuo, azeotroped with heptane and dried to give desired compound (0.376 g, 99%) as the mono TFA salt.

ES-MS (M+H) + = 254.

Synthesis of Various Arvl Sulfbnylurea Analogs The sulfonyl urea targets above were prepared using the procedure outlined in Example 1146 Step C, reacting the aniline from Example 1146 with the following 13 commercially available sulfonamides : 5-nitrothiophene-2-sulfonamide ; thiophene-2- sulfonamide ; 5-chloro-3-methylbenzothiophene-2-sulfonamide ; 3,5-dimethylisoxazole-4- sulfonamide ; N- (3-methyl-5-sulfamoyl)-3H (1, 3,4) thiadiazol-2-ylidene) acetamide; 2,4- dimethyl-1, 3-thiazole-5-sulfonamide ; 3-bromo-5-chlorothiophene-2-sulionamide ; azetazolamide; 5-isoxazol-3-ylthiophene-2-sulfonamide ; 2-chlorobenzenesulionamide ; 3- chlorobenzenesulfonamide ; 4-methoxybenzenesulfonamide; 4- (trifluoromethyl) benzene- sulfonamide.

Example 1148 N- [4- (2, 4-dioxo (1, 3-dihydroquinazolin-3-yl)) phenyl] {[(5-nitro(2-thienyl))sulfonyl]- amino} carboxamide. ES-MS (M+H) + = 488.

Example 1149 N- [4- (2, 4-dioxo (1, 3-dihydroquinazolin-3-yl)) phenyl] [ (2- thienylsulfonyl) amino] carboxamide. ES-MS (M+H) += 443.0.

Example 1150 N- [4- (2, 4-dioxo (1, 3-dihydroquinazolin-3-yl)) phenyl] {[(5-chloro-3-methyl- benzo [b] thiophen-2-yl) sulfonyl] amino} carboxamide. ES-MS (M+H) += 541,543 (Cl).

Example 1151 { [ (3, 5-dimethylisoxazol-4-yl) sulfonyl] amino}-N-[4-(2,4-dioxo(1,3-dihydroquinazolin-3- yl) ) phenyl] carboxamide. ES-MS (M+H) + = 456.

Example 1152 ( { [2- (1-aza-2-oxopropylidene)-3-methyl (1, 3, 4-thiadiazolin-5-yl)] sulfonyl} amino)-N- [4- (2,4-dioxo (1, 3-dihydroquinazolin-3-yl)) phenyl] carboxamide. ES-MS (M+H) +=516.

Example 1153 {[(2,4-dimethyl(1,3-thiazol-5-yl))sulfonyl]amino}-N-[4-(2, 4-dioxo (l, 3- dihydroquinazolin-3-yl))phenyl]carboxamide. ES-MS (M+H) + = 472.

Example 1154 N- [4- (2, 4-dioxo (1, 3-dihydroquinazolin-3-yl)) phenyl] { [ (3-bromo-5-chloro (2-thienyl) )- sulfonyl] amino} carboxamide. ES-MS (M+H) +=554. 8,556. 9,558. 8 (BrCl).

Example 1155 N- {5- [ ( {N- [4- (2, 4-dioxo-l, 3-dihydroqumazolin-3-yl) phenyl] carbamoyl} amino) sulfonyl]-1, 3, 4-thiadiazol-2-yl} acetamide. ES-MS (M+H) + = 502.

Example 1156 N- [4- (2, 4-dioxo (1, 3-dihydroquinazolin-3-yl)) phenyl] { [ (5-isoxazol-3-yl (2-thienyl) )- sulfonyl] amino} carboxamide. ES-MS (M+H) +=510.

Example 1157 N-[4-(2, 4-dioxo (1, 3-dihydroquinazolin-3-yl) ) phenyl] { [ (2-chlorophenyl) sulfonyl amino}-carboxamide. ES-MS (M+H) +=471, 473 (Cl).

Example 1158 N- [4- (2, 4-dioxo (1, 3-dihydroquinazolin-3-yl)) phenyl] {[(3-chlorophenyl) sulfonyl]- amino} carboxamide. ES-MS (M+H) +=471, 473 (Cl).

Example 1159 N- [4- (2, 4-dioxo (1, 3-dihydroquinazolin-3-yl) ) phenyl] { [ (4- methoxyphenyl) sulfonyl] amino}-carboxamide. ES-MS (M+H) +=467.

Example 1160 N- [4- (2, 4-dioxo (1, 3-dihydroquinazolin-3-yl) ) phenyl] ( {[4-(trifluoromethyl) phenyl]- sulfonyl} amino) carboxamide. ES-MS (M+H) + = 505.

An additional 6 sulfonamides were prepared from the following commercially available sulfonyl chlorides, and were subsequently coupled with the aniline using the procedure in Example 1146 step C: 2-acetamido-4-methyl-5-tlliazolesulfonyl chloride ; 4-fluorobenzenesulfonyl chloride ; 5-(pyrid-2-yl)thiophene-2-sulfonyl chloride; 3,4- dichlorobenzenesulfonyl chloride; 2-(trifluoromethyl)benzenesulfonyl chloride; 3- (trifluoromethyl) benzenesulfonyl chloride.

Example 1161 N- {5- [ ( {N- [4- (2, 4-dioxo (1, 3-dihydroquunazolin-3-yl)) phenyl] carbamoyl} amino) sulfonyl]-4-methyl-1, 3-thiazol-2-yl} acetamide. ES-MS (M+H) + = 515.

Example 1162 N-[4-(2,4-dioxo(1, 3-dihydroquinazolin-3-yl) ) phenyl] f [ (4-fluoropheenyl) sulfonyl] amino}- carboxamide. ES-MS (M+H) + = 455. 1.

Example 1163 N- [4- (2, 4-dioxo (1, 3-dihydroquinazolin-3-yl) ) phenyl] {[(5-(2-pyridyl) (2- thienyl) ) sulfonyl]-amino} carboxamide. ES-MS (M+H) +=520.

Example 1164 { [ (3, 4-dichlorophenyl) sulfonyl]amino}-N-[4-(2, 4-dioxo (l, 3-dihydroquinazolin-3- yl) ) phenyl] carboxamide. ES-MS (M+H) + = 505,507 (2C1).

Example 1165 N- [4- (2, 4-dioxo (1, 3-dihydroquinazolin-3-yl)) phenyl] ( { [2- (trifluoromethyl) phenyl] sulfonyl}-amino) carboxamide. ES-MS (M+H) + = 505.

Example 1166 N- [4- (2, 4-dioxo (1, 3-dihydroquinazolin-3-yl)) phenyl] ({[3-(trifluoromethyl)phenyl]- sulfonyl} amino) carboxamide. ES-MS (M+H) + = 505.

Example 1167 Preparation of N- [4- (2, 4-dioxo (1, 3-dihydroquinazolin-3-yl)) phenyl] [(1, 3-thiazol-2- ylsulfonyl) amino] carboxamide A. Synthesis of (tert-butyl) (1,3-thiazol-2-ylsulfonyl) amine To a suspension of 2-mercaptothiazole (0.16 g, 1.37 mmol) in CH2C12 (14 mL) was added water (7 mL) followed by N-chlorosuccinimide (0. 75 g, 5. 6 mmol). The reaction mixture was stirred vigorously for 1.5 hr, diluted with CH2C12, washed with sat.

NaHCO3, water and brine, dried and concentrated in vacuo to give the crude sulfonyl chloride (0.25 g). A solution of the sulfonyl chloride and t-butylamine (0.75 mL, 7.1 mmol) in THF (2.5 mL) was stirred at room temp for 3 hr. The reaction was diluted with EtOAc, washed with IN HC1, water and brine, dried and concentrated in vacuo to give desired compound (0.16 g, 53%).

B. Synthesis of 1, 3-thiazole-2-sulfonamide To a solution of (teut-butyl) (1, 3-thiazol-2-ylsulfonyl) amine (0.22 g, 1.0 mmol) in 1, 2-dichloroethane (10 mL) was added methaazesulfonic acid (0.26 mL, 4 mmol). The reaction mixture was heated at 80 °C for 9 hr, concentrated in vacuo and chromatographed to give pure sulfonamide (0.14 g, 88%). ES-MS (M+H) + = 164. 9.

C. Synthesis of [4-(2,4-dioxo(1,3-dihydroquinazolin-3-yl))phenyl][(1, 3-thiazol-2- ylsulfbnyl) amino] carboxaniide The sulfonyl urea was prepared by coupling the aniline from Example 1147 with 1, 3-thiazole-2-sulfonamide using the procedure outlined in Example 1146 step C. ES- MS (M+H) + = 444. 0.

Example 1168 Preparation ot-4- (2, 4-dioxo (l, 3-dihydroquinazolin-3-yl))phenyl][(5-chloro-1,3- thiazol-2-ylsulfonyl) amino] carboxamide A. Synthesis of (tert-butyl)[(5-chloro(1,3-thiazol-2-yl))sulfonyl]amine To a solution of (tert-butyl) (1, 3-thiazol-2-ylsulfonyl) amine (0. 15 g, 0.7 mmol) in ethyl ether (3 mL) at-78 °C was added a 1.6M solution of n-butyllithium (0.875 mL, 1.4 mmol) in hexanes via syringe under argon. The reaction mixture was stirred at-78 °C for 1 hr, then neat benzenesulfonyl chloride (90 µL, 0.7 mmol) was added. The resulting suspension was stirred at room temp for 2 hr. The reaction was diluted with EtOAc, washed with water and brine, dried, concentrated in vacuo and chromatographed (15% EtOAc/hexane) to give pure desired compound (58 mg, 33%). ES-MS (M+Na) + = 277, 279 (Cl), (M-tBu+H) + = 199, 201 (Cl).

B. Synthesis of 5-chloro-1b3-thiazole-2-sulfonamide To a solution of (tert-butyl) [ (5-chloro (1, 3-thiazol-2-yl)) sulfonyl] amine (56 mg, 0.22 mmol) in 1, 2-dichloroethane (2 mL) was added methanesulfonic acid (50 µL, 0.77 mol). The reaction mixture was heated at 80 °C for 3 hr, concentrated in vacuo and chromatographed (30% EtOAc/hexane) to give pure sulfonamide (42 mg, 96%). ES-MS (M+H) + =199 (Cl).

C. Synthesis of N-[4-(2,4-dioxo(1,3-dihydroquinazolin-3-yl))phenyl][(5-chlor o-1, 3- thiazol-2-ylsulfonyl)amino]carboxamide The sulfonyl urea was prepared by coupling the aniline from Example 1147 with 5-chloro-1, 3-thiazole-2-sulfonamide using the procedure outlined in Example 1146 step C. ES-MS (M+H) + = 478,480 (Cl).

Example 1169 Preparation of [ (b enzo [bjthiophen-2-ylsulfonyl) amino]-N- [4- (2, 4-dioxo (l, 3- dihydroquinazolin-3-yl)) phenyl] carboxamide A. Synthesis of benzo[b]thiophene-2-sulfonamide To a solution of benzothiophene (1. 63 g, 12.1 mmol) in THF (8 mL) at 0 °C was added a 1.6M solution of n-butyllithium (8.5 mL, 13.6 mmol) in hexanes slowly over 10 min via syringe. The reaction was stirred cold for 10 min. THF (8 mL) was added and the entire reaction was transferred via cannula to a vessel containing sulfuryl chloride (2 mL, 25 mmol) in hexane (8 mL) at 0 °C. The resulting yellow suspension was stirred at 0 °C for 1 hr and eventually became a clear yellow solution. This solution was concentrated to about 10 mL volume, diluted with acetone (12 mL) and added to a solution of ammonium hydroxide (8 mL) in acetone (25 mL). The reaction mixture was stirred at room temp for 2 hr, added to 200 mL of water on ice bath, acidified with conc.

HC1 (6 mL). A precipitate was filtered to obtain light yellow solid (1.78 g). This crude product was dissolved in 0.5 N KOH (100 mL) and washed with ethyl ether (50 mL).

Upon acidification with cone. HCl (6 mL), the product was extracted into EtOAc (2 x 60 mL), washed with water and brine, dried and concentrated in vacuo to give pure sulfonamide (0.99 g, 39%).

B. Synthesis of fbenzo [b]'thiophen-2-ylsulfonvl aminol-N-4- (2, 4-dioxo l, 3- dihydroquinazolin-3-yll) phenvl] carboxamide The sulfonyl urea was prepared by coupling the aniline from Example 1147 with benzo [b] thiophene-2-sulfonamide using the procedure outlined in Example 1146 step C.

ES-MS (M+H) + = 493.

Example 1170 Preparation of N-[4-(2, 4-dioxo (1, 3-dihydroquinazolin-3-yl)) phenyl] { [ (5-methoxy (2- thienyl) ) sulfonylJamino} carboxarnide A. Synthesis of 5-methoxvthiophene-2-sulfonamide To a solution of 2-methoxythiophene (1 mL, 10 mmol) in dry THF (36 mL) at- 78 °C was added a 1.6 M solution of n-butyllithium (8 mL, 12.8 mmol) in hexanes over 10 min via syringe. The reaction was stirred at-78 °C for 2 hr. S02 (gas) was bubbled into the reaction mixture for about 10 min, then the reaction was allowed to come to room temp and stirred for 1 hr. A solution of sodium acetate (6.56 g, 80 mmol) and hydroxylamine-O-sulfonic acid (3.14 g, 27.8 mmol) in water (40 mL) was then added, and the reaction was stirred vigorously for 2 hr. The reaction was basified with 4N NaOH (15 mL), washed with ethyl ether, acidified with 6N HCl (15 mL), extracted with CH2C12, washed with water and brine, dried and concentrated in vacuo to give pure sulfonamide (1.01 g, 53%). ES-MS (M+H) + = 194.

B. Synthesis of N-[4-(2,4-dioxo(1,3-dihydroquinazolin-3-yl))phenyl]{[(5- methoxy (2-thienyl !) sulfonvlaamino T carboxamide The sulfonyl urea was prepared by coupling the aniline from Example 1147 with 5-methoxytliiopllene-2-sulfonamide using the procedure outlined in Example 1146 step C. ES-MS (M+H) + = 473.

Example 1171 Preparation ofN- [4- (2, 4-dioxo (l, 3-dihydroqumazolin-3-yl)) phenyl] ( [ (l, l- dioxobenzo [d] thiol-2-yl) sulfonyl] amino} carboxamide A. Synthesis of N-[4-(1,3-dioxobenzo[c]azolidin-2-yl)naphthyl]{[(5-chloro(2- thienyl)) sulfonyl] amino} carboxamide To a solution of the sulfonamide from Example 7 (0.213 g, 1 mmol) in CH2C12 (4 mL) was added m-chloroperbenzoic acid (0.49 g, 2.2 mmol). The reaction mixture was refluxed for 20 hr, diluted with EtOAc, washed with 5% NaHCOs, 1NHC1 and brine, dried and concentrated in vacuo to give sulfonamide (0.17 g, 71%). ES-MS (M+H) + = 246.

B. Synthesis of N-[4-(2,4-dioxo(1,3-dihydroquinazolin-3-yl)phenyl]{[(1,1- dioxobenzo [d] thiol-2-yI) sulfonyl] amino} carboxamide The sulfonyl urea was prepared by coupling the aniline from Example 1147 with N- [4- (1, 3-dioxobenzo [o] azolidin-2-yl) naphthyl] {[(5-chloro (2- thienyl)) sulfonyl] amino} carboxamide using the procedure outlined in Example 1146 step C. ES-MS (M+H) + = 525.

Example 1172 Preparation of { [ (5-amino (2-thienyl)) sulfonyl] amino}-N- [4- (2, 4-dioxo (1, 3- dihydroquinazolin-3-yl)) phenyl] carboxamide To a solution of N- [4- (2, 4-dioxo (1, 3-dihydroquinazolin-3-yl)) phenyl] { [ (5-nitro (2- thienyl)) sulfonyl] amino carboxamide (from Example 1148) (20 mg, 0.041 mmol) in methanol (1.5 mL) and triethylamine (11 pL, 0. 08 mmol) was added 10% Pd/C (5 mg, 0.005 mmol) under argon. The reaction mixture was hydrogenated under 1 atm H2 for 3 hr, filtered, concentrated and HPLC purified to give the aniline (6 mg, 33%). ES-MS (M+H) + = 458.

Example 1173 Preparation of N- [4- (2, 4-dioxo (1, 3-dihydroquinazolin-3-yl)) phenyl] { [ (3- methylb enzo [b] thiophen-2-yl) sulfonyl] amino} carboxamide To a solution of the sulfonylurea from Example 1150 (52 mg, 0.046 mmol) in methanol (1.5 mL) and tnethylamine (12 µL) was added 10% Pd/C (50 mg) and PtO2 (7 mg). The reaction mixture was hydrogenated under 250 psi Ha for 4 days, filtered, concentrated and HPLC purified to give the dehalogenated product (2 mg, 10%). ES-MS (M+H) + = 507.

Examples 1174-1176 The sulfonyl urea targets above were prepared by reaction of the aniline 3- (4- aminophenyl)-1, 3-dihydroquinazoline-2, 4-dione trifluoroacetate salt (Example 1147) with 3 commercially available substituted phenylsulfonylisocyanates (1.5 eq. ) (R = H, Cl, CH3) in DMF. Products were typically isolated by precipitation from DMF reaction mixture with water and filtration.

Example 1174 N- [4- (2, 4-dioxo (1, 3-dihydroquinazolin-3- yl)) phenyl] [ (phenylsulfonyl) amino] carboxamide. ES-MS (M+H) + = 437. 0.

Example 1175 N- [4- (2, 4-dioxo (1, 3-dihydroquinazolin-3-yl) ) phenyl] {[(4-chlorophenyl)sulfonyl]amino} carboxamide. ES-MS (M+H) += 471,473 (Cl).

Example 1176 N- [4- (2, 4-dioxo (1, 3-dihydroquinazolin-3-yl)) phenyl] { [ (4-methylphenyl) sulibnyl] amino} carboxamide. ES-MS (M+H) += 451.

Example 1177 Preparation of N-[5-(2, 4-dioxo (1, 3-dihydroquinazolin-3-yl)) (2-pyrìdyl)] {[(5-chloro (2-. thienyl) ) sulfonyl] amino} carboxamide A. Synthesis of (tert-butoxy)-N- (5-nitrof2-pyridylcarboxamide To a solution of2-amino-5-nitropyridine (0.555 g, 4 mmol) in THF (10 mL) was added 1M NaHMDS in THF (8 mL, 8 mmol). The resulting dark red suspension was stirred for 15 min, followed by addition of a solution of Boc anhydride (0. 87 mL, 3.8 mmol) in THF (5 mL). The reaction mixture was stirred at room temp for 21 hr, dilute with EtOAc, washed with IN HCl and brine, dried and concentrated in vacuo to give desired compound (0.63 g, 70%). ES-MS (M+H) + = 240, (M-tBu+H) + = 184.

B. Synthesis of N-(5-amino(2-pyridyl))(tert-butoxy)carboxamide To a suspension of (tert-butoxy)-N- (5-nitro (2-pyridyl)) carboxamide (0.27 g, 1.13 mmol) in methanol (2 mL), ethyl acetate (4 mL) and TEA (0. 16 mL) was added 10% Pd/C (60 mg, 0.056 mmol) under argon. The reaction mixture was hydrogenated under 1 atm H2 for 20 hr, filtered through Celite and concentrated in vacuo to give desired compound (0. 226 g, 97%).

C. Synthesis of [(tert-butyl)amino]-N-[5-(2,4-dioxo(1,3-dihydroquinazolin-3- yl))(2- pyridyD] carboxamide The above named compound was prepared using the procedure outlined in Example 1146 step A by reaction of N- (5-amino (2-pyridyl) ) (tert-butoxy) carboxamide with methyl 2-isocyanatobenzoate. ES-MS (M+H) += 355.

D. Synthesis of N-[5-(2,4-dioxo(1,3-dihydroquinazolin-3-yl))(2-pyridyl)]{[(5 - chloro 2-thienyl))sulfonyl]amino}carboxamide To a solution of 5-chlorothiophene-2-sulfonamide (20 mg, 0.1 mmol) and [ (tert- butyl) amino [5- (2, 4-dioxo (1, 3-dihydroquinazolin-3-yl)) (2-pyridyl) ] carboxamide (35 mg, 0.1 mmol) in DMF (1 mL) was added DBU (30 aL). The reaction mixture was heated at 90 °C for 3 days, acidified and HPLC purified to give the sulfonyl urea (7 mg, 16%). ES-MS (M+H) + = 478, 480 (Cl).

Example 1178 Preparation of N-[5-(2, 4-dioxo (1, 3-dihydroquinazolin-3-yl)) (2-pyridyl)] [(phenylsulfonyl)amino]carboxamide This compound was prepared by TFA deprotection of [ (tert-butyl) amino]-N- [5- (2, 4-dioxot (1, 3-dihydroquinazolin-3-yl) ) (2-pyridyl)] carboxamide from Example 1177, step C, followed by reaction of the aminopyridine with phenylsulfonylisocyanate (1.5 eq) in DMF, precipitation from 0. 1% TFA and filtration of product to give the sulfonyl urea desired compound (40% yield). ES-MS (M+H) + = 438.

Example 1179 N- [4- (2, 4-dioxo (1, 3-dihydroquinazolin-3-yl)) phenyl] {[(5-chIoro-3-fluoro (2- thienyl)) sulfonyl] amino} carboxamide A. Synthesis of (tert-butvl [(5-chloro(2-thienyl))sulfonyl]amine A solution of 5.5 g (27.5 mmol) of 5-chlorothiophenesulfollyl chlolide in dry THF at 0°C was treated with a solution of 5.7 mL (75.5 mmol) of t-butylamine. After wanning to 23°C, the reaction mixture was diluted with 125 mL of diethyl ether, filtered, and washed with 1 N HC1, brine, and dried (M8, SO4). Corlcentratioll in vacuo affords 6.4 g (98%) of the named compound as an oil.

B. Synthesis of (tert-butyl)[(5-chloro-3-fluoro(2-thienyl))sulfonyl]amine A THF solution (1. 5 mL) of 128 mg (0. 50 mmol) of (tert-butyl) [ (5-chloro (2- thienyl) ) sulfonyl] amine was cooled to-78°C and treated with 954 pL (1.5 mmol) of a 1.6 M solution of butyl lithium in hexane. After 1 h, 159 mg (0. 5 mmol) of bis (phenylsulfonyl) fluoroamine was added and the solution was allowed to warm to 23 °C. The reaction was quenched with 1 mL of sat. NH4Cl, extracted 3 times with diethyl ether, dried (MgS04), concentrated in vacuo to afford a quantitative yield (147 mg) of the desire product. 19F-NMR (CDCl3) 8 (ppm) :-113. 4.

C. Synthesis of [4-(2,4-dioxo(1,3-dihydroquinazolin-3-yl))phenyl]{[(5-chloro -3- fluoro(2-thienyl))sulfonyl]amino}carboxamide A 19 mg-sample (0.07 mmol) of (tert-butyl) [ (5-chloro-3-fluoro (2- thienyl)) sulfonyl] amine was dissolved in neat TFA and stirred for 1 h, concentrated in vacuo and used directly in the next transformation. This sample was dissolved in 150 uL of DCM and 21 mg (0. 084 mmol) of DSC was added followed by 21 pL (0. 14 mmol) of DBU. This solution was stirred for 18h, 26 mg (0.07) of 3- (4-aminophenyl)-1, 3- dihydroquinazoline-2, 4-dìone tri : fluoroacetate salt was added plus 150 pL of dry acetonitrile and refluxed for 2h. This material was then purified on RP-HPLC to afford 11 mg (34%) of the desired product. ES-MS: M+H+= 495 (Cl).

Pharmaceutical Compositions and Methods of Treatment A compound of formulae (I)- (VIII) according to the invention may be formulated into pharmaceutical compositions. Accordingly, the invention also relates to a pharmaceutical composition for preventing or treating thrombosis in a mammal, particularly those pathological conditions involving platelet aggregation, containing a therapeutically effective amount of a compound of formulae (I)- (VIII) or a pharmaceutically acceptable salt thereof, each as described above, and a pharmaceutically acceptable carrier or agent. Preferably, a pharmaceutical composition of the invention contains a compound of formulae (I)- (VIII), or a salt thereof, in an amount effective to inhibit platelet aggregation, more preferably, ADP-dependent aggregation, in a mammal, in particular, a human. Pharmaceutically acceptable carriers or agents include those known in the art and are described below.

Pharmaceutical compositions of the invention may be prepared by mixing the compound of formulae (I)-(VIII) with a physiologically acceptable carrier or agent.

Pharmaceutical compositions of the invention may further include excipients, stabilizers, diluents and the like and may be provided in sustained release or timed release formulations. Acceptable carriers, agents, excipients, stablilizers, diluents and the like for therapeutic use are well known in the pharmaceutical field, and are described, for example, in Remi7gto7a's Pharmaceutcal Scie7çces, Mack Publishing Co. , ed. A. R.

Gennaro (1985). Such materials are nontoxic to the recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, acetate and other organic acid salts, antioxidants such as ascorbic acid, low molecular weight (less than about ten residues) peptides such as polyarginine, proteins, such as serum albumin, gelatin, or immunoglobulins, hydrophilic polymers such as polyvinylpyrrolidinone, amino acids such as glycine, glutamic acid, aspartic acid, or arginine, monosaccharides, disaccharides, and other carbohydrates including cellulose or its derivatives, glucose, mannose or dextrins, cheating agents such as EDTA, sugar alcohols such as mannitol or sorbitol, counterions such as sodium and/or nonionic surfactants such as TWEEN, or polyethyleneglycol.

Methods for preventing or treating thrombosis in a mammal embraced by the invention administer a therapeutically effective amount of a compound of formulae (I)- (VIII) alone or as part of a pharmaceutical composition ot the invention as described above to a mammal, in particular, a human. Compounds of formulae (I)- (VIII) and pharmaceutical compositions of the invention containing a compound of formulae (I) - (VIII) of the invention are suitable for use alone or as part of a multi-component treatment regimen for the prevention or treatment of cardiovascular diseases, particularly those related to thrombosis. For example, a compound or pharmaceutical composition of the invention may be used as a drug or therapeutic agent for any thrombosis, particularly a platelet-dependent thrombotic indication, including, but not limited to, acute myocardial infarction, unstable angina, chronic stable angina, transient ischemic attacks, strokes, peripheral vascular disease, preeclampsia/eclampsia, deep venous thrombosis, embolism, disseminated intravascular coagulation and thrombotic cytopenic purpura, thrombotic and restenotic complications following invasive procedures, e. g. , angioplasty, carotid endarterectomy, post CABG (coronary artery bypass graft) surgery, vascular graft surgery, stent placements and insertion of endovascular devices and protheses.

Compounds and pharmaceutical compositions of the invention may also be used as part of a multi-component treatment regimen in combination with other therapeutic or diagnostic agents in the prevention or treatment of thrombosis in a mammal. In certain preferred embodiments, compounds or pharmaceutical compositions of the invention may be coadministered along with other compounds typically prescribed for these conditions according to generally accepted medical practice such as anticoagulant agents, thrombolytic agents, or other antithrombotics, including platelet aggregation inhibitors, tissue plasminogen activators, urokinase, prourokinase, streptokinase, heparin, aspirin, or warfarin. Coadministration may also allow for application of reduced doses of the thrombolytic agents and therefore minimize potential hemorrhagic side-effects.

Compounds and pharmaceutical compositions of the invention may also act in a synergistic fashion to prevent reocclusion following a successful thrombolytic therapy and/or reduce the time to reperfusion.

The compounds and pharmaceutical compositions of the invention may be utilized in vivo, ordinarily in mammals such as primates, (e. g. , humans), sheep, horses, cattle, pigs, dogs, cats, rats and mice, or in vitro. The biological properties, as defined above, of a compound or a pharmaceutical composition of the invention can be readily characterized by methods that are well known in the art such as, for example, by in vivo studies to evaluate antithrombotic efficacy, and effects on hemostasis and hematological parameters.

Compounds and pharmaceutical compositions of the invention may be in the form of solutions or suspensions. In the management of tluombotic disorders the compounds or pharmaceutical compositions of the invention may also be in such forms as, for example, tablets, capsules or elixirs for oral administration, suppositories, sterile solutions or suspensions or injectable administration, and the like, or incorporated into shaped articles. Subjects (typically mammalian) in need of treatment using the compounds or pharmaceutical compositions of the invention may be administered dosages that will provide optimal efficacy. The dose and method of administration will vary from subject to subject and be dependent upon such factors as the type of mammal being treated, its sex, weight, diet, concurrent medication, overall clinical condition, the particular compound of formulae (I)- (VIII) employed, the specific use for which the compound or pharmaceutical composition is employed, and other factors which those skilled in the medical arts will recognize.

Dosage formulations of compounds of formulae (I)- (VIII), or pharmaceutical compositions contain a compound of the invention, to be used for therapeutic administration must be sterile. Sterility is readily accomplished by filtration through sterile membranes such as 0. 2 micron membranes, or by other conventional methods.

Formulations typically will be stored in a solid form, preferably in a lyophilized form.

While the preferred route of adminsitration is orally, the dosage formulations of compounds of formulae (I)- (VIII) or pharmaceutical compositions of the invention may also be administered by injection, intravenously (bolus and/or infusion), subcutaneously, intramuscularly, colonically, rectally, nasally, transdermally or intraperitoneally. A variety of dosage forms may be employed as well including, but not limited to, suppositories, implanted pellets or small cylinders, aerosols, oral dosage formulations and topical formulations such as ointments, drops and dermal patches. The compounds of formulae (I)- (VIII) and pharmaceutical compositions of the invention may also be incorporated into shapes and articles such as implants which may employ inert materials such biodegradable polymers or synthetic silicones as, for example, SILASTIC, silicone rubber or other polymers commercially available. The compounds and pharmaceutical compositions of the invention may also be administered in the fonn of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of lipids, such as cholesterol, stearylamine or phosphatidylcholines.

Therapeutically effective dosages may be determined by either in-vitro or in vivo methods. For each particular compound or pharmaceutical composition of the invention, individual determinations may be made to determine the optimal dosage required. The range of therapeutically effective dosages will be influenced by the route of administration, the therapeutic objectives and the condition of the patient. For injection by hypodermic needle, it may be assumed the dosage is delivered into the bodily fluids.

For other routes of administration, the absorption efficiency must be individually determined for each compound by methods well known in pharmacology. Accordingly, it may be necessary for the therapist to titer the dosage and modify the route of administration as required to obtain the optimal therapeutic effect.

The determination of effective dosage levels, that is, the dosage levels necessary to achieve the desired result, i. e. , platelet ADP receptor inhibition, will be readily determined by one skilled in the art. Typically, applications of a compound or pharmaceutical composition of the invention are commenced at lower dosage levels, with dosage levels being increased until the desired effect is achieved. The compounds and compositions of the invention may be administered orally in an effective amount within the dosage range of about 0.01 to 1000 mg/kg in a regimen of single or several divided daily doses. If a pharmaceutically acceptable carrier is used in a pharmaceutical composition of the invention, typically, about 5 to 500 mg of a compound of formulae (I)- (VIII) is compounded with a pharmaceutically acceptable carrier as called for by accepted pharmaceutical practice including, but not limited to, a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, dye, flavor, etc.

The amount of active ingredient in these compositions is such that a suitable dosage in the range indicated is obtained.

Typical adjuvants which may be incorporated into tablets, capsules and the like include, but are not limited to, binders such as acacia, com starch or gelatin, and excipients such as microcrystalline cellulose, disintegrating agents like corn starch or alginic acid, lubricants such as magnesium stearate, sweetening agents such as sucrose or lactose, or flavoring agents. When a dosage form is a capsule, in addition to the above materials it may also contain liquid carriers such as water, saline, or a fatty oil. Other materials of various types may be used as coatings or as modifiers of the physical form of the dosage unit. Sterile compositions for injection can be formulated according to conventional pharmaceutical practice. For example, dissolution or suspension of the active compound in a vehicle such as an oil or a synthetic fatty vehicle like ethyl oleate, or into a liposome may be desired. Buffers, preservatives, antioxidants and the like can be incorporated according to accepted pharmaceutical practice.

Pharmacological Assays The pharmacological activity of each of the compounds according to the invention is determined by the following iii vitro assays: I. Inhibition of ADP-Mediated Platelet Agregation in vitro The effect of testing the compound according to the invention on ADP-induced human platelet aggregation is preferably assessed in 96-well microtiter assay (see generally the procedures. in Jantzen, H. M. et al. (1999) Chromb. Hemost. 81 : 111-117).

Human venous blood is collected from healthy, drug-free volunteers into ACD (85 mM sodium citrate, 111 mM glucose, 71.4 mM citric acid) containing PGI2 (1. 25 ml ACD containing 1.6 uM PGL/10 ml blood; PGI2 was from Sigma, St. Louis, MO). Platelet- rich plasma (PRP) is prepared by centrifugation at 160 x g for 20 minutes at room temperature. Washed platelets are prepared by centrifuging PRP for 10 minutes at 730 g and resuspending the platelet pellet in CGS (13 mM sodium citrate, 30 mM glucose, 120 mM NaCl ; 2 ml CGS/10 ml original blood volume) containing lU/ml apyrase (grade V, Sigma, St. Louis, MO). After incubation at 37 °C for 15 minutes, the platelets are collected by centrifugation at 730 g for 10 minutes and resuspended at a concentration of 3xlO'platelets/ml in Hepes-Tyrode's buffer (10 mM Hepes, 138 rnM NaCl, 5.5 mM glucose, 2.9 mM KC1, 12 mM NaHC03, pH 7.4) containing 0.1% bovine serum albumin, 1 mM CaCl2 and 1 mM MgCl2. This platelet suspension is kept >45 minutes at 37 °C before use in aggregation assays.

Inhibition of ADP-dependent aggregation is preferably determined in 96-well flat- bottom microtiter plates using a microtiter plate shaker and plate reader similar to the procedure described by Frantantoni et al., Am. J Clin. Pathol. 94,613 (1990). All steps are performed at room temperature. The total reaction volume of 0.2 ml/well includes in Hepes-Tyrodes buffer/0. 1% BSA: 4.5 x 107 apyrase-washed platelets, 0.5 mg/ml human fibrinogen (American Diagnostica, Inc. , Greenwich, CT), serial dilutions of test compounds (buffer for control wells) in 0.6% DMSO. After about 5 minutes preincubation at room temperature, ADP is added to a final concentration of 2: M which induces submaximal aggregation. Buffer is added instead of ADP to one set of control wells (ADP-control). The OD of the samples is then determined at 490 nm using a microtiter plate reader (Softmax, Molecular Devices, Menlo Park, CA) resulting in the 0 minute reading, The plates are then agitated for 5 min on a microtiter plate shaker and the 5 minute reading is obtained in the plate reader. Aggregation is calculated from the decrease of OD at 490 nm at t = 5 minutes compared to t = 0 minutes and is expressed as % of the decrease in the ADP control samples after correcting for changes in the unaggregated control samples.

II. Inhibition of [3H2-MeS-ADP Binding to Platelets Having first determined that the compounds according to the invention inhibit ADP-dependent platelet aggregation with the above assay, a second assay is used to determine whether such inhibition is mediated by interaction with platelet ADP receptors.

Utilizing the second assay the potency of inhibition of such compounds with respect to [3H] 2-MeS-ADP binding to whole platelets is determined. 3H] 2-MeS-ADP binding experiments are routinely performed with outdated human platelets collected by standard procedures at hospital blood banks. Apyrase-washed outdated platelets are prepared as follows (all steps at room temperature, if not indicated otherwise): Outdated platelet suspensions are diluted with 1 volume of CGS and platelets pelleted by centrifugation at 1900 x g for 45 minutes. Platelet pellets are resuspended at 3-6x109 platelets/ml in CGS containing 1 U/ml apyrase (grade V, Sigma, St. Louis, MO) and incubated for 15 minutes at 37°C. After centrifugation at 730 x g for 20 minutes, pellets are resuspended in Hepes-Tyrode's buffer containing 0. 1% BSA (Sigma, St.

Louis, MO) at a concentration of 6. 66x108 platelets/ml. Binding experiments are performed after > 45 minutes resting of the platelets.

Alternatively, binding experiments are performed with fresh human platelets prepared as described in I. (Inhibition of ADP-Mediated Platelet Aggregation in vitro), except that platelets are resuspended in Hepes-Tyrode's buffer containing 0. 1% BSA (Sigma, St. Louis, MO) at a concentration of 6. 66x10 platelets/ml. Very similar results are obtained with fresh and outdated platelets.

A platelet ADP receptor binding assay using the tritiated potent agonist ligand [3H] 2-MeS-ADP (Jantzen, H. M. et al. (1999) Thromb. Hemost. 81: 111-117) has been adapted to the 96-well microtiter format. In an assay volume of 0.2 ml Hepes-Tyrode's buffer with 0.1% BSA and 0. 6% DMSO, 1x108 apyrase-washed platelets are preincubated in 96-well flat bottom microtiter plates for 5 minutes with serial dilutions of test compounds before addition of lnM [3H] 2-MeS-ADP ([3H] 2-methylthioadenosine-5'- diphosphate, ammonium salt; specific activity 48-49 Ci/mmole, obtained by custom synthesis from Amersham Life Science, Inc. , Arlington Heights, IL, or NEN Life Science Products, Boston, MA). Total binding is determined in the absence of test compounds.

Samples for nonspecific binding may contain 10-5 M unlabelled 2-MeS-ADP (RBI, Natick, MA). After incubation for 15 minutes at room temperature, unbound radioligand is separated by rapid filtration and two washes with cold (4-8 °C) Binding Wash Buffer (10 mM Hepes pH 7.4, 138 mM NaCI) using a 96-well cell harvester (Minidisc 96, Skatron Instruments, Sterling, VA) and 8x12 GF/C glassfiber filtermats (Printed Filtermat A, for 1450 Microbeta, Wallac Inc. , Gaithersburg, MD). The platelet-bound radioactivity on the filtermats is determined in a scintillation counter (Microbeta 1450, Wallac Inc., Gaithersburg, MD). Specific binding is determined by subtraction of non- specific binding from total binding, and specific binding in the presence of test compounds is expressed as % of specific binding in the absence of test compounds dilutions.

It should be understood that the foregoing discussion, embodiments and examples merely present a detailed description of certain preferred embodiments. It will be apparent to those of ordinary skill in the art that various modifications and equivalents can be made without departing from the spirit and scope of the invention. All the patents, journal articles and other documents discussed or cited above are herein incorporated by reference.