SK7692001A3 - Thiourea inhibitors of herpes viruses - Google Patents

Description

Thiourea compounds as inhibitors of herpes viruses

BACKGROUND OF THE INVENTION

Eight viruses have been identified that are members of the Herpesviridae family. An overview is given in Roizman, B. 1996. Herpesviridae, p. 2221-2230. In B.N. Fields D. M. Knipe, and, P. M. Howley (Ed.), Fields Virology, 3rd Ed. Lippincott-Raven Publishers, Philadelphia, PA). Each member of this family is characterized by a enveloped virus comprising a proteinaceous coat and a nucleocapsid, the latter containing the viral relatively large double stranded DNA genome (e.g., about 80 to 250 kilobases). Members of the human alphaherpesvirus subfamily are neurotrophic and include herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) and varicella-zoster virus (VZV). Human betaherpesviruses are cytomegalovirus (HCMV), human herpesvirus 6 (HHV-6) and human herpesvirus 7 (HHV-7). Gammaherpesviruses are lymphotropic and include Epstein-Barr virus (EBV) and Kaposi's herpesvirus (HHV-8). Each of these viruses is causally related to human disease, including herpes labialis and herpes genitalis (HSV-1 and HSV-2 [Whitley, RJ 1996. Herpes Simplex Viruses, pp. 2297-2342. In B.N Fields, DM Knipe and PM Howley (ed.), Fields Virology, 3rd ed., Lippincott-Raven Publishers, Philadelphia, PA]; chickenpox and shingles (VZV [Arvin, A. 1996. Varicella-Zoster Virus, pp. 2547-2585. In BN Fields, DM Knipe and PM Howley (ed.), Fields Virology, 3rd ed. Lippincott-Raven Publishers , Philadelphia, PA]; infectious mononucleosis (EBV [Rickinson, A. B. and Kieff, E. 1966. Epstein-Barr Virus, pp. 2397-2446.

B. N. Fields, D. M. Knipe, and P. M. Howley (Ed.), Fields Virology. 3. vyd. Lippincott-Raven Publishers, Philadelphia, PA]; pneumonia and retinitis (HCMV [(Britt, W.J. and Alford, C.A. 199J. Cytomegalovirus, pp. 2493-2523). B. N. Fields, D. M. Knipe, and P. M. Howley, (Ed.) Fields Virology, 3rd Ed.

Philadelphia PA]); exanthem [(Pellet, P. E. and Black, J. B. 1996. Human

Lippincott-Raven Publishers, subitum (HHV-6

Herpesvirus 6,

D.

p. 2587-2608. B. B. Fields, D. M. Knipe, and P. M.

3. vyd. Lippincott-Raven and HHV-7 [Frenkel, N. and Roffman, E.

Howley (Ed.),

Publishers

1996th

B.N. Fields, D.M.

Knipe

Raven

Fields Virology.

, Philadelphia, PA]

Human Herpesvirus 7, p.

and P. M. Howley (Ed.) Fields Virology, 3rd Ed., LippincottPublishers, Philadelphia, PA]; and Kaposi's sarcoma (HHV-8

C. and Fleckeinstein, B. Cell [Neipel, F., Albrecht, J.

homologous genes in Kaposi's sarcoma-associated rhadinovirus human herpesvirus 8: determinants of its pathogenicity? J. Virol.

71: 4187-92, 1997]. HCMV is evaluated in more detail below. After a primary infection, herpesvirus creates latency in the infected individual and remains there for the rest of the life. Periodic reactivation of latent virus is clinically relevant. In the case of HSV, reactivated virus can be transmitted to infants during childbirth and cause skin or eye infection or diffuse infection of the systems). Shingles is a treatment for HSV and VZV with general infection of the central nervous system (such as large organs or clinical manifestation of VZV reactivation) with antiviral drugs such as acyclovir (Glaxo Welcome), ganciclovir (Roche) and foscarnet (Asta) that target viral encoded DNA polymerase.

HCMV is a ubiquitous opportunistic pathogen infecting 50 to 90% of the adult population (Britt. WJ and Alford CA 1996. Cytomegalovirus, pp. 2493-2523. In BN Fields DM Knipe and, PM Howley (ed.) Fields Virology, 3rd ed. Lippincottott -Raven Publishers, Philadelphia, PA). Primary infection with HCMV is usually asymptomimatic, although heterophilic negative mononucleosis has been observed. The virus is transmitted through sexual intercourse, breast milk and saliva. Intrauterinal transmission of HCMV from the pregnant mother to the fetus is often the cause of serious clinical consequences. HCMV remains latent in the infected person for the remainder of his life. Cell-mediated immunity plays a useful role in controlling reactivation from latency. Impaired cellular immunity leads to reactivation of latent HCMV in seropositive individuals

HCMV is associated with immune deficiency or incomplete.

There are 3 main categories of people with HCMV (reviewed by Britt and Alford, 1996). (1) In patients at risk of AIDS, HCMV is one of the two most important pathogens causing clinical disease (the other being Pneumocystis). The most common manifestation of HCMV in AIDS is retinitis, although infection of other organs, including the adrenal and lung glands, is possible. The gastrointestinal tract and central nervous system are also frequently reported. 90% of AIDS patients have active HCMV infection: 25 to 40% (about 85,000 patients in the US) have life or vision threatening HCMV. HCMV is the cause of death in 10% of AIDS patients. (2) Due to suppression of the immune system to reduce the risk of transplant rejection, reactivation or reinfection of HCMV, it is common among patients with transplanted kidney, liver, heart or bone marrow. Pneumonia is the most common HCMV disease occurring in 70% of these transplanted patients. (3) Congenital infection occurs in 1% of newborns, about 40,000 annually. Up to 25% of these children have symptoms of HCMV at 0 to 3 years of age. HCMV is progressive, causing mental retardation and neurological abnormalities in children. Recent studies have shown that treatment with anti-HCMV drugs may reduce morbidity in these children.

Some antiviral drugs are commonly marketed (Bron, D., R. Snoeck, and L. Lagneaux. 1996. New insights into the pathogenesis and treatment of cytomegalovirus. Exp. Opin.

Invest. Drugs 5: 337-344; Crumpacker, C. 1996. Ganciclovir. New Eng. J. Med. 335: 721-729; Sachs, S. and F. Alrabiah. 1996. Novel Herpes Treatments: a Review. Exp. Opin. Invest Drugs 5: 169-183. These include: ganciclovir (Roche), a nucleoside analog with haematopoietic cell toxicity; foscarnet (Astra), a pyrophosphate analogue with nephrotoxicity; and cidofovir, Gilead), a nucleoside phosphonate with acute nephrotoxicity. All of these drugs target viral encoded DNA polymerase and are typically administered intravenously due to their low bioavailability and, as mentioned above, are a source of considerable toxicity. Ganciclovir resistant mutants are also often resistant to cidofovir. Therefore, there is a need for a safer (i.e., less toxic), orally bioavailable antiviral drug that targets new viruses.

The use of phenylthioureas is described in a number of applications dealing with the field of pharmacy. Armistead et al., WO 97/40028 discloses phenyl ureas and thioureas as inhibitors of inosine monophosphate dehydriogenase (IMPDH), an enzyme reported to play a role in the replication of viral diseases such as herpes.

Widdowson et al., WO 96/25157 discloses phenyl urea and thiourea compounds of the following formula for the treatment of chemokine-mediated diseases, interleukin-8.

[OF REVENUE

Morin Jr., et al., U.S. Patent 5,593,993 discloses certain thiourea compounds for the treatment of AIDS and inhibition of HIV and related virus replication.

It is an object of the present invention to provide compounds and their pharmaceutically acceptable salts for inhibiting and / or treating diseases associated with herpes viruses, including human cytomegalovirus, herpes simplex viruses, Epstein-Barr virus, varicella-zoster virus, human herpesvirus-6 and -7 and Kaposi herpesvirus.

SUMMARY OF THE INVENTION

The present invention provides compounds of formula

where

R 1 -R 5 are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 perhaloalkyl, C 3 -C 10 cycloalkyl atoms, heterocycloalkyl of 3 to 10 carbon atoms, aryl, heteroaryl, halogen, -CN, -NO2, -CO2R6, -COR, ^- ORO, - SR e, ^- SOR 6, SO 2 R 6 ~, -CONR7R8, -NRgN (R7R8); -N (R 7, R 5) or WY- (CH ₂ ) _n -Z; or R 2 and R ₃ or R ₃ and R ₄ together form a 3 to 7 membered heterocycloalkyl or 3 to 7 membered heteroaryl;

R e and R 7 are independently hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, or aryl;

R ₈ is hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10 cells, aryl or heteroaryl, or

R ₇ and R 8 together may form a 3 to 7 membered heterocycloalkyl;

A is heteroaryl;

W is O, NR ₆ or absent;

Y is - (CO) - or - (CO ₂ ) - or is absent;

Z is alkyl of 1 to 4 carbon atoms, -CN, -CO ₂ R 6, _R -COR.6 -CONRiRe, OCOR _6, NR ₆ COR _7, -OCONRg, OR _6, -SR _6, -SOR _6, - SO ₂ R ₆ , -SR ₅ N (R ₇ R ₈ ), -N (R ₇ , R ₈ ) or phenyl;

G is aryl or heteroaryl;

X is a bond, -NH, alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, thioalkyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms, or (CH) J;

J is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl or benzyl, and n is an integer of 1 to 6, or pharmaceutically acceptable salts thereof.

In a preferred embodiment, at least one R 1 -R 5 is not hydrogen and preferably at least one to three R 1 -R 5 are not hydrogen. Preferably R 1 -R 5 is selected from hydrogen, C 1 -C 6 alkoxy, C 1 -C 6 perhaloalkyl and halo.

Preferably X is (CH) J, wherein J is alkyl of 1 to 6 carbon atoms. More preferably, J is alkyl of 1 to 3 carbon atoms, most preferably J is methyl.

In some embodiments of the present invention, A may be substituted with at least one hydrogen atom, C 1 -C 4 alkyl, C 1 -C 4 perhaloalkyl, halogen, C 1 -C 4 alkoxy or cyano. A is most preferably unsubstituted.

G is preferably a 5 to 6 membered heteroaryl containing 1 to 2 heteroatoms. More preferably, G is oxazolyl, furyl, thiazolyl or thiadiazolyl, more preferably G is 1,2,3-thiadiazolyl, 1,3-thiazolyl or 2-furyl. G is most preferably thiazolyl and especially 1,3thiazolyl.

Preferred compounds of the invention are the following compounds which include their pharmaceutical salts.

Furan-2-carboxylic acid {5- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -pyridin-2-yl} -amide, {5- [3- (5-Chloro-2,4-dimethoxy-phenyl)] [1,2,3] Thiadiazole-4-carboxylic acid thioureido] pyridin-2-yl} amide pyridine {5- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] pyridin-2-yl} amide Pyridine-2-carboxylic acid {6- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -pyridin-3-yl} -amide, {6- (3- (5-Chloro-) -2-carboxylic acid) Furan-2-carboxylic acid 2,4-dimethoxyphenyl) thioureido] pyridin-3-yl} amide [6- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] pyridin-3-yl} amide [1 [1,2,3] Thiadiazole-4-carboxylic acid {5- [3- (3,5-Dichloro-phenyl) -thioureido] -pyridin-2-yl} -amide, 2,3] thiadiazole-4-carboxylic acid,

N- [5 - [[[(5-Chloro-2,4-dimethoxyphenyl) amino] thioxomethyl] amino] -2-pyridinyl] -2-methylbenzamide,

N- {5- (3- (5-Chloro-2,4-dimethoxy-phenyl) -thiouredio] -pyridin-2

yl} -2-fluoro-benzamide,

N- {6- (3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -pyridin-3

-yl} -2-fluorobenzamide,

Ν- {5 - _[({[3-f 5 bis (trifluoromethyl) benzyl] amino} carbothioyl) amino] -2-pyridinyl} -1,2,3-thiadiazol-4-carboxamide,

N- (5 - {[({(1S) -1- [3,5-Bis (trifluoromethyl) phenyl] ethyl] amino) carbothioyl] amino] -2-pyridinyl) -1,2,3-thiadiazole-4- carboxamide

N- (5 - {[({(1S) -1- [3,5-Bis (trifluoromethyl) phenyl] ethyl] amino) carbothioyl] amino] -2-pyridinyl) -1,3-thiazole-4-carboxamide,

N- (5 - {[({1- (2-Fluoro-5- (trifluoromethyl) phenyl] ethyl} amino) carbothioyl] amino] -2-pyridinyl) -1,3-thiazole-4-carboxamide,

N- (5 - {[({1- [2-Fluoro-4- (trifluoromethyl) phenyl] ethyl} amino) carbothioyl] amino] -2-pyridinyl) -1,3-thiazole-4-carboxamide,

N- (5 - {(({1- [3-Fluoro-5- (trifluoromethyl) phenyl] ethyl} amino) carbothioyl] amino} -2-pyridinyl) -1,3-thiazole-4-carboxamide,

N- (5 - {[({(1S) -1- [3,5-Bis (trifluoromethyl) phenyl] ethyl} amino) carbonyl] amino} -2-pyridinyl) -1,3-thiazole-4-carboxamide,

N- {5 - [({(1- (3-bromophenyl) ethyl] amino} carbothioyl) amino] -2

pyridinyl} -1,3-thiazole-4-carboxamide,

N - {5 - [({(1- (2-Bromophenyl) ethyl] amino] carbothioyl) amino] -2

pyridinyl} -1,3-thiazole-4-carboxamide,

N- (5 - {[({1- [3- (Trifluoromethyl) phenyl] ethyl} amino) carbothioyl] amino} -2-pyridinyl) -1,3-thiazole-4-carboxamide,

N- (5 - {[({1- [4-Chloro-3- (trifluoromethyl) phenyl] ethyl} amino) carbothioyl] amino} -2-pyridinyl) -1,3-thiazole-4-carboxamide,

N- {5 - [({[1- (4-Chloro-3-fluorophenyl) ethyl] amino} carbothioyl) amino] -2-pyridinyl} -1,3-thiazole-4-carboxamide,

N- {5 - [({[1- (4-Chloro-2-fluorophenyl) ethyl] amino} carbothioyl) amino] -2-pyridinyl} -1,3-thiazole-4-carboxamide,

N- {6 - [({[1- (4-Fluorophenyl) ethyl] amino} carbothioyl) amino] -3

-pyridinyl} -1,2,3-thiadiazole-4-carboxamide,

N- (6 - {[({(1S) -1- [3,5-Bis (trifluoromethyl) phenyl] ethyl} amino) carbothioyl] amino} -3-pyridinyl) -1,2,3-thiadiazole-4- carboxamide and their pharmaceutical salts.

Unless otherwise indicated, the terms used herein have the following meanings.

Alkyl, as used herein, means a straight or branched lower alkyl group containing up to 6 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl.

Alkenyl, as used herein, means a straight or branched lower alkyl group having 2 to 6 carbon atoms containing at least one carbon-carbon double bond. Alkenyl includes vinyl groups.

Alkynyl, as used herein, means a straight or branched lower C 2 -C 6 alkyl group containing at least one carbon-carbon triple bond.

The alkyl, alkenyl and alkynyl groups of the present invention may be substituted or unsubstituted.

Cycloalkyl includes a saturated mono or bicyclic ring having from 3 to 10 carbon atoms. Examples of cycloalkyl groups include cyclopentyl, cyclohexyl and cycloheptyl. The cycloalkyl groups of the invention may be substituted or unsubstituted.

Heterocycloalkyl means a saturated mono or bicyclic ring system containing 3 to 10 cells having 1 to 3 heteroatoms selected from N, S and O, including but not limited to aziridinyl, azetidinyl, imidazolidinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrazolidinyl, piperidinyl and pyrrolidinyl. The heterocycloalkyl groups of the present invention may be substituted or unsubstituted.

Aryl as used herein means an aromatic mono or bicyclic ring of 6 to 10 carbon atoms. Examples of aryl groups include phenyl, naphthyl and biphenyl. The aryl groups of the present invention may be substituted or unsubstituted.

Heteroaryl, as used herein, means an aromatic mono or bicyclic ring containing from 5 to 10 members, having 1 to 3 heteroatoms selected from N, O or S, including, but not limited to, thiazolyl, thiadiazolyl, oxazolyl, furyl, indolyl, benzothiazolyl , benzotriazolyl, benzodioxylolyl, indazolyl and benzofuryl. Preferred heteroaryls include quinolyl, isoquinolyl, naphthalenyl, benzofuranyl, benzothienyl, indolyl, pyridyl, pyrazinyl, thienyl, furyl, pyrrolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, pyrazolyl, triazolyl, thiadiazolyl and imidazolyl. The heteroaryl groups of the present invention may be substituted or unsubstituted.

Perhaloalkyl means an alkyl group having 1 to 6 carbon atoms in which three or more hydrogen atoms are replaced by halogen.

Phenyl, as used herein, means a 6-membered aromatic ring.

Halogen, as used herein, means chlorine, bromine, iodine and fluorine.

Unless otherwise stated, the substituents are unsubstituted and may include alkyl of 1 to 6 carbon atoms, cycloalkyl of 1 to 6 carbon atoms, heterocycloalkyl of 1 to 6 cells, perhaloalkyl of 1 to 6 carbon atoms, amino, azido, hydroxy, alkylamino , dialkylamino, aryl or heteroaryl.

The number of carbon atoms refers to the number of carbon atoms in the carbon backbone and does not include carbon atoms in substituents such as an alkyl or alkyloxy substituent.

When used in combination, unless otherwise stated, the definition applies to each individual part of the combination. For example, alkylcycloalkyl is an alkylcycloalkyl group in which the alkyl and cycloalkyl groups are described above.

Pharmaceutically acceptable salts are acid addition salts which may be formed from a compound of the above formula and a pharmaceutically acceptable acid such as phosphoric, sulfuric, hydrochloric, hydrobromic, citric, maleic, succinic, fumaric, acetic, lactic, nitric, sulfonic, p-toluenesulfonic, methanesulfonic and the like.

The compounds of the invention contain a chiral center providing various stereoisomeric forms of the compounds, such as racemic mixtures, as well as the individual optical isomers. In some preferred embodiments of the present invention, the compounds of the invention are substantially pure optical isomers. By substantially pure optical isomers is meant a composition comprising more than 75% of the desired isomer and may contain no more than 25% of the undesired isomer. In more preferred embodiments, the pure optical isomer contains more than 90% of the desired isomer. The individual isomers may be prepared directly or by asymmetric or stereospecific synthesis or by conventional resolution of optical isomers from a racemic mixture.

Compounds of the present invention can be prepared by those skilled in the art using the methods described below, employing readily available reagents and starting materials unless otherwise noted. The compounds of the invention are thus prepared according to the following schemes.

The novel compounds of the present invention are prepared according to the following schemes.

Referring to Methods 31 (2 and 3 above) and 34 (4 and 5 below), reacting the appropriately substituted amines 2, wherein R ₁ and R ₅ are as defined above, with the appropriately substituted isothiocyanates 3, wherein A and G j are described. from above, either in pure form or in a suitable solvent such as tetrahydrofuran, acetonitrile, ethyl acetate, dichloromethane or N, N-dimethylformamide, the desired thioureas 1 are obtained. Similarly, by reaction of appropriately substituted isothiocyanates 4 where R 1 -R ₅ and X are as defined above. said above with an appropriately substituted amine 5, wherein substituents A and G are as described above, in a conventional solvent such as those

First

the above thioureas are obtained

Methods 31 and 34

I?

SwCaW-'A ¹ ') - CTTO

Alternatively, appropriately substituted thioureas 1 as described in Methods 32 and 33 may be prepared by reacting anilines 2 and 5 wherein R 1 -R ₅ , A and G are as defined above in the presence of 1 molar equivalent of 1,1'-thiocarbonyldiimidazole in a suitable solvent such as dichloromethane and tetrahydrofuran or a mixture thereof or one molar equivalent of 1,1'-thiocarbonyl-di- (1,2,4) -triazole in a suitable solvent such as dichloromethane and tetrahydrofuran or a mixture thereof at room temperature.

In some cases, chemical modification of the final thioureas 1 is required. These methods, methods 35-39 are summarized below.

Thioureas 1 wherein at least one of R 1 -R 5 is 1-hydroxyethoxy or carboxymethoxy, A and G are as defined above and X is a bond may be prepared from the corresponding alkyl esters by alkaline hydrolysis with aqueous sodium or potassium hydroxide in a suitable solvent such as methanol , tetrahydrofuran or mixtures thereof at room temperature according to methods 35 and 36.

Thioureas 1 wherein at least one substituent of R 1 -R 5 is 1acyloxyethoxy or methanesulfonoxyethoxy, A and G are as defined above and X is a bond may be prepared from the corresponding 1-hydroxy derivative by acylation with suitable acylating agents such as benzoic chloride or acid chloride methanesulfonic acid in the presence of a suitable tertiary amine base such as triethylamine or diisopropylethylamine in a suitable solvent such as dichloromethane or the like at room temperature according to methods 37 and 38.

Thioureas 1 wherein at least one of R 1 -R 5 is 1-aminoethoxy, A and G are as defined above and X is a bond may be prepared from the corresponding 1-methanesulfonoxyethoxy derivative by reaction with a suitable secondary amine such as dimethylamine in a suitable solvent mixture such as is tetrahydrofuran and water or the like at room temperature according to Method 39.

Thioureas 1 wherein at least one of R 1 -R 5 is 1-aminoalkyl, A and G are as defined above and X is equal to a bond may be prepared from the corresponding 1-azidoalkyl derivative by reaction with tin tetrachloride in a suitable solvent such as methanol, ethanol or the like at room temperature according to Method 40.

The intermediate isothiocyanates 3 and 4 listed above in Methods 31 and 34 are prepared according to Method 41 (hereinafter) essentially according to the procedures described by Staab, H. A. and Walther, G. Justus Liebigs Ann. Chem. 657, 104 (1962)] by the reaction of suitably substituted amines 5 or 2, wherein R 1 -R 5, A and G are as described above and X is as defined above, with one molar equivalent of 1,1'-thiocarbonyldiimidazole in a suitable solvent such as dichloromethane and tetrahydrofuran or mixtures thereof.

Method 41 «2

A-X-NM?

----- A - X-

Intermediates 2 and 5 can be prepared according to the following protocols:

According to Methods 1A-1G, amines 2 wherein R 1 -R 5 are as defined above and X is defined as above and amines 5 wherein A is as defined above may be prepared by reduction of appropriately substituted nitrobenzenes according to a variety of procedures known to those skilled in the art and described by RJ. Lindsay, Comprehensive Orqanic Chemistry (ed. Sutherland), Volume 2, Chapter 6.3.1, Aromatic Amines, 1979. Such procedures include the reduction of nitrobenzenes to form anilines upon exposure to:

(a) iron powder and a strong acid, such as hydrochloric acid (method ΙΑ), either neat or in an alcoholic solvent, such as methanol or ethanol, at a temperature ranging from room temperature to the reflux temperature of the solvent, or;

(b) iron powder and glacial acetic acid (Method 1B), either pure or in an alcoholic solvent such as methanol or ethanol, at a temperature ranging from room temperature to the reflux temperature of the solvent, or;

(c) iron powder and aqueous ammonium chloride (Method 1C) either neat or in an alcoholic solvent such as methanol or ethanol at a temperature ranging from room temperature to the reflux temperature of the solvent, or;

(d) tin and a strong acid, such as hydrochloric acid (method ID), either pure or in an alcoholic solvent, such as methanol or ethanol, at a temperature ranging from room temperature to the reflux temperature of the solvent, or;

e) when R 1 -R 5 and substituent A are selected from Cl, Br, I, - (OSC 2) -CF ₃ or - (OSO ₂ ) -1- (4-methylphenyl), by catalytic reduction, with hydrogen and palladium on coal (Method IE) in a suitable solvent such as methanol, ethanol or ethyl acetate under one or more atmospheres pressure or;

f) when R 1 -R 5 and R 9 -R 12 are selected from Cl, Br, I, - (OSO ₂ ) -CF ₃ or - (OSO ₂ ) -1- (4-methylphenyl), by catalytic reduction, with cyclohexene and palladium on carbon (Method 1F) in a suitable solvent such as methanol or ethanol at a temperature ranging from room temperature to the reflux temperature of the solvent, or;

g) aqueous sodium bisulfite in an alcoholic solvent at a temperature ranging from room temperature to the reflux temperature of the solvent (IG method).

Alternatively, according to methods 3A-3C, amines 2 wherein R 1 -R 5 are as defined above and X is as defined above and anilines 5, where A is as defined above, may be prepared by cleaving the aniline nitrogen-carbon bond of the amide and carbamate derivatives of these anilines according to a variety of procedures known to those skilled in the art and described by Greene, Protective Groups in Organic Synthesis, Volume 2, Chapter 7, 1991, and references cited therein. Such procedures include:

(a) exposure of appropriately substituted arylamino-tert-butylcarbamates to a strong acid, such as trifluoroacetic acid (Method 3A), either neat or in a suitable solvent, such as dichloromethane, at a temperature between 0 ° C and room temperature;

b) exposing the appropriately substituted arylamino- (2-trimethylsilylethyl) carbamates to a fluoride ion source such as tetrabutylammonium fluoride or potassium fluoride (Method 3B) in aqueous acetonitrile or tetrahydrofuran or a mixture thereof from room temperature to the reflux temperature of the solvent, or;

c) subjecting the respective substituted arylaminotrifluoroacetamides to a strong base such as sodium hydroxide or potassium hydroxide or sodium or potassium carbonate in an alcohol solvent such as methanol or ethanol (Method 3C) at a temperature ranging from room temperature to the reflux temperature of the solvent.

Alternatively, according to Method 11, amines 2 wherein R 1 -R 5 are as defined above and X is a bond wherein at least one of R 1 -R 5 is defined as vinyl may be prepared by palladium catalyzed coupling of a vinyltrialkyltin reagent such as tributylvinyl tin with respectively substituted bromo or iodoanilene, for example 3-chloro-4-iodoaniline, using a palladium catalyst such as tris (dibenzylideneacetone) bipalladium and a ligand such as triphenylarzine in a suitable solvent such as tetrahydrofuran or N-methylpyrrolidinone at temperatures ranging from temperature room temperature to the reflux temperature of the solvent, essentially according to the procedures described by V. Farin and GP Roth in Advances in Metal-Organic Chemistry, vol. 5, 1-53, 1996 and references cited therein.

Alternatively, according to Method 42 and amines 2, wherein R 1 -R 5 are as defined above and X is as defined above and at least one of R ₂ or R ₄ is defined as dialkylamino, may be prepared by palladium catalyzed amination of an appropriately substituted 3- or 5-bromo - or iodoaniline, for example 3 amino-5-bromobenzotrifluoride, by secondary amines under conditions using a palladium catalyst such as bis (dibenzylideneacetone) palladium and a ligand such as tri-o-tolylphosphine and at least two molar equivalents of a strong base such as lithium bis (trimethylsilyl) amide in a sealed tube, in a suitable solvent such as tetrahydrofuran or toluene, at temperatures ranging from room temperature to 100 ° C, essentially according to the procedures described by JF Hartwik and J. Louie Tetrahedron Letters 36 (21) , 3609 (1995).

. Alternatively, according to Method 43, amines 2 wherein R 1 -R 5 are as defined above and X is as defined above and at least one of R ₂ or R ₄ is defined as alkyl may be prepared by palladium catalyzed alkylation of an appropriately substituted 3 or 5-bromo- or iodoaniline, for example

3-amino-5-bromobenzotrifluoride with alkenes under conditions using a palladium catalyst such as [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) chloride-dichloromethane complex and in the presence of 9-borabicyclo [3.3.1] nonane and a suitable base such as aqueous sodium hydroxide in a suitable solvent such as tetrahydrofuran or the like at temperatures ranging from room temperature to the reflux temperature of the solvent.

Acyl and carbamoylamine derivatives used as starting materials in Methods 3A-3C can be prepared by derivatizing the corresponding amines as described in Methods 2A-2G according to various procedures known to those skilled in the art and as described by Greene in Protective Groups in Organic Synthesis, Volume 2, Chapter 7, 1991 and references cited herein. Such procedures include:

a) reacting an appropriately substituted amine with di-tert-butyl dicarbonate (Method A) in the presence or absence of one or more molar equivalents of a tertiary amine such as triethylamine or N, Ndiisopropylethylamine in a suitable solvent such as acetone, tetrahydrofuran, dimethylformamide, dichloromethane and the like at temperatures ranging from room temperature to the reflux temperature of the solvent to give the corresponding arylamino tert-butyl carbamate, or;

b) reacting an appropriately substituted aniline with 1- [2- (trimethylsilyl) ethoxycarbonyloxy] benzotriazole (Method 2B) in the presence of a tertiary amine such as triethylamine or diisopropylethylamine in a suitable solvent such as dimethylformamide at room temperature to give the corresponding arylaminoethyl (2) carbamate, or;

c) reacting an appropriately substituted aniline with a carboxylic acid chloride or anhydride (Method 2C) either in a pure state or in a suitable solvent such as tetrahydrofuran, dimethylformamide, dichloromethane, pyridine and the like in the presence of one or more molar equivalents of a tertiary amine base triethylamine or N, Ndiisopropylethylamine, to form the corresponding arylaminoamide, or;

d) reacting an appropriately substituted nitroaniline with a carboxylic acid chloride (2D method) in the presence of one or more molar equivalents of a tertiary amine base, such as triethylamine or N, N-diisopropylethylamine, either neat or in a suitable solvent such as tetrahydrofuran; 4-dioxane and the like, at temperatures ranging from room temperature to the reflux temperature of the solvent to give the corresponding nitroarylaminoamide; or

e) reacting the appropriately substituted aniline with a carboxylic acid (method 2E) in the presence of a coupling agent such as benzotriazol-1-yloxy tris (dimethylamino) phosphonium hexafluorophosphate, 2- (1H-benzotriazol-1yloxy) -1,1,3,3-tetramethyluronium phosphate , dicyclohexylcarbodiimide and the like, in the presence of a tertiary amine such as triethylamine or diisopropylethylamine, in a suitable solvent such as dichloromethane, dimethylformamide and the like, at room temperature, to give the corresponding arylaminoamide, or;

f) reacting an appropriately protected aniline, such as arylaminoterbutylcarbamate or the like, wherein at least one R 5 and A substituent is defined as -WY- (CH ₂ ) _n Z, wherein W, Y and Z are as defined above, with anhydride carboxylic acid (Method 2F) in the presence of a suitable base such as pyridine in a suitable solvent such as dichloromethane, dimethylformamide or the like at temperatures ranging from 0 ° C to room temperature to form the corresponding carboxylic acid ester; the sky;

g) reacting an appropriately substituted aniline in which at least one of the substituents R 1 -R 5 is defined as hydroxyl with di-tert-butyl dicarbonate (Method 2G) in the presence of one or more molar equivalents of tert-amine such as triethylamine;

N, N-diisopropylethylamine in a suitable solvent, such as acetone, tetrahydrofuran, dimethylformamide, dichloromethane and the like, at temperatures ranging from room temperature to the reflux temperature of the solvent, to give the corresponding arylaminoterbutylcarbamate.

Nitrobenzene intermediates which are finally converted to amines 2 and 5 by the methods outlined in Methods 1A-1G can be prepared according to Methods 4A, 4C, 4E-4F.

Referring to Methods 4A, 4C, and 4E-4H, nitrobenzene intermediates that are ultimately converted to amines 2, R2 and R4 are as defined above and R1, R3 and / or R5 are defined as alkoxy, thioalkoxy, alkylsulfenyl, alkylsulfinyl, and alkyl. dialkylamino can be prepared by nucleophilic displacement of appropriately substituted 2-, 4, and / or 6-fluoro-, chloro, bromo, iodo, trifluoromethylsulfonyloxy or (4-methylphenyl) sulfonyl-substituted nitrobenzenes, by methods including:

(a) reaction of alcohols with appropriately substituted 2- or 4-halo or sulphonate esters of nitrobenzenes or benzonitriles (Method 4A) either in pure form or in a suitable solvent such as tetrahydrofuran, dioxane, acetonitrile, N, N-dimethylformamide or dimethylsulphoxide in the presence or absence one or more molar equivalents of a base, such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride or the like, at temperatures ranging from room temperature to the reflux temperature of the solvent;

(b) reacting pre-treated sodium, lithium or potassium phenoxides with the appropriately substituted 2- or 4-halo- or sulphonate esters of nitrobenzenes or benzonitriles (Method 4H) either in pure form or in a suitable solvent such as tetrahydrofuran, dioxane, acetonitrile, N, N-dimethylformamide or dimethylsulfoxide at temperatures ranging from room temperature to the reflux temperature of the solvent, or;

(c) reaction of ammonia, primary or secondary amines with the appropriately substituted 2- or 4-halo- or sulphonate esters of nitrobenzenes or benzonitriles (methods 4C, F) either in pure form or in a suitable solvent such as tetrahydrofuran, dioxane, acetonitrile, N N-dimethylformamide or dimethylsulfoxide at temperatures ranging from room temperature to the reflux temperature of the solvent, or;

d) reacting the pre-treated sodium, lithium or potassium salts of amines with the appropriately substituted 2- or 4-halo- or sulfonate esters of nitrobenzenes or benzonitriles (Method 4G) in a suitable solvent such as tetrahydrofuran at temperatures ranging from 0 ° C to temperature solvent reflux; or;

e) reacting sodium sulphide with the appropriately substituted 2- or 4-halo- or sulphonate esters of nitrobenzenes or benzonitriles either in pure form or in a suitable solvent such as tetrahydrofuran, dioxane, acetonitrile, N, N-dimethylformamide or dimethylsulfoxide at temperatures ranging from room temperature to the reflux temperature of the solvent, and then adding the alkyl halide directly to the reaction mixture (Method 4E).

Alternatively, with reference to Methods 5C and 6, nitrobenzene intermediates that are ultimately converted to amines 2, wherein at least one of R 1 -R ₅ is defined as alkoxy, can be prepared from the corresponding substituted hydroxynitrobenzenes by methods including:

(a) reaction of hydroxynitrobenzene with an alkyl halide or dialkyl sulfonate ester (Method 5C) in the presence of a base such as potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium hydride or sodium hydride in a suitable solvent such as acetone, N, N-dimethylformamide; tetrahydrofuran or dimethylsulfoxide, at a temperature ranging from room temperature to the reflux temperature of the solvent, or;

b) reacting hydroxynitrobenzene with an alkyl alcohol, triphenylphosphine and a dialkyl azadicarboxylate reagent (method 6), such as diethyl azodicarboxylate, in an anhydrous aprotic solvent such as diethyl ether or tetrahydrofuran at temperatures ranging from 0 ° C to the reflux temperature of the method; which is described by Mitsunobu, 0, Synthesis, 1981, 1 and references cited therein.

Further, with reference to Methods 5A and 5E, carbamoyl amine derivatives used as starting materials in Methods 3A-3C that are ultimately converted to amines 2, wherein at least one of R 1 -R 5 is defined as alkoxy, may be prepared from of a corresponding substituted hydroxyarylamino tert-butylcarbamate by reaction with alkyl halides, trifluoromethanesulfonates, 4-methylbenzenesulfonates, dialkylsulfonates, ethylene carbonates, and the like, in the presence of a suitable base such as potassium carbonate, in a suitable solvent such as acetone, toluene, from room temperature to the reflux temperature of the solvent.

Alternatively, referring to Methods 7A-G, the nitrobenzene intermediates which are ultimately converted into amines 2, R _x, and / or R3 is alkoxy, and R 2 and / or R ₄ is halogen, and X equals a bond, may be prepared by standard halogenation reactions , which include the following:

a) reacting 2- or 4-hydroxynitrobenzene with aqueous hypochlorite. sodium (methods 7A and 7B) at room temperature or;

b) reacting 2-hydroxy-4-methoxy or 2,4-dimethoxynitrobenzene (methods 7C and 7D) with bromine in a suitable solvent such as chloroform, dichloromethane, glacial acetic acid or the like in the presence or absence of silver trifluoroacetate at room temperature; ;

c) reacting 2,4-dimethoxynitrobenzene (Method 7E) with benzyltrimethylammonium dichloroiodate in the presence of anhydrous zinc chloride in a suitable solvent such as glacial acetic acid at room temperature or;

d) reacting 2-hydroxy-4-methoxynitrobenzene (Method 7F) with benzyltrimethylammonium dichloroiodate in the presence of sodium bicarbonate in a suitable solvent mixture such as dichloromethane and methanol at room temperature or;

e) reacting 2,4-dimethoxynitrobenzene (Method 7G) with 3,5-dichloro-1-fluoropyridine triflate in a suitable solvent such as carbon tetrachloride at a temperature ranging from room temperature to the reflux temperature of the solvent.

Referring to Method 8, nitrobenzene intermediates that are ultimately converted to amines 2, where R ₄ = -CF ₃ and R 1 -R ₃ and R 5 -R _e are as defined above and X represents a bond, can be prepared from the corresponding substituted 4 iodonitrobenzenes by reaction with trimethyl (trifluoromethyl) silane in the presence of copper (I) iodide and potassium fluoride, in a suitable solvent such as N, boiling tulle formamide or the like, at a temperature from room temperature to the reflux temperature of the solvent in the sealed reaction vessel.

Referring to Methods 19A and 19B, nitrobenzene intermediates that are ultimately converted to amines 2 where R 4 = HNCOCH ₂ NR 7 R 8 or -HNCOCH ₂ SR ₆ , and R 1 -R ₃ and R ₅ -R ₀ are as defined above and X is the bond, may be prepared from the corresponding substituted 4- (N-chloroacetyl) nitroaniline by reaction with either a suitable secondary amine such as dimethylamine, morpholine or the like in a suitable solvent such as tetrahydrofuran and / or water at temperatures ranging from room temperature to temperature solvent reflux or by reaction of a suitable thiol in the presence of a suitable base such as sodium carbonate or potassium carbonate or the like in a suitable solvent such as tetrahydrofuran, 1,4-dioxane or the like at a temperature ranging from room temperature to the reflux temperature of the solvent.

Referring to Method 25, nitrobenzene intermediates that are ultimately converted to amines 2, wherein at least one of R 1 -R 5 is defined as triflate and X is a bond, can be prepared from the corresponding phenol by reaction with trifluoromethanesulonic anhydride in the presence of tertiary amines such as is triethylamine or diisopropylethylamine or the like in a suitable solvent such as dichloromethane at a temperature from 0 ° C to room temperature.

Referring to Methods 9, 9B and 10, carbamoylamine derivatives used as starting materials in Methods 3A-3C, which are ultimately converted to amines 2, wherein at least one R 1 -R 5 substituent is defined as either alkylsulfenyl or alkylsulfinyl may be prepared by reaction of a suitable 4. an alkylthioacylarylamino or carbamoylarylamine derivative with a suitable oxidizing agent such as dimethyloxirane or sodium periodate in a suitable solvent mixture such as acetone and dichloromethane or water at room temperature.

Referring to Method 12, carbamoylamine derivatives used as starting materials in Methods 3A-3C that are ultimately converted to amines 2, wherein R ₄ is defined as 1-hydroxyethyl and R 1 -R 3 and R 5 are as defined above and X is a bond, may be prepared by reacting the corresponding 4-vinylcarbamoylaniline with sodium borohydride in the presence of mercuric acetate in a suitable solvent such as tetrahydrofuran, 1,4-dioxane or the like and water at room temperature.

Referring to Method 13, carbamoylamine derivatives used as starting materials in Methods 3A-3C, which are ultimately converted to amines 2, where R ₄ is defined as 2-hydroxyethyl and R 1 -R 3 and R 5 are as defined above and X is a bond, can be prepared by reacting the corresponding 4-vinylcarbamoylaniline with sodium borohydride in the presence of glacial acetic acid in a suitable solvent such as tetrahydrofuran, 1,4-dioxane or the like and water at a temperature of 0 ° C to room temperature.

Referring to Method 14, carbamoylamine derivatives used as starting materials in Methods 3A-3C, which are ultimately converted to amines 2, wherein R ₄ is defined as 1-azidoethyl and R 1 -R 3 and R 5 are as defined above and X is as defined above from above, they can be prepared by reacting the corresponding 4- (1-hydroxyethyl) carbamoylaniline with hydrazonic acid in the presence of a dialkyl azodicarboxylate such as diethyl azodicarboxylate and triphenylphosphine in a suitable solvent mixture such as tetrahydrofuran and dichloromethane at a temperature ranging from 0 ° C to room temperature.

Referring to Method 15, carbamoylamine derivatives used as starting materials in Methods 3A-3C, which are ultimately converted to amines 2, wherein R ₄ is defined as 3-dimethylaminoprop-linyl and R 1 -R 3 and R ₅ are as defined above and X as defined above, may be prepared by reacting the corresponding 4-iodocarbamoylaniline with 1-dimethylamino-2-propyne in a suitable tertiary amine solvent such as triethylamine or diisopropylethylamine in the presence of bis (triphenylphosphine) palladium (II) chloride and cuprous iodide at temperatures ranging from of room temperature to the reflux temperature of the solvent.

Referring to Method 16, carbamoylamine derivatives used as starting materials in Methods 3A-3C, which are ultimately converted to amines 2, wherein R ₄ is defined as 3dimethylaminoacryloyl and R 1 -R 3 and R 5 are as defined above and X is a bond, can be prepared by reacting the corresponding 4- (326 dimethylaminoprop-1-ynyl) carbamoylaniline with a suitable peracid such as 3-chloroperoxybenzoic acid in a suitable solvent mixture such as dichloromethane and methanol at a temperature ranging from 0 ° C to room temperature.

Referring to Methods 17 and 18, carbamoylamine derivatives used as starting materials in Methods 3A-3C, which are ultimately converted to amines 2, wherein R ₄ is defined as either 4-isoxazol-5-yl or 4- (1H-pyrazole-3- yl) and R 1 -R 3 and R ₅ are as defined above and X is a bond, may be prepared by reacting the corresponding 4- (3-dimethylaminoacryloyl) carbamoylaniline with either hydroxylamine hydrochloride or hydrazine hydrate in a suitable solvent such as 1,4-dioxane or ethanol and the like at room temperature.

Referring to Method 20, carbamoylamine derivatives used as starting materials in Methods 3A-3C, which are ultimately converted to amines 2, where R ₄ = -HNCO 2 Z and R 1 -R 3, and R 5 and Z are as defined above and X is a bond, may be prepared by reacting the corresponding 4-aminocarbamoylaniline with 1,1-carbonyldi- (1,2,4) triazole and an appropriately substituted alcohol in a suitable solvent mixture such as tetrahydrofuran and dichloromethane and the like at a temperature ranging from room temperature to reflux temperature solvent.

Referring to Methods 26 and 30, carbamoylamine derivatives used as starting materials in Methods 3A-3C, which are ultimately converted to amines 2, wherein at least one of R 1 -R 5 is defined as dialkylamino and X is as defined above may be prepared by reaction appropriately substituted aldehydes in the presence of either sodium cyanoborohydride or hydrogen and 10% palladium on carbon in a suitable solvent such as water, methanol, tetrahydrofuran mixture or toluene or the like at room temperature.

Referring to Methods 27 and 28, amines 2 wherein at least one of R 1 -R 5 is defined as hydroxy and X is as defined above may be prepared by reacting a corresponding ester, such as acetate, with a suitable base such as sodium bicarbonate or sodium hydroxide in a suitable solvent mixture such as a mixture of methanol and water at a temperature ranging from room temperature to the reflux temperature of the solvent.

Referring to Method 29, amines 2 wherein at least one of R 1 -R 5 is defined as 2-hydroxybenzamido and X is as defined above may be prepared by reacting the corresponding N- (4-aminophenyl) phthalimide with lithium borohydride in a suitable solvent such as tetrahydrofuran , diethyl ether or the like, at room temperature.

Intermediate amines 2 wherein R 1 -R 5 are as defined above and X is either -CH ₂ - or - (CH ₂ ) 2 - can be prepared by the following procedures:

a) reduction of the appropriately substituted benzo- or phenylacetonitrile with borane-dimethylsulfide complex in a suitable solvent, such as ethylene glycol dimethyl ether, tetrahydrofuran or the like, at temperatures ranging from room temperature to the reflux temperature of the solvent (method 44).

(b) reduction under a hydrogen atmosphere at a pressure of 100 psi or more, in the presence of a suitable catalyst, such as 5%; 10% palladium on carbon and acid, such as 4-methylbenzenesulfonic acid, hydrochloric acid or the like, in a suitable solvent such as ethylene glycol monomethyl ether, ethyl acetate, ethanol or the like, at room temperature (method 50).

c) reduction with lithium aluminum hydride in a suitable solvent such as tetrahydrofuran or diethyl ether at temperatures ranging from 0 ° C to room temperature (method 51).

Unsaturated nitro precursors which are used as starting materials in Method 51 and which are ultimately converted to amines 2, where R 1 -R 5 are as defined above and X is equal to - (CH ₂ ) ₂ ^- can be prepared by reacting an appropriately substituted benzaldehyde with nitromethane in the presence of ammonium acetate in a suitable solvent such as acetic acid at a temperature ranging from room temperature to the reflux temperature of the solvent (Method 53). The benzaldehydes used as starting materials in Method 53 can be prepared by reduction of an appropriately substituted benzonitrile with diisobutylaluminum hydride (Method 52).

The substituted benzonitriles used as starting materials in Method 52 can be prepared from the corresponding aryl bromide by reaction with copper cyanide in a suitable solvent, such as N, N-dimethylformamide, at a temperature ranging from room temperature to the reflux temperature of the solvent (method 59).

For amines 2 wherein R 1 -R 5 are as defined above and X is either 0 (CH ₂ ) ₂ NH ₂ or -S (CH ₂ ) ₂ -NH ₂ , the desired nitrile precursors can be prepared by reacting a suitably substituted phenol or thiophenol with bromoacetonitrile in the presence of a suitable base such as potassium carbonate in a suitable solvent such as acetone at room temperature according to Method 49.

Alternatively, for amines 2 wherein R 1 -R 5 are as defined above and X is equal to - (CH ₂ ) 3 - the nitrile precursors can be prepared essentially according to the method described by Wilk, B. Synthetic Comm. 23, 2481 (1993), by reacting an appropriately substituted phenethanol with acetone cyanohydride and triphenylphosphine in the presence of a suitable azodicarboxylate such as diethyl azodicarboxylate in a suitable solvent such as diethyl ether or tetrahydrofuran or the like at temperatures ranging from 0 ° C to room temperature (method 54) .

Alternatively, intermediate amines 2 wherein R 1 -R 5 are as defined above and X is equal to - (CH (CH ₃ )) - may be prepared by acid or base catalyzed hydrolysis of the corresponding formamide using a suitable acid catalyst such as 6N hydrochloric acid or a suitable basic acid. a catalyst such as 5N sodium or potassium hydroxide in a suitable solvent mixture such as water and methanol or water and ethanol at temperatures ranging from room temperature to the reflux temperature of the solvent (method 46).

Formamide precursors used as starting materials in Method 46 and subsequently converted to amines 2 are prepared according to Method 45 by treating suitably substituted acetophenone with ammonium formate, formic acid and formamide, at temperatures ranging from room temperature to reflux. solvent.

Alternatively, amines 2 wherein R 1 -R 5 are as defined above and X is equal to - (CH (CH ₃ )) - may be prepared by reduction of an appropriately substituted O-methyloxime in the presence of sodium borohydride and zirconium chloride in a suitable solvent such as tetrahydrofuran or diethyl ether at room temperature according to Method 48, essentially as described by Itsuno, S., Sakurai, Y., Ito, K. Synthesis 1988, 995. The desired O-methyloximes can be prepared from the corresponding acetophenone by reaction with methoxylamine hydrochloride and pyridine in a suitable solvent, such as ethanol or methanol, at temperatures ranging from room temperature to the reflux temperature of the solvent (method 47).

Amines 2 for which R 1 -R 5 are defined above and X is equal to -CH (J) -, where J is as defined above, can be prepared by reduction of an appropriately substituted ketone by the method described above (Methods 45, 47 and 48). These desired ketones, if not commercially available, can be prepared by reacting a suitably substituted benzaldehyde with a suitable organometallic reagent such as phenyllithium, isopropylmagnesium bromide or ethylmagnesium bromide or the like in a suitable solvent such as diethyl ether or tetrahydrofuran at temperatures ranging from -78 ° C. up to 0 ° C (method 57). The resulting alcohols may be oxidized to the corresponding ketone with a suitable oxidizing agent, such as chromium trioxide in aqueous sulfuric acid, and acetone or pyridinium chlorochromate or pyridium dichlorochromate in a suitable solvent such as dichloromethane or the like at room temperature (method 58).

Intermediate anilines 5 can be prepared as described above in Method 3A. Phenylcarbamic acid tert-butyl ester 6, where G is as defined above, is treated at room temperature with pure trifluoroacetic acid and then neutralized with aqueous sodium hydroxide to give the desired anilines 5. The desired carbamic acid esters 6, where A and G are as defined above. said above prepared according to Method 2C, by reacting a substituted acid chloride 8 wherein G is as defined above and tert-butyl esters of 4-aminophenylcarbamic acid 7 or the corresponding heteroaryl wherein A is as defined above in the presence of triethylamine in a suitable solvent such as dichloromethane , dimethylsulfoxide or dimethylformamide or mixtures thereof. The carboxylic acid chlorides 8 are either commercially available or are prepared from the corresponding carboxylic acid by reaction with oxalyl chloride in a suitable solvent such as dichloromethane at room temperature.

Method 3A, 2C

O-COOH

Alternatively, amines 5 can be prepared as described in Methods 1A-1G. Thus, treatment of 2-amino-5-nitropyridine 7 with heterocyclic acid chloride 8 or another activated derivative as described in Methods 2C-2E affords the nitroamide 6 wherein G is as defined above. Subsequent reduction as described in Methods 1A-1G affords amines 5.

Alternatively, carbamic acid esters 6, where A and G are as defined above, can be prepared as outlined in Method 2E, by reacting substituted carboxylic acids 8a, wherein G is as defined above and suitably substituted 4-aminophenylcarbamic acid tert-butyl ester 7 or the corresponding heteroaryl in the presence of a suitable coupling agent such as benzotriazol-1-yloxy-tris- (dimethylamino) -phosphonium hexafluorophosphate, 2- (ot-benzotriazol-1-yloxy) -1,1,3,3-tetramethyluronium hexafluorophosphate, dicyclohexylcarbonyl or dicyclohexyl in the presence of a tertiary amine base such as triethylamine or diisopropylethylamine in a suitable solvent such as dichloromethane, dimethylformamide and the like at room temperature to give the corresponding arylaminoamide.

The carboxylic acids 8a are either commercially available or are prepared according to methods described in the literature. For example, when G is a substituted thiadiazole, the acid is available from the corresponding carboxylic acid ester by reaction with a suitable base such as sodium hydroxide or potassium hydroxide in a suitable solvent mixture such as methanol or ethanol and water at room temperature.

Similarly, when G is either a substituted or unsubstituted thiazole, a substituted or unsubstituted oxazole, a substituted or unsubstituted isothiazole, or a substituted or unsubstituted isoxazole that is not commercially available, the corresponding carboxylic acid 8a is obtained from the corresponding ethyl or methyl ester by reaction with a suitable base such as sodium hydroxide or potassium hydroxide in a suitable solvent mixture such as methanol or ethanol and water at room temperature. These esters are either commercially available or can be prepared according to methods described in the literature.

If the carboxylic acid ester precursors which are then converted to acids 8a are not commercially available, they can be prepared according to methods known in the literature. For example, 5-substituted-1,2,3-thiadiazole-4-carboxylic acid esters can be prepared essentially according to the procedure described by Caron, M. J. Org. Chem. 51, 4075 (1986) and Taber, D. F., Ruckle, R. E. J. Amer. Chem. Soc. 108, 7686 (1986). Thus, according to Method 21, treating a beta-ketocarboxylic acid ester with 4-methylbenzenesulfonylazide or methanesulfonylazide or the like, in the presence of a tertiary amine base such as triethylamine or diisopropylethylamine in a suitable solvent such as acetonitrile gives the corresponding diazo-beta-ester ester. . Treatment of this compound with 2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphethane

2,4-disulfide in a suitable solvent such as benzene or toluene or the like at a temperature ranging from room temperature to the reflux temperature of the solvent yields the desired substituted-1,2,3-thiadiazole-4-carboxylic acid ester 5.

Alternatively, 4-substituted-1,2,3-thiadiazole-5-carboxylic acid esters can be prepared essentially according to the method described by Shafiee, A., Lalezari, I., Yazdani, S., Shahbazian, FM, Partovi, TJ. Pharmaceutical Sci. 65, 304 (1976). Thus, according to Methods 22 and 23, reacting a suitably substituted betaketocarboxylic acid ester in a suitable alcoholic solvent such as methanol or ethanol with an aqueous solution of semicarbazide hydrochloride at a temperature ranging from room temperature to the reflux temperature of the solvent in the presence of a suitable base such as pyridine. yields the corresponding semicarbazone derivative. Treatment of this compound with pure thionyl chloride at 0 ° C followed by treatment with an excess of aqueous sodium bicarbonate gives the corresponding 4-substituted-1,2,3-thiadiazole-5-carboxylic acid esters.

The 4-carboalkoxythiazoles are prepared essentially according to the procedure described by Schollkopf, U. Porsch, P., Lau, H.

Liebigs Ann. Chem. 1444 (1979). Thus, according to methods 55 and 56, reaction of ethyl isocyanate with N, N-dimethylformamide dimethylacetal in a suitable alcoholic solvent such as ethanol at room temperature affords the corresponding 3-dimethylamino-2-isocyanate-acrylic acid ethyl ester. A solution of this compound in a suitable solvent such as tetrahydrofuran is treated with hydrogen sulfide gas in the presence of a suitable tertiary base such as triethylamine or diisopropylethylamine or the like at room temperature to give the corresponding 4-carboethoxythiazole.

Other appropriately substituted thiazoles may be prepared essentially following the procedure described by Bredenkamp, M.V., Holzafel, C.W., van Zyl, W.J. Synthetic Comm. 20, 2235 (1990). Suitably unsaturated oxazoles are prepared essentially according to the procedure described by Henneke, K. H., Schollkopf, U.

Neudecker, T. Liebigs, Ann. Chem. 1979 (1979). Substituted oxazoles may be prepared according to the procedure described by Galeotti,

N., Montagne, C., Poncet, J., Jouin, P. Tetrahedron Lett. 33.

2807 (1992) and Shin, C., Okumura, K., Ito, A. Nakamura, Y.

Chemistry Lett. 1305 (1994).

The following examples are provided by way of illustration only and are not intended to limit the scope of the present invention in any way.

Examples

Example 1 (Method IA)

4-Methoxy-3-trifluoromethyl-phenylamine

A suspension of 4-methoxy-3-trifluoromethylnitrobenzene (2.2 g) and iron powder (1.68 g) in ethanol (35 mL) and water (15 mL) was treated with a solution of concentrated hydrochloric acid (0.42 mL) in ethanol (6 mL) and water (3 mL) and the mixture was heated to reflux for about 1 hour. The mixture was then cooled, filtered and concentrated under reduced pressure. The resulting oil was dissolved in ethyl acetate and extracted three times with 5% aqueous hydrochloric acid. The combined acid extracts are then cooled in an ice bath and basified with solid potassium carbonate, and then extracted with ethyl acetate. These organic extracts were washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure and then passed through a short silica gel column (ethyl acetate used as eluent) to give the title compound as an amber yellow oil.

The following compounds were prepared as described above, using appropriate starting materials:

2,6-Dichlorobenzene-l, 4-diamine

3-Chloro-4-metylsulfanylfenylamin

2,6-Dibromobenzene-1,4-diamine

3-Chloro-4-trifluoromethyl-phenylamine

3-Chloro-4-ethylsulfanylphenylamine ·

4-Methoxy-3-trifluoromethylphenylamine

3,5-Dichloro-4-methoxy-2-methylphenylamine

5-Chloro-2-ethoxy-4-methoxyphenylamine

5-Chloro-4-ethoxy-2-methoxy-phenylamino

5-Iodo-2,4-dimethoxy-phenylamino

3,5-Diodo-2,4-dimethoxyphenylamine

3,5-Dibromo-2,4-dimethoxyphenylamine

5-Chloro-2-methoxy-4-methylphenylamino

2-Chloro-N (1), N (1) -dimethylbenzene-1,4-diamine

3-Chloro-4-piperidin-1-yl-phenylamine

3-Chloro-4-pyrrolidin-l-yl-phenylamine

N (1) -benzyl-2-chlorobenzene-l, 4-diamine

3-Chloro-4- (4-methylpiperazin-l-yl) -phenylamine

2-Chloro-N (1) -methyl-N (1) - (l-methylpiperidin-4-yl) -benzene-1,4-diamine

2-Chloro-N (l) -methyl-N (1) - (l-methylpyrrolidin-3-yl) benzene-1,4-diamine

2-Chloro-N (1) -methyl-N (1) -fenylbenzén-1,4-diamine

N (1) - (l-benzyl-pyrrolidin-3-yl) -2-chloro-N (1) methylbenzene-1,4-diamine

2-Chloro-N (1) -cyclopentyl-N (1) -methylbenzene-1,4-diamine

2 - [(4-amino-2-chloro-phenyl) - (2-hydroxyethyl) -amino] -ethanol

2-Chloro-N (1) -hexyl-N (1) methylbenzene-1,4-diamine

2-Chloro-N (1) -isobutyl-N (1) methylbenzene-1,4-diamine

2 - [(4-amino-2-chloro-phenyl) -methyl-amino] -ethanol

2-Chloro-N (1) - (3-dimethylaminopropyl) -N- (1) methylbenzene-1,4-diamine

2-Chloro-N (1) - (2-dimethylamino-ethyl) -N (1) methylbenzene-1,4-diamine

2-Chloro-N (1) - (2-dimethylaminomethyl) benzene-1,4-diamine

N (1) - (1-Benzylpiperidin-4-yl) -2-chlorobenzene-1,4-diamine

2-Chloro-N (1) - (2-methoxyethyl) -N- (1) methylbenzene-1,4-diamine

2-Chloro-N (1) - (3-dimethylaminopropyl) benzene-1,4-diamine

N (1) - (1-Benzylpyrrolidin-3-yl) -2-chlorobenzene-1,4-diamine

3-Chloro-4- (1-methylpiperidin-4-yloxy) phenylamine

3-Chloro-4- (2-dimethylamino-ethoxy) -phenylamine

3-Chloro-4- (3-dimethylaminopropoxy) phenylamine 3-Chloro-4- (1-methylpyrrolidin-3-yloxy) phenylamine

3-Chloro-4-cyclohexyloxyphenylamine

Example 2 (Method IB)

4-Bromo-2,4-dimethoxyphenylamine

A suspension of 4-bromo-2,4-dimethoxynitrobenzene (0.48 g) and iron powder (0.42 g) in acetic acid (10 mL) and ethanol (10 mL) was heated at 120 ° C for about 5 hours. The mixture was then cooled, filtered and concentrated under reduced pressure. Water was added and the mixture was cooled in an ice bath and neutralized with solid potassium carbonate and then extracted with dichloromethane.

These organic extracts were washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then chromatographed on silica gel (using 20% ethyl acetate in hexanes as eluent) to give the title compound as an amber yellow oil.

Example 3 (Method 1C) (4-Amino-2,6-dichlorophenoxy) -acetic acid tert-butyl ester

A solution of (4-nitro-2,6-dichloro-phenoxy) -acetic acid tert-butyl ester (1 g) in ethanol (17 ml) and water (8.6 ml) was treated with iron powder (0.861 g) and ammonium chloride (86 ml). mg) and the mixture was heated to reflux for about 1 hour. The mixture was then filtered and concentrated under reduced pressure. The resulting oil was partitioned between water and ethyl acetate, and the organic phase was then washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a pale yellow oil.

The following compounds were prepared as described above, using appropriate starting materials:

4-chlorobenzene-l, 2-diamine

(4-Amino-2,6-dichloro-phenoxy) -acetamide (4-Amino-2,6-dichloro-phenoxy) -acetonitrile (2-Amino-4-chloro-5-tert-butyl ester) methoxyphenoxy) acetonitrile

(4-Amino-2-chloro-5-methoxyphenoxy) acetic acid methyl ester tert -Butyl (4-amino-2-chloro-5-methoxyphenoxy) acetic acid tert-butyl ester (2-Amino-4-chloro-5-methoxyphenoxy) acetic acid N (1) -Benzyl-4-chloro-5-methoxybenzene-1,2-diamine

N- (4-Amino-2-chloro-phenyl) -2-fluoro-benzamide

N- (4-amino-5-chloro-2-hydroxyphenyl) acetamide

Furan-2-carboxylic acid N- (4-amino-5-chloro-2-hydroxyphenyl) -2-fluorobenzamide (4-amino-2-chlorophenyl) amide

(4-Amino-2-chloro-phenyl) -carbamic acid ethyl ester

N- (4-amino-5-chloro-2-methylphenyl) acetamide

Furan-2-carboxylic acid N- (4-amino-5-chloro-2-methylphenyl) -2-fluorobenzamide (4-amino-5-chloro-2-methylphenyl) amide N- (4-amino-3-chlorophenyl) Furan-2-carboxylic acid -2-fluorobenzamide (4-Amino-3-chlorophenyl) amide

N- (4-Amino-2-chloro-phenyl) -2-dimethylamino-acetamide

N- (4-Amino-2-chloro-phenyl) -2-piperidin-l-yl-acetamide

N- (4-Amino-2-chloro-phenyl) -2-morpholin-4-yl-acetamide

N- (4-amino-2-chlorophenyl) methanesulfonamide

N- (4-amino-2-chlorophenyl) benzamide

N- (4-Amino-2-chloro-phenyl) -2-dietylaminoacetamid

N- (4-Amino-2-chloro-phenyl) -2-pyrrolidin-l-yl-acetamide

N- (4-Amino-2-chloro-phenyl) -2-azepan-l-yl-acetamide

N- (4-amino-2-chlorophenyl) -2- (2-methylpiperidin-l-yl) acetamide

N- (4-Amino-2-chlorophenyl) -2- (3-methylpiperidin-1-yl) acetamide 3-Chlorobenzene-1,2-diamine

4-Chloro-N, N-dimethylbenzene-1,2-diamine

Example 4 (ID method)

3,5-Dichloro-4-phenoxyphenylamine

To a slurry of 3,5-dichloro-4-phenoxynitrobenzene (6.1 g) and tin powder (12 g) was added dropwise concentrated hydrochloric acid (60 mL). Ethanol (60 mL) was added and the mixture was heated to reflux for about 1 hour. The mixture was then cooled in an ice bath and basified by addition of solid sodium hydroxide. The resulting suspension was filtered through a pad of diatomaceous earth and extracted three times with ethyl acetate.

The combined organic extracts were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the desired product as a yellow solid. Recrystallization from ethyl acetate / hexane gave the product as a pale yellow solid.

The following compounds were prepared as described above, using appropriate starting materials:

1-Furan-2-ylethylamine

3-Chloro-4-isopropoxyphenylamine

2-Butoxy-5-chloro-4-methoxyphenylamine

3,5-Dichloro-2-methoxy-4-methylphenylamine 2-Benzyloxy-5-chloro-4-methoxyphenylamine

4-Benzyloxy-5-chloro-2-methoxyphenylamine

5-Fluoro-2,4-dimethoxyphenylamine

(4-Amino-2,6-dichloro-phenoxy) -acetic acid ethyl ester

3,5-Dichloro-4-phenoxyphenylamine

2- (4-Amino-2-chloro-5-methoxyphenoxy) acetamide (4-Amino-2-chloro-5-methoxyphenoxy) acetonitrile

2- (2-amino-4-chloro-5-methoxy-phenoxy) -ethanol

2- (4-amino-2-chloro-5-methoxy-phenoxy) -ethanol

4- (4-Amino-2-chloro-5-methoxyphenoxy) butyronitrile

4-Amino-2-chloro-5-methoxyphenol

2-Amino-4-chloro-5-methoxyphenol

5-Chloro-4-methoxy-2-morpholin-4-yl-phenylamine

4-Chloro-5-methoxy-N (1), N (1) -dimethylbenzene-1,2-diamine

5-Chloro-4-methoxy-2-piperidin-1-yl-phenylamine

5-Chloro-4-methoxy-2-pyrrolidin-l-yl-phenylamine

2-Chloro-N (1) -cyclohexyl-N (1) methylbenzene-1,4-diamine

N (2) benzyl-4-methoxy-benzene-l, 2-diamine

2- (4-amino-2-chloro-phenoxy) -ethanol

2-Chloro-N (1) -cyclohexyl-N (1) -ethylbenzene-1,4-diamine

4-Butoxy-3-chlorophenylamine (4-Amino-2-chlorophenoxy) acetonitrile

2-Chloro-N (1) -cyklohexylbenzén-1,4-diamine

2-Chloro-N (1), N (1) -dipropylbenzene-1,4-diamine

3-Chloro-4- (2,2,2-trifluoroethoxy) phenylamine

3-Chloro-4- (octahydro-quinolin-l-yl) -phenylamine

N (1) -Allyl-2-chloro-N (1) -cyclohexylbenzane-1,4-diamine

Furan-2-carboxylic acid N- (4-amino-2-methoxy-5-methylphenyl) -2-fluorobenzamide (4-amino-2-methoxy-5-methylphenyl) amide

N- (4-Aminonaphthalen-1-yl) -2-fluorobenzamide

3-Chloro-N, N-dimethylbenzene-1,2-diamine

3-Chloro-4-propoxy-phenylamino

3-Iodo-4-methoxy-phenylamino

3-chloro-2,4-dimethoxyaniline

3-Bromo-4-methoxy-phenylamino

3-Chloro-4-ethoxy-phenylamine

Example 5 (IE method)

(4-Aminophenyl) carbamic acid isobutyl ester

To a solution of N- (4-Nitrophenyl) isobutyrylamide (2.0 g) in 100 mL of ethylene glycol monomethyl ether (100 mL) was added 10% palladium on carbon (275 mg). The mixture was hydrogenated for 2 hours at room temperature under 50 psi on a Parr hydrogenation apparatus. The catalyst was then removed by filtration through diatomaceous earth and the filtrate was evaporated to dryness under reduced pressure by azeotroping three times with heptane. Trituration of the residue with heptane gives the desired product as a white solid.

The following compounds were prepared as described above, using appropriate starting materials:

2-Methyl-3H-benzoimidazol-5-ylamine

1H-Benzoimidazol-5-ylamine N- (4-Aminophenyl) formamide N- (4-Aminophenyl) isobutyramide isobutyl ester

Furan-2-carboxylic acid N- (5-aminopyridin-2-yl) -2-methylbenzamide (5-aminopyridin-2-yl) amide

[6- (2,2,2-Trifluoro-acetylamino) -pyridin-3-yl] -carbamic acid N- (5-amino-pyridin-2-yl) -2-fluoro-benzamide

(4-Amino-benzyl) -carbamic acid N- (5-aminopyridin-2-yl) -2,2,2-trifluoroacetamide

2- (3,5-Bis-trifluoromethylphenyl) ethylamine

1-tert-Butyl-lH-imidazol-2-ylamine

3- (3-Dimethylaminopropyl) -5-trifluoromethylphenylamine

Example 6 (Method 1F)

N- (4-amino-2-methyl-phenyl) -2-fluoro-benzamide

A mixture of 2-fluoro-N- (2-methyl-4-nitrophenyl) benzamide (4.55 g), cyclohexane (30 mL), ethanol (70 mL), water (30 mL) and 10% palladium on charcoal (3). g) is heated to reflux for 30 minutes. The mixture was filtered through diatomaceous earth and concentrated under reduced pressure. The resulting oil was dissolved in 50 mL of ethyl acetate and cooled at 4 ° C for 12 hours. Filtration gave the product as a brownish solid.

The following compounds were prepared as described above, using appropriate starting materials:

N- (4-amino-2-methyl-phenyl) -acetamide

2-methyl-benzooxazol-6-ylamine

N- (4-amino-3-methoxy-phenyl) -acetamide

2-Acetylamino-5-aminobenzoic acid

[4- (3-Amino-benzoylamino) -phenyl] -carbamic acid tert-butyl ester [4- (2-Amino-benzoylamino) -phenyl] -carbamic acid N- (4-amino-phenyl) -acetamide

N- (4-amino-2-cyanophenyl) acetamide

Furan-2-carboxylic acid N- (4-amino-2,5-dimethoxyphenyl) -2-fluorobenzamide (4-amino-2,5-dimethoxyphenyl) amide

Furan-2-carboxylic acid N- (4-amino-2-cyanophenyl) -2-fluorobenzamide (4-amino-2-methoxyphenyl) amide

N- (4-amino-2-methoxyphenyl) -2-fluoro-benzamide

N- (4-Amino-2-methoxy-5-methylphenyl) acetamide

N- (4-amino-2-benzoylphenyl) acetamide

Furan-2-carboxylic acid N- (4-amino-2-benzoylphenyl) -2-fluorobenzamide (4-amino-2-benzoylphenyl) amide

N- (4-amino-3-methyl-phenyl) -acetamide

Furan-2-carboxylic acid N- (4-amino-3-methylphenyl) -2-fluorobenzamide (4-amino-3-methylphenyl) amide 5-Amino-2 - [(2-fluorobenzoyl) amino] -N-phenylbenzamide ( Furan-2-carboxylic acid 4-amino-2-phenylcarbamoyl-phenyl) -amide

Furan-2-carboxylic acid N- (4-amino-naphthalen-1-yl) -acetamide (4-amino-naphthalen-1-yl) -amide

Furan-2-carboxylic acid (4-amino-2-cyanophenyl) furan-2-carboxylic acid (4-amino-2-cyanophenyl) amide N- (4-Amino-4-amino-2-trifluoromethylphenyl) amide 5-Amino-2- (2-fluorobenzoylamino) benzoic acid (4-Amino-2-methylphenyl) furan-2-carboxylic acid -2-methylphenyl) 5-amino-2 - [(furan-2-) carbonyl) amino] benzoic acid N- (4-Amino-2-cyanophenyl) -2,2,2-trifluoroacetamide N- (4-Amino-3-methylphenyl) -2,6-difluorobenzamide N- (4-Amino-3 -trifluoromethylphenyl) acetamide N- (4-Amino-3-trifluoromethylphenyl) -2-fluorobenzamide N- (4-Amino-2-trifluoromethylphenyl) -2,2,2-trifluoroacetamide N- (4-Amino-2-methoxyphenyl) - 2,2-Trifluoroacetamide N- (4-Amino-2-trifluoromethylphenyl) -2-fluoro-N- (2-fluorobenzoyl) benzamide

N- (4-amino-2-trifluoromethyl-phenyl) -2-fluoro-benzamide

Example 7 (IG method)

N- (4-amino-2-chlorophenyl) -2-thiomorpholino-4-yl-acetamide

A solution of N- (2-chloro-4-nitrophenyl) -2-thiomorpholino-4-ylacetamide (3.02 g) in ethanol (200 mL) was added to a solution of sodium thiosulfate (12 g) in water (60 mL). The mixture was heated at reflux for 12 hours, cooled and poured into water. The mixture was then extracted with ethyl acetate. The ethyl acetate solution was washed twice with saturated aqueous sodium chloride, dried over anhydrous potassium carbonate, filtered through a pad of diatomaceous earth, concentrated under reduced pressure to give an oil. Toluene was added and the solution was cooled to give the desired product as a pale orange crystalline solid.

The following compounds were prepared as described above, using appropriate starting materials:

N- (4-Amino-2-chloro-phenyl) -2-thiomorpholin-4-ylacetam.id

N- (4-Amino-2-chloro-phenyl) -2-dipropylamino

Example 8 (Method 2A) (3-Chloro-4-iodo-phenyl) -carbamic acid tert-butyl ester

To a solution of 3-chloro-4-iodoaniline (10 g) in tetrahydrofuran (40 mL) containing diisopropylethylamine (6.9 mL) was added di-tert-butyl bicarbonate (8.6 g) and the mixture was heated to reflux. After about 15 hours, diisopropylethylamine (6.9 mL) and di-tert-butyl bicarbonate (21 g) were added portionwise and heating was continued for another 24 hours. The solution was then cooled, concentrated under reduced pressure, diluted with ethyl acetate, and washed three times successively with 5% aqueous hydrochloric acid and then once with saturated aqueous sodium chloride. The solution was dried over anhydrous sodium sulfate, then concentrated under reduced pressure to give the desired crude product as a brown oil. Crystallization is induced by the addition of hexanes, and the collected solid is recrystallized from hexanes to give the desired product as a white solid.

The following compounds were prepared as described above, using appropriate starting materials:

N '- (4-nitrobenzoyl) hydrazinecarboxylic acid tert-butyl ester tert -Butyl (3-chloro-4-iodophenyl) carbamic acid tert-butyl (4-bromo-3-chlorophenyl) carbamic acid tert-butyl ester (3-chloro-4) (3-Chloro-4-methylsulfanyl-phenyl) -carbamic acid tert-butyl (4-amino-3-chloro-phenyl) -carbamic acid tert-butyl (4-chloro-2-nitrophenyl) -carbamic acid tert-butyl ester (3-Bromo-5-trifluoromethyl-phenyl) -carbamic acid tert-butyl (4-nitrobenzyl) -carbamic acid tert-butyl (3-bromo-5-trifluoromethyl-phenyl) -carbamic acid tert-butyl (2-amino-3-chloro-5-trifluoromethyl-phenyl) -carbamate of

Example 9 (method 2B)

(3-Chloro-4-vinyl-phenyl) -carbamic acid 2-trimethylsilanylethyl ester

To a solution of 3-chloro-4-vinylphenylamine (3.4 g) in N, N-dimethylformamide (44 mL) containing diisopropylethylamine (5.8 mL) was added 1- [2- (trimethylsilyl) ethoxycarbonyloxy] benzotriazole (7 mL). , 1 g) and the mixture was stirred at room temperature under argon for three days. The solution was then diluted with water and extracted three times with diethyl ether. The combined organic extracts were washed successively with water, saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue is chromatographed on silica gel (10% ethyl acetate in hexanes is used as eluent) to give the desired product as a yellow oil.

Example 10 (Method 2C) [4- (2-Fluorobenzoylamino) phenyl] carbamic acid tert -butyl ester

To a solution of mono-N- (t-butoxycarbonyl) -1,4-phenylenediamine (1.58 g) and triethylamine (1.50 mL) in 25 mL of dichloromethane was added o-fluorobenzoyl chloride (1.20 g). Immediately a solid formed which was filtered and washed with fresh solvent to give a white solid, 1.90 g.

The following compounds were prepared as described above, using appropriate starting materials:

N- (3-methoxy-4-nitro-phenyl) -acetamide

N- (4-Amino-phenyl) -isobutyramide

[4- (2-Methyl-benzoylamino) -phenyl] -carbamic acid tert-butyl ester 2,2,2-Trifluoro-N- (2-methoxy-4-nitrophenyl) -acetamide

2- (4-tert-Butoxycarbonylaminophenylcarbamoyl) phenyl acetic acid tert-butyl [4- (4-fluorobenzoylamino) phenyl] carbamic acid tert-butyl [4- (3-fluorobenzoylamino) phenyl] carbamic acid tert-butyl ester [4- (2) [4- (2-Methoxybenzoylamino) phenyl] carbamate tert -Butyl ester [4- (3-methoxybenzoylamino) phenyl] carbamic acid tert-butyl [4- (4-methoxybenzoylamino) phenyl] carbamic acid-fluorobenzoylamino) phenyl] carbamate [4- (2,2-Dimethyl-propionylamino) -phenyl] -carbamic acid tert-butyl ester tert-Butyl [4- (2-bromoacetylamino) -phenyl] -carbamic acid tert-butyl [4- (2,2,2-trifluoroacetamino) -phenyl] -carbamic acid tert-butyl ester (4-Benzoylaminophenyl) carbamic acid tert-butyl ester (4-Methanesulfonylaminophenyl) carbamic acid tert-butyl (4-phenylacetylaminophenyl) carbamic acid tert-butyl {4 - [(thiophene-2-carbonyl) amino] phenyl] carbamic acid tert-butyl ester [4- (3-Nitrobenzoylamino) phenyl] tert-butyl ester (4- (3-Acetylaminobenzoylamino) phenyl) carbamic acid tert-butyl ester (4- (3-Methanesulfonylaminobenzoylamino) phenyl) carbamic acid tert-butyl ester

(4- (2-Trifluoromethylbenzoylamino) phenyl) carbamic acid tert-butyl ester [4- (2-trifluoromethylbenzoylamino) phenyl] carbamate tert -Butyl ester [4- [2 - [[4 - [[(1,1-dimethylethoxy) carbonyl] amino] phenyl] carbonyl] phenyl (2,6-difluorobenzoylamino) phenyl] carbamic acid

tert-butyl (4- (2-chlorobenzoylamino) phenyl) carbamic acid tert-butyl (4- (2-bromobenzoylamino) phenyl) carbamic acid tert-butyl (4- (2-nitrobenzoylamino) phenyl) carbamic acid tert-butyl {4 - [(benzo [b] thiophene-2-carbonyl) -

amino] phenyl} carbamic acid

tert-butyl of {4 - [(pyridin-4-carbonyl) -amino] -phenyl} -carbamic tert-butyl acid ester {4 - [(naphthalene-2-carbonyl) -amino] -phenyl} -carbamic tert-butyl acid ester {4 - [(naphthalen-carbonyl) amino] phenyl} carbamate tert-butyl {4 - [(3-bromothiophene-2-carbonyl) amino]

{4 - [(biphenyl-2-carbonyl) amino] phenyl} carbamic acid tert-butyl ester

N- (4-tert-Butoxycarbonylaminophenyl) phthalic acid

tert-butyl of [4- (2,3-difluorobenzoylamino) phenyl] carbamate tert-butyl of [4- (2,5-difluorobenzoylamino) phenyl] carbamate tert-butyl of [4- (2,4-difluorobenzoylamino) phenyl] carbamate tert-butyl of [4- (2-acetylaminobenzoylamino) phenyl] carbamate tert-butyl [4- (2-metánsulfonylaminobenzoylamino) -

phenyl] carbamic acid

tert-butyl of [4- (2,3,4-trifluórbenzoylamino) phenyl] carbamate

[4- (2,3,4,5,6-Pentafluorobenzoylamino) phenyl] carbamic acid tert-butyl ester

N- (4-tert-butoxycarbonylaminophenyl) isophthalic acid methyl ester

2-Methylsulfanyl-N- [4- (2,2,2-trifluoroacetylamino) phenyl] benzamide [4- (3-benzyloxybenzoylamino) phenyl] carbamic acid tert-butyl [4- (3-butoxybenzoylamino) phenyl] carbamate {4 - [(5-Difluoromethylfuran-2-carbonyl) amino] phenyl} carbamic acid tert-butyl ester {4 - [(thiophene-3-carbonyl) amino] phenyl} tert -Butyl ester {4 - [(5 {4 - [(5-Bromo-furan-2-carbonyl) -amino] -phenyl} -carbamic acid tert-butyl (4-hexanoylaminophenyl) -carbamic acid tert-butyl ester [4-methylfuran-2-carbonyl) amino] phenyl} carbamate [4 - (2-Thiophen-2-ylacetylamino) phenyl] carbamic acid tert-butyl {4 - [(pyridine-3-carbonyl) amino] phenyl} carbamic acid tert-butyl {4 - [(4-bromofuran-2-carbonyl)] amino] phenyl} carbamic acid tert-butyl {4 - [(furan-3-carbonyl) amino] phenyl} carbamic acid tert-butyl (4-phenoxycarbonylaminophenyl) carbamic acid tert-butyl {4 - [(benzo [1,3]] dioxo-9-carboxylate onyl) amino] phenyl} carbamic acid tert-butyl [4- (3-trifluoromethoxybenzoylamino) phenyl] carbamic acid tert-butyl ester

N- (2,5-Dimethoxy-4-nitrophenyl) -2-fluorobenzamide {4 - [(furan-2-carbonyl) amino] phenyl} carbamic acid tert-butyl ester [4- (2-phenoxyacetylamino) phenyl] {4 - [(5-Nitrofuran-2-carbonyl) amino] phenyl} carbamic acid tert-butyl {4 - [(5-chlorofuran-2-carbonyl) amino] phenyl} carbamic acid tert-butyl ester { 4 - [(3-Methylfuran-2-carbonyl) amino] phenyl} 48 [4- (2-methoxyacetylamino) phenyl] carbamic acid tert-butyl ester {4 - [(4-furan-3-yl- [1,2,3] Thiadiazole-5-carbonyl) amino] phenyl} carbamic acid tert-butyl {4 - [(5-tert-butylfuran-2-carbonyl) amino] phenyl} carbamic acid tert-butyl ester

Furan-2-carboxylic acid N- [3-cyano-4- (2,2,2-trifluoroacetylamino) phenyl] -2-fluorobenzamide [3-Cyano-4- (2,2,2-trifluoroacetylamino) phenyl] amide

N- (4-amino-2-cyanophenyl) -2,2,2-trifluoroacetamide

2.2.2-Trifluoro-N- (4-nitro-2-trifluoromethylphenyl) acetamide

N- (4-Acetylamino-2-trifluoromethylphenyl) -2,2,2-trifluoroacetamide

Furan-2-carboxylic acid 2-fluoro-N- [4- (2,2,2-trifluoroacetylamino) -3-trifluoromethylphenyl] benzamide [4- (2,2,2-Trifluoroacetylamino) -3-trifluoromethylphenyl] amide

2-Fluoro-N- (2-methyl-benzooxazol-6-yl) -benzamide

4- (2-Fluorobenzoylamino) -2-hydroxybenzoic acid tert-butyl {4 - [(isoxazole-5-carbonyl) amino] phenyl} carbamic acid tert-butyl ester

N- (4-Acetylamino-2-methoxyphenyl) -2,2,2-trifluoroacetamide

2-Fluoro-N- [3-methoxy-4- (2,2,2-trifluoro-acetylamino) -phenyl] -benzamide

{4 - [(1H-pyrazole-4-carbonyl) amino] phenyl} carbamic acid tert-butyl ester 2-fluoro-N- (2-fluorobenzoyl) -N- (4-nitro-2-trifluoromethylphenyl) benzamide 4 - [(1H-imidazole-4-carbonyl) amino] phenyl} carbamic acid tert-butyl {4 - [(5-methyl- [1,2,3] thiadiazole-4-carbonyl) amino) phenyl} carbamic acid tert-butyl ester {4 - [(5-Furan-3-yl- [1,2,3] thiadiazole-4-carbonyl) amino] phenyl} carbamic acid butyl ester

2.2.2- {4 - [(1-Methyl-1H-pyrazole-4-carbonyl) amino] phenyl} carbamic acid tert-butyl ester, trifluoro-N- (5-nitropyridin-2-yl) acetamide

4- (2-Fluorobenzoylamino) -2-hydroxybenzoic acid methyl ester

Isoxazole-5-carboxylic acid N- (5-chloro-2,4-dimethoxyphenyl) oxalamic acid (4-aminophenyl) amide

2-Fluoro-N- (4-nitro-benzyl) -benzamide

Furan-2-carboxylic acid 4-nitrobenzylamide

N- [3-chloro-5- (2,2,2-trifluoro-acetylamino) -phenyl] -2,2,2-trifluoroacetamide

[4- (2-Fluorobenzoylamino) benzyl] carbamic acid tert-butyl ester [4- (2,6-difluorobenzoylamino) benzyl] carbamic acid N- (3-amino-5-chlorophenyl) -2,2,2-trifluoroacetamide of

{4 - [(Furan-2-carbonyl) amino] benzyl] carbamic acid tert-butyl ester 2,6-difluoro-N- (4-nitrobenzyl) benzamide

[4- (3-Chloro-benzoylamino) -phenyl] -carbamic acid N- (3-Amino-5-chloro-phenyl) -acetamide [4- (4-Chloro-benzoylamino) -phenyl] -carbamic acid tert-butyl ester [4- (4) (4-Benzenesulfonylamino-phenyl) -carbamic acid tert-butyl [4- (3-trifluoromethyl-benzoylamino) -phenyl] -carbamic acid-dimethylaminobenzoylamino) -phenyl] -carbamic acid

2,2,2-trifluoro-N- (5-nitro-pyrimidin-2-yl) acetamide

Example 11 (2D method)

2-Chloro-N- (2-chloro-4-nitrophenyl) acetamide

A solution of 2-chloro-4-nitroaniline (19.0 g) and chloroacetyl chloride (30 mL) in tetrahydrofuran (150 mL) was heated at reflux for 1 hour. The solution was cooled and concentrated under reduced pressure to give a wet yellow solid. Ether (250 mL) was added and the yellow solid was collected.

The following compounds were prepared as described above, using appropriate starting materials:

N- (4-Nitro-3-trifluoromethyl-phenyl) -acetamide

(2-Chloro-4-nitrophenyl) carbamic acid ethyl ester

Furan-2-carboxylic acid (5-chloro-2-hydroxy-4-nitrophenyl) furan-2-carboxylic acid (2-methyl-4-nitrophenyl) amide (2-Methoxy-4) 2-acetylamino-5-nitrobenzoic acid Furan-2-carboxylic acid -nitrophenyl] amide

N- (2-Chloro-4-nitro-phenyl) -benzamide

2-Methoxy-N- (4-nitrophenyl) acetamide

N- (4-Nitro-phenyl) -acrylamide

[4- (Acryloylamido) phenyl] carbamic acid N- (4-nitrophenyl) isobutyrylamide

[1,2,3] Thiadiazole-4-carboxylic acid (5-nitropyridin-2-yl) furan-2-carboxylic acid (4-nitrophenyl) carbamic acid isobutyl ester

2-Fluoro-N- (5-nitropyridin-2-yl) -benzamide

Furan-2-carboxylic acid N- (2-chloro-4-nitrophenyl) -2-fluorobenzamide (2,5-Dimethoxy-4-nitrophenyl) amide

N- (2-cyano-4-nitrophenyl) -2-fluoro-benzamide

2-Fluoro-N- (2-methoxy-4-nitro-phenyl) -benzamide

Furan-2-carboxylic acid 2-methyl-N- (5-nitropyridin-2-yl) benzamide (2-Methoxy-5-methyl-4-nitrophenyl) amide

2-Fluoro-N- (2-methoxy-5-methyl-4-nitrophenyl) benzamide

N- (2-Benzoyl-4-nitrophenyl) acetamide

Furan-2-carboxylic acid N- (2-benzoyl-4-nitrophenyl) -2-fluorobenzamide (2-Benzoyl-4-nitrophenyl) amide

N '(3-P-ethyl-4-nitrophenyl) acetamide

Furan-2-carboxylic acid 2-fluoro-N- (3-methyl-4-nitrophenyl) benzamide (3-Methyl-4-nitrophenyl) amide

2-Acetylamino-5-nitro-N-phenylbenzamide

Furan-2-carboxylic acid 2 - [(2-fluorobenzoyl) amino] -5-nitro-N-phenylbenzamide (4-Nitro-2-phenylcarbamoylphenyl) amide

Furan-2-carboxylic acid 2-fluoro-N- (4-nitronaphthalen-1-yl) benzamide (4-Nitronaphthalen-1-yl) amide

N- (5-chloro-2-hydroxy-4-nitrophenyl) acetamide

Furan-2-carboxylic acid N- (5-chloro-2-hydroxy-4-nitrophenyl) -2-fluorobenzamide (2-chloro-4-nitrophenyl) amide

Furan-2-carboxylic acid N- (4-nitro-2-trifluoromethyl-phenyl) -acetamide (2-Cyano-4-nitrophenyl) -amide

Furan-2-carboxylic acid 2-fluoro-N- (4-nitro-2-trifluoromethylphenyl) benzamide (4-Nitro-2-trifluoromethylphenyl) amide

2-Fluoro-N- (2-methyl-4-nitrophenyl) benzamide

Furan-2-carboxylic acid N- (5-chloro-2-methyl-4-nitrophenyl) -2-fluorobenzamide (5-chloro-2-methyl-4-nitrophenyl) amide

2- (2-Fluorobenzoylamino) -5-nitrobenzoic acid

2 - [(Furan-2-carbonyl) amino] -5-nitrobenzoic acid

Furan-2-carboxylic acid N- (3-chloro-4-nitrophenyl) -2-fluorobenzamide (3-Chloro-4-nitrophenyl) amide

2,6-Difluoro-N- (3-methyl-4-nitrophenyl) benzamide

Furan-2-carboxylic acid 2-fluoro-N- (4-nitro-3-trifluoromethylphenyl) benzamide (4-Nitro-3-trifluoromethylphenyl) amide

2-Chloro-N- (2-chloro-4-nitrophenyl) acetamide

Furan-2-carboxylic acid N- (2-chloro-4-nitrophenyl) methanesulfonamide [3-Methoxy-4- (2,2,2-trifluoroacetylamino) phenyl] amide

N- (2-chloro-4-nitrophenyl) -2,2,2-trifluoroacetamide

Example 12 tert -Butyl {4 - [(4-phenyl- [1,2,3] thiadiazole-5-carbonyl) amino] phenyl} carbamic acid

To a solution of 1- (N-tert-butoxycarbonyl) -1,4-phenylenediamine (0.8

g) and 4-phenyl [1,2,3] thiadiazole-5-carboxylic acid (0.7 g) in dichloromethane (10 ml) was treated with triethylamine (1.3 ml) and benzotriazol-1-yloxy tris (dimethylamino) phosphonium hexafluorophosphate (1.6 g). After stirring at room temperature, the reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was washed with 0.5 N hydrochloric acid, saturated sodium bicarbonate and water, then dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the desired product.

The following compounds were prepared as described above, using appropriate starting materials:

(4 - [(1H-Pyrrole-2-carbonyl) amino] phenyl} carbamic acid tert-butyl ester tert-butyl {4 - [(pyrazine-2-carbonyl) amino] phenyl] carbamic acid tert-butyl ester {4 - (( 5-methylthiophene-2-carbonyl) amino] phenyl} carbamic acid tert-butyl {4 - [(1-methyl-1H-pyrrole-2-carbonyl) amino] phenyl} carbamic acid tert-butyl {4 - [(quinoline- 8-carbonyl) amino) phenyl} carbamic acid {4 - [(benzofuran-2-carbonyl) amino] phenyl} carbamic acid tert-butyl (4 - [(isoquinoline-1-carbonyl) amino] phenyl} carbamic acid tert-butyl ester {4 - [(quinoline-2-carbonyl) amino] phenyl} carbamic acid tert-butyl ester tert-butyl {4 - [(pyridine-2-carbonyl) amino] phenyl} carbamic acid tert-butyl {4 - [(isoquinoline- 4-carbonyl) amino] phenyl} carbamic acid tert-butyl [([1,2,3] thiadiazole-4-carbonyl) amino] phenyl} carbamic acid tert-butyl ester {4 - [(1H- [1,2,3] triazole-4-carbonyl) amino] phenyl} carbamic acid tert-butyl [4- (2-methylsulfanylbenzoylamino) phenyl] carbamate {4 - [(quinoline-4-carbonyl) amino] phenyl} carbamic acid tert-butyl ester {4 - [(4-methyl- [1,2,3] thiadiazole-5-carbonyl) amino] phenyl tert-butyl ester [4 - [(4-phenyl- [1,2,3] thiadiazole-5-carbonyl) amino] phenyl} carbamic acid tert-butyl ester [4 - [(1H-indole-2-carbonyl)} amino] phenyl} carbamic acid

[1,2,3] Thiadiazole-4-carboxylic acid 4-nitrobenzylamide tert-butyl {4 - [((1,2,3] Thiadiazole-4-carbonyl) amino] benzyl} carbamic acid tert-butyl ester

4- (4-tert-Butoxycarbonylaminophenylcarbamoyl) phenyl acetic acid tert-butyl [4 - [(quinoline-6-carbonyl) amino] phenyl} carbamic acid tert-butyl ester

Example 12 (Method 2F)

Acetic acid 2- (4-tert-butoxycarbonylamino-2,6-dichlorophenyl) ethyl ester

A solution of [3,5-dichloro-4- (2-hydroxy-ethoxy) -phenyl) -carbamic acid tert-butyl ester (0.85 g) in pyridine (14 mL) was treated with acetic anhydride (1.24 mL) and the mixture was stirred 15 hours at room temperature. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate. This solution was then washed twice with 5% aqueous hydrochloric acid, once with saturated aqueous sodium bicarbonate and then with saturated aqueous sodium chloride. Dry the solution over anhydrous magnesium sulfate and remove the solvent under reduced pressure to give the desired product as a colorless oil.

The following compounds were prepared as described above, using appropriate starting materials:

Fenylsulfanylacetônitrií

Acetic acid 2- (4-tert-butoxycarbaylamino-2,6-dichlorophenoxy) ethyl ester

Example 14 (Method 2G) (3,5-Dichloro-4-hydroxy-phenyl) -carbamic acid tert-butyl ester

To a solution of 2,6-dichloro-4-aminophenol (9.5 g) in tetrahydrofuran (130 mL) was added di-tert-butyl dicarbonate (11.7 g) and the mixture was heated under reflux for about 15 hours. The solution was then cooled, concentrated under reduced pressure, diluted with ethyl acetate and washed successively with 5% aqueous hydrochloric acid three times and once with saturated aqueous sodium chloride. The solution is dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give the desired crude product. This material was then treated with cold dichloromethane to give the product as a white solid.

The following compound was prepared as described above, using appropriate starting materials:

(3-Amino-5-chloro-phenyl) -carbamic acid tert-butyl ester

Example 15 (Method 3A)

3-5-dichloro-4-ethoxy-phenylamine

Trifluoroacetic acid (5 mL) was added to solid (3,5-dichloro-4-ethoxyphenyl) carbamic acid tert-butyl ester (0.97 g) and the mixture was stirred at room temperature for about 45 minutes. Water is then added, and the mixture is cooled in an ice bath and basified with solid potassium carbonate. The solution was extracted three times with ethyl acetate and the combined organic phases were washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate. Concentration under reduced pressure and recrystallization from hexanes gave the desired product as a pale yellow crystalline solid.

The following compounds were prepared as described above, using appropriate starting materials:

5-Bromo-pyridine-3-ylamine

3-Chloro-4-methanesulfonylphenylamine N- (4-Aminophenyl) -2-methylbenzamide

Acetic acid 2- (4-aminophenylcarbamoyl) phenyl ester

N- (4-Aminophenyl) -4-fluprbenzamide N- (4-Aminophenyl) -3-fluorobenzamide N- (4-Aminophenyl) -2-fluorobenzamide N- (4-Aminophenyl) -2-methoxybenzamide N- (4-Aminophenyl) ) -3-Methoxybenzamide N- (4-Aminophenyl) -4-methoxybenzamide N- (4-Aminophenyl) -2-phenylacetamide N- (4-Aminophenyl) -2,2-dimethylpropionamide N- (4-Aminophenyl) -2, Thiophene-2-carboxylic acid (4-aminophenyl) amide 1H-pyrrole-2-carboxylic acid (4-aminophenyl) amide N- (4-aminophenyl) -3-nitrobenzamide 2,2-trifluoroacetamide

3-Acetylamino-N- (4-aminophenyl) benzamide

N- (4-Aminophenyl) -3-dimethylaminobenzamide

N- (4-Aminophenyl) -3-methanesulfonylamino-benzamide

N- (4-Aminophenyl) -2-trifluoromethyl-benzamide

N- (4-Aminophenyl) -2,6-difluorobenzamide

N- (4-Aminophenyl) -2-chlorobenzamide

N- (4-Aminophenyl) -2-bromobenzamide

5-Methyl-thiophene-2-carboxylic acid (4-amino-phenyl) -2-nitrobenzamide (4-Aminophenyl) -amide 4-Aminophenyl) quinoline-8-carboxylic acid (4-amino-phenyl) -amide 1-Methyl-1H-pyrrole-2-carboxylic acid (4-aminophenyl) amide Benzo [b] thiophene-2-carboxylic acid (4-aminophenyl) amide Benzofuran-2-carboxylic acid (4-aminophenyl) amide

Naphthalene-2-carboxylic acid N- (4-aminophenyl) isonicotinamide (4-Aminophenyl) naphthalene-1-carboxylic acid (4-aminophenyl) isoquinoline-1-carboxylic acid (4-aminophenyl) amide Quinoline-2-carboxylic acid aminophenyl) amide

3,5-Dichloro-4-ethoxy-phenylamine

[1,2,3] Thiadiazole-4-carboxylic acid (4-amino-phenyl) -amide (4-aminophenyl) -isoquinoline-4-carboxylic acid (4-amino-phenyl) -amide 1H- [1] 2,3] triazole-4-carboxylic acid 3-bromothiophene-2-carboxylic acid (4-aminophenyl) amide

4-Benzyloxy-3,5-dichlorophenylamino

2- (4-Amino-2,6-dichloro-phenoxy) -acetamide

(4-Amino-2,6-dichloro-phenoxy) -acetic acid methyl ester

[3- (4-Amino-phenylcarbamoyl) -phenyl] -carbamic acid ethyl ester

Biphenyl-2-carboxylic acid 2-amino-N- (4-aminophenyl) benzamide (4-aminophenyl) amide

N- (4-Aminophenyl) -2,3-difluorobenzamide

N- (4-Aminophenyl) -2,5-difluorobenzamide

N- (4-Aminophenyl) -2,4-difluorobenzamide

2-Acetylamino-N- (4-aminophenyl) -benzamide

N- (4-Aminophenyl) -2-methanesulfonylaminobenzamide

N- (4-Aminophenyl) -2,3,4-trifluorobenzamide

N- (4-Aminophenyl) -2,3,4,5,6-pentafluorobenzamide

N- (4-Aminophenyl) -2-metylsulfanylbenzamid

Acetic acid 2- (4-amino-2,6-dichlorophenoxy) ethyl ester

N- (4-Aminophenyl) isophthalic acid methyl ester

N- (4-Aminophenyl) -3-benzyloxybenzamido

N- (4-Aminophenyl) -3-butoxybenzamide

Pyridine-2-carboxylic acid [3- (4-aminophenylcarbamoyl) phenoxy] acetic acid (4-Aminophenyl) quinoline-4-carboxylic acid (4-aminophenyl) amide 5-methylfuran-2-carboxylic acid (4-aminophenyl) amide 5-Difluoromethylfuran-2-carboxylic acid (4-aminophenyl) -1H-indole-2-carboxylic acid (4-aminophenyl) amide 4-methyl- [1,2,3] thiadiazole-5- (4-aminophenyl) amide 5-Chloro-furan-2-carboxylic acid (4-amino-phenyl) -thiophene-3-carboxylic acid (4-amino-phenyl) -amide 5-nitrofuran-2-carboxylic acid (4-amino-phenyl) -amide (4-amino-phenyl) -amide

5-Bromo-furan-2-carboxylic acid (4-amino-phenyl) -amide (4-amino-phenyl) -amide (4-amino-phenyl) -amide (4-amino-phenyl) -amide (4-amino-phenyl) -amide (4-amino-phenyl) -amide 4 -bromofuran-2-carboxylic acid

N- (4-Aminophenyl) -nicotinamide

4-Phenyl- [1,2,3] thiadiazole-5-carboxylic acid N- (4-amino-phenyl) -3-furancarboxamide (4-amino-phenyl) -amide

Benzo [1,3] dioxole-4-carboxylic acid (4-aminophenyl) -phenyl acetic acid 3- (4-aminophenylcarbamoyl) phenyl ester

N- (4-Aminophenyl) -3- (2-dimethylamino-ethoxy) -benzamide

N- (4-Aminophenyl) -3-trifluoromethoxybenzamide

N- (4-Aminophenyl) -3- (2-morpholin-4-ylethoxy) benzamide

Furan-2-carboxylic acid (4-aminophenyl) carbamic acid hexyl ester (4-Aminophenyl) amide

(4-Aminophenyl) carbamic acid phenyl ester (4-Aminophenyl) hexanoic acid amide

N- (4-Aminophenyl) -acrylamide

4-Furan-3-yl- [1,2,3] thiadiazole-5-carboxylic acid N- (4-amino-phenyl) -2-methoxy-acetamide (4-amino-phenyl) -amide (4-amino-phenyl) -amide 5-tert-butyl-furan- Of 2-carboxylic acid

5-Methyl- [1,2,3] thiadiazole-4-carboxylic acid 3-chloro-4-methanesulfinyl-phenylamine (4-Aminophenyl) -amide

2- (amino-2-chloro-phenyl) -ethanol

(4-Amino-2-chloro-phenyl) -carbamic acid 2-piperidin-1-yl-ethyl ester,

5-Chloro-N, N-dimethylbenzene-1,3-diamine

3- (2-Methylbutyl) -5-trifluoromethylphenylamine

Furan-2-carboxylic acid 3-isobutyl-5-trifluoromethyl-phenylamine (4-Aminomethyl-phenyl) -amide

[1,2,3] Thiadiazole-4-carboxylic acid N- (4-aminomethylphenyl) -2-fluorobenzamide (4-aminomethylphenyl) amide

Oxazole-4-carboxylic acid N- (4-aminomethylphenyl) -2,6-difluorobenzamide (4-Aminophenyl) amide

N- (4-Aminophenyl) -3-chlorobenzamide

N- (4-Aminophenyl) -4-chlorobenzamide

Acetic acid 4- (4-aminophenylcarbamoyl) phenyl ester

N- (4-Aminophenyl) -4-dimethylaminobenzamide

1- (4-Aminophenyl) -3- (3,5-Bis-trifluoromethylphenyl) thiourea

N- (4-Aminophenyl) -2-iodobenzamide

N- (4-Aminophenyl) -3-trifluoromethyl-benzamide

Example 16 (method 3B)

1- (4-Amino-2-chloro-phenyl) -ethanol

A solution of 1M tetrabutylammonium fluoride in tetrahydrofuran (5.7 ml) was added to [3-chloro-4- (1-hydroxy-ethyl) -phenyl] -carbamic acid 2-trimethylsilanylethyl ester (0.5 g) and the mixture was stirred at room temperature for approximately 3.5 hours. The solution was then concentrated under reduced pressure, dissolved in a 1: 1 mixture of ethyl acetate and hexanes, washed successively with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate.

Removal of the solvent under reduced pressure followed by silica gel chromatography (40% ethyl acetate in hexanes is used as the eluent) afforded the product as an amber oil.

Example 17 (Method 3C)

N- (4-amino-3-cyanophenyl) -2-fluoro-benzamide

Potassium carbonate (5.0 g) was added to a solution of N- (3-cyano-4- (2,2,2-trifluoroacetylamino) phenyl] -2-fluorobenzamide (2.5 g) in methanol (270 mL) and water ( After removing the solvent under reduced pressure, the residue is suspended in water and extracted with dichloromethane, the organic extracts are combined, washed with water and then with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrate under reduced pressure to give the title compound as a white solid.

The following compounds were prepared as described above, using appropriate starting materials:

N- (4-Aminophenyl) -2-methanesulfinyl

Furan-2-carboxylic acid N- (4-amino-3-cyanophenyl) -2-fluorobenzamide (4-amino-3-cyanophenyl) amide

Furan-2-carboxylic acid N- (4-amino-3-cyanophenyl) acetamide (4-amino-3-trifluoromethylphenyl) amide N- (4-amino-3-methoxyphenyl) acetamide

Furan-2-carboxylic acid N- (4-amino-3-methoxyphenyl) -2-fluorobenzamide (4-amino-3-methoxyphenyl) amide

Example 17 (method 4A)

2-Chloro-l-cyclohexyloxy-4-nitrobenzene

Cyclohexanol (2.9 g) in dimethylsulfoxide (20 ml) is slowly added to a flask containing potassium hydride (0.90 g, first washed three times with hexanes) under an argon atmosphere and this solution is then stirred for about 1 hour at room temperature. . A solution of 3-chloro-4-fluoronitrobenzene (1 g) in dimethylsulfoxide (10 mL) was added and the resulting solution, now dark red in color, was then heated at about 100 degrees for 3 hours. The reaction mixture was then cooled, diluted with diethyl ether (300 mL), and washed sequentially with saturated aqueous ammonium chloride, three times with water and saturated aqueous sodium chloride. The organic layer was then dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure, and the resulting oil was chromatographed on silica gel (using 5% ethyl acetate in hexanes as eluent) to give the desired product as an orange solid.

Example 18 (Method 4C) (2-Chloro-4-nitrophenyl) methyl- (1-methylpyrrolidin-3-yl) amine

3-Chloro-4-fluoronitrobenzene (1.0 g) and N, N'-dimethyl-3-aminopyrrolidine (1.72 g) were combined and stirred for about 24 hours. The mixture was then diluted with ethyl acetate, washed twice with water and once with saturated sodium chloride, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was then chromatographed on silica gel (pure ethyl acetate followed by pure methanol was used as eluent) to give the desired product as a yellow oil.

The following compounds were prepared as described above, using appropriate starting materials:

(2-Chloro-4-nitro-phenyl) dipropylamine

1- (2-Chloro-4-nitro-phenyl) -piperidine

1- (2-Chloro-4-nitrophenyl) pyrrolidine (2-Chloro-4-nitrophenyl) cyclohexylmethylamine

Benzyl- (2-chloro-4-nitrophenyl) amine (2-Chloro-4-nitrophenyl) methyl- (1-methylpiperidin-4-yl) amine (2-Chloro-4-nitrophenyl) cyclohexylethylamine (2-Chloro-4- nitrophenyl) cyclohexylamine (2-Chloro-4-nitrophenyl) methyl- (1-methylpyrrolidin-3-yl) amine (1-Benzylpyrrolidin-3-yl) - (2-chloro-4-nitrophenyl) methylamine (2-Chloro-4) nitrophenyl) cyclopentylmethylamino

1- (2-Chloro-4-nitrophenyl) decahydroquinoline

Allyl (2-chloro-4-nitro-phenyl) cyclohexylamine

2 - [(2-Chloro-4-nitrophenyl) - (2-hydroxyethyl) amino] ethanol (2-Chloro-4-nitrophenyl) isobutylmethylamine (2-Chloro-4-nitrophenyl) hexylmethylamine

2 - [(2-Chloro-4-nitro-phenyl) -methyl-amino] -ethanol

N- (2-Chloro-4-nitrophenyl) -N, N ', N'-trimethylethane-1,2-diamine

N- (2-Chloro-4-nitrophenyl) -N, N ', N'-trimethylpropane-1,3-diamine (1-Benzylpiperidin-4-yl) - (2-chloro-4-nitrophenyl) amine

N- (2-Chloro-4-nitrophenyl) -N ', N'-dimethylethane-1,2-diamine

N- (2-Chloro-4-nitrophenyl) -N ', N'-dimethylpropane-1,3-diamine (2-Chloro-4-nitrophenyl) - (2-methoxyethyl) methylamine (1-Benzylpyrrolidin-3-yl) - (2-chloro-4-nitro-phenyl) -amine

4-Piperidin-l-yl-3-trifluoromethyl-benzonitrile

4-Dimethylamino-3-trifluoromethyl-benzonitrile

4- (4-Methyl-piperazin-l-yl) -3-trifluoromethyl-benzonitrile

Example 19 (method 4E)

Butyl- (2-chloro-4-nitro-phenyl) thioether

A solution of 3-chloro-4-fluoronitrobenzene (5.0 g) and sodium sulfide (2.5 g) in N, N-dimethylformamide (30 mL) was stirred at room temperature for 1 hour and then treated with 1-iodobutane ( 12.6 g). The solvent was then removed under reduced pressure and the resulting residue was treated with ethyl acetate and hexanes to precipitate inorganic salts. The solids were removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue is then passed through a magnesium silicate containing water using dichloromethane as eluent to give the desired compound as a yellow solid.

The following compounds were prepared as described above, using appropriate starting materials:

1-Butylsulfanyl-2-chloro-4-nitrobenzene

2-Chloro-1-cyclohexylsulfanyl-4-nitrobenzene

2-Chloro-l-ethylsulfanyl-4-nitrobenzene

Example 20 (Method 4F) (4-Chloro-5-methoxy-2-nitrophenyl) dimethylamine

To a solution of trifluoromethanesulfonic acid 4-chloro-5-methoxy-2-nitrophenyl ester (1.0 g) in tetrahydrofuran (2.0 mL) was added dimethylamine (4.0 mL of a 40% aqueous solution) and the mixture was stirred at room temperature for approximately 15 hours. The solution was then concentrated under reduced pressure and the residue was dissolved in ethyl acetate and then washed with water. The aqueous layer was extracted once with ethyl acetate and the combined organic layers were washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure and the residue was treated with hexanes to give the desired product as a colorless solid.

The following compounds were prepared as described above, using appropriate starting materials:

(4-Chloro-2-nitro-phenyl) -dimethyl-amine

4- (4-Chloro-5-methoxy-2-nitrophenyl) morpholine (4-Chloro-5-methoxy-2-nitrophenyl) dimethylamine

1- (4-Chloro-5-methoxy-2-nitro-phenyl) -piperidine

1- (4-Chloro-5-methoxy-2-nitrophenyl) pyrrolidine Benzyl- (4-chloro-5-methoxy-2-nitrophenyl) amine (2-Chloro-6-nitrophenyl) dimethylamine

Example 21 (Method 4G) (2-Chloro-4-nitrophenyl) methylphenylamine n-Butyl lithium (12.3 mL of a 2.5 M solution in hexanes) was added dropwise to a solution of N-methylaniline (3.0 g) in tetrahydrofuran (75 mL) at 0 ° C. The mixture was slowly warmed to room temperature and then re-cooled to 0 ° C and then added via cannula to a solution of 3-chloro-4-fluoronitrobenzene (4.9 g) in tetrahydrofuran (35 mL) maintained at -78 °. C. The reaction mixture was then allowed to warm to room temperature for 1 hour and concentrated under reduced pressure, quenched by the addition of saturated aqueous ammonium chloride and extracted three times with ethyl acetate. The combined organic extracts were washed three times with 5% aqueous hydrochloric acid, once with water, once with saturated aqueous sodium bicarbonate, once with saturated aqueous sodium chloride, and then dried over magnesium sulfate. This is followed by removal of the solvent under reduced pressure, after which the residue is chromatographed on silica gel (5% diethyl ether in hexanes is used as the eluent) to give the desired product as a clear colorless oil.

Example 22 (method 4H)

2,6-dichloro-4-nitrophenol

3,4,5-Trichloronitrobenzene (14.86 g) was added to a solution of potassium phenoxide (8.66 g) in diethylene glycol (66 ml) and the mixture was heated at 160 ° C for about 15 hours. The resulting dark brown solution was cooled to room temperature, poured into 100 mL of cold water and extracted twice with diethyl ether. The combined organic extracts were washed with water, 10% aqueous sodium hydroxide, and then dried over anhydrous magnesium sulfate. This is followed by removal of the solvent under reduced pressure, after which the resulting oil is distilled in a Kugelrohr apparatus to give a yellow oil which solidifies on standing. Recrystallization from ethanol-water gave the desired product as a pale yellow solid.

Example 23 (Method 5A) (3,5-Dichloro-4-ethoxy-phenyl) -carbamic acid tert-butyl ester

To a solution of (3,5-dichloro-4-hydroxy-phenyl) -carbamic acid tert-butyl ester (1.0 g) and potassium carbonate (1.0 g) in acetone (18 mL) was added ethyl iodide (0.36 mL) and the mixture was stirred at room temperature for about 15 hours. The solution was then filtered, concentrated under reduced pressure and partitioned between ethyl acetate and water. The separated aqueous layer was further extracted twice with ethyl acetate, and the combined organic extracts were washed successively with 10% aqueous sodium hydroxide, water, and then dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure gave the desired product as a brownish solid.

The following compounds were prepared as described above, using appropriate starting materials:

(3,5-Dichloro-4-ethoxy-phenyl) -carbamic acid tert-butyl ester tert-Butyl (4-butoxy-3,5-dichloro-phenyl) -carbamic acid tert-butyl (4-benzyloxy-3,5-dichloro-phenyl) -carbamic acid tert. (4-Carbamoylmethoxy-3,5-dichlorophenyl) carbamic acid butyl ester tert -Butyl [3,5-dichloro-4- (2-nitrilethoxy) phenyl] carbamic acid butyl ester

(4-tert-Butoxycarbonylamino-2,6-dichlorophenoxy) -acetic acid methyl ester

3-Butoxybenzoic acid methyl ester

3-tert-Butoxycarbonylmethoxybenzoic acid methyl ester

3-Carbamoylmethoxybenzoic acid methyl ester tert -Butyl [4- (3-carbamoylmethoxybenzoylamino) phenyl] carbamic acid tert -Butyl {4- [3- (2-chloroethoxy) benzoylamino] phenyl} carbamate

Example 24 (Method 5C) (2,6-Dichloro-4-nitrophenoxy) -acetic acid tert-butyl ester

To a solution of 2,6-dichloro-4-nitro-phenol (2.5 g) and potassium carbonate (3.3 g) in dimethylformamide (50 ml) was added tert-butyl bromoacetate (10 ml) and the mixture was stirred for 2 days at room temperature. The solution is then poured into 500 ml of water, extracted three times with hexanes and the combined organic extracts are washed with saturated aqueous ammonium chloride and then dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure followed by trituration of the resulting oil with hexanes afforded the desired product as a white solid.

The following compounds were prepared as described above, using appropriate starting materials:

3-Dimethylamino-1- (4-nitrophenyl) propenone

2-Chloro-l-isopropoxy-4-nitrobenzene

1,3-Dichloro-2-methoxy-4-methyl-5-nitrobenzene 1-Chloro-4-ethoxy-2-methoxy-5-nitrobenzene 1-Butoxy-4-chloro-5-methoxy-2-nitrobenzene 1-Chlorine -2-methoxy-5-nitro-4- (phenylmethoxy) benzene (CA name) 1-Chloro-4-methoxy-5-nitro-2- (phenylmethoxy) benzene (CA name) tert-butyl ester (2,6-dichloro) -4-nitrophenoxy) acetic acid (2,6-Dichloro-4-nitrophenoxy) acetonitrile

1-Chloro-4-methoxy-2-methyl-5-nitrobenzene

2- (4-Chloro-5-methoxy-2-nitrophenoxy) acetamide

2- (2-Chloro-5-methoxy-4-nitrophenoxy) acetamide (4-Chloro-5-methoxy-2-nitrophenoxy) acetonitrile (2-Chloro-5-methoxy-4-nitrophenoxy) acetonitrile

4- (2-Chloro-5-methoxy-4-nitrophenoxy) butyronitrile

2- (4-chloro-5-methoxy-2-nitro-phenoxy) -ethanol

2- (2-Chloro-5-methoxy-4-nitrophenoxy) ethanol tert-butyl (2-chloro-5-methoxy-4-nitrophenoxy) acetic acid tert-butyl ester

(2-Chloro-5-methoxy-4-nitrophenoxy) acetic acid methyl ester (4-Chloro-5-methoxy-2-nitrophenoxy) acetic acid methyl ester tert -Butyl (4-chloro-5-methoxy-2-nitrophenoxy) acetic acid methyl ester (2-Chloro-4-nitro-phenoxy) -acetonitrile

1-Butoxy-2-chloro-4-nitrobenzene

2-Chloro-4-nitro-1- (2,2,2-trifluoroethoxy) benzene 2-Chloro-4-nitro-1-propoxybenzene

2-Chloro-1-ethoxy-4-nitrobenzene

1,3-Diodo-2,4-dimethoxy-5-nitrobenzene

1,3-Dibromo-2,4-dimethoxy-5-nitrobenzene

3-Chloro-2,4-dimethoxynitrobenzene

Example 25 (Method 5E) [3,5-Dichloro-4- (2-hydroxy-ethoxy) -phenyl] -cardanic acid tert-butyl ester

To a solution of (3,5-dichloro-4-hydroxy-phenyl) -carbamic acid tert-butyl ester (1.0 g) and potassium carbonate (0.55 g) in toluene (20 mL) was added ethylene carbonate (1.6 g) and heated. at reflux for 3 hours. To the cooled reaction mixture was added 2M aqueous sodium hydroxide (50 mL), and the separated organic layer was then washed sequentially with water, then saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent is then removed by evaporation under reduced pressure and the resulting residue is chromatographed on silica gel (30% ethyl acetate in hexanes is used as the eluent) to give the desired product as a white foam.

Example 26 (method 6)

3- (2-chloro-4-nitrophenoxy) -1-methylpyrrolidine

To a solution of 2-chloro-4-nitrophenol (2.0 g) in tetrahydrofuran (60 mL) was added 1-methyl-3-pyrrolidinol (2.3 g), triphenylphosphine (6.0 g), and diethyl azodicarboxylate (3, 3 g). 6 ml) and stirred under argon at room temperature for 1.5 hours. This solution was then concentrated under reduced pressure, diluted with ethyl acetate, washed successively with 10% aqueous sodium hydroxide, water, saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure and the residue was chromatographed on silica gel (ethyl acetate followed by 10% methanol in dichloromethane). The combined product fractions were then recrystallized from hexanes to give the desired product as a yellow solid.

The following compounds were prepared as described above, using appropriate starting materials:

4- (2-chloro-4-nitrophenoxy) -1-methyl-piperidine

3- (2-Chloro-4-nitrophenoxy) -1-methylpyrrolidine [2- (2-Chloro-4-nitrophenoxy) ethyl] dimethylamine [3- (2-Chloro-4-nitrophenoxy) propyl] dimethylamine

Example 27 (method 7A)

2-Chloro-3-methoxy-6-nitrophenol and 2,4-Dichloro-3-methoxy-6-nitrophenol

To a flask containing 3-methoxy-6-nitrophenol (0.5 g) was added aqueous sodium hypochlorite (5.25% aqueous solution, 21 mL), and the mixture was stirred at room temperature for about 24 hours. The mixture was then cooled in an ice bath, acidified by the addition of concentrated hydrochloric acid and then extracted twice with ethyl acetate. These organic extracts were dried over anhydrous magnesium sulfate, the solvent was removed by evaporation under reduced pressure, and the residue was chromatographed on silica gel (using 15% acetone in hexanes as eluent) to give both the mono- and dichloro-product as a yellow solid.

The following compounds were prepared as described above, using appropriate starting materials:

3-Chloro-2-hydroxy-4-methoxynitrobenzene

3,5-Dichloro-2-hydroxy-4-methoxy-nitrobenzene

Example 28 (method 7B)

2,4-Dichloro-3-methyl-6-nitrophenol

To a solution of 3-methyl-4-nitrophenol (5.0 g) in water (150 mL) was added aqueous sodium hypochlorite (5.25% aqueous solution, 230 mL), and the mixture was stirred at room temperature for about 15 hours. Additional aqueous sodium hypochlorite (5.25% aqueous solution, 230 mL) was added and the mixture was stirred at room temperature for 2.5 days. The mixture was then cooled in an ice bath, acidified by the addition of concentrated hydrochloric acid, and then extracted twice with ethyl acetate. These organic extracts are dried over anhydrous magnesium sulfate, the solvent is removed under reduced pressure and the residue is chromatographed on silica gel (ethyl acetate is used as the eluent) to give the desired product as a yellow solid. An analytically pure sample was obtained by a single recrystallization from chloroform.

Example 29 (Method 7C) 1-Bromo-2,4-dimethoxy-5-nitrobenzene

To a solution of 2,4-dimethoxynitrobenzene (0.50 g) in chloroform (3 mL) was added dropwise a solution of bromine (0.23 g) in chloroform (1 mL), and the mixture was stirred at room temperature for about 15 hours. Additional bromine (0.15 g) in chloroform (1 mL) was added and the reaction stirred for an additional 4 hours. The mixture was then poured into 5% aqueous sodium bisulfite and then extracted with chloroform. The combined organic extracts were then washed successively with 5% aqueous sodium bisulfite, then saturated sodium chloride, and then dried over anhydrous sodium sulfate. Removal of the solvent under reduced pressure and recrystallization of the residue from toluene gave the desired product as a yellow solid.

Example 30 (method 7D)

2,4-Dibromo-3-methoxy-6-nitrophenol

To a solution of 5-methoxy-2-nitrophenol (0.25 g) and silver trifluoroacetate (0.49 g) in glacial acetic acid (3 mL) was added.

A solution of bromine (1.42 g) in glacial acetic acid (3 mL) was added dropwise and the mixture was stirred at room temperature for about 24 hours. The solution was then partitioned between ethyl acetate and water, and the organic layer was then washed successively three times with 5% aqueous sodium bisulfite, three times with saturated aqueous sodium bicarbonate, and once with saturated aqueous sodium chloride. The organic layer was then dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue is chromatographed on silica gel (20% ethyl acetate in hexanes is used as the eluent) then recrystallized from chloroform to give the desired dibrominated product as an orange solid.

Example 31 (Method 7E) 1-Iodo-2,4-dimethoxy-5-nitrobenzene

To a solution of 2,4-dimethoxynitrobenzene (1.0 g) in glacial acetic acid (30 mL) was added benzyltrimethylammonium dichloroiodate (1.90 g) and anhydrous zinc chloride (1.0 g), and the mixture was stirred at room temperature under argon. . After 5 hours, additional benzyltrimethylammonium iodate was added and again after 24 hours. After 24 hours, zinc chloride (0.5 g) and glacial acetic acid (15 ml) were added. The mixture was stirred at room temperature for 3 days and then filtered, diluted with 5% aqueous sodium bisulfite and extracted three times with ethyl acetate. The combined extracts were washed successively with 5% aqueous sodium bisulfite and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure, the residue was treated with hexanes to give the desired product as a pale yellow solid.

Example 32 (method 7F)

2,4-diiodo-3-methoxy-6-nitrophenol

To a solution of 5-methoxy-2-nitrophenol (0.25 g) in dichloromethane (15 mL) and methanol (6 mL) was added benzyltrimethylammonium iodate (1.08 g) and sodium bicarbonate (0.85 g) and the mixture was stirred for 24 hours. hours at room temperature. The solution is then filtered, the filtrate is concentrated under reduced pressure, the residue is dissolved in ethyl acetate and then washed successively with 5% aqueous sodium bicarbonate, 5% aqueous sodium bisulfite, and saturated aqueous sodium chloride. The solution is dried over anhydrous magnesium sulfate and the solvent is then removed by evaporation under reduced pressure and the residue is recrystallized from toluene to give the desired product as yellow needles.

Example 33 (Method 7G) 1-Fluoro-2,4-dimethoxy-5-nitrobenzene

To a solution of 2,4-dimethoxynitrobenzene (1.0 g) in carbon tetrachloride (10 mL) was added 3,5-dichloro-1-fluoropyridinium triflate (85%, 5.07 g) and the mixture was heated at 120 ° C for 5 hours. . Additional 3,5-dichloro-1-fluoropyridinium triflate (85%, 0.25 g) was added and heating continued for 1 hour. The solution was then cooled to room temperature and passed through a silica gel column (hexanes then 30% ethyl acetate in hexanes was used as eluent). Fractions containing product were combined, evaporated under reduced pressure and the residue crystallized from hexane to give the desired product as a brownish solid.

Example 34 (method 8)

3-Chloro-4-trifluoromethyl-nitrobenzene

A solution of 3-chloro-4-iodonitrobenzene (2.26 g) in trimethyl (trifluoromethyl) silane (5.68 g), copper (I) iodide (2.28 g) and potassium fluoride (0.56 g) in N, N'- dimethylformamide (8 mL) was heated in a sealed tube at 80 ° C for 40 hours. The solution was then cooled, diluted with diethyl ether, filtered through diatomaceous earth, and the filtrate was washed successively with water, saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was chromatographed on silica gel (1% diethyl ether in hexanes was used as eluent) followed by 10% ethyl acetate in hexanes to give the desired product as a colorless oil.

Example 35 (Method 9) (3-Chloro-4-methanesulfinyl-phenyl) -carbamic acid tert-butyl ester

To a solution of (3-chloro-4-thiomethyl-phenyl) -carbamic acid tert-butyl ester (0.89 g) in dichloromethane (15 mL) at 0 ° C was added a solution of dimethyldioxirane (ca. 0.11 M in acetone, 34 mL) and the mixture was stirred at 0 ° C for 1 hour. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane, washed with saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure gave the desired product as an orange foam.

Example 36 (Method 9B) [4- (2-Methylsulfinylbenzoylamino) phenyl] carbamic acid tert -butyl ester

To a solution of 2-methylsulfanyl-N- [4- (2,2,2-trifluoroacetylamino) phenyl] benzamide (234 mg) was added saturated sodium periodate (5 mL) and the mixture was stirred for 12 hours. The purple mixture is poured

Ti to water, extracted with ethyl acetate, dried over anhydrous magnesium sulfate and evaporated to give 101 mg of a red solid.

The following compounds were prepared as described above, using appropriate starting materials:

[4- (2-Methanesulfinyl-benzoylamino) -phenyl] -carbamic acid tert-butyl ester

2- Methanesulfinyl-N- [4- (2,2,2-trifluoroacetylamino) phenyl] benzamide

Example 37 (Method 10) (3-Chloro-4-methanesulfonyl-phenyl) -carbamic acid tert-butyl ester

To a solution of (3-chloro-4-thiomethyl-phenyl) -carbamic acid tert-butyl ester (0.90 g) in dichloromethane (30 mL) at 0 ° C was added a solution of dimethyldioxirane (ca. 0.11 M in acetone, 80 mL) and the mixture was stirred at 0 ° C for 1 hour. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane, washed with saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure gave the desired product as an orange foam.

Example 38 (method 11)

3-Chloro-4-vinylphenylamine

To a deoxygenated solution of 3-chloro-4-iodoaniline (6.95 g), triphenylarzine (0.67 g) and tris (dibenzylideneacetone) palladium (0) (0.50)

g) in tetrahydrofuran (120 mL) at 50 ° C was added tributylvinyltin (10 g) and the mixture was stirred at 50 ° C for about 15 hours under an argon atmosphere. The reaction mixture was then cooled, filtered through diatomaceous earth, and the filtrate was evaporated to dryness under reduced pressure. The residue was dissolved in hexanes and then extracted three times with 5% aqueous hydrochloric acid. The aqueous acid extracts were then basified with solid potassium carbonate and extracted three times with ethyl acetate. The combined organic extracts were then washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The resulting residue is chromatographed on silica gel (hexanes then 10% ethyl acetate in hexanes is used as the eluent) to give the desired product as an amber oil.

Example 39 (method 12)

[3-Chloro-4- (1-hydroxy-ethyl) -phenyl] -carbamic acid 2-trimethylsilanylethyl ester

(3-Chloro-4-vinyl-phenyl) -carbamic acid 2-trimethylsilylethyl ester (2.6 g) was added to a solution of mercuric acetate (3.48 g) in water (7 ml) and tetrahydrofuran (5.25 ml) and the mixture was stirred about 15 hours. Then, 3N aqueous sodium hydroxide (8.7 ml) and a 0.5 M solution of sodium borohydride in 3N aqueous sodium hydroxide (8.7 ml) were added and stirring was continued for 6 hours. The solution was then saturated with sodium chloride and extracted with ethyl acetate. These organic extracts were then washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, followed by chromatography of the residue on silica gel (using 20% ethyl acetate in hexanes as eluent) to give the desired product as a white solid.

Example 40 (Method 13) [3-Chloro-4- (2-hydroxy-ethyl) -phenyl] -carbamic acid tert-butyl ester

To a stirred suspension of sodium borohydride (0.45 g) in tetrahydrofuran (13 mL) at 0 ° C was added glacial acetic acid (0.75 mL), and the mixture was stirred at 0 ° C for 1 hour.

The solution was then warmed to room temperature and (3-chloro-4-vinylphenyl) carbamic acid 2-trimethylsilanylethyl ester (1.0 g) was added. The reaction mixture was stirred at room temperature for about 15 hours and then heated to reflux for about 20 hours. The mixture was then cooled and solutions of 5N aqueous sodium hydroxide (0.80 mL) and 30% aqueous hydrogen peroxide (0.56 mL) were added. The mixture was stirred for an additional 15 hours and the layers were separated, the aqueous layer was extracted three times with diethyl ether, and these organic extracts were dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure followed by silica gel chromatography (40% ethyl acetate in hexanes was used as eluent) to give the desired product as an amber oil.

Example 41 (method 14)

[4- (1-Azidoethyl) -3-chlorophenyl] carbamic acid 2-trimethylsilanylethyl ester

To a solution of [3-chloro-4- (1-hydroxy-ethyl) -phenyl] -carbamic acid 2-trimethylsilanylethyl ester (1.25 g) in tetrahydrofuran (20 mL) at 0 ° C under argon was added triphenylphosphine (2.6 g). Hydrochloric acid (approximately 2.5 molar equivalents in dichloromethane, prepared according to the method of Fieser and Fieser, Reagents for Organic Synthesis, Volume 1, p. 446; Wiley, New York) and diethylazodicarboxylate. After about 10 minutes, the solvent was removed under reduced pressure and the residue was chromatographed on silica gel (5% ethyl acetate in hexanes was used as eluent) to give the desired product as a colorless oil.

Example 42 (Method 15) [3-Chloro-4- (3-dimethylamino-prop-1-ynyl) -phenyl] -carbamic acid tert-butyl ester

To a deoxygenated solution of (3-chloro-4-iodophenyl) carbamic acid tert-butyl ester (10.0 g) in triethylamine (120 mL) was added 1-dimethylamino-2-propyne (2.82 g) palladium (II) bis (triphenylphosphine) chloride (0.4 g) and cuprous iodide (0.054 g). The mixture was stirred at room temperature under argon for about 6 hours and then heated briefly at 60 ° C (about 10 minutes). The reaction mixture was then cooled, filtered through diatomaceous earth, and the solvent was removed by evaporation under reduced pressure. The residue was dissolved in ethyl acetate, washed three times with water, once with saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure and the residue was chromatographed on silica gel (80% ethyl acetate in hexanes was used as eluent) to give the refined product as an amber oil which solidified on standing.

The following compounds were prepared as described above, using appropriate starting materials:

[3-Chloro-4- (3-dimethylaminoprop-1-ynyl) phenyl] carbamic acid [3- (4-methoxyphenyl) prop-2-ynyl] dimethylamine tert-butyl ester

4- (3-Dimethylaminoprop-1-ynyl) benzonitrile Dimethyl- [3- (4-nitrophenyl) prop-2-ynyl] amine

Example 43 (Method 16) [3-Chloro-4- (3-dimethylamino-acryloyl) -phenyl] -carbamic acid tert-butyl ester

To a ice-cold solution of [3-chloro-4- (3-dimethylaminoprop-1-ynyl) phenyl] carbamic acid tert-butyl ester (4.0 g) in dichloromethane (30 mL) was added in small portions

3-chloroperoxybenzoic acid (2.34 g). The reaction mixture was stirred at 0 ° C for 20 minutes, then the mixture was passed through twenty weight equivalents of basic alumina (Brockman Grad I, 150 mesh) and the N-oxide eluted using 5% methanol in dichloromethane. All fractions containing the desired amine Noxide are combined and evaporated to dryness under reduced pressure. The residue is treated successively with three portions of methanol (about 50 mL), followed by evaporation to near dryness under reduced pressure, and the volume of the solution is adjusted to 250 mL by adding methanol. The methanolic N-oxide solution is then heated at reflux for about 15 hours, then cooled and the solvent is evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography (80% ethyl acetate in hexanes was used as eluent) to give the desired product as a pale yellow solid.

Example 44 (Method 17) (3-Chloro-4-isoxazol-5-yl-phenyl) -carbamic acid tert-butyl ester

A solution of (3-chloro-4- (3-dimethylaminoacryloyl) phenyl) carbamic acid tert -butyl ester (270 mg) in dioxane (3 mL) was treated with hydroxylamine hydrochloride (122 mg) and the mixture was stirred at room temperature for 10 days. Dilute with ethyl acetate, wash sequentially with water, 5% aqueous sodium bicarbonate, saturated aqueous sodium chloride, and then dry over anhydrous magnesium sulfate. ) to give the desired product as a colorless solid.

Example 45 (Method 18) [3-Chloro-4- (1H-pyrazol-3-yl) -phenyl] -carbamic acid tert-butyl ester

A solution of [3-chloro-4- (3-dimethylamino-acryloyl) -phenyl] -carbamic acid tert-butyl ester (250 mg) in ethanol (1.25 mL) was treated with hydrazine hydrate (0.25 mL) and the mixture was stirred for 3 hours at room temperature. The mixture was then diluted with 30 mL of diethyl ether, washed three times with water, once with saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent is removed by evaporation under reduced pressure and the resulting residue is chromatographed on silica gel (67% ethyl acetate in hexanes is used as the eluent) to give the desired product as an oil.

Example 46 (method 19A)

N- (2-chloro-4-nitrophenyl) -2-thiomorpholin-4-yl-acetamide

To a solution of N- (chloroacetyl) -2-chloro-4-nitroanaline (3.80 g) in tetrahydrofuran (50 mL) was added thiomorpholine (10 mL) and the solution was allowed to stand for 1 hour. The reaction mixture was poured into water and the pale yellow solid was collected and then recrystallized from hot 2-propanol to give a pale yellow crystalline solid.

The following compounds were prepared as described above, using appropriate starting materials:

(4- {2- [Bis- (2-hydroxy-ethyl) -amino] -acetylamino] -phenyl) -carbamic acid tert-butyl ester tert-Butyl [4- (2-dimethylamino-acetylamino) -phenyl] -carbamic acid tert-butyl ester (4- [3- ( 2-Dimethylaminoethoxy) benzoylamino] 79 phenyl} carbamic acid tert -Butyl {4- [3- (2-morpholin-4-ylethoxy) benzoylamino] phenyl} carbamate

N- (2-chloro-4-nitrophenyl) -2-dimethylamino-acetamide

N- (2-Chloro-4-nitrophenyl) -2-piperidin-1-ylacetamide

N- (2-chloro-4-nitrophenyl) -2-acetamide-morfolín_4

N- (2-chloro-4-nitrophenyl) -2-dipropylamino

N- (2-chloro-4-nitrophenyl) -2-thiomorpholin-4-yl-acetamide

N- (2-chloro-4-nitrophenyl) -2-dietylaminoacetamid

N- (2-chloro-4-nitrophenyl) -2-pyrrolidin-l-yl-acetamide

2-azepan-l-yl-N- (2-chloro-4-nitrophenyl) acetamide

N- (2-chloro-4-nitrophenyl) -2- (2-methylpiperidin-l-yl) acetamide

N- (2-chloro-4-nitrophenyl) -2- (3-methylpiperidin-l-yl) acetamide

N- (2-chloro-4-nitrophenyl) -2- (4-methylpiperidin-l-yl) acetamide

Example 47 (method 19B)

N- (2-chloro-4-nitrophenyl) -2- (2-ethylsulfanyl)

Acetamid

To a solution of N- (chloroacetyl) -2-chloro-4-nitroaniline (3.01 g) in N, N-dimethylformamide (100 mL) was added powdered sodium carbonate (6.0 g) and 2-dimethylaminoethanethiol hydrochloride (6.0 g). The mixture was stirred at 25 ° C for 1 hour, poured into water and extracted with ethyl acetate. The ethyl acetate solution was dried over anhydrous potassium carbonate and concentrated under reduced pressure to give an oil.

The oil was crystallized from toluene-hexanes (3: 1) to give a pale yellow crystalline solid.

Example 48 (method 20)

(4-tert-Butoxycarbonylamino-2) 2-piperidin-1-yl-ethyl ester

(chlorophenyl) carbamic acid

To a suspension of 1,1-carbonyl-di- (1,2,4) triazole (4.0 g) in dichloromethane (40 mL) was added dropwise a solution of tert-butyl ester (4-amino-3-chlorophenyl) over 20 minutes. carbamic acid (5.0 g) in dichloromethane (45 mL). The reaction mixture was stirred at room temperature for 30 minutes until a precipitate began to form. To this mixture was added piperidineethanol (6.6 mL) and tetrahydrofuran (20 mL) to maintain homogeneity. The reaction mixture was stirred at reflux overnight, then cooled and poured into water, the organic layer separated and then washed with saturated aqueous sodium chloride. The solution was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Crude oil was obtained, which was purified by silica gel chromatography (5% methanol in dichloromethane was used as the eluent) to give the desired product as a white foam.

Example 49 (method 21)

5-Phenyl- [1,2,3] thiadiazole-4-carboxylic acid methyl ester

A solution of ethylbenzoylacetate (1.1 g) in acetonitrile (10 mL) was treated with 4-methylbenzenesulfonylazide (1.3 g) and triethylamine (1.6 g). The reaction mixture was stirred overnight at room temperature, then concentrated under reduced pressure, and the resulting crude product was dissolved in ethyl acetate and washed with 1N sodium hydroxide. The organic layer was then dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a yellow oil. This oil was taken up in dichloromethane and filtered through a pad of magnesium silicate containing water, eluting with dichloromethane to give a partially pure diazoketone as a colorless oil. A sample of diazoketone collected from above (1.2 g) was dissolved in toluene (25 ml) and treated with 2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetane-2,4-disulfide ( 2.8 g) and the reaction mixture is heated to reflux. After 3 hours, warm the reaction mixture to room temperature, place it on a pad of silica gel and elute with dichloromethane. After removal of the solvent under reduced pressure, the residual oil was purified by silica gel chromatography (30% diethyl ether in petroleum ether was used as eluent) and then recrystallized from hexanes to give the desired product as yellow needles.

The following compounds were prepared as described above, using appropriate starting materials:

5-Phenyl- [1,2,3] thiadiazole-4-carboxylic acid ethyl ester 5-Methyl- [1,2,3] thiadiazole-4-carboxylic acid ethyl ester

Example 50

Ethylbenzoylacetate semicarbazide

Ethylbenzoylacetate (5.0 g) was dissolved in methanol (10 mL) and added rapidly to a hot solution of semicarbazide hydrochloride (29 g) in water (130 mL). To this was added pyridine (4.1 g), the reaction mixture was heated at reflux for 5 minutes and then cooled overnight at -20 ° C. The resulting semicarbazone solid is collected by filtration, washed with water and then with diethyl ether to give the desired product as white crystals.

The following compounds were prepared as described above, using appropriate starting materials:

Ethyl (Z) -3 - [(aminocarbonyl) hydrazono] -4,4,4-trifluorobutanoate 3 - [(Z) -2- (aminocarbonyl) hydrazono] -3-phenylpropanoic acid ethyl ester

3 - [(E) -2- (Aminocarbonyl) hydrazono] -3- (3-furyl) propanoic acid ethyl ester

Example 51

5-Phenyl- [1,2,3] thiadiazole-5-carboxylic acid ethyl ester

A solution of semicarbazone ethylbenzoylacetate (2.5 g) in neat thionyl chloride (5 mL) was stirred at 0 ° C for 1 h. Dichloromethane (25 mL) was then added and excess thionyl chloride was slowly removed with saturated aqueous sodium bicarbonate. The precipitate formed by quenching is removed by filtration and the filtrate is extracted with dichloromethane. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Silica gel chromatography (50% hexane in dichloromethane is used as the eluent) gives the desired product as a colorless oil.

The following compounds were prepared as described above, using appropriate starting materials:

4-Methyl- [1,2,3] thiadiazole-5-carboxylic acid methyl ester 4-Phenyl- [1,2,3] thiadiazole-5-carboxylic acid ethyl ester 4-Furan-3-yl- [1,2, 3] thiadiazole-5-carboxylic acid

Example 52

4-Methyl- [1,2,3] thiadiazole-5-carboxylic acid

4-Methyl- [1,2,3] thiadiazole-5-carboxylic acid methyl ester (1.7 g) was dissolved in methanol (15 mL) and treated with 1 N sodium hydroxide (16 mL). The reaction mixture was stirred at room temperature for 1 hour, then treated with concentrated hydrochloric acid (1.5 mL) and concentrated under reduced pressure. The resulting cloudy aqueous layer was extracted twice with diethyl ether, and the combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound as a white powder.

The following compounds were prepared as described above, using appropriate starting materials:

3- Ethoxycarbonylmethoxybenzoic acid

5-Furan-3-yl- [1,2,3] thiadiazole-4-carboxylic acid Thiazole-4-carboxylic acid

4-Methyl- [1,2,3] thiadiazole-5-carboxylic acid

5-Methyl- [1,2,3] thiadiazole-4-carboxylic acid

Example 53 (method 25)

Trifluoromethanesultonic acid 4-chloro-5-methoxy-2-nitrophenyl ester

To a solution of 4-chloro-5-methoxy-2-nitrophenol (6.5 g) in dichloromethane (150 mL) at 0 ° C was added triethylamine (10 g) followed by a solution of trifluoromethanesulfonic anhydride (13.5 g). g) in dichloromethane (30 mL). The solution was stirred at 0 ° C for 10 minutes, then diluted with dichloromethane and washed sequentially with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent is removed by evaporation under reduced pressure and the residue is dissolved in a solution of 20% dichloromethane in hexanes and passed through a short column of hydrated magnesium silicate (20% dichloromethane in hexanes is used as eluent). Fractions containing product were combined and the solvents were removed by evaporation under reduced pressure to give the desired product as a yellow oil.

The following compounds were prepared as described above, using appropriate starting materials:

Trifluoromethanesulfonic acid 4-chloro-5-methoxy-2-nitrophenyl ester

Trifluoromethanesulfonic acid 4-chloro-2-nitrophenyl ester

Trifluoromethanesulfonic acid 2-chloro-6-nitrophenyl ester

Example 54 (Method 26) [4- (3-Dimethylamino-benzoylamino) -phenyl] -carbamic acid tert-butyl ester

A solution of [4- (3-aminobenzoylamino) phenyl] carbamic acid tert-butyl ester (505 mg), sodium cyanoborohydride (250 mg), acetic acid (3 drops) and 40% aqueous formaldehyde (4 mL) in tetrahydrofuran-methanol (1: 2) (15 mL) was stirred for 15 minutes, then poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The ethyl acetate solution was dried over anhydrous potassium carbonate and concentrated under reduced pressure to give a solid which was recrystallized from acetonitrile to give a light pink crystalline solid.

The following compounds were prepared as described above, using the appropriate starting materials:

[4- (3-Dimethylaminobenzoylamino) phenyl] carbamic acid tert-butyl ester (3-Bromo-5-trifluoromethylphenyl) dimethylamine

N- (3-Chloro-5-dimethylamino-phenyl) -acetamide

Example 55 (method 27)

N- (4-Aminophenyl) -2-hydroxybenzamide

To a solution of 2- (4-aminophenylcarbamoyl) phenylacetate (580 mg) in methanol (10 mL) was added saturated sodium bicarbonate (2 mL) and water (3 mL). The mixture was heated at 80 ° C for 30 min, then poured into half-saturated aqueous sodium chloride and extracted with ethyl acetate. The ethyl acetate solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an oil which was treated with diethyl ether to give the desired product as a white solid.

Example 56 (method 28)

[4- (3-Hydroxybenzoylamino) phenyl] carbamic acid butyl ester

To a solution of 3- (4-aminophenylcarbamoyl) phenylacetate (4.34 g) in methanol (75 mL) was added 0.1 N aqueous sodium hydroxide (25 mL) and tetrahydrofuran (25 mL). This solution was heated at 40 ° C for 30 minutes, then cooled, poured into 1M hydrochloric acid and extracted with ethyl acetate. The ethyl acetate solution was dried over anhydrous sodium sulfate, concentrated under reduced pressure to give an oil, which was further purified by trituration with diethyl ether.

Example 57 (method 29)

N- (4-Aminophenyl) -2-hydroxymethylbenzamide

To a solution of N- (4-aminophenyl) phthalimide (332 mg) in tetrahydrofuran (4 mL) was added lithium borohydride (1.0 g) and the mixture was stirred at 25 ° C for 1 hour. The mixture was poured into water and extracted with ethyl acetate. The ethyl acetate solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a white foam which was then treated with diethyl ether to give the desired product as a white powder.

Example 58 (Method 30) (3-Chloro-5-dimethylaminophenyl) -carbamic acid tert-butyl ester

To a solution of (3-amino-5-chloro-phenyl) -carbamic acid tert-butyl ester (0.32 g) in toluene (10 mL) was added aqueous formaldehyde (37%, 1.5 mL), followed by 10% palladium on carbon (0). , 50 g) and stirred under a hydrogen atmosphere for about 15 hours. The solution was then filtered through diatomaceous earth and the filtrate was concentrated under reduced pressure. The residue is chromatographed on silica gel (50% dichloromethane in hexanes is used as the eluent) to give the desired product as a white solid.

Example 59 (method 35)

N- (4- {3- (3,5-Dichloro-4- (2-hydroxyethoxy) phenyl] thioureido} -phenyl) -acetamide

To a solution of acetic acid 2- {4- [3- (4-acetylaminophenyl) thioureido] -2,6-dichloro-phenoxyethyl ester (0.16 g) in a 1: 1 mixture of tetrahydrofuran and methanol (2.5 mL) was added 1N aqueous sodium hydroxide (1 mL) and the mixture was stirred at room temperature for about 2 hours. The solution was then poured into 2M aqueous hydrochloric acid (3 mL), extracted with ethyl acetate, and the extracts dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure and the residue was treated with diethyl ether to give the desired product as a white solid.

Example 60 (Method 36) {4- [3- (4-Acetylaminophenyl) thioureido] -2,6-dichlorophenoxy] acetic acid

To a solution of {4- (3- (4-acetylaminophenyl) thioureido) 2,6-dichlorophenoxylacetic acid ethyl ester (0.29 g) in a 1: 1 mixture of tetrahydrofuran and methanol (4 mL) was added 1 N aqueous sodium hydroxide (2). The solution was then poured into 2M aqueous hydrochloric acid (5 mL), extracted with ethyl acetate, and the extracts were dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to leave a residue. with diethyl ether to give the desired product as a white solid.

The following compounds were prepared as described above, using appropriate starting materials:

{4- [3- (4-Acetylaminophenyl) thioureido] -2,6-dichlorophenoxy] acetic acid {2- [3- (4-Acetylaminophenyl) thioureido] -4-chloro-5-methoxyphenoxy} acetic acid {4- [ 3- (4-Acetylaminophenyl) thioureido] -2-chloro-5-methoxyphenoxy} acetic acid

Example 61 (method 37)

Benzoic acid 2- {4- [3- (4-acetylaminophenyl) thioureido] -2,6-dichlorophenoxy} ethyl ester

To an ice-cold solution of N- (4- {3- [3,5-dichloro-4- (2-hydroxy-ethoxy) -phenyl] -thioureido] -phenyl) -acetamide (0.20 g) in pyridine (2 mL) and tetrahydrofuran (0). (5 mL) was added benzoyl chloride (0.08 g) and the mixture was stirred at 0 ° C for 1.5 h. The mixture was then diluted with ethyl acetate, washed successively twice with 2% aqueous hydrochloric acid, once with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was then chromatographed on silica gel (5% methanol in dichloromethane was used as the eluent) and the product containing fractions were combined, evaporated under reduced pressure, and the residue was recrystallized from acetone-hexanes to give the desired product. as a white powder.

Example 62 (method 38)

Methanesulfonic acid 2- {4- [3- (4-acetylaminophenyl) thioureido] -2,6-dichlorophenoxy} ethyl ester

To an ice-cold solution of N- (4- {3- [3,5-dichloro-4- (2-hydroxyethoxy) phenyl] thioureido) phenyl) acetamide (0.20 g) in pyridine (2 mL) and tetrahydrofuran (0, 5 mL) was added methanesulfonyl chloride (0.11 g) and the solution was stirred at 0 ° C for 45 min. The reaction mixture was then diluted with ethyl acetate, washed successively twice with 2% aqueous hydrochloric acid, once with saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was then recrystallized from acetone / hexanes to give the desired product as a white powder.

Example 63 (method 39)

N- (4- {3- [3,5-Dichloro-4- (2-dimethylaminoethoxy) phenyl] thioureido} phenyl) acetamide

To a solution of methanesulfonic acid 2- {4- [3- (4-acetylaminophenyl) thioureido] -2,6-dichloro-phenoxy] -ethyl ester (0.33 g) in tetrahydrofuran (6 mL) was added aqueous dimethylamine [8.8 M, 0.5 ml) and the mixture was stirred at room temperature for 5 days. The reaction mixture was then diluted with ethyl acetate, then washed with saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was then chromatographed on silica gel (using pure methanol as eluent). The combined product containing fractions was evaporated under reduced pressure and the residue was recrystallized from acetonitrile to give the desired product as a white powder.

The following compounds were prepared as described above, using appropriate starting materials:

N- (4- {3- [3,5-Dichloro-4- (2-dimethylaminoethoxy) phenyl] thioureido} phenyl) acetamide

Benzoic acid 2- {4- (3- (4-acetylaminophenyl) thioureido], -2,6-dichlorophenoxy} ethyl ester

Example 64 (method 40) Furan-2-carboxylic acid 4- (3- (4- (1-aminoethyl) -3-chlorophenyl) thioureido} phenyl) amide

To a solution of stannous chloride dihydrate (0.25 g) in methanol (2.5 mL) was added furan-2-carboxylic acid (4- {3- [4- (1-azidoethyl) -3-chlorophenyl] thioureido} phenyl) amide. acid (0.22 g) and the solution was stirred at room temperature for about 15 hours. The solution was then diluted with ethyl acetate, washed successively with saturated aqueous sodium bicarbonate, then saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure and the residue was then chromatographed on silica gel (8% methanol in dichloromethane containing 1% triethylamine as eluent) to give the desired product as a yellow solid.

Example 65 (Method 41) [1,2,3] Thiadiazole-4-carboxylic acid (4-isothiocyanatophenyl) amide

To an ice cold solution of 1,1'-thiocarbonyldiimidazole (7.28

g) [1,2,3] Thiadiazole-4-carboxylic acid (4-aminophenyl) amide (9.0 g) in tetrahydrofuran (100 ml) was added in tetrahydrofuran (50 ml). After about 1 hour, the solvent was removed by evaporation under reduced pressure and the residue was dissolved in ethyl acetate. Diethyl ether was added and the crude product precipitated, which was then collected by filtration, dissolved in dichloromethane, and passed through a hydrous magnesium silicate step. The solvents were removed and the residue was then recrystallized from ethyl acetate / hexane to give the desired product as a slightly yellow solid.

The following compounds were prepared as described above, using appropriate starting materials:

[1,2,3] Thiadiazole-4-carboxylic acid (4-isothiocyanato-phenyl) -amide (4-isothiocyanatophenyl) -amide (4-isothiocyanatophenyl) -amide (4-isothiocyanatophenyl) amide Thiazole 2-fluoro-N- (4-isothiocyanatophenyl) -4-carboxylic acid

Example 66 (method 42)

N, N-dimethyl-5-trifluoromethyl-benzene-1,3-diamine

To a solution of 3-amino-5-bromobenzotrifluoride (1.0 g) in degassed (argon) tetrahydrofuran (2 mL) was added bis (tri-o-tolylphosphine) palladium (0.15 g), a solution of dimethylamine in tetrahydrofuran (2M, 4.2 mL), and a solution of lithium bis (trimethylsilyl) amide in tetrahydrofuran (1M, 10.4 mL). The reaction mixture is stirred in a sealed vessel at 100 ° C for about 2.5 hours to complete the reaction. The mixture was then cooled to room temperature, quenched with water and diluted with ethyl acetate. The product was extracted three times with 5% aqueous hydrochloric acid, and the combined acid extracts were then basified by cooling with 5N aqueous sodium hydroxide while cooling. This basic solution was then extracted with ethyl acetate, and the combined organic extracts were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and evaporated to dryness under reduced pressure. The resulting residue is chromatographed on silica gel (20-30% ethyl acetate in hexanes is used as the eluent) to give the desired product as a slightly colored solid.

The following compounds were prepared as described above, using appropriate starting materials:

3- (4-Methyl-piperazin-l-yl) -5-trifluoromethyl-phenylamine

3-morpholin-4-yl-5-trifluoromethyl-phenylamine

3-Piperidin-l-yl-5-trifluoromethyl-phenylamine

3-pyrrolidin-l-yl-5-trifluoromethyl-phenylamine

N, N-Dimethyl-5-trifluoromethylbenzene-1,3-diamine N-Isobutyl-N-methyl-5-trifluoromethylbenzene-1,3-diamine N-Butyl-N-methyl-5-trifluoromethylbenzene-1,3-diamine

Example 67 (Method 43) (3-Isobutyl-5-trifluoromethyl-phenyl) -carbamic acid tert-butyl ester

Isobutylene was bubbled through a sealed tube containing tetrahydrofuran (5 mL), sealed with a rubber plug, and cooled in a dry ice-acetone bath for approximately 5 minutes. A solution of 9-borabicyclo [3.3.1] nonane in tetrahydrofuran (0.5 M, 11 mL) is added, the vessel is sealed with a Teflon cap and slowly warmed to room temperature, where it is maintained for about 2.5 hours. The mixture was then re-cooled in dry Zad-acetone bath, the Teflon step was replaced with a rubber plug, and argon was bubbled through the mixture to vent excess isobutylene. First, a solution of (3-bromo-5-trifluoromethyl-phenyl) -carbamic acid tert-butyl ester (1.7 g) in tert-butyl ester was added. tetrahydrofuran (12 mL), followed by [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) chloride (0.12 g), then 3N aqueous sodium hydroxide. The vessel was resealed with a Teflon cap and then heated at 65 ° C for about 15 hours. The mixture was then cooled to room temperature, diluted with hexanes, washed with water, saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The resulting oil is chromatographed on silica gel (5% ethyl acetate in hexanes is used as eluent) to give the desired product as a white powder.

The following compounds were prepared as described above, using appropriate starting materials:

[3- (2-Methyl-butyl) -5-trifluoromethyl-phenyl] -carbamic acid tert-butyl ester tert-Butyl (3-isobutyl-5-trifluoromethyl-phenyl) -carbamic acid tert-butyl ester

Example 68 (method 44)

2- (3,5-Dichloro-phenylsulfanyl) -ethylamine

To a solution of (3,5-dichlorophenylthio) acetonitrile (1.2 g) in 3.0 mL of ethylene glycol dimethyl ether was added 0.61 mL of 10 M borane-dimethylsulfide complex and the mixture was heated under reflux for 0.5 h. The reaction mixture was cooled in an ice bath and 2.0 mL of water and 2.0 mL of concentrated hydrochloric acid were added. The mixture was heated to reflux for 0.5 hours. The clear solution was then cooled and basified with 5N sodium hydroxide and extracted with ether. The ether extract was dried over potassium carbonate, filtered and concentrated to give 1.0 g of a colorless oil.

The following compounds were prepared as described above, using appropriate starting materials:

2- (3-Bromo-phenylsulfanyl) -ethylamine

2- (4-Bromophenoxy) ethylamine

2- (4-Iodophenoxy) ethylamine

2- (3,4-Dichloro-phenoxy) -ethylamine

2- (3-Chlorophenylsulfanyl) ethylamine

2- (3,4-Dichlorophenylsulfanyl) ethylamine

3- (4-Bromophenyl) propylamine

2- (2-Fluoro-phenoxy) -ethylamine

2- (2-Chlorophenoxy) ethylamine

2- (3-Bromophenoxy) ethylamine

2- (3-Fluoro-phenoxy) -ethylamine

2- (3-Iodophenoxy) ethylamine

2- (3,5-Dichloro-phenylsulfanyl) -ethylamine

2-Phenylsulfanyl

1- (2-Chloro-phenyl) -ethylamine

Example 69 (method 45)

N- (l-naphthalen-2-ylethyl) formamide

A mixture of 2-acetylnaphthylene (3.0 g), ammonium formate (11.0 g), formic acid (3.3 ml), and formamide (3.5 ml) was heated at 190 ° C for 3 hours. The mixture was cooled, poured into water and extracted with ether. The ether extract was dried over anhydrous potassium carbonate, filtered and concentrated to give a yellow oil which was crystallized from toluene-hexanes to give 1.97 g of a white solid.

The following compounds were prepared as described above, using appropriate starting materials:

N- [1- (4-Fluorophenyl) -2-methylpropyl] formamide

N- (l-naphthalen-2-ylethyl) formamide

Example 70 (method 46)

1- (2-Naphthyl) ethylamine

A mixture of N- (1-naphthalen-2-ylethyl) formamide (1.12 g), ethanol (10 mL), and 5N sodium hydroxide (10 mL) was heated at reflux for 1 hour. The solution was cooled, poured into water and extracted with ether.

The ether solution was dried over anhydrous potassium carbonate, filtered and concentrated to give the product (0.95 g) as a pale yellow oil.

The following compounds were prepared as described above, using appropriate starting materials:

1- (3-trifluoromethylphenyl) -ethylamine

1- (4-Fluorophenyl) -2-methylpropylamine [3- (1-Aminoethyl) phenyl] dimethylamine

3- (1-Amino-ethyl) -benzonitrile

Example 71 (method 47)

O-Methyloxime 1- (3-trifluoromethylphenyl) ethanone

Methoxylamine hydrochloride (2.33 g) was added to a solution of 3 '(trifluoromethyl) acetophenone (1.5 g) in ethanol (20 mL) and pyridine (2 mL). The solution was heated to reflux for 45 minutes. The reaction mixture was then cooled, concentrated under reduced pressure and partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the desired product as a colorless oil (1.61 g).

The following compounds were prepared as described above, using appropriate starting materials:

3,5-Bistrifluoromethylbenzaldehyde oxime

1- (4-Fluorophenyl) propan-1-one O-methyloxime

O-Methylloxime of 1- (2-chlorophenyl) ethanone

O-Methylloxime of 1- (3-bromophenyl) ethanone

O-Methylloxime of 1- (3-chlorophenyl) ethanone

O-Methylloxime of 1-p-tolylethanone

O-Methylloxime of 1- (4-fluorophenyl) pentan-1-one

O-Methylloxime of 1- (4-fluorophenyl) -2-phenylethanone

O-Methyloxime of 1-o-tolylethanone

O-Methyloxime of 1-m-tolylethanone

O-Methylloxime of 1- (2-fluorophenyl) ethanone

3- (1-Methoxyiminomethyl) benzonitrile

4- (1-Methoxyiminomethyl) benzonitrile

O-Methylloxime of 1- (4-methoxyphenyl) ethanone

O-Methylloxime of 1- (2-methoxyphenyl) ethanone

O-Methyloxime of 1- (4-dimethylaminophenyl) ethanone

O-Methylloxime of 1- (2-trifluoromethylphenyl) ethanone

O-Methylloxime of 1- (3-methoxyphenyl) ethanone

O-Methylloxime of 1- (3-trifluoromethylphenyl) ethanone

O-Methylloxime of 1- (4-trifluoromethylphenyl) ethanone

O-Methyloxime of 1-furan-2-ylethanone

O-Methyloxime 1-pyridin-4-ylethanone

O-Methyloxime 1- (1-methyl-1H-pyrrol-2-yl) ethanone

O-Methyloxime of 1-thiophen-3-ylethanone

O-Methyloxime (4-fluorophenyl) phenylmethanone

O-Methylloxime of 1- (4-methoxyphenyl) ethanone

O-Methylloxime of 1- (3-chloro-4-methoxyphenyl) ethanone

4- (1-Metoxyiminetyl) -benzenesulfonamide

4- (1-Methoxyiminetyl) -N, N-dimethylbenzenesulfonamide

O-Methylloxime of 1- (4- (piperidine-1-sulfonyl) phenyl) ethanone

4- (1-Metoxyiminetyl) -N, N-dipropylbenzénsulfonamid

2-Fluoro-N- [4- (1-metoxyiminetyl) -phenyl] -benzamide

O-Methylloxime of 1- (3,5-bistrifluoromethylphenyl) ethanone

O-Methylloxime 1- [4- (1H-imidazol-1-yl) phenyl] -1-ethanone

O-Methylloxime of 1- [4- (trifluoromethyl) phenyl] -1-ethanone

O-Methylloxime of 1- [1,1-Biphenyl] -4-yl-1-ethanone

1- (4-Methylphenyl) -1-ethanone O-methyloxime

O-Methylloxime of 1- [4-fluoro-3- (trifluoromethyl) phenyl] ethanone

O-Benzyloxime 1- [3,5-bis (trifluoromethyl) phenyl] ethanone

O-methyl-oxime 1- (4-Chloro-3 (trifluoromethyl) phenyl] ethanone O-methyl-oxime 1- [3-fluoro-5- (trifluoromethyl) phenyl] ethanone O-methyl-oxime 1- (2-fluoro-4- (trifluoromethyl) phenyl] ethanone O-methyl-oxime 1- [2-fluoro-5- (trifluoromethyl) phenyl] ethanone O-methyl-oxime 1- (2,4-dichlorophenyl) ethanone O-methyl-oxime 1- (2,4-dimethylphenyl) ethanone O-methyl-oxime 1- [2,4-bis (trifluoromethyl) phenyl] ethanone O-methyl-oxime 1- (3-bromophenyl) ethanone O-methyl-oxime 1- (3-methylphenyl) ethanone O-methyl-oxime 1- [4- (4-morpholinyl) phenyl] ethanone O-methyl-oxime 1- (2-chloro-4-fluorophenyl) ethanone O-methyl-oxime 1- (4-bromo-2-fluorophenyl) ethanone O-methyl-oxime 1- (3,4-difluorophenyl) ethanone O-methyl-oxime 1- [3- (trifluoromethyl) phenyl] ethanone O-methyl-oxime 1- [2- (trifluoromethyl) phenyl] ethanone O-methyl-oxime O-methyl-oxime 1- (2,4-difluorophenyl) ethanone 1- [3-fluoro-4- (trifluoromethyl) phenyl] ethanone O-methyl-oxime 1- (3,4-dichlorophenyl) ethanone O-methyl-oxime 1- [4-fluoro-2- (trifluoromethyl) phenyl] ethanone O-methyl-oxime 1- (3-chloro-4-fluorophenyl) ethanone O-methyl-oxime 1- (4-chloro-3-fluorophenyl) ethanone O-methyl-oxime 1- (2,5-difluorophenyl) ethanone O-methyl-oxime 1- (2-bromo-4-fluorophenyl) ethanone

O-Methylloxime of 1- (3,4-dibromophenyl) ethanone

O-Methyloxime 1- (2-bromophenyl) ethanone

Example 72 (method 48)

2- (2-trifluoromethylphenyl) ethylamine

Sodium borohydride (1.17 g) was slowly added to a flask containing zirconium tetrachloride (1.8 g) in tetrahydrofuran (27 mL). A solution of 1- (2-trifluoromethylphenyl) ethanone O-methyloxime (1.34 g) in tetrahydrofuran (7.7 mL) was added and the resulting solution was stirred at 25 ° C for 12 h. The reaction mixture was then cooled to 0 ° C and water (16 mL) was added slowly. Excess ammonium hydroxide was added and the solution was extracted twice with ethyl acetate. The organic portion was washed twice with 1N hydrochloric acid. The aqueous (acidic) layer was basified with sodium hydroxide and extracted twice with ethyl acetate. The organic layer was then washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the desired product as a yellow oil (0.20 g).

The following compounds were prepared as described above, using appropriate starting materials:

1- (3-methoxyphenyl) ethylamine

1- (4-Fluorophenyl) propylamine 1-Naphthalen-2-ylethylamine

4- (l-Amino-ethyl) -benzonitrile

1- (4-Trifluoromethyl-phenyl) -ethylamine

1- (4-Methoxyphenyl) ethylamine 1-Prop-2-ynylpyrrolidine 1- (2-Methoxyphenyl) ethylamine 1-m-Tolylethylamine

1- (2-Bromo-phenyl) -ethylamine

1-on-tolylethylamine

C- (4-Fluoro-phenyl) -C-phenylamine

1- (4-fluorophenyl) pentyl amine

I- (4-Fluorophenyl) -2-phenylethylamine

1- (2-Trifluoromethylphenyl) ethylamine

1- (3-Bromophenyl) ethylamine

1- (3-Chlorophenyl) ethylamine [4- (1-Aminoethyl) phenyl] dimethylamine

1- (1-Methyl-1H-pyrrol-2-yl) ethylamine 1-Thiophen-3-ylethylamine

1- [3,5-Bis (trifluoromethyl) phenyl] propylamine

1- [3,5-Bis (trifluoromethyl) phenyl] -1-butanamine;

1- [3,5-bis (trifluoromethyl) phenyl] butylamine

1- [3,5-bis (trifluoromethyl) phenyl] -1-pentaneamine

1- (4-methylphenyl) ethanamine

1- [3- (trifluoromethyl) phenyl] ethylamine

1- [4- (trifluoromethyl) phenyl] ethylamine

1- (3-methylphenyl) ethanamine

1- (3,4-dichlorophenyl) ethanamine

1- (2-Bromo-phenyl) -ethylamine

1- (2-trifluoromethylphenyl) ethylamine

1- (3-Bromo-phenyl) -ethylamine

1- (3-Chloro-4-methoxy-phenyl) -ethylamine

4- (1-Aminoethyl) -N, N-dimethylbenzenesulfonamide

1- [4- (Piperidine-1-sulfonyl) phenyl] ethylamine 1-quinolin-6-ylethylamine

1- (3,5-Bis-trifluoromethylphenyl) ethylamine

4 - [(1S) -1-aminoethyl] benzonitrile (S) -alpha-methyl-3,5-bis (trifluoromethyl) benzenemethanamine (S) -alpha-methyl-3,5-bis (trifluoromethyl) benzenemethanamine 1-Biphenyl-4- ethylamine

1- (4-Fluoro-phenyl) -ethylamine

1- [4-Fluoro-3- (trifluoromethyl) phenyl] ethanamine

1- [4-Chloro-3- (trifluoromethyl) phenyl] ethanamine

N- {4 - [(1R) -1-aminoethyl] phenyl} -1,2,3-thiadiazole-4-carboxamide

N- {4 - ((1S) -1-aminoethyl] phenyl] -1,2,3-thiadiazole-4-carboxamide

1- [3-fluoro-5- (trifluoromethyl) phenyl] ethylamine

1- [2-Fluoro-4- (trifluoromethyl) phenyl] ethylamine

1- [2-fluoro-5- (trifluoromethyl) phenyl] ethylamine

1- (2,4-Dichlorophenyl) ethylamine

1- (2,4-Dimethyl-phenyl) -ethylamine

1- [2,4-Bis (trifluoromethyl) phenyl] ethylamine

1- (2-chloro-4-fluoro-phenyl) -ethylamine

1- (3,4-Difluorophenyl) ethylamine

1- (4-Bromo-2-fluorophenyl) ethylamine

1- (3-Fluoro-phenyl) -ethylamine

1- (2,4-Difluorophenyl) ethylamine

1- [3-Fluoro-4- (trifluoromethyl) phenyl] ethylamine

1- [4-Fluoro-2- (trifluoromethyl) phenyl] ethylamine

1- (3-chloro-4-fluoro-phenyl) -ethylamine

1- (4-Chloro-3-fluoro-phenyl) -ethylamine

1- (3,4-dibromophenyl) ethylamine

1- (2-Bromo-4-fluorophenyl) ethanamine-1- (2-bromo-4-fluorophenyl) ethylamine

Example 73 (Method 49) (2-Fluoro-5-trifluoromethylphenoxy) acetonitrile

A solution of 2-fluoro-5-trifluoromethylphenol (25 g) in acetone of the reaction step (0.55 L) was treated with solid potassium carbonate (7.7 g), followed by rapid addition of pure bromoacetonitrile (10 mL). The heterogeneous mixture was stirred vigorously for about 20 hours, then poured into water and extracted with diethyl ether. The combined ether extracts were washed with saturated sodium chloride and dried over anhydrous potassium carbonate. Filtration and concentration under reduced pressure gave a pale orange solid, which was then chromatographed on silica gel (dichloromethane used as eluent) to give the desired product as a white solid (28.3 g).

The following compounds were prepared as described above, using appropriate starting materials:

(3-Bromo-phenylsulfanyl) -acetonitrile

100 (3-Chlorophenylsulfanyl) acetonitrile (4-Iodophenoxy) acetonitrile (3-Trifluoromethylphenylsulfanyl) acetonitrile (3,5-Dichlorophenylsulfanyl) acetonitrile (3,4-Dichlorophenylsulfanyl) acetonitrile (3,4-Dichlorophenoxy) acetonitrile (3,4-Dichlorophenoxy) acetonitrile (3,4-Dichlorophenoxy) 3-Fluorophenoxy) acetonitrile (2-Chlorophenoxy) acetonitrile (3-bromophenoxy) acetonitrile (2-Fluoro-5-trifluoromethylphenoxy) acetonitrile (3-iodophenoxy) acetonitrile (4-bromophenoxy) acetonitrile

Example 74 (method 50)

3-Fluoro-5-trifluoromethylphenethylamine tosylate

A solution of 3-fluoro-5-trifluoromethylphenylacetonitrile and 2.34 g (12.3 mmol) of p-toluenesulfonic acid in 75 ml of ethylene glycol monomethyl ether was hydrogenated for 3 hours at room temperature at 50 psi using 200 mg of 10% palladium on carbon catalyst. The catalyst was filtered off and the solvent was evaporated. in half. Upon standing, the p-toluenesulfonic acid salt of the desired 3-fluoro-5-trifluoromethylphenethylamine crystallizes. White crystals, 4.26 g (91%), were collected by filtration.

The following compounds were prepared as described above, using appropriate starting materials:

2- (3,5-Difluorophenyl) ethylamine

2- (4-Trifluoromethylphenyl) ethylamine

2- (3,4-Difluorophenyl) ethylamine

101

2- (2-fluorophenyl) ethylamino

2- (3-Fluoro-5-trifluoromethyl-phenyl) -ethylamine

2- (2-fluoro-3-trifluoromethylphenyl) ethylamine

2- (2,4-Bis-trifluoromethylphenyl) ethylamine

2- (4-Fluoro-3-trifluoromethylphenyl) ethylamine

Example 75 (Method 51) (4-Aminomethyl-2-trifluoromethyl-phenyl) -dimethylamine

A solution of 4-dimethylamino-3-trifluoromethylbenzonitrile (0.35 g) in tetrahydrofuran (2 mL) was slowly added to a suspension of lithium aluminum hydride (0.1 g) in tetrahydrofuran (2 mL) and stirred at 0 ° C under argon 2. hours. After a while, water (0.1 mL) was added slowly at 0 ° C, followed by 5% sodium hydroxide (0.1 mL) and water (0.3 mL). The resulting gray solid was filtered and washed with tetrahydrofuran. The filtrates were collected and concentrated under reduced pressure and the resulting oil was chromatographed on silica gel (15% methanol in methylene chloride was used as eluent) to give the desired product as a pale orange oil (0.164 g).

The following compounds were prepared as described above, using appropriate starting materials:

4-Piperidin-1-yl-3-trifluoromethylbenzylamine (4-Aminomethyl-2-trifluoromethylphenyl) dimethylamine 4- (4-Methylpiperazin-1-yl) -3-trifluoromethylbenzylamine (3-Aminomethyl-5-trifluoromethylphenyl) dimethylamine [3- ( 2-Aminomethyl) -5-trifluoromethylphenyl] dimethylamine [4- (2-Aminoethyl) -2-methylphenyl] dimethylamine

Example 76 (method 52)

3-dimethylamino-5-trifluoromethylbenzaldehyde

102

Diisobutylaluminium hydride (10 ml of 1M solution in methylene chloride) was added dropwise to a solution of 3-dimethylamino-5-trifluoromethylbenzonitrile (1.06 g) in methylene chloride (25 ml) and the mixture was stirred at 0 ° C for 2 hours. After a while, a saturated aqueous solution of sodium and potassium tartrate is added slowly at 0 ° C and the solution is stirred for 1.5 hours. The reaction mixture was then extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the desired product as a yellow solid (0.97 g).

The following compounds were prepared as described above, using appropriate starting materials:

3-Dimethylamino-5-trifluoromethylbenzaldehyde

4-Dimethylamino-3-methylbenzaldehyde

Example 77 (method 53)

Dimethyl- [3- (2-nitro-vinyl) -5-trifluoromethyl-phenyl] -amine

Nitromethane (0.473 g) was added to a solution of 3-dimethylamino-5-trifluoromethylbenzaldehyde (0.885 g) and ammonium acetate (0.339 g) in acetic acid (3.4 mL) and the solution was heated at 110 ° C for 6 hours. The reaction mixture was cooled to 0 ° C and a solid formed which was filtered and washed with water-acetic acid (1: 1). This solid was recrystallized from ethanol to give the desired product as a red solid (0.39 g).

The following compounds were prepared as described above, using appropriate starting materials:

Dimethyl- [3- (2-nitrophenyl) -5-trifluórmethyfenyl] amine

Dimethyl- [2-methyl-4- (2-nitro-vinyl) -phenyl] -amine

103

Example 78 (method 54)

3- (4-Bromophenyl) propionitrile

Diethyl azodicarboxylate (5.2 g) was added dropwise to the solution

4-bromophenethyl alcohol (2.01 g) and triphenylphosphane (7.9 g) in diethyl ether (16 mL) at 0 ° C. The reaction mixture was stirred for 10 minutes and a solution of acetone cyanohydrin (2.6 g) in diethyl ether (10 mL) was added. The clear orange solution was stirred at 0 ° C for 5 minutes and then at 25 ° C for 12 hours. The reaction mixture was then filtered and washed with diethyl ether. The filtrate was concentrated under reduced pressure and chromatographed on silica gel (10% ethyl acetate-hexanes was used as eluent) to give the desired product as a pale yellow solid (2.04 g).

Example 79 (method 55)

3-Dimethylamino-2-isocyanacrylic acid ethyl ester

To a solution of ethyl isocyanate (5.0 g) in ethanol (100 mL) was added N, N'-dimethylformamide dimethylacetal (6.5 g) dropwise over 10 minutes with stirring. The reaction mixture was stirred for 24 hours and then evaporated. The resulting oil was passed over magnesium silicate using 50% ethyl acetate in hexanes as eluent. The solids were removed and the resulting oil was crystallized from a mixture of ethyl acetate and hexane to give pale yellow needles, 3.0 g.

Example 80 (method 56)

4carboethoxythiazol

To a solution of 3-dimethylamino-2-isocyanacrylic acid ethyl ester (1.0 g) and triethylamine (3.0 g) in tetrahydrofuran (30 mL)

104 is treated with hydrogen sulfide gas until all of the starting material is consumed. The mixture was concentrated to an oil and purified by column chromatography using silica and 25% ethyl acetate in hexanes as eluent. Pure material (0.61 g) was isolated as an oil.

Example 81 (method 34)

N- {4- (3- (5-Chloro-2,4-dimethoxy-phenyl) -ureido] -phenyl} -2-fluoro-benzamide

A suspension of N- (4-aminophenyl) -2-fluorobenzamide (0.43 g) in acetonitrile (4 mL) was treated with 5-chloro-2,4-dimethoxyphenyl isocyanate (0.40 g). The mixture became a solution and allowed to stand for 12 hours. A white solid formed and was collected by filtration (0.79 g). [M + H] 444.

The following compounds were prepared as described above, using appropriate starting materials:

Pr. no. M + H NAME OF Z1ÚČENINY 81 445 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -ureido] -phenyl} -2-fluoro-benzamide 82 441 {N-4- [3 (5-Chloro-2,4-dimethoxy-phenyl) -ureido] - phenyl} -2-methylbenzamide 83 435 {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -ureido] -phenyl} -amide [1,2,3] thiadiazole-4-carboxylic acid 84 443 [4- [3- (4-Chloro-3-trifluormethylfenyllureido] - [1,2,3] Thiadiazole-4-carboxylic acid phenyl} amide 85 453 N- {4- [3- (4-Chloro-3-trifluoromethylphenyl) -ureido] -phenyl} -2-fluoro-benzamide 86 409 {4- [3- (3,5-Dichloro-phenyl) -ureido] -phenyl} -amide [1,2,3] thiadiazole-4-carboxylic acid 87 486 N- {4- [3- (3,5-Bistrifluoromethyl-phenyl) -ureido] -phenyl} -

105

-2-fluoro-benzamide 88 458 Furan-2-carboxylic acid {4- [3- (3,5-Bistrifluoromethyl-phenyl) -ureido] -phenyl} -amide 89 476 [4- [3- (3,5-Bis-trifluoromethylphenyl) -ureido] fenyljamid [1,2,3] thiadiazole-4-carboxylic acid 90 423 [4- [3- [3,4-dichloro-benzyl) -ureido] fenyljamid [1,2,3] thiadiazole-4-carboxylic acid

Example 91

Method 31

N- (5 - {[({(1S) -1- [3,5-

Bis (trifluoromethyl) phenyl] ethyl} amino) carbothioyl] amino} -2-pyridinyl) -1,3-thiazole-4-carboxamide

A mixture of N- (5-isothiocyanato-2-pyridinyl) -1,3-thiazole-4-carboxamide (0.36 g) and (S) -alfamethyl-3,5-bis (trifluoromethyl) benzenemethanamine (0.36 g) Heat with acetonitrile (10 mL) until the solid dissolved. The solution was allowed to stand for 12 hours. The white solid was collected by filtration (0.40 g) [M + H] 520.

Using the above procedure and suitable starting materials, the following compounds were prepared:

EX M + H

NAME OF THE COMPOUND

506 · tert -Butyl ester [3-chloro-5- (3- {4 [([1,2,3] thiadiazole-493 409)]

(carbonyl) amino] phenyl} thioureido) phenyl] carbamic acid

1- (5-chloro-2,4, dimethoxy-phenyl) -3- (4-morpholin-4-yl-phenyl) -thiourea

106

94 370 1- (5-Chloro-2,4-dimethoxyphenyl) -3- (4-methylsulfanyl-phenyl) -thiourea 95 338 1- (5-Chloro-2,4-dimethoxyphenyl) -3-p-tolylthiourea 96 414 {4- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] phenylsulfanyl] acetic acid 97 384 1- (5-Chloro-2,4-dimethoxyphenyl) -3- [4-2-hydroxy- ethoxy) phenyl] thiourea 98 340 1- (5-Chloro-2,4-dimethoxyphenyl) -3- (4-hydroxyphenyl) thiourea 99 395 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] - phenyl} -N-methylacetamide 100 381 N- {3- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] - phenyl} acetamide 101 411 {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -carbamic acid ethyl ester 102 319 1- (2,4-Dimethoxyphenyl) -3- (4- methoxyphenyl) thiourea 103 346 N- {4- [3- (2,4-dimethoxyphenyl) thioureido] -phenyl} -acetamide 104 316 N- {4- [3- (4-Methoxy-phenyl) thioureido] -phenyl} -acetamide 105 316 N- {4- [3- (2-Methoxy-phenyl) thioureido] -phenyl] -acetamide 106 351 N- {4- [3- (3-Chloro-4-methoxy-phenyl) thioureido] -phenyl} -acetamide 107 351 N- {4- [3- (5-Chloro-2-methoxy-phenyl) thioureido] -phenyl} -acetamide 108 371 N- {4- [3- (3,5-Dichloro-4-hydroxy-phenyl) -thioureido] -phenyl} -acetamide 109 385 N- {4- [3- (3,5-Dichloro-4-methoxy-phenyl) -thioureido] -phenyl} -acetamide 110 381 N- {4- [3- (4-Chloro-2,5-dimethoxy-phenyl) -thioureido] -phenyl} -acetamide 111 389 N- {4- [3- (2-Chloro-5-trifluoromethyl-phenyl) thioureido] -

389

422

457

501

461

461

461

473

473

474

443

417

331

339

337

439

107 phenyl} acetamide

N- {4- [3- (4-Chloro-3-trifluoromethyl-phenyl] thioureido] -phenyl} -acetamide

Benzoic acid 4- [3- (4-acetylaminophenyl) thioureido] -3-hydroxyphenyl ester

N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -2-methyl-benzamide

Acetic acid 2- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenylcarbamoyl} -phenyl ester

N- {4- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] -phenyl} -4-fluoro-benzamide

N- {4- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] -phenyl} -3-fluoro-benzamide

N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) thioureido) phenyl} -2-fluoro-benzamide

N- {4- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] -phenyl} -2-methoxy-benzamide

N- {4- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] -phenyl) -3-methoxybenzamide

N- {4- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] -phenyl} -4-methoxybenzamide

N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -benzamide

N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) thioureido] phenyl) methanesulfonamide

N- {4- [3- (3-Nitro-phenyl) thioureido] -phenyl} -acetamide

1- (3-chloro-4-methoxyphenyl) -3- (3-nitrophenyl) thiourea

N- {4- [3- (5-Chloro-2-hydroxy-phenyl) -thioureido] -phenyl} -acetamide {4- [3- [5-chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -carbamic acid

108

351

385

318

414

332

465

500

488

486

536

511

459

479

477

522

488

445

N- {4- [3- (3-Chloro-4-hydroxy-5-methyl-phenyl) thioureido] -phenyl} -acetamide

N- {4- [3- (3,5-Dichloro-4-hydroxy-2-methyl-phenyl) -thioureido] -phenyl} -acetamide

N- {4- [3- (2,4-dihydroxyphenyl) thioureido] -phenyl} -acetamide

N- {4- [3- (2,4-Dimethoxy-5-trifluoromethyl-phenyl) thioureido] -phenyl} -acetamide

N- {4- [3- (2-hydroxy-4-methoxy-phenyl) thioureido] -phenyl} -acetamide

N- {4- [3- (3,5-Dichloro-4-methoxy-phenyl) thioureido] phenyl} -4-fluoro-benzamide

3-Acetylamino-N- {4- [3- (5-chloro-2,4-dimethoxyphenyl) thioureido] fenylJbenzamid

N- {4- [3- (S-Chloro-2,4-dimethoxyphenyl) thioureido] -phenyl} -3-nitrobenzamide

N- {4- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] -phenyl} -3-dimethylaminobenzamide

N- {4- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] -phenyl} -3-methanesulfonylamino-benzamide

N- {4- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] -phenyl} -2-trifluoromethyl-benzamide

N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) thioureido] phenyl} -2-hydroxybenzamide

N- {4- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] -phenyl} -2,6-difluoro-benzamide

2-Chloro-N- {4- [3- (5-chloro-2,4-dimethoxyphenyl) thioureido] fenylJbenzamid

2-Bromo-N- {4- [3- (5-chloro-2,4-dimethoxyphenyl) thioureido] phenyl} benzamide

N- {4- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] phenyl} -2-nitrobenzamide {4- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] phenyl} pyrazine- 2109

463

494

446

369

369

425

376

399

499

483

444

493

493 5-Methyl-thiophene-2-carboxylic acid {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -amide {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} - 1-methyl-1H-pyrrole-2-carboxylic acid {4- [3- (5-chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -amide quinoline-8-carboxylic acid amide

1- (5-Chloro-2,4-dimethoxyphenyl) -3- (2-nitrophenyl) thiourea

1- (5-Chloro-2,4-dimethoxyphenyl) -3- (4-nitrophenyl) thiourea

N- {4- [3- (5-Bromo-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -acetamide

N- {4- [3- (3,4,5-trimethoxy-phenyl) thioureido] -phenyl} -acetamide

Benzo [b] N- {4- [3- (3,5-Dichloro-2-methoxy-4-methyl-phenyl) -thioureido] -phenyl} -acetamide {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -amide ] Benzofuran-2-carboxylic acid {4- [3- [5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -thiophene-2-carboxylic acid thiophene

Naphthalene-2-carboxylic acid N- {4- [3- (5-chloro-2,4-dimethoxyphenyl) thioureido] phenyl} isonicotinamide {4- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] phenyl} amide { Naphthalene-1-carboxylic acid 4- [3- (5-chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -amide

110 {4- [3- (5-Chloro-2,4494)

494

444

478

459

467

439

397

433

447

512

512

433 Isoquinoline-1-carboxylic acid dimethoxyphenyl) thioureido] phenyl} quinoline-2-carboxylic acid [4- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] phenyl} amide

N- {4- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] fenylJnikotinamid

{4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl-4-nitro-furan-2-carboxylic acid phenyl ester 5-Chlorofuran-2-carboxylic acid phenyl} {4- [3- (5-chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -amide

{4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -carbamic acid isobutyl ester

{4- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] phenyl} carbamic acid {4- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] phenyl} furan-3-carboxylic acid amide { 4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -amide 3-methyl-furan-

5-Bromo-furan-2-carboxylic acid {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -amide {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} - 2-carboxylic acid 4-Bromo-furan-2-carboxylic acid amide {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -furan-2111 amide

carboxylic acid 171 467 {4- [3- (5-Chloro-2,4-dimethoxyphenyl) -] - thioureido] phenyl} carbamic acid 172 494 [4- [3- (5-chloro-2,4- isoquinolin-4-dimethoxyphenyl) thioureido] phenyl} amide carboxylic acid 173 451 {4- [3- (5-chloro-2,4- dimethoxyphenyl) thioureido] phenyl} amide [1,2,3] thiadiazole-4-carboxylic acid 174 434 {4- [3- (5-chloro-2,4- dimethoxyphenyl) thioureido] phenyl} amide 1H- [1,2,3] triazole-4-carboxylic acid 175 528 {4- (3- (5-chloro-2,4- 3-Bromothiophene-dimethoxyphenyl) thioureido] phenyl} amide Of 2-carboxylic acid 176 399 N- {4- [3- (3,5-Dichloro-4-ethoxy-phenyl) -thioureido] -phenyl} -acetamide 177 427 N- {4- [3- (4-Butoxy-3,5-dichloro-phenyl) -thioureido] -phenyl} -acetamide 178 461 N- {4- [3- (4-Benzyloxy-3,5-dichloro-phenyl) thioureido] -phenyl} -acetamide 179 381 N- {4- [3- (3-Chloro-2,4-dimethoxyphenyl) thioureido] -phenyl} -acetamide 180 530 (3- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenylcarbamoyl} -phenyl) -carbamic acid ethyl ester 181 458 2-Amino-N- {4- [3- (5-chloro-2,4-dimethoxyphenyl) thioureido] -phenyl} -benzamide 182 519 {4- [3- (5-chloro-2,4- biphenyl-2-carboxylic acid dimethoxyphenyl) thioureido] phenyl} amide 183 469 1- (5-Chloro-2,4-dimethoxyphenyl) -3- [4- (1,3-dioxo -1,3-dihydro-isoindol-2-yl) -phenyl] -thiourea 189 487 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -phthalic acid

112

185 473 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) thioureido] phenyl} -2-hydroxymethylbenzamide 186 479 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -2,3-difluoro-benzamide 187 479 N- {4- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] -phenyl} -2,5-difluoro-benzamide 188 479 N- {4- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] -phenyl} -2,4-difluorobenzamide 189 500 2-Acetylamino-N- {4- [3- (5-chloro-2,4-dimethoxyphenyl) - thioureido] phenyl] benzamide 190 441 1- (5-Chloro-2,4-dimethoxyphenyl) -3- (6-oxo-5,6-dihydrophenanthridine-2-yl) thiourea 191 536 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) thioureido] phenyl} -2-methanesulfonylamino-benzamide 192 497 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl] -2,3,4-trifluorobenzamide 193 533 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) thioureido] phenyl) -2,3,4,5,6-pentafluorobenzamide 194 489 N- {4- [3- (5-Chloro-2,4-dimethoxyphenyl) tiouraido] phenyl} -2-metylsulfanylbenzamid 195 431 {4- (3- (5-Chloro-2,4-dimethoxy-phenyl) -ureido] -phenyl} -amide 5-methylfuran-2-carboxylic acid 196 467 {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -ureido] -phenyl} -amide 5-difluoromethylfuran-2-carboxylic acid 197 472 N- {4- (3- (5-Iodo-2,4-dimethoxyphenyl) thioureido] -phenyl} -acetamide 198 364 N- {4- [3- (5-Fluoro-2,4-dimethoxy-phenyl) thioureido] phenyl) acetamide 199 365 N- {4- [3- (5-Chloro-2-methoxy-4-methyl-phenyl) - thioureido] -phenyl} -acetamide 200 459 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (4-chloro-3-trifluoromethyl-phenyl) -thioureido] -phenyl} -amide 201 455 {4- [3- (3,5-Dichloro-4- phenyl) thioureido] -phenyl) -amide

392

432

506

406

443

372

501

487

549

434

406

406

411

411

481 [1,2,3] Thiadiazole-4-carboxylic acid

N- {4- [3- (3-chloro-9-diethylamino) thioureido] -phenyl} -acetamide

1-hydroxynaphthalene-2- {4- [3- (3-Chloro-4- (cyclohexylmethylamino) phenyl} thioureido) phenyl [acetamide {4- [3- (4-Acetylaminophenyl) thioureido] -2-chlorophenyl} amide carboxylic acid

N- {4- [3- (3-chloro-4-morpholin-4-yl-phenyl) thioureido] phenyl [acetamide

1- (5-Chloro-2,4-dimethoxyphenyl) -3- (3-chloro-4-morpholin-4-yl-phenyl) -thiourea

1- (5-Chloro-2,4-dimethoxyphenyl) -3- (5-chloro-2-methyl-phenyl} -thiourea

N- {4- (3- (5-chloro-2,4-dimethoxyphenyl) thioureido] phenyl [isophthalic acid methyl ester]

N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -isophthalic acid

3-Benzyloxy-N- {4- [3- (5-chloro-2,4-dimethoxyphenyl) thioureido] -phenyl [benzamide

N- (4- {3- [5-chloro-2-methoxy-4- (4nitrilobutoxy) phenyl) thioureido} phenyl) acetamide

N- (4- {3- [5-chloro-2-methoxy-4- (2nitroloetoxy) phenyl) thioureido} phenyl) acetamide

N- (4- {3- [5-Chloro-4-methoxy-2- (2nitroloetoxy) phenyl] thioureido} -phenyl) -acetamide

N- {4- {3- [5-Chloro-2- (2-hydroxyethoxy) -4-methoxy-phenyl] thioureido} -phenyl) -acetamide

N- {4- (3- [5-Chloro-4- (2-hydroxyethoxy) -2-methoxyphenyl] thioureido} phenylacetamide) {4- [3- (4-acetylaminophenyl) thioureido] -2-chloro-tert-butyl ester 5

439

481

515

505

545

517

367

444

494

436

394

420

434

405

415 methoxyphenoxy} acetic acid

{4- [3- (4-Acetylaminophenyl) thioureido] -2-chloro-5-methoxyphenoxy) acetic acid tert-butyl ester (2- [3- (4-acetylaminophenyl) thioureido] -4-chloro-5-methoxyphenoxy} methyl ester acetic acid

3-Butoxy-N- {4- [3- (5-chloro-2,4-dimethoxyphenyl) thioureido] phenyl} benzamide

N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) thioureido] phenyl} -2-methanesulfinyl

(3- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenylcarbamoyl} -phenoxy) -acetic acid ethyl ester (3- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido) Phenylcarbamoyl} phenoxy) acetic acid

Pyridine-2-carboxylic acid N- {4- [3- (5-chloro-4-hydroxy-2-methoxyphenyl) thioureido] phenyl} acetamide {4- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] phenyl} amide quinoline-4-carboxylic acid {4- [3- (5-chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -amide

N- {4- [3- (5-Chloro-4-methoxy-2-morpholin-4-yl-phenyl) -thiureido] -phenyl} -acetamide

N- {4- [3- (5-Chloro-2-dimethylamino-4-methoxy-phenyl) thioureido] -phenyl} -acetamide

N- {4- [3- (5-Chloro-4-methoxy-2-pyrrolidin-l-yl-phenyl) thioureido] phenyl} acetamide.

N- {4- [3- (5-Chloro-4-methoxy-2-piperidin-1-ylphenyl) thioureido] phenyl} acetamide [4- [3- (3-Chloro-4-methylphenyl) thioureido] phenyl] amide [1 [2,3] thiadiazole-4-carboxylic acid

N- {4- [3- (3-Chloro-4-methyl-phenyl) thioureido] phenyl} -2-fluoro-benzamide

115

232 427 N- {4- [3- (3-Chloro- 4-Methylphenyl) thioureido] phenyl} -3-methoxybenzamide 233 387 Furan-2-carboxylic acid 4- [3- (3-chloro-4-methyl-phenyl) -thioureido] -phenyl} -amide 234 411 N- {4- [3- (3-Chloro-4-methyl-phenyl) thioureido] -phenyl} -2-methylbenzamide 235 433 N- {4- [3- (3-Chloro-4-methyl-phenyl) thioureido] -phenyl} - -2,6-difluorobenzamide 236 398 Pyridine-2-carboxylic acid {4- [3- (3-chloro-4-methyl-phenyl) -thioureido] -phenyl} -amide 237 502 [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- (3-chloro-4- (cyclohexylmethylamino) phenyl] thioureido} phenyl) amide 238 512 N- (4- {3- [3-Chloro-4- (cyclohexylmethylamino) phenyl] thioureido} phenyl) -2-fluorobenzamide 239 404 N- {4- [3- (3-Chloro-4-piperidin-1-yl-phenyl) -thioureido] -phenyl} -acetamide 240 364 N- {4- [3- (3-Chloro-4- dimethylamino-phenyl) thioureido] -phenyl} - acetamide 241 426 N- {4- [3- (4-benzylamino-3- chlorophenyl) thioureido (phenyl) acetamide 242 390 N- {4- [3- (3-Chloro-4-pyrrolidin-1-yl-phenyl) -thioureido] -phenyl} -acetamide 243 419 N- (4- {3- [3-chloro-4- (4-methylpiperazin-l-yl) phenyl] thioureido} -phenyl) -acetamide 244 469 N- {4- [3- (4-Chloro-3-trifluoromethyl-phenyl) thioureido] - phenyl} -2-fluoro-benzamide 245 422 N- {4- [3- (2-benzylamino-4-methoxy-phenyl) thioureido] - phenyl} acetamide 246 484 Furan-2-carboxylic acid (4- [3- [3-chloro-4- (cyclohexylmethylamino) phenyl] thioureido} phenyl) amide 247 508 N- (4- {3- [3-Chloro-4- (cyclohexylmethylamino) phenyl] thioureido} phenyl) -2-methylbenzamide

530

495

524

376

393

501

459

487

527

530

572

406

521

441

527

116

N- (4- {3- [3-Chloro-4- (cyclohexylmethylamino) phenyl] thioureido] phenyl) -2,6-difluorobenzamide (4- {3- [3-Chloro-4- (cyclohexylmethylamino) phenyl] thioureido] pyridine-2-carboxylic acid phenyl) amide

N- (4- {3- [3-Chloro-4- (cyclohexylmethylamino) phenyl] thioureido] phenyl-3T-methoxybenzamide

N- (4 - [{3- [3-chloro-4- (2-nitrilo-ethoxy) -phenyl] thioureido) phenyl) acetamide

N- {4- [3- [4-sec-Butoxy-3-chloro-phenyl) -thioureido] -phenyl} -acetamide

Acetic acid 3- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenylcarbamoyl) -phenyl ester

N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -3-hydroxy-benzamide {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -amide benzo [ 1,3] dioxole-4-carboxylic acid

N- {4- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] -phenyl} -3-trifluoromethoxybenzamide

N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl) -3- (2-dimethylamino-ethoxy) -benzamide

N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -3- (2-morpholin-4-yl-ethoxy) -benzamide

N- {4- [3- [5-Chloro-2,4-dimethoxyphenyl) thioureido] -2-cyanophenyl] acetamide

N- {4- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] -2,5-dimethoxy-phenyl} -2-fluoro-benzamide

N- {4- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] -2,5-dimethoxyphenyl} acetamide

2- {4- [3- (4-Acetylaminophenyl) thioureido] -2-chlorophenoxy] -5-chlorobenzenesulfonic acid

562

aminophenyl) thioureido]

117

phenoxy) -4,5-dichlorobenzenesulfonic acid 264 527 [4- [3- (5-chloro-2,4- dimethoxyphenyl) thioureido] phenyl} amide 4-phenyl- [1,2,3] thiadiazole-5-carboric acid 265 381 N- (4- {3- [3-chloro-4- (2-hydroryetoxy) phenyl] - thioureido] phenyl) acetamide 266 393 N- {4- [3- (4-Butoxy-3-chloro-phenyl) -thioureido] -phenyl] -acetamide 267 446 N- (4- {3- [3-Chloro-4- (cyclohexyl-ethylamino) -phenyl] - tiouteido] phenyl) acetamide 268 365 N- {4- [3- (3-Chloro-4-ethoxy-phenyl) -thioureido] -phenyl) -acetamide 269 427 N- {4- [3- (4-benzyloxy-3-chloro-phenyl) thioureido] -phenyl} -acetamide 270 317 {4 - [(3-Methyl-furan-2-carbonyl) -amino] -phenyl] -carbamic acid tert-butyl ester 271 456 N- {4- [3- (2-benzylamino-5-chloro-4-methoxyphenyl) - thioureido] -phenyl} -acetamide 272 420 N- {4- [3- (3-chloro-4-dimethylaminophenyl) thioureido] -phenyl} -acetamide 273 458 N- (4- {3- [4- (3-Allylcyklohexylaminol-chloro-phenyl] thioureido} -phenyl) -acetamide 274 411 N- {4- [3- (5-chloro-2,9-dimethoxyphenyl) thioureido] -2-methoxyphenyl] acetamide 275 415 N- {2-Chloro-4- (3- [5-chloro-2,4-dimethoxyphenyl) - thioureido] -phenyl} -acetamide 276 493 {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -2,5- furan-2-carboxylic acid-dimethoxyphenyl} amide 277 986 N- {4- (3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] -2- cyano-phenyl} -2-fluoro-benzamide 278 495 N- {2-Chloro-4- (3- (5-chloro-2,4-dimethoxyphenyl) - thioureido] -phenyl} -2-fluoro-benzamide 279 465 {4- [3- (5-Chloro-2,4-) dimethoxyphenyl) thioureido] phenyl} amide 5-

517

527

458

458

434

425

505

477

517

462

384

394

485

565 5-Furan-3-yl [1,2,3] thiadiazole-4-carboxylic acid methyl (1,2,3) -thiadiazole-4-carboxylic acid {4- (3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -amide [1,2,3] 5-Phenyl [1,2,3] thiadiazole-4-carboxylic acid (4- [3- (5-chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -amide of thiadiazole-4-carboxylic acid

N- (4- {3- [3-Chloro-4- (octahydro-quinolin-l-yl) phenyl] thioureido} -phenyl) -acetamide

N- [5 - [[[(5-Chloro-2,4-dimethoxyphenyl) amino] thioxomethyl] amino-2-pyridinyl] -2-methylbenzamide {5- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] Furan-2-carboxylic acid pyridin-2-yl} amide

N- {4- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] -2-methoxy-5-methyl-phenyl} acetamide

N- {4- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] -2-methoxy-5-methylphenyl} -2-fluorobenzamide {4- [3- (5-Chloro-2,4-dimethoxyphenyl) Furan-2-carboxylic acid {thireido] -2-methoxy-5-methylphenyl} amide {4- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] phenyl} amide 4-furan-3-yl [1,2, 3] thiadiazole-5-carboxylic acid

N- {5- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] -pyridin-2-yl} -2-fluoro-benzamide

N- [4- [3- (4-Methoxy-3-trifluoromethylphenyl) thioureido] -phenyl} -acetamide

N- [4- (3- {3-Chloro-4 - [(2-hydroxy-ethyl) -methyl-amino] -phenyl} thioureido] -phenyl] -acetamide

N- (2-Benzoyl-4- [3- (5-chloro-2,4-dimethoxyphenyl) thioureido] phenyl} acetamide

N- {2-Benzoyl-4- [3- (5-chloro-2,4-dimethoxyphenyl) 119

537

475

447

395

435

418

421

580

552

491

463

449

458

467

501 N- {4- [3- (5-chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -amide-2-fluoro-benzamide {2-benzoyl-4- [3- (5-chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -amide Furan-2-carboxylic acid 5-chloro-2,4-dimethoxyphenylthioureido] -3-methylphenyl} -2-fluorobenzamide {4- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] -3-methylphenyl} amide N- {4- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] -3-methyl-phenyl} acetamide

N- [4- (3- {3-Chloro-4 - [(3-dimethylaminopropyl) -methyl-amino] -phenyl} thioureido) -phenyl] -acetamide

N- {4- [3- (3-Chloro-4cyclohexylaminofenyl) thioureido] phenyl) acetamide

N- [4- (3- {3-Chloro-4 - [(2-dimethylamino-ethyl) -methyl-amino] -phenyl} thioureido) -phenyl] -acetamide

5 - [[[(5-Chloro-2,4-dimethoxyphenyl) amino thioxomethyl] amino] -2 - [(2-fluorobenzoyl) amino] -N-phenylbenzamide {4- [3- (5-Chloro-2,4) furan-2-carboxylic acid-dimethoxyphenyl) thioureido] -2-phenylcarbamoylphenyl} amide

N- {4- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] -2-methoxyphenyl} -2-fluorobenzamide {4- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] - Furan-2-carboxylic acid 2-methoxyphenyl} amide N- {4- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] -2-trifluoromethylphenyl) acetamide {4- [3- (5-Chloro-2)] Furan-2-carboxylic acid (2-Chloro-4- [3- (5-chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -amide) furan-2-carboxylic acid, 4-dimethoxy-phenyl) -thioureido] -2-cyano-phenyl} -amide - [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] -2120

395

475

447

378

408

382

509

407

408

421

495

483

431

511

451

Furan-2-carboxylic acid-trifluoromethyl-phenyl} -amide

N- {4- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] -2-methyl-phenyl} acetamide

N- {4- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] -2-methylphenyl} -2-fluorobenzamide {4- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] - Furan-2-carboxylic acid 2-methyl-phenyl} -amide

N- {4- [3- (4-acetylamino-phenyl) thioureido] -2-chlorophenyl} acetamide

{4- (3- (4-Acetylaminophenyl) thioureido] -2-chlorophenyl) carbamic acid ethyl ester

N- {5- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -pyridin-2-yl} -acetamide

N- (4- {3- [4- (l-Benzyl-piperidin-4-ylamino) -3-chloro-phenyl] thioureido} -phenyl) -acetamide

N- (4- {3- (3-Chloro-4- (2-dimethylaminoethylamino) phenyl] thioureido} phenyl) acetamide

N- [4- (3- {3-Chloro-4 - [(2-methoxy-ethyl) -methyl-amino] -phenyl)} -phenyl] -acetamide

N- (4- {3- [3-Chloro-4- (3-dimethylamino-propylamino) -phenyl] thioureido] phenyl) acetamide

N- (4- {3- [4- (1-Benzyl-pyrrolidin-3-ylamimo) -3-chloro-phenyl] -thioureido} -phenyl) -acetamide {5-Chloro-4- [3- (5-chloro-2,4-dimethoxy-phenyl) -thioureido Furan-2-carboxylic acid -2-hydroxyphenyl} amide

N- {5-Chloro-4- [3- (5-chloro-2,4-dimethoxy-phenyl) -thioureido] -2-hydroxy-phenyl} -acetamide (5H, HH-Benzo [e] pyrrolo [1,2-a] [1] 4] diazepin-10-yl) - (2-chloro-4-imidazol-1-ylphenyl) methanone {4- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] phenyl} amide [1,2, 3] thiadiazole-5-carboxylic acid

483

511

429

509

481

431

416

561

513

463

420 .434

422

425

505

121 N- {4- [3- (5-Chloro-2,4-) - {4- [3- (5-chloro-2,4-dimethoxy-phenyl) -thioureido] -naphthalen-1-yl} -amide} furan-2-carboxylic acid amide dimethoxyphenyl) thioureido] naphthalen-l-yl) -2-fluoro-benzamide

N- {5-Chloro-4- [3- (5-chloro-2,4-dimethoxy-phenyl) -thioureido] -2-methyl-phenyl} -acetamide

N- {5-Chloro-4- [3- (5-chloro-2,4-dimethoxyphenylthioureido) -2-methylphenyl} -2-fluorobenzamide [5-chloro-4- [3- (5-chloro-2,4-dimethoxyphenyl)] Furan-2-carboxylic acid thioureido] -2-methyl-phenyl} -amide

Furan-2- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -naphthalen-1-yl} -acetamide {4- [3- (3-Chloro-4-dimethylamino-phenyl) -thioureido] -phenyl} -amide Furan-2-carboxylic acid [4- (3- {4 - [(1-Benzylpyrrolidin-3-yl) methylamino] -3-chlorophenyl} thioureido) phenyl] -amide

N- [4- (3- {3-Chloro-4- [methyl- (l-methylpyrrolidin-3-yl) amino] phenyl [thioureido) phenyl] -2-fluoro-benzamide

N- [4- (3- {5-chloro-2-methoxy-4-methyl-phenyl) thioureido] phenyl] -2,6-difluorobenzamide

N- (4- {3- [3-chloro-4- (l-methylpyrrolidin-3-yloxy) phenyl] thioureido} -phenyl) -acetamide

N- (4- {3- [3-chloro-4- (l-methylpiperidin-4-yloxy) phenyl] thioureido} -phenyl) -acetamide

N- (4- [3- [3-Chloro-4- (3-dimethylamino-propoxy) -phenyl] thioureido} -phenyl) -acetamide

2-Acetylamino-5- [3- (5-chloro-2,4-dimethoxyphenyl) thioureido] benzoic acid

5- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -2- (2-fluoro-benzoylamino) -benzoic acid

339

122

- [(furan-2-carbonyl) amino] benzoic acid

545 N- (4- (3- {3-Chloro-4- [methyl- (1-methylpiperidin-4-yl) amino] phenyl} thioureido) phenyl] -2,6-difluorobenzamide

503 [1,2,3] Thiadiazole-4-carboxylic acid [4- (3- (3-chloro-4- [methyl-1-methylpyrrolidin-3-yl) amino] phenyl} thioureido) phenyl] amide

443 N- {4- [3- (3-Chloro-4-methylsulfanyl-phenyl) -thioureido] -phenyl) -2-methyl-benzamide

408 N- (4- {3- [3-Chloro-4- (2-dimethylaminoethoxy) phenyl] thioureido} phenyl) acetamide

499 Furan-2-carboxylic acid [4- (3- {3-chloro-4- [methyl (1-methylpiperidin-4-yl) amino] phenyl} thioureido) phenyl] amide

419 N- {4- [3- (3-Chloro-4-cyclohexyloxy-phenyl) -thioureido] -phenyl} -acetamide

440 N- {4- (3- (3-Chloro-4-dimethylaminophenyl) thioureido] phenyl} -2-methylbenzamide

493 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -3-methyl-phenyl} -2,6-difluoro-benzamide 462 N- {4- [3- (3-Chloro-4-dimethylaminophenyl)] thioureido] -phenyl} -2,6-difluoro-benzamide

531 N- [4- (3- {3-Chloro-4- [methyl- (1-methylpyrrolidin-3-yl) amino] phenyl} thioureido) phenyl] -2,6-difluorobenzamide

427 Pyridine-2-carboxylic acid [4- (3- (3-chloro-4-dimethylaminophenyl) thioureido] phenyl} amide

430 Pyridine-2-carboxylic acid {4- [3- (3-chloro-4-methylsulfanyl-phenyl) -thioureido] -phenyl} -amide

428 Pyridine-2-carboxylic acid {4- [3- [5-chloro-2-methoxy-4-methyl-phenyl) -thioureido] -phenyl} -amide

417 Furan-2-carboxylic acid {4- [3- (5-chloro-2-methoxy-4-methyl-phenyl) -thioureido] -phenyl} -amide

354

496 [4- (3- {3-Chloro-4- [methyl

123

495

467

515

449

529

421

473

501

461

541

513

463

543

515

Pyridine-2-carboxylic acid (1-methylpyrrolidin-3-yl) amino] phenyl] thioureido) phenyl] amide 414

N- {3-Chloro-4- [3- (5-chloro-2,4-dimethoxyphenyl) thioureido] phenyl} -2-fluorobenzamide {3-Chloro-4- [3- (5-chloro-2,4-dimethoxyphenyl)] furan-2-carboxylic acid thioureido] phenyl] amide

N- {4- [3- (3-Chloro-4-cyclohexylsulfanyl-phenyl) -thioureido] -phenyl] -2-fluoro-benzamide

N- {4- (3- (5-Chloro-2,4-dimethoxyphenyl) tioreido] -3trifluórmetylfenyl} acetamide

N- {4- [3- (5-Chloro-2,4-dimethoxyphenyl) tiouteido] -3trifluórmetylfenyl) -2-fluoro-benzamide

N- {4- [3- (4-Acetylaminophenyl) thioureido] -2-chloro phenyl) -2-dimethylaminoacetamide (4- {3- [3-Chloro-4- (2-dimethylaminoacetylamino) phenyl] thioureido] phenyl) amide furan-2-carboxylic acid N- (4- {3- [3-Chloro-4- (2-dimethylaminoacetylamino) phenyl] thioureido] phenyl) -2-fluorobenzamide

N- {4- [3- (4-Acetylaminophenyl) thioureido] -2-chlorophenyl) -2-piperidin-1-yl-acetamide

N- (4- {3- [3-Chloro-4- (2-piperidin-1-yl-acetylamino) -phenyl] -thioureido} -phenyl) -2-fluoro-benzamide (4- {3- [3-Chloro-4- ( Furan-2-carboxylic acid 2-piperidin-1-ylacetylamino) phenyl] thioureido} phenyl) amide

N- {4- [3- (4-Acetylaminophenyl) thioureido] -2-chlorophenyl} -2-morpholin-4-ylacetamide

N- (4- {3- [3-Chloro-4- (2-morpholin-4-ylacetylamino) phenyl] thioureido} phenyl) -2-fluorobenzamide (4- [3- [3-Chloro-4- (2- Furan-2-carboxylic acid morpholin-4-yl-acetylamino) -phenyl] -thioureido] -phenyl} -amide

N- (4- [3- (3-Chloro-4-methanesulfonylamino-phenyl) 494

466

481

561

585

523

510

347

441

452

487

486

458

406

124 thioureido] phenyl} acetamide

Furan-2-carboxylic acid N- {4- [3- [3-chloro-4-methanesulfonylaminophenyl) thioureido] phenyl} -2-fluorobenzamide {4- [3- (3-Chloro-4-methanesulfonylaminophenyl) thioureido] phenyl} amide

N- {4- [3- (4-Acetylaminophenyl) thioureido] -2-chlorophenyl} -2- (2-dimethylaminoethylsulfanyl) acetamide

N- [4- (3- {3-Chloro-4- [2- (2-dimethylaminoethylsulfanyl) acetylamino] phenyl} thioureido) phenyl] -2-fluorobenzamide

N- {4- (3- [4 - [(l-Benzyl-pyrrolidin-3-yl) methylamino] -3-chloro-phenyl} thioureido) phenyl] -2-methylbenzamide

N- [4- (3- {3-Chloro-4- [methyl- (1-methylpiperidin-4-yl) amino] phenyl} thioureido) phenyl] -2-methylbenzamide (4- (3- {3-Chloro- Pyridine-2-carboxylic acid 4- [methyl- (1-methylpiperidin-4-yl) amino] phenyl} thioureido) phenyl] amide

Furan-2-carboxylic acid {4- [3- (4-chloro-3-trifluoromethyl-phenyl) -thioureido] -phenyl} -amide {4 - [3- (3-Chloro-4-vinyl-phenyl) -thioureido] -phenyl} -acetamide Pyridine-2-carboxylic acid - [3- (4-chloro-3-trifluoromethyl-phenyl) -thioureido] -phenyl} -amide

N- {4- [3- (4-Chloro-3-trifluoromethyl-phenyl) thioureido] -phenyl} -2,6-difluoro-benzamide

N- {4- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] -3-cyanophenyl} -2-fluorobenzamide [4- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] - Furan-2-carboxylic acid 3-cyanophenyl] amide

N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -3-cyanophenyl} -acetamide

384

395

{- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -2-methyl-iso] 125

396

461

489

411

491

463

531

481

497

459

429

533

458

460

488 Thioureido] phenyl} acetamide

N- {4- (3- (5-Chloro-2,4-dimethoxyphenyl) -2-methylisothioureido] phenyl} acetamide

N- {4- [3- (3-Chloro-4-ethylsulfanylphenyl) thioureido] phenyl} -2-fluorobenzamide

N- {4- [3- (4-Butylsulfanyl-3-chlorophenyl) thioureido] phenyl} -2-fluorobenzamide

N- {4- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] -3-methoxy-phenyl} acetamide

N- {4- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] -3-methoxyphenyl} -2-fluorobenzamide {4- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] - 1,2,3] Thiadiazole-4-carboxylic acid 3-methoxyphenyl} furan-2-carboxylic acid (4- {3- [3-Chloro-4- (2-piperidin-1-acetylamino) phenyl] thioureido} phenyl) amide of

N- {4- [3- (3-Chloro-4-methanesulfinyl-phenyl) thioureido] -phenyl} -2,6-difluoro-benzamide

N- {4- [3- (3-Chloro-4-methanesulfonyl-phenyl) -thioureido] -phenyl} -2,6-difluoro-benzamide

N- {4- [3- (5-Chloro-2-methoxy-4-methyl-phenyl) thioureido] -2-methyl-phenyl} -2-fluoro-benzamide

N- {4- [3- (3-Chloro-4-methylphenyl) thioureido] -2-methylphenyl} -2-fluorobenzamide [4- (3- {3-Chloro-4- [2- (2-dimethylaminoethylsulfanyl) acetylamino]] Furan-2-carboxylic acid [phenyl] (thioureido) -phenyl] -amide

N- {4- [3- (4-Acetylamino-3-chloro-phenyl) thioureido] phenyl} -2-fluoro-benzamide

[2-Chloro-4- (3- {4 - [(furan-2-carbonyl) -amino] -phenyl} -thioureido) -phenyl] -carbamic acid ethyl ester

(2-Chloro-4- {3- [4- (2-fluoro-benzoylamino) -phenyl] -thioureido} -phenyl) -carbamic acid ethyl ester

126

440

520

529

492

416

479

531

559

461

430

477

529

449

501

529

N- {4- [3- (4-Acetylamino-phenyl) -thioureido] -2-chloro-phenyl} benzamide

N- {4 - [({[4- (Benzoylamino) -3-chlorophenyl] amino} thioxomethyl) amino] phenyl} -2-fluorobenzamide

N- {4- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] -2-trifluoromethylphenyl) -2-fluorobenzamide {4- (3- (4-Benzoylamino-3-chlorophenyl) thioureido] phenyl] furan- Of 2-carboxylic acid

N- {4- [3- (4-amino-3-chloro-phenyl) thioureido] phenyl} -2-fluoro-benzamide

N- {4- [3- (4-Acetylaminophenyl) thioureido] -2-chlorophenyl} -2-thiomorpholin-4-ylacetamide (4- {3- [3-Chloro-4- (2-thiomorpholin-4-ylacetylamino)) phenyl] thioureido} phenyl) furan-2-carboxylic acid amide

N- [4- {3- [3-Chloro-4- (2-thiomorpholin-4-ylacetylamino) phenyl] thioureido] phenyl} -2-fluorobenzamide

Furan-2-carboxylic acid N- (4- [3- (3-Chloro-4-methylsulfanylphenyl) thioureido] -2-methylphenyl) -2-fluorobenzamide {4- [3- (4-Acetylamino-3-chlorophenyl) thioureido] phenyl} amide of

Furan-2 N- {4- [3- (4-Acetylaminophenyl) thioureido] -2-chlorophenyl} -2-dipropylaminoacetamide {4- [3- [3-Chloro-4- (2-dipropylaminoacetylamino) phenyl] thioureido} phenyl] amide -carboxylic acid

Furan N- {4- [3- (4-Acetylaminophenyl) thioureido] -2-chlorophenyl} -2-diethylaminoacetamide (4- {3- (3-Chloro-4- (2-diethylaminoacetylamino) phenyl) thioureido} phenyl) amide -2-carboxylic acid

N- {4- (3- [3-Chloro-4- (2-diethylaminoacetylamino) phenyl] thioureido} phenyl) -2-fluorobenzamide

127

447

499

527

475

445

477

388

527

555

527

555

339

339

367

339

353

4- {4- [3- (4-Acetylaminophenyl) thioureido] -2-chlorophenyl} -2-pyrrolidin-1-ylacetamide (4- {3- (3-Chloro-4- (2-pyrrolidine-lylacetylamino) phenyl)] Furan-2-carboxylic acid thioureido-phenyl) -amide

N- (4- {3- [3-chloro-4- (2-pyrrolidin-l-yl-acetylamino) -phenyl] thioureido] phenyl) -2-fluoro-benzamide

N- {4- [3- (5-Chloro-2-methoxy-4-metylfenyltioureido] -3-methoxy-phenyl) -2-fluoro-benzamide

N- {4- [3- (3-Chloro-4-methyl-phenyl) -thioureide] -3-methoxy-phenyl} -2-fluoro-benzamide

N- {4- [3- (3-Chloro-4-methylsulfanylphenyl) thioureido] -3-methoxyphenyl} -2-fluorobenzamide {4- [3- (4-Amino-3-chlorophenyl) thioureido] phenyl] amide furan-2- carboxylic acid (4- {3- [4- (2-Azepan-1-ylacetylamino) -3-chloro-phenyl] -thioureido] -phenyl) -amide N- (4- {3- [4- (2- Azepan-1-ylacetylamino) -3-chlorophenyl] thioureido} phenyl) -2-fluorobenzamide [4- (3- {3-Chloro-4- [2- (2-methylpiperidin-1-yl) acetylamino] phenyl} thioureido) furan-2-carboxylic acid phenyl] amide

N- [4- (3- {3-Chloro-4- [2- (2-methyl-piperidin-1-yl) -acetylamino] -phenyl} -thioureido) -phenyl] -2-fluoro-benzamide [4- (3-Pyridin-2-yl-thioureido) -phenyl] Furan-2-carboxylic acid amide [4- (3-Pyridin-4-yl-thioureido) phenyl] furan-2-carboxylic acid amide

Furan-2-carboxylic acid 2-fluoro-N- [4- (3-pyridin-3-ylthioureido) phenyl] benzamide [4- (3-Pyridin-3-ylthioureido) phenyl] amide {4- [3- (3) Furan-2128-Aminophenyl) thioureido] phenyl} amide

406

380

434

381

388

352

416

571

543

388

363

416

367

367

374

388

-furan-2-carboxylic acid {4- [3- (3-Trifluoromethyl-phenyl) -thioureido] -phenyl} -amide

2-Fluoro-N- [4- (3-m-tolyltioureido) -phenyl] -benzamide

2-Fluoro-N- (4- [3- (3-trifluoromethyl-phenyl) thioureido] -phenyl) -benzamide

Furan-2-carboxylic acid N- {9- [3- (3-amino-phenyl) -thioureido] -phenyl} -2-fluorobenzamide [4- [3- (3-Amino-5-chloro-phenyl) -thioureido] -phenyl} -amide Furan-2-carboxylic acid (3-m-tolyl-thioureido) -phenyl] -amide

N- {4- [3- (2-amino-5-chlorophenyl) thioureido] phenyl} -2-fluoro-benzamide

(2-Chloro-4- {3- [4- (2-fluoro-benzoylamino) -phenyl] -thioureido} -phenyl) -carbamic acid 2-piperidin-1-yl-ethyl ester

[2-Chloro-4- (3- (4 - [(furan-2-carbonyl) amino] phenyl} thioureido) phenyl] carbamic acid {4- [3- (2-amino-5-chlorophenyl) 2-piperidin-1-yl] ester Furan-2-carboxylic acid {thireido] phenyl} amide Furan-2-carboxylic acid {4- [3- (3-cyanophenyl) thioureido] phenyl} amide

N- (4- [3- (3-Amino-5-chlorophenyl) thioureido] phenyl) -2-fluorobenzamide

2-Fluoro-N- [4- (3-pyridin-2-yltioureido) -phenyl] -benzamide

Furan-2-carboxylic acid 2-fluoro-N- [4- [3-pyridin-9-yl-thioureido) -phenyl] -benzamide {4- (3- (6-Chloro-pyridin-3-yl) -thioureido] -phenyl} -amide [3- (2-Amino-3-chloro-phenyl) thioureido] -phenyl} -amide

129

furan-2-carboxylic acid 447 396 {4- [3- (3- Furan-2-carboxylic acid hydrazinocarbonylphenyl) thioureido] phenyl) amide 448 410 2-Fluoro-N- (4- {3- [3- (1-hydroxyethyl) phenyl] thioureido} -phenyl) -benzamide 449 414 [4- [3- (3- Hydrazinokarbonylfenyl) thioureido] -phenyl) -amide [1,2,3] thiadiazole-4-carboxylic acid 450 399 [4- [3- (3-Isopropyl-phenyl) thioureido] -phenyl} -amide [1,2,3] thiadiazole-4-carboxylic acid 451 380 Furan- [4- [3- (3-Isopropyl-phenyl) -thioureido] -phenyl] -amide -2-carboxylic acid 452 409 2-Fluoro-N- {4- [3- (3-isopropyl-phenyl) thioureido] -phenyl / -benzamide 453 381 [4- [3- (3-Cyanophenyl) thioureido] phenyl] amide [1,2,3] thiadiazole-4-carboxylic acid 454 410 N- {4- [3- (3-Dimethylamino-phenyl) thioureido] phenyl} -2-fluoro-benzamide 455 381 Furan-2-carboxylic acid {4- [3- (3-dimethylaminophenyl) thioureido] phenyl) amide 456 370 [4- (3-m-Tolyltioureido) -phenyl) [1,2,3] thiadiazole-4-carboxylic acid 457 424 {4- [3- (3-Trifluoromethyl-phenyl) -thioureido) -phenyl} -amide [1,2,3] thiadiazole-4-carboxylic acid 458 479 N- (3-Chloro-4- [3- (5-chloro-2-methoxy-4-methyl-phenyl) - thioureido] -phenyl) -2-fluoro-benzamide 459 449 N- {3-Chloro-4- [3- (3-chloro-4-methyl-phenyl) - thioureido) phenyl} -2-fluoro-benzamide 460 481 N- {3-Chloro-4- [3- (3-chloro-4-methylsulfanyl-phenyl) thioureido) phenyl} -2-fluoro-benzamide 461 391 N- {4- [3- (3-Cyanophenyl) thioureido) phenyl} -2-fluorobenzamide 462 395 {4- [3- (3-acetylamino-phenyl) thioureido) phenyl} -amide

130

furan-2-carboxylic acid 463 424 2-Fluoro-N- {4- [3- (3-hydrazinokarbonylfenyl) - thioureido) phenyl} benzamide 464 400 (4- {3- [3- (l- Hydroxyethyl) phenyl) thioureido} phenyl) -amide [1,2,3] thiadiazole-4-carboxylic acid 465 434 N- [4- [3- (2-Amino-3-chloro-phenyl) thioureido) phenyl} - -2,6-difluorobenzamide 466 406 [4- [3- [3-amino-5-chlorophenyl) thioureido) phenyl] amide [1,2,3] thiadiazole-4-carboxylic acid 467 398 {4- [3- (3,5-dimethoxyphenyl) thioureido) phenyl) -amide furan-2-carboxylic acid 468 416 [4- [3- (3,5-dimethoxyphenyl) thioureido] fenyljamid [1,2,3] thiadiazole-4-carboxylic acid 469 454 5- (3- {4 - [(Furan-2-carbonyl) amino] phenyl} thioureido) isophthalic acid dimethyl ester 470 434 {4- [3- (5-chloro-2,4- dimethoxyphenyl) thoureido] phenyl} isoxazole-5-carboxylic acid 471 392 {4- [3- (6-Chloro-pyridin-3-yl) thioureido) phenyl] amide [1,2,3] thiadiazole-4-carboxylic acid 472 382 (4- {3- [3- (1- Furan-2-carboxylic acid hydroxyethyl) phenyl] thioureido] phenyl) amide 473 368 Furan-2- {4- [3- [3-Methoxy-phenyl) -thioureido] -phenyl} -amide -carboxylic acid 474 354 Furan-2- {4- [3- (3-Hydroxy-phenyl) -thioureido] -phenyl] -amide -carboxylic acid 475 382 2-Fluoro-N- {4- [3- (3-hydroxy-phenyl) thioureido) - fenylJbenzamid 476 396 2-Fluoro-N- {4- [3- (3-hydroxymethylphenyl) thioureido) phenyl] benzamide 477 423 N- {4- [3- (3-acetylamino-phenyl) thioureido] phenyl) -

131

-2-fluoro-benzamide 478 413 {4- [3- (3-acetylamino-phenyl) thioureido] -phenyl) -amide [1,2,3] thiadiazole-4-carboxylic acid 479 400 {4- [3- (3-Dimethylamino-phenyl) thioureido] -phenyl) -amide [1,2,3] thiadiazole-4-carboxylic acid 480 340 Furan-2- [4- (3-Pyrimidin-9-yl-thioureido) -phenyl] -amide -carboxylic acid 481 38 Furan- [4- [3- (1H-Indazol-5-yl) -thioureido] -phenyl) -amide Of 2-carboxylic acid 482 395 Furan- [4- (3-Benzothiazol-5-yl-thioureido) -phenyl] -amide Of 2-carboxylic acid 483 406 2-Fluoro-N- {4- [3- (lH-indazol-5-yl) thioureido] fenylíbenzamid 484 424 N- [4- (3-benzothiazol-5-yltioureido) phenyl] -2-fluoro-benzamide 485 473 5- (3- {4 - [([1,2,3] Thiadiazal-4-carbonyl) -) dimethyl ester - amino] phenyl} thioureido) isophthalic acid 486 442 Furan-2-carboxylic acid (4- {3- [4- (1-azidoethyl) -3-chlorophenyl] thioureido} phenyl) amide 487 396 2-Fluoro-N- {4- [3- (3-methoxy-phenyl) thioureido] - fenylJbenzamid 488 368 Furan-2-carboxylic acid [4- [3- (3-hydroxymethyl-phenyl) -thioureido] -phenyl) -amide 489 416 [4- [3- (5-chloro-2- dimethylamino-phenyl] thioureido) phenyl) - furan-2-carboxylic acid amide 490 444 N- {4- [3- (5-Chloro-2-dimethylamino-phenyl) thioureido] phenyl} -2-fluoro-benzamide 491 506 tert -Butyl ester [3-chloro-5- (3- {4- [([1,2,3] thiadiazole-4 carbonyl) amino] phenyl) thioureido) phenyl] carbamic acid 4 92 470 N- (4- {3- (4- (1-Azidoethyl) -3-chloro-phenyl] thioureido} -

132

337

378

392

406

420

452

445

434

484

494

434

62

416 phenyl) furan-2-carboxylic acid {4- (3- (1H-Benzoimidazol-5-yl) thioureido) -2-fluorobenzamide [4-1H-thiazolo [5,4-b] pyridin-2-ylideneamino) phenyl] amide Furan-2-carboxylic acid phenyl} amide {4- [3- (2-Methyl-1H-benzoimidazol-5-yl) -thioureido] phenyl} -amide

N- {4- [3- (lH-benzoimidazol-5-yl) thioureido] -phenyl} -2-fluoro-benzamide

2-Fluoro-N- {4- [3- (2-methyl-1H-benzoimidazol-5-yl) thioureido] phenylbenzamide {5- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] pyridin-2-yl [1,2,3] Thiadiazole-4-carboxylic acid amide {5- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -pyridin-2-yl] -pyridine-2-carboxylic acid amide {4- [3- ( [1,2,3] Thiadiazole-4-carboxylic acid 5-chloro-2-dimethylaminophenyl) thioureido] phenyl} amide (4- {3- [4- (2-Aminopyrimidin-4-yl) -3-chlorophenyl] thioureido} phenyl [1,2,3] Thiadiazole-4-carboxylic acid amide

N- (4- {3- [4- (2-Aminopyrimidin-4-yl) -3-chlorophenyl] thioureido} phenyl) -2-fluorobenzamide [4- [3- (3-Chloro-2-dimethylaminophenyl) thioureido] phenyl] [1,2,3] Thiadiazole-4-carboxylic acid} amide

Furan-2-carboxylic acid N- {4- [3- (3-Chloro-2-dimethylaminophenyl) thiouride] phenyl) -2,6-difluorobenzamide {4- [3- (3-Chloro-2-dimethylaminophenyl) thiouride] phenyl} amide of

445

462

482

413

387

415

434

435

452

426

474

502

450

539

392

Pyridine-2-carboxylic acid {6- [3- (5-chloro-2,4-dimethoxy-phenyl) -thioureido] -pyridin-3-yl} -amide

N- {6- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -pyridin-3-yl} -2-fluoro-benzamide {4- [3- (3-iodo-phenyl) -thioureido] -phenyl} -amide [1, [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- [3-tert-butyl-phenyl] -thioureido] -phenyl] -amide {4- [3- (3-chloro-benzyl)] furan-2-carboxylic acid thioureido] phenyl] amide

Furan-2-carboxylic acid N- {4- [3- (3-chloro-benzyl] -thioureido] -phenyl} -2-fluoro-benzamide {6- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -pyridin-3-yl} -amide { [1,2,3] Thiadiazole-4-carboxylic acid 4- [3- (3-bromo-phenyl) -thioureido] -phenyl} -amide {6- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -pyridin-3-yl [1,2,3] Thiadiazole-4-carboxylic acid [5- [3- (3,5-Dichloro-phenyl) -thioureido] -pyridin-2-yl] -amide [1,2,3] thiadiazole-4-carboxylic acid {4- [ Furan-2-carboxylic acid 3- (3,5Bistrifluoromethylphenyl) thioureido] phenyl} amide

N- {4- [3- (3,5-Bistrifluoromethylphenyl) -thiocreido] phenyl} -2-fluorobenzamide

N- {4- [3- (4-amino-3,5-dichloro-phenyl) thioureido] phenyl} -2-fluoro-benzamide

N- {4- [3- (4-Amino-3,5-dibromophenyl) thioureido] phenyl} -2-fluorobenzamide {4- [3- (5-Chloropyridin-3-yl) thioureido] phenyl] amide

134

[1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (4-amino-3,5-dibromo-phenyl) -thioureido] -phenyl} -amide

434 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (3-chloro-5-dimethylaminophenyl) -thioureido] -phenyl} -amide

444 N- {4- [3- (3-Chloro-5-dimethylaminophenyl) thioureido] phenyl) -2-fluorobenzamide

416 Furan-2-carboxylic acid {4- [3- (3-Chloro-5-dimethylaminophenyl) -thioureido] -phenyl} -amide

436 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (5-bromo-pyridin-3-yl) -thioureido] -phenyl} -amide

379 Furan-2-carboxylic acid {4- [3- (1H-Benzotriazol-5-yl) -thioureido] -phenyl] -amide

425 N- {4- [3- (1H-Benzotriazol-5-yl) -thioureido] phenyl} -2, β-difluorobenzamide

388 N- [4 - (([2- (3-Chlorophenyl) hydrazino] thioxomethyl) amino) phenyl] furan-2-carboxamide

416 N- [4 - ({[2- (3-Chlorophenyl) hydrazino] thioxomethyl} amino) phenyl] -2-fluorobenzamide

456 Furan-2-carboxylic acid {4- [3- (2-Amino-3-chloro-5-trifluoromethyl-phenyl) -thioureido] -phenyl) -amide

513 N- {4- [3- (3-Bromo-5-trifluoromethyl-phenyl) -thioureido] -phenyl) -2-fluoro-benzamide

[1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (3-bromo-5-trifluoromethyl-phenyl) -thioureido] -phenyl} -amide

374 {4 - [(Furan-2-carbonyl) amino] -phenyl} -thiocarbamic acid O- (3-chlorophenyl) ester

474 {4- [3- (2-Amino-3-chloro-5-trifluoromethyl-phenyl) -thioureido] -phenyl] -amide [1,2,3] thiadiazole-4-carboxylic acid

508 [4- [3- (3-Piperidin-1-yl-5-trifluoromethyl-phenyl)] 135

380

439

449

370

424

414

506

516

352

421

396

488

503

529

[1,2,3] Thiadiazole-4-carboxylic acid thioureido] phenyl} amide

N- [4- (3-Benzylthioureido) phenyl] -2-fluorobenzamide {4- [3- (3,4-Dichlorobenzyl) thioureido] phenyl] amide [1,2,3] thiadiazole-4-carboxylic acid

[1,2,3] Thiadiazole-4-carboxylic acid N- {4- [3- (3,4-dichlorobenzyl) thioureido] phenyl} -2-fluorobenzamide [4- (3-Benzylthioureido) phenyl] amide

N- [4- (3-Benzo [1,3] dioxol-5-ylmethylthioureido) phenyl] -2-fluorobenzamide [4- (3-Benzo [1,3] dioxol-5-ylmethylthioureido) phenyl] amide [1,2,3] (1,2,3) Thiadiazole-4-carboxylic acid {4- [3- (3,5Bistrifluoromethyl-benzyl) -thioureido] -phenyl} -amide of thiadiazole-4-carboxylic acid

Furan-2-carboxylic acid N- {4- [3- (3,5-Bistrifluoromethylbenzyl) thioureido] phenyl} -2-fluorobenzamide [4- (3-Benzylthioureido) phenyl] amide {4- [3- (3,4-Dichlorobenzyl) Furan-2-carboxylic acid [4- [3-Benzo [1,3] dioxol-5-ylmethyl-thioureido) -phenyl] -furan-2-carboxylic acid {4- [3- (3,5-Bistrifluoromethyl-benzyl) -thioureido] -thioureido] -phenyl} -amide [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (4-bromo-3-trifluoromethyl-phenyl) -thioureido] -phenyl] -amide-phenyl-amide

N- {4- [3- (3-Bromo-4-trifluoromethoxyphenyl) thioureido] phenyl} -2-fluorobenzamide {4- [3- (3-Bromo-4-trifluoromethoxyphenyl) thioureido] 136 phenyl} amide [1,2] 3] thiadiazole-4-carboxylic acid

473 Furan-2-carboxylic acid 4- [3- (3-chloro-4-trifluoromethylsulfanyl-phenyl) -thioureido] -phenyl} -amide

412 2-Fluoro-N- (4- {3- [2- (3-fluorophenyl) ethyl] thioureido) phenyl} benzamide

412 2-Fluoro-N- (4- {3- [2- (4-fluorophenyl) ethyl] thioureido) phenyl} benzamide

[1,2,3] Thiadiazole-4-carboxylic acid 4- (3- [2- (3-fluorophenyl) ethyl] thioureido; phenyl) amide

[1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [2- (4-fluoro-phenyl) -ethyl] -thioureido} -phenyl) -amide

495 (1,2,3) Thiadiazole-4-carboxylic acid 4- [3- [3- (2-methylbutyl) -5-trifluoromethylphenyl] thioureido} phenyl) amide

481 [1,2,3] Thiadiazole-4-carboxylic acid [4- [3- [3-isobutyl-5-trifluoromethyl-phenyl) -thioureido] -phenyl-amide

[1,2,3] Thiadiazole-4-carboxylic acid 4- {3- [3- (4-methyl-piperazin-1-yl) -5-trifluoromethyl-phenyl] -thioureido) -phenyl} -amide

510 {4- [3- (3-Morpholin-4-yl-5-trifluoromethyl-phenyl) -thioureido] -phenyl] -amide [1,2,3] thiadiazole-4-carboxylic acid

494 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (3-pyrrolidin-1-yl-5-trifluoromethyl-phenyl) -thioureido] -phenyl] -amide

384 Furan-2-carboxylic acid (4- {3- [2- (4-fluorophenyl) ethyl] thioureido} phenyl) amide

419 [1,2,3] Thiadiazole-4-carboxylic acid 4- {3- [2- (3-chloro-phenyl) -ethyl] -thioureido] -phenyl) -amide

429 N- (4- [3- [2- (3-Chlorophenyl) ethyl] thioureido} phenyl) -2-fluorobenzamide

401 Furan-2-carboxylic acid 4- [3- [2- (3-chloro-phenyl) -ethyl] -thioureido} -phenyl) -amide

402 (4- {3- [1- (4-Fluorophenyl) ethyl] thioureido} phenyl) amide

137 [1.2.3] Thiadiazole-4-carboxylic acid

504 2-Fluoro-N- {4- [3- (3-pyrrolidin-1-yl-5-trifluoromethyl-phenyl) -thioureido] -phenyl} -benzamide

477 N- {4- [3- [3-Dimethylamino-5-trifluoromethyl-phenyl) -thioureido] -phenyl} -2-fluoro-benzamide

520 2-Fluoro-N- [4- [3- (3-morpholin-4-yl-5-trifluoromethyl-phenyl) -thioureido] -phenyl] -benzamide

533 2-Fluoro-N- (4- [3- (3- (4-methylpiperazin-1-yl) -5-trifluoromethylphenyl] thioureido} phenyl) benzamide

518 2-Fluoro-N- {4- [3- (3-piperidin-1-yl-5-trifluoromethyl-phenyl) -thioureido] -phenyl} -benzamide

468 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (3-Dimethylamino-5-trifluoromethyl-phenyl) -thioureido] -phenyl] -amide

405 {4- [3- (3-Chlorobenzyl) thioureido] phenyl] amide [1.2.3] thiadiazole-4-carboxylic acid

384 Furan-2-carboxylic acid (4- {3- [2- (3-fluorophenyl) ethyl] thioureido] phenyl] amide

366 Furan-2-carboxylic acid (4- {3-phenethylthioureido) phenyl] amide

[1,2,3] Thiadiazole-4-carboxylic acid [4- (3-phenethylthioureido) phenyl] amide

394 2-Fluoro-N- [4- (3-phenethylthioureido) phenyl] benzamide

505 2-Fluoro-N- (4- {3- [3- (2-methylbutyl) -5-trifluoromethylphenyl] thioureido} phenyl) benzamide

491 2-Fluoro-N- {4- [3- (3,5-difluoro-benzyl) -thioureido] -phenyl} -benzamide

388 Furan-2-carboxylic acid [4- [3- (3,5-difluorobenzyl) thioureido] phenyl] amide

416 N- {4- (3- (3,5-Difluorobenzyl) thioureido] phenyl} -2-fluorobenzamide

406 [4- [3- (3,5-Difluorobenzyl) thioreido] phenyl] amide [1.2.3] thiadiazole-4-carboxylic acid

138

421 Furan-2-carboxylic acid {4- [3- (3,5-Dichlorobenzyl) thioureido] phenyl} amide

449 N- {4- [3- (3,5-Dichloro-benzyl) -thioureido] -phenyl) -2-fluoro-benzamide

439 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (3,5-Dichloro-benzyl) -thioureido] -phenyl-amide

438 Furan-2-carboxylic acid {4- [3- (3-fluoro-5-trifluoromethyl-benzyl) -thioureido] -phenyl] -amide

466 2-Fluoro-N- {4- [3- (3-fluoro-5-trifluoromethylbenzyl) thioureido] phenyl} benzamide

456 (1,2,3) Thiadiazole-4-carboxylic acid {4- [3- (3-fluoro-5-trifluoromethyl-benzyl) -thioureido] -phenyl} -amide

[1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (1-phenylethyl) thioureido] phenyl} amide

394 2-Fluoro-N- {4- [3- (1-phenylethyl) thioureido] phenyl] benzamide

366 Furan-2-carboxylic acid {4- [3- (1-phenylethyl) thioureido] phenyl} amide

412 2-Fluoro-N- (4- {3- [1- [4-fluorophenyl) ethyl] thioureido} phenyl} benzamide

384 Furan-2-carboxylic acid (4- {3- [1- (4-fluorophenyl) ethyl] thioureido} phenyl) amide

413 N- {4- [3- (1-tert-Butyl-1H-imidazol-2-yl) thioureido] phenyl} -2-fluorobenzamide

510 [1,2,3] Thiadiazole-4-carboxylic acid 4- (3- [3- (isobutylmethylamino-5-trifluoromethyl-phenyl) -thioureido} -phenyl) -amide

[1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [3- (3-hydroxy-pyrrolidin-1-yl) -5-trifluoromethyl-phenyl] -thioureido} -phenyl) -amide

520 2-Fluoro-N- (4- {3- [3- (isobutylmethylamino) -5-trifluoromethylphenyl] thioureido] phenyl) benzamide

510 [1,2,3] Thiadiazole-4-carboxylic acid 4- [3- [3- (Butylmethylamino) -5-trifluoromethylphenyl] thioureido} phenyl) amide

139 acids

520 N- (4- {3- [3- (Butylmethylamino) -5-trifluoromethylphenyl] thioureido} phenyl) -2-fluorobenzamide

[1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [2- (3,5-Bistrifluoromethyl-phenyl) -ethyl] -thioureido} -phenyl) -amide

442 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (4-fluoro-3-trifluoromethyl-phenyl) -thioureido] -phenyl} -amide

522 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (4-piperidin-1-yl-3-trifluoromethyl-benzyl) -thioureido} -phenyl amide

482 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (4-dimethylamino-3-trifluoromethyl-benzyl) -thioureido] -phenyl} -amide

381 Furan-2-carboxylic acid 4- (3- [2- (4-aminophenyl-ethyl) -thioureido} -phenyl) -amide

445 Furan-2-carboxylic acid (4- {3- [2- (4-bromo-phenyl) -ethyl] -thioureido} -phenyl) -amide

380 Furan-2-carboxylic acid {4- [3- (2-p-tolyl-ethyl) -thioureido] -phenyl] -amide

[1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [2- (4-bromo-phenyl) -ethyl] -thioureido} -phenyl) -amide

396 Furan-2-carboxylic acid (4- {3- [2- (3-methoxyphenyl) ethyl] thioureido} phenyl) amide

403 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (1-tert-butyl-1H-imidazol-2-yl) -thioureido] -phenyl} -amide

384 Furan-2-carboxylic acid {4- [3- (1-tert-butyl-ΙΗ-imidazol-2-yl) -thioureido] -phenyl} -amide

492 N- {4- [3- (4-Dimethylamino-3-trifluoromethylbenzyl) thioureido] phenyl} -2-fluorobenzamide

427 Furan-2-carboxylic acid {4- (3- [2- (3,4-dimethoxyphenyl) ethyl] thioureido} phenyl) amide

380 Furan-2140 {4- [3- (3-Phenyl-propyl) -thioureido] -phenyl} -amide

-carboxylic acid

613 399 {4- [3- (3-phenylpropyl) thioureido] fenyljamid [1,2,3] thiadiazole-4-carboxylic acid 614 502 (4- {3- [2- (3,5-Bis-trifluoromethylphenyl) ethyl] - furan-2-carboxylic acid thiourea) phenyl) amide 615 550 {4- [3- (4-Iodo-3-trifluoromethyl-phenyl) thioureido] fenylj- [1,2,3] thiadiazole-4-carboxylic acid amide 616 532 2-Fluoro-N- {4- [3- (4-piperidin-l-yl-3-trifluoromethyl-benzyl) thioureido] fenylJbenzamid 617 537 [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [4- (4-methyl-piperazin-1-yl) -3-trifluoromethyl-benzyl] -thioureido} -phenyl) -amide 618 482 {4- [3- (3-Dimethylamino-5-trifluoromethyl-benzyl) - Thioureido] phenyl] amide [1,2,3] thiadiazole-4-carboxylic acid 615 488 Furan-2-carboxylic acid {4- [3- (3,5-Bistrifluoromethyl-phenyl) -thioureidomethyl] -phenyl] -amide 620 421 {4- [3- (3,5-dichlorophenyl) tioureidometyl] fenyljamid furan-2-carboxylic acid 621 421 Furan-2-carboxylic acid {4- [3- (3,4-Dichloro-phenyl) -thioureidomethyl] -phenyl] -amide 622 455 Furan-2-carboxylic acid {4- [3- (4-Chloro-3-trifluoromethyl-phenyl) -thioureidomethyl] -phenyl] -amide 623 466 2-Fluoro-N- {4- [3- (4-fluoro-3-trifluoromethylbenzylthioureido) phenyl] benzamide 624 456 [1,2,3] Thiadiazole-4-carboxylic acid {4- (3- (4-fluoro-3-trifluoromethylbenzyl) thioureido] phenyl) amide 625 410 2-Fluoro-N- [4- [3- (2-phenoxyethyl) thioureido] fenylJbenzamid 626 382 Furan-2- {4- [3- (2-Phenoxyethyl) thioureido] phenyl] amide -carboxylic acid 627 400 {4- [3- (2-Phenoxyethyl) thioureido] phenyl] amide [1,2,3] thiadiazole-4-carboxylic acid 628 409 2-Fluoro-N- {4- [3- (3-phenylpropyl) thioureido] -

141 phenyl} benzamide

629 425 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (5-trifluoromethyl-pyridin-3-yl) -thioureido] -phenyl} -amide 630 439 {4- [3- (3,4-Dichlorophenyl) tioureidometyl] fenyljamid [1,2,3] thiadiazole-4-carboxylic acid 631 473 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (4-chloro-trifluoromethyl-benzyl) -phenyl] -thioureido-methyl-phenyl} -amide 632 381 2-Fluoro-N- [4- (3-pyridin-3-ylmetyltioureidolfenyl] benzamide 633 353 Furan-2- [4- (3-Pyridin-3-ylmethylthioureido) phenyl] amide -carboxylic acid 634 371 [4- (3-pyridin-3-ylmetyltioureido) -phenyl] -amide [1,2,3] thiadiazole-4-carboxylic acid 635 439 {4- [3- (3,5-dichlorophenyl) tioureidometyl] -phenyl} [1,2,3] thiadiazole-4-carboxylic acid 636 492 N- {4- (3- (3-Dimethylamino-5-trifluoromethyl-benzyl) - thioureido] -phenyl} -2-fluoro-benzamide 637 415 (4- {3- [2- (3-methoxyphenyl) -ethyl] thioureido} -phenyl) -amide [1,2,3] thiadiazole-94-carboxylic acid 638 399 {4- [3- (2 p -tolyl-ethyl) thioureido] fenyljamid [1,2,3] thiadiazole-4-carboxylic acid 639 445 [1,2,3] Thiadiazole-4-carboxylic acid {4- {3- [2- (3,4-Dimethoxy-phenyl) -ethyl] -thioureido} -phenyl) -amide 640 506 {4- [3- (3,5-bis- phenyl] tioureidomethyl] fenyljamid [1,2,3] thiadiazole-4-carboxylic acid 641 516 N- {4- [3- (3,5-Bis-trifluoromethyl-phenyl) -thioureidomethyl] -phenyl} -2-fluoro-benzamide 642 449 N- {4- [3- (3,5-dichlorophenyl) tioureidometyl] - phenyl} -2-fluoro-benzamide 643 449 N- {4- [3,4-Dichloro-phenyl) tioureidometyl] methyl-2- fluorobenzamide 644 448 {4- [3- (3-Acetylamino-5-chloro-phenyl) thioureido] -phenyl} -

142 [1,2,3] Thiadiazole-4-carboxylic acid amide

[1,2,3] Thiadiazole-4-carboxylic acid [4- {3- [2- (3,4-dichloro-phenyl) -ethyl] -thioureido} -phenyl) -amide

413 [1,2,3] Thiadiazole-4-carboxylic acid [4- [3- (1-methyl-3-phenyl-propyl) -thioureido] -phenyl} -amide

463 [1,2,3] Thiadiazole-4-carboxylic acid 4- {3- [1- (4-bromo-phenyl) -ethyl] -thioureido} -phenyl) -amide

[1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (4-phenyl-butyl) -thioureido] -phenyl} -amide

[1,2,3] Thiadiazole-4-carboxylic acid [4- (3-indan-1-yl-thioureido) -phenyl] -amide

400 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (2-methoxy-benzyl) -thioureido] -phenyl} -amide

415 [1,2,3] Thiadiazole-4-carboxylic acid 4- [3- [2- (2-methoxyphenyl) ethyl] thioureido} phenyl) amide

415 [1,2,3] Thiadiazole-4-carboxylic acid 4- {3- [2- (4-methoxy-phenyl) -ethyl] -thioureido} -phenyl) -amide

506 N- (4- {3- [2- (3-Dimethylamino-5-trifluoromethylphenyl) ethyl] thioureido} phenyl) -2-fluorobenzamide

510 [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [3- (3-dimethylaminopropyl) -5-trifluoromethyl-phenyl] -thioureido} -phenyl) -amide

[1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (2-phenylsulfanylethyl) thioureido] phenyl} amide

427 2-Fluoro-N- {4- [3- (2-phenylsulfanylethyl) thioureido] phenyl} benzamide

399 Furan-2-carboxylic acid [4- [3- (2-phenylsulfanylethyl) thioureido] phenyl] amide

3B1 2-Fluoro-N- [4- (3-pyridin-4-ylmethylthioureido) phenyl] benzamide

353 Furan-2-carboxylic acid [4- (3-pyridin-4-ylmethyl-thioureido) -phenyl] -amide

371 [1,2,3] Thiadiazole-4-carboxylic acid [4- (3-pyridin-4-ylmethyl-thioureido) -phenyl] -amide

143

506 2-Fluoro-N- {4- [3- (3-iodobenzyl) thioureido] phenyl} benzamide

478 Furan-2- {4- [3- (3-Iodo-benzyl) -thioureido] -phenyl} -amide

-carboxylic acid

496 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (3-iodo-benzyl) -thioureido] -phenyl} -amide

479 N- (4- {3- [2- (3,5-Dichlorophenoxy) ethyl] thioureido} phenyl) -2-fluorobenzamide

451 Furan-2-carboxylic acid 4- [3- [2- (3,5-Dichlorophenoxy) ethyl] thioureido} phenyl) amide

445 N- (4- {3- [2- (3-Chloro-phenoxy) -ethoxy] -thioureido} -phenyl) -2-fluoro-benzamide

417 Furan-2-carboxylic acid (4- {3- [2- (3-Chloro-phenoxy) -ethyl] -thioureido} -phenyl) -amide

435 [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [2- (3-chloro-phenoxy) -ethyl] -thioureido} -phenyl) -amide

466 2-Fluoro-N- {4- [3- (2-fluoro-5-trifluoromethylbenzyl) thioureido] phenyl} benzamide

438 Furan-2-carboxylic acid {4- [3- (2-fluoro-5-trifluoromethyl-benzyl) -thioureido] -phenyl} -amide

[1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (2-fluoro-5-trifluoromethyl-benzyl) -thioureido] -phenyl) -amide

416 N- {4- [3- (3,4-Difluorobenzyl) thioureido] phenyl} -2-fluorobenzamide

452 N- (4- {3- [2- (4-Dimethylamino-3-methylphenyl) ethyl] thioureido} phenyl) -2-fluorobenzamide

496 [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [2- (3-Dimethylamino-5-trifluoromethyl-phenyl) -ethyl] -thioureido} -phenyl) -amide

388 Furan-2-carboxylic acid {4- [3- (3,4-difluorobenzyl) thioureido] phenyl} amide

[1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (3,4-difluoro-benzyl) -thioureido] -phenyl} -amide

433 N- {4- [3- (3-Chloro-4-fluoro-benzyl) -thioureido] -phenyl} 144

-2-fluoro-benzamide

678 495 [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [2- (3-bromo-phenylsulfanyl) -ethyl] -thioureido} -phenyl) -amide 679 477 (4- {3- [2- (3-Bromo-phenylsulfanyl) -ethyl] thioureido} - phenyl) furan-2-carboxylic acid amide 680 505 N- (4- {3- [2- (3-Bromophenylsulfanyl) ethyl] thioureido} - phenyl) -2-fluoro-benzamide 681 493 [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [2- (3-bromo-4-methoxy-phenyl) -ethyl] -thioureido} -phenyl) -amide 682 493 [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [2- (5-bromo-2-methoxy-phenyl) -ethyl] -thioureido} -phenyl) -amide 683 419 (4- {3- [2- (2-Chloro-phenyl) -ethyl] -thioureido} -phenyl) -amide [1,2,3] thiadiazole-4-carboxylic acid 684 402 (4- {3- [2- (2-Fluorophenyl) ethyl] thioureido) phenyl} amide [1,2,3] thiadiazole-4-carboxylic acid 685 419 (4- {3- [2- (4-Chloro-phenyl) -ethyl] -thioureido} -phenyl) -amide [1,2,3] thiadiazole-4-carboxylic acid 686 475 {4- [3- (3,3-Diphenylpropyl) thioureido] -phenyl} -amide [1,2,3] thiadiazole-4-carboxylic acid 687 547 2-Fluoro-N- (4- {3- [4- (4-methylpiperazin-l-yl) -3-trifluoromethylbenzyl] thioureido} -phenyl) -benzamide 688 469 (4- {3- [2- (3,5-Dichlorophenoxy) ethyl] thioureido} phenyl) - [1,2,3] thiadiazole-4-carboxylic acid amide 689 423 {4- [3- (3-chloro-4-fluoro-benzyl) thioureido] -phenyl} -amide [1,2,3] thiadiazole-4-carboxylic acid 690 427 {4- [3- (4-tert-butylbenzyl) thioureido] -phenyl} -amide [1,2,3] thiadiazole-4-carboxylic acid 691 399 {4- [3- (3,5-Dimethyl-benzyl) -thioureido] -phenyl} -amide [1,2,3] thiadiazole-4-carboxylic acid 692 442 (4- {3- [2- (4-Dimethylamino-3-methyl-phenyl) -ethyl] - Thioureido] phenyljamide [1,2,3] thiadiazole-4-carboric acid 693 479 (4- {3- [2- (4-Bromo-phenoxy) -ethyl] -thioureido} -phenyl) -amide [1,2,3] thiadiazole-4-carboxylic acid

145

526 [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [2- (4-iodo-phenoxy) -ethyl] -thioureido] -phenyl) -amide

489 N- (4- {3- [2- (4-Bromophenoxy) ethyl] thioureido} phenyl) -2-fluorobenzamide

536 2-Fluoro-N- (4- {3- [2- (4-iodophenoxy) ethyl] thioureido] phenyl) benzamide

461 Furan-2-carboxylic acid (4- {3- [2- (4-bromophenoxy) ethyl] thioureido} phenyllamide

508 Furan-2-carboxylic acid (4- {3- [2- (4-iodo-phenoxy) -ethyl] -thioureido] -phenyl) -amide

408 {4- [3- (3,4-Dichloro-phenyl) -thioureido] -phenyl} -amide oxazole-

4-carboxylic acid

424 Thiazole-4-carboxylic acid {4- [3- (3,5-dichloro-phenyl) -thioureido] -phenyl} -amide

491 Thiazole-4-carboxylic acid {4- [3- (3,5-Bistrifluoromethyl-phenyl) -thioureido] -phenyl} -amide

408 Oxazole-4-carboxylic acid {4- [3- (3,5-Dichloro-phenyl) -thioureido] -phenyl] -amide

469 <4- {3- [2- (3,4-Dichlorophenoxy) ethyl] thioureido] phenyl] amide [1,2,3] thiadiazole-4-carboxylic acid

424 Thiazole-4-carboxylic acid {4 * - [3- (3,4-Dichloro-phenyl) -thioureido] -phenyl] -amide

458 Thiazole-4-carboxylic acid {4- [3- (4-chloro-3-trifluoromethyl-phenyl) -thioureido] -phenyl] -amide

400 {4- [3- (2-Phenylaminoethyl) thioureido] phenyl] amide [1,2,3] thiadiazole-4-carboxylic acid

453 [1,2,3] Thiadiazole-4-carboxylic acid 4- {3- [2- (2,4-Dichloro-phenyl) -ethyl] -thioureido} -phenyl) -amide

452 [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- (2- (3-trifluoromethyl-phenyl) -ethyl] -thiourea) -phenyl) -amide

453 [1,2,3] Thiadiazole-4-carboxylic acid 4- {3- [2- (2,5-Dichloro-phenyl) -ethyl] -thioureido] -phenyl) -amide

485 [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [2- (3,4-Dichloro-phenylsulfanyl) -ethyl] -thioureidophenyl) -amide

146

711 503 [1,2,3] Thiadiazole-4-carboxylic acid (4- [3- (2- (2-fluoro-5-trifluoromethyl-phenylsulfanyl) -ethyl] -thioureido) -phenyl) -amide 712 668 N- (4- {3- (3-chloro-5- (3- {4 - [([1,2,3] thiadiazole-4-carbonyl) amino] phenyl] thioureido) phenyl] thioureido} phenyl) [1 , 2,3] thiadiazole-4-carboxamide 713 413 (4- {3- [2- (4-Ethyl-phenyl) -ethyl] thioureido] -phenyl) -amide [1,2,3] thiadiazole-4-carboxylic acid 714 442 (4- {3- (4-Chloro-3-trifluoromethyl-phenyl) thioureido] - oxazole-4-carboxylic acid phenyl) amide 715 475 Oxazole-4-carboxylic acid {4- [3- (3,5-Bistrifluoromethyl-phenyl) -thioureido] -phenyl} -amide 716 420 [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [2- (3,4-difluorophenyl) ethyl] thioureido] phenyl) amide 717 452 [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [2- (4-trifluoromethyl-phenyl) -ethyl] -thioireido} -phenyl) -amide 718 435 (4- {3- [2- (3,4-Dichlorophenyl) ethyl] thioureido] phenyl) - furan-2-carboxylic acid amide 719 463 N- (4- {3- [2- (3,4-Dichlorophenyl) ethyl] thioureido} - phenyl) -2-fluoro-benzamide 720 420 [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [2- (3,5-difluorophenyl) ethyl] thioureido] phenyl) amide 721 412 2-Fluoro-N- (4- {3- [2- (2-fluoro-phenyl) -ethyl] thioureido} -phenyl) -benzamide 722 429 (4- {3- [2- (4-Nitro-phenyl) -ethyl] thioureido} -phenyl) -amide [1,2,3] thiadiazole-4-carboxylic acid 723 399 [4- [3- (l-methyl-2-phenyl-ethyl) thioureido] fenyljamid [1,2,3] thiadiazole-4-carboxylic acid 724 437 N- {4- [3- (4-tert-butylbenzyl) thioureido] -phenyl} -2- fluorobenzamide 725 409 N- {4- [3- (3,5-Dimethylbenzyl) thioureido] phenyl} -2-fluorobenzamide 726 400 {4- [3- (2-hydroxy-l-phenyl-ethyl) thioureido] -phenyl} -amide [1,2,3] thiadiazole-4-carboxylic acid

147

409 2-Fluoro-N- {4- [3- (1-methyl-1-phenylethyl) thioureido] phenyl} benzamide

[1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (1-methyl-1-phenylethyl) -thioureido] -phenyl] -amide

[1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (2-chloro-benzyl) -thioureido] -phenyl} -amide

388 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (2-fluorobenzyl) thioureido] phenyl] amide

438 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (3-trifluoromethyl-benzyl) -thioureido] -phenyl} -amide

388 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (3-fluoro-benzyl) -thioureido] -phenyl} -amide

435 [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [2- (2-chloro-phenoxy) -ethyl] -thioureido} -phenyl) -amide

479 [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [2- (3-bromo-phenoxy) -ethyl] -thioureido} -phenyl) -amide

418 [1,2,3] Thiadiazole-4-carboxylic acid 4- {3- [2- (2-fluoro-phenoxy) -ethyl] -thioureido} -phenyl) -amide

418 [1,2,3] Thiadiazole-4-carboxylic acid {4- {3- [2- (3-fluoro-phenoxy) -ethyl] -thioureido} -phenyl) -amide

486 [1,2,3] Thiadiazole-4-carboxylic acid 4- {3- [2- (2-fluoro-5-trifluoromethyl-phenoxy) -ethyl] -thiouraido) -phenyl} -amide

384 Furan-2-carboxylic acid 4- [3- [2- (2-fluorophenyl) ethyl] thioureido} phenyl) amide

435 [1,2,3] Thiadiazole-4-carboxylic acid {4- (3- (4-bromo-phenyl) -thioureido] -phenyl} -amide

374 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (4-fluorophenyl) -thioureido] -phenyl] -amide

388 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (4-fluorobenzyl) thioureido] phenyl] amide

405 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (4-chlorobenzyl) thioureido] phenyl] amide

449 {4- [3- (4-Bromobenzyl) thioureido] phenyl} amide

148 [1,2,3] thiadiazole-4-carboxylic acid

332 N- (4- {3- [1- (4-Fluorophenyl) ethyl] thioureido} phenyl) acetamide

438 Thiazole-4-carboxylic acid {4- [3- (3,4-dichloro-benzyl) -thioureido] -phenyl] -amide

455 Thiazole-4-carboxylic acid {4- [3- (2-fluoro-5-trifluoromethyl-benzyl) -thioureido] -phenyl} -amide

426 Thiazole-4-carboxylic acid {4- [3- (4-tert-butylbenzyl) thioureido] phenyl] amide

374 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (2-fluoro-phenyl) -thioureido] -phenyl) -amide

374 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (3-fluorophenyl) -thioureido] -phenyl] -amide

526 [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [2- (3-iodo-phenoxy) -ethyl] -thioureido} -phenylamide

409 N- (4- {3- [1- (4-Fluorophenyl) ethyl] thioureido} phenyl) -2-phenylacetamide

425 N- (4- {3- [1- (4-Fluorophenyl) ethyl] thioureido} phenyl) -2-methoxybenzamide

425 N- (4- {3- [1- (4-Fluorophenyl) ethyl] thioureido} phenyl) -3-methoxybenzamide

425 N- (4- {3- [1- (4-Fluorophenyl) ethyl] thioureido} phenyl) -4-methoxybenzamide

429 2-Chloro-N- (4- {3- [1- (4-fluorophenyl) ethyl] thioureido} phenyl) benzamide

429 4-Chloro-N- (4- {3- [1- (4-fluorophenyl) ethyl] thioureido} phenyl) benzamide

453 Acetic acid 4- (4- {3- [1- (4-Fluorophenyl) ethyl] thioureido} phenylcarbamoyl) phenyl ester

394 N- (4- {3- [1- (4-Fluorophenyl) ethyl] thioureido} phenyl) benzamide

395 N- (4- {3- [1- (4-Fluorophenyl) ethyl] thioureido} phenyl) isonicotinamide

410 N- (4- {3- [1- (4-Fluorophenyl) ethyl] thioureido} phenyl)

-4-hydroxybenzamide 761 429 3-Chloro-N- (4- {3- [1- (4-fluorophenyl) ethyl] thioureido} - phenyl) benzamide 7 62 470 (4- {3- [2- (3-Fluoro-5-trifluoromethyl-phenyl) -ethyl] - [1,2,3] Thiadiazole-4-carboxylic acid thiourea} phenyl) amide of 763 520 [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [2- (2,4-Bistrifluoromethyl-phenyl) -ethyl] -thioureido} -phenyl) -amide 764 470 [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [2- (4-fluoro-3-trifluoromethyl-phenyl) -ethyl] -thioureido} -phenyl) -amide 765 438 4-Dimethylamino-N- (4- {3- [1- (4-fluorophenyl) ethyl] thioureido} phenylbenzamide 766 470 [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [2- (2-fluoro-3-trifluoromethyl-phenyl) -ethyl] -thioureido} -phenyl) -amide 767 470 [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [2- (2-fluoro-5-trifluoromethyl-phenyl) -ethyl] -thioureido} -phenyl) -amide 768 510 (4- {3- [2- (3-iodophenyl) ethyl] thioureido} -phenyl) -amide [1,2,3] thiadiazole-4-carboxylic acid 769 470 (4- {3- [2- (4-fluoro-2-trifluoromethylphenyl) ethyl] - [1,2,3] Thiadiazole-4-carboxylic acid thiourea} phenyl) amide of 770 463 (4- {3- [2- (3-Bromo-phenyl) -ethyl] thioureido} -phenyl) -amide [1,2,3] thiadiazole-4-carboxylic acid 771 427 2-Fluoro-N- (4- {3- [1- (4-fluorophenyl) propyl] thioureido} -phenyl) -benzamide 772 475 2-Fluoro-N- (4- {3 - [(4-fluorophenyl) phenylmethyl] - thioureido} -phenyl) -benzamide 773 455 2-Fluoro-N- (4- {3- [1- (4-fluorophenyl) pentyl] thioureido} -phenyl) -benzamide 774 489 2-Fluoro-N- (4- {3- [1- (4-fluorophenyl) -2-phenylethyl] -

150 thioureido (phenyl) benzamide

775 409 2-Fluoro-N- {4- [3- (1-o-tolyl-ethyl) thioureido] -phenyl} -benzamide 776 409 2-Fluoro-N- {4- [3- (1-m-tolyl-ethyl) thioureido] -phenyl} -benzamide 777 425 2-Fluoro-N- (4- {3- [1- (4-methoxyphenyl) ethyl] thioureido} phenyl) benzamide 778 412 2-Fluoro-N- (4- {3- (1- (2-fluorophenyl) -ethyl] thioureido} -phenyl) -benzamide 779 429 N- (4- {3- [1- (3-Chloro-phenyl) -ethyl] thioureido} -phenyl) - -2-fluoro-benzamide 780 473 N- (4- {3- [1- (3-Bromo-phenyl) -ethyl] thioureido} -phenyl) - -2-fluoro-benzamide 781 429 N- (4- {3- (1- (4-Chloro-phenyl) -ethyl] thioureido} -phenyl) - -2-fluoro-benzamide 782 409 2-Fluoro-N- {4- [3- (1-p -tolyl-ethyl) thioureido] -phenyl} -benzamide 783 473 N- (4- {3- [1- (2-Bromo-phenyl) -ethyl] thioureido} -phenyl) - 2-fluoro-benzamide 784 429 N- (4- {3- [1- (2-Chloro-phenyl) -ethyl] thioureido} -phenyl) -2-fluoro-benzamide 785 4 62 2-Fluoro-N- (4- {3- [1- (2-trifluoromethyl-phenyl) -ethyl] thioureido} -phenyl) -benzamide 786 462 2-Fluoro-N- (4- {3- [1- (3-trifluoromethyl-phenyl) -ethyl] thioureido} -phenyl) -benzamide 787 462 2-Fluoro-N- (4- {3- [1- (4-trifluoromethyl-phenyl) -ethyl] thioureido} -phenyl) -benzamide 788 425 2-Fluoro-N- (4- {3- [1- (2-methoxy-phenyl) -ethyl] thioureido} -phenyl) -benzamide 789 425 2-Fluoro-N- (4- {3- [1- (3-methoxy-phenyl) -ethyl] thioureido} -phenyl) -benzamide 790 441 2-Fluoro-N- (4- {3- [1- (4-fluorophenyl) -2-methylpropyl] thioureido} -phenyl) -benzamide 791 419 N- (4- {3- [1- (3-cyanophenyl) ethyl] thioureido} phenyl) -

151

-2-fluoro-benzamide

792 419 N- (4- {3- [1- (4-cyanophenyl) ethyl] thioureido} fenylJ- -2-fluoro-benzamide 793 438 N- {4- {3- [1- (4-dimethylaminophenyl) ethyl] thioureido) phenyl) -2-fluoro-benzamide 794 438 N- (4- {3- [1- (3-dimethylaminophenyl) ethyl] thioureido) phenyl) -2-fluoro-benzamide 795 473 2-Bromo-N- (4- {3- (1- (4-fluorophenyl) ethyl) thioureido) - phenyl) benzamide 796 446 (4- {3- [1- (4-fluorophenyl) ethyl] thioureido] -phenyl) -amide quinoline-2-carboxylic acid 797 410 2-Fluoro-N- {4- [3- (2-hydroxy-l-phenyl-ethyl) thioureido] fenylJbenzamid 798 332 2-Fluoro-N- [4- (3-izopropyltioureido) -phenyl] -benzamide 799 445 2-Fluoro-N- {4- [3- (l-naphthalen-2-yl-ethyl) tioureidojfenylJbenzamid 800 412 3-Fluoro-N- (4- {3- [1- (4-fluorophenyl) ethyl] thioureido] phenyl) benzamide 801 412 4-Fluoro-N- (4- {3- [1- (4-fluorophenyl) ethyl] tioureidojfenyl) benzamide 802 384 2-Fluoro-N- {4- [3- (l-furan-2-yl-ethyl) thioureido] fenyljbenzamid 803 395 2-Fluoro-N- {4- [3- (1-pyridin-4-yl-ethyl) thioureido] fenylJbenzamid 804 397 2-Fluoro-N- (4- {3- [1- (1-methyl-1H-pyrrol-2-yl) ethyl] thioureido] phenyl) benzamide 805 401 2-Fluoro-N- {4- [3- (l-thiophen-3-yl-ethyl) thioureido] fenylJbenzamid 806 44 5 N- {4- [3- (3-Chloro-4-ethoxy-phenyl) thioureido] phenyl} -2-fluoro-benzamide 807 459 N- {4- [3- (3-chloro-4-propoxy-phenyl) thioureido] -phenyl-2-fluoro-benzamide 808 459 N- {4- [3- (3-Chloro-4-isopropoxy-phenyl) thioureido] -phenyl-2-fluoro-benzamide

152

473 N- {4- [3- (4-Butoxy-3-chlorophenyl) thioureido] phenyl} -2

fluorobenzamide

522 2-Fluoro-N- {4- [3- (3-iodo-4-methoxy-phenyl) -thioureido] -phenyl} -benzamide

475 N- {4- [3- (3-Bromo-4-methoxy-phenyl) -thioureido] -phenyl} -2-fluoro-benzamide

520 N- (4- {3- [1- (4-Fluorophenyl) ethyl] thioureido} phenyl) -2-iodobenzamide

346 N- (4- {3- [1- (4-Fluorophenyl) ethyl] thioureido} phenyl) propionamide

286 N- [4- (3-Phenylthioureido) phenyl] acetamide

507 N- {5 - [({[3,5Bis (trifluoromethyl) benzyl] amino} carbothioyl) amino] -2-pyridinyl} -1,2,3-thiadiazole-4-carboxamide

521 N— (5— {[({(1S) -1- [3,5-

Bis (trifluoromethyl) phenyl] ethyl} amino) carbothioyl] amino} 2-pyridinyl) -1,2,3-thiadiazole-4-carboxamide

520 N- (5 - {[({(1S) -1- [3,5-Bis (trifluoromethyl) phenyl] ethyl} amino) carbothioyl] amino} -2-pyridinyl) -1,3-thiazole-4-carboxamide

470 N - (5 - {[([1- [2-Fluoro-5 (trifluoromethyl) phenyl] ethyl} amino) carbothioyl] amino} -2-pyridinyl) -1,3-thiazole-4-carboxamide

470 N- (5 - {[({1- [2-Fluoro-4- (trifluoromethyl) phenyl] ethyl} amino) kaxbothioyl] amino} -2-pyridinyl) -1,3-thiazole-4-carboxamide

470 N- (5 - {[({1- [3-Fluoro-5 (trifluoromethyl) phenyl] ethyl} amino) carbothioyl] amino} -2-pyridinyl) -1,3-thiazole-4-carboxamide

504 N- (5 - {[({(1S) -1- [3,5-Bis (trifluoromethyl) phenyl] ethyl})

153 amino) carbonyl] amino} -2-pyridinyl) -1,3-thiazole-4-carboxamide

822

463 N- {5 - [({[1- (3Bromophenyl) ethyl] amino} carbothioyl) amino] -2-pyridinyl} -1,3-thiazole-4-carboxamide

823 463

N- {5 - [({[1- (2Bromophenyl) ethyl] amino} carbothioyl) amino] -2-pyridinyl} -1,3-thiazole-4-carboxamide

824 452 N- (5 - {[({1- [3- (Trifluoromethyl) phenyl] ethyl) amino) carbothioyl] amino} -2-pyridinyl) -1,3-thiazole-4-carboxamide

825 486

N- (5 - {[({1- [4-Chloro-3 (trifluoromethyl) phenyl] ethyl} amino) carbothioyl] amino) -2-pyridinyl) -1,3-thiazole-4-carboxamide

826 436

N- {5 - [({[1- (4-Chloro-3-fluorophenyl) ethyl] amino) carbothioyl) pyridinyl} -1,3-thiazole-4-carboxamide amino] -2827 436

N- {5 - [({[1- (4-Chloro-2-fluorophenyl) ethyl] amino} carbothioyl) pyridinyl) -1,3-thiazole-4-carboxamide amino] -2828 434

N- {6 - [({[1- (4Fluorophenyl) ethyl] amino} carbothioyl) amino] 3-pyridinyl] -1,2,3-thiadiazole-4-carboxamide

829

426 N- (6 - {[({(1S) -1- [3,5-Bis (trifluoromethyl) phenyl] ethyl) amino) carbothioyl] amino) -3-pyridinyl) -1,2,3-thiadiazole

4-carboxamide

Example 830

Method 32

154 [1,2,3] Thiadiazole-4-carboxylic acid 4- [3- (2,5-dichlorophenyl) -thioureido] -phenyl} -amide

To a solution of 2,5-dichloroaniline (0.16 g) in tetrahydrofuran (20 mL) was added freshly prepared 1,1'-thiocarbonyldiimidazole (0.20 g) and the mixture was stirred at room temperature for about 30 minutes.

[1,2,3] Thiadiazole-4-carboxylic acid (4-aminophenyl) amide (0.22 g) was added to the reaction flask and stirred for about 6 hours. The solvent was then removed by evaporation under reduced pressure and hot acetonitrile (3 mL) was added. After 15 hours, the mixture was filtered and the collected precipitate was washed with acetonitrile and then with diethyl ether, air dried to give the desired product as a white powder.

Using the above procedure and suitable starting materials, the following compounds were prepared:

EX M + H

NAME OF THE COMPOUND

831321

832443

833443

834443

835443

836431

837431

838 431

N- {4 - [[3- (3-Chloro-phenyl) thioureido] -phenyl} -acetamide

N- (4- [3- (3-chloro-4-metoxyfenylltioureido] phenyl} benzamide

N- {4- [3- (3-Chloro-4-methoxy-phenyl) -thioureido] -phenyl} -2-methoxy-benzamide

N- {4- [3- (3-Chloro-4-methoxy-phenyl) thioureido] phenyl} -3-methoxybenzamide

N- {4- [3- (3-Chloro-4-methoxy-phenyl) thioureido] phenyl} -4-methoxybenzamide

N- {4- [3- (3-Chloro-4-methoxy-phenyl) thioureido] phenyl} -4-methoxybenzamide

N- {4- [3- (3-Chloro-4-methoxy-phenyl) thioureido] -phenyl}

-3-fluoro-benzamide

N- {4- [3- (3-Chloro-4-methoxy-phenyl) thioureido] -phenyl} 155

4-fluorobenzamide

839 437 Furan-2-carboxylic acid {4- [3- (3,5-Dichloro-4-methoxy-phenyl) -thioureido] -phenyl} -amide 840 511 {4- [3- (5-Bromo-2,4-dimethoxy-phenyl) -thioureido] -phenyl] -carbamic acid hexyl ester 841 481 {4- [3- (5-bromo-2,4-dimethoxyphenyl) thioureido] -phenyl} - hexanoic acid amide 842 505 N- {4- [3- (5-bromo-2,4-dimethoxyphenyl) thioureido] - phenyl} -2-fluoro-benzamide 843 477 {4- [3- (5-bromo-2,4-dimethoxyphenyl) thioureido] -phenyl} - furan-2-carboxylic acid amide 844 501 N- {4- [3- (5-bromo-2,4-dimethoxyphenyl) thioureido] -phenyl} -2-methylbenzamide 845 517 N- {4- [3- (5-Bromo-2,4-dimethoxyphenyl) thioureido] phenyl} -4-methoxybenzamide 846 395 N- {4- [3- (5-chloro-2-ethoxy-4-methoxy-phenyl) thioureido] -phenyl} -acetamide 847 395 N- {4- [3- (5-Chloro-4-ethoxy-2-methoxy-phenyl) thioureido] -phenyl] -acetamide 848 423 N- {4- [3- (2-Butoxy-5-chloro-4-methoxyphenyl) - thioureido] -phenyl] -acetamide 849 423 N- {4- [3- (4-Butoxy-5-chloro-2-methaxyphenyl) thioureido] phenyl] acetamide 850 457 N- {4- [3- (2-benzyloxy-5-chloro-4-methoxyphenyl) - thioureido] -phenyl] -acetamide 851 457 N- {4- [3- (4-Benzyloxy-5-chloro-2-methoxyphenyl) - thioureido] -phenyl] -acetamide 852 421 {4- [3- (3-Chloro-4-methoxy-phenyl) thioureido] -phenyl} -amide [1,2,3] thiadiazole-4-carboxylic acid 853 424 2- {4- [3- (4-Acetylamino-phenyl) -thioureido] -2-chloro-5- methoxyphenoxy) acetamide 854 367 N- {4- [3- (5-chloro-2-hydroxy-4-methoxyphenyl) - thioureido] -phenyl} -acetamide 855 367 N- {4- [3- (3-chloro-4-methylsulfanyl-phenyl) -

156 thioureido] phenyl] acetamide

856 447 N- [4- (3- {3-Chloro-4- [methyl- (l-methylpiperidin-4-yl) amino] phenyl} thioureido) -phenyl] -acetamide 857 426 N- (4- {3- [3-chloro-4- (methylphenylamino) phenyl] - thioureido] phenyl) acetamide 858 509 N- [4- (3- {4 - [(l-Benzyl-pyrrolidin-3-yl) methylamino] -3-chloro-phenyl} thioureido) -phenyl] -acetamide 859 418 N- (4- {3- [3-chloro-4- (cyclopentylmetylamino) phenyl] thioureido {phenyl) acetamide 860 433 N- [4- (3- {3-Chloro-4- [methyl- (l-methylpyrrolidin-3-yl) amino] phenyl] thioureido) -phenyl] -acetamide 861 419 Furan-2-carboxylic acid {4- [3- (3-chloro-4-methylsulfanyl-phenyl) -thioureido] -phenyl] -amide 8 62 447 N- {4- [3- (3-chloro-4-methylsulfanyl-phenyl) thioureido] -phenyl-2-fluoro-benzamide 863 465 N- {4- [3- (3-chloro-4-methylsulfanyl-phenyl) thioureido] -phenyl-2,6-difluoro-benzamide 864 445 N- [4- [3- (5-Chloro-2-methoxy-4-methyl-phenyl) - thioureido] -phenyl-2-fluoro-benzamide 865 441 N- {4- [3- (5-Chloro-2-methoxy-4-methyl-phenyl) -thioureido] -phenyl] -2-methyl-benzamide 866 434 {4- [3- (3-Chloro-4-dimethylaminophenyl) thioureido] phenyl] - [1,2,3] thiadiazole-4-carboxylic acid amide 867 444 N- {4- [3- (3-Chloro-4-dimethylamino-phenyl) thioureido] -phenyl-2-fluoro-benzamide 868 517 [1,2,3] Thiadiazole-4-carboxylic acid [4- (3- {3-chloro-4- [methyl- (1-methylpiperidin-4-yl) amino] phenyl] thioureido) phenyl] amide 869 579 [1,2,3] Thiadiazole-4-carboxylic acid [4- (3- {4 - [(1-Benzyl-pyrrolidin-3-yl) -methyl-amino] -3-chloro-phenyl] -thioureido) -phenyl] -amide 870 527 N- [4- (3- {3-Chloro-4- [methyl- (l-methylpiperidin-4-ylamino] fenylJtioureido) phenyl] -2-fluoro-benzamide 871 435 {4- [3- (5-Chloro-2-methoxy-4-methyl-phenyl) thioureido] -

157 Phenyljamide [1,2,3] thiadiazole-4-carboxylic acid

589 N- [4- (3- {4 - [(1-Benzyl-pyrrolidin-3-yl) -methyl-amino] -3-chloro-phenyl] -thioureido) -phenyl] -2-fluoro-benzamide

501 Furan-2-carboxylic acid {4- [3- (5-chloro-2,4-dimethoxy-phenyl) -thioureido] -3-trifluoromethyl-phenyl-amide

366 2-Fluoro-N- [4- (3-phenylthioureido) phenyl] benzamide

338 Furan-2-carboxylic acid [4- (3-phenylthioureido) phenyl] amide

356 [1,2,3] Thiadiazole-4-carboxylic acid [4- (3-phenylthioureido) phenyl] amide

365 N- (4- {3- [3-Chloro-4- (1-hydroxyethyl) phenyl] thioureido} phenyl) acetamide

435 [1,2,3] Thiadiazole-4-carboxylic acid 4- {3- [3-chloro-4- (1-hydroxy-ethyl) -phenyl] -thioureidophenyl) -amide

365 N- (4- {3- [3-Chloro-4- (2-hydroxyethyl) phenyl] thioureido} phenyl) acetamide

445 N- (4- {3- [3-Chloro-4- (1-hydroxyethyl) phenyl] -thioureido} phenyl) -2-fluorobenzamide

417 Furan-2-carboxylic acid 4- (3- [3-chloro-4- (1-hydroxyethyl) phenyl] thioureido} phenyl) amide

371 [1,2,3] Thiadiazole-4-carboxylic acid 4- [3- (3- (amino-phenyl) -thioureido] -phenyl} -amide

501 Furan-2-carboxylic acid {4- [3- (3-bromo-4-trifluoromethoxy-phenyl) -thioureido] -phenyl] -amide

423 N- {4- [3- (3-tert-Butylphenyl) thioureido] phenyl} -2-fluorobenzamide

440 [4- [3- (4-Chloro-3,5-dichloro-phenyl) -thioureido] -phenyl] -amide [1,2,3] thiadiazole-4-carboxylic acid

485 N- {4- [3- (1-Benzofuran-2-yl-ethyl) -thioureido] -phenyl] -2-trifluoromethyl-benzamide

412 N- (4-Fluorophenyl) -4- {3- [1- (4-fluorophenyl) ethyl] thioureido] benzamide

446 Isoquinoline-1-carboxylic acid (4- {3- [1- (4-fluorophenyl) ethyl] thioureido] phenyl) amide

158

468 Isoquinoline-1-carboxylic acid {4- [3- (1-Benzofuran-2-yl-ethyl) -thioureido] -phenyl] -amide

506 Isoquinoline-1-carboxylic acid (4- {3- [1- (4-bromophenyl) ethyl] thioureido} phenyl) amide

453 Isoquinoline-1-carboxylic acid (4- {3- [1- (4-cyanophenyl) ethyl] thioureido] phenyl) amide

435 Benzofuran-2-carboxylic acid (4- {3- [1- (4-fluorophenyl-ethyl) -thioureido] -phenyl) -amide

457 Benzofuran-2-carboxylic acid {4- [3- (1-Benzofuran-2-yl-ethyl) -thioureido] -phenyl] -amide

495 Benzofuran-2-carboxylic acid (4- {3- [1- (4-bromophenyl) ethyl] thioureido] phenyl) amide

442 Benzofuran-2-carboxylic acid (4- {3- [1- (4-cyanophenyl) ethyl] thioureido} phenyl) amide

446 Isoquinoline-3-carboxylic acid (4- {3- [1- (4-fluorophenyl) ethyl] thioureido} phenyl) amide

468 Isoquinoline-3-carboxylic acid {4- [3- (1-benzofuran-2-ylethyl) thioureido] phenyl] amide

453 Isoquinoline-3-carboxylic acid (4- {3- [1- (4-cyanophenyl) ethyl] thioureido} phenyl) amide

506 Isoquinoline-3-carboxylic acid (4- {3- [1- (4-bromophenyl) ethyl] thioureido} phenyl) amide

446 Quinoline-3-carboxylic acid 4- (3- [1- (4-fluorophenyl) ethyl] thioureido} phenyl) amide

446 Quinoline-4-carboxylic acid (4- {3- [1- (4-fluorophenyl) ethyl] thioureido} phenyl) amide

446 Quinoline-6-carboxylic acid (4- {3- [1- (4-fluorophenyl) ethyl] thioureido} phenyl) amide

446 Quinoline-8-carboxylic acid (4- {3 - [(4-fluorophenyl) ethyl] thioureido} phenyl) amide

462 N- (4- {3- (1- (4-Fluorophenyl) ethyl] thioureido} phenyl) -2-trifluoromethylbenzamide

419 2-Cyano-N- (4- {3- [1- (4-fluorophenyl) ethyl] thioureido} phenyl) benzamide

159

1009 473 N- {4- [3- (3-chloro-4-izobutoxyfenyltioureido] phenyl} -2-fluoro-benzamide 1010 414 2-Fluoro-N- {4- (3- [3-fluoro-4-methoxy-phenyl) thioureido] -phenyl} -benzamide 1011 475 N- (4- {3- [3-Chloro-4- (2-methoxyethoxy) phenyl] thioureido] phenyl) -2-fluorobenzamide 1012 398 2-Fluoro-N- {4- [3- (3-fluoro-4-methylphenyl) thioureido] - phenyl} benzamide 1013 464 2-Fluoro-N- {4- [3- (4-methoxy-3-trifluoromethyl-phenyl) - thioureido] fenylJbenzamid 1014 449 N- {4- [3- (2-Amino-5-trifluoromethyl-phenyl) thioureido] - phenyl} -2-fluoro-benzamide 1015 459 N- (4- {3- [3- [1- (3-Chloro-4-methoxy-phenyl) -ethyl] thioureido} -phenyl) -2-fluoro-benzamide 1016 417 N- {4- [3- (5-chloro-2-hydroxy-phenyl) thioureido] -phenyl} - -2-fluoro-benzamide 1017 435 N- {4- [3- (benzofuran-2-yl-ethyl) thioureido] -phenyl} - -2-fluoro-benzamide 1018 448 2-Fluoro-N- {4- [3- (4-methyl-3-trifluoromethylphenyl) - thioureido] -phenyl} -benzamide 1019 473 (S) -N- (4- {3- [1- (4-Bromo-phenyl) -ethyl] thioureido} -phenyl) -2-fluoro-benzamide 1020 473 N- (4- {3 - [(R) -1- (4-bromophenyl) ethyl] thioureido} -phenyl) -2-fluoro-benzamide 1021 494 2-Fluoro-N- (4- {3- [2-methoxy-4- (2,2,2-trifluoroethoxy) phenyl] thioureido} -phenyl) -benzamide 1022 399 N- {4- [3- (2-Amino-5-fluoro-phenyl) thioureido] phenyl} -2 fluorobenzamide 1023 502 N- (4- {3- [1- (4-Dimetylsulfamoylfenyl) -ethyl] thioureido} -phenyl) -2-fluoro-benzamide 1024 542 2-Fluoro-N- [4- (3- {l- [4- (piperidin-sulfonyl) phenyl] ethyl} thioureido) -phenyl] -benzamide 1025 562 N- (4- {3- [2,4-bis (2,2,2-trifluoroethoxy) phenyl] thioureido} -phenyl) -2-fluoro-benzamide

160

1026 409 2-Fluoro-N- {4- [3-1 (1 S) -1- p -tolyl-ethyl) thioureido] - fenylJbenzamid 1027 409 2-Fluoro-N- {4- [3 - ((R) -1- p -tolyl-ethyl) tioreido] fenylJbenzamid 1028 394 2-Fluoro-N- {4- [3 - ((1 S) -1-phenyl-ethyl) thioureido] - fenylJbenzamid 1029 429 N- (4- {3 - [(R) -1- (4-Chlorophenyl) ethyl] tioureidojfenyl) -2-fluoro-benzamide 1030 429 N- (4- {3 - [(1 S) -1- (4-Chloro-phenyl) -ethyl] thioureido} -phenyl) -2-fluoro-benzamide 1031 394 2-Fluoro-N- {4- [3 - ((R) -1-phenyl-ethyl) thioureido] fenylJbenzamid 1032 432 N- (4- {3- [1- (4-cyanophenyl) ethyl] thioureido] phenyl) -2-methoxy-benzamide 1033 447 N- {4- [3- (benzofuran-2-yl-ethyl) thioureido] -phenyl-2-methoxybenzamide 1034 485 N- (4- {3- [1- (4-Bromo-phenyl) -ethyl] thioureido} -phenyl) -2-methoxybenzamide 1035 419 3-Cyano-N- (4- {3- [1- (4-fluorophenyl) ethyl] thioureido] phenyl) benzamide 1036 462 N- (4- {3- [1- (4-fluorophenyl) -ethyl] thioureido} -phenyl) -4-trifluoromethyl-benzamide 1037 419 4-Cyano-N- (4- {3- [1- (4-fluorophenyl) ethyl] thioureido} -phenyl) -benzamide 1038 469 2-Fluoro-N- (4- {3- [1- (4-fluorophenyl) ethyl] thioureido] 2,3,5, β-tetrametylfenylJbenzamid 1039 480 N- (4- [3- [1- (4-Cyanophenyl) ethyl] thioureido) -2,5-dimethoxyphenyl) -2-fluorobenzamide 1040 473 2-Fluoro-N- {4- {3- [1- (4-fluorophenyl) ethyl] thioureido} -2,5-dimethoxyphenyl) benzamide 1041 530 N- {3,5-Dichloro-4- [3- (5-chloro-2,4-dimethoxyphenyl) thioureido] phenyl} -2-fluorobenzamide 1042 447 N- (3-Chloro-4- {3- [1- (4-fluorophenyl) ethyl] thioureido]

phenyl) -2-fluoro-benzamide

161

1043 480 2,3,4,5-tetrafluoro-N- (4- {3- [1- (4-fluorophenyl) ethyl] thioureido} -3-methyl-phenyl) -benzamide 1044 462 2,4,5-Trifluoro-N- (4- {3- [1- (4-fluorophenyl) ethyl] thioureido} -3-methyl-phenyl) -benzamide 1045 427 2-Fluoro-N- (4- {3- [1- (4-fluorophenyl) ethyl] thioureido} - -3-methyl-phenyl) -benzamide in 1046 457 2-Fluoro-N- (4- {3- [1- (4-fluorophenyl) ethyl] thioureido} - 2-methoxy-5-methyl-phenyl) -benzamide 1047 443 2-Fluoro-N- (4- {3- [1- (4-fluorophenyl) ethyl] thioureido} -3- methoxyphenyl) benzamide 1048 570 N- (2,6-Dibromo-4- {3- [1- (4-fluorophenyl) ethyl] thioureido} -phenyl) -2-fluoro-benzamide 1049 480 2-Fluoro-N- (4- {3- [1- (4-fluorophenyl) ethyl] thioureido} -2- trifluoromethylphenyl) benzamide 1050 541 N- (4- {3- [1- (4-Bromo-phenyl) -ethyl] thioureido} -2 -trifluórmetylfenyl1-2-fluorobenzamide in 1051 437 N- (4- {3- [1- (4-cyanophenyl] ethyl] -2-thioureido} phenyl) -2-fluoro-benzamide 1052 503 N- {4- [3- (1-Benzofuran-2-ylethyl) thioureido] -2-trifluoromethylphenyl} -2-fluorobenzamide 1053 447 N- (2-Chloro-4- {3- [1- (4-fluorophenyl) ethyl] thioureido} - phenyl) -2-fluoro-benzamide 1054 454 N- (2-Chloro-4- {3- [1- (4-cyanophenyl) ethyl] thioureido} phenyl) -2-fluorobenzamide 1055 437 N- (2-Cyano-4- {3- [1- (4-fluorophenyl) ethyl] thioureido} -phenyl) -2-fluoro-benzamide 1056 498 N- (4- {3- [1- (4-Bromo-phenyl) -ethyl] thioureido} -2-cyanophenyl) -2-fluoro-benzamide 1,057 445 N- (2-Cyano-4- {3- [1- (4-cyanophenyl) -ethyl] thioureido} -phenyl) -2-fluoro-benzamide 1058 460 N- {4- [3- (benzofuran-2-yl-ethyl] thioureido} -2-cyano- phenyl-2-fluoro-benzamide 1059 517 N- (2-Benzoyl-4- {3- [1- (4-fluorophenyl) ethyl] -

thioureido} -phenyl) -2-fluoro-benzamide

162

427 2-Fluoro-N- (4- {3- [1- (4-fluorophenyl) ethyl] thioureido} -2-methylphenyl) benzamide

487 N- (4- {3- [1- (4-Bromophenyl) ethyl] thioureido} -2-methylphenyl) -2-fluorobenzamide

434 N- (4- {3- [1- (4-Cyanophenyl) ethyl] thioureido} -2-methylphenyl) -2-fluorobenzamide

449 N- {4- [3- (1-Benzofuran-2-ylethyl) thioureido] -2-methylphenyl} -2-fluorobenzamide

456 N- (2-Dimethylamino-4- {3- [1- (4-fluoro-phenyl) -ethyl] -thioureido] -phenyl) -2-fluoro-benzamide

526 N- (2-Benzyloxy-4- {3- [1- (4-cyanophenyl) ethyl] thioureido} phenyl) -2-fluorobenzamide

519 N- (2-Benzyloxy-4- {3- [1- (4-fluorophenyl) ethyl] thioureido} phenyl) -2-fluorobenzamide

603 N- [4- {3- [1- (4-Bromophenyl) ethyl] thioureido} -2- (2-morpholin-4-ylethoxy) phenyl] -2-fluorobenzamide

603 N- [4- {3- [1- (4-Bromophenyl) ethyl] thioureido} -2- (2-morpholin-4-ylethoxy) phenyl] -2-fluorobenzamide

542 2-Fluoro-N- [4- {3- [1- (4-fluorophenyl) ethyl] thioureido} -2- (2-morpholin-4-ylethoxy) phenyl] benzamide

485 N- (2-Butoxy-4- {3- [1- (4-fluorophenyl) ethyl] thioureido} phenyl) -2-fluorobenzamide

492 N- (2-Butoxy-4- {3- [1- (4-cyanophenyl) ethyl] thioureido} phenyl) -2-fluorobenzamide

589 N- [4- {3- [1- (4-Bromophenyl) ethyl] thioureido} -2- (2-diethylaminoethoxy) phenyl] -2-fluorobenzamide

528 N- (2- (2-Diethylaminoethoxy) -4- {3- [1- (4-fluorophenyl) -2-fluorobenzamide)

589 N- [4- {3- [1- (4-Bromophenyl) ethyl] thioureido} -2- (2-diethylaminoethoxy) phenyl] -2-fluorobenzamide

457 N- (2-Ethoxy-4- {3- [1- (4-fluorophenyl) ethyl] thioureido} phenyl) -2-fluorobenzamide

464 N- (4- {3- [1- (4-Cyanophenyl) ethyl] thioureido} -2-ethoxyphenyl) -2-fluorobenzamide

163

468 2-Fluoro-N- [4- {3- [1- (4-fluorophenyl) ethyl] thioureido} -2

- (2-nitriloetoxy) -phenyl] -benzamide

475 N- (4- {3- [1- (4-Cyanophenyl) ethyl] thioureido} -2- (2-nitriloethoxy) phenyl] -2-fluorobenzamide

443 2-Fluoro-N- (4- {3- [1- (4-fluorophenyl) ethyl] thioureido} -2-methoxyphenyl) benzamide

489 2-Fluoro-N- (5- {3- [1- (4-fluoro-phenyl) -ethyl] -thioureido-phenyl-2-yl) -benzamide

514 Isoquinoline-1-carboxylic acid 4- {3- [1- (4-fluorophenyl) ethyl] thioureido} -2-trifluoromethylphenyl) amide

503 Benzofuran-2-carboxylic acid 4- {3- [1- (4-fluorophenyl) ethyl] thioureido] -2-trifluoromethylphenyl) amide

514 Isoquinoline-3-carboxylic acid 4- {3- [1- (4-fluorophenyl) ethyl] thioureido} -2-trifluoromethylphenyl) amide

471 Isoquinoline-1-carboxylic acid (2-cyano-4- {3- [1- (4-fluorophenyl) ethyl] thioureido} phenyl) amide

460 Benzofuran-2-carboxylic acid (2-cyano-4- {3- [1- (4-fluorophenyl) ethyl] thioureido} phenyl jamide

471 Isoquinoline-3-carboxylic acid (2-cyano-4- {3- [1- (4-fluorophenyl) ethyl] thioureido} phenyl) amide

460 isoquinoline-1-carboxylic acid (4- {3- [1- (4-fluorophenyl) ethyl] thioureido} -2-methylphenyl) amide

449 Benzofuran-2-carboxylic acid 4- (3- [1- (4-fluorophenyl) ethyl] thiureido} -2-methylphenyl) amide

460 Isoquinoline-3-carboxylic acid (4- {3- [1- (4-fluorophenyl) ethyl] thioureido} -2-methylphenyl) amide

396 Pyrazine-2-carboxylic acid (4- {3- [1- (4-fluorophenyl) ethyl] thioureido} phenyl) amide

401 Thiophene-2-carboxylic acid (4- {3- [1- (4-fluorophenyl) ethyl] thioureido} phenyl) amide

401 (4- {3- [1- (4-Fluorophenyl) ethyl] thioureido} phenyl) amide

164

thiophene-3-carboxylic acid 1093 500 2-Isopropyl-thiazole-4-carboxylic acid {4- [3- (4-chloro-3-trifluoromethyl-phenyl) -thioureido] -phenyl} -amide 1094 466 {4- (3- (3,5-Dichloro-phenyl) -thioureido] -phenyl} -amide Of 2-isopropylthiazole-4-carboxylic acid 1095 466 {4- [3- (3,4-Dichlorophenyl) thioureido] phenyl] amide 2-isoproylthiazole-4-carboxylic acid 1096 500 {4- [3- (3,5-Bistrifluoromethylphenyl) thioureido] phenyl} - 2-isopropylthiazole-4-carboxylic acid amide 1097 480 {4- (3- (3,4-Dichlorophenyl) thioureido] phenyl} amide Of 2-butylthiazole-4-carboxylic acid 1098 514 2-Butyl-thiazole-4-carboxylic acid {4- [3- (4-chloro-3-trifluoromethyl-phenyl) -thioureido] -phenyl] -amide 1099 480 {4- [3- (3,5-Dichlorophenyl) thioureido] fenyljamid Of 2-butylthiazole-4-carboxylic acid 1100 548 2-Butylthiazole-4-carboxylic acid {4- [3- (3,5-bistrifluoromethyl-phenyl) -thioureido] -phenyl} -amide 1101 438 (4- [3- (3,5-Dichloro-phenyl) -thioureido] -phenyl) -amide 2-methylthiazole-4-carboxylic acid 1102 438 {4- [3- (3,4-Dichlorophenyl) thioureido] -phenyl} -amide 2-methylthiazole-4-carboxylic acid 1103 505 2-Methyl-thiazole-4-carboxylic acid {4- (3- (3,5-bistrifluoromethyl-phenyl) -thioureido] -phenyl} -amide 1104 534 2-Phenylthiazole-4-carboxylic acid {4- [3- (4-chloro-3-trifluoromethyl-phenyl) -thioureido] -phenyl} -amide 1105 500 {4- (3- (3,5-Dichlorophenyl) thioureido] -phenyl} -amide Of 2-phenylthiazole-4-carboxylic acid 1106 500 {4- (3- (3,4-Dichlorophenyl) thioureido] -phenyl} -amide Of 2-phenylthiazole-4-carboxylic acid 1107 568 2-Phenylthiazole-4-carboxylic acid {4- (3- (3,5-bistrifluoromethyl-phenyl) -thioureido] -phenyl} -amide 1108 401 2-Fluoro-N- {4- [3- (l-thiazol-2-yl-ethyl) thioureido] - fenylJbenzamid 1109 588 2-Fluoro-N- [4- (3- (1- (1- (toluene-4-sulfonyl) -lH-indole

165

2-yl] ethyl} thioureido) -phenyl] -benzamide 1110 446 2-Fluoro-N- {4- [3- (1-quinolin-2-ylethyl) thioureido] - fenylJbenzamid 1111 446 2-Fluoro-N- {4- [3- (l-quinolin-4-yl-ethyl) thioureido] - phenyl} benzamide 1112 446 2-Fluoro-N- {4- [3- (1-isoquinolin-3-ylethyl) thioureido] phenyl} benzamide 1113 446 2-Fluoro-N- {4- [3- (1-isoquinolin-1-ylethyl) thioureido] phenyl} benzamide 1114 446 2-Fluoro-N- {4- [3- (l-quinolin-6-yl-ethyl) thioureido] - phenyl} benzamide 1115 446 2-Fluoro-N- {4- [3- (l-quinolin-3-yl-ethyl) thioureido] - fenylJbenzamid 1116 413 2-Methoxy-N- {4- [3- (l-thiophen-3-yl-ethyl) thioureido] - phenyl} benzamide

Example 886

Method 33 {4- [3- (3,5-Dichlorophenyl) thioureido] phenyl] amide [1,2,3] thiadiazole-4-carboxylic acid

To a solution of 3,5-dichloroaniline (0.16 g) in tetrahydrofuran (20 mL) was added freshly prepared 1,1'-thiocarbonyl-di- (1,2,4) triazole (0.20 g) and the mixture was stirred about 30 minutes at room temperature. [1,2,3] Thiadiazole-4-carboxylic acid (4-aminophenyl) amide (0.22 g) was added to the reaction flask and stirred for about 6 hours. The solvent was then removed by evaporation under reduced pressure and hot acetonitrile (3 mL) was added. After 15 hours the mixture was filtered and the collected precipitate was washed with acetonitrile and then with diethyl ether, air-dried to give the desired product as a white powder. [M + H] 424.

166

Using the above procedure and suitable starting materials, the following compounds were prepared:

M + H Z1UCENINA CIŠLO

465 N- {4- [3- (3,5-Dichloro-4-methoxy-phenyl) -thioureido] -phenyl} -3-fluoro-benzamide

477 N- {4- (3- (3,5-Dichloro-4-methoxy-phenyl) -thioureido] -phenyl} -2-methoxy-benzamide

465 N- {4- [3- (3,5-Dichloro-4-methoxy-phenyl) -thioureido] -phenyl} -2-fluoro-benzamide

477 N- {4- [3- (3,5-Dichloro-4-methoxy-phenyl) -thioureido] -phenyl} -3-methoxy-benzamide

399 N- {4- [3- (3,5-Dichloro-2-methoxy-4-methyl-phenyl) -thioureido] -phenyl} -acetamide

365 N- {4- [3- (3-Chloro-4-methoxy-5-methyl-phenyl) -thioureido] -phenyl} -acetamide

331 N- {4- [3- (2-Nitrophenyl) thioureido] phenyl} acetamide

331 N- {4- [3- (4-Nitro-phenyl) -thioureido] -phenyl} -acetamide

477 N- {4- (3- (3,5-Dichloro-4-methoxy-phenyl) -thioureido] -phenyl} -4-methoxy-benzamide

351 N- {4- [3- (2-Chloro-5-methoxy-phenyl) -thioureido] -phenyl} -acetamide

428 2- {4- 3- (4-Acetylaminophenyl) thioureido] -2,6-dichlorophenoxy} acetamide

443 {4- [3- (4-Acetylaminophenyl) thioureido] -2,6-dichlorophenoxy} acetic acid methyl ester

457 {4- [3- (4-Acetylaminophenyl) -thioureido] -2,6-dichloro-phenoxy} -acetic acid ethyl ester

447 N- {4- [3- (3,5-Dichloro-4-phenoxy-phenyl) -thioureido] -phenyl} -acetamide

410 N- (4- {3- [3,5-Dichloro-4- (2-nitriloethoxy) phenyl] 167 thioureido} phenyl) acetamide

485 {4- [3- (4-Acetylaminophenyl) thioureido] -2,6-dichlorophenoxy} acetic acid tert-butyl ester

469 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- [3,5-Dichloro-2-methoxy-methyl-phenyl) -thioureido] -phenyl] -amide

335 N- {4- [3- (3-Chloro-4-methyl-phenyl) -thioureido] -phenyl} -acetamide

335 N- {4- [3- (5-Chloro-2-methyl-phenyl) -thioureido] -phenyl} -acetamide

703 N- {4- [3- (4- {4- [3- (4-Acetylaminophenyl) thioureido] -2-chlorophenyldisulfanyl} -3-chlorophenyl) thioureido] phenyl} acetamide

369 N- {4- [3- (3,5-Dichloro-4-methyl-phenyl) -thioureido] -phenyl} -acetamide

598 N- {4- [3- (3,5-Diodo-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -acetamide

504 N- {4- [3- (3,5-Dibromo-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -acetamide

317 N- {4- [3- (6-Methoxy-pyridin-3-yl) -thioureido] -phenyl} -acetamide

347 N- {4- [3- (2,6-Dimethoxypyridin-3-yl) thioureido] phenyl} acetamide

457 2- {4- [3- (4-Acetylaminophenyl) thioureido] -2,6-dichloro-phenoxy} -acetic acid ethyl ester

365 4- [3- (4-Acetylaminophenyl) thioureido] -2-chlorobenzoic acid

346 N- {4- [3- (3-Chloro-4-cyanophenyl) thioureido] phenyl} acetamide

512 N- (4- {3- [5-Chloro-2- (4-chloro-phenoxy) -4-pyrrol-1-yl-phenyl] -thioureido} -phenyl) -acetamide

355 N- {4- [3- (3,4-Dichloro-phenyl) -thioureido] -phenyl} -acetamide

339 N- {4- [3- (3-Chloro-4-fluoro-phenyl) -thioureido] 168-phenyl} -acetamide

447 N- {4- [3- (3-Chloro-4-iodo-phenyl) -thioureido] -phenyl} -acetamide

400 N- {4- [3- (4-Bromo-3-chloro-phenyl) -thioureido] -phenyl} -acetamide

424 N- [4- (3- (4- [Bis- (2-hydroxyethyl) amino] -3-chlorophenyl} thioureido) phenyl] acetamide

434 N- (4- [3- [3-Chloro-4- (hexylmethylamino) phenyl] thioureido} phenyl) acetamide

406 N- (4- {3- [3-Chloro-4- (isobutylmethylamino) phenyl] thioureido} phenyl) acetamide

389 N- {4- [3- (3-Chloro-4-trifluoromethyl-phenyl) -thioureido] -phenyl} -acetamide

441 Furan-2-carboxylic acid {4- [3- (3-Chloro-trifluoromethyl-phenyl) -thioureido] -phenyl} -amide

[1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (3-chloro-4-trifluoromethyl-phenyl) -thioureido] -phenyl} -amide

469 N- {4- [3- (3-Chloro-4-trifluoromethyl-phenyl) -thioureido] -phenyl} -2-fluoro-benzamide

435 N- {4- [3- (3,4-Dichloro-phenyl) -thioureido] -phenyl) -2-

fluorobenzamide

407 Furan- {4- [3- (3,4-Dichloro-phenyl) -thioureido] -phenyl} -amide

-2-carboxylic acid

[1,2,3] Thiadiazole-4-carboxylic acid [4- [3- (3,4-dichlorophenyl) -thioureido] -phenyl} -amide

480 N- {4- [3- (4-Bromo-3-chlorophenyl) thioureido] phenyl} -2-fluorobenzamide

527 N- {4- [3- (3-Chloro-4-iodo-phenyl) -thioureido] -phenyl} -2-fluoro-benzamide

452 Furan-2-carboxylic acid {4- [3- (4-bromo-3-chloro-phenyl) -thioureido] -phenyl} -amide

499 Furan-2-carboxylic acid [4- [3- (3-chloro-4-iodo-phenyl) -thioureido] -phenyl} -amide

391 {4- [3- (3-Chloro-4-fluoro-phenyl) -thioureido] -phenyl} -amide

169 furan-2-carboxylic acid

935 470 {4- [3- (4-Bromo-3-chloro-phenyl) thioureido] -phenyl} -amide [1,2,3] thiadiazole-4-carboxylic acid 936 517 {4- [3- (3-Chloro-4-iodo-phenyl) thioureido] fenyljamid [1,2,3] thiadiazole-4-carboxylic acid 937 419 N- {4- [3- (3-chloro-4-fluoro-phenyl) thioureido] -phenyl} - -2-fluoro-benzamide 938 409 {4- [3- (3-chloro-4-fluoro-phenyl) thioureido] -phenyl} -amide [1,2,3] thiadiazole-4-carboxylic acid 939 388 N- {4- [3- (3-Chloro-4-isoxazol-5-yl-phenyl) thioureido] phenyl} acetamide 940 387 N- (4- {3- [3-Chloro-4- (lH-pyrazol-3-yl) phenyl] thioureido} phenyl) acetamide 941 355 N- {4- [3- (2,3-Dichlorophenyl) thioureido] phenyl} acetamide 942 435 N- {4- [3- (2,3-Dichlorophenyl) thioureido] phenyl} -2fluórbenzamid 943 407 Furan-2-carboxylic acid {4- [3- (2,3-Dichloro-phenyl) -thioureido] -phenyl} -amide 944 425 {4- [3- (2,3-Dichlorophenyl) thioureido] -phenyl} -amide [1,2,3] thiadiazole-4-carboxylic acid 945 355 N- {4- [3- (2,5-Dichlorophenyl) thioureido] phenyl} acetamide 946 435 N- {4- [3- (2,5-Dichlorophenyl) thioureido] phenyl} -2fluórbenzamid 947 407 Furan-2- {4- [3- (2,5-Dichloro-phenyl) -thioureido] -phenyl} -amide carboxylic acid 948 355 N- {4- [3- (3,5-Dichlorophenyl) thioureido] phenyl} acetamide 949 435 N- {4- [3- (3,5-Dichlorophenyl) thioureido] phenyl} -2 fluorobenzamide 950 407 Furan-2- {4- [3- (3,5-Dichloro-phenyl) -thioureido] -phenyl} -amide -carboxylic acid 951 390 N- {4- [3- (3,4,5-Trichloro-phenyl) thioureido] -phenyl} -acetamide 952 470 2-Fluoro-N- {4- [3- (3,4,5-trichlorophenyl) thioureido] fenylJbenzamid 953 442 {4- [3- (3,4,5-Trichloro-phenyl) -thioureido] -phenyl} -amide

170 furan-2-carboxylic acid

[1,2,3] Thiadiazole-4-carboxylic acid {4- (3- (3,4,5-trichlorophenyl) thioureido] phenyl} amide

[1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (3-chloro-4-isoxazol-5-yl-phenyl) -thioureido] -phenyl} -amide

[1,2,3] Thiadiazole-4-carboxylic acid [4- {3- [3-chloro-4- (1H-pyrazol-3-yl) -phenyl] -thioureido] -phenyl) -amide

391 {4- [3- (3-Chloro-phenyl) -thioureido] -phenyl] -amide [1,2,3] thiadiazole-4-carboxylic acid

373 Furan {4- [3- (3-Chloro-phenyl) -thioureido] -phenyl] -amide

-2-carboxylic acid

401 N- {4- [3- (3-Chloro-phenyl) -thioureido] -phenyl} -2-fluoro-benzamide

373 Furan-2-carboxylic acid {4- [3- (4-chloro-phenyl) -thioureido] -phenyl] -amide

401 N- {4- [3- (4-Chloro-phenyl) -thioureido] -phenyl} -2-fluoro-benzamide

391 [1,2,3] Thiadizaole-4-carboxylic acid {4- [3- (4-chloro-phenyl) -thioureido] -phenyl-amide

401 N- {4- [3- (2-Chloro-phenyl) -thioureido] -phenyl} -2-fluoro-benzamide

396 3- (3- {4 - [(Furan-2-carbonyl) amino] phenyl} thioureido) benzoic acid methyl ester

424 3- {3- [4- (2-Fluorobenzoylamino) phenyl] thioureido} benzoic acid methyl ester

414 3- (3- {4 - [((1,2,3) Thiadiazole-4-carbonyl) amino] phenyl} thioureido) benzoic acid methyl ester

409 N- [4 - [[[[3- (Aminocarbonyl) phenyl] amino] thioxomethyl] amino] phenyl] -2-fluorobenzamide

373 Furan-2-carboxylic acid [4- [3- (2-chloro-phenyl) -thioureido] -phenyl] -amide

381 Furan-2-carboxylic acid {4- [3- (3-carbamoyl-phenyl) -thioureido] -phenyl] -amide

399 {4- [3- (3-Carbamoylphenyl) thioureido] phenyl] amide

171 [1,2,3] thiadiazole-4-carboxylic acid

391 {4- [3- (2-Chloro-phenyl) -thioureido] -phenyl] -amide [1,2,3] thiadiazole-4-carboxylic acid

356 Furan-2-carboxylic acid {4- [3- (3-fluorophenyl) -thioureido] -phenyl] -amide

383 Furan-2-carboxylic acid {4- [3- (3-nitrophenyl) thioureido] phenyl} amide

411 2-Fluoro-N- [4- [3- (3-nitrophenyl) thioureido] phenyl] benzamide

422 Furan-2-carboxylic acid {4- [3- (3-trifluoromethoxy-phenyl) -thioureido] -phenyl} -amide

450 2-Fluoro-N- {4- [3- (3-trifluoromethoxyphenyl) thioureido] phenyl] benzamide

384 2-Fluoro-N- {4- [3- (3-fluoro-phenyl) -thioureido] -phenyl} -benzamide

410 3- [3- [4- (2-Fluorobenzoylamino) phenyl] thioureido] benzoic acid

382 3- (3- {4 - [(Furan-2-carbonyl) amino] phenyl} thioureido) benzoic acid

408 N- {4- [3- (3-Acetyl-phenyl) -thioureido] -phenyl} -

-2-fluoro-benzamide

502 N- {4- [3- (3-Butylsulfamoylphenyl) thioureido] phenyl} -2-fluorobenzamide

380 Furan-2-carboxylic acid {4- [3- (3-acetyl-phenyl) -thioureido] -phenyl} -amide

447 Furan-2-carboxylic acid 4- {3- [3- (2-hydroxy-ethanesulfonyl) -phenyl] -thioureido} -phenyl) -amide

475 2-Fluoro-N- (4- {3- [3- (2-hydroxyethanesulfonyl) phenyl] thioureido} phenyl) benzamide

2-Carboxylic acid {4- [3- (3-Butylsulfamoyl-phenyl) -thioureido] -phenyl} -amide

172

Example 986

Method 57

1- (4-fluorophenyl) -2-methylpropan-l-ol

To a solution of 4-fluorobenzaldehyde (2.0 g) in diethyl ether (40 mL) at 0 ° C was added dropwise isopropylmagnesium bromide (2.0 M, 9.6 mL) with stirring. After 1.5 hours, the reaction is quenched by addition of aqueous ammonium chloride and extracted with diethyl ether. The diethyl ether extracts were washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered and evaporated to give an oil. The oil was purified by silica gel chromatography eluting with 10% dichloromethane / hexanes to give the product as a yellow oil (1.76 g).

Example 987

Method 58

1- (4-Fluorophenyl) -2-methyl-propan-l-one

To a solution of 1- (4-fluorophenyl) -2-methylpropan-1-ol (1.6 g) in acetone (10 mL) was added Jones reagent (20 mL) with stirring at 0 ° C. After 10 minutes, excess Jones reagent was removed by addition of isopropyl alcohol. Diethyl ether was added followed by anhydrous magnesium, and the mixture was filtered and evaporated to give the product as a yellow oil (1.2 g).

Example 988

Method 59

173

3-Dimethylamino-5-trifluoromethyl-benzonitrile

To a solution of 3-dimethylamino-5-trifluoromethylbromobenzene (7.3 g) in N, N'-dimethylformamide (20 mL) was added copper (I) cyanide (2.7 g) and the reaction mixture was heated at reflux for 12 hours. The reaction mixture was diluted with water (40 mL) and dichloromethane was added. The dichloromethane fractions were washed with concentrated ammonium hydroxide and then with water. The solution was dried over anhydrous magnesium sulfate, filtered and concentrated to give a yellow solid which was recrystallized from hexane to give a yellow solid (4.7 g).

The above compounds were tested for activity as inhibitors of herpes virus.

Human cytomegalovirus

Extract test

Single-layer cultures of human foreskin fibroblasts are infected with wild-type HCMW, typically at a multiplicity of infection of up to 0.2 in the presence of inhibitor compound (varying concentrations). On the third day after infection, the total amount of virus produced in these cultures (i.e. virus yield) is examined by harvesting and titrating the virus in 12-well plates with cultured human foreskin fibroblasts (transferred in the absence of inhibitor). Slices are quantified 2 weeks after infection. The HCMV inhibitor is identified by decreasing the virus yield titer in the presence of the compound with the titer in the absence of the compound.

In this assay, the relative antiviral activity of HCMV is typically determined by calculating an IC 50 or IC 90 value, ie. the amount of compound that reduces the yield by 50% and 90%, respectively.

Table I shows IC50 data for compounds tested against HCMV.

174

A microtiter plate assay of a well for human foreskin fibroplast culture is infected in the presence of an inhibitor compound with HCMV recombinant mutant virus whose genome contains the prokaryotic beta-glucuronidase gene (Jefferspn, RA, SM Burges and D. Hirsh. 1986. Beta-glucuronidase from Escherichia coli) as a gene fusion marker (Proc. Natl. Acad. Sci. USA 83: 8447-8451) whose expression is monitored by the viral promoter. An example of such a virus is RV145 (Jones, T. R., V. P. Muzithras, and Y Gluzman. 1991. Replacement of human cytomegalovirus genome: US10 and US11 gene products are nonessential. J. Virol. 65: 5860-5872). Since it is regulated by the viral promoter, beta-glucuronidase expression is an indirect indicator of the growth of HCMV replication in this assay. 96 hours after infection, lysates of infected cells (using 50 mM sodium phosphate [pH 7.0] containing 0.1% Triton X-100 and 0.1% sarcose) are prepared and examined for beta-glucuronidase activity using the enzyme substrate, which after cleavage provides either a product which can be measured colorimetrically in a spectrophotometer or fluorescently in a microfluorimeter. Examples of such substrates are p-nitrophenyl-beta-D-glucuronide and methylumbelliferyl glucuronide. The presence of the antiviral compound is indicated by an overexpression of the beta-glucuronidase gene resident in the HCMV genome as compared to the absence of inhibitor. Thus, the generation of the chromophore or fluorophore product in this assay is reduced accordingly. Data from this assay generated using different amounts of inhibitor compound is also used to estimate the IC 50 of the inhibitor compound.

HSV Virus Test (ELISA)

175

Vero cells (ATCC # CCL-81) are coated in 96-well culture plates at 3.5 x 10 ⁴ cells of 100 μΐ tissue culture DMEM (Dublin Modified Eagle Medium) supplemented with 2% fetal bovine serum (FBS) per well. 30 minutes of incubation at 37 ° C (5% CO ₂ ) and 30 minutes before infection with HSV-1 (multiplicity of infection equals 0.006) cells are not treated or treated with test compound (multiple concentrations) or reference standard drug for control. The cells are subjected to an ELISA approximately 24 hours post-infection (in 5% CO ₂ ) The primary antibody is a mouse anti-HSV clycoprotein D monoclonal primary antibody and the secondary antibody is a goat anti-mouse IgG bound to β-galactosidase. replication determined by determining (β-galactosidase activity by quantifying the generation of 4-methyl umbelliferone fluorescent steppe product after addition of methyl umbell iferyl-β-D-galactoside (Sigma # M1633) substrate on a microfluorimeter (365 nm at excitation and 450 nm at emission). The antiviral activity (IC 50) of the test compound is determined by comparing the fluorescence obtained in the absence of the compound to that obtained in the presence of the compound. Data are shown in Table I.

VZV antivirus test (ELISA)

VZV is used to generate inventory in this test. VZV Elien strain (ATCC # VR-1367) is used to infect human foreskin fibroblast (HFF) cells at low multiplicity (less than 0.1) and incubated overnight at 37 ° C in 5% CO 2. After overnight incubation, a mixture of uninfected and VZV-infected HFF infected cells is harvested and added to each well of 96-well plates (3.5 x 10 ⁴ cells in 100 μΐ DMEM supplemented with 2% FBS),

176 which contains the test compound or reference standard control drug (in 100 μΐ DMEM supplemented with 2% FBS per well). These cells are then incubated for three days at 37 ° C in 5% CO ₂ and subjected to an ELISA assay. The primary antibody is a murine anti-VZV glycoprotein II monoclonal antibody (Applied Biosystems, Inc. # 13-145-100) and the secondary antibody is a goat anti-mouse IgG bound to (β-galactosidase), so the viral replication rate is determined by (β - galactosidase activity by quantifying the generation of a 4-methyl umbelliferone fluorescent Step Product after addition of methylumbelliferyl- (β-D-galactoside (Sigma # M1633) substrate on a microfluorimeter (355 nm at excitation and 450 nm at emission). comparing the fluorescence obtained in the absence of the compound with the fluorescence obtained in the presence of the compound The data are shown in Table I.

Table I gives IC50 data for compounds tested against herpes viruses.

177

Table I

Example IC ₅₀ IC50 % inhibition of IC50 (Ug / ml) HCMV (µg / ml) HSV 10 µg / ml VZV (µg / ml) VZV 283 7 0.6 17 > 10 284 0.4 3 100 > 15 289 > 10 0.6 30 > 10 498 00:14 6 14 > 10 499 3 . 5 25 > 10 506 > 10 > 10 68 > 10 507 1.2 10 90 4 512 0.7 0.5 70 4 514 12 4 62 > W 515 > 1o > 10 30 > 10 815 0.0024 > 7.5 816 0.0015 > 7.5 8Π. 0,001 > 7.5 818 0.0022 > 7.5 819 0.0022 > 7.5 820 0.0013 3.4 821 0.014 * > 7.5 822 00:05 > 7.5 «23 AO5 > 7.5 «24 0.004 3.20 «25 0.003 6.12 826 0.020 Λ 0.86 827 0026 «28 00:45 > 7.5 «29 00:08 > 7.5

Thus, the compounds of the present invention are potent inhibitors of herpesvirus growth and replication, including HCMV, VZV and HSV, and effectively inhibit viral yield.

The compounds of the present invention may be administered in accordance with the invention to patients suffering from herpes virus, including HCMV, VZV and HSV in an amount effective to inhibit the viruses. Thus, the compounds of the invention are useful for alleviating or eliminating the symptoms of herpes virus infections in mammals, including but not limited to humans.

178

The compounds of the invention may be administered to the patient either in pure form or with a conventional pharmaceutical carrier.

Suitable solid carriers may include one or more substances which may act as flavorings, lubricants, solvents, suspending agents, binders, glidants, compression aids, binders or tablet disintegrating agents or encapsulating material. In the case of a powder, the carrier is a finely divided substance which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, low shear waxes, and ion exchange resins.

Liquid carriers can be used in the preparation of solutions, suspensions, emulsions, syrups and elixirs. The active ingredient of the invention may be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of pharmaceutically acceptable oils or fats. The liquid carrier may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, aromatics, susceptible agents, thickeners, colorants, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (especially containing additives such as those mentioned above, for example cellulose derivatives, preferably sodium carboxymethylcellulose solution), alcohols (including monohydric alkghols and polyhydric alcohols, for example glycols) and derivatives and oils (for example fractionated) coconut oil or peanut oil). For parenteral administration, the carrier may also be an oily ester such as ethyl oleate and isopropyl myristate. IN

Sterile liquid carriers are used for sterile liquid compositions for parenteral administration.

Liquid pharmaceutical compositions which are sterile solutions or suspensions may be used, for example, for intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can be administered intravenously. Oral administration may be in either liquid or solid form.

The pharmaceutical compositions are preferably in unit dosage form, such as tablets or capsules. In such form, the composition is subdivided into a unit dosage form containing a suitable amount of active ingredient. The unit dosage form may be in packaged form, for example, as packaged powders, vials, ampoules, prefilled syringes or sachets containing liquids. Unit dosage forms can be, for example, capsules or tablets alone, or there can be a suitable number of any such composition in packaged form.

The therapeutically effective dose to be used to treat herpes virus infection will be determined by the attending physician. Variables that affect the dose include the condition, age, and weight of the patient. The novel methods of the invention for treating herpes virus infection include administering to a subject to be treated an effective amount of at least one compound of Formula 1 or a non-toxic pharmaceutically acceptable salt thereof. The compounds may be administered orally, rectally, parenterally or topically to the skin and mucosa. The usual daily dose is dependent on the specific compound, the mode of treatment and the condition of the patient. The usual daily dose is 0.01 to 1000 mg / kg for oral administration, more preferably 0.5 to 500 mg / kg and 0.1 to 100 mg / kg for parenteral administration, preferably 0.5 to 50 mg / kg.

Claims (5)

PATENT CLAIMS A compound of the general formula NHr — θ'— G where R 1 -R 5 are independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms carbon atoms, heterocycloalkyl of 3 to 10 carbon atoms, aryl, heteroaryl, halogen, -CN, -NO ₂ , -CO ₂ R ₆ , -COR ₆ , "OR 6, -SR 6, -SOR 6, -SO ₂ R 8, ~ CONR 7 R 8, -NR e N (R ₇ R e) t -N (R ₇ , R ₈ ) or WY- (CH ₂ ) _n -Z, or R ₂ and R 3 or R 3 and R ₄ together form a 3-7 membered heterocycloalkyl or 3-7 membered heteroaryl; R ₆ and R 7 are independently hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, or aryl; R ₈ is hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10 cells, aryl or heteroaryl, or R7 and R6 taken together can form a 3-7 membered heterocycloalkyl; A is heteroaryl; 181 W is O, NR ₆ or absent; Y is - (CO) - or - (CO ₂ ) - or is absent; Z is C 1 -C 4 alkyl, -CN, -CO ₂ R 8 t -COR 6, -CONR 7 R 8, OCOR ₆ , -NR 6 COR 7, -OC ₆ NR ₆ , OR ₆ t -SR ₆ , -SOR 8, -SO ₂ R 6, t -SR ₆ N (R ₇ R ₈ ) _n -N (R ₇ , R ₈ ) or phenyl; G is aryl or heteroaryl, X is a bond, -NH, alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, thioalkyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms, or (CH) J; J is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl or benzyl, and n is an integer of 1 to 6, or a pharmaceutically acceptable salt thereof. The compound of claim 1, wherein at least one of R 1 -R ₅ is not hydrogen. The compound of claim 1, wherein R 1 -R 5 are independently selected from hydrogen, C 1 -C 6 alkoxy, C 1 -C 6 perhaloalkyl, and halogen. The compound of claim 1, wherein X is CH (J) and J is alkyl of 1 to 6 carbon atoms. A compound according to claim 4, wherein J is methyl. 182 6th compound by claim 1 where And it is substituted. 7. compound by claim 1 where And it is pyridinyl. 8th compound by claim I where G is unsubstituted 5 or articulated heteroaryl. 9th compound by claim 8 where G is furyl, thiazolyl or thiadiazolyl. 10th compound by claim θ, where je 2- • furyl. 11th compound by claim 8 where is 1, 2,3-thiadiazolyl. 12th compound by claim 8 where G is 1,3-thiazolyl. 13th compound by claim 1 where G is phenyl. 14th compound by claim 1 where G is substituted phenyl. 15th compound by claim 14 where i G is substituted with one or more substituents selected from halogen or alkoxy of 1 to 6 carbon atoms. The compound of claim 1, wherein X is CH (J), J is methyl, A is pyridyl, and G is thiazolyl. 17. A compound according to claim 1 which is: Furan-2-carboxylic acid {5- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -pyridin-2-yl} -amide, {5- [3- (5-Chloro-2,4-dimethoxy-phenyl)] [1,2,3] Thiadiazole-4-carboxylic acid thioureido] pyridin-2-yl} amide, {5- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] pyridin-2-yl} amide 183 Pyridine-2-carboxylic acid pyridine-2-carboxylic acid {6- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -pyridin-3-yl} -amide, {6- [3- (5- Furan-2-carboxylic acid chloro-2,4-dimethoxyphenyl) thioureido] pyridin-3-yl} amide {6- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] pyridin-3-yl} amide [1,2,3] Thiadiazole-4-carboxylic acid [1,2,3] thiadiazole-4-carboxylic acid {5- [3- (3,5-Dichloro-phenyl) -thioureido] -pyridin-2-yl} -amide, N- [5 - [[[(5-Chloro-2,4-dimethoxyphenyl) amino] thioxomethyl] amino] -2-pyridinyl] -2-methylbenzamide, N- {5- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thiouredio] -pyridin-2-yl] -2-fluoro-benzamide, N- {6- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -pyridin-3-yl} -2-fluoro-benzamide, N- [5 - [({[3,5-Bis (trifluoromethyl) benzyl] amino] carbothioyl) amino] -2-pyridinyl} -1,2,3-thiadiazole-4-carboxamide, N- (5 - {[({(1S) -1- [3,5-Bis (trifluoromethyl) phenyl] ethyl] amino) carbothioyl] amino] -2-pyridinyl) -1,2,3-thiadiazole-4- carboxamide N- (5 - {[({(1S) -1- (3,5-Bis (trifluoromethyl) phenyl] ethyl] amino) carbothioyl] amino] -2-pyridinyl) -1,3-thiazole-4-carboxamide, N- (5 - {[({1- [2-Fluoro-5- (trifluoromethyl) phenyl] ethyl} amino) carbothioyl] amino] -2-pyridinyl) -1,3-thiazole-4-carboxamide, N- (5 - {[({1- [2-Fluoro-4- (trifluoromethyl) phenyl] ethyl] amino) carbothioyl] amino] -2-pyridinyl) -1,3-thiazole-4-carboxamide, N- (5 - {[({1- [3-Fluoro-5- (trifluoromethyl) phenyl] ethyl] amino) carbothioyl] amino] -2-pyridinyl) -1,3-thiazole-4-carboxamide, N- (5 - {[({(1S) -1- [3,5-Bis (trifluoromethyl) phenyl] ethyl] amino) carbonyl] amino] -2-pyridinyl) -1,3-thiazole-4-carboxamide, N- {5 - [({[1- (3-Bromophenyl) ethyl] amino] carbothioyl) amino] -2-pyridinyl} -1,3-thiazole-4-carboxamide, N- {5 - (({[1- (2-bromophenyl) ethyl] amino} carbothioyl) amino] -2 pyridinyl} -1,3-thiazole-4-carboxamide, N- (5 - {[({1- [3- (trifluoromethyl) phenyl] ethyl] amino) 184 carbothioyl] amino} -2-pyridinyl) -1,3-thiazole-4-carboxamide, N- (5 - {[({1- [4-Chloro-3- (trifluoromethyl) phenyl] ethyl} amino) carbothioyl] amino} -2-pyridinyl) -1,3-thiazole-4-carboxamide, N- {5 - (({(1- (4-Chloro-3-fluorophenyl) ethyl] amino} carbothioyl) amino) -2-pyridinyl} -1,3-thiazole-4-carboxamide, N- {5 - [({[1- (4-Chloro-2-fluorophenyl) ethyl] amino} carbothioyl) amino] -2-pyridinyl} -1,3-thiazole-4-carboxamide, N- {6 - [({[1- (4-fluorophenyl) ethyl] amino} karbotiayl) amino] -3-pyridinyl} -l, 2,3-thiadiazol-4-carboxamide, N- (6 - {[({(1S) -1- [3,5-Bis (trifluoromethyl) phenyl] ethyl} amino) carbothioyl] amino} -3-pyridinyl) -1,2,3-thiadiazole-4- carboxamide and its pharmaceutical salts. 18. A pharmaceutical composition comprising a compound of the formula R 1 -R ₅ are independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms 10 carbon atoms, heterocycloalkyl of 3 to 10 carbon atoms, aryl, heteroaryl, halogen, -CN, -NO2, -CO2R6, -cor ₆ , -or ₆ , -sr ₆ , -sor ₆ , -SO ₂ R ₆ , -CONR ₇ R ₈ , -NR ₆ N (R ₇ R ₈ ), N (R ₇ , R E) or WY- (CH ₂ ) _n -Z, or R 2 and R 3 or R 3 and R ₄ together form a 3 to 7 membered heterocycloalkyl; up to 7-membered heteroaryl; R ₆ and R ₇ are independently hydrogen, alkyl of 1 to 6 carbon atoms, 185 perhaloalkyl of 1 to 6 carbon atoms or aryl; R ₈ is hydrogen, C 1 -C 6 alkyl, perhaloalkyl (C 1 -C 6), (C 3 -C 10) cycloalkyl, (C 3 -C 10) heterocycloalkyl, aryl or heteroaryl; or R ·? and R ₈ together may form a 3-7 membered heterocycloalkyl; A is heteroaryl; W is O, NR ₆ or absent; Y is - (CO) - or - (CO ₂ ) - or is absent; Z is alkyl of 1 to 4 carbon atoms, -CN, -CO ₂ R 6, -COR 6, -CONR7R8 t oCOR6, -NR6COR7 '- OCONR6, Oro, -SRďz -SOR6, ~ SO ₂ R6z / -SR ₆ N (R R _7), -N (R ₇ R ₈₎ or phenyl; G is aryl or heteroaryl, X is a bond, -NH, alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, thioalkyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms, or (CH) J; J is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl or benzyl, and n is an integer of 1 to 6, or a pharmaceutically acceptable salt or pharmaceutically acceptable carrier or diluent thereof. 186 19. A method of inhibiting herpes virus replication, comprising contacting a compound of formula R 1 -R ₅ are independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms 10 carbon atoms, heterocycloalkyl of 3 to 10 carbon atoms, aryl, heteroaryl, halogen, -CN, -NO 2, -CO ₂ R _6, -COR 6, ^- Oro, -SR 6, "IBMA, ^- S02 ch, ^- CONR7R8, ~ NR ₈ N (R ₇ R ₈ ), -N (R ₇ , R ₈ ) or WY- (CH ₂ ) _n -Z, or R ₂ and R ₃ or R ₃ and R ₄ together form a 3 to 7 membered heterocycloalkyl or 3 to 7 membered heterocycloalkyl; 7 membered heteroaryl; R 6 and R ₇ are independently hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, or aryl; R ₈ is hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10 cells, aryl or heteroaryl, or R ₇ and R ₈ together may form a 3 to 7 membered heterocycloalkyl; is heteroaryl; 187 W is O, NR ₆ or absent; Y is - (CO) - or - (CO2) - or is absent; Z is alkyl of 1 to 4 carbon atoms, -CN, -CO 2 R ₆ , -COR ₆ , -conr _7, R ₈ , OCOR ₆ , -NR ₆ COR ₇ , -OCONR ₆ , or ₆ , -sr ₆ , -sor ₆ , -so ₂ R ₆ , -SR e N (R ₇ R ₈ ), -N (R ₇ , R ₈ ) or phenyl; G is aryl or heteroaryl, X is a bond, -NH, alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, thioalkyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms, or (CH) J; J is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl or benzyl, and n is an integer of 1 to 6, or a pharmaceutically acceptable salt thereof with a herpes virus. The method of claim 19, wherein the herpes virus is a human cytomegalovirus. m. The method of claim 19, wherein the herpes virus is a herpes y n and a simplex virus. The method of claim 19, wherein the herpes virus is varicella sestervirus. hear The method of claim 22, wherein the varicella zoster virus is treated with a substantially pure optical isomer (S). 29. A method of treating a patient suffering from a herpes virus infection, m, m, m, 188 wherein the patient is administered a therapeutically effective amount of a compound of the formula wherein R 1 -R 5 are independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms carbon atoms, heterocycloalkyl of 3 to 10 carbon atoms, aryl, heteroaryl, halogen, -CN, -NO ₂ , -CO ₂ R ₆ -OR ₆ , -OR ₆ , -SR ₆ , -SOR ₆ , -SO ₂ R 6, ~ CONRvR 5 - NR ₈ N (R 7 R ₈ ), N (R 7, R ₈ ) or WY- (CH ₂ ) _n -Z, or R ₂ and R 3 or R 3 and R ₄ together form a 3 to 7 membered heterocycloalkyl or 3 to 7 membered heteroaryl; R 6 and R 7 are independently hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, or aryl; R ₈ is hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10 cells, aryl or heteroaryl, or R ₇ and R ₈ together may form a 3 to 7 membered heterocycloalkyl; A is heteroaryl; W is O, NR ₆ or absent; Y is - (CO) - or - (CO ₂ ) - or is absent; 189 Z is C 1 -C 4 alkyl, -CN, -CO ₂ R ₆ , -COR ₆ , -CONR ₇ R ₈ , OCOR ₆ , -NR ₆ COR ₇ , -OCONR ₆ , OR ₆ , -SR ₆ , -SOR ₆ , SO ₂ R ₆ , -SR ₆ N (R ₇ R ₈ ), -N (R ₇ , R ₈ ) or phenyl; G is aryl or heteroaryl, X is a bond, -NH, alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, thioalkyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms, or (CH) J; J is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl or benzyl, and n is an integer of 1 to 6, or a pharmaceutically acceptable salt thereof. 25th The method of claim 24, wherein the herpes virus is a human cytomegalovirus. m. 26th The method of claim 24, v 27th 28th that the herpes virus is herpes The method of claim 24, wherein the simplex is a virus. m, y z n and that the herpes virus is varicella sestervirus. m, The method of claim 27, wherein the varicella sestervirus is treated with a substantially optical isomer (S).