CZ20011958A3 - Thiourea compounds functioning as 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 (reviewed in Roizman, B. 1996. Herpesviridae, pp. 2221-2230. In BN Fields, DM Knipe, and M. M. Howley (Ed.), Fields Virology, 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 of which comprises the viral relatively large double-stranded DNA genome (for example, approximately 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. V N N Fields, DM Knipe and M. M. Howley (ed.), Fields Virology, 3rd ed., LippincottRaven Publishers, Philadelphia, PA]; chickenpox and shingles (VZV [Arvin, A. 1996. Varicella-Zoster Virus, pp. 25472585. In N. Fields, DM Knipe and M. 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. In N. N. Fields, D. M. Knipe, and L. M. Howley (Ed.), Fields Virology.

3rd ed. Lippincott-Raven Publishers, Philadelphia, PA];

pneumonia and retinitis (HCMV [(Britt, W.J. and Alford, C.A.)

1996. Cytomegalovirus, pp. 2493-2523. V Β. N. Fields, D.M.

Knipe, and P. M. Howley (Ed.) Fields Virology, 3rd Ed. Lippincott-Raven Publishers, Philadelphia, PA]; exanthem subitum (HHV-6 [(Pellet, PE and Black, JB 1996). Human Herpesvirus 6, pp. 2587-2608. In BN Fields, DM Knipe and PM Howley (ed.), Fields Virology. 3rd ed. Lippincott- Raven Publishers, Philadelphia, PA] and HHV-7 [Frenkel, N. and Roffman, E. 1996. Human Herpesvirus 7, pp. 2609-2622. In BN Fields, DM Knipe and PM Howley (Ed.), Fields Virology, Lippincott-Raven Publishers, Philadelphia, PA] and Kaposi's sarcom (HHV-8 [Neipel, F., Albrecht, JC, and Fleckeinstein, B. 1997. Cell-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 primary infection herpesvirus creates latency in the infected individual and remains in it for the rest of life. In the case of HSV, reactivated virus can be transmitted to infants during childbirth and cause skin or eye infections, infections central nervous system or diffuse infection (e.g., multiple organs or systems). Shingles is a clinical manifestation of VZV reactivation. Treatment of HSV and VZV is generally performed with antiviral drugs such as acyclovir (Glaxo welcome), ganciclovir (Roche) and foscarnet (Asta), which 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. Lippincott-Raven Publishers, Philadelphia, PA). Primary infection with HCMV is usually asymptomimatic, although heterophilic negative mononucleosis has been observed. The virus is transmitted by sexual intercourse, breast milk and saliva. Intrauterine transmission of HCMV from the pregnant mother to the fetus occurs and is often the cause of serious clinical consequences. HCMV remains in a latent state in the infected person for the rest of his life. Cell-mediated immunity plays an important role in controlling reactivation from latency. Impaired cellular immunity leads to reactivation of latent HCMV in seropositive individuals.

HCMV is associated with interrupted or incomplete immunity. 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 is Pneumocystis). The most common manifestation of HCMV in AIDS is retinitis, although infection of other organs, including the adrenal glands and lungs, 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-threatening 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 the age of 0 to 3 years. 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: 169183). 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 virally 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 (ie, less toxic) orally bioavailable antiviral drug that targets new viruses.

The use of phenylthioureas is described in a number of pharmaceutical applications. 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.

n (Y) (R1) m

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 pharmaceutically acceptable salts thereof for the inhibition and / or treatment of diseases associated with herpes viruses, including human cytomegalovirus, herpes simplex virus. Epstein-Barr virus, varicella-zoster virus, human herpesvirus-6 and -7 and Kaposi's herpesvirus.

SUMMARY OF THE INVENTION

The present invention provides compounds of the general formula

where

R ₁ -R ₅ is 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 atoms carbon, 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 ₆ , -CONR ₇ R _8, -NR ₆ 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 a 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 members, 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 C 1 -C 4 alkyl, -CN, -CO ₂ R ₆ , -COR ₆ , -CONR ₇ R ₈ , -OCOR ₈ , -NR ₈ COR-7, -OCONR 8, -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 from 1 to 6, or a pharmaceutically acceptable salt thereof.

In a preferred embodiment, at least one of 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 halogen.

Preferably X is (CH) J where 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. Most preferably, it is unsubstituted.

G is preferably a 5 or 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 1,3-thiazolyl.

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)] thioureido] pyridin-2-yl} amide [1,2,3] thiadiazole-4-carboxylic acid {5- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] pyridin-2-yl} amide pyridine 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-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-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 chain lower alkyl group containing from 1 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 C 2 -C 6 alkyl group 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 system containing 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 members 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 containing 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 of 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, and the like. 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 members, 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 expressions are 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 that may be formed from a compound of the above formula and pharmaceutically acceptable acids 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.

A substantially pure optical isomer is a mini-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 racemic mixtures.

The compounds of the present invention can be prepared by one skilled in the art using the methods described below, employing readily available reactants 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 (reacting 2 and 3 above) and 34 (reacting 4 and 5 below), reacting the appropriately substituted amines 2 wherein R 1 -R 5 and X are as defined above with the appropriately substituted isothiocyanates 3 wherein A and G as described above, either in the pure state 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 wherein R 1 -R 5 and X have as defined above with the appropriately substituted amine 5, wherein substituents A and G are as described above, in a conventional solvent such as those set forth above, the desired thioureas 1 are obtained.

• ··· · ··· ··· · ·

Methods 31 and 34

Alternatively, appropriately substituted thioureas 1 as described in Methods 32 and 33 can be prepared by reacting amines 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 is dichloromethane and tetrahydrofuran or mixtures thereof or one molar equivalent of 1,1'-thiocarbonyl-di- (1,2,4) -triazole in a suitable solvent such as dichloromethane and tetrahydrofuran and mixtures 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 substituent 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 1-acyloxyethoxy 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 methanesulfonic acid chloride 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-aminethoxy, 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 tetrahydrofuran and water or the like at room temperature according to Method 39.

Thioureas 1 wherein at least one substituent 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 stannous chloride in a suitable solvent such as methanol, ethanol or the like at room temperature according to Method 40.

The intermediate isothiocyanates 3 and 4 above in Methods 31 and 34 were prepared according to Method 41 (hereinafter) essentially following 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

^H 2 ^N— 2 S = C = N — —N — C — G H 5 3

A-X-NH ₂

A — X — N = C — S

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 as defined above and amines 5, wherein A is as defined above, can be prepared by reduction of appropriately substituted nitrobenzenes according to a variety of procedures known to those skilled in the art. Lindsay, Comprehensive Organic 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 1A), either pure or in an alcoholic solvent, such as methanol or ethanol, at a temperature of:

«« 4 *

In the range from room temperature to the reflux temperature of the solvent, or;

(b) iron powder and glacial acetic acid (Method 1B), 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;

(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 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;

e) when R 1 -R 5 and substituent A are selected from Cl, Br, I, - (OSO ₂ ) CF ₃ or - (OSO ₂ ) -1- (4-methylphenyl), by catalytic reduction, with hydrogen and palladium on carbon (Method 1E) 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 8 -R _{12 are} selected from Cl, Br, I, - (OSO ₂ ) -CF _3, or

- (0S0 ₂₎ -1- (4 methylphenyl), by catalytic reduction such as with cyclohexene and palladium on carbon (Method 1F) in an appropriate solvent such as methanol or ethanol, at temperatures 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 (Method 1G).

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 amide and carbamate derivatives thereof. anilines according to a number of procedures known to those skilled in the art and which «···

S- · 1 · 9 · φ »9 · 9 99 φ« «9 · · ·

Ϊ * · »· · ·, 9» * · · ^- · described in Greene, Protective Groups in Organic Synthesis volume 2, Chapter 7, 1991, and references 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) subjecting 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 ranging from room temperature to the reflux temperature of the solvent, or;

c) exposing the appropriately 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 tributylvinyltin, with substituted bromo or iodanilene, for example 3-chloro-4-iodoaniline, using a palladium catalyst such as tris (dibenzylideneacetone) bipalladium and a ligand such as triphenylarsine 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, 153, 1996 and references cited therein.

Alternatively, according to Method 42, 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 iodaniline, for example

3-amino-5-bromobenzotrifluoride, secondary amines, under conditions using a palladium catalyst such as bis (dibenzylideneacetone) palladium and a ligand such as tri-otolylphosphine 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 iodaniline, for example

3-amino-5-bromobenzotrifluoride alkenes under conditions employing a palladium catalyst, such as [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) chloride-dichloromethane complex and in the presence of 9-borabicyclo [3.3. Ionane 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 Ί, 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; temperatures ranging from room temperature to the reflux temperature of the solvent to give the corresponding arylamino-tert-butylcarbamate, 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 arylamino- (2-trimethylsilylethyl) carbamate, or;

c) reacting the 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 give the corresponding arylaminoamide, or;

d) reacting an appropriately substituted nitroaniline with a carboxylic acid chloride (method 2D) in the presence of one or more molar equivalents of a tertiary amine base such as triethylamine or N, N-diisopropylethylamine either in pure form or in a suitable solvent such as tetrahydrofuran;

1,4-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 reagent such as benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate, 2- (1H-benzotriazol-1-yloxy) -1,1,3, 3-tetramethyluronium hexafluorophosphate, 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 of R ₅ and A is defined as -WY- (CH ₂ ) _n Z, wherein W, Y and Z are as defined above; carboxylic acid anhydride (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 give the corresponding carboxylic acid ester; or;

g) reacting an appropriately substituted aniline in which at least one of R 1 -R 5 is defined as hydroxyl with tert-butyldicarbonate (Method 2G) in the presence of one or more molar equivalents of a tertiary amine such as triethylamine or 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 arylamino-tert-butyl carbamate.

··· * ·· ··

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

Referring to Methods 4A, 4C, and 4E-4H, nitrobenzene intermediates that ultimately convert to amines 2, R ₂ and R ₄ are as defined above and R 1, R ₃ and / or R 5 are defined as alkoxy, thioalkoxy, alkylsulfenyl , alkylsulfinyl and dialkylamino may be prepared by nucleophilic displacement of appropriately substituted 2-, 4-, and / or 6-fluoro-, chloro-, bromo-, iodo-, trifluoromethylsulfonyl- or (4-methylphenyl) sulfonyl-substituted nitrobenzenes, by methods including:

(a) reacting the alcohols with the appropriately substituted 2- or 2-carboxylic acids;

4-halo- or sulfonate 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 dimethylsulfoxide in the presence or absence of one or more molar equivalents of base such as is 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 the pretreated sodium, lithium or potassium phenoxides with appropriately substituted 2- or 2-phenoxides

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 dimethylsulphoxide 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 a pure state 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 pretreated sodium, lithium or potassium amine salts 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 an appropriately substituted 2- or 2-carboxylic acid

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 addition an alkyl halide directly into 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, may be prepared from the corresponding substituted hydroxynitrobenzenes by methods including:

(a) reaction of hydroxynitrobenzenes 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) reaction of hydroxynitrobenzenes 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 solvent, essentially according to the methods described by Mitsunobu, 0, Synthesis, 1981, 1 and references listed here.

Further, with reference to Methods 5A and 5E, carbamoyl amine 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 alkoxy, may be prepared from the 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 or N, N-dimethylformamide at temperatures ranging from room temperature to the reflux temperature of the solvent.

Alternatively, with reference to Methods 7A-G, nitrobenzene intermediates that are ultimately converted to amines 2, R _x and / or R ₃ is alkoxy, and R ₂ and / or R ₄ is halogen and X is a bond, can be prepared by standard halogenation reactions, which include the following:

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

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, or ;

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 which are ultimately converted to amines 2, where R ₄ = -CF ₃ and R 1 -R ₃ and R ₅ -R 8 are as defined above and X represents a bond, can be prepared from the corresponding substituted 4-iodonitrobenzenes by reaction with strong trimethyl (trifluoromethyl) in the presence of cuprous iodide and potassium fluoride, in a suitable solvent such as N, N-dimethylformamide or the like, at a temperature from room temperature to the reflux temperature of the solvent in a 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 ₈ are as defined above and X is a 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 reflux solvent or 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 triphlate and X is a bond, can be prepared from the corresponding phenol by reaction with trifluoromethanesulfonic 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 an appropriate 4 an alkylthio acylarylamino 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, which 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 225

-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 glacial acetic acid in a suitable solvent such as tetrahydrofuran, 1,4-dioxane or the like; from 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, may 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, where R ₄ is defined as

3-dimethylaminoprop-1-ynyl and R 1 -R 3 and R ₅ are as defined above and X is 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 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, where R ₄ is defined as · ·

3-dimethylaminoacryloyl and R 1 -R 3 and R 5 are as defined above and X represents a bond, may be prepared by reaction of

4- (3-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, where R ₄ is defined as either

4-isoxazol-5-yl or 4- (1H-pyrazol-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, wherein R ₄ = -HNCO ₂ Z and R 1 -R 3, R 5 and Z are as defined above and X represents a bond may be prepared by reacting the corresponding 4-aminocarbamoylaniline with 1,1-carbonyldi- (1,2,4) -triazole and a suitably substituted alcohol in a suitable solvent mixture such as tetrahydrofuran and dichloromethane and the like at a temperature ranging from room temperature to room temperature solvent reflux.

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 mixtures 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.

With regard 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 is 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% or 10% palladium on carbon and an 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 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 equal to either O (CH ₂ ) ₂ NH ₂ or -S (CH ₂ ) ₂ -NH ₂ , the desired nitrile precursors can be prepared by reacting an appropriately 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 -, 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

is 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 )) - can be prepared by acid and 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. solvents.

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 as 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 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 chlorochroman or pyridium dichloromethane 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 or the corresponding heteroaryl, 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 wherein A and G is as defined above according to Method 2C, by reacting substituted acid chloride 8, wherein G is as defined above, and 4-aminophenylcarbamic acid tert-butyl esters 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. Carboxylic acid chlorides 8 are either commercially available or prepared from the corresponding carboxylic acid by reaction with oxalyl chloride in a suitable solvent such as dichloromethane at room temperature.

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 wherein A and G are as defined above may 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- (1H-benzotriazol-1-yloxy) -1,1,3,3-tetramethyluronium hexafluorophosphate, dicyclohexylcarbodiimide or the like, in the presence of tertiary an 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 substituted or unsubstituted thiazole, substituted or unsubstituted oxazole, substituted or unsubstituted isothiazole, or substituted or unsubstituted isoxazole that are 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 a hydroxide sodium 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 yields the corresponding diazo-beta- ester. ketocarboxylic acids. Treatment of this compound with 2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphethan-

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 5-substituted-1,2,3-thiadiazole-4-carboxylic acid ester.

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 beta-ketocarboxylic 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 , the corresponding semicarbazone derivative is obtained. 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 were 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 diisopropyl ether or the like at room temperature to provide the corresponding 4-carboethoxythiazole.

Other appropriately substituted thiazoles can be prepared essentially according to the procedure described by Bredenkamp, Μ. V., Holzafel, C.W., van Zyl, W.J. Synthetic Coram. 20, 2235 (1990). Suitably unsaturated oxazoles are prepared essentially according to the procedure of 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 given by way of illustration only and are not intended to limit the scope of the present invention in any way.

···· · · · ··· · ··· · · · · · · · · ·

DETAILED DESCRIPTION OF THE INVENTION

Example 1 (Method 1A)

4-Methoxy-3-trifluoromethylphenylamine

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 were 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 column of silica gel (ethyl acetate was used as eluent) to give the title compound as an amber oil.

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

2,6-Dichlorobenzene-1,4-diamine

3-Chloro-4-methylsulfanyl-phenylamine

2,6-Dibromobenzene-1,4-diamine

3-Chloro-4-trifluoromethylphenylamine

3-Chloro-4-ethylsulfanyl-phenylamine

4-Methoxy-3-trifluoromethylphenylamine

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

5-Chloro-2-ethoxy-4-methoxyphenylamine

5-Chloro-4-ethoxy-2-methoxyphenylamine

5-Iodo-2,4-dimethoxyphenylamine

3,5-Diodo-2,4-dimethoxyphenylamine

3,5-Dibromo-2,4-dimethoxyphenylamine

5-Chloro-2-methoxy-4-methyl-phenylamine

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

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

3-Chloro-4-pyrrolidin-1-yl-phenylamine

N (1) -Benzyl-2-chlorobenzene-1,4-diamine

3-Chloro-4- (4-methyl-piperazin-1-yl) -phenylamine

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

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

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

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

2-Chloro-N (1) -cyclopentyl-N (1) -methyl-benzene-1,4-diamine

2 - [(4-Amino-2-chlorophenyl) - (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-chlorophenyl) methylamino] ethanol

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

2-Chloro-N (1) - (2-dimethylaminoethyl) -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-dimethylaminoethoxy) 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-dichloro-phenoxy) -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-1,2-diamine

N- (4-Amino-2-chlorophenyl) acetamide (4-Amino-2,6-dichlorophenoxy) acetonitrile (4-amino-2,6-dichlorophenoxy) acetic acid tert-butyl ester (2-Amino-4-chloro-5) (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-chlorophenyl) -2-fluorobenzamide

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

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

N- (4-Amino-2-chlorophenyl) -2-dimethylaminoacetamide

N- (4-Amino-2-chlorophenyl) -2-piperidin-1-ylacetamide

N- (4-Amino-2-chlorophenyl) -2-morpholin-4-ylacetamide

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

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

N- (4-Amino-2-chlorophenyl) -2-diethylaminoacetamide

N- (4-Amino-2-chlorophenyl) -2-pyrrolidin-1-ylacetamide

N- (4-Amino-2-chlorophenyl) -2-azepan-1-ylacetamide

N- (4-Amino-2-chlorophenyl) -2- (2-methylpiperidin-1-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 / hexanes 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-methoxyphenoxy) ethanol ···· · · ·· ¹

2- (4-Amino-2-chloro-5-methoxyphenoxy) 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-1-yl-phenylamine

2-Chloro-N (1) -cyclohexyl-N (1) -methyl-benzene-1,4-diamine

N (2) -Benzyl-4-methoxybenzene-1,2-diamine

2- (4-Amino-2-chlorophenoxy) 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) -cyclohexylbenzene-1,4-diamine

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

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

3-Chloro-4- (octahydroquinolin-1-yl) phenylamine

N (1) -Allyl-2-chloro-N (1) -cyclohexylbenzene-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-propoxyphenylamine

3-Iodo-4-methoxyphenylamine

3-Chloro-2,4-dimethoxyaniline

3-Bromo-4-methoxyphenylamine

3-Chloro-4-ethoxyphenylamine

Example 5 (Method 1E)

(4-Aminophenyl) carbamic acid isobutyl ester ··· ·· ·· ♦ · ·· · · '

To a solution of Ν- (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

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

(4-Aminophenyl) -carbamic acid isobutyl ester

N- (4-Aminophenyl) isobutyramide

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

N- (5-Aminopyridin-2-yl) -2,2,2-trifluoroacetamide (4-aminobenzyl) carbamic acid tert-butyl ester

2- (3,5-Bis-trifluoromethylphenyl) ethylamine 1-tert-butyl-1H-imidazol-2-ylamine

3- (3-Dimethylaminopropyl) -5-trifluoromethylphenylamine

Example 6 (Method 1F)

N- (4-Amino-2-methylphenyl) -2-fluorobenzamide

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 activated carbon (3 g) was heated at 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-methylphenyl) acetamide 2-Methylbenzooxazol-6-ylamine

N- (4-Amino-3-methoxyphenyl) acetamide 2-Acetylamino-5-aminobenzoic acid

N- (4-Aminophenyl) acetamide tert -Butyl [4- (3-aminobenzoylamino) phenyl] carbamate tert -butyl [4- (2-aminobenzoylamino) phenyl] carbamate

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-fluorobenzamide

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-methylphenyl) acetamide

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

Furan-2-carboxylic acid 5-amino-2 - [(2-fluorobenzoyl) amino] -N-phenylbenzamide (4-amino-2-phenylcarbamoylphenyl) amide • Furan-2-carboxylic acid 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-trifluoromethylphenyl) acetamide (4-amino-2-trifluoromethylphenyl) amide

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

5-Amino-2- (2-fluorobenzoylamino) benzoic acid

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) -2,2,2-trifluoroacetamide

N- (4-Amino-2-trifluoromethylphenyl) -2-fluoro-N- (2-fluorobenzoyl) benzamide

N- (4-Amino-2-trifluoromethylphenyl) -2-fluorobenzamide

Example 7 (Method 1G)

N- (4-Amino-2-chlorophenyl) -2-thiomorpholino-4-ylacetamide

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 under 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 the appropriate starting materials:

N- (4-Amino-2-chlorophenyl) -2-thiomorpholin-4-ylacetamide

N- (4-Amino-2-chlorophenyl) -2-dipropylaminoacetamide

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:

tert-Butyl- (4-nitrobenzoyl) hydrazinecarboxylic acid butyl ester

terč.Butylester (3-chloro-4-iodophenyl) carbamic acid terč.Butylester (4-bromo-3-chlorophenyl) carbamic acid terč.Butylester (3-chloro-4-vinylphenyl) carbamic acid

(3-chloro-4-methylsulfanylphenyl) carbamic acid tert-butyl ester tert-butyl (4-amino-3-chlorophenyl) carbamic acid tert-butyl (4-chloro-2-nitrophenyl) carbamic acid tert-butyl ester (3-tert. butoxycarbonylamino-5-chlorophenyl) carbamic acid tert-butyl (4-nitrobenzyl) carbamic acid tert-butyl (3-bromo-5-trifluoromethylphenyl) carbamic acid tert-butyl (2-amino-3-chloro-5-trifluoromethylphenyl) carbamic acid tert-butyl ester

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 Ν, Ν-dimethylformamide (44 mL) containing diisopropylethylamine (5.8 mL) was added 1- [2- (trimethylsilyl) ethoxycarbonyloxy] benzotriazole (7.1 mL). 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 brine, 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] carbamate tert -butyl ester

• <φ • φ φ ·

Φ · · · '' '«« «« «

Φ Φ ·

Φ · · · ·

Κ a solution of mono-N- (t-butoxycarbonyl) -1,4-phenylenediamine (1.58

g) and triethylamine (1.50 ml) in 25 ml of dichloromethane were 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-nitrophenyl) acetamide

N- (4-Aminophenyl) isobutyrylamide

[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] carbamate tert-butyl [4- (3-fluorobenzoylamino) phenyl] carbamate tert-butyl [4- (2-fluorobenzoylamino) phenyl] [4- (2-Methoxy-benzoylamino) -phenyl] -carbamic acid tert-butyl ester [4- (3-methoxy-benzoylamino) -phenyl] -carbamic acid tert-butyl [4- (4-methoxy-benzoylamino) -phenyl] -carbamic acid tert-butyl ester [4- (2,2) tert -Butyl [4- (2-bromoacetylamino) phenyl] carbamate t -butyl ester [4- (2,2,2-trifluoroacetamino) phenyl] carbamate% tert-butyl (4-benzoylaminophenyl) carbamic acid tert-butyl ester (4-Methanesulfonylaminophenyl) carbamic acid tert-butyl ester (4-Phenylacetylaminophenyl) carbamic acid tert-butyl tert-butyl {4 - [(thiophene-2-carbonyl) amino] phenyl} carbamic acid tert-butyl ester [4- (3-nitrobenzoylamino) (phenyl) carbamic acids tert -Butyl [4- (3-acetylaminobenzoylamino) phenyl] carbamic acid tert -Butyl [4- (3-methanesulfonylaminobenzoylamino) phenyl] carbamate

Ethyl [3 - [[[4 - [[(1,1-dimethylethoxy) carbonyl] amino] phenyl] carbonyl] phenyl] carbamate tert -Butyl [4- (2-trifluoromethylbenzoylamino) phenyl] carbamic acid tert -butyl ester [4- (2 [4- (2-chlorobenzoylamino) phenyl] carbamic acid tert -Butyl ester [4- (2-bromobenzoylamino) phenyl] carbamic acid tert-butyl ester [4- (2-nitrobenzoylamino), 6-difluorobenzoylamino) phenyl] carbamic acid tert-butyl {4 - [(benzo [b] thiophene-2-carbonyl) amino] phenyl} carbamic acid tert-butyl ester tert. {4 - [(Pyridine-4-carbonyl) amino] phenyl} carbamic acid tert-butyl ester {4- [(Naphthalene-2-carbonyl) amino] phenyl} carbamic acid tert-butyl ester (4 - [(Naphthalene-1) tert -Butyl (4 - [(3-bromothiophene-2-carbonyl) amino] phenyl} carbamic acid tert-butyl {4 - [(biphenyl-2-carbonyl) amino] phenyl} carbamic acid tert-butyl ester

N- (4-t-butoxycarbonylaminophenyl) phthalamic acid tert-butyl [4- (2,3-difluorobenzoylamino) phenyl] carbamate tert-butyl [4- (2,5-difluorobenzoylamino) phenyl] carbamate tert-butyl ester [4- (2, 4-Difluorobenzoylamino) phenylcarbamic acid tert-butyl [4- (2-acetylaminobenzoylamino) phenyl] carbamate tert -Butyl ester [4- (2-methanesulfonylaminobenzoylamino) phenyl] carbamate tert -Butyl ester [4- (2,3,4-trifluobenzoylamino) phenyl] carbamate [4- (2,3,4,5,6-Pentafluorobenzoylamino) phenyl] carbamate butyl ester

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

2-Methylsulfanyl-N- [4- (2,2,2-trifluoroacetylamino) phenyl] benzamide tert-butyl [4- (3-benzyloxybenzoylamino) phenyl] carbamate tert-butyl [4- (3-butoxybenzoylamino) phenyl] carbamate t-butyl ester {4 {4 - [(Thiophene-3-carbonyl) aminobiphenyl] carbamate {4 - [(5-methylfuran-2-carbonyl) aminobiphenyl] carbamate - tert-butyl ester - [(5-difluoromethylfuran-2-carbonyl) aminobiphenyl] carbamate {4 - [(5-Bromo-furan-2-carbonyl) -amino] -phenyl} -carbamic acid

Tert -Butyl (4-hexanoylaminophenyl) carbamic acid tert -butyl tert -Butyl [4- (2-thiophen-2-ylacetylamino) phenyl] carbamate tert -butyl {4- {4 - [(4-Bromo-furan-2-carbonyl) -amino] -phenyl} -carbamic acid tert-butyl {4 - [(furan-3-carbonyl) -amino} -phenyl] -carbamic acid tert. (4-Phenoxycarbonylaminophenyl) carbamic acid butyl ester tert -Butyl {4 - [(benzo [1,3] dioxole-4-carbonyl) aminobiphenyl] carbamate tert -butyl [4- (3-trifluoromethoxybenzoylamino) phenyl] carbamate

N- (2,5-Dimethoxy-4-nitrophenyl) -2-fluorobenzamide tert-butyl {4 - [(furan-2-carbonyl) amino] phenyl] carbamate tert-butyl [4- (2-phenoxyacetylamino) phenyl] carbamate t-butyl ester { {4- [(5-Chloro-furan-2-carbonyl) -amino} -phenyl] -carbamic acid tert-butyl ester (4 - [(3-methyl-furan-2-carbonyl) -amino} -phenyl) {4- [(4-furan-3-yl- [1,2,3] -thiadiazole-5-carbonyl) -amino} -phenyl] -carbamic acid tert-butyl ester {4- (2-methoxyacetlyamino) -phenyl] -carbamic acid tert-butyl ester [(5-tert-butylfuran-2-carbonyl) amino] phenyl] carbamate

N- [3-Cyano-4- (2,2,2-trifluoroacetylamino) phenyl] -2-fluorobenzamide

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

N- (4-acetylamino-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-methylbenzooxazol-6-yl) benzamide

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

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

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

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

2.2.2-Trifluoro-N- (5-nitropyridin-2-yl) acetamide tert -Butyl (4 - [(1-methyl-1H-pyrazole-4-carbonyl) aminobiphenyl} carbamic acid tert-butyl ester

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-nitrobenzyl) benzamide

Furan-2-carboxylic acid 4-nitrobenzylamide

N- [3-Chloro-5- (2,2,2-trifluoroacetylamino) phenyl] -2,2,2-trifluoroacetamide

N- (3-Amino-5-chlorophenyl) -2,2,2-trifluoroacetamide [4- (2-fluorobenzoylamino) benzyl] carbamate tert-butyl [4- (2,6-difluorobenzoylamino) benzyl] carbamate

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

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

2,2,2-Trifluoro-N- (5-nitropyrimidin-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 the appropriate starting materials:

N- (4-Nitro-3-trifluoromethylphenyl) 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) -acetylamino-5-nitrobenzoic acid furan-2-carboxylic acid-nitrophenyl) amide

N- (2-Chloro-4-nitrophenyl) benzamide

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

N- (4-Nitrophenyl) acrylamide

[4- (Acryloylamido) phenyl] carbamate tert-butyl ester N- (4-nitrophenyl) isobutyrylamide

[1,2,3] Thiadiazole-4-carboxylic acid (5-nitropyridin-2-yl) amide [5-Nitropyridin-2-yl] amide Furan-2-carboxylic acid (5-nitropyridin-2-yl) amide

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-fluorobenzamide

2-Fluoro-N- (2-methoxy-4-nitrophenyl) 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-Methyl-4-nitrophenyl) acetamide

2-Fluoro-N- (3-methyl-4-nitrophenyl) benzamide furan-2-amide-3-methyl-4-nitrophenyl) amide -carboxylic acids 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-trifluoromethylphenyl) acetamide (2-Cyano-4-nitrophenyl) amide 2-Fluoro-N- (4-nitro-2-trifluoromethylphenyl) benzamide (4-Nitro-2) Furan-2-carboxylic acid 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-5carbonyl) amino] phenyl] carbamate

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-yloxytris (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} carbamate tert-butyl {4 - [(pyrazine-2-carbonyl) amino] phenyl} carbamic acid tert-butyl {4 - [(5-methylthiophene-2-) {4 - [(1-methyl-1H-pyrrole-2-carbonyl) amino] phenyl} carbamic acid tert-butyl {4 - [(quinoline-8-carbonyl) amino] phenyl} carbamate tert-butyl ester { {4 - [(isoquinoline-1-carbonyl) amino] phenyl} carbamic acid tert-butyl {4 - [(quinoline-2-carbonyl) amino] phenyl} carbamic acid 4 - [(benzofuran-2-carbonyl) aminobiphenyl] carbamate target. {4 - [(isoquinoline-4-carbonyl) amino] phenyl} carbamic acid tert-butyl ester [([1,2,3,3] {thiadiazole-4-carbonyl) amino] phenyl} carbamic acid tert-butyl {4 - [(1H- [1,2,3] triazole-4-carbonyl) amino] phenyl} carbamic acid tert-butyl ester [4- ( 2-Methylsulfanylbenzoylamino) phenyl] carbamic acid tert-butyl {4 - [(quinoline-4-carbonyl) amino] phenyl} carbamic acid tert-butyl ester {4 - [(4-methyl- [1,2,3] thiadiazole-5) {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 butyl ester

Acetic acid 4- (4-tert-butoxycarbonylaminophenylcarbamoyl) phenyl ester tert. {4 - [(Quinoline-6-carbonyl) amino] phenyl} carbamic acid 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 for 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. The solution was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure to give the desired product as a colorless oil.

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

Phenylsulfanylacetonitrile

Acetic acid 2- (4-tert-butoxycarbonylamino-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-butyldicarbonate (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 was 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-Dichlo-4-ethoxyphenylamine

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 was then added, and the mixture was 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-Bromopyridin-3-ylamine

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

Acetic acid 2- (4-aminophenylcarbamoyl) phenyl ester

N- (4-Aminophenyl) -4-fluorobenzamide 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

Thiophene-2-carboxylic acid Ν- (4-aminophenyl) -2,2,2-trifluoroacetamide (4-aminophenyl) -1H-pyrrole-2-carboxylic acid amide (4-aminophenyl) amide

N- (4-Aminophenyl) -3-nitrobenzamide

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

N- (4-Aminophenyl) -3-dimethylaminobenzamide

N- (4-Aminophenyl) -3-methanesulfonylaminobenzamide

N- (4-Aminophenyl) -2-trifluoromethylbenzamide

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

N- (4-Aminophenyl) -2-chlorobenzamide

N- (4-Aminophenyl) -2-bromobenzamide

5-Methyl-thiophene-2-carboxylic acid (4-aminophenyl) -amide (4-Aminophenyl) -amide (4-Aminophenyl) -amide (4-Aminophenyl) -quinoline-8-carboxylic acid (4-amino-phenyl) -amide (4-Aminophenyl) -amide 1-Methyl-1H-pyrrole-2-carboxylic acid 4-aminophenyl) 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 (4-aminophenyl) amide quinoline-2-carboxylic acids

3,5-Dichloro-4-ethoxyphenylamine

[1,2,3] Thiadiazole-4-carboxylic acid (4-aminophenyl) amide 1H- [1] isoquinoline-4-carboxylic acid (4-aminophenyl) amide [4, 3-aminophenyl] amide 2,3-triazole-4-carboxylic acid 3-bromo-thiophene-2-carboxylic acid (4-aminophenyl) amide 4-Benzyloxy-3,5-dichlorophenylamine

2- (4-Amino-2,6-dichlorophenoxy) 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-methylsulfanylbenzamide

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

N- (4-Aminophenyl) isophthalamic acid methyl ester

N- (4-Aminophenyl) -3-benzyloxybenzamide

N- (4-Aminophenyl) -3-butoxybenzamide

5-Methyl-furan-2-carboxylic acid (4-aminophenyl) -pyridine-2-carboxylic acid [3- (4-aminophenylcarbamoyl) -phenoxy] -acetic acid (4-Aminophenyl) -amide (4-Aminophenyl) -amide (4-Aminophenyl) -amide (4-Aminophenyl) 5-Difluoromethylfuran-2-carboxylic acid 4-aminophenyl) amide 1H-Indole-2-carboxylic acid 4-methyl- [1,2,3] thiadiazole-5-carboxylic acid (4-aminophenyl) amide 4-Aminophenyl) thiophene-3-carboxylic acid (4-aminophenyl) 5-chlorofuran-2-carboxylic acid (4-aminophenyl) amide 5-nitrofuran-2-carboxylic acid (4-aminophenyl) amide

5-Bromo-furan-2-carboxylic acid (4-aminophenyl) -amide (4-Aminophenyl) amide 4-methylfuran-2-carboxylic acid (4-aminophenyl) amide (4-Aminophenyl) amide 4 -bromofuran-2-carboxylic acid

N- (4-Aminophenyl) nicotinamide

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

3- (4-Aminophenylcarbamoyl) -phenyl acetic acid benzo [1,3] dioxole-4-carboxylic acid (4-aminophenyl) -amide

N- (4-Aminophenyl) -3- (2-dimethylaminoethoxy) benzamide

N- (4-Aminophenyl) -3-trifluoromethoxybenzamide

N- (4-Aminophenyl) -3- (2-morpholin-4-yl-ethoxy) -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-aminophenyl) -2-methoxyacetamide (4-aminophenyl) amide 5-tert-butylfuran- 2-carboxylic acids

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

2- (Amino-2-chlorophenyl) 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-bistrifluoromethylphenyl) thiourea

N- (4-Aminophenyl) -2-iodobenzamide · · · • · • · • · ♦

N- (4-Aminophenyl) -3-trifluoromethylbenzamide

Example 16 (Method 3B)

1- (4-Amino-2-chlorophenyl) ethanol

A solution of 1M tetrabutylammonium fluoride in tetrahydrofuran (5.7 mL) was added to [3-chloro-4- (1-hydroxyethyl) 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-fluorobenzamide

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 ( 16 ml) and the mixture was heated at reflux overnight. After removal of the solvent under reduced pressure, the residue was suspended in water and extracted with dichloromethane. The organic extracts were combined, washed with water and then saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound as a white solid.

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

Μ · ·· ·

N- (4-Aminophenyl) -2-methanesulfinylbenzamide

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-1-cyclohexyloxy-4-nitrobenzene

Cyclohexanol (2.9 g) in dimethylsulfoxide (20 ml) was slowly added to a flask containing potassium hydride (0.90 g, first washed three times with hexanes) under an argon atmosphere, and this solution was 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 successively 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 approximately 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 (using pure ethyl acetate followed by pure methanol 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-nitrophenyl) dipropylamine

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

1- (2-Chloro-4-nitrophenyl) decahydroquinoline Allyl- (2-chloro-4-nitrophenyl) cyclohexylamine

2 - [(2-Chloro-4-nitrophenyl) - (2-hydroxyethyl) aminojethanol (2-Chloro-4-nitrophenyl) isobutylmethylamine (2-Chloro-4-nitrophenyl) hexylmethylamine

2 - [(2-Chloro-4-nitrophenyl) methylamino] ethanol

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

N- (2-Chloro-4-nitrophenyl) -N, N ^Z , 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 · · · · · · · · · · · ·- • 4 · Φ · Φ · φ · · · · · · · ·

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

4-Piperidin-1-yl-3-trifluoromethyl-benzonitrile

4-Dimethylamino-3-trifluoromethylbenzonitrile

4- (4-Methylpiperazin-1-yl) -3-trifluoromethylbenzonitrile

Example 19 (Method 4E)

Butyl (2-chloro-4-nitrophenyl) 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 was 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-1-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 brine 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-nitrophenyl) dimethylamine

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

1- (4-Chloro-5-methoxy-2-nitrophenyl) 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 over 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. Removal of the solvent under reduced pressure followed by chromatography on silica gel (using 5% diethyl ether in hexanes as eluent) gave 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:

tert-Butyl (3,5-dichloro-4-ethoxyphenyl) carbamic acid tert-butyl (4-butoxy-3,5-dichlorophenyl) carbamic acid tert-butyl (4-benzyloxy-3,5-dichlorophenyl) carbamic acid tert. (4-Carbamoylmethoxy-3,5-dichloro-phenyl) -carbamic acid butyl ester tert -Butyl [3,5-dichloro-4- (2-nitro-ethoxy) -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] carbamate tert -Butyl (4- [3- (2-chloroethoxy) benzoylamino) phenyl} carbamic acid tert-butyl ester

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

To a solution of 2,6-dichloro-4-nitrophenol (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 at room temperature for 2 days. . The solution was then poured into 500 ml of water, extracted three times with hexanes, and the combined organic extracts were 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 gave 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-1-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-Chloro -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-nitrophenoxy) ethanol

2- (2-Chloro-5-methoxy-4-nitrophenoxy) ethanol ··· ·· ·· · t-Butyl (2-chloro-5-methoxy-4-nitrophenoxy) acetic acid butyl ester

(2-Chloro-5-methoxy-4-nitrophenoxy) -acetic acid methyl ester (4-Chloro-5-methoxy-2-nitrophenoxy) acetic acid tert-butyl (4-chloro-5-methoxy-2-nitrophenoxy) acetic acid methyl ester (2-Chloro-4-nitrophenoxy) 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] -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 (0.55 g) in toluene (20 mL) was added ethylene carbonate (1.6 g) and the mixture was 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 was then removed by evaporation under reduced pressure and the resulting residue was chromatographed on silica gel (using 30% ethyl acetate in hexanes as eluent) to give the desired product as a white foam.

Example 26 (method 6)

ΊΟ

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 the mixture was stirred under argon at room temperature for 1.5 hours. This solution was then concentrated under reduced pressure, diluted with t

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 was used as eluent). 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-methylpiperidine

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 approximately 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 di-chlorinated 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-Dichlo-2-hydroxy-4-methoxynitrobenzene

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 is 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 dropwise a solution of bromine (1.42 g) in glacial acetic acid (3 mL). ml) and the mixture was stirred at room temperature for approximately 24 hours. The solution was then partitioned between ethyl acetate and water, and the organic layer was then washed 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 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 was then filtered, the filtrate was concentrated under reduced pressure, the residue was dissolved in ethyl acetate and then washed successively with 5% aqueous sodium bicarbonate, 5% aqueous sodium bisulfite, and saturated aqueous sodium chloride. The solution was dried over anhydrous magnesium sulfate, and then the solvent was removed by evaporation under reduced pressure, and the residue was 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 hexanes to give the desired product as a brownish solid.

Example 34 (method 8)

3-Chloro-4-trifluoromethylnitrobenzene

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 ^from - 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 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 was poured into 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 (about 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), triphenylarsin (0.67 g) and tris (dibenzylideneacetone) palladium (0) (0.50 g) in tetrahydrofuran (120 mL) at 50 ° C was added tributylvinyl tin (10 g) and the mixture was stirred at 50 ° C under argon for about 15 hours. 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 are used as eluent)

(And then 10% ethyl acetate in hexanes) 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 and subsequent chromatography of the residue on silica gel (using 20% ethyl acetate in hexanes as eluent) gave 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-chloro-phenyl] -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), acid hydrogen azide (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 diethyl azodicarboxylate. 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 (using 80% ethyl acetate in hexanes 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 an ice cold solution of [3-chloro-4- (3-dimethylamino-prop-1-ynyl) -phenyl] -carbamic acid tert-butyl ester (4.0 g) in dichloromethane (30 ml) is added in small portions:. ::. . . · · · · ··· · ··· ···

3-chloroperoxybenzoic acid (2.34 g). The reaction mixture was stirred at 0 ° C for 20 minutes and then the mixture was transferred over 20 equivalents of basic alumina (Brockman Grade I, 150 mesh) and the N-oxide was eluted using a 5% methanol in dichloromethane solution. All fractions containing the desired amine N-oxide were 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 was then heated to reflux for about 15 hours, then cooled and the solvent was evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography (using 80% ethyl acetate in hexanes 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-dimethylamino-acryloyl) -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. The mixture was diluted with ethyl acetate, washed sequentially with water, 5% aqueous sodium bicarbonate, saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure and the resulting residue was chromatographed on silica gel (using 22% ethyl acetate in hexanes as eluent) 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 at room temperature for 3 hours. 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 was removed by evaporation under reduced pressure and the resulting residue was chromatographed on silica gel (67% ethyl acetate in hexanes was used as eluent) to give the desired product as an oil.

Example 46 (Method 19A)

N- (2-Chloro-4-nitrophenyl) -2-thiomorpholin-4-ylacetamide

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 light yellow solid was collected and then recrystallized from hot 2-propanol to give a light 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 ester · ·

target. {4- [3- (2-Dimethylamino-ethoxy) -benzoylamino] -phenyl} -carbamic acid tert-butyl ester {4- [3- (2-Morpholin-4-ylethoxy) -benzoylamino] -phenyl} -carbamic acid butyl ester

N- (2-Chloro-4-nitrophenyl) -2-dimethylaminoacetamide

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

N- (2-Chloro-4-nitrophenyl) -2-morpholin-4-ylacetamide

N- (2-Chloro-4-nitrophenyl) -2-dipropylaminoacetamide

N- (2-Chloro-4-nitrophenyl) -2-thiomorpholin-4-ylacetamide

N- (2-Chloro-4-nitrophenyl) -2-diethylaminoacetamide

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

2-Azepan-1-yl-N- (2-chloro-4-nitrophenyl) acetamide

N- (2-Chloro-4-nitrophenyl) -2- (2-methylpiperidin-1-yl) acetamide

N- (2-Chloro-4-nitrophenyl) -2- (3-methylpiperidin-1-yl) acetamide

N- (2-Chloro-4-nitrophenyl) -2- (4-methylpiperidin-1-yl) acetamide

Example 47 (method 19B)

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

To a solution of N- (chloroacetyl) -2-chloro-4-nitroaniline (3.01 g) in Ν, Ν-dimethylformamide (100 mL) was added powdered sodium carbonate (6.0 g) and 2-dimethylaminoethanthiol 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-chloro-phenyl) -carbamic acid 2-piperidin-1-yl-ethyl ester · 9 · 9 · 9 9 β · · 9 .

· · · · · · · ·

Κ suspension of 1,1-carbonyl-di- (1,2,4) triazole (4.0 g) in dichloromethane (40 ml) was added dropwise over 20 minutes a solution of tert-butyl ester (4-amino-3-chlorophenyl) carbamic acid (5.0 g) in dichloromethane (45 mL). The reaction mixture was stirred at room temperature for 30 minutes until precipitation began to form. To this mixture was added piperidinethanol (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 was 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 formed 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 at room temperature overnight, 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 the diazoketone collected above (1.2 g) was dissolved in toluene (25 mL) and treated with 2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetan-2,49

· * ·· • »

9 · 4 4 4 4 4 4 4 4 »9 9 9 * * * * * * 9 9 9 9 9 9

disulfide (2.8 g) and the reaction mixture was 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 remaining 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 was collected by filtration, washed with water and then 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% hexanes 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] thiadiazo-1-5-carboxylic acid

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

Example 53 (method 25)

Trifluoromethanesulfonic 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 the 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 4-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] carbamate (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 and 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 appropriate starting materials:

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

N- (3-Chloro-5-dimethylaminophenyl) 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). The solution was heated at 40 ° C for 30 min, 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 h. 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 the mixture was stirred under an atmosphere of hydrogen 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 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-phenoxy-ethyl ester (0.16 g) in a 1: 1 mixture of tetrahydrofuran and methanol (2.5 mL) was added IN 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-dichloro-phenoxy] -acetic acid

To a solution of {4- [3- (4-acetylaminophenyl) thioureido] -2,6-dichlorophenoxy} acetic acid ethyl ester (0.29 g) in a mixture of (1: 1) tetrahydrofuran and methanol (4 mL) was added 1N aqueous hydroxide sodium (2 mL) and the mixture was stirred at room temperature for about 2 hours. The solution was then poured into 2M aqueous hydrochloric acid (5 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.

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-hydroxyethoxy) 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 hours. 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). 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 (pure methanol was used 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-amino-ethyl) -3-chloro-phenyl] -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) in tetrahydrofuran (50 mL) was added [1,2,3] thiadiazole-4-carboxylic acid (4-aminophenyl) amide (9.0 g) in tetrahydrofuran (100 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 to precipitate the crude product, which was then collected by filtration, dissolved in dichloromethane, and passed through a plug of hydrated magnesium silicate. The solvents were removed and the residue was then recrystallized from ethyl acetate / hexanes 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-isothiocyanatophenyl) amide thiazole furan-2-carboxylic acid (4-isothiocyanatophenyl) amide 2-Fluoro-N- (4-isothiocyanatophenyl) benzamide -4-carboxylic acids

Example 66 (method 42)

N, N-Dimethyl-5-trifluoromethylbenzene-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 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-Methylpiperazin-1-yl) -5-trifluoromethylphenylamine 3-Morpholin-4-yl-5-trifluoromethylphenylamine 3-Piperidin-1-yl-5-trifluoromethylphenylamine 3-Pyrrolidin-1-yl-5-trifluoromethylphenylamine

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 stopper and cooled in a dry ice-acetone bath for approximately 5 minutes. A solution of 9-borabicyclo [3.3.1.0] nonane in tetrahydrofuran (0.5 M, 11 ml) was added, the vessel was sealed with a Teflon stopper and slowly warmed to room temperature, where it was maintained for about 2.5 hours. The mixture is then re-cooled in a dry ice-acetone bath, the Teflon plug is replaced with a rubber plug, and argon is bubbled through the mixture to vent excess isobutylene. A solution of (3-bromo-5-trifluoromethyl-phenyl) -carbamic acid tert-butyl ester (1.7 g) in tetrahydrofuran (12 ml) was added first, followed by [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloromethane / dichloride complex. 12 g), followed by 3N aqueous sodium hydroxide. The vessel was resealed with a Teflon plug and then heated at 65 ° C for approximately 15 hours. The mixture was then cooled to room temperature, diluted with hexanes, washed with water, saturated brine, 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-Dichlorophenylsulfanyl) 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 h. 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-Bromophenylsulfanyl) ethylamine

2- (4-Bromophenoxy) ethylamine

2- (4-Iodophenoxy) ethylamine

2- (3,4-Dichlorophenoxy) ethylamine

2- (3-Chlorophenylsulfanyl) ethylamine

2- (3,4-Dichlorophenylsulfanyl) ethylamine

3- (4-Bromophenyl) propylamine

2- (2-Fluorophenoxy) ethylamine

2- (2-Chlorophenoxy) ethylamine

2- (3-Bromophenoxy) ethylamine

2- (3-Fluorophenoxy) ethylamine

2- (3-Iodophenoxy) ethylamine

2- (3,5-Dichlorophenylsulfanyl) ethylamine

2-Phenylsulfanylethylamine

1- (2-Chlorophenyl) ethylamine

Example 69 (Method 45)

N- (1-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- (1-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-Aminoethyl) benzonitrile

Example 71 (Method 47)

O-Methyloxime of 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 brine, 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

O-Methyloxime of 1- (4-fluorophenyl) propan-1-one

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

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

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

O-Methyloxime of 1-p-tolylethanone

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

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

O-Methyloxime of 1-o-tolylethanone

O-Methyloxime of 1-m-tolylethanone

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

3- (1-Methoxyimethyl) benzonitrile

4- (1-Methoxyimethyl) benzonitrile

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

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

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

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

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

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

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

O-Methyloxime of 1-furan-2-ylethanone

O-Methyloxime 1-pyridin-4-ylethanone

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

O-Methyloxime of 1-thiophen-3-ylethanone

O-Methyloxime (4-fluorophenyl) phenylmethanone

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

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

4- (1-Methoxyiminethyl) benzenesulfonamide

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

O-Methyloxime of 1- [4- (piperidine-1-sulfonyl) phenyl] ethanone

4- (1-Methoxyiminethyl) -N, N-dipropylbenzenesulfonamide

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

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

1- [4- (1H-Imidazol-1-yl) phenyl] -1-ethanone O-methyl-oxime

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

O-Methyloxime 1- [1,1'-Biphenyl] -4-yl-1-ethanone

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

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

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

O-Methyloxime of 1- [4-chloro-3- (trifluoromethyl) phenyl] ethanone

O-Methyloxime of 1- [3-fluoro-5- (trifluoromethyl) phenyl] ethanone

1- [2-Fluoro-4- (trifluoromethyl) phenyl] ethanone O-methyl oxime

O-Methyloxime of 1- [2-fluoro-5- (trifluoromethyl) phenyl] ethanone

O-Methyloxime of 1- (2,4-dichlorophenyl) ethanone

O-Methyloxime of 1- (2,4-dimethylphenyl) ethanone

O-Methylloxime of 1- [2,4-bis (trifluoromethyl) phenyl] ethanone

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

O-Methyloxime of 1- (3-methylphenyl) ethanone

O-Methyloxime of 1- [4- (4-morpholinyl) phenyl] ethanone

100 ··· ·· · · · «

O-Methyloxime of 1- (2-chloro-4-fluorophenyl) ethanone

O-Methyloxime of 1- (4-bromo-2-fluorophenyl) ethanone

O-Methyloxime of 1- (3,4-difluorophenyl) ethanone

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

O-Methylloxime 1- [2- (trifluoromethyl) phenyl] ethanone

O-Methyloxime of 1- (2,4-difluorophenyl) ethanone

1- [3-Fluoro-4- (trifluoromethyl) phenyl] ethanone O-methyl oxime

O-Methyloxime of 1- (3,4-dichlorophenyl) ethanone

O-Methylloxime of 1- [4-fluoro-2- (trifluoromethyl) phenyl] ethanone

O-Methyloxime of 1- (3-chloro-4-fluorophenyl) ethanone

O-Methyloxime of 1- (4-chloro-3-fluorophenyl) ethanone

O-Methyloxime of 1- (2,5-difluorophenyl) ethanone

O-Methyloxime of 1- (2-bromo-4-fluorophenyl) ethanone

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

O-Methyloxime of 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. Remove the solvent

101 under reduced pressure to give the desired product as a yellow oil (0.20 g).

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

1- (3-Methoxyphenyl) ethylamine

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

4- (1-Aminoethyl) benzonitrile

1- (4-Trifluoromethylphenyl) ethylamine

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

1- (2-Methoxyphenyl) ethylamine

1-m-Tolylethylamine

1- (2-Bromophenyl) ethylamine

1-o-Tolylethylamine

C- (4-Fluorophenyl) -C-phenylamine

1- (4-Fluorophenyl) pentylamine

1- (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 or - [3,5-Bis (trifluoromethyl) phenyl] butylamine 1- [3,5-Bis (trifluoromethyl) phenyl] -1-pentanamine

1- (4-Methylphenyl) ethanamine

1- [3- (Trifluoromethyl) phenyl] ethylamine

1- [4- (Trifluoromethyl) phenyl] ethylamine

102

1- (3-Methylphenyl) ethanamine

1- (3,4-Dichlorophenyl) ethanamine

1- (2-Bromophenyl) ethylamine

1- (2-Trifluoromethylphenyl) ethylamine

1- (3-Bromophenyl) 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-Bistrifluoromethylphenyl) 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-ylethylamine

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

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

1- (3,4-Difluorophenyl) ethylamine

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

1- (3-Fluorophenyl) ethylamine

1- (2,4-Difluorophenyl) ethylamine 1- [3-Fluoro-4- (trifluoromethyl) phenyl-ethylamine 1- [4-Fluoro-2- (trifluoromethyl) phenyl] ethylamine

1- (3-Chloro-4-fluorophenyl) ethylamine

103

1- (4-Chloro-3-fluorophenyl) 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 stage (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-Bromophenylsulfanyl) acetonitrile (3-Chlorophenylsulfanyl) acetonitrile (4-iodophenoxy) acetonitrile (3-Trifluoromethylphenylsulfanyl) acetonitrile (3,5-Dichlorophenylsulfanyl) acetonitrile (3,4-Dichlorophenylsulfanyl) acetonitrile (3,4-Dichlorophenylsulfanyl) -Fluorophenoxy) acetonitrile (3-Fluorophenoxy) acetonitrile (2-Chlorophenoxy) acetonitrile

104 (3-Bromophenoxy) acetonitrile (2-Fluoro-5-trifluoromethylphenoxy) acetonitrile (3-iodophenoxy) acetonitrile (4-Bromophenoxy) acetonitrile

Example 74 (method 50)

3-Fluoro-5-trifluoromethylphenethylamintosylate

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 at room temperature at 20 psi for 3 hours using 200 mg of 10% palladium on carbon catalyst. The catalyst was filtered off and the solvent was evaporated to half the amount. 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

2- (2-Fluorophenyl) ethylamine

2- (3-Fluoro-5-trifluoromethylphenyl) ethylamine

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

2- (2,4-Bistrifluoromethylphenyl) ethylamine

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

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

105

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. clock. 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 (using 15% methanol in methylene chloride 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

Diisobutylaluminium hydride (10 ml of a 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, still at 0 ° C, and the solution is stirred for 1.5 hours. The reaction mixture was then added

106 was 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-nitrovinyl) -5-trifluoromethylphenyl] 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 (1: 1) with acetic acid. 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-trifluoromethylphenyl] amine Dimethyl- [2-methyl-4- (2-nitrovinyl) phenyl] amine

Example 78 (method 54)

3- (4-Bromophenyl) propionitrile

107

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 dropwise Ν, Ν'-dimethylformamide dimethylacetal (6.5 g) with stirring over 10 minutes. 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 hexanes to give pale yellow needles, 3.0 g.

Example 80 (method 56)

4-Carboethoxythiazole

A solution of 3-dimethylamino-2-isocyanacrylic acid ethyl ester (1.0 g) and triethylamine (3.0 g) in tetrahydrofuran (30 mL) was treated with hydrogen sulfide gas until all the starting material was consumed. Concentrate the mixture to an oil and purify by column chromatography using silica and 25%

108 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:

109 ··

Ex. C . M + H COMPOUND NAME 81 445 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -ureido] - phenyl] -2-fluorobenzamide 82 441 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -ureido] - phenyl} -2-methylbenzamide 83 435 (4- [3- (5-Chloro-2,4-dimethoxyphenyl) ureido] phenyl) amide [1,2,3] thiadiazole-4-carboxylic acid 84 443 {4- [3- (4-Chloro-3-trifluoromethyl-phenyl) -ureido] -phenyl] -amide [1,2,3] thiadiazole-4-carboxylic acid 85 453 N- {4- [3- (4-Chloro-3-trifluoromethyl-phenyl) -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-Bistrifluoromethylphenyl) ureido] phenyl} -2-fluorobenzamide 88 458 {4- [3- (3,5-Bistrifluoromethyl-phenyl) -ureido] -phenyl} -amide furan-2-carboxylic acid 89 476 {4- [3- (3,5-Bistrifluoromethyl-phenyl) -ureido] -phenyl} -amide [1,2,3] thiadiazole-4-carboxylic acid 90 423 {4- [3- (3,4-Dichlorobenzyl) ureido] phenyl} amide [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

COMPOUND NAME

110

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

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

409 1- (5-Chloro-2,4'-dimethoxyphenyl) -3- (4-morpholin-4-ylphenyl) thiourea

370 1- (5-Chloro-2,4-dimethoxyphenyl) -3- (4-methylsulfanylphenyl) thiourea

338 1- (5-Chloro-2,4-dimethoxyphenyl) -3-p-tolylthiourea

414 {4- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] phenylsulfanyl} acetic acid

384 1- (5-Chloro-2,4-dimethoxyphenyl) -3- [4-2-hydroxyethoxy) phenyl] thiourea

340 1- (5-Chloro-2,4-dimethoxyphenyl) -3- (4-hydroxyphenyl) thiourea

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

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

411 {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -carbamic acid ethyl ester

319 1- (2,4-Dimethoxyphenyl) -3- (4-methoxyphenyl) thiourea

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

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

316 N- {4- [3- (2-Methoxy-phenyl) -thioureido] -phenyl} -acetamide

351 N- {4- (3- (3-Chloro-4-methoxy-phenyl) -thioureido] -phenyl} -acetamide

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

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

385 N- (4- (3- (3,5-Dichloro-4-methoxyphenyl) thioureido) phenyl) acetamide

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

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

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

422 4- [3- (4-Acetylaminophenyl) thioureido] -3X •

4 «a« «

111 a

benzoic acid hydroxyphenyl ester

114 457 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -2-methyl-benzamide 115 501 Acetic acid 2- {4- [3- (5-chloro-2,4-dimethoxyphenyl) thioureido] phenylcarbamoyl} phenyl ester 116 461 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] - phenyl} -4-fluorobenzamide 117 461 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] - phenyl} -3-fluorobenzamide 118 461 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] - phenyl} -2-fluorobenzamide 119 473 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] - phenyl} -2-methoxybenzamide 120 473 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -3-methoxy-benzamide 121 474 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -4-methoxy-benzamide 122 443 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -benzamide 123 417 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] - phenylmethanesulfonamide 124 331 N- {4- [3- (3-Nitrophenyl) thioureido] phenyl} acetamide 125 339 1- (3-Chloro-4-methoxyphenyl) -3- (3-nitrophenyl) - thiourea 126 337 N- {4- [3- (5-Chloro-2-hydroxy-phenyl) -thioureido] -phenyl} -acetamide 127 439 {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -carbamic acid tert-butyl ester 128 351 N- {4- [3- (3-Chloro-4-hydroxy-5-methyl-phenyl) -thioureido] -phenyl} -acetamide 129 385 N- {4- [3- (3,5-Dichloro-4-hydroxy-2-methylphenyl) thioureidophenyl] acetamide 130 318 N- {4- [3- (2,4-Dihydroxyphenyl) thioureido] phenyl} acetamide 131 414 N- {4- [3- (2,4-Dimethoxy-5-trifluoromethyl-phenyl) -thioureido] -phenyl} -acetamide 132 332 N- {4- [3- (2-Hydroxy-4-methoxy-phenyl) -thioureido] - phenyl} acetamide 133 465 N- {4- [3- (3,5-Dichloro-4-methoxy-phenyl) -thioureido] - Phenyl} -4-fluorobenzamide 134 500 3-Acetylamino-N- {4- [3- (5-chloro-2,4-dimethoxy-phenyl) -

112 • 4 (t. 4) thioureido] phenyl} benzamide

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

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

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

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

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

479 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -2,6-difluorobenzamide

477 2-Chloro-N- {4- [3- (5-chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -benzamide

522 2-Bromo-N- {4- [3- (5-chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -benzamide

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

445 Pyrazine-2-carboxylic acid {4- [3- (5-chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -amide

463 5-Methyl-thiophene-2-carboxylic acid {4- [3- (5-chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -amide

Quinoline-8-carboxylic acid {4- [3- (5-chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -amide

446 1-Methyl-1H-pyrrole-2-carboxylic acid {4- [3- (5-chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -amide

369 1- (5-Chloro-2,4-dimethoxyphenyl) -3- (2-nitrophenyl) thiourea

369 1- (5-Chloro-2,4-dimethoxyphenyl) -3- (4-nitrophenyl) thiourea

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

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

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

499 Benzo [b] thiophene-2-carboxylic acid 4- (3- (5-chloro-2,4-dimethoxyphenyl) thioureido] phenyl} amide

483 Benzofuran-2-carboxylic acid {4- [3- (5-chloro-2,4-dimethoxyphenyl) thioureido] phenyl} amide

113

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

493 Naphthalene-2-carboxylic acid {4- [3- (5-chloro-2,4-dimethoxyphenyl) thioureido] phenyl} amide

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

494 Isoquinoline-1-carboxylic acid (4- [3- (5-chloro-2,4-dimethoxyphenyl) thioureido] phenyl} amide

494 Quinoline-2-carboxylic acid {4- [3- (5-chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -amide

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

478 {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl) -amide-carbamic acid phenyl ester of 5-nitrofuran-2-carboxylic acid

459 5-Chlorofuran-2-carboxylic acid {4- [3- (5-chloro-2,4-dimethoxyphenyl) thioureido] phenyl} 467 {4- [3- (5-Chloro-2,4-dimethoxyphenyl} thioureido] phenyl] amide acid

439 {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -carbamic acid isobutyl ester

397 {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -carbamic acid methyl ester

433 Furan-3-carboxylic acid {4- [3- (5-chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -amide

447 3-Methyl-furan-2-carboxylic acid {4- [3- (5-chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl] -amide

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

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

433 Furan-2-carboxylic acid {4- [3- (5-chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -amide

467 {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -carbamic acid hexyl ester

494 Isoquinoline-4-carboxylic acid {4- [3- (5-chloro-2,4-dimethoxyphenyl) thioureido] phenyl} amide

[1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (5-chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -amide

434 1H- [1,2,3] Triazole-4-carboxylic acid {4- [3- (5-chloro-2,4-dimethoxyphenyl) thioureido] phenyl} amide

114

528 3-Bromo-thiophene-2-carboxylic acid {4- [3- (5-chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl] -amide

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

427 N- {4- [3- (4-Butoxy-3,5-dichloro-phenyl) -thioureido] -phenyl} -acetamide

461 N- {4- [3- (4-Benzyloxy-3,5-dichloro-phenyl) -thioureido] -phenyl} -acetamide

381 N- {4- [3- (3-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl) -acetamide

530 (3- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenylcarbamoyl} -phenyl) -carbamic acid ethyl ester

458 2-Amino-N- {4- [3- (5-chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -benzamide

519 Biphenyl-2-carboxylic acid {4- [3- (5-chloro-2,4-dimethoxyphenyl) thioureido] phenyl] amide

469 1- (5-Chloro-2,4-dimethoxyphenyl) -3- [4- (1,3-dioxo-1,3-dihydroisoindol-2-yl) phenyl] thiourea

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

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

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

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

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

500 2-Acetylamino-N- {4- [3- (5-chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -benzamide

441 1- (5-Chloro-2,4-dimethoxyphenyl) -3- (6-oxo-5,6-dihydrophenanthridin-2-yl) thiourea

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

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

533 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -2,3,4,5,6-pentafluorobenzamide

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

431 {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -ureido] -phenyl} -amide •

115

Of 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-dimethoxy-phenyl) -thioureido] - phenyl} acetamide 198 364 N- {4- [3- (5-Fluoro-2,4-dimethoxyphenyl) thioureido] phenyl} acetamide 199 365 N- {4- [3- (5-Chloro-2-methoxy-4-methyl-phenyl) -thioureido] -phenyl} -acetamide 200 459 {4- [3- (4-Chloro-3-trifluoromethyl-phenyl) -thioureido] - [1,2,3] thiadiazole-4-carboxylic acid phenyl iamide 201 455 [1,2,3] Thiadiazole-4-carboxylic acid (4- (3- (3,5-dichloro-4-methoxyphenyl) thioureido) phenyl} amide 202 392 N- {4- [3- (3-Chloro-4-diethylaminophenyl) thioureido] phenyl} acetamide 203 432 N- (4- {3- [3-Chloro-4- (cyclohexylmethylamino) phenyl] thioureido} phenyl) acetamide 204 506 1-hydroxynaphthalene-2-carboxylic acid {4- [3- (4-acetylaminophenyl) thioureido] -2-chlorophenyl} amide 205 406 N- {4- [3- (3-Chloro-4-morpholin-4-yl-phenyl) -thioureido] -phenyl} -acetamide 206 443 1- (5-Chloro-2,4-dimethoxy-phenyl) -3- (3-chloro-4- (morpholin-4-ylphenyl) thiourea 207 372 1- (5-Chloro-2,4-dimethoxyphenyl) -3- (5-chloro-2-methyl- phenyl) thiourea 208 501 N- {4- [3- (5-chloro-2,4-dimethoxyphenyl) thioureido] phenyl} isophthalamic acid methyl ester 209 487 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -isophthalamic acid 210 549. 3-Benzyloxy-N- {4- [3- (5-chloro-2,4-dimethoxyphenyl) thioureido] phenyl} benzamide 211 434 N- (4- {3- [5-Chloro-2-methoxy-4- (4-nitrilobutoxy) phenyl] thioureido) phenyl} acetamide 212 406 N- (4- {3- [5-Chloro-2-methoxy-4- (2-nitroloethoxy) phenyl] thioureido} phenyl) acetamide 213 406 N- (4- {3- [5-Chloro-4-methoxy-2- (2-nitroloethoxy) phenyl] thioureido) phenyl} acetamide 214 411 N- (4- {3- [5-Chloro-2- (2-hydroxyethoxy) -4-methoxyphenyl] thioureido) phenyl} acetamide 215 411 • N- (4- {3- [5-Chloro-4- (2-hydroxyethoxy) -2-methoxy-

phenyl] thioureido} phenyl) acetamide

116

481 {4- [3- (4-Acetylaminophenyl) thioureido] -2-chloro-5-methoxyphenoxy) acetic acid tert-butyl ester

439 {4- [3- (4-Acetylaminophenyl) thioureido] -2-chloro-5-methoxyphenoxy) acetic acid methyl ester

481 {2- [3- (4-Acetylaminophenyl) thioureido] -4-chloro-5-methoxyphenoxy) acetic acid tert-butyl ester

515 3-Butoxy-N- {4- [3- (5-chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -benzamide

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

545 (3- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenylcarbamoyl} -phenoxy) -acetic acid ethyl ester

517 (3- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenylcarbamoyl) -phenoxy) -acetic acid

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

444 Pyridine-2-carboxylic acid {4- [3- (5-chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -amide

494 Quinoline-4-carboxylic acid {4- [3- (5-chloro-2,4-dimethoxyphenyl) thioureido] phenyl} amide

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

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

420 N- {4- [3- (5-Chloro-4-methoxy-2-pyrrolidin-1-yl-phenyl) -thioureido] -phenyl} -acetamide

434 N- {4- [3- (5-Chloro-4-methoxy-2-piperidin-1-yl-phenyl) -thioureido] -phenyl} -acetamide

[1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (3-chloro-4-methyl-phenyl) -thioureido] -phenyl} -amide

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

427 N- {4- [3- (3-Chloro-4-methyl-phenyl) -thioureido] -phenyl} -3-methoxy-benzamide

387 Furan-2-carboxylic acid 4- [3- (3-chloro-4-methyl-phenyl) -thioureido] -phenyl) -amide

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

433 N- {4- [3- (3-Chloro-4-methyl-phenyl) -thioureido] -phenyl} -2,6-difluorobenzamide

398 {4- [3- (3-Chloro-4-methyl-phenyl) -thioureido] -phenyl} -amide

117

pyridine-2-carboxylic acid

502 [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [3-chloro-4- (cyclohexylmethylamino) phenyl] thioureido} phenyl) amide

512 N- (4- {3- [3-Chloro-4- (cyclohexylmethylamino) phenyl] thioureido} phenyl) -2-fluorobenzamide

404 N- {4- [3- (3-Chloro-4-piperidin-1-yl-phenyl) -thioureido] -phenyl} -acetamide

364 N- {4- [3- (3-Chloro-4-dimethylamino-phenyl) -thioureido] -phenyl} -acetamide

426 N- {4- [3- (4-Benzylamino-3-chloro-phenyl) -thioureido] -phenyl} -acetamide

390 N- {4- [3- (3-Chloro-4-pyrrolidin-1-yl-phenyl) -thioureido] -phenyl} -acetamide

419 N- (4- {3- [3-Chloro-4- (4-methyl-piperazin-1-yl) -phenyl] -thioureido) -phenyl} -acetamide

469 N- [4- [3- (4-Chloro-3-trifluoromethylphenyl) thioureido] phenyl} -2-fluorobenzamide

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

484 Furan-2-carboxylic acid (4- {3- [3-chloro-4- (cyclohexylmethylamino) phenyl] thioureido] phenyl) amide

508 N- (4- (3- [3-Chloro-4- (cyclohexylmethylamino) phenyl] thioureido) phenyl) -2-methylbenzamide

530 N- (4- {3- [3-Chloro-4- (cyclohexylmethylamino) phenyl] thioureido) phenyl) -2,6-difluorobenzamide

495 Pyridine-2-carboxylic acid (4- {3- [3-chloro-4- (cyclohexyl-methylamino) -phenyl] -thioureido) -phenyl} -amide

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

376 N- (4- {3- [3-Chloro-4- (2-nitro-ethoxy) -phenyl] -thioureido} -phenyl) -acetamide

393 N- [4- [3- (4-sec-Butoxy-3-chloro-phenyl) -thioureido] -phenyl) -acetamide

501 Acetic acid 3- {4- [3- (5-chloro-2,4-dimethoxyphenyl) -thioureido] phenylcarbamoyl} phenyl ester

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

487 Benzo [1,3] dioxole-4-carboxylic acid {4- [3- (5-chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} 118

256 527 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -3-trifluoromethoxy-benzamide 257 530 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -3- (2-dimethylamino-ethoxy) -benzamide 258 572 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] - phenyl} -3- (2-morpholin-4-yl-ethoxy) benzamide 259 406 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] - -2-cyanophenyl} acetamide 260 521 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] - -2,5-dimethoxyphenyl} -2-fluorobenzamide 261 441 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] - -2,5-dimethoxyphenyl} acetamide 262 527 2- {4- [3- (4-Acetylaminophenyl) thioureido] -2-chloro- phenoxy) -5-chlorobenzenesulfonic acid 263 562 2- {4- [3- (4-Acetylaminophenyl) thioureido] -2-chloro- phenoxy) -4,5-dichlorobenzenesulfonic acid 264 527 4-Phenyl- [1,2,3] thiadiazole-5-carboxylic acid {4- [3- (5-chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl] -amide 265 381 N- (4- {3- [3-Chloro-4- (2-hydroxyethoxy) 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- (cyclohexylethylamino) phenyl] thioureido) 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-methoxy-phenyl) -thioureido] -phenyl} -acetamide 272 420 N- {4- [3- (3-Chloro-4-dipropylaminophenyl) thioureido] phenyl} acetamide 273 458 N- (4- {3- [4- (Allylcyclohexylamino) -3-chlorophenyl] thioureido) phenyl} acetamide 274 411 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -2-methoxy-phenyl} -acetamide 275 415 ’N- {2-Chloro-4- [3- (5-chloro-2,4-dimethoxyphenyl) -

thioureido] phenyl} acetamide

119

493 Furan-2-carboxylic acid {4- [3- (5-chloro-2,4-dimethoxyphenyl) thioureido] -2,5-dimethoxyphenyl} amide

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

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

465 5-Methyl [1,2,3] thiadiazole-4-carboxylic acid {4- [3- (5-chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -amide

5-Furan-3-yl [1,2,3] thiadiazole-4-carboxylic acid {4- [3- (5-chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -amide

5-Phenyl [1,2,3] thiadiazole-4-carboxylic acid {4- [3- (5-chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -amide

458 N- (4- {3- [3-Chloro-4- (octahydroquinolin-1-yl) phenyl] thioureido} phenyl) acetamide

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

434 Furan-2-carboxylic acid {5- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -pyridin-2-yl} -amide

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

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

477 Furan-2-carboxylic acid {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -2-methoxy-5-methyl-phenyl) -amide

4-Furan-3-yl [1,2,3] thiadiazole-5-carboxylic acid {4- [3- (5-chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -amide

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

384 N- {4- [3- (4-Methoxy-3-trifluoromethyl-phenyl) -thioureido] -phenyl} -acetamide

394 N- [4- (3- {3-Chloro-4 - [(2-hydroxyethyl) methylamino] phenyl} thioureido) phenyl] acetamide

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

565 N- {2-Benzoyl-4- [3- (5-chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -2-fluoro-benzamide

537 {2-Benzoyl-4- [3- (5-chloro-2,4-dimethoxy-phenyl)] - 120

furan-2-carboxylic acid thioureido] phenyl) amide 295 475 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenylthioureido) -3-] methylmethyl-2-fluorobenzamide 296 447 {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -3-methyl- furan-2-carboxylic acid phenyljamide 297 395 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -3- -methylphenyl} acetamide 298 435 N- [4- (3- {3-Chloro-4 - [(3-dimethylaminopropyl) methylamino] phenyl} thioureido) phenyl] acetamide 299 418 N- {4- [3- (3-Chloro-4-cyclohexylamino-phenyl) -thioureido] - phenyl} acetamide 300 421 N- [4- (3- {3-Chloro-4 - [(2-dimethylaminoethyl) methylamino] phenyl} thioureido) phenyl] acetamide 301 580 5 - [[[(5-Chloro-2,4-dimethoxyphenyl) amino] thioxomethyl] amino] -2 - [(2-fluorobenzoyl) amino] -N-phenylbenzamide 302 552 {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -2- furan-2-carboxylic acid-phenylcarbamoyl-phenyl-amide 303 491 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] - -2-methoxyphenyl} -2-fluorobenzamide 304 463 {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -2- furan-2-carboxylic acid-methoxyphenyl iamide 305 449 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] - -2-trifluoromethylphenyl} acetamide 306 458 {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -2-cyano- furan-2-carboxylic acid phenyljamide 307 467 {2-Chloro-4- [3- (5-chloro-2,4-dimethoxy-phenyl) -thioureido] - furan-2-carboxylic acid phenyl} amide 308 501 {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -2- Furan-2-carboxylic acid-trifluoromethyl-phenyl} -amide 309 395 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] - -2-methylphenyl} acetamide 310 475 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -2-methyl-phenyl} -2-fluoro-benzamide 311 447 Furan-2-carboxylic acid {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -2-methyl-phenyl] -amide 312 378 N- {4- [3- (4-Acetylaminophenyl) thioureido] -2-chlorophenyl} acetamide 313 408 • {4- [3- (4-Acetylaminophenyl) thioureido] -2- ethyl ester -chlorophenyl} carbamic acids

• · ·

121

382 N- {5- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -pyridin-2-yl} -acetamide

509 N- (4- {3- [4- (1-Benzyl-piperidin-4-ylamino) -3-chloro-phenyl] -thioureido] -phenyl) -acetamide

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

408 N- [4- (3- {3-Chloro-4 - [(2-methoxy-ethyl) -methyl-amino] -phenyl} -thioureido) -phenyl] -acetamide

421 N- (4- {3- [3-Chloro-4- (3-dimethylaminopropylamino) phenyl] thioureido] phenyl) acetamide

495 N- (4- {3- [4- (1-Benzyl-pyrrolidin-3-ylamino) -3-chloro-phenyl] -thioureido) -phenyl} -acetamide

483 Furan-2-carboxylic acid {5-chloro-4- [3- (5-chloro-2,4-dimethoxyphenyl) thioureido] -2-hydroxyphenyl] amide

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

511 (5H, HH-Benzo [e] pyrrolo [1,2-a] [1,4] diazepin-10-yl) - (2-chloro-4-imidazol-1-yl-phenyl) -methanone

[1,2,3] Thiadiazole-5-carboxylic acid {4- [3- (5-chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -amide

483 Furan-2-carboxylic acid {4- [3- (5-chloro-2,4-dimethoxyphenyl) thioureido] napthalen-1-yl} amide

511 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -naphthalen-1-yl} -2-fluoro-benzamide

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

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

481 Furan-2-carboxylic acid {5-chloro-4- [3- (5-chloro-2,4-dimethoxy-phenyl) -thioureido] -2-methyl-phenyl-amide

431 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -naphthalen-1-yl} -acetamide

416 Furan-2-carboxylic acid {4- [3- (3-chloro-4-dimethylaminophenyl) thioureido] phenyl} amide

561 Furan-2-carboxylic acid [4- (3- {4 - [(1-Benzylpyrrolidin-3-yl) methylamino] -3-chlorophenyl} thioureido) phenyl] amide

513 N- [4- (3- {3-Chloro-4- [methyl- (1-methylpyrrolidin-3-yl) amino] phenyl] thioureido) phenyl] -2-fluorobenzamide

463 N- [4- (3- {5-Chloro-2-methoxy-4-methyl-phenyl) -thioureido] -phenyl} -2,6-difluorobenzamide

122

420 N- (4- {3- [3-Chloro-4- (1-methyl-pyrrolidin-3-yloxy) -phenyl] -thioureido] -phenyl) -acetamide

434 N- (4- {3- [3-Chloro-4- (1-methyl-piperidin-4-yloxy) -phenyl] -thioureido] -phenyl) -acetamide

422 N- (4- {3- [3-Chloro-4- (3-dimethylaminopropoxy) phenyl] thioureido] phenyl) acetamide

425 2-Acetylamino-5- [3- (5-chloro-2,4-dimethoxyphenyl) thioureido] benzoic acid

505 5- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] -2- (2-fluorobenzoylamino) benzoic acid

477 5- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] -2 - [(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-methyl-pyrrolidin-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-difluorobenzamide

531 N- [4- (3- {3-Chloro-4- [methyl- (1-methyl-pyrrolidin-3-yl) -amino] -phenyl} -thioureido) -phenyl] -2,6-difluorobenzamide

427 Pyridine-2-carboxylic acid [4- [3- (3-chloro-4-dimethylaminophenyl) thioureido] phenyl] amide

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

X • «

123

353 417 {4- [3- (5-Chloro-2-methoxy-4-methyl-phenyl) -thioureido] - furan-2-carboxylic acid phenyljamide 354 496 [4- (3- {3-Chloro-4- [methyl- Pyridine-2-carboxylic acid (1-methylpyrrolidin-3-yl) amino] phenyl} thioureido) phenyl 355 495 N- {3-Chloro-4- [3- (5-chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -2-fluoro-benzamide 356 467 {3-Chloro-4- [3- (5-chloro-2,4-dimethoxy-phenyl) -thioureido] - furan-2-carboxylic acid phenyljamide 357 515 N- {4- [3- (3-Chloro-4-cyclohexylsulfanyl-phenyl) -thioureido] -phenyl} -2-fluoro-benzamide 358 449 N- (4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] - -3-Trifluoromethylphenyl} acetamide 359 529 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] - -3-trifluoromethylphenyl} -2-fluorobenzamide 360 421 N- {4- [3- (4-Acetylaminophenyl) thioureido] -2-chloro- phenyl} -2-dimethylaminoacetamide 361 473 (4- {3- [3-Chloro-4- (2-dimethylamino-acetylamino) -phenyl] - Furan-2-carboxylic acid thioureido (phenyl) amide 362 501 N- (4- (3- [3-Chloro-4- (2-dimethylaminoacetylamino) phenyl] thioureido] phenyl) -2-fluorobenzamide 363 461 N- {4- [3- (4-Acetylaminophenyl) thioureido] -2-chlorophenyl} -2-piperidin-1-yl acetamide 364 541 N- (4- {3- [3-Chloro-4- (2-piperidin-1-yl-acetylamino) -phenyl] -thioureido) -phenyl} -2-fluorobenzamide 365 513 (4- (3- (3-Chloro-4- (2-piperidin-1-yl-acetylamino) phenyl) - furan-2-carboxylic acid thioureido} phenyl) amide 366 463 N- (4- [3- (4-Acetylaminophenyl) thioureido] -2- chlorophenyl} -2-morpholin-4-ylacetamide 367 543 N- (4- (3- (3-Chloro-4- (2-morpholin-4-ylacetylamino)) phenyl] thioureido) phenyl) -2-fluorobenzamide 368 515 (4- (3- (3-Chloro-4- (2-morpholine- -4-ylacetylamino) phenyl] thioureido] phenyl) amide furan-2-carboxylic acid 369 414 N- {4- [3- (3-Chloro-4-methanesulfonylaminophenyl) thioureido] phenyl} acetamide 370 494 N- {4- [3- (3-Chloro-4-methanesulfonylaminophenyl) thioureido] phenyl} -2-fluorobenzamide 371 466 {4- [3- (3-Chloro-4-methanesulfonylamino-phenyl) -thioureido] - furan-2-carboxylic acid phenyljamide

124

481 N- {4- [3- (4-Acetylaminophenyl) thioureido] -2-chlorophenyl} -2- (2-dimethylaminoethylsulfanyl) acetamide

561 N- [4- (3- {3-Chloro-4- [2- (2-dimethylamino-ethylsulfanyl) -acetylamino] -phenyl} -thioureido) -phenyl] -2-fluoro-benzamide

585 N- [4- (3- {4 - [(1-Benzylpyrrolidin-3-yl) methylamino] -3-chlorophenyl} thioureido) phenyl] -2-methylbenzamide

523 N- [4- (3- {3-Chloro-4- [methyl- (1-methylpiperidin-4-yl) amino] phenyl} thioureido) phenyl] -2-methylbenzamide

510 Pyridine-2-carboxylic acid [4- (3- {3-chloro-4- [methyl- (1-methylpiperidin-4-yl) amino] phenyl) thioureido) phenyl] amide

347 N- {4- [3- (3-Chloro-4-vinyl-phenyl) -thioureido] -phenyl} -acetamide

441 Furan-2-carboxylic acid {4- [3- (4-Chloro-3-trifluoromethyl-phenyl) -thioureido] -phenyl] -amide

452 Pyridine-2-carboxylic acid {4- [3- (4-chloro-3-trifluoromethyl-phenyl) -thioureido] -phenyl} -amide

487 N- {4- [3- (4-Chloro-3-trifluoromethyl-phenyl) -thioureido] -phenyl) -2,6-difluorobenzamide

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

458 Furan-2-carboxylic acid {4- [3- (5-chloro-2,4-dimethoxy-phenyl) -thioureido] -3-cyanophenyl-amide

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

395 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -2-methyl-isothioureido] -phenyl} -acetamide

396 N- {4- (3- (5-Chloro-2,4-dimethoxy-phenyl) -2-methyl-isothioureido] -phenyl} -acetamide

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

489 N- {4- [3- (4-Butylsulfanyl-3-chlorophenyl) thioureido] phenyl} -2-fluorobenzamide

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

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

Furan-2-carboxylic acid {4- [3- (5-chloro-2,4-dimethoxy-phenyl) -thioureido] -3-methoxy-phenyl} -amide • · · · · · · · · · · Φ · · · ·

125

• · · · · · · · · · · 391 531 [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [3-chloro-4- (2-piperidin-1-acetylamino) -phenyl] -thioureido) -phenyl} -amide 392 481 N- {4- [3- (3-Chloro-4-methanesulfinyl-phenyl) -thioureido] -phenyl} -2,6-difluorobenzamide 393 497 N- {4- [3- (3-Chloro-4-methanesulfonyl-phenyl) -thioureido] - phenyl} -2,6-difluorobenzamide 394 459 N- {4- [3- (5-Chloro-2-methoxy-4-methyl-phenyl) -thioureido] -2-methyl-phenyl} -2-fluoro-benzamide 395 429 N- {4- [3- (3-Chloro-4-methyl-phenyl) -thioureido] -2-methyl-phenyl} -2-fluoro-benzamide 396 533 Furan-2-carboxylic acid [4- (3- {3-chloro-4- [2- (2-dimethylaminoethylsulfanyl) acetylamino] phenyl} thioureido) phenyl] amide 397 458 N- {4- [3- (4-Acetylamino-3-chloro-phenyl) -thioureido] -phenyl} -2-fluoro-benzamide 398 460 [2-Chloro-4- (3- {4 - [(furan-2-carbonyl) amino] phenyl} thioureido) phenyl] carbamic acid ethyl ester 399 488 (2-Chloro-4- {3- [4- (2-fluoro-benzoylamino) -phenyl] -thioureido} -phenyl) -carbamic acid ethyl ester 400 440 N- {4- [3- (4-Acetylaminophenyl) thioureido] -2-chlorophenyl} benzamide 401 520 N- {4 - [({[4- (Benzoylamino) -3-chlorophenyl] amino} thioxomethyl) amino] phenyl) -2-fluorobenzamide 402 529 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -2- -trifluoromethylphenyl} -2-fluorobenzamide 403 492 {4- [3- (4-Benzoylamino-3-chloro-phenyl) -thioureido] -phenyl} - furan-2-carboxylic acid 404 416 N- {4- [3- (4-Amino-3-chlorophenyl) thioureido] phenyl} -2-fluorobenzamide 405 479 N- {4- [3- (4-Acetylaminophenyl) thioureido] -2-chlorophenyl) -2-thiomorpholin-4-ylacetamide 406 531 (4- {3- [3-Chloro-4- (2-thiomorpholin-4-yl-acetylamino)] - furan-2-carboxylic acid phenyl] thioureido] phenyl) amide 407 559 N- (4- {3- [3-Chloro-4- (2-thiomorpholin-4-ylacetylamino) phenyl] thioureido] phenyl) -2-fluorobenzamide 408 461 N- {4- [3- (3-Chloro-4-methylsulfanyl-phenyl) -thioureido] - -2-methylphenyl} -2-fluorobenzamide 409 430 Furan-2-carboxylic acid {4- [3- (4-acetylamino-3-chloro-phenyl) -thioureido] -phenyl} -amide

• · · ·

126

410 477 N- {4- [3- (4-Acetylaminophenyl) thioureido] -2-chlorophenyl) -2-dipropylaminoacetamide 411 529 Furan-2-carboxylic acid (4- {3- [3-chloro-4- (2-dipropylamino-acetylamino) -phenyl] -thioureido) -phenyl} -amide 412 449 N- {4- [3- (4-Acetylaminophenyl) thioureido] -2-chlorophenyl} -2-diethylaminoacetamide 413 501 Furan-2-carboxylic acid (4- {3- [3-chloro-4- (2-diethylamino-acetylamino) -phenyl] -thioureido] -phenyl) -amide 414 529 N- (4- {3- [3-Chloro-4- (2-diethylaminoacetylamino) phenyl] thioureido) phenyl} -2-fluorobenzamide 415 447 N- (4- [3- (4-Acetylaminophenyl) thioureido] -2-chloro- phenyl} -2-pyrrolidin-1-ylacetamide 416 499 Furan-2-carboxylic acid (4- (3- [3-chloro-4- (2-pyrrolidin-1-ylacetylamino) phenyl] thioureido) phenyl) amide 417 527 N- (4- {3- [3-Chloro-4- (2-pyrrolidin-1-ylacetylamino) phenyl] thioureido] phenyl) -2-fluorobenzamide 418 475 N- {4- [3- (5-Chloro-2-methoxy-4-methyl-phenyl) -thioureido] -3-methoxy-phenyl} -2-fluoro-benzamide 419 445 N- {4- [3- (3-Chloro-4-methyl-phenyl) -thioureido] - -3-methoxyphenyl} -2-fluorobenzamide 420 477 N- {4- [3- (3-Chloro-4-methylsulfanyl-phenyl) -thioureido] - -3-methoxyphenyl} -2-fluorobenzamide 421 388 {4- [3- (4-Amino-3-chloro-phenyl) -thioureido] -phenyl] -amide furan-2-carboxylic acid 422 527 Furan-2-carboxylic acid (4- {3- [4- (2-azepan-1-ylacetylamino) -3-chloro-phenyl] -thioureido} -phenyl) -amide 423 555 N- (4- {3- [4- (2-Azepan-1-ylacetylamino) -3-chlorophenyl] thioureido) phenyl} -2-fluorobenzamide 424 527 Furan-2-carboxylic acid [4- (3- {3-chloro-4- [2- (2-methyl-piperidin-1-yl) -acetylamino] -phenyl} -thioureido) -phenyl] -amide 425 555 N- [4- (3- {3-Chloro-4- [2- (2-methyl-piperidin-1-yl) -acetylamino] -phenyl} -thioureido) -phenyl] -2-fluoro-benzamide 426 339 Furan-2- [4- (3-Pyridin-2-ylthioureido) phenyl] amide -carboxylic acids 427 339 Furan-2- [4- (3-Pyridin-4-yl-thioureido) -phenyl] -amide -carboxylic acids 428 367 2-Fluoro-N- [4- (3-pyridin-3-ylthioureido) phenyl] - benzamide 429 339 . Furan-2- [4- (3-Pyridin-3-ylthioureido) phenyl] amide -carboxylic acids

• · · ·

127

430 353 Furan-2- {4- [3- (3-Aminophenyl) thioureido] phenyl] amide -carboxylic acids 431 406 {4- [3- (3-Trifluoromethyl-phenyl) -thioureido] -phenyl} -amide furan-2-carboxylic acid 432 380 2-Fluoro-N- [4- (3-m-tolylthioureido) phenyl] benzamide 433 434 2-Fluoro-N- {4- [3- (3-trifluoromethylphenyl) thioureido) phenyl} benzamide 434 381 N- {4- [3- (3-Amino-phenyl) -thioureido] -phenyl} - -2-fluorobenzamide 435 388 {4- [3- (3-Amino-5-chloro-phenyl) -thioureido] -phenyl} -amide furan-2-carboxylic acid 436 352 Furan-2-carboxylic acid [4- (3-m-tolylthioureido) phenyl] amide acid 437 416 N- {4- [3- (2-Amino-5-chloro-phenyl) -thioureido] - phenyl} -2-fluorobenzamide 438 571 2-Piperidin-1-yl-ethyl ester (2-chloro-4- {3- [4- (2-fluoro- benzoylamino) phenyl (thioureido) phenyl) carbamic acid 439 543 2-Piperidin-1-yl-ethyl ester [2-chloro-4- (3- {4 - [(furan-2- (carbonyl) amino (phenyl) thioureido) phenyl] carbamic acid 440 388 Furan-2-carboxylic acid {4- [3- (2-amino-5-chloro-phenyl) -thioureido] -phenyl} -amide 441 363 Furan-2- {4- [3- (3-Cyanophenyl) thioureido] phenyl} amide -carboxylic acids 442 416 N- {4- [3- (3-Amino-5-chloro-phenyl) -thioureido] -phenyl} - -2-fluorobenzamide 443 367 2-Fluoro-N- [4- (3-pyridin-2-ylthioureido) phenyl] - benzamide 444 367 2-Fluoro-N- [4- (3-pyridin-4-ylthioureido) phenyl] - benzamide 445 374 Furan-2-carboxylic acid {4- [3- (6-chloro-pyridin-3-yl) -thioureido] -phenyl} -amide 446 388 Furan-2-carboxylic acid {4- [3- (2-amino-3-chloro-phenyl) -thioureido] -phenyl} -amide 447 396 Furan-2-carboxylic acid {4- [3- (3-hydrazinocarbonylphenyl) thioureido] phenyl} amide 448 410 2-Fluoro-N- (4- {3- [3- (1-hydroxyethyl) phenyl] thioureido} phenyl) benzamide 449 414 {4- [3- (3-Hydrazinocarbonylphenyl) thioureido] phenyl} amide

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

128

[1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (3-isopropyl-phenyl) -thioureido] -phenyl] -amide

380 Furan-2-carboxylic acid {4- [3- (3-isopropyl-phenyl) -thioureido] -phenyl} -amide

409 2-Fluoro-N- {4- [3- (3-isopropyl-phenyl) -thioureido] -phenyl} -benzamide

381 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (3-cyanophenyl) thioureido] phenyl) amide

410 N- {4- [3- (3-Dimethylaminophenyl) thioureido] phenyl} -2-fluorobenzamide

381 Furan-2-carboxylic acid {4- [3- (3-dimethylaminophenyl) thioureido] phenyl] amide

[1,2,3] Thiadiazole-4-carboxylic acid [4- (3-m-tolyl-thioureido) -phenyl] -amide

424 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (3-trifluoromethyl-phenyl) -thioureido) -phenyl} -amide

479 N- {3-Chloro-4- [3- (5-chloro-2-methoxy-4-methyl-phenyl) -thioureido] -phenyl} -2-fluoro-benzamide

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

481 N- {3-Chloro-4- [3- (3-chloro-4-methylsulfanyl-phenyl) -thioureido) -phenyl} -2-fluoro-benzamide

391 N- {4- [3- (3-Cyanophenyl) thioureido) phenyl} -2-fluorobenzamide

395 Furan-2-carboxylic acid {4- [3- (3-acetylaminophenyl) thioureido) phenyl} amide

424 2-Fluoro-N- {4- [3- (3-hydrazinocarbonylphenyl) thioureido) phenyl} benzamide

400 [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [3- (1-hydroxy-ethyl) -phenyl) -thioureido) -phenyl} -amide

434 N- {4- [3- (2-Amino-3-chloro-phenyl) -thioureido) -phenyl} -2,6-difluorobenzamide

406 {4- [3- (3-Amino-5-chloro-phenyl) -thioureido) -phenyl] -amide [1,2,3] thiadiazole-4-carboxylic acid

398 Furan-2-carboxylic acid {4- [3- (3,5-dimethoxy-phenyl) -thioureido) -phenyl] -amide

[1,2,3] Thiadiazole-4-carboxylic acid [4- (3- (3,5-dimethoxyphenyl) thioureido) phenyl] amide

454 5- (3- {4 - ((Furan-2-carbonyl) amino] phenyl} thioureido) isophthalic acid dimethyl ester

129

434 {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido) -phenyl} -oxazole-5-carboxylic acid

392 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (6-chloro-pyridin-3-yl) -thioureido) -phenyl] -amide

382 Furan-2-carboxylic acid (4- {3- [3- (1-hydroxy-ethyl) -phenyl] -thioureido} -phenyl) -amide

368 Furan-2-carboxylic acid {4- [3- (3-methoxy-phenyl) -thioureido] -phenyl} -amide

354 Furan-2-carboxylic acid {4- [3- (3-hydroxy-phenyl) -thioureido] -phenyl) -amide

382 2-Fluoro-N- {4- [3- (3-hydroxy-phenyl) -thioureido) -phenyl] -benzamide

396 2-Fluoro-N- {4- [3- (3-hydroxymethyl-phenyl) -thioureido) -phenyl] -benzamide

423 N- {4- [3- (3-Acetylaminophenyl) thioureido] phenyl} -

-2-fluorobenzamide

413 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (3-acetylaminophenyl) thioureido] phenyl} amide

400 (4- [3- (3-Dimethylaminophenyl) thioureido] phenyl] amide [1,2,3] thiadiazole-4-carboxylic acid

340 Furan-2-carboxylic acid [4- (3-pyrimidin-4-ylthioureido) phenyl] amide furan-2-carboxylic acid {4- [3- (1H-Indazol-5-yl) thioureido] phenyl} amide

395 Furan-2- [4- (3-Benzothiazol-5-yl-thioureido) phenyl] amide

-carboxylic acids

06 2-Fluoro-N- {4- [3- (1H-indazol-5-yl) -thioureido] -phenyl} -benzamide

424 N- [4- (3-Benzothiazol-5-yl-thioureido) -phenyl] -2-

-fluorobenzamide

473 5- (3- {4 - [([1,2,3] Thiadiazole-4-carbonyl) amino] phenyl} thioureido) isophthalic acid dimethyl ester

442 Furan-2-carboxylic acid 4- (3- [4- (1-azidoethyl) -3-chlorophenyl] thioureido} phenyl) amide

396 2-Fluoro-N- {4- [3- (3-methoxy-phenyl) -thioureido] -phenyl} -benzamide

368 Furan-2-carboxylic acid {4- [3- (3-hydroxymethyl-phenyl) -thioureido] -phenyl] -amide

416 Furan-2-carboxylic acid {4- [3- (5-chloro-2-dimethylaminophenyl) thioureido] phenyl] amide

130

490 444 N- {4- [3- (5-Chloro-2-dimethylamino-phenyl) -thioureido] - phenyl) 2-fluorobenzamide 491 506 tert -Butyl ester [3-chloro-5- (3- {4 - [([1,2,3] thiadiazole-4)] (carbonyl) amino] phenyl) thioureido) phenyl] carbamic acid 492 470 N- (4- {3- [4- (1-Azidoethyl) -3-chlorophenyl] thioureido) phenyl} -2-fluorobenzamide 493 337 Furan-2-carboxylic acid [4-1H-thiazolo [5,4-b] pyridin-2-ylideneamino) -phenyl] -amide 494 378 {4- [3- (1H-Benzoimidazol-5-yl) thioureido] phenyl) amide furan-2-carboxylic acid 495 392 Furan-2-carboxylic acid {4- [3- (2-methyl-1H-benzoimidazol-5-yl) thioureido] phenyl] amide 496 406 N- {4- [3- (1H-Benzoimidazol-5-yl) thioureido] phenyl} -2-fluorobenzamide 497 420 2-Fluoro-N- {4- [3- (2-methyl-1H-benzoimidazol-5-yl) thioureido] phenylbenzamide 498 452 {5- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -pyridine- [1,2,3] Thiadiazole-4-carboxylic acid -2-yl} -amide 499 445 {5- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -pyridine- Pyridine-2-carboxylic acid-2-yl] amide 500 434 {4- [3- (5-Chloro-2-dimethylamino-phenyl) -thioureido] -phenyl) - [1,2,3] thiadiazole-4-carboxylic acid amide 501 484 [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [4- (2-amino-pyrimidin-4-yl) -3-chloro-phenyl] -thioureido) -phenyl} -amide 502 494 N- (4- {3- [4- (2-Aminopyrimidin-4-yl) -3-chlorophenyl] thioureido) phenyl} -2-fluorobenzamide 503 434 {4- [3- (3-Chloro-2-dimethylaminophenyl) thioureido] phenyl] amide [1,2,3] thiadiazole-4-carboxylic acid 504 4 62 N- {4- [3- (3-Chloro-2-dimethylaminophenyl) thioureido] phenyl} -2,6-difluorobenzamide 505 416 Furan-2-carboxylic acid {4- [3- (3-chloro-2-dimethylaminophenyl) thioureido] phenyl] amide 506 445 {6- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -pyridine- Pyridine-2-carboxylic acid-3-yl) amide 507 4 62 N- {6- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -pyridin-3-yl} -2-fluoro-benzamide 508 482 1,2- [1,2,3] - {4- [3- (3-Iodo-phenyl) -thioureido] -phenyl} -amide thiadiazole-4-carboxylic acids

131

509 413 {4- [3- (3-tert-Butylphenyl) thioureido] phenyl] amide [1,2,3] thiadiazole-4-carboxylic acid 510 387 Furan-2- {4- [3- (3-Chloro-benzyl) -thioureido] -phenyl) -amide -carboxylic acids 511 415 N- {4- [3- (3-Chlorobenzyl) thioureido] phenyl} -2-fluorobenzamide 512 434 (6- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -pyridine- 3-yl) furan-2-carboxylic acid amide 513 435 (4- [3- (3-Bromo-phenyl) -thioureido] -phenyl) -amide [1,2,3] thiadiazole-4-carboxylic acid 514 452 (6- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -pyridine- [1,2,3] Thiadiazole-4-carboxylic acid -3-yl} -amide 515 426 (5- [3- (3,5-Dichloro-phenyl) -thioureido] -pyridin-2-yl} -amide [1,2,3] thiadiazole-4-carboxylic acid 516 474 Furan-2-carboxylic acid (4- (3- (3,5-Bistrifluoromethyl-phenyl) -thioureido] -phenyl) -amide 517 502 N- {4- [3- (3,5-Bistrifluoromethylphenyl) thioureido] phenyl} -2-fluorobenzamide 518 450 N- {4- [3- (4-Amino-3,5-dichloro-phenyl) -thioureido] - phenyl) -2-fluorobenzamide 519 539 N- {4- [3- (4-Amino-3,5-dibromophenyl) thioureido] phenyl} -2-fluorobenzamide 520 392 (4- (3- (5-Chloropyridin-3-yl) thioureido) phenyl} amide [1,2,3] thiadiazole-4-carboxylic acid 521 529 (4- (3- (4-Amino-3,5-dibromophenyl) thioureido) phenyl} amide [1,2,3] thiadiazole-4-carboxylic acid 522 434 (4- (3- (3-Chloro-5-dimethylaminophenyl) thioureido) phenyl) - [1,2,3] thiadiazole-4-carboxylic acid amide 523 444 N- {4- [3- (3-Chloro-5-dimethylaminophenyl) thioureido] phenyl} -2-fluorobenzamide 524 416 {4- [3- (3-Chloro-5-dimethylaminophenyl) thioureido] phenyl} - furan-2-carboxylic acid amide 525 436 {4- [3- (5-Bromo-pyridin-3-yl) -thioureido] -phenyl] -amide [1,2,3] thiadiazole-4-carboxylic acid 526 379 {4- [3- (1H-Benzotriazol-5-yl) -thioureido] -phenyl) -amide furan-2-carboxylic acid 527 425 N- {4- [3- (1H-Benzotriazol-5-yl) -thioureido] -phenyl} - -2,6-difluorobenzamide 528 388 . N- [4 - ({[2- (3-Chlorophenyl) hydrazino] thioxomethyl} amino) phenyl] furan-2-carboxamide

132 • ·

416 Ν- [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 1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (2-Amino-3-chloro-5-trifluoromethyl-phenyl) -thioureido] -phenyl) -amide

[1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (3-piperidin-1-yl-5-trifluoromethyl-phenyl) -thioureido] -phenyl} -amide

380 N- [4- (3-Benzylthioureido) phenyl] -2-fluorobenzamide

439 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (3,4-dichloro-benzyl) -thioureido] -phenyl} -amide

449 N- {4- [3- (3,4-Dichlorobenzyl) thioureido] phenyl} -2-fluorobenzamide

[1,2,3] Thiadiazole-4-carboxylic acid [4- (3-benzylthioureido) phenyl] amide

424 N- [4- (3-Benzo [1,3] dioxol-5-ylmethylthioureido) phenyl] -2-fluorobenzamide

[1,2,3] Thiadiazole-4-carboxylic acid [4- (3-benzo [1,3] dioxol-5-ylmethylthioureido) phenyl] amide

506 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (3,5-Bistrifluoromethyl-benzyl) -thioureido] -phenyl) -amide

516 N- {4- (3- (3,5-Bistrifluoromethylbenzyl) thioureido] phenyl} -2-fluorobenzamide

352 Furan-2-carboxylic acid [4- (3-benzylthioureido) phenyl] amide

421 Furan-2-carboxylic acid (4- [3- (3,4-dichloro-benzyl) -thioureido] -phenyl) -amide

396 Furan-2-carboxylic acid [4- (3-benzo [1,3] dioxol-5-ylmethyl-thioureido) -phenyl] -amide

488 Furan-2-carboxylic acid 4- (3- (3,5-bistrifluoromethyl-benzyl) -thioureido] -phenyl} -amide

503 {4- [3- (4-Bromo-3-trifluoromethyl-phenyl) -thioureido] -phenyl} 133

[1,2,3] thiadiazole-4-carboxylic acid amide 549 529 N- {4- [3- (3-Bromo-4-trifluoromethoxyphenyl) thioureido] phenyl} -2-fluorobenzamide 550 519 {4- [3- (3-Bromo-4-trifluoromethoxyphenyl) thioureido] phenyl] amide [1,2,3] thiadiazole-4-carboxylic acid 551 473 Furan-2-carboxylic acid {4- [3- (3-chloro-4-trifluoromethylsulfanyl-phenyl) -thioureido] -phenyl} -amide 552 412 2-Fluoro-N- (4- {3- [2- (3-fluorophenyl) ethyl] thioureido} phenyl) benzamide 553 412 2-Fluoro-N- (4- {3- [2- (4-fluorophenyl) ethyl] thioureido) phenyl} benzamide 554 402 (4- {3- [2- (3-Fluorophenyl) ethyl] thioureido] phenyl) amide [1,2,3] thiadiazole-4-carboxylic acid 555 402 (4- (3- (2- (4-Fluorophenyl) ethyl) thioureido] phenyl) amide [1,2,3] thiadiazole-4-carboxylic acid 556 495 [1,2,3] Thiadiazole-4-carboxylic acid (4- (3- (3- (2-methylbutyl) -5-trifluoromethylphenyl) thioureido} phenyl) amide 557 481 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (3-isobutyl-5-trifluoromethyl-phenyl) -thioureido] -phenyl] -amide 558 523 [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [3- (4-methyl-piperazin-1-yl) -5-trifluoromethyl-phenyl] -thioureido] -phenyl) -amide 559 510 [1,2,3] Thiadiazole-4-carboxylic acid (4- [3- (3-morpholin-4-yl-5-trifluoromethyl-phenyl) -thioureido] -phenyl} -amide 560 494 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (3-pyrrolidin-1-yl-5-trifluoromethyl-phenyl) -thioureido] -phenyl} -amide 561 384 Furan-2-carboxylic acid (4- (3- (2- (4-fluorophenyl) ethyl) thioureido) phenyl) amide 562 419 (4- (3- (2- (3-Chlorophenyl) ethyl) thioureido] phenyl) amide [1,2,3] thiadiazole-4-carboxylic acid 563 429 N- (4- {3- [2- (3-Chloro-phenyl) -ethyl] -thioureido) - phenyl) -2-fluorobenzamide 564 401 (4- (3- (2- (3-Chlorophenyl) ethyl) thioureido} phenyl) amide furan-2-carboxylic acid 565 402 (4- {3- [1- (4-Fluorophenyl) ethyl] thioureido) phenyl} amide [1,2,3] thiadiazole-4-carboxylic acid 566 504 2-Fluoro-N- {4- [3- (3-pyrrolidin-1-yl) -5-trifluoromethyl-

• ·

134

phenyl) thioureido] phenyl} benzamide 567 477 N- {4- [3- (3-Dimethylamino-5-trifluoromethyl-phenyl) -thioureido] -phenyl} -2-fluoro-benzamide 568 520 2-Fluoro-N- {4- [3- (3-morpholin-4-yl-5-trifluoromethyl-phenyl) -thioureido] -phenyl} -benzamide 569 533 2-Fluoro-N- (4- {3- [3- (4-methylpiperazin-1-yl) -5-trifluoromethylphenyl] thioureido) phenyl} benzamide 570 518 2-Fluoro-N- (4- [3- (3-piperidin-1-yl-5-trifluoromethylphenyl) thioureido] phenyl) benzamide 571 468 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (3-dimethylamino-5-trifluoromethyl-phenyl) -thioureido] -phenyl} -amide 572 405 {4- [3- (3-Chloro-benzyl) -thioureido] -phenyl) -amide [1,2,3] thiadiazole-4-carboxylic acid 573 384 (4- {3- [2- (3-Fluorophenyl) ethyl] thioureido} phenyl) amide furan-2-carboxylic acid 574 366 Furan-2- [4- (3-Phenethylthioureido) phenyl] amide -carboxylic acids 575 384 [1,2,3] Thiadiazole- [4- (3-Phenethylthioureido) phenyl] amide -4-carboxylic acids 576 394 2-Fluoro-N- [4- (3-phenethylthioureido) phenyl] benzamide 577 505 2-Fluoro-N- (4- {3- [3- (2-methylbutyl) -5-trifluoromethylphenyl] thioureido) phenyl} benzamide 578 491 2-Fluoro-N- {4- [3- (3,5-difluorobenzyl) thioureido] phenyl) benzamide 579 388 Furan- {4- (3- (3,5-Difluorobenzyl) thioureido] phenyl) amide -2-carboxylic acids 580 416 N- {4- [3- (3,5-Difluoro-benzyl) -thioureido] -phenyl} - -2-fluorobenzamide 581 406 {4- [3- (3,5-Difluorobenzyl) thioureido] phenyl} amide [1,2,3] thiadiazole-4-carboxylic acid 582 421 (4- (3- (3,5-Dichlorobenzyl) thioureido) phenyl) amide furan- -2-carboxylic acids 583 449 N- (4- (3- (3,5-Dichlorobenzyl) thioureido] phenyl) -2-fluorobenzamide 584 439 (4- (3- (3,5-Dichlorobenzyl) thioureido] phenyl) amide [1,2,3] thiadiazole-4-carboxylic acid 585 438 {4- [3- (3-Fluoro-5-trifluoromethyl-benzyl) -thioureido] - phenyl) furan-2-carboxylic acid amide 586 466 2-Fluoro-N- {4- [3- (3-fluoro-5-trifluoromethylbenzyl) -

135 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- (Isobutyl-methylamino) -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

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 (4- (3- (2- (4-Aminophenyl) ethyl) thioureido] phenyl) amide

X

136 furan-2-carboxylic acid

445 Furan-2-carboxylic acid 4- {3- [2- (4-bromophenyl) ethyl] thioureido} phenyl) amide

380 Furan-2-carboxylic acid {4- [3- (2-p-tolyl-ethyl) -thioureido] -phenyl] -amide

463 [1,2,3] Thiadiazole-4-carboxylic acid (4- (3- (2- (4-bromophenyl) ethyl) thioureido] phenyl) amide

396 Furan-2-carboxylic acid 4- (3- (2- (3-methoxyphenyl) ethyl] thioureido) phenyl) amide

403 (4- [3- (1-tert-Butyl-1H-imidazol-2-yl) thioureido] phenyl] amide [1,2,3] thiadiazole-4-carboxylic acid

384 Furan-2-carboxylic acid 4- (3- (1-tert-butyl-1H-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-2-carboxylic acid 4- [3- (3-phenylpropyl) thioureido] phenyl) amide

[1,2,3] Thiadiazole-4-carboxylic acid [4- (3- (3-phenylpropyl) thioureido] phenyl} amide

502 Furan-2-carboxylic acid 4- (3- (2- (3,5-Bistrifluoromethyl-phenyl) -ethyl] -thioureido) -phenyl) -amide

[1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (4-iodo-3-trifluoromethyl-phenyl) -thioureido] -phenyl] -amide

532 2-Fluoro-N- {4- [3- (4-piperidin-1-yl-3-trifluoromethyl-benzyl) -thioureido] -phenyl} -benzamide

537 [1,2,3] Thiadiazole-4-carboxylic acid 4- (3- (4- (4-methylpiperazin-1-yl) -3-trifluoromethylbenzyl] thioureido) phenyl) amide

482 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (3-dimethylamino-5-trifluoromethyl-benzyl) -thioureido] -phenyl} -amide

488 Furan-2-carboxylic acid (4- (3- (3,5-Bistrifluoromethyl-phenyl) -thioureidomethyl) -phenyl) -amide

421 Furan-2-carboxylic acid 4- (3- (3,5-dichlorophenyl) thioureidomethyl] phenyl} amide

421 Furan-2-carboxylic acid (4- (3- (3,4-dichlorophenyl) thioureidomethyl) phenyl) amide

455 {4- (3- (4-Chloro-3-trifluoromethyl-phenyl) -thioureido) · · · ·

137 ··· ················

furan-2-carboxylic acid methyl] phenyl} amide 623 466 2-Fluoro-N- {4- [3- (4-fluoro-3-trifluoromethylbenzylthioureido) phenyl} benzamide 624 456 {4- [3- (4-Fluoro-3-trifluoromethylbenzyl) thioureido] phenyl] amide [1,2,3] thiadiazole-4-carboxylic acid 625 410 2-Fluoro-N- {4- [3- (2-phenoxyethyl) thioureido] phenyl} benzamide 626 382 Furan-2- {4- [3- (2-Phenoxyethyl) thioureido] phenyl] amide -carboxylic acids 627 400 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (2-phenoxyethyl) thioureido] phenyl} amide 628 409 2-Fluoro-N- {4- [3- (3-phenylpropyl) thioureido] phenyl} benzamide 629 425 {4- [3- (5-Trifluoromethyl-pyridin-3-yl) -thioureido] -phenyl] -amide [1,2,3] thiadiazole-4-carboxylic acid 630 439 {4- (3- (3,4-Dichlorophenyl) thioureidomethyl] phenyl} amide [1,2,3] thiadiazole-4-carboxylic acid 631 473 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (4-chloro-trifluoromethyl-benzyl) -phenyl] -thioureidomethyl-phenyl} -amide 632 381 2-Fluoro-N- [4- (3-pyridin-3-ylmethylthioureido) phenyl] - benzamide 633 353 Furan-2- [4- (3-Pyridin-3-ylmethyl-thioureido) -phenyl] -amide -carboxylic acids 634 371 [4- (3-Pyridin-3-ylmethyl-thioureido) -phenyl] -amide [1,2,3] thiadiazole-4-carboxylic acid 635 439 {4- [3- (3,5-Dichloro-phenyl) -thioureidomethyl] -phenyl) -amide [1,2,3] thiadiazole-4-carboxylic acid 636 492 N- {4- [3- (3-Dimethylamino-5-trifluoromethylbenzyl) thioureido] phenyl} -2-fluorobenzamide 637 415 (4- {3- [2- (3-Methoxy-phenyl) -ethyl] -thioureido} -phenyl) -amide [1,2,3] thiadiazole-4-carboxylic acid 638 399 {4- [3- (2-p-Tolylethyl) thioureido] phenyl} amide [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-trifluoromethylphenyl) thioureidomethyl) - [1,2,3] thiadiazole-4-carboxylic acid phenyl iamide 641 516 N- {4- [3- (3,5-Bis-trifluoromethyl-phenyl) -thioureidomethyl] -phenyl} -2-fluoro-benzamide 642 449 N- {4- [3- (3,5-Dichloro-phenyl) -thioureidomethyl] -

138

···················

phenyl} -2-fluorobenzamide 643 449 N- {4- [3,4-Dichlorophenyl) thioureidomethyl] methyl- -2-fluorobenzamide 644 448 {4- [3- (3-Acetylamino-5-chloro-phenyl) -thioureido] -phenyl} - [1,2,3] thiadiazole-4-carboxylic acid amide 645 453 (4- {3- [2- (3,4-Dichloro-phenyl) -ethyl] -thioureido] -phenyl) - [1,2,3] thiadiazole-4-carboxylic acid amide 646 413 {4- [3- (1-Methyl-3-phenylpropyl) thioureido] phenyl] amide [1,2,3] thiadiazole-4-carboxylic acid 647 463 (4- {3- [1- (4-Bromo-phenyl) -ethyl] -thioureido] -phenyl) -amide [1,2,3] thiadiazole-4-carboxylic acid 648 413 {4- [3- (4-Phenylbutyl) thioureido] phenyl] amide [1,2,3] thiadiazole-4-carboxylic acid 649 397 [4- (3-Indan-1-yl-thioureido) -phenyl] -amide [1,2,3] thiadiazole-4-carboxylic acid 650 400 {4- [3- (2-Methoxybenzyl) thioureido] phenyl] amide [1,2,3] thiadiazole-4-carboxylic acid 651 415 (4- {3- [2- (2-Methoxy-phenyl) -ethyl] -thioureido} -phenyl) -amide [1,2,3] thiadiazole-4-carboxylic acid 652 415 (4- {3- [2- (4-Methoxy-phenyl) -ethyl] -thioureido) -phenyl) -amide [1,2,3] thiadiazole-4-carboxylic acid 653 506 N- (4- {3- [2- (3-Dimethylamino-5-trifluoromethylphenyl) ethyl] thioureido] phenyl) -2-fluorobenzamide 654 510 [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [3- (3-dimethylaminopropyl) -5-trifluoromethylphenyl] thioureido) phenyl} amide 655 417 {4- [3- (2-Phenylsulfanylethyl) thioureido] phenyl} amide [1,2,3] thiadiazole-4-carboxylic acid 656 427 2-Fluoro-N- {4- [3- (2-phenylsulfanylethyl) thioureido] phenyl} benzamide 657 399 {4- [3- (2-Phenylsulfanylethyl) thioureido] phenyl} amide furan-2-carboxylic acid 658 381 2-Fluoro-N- [4- (3-pyridin-4-ylmethylthioureido) phenyl] - benzamide 659 353 Furan-2- [4- (3-Pyridin-4-ylmethyl-thioureido) -phenyl] -amide -carboxylic acids 660 371 [4- (3-Pyridin-4-ylmethyl-thioureido) -phenyl] -amide [1,2,3] thiadiazole-4-carboxylic acid 661 506 2-Fluoro-N- {4- [3- (3-iodo-benzyl) -thioureido] -phenyl} -

• * · ·

139

benzamide 662 478 Furan-2- {4- [3- (3-Iodo-benzyl) -thioureido] -phenyl) -amide -carboxylic acids 663 496 {4- [3- (3-Iodo-benzyl) -thioureido] -phenyl} -amide [1,2,3] thiadiazole-4-carboxylic acid 664 479 N- (4- (3- [2- (3,5-Dichlorophenoxy) ethyl] thioureido) phenyl) -2-fluorobenzamide 665 451 Furan-2-carboxylic acid (4- {3- [2- (3,5-Dichloro-phenoxy) -ethyl] -thioureido) -phenyl} -amide 666 445 N- (4- {3- [2- (3-Chloro-phenoxy) -ethyl] -thioureido] -phenyl) - -2-fluorobenzamide 667 417 (4- {3- [2- (3-Chloro-phenoxy) -ethyl] -thioureido] -phenyl) -amide furan-2-carboxylic acid 668 435 (4- {3- [2- (3-Chloro-phenoxy) -ethyl] -thioureido} -phenyl) -amide [1,2,3] thiadiazole-4-carboxylic acid 669 466 2-Fluoro-N- {4- [3- (2-fluoro-5-trifluoromethylbenzyl) thioureido] phenyl} benzamide 670 438 Furan-2-carboxylic acid {4- [3- (2-fluoro-5-trifluoromethyl-benzyl) -thioureido] -phenyl] -amide 671 456 {4- [3- (2-Fluoro-5-trifluoromethylbenzyl) thioureido] phenyl] amide [1,2,3] thiadiazole-4-carboxylic acid 672 416 N- {4- [3- (3,4-Difluoro-benzyl) -thioureido] -phenyl} - -2-fluorobenzamide 673 452 N- (4- {3- [2- (4-Dimethylamino-3-methylphenyl) ethyl] thioureido] phenyl) -2-fluorobenzamide 674 496 [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [2- (3-Dimethylamino-5-trifluoromethyl-phenyl) -ethyl] -thioureido] -phenyl) -amide 675 388 Furan- {4- [3- (3,4-Difluorobenzyl) thioureido] phenyl] amide -2-carboxylic acids 676 406 {4- [3- (3,4-Difluorobenzyl) thioureido] phenyl) amide [1,2,3] thiadiazole-4-carboxylic acid 677 433 N- {4- [3- (3-Chloro-4-fluorobenzyl) thioureido] phenyl} -2-fluorobenzamide 678 495 (4- {3- [2- (3-Bromo-phenylsulfanyl) -ethyl] -thioureido} -phenyl) -amide [1,2,3] thiadiazole-4-carboxylic acid 679 477 Furan-2-carboxylic acid (4- {3- [2- (3-Bromo-phenylsulfanyl) -ethyl] -thioureido) -phenyl} -amide 680 505 N- (4- {3- [2- (3-Bromophenylsulfanyl) ethyl] thioureido) phenyl) -2-fluorobenzamide

· · · · · • · · • · · · · · · · · · · • • • · ·· ··

140

681 493 (4- {3- [2- (3-Bromo-4-methoxy-phenyl) -ethyl] -thioureido} -phenyl) -amide [1,2,3] thiadiazole-4-carboxylic acid 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-1-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-Dimethylbenzyl) thioureido) phenyl} amide [1,2,3] thiadiazole-4-carboxylic acid 692 442 [1,2,3] Thiadiazole-4-carboxylic acid (4- (3- (2- (4-Dimethylamino-3-methylphenyl) ethyl) thioureido) phenyl) amide 693 479 (4- (3- (2- (4-Bromophenoxy) ethyl) thioureido} phenyl) amide [1,2,3] thiadiazole-4-carboxylic acid 694 526 (4- (3- (2- (4-Iodophenoxy) ethyl) thioureido) phenyl) amide [1,2,3] thiadiazole-4-carboxylic acid 695 489 N- {4- {3- [2- (4-Bromophenoxy) ethyl] thioureido) phenyl} -2-fluorobenzamide 696 536 2-Fluoro-N- (4- (3- (2- (4-iodophenoxy) ethyl) thioureido) phenyl) benzamide 697 461 (4- (3- (2- (4-Bromophenoxy) ethyl) thioureido} phenyl) amide furan-2-carboxylic acid 698 508 Furan-2-carboxylic acid (4- {3- [2- (4-iodophenoxy) ethyl] thioureido) phenyl) amide 699 408 Oxazole- (4- (3- (3,4-Dichlorophenyl) thioureido] phenyl) amide 4-carboxylic acids

141

424 Thiazole-4-carboxylic acid {4- (3- (3,5-dichlorophenyl) thioureido] phenyl} amide

491 Thiazole-4-carboxylic acid 4- (3- (3,5-bistrifluoromethyl-phenyl) -thioureido] -phenyl} -amide

408 Oxazole- {4- [3- (3,5-Dichloro-phenyl) -thioureido] -phenyl] -amide

-4-carboxylic acids

469 [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [2- (3,4-Dichloro-phenoxy) -ethyl] -thioureido] -phenyl) -amide

424 Thiazole-4-carboxylic acid (4- (3- (3,4-dichlorophenyl) thioureido) phenyl] amide

458 Thiazole-4-carboxylic acid {4- [3- (4-chloro-3-trifluoromethyl-phenyl) -thioureido] -phenyl] -amide

400 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (2-phenylamino-ethyl) -thioureido] -phenyl} -amide

453 [1,2,3] Thiadiazole-4-carboxylic acid (4- (3- (2- (2,4-Dichloro-phenyl) -ethyl] -thioureido) -phenyl) -amide

[1,2,3] Thiadiazole-4-carboxylic acid [4- (3- (2- (3-trifluoromethyl-phenyl) -ethyl] -thioureido] -phenyl) -amide

453 [1,2,3] Thiadiazole-4-carboxylic acid (4- (3- (2- (2,6-Dichlorophenyl) ethyl) thioureido] phenyl) amide

485 [1,2,3] Thiadiazole-4-carboxylic acid (4- (3- (2- (3,4-Dichloro-phenylsulfanyl) -ethyl) -thioureido] -phenyl) -amide

503 [1,2,3] Thiadiazole-4-carboxylic acid 4- {3- [2- (2-fluoro-5-trifluoromethyl-phenylsulfanyl) -ethyl] -thioureido] -phenyl) -amide

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

413 [1,2,3] Thiadiazole-4-carboxylic acid 4- (3- [2- (4-ethyl-phenyl) -ethyl] -thioureido} -phenyl) -amide

442 Oxazole-4-carboxylic acid {4- [3- (4-chloro-3-trifluoromethyl-phenyl) -thioureido] -phenyl) -amide

475 Oxazole-4-carboxylic acid 4- (3- (3,5-bistrifluoromethyl-phenyl) -thioureido] -phenyl} -amide

420 [1,2,3] Thiadiazole-4-carboxylic acid 4- [3- [2- (3,4-difluorophenyl) ethyl] thioureido} phenyl) amide

452 [1,2,3] Thiadiazole-4-carboxylic acid 4- (3- [2- (4-Trifluoromethyl-phenyl) -ethyl] -thioureido} -phenyl) -amide

435 'Furan-2-carboxylic acid (4- [3- [2- (3,4-dichlorophenyl) ethyl] thioureido] phenyl) amide

142 • · · · ··· ·· ·· ·· ·· ·

463 N- (4- (3- (2- (3,4-Dichlorophenyl) ethyl) thioureido} phenyl) -2-fluorobenzamide

420 [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [2- (3,5-difluorophenyl) ethyl] thioureido] phenyl) amide

412 2-Fluoro-N- (4- {3- [2- (2-fluorophenyl) ethyl] thioureido} phenyl) benzamide

429 [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [2- (4-nitrophenyl) ethyl] thioureido] phenyl) amide

[1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (1-methyl-2-phenylethyl) thioureido] phenyl} amide

437 N- {4- [3- (4-tert-Butylbenzyl) thioureido] phenyl} -2-

-fluorobenzamide

409 N- {4- (3- (3,5-Dimethylbenzyl) thioureido] phenyl) -2-fluorobenzamide

400 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (2-hydroxy-1-phenylethyl) thioureido] phenyl} amide

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-fluoro-benzyl) -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-fluorobenzyl) thioureido] phenyl) amide

435 [1,2,3] Thiadiazole-4-carboxylic acid (4- (3- (2- (2-chloro-phenoxy) -ethyl] -thioureido) -phenyl) -amide

[1,2,3] Thiadiazole-4-carboxylic acid (4- (3- (2- (3-bromophenoxy) ethyl) thioureido} phenyl) amide

418 [1,2,3] Thiadiazole-4-carboxylic acid (4- (3- (2- (2-fluorophenoxy) ethyl) thioureido} phenyl) amide

418 [1,2,3] Thiadiazole-4-carboxylic acid (4- (3- [2- (3-fluorophenoxy) ethyl] thioureido) phenyl) amide

486 [1,2,3] Thiadiazole-4-carboxylic acid (4- (3- (2- (2-Fluoro-5-trifluoromethyl-phenoxy) -ethyl] -thioureido) -phenyl) -amide

143

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-bromophenyl) thioureido] phenyl] amide

374 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (4-fluoro-phenyl) -thioureido] -phenyl} -amide

388 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (4-fluoro-benzyl) -thioureido] -phenyl) -amide

405 [1,2,3] Thiadiazole-4-carboxylic acid (4- [3- (4-chloro-benzyl) -thioureido] -phenyl} -amide

449 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (4-bromobenzyl) thioureido] phenyl] amide

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 {4- [3- (2-Fluorophenyl) thioureido] phenyl] amide [1,2,3] thiadiazole-4-carboxylic acid

374 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (3-fluoro-phenyl) -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-fluoro-phenyl) -ethyl] -thioureidophenyl) -benzamide

429 4-Chloro-N- {4- {3- [1- (4-fluoro-phenyl) -ethyl] -thioureido} -phenyl) -benzamide

453 ´ 4- (4- (3- [1- (4-Fluorophenyl) ethyl] thioureido} phenylcarbamoyl) phenyl acetic acid ester

144

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

429 3-Chloro-N- (4- {3- [1- (4-fluoro-phenyl) -ethyl] -thioureido} -phenyl) -benzamide

[1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [2- (3-fluoro-5-trifluoromethyl-phenyl) -ethyl] -thioureido] -phenyl) -amide

[1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [2- (2,4-Bistrifluoromethyl-phenyl) -ethyl] -thioureido] -phenyl) -amide

[1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [2- (4-fluoro-3-trifluoromethyl-phenyl) -ethyl] -thioureido) -phenyl} -amide

438 4-Dimethylamino-N- (4- {3- [1- (4-fluorophenyl) ethyl] thioureido] phenylbenzamide

[1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [2- (2-fluoro-3-trifluoromethyl-phenyl) -ethyl] -thioureido} -phenyl) -amide

[1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [2- (2-fluoro-5-trifluoromethyl-phenyl) -ethyl] -thioureido) -phenyl} -amide

510 [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [2- (3-iodo-phenyl) -ethyl] -thioureido] -phenyl) -amide

[1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [2- (4-fluoro-2-trifluoromethyl-phenyl) -ethyl] -thioureido) -phenyl} -amide

463 [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [2- (3-bromo-phenyl) -ethyl] -thioureido} -phenyl) -amide

427 2-Fluoro-N- (4- {3- [1- (4-fluorophenyl) propyl] thioureido} phenyl) benzamide

475 2-Fluoro-N- (4- {3 - [(4-fluorophenyl) phenylmethyl] thioureido} phenyl) benzamide

455 2-Fluoro-N- (4- {3- [1- (4-fluorophenyl) pentyl] thioureido} phenyl) benzamide

489. 2-Fluoro-N- (4- {3- [1- (4-fluorophenyl) -2-phenylethyl] thioureido} phenyl) benzamide

145

409 2-Fluoro-N- {4- [3- (1-o-tolylethyl) thioureido] phenyl} benzamide

409 2-Fluoro-N- {4- [3- (1-m-tolylethyl) thioureido] phenyl} benzamide

425 2-Fluoro-N- (4- {3- [1- (4-methoxyphenyl) ethyl] thioureido} phenyl) benzamide

412 2-Fluoro-N- (4- (3- (1- (2-fluorophenyl) ethyl) thioureido] phenyl) benzamide

429 N- (4- (3- (1- (3-Chlorophenyl) ethyl) thioureido} phenyl) -2-fluorobenzamide

473 N- (4- {3- (1- (3-Bromophenyl) ethyl] thioureido] phenyl) -2-fluorobenzamide

429 N- (4- (3- [1- (4-Chlorophenyl) ethyl) thioureido) phenyl) -2-fluorobenzamide

409 2-Fluoro-N- {4- [3- (1-p-tolylethyl) thioureido] phenyl} benzamide

473 N- (4- (3- (1- (2-Bromophenyl) ethyl) thioureido} phenyl) -2-fluorobenzamide

429 N- (4- (3- (1- (2-Chlorophenyl) ethyl) thioureido) phenyl) -2-fluorobenzamide

462 2-Fluoro-N- (4- (3- (1- (2-trifluoromethylphenyl) ethyl) thioureido] phenyl) benzamide

462 2-Fluoro-N- (4- (3- (1- (3-trifluoromethylphenyl) ethyl) thioureido} phenyl) benzamide

462 2-Fluoro-N- (4- (3- (1- (4-trifluoromethylphenyl) ethyl) thioureido} phenyl) benzamide

425 2-Fluoro-N- (4- (3- [1- (2-methoxyphenyl) ethyl] thioureido} phenyl) benzamide

425 2-Fluoro-N- {4- {3- [1- (3-methoxy-phenyl) -ethyl] -thioureido} -phenyl) -benzamide

441 2-Fluoro-N- (4- (3- (1- (4-fluorophenyl) -2-methylpropyl) thioureido} phenyl) benzamide

419 N- (4- (3- (1- (3-Cyanophenyl) ethyl) thioureido} phenyl) -2-fluorobenzamide

419 N- (4- (3- (1- (4-Cyanophenyl) ethyl) thioureido} phenyl) -2-fluorobenzamide

438 N- (4- {3- [1- (4-Dimethylaminophenyl) ethyl] thioureido} phenyl) -2-fluorobenzamide

438 N- (4- {3- [1- (3-Dimethylaminophenyl) ethyl] thioureido} phenyl) -2-fluorobenzamide

473 2-Bromo-N- (4- {3- [1- (4-fluorophenyl) ethyl] thioureido} N

146 • ·

phenyl) benzamide

446 Quinoline-2-carboxylic acid (4- {3- [1- (4-fluorophenyl) ethyl] thioureido] phenyl) amide

410 2-Fluoro-N- {4- [3- (2-hydroxy-1-phenylethyl) thioureido] phenyl] benzamide

332 2-Fluoro-N- [4- (3-isopropylthioureido) phenyl] benzamide

445 2-Fluoro-N- {4- [3- (1-naphthalen-2-ylethyl) thioureido] phenyl} benzamide

412 3-Fluoro-N- (4- {3- [1- (4-fluorophenyl) ethyl] thioureido] phenyl) benzamide

412 4-Fluoro-N- (4- {3- [1- (4-fluorophenyl) ethyl] thioureido) phenyl} benzamide

384 2-Fluoro-N- {4- [3- (1-furan-2-ylethyl) thioureido] phenyl} benzamide

395 2-Fluoro-N- {4- [3- (1-pyridin-4-ylethyl) thioureido] phenyl} benzamide

397 2-Fluoro-N- (4- (3- (1- (1-methyl-1H-pyrrol-2-yl) ethyl) thioureido} phenyl) benzamide

401 2-Fluoro-N- {4- [3- (1-thiophen-3-yl-ethyl) -thioureido] -phenyl} -benzamide

445 N- {4- [3- (3-Chloro-4-ethoxy-phenyl) -thioureido] -phenyl) -2-fluoro-benzamide

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

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

473 N- {4- [3- (4-Butoxy-3-chloro-phenyl) -thioureido] -phenyl} -2-fluoro-benzamide

522 2-Fluoro-N- {4- [3- (3-iodo-4-methoxy-phenyl) -thioureido] -phenyl} -benzamide

475 N- (4- (3- (3-Bromo-4-methoxyphenyl) thioureido) phenyl} -2-fluorobenzamide

520 N- (4- (3- (1- (4-Fluorophenyl) ethyl) thioureido) phenyl) -2-

-benzamide

346 N- (4- (3- (1- (4-Fluorophenyl) ethyl) thioureido] phenyl) propionamide

286 N- [4- (3-Phenylthioureido) phenyl] acetamide

507 N- [5 - ((((3,5-Bis (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 · · · · · · · · ·

147

-carboxamide

817

818

819

820

821

822

823

824

825

826

827

828

829

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) carbothioyl] 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] amino) carbonyl] amino} -2-pyridinyl) -1,3-thiazole-4

-carboxamide

463

463

452

486

436

436

434

426

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

Example 830

Method 32 [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.

148 ·····················

[1,2,3] Thiadiazole-4-carboxylic acid (4-aminophenyl) amide (0.22 g) was added to the reaction flask and the mixture was 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 appropriate starting materials, the following compounds were prepared:

Ex. C. M + H COMPOUND NAME 831 321 N- {4- [3- (3-Chloro-phenyl) -thioureido] -phenyl} -acetamide 832 413 N- {4- [3- (3-Chloro-4-methoxy-phenyl) -thioureido] -phenyl} -benzamide 833 443 N- {4- [3- (3-Chloro-4-methoxy-phenyl) -thioureido] -phenyl} -2-methoxy-benzamide 834 443 N- {4- [3- (3-Chloro-4-methoxy-phenyl) -thioureido] -phenyl} -3-methoxy-benzamide 835 443 N- {4- [3- (3-Chloro-4-methoxy-phenyl) -thioureido] -phenyl} - -4-methoxybenzamide 836 * 431 N- {4- [3- (3-Chloro-4-methoxy-phenyl) -thioureido] -phenyl} -4-methoxy-benzamide 837 431 N- {4- [3- (3-Chloro-4-methoxy-phenyl) -thioureido] -phenyl] - -3-fluorobenzamide 838 431 N- {4- [3- (3-Chloro-4-methoxy-phenyl) -thioureido] -phenyl] - -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 Hexanoic acid {4- [3- (5-bromo-2,4-dimethoxyphenyl) thioureido] phenyl} amide 842 505 N- {4- [3- (5-Bromo-2,4-dimethoxy-phenyl) -thioureido] - phenyl} -2-fluorobenzamide 843 477 Furan-2-carboxylic acid {4- [3- (5-bromo-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -amide 844 501 N- {4- [3- (5-Bromo-2,4-dimethoxyphenyl) thioureido] phenyl} -2-methylbenzamide 845 517  N- {4- [3- (5-Bromo-2,4-dimethoxy-phenyl) -thioureido] -

phenyl} -4-methoxybenzamide

149

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

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

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

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

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

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

421 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (3-chloro-4-methoxyphenyl) thioureido] phenyl] amide

424 2- {4- [3- (4-Acetylaminophenyl) thioureido] -2-chloro-5-methoxyphenoxy) acetamide

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

367 N- {4- [3- (3-Chloro-4-methylsulfanyl-phenyl) -thioureido] -phenyl} -acetamide

447 N- [4- (3- {3-Chloro-4- [methyl- (1-methylpiperidin-4-yl) amino] phenyl) thioureido) phenyl] acetamide

426 N- (4- {3- [3-Chloro-4- (methyl-phenylamino) -phenyl] -thioureido} -phenyl) -acetamide

509 N- [4- (3- {4 - [(1-Benzylpyrrolidin-3-yl) methylamino] -3-chlorophenyl} thioureido) phenyl] acetamide

418 N- (4- {3- [3-Chloro-4- (cyclopentylmethylamino) phenyl] thioureido} phenyl) acetamide

433 N- [4- (3- {3-Chloro-4- [methyl- (1-methyl-pyrrolidin-3-yl) -amino] -phenyl} -thioureido) -phenyl] -acetamide

419 Furan-2-carboxylic acid {4- [3- (3-Chloro-4-methylsulfanyl-phenyl) -thioureido] -phenyl] -amide

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

465 N- {4- [3- (3-Chloro-4-methylsulfanyl-phenyl) -thioureido] -phenyl] -2,6-difluorobenzamide

445 N- (4- (3- (5-Chloro-2-methoxy-4-methylphenyl) thioureido) phenyl} -2-fluorobenzamide

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

434 (4- [3- (3-Chloro-4-dimethylaminophenyl) thioureido] phenyl} 150

[1,2,3] thiadiazole-4-carboxylic acid amide

444 N- {4- [3- (3-Chloro-4-dimethylaminophenyl) thioureido] phenyl} -2-fluorobenzamide

517 [1,2,3] Thiadiazole-4-carboxylic acid [4- (3- {3-chloro-4- [methyl- (1-methylpiperidin-4-yl) amino] phenyl] thioureido) phenyl] amide

579 [1,2,3] Thiadiazole-4-carboxylic acid [4- (3- {4 - [(1-Benzylpyrrolidin-3-yl) methylamino] -3-chlorophenyl} thioureido) phenyl] amide

527 N- [4- (3- {3-Chloro-4- [methyl (1-methylpiperidin-4-yl) amino] phenyl} thioureido) phenyl] -2-fluorobenzamide

435 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (5-Chloro-2-methoxy-4-methyl-phenyl) -thioureido] -phenyl-amide

589 N- [4- (3- {4 - [(1-Benzylpyrrolidin-3-yl) methylamino] -3-chlorophenyl} thioureido) phenyl] -2-fluorobenzamide

501 [4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -3-

Furan-2-carboxylic acid-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-phenyl-thioureido) -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] -thioureido} -phenyl) -amide

365 N- (4- {3- [3-Chloro-4- (2-hydroxy-ethyl) -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-hydroxy-ethyl) -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

151

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

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-ylethyl) 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

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

473 N- {4- [3- (3-Chloro-4-isobutoxy-phenylthioureido)] 152

phenyl} -2-fluorobenzamide

414 2-Fluoro-N- {4- [3- (3-fluoro-4-methoxy-phenyl) -thioureido] -phenyl} -benzamide

475 N- (4- {3- [3-Chloro-4- (2-methoxyethoxy) phenyl] thioureido) phenyl} -2-fluorobenzamide

398 2-Fluoro-N- {4- [3- (3-fluoro-4-methyl-phenyl) -thioureido] -phenyl} -benzamide

464 2-Fluoro-N- {4- [3- (4-methoxy-3-trifluoromethyl-phenyl) -thioureido] -phenyl} -benzamide

449 N- {4- [3- (2-Amino-5-trifluoromethyl-phenyl) -thioureido] -phenyl) -2-fluoro-benzamide

459 N- (4- {3- [3- [1- (3-Chloro-4-methoxy-phenyl) -ethyl] -thioureido] -phenyl) -2-fluoro-benzamide

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

435 N- {4- [3- (1-Benzofuran-2-ylethyl) thioureido] phenyl} -2-fluorobenzamide

448 2-Fluoro-N- {4- [3- (4-methyl-3-trifluoromethyl-phenyl) -thioureido] -phenyl} -benzamide

473 (S) -N- (4- {3- [1- (4-Bromophenyl) ethyl] thioureido) phenyl} -2-fluorobenzamide

473 N- (4- {3 - [(1R) -1- (4-Bromophenyl) ethyl] thioureido} phenyl) -2-fluorobenzamide

94 2-Fluoro-N- (4- {3- [2-methoxy-4- (2,2,2-trifluoroethoxy) phenyl] thioureido] phenyl) benzamide

399 N- {4- [3- (2-Amino-5-fluorophenyl) thioureido] phenyl} -2-fluorobenzamide

502 N- (4- {3- [1- (4-Dimethylsulfamoylphenyl) ethyl] thioureido] phenyl) -2-fluorobenzamide

542 2-Fluoro-N- [4- (3- {1- [4- (piperidine-1-sulfonyl) phenyl] ethyl} thioureido) phenyl] benzamide

562 N- (4- {3- [2,4-Bis (2,2,2-trifluoroethoxy) phenyl] thioureido) phenyl} -2-fluorobenzamide

409 2-Fluoro-N- {4- [3 - ((1S) -1-p-tolylethyl) thioureido] phenyl} benzamide

409 2-Fluoro-N- {4- [3 - ((IR) -1-p-tolylethyl) thioureido] phenyl} benzamide

394 2-Fluoro-N- {4- [3 - ((1S) -1-phenylethyl) thioureido] phenyl} benzamide

429. N- (4- {3 - [(1R) -1- (4-Chlorophenyl) ethyl] thioureido} phenyl) -2-fluorobenzamide

153

429 N- (4- {3 - [(1S) -1- (4-Chlorophenyl) ethyl] thioureido) phenyl) -2-fluorobenzamide

394 2-Fluoro-N- {4- [3 - ((IR) -1-phenylethyl) thioureido] phenyl} benzamide

432 N- (4- (3- (1- (4-Cyanophenyl) ethyl) thioureido} phenyl) -2-methoxybenzamide

447 N- {4- [3- (1-Benzofuran-2-yl-ethyl) -thioureido] -phenyl} -

-2-methoxybenzamide

485 N- (4- {3- [1- (4-Bromophenyl) ethyl] thioureido) phenyl} -2-methoxybenzamide

419 3-Cyano-N- (4- (3- (1- (4-fluorophenyl) ethyl) thioureido) phenyl) benzamide

462 N- (4- {3- [1- (4-Fluoro-phenyl) -ethyl] -thioureidophenyl) -4-trifluoromethyl-benzamide

419 4-Cyano-N- (4- {3- [1- (4-fluorophenyl) ethyl] thioureido] phenyl) benzamide

469 2-Fluoro-N- (4- (3- (1- (4-fluorophenyl) ethyl) thioureido) -2,3,5,6-tetramethylphenyl} benzamide

480 N- (4- {3- [1- (4-Cyanophenyl) ethyl] thioureido) -2,5-dimethoxyphenyl) -2-fluorobenzamide

473 2-Fluoro-N- (4- {3- [1- (4-fluorophenyl) ethyl] thioureido} -2,5-dimethoxyphenyl) benzamide

530 N- {3,5-Dichloro-4- [3- (5-chloro-2,4-dimethoxyphenyl) thioureido] phenyl} -2-fluorobenzamide

447 N- (3-Chloro-4- {3- [1- (4-fluoro-phenyl) -ethyl] -thioureido] -phenyl) -2-fluoro-benzamide

480 2,3,4,5-Tetrafluoro-N- (4- (3- (1- (4-fluorophenyl) ethyl) thioureido} -3-methylphenyl) benzamide

462 2,4,5-Trifluoro-N- (4- (3- (1- (4-fluorophenyl) ethyl) thioureido) -3-methylphenyl) benzamide

427 2-Fluoro-N- (4- {3- [1- (4-fluorophenyl) ethyl] thioureido} -

-3-methylphenyl) benzamide

457 2-Fluoro-N- (4- (3- (1- (4-fluorophenyl) ethyl) thioureido} -2-methoxy-5-methylphenyl) benzamide

443 2-Fluoro-N- (4- (3- (1- (4-fluorophenyl) ethyl) thioureido) -3-

(methoxyphenyl) benzamide

570 N- (2,6-Dibromo-4- {3- [1- (4-fluorophenyl) ethyl] thioureido] phenyl) -2-fluorobenzamide

480 2-Fluoro-N- (4- {3- [1- (4-fluorophenyl) ethyl] thioureido] -2-trifluoromethylphenyl) benzamide

541 N- (4- {3- [1- (4-Bromo-phenyl) -ethyl] -thioureido] -2N

154 • · · · · ··· ·· ·· · ·

(trifluoromethylphenyl) -2-fluorobenzamide

1051 487 N- (4- {3- [1- (4-Cyanophenyl) ethyl] thioureido} -2-trifluoromethylphenyl) -2-fluorobenzamide 1052 503 N- {4- [3- (1-Benzofuran-2-ylethyl) thioureido] -2-trifluoromethylphenyl} -2-fluorobenzamide 1053 447 N- (2-Chloro-4- {3- [1- (4-fluoro-phenyl) -ethyl] -thioureido} - phenyl) -2-fluorobenzamide 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-fluorobenzamide 1056 498 N- (4- {3- [1- (4-Bromophenyl) ethyl] thioureido} -2-cyanophenyl) -2-fluorobenzamide 1057 445 N- (2-Cyano-4- {3- [1- (4-cyanophenyl) ethyl] thioureido} - phenyl) -2-fluorobenzamide 1058 460 N- {4- [3- (1-Benzofuran-2-ylethyl) thioureido] -2-cyano- phenyl} -2-fluorobenzamide 1059 517 N- (2-Benzoyl-4- {3- [1- (4-fluoro-phenyl) -ethyl] - thioureido] phenyl) -2-fluorobenzamide 1060 427 2-Fluoro-N- (4- {3- [1- (4-fluorophenyl) ethyl] thioureido} -2- (methylphenyl) benzamide 1061 487 N- (4- {3- [1- (4-Bromophenyl) ethyl] thioureido} -2-methylphenyl) -2-fluorobenzamide 1052 434 N- (4- {3- [1- (4-Cyanophenyl) ethyl] thioureido} -2-methylphenyl) -2-fluorobenzamide 1063 449 N- {4- [3- (1-Benzofuran-2-ylethyl) thioureido] -2-methylphenyl} -2-fluorobenzamide 1064 456 N- (2-Dimethylamino-4- {3- [1- (4-fluoro-phenyl) -ethyl] - thioureido) phenyl) -2-fluorobenzamide 1065 526 N- (2-Benzyloxy-4- {3- [1- (4-cyanophenyl) ethyl] thioureido) phenyl} -2-fluorobenzamide 1066 519 N- (2-Benzyloxy-4- {3- [1- (4-fluorophenyl) ethyl] thioureido] phenyl) -2-fluorobenzamide 1067 603 N- [4- {3- [1- (4-Bromo-phenyl) -ethyl] -thioureido} - -2- (2-morpholin-4-ylethoxy) phenyl] -2-fluorobenzamide 1068 603 N- [4- {3- [1- (4-Bromo-phenyl) -ethyl] -thioureido} - -2- (2-morpholin-4-ylethoxy) phenyl] -2-fluorobenzamide 1069 542 2-Fluoro-N- [4- {3- [1- (4-fluorophenyl) ethyl] thioureido] - -2- (2-morpholin-4-ylethoxy) phenyl] benzamide 1070 485 N- (2-Butoxy-4- {3- [1- (4-fluoro-phenyl) -ethyl] -

thioureido) phenyl) -2-fluorobenzamide

155

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

468 2-Fluoro-N- [4- {3- [1- (4-fluorophenyl) ethyl] thioureido] -2- (2-nitriloethoxy) 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-fluorophenyl) ethyl) thioureido) biphenyl-2-yl) benzamide

514 Isoquinoline-1-carboxylic acid (4- (3- (1- (4-fluorophenyl) ethyl) thioureido} -2-trifluoromethylphenyl) amide

503 (4- (3- (1- (4-Fluorophenyl) ethyl) thioureido) -2-

benzofuran-2-carboxylic acid trifluoromethylphenyl) amide

514 Isoquinoline-3-carboxylic acid (4- (3- (1- (4-fluorophenyl) ethyl) thioureido} -2-trifluoromethylphenyl) amide

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] amide

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] thioureido} -2-methylphenyl) amide

460 isoquinoline-3-carboxylic acid (4- (3- (1- (4-fluorophenyl) ethyl) thioureido} -2-methylphenyl) amide

156

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 Thiophene-3-carboxylic acid (4- {3- [1- (4-fluorophenyl) ethyl] thioureido) phenyl} amide

2-Isopropyl-thiazole-4-carboxylic acid {4- [3- (4-chloro-3-trifluoromethyl-phenyl) -thioureido] -phenyl] -amide

466 {4- [3- (3,5-Dichloro-phenyl) -thioureido] -phenyl] -amide

2-isopropylthiazole-4-carboxylic acid

466 {4- [3- (3,4-Dichloro-phenyl) -thioureido] -phenyl} -amide

2-isopropylthiazole-4-carboxylic acid

534 2-Isopropyl-thiazole-4-carboxylic acid {4- [3- (3,5-Bistrifluoromethyl-phenyl) -thioureido] -phenyl] -amide

480 {4- [3- (3,4-Dichloro-phenyl) -thioureido] -phenyl} -amide

2-butylthiazole-4-carboxylic acid

514 2-Butyl-thiazole-4-carboxylic acid {4- [3- (4-chloro-3-trifluoromethyl-phenyl) -thioureido] -phenyl] -amide

480 {4- [3- (3,5-Dichloro-phenyl) -thioureido] -phenyl) -amide

2-butylthiazole-4-carboxylic acid

548 2-Butylthiazole-4-carboxylic acid {4- [3- (3,5-bistrifluoromethyl-phenyl) -thioureido] -phenyl} -amide

438 {4- [3- (3,5-Dichloro-phenyl) -thioureido] -phenyl] -amide

2-methylthiazole-4-carboxylic acid

438 {4- [3- (3,4-Dichloro-phenyl) -thioureido] -phenyl] -amide

2-methylthiazole-4-carboxylic acid

505 2-Methylthiazole-4-carboxylic acid {4- [3- (3,5-Bistrifluoromethyl-phenyl) -thioureido] -phenyl} -amide

534 2-Phenylthiazole-4-carboxylic acid {4- [3- (4-chloro-3-trifluoromethyl-phenyl) -thioureido] -phenyl] -amide

500 {4- (3- (3,5-Dichloro-phenyl) -thioureido] -phenyl} -amide

2-phenylthiazole-4-carboxylic acid

500 (4- (3- (3,4-Dichlorophenyl) thioureido] phenyl) amide

2-phenylthiazole-4-carboxylic acid

568 2-Phenylthiazole-4-carboxylic acid 4- (3- (3,5-bistrifluoromethyl-phenyl) -thioureido] -phenyl} -amide

401 2-Fluoro-N- {4- [3- (1-thiazole-2-ylethyl) thioureido] phenyl} benzamide

588 2-Fluoro-N- [4- (3- (1- (1- (toluene-4-sulfonyl) -1H-indol-2-yl) ethyl) thioureido) phenyl] benzamide

446 2-Fluoro-N- {4- [3- (1-quinolin-2-ylethyl) thioureido] • ·· »

157

phenyl} benzamide 1111 446 2-Fluoro-N- (4- [3- (1-quinolin-4-ylethyl) 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- (1-quinolin-6-ylethyl) thioureido] phenyl} benzamide 1115 446 2-Fluoro-N- {4- [3- (1-quinolin-3-ylethyl) thioureido] phenyl} benzamide 1116 413 2-Methoxy-N- {4- [3- (1-thiophen-3-ylethyl) thioureido] -

phenyl} benzamide

Example 886

Method 33 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (3,5-dichloro-phenyl) -thioureido] -phenyl} -amide

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 the mixture was 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.

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

Ex. M + H

COMPOUND NUMBER

887

465 N- {4- [3- (3,5-Dichloro-4-methoxy-phenyl) -thioureido] 888

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

889 465

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

158. Phenyl) -2-fluorobenzamide

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-dichlorophenoxy} 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] 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-4-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-Dihydro-2,4-dimethoxyphenyl) thioureido] phenyl} acetamide

504 N- {4- [3- (3,5-Dibromo-2,4-dimethoxyphenyl) thioureido] phenyl} acetamide

317 N- {4- [3- (6-Methoxypyridin-3-yl) thioureido] phenyl} | Ι «« »» »» »» «

159

Acetamide

347 N- (4- [3- (2,6-Dimethoxypyridin-3-yl) thioureido] phenyl} acetamide

457 2- {4- [3- (4-Acetylaminophenyl) thioureido] -2,6-dichlorophenoxy] 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] -phenyl} -acetamide

447 N- (4- [3- (3-Chloro-4-iodophenyl) 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-4-trifluoromethylphenyl) 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-Dichlorophenyl) thioureido) phenyl) -2-

-fluorobenzamide

407 Furan-2-carboxylic acid {4- [3- (3,4-dichloro-phenyl) -thioureido] -phenyl] -amide

425 [1,2,3] Thiadiazole-4-carboxylic acid (4- [3- (3,4-dichloro-phenyl) -thioureido] -phenyl] -amide

480 N- {4- [3- (4-Bromo-3-chloro-phenyl) -thioureido] -phenyl) -

-2-fluorobenzamide

160 · φ φ φ φ φ · Φ · Φ

931 527 {- {4- [3- (3-Chloro-4-iodophenyl) thioureido] phenyl) -2- -fluorobenzamide 932 452 Furan-2-carboxylic acid {4- [3- (4-bromo-3-chloro-phenyl) -thioureido] -phenyl] -amide 933 499 Furan-2-carboxylic acid {4- [3- (3-chloro-4-iodophenyl) thioureido] phenyl) amide 934 391 {4- [3- (3-Chloro-4-fluoro-phenyl) -thioureido] -phenyl] -amide 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] -phenyl} -amide [1,2,3] thiadiazole-4-carboxylic acid 937 419 N- {4- [3- (3-Chloro-4-fluorophenyl) thioureido] phenyl} -2-fluorobenzamide 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- (1H-pyrazol-3-yl) -phenyl] -thioureido} -phenyl) -acetamide 941 355 N- {4- [3- (2,3-Dichloro-phenyl) -thioureido] -phenyl} -acetamide 942 435 N- {4- [3- (2,3-Dichloro-phenyl) -thioureido] -phenyl} -2- -fluorobenzamide 943 407 {4- (3- (2,3-Dichloro-phenyl) -thioureido] -phenyl} -amide furan-2-carboxylic acid 944 425 {4- [3- (2,3-Dichloro-phenyl) -thioureido] -phenyl} -amide [1,2,3] thiadiazole-4-carboxylic acid 945 355 N- {4- [3- (2,5-Dichloro-phenyl) -thioureido] -phenyl} -acetamide 946 435 N- {4- [3- (2,5-Dichloro-phenyl) -thioureido] -phenyl} - -2-fluorobenzamide 947 407 {4- (3- (2,5-Dichloro-phenyl) -thioureido] -phenyl} -amide furan-2-carboxylic acid 948 355 N- {4- [3- (3,5-Dichloro-phenyl) -thioureido] -phenyl} -acetamide 949 435 N- {4- [3- (3,5-Dichloro-phenyl) -thioureido] -phenyl} - -2-fluorobenzamide 950 407 Furan-2-carboxylic acid {4- (3- (3,5-dichlorophenyl) thioureido] phenyl) amide 951 390 N- (4- (3- (3,4,5-Trichlorophenyl) thioureido] phenyl) -

161 ··· · · · ················

acetamide 952 470 2-Fluoro-N- {4- [3- (3,4,5-trichlorophenyl) thioureido] phenyl} benzamide 953 442 Furan-2-carboxylic acid {4- [3- (3,4,5-trichloro-phenyl) -thioureido] -phenyl] -amide 954 460 {4- [3- (3,4,5-Trichlorophenyl) thioureido] phenyl] amide [1,2,3] thiadiazole-4-carboxylic acid 955 458 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (3-chloro-4-isoxazol-5-yl-phenyl) -thioureido] -phenyl] -amide 956 457 1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [3-chloro-4- (1H-pyrazol-3-yl) phenyl] thioureido} phenyl) amide 957 391 (4- [3- (3-Chloro-phenyl) -thioureido] -phenyl) -amide [1,2,3] thiadiazole-4-carboxylic acid 958 373 Furan- {4- (3- (3-Chloro-phenyl) -thioureido] -phenyl} -amide -2-carboxylic acids 959 401 N- {4- [3- (3-Chloro-phenyl) -thioureido] -phenyl} -2-fluoro-benzamide 960 373 Furan- {4- [3- (4-Chloro-phenyl) -thioureido] -phenyl} -amide -2-carboxylic acids 961 401 N- {4- [3- (4-Chloro-phenyl) -thioureido] -phenyl} -2-fluoro-benzamide 962 391 (4- (3- (4-Chlorophenyl) thioureido] phenyl) amide [1,2,3] thiadizaole-4-carboxylic acid 963 401 N- {4- [3- (2-Chloro-phenyl) -thioureido] -phenyl} -2- fluorobenzamide 964 396 3- (3- (4 - ((Furan-2-carbonyl) amino) phenyl} thioureido) benzoic acid methyl ester 965 424 3- {3- [4- (2-Fluoro-benzoylamino) -phenyl] -thioureido} -benzoic acid methyl ester 966 414 3- (3- (4 - (((1,2,3] Thiadiazole-4-carbonyl) amino) phenyl} thioureido) benzoic acid methyl ester 967 409 N- [4 - [[[(3- (Aminocarbonyl) phenyl] amino] thioxomethyl] amino] phenyl] -2-fluorobenzamide 968 373 Furan-2- {4- [3- (2-Chloro-phenyl) -thioureido] -phenyl} -amide -carboxylic acids 969 381 Furan- {4- [3- (3-Carbamoyl-phenyl) -thioureido] -phenyl} -amide -2-carboxylic acids 970 399 (4- (3- (3-Carbamoylphenyl) thioureido) phenyl) amide [1,2,3] thiadiazole-4-carboxylic acid 971 391 {4- (3- (2-Chloro-phenyl) -thioureido] -phenyl) -amide

162 »·· ·· ·· ··

972

973

974

975

976

977

978

979

980

981

982

983

984

985 [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-trifluoromethoxy-phenyl) -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-fluorobenzamide

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 furan {4- [3- (3-Butylsulfamoyl-phenyl) -thioureido] -phenyl} -amide

Example 986

Method 57

1- (4-Fluorophenyl) -2-methylpropan-1-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

163% 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-methylpropan-1-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

3-Dimethylamino-5-trifluoromethylbenzonitrile

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 under 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 hexanes to give a yellow solid (4.7 g).

164

The above compounds were tested for activity as inhibitors of herpes virus.

Human cytomegalovirus

Yield 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 (performed in the absence of inhibitor). Slices are quantified 2 weeks after infection. The HCMV inhibitor is identified by reducing 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 ₉ oz i.e. an amount of compound that reduces the yield by 50% and 90%, respectively. Table I describes _IC50 data for compounds tested against HCMV.

A microtiter plate assay A well plate with cultures of human foreskin fibroplasts 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 a viral promoter. An example of such a virus is RV145 (Jones, T. R., V. P. Muzithras, and Y Gluzman. 1991).

165 of the 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 X100 and 0.1% sarcose) were prepared and assayed for beta-glucuronidase activity using an enzyme substrate that cleavage provides either a product that 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 the reduced expression 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)

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 (Dublec's Modified Medium Eagle) supplemented with 2% fetal bovine serum (FBS) per well. 30 minutes of incubation at 37 ° C (in 5% CO ₂ ) and 30 minutes prior to HSV-1 infection (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 glycoprotein D monoclonal primary antibody and the secondary antibody is a goat anti-mouse IgG bound to β

166 galactosidase. Thus, the level of viral replication is determined by determining β-galactosidase activity by quantifying the generation of a 4-methyl umbelliferone fluorescent cleavage product after addition of a methyl umbelliferyl-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. The data are shown in Table I.

VZV antivirus test (ELISA)

VZV is used to generate inventory in this test. VZV Ellen 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. a mixture of uninfected and VZV-infected HFF infected cells is collected and added to each well of 96-well plates (3.5 x 10 ⁴ cells in 100 μΐ DMEM supplemented with 2% FBS) containing the test compound or reference standard control drug (at 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 ELISA. 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. Thus, the viral replication rate is determined by determining β-galactosidase activity by quantifying the generation of a 4-methyl umbelliferone fluorescent cleavage product upon addition of methyl umbelliferyl 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

167 with fluorescence obtained in the presence of the compound. The data are shown in Table I.

Table I shows IC ₅₀ data for compounds tested against herpes viruses

Table I

Example IC50 1C50 % inhibition IC50 (µg / ml) (µg / ml) 10 µg / ml (µg / ml) HCMV HSV vzv VZV 283 7 0.6 17 > 10 284 0.4 3 100 ALIGN! > 15 289 > 10 0.6 30 > 10 498 0.14 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 1.2 4 62 > 10 515 > 10 > 10 30 > 10 815 0.0024 > 7.5 816 0.0015 > 7.5 817. 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 0.05 > 7.5 823 0.05 > 7.5 824 0.004 3.20 825 0.003 6.12 826 0.020 0.86 827 0.026 828 0.45 > 7.5 829 0.08 > 7.5

168

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 virus. 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.

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 component.

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% active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, low melting 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, flavorings, suspending agents.

169 agents, thickeners, colorants, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (especially containing additives as mentioned above, e.g., cellulose derivatives, preferably sodium carboxymethylcellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and derivatives and oils (e.g. 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 compositions for parenteral administration, sterile liquid carriers are employed.

Liquid pharmaceutical compositions which are sterile solutions or suspensions may be used, for example, by 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 an appropriate amount of the 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 may be, for example, capsules or tablets alone, or there may be a suitable number of any such composition in packaged form.

The therapeutically effective dose to be used to treat herpes virus infection is determined by the attending physician. Variables that affect dose include patient condition, age, and weight. The novel methods of the invention for treating herpes virus infection comprise 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

170 mucous membranes. 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 (28)

PATENT CLAIMS A compound of the general formula wherein R ₁ -R ₅ is 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 atoms carbon, 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 ₆ , -CONR ₇ R _8, -NR ₆ N (R ₇ R _8), N (R ₇ R g) 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 a 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 members, 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, -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; 172 ··························· 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 from 1 to 6, or a pharmaceutically acceptable salt thereof. The compound of claim 1, wherein at least one substituent of R 1 -R 5 is not hydrogen. The compound of claim 1, wherein R 1 -R 5 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkoxy, C 1 -C 6 perhaloalkyl, and halogen. A compound according to claim 1, having up to 6 carbon atoms. A compound according to claim 4, The compound of claim 1, i A compound according to claim 1, A compound according to claim 1, 6 membered heteroaryl. wherein X is CH (J) aJ is alkyl with 1 wherein J is methyl. where A is unsubstituted. wherein A is pyridinyl. wherein G is unsubstituted 5 or The compound of claim 8, wherein G is furyl, thiazolyl or thiadiazolyl. The compound of claim 8, wherein G is 2-furyl. The compound of claim 8, wherein G is 1,2,3-thiadiazolyl. 173 The compound of claim 8, wherein G is 1,3-thiazolyl. The compound of claim 1, wherein G is phenyl. The compound of claim 1, wherein G is substituted phenyl. The compound of claim 14, wherein 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. The compound of 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 pyridine-2-carboxylic acid pyridine-2-carboxylic acid {6- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] pyridin-3-yl} amide, {6- [3- (5-Chloro) Furan-2-carboxylic acid -2,4-dimethoxyphenyl) thioureido] pyridin-3-yl} amide {6- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] pyridin-3-yl} amide [ 1,2,3] 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] -pyridine-2174 -yl} -2-fluorobenzamide, 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) 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; 175 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 its pharmaceutical salts. 18. A pharmaceutical composition comprising a compound of the formula R ₁ -R ₅ is 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 atoms carbon, heterocycloalkyl of 3 to 10 carbon atoms, aryl, heteroaryl, halogen, -CN, -NO ₂ , -CO ₂ R 6, -COR ₆ , -OR ₆ , -SR _6z -SOR ₆ , -SO ₂ R ₆ , - CONR ₇ R _{8 from} -NR ₆ 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 a 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 5 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 members, 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 C 1 -C 4 alkyl, -CN, -CO ₂ R ₈ , -COR _8z -> ·> 176 -CONR ₇ R ₈ , -OCOR ₈ , -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 ) Rg ₇₎ 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 from 1 to 6, or a pharmaceutically acceptable salt or pharmaceutically acceptable carrier or diluent thereof. 19. A method of inhibiting herpes virus replication, comprising contacting a compound of formula R ₁ -R ₅ is 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 atoms carbon, heterocycloalkyl of 3 to 10 carbon atoms, aryl, heteroaryl, halogen, -CN, -NO ₂ , -CO ₂ R 6, -CO 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 ₈₎ or WY- (CH _{2) n} Z; or _R2 and R3 or R3 and _R4 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; 177; \ A. X A.. X: n - »“> 7 7 τ '' - '' ¹ 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 members, 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 C 1 -C 4 alkyl, -CN, -CO ₂ R ₆ , -COR ₈ , -CONR ₇ R 8, -OCOR 8, -NR ₆ COR ₇ , -OCONR 8, -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 from 1 to 6, or a pharmaceutically acceptable salt thereof with a herpes virus. 20. The method of claim 19 wherein the herpes virus is a human cytomegalovirus. The method of claim 19, wherein the herpes virus is a herpes simplex virus. 22. The method of claim 19 wherein the herpes virus is varicella zostervirus. 23. The method of claim 22, wherein the varicella zoster virus is treated with a substantially pure optical isomer (S). 24. A method of treating a patient suffering from a herpes virus infection 178 comprising administering to the patient a therapeutically effective amount of a compound of formula (I) NH — G — G where R ₄ -R ₅ is 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 up to 10 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 , -conr ₇ r ₈ , -NR ₆ 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 a 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 members, 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 C 1 -C 4 alkyl, -CN, -CO ₂ R ₆ , -COR ₆ , -CONR ₇ R ₈ , -OCOR ₆ , -NR ₆ COR ₇ , -OCONR 8, -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; 179 • · · · · · 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 from 1 to 6, or a pharmaceutically acceptable salt thereof. 25. The method of claim 24, wherein the herpes virus is a human cytomegalovirus. 26. The method of claim 24, wherein the herpes virus is a herpes simplex virus. 27. The method of claim 24, wherein the herpes virus is varicella zostervirus. The method of claim 27, wherein the varicella zoster virus is treated with a substantially pure optical isomer (S).