HUP0200232A2 - Phenylenediamine group and heterocyclic carboxamide-containing thiourea inhibitors of herpes viruses their use and pharmaceutical compositions containing them - Google Patents

Abstract

The invention relates to compounds of general formula (I) and their pharmaceutically acceptable salts, where R1-R5 are independently hydrogen, alkyl, alkenyl, alkynyl, perhaloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halogen, cyano, nitro . alkyl, perhaloalkyl, or aryl group; R8 is a hydrogen atom, alkyl, perhaloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl group, or R7 and R8 together can form a 3- to 7-membered heterocycloalkyl group; W is an oxygen atom, a group of general formula -NR6, or is absent; Y is -(CO)- or -(CO2)- or absent; Z is alkyl, cyano, -CO2R6, -COR6, -CONR7R8, -OCOR6, -NR6COR7, -OCONR6, -OR6, -SR6, -SOR6, -SO2R6, SR6N(R7R8), -N(R7R8) or phenyl; G represents a monocyclic heteroaryl group; X is a valence bond, -NH, alkyl, alkenyl, alkoxy, alkylthio, alkylamino or (CH)J; J is alkyl, cycloalkyl, phenyl or benzyl; and n is 1-6. The compounds inhibit and/or cure diseases caused by herpes viruses such as human cytomegalovirus, herpes simplex virus, Epstein-Barr virus, varicella-zoster virus, human herpes virus-6 and -7 and Kaposi's herpes virus. The invention also relates to pharmaceutical preparations containing the compounds and to the use of the compounds. HE

Description

The invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein R1 - _R5 are independently hydrogen, alkyl, alkenyl, alkynyl, perhaloalkyl, cycloalkyl, heterocycloalkyl, _aryl , _heteroaryl , halogen, cyano, nitro, -CO2R6, -COR6, _-OR6 , _-SR6 , -SOR _{e ,} -SO2R6, _-CONR7R8 , _-NR6N ( _R7R8 ), _-N ( _R7R8 ) or WY-( _CH2 ) _n -Z with the hydrogen atom; or _{R2 and} -Rj or Rs and _R4 together are a 3-7-membered heterocyclic group or _a 3-7- _membered group.

R ₅ and R ₇ are independently hydrogen, alkyl, perhaloalkyl, or aryl;

R ₈ represents a hydrogen atom, an alkyl, perhaloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl group, or R ₇ and R ₈ together may form a 3-7 membered heterocycloalkyl group;

W is oxygen, -NR ₆ , or absent;

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

-2Z is an alkyl, cyano group, a group of _{the general} formula -CO2R6, -COR _S , -CONRyRs, _-OCOR6 , _-NR6COR7 , _-OCONR6 , _-OR6i , _-SR6 , _-SOR6 , -SO2R6, _SR6N ( _R7R8 ), -N( _{R7R8 )} or a phenyl group;

G is a monocyclic heteroaryl group;

X represents a bond, -NH, alkyl, alkenyl, alkoxy, alkylthio, alkylamino or a group of the general formula (CH)J;

J is alkyl, cycloalkyl, phenyl or benzyl; and n is 1-6.

The compounds inhibit and/or cure diseases caused by herpes viruses, such as human cytomegalovirus, herpes simplex virus, Epstein-Barr virus, varicella-zoster virus, human herpesvirus-6 and -7, and Kaposi's herpesvirus.

The invention also relates to pharmaceutical compositions containing the compounds and to the use of the compounds.

£0200232 ^: ·ί· · :·<· ^:

THIOUREA DERIVATIVES WITH HERPESVIRUS INHIBITOR EFFECT CARRYING A PHENYLENE DIAMINE GROUP AND A HETEROCYCLIC CARBXAMIDE GROUP, ^Λ PUBLICATION COPY

Eight viruses are known to belong to the family Herpesviridae [for a review, see Roizman, B. Herpesviridae, pp. 2221-2230, in Fields, B.N.; Knipe, D.M. and Howley, P.M. (eds.), Fields Virology, 3rd ed., Lippincott-Raven Publishers, Philadelphia, PA (1996)]. Each member of the family is a proteinaceous envelope virus and contains a nucleocapsid, in which the protein envelope is surrounded by a membrane and the nucleocapsid contains the virus's relatively large double-helical DNA genome, approximately 80-250 kilobases in size. Members of the human alphaherpesvirus subfamily are neurotropic viruses and include herpes simplex virus types 1 (HSV-1) and 2 (HSV-2), and varicella-zoster virus (VZV). Human beta-herpesviruses include cytomegalovirus, human herpesvirus 6 (HHV-6), and human herpesvirus 7 (HHV-7). Gamma-herpesviruses are lymphotropic viruses that include Epstein-Barr virus (EBV) and Kaposi's herpesvirus (HHV-8). All of these viruses cause human diseases, including herpes labialis (HSV-1) and herpes simplex (HSV-2).

94573-1 846A-BÉ/BB/wood

-2genital (HSV-1 and HSV-2) [Whitley, R.J. Herpes Simplex Viruses, pp. 2297-2342, in Fields, B.N.; Knipe, D.M. and Howley, P.M. (eds.), Fields Virology, 3rd ed., Lippincott-Raven Publishers, Philadelphia, PA (1996)]; chickenpox and shingles (VZV) [Arvin, A. Varicella-Zoster Virus, pp. 2547-2585, in Fields, B.N.; Knipe, D.M. and Howley, P.M. (eds.), Fields Virology, 3rd ed., Lippincott-Raven Publishers, Philadelphia, PA (1996)]; infectious mononucleosis (EBV) [Rickinson, A.B.; Kieff, E. Epstein-Barr Virus, pp. 2397-2446, in Fields, B.N.; Knipe, D.M. and Howley, P.M. (eds.), Fields Virology, 3rd ed., Lippincott-Raven Publishers, Philadelphia, PA (1996)]; pneumonia and retinitis (HCMV) [Britt, W.J. and Alford, C.A. Cytomegalovirus, pp. 2493-2523, in Fields, B.N.; Knipe, D.M. and Howley, P.M. (eds.), Fields Virology, 3rd ed., Lippincott-Raven Publishers, Philadelphia, PA (1996)]; rubella (HHV-6) [Pellet, P.E. and Black, J.B. Human Herpesvirus 6, pp. 2587-2608, in Fields, B.N.; Knipe, D.M. and Howley, P.M. (eds.), Fields Virology, 3rd ed., Lippincott-Raven Publishers, Philadelphia, PA (1996)]; HHV-7 [Frenkel, N. and Roffman, E. Human Herpesvirus 7, pp. 2609-2622, in Fields, B.N.; Knipe, D.M. and Howley, P.M. (eds.), Fields Virology, 3rd ed., Lippincott-Raven Publishers, Philadelphia, PA (1996)]; Kaposi's sarcoma (HHV-8) [Neipel, F.; Albrecht, J.C.; and Fleckenstein, B. Cell-homologous genes in the Kaposi's sarcoma-associated rhadinovirus human herpesvirus 8: determinants of its

-3pathogenicity? J. Virol. 71, 4187-92 (1997)]. HCMV is discussed in more detail below. After the initial infection, the herpes virus remains latent in the infected person for the rest of his life. Periodic reactivation of the latent virus is clinically relevant. In the case of HSV, reactivated virus can be transmitted to the newborn infant, causing skin or eye infections, central nervous system infections, or widespread infection of multiple organs or systems. The clinical manifestation of VZV reactivation is herpes zoster. HSV and VZV are usually treated with antiviral drugs such as acyclovir (Glaxo Wellcome), ganciclovir (Roche), or foscarnet (Ásta), which inhibit the DNA polymerase encoded by the virus.

HCMV is a ubiquitous opportunistic pathogen that infects 50-90% of the adult population [Britt, W.J. and Alford, C.A. Cytomegalovirus, pp. 2493-2523, in Fields, B.N.; Knipe, D.M. and Howley, P.M. (eds.), Fields Virology, 3rd ed., Lippincott-Raven Publishers, Philadelphia, PA (1996)]. Primary infection with HCMV is usually asymptomatic, although heterophilic negative mononucleosis has been observed. The virus is transmitted horizontally by sexual contact, breast milk, and saliva. In utero, the fetus can be infected with HCMV from the pregnant mother, often with serious clinical consequences. HCMV virus remains latent in the infected individual for the rest of his or her life. Cell-mediated immunity plays a central role in the control of latent infection.

-4 to suppress activation from the state. In seropositive individuals, insufficient cell-mediated immunity leads to reactivation of latent HCMV.

HCMV disease is attributed to deficient or immature cell-mediated immunity. There are three main groups of individuals infected with HCMV (Britt and Alford, 1996): (a) in immunocompromised AIDS patients, HCMV is one of the most common pathogens causing clinical symptoms (the other being Pneumocystis). The most common manifestation of HCMV infection in AIDS is retinitis, but infections of the adrenal glands, lungs, gastrointestinal tract, and central nervous system are also frequently described in the literature. 90% of AIDS patients have active HCMV infection; 25-40% (approximately 85,000 patients in the United States) have life-threatening or sight-threatening HCMV infection. In AIDS patients, 10% of deaths are attributable to HCMV, (b) In organ transplants, due to the suppressed immune system to prevent rejection, HCMV reactivation or reinfection is common in kidney, liver, heart and allogeneic bone marrow transplant recipients. In these patients, pneumonia is the most common HCMV-related disease, accounting for 70% of cases, (c) Congenital HCMV infection occurs in 1% of births, approximately 40,000 per year. Between the ages of 0 and 3, 25% of these children develop symptoms of HCMV infection. HCMV disease is progressive, intellectually

-5 causes disability and neurological abnormalities in children. Recent studies suggest that anti-HCMV drugs reduce symptoms in these children.

Several antiviral drugs are currently available [Bron, D.; Snoeck, R. and Lagneaux, L. New insights into the pathogenesis and treatment of cytomegalovirus. Exp. Opin. Invest. Drugs 5, 337-344 (1996); Crumpacker, C. Ganciclovir. New Eng. J. Med. 335, 721-729 (1996); Sachs, S. and Alrabiah, F. Novel herpes treatments: a review. Exp. Opin. Invest. Drugs 5, 169-183 (1996)]. These drugs include ganciclovir (Roche), a nucleoside analog with hemopoietic cell toxicity; foscarnet (Astra), a pyrophosphate analog with nephrotoxicity; and cidofovir (Gilead), a nucleoside phosphonate with acute nephrotoxicity. All of these drugs inhibit the virally encoded DNA polymerase, are typically administered intravenously due to their low bioavailability, and, as mentioned above, exhibit significant toxicity. Ganciclovir-resistant mutants that emerge in clinical practice often exhibit cross-resistance to cidovir. Therefore, there is a need for safer, i.e., less toxic, orally administered antiviral drugs that have novel viral targets.

A number of phenylthiourea derivatives are known to have a wide range of medicinal uses. Armistead et al. published international patent application WO 97/40028

-6 describes phenylureas and phenylthioureas that inhibit inosine monophosphate dehydrogenase (IMPDH). This enzyme is involved in the replication of viruses, such as herpesviruses. Widdowson et al., in their international patent application WO96/25157, describe phenylureas and phenylthioureas of formula (9) for the treatment of diseases in which the chemokine interleukin-8 is involved.

Morin, Jr. et al., U.S. Patent No. 5,593,993, disclose phenylthiourea derivatives useful in the treatment of AIDS and in inhibiting the proliferation of HIV and related viruses.

It is therefore an object of the invention to provide compounds and pharmaceutically acceptable salts thereof which inhibit and/or cure diseases caused by herpes viruses, such as human cytomegalovirus, herpes simplex viruses, Epstein-Barr virus, varicella-zoster virus, human herpesvirus-6 and -7 and Kaposi's herpesvirus.

The invention relates to compounds of general formula (I) and pharmaceutically acceptable salts thereof, wherein R1 - R2 independently represent hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 perhaloalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, aryl, heteroaryl, halogen, cyano, nitro,

-CO2R6, -CORe, -ORe, -SRe, -SORe, -SO2R6, -CONRyRe,

-7 - · *

a group of the general formula -NR ₆ N(R ₇ R8), -N(R ₇ R ₈ ) or WY-(CH ₂ ) n Z, with the proviso that at least one of the groups R ₁ - r ₅ is not a hydrogen atom; or R ₂ and R ₃ or R ₃ and R ₄ together form a 3-7 membered heterocycloalkyl group or a 3-7 membered heteroaryl group;

R 6 and R ₇ are independently hydrogen, C 1-6 alkyl, C 1-6 perhaloalkyl, or aryl;

Re represents a hydrogen atom, a C1-6 alkyl, a C1-6 perhaloalkyl, a C3-10 cycloalkyl, a C3-10 heterocycloalkyl, aryl, heteroaryl, or R ₇ and Re together may form a 3-7 membered heterocycloalkyl group;

W is oxygen, -NR ₆ , or absent;

Y is -(CO)- or -(CO2)-, or is absent;

Z is a C1-4 alkyl, cyano, -CO2R6, -CORe, _-CONR7Re , -OCORe, _-NReCOR7 , -OCONRe, -ORe, -SRe, -SORe, -SO2R6, SReN( _R7R8 ), -N( _R7R8 ) or phenyl;

G is a monocyclic heteroaryl group;

X is a bond, -NH-, C1-6 alkyl, C1-6 alkenyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino or (CH)J;

J is C1-6 alkyl, C3-7 alkyl

-8cycloalkyl, phenyl or benzyl; and n is 1-6.

In some preferred embodiments of the invention, at least one of the groups R1 - R2 is not hydrogen. In other preferred embodiments of the invention, R1 - R3 is independently hydrogen, C1-6 alkyl, halogen, C1-6 perhaloalkyl, -ORe or -NfRyRs). Preferably, 1-3 of the groups R1 - _R5 are not hydrogen. Most preferably, two of the groups R1 - R5 are not hydrogen. In preferred compounds of the invention, _R3 and _R5 or _R4 and _R5 are preferably independently halogen or trifluoromethyl.

In some embodiments of the invention, G is a monocyclic heteroaryl group, preferably thiazolyl, thiadiazolyl, oxazolyl or furyl. It is preferred that the group G is unsubstituted.

In some embodiments of the invention, X is a bond or a C1-4 alkyl group. Preferably, when X is a C1-4 alkyl group, the alkyl group is a straight chain alkyl group. When X is a group of the general formula CH(J), J is preferably a methyl group.

Preferred compounds of the invention and their pharmaceutically acceptable salts include:

:.:. <· <· J.

-9 following compounds:

[1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl-benziO-thioureido]-phenyl]-amide,

[1,2,3]thiadiazole-4-carboxylic acid {4-[3-(4-piperidin-1-yl-3-trifluoromethylbenzyl)thioureido]phenyl}-amide,

[1,2,3]thiadiazole-4-carboxylic acid {4-[3-(4-dimethylamino-3-trifluoromethyl-benziO-thioureidol-phenyl]-amide,

[1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3-dimethylamino-5-trifluoromethylbenzyl)thioureido]phenyl}-amide,

[1,2,3]thiadiazole-4-carboxylic acid {4-[3-(4-fluoro-3-trifluoromethylbenzyl)thioureido]phenyl}-amide, thiazole-4-carboxylic acid {4-[3-(4-tert-butylbenzyl)thioureido]phenyl}-amide,

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

[1,2,3]thiadiazole-4-carboxylic acid-(4-{3-[2-(4-bryo-phenyl)-ethyl]-thioureido}-phenyl)-amide, thiazole-4-carboxylic acid-{4-[3-(3,4-dichlorobenzyl)-thioureido]-phenyl}-amide,

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

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

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

[1,2,3]thiadiazole-4-carboxylic acid-(4-{3-[2-(4-trifluoromethyl·

-fen il )-et i I ]-t i ourei do}-f en i I)-a m id,

-10[1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(3-chlorophenyl)ethyl]thioureido}phenyl)amide,

[1,2,3]thiazol-4-carboxylic acid-{4-[3-(4-terebutyl-benzyl)-1-ioureido]-phenyl}-amide, thiazole-4-carboxylic acid-{4-[3-(3,5-dichlorophenyl)-thioureido]-phenyl}-amide,

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

[1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(2,4-bis-trifluoromethylphenyl)ethyl]thioureido}-phenyl)amide,

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

[1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3-fluoro-5-trifluoromethylbenzyl)thioureido]phenyl}-amide,

[1,2,3]thiadiazole-4-carboxylic acid {4-{3-[2-(3,5-bis-trifluoromethylphenyl)ethyl]thioureido}phenyl)amide,

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

[1,2,3]thiadiazole-4-carboxylic acid {4-[3-(2-fluoro-5-trifluoromethylbenzyl)thioureido]phenyl}-amide,

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

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

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

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

-11 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(2-fluoro-5-trifluoromethyl-phenoxy)-ethyl]-thioureido}-phenyl)-amide, thiazol-4-carboxylic acid-{4-[3-(2-fluoro-5-trifluoromethyl-benzyl)-thioureido]-phenyl}-amide,

[1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(3-iodophenyl)ethyl]thioureido}-phenyl)amide, furan-2-carboxylic acid {4-[3-(3,5-bis-trifluoromethylbenzyl)thioureido]-phenyl}-amide,

[1,2,3]thiadiazole-4-carboxylic acid (4-{3-[3-(3-methyl-biethyl)-5-trifluoromethyl-pheniol]-thiourei do}-pheniol)-amide,

[1 ₎ 2,3]thiadiazole-4-carboxylic acid {4-[3-(3-isobutyl-5-trifluoromethylphenyl)thioureido]phenyl}-amide,

[1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(3-dimethylamino-5-trifluoromethylphenyl)ethyl]thioureido}phenyl)amide,

[1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(5-bromo-2-methoxyphenyl)ethyl]thioureido}phenyl)amide,

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

[1,2,3]thiadiazole-4-carboxylic acid-(4-{3-[2-(3,5-dichlorophenoxy)ethyl]thioureido}-phenyl)-amide, thiazole-4-carboxylic acid-{4-[3-(3,4-dichlorophenyl)thioureidophenyl}-amide, thiazole-4-carboxylic acid-{4-[3-(4-chloro-3-trifluoromethylphenyl)~

-thioureido]-phenyl}-amide,

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

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

- 12 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(2-fluoro-5-trifluoromethyl-phenyl)-eth i I ]-thioureido}-phen i I )-amide,

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

[1,2,3]thiadiazole-4-carboxylic acid (4-(3-(3-chloro-4-trifluoromethylphenyl)thioureido]phenyl}-amide,

[1,2,3]thiadiazole-4-carboxylic acid (4-[3-(3-chloro-4-iodophenyl)thioureido]phenyl}-amide, furan-2-carboxylic acid [4-(3-benzo[1,3]dioxol-5-ylmethylthioureido)phenyl]-amide,

[1,2,3]thiadiazole-4-carboxylic acid (4-{3-[1-(4-bromo-phenyl)-eth i I ]-thioureido}-phen i I )-amide,

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

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

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

[1,2,3]thiazole-4-carboxylic acid-{4-[3-(3-trifluoromethylbenzyl)thioureido]phenyl}-amide,

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

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

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

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

- 13[1,2,3]thiadiazole-4-carboxylic acid-(4-{3-[3-(butylmethylamino)-5-trifluoromethylphenyl]thioureido}-phenyl]-amide,

[1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3,5-dimethylbenzyl)thioureido]phenyl}-amide, thiazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoromethylphenyl)thioureido]phenyl}-amide,

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

[1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3-bromo-5-trifluoromethylphenyl)thioureido]phenyl}-amide,

[1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(3-chlorophenoxy)ethyl]-thioureido)-pheniyl)-amide,

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

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

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

[1,2,3]thiadiazole-4-carboxylic acid-{4-[3-(5-chloro-2-methoxy-4~

-methylphenyl)thioureido]phenyl}-amide,

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

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

[1,2,3]thiadiazole-4-carboxylic acid-{4-[3-(3,5-difluorobenzyl)-thioureido]-phenyl}-amide, furan-2-carboxylic acid-{4-[3-(3,5-difluorobenzyl)-thioureido]-phenyl}-amide, _ «*_···<· * ♦’ · : . < ι í ' ·>·· ' * V' ' **

- 14 [1,2,3]thiadiazole-4-carboxylic acid-{4-[3-(2-p-tolylethyl)thioureido]phenyl}-amide,

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

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

[1,2,3]thiadiazole-4-carboxylic acid-{4-[3-(3-iodobenzyl)-thioureido]-phenyl}-amide, furan-2-carboxylic acid-(4-{3-[2-(3-bromophenylsulfanyl)-ethyl]-thioureido}-phenyl)-amide, oxazole-4-carboxylic acid-}4-[3-(3,5-dichlorophenyl)-thioureido]-phenyl}-amide,

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

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

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

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

[1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3-amino-5-chlorophenyl)thioureido]phenyl)amide,

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

[1,2,3]thiadiazole-4-carboxylic acid (4-{3-[3-(isobutylmethylamino)-5-trifluoromethylphenyl]thioureido}-phenyl)amide,

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

- 15[1,2,3]thiadiazole-4-carboxylic acid-{4-[3-(3-chloro-4-fluorophenyl)-thioureido]-phenyl}-amide,

[1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3,4,5-trichlorophenyl)thioureido]phenyl}-amide, furan-2-carboxylic acid {4-[3-(3,4-dichlorobenzyl)thioureido]phenyl}-amide,

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

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

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

[1,2,3]thiadiazole-4-carbonic acid-{4-[3-(3-iodo-phenyl)-thicilido]-phenyl}-amide,

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

[1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3-dimethylamino-5-trifluoromethylphenyl)thioureido]phenyl}-amide,

[1,2,3]thiadiazole-4-carboxylic acid (4-{3-[4-(4-methyl-piperazin-1-yl)-3-trifluoromethyl-benzyl]-thioureido}-phenyl)-amide,

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

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

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

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

-16[1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(3-methoxy-phenyl)-ethyl]-thioureido}-phenyl)-amide,

[1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3-chloro-4-methylphenyl)thioureido]phenyl}-amide, furan-2-carboxylic acid {4-[3-(3-fluoro-5-trifluoromethylbenzyl)thioureido]phenyl}-amide,

[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-(3-piperidin-1-yl-5-trifluoromethylphenyl)thioureido]phenyl}-amide, oxazole-4-carboxylic acid {4-[3-(3,4-dichlorophenyl)thioureido]phenyl}-amide, furan-2-carboxylic acid {4-[3-(3,4,5-trichlorophenyl)thioureido]phenyl}-amide,

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

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

[1,2,3]thiadiazole-4-carboxylic acid [4-(3-phenethylthioureido)phenyl]-amide,

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

[1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoromethylphenyl)thioureido]phenyl}-amide,

[1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3,5-dichloro-2-methoxy-4-methylphenyl)thioureido]phenyl}-amide,

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

- 17 [1,2,3]thiadiazole-4-carboxylic acid-(4-{3-[3-chloro-4-(2-piperidin-1-yl-acetylamino)-phenyl]-thioureido}-phenyl)-amide,

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

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

[1,2,3]thiadiazole-4-carboxylic acid (4-{3-[3-chloro-4-(cyclohexylmethylamino)phenyl]thioureido}-phenyl)amide, furan-2-carboxylic acid [4-(3-benzylthioureido)-phenyl]amide, furan-2-carboxylic acid (4-{3-[2-(3,5-dichlorophenoxy)ethyl]thioureido}-phenyl)amide, furan-2-carboxylic acid {4-[3-(2-fluoro-5-trifluoromethylbenzyl)thioureido]-phenyl}amide,

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

[1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(2-chlorophenyl)ethyl]thioureido}-phenyl)amide, oxazole-4-carboxylic acid (4-{3-(4-chloro-3-trifluoromethylphenyl)thioureido]-phenyl}-amide, furan-2-carboxylic acid (4-{3-[2-(3,4-dichlorophenyl)ethyl]thioureido}-phenyl)amide,

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

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

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

- 18furan-2-carboxylic acid-{4-[3-(4-bromo-3-chlorophenyl)thioureido]phenyl}-amide,

[1,2,3]thiadiazole-4-carboxylic acid (4-{3-[(1 S)-1 -(4-bromophenyl)ethyl]thioureido}-phenyl)amide,

[1,2,3]thiadiazole-4-carboxylic acid (4-{3-[(1 R )-1 -(4-bromo-phen i l )-eth i l]-thioureid o}-phen i l)-amide,

[1,2,3]thiadiazole-4-carboxylic acid (4-{3-[1-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-thioredo}-pheniyl)-amide,

[1,2,3]thiadiazole-4-carboxylic acid (4-{3-[(1S)-1-(4-chlorophenyl)ethyl]thioureido}-phenyl)amide,

[1 ₎ 2,3]thiadiazole-4-carboxylic acid (4-{3-[(1 R)-1 -(4-chlorophenyl)ethyl]thioureido}-phenyl)amide,

N-[4-[[[[1-(4-cyanophenyl)ethyl]amino]thioxomethyl]amino]phenyl]-1,2,3-thiadiazole-4-carboxamide, thiazole-4-carboxylic acid-(3-{3-[1-(4-bromophenyl)ethyl]thioureido}-phenyl]amide,

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

N-(4-{[({ 1 -[4-fluoro-3-(trifluoromethyl)-phenyl]-ethyl}-amino)-

-carbotilyl]-amino}-phenyl)-1,2,3-thiadiazole-4-carboxamide,

N-(4-{[({1-[4-chloro-3-thiadiazole-4-carboxamide,

N-(4-{[({(1 S)-1-[3,5-thiazole-4-carboxamide,

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

N-(4-{[({1-[2-fluoro-4-trifluoromethyl)phenyl]ethyl}amino)-

-carboti oi I]-am i n o}-phen i I)-1,3-thiazole-4-carboxamide,

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

-19 N-(4-{[({1-[2,4-bis(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}phenyl)-1,3-thiazole-4-carboxamide,

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

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

N-{4-[({[1-(3-methylphenyl)-ethyl]-amino}-carbothiolamino]-pheni l}-1,3-thiazole-4-carboxamide,

N-(4-{[({1-[4-fluoro-3-(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}phenyl)-1,3-thiazole-4-carboxamide,

N-{4-[({[ 1 -(2-Chloro-4-fluoropheniol)-ethi]-amino}carbothiol)-amino]-phenyl}-1,3-thiazole-4-carboxamide,

N-{4-[({[1-(3,4-difluorophenyl)ethyl]amino}-carbothioyl)amino]-phenyl}-1,3-thiazole-4-carboxamide,

N-{4-[({[1-(4-bromo-2-fluorophenyl)-ethyl]-amino}-carbothioyl)-amino]-phenyl}-1,3-thiazole-4-carboxamide,

N-{4-[({[1-(3-fluorophenyl)ethyl]amino}-carbothioyl)amino]-phenyl}-1,3-thiazole-4-carboxamide,

N-{4-[({[1-(2-bromophenyl)-ethyl]-amino}-carbothiol)-amino]-phenyl}-1,3-thiazole-4-carboxamide,

N-{4-[({[1-(3-bromophenyl)ethyl]amino}-carbothioyl)amino]phenyl}-1,3-thiazole-4-carboxamide,

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

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

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

-20N-{4-[({[1-(3,4-dichlorophenyl)ethyl]amino}-carbothioyl)amino]phenyl}-1,3-thiazole-4-carboxamide,

N-(4-{[({(1-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl}-amino)carbothioyl]-amino}-phenyl)-1,3-thiazole-4-carboxamide,

N-(4-{[({(1-[4-chloro-3-(trifluoromethyl)phenyl]ethyl}-amino)carbothioyl]-amino}-phenyl)-1,3-thiazole-4-carboxamide,

N-{4-[({[ 1 -(4-chloro-2-fluorophenyl)-ethyl]-amino}-carbothiol)-amino]-phenyl}-1,3-thiazole-4-carboxamide,

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

N-{4-[({[ 1 -(4-Chloro-3-fluorophenyl)-ethyl]-amino}carboxyl)-amino]-phenyl}-1,3-thiazole-4-carboxamide,

N-{4-[({[1-(2-bromo-4-fluorophenyl)-ethyl]-amino}-carbothiol)-amino]-phenyl}-1,3-thiazole-4-carboxamide,

N-{4-[({[1-(3,4-dibromophenyl)ethyl]amino}-carbothioyl)amino]-phenyl}-1,3-thiazole-4-carboxamide,

N-{4-[({[1-(3-chloro-4-fluorophenyl)ethyl]amino}-carbothioyl)amino]-phenyl}-1,3-thiazole-4-carboxamide,

N-(4-{[({1-[3,5-bis(trifluoromethyl)phenyl]propyl}-amino)carbothioyl]-amino}-phenyl)-1,2,3-thiadiazole-4-carboxamide,

N-(4-{[({1-[3,5-bis(trifluoromethyl)-phenyl]-butyl}-amino)-carbothioyl]-amino}-phenyl)-1,2,3-thiadiazole-4-carboxamide,

N-(4-{[({1-[3,5-bis(trifluoromethyl)phenyl]pentyl}-amino)carbothioyl]-amino}-phenyl)-1,2,3-thiadiazole-4-carboxamide,

N-{4-[({[[3,5-bis(trifluoromethyl)phenyl]-(phenyl)methyl]amino}-carbothioyl)amino]phenyl}-1,2,3-thiadiazole-4-carboxamide,

-21 N-(4-{[({1-[3,5-bis(trifluoromethyl)phenyl]-1-methylethyl}-amino)carbothioyl]amino)phenyl)-1,2,3-thiadiazole-4-carboxamide,

N-{4-[({[3,5-bis(trifluoromethyl)benzyl]amino}-carbothioyl)amino]-phenyl}-1H-imidazole-4-carboxamide,

N-{4-[({[1-(4-fluorophenyl)-ethyl]-amino}-carbothioyl)-amino]-phenyl}-1 H -imidazole-4-carboxamide,

N-{4-[({[3,5-bis(trifluoromethyl)benzyl]amino}-carbothioyl)amino]phenyl}-1-methyl-1H-imidazole-4-carboxamide,

N-(4-{[({1-[3,5-bis(trifluoromethyl)phenyl]propyl}amino)carbothioyl]amino)phenyl)-1,3-thiazole-4-carboxamide and pharmaceutically acceptable salts thereof.

Unless otherwise defined, the terms used in this specification have the following meanings.

The term "alkyl" as used herein refers to a straight or branched chain, short alkyl group having 1 to 6 carbon atoms. Examples of such alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl.

The term "alkenyl" as used herein refers to a straight or branched chain, short alkyl group of 1 to 6 carbon atoms containing at least one carbon-carbon double bond. Examples of alkenyl groups include vinyl groups.

The term "alkynyl" as used herein refers to a straight or branched chain, short alkyl group of 1-6 carbon atoms containing at least one carbon-carbon triple bond.

-22 The alkyl, alkenyl and alkynyl groups of the invention may be substituted or unsubstituted.

The term "cycloalkyl" refers to a saturated or unsaturated, mono- or bicyclic ring system having 3 to 10 carbon atoms. Typical cycloalkyl groups include cyclopentyl, cyclohexyl, or cycloheptyl. The cycloalkyl groups of the invention may be substituted or unsubstituted.

The term "heterocycloalkyl" refers to 3-10 membered saturated mono- or bicyclic ring systems containing a total of 1-3 heteroatoms selected from nitrogen, sulfur, and oxygen, such as, but not limited to, aziridinyl, azetidinyl, imidazolidinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrazolidinyl, piperidinyl, and pyrrolidinyl. The heterocycloalkyl groups of the invention may be substituted or unsubstituted.

The term "aryl" as used herein refers to an aromatic mono- or bicyclic ring having 5 to 10 carbon atoms. Examples of such groups include phenyl, naphthyl, and biphenyl. The aryl groups of the invention may be substituted or unsubstituted.

The term “heteroaryl” as used herein refers to 5-10 membered aromatic mono- or bicyclic ring systems containing a total of 1-3 nitrogen, sulfur, and oxygen atoms.

-23 heteroatoms, such as, but not limited to, the following groups: thiazolyl, thiazolyl, oxazolyl, furyl, indolyl, benzthiazolyl, benztriazolyl, benzodioxyl, indazolyl, and benzofuryl. Preferred heteroaryl groups include quinolyl, isoquinolyl, naphthalenyl, benzofuranyl, benzothienyl, indolyl, pyridyl, pyrazinyl, thienyl, furyl, pyrrolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, pyrazolyl, triazolyl, thiadiazolyl, and imidazolyl. The heteroaryl groups of the invention may be substituted or unsubstituted.

The term "perhaloalkyl" as used herein refers to alkyl groups of 1-6 carbon atoms in which three or more hydrogen atoms are replaced by halogen atoms.

The term “phenyl” used in this specification refers to a 6-membered aromatic ring.

The term "halogen" as used herein refers to chlorine, bromine, iodine and fluorine atoms.

Unless otherwise defined, substituents are unsubstituted and may be C1-6 alkyl, C1-6 cycloalkyl, C1-6 heterocycloalkyl, C1-6 perhaloalkyl, alkylamino, dialkylamino, aryl or heteroaryl groups.

In the specification, the term "carbon number" refers to the number of carbon atoms forming the carbon chain, but does not refer to carbon atoms in substituents, such as alkyl or alkoxy substituents.

-24- l·;. . · • . - *

In the case of compound names, unless otherwise defined, the above definitions apply to each individual element of the compound name. For example, the name alkylcycloalkyl means an alkylcycloalkyl group, the constituent alkyl and cycloalkyl groups of which are as defined above.

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

The compounds of the invention contain an asymmetric center, which results in the existence of different stereoisomers of the compounds, such as racemic mixtures as well as individual optical isomers. In some preferred embodiments of the invention, the compounds are substantially pure optical isomers. By "substantially pure" is meant that the composition consists of more than 75% of the desired isomer and does not contain more than 25% of the undesired isomer. In more preferred embodiments, the pure optical isomer consists of more than 90% of the desired isomer. Individual isomers can be prepared directly, either by asymmetric or stereospecific reactions, or by

-25by the usual separation of optical isomers from a racemic mixture.

Unless otherwise specified, the compounds of the invention can be prepared by one skilled in the art of preparative organic chemistry using readily available reagents and starting materials by the methods described below. The compounds of the invention can therefore be prepared as illustrated in the following reaction schemes.

The novel compounds of the invention can be prepared as illustrated in the following reaction schemes.

According to methods 31 and 34, the suitably substituted amines of formula (2), where the R ₅ substituents and the X group are as defined above, are reacted with the suitably substituted isothiocyanate of formula (3), where the G group is as defined above, directly or in a suitable solvent, for example, tetrahydrofuran, acetonitrile, ethyl acetate, methylene dichloride or N,N-dimethylformamide, to give the desired thioureas of formula (I). Similarly, the suitably substituted isocyanates of formula (4), where the R 1 - R ₅ substituents and the X group are as defined above, are reacted with the suitably substituted aniline of formula (5), where the G group is as defined above, in a suitable solvent, for example, listed above, to give the desired thioureas of formula (I).

-26 desired thioureas of general formula (I) are obtained (Scheme 1: Methods 31 and 34).

Alternatively, the appropriately substituted thioureas of formula (I) can be prepared by methods 32 or 33 by reacting amines of formula (2) and (5), where Rt - _Rs and G are as defined above, with one molar equivalent of 1,1'-thiocarbonyldiimidazole in a suitable solvent, for example methylene dichloride, tetrahydrofuran or a mixture thereof, or with one molar equivalent of 1,1'-thiocarbonyldi-(1,2,4)-triazole in a suitable solvent, for example methylene dichloride, tetrahydrofuran or a mixture thereof, at room temperature (Scheme 2: Methods 32 and 33).

In some cases, subsequent chemical modification of the final thioureas of general formula (I) is desirable (Scheme 3: Methods 35-40).

Thioureas of general formula (I), where at least one of the R-ι Rs substituents is a 1-hydroxyethyl or carboxymethoxy group and G is as defined above and X is a single bond, can be prepared by alkaline hydrolysis at room temperature using aqueous potassium or sodium hydroxide in a suitable solvent, for example methanol, tetrahydrofuran or a mixture thereof, starting from the corresponding alkyl ester using method 35 or 36.

Thioureas of general formula (I) wherein at least one of the substituents Rt _R5 has the meaning

-271-acetyloxy or methanesulfonyloxyethoxy group and G is as defined above and X is a single bond, can be prepared starting from the corresponding 1-hydroxyethoxy derivative using Method 37 or 38 using a suitable acylating reagent, such as benzoyl chloride or methanesulfonyl chloride, and a suitable tertiary base, such as triethylamine or diisopropylethylamine, in a suitable solvent, such as methylene dichloride or the like, at room temperature.

Thioureas of formula (I), wherein at least one of the substituents _R1 , R5 is 1-aminoethoxy and G is as defined above and X is a single bond, can be prepared by reaction of the corresponding 1-methanesulfonyloxyethoxy derivative and a suitable secondary amine, such as dimethylamine, in a suitable solvent mixture, such as tetrahydrofuran and water or the like, using Method 39, at room temperature.

Thioureas of general formula (I), wherein at least one of the substituents R ₁ Rs is a 1-aminoalkyl group, G is as defined above and X is a single bond, can be prepared by using Method 40, by reacting the corresponding 1-azidoalkyl derivative and tin(II) chloride in a suitable solvent, for example methanol, ethanol or a similar solvent, at room temperature.

The intermediate isothiocyanates of general formula (3) and (4), which were prepared by methods 31 and 34,

-28 described above, essentially according to the procedure of Staab, HA and Walther, G. [Justus Liebigs Ann. Chern. 657, 104 (1962)], is prepared according to Method 41 by reacting the appropriately substituted amines of formula (5) or (2), where Rt - r _5i and G and X are as defined above, with one molar equivalent of 1,Γ-thiocarbonyldiimidazole in a suitable solvent, for example methylene dichloride or tetrahydrofuran or a mixture thereof (Scheme 4: Method 41).

Intermediates (2) and (5) can be prepared according to the following method:

Amines of formula (2), wherein R1 - _R5 and X are as defined above, and amines of formula (5) are prepared by reduction of appropriately substituted nitrobenzenes using methods 1A - 1G, one of a number of methods known in the art [Lindsay, RJ, Comprehensive Organic Chemistry, Sutherland ed., Vol. 2, Chapter 6.3.1, Aromatic Amines (1979)]. In these reactions, nitrobenzene is reduced to aniline under the following reaction conditions:

(a) in the presence of iron powder and a strong acid, such as hydrochloric acid (Method 1A), in a suitable solvent, such as methanol or ethanol, or without solvent, at a temperature ranging from room temperature to the boiling point of the solvent; or

(b) in the presence of iron powder and glacial acetic acid (Method 1B), in a suitable solvent such as methanol or ethanol

-29or without solvent in a temperature range from room temperature to the boiling point of the solvent;

(c) in the presence of iron powder and aqueous ammonium chloride solution (Method 1C) in a suitable solvent such as methanol or ethanol or without solvent at a temperature range from room temperature to the boiling point of the solvent; or

(d) in the presence of tin and a strong mineral acid such as hydrochloric acid (Method 1D) in a suitable solvent such as methanol or ethanol or without solvent at a temperature ranging from room temperature to the boiling point of the solvent; or

e) if R1 - R2 is Cl, Br, I, -( _OSO2 ) _-CF3 or -(OSO2)-1-(4-methylphenyl) in a solvent such as methanol, ethanol or ethyl acetate, under one or more atmospheres of pressure, in the presence of hydrogen and palladium on activated carbon by catalytic reduction (Method 1E); or

f) if R1 - R2 and Rg - _R2 are Cl, Br, I, -(OSO2) _-CF3 or -(OSO2)-1 -(4-methylphenyl) in a suitable solvent, for example methanol or ethanol, at a temperature range from room temperature to the boiling point of the solvent, by catalytic reduction in the presence of cyclohexene and palladium on activated carbon (Method 1F); or

g) in the presence of aqueous sodium hydrosulfite in an alcoholic solvent, in a temperature range from room temperature to the boiling point of the solvent (1G.

-30 methods).

Amines of formula (2) wherein Rt - _r5 and X are as defined above and anilines of formula (5) can be prepared by cleavage of the aniline nitrogen carbon atom in the amide or carbamate derivatives of anilines by a number of methods known in the art, as described in Methods 3A - 3C [Greene, Protective Groups in Organic Synthesis, Vol. 2, Chapter 7 (1971), and references therein]. These reactions can be carried out under the following reaction conditions: a) the appropriately substituted arylamino-tert-butylcarbamate is reacted with a strong acid, such as trifluoroacetic acid (Method 3A), in a suitable solvent, such as methylene chloride, or without solvent, at a temperature range of 0°C to room temperature (Method 3A); or b) the appropriately substituted arylamino-(2-trimethylsilylethyl)carbamate is reacted with a fluorine ion source, such as tert-butylammonium fluoride or potassium fluoride, in aqueous acetonitrile or tetrahydrofuran at a temperature range from room temperature to the boiling point of the solvent (Method 3B); or c) the appropriately substituted arylaminotrifluoroacetamide is reacted with a strong base, such as sodium or potassium hydroxide or sodium or potassium carbonate, in an alcoholic solvent, such as methanol or ethanol, at a temperature range from room temperature to the boiling point of the solvent (Method 3C).

-31 Amines of formula (2), wherein R ₁ - r ₅ and X are as defined above and at least one R 1 - R 5 substituent is a vinyl group, can be prepared (Method 11) by coupling a vinyl trialkyltin reagent, for example tributylvinyltin, under palladium-catalyzed conditions, for example tris(dibenzylideneacetone)dipalladium catalyst, triphenylarsine as ligand, in the presence of a suitably substituted bromo- or iodoaniline, for example 3-chloro-4-iodoaniline, in the temperature range from room temperature to the boiling point of the solvent, essentially using the method of Farina, V. and Roth, GP [Advances in Metal-Organic Chemistry 5, 1-53, (1996) and references therein].

Amines of formula (2), wherein R1 - _R5 are as defined above, X is a covalent bond and at least one of the substituents _R2 and R6 is a dialkylamino group, can also be prepared (Method 42) by reacting a suitably substituted 3- or 5-bromo- or -iodoaniline, for example 3-amino-5-bromo-trifluoromethylbenzene, with a palladium catalyst, for example bis(dibenzylideneacetone)palladium catalyst, tri-o-tolylphosphine ligand, in the presence of at least two molar equivalents of a strong base, for example lithium bis(trimethylsilylamide), in a closed tube, in a suitable solvent, for example tetrahydrofuran or toluene, at a temperature ranging from room temperature to 100°C.

Amination with secondary amines is carried out in the temperature range -32, essentially according to the method of Hartwig, J.F. and Louie, J. [Tetrahedron Letters 36(21), 3609 (1995)].

Amines of formula (2), wherein Rt - _r5 and X are as defined above and at least one of the substituents R2 and R4 is an alkyl group, can also be prepared (Method 43) by alkylating a suitably substituted 3- or 5-bromo- or -iodoaniline, for example 3-amino-5-bromo-trifluoromethylbenzene, in the presence of a palladium catalyst, for example [1, T-bis(diphenylphosphino)ferrocene]palladium(II) chloride-methylene dichloride complex, and 9-borabicyclo[3.3.1]nonane (9-BBN) and a simple base, for example sodium hydroxide, in a suitable solvent, for example tetrahydrofuran or a similar solvent, at a temperature range from room temperature to the boiling point of the solvent.

The acyl and carbamoyl amine derivatives used as starting materials in Methods 3A-3C can be prepared by art-known transformations of the corresponding amines as described in Methods 2A-2G [Greene, Protective Groups in Organic Synthesis, Vol. 2, Chapter 7 (1971), and references therein]. These reactions can be carried out under the following reaction conditions:

a) a suitably substituted amine in the presence or absence of one or more molar equivalents of a tertiary amine, for example triethylamine or diisopropylethylamine,

-33 is reacted with di-tert-butyl dicarbonate in a suitable solvent, such as acetone, tetrahydrofuran, N,N-dimethylformamide, methylene dichloride or a similar solvent, at a temperature ranging from room temperature to the boiling point of the solvent (Method 2A), resulting in the corresponding carbamic acid arylamino-tert-butyl ester; or

b) a suitably substituted aniline (Method 2B) is reacted with 1-[2-(trimethylsilyl)ethoxycarbonyloxy]benzotriazole in the presence of a tertiary amine, such as triethylamine or diisopropylethylamine, in a suitable solvent, such as N,N-dimethylformamide, at room temperature, to give the corresponding carbamic acid arylamino-(2-trimethylsilylethyl)ester; or

c) reacting an appropriately substituted aniline with a carboxylic acid chloride or carboxylic acid anhydride in the absence of solvent or in a suitable solvent such as tetrahydrofuran, N,N-dimethylformamide, methylene dichloride, pyridine or the like in the presence of one or more molar equivalents of a tertiary amine such as triethylamine or diisopropylethylamine (Method 2C) to give the corresponding arylaminoamide; or

d) a suitably substituted nitroaniline in the presence or absence of one or more molar equivalents of a tertiary amine, for example triethylamine or diisopropylethylamine, without solvent or in a suitable solvent, for example

-34 is reacted with a carboxylic acid chloride in tetrahydrofuran, 1,4-dioxane or a similar solvent at a temperature range from room temperature to the boiling point of the solvent (Method 2D), resulting in the corresponding nitro-aryl-amino-amide; or e) a suitably substituted aniline is reacted with a carboxylic acid in the presence of a coupling reagent, such as benztriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate, 2-(1H-benzotriazol-1-yloxy)-1,1,3,3-tetramethyluronium hexafluorophosphate, dicyclohexylcarbodiimide or another similar reagent, and in the presence of a tertiary amine, such as triethylamine or diisopropylethylamine, in a suitable solvent, such as methylene dichloride, N,N-dimethylformamide or a similar solvent, at room temperature (Method 2E), resulting in the corresponding arylaminoamide; or f) a suitably protected aniline, for example an arylaminocarbamic acid tert-butyl ester or the like, wherein at least one of the groups R1 - R2 is -WY-( _CH2 )-Z, where W, Y and Z are as defined above, is reacted with a carboxylic acid anhydride in the presence of a suitable base, for example pyridine, in a suitable solvent, for example methylene dichloride, N,N-dimethylformamide or a similar solvent, at a temperature range of 0°C to room temperature (Method 2F), resulting in the corresponding carboxylic acid ester; or

-35 g) a suitably substituted aniline, where at least one of the groups R ₁ - r ₅ is a hydroxyl group, is reacted with di-tert-butyl dicarbonate in the presence of one or more molar equivalents of a tertiary amine, for example triethylamine or diisopropylethylamine, in a suitable solvent, for example acetone, tetrahydrofuran, N,N-dimethylformamide, methylene dichloride or the like, at a temperature range from room temperature to the boiling point of the solvent (Method 2G) to give the corresponding arylaminocarbamic acid tert-butyl ester.

The nitrobenzene intermediates, which are ultimately converted to the amines of formula (2) and (5) using Methods 1A - 1G described above, can be prepared by Methods 4A, 4C and 4E - 4F.

In Methods 4A, 4C and 4E-4F, the nitrobenzene intermediates, which are ultimately converted to amines of formula (2), and where _R2 and _R4 are as defined above and R1, _R3 and/or _R5 are alkoxy, thioalkoxy, alkylsulfenyl, alkylsulfinyl and dialkylamino groups, can be prepared by nucleophilic substitution reaction of nitrobenzenes substituted with appropriately substituted 2-, 4- and/or 6-fluoro, chloro, bromo, iodo, trifluoromethylsulfonyl or 4-(methylphenyl)sulfonyl groups, by the following methods: a) 2- or 4-halo or sulfonate esters of appropriately substituted nitrobenzenes or benzonitriles without solvent or in a suitable solvent, e.g.

-36 is reacted with alcohols in tetrahydrofuran, dioxane, acetonitrile, N,N-dimethylformamide or dimethyl sulfoxide, in the presence or absence of one or more molar equivalents of a base, such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride or the like, at a temperature range from room temperature to the boiling point of the solvent (Method 4A); or

b) the 2- or 4-halo- or sulfonate esters of the appropriately substituted nitrobenzenes or benzonitriles are reacted with pre-prepared sodium, lithium or potassium phenoxide without solvent or in a suitable solvent, such as tetrahydrofuran, dioxane, acetonitrile, N,N-dimethylformamide or dimethylsulfoxide, at a temperature range from room temperature to the boiling point of the solvent (Method 4H); or c) the 2- or 4-halo- or sulfonate esters of the appropriately substituted nitrobenzenes or benzonitriles are reacted with ammonia, primary or secondary amine without solvent or in a suitable solvent, such as tetrahydrofuran, dioxane, acetonitrile, N,N-dimethylformamide or dimethylsulfoxide, at a temperature range from room temperature to the boiling point of the solvent (Methods 4C and 4F); or

d) 2- or 4-halo- or sulfonate esters of appropriately substituted nitrobenzenes or benzonitriles

-37 in a suitable solvent, for example tetrahydrofuran, at a temperature range of 0°C to room temperature with pre-prepared sodium, lithium or potassium salts of amines (Method 4G); or e) 2- or 4-halo- or sulfonate esters of appropriately substituted nitrobenzenes or benzonitriles are reacted without solvent or in a suitable solvent, for example tetrahydrofuran, dioxane, acetonitrile, N,N-dimethylformamide or dimethylsulfoxide, at a temperature range from room temperature to the boiling point of the solvent with sodium sulfide, followed by an alkyl halide added directly to the reaction mixture (Method 4E).

The nitrobenzene intermediates, which are ultimately converted into amines of formula (2), where Rt - _r5 are alkoxy groups, are prepared from the appropriately substituted hydroxynitrobenzenes by methods 5C and 6 under the reaction conditions listed below: a) a hydroxynitrobenzene is reacted with an alkyl halide or dialkyl sulfonate 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 dimethyl sulfoxide, at a temperature range from room temperature to the boiling point of the solvent (method 5C); or

- 38 b) a hydroxynitrobenzene is reacted with an alkyl alcohol and triphenylphosphine in the presence of a dialky l-azadicarboxylate reagent, for example diethyl azodicarboxylate, in an anhydrous aprotic solvent, for example diethyl ether or tetrahydrofuran, at a temperature range of 0°C to room temperature, essentially according to the method described by Mitsunobu, O. [Synthesis 1, (1981) and references therein] (Method 6).

The carbamoylamine derivatives, which are used as starting materials in Methods 3A. 3C. and which are finally converted into amines of the general formula (2), wherein at least one of the groups R1 - R2 is an alkoxy group, can be prepared by reacting the appropriately substituted hydroxyarylaminocarbamic acid tert-butyl ester with alkyl halides, trifluoromethylsulfonate, 4-methylbenzenesulfonate, dialkylsulfonate, ethylene carbonate or the like in the presence of a suitable base, for example potassium carbonate, in a suitable solvent, for example acetone, toluene or N,N-dimethylformamide, at a temperature range from room temperature to the boiling point of the solvent (Methods 5A and 5E.)

The nitrobenzene intermediates, which are ultimately converted into amines of formula (2), where R1 and/or _R3 are alkoxy, _R2 and/or _R4 are halogen and X is a covalent bond, can be prepared using standard halogenation methods under the reaction conditions listed below (7A. - G.

- 39 - · · , %, * methods):

a) a 2- or 4-hydroxynitrobenzene is reacted with an aqueous sodium hypochlorite solution at room temperature (Methods 7A and 7B); or

b) a 2-hydroxy-4-methoxy- or 2,4-dimethoxybenzene is reacted with bromine in a suitable solvent, for example chloroform, methylene chloride, glacial acetic acid or a similar solvent, in the presence or absence of a silver salt of trifluoroacetic acid, at room temperature (Method 7C);

or

c) a 2,4-dimethoxynitrobenzene in a suitable solvent, for example glacial acetic acid, in the presence of anhydrous zinc chloride at room temperature with benzyltrimethylammonium dichloro-

-react with iodate (Method 7E); or

d) a 2-hydroxy-4-methoxynitrobenzene is reacted with benzyltrimethylammonium dichloroiodate in a suitable solvent mixture, for example a mixture of methylene dichloride and methanol, in the presence of sodium bicarbonate at room temperature (Method 7F); or

e) a 2,4-dimethoxynitrobenzene in a suitable solvent, for example tetrachloroethane, at a temperature range from room temperature to the boiling point of the solvent

3,5-dichloro-1-fluoropyridine trifluoromethanesulfonic acid salt (Method 7G).

The nitrobenzene intermediates, which are finally converted into amines of general formula (2), where _R4 is a trifluoromethyl group, R1 - _R3 and R5 - R6 are as defined above and X is a covalent bond, are prepared in the following manner:

The method involves reacting the appropriately substituted 4-iodo-nitrobenzene with trimethyl-(trifluoromethyl)silane in the presence of copper(I) iodide and potassium fluoride in a suitable solvent, such as N,N-dimethylformamide or a similar solvent, in a closed reaction vessel at a temperature ranging from room temperature to the boiling point of the solvent (Method 8).

The nitrobenzene intermediates, which are ultimately converted to amines of formula (2), wherein _R4 is -HNCOCH2NR7R8 or _-HNCOCH2SR6 , R1 - R3 and R5 - _R6 are as defined above and X is a covalent bond, can be prepared by reacting the appropriately substituted 4-(n-chloroacetyl)nitroaniline in a suitable solvent, such as tetrahydrofuran and/or an aqueous mixture thereof, at a temperature range from room temperature to the boiling point of the solvent, with a suitable secondary amine, such as dimethylamine, morpholine or a similar base, or in the presence of a suitable base, such as sodium or potassium carbonate or a similar base, in a suitable solvent, such as tetrahydrofuran, 1,4-dioxane or a similar solvent, at a temperature range from room temperature to the boiling point of the solvent, with a suitable with thiol (Methods 19A and 19B).

The nitrobenzene intermediates, which are finally converted to amines of general formula (2), where at least one of the groups Rt - _r5 is a trifluoromethanesulfonate group and X is a covalent bond, are thus

-41 can be prepared by reacting the corresponding phenol with trifluoromethanesulfonic anhydride in the presence of a tertiary amine, such as triethylamine or diisopropylethylamine or a similar base, in a suitable solvent, such as methylene dichloride, at a temperature range of 0°C to room temperature (Method 25).

The carbamoylamine derivatives used as starting materials in Methods 3A-3C, which are ultimately converted into amines of the general formula (2), where at least one of the groups Rt- _r5 is an alkylsulfenyl or alkylsulfinyl group, can be prepared by reacting the corresponding 4-alkylthioacylarylamino or carbamoylarylamino derivative in a suitable solvent mixture, for example a mixture of acetone and methylene chloride or water, at room temperature, with a suitable oxidizing agent, for example dimethyloxirane or sodium periodate (Methods 9 and 9B).

The carbamoylamine derivatives used as starting materials in Methods 3A. - 3C., which are finally converted into amines of the general formula (2), where R ₄ is a 1-hydroxyethyl group, R 1 - R ₃ and Rs are as defined above and X is a covalent bond, can be prepared by reacting the corresponding 4-vinylcarbamoylaniline with sodium borohydride in a suitable solvent, for example, a mixture of tetrahydrofuran, 1,4-dioxane or a similar solvent and water, at room temperature, in the presence of mercury (II) acetate (Method 12).

-42 The carbamoylamine derivatives used as starting materials in Methods 3A. - 3C., which are finally converted into amines of the general formula (2), where R ₄ is 2-hydroxyethyl, R 1 - R 3 and R ₅ and X are as defined above, can be prepared by reacting the corresponding 4-vinylcarbamoylaniline with sodium borohydride in a suitable solvent, such as tetrahydrofuran, 1,4-dioxane or a similar solvent, in the temperature range of 0°C to room temperature, in the presence of glacial acetic acid (Method 13).

The carbamoylamine derivatives used as starting materials in Methods 3A. - 3C., which are finally converted into amines of the general formula (2), where R ₄ is a 1-azidoethyl group, R 1 - R 3 and R 5 and X are as defined above, can be prepared by reacting the corresponding 4-(1-hydroxyethyl)carbamoylaniline with HN 3 in a suitable solvent mixture, for example tetrahydrofuran and methylene chloride, at a temperature range of 0°C to room temperature, in the presence of a diazadicarboxylate, for example diethyl azodicarboxylate, and triphenylphosphine (Method ₁₄ ).

The carbamoylamine derivatives used as starting materials in Methods 3A. - 3C., which are finally converted into amines of the general formula (2), where R ₄ is a 3-dimethylaminoprop-1-ynyl group, R 1 - R ₃ and Rs are as defined above and X is a covalent bond, can be prepared by reacting the corresponding 4-iodocarbamoylaniline with 1-dimethylamino-2-propyne in a suitable tertiary amine solvent, for example triethylamine or diisopropylethylamine, in the presence of bis(triphenylphosphine)palladium(II) catalyst and copper(II) iodide at a temperature range from room temperature to the boiling point of the solvent (Method 15).

The carbamoylamine derivatives used as starting materials in Methods 3A. - 3C., which are finally converted into amines of the general formula (2), where R ₄ is a 3-dimethylaminoacryloyl group, R 1 - R 3 and R 5 are as defined above and X is a covalent bond, can be prepared by reacting the corresponding 4-(3-dimethylaminoprop-1-ynyl)carbamoylaniline in a suitable solvent mixture, for example a mixture of methylene dichloride and methanol, with a suitable peracid, for example chloroperbenzoic acid, at a temperature range of 0°C to room temperature (Method 16).

The carbamoylamine derivatives used as starting materials in Methods 3A. - 3C., which are finally converted into amines of the general formula (2), where R ₄ is a 4-isoxazol-5-yl group or a 4-(1H-pyrazol-3-yl) group, R 1 - R 3 and R 5 are as defined above and X is a covalent bond, can be prepared by reacting the corresponding 4-(3-dimethylaminoacryloyl)carbamoylaniline with hydroxylamine hydrochloride or hydrazine hydrate in a suitable solvent mixture, for example 1,4-dioxane or ethanol, or similar solvents, at room temperature (Methods 17 and 18).

-44 The carbamoylamine derivatives used as starting materials in Methods 3A. - 3C., which are finally converted to amines of the general formula (2), where R ₄ is a group of the general formula -HNCO2Z, R! - r ₃ , r ₅ and Z are as defined above and X is a covalent bond, can be prepared by reacting the corresponding 4-aminocarbamoylaniline with 1,1-carbonyldi-(1,2,4)-triazole and an appropriately substituted alcohol in a suitable solvent mixture, for example tetrahydrofuran and methylene dichloride or similar solvents, at a temperature range from room temperature to the boiling point of the solvent (Method 20).

The carbamoylamine derivatives used as starting materials in Methods 3A. - 3C., which are finally converted to amines of the general formula (2), where at least one of the groups R1 - _R5 is a dialkylamino group and X is as defined above, can be prepared from the appropriately substituted aldehyde in a suitable solvent, for example water, methanol, tetrahydrofuran mixture or toluene or a similar solvent, at room temperature, using sodium cyanoborohydride or hydrogen gas and 10% palladium on activated carbon (Methods 26 and 30).

Amines of general formula (2), wherein at least one of the groups Rt - _r5 is a hydroxyl group and X is as defined above, are treated with the corresponding ester, e.g. acetate, in the presence of a suitable base, e.g. sodium bicarbonate or sodium hydroxide,

-45 can be prepared by reacting it in a suitable solvent, such as a methanol-water mixture, at a temperature range from room temperature to the boiling point of the solvent (Methods 27 and 28).

Amines of formula (2), wherein at least one of Rt to _R5 is hydroxybenzamido and X is as defined above, can be prepared by reacting the corresponding N-(4-aminophenyl)phthalimide with lithium borohydride in a suitable solvent, such as tetrahydrofuran, diethyl ether or the like (Method 29).

The amine intermediates of formula (2), where Rt - Rs are as defined above and X is -CH2- or -(CH2)2~, can be prepared by ^the following methods: a) reduction of the appropriately substituted benzo- or phenylacetonitrile, carried out in a suitable solvent, such as ethylene glycol, dimethyl ether, tetrahydrofuran or the like, at a temperature range from room temperature to the boiling point of the solvent, using borane-dimethylsulfide complex (Method 44);

b) by reduction carried out in one or more atmospheres of hydrogen gas, in the presence of a suitable catalyst, for example 5% or 10% palladium on activated carbon, and an acid, for example 4-methylbenzenesulfonic acid, hydrochloric acid or the like, in a suitable solvent, for example ethylene glycol monomethyl ether, ethyl acetate, ethanol or the like, at room temperature (50).

-46 methods);

c) reduction carried out using lithium aluminum hydride in a suitable solvent, such as tetrahydrofuran or diethyl ether, at a temperature range of 0°C to room temperature (Method 51).

The unsaturated nitro compounds used as starting materials in Method 51 and finally converted to amines of formula (2) where Rt - _r5 are as defined above and X is -(CH2)2- can be prepared by reacting the appropriately substituted benzaldehyde with nitromethane in a suitable solvent, such as acetic acid, at a temperature ranging from room temperature to the boiling point of the solvent (Method 53): the benzaldehydes used as starting materials in Method 53 can be prepared by reducing the appropriately substituted benzonitrile with diisobutylaluminum hydride (Method 52). The benzonitriles used as starting materials in Method 52 can be prepared by the reaction of the appropriate aryl bromide with copper cyanide in a suitable solvent, such as N,N-dimethylformamide, at a temperature range from room temperature to the boiling point of the solvent (Method 59).

The nitrile starting compounds required for the preparation of amines of general formula (2), where the groups Rt - _r5 are as defined above and X is -O( _CH2 ) _2NH2 or -S( _CH2 ) _{2NH21, can} be prepared in the following manner:

-47 that the appropriately substituted phenol or thiophenol is reacted with bromoacetonitrile in the presence of a suitable base, such as potassium carbonate, in a suitable solvent, such as acetone, at room temperature (Method 49).

Alternatively, the nitrile starting compounds required for the preparation of amines of formula (2), wherein R1 - R2 groups are as defined above and X is -(OH?^·. can be prepared essentially according to the method of Wilk, B. [Synthetic Comm. 23, 2481 (1993)] by reacting the appropriately substituted phenethanol with acetone cyanohydrin and triphenylphosphine in a suitable solvent, such as diethyl ether, tetrahydrofuran or a similar solvent, at a temperature range of 0°C to room temperature, in the presence of a suitable azodicarboxylate, such as diethyl azodicarboxylate (Method 54).

Alternatively, the amines of formula (2), where R1 - R2 are as defined above and X is -CH( _CH3 )-, can be prepared by subjecting the corresponding formamide to acid or base catalyzed hydrolysis in a suitable solvent mixture, for example a methanol-water or ethanol-water mixture, at a temperature range from room temperature to the boiling point of the solvent, in the presence of a suitable acid catalyst, for example 6N hydrochloric acid, or a suitable base catalyst, for example 5N sodium or potassium hydroxide (Method 46).

-48The formamide starting compounds used in Method 46, which are ultimately converted to amines of general formula (2), can be prepared by reacting the appropriately substituted acetophenone with ammonium formate, formic acid and formamide at temperatures ranging from room temperature to the boiling point of the solvent (Method 45).

Alternatively, the amines of formula (2), wherein R1 - R2 are as defined above and X is -CH( _CH3 )-, can be prepared by reducing the appropriately substituted O-methyloxime substantially according to the method of Itsuno, S., Sakurai, Y. and Ito, K. [Synthesis 995 (1988)] in a suitable solvent, such as tetrahydrofuran or diethyl ether, at room temperature in the presence of sodium borohydride and zirconium tetrachloride (Method 48). The required O-methyloximes are prepared by reacting the corresponding acetophenone with O-methylhydroxylamine and pyridine in a suitable solvent, such as ethanol or methanol, at room temperature to the boiling point of the solvent (Method 47).

Amines of formula (2), where R1 - _R5 are as defined above and X is -CH(J)-, where J is as defined above, can be prepared by reduction of the appropriately substituted ketones using methods 45, 47 and 48 described above. These required ketones, if not commercially available, are

-49 be, can be prepared by reacting the appropriately substituted benzaldehyde with a suitable organometallic reagent, such as phenyllithium, isopropylmagnesium bromide, ethylmagnesium bromide or the like, in a suitable solvent, such as diethyl ether or tetrahydrofuran, at a temperature in the range of -78°C to 0°C (Method 57). The resulting alcohols are oxidized to the corresponding ketone with a suitable oxidizing agent, such as chromium trioxide in a mixture of aqueous sulfuric acid and acetone or with pyridinium chlorochromate or pyridinium dichromate in a suitable solvent, such as methylene dichloride, at room temperature (Method 58).

The aniline intermediates of formula (5) can be prepared as described in Method 3A above. Thus, the reaction of phenylcarbamic acid tert-butyl ester of formula (6), where G is as defined above, with trifluoroacetic acid at room temperature without solvent, followed by neutralization with aqueous sodium hydroxide, yields the desired anilines of formula (5). The required carbamic acid esters of formula (6), where G is as defined above, are prepared by reacting the substituted acid chloride of formula (8), where G is as defined above, with 4-aminophenylcarbamic acid tert-butyl ester of formula (7) in a suitable solvent, such as methylene dichloride, dimethyl sulfoxide, N,N-dimethylformamide or a mixture thereof, in the presence of triethylamine (Method 2C.

-Method 50). Carboxylic acid chlorides of general formula (8) are commercially available or can be prepared by the reaction of the appropriate carboxylic acid and oxalyl chloride in a suitable solvent, for example methylene dichloride, at room temperature (Scheme 5: Methods 2C and 3A).

Alternatively, the carbamic acid esters of formula (6), where G is as defined above, can be prepared by reacting the substituted carboxylic acid of formula (8a), where G is as defined above, with a suitably substituted 4-aminophenylcarbamic acid tert-butyl ester of formula (7) in a suitable solvent, such as methylene chloride, N,N-dimethylformamide or the like, at room temperature, in the presence of a tertiary amine, such as triethylamine or diisopropylethylamine, and a suitable coupling reagent, such as benztriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, 2-(1H-benztriazol-1-yloxy)-1,1,3,3-tetramethyluronium hexafluorophosphate, dicyclohexylcarbodiimide or the like (Method 2E).

Carboxylic acids of formula (8a) are commercially available or can be prepared by methods described in the literature. For example, in the case where group G is a substituted thiadiazole, the acid can be prepared from the corresponding carboxylic acid ester in a suitable solvent mixture, for example methanol or ethanol and water, at room temperature, in the presence of a suitable base, for example

-51 by hydrolysis in the presence of sodium or potassium hydroxide.

Similarly, if G is a substituted or unsubstituted thiazole, a substituted or unsubstituted oxazole, a substituted or unsubstituted isothiazole or a substituted or unsubstituted isoxazole, which are not commercially available, the corresponding carboxylic acid of formula (8a) can be prepared from the corresponding methyl or ethyl ester by hydrolyzing the ester in a suitable solvent mixture, such as methanol or ethanol and water, at room temperature, in the presence of a suitable base, such as sodium or potassium hydroxide. These esters are commercially available or can be prepared by methods described in the literature.

If the carboxylic acid ester starting materials required for the preparation of carboxylic acids of formula (8a) are not commercially available, they can be prepared by methods described in the literature. For example, 5-substituted 1,2,3-thiadiazole-4-carboxylic acid esters can be prepared by methods described in Caron, M. J. Org. Chem. 51, 4075 (1986) and Taber, D.F.; Ruckle, R.E. J. Amer. Chem. Soc. 108, 7686 (1986). Accordingly, according to Method 21, reaction of a β-ketocarboxylic acid ester with 4-methylbenzenesulfonyl azide, methanesulfonyl azide or the like in a suitable solvent such as acetonitrile in the presence of a tertiary amine base such as triethylamine or diisopropylethylamine affords the corresponding diazo-β-ketocarboxylic acid 52-,

-ester. Reaction of this compound with 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide in a suitable solvent, such as benzene, toluene or the like, at a temperature ranging from room temperature to the boiling point of the solvent, yields the desired 5-substituted 1,2,3-thiadiazole-4-carboxylic acid ester.

The 4-substituted 1,2,3-triazole-4-carboxylic acid esters can be prepared essentially by the method described by Shafiee, A., Lalezari, I., Yazdani, S. Shahbazian, F.M., and Partovi, T.J. in Pharmaceutical Sci. 65, 304 (1976). Accordingly, according to methods 22 and 23, the reaction of an aqueous solution of an appropriately substituted β-ketocarboxylic acid ester and semicarbazide hydrochloride in a suitable solvent, such as methanol or ethanol, at a temperature range from room temperature to the boiling point of the solvent, in the presence of a suitable base, such as pyridine, provides the corresponding semicarbazone derivative. The compound thus obtained is reacted with thionyl chloride at 0°C without the use of a solvent, followed by treatment with an excess of aqueous sodium bicarbonate solution to give the corresponding 4-substituted 1,2,3-thiadiazole-4-carboxylic acid ester.

The thiazole-4-carboxylic acid esters are prepared essentially by the method described by Schöllkopf, U., Porsch, P., Lau, H. in Liebigs. Ann. Chern. 1444 (1979).

-53 Accordingly, using Methods 55 and 56, the reaction of isocyanoacetic acid ethyl ester and N,N-dimethylformamide dimethyl acetal in a suitable alcoholic solvent, such as ethanol, at room temperature affords the corresponding 3-dimethylamino-2-isocyanoacrylic acid ethyl ester. This compound is treated with hydrogen sulfide gas in a suitable solvent, such as tetrahydrofuran, in the presence of a suitable tertiary amine, such as triethylamine or diisopropylethylamine or a similar base, to afford the corresponding thi azo 1-4-carboxylic acid ethyl ester.

Further suitably substituted thiazoles can be prepared essentially as described in the following references: Bredenkamp, M.W., Holzafel, C.W., van Zyl, W.J. Synthetic Comm. 20., 2235 (1990). Suitable unsaturated oxazoles can be prepared essentially as described in the following references: Henneke, K.H., Schöllkopf, U., Neudecker, T. Liebigs Ann. Chern. 1979 (1979). Substituted oxazoles can be prepared essentially as described in the following references: 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 for illustrative purposes and do not limit the scope of the invention.

-54 degrees Celsius

Example 1 (Method 1 A) Preparation of 4-Methoxy-3-trifluoromethylphenylamine

2.2 g of 4-methoxy-3-trifluoromethyl-nitrobenzene and 1.68 g of iron powder are suspended in a mixture of 35 ml of ethanol and 15 ml of water, 0.42 ml of concentrated hydrochloric acid solution, 6 ml of ethanol and 3 ml of water are added, and the mixture is then refluxed at room temperature for about 1 hour. The mixture is then cooled, filtered and concentrated in vacuo. The resulting oil is dissolved in ethyl acetate and extracted three times with 5% aqueous hydrochloric acid solution. The combined acid extracts are cooled in an ice-water cooler, neutralized with solid sodium carbonate and then extracted with ethyl acetate. The organic extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated in vacuo, and the residue was purified by short column chromatography using silica gel and ethyl acetate as eluent to give the product as an amber oil.

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

2,6- dichlorobenzo 1-1,4-diamine 3-chloro-4-methylsulfanylphenylamine 2,6-dibromobenzene-1,4-diamine 3-chloro-4-trifluoromethylphenylamine

3-chloro-4-ethylsulfanylphenylamine 4-methoxy-3-trifluoromethylphenylamine 3,5-dichloro-4-methoxy-2-methylphenylamine 5-chloro-2-ethoxy-4-methoxyphenylamine 5-chloro-4-ethoxy~2-methoxyphenylamine 5-iodo-2,4-dimethoxyphenylamine 3,5-diiodo-2,4-dimethoxyphenylamine 3,5-dibromo-2,4-dimethoxyphenylamine 5-chloro-2-methoxy-4-methylphenylamine

2-chloro-N(1),N(1)-dimethyl-benzo 1-1,4-diamine 3-chloro-4-piperidin-1-yl-phenylamine 3-chloro-4-pyrrolidin-1-yl-phenylamine

N(1)-benzyl-2-chloro-benzo 1-1,4-diamine 3-chloro-4-(4-methyl-piperazin-1-yl)-phenylamine 2-chloro-N(1)-methyl I-N (1)-(1-methyl-piperidin-4-yl)-benzene-1,4-diamine

2-chloro-N(1)-methyl-N(1)-(1-methyl-pyrrolidin-3-yl)-benzo 1-1,4-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 )-methylbenzo 1-1,4-diamine 2-[(4-amino-2-chlorophenyl)-(2-hydroxyethyl)-amino]-ethanol 2-chloro-N(1 )-hexyl-N(1 )-methyl-benzo 1-1,4-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

-56- J.'·

2-chloro-N(1)-(2-dimethylaminoethyl)-N(1)-methylbenzene-1,4-diamine

2-chloro-N(1)-(2-dimethylaminoethyl)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-dimethylamino-prop yl)-benzene-1,4-diamine N(1 )-(1 - benzylpyrrol id in-3-i I )-2-chlorobenzene-1,4-diamine 3-chloro-4-(1-methyl-piperidin-4-yloxy)-phenylamine 3-chloro-4-(2-dimethylaminoethoxy)-phenylamine 3-chloro-4-(3-dimethylamino-propoxy)-phenylamine 3-chloro-4-(T-methylpyrrolidin-3-yloxy)phenylamine 3-chloro-4-cyclohexyloxyphenylamine

Example 2 (Method 1 B)

Preparation of 4-Bromo-2,4-dimethoxyphenylamine

0.48 g of 4-bromo-2,4-dimethoxynitrobenzene and 0.42 g of iron powder are suspended in a mixture of 10 ml of acetic acid and 10 ml of ethanol, and then heated at 120°C for about 5 hours. The mixture is then cooled, filtered and concentrated in vacuo. Water is added to the mixture, cooled in an ice-water bath, neutralized with solid sodium carbonate and extracted with methylene chloride. The organic extracts are washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated in vacuo and the residue is purified by chromatography using silica gel and 20% ethyl acetate in hexane as eluent. The product is obtained as an amber oil.

Example 3 (Method 1C) Preparation of (4-amino-2,6-dichlorophenoxy)acetic acid tert-butyl ester g (4-nitro-2,6-dichlorophenoxy)acetic acid tert-butyl ester is dissolved in a mixture of 17 ml of ethanol and 8.6 ml of water, 0.861 g of iron powder and 86 mg of ammonium chloride are added, and the reaction mixture is refluxed at room temperature for about 1 hour. The mixture is then filtered and concentrated in vacuo. The resulting oil is partitioned between water and ethyl acetate, the organic phase is washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated in vacuo. The desired product is obtained as a pale yellow solid.

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

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 0-2-chloro-5-methoxyphenoxy)acetic acid methyl ester (4-amino-2-chloro-5-methoxyphenoxy)acetic acid tert-butyl ester (2-amino-4-chloro-5-methoxyphenoxy)acetic acid tert-butyl ester

-58N(1)-benzyl-4-chloro-5-methoxybenzene-1,2-diamine

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

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

N-(4-amino-5-chloro-2-hydroxyphenyl)~2-fluorobenzamide furan-2-carboxylic acid-(4-amino-2-chlorophenyl)-amide (4-amino-2-chlorophenyl)-carbamic acid ethyl ester N-(4-amino-5-chloro-2-methylphenyl)-acetamide

N-(4-amino-5-chloro-2-methylphenyl)-2-fluorobenzamide furan-2-carboxylic acid-(4-amino-5-chloro-2-methylphenyl)-amide N-(4-amino-3-chlorophenyl)-2-fluorobenzamide furan-2-carboxylic acid-(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 (Method 1 D)

Preparation of 3,5-dichloro-4-phenoxyphenylamine

To a mixture of 6.1 g of 3,5-dichloro-4-phenoxynitrobenzene and 12 g of tin powder, 60 ml of concentrated

- 59 hydrochloric acid solution. 60 ml of ethanol are added to the mixture, and the mixture is then refluxed at room temperature for about 1 hour. The reaction mixture is then cooled in an ice-water bath and made alkaline by adding solid sodium hydroxide. The resulting suspension is filtered through a pad of diatomaceous earth and extracted three times with ethyl acetate. The combined organic phases are washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated in vacuo. The product is recrystallized from ethyl acetate:hexane to give the desired product as a pale yellow solid.

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

-furan-2-ylethylamine

3-chloro-4-isopropoxy-phenylamine 2-butoxy-5-chloro-4-methoxy-phenylamine 3,5-dichloro-2-methoxy-4-methyl-phenylamine 2-benzyloxy-5-chloro-4-methoxy-phenylamine 2-benzyloxy-5-chloro-2-methoxy-phenylamine 5-fluoro-2,4-dimethoxy-phenylamine (4-amino-2,6-dichlorophenoxy)-acetic acid ethyl ester 3,5-dichloro-4-phenoxy-phenylamine

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

-60 2-(4-amino-4-chloro-5-methoxy-phenoxy)-ethanol 2-(4-amino-2-chloro-5-methoxy-phenoxy)-ethanol 2-(4-amino-2-chloro-5-methoxy-phenoxy)-butyronitrile 4-amino-2-chloro-5-methoxy-phenol 2-amino-4-chloro-5-methoxy-phenol

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)-meth i l-benzo 1-1,4-diamine N(2)-benzyl-4-methoxybenzene-1,2-diamine 2-(4-amino-2-chlorophenoxy)-ethanol

2-Chloro-N (1)-cyclohexyl-N (1)-ethyl-benzene-1,4-diamine 4-butoxy-3-chloro-phenylamine (4-amino-2-chloro-phenoxy)-acetonitrile 2-Chloro-N (1)-cyclohexylbenzene-1,4-diamine 2-Chloro-N (1),N (1)-dipropyl-benzene-1,4-diamine 3-Chloro-4-(2,2,2-trifluoroethoxy)-phenylamine 3-Chloro-4-(octahydro-quinolin-1 -yl)-phenylamine N (1)-allyl-2-chloro-N (1)-cyclohexylbenzene-1,4-diamine

N-(4-amino-2-methoxy-5-methyl-phenyl)-2-fluoro-benzamide furan-2-carboxylic acid-(4-amino-2-methoxy-5-methyl-phenyl)-amide N-(4-amino-naphthalen-1-yl)-2-fluoro-benzamide 3-chloro-N,N-dimethyl-benzene-1,2-diamine 3-chloro-4-propoxy-phenylamine 3-iodo-4-methoxy-phenylamine 3-chloro-2,4-dimethoxy-aniline 3-bromo-4-methoxy-phenylamine

-61 3-chloro-4-ethoxyphenylamine

Example 5 (Method 1 E) Preparation of (4-aminophenyl)carbamic acid isobutyl ester

2.0 g of N-(4-nitrophenyl)isobutyramide were dissolved in 100 ml of ethylene glycol monomethyl ether and 275 g of 10% palladium on carbon were added. The mixture was hydrogenated in a Parr hydrogenator at 30 psi for 2 hours at room temperature. The catalyst was then removed by filtration through diatomaceous earth and the filtrate was evaporated to dryness in vacuo by azeotropic distillation with heptane three times. The residue was triturated with heptane to give the desired product as a white solid.

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

2-Methyl-3H-benzimidazol-5-yl-amine N-(4-aminophenyl)formamide

H-benzimidazol-5-ylamine (4-aminophenyl)carbamic acid isobutyl ester N-(4-aminophenyl)isobutyramide

N-(5-amino-pyridin-2-yl)-2-methyl-benzamide Furan-2-carboxylic acid-(5-amino-pyridin-2-yl)-amide N-(5-amino-pyridin-2-yl)-2-fluoro-benzamide [6-(2,2,2-trifluoroacetylamino)-pyridin-3-yl)]-carbamic acid 62-tert-butyl ester

N-(5-amino-pyridin-2-yl)-2,2,2-trifluoroacetamide (4-amino-benzyl)-carbamic acid tert-butyl ester 2-(3,5-bis-trifluoromethyl-phenyl)-ethyl-amine 1-tert-butyl-1H-imidazol-2-yl-amine 3-(3-dimethyl-amino-propyl)-5-trifluoromethyl-phenyl-amine

Example 6 (Method 1 F) Preparation of N-(4-amino-2-methylphenyl)-2-fluorobenzamide

A mixture of 4.55 g of 2-fluoro-N-(2-methyl-4-nitrophenyl)benzamide, 30 ml of cyclohexene, 70 ml of ethanol, 30 ml of water and 3 g of 10% palladium on activated carbon was refluxed for 30 minutes. The catalyst was removed by filtration through diatomaceous earth and the filtrate was evaporated. The resulting oil was dissolved in 50 ml of ethyl acetate and kept at 4°C for 12 hours. The light brown product was filtered off.

Using the above procedure, the following compounds were prepared from the appropriate starting materials.

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

2-methylbenzoxazol-6-ylamine

N-(4-amino-3-methoxyphenyl)acetamide

2-acetylamino-5-aminobenzoic acid

N-(4-aminophenyl)acetamide

[4-(3-Amino-benzoyl-amino)-phenyl]-tert-butyl ester

-63[4-(2-amino-benzoylamino)-phenyl]-tert-butyl ester N-[4-amino-2-cyano-phenyl)-acetamide N-(4-amino-2,5-dimethoxy-phenyl)-2-fluoro-benzamide furan-2-carboxylic acid-(4-amino-2,5-dimethoxy-phenyl)-amide N-(4-amino-2-cyano-phenyl)-2-fluoro-benzamide furan-2-carboxylic acid-(4-amino-2-methoxy-phenyl)-amide N-(4-amino-2-methoxy-phenyl)-2-fluoro-benzamide N-(4-amino-2-methoxy-5-methyl-phenyl)-acetamide N-(4-amino-2-benzoylphenyl)-acetamide

N-(4-amino-2-benzoylphenyl)-2-fluorobenzamide furan-2-carboxylic acid-(4-amino-2-benzoylphenyl)-amide N-(4-amino-3-methylphenyl)-acetamide

N-(4-amino-3-methyl-phenyl)-2-fluoro-benzamide furan-2-carboxylic acid-(4-amino-3-methyl-phenyl)-amide 5-amino-2-[(2-fluoro-benzoyl)-amino]-N-phenyl-benzamide furan-2-carboxylic acid-(4-amino-2-phenyl-carbamoyl-phenyl)-amide N-(4-amino-naphthalen-1-yl)-acetamide furan-2-carboxylic acid-(4-amino-naphthalen-1-yl)-amide N-(4-amino-2-trifluoromethyl-phenyl)-acetamide furan-2-carboxylic acid-(4-amino-2-cyano-phenyl)-amide furan-2-carboxylic acid-(4-amino-2-trifluoromethyl-phenyl)-amide N-(4-amino-2-methyl-phenyl)-2-fluoro-benzamide furan-2-carboxylic acid-(4-amino-2-methyl-phenyl)-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

-64 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) Preparation of N-(4-amino-2-chlorophenyl)-2-thiomorpholin-4-ylacetamide

3.02 g of N-(2-chloro-4-nitrophenyl)-2-thiomorpholin-4-ylacetamide were dissolved in 200 ml of ethanol and added to a solution of 12 g of sodium thiosulfate in 60 ml of water. The reaction mixture was refluxed for 12 hours, cooled and poured into water. The mixture was extracted with ethyl acetate. The ethyl acetate solution was washed twice with saturated aqueous sodium chloride solution, dried over anhydrous potassium carbonate, filtered through a pad of diatomaceous earth and concentrated in vacuo to give an oil. Toluene was added to the oil and the solution was cooled, whereupon the desired product precipitated as a pale orange crystalline solid.

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

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

-65 N-(4-amino-2-chlorophenyl)-2-dipropylaminoacetamide

Example 8 (Method 2A) Preparation of (3-chloro-4-iodophenyl)carbamic acid tert-butyl ester g 3-chloro-4-iodoaniline is dissolved in 40 ml of tetrahydrofuran containing 6.9 ml of diisopropylethylamine, then 8.6 g of di-tert-butyldicarbonate is added, then the mixture is heated to reflux. After about 15 hours, another 6.9 ml of diisopropylethylamine and 21 g of di-tert-butyldicarbonate are added to the mixture, then the mixture is heated to reflux for a further 24 hours. The solution is cooled, concentrated in vacuo, diluted with ethyl acetate, washed three times with 5% aqueous hydrochloric acid solution and once with saturated aqueous sodium chloride solution. The solution was dried over anhydrous sodium sulfate and concentrated in vacuo to give the desired crude product as a brown oil. Crystallization was initiated by addition of hexane, the solid product was isolated and recrystallized from hexane to give the desired product as a white solid.

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

N'-(4-nitrobenzoyl)hydrazinecarboxylic acid tert-butyl ester (3-chloro-4-iodophenyl)carbamic acid tert-butyl ester

-66 (4-bromo-3-chlorophenyl)carbamic acid tert-butyl ester (3-chloro-4-vinylphenyl)carbamic acid tert-butyl ester (3-chloro-4-methylsulfanylphenyl)carbamic acid tert-butyl ester (4-amino-3-chlorophenyl)carbamic acid tert-butyl ester (4-chloro-2-nitrophenyl)carbamic acid tert-butyl ester (3-tert-butoxycarbonylamino-5-chlorophenyl)carbamic acid tert-butyl ester (4-nitrobenzyl)carbamic acid tert-butyl ester (3-bromo-5-trifluoromethylphenyl)carbamic acid tert-butyl ester (2-amino-3-chloro-5-trifluoromethylphenyl)carbamic acid tert-butyl ester

Example 9 (Method 2B) Preparation of (3-chloro-4-vinylphenyl)carbamic acid 2-trimethylsilanylethyl ester

3.4 g of 3-chloro-4-vinylphenylamine are dissolved in 44 ml of N,N-dimethylformamide, to the solution are added first 5.8 ml of diisopropylethylamine and then 7.1 g of 1-[2-(terimethylsilyl)ethoxycarbonyloxy]benzotriazole, and the mixture is stirred under argon atmosphere for 3 days at room temperature. The solution is then diluted with water and extracted three times with diethyl ether. The combined organic extracts are washed with water and then with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue is purified by chromatography using a mixture of silica gel and hexane containing 10% by volume ethyl acetate.

-67 As a result, the desired product is obtained in the form of a yellow oil.

Example 10 (Method 2C)

Preparation of [4-(2-fluoro-benzoyl-amino)-phenyl-carbamic acid tert-butyl ester]

To a solution of 1.58 g of mono-N-(tert-butoxycarbonyl)-1,4-phenylenediarnine and 1.50 ml of triethylamine in 25 ml of methylene chloride was added 1.20 g of o-fluorobenzoyl chloride. The product which immediately separated was filtered and washed with fresh solvent. The result was 1.90 g of a white solid.

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

N-(3-Methoxy-4-nitrophenyl)acetamide

N-(4-aminophenyl)isobutyramide

2,2,2-trifluoro-N-(2-methoxy-4-nitrophenyl)acetamide [4-(2-methyl-benzoylamino)phenyl]carbamic acid tert-butyl ester acetic acid 2-(4-tert-butoxycarbonylaminophenylcarbamoyl)phenyl ester

[4-(4-fluorobenzoylamino)phenyl]carbamic acid tert-butyl ester

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

-68 [4-(2-fluorobenzoylamino)phenyl]carbamic acid tert-butyl ester

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

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

[4-(4-methoxybenzoylamino)phenyl]carbamic acid tert-butyl ester

[4-(2,2-dimethylpropionylamino)phenyl]carbamine v-tert-butyl

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

[4-(2,2,2-trifluoroacetylamino)phenyl]carbamic acid tert-butyl ester (4-benzoylaminophenyl)carbamic acid tert-butyl ester (4-methanesulfonylaminophenyl)carbamic acid tert-butyl ester (4-phenylacetylaminophenyl)carbamic acid tert-butyl ester {4-[(thiophene-2-carbonyl)amino]phenyl}carbamic acid tert-butyl ester

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

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

[4-(3-methanesulfonylaminobenzoylamino)phenyl]-

- carbamate terebutyl ester ethyl [3-[[[4-[[(1,1-dimethylethoxy)carbonyl]amino]phenyl]amino]carbonyl]phenyl]carbamate

-69 [4-(2-trifluoromethylbenzoylamino)phenyl]carbamic acid tert-butyl ester

[4-(2,6-Difluorobenzoylamino)phenyl]carbamic acid tert-butyl ester

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

[4-(2-bromo-benzoyl-amino)-phenyl]-carbamate, tert-butyl ester

[4-(2-nitro-benzoyl-amino)-phenyl]-carbamic acid tert-butyl ester {4-[(benzo[b]thiophene-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester {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-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester {4-[(3-bromo-thiophene-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester {4-[(biphenyl-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester

N-(4-tert-butoxycarbonylaminophenyl)phthalic acid

[4-(2,3-Difluorobenzoylamino)phenyl]carbamic acid tert-butyl ester

[4-(2,5-difluorobenzoylamino)phenyl]carbamic acid tert-butyl ester

-70 [4-(2,4-difluorobenzoylamino)phenyl]carbamic acid tert-butyl ester

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

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

[4-(2,3,4-trifluorobenzoylamino)phenyl]carbamic acid tert-butyl ester

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

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

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

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

[4-(3-Butoxybenzoylamino)phenyl]carbamic acid tert-butyl ester {4-[(5-difluoromethylfuran-2-carbonyl)amino]phenyl}carbamic acid tert-butyl ester {4-[(thiophene-3-carbonyl)amino]phenyl}carbamic acid tert-butyl ester {4-[(5-methylfuran-2-carbonyl)amino]phenyl}carbamic acid tert-butyl ester {4-[(5-bromofuran-2-carbonyl)amino]phenyl}carbamic acid tert-butyl ester (4-hexanoylaminophenyl)carbamic acid tert-butyl ester

-71 [4-(2-thiophen-2-yl-acetyl-amino)-phenyl]-carbamic acid-tert-butyl·

-ester {4-[(pyridine-3-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester {4-[(4-bromo-furan-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester {4-[(furan-3-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl·

-ester (4-phenoxycarbonylaminophenyl)carbamic acid tert-butyl ester {4-[(benzo[1,3]dioxole-4-carbonyl)amino]phenyl}carbamic acid tert-butyl ester

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

N-(2,5-dimethoxy-4-nitrophenyl)-2-fluorobenzamide {4-[(furan-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester

[4-(2-phenoxy-acetyl-amino)-phenyl}-carbamic acid tert-butyl ester {4-[(5-nitro-furan-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester {4-((5-chloro-furan-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester {4-[(3-methyl-furan-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester

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

-72{4-[(4-furan-3-yl-[1,2,3]thiadiazole-5-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester {4-[(5-tert-butyl-furan-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester

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

2-Fluoro-N-[4-(2,2,2-trifluoroacetylamino)-3-trifluoromethyl-phenyl]-benzamide furan-2-carbon a v-[4-(2,2,2-trifluoroacetylamino)-3-trifluoromethyl-phenyl]-amide

2-Fluoro-N-(2-methylbenzoxazol-6-yl)benzamide

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

N-(4-acetylamino-2-methoxyphenyl)-2,2,2-trifluoroacetamide 2-fluoro-N-[3-methoxy-4-(2,2,2-trifluoroacetylamino)phenyl]benzamide

2-fluoro-N-(2-fluoro-benzoyl)-N-(4-nitro-2-trifluoromethyl-phenyl)-benzamide {4-[(1H-pyrazole-4-carbonyl)amino]-phenyl}carbamic acid tert-butyl ester

-73 {4-[(1 H-imidazole-4-carbonyl)-amino]-phenyl)-carbamic acid tert-butyl ester {4-[(5-methyl-[1,2,3]thiadiazole-4-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester {4-[(5-furan-3-yl-[1,2,3]thiadiazole-4-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester

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

4-(2-fluorobenzoylamino)-2-hydroxybenzoic acid methyl ester N-(5-chloro-2,4-dimethoxyphenyl)oxamic acid isoxazole-5-carboxylic 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]carbamic acid tert-butyl ester

[4-(2,6-Difluorobenzoylamino)benzyl]carbamic acid tert-butyl ester

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

N-(3-amino-5-chlorophenyl)acetamide

[4-(3-Chloro-benzoyl-amino)-phenyl]-carbamic acid tert-butyl ester

-74[4-(4-Chlorobenzene-amino)phenyl]carbamic acid tert-butyl ester

[4-(4-Dimethylaminobenzoylamino)phenyl]carbamic acid tert-butyl ester (4-Benzenesulphonylaminophenyl)carbamic acid tert-butyl ester

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

2,2,2-trifluoro-N-(5-nitropyrimidin-2-yl)acetamide

Example 11 (Method 2D) Preparation of 2-chloro-N-(2-chloro4-nitrophenyl)acetamide

19.0 g of 2-chloro-4-nitroaniline and 30 ml of chloroacetic acid chloride were dissolved in 150 ml of tetrahydrofuran and heated under reflux for 1 hour. The solution was cooled and concentrated in vacuo to give a wet yellow solid. 250 ml of diethyl ether was added and the yellow solid was collected.

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

N-(4-nitro-3-trifluoromethylphenyl)acetamide (2-chloro-4-nitrophenyl)carbamic acid ethyl ester 2-acetylamino-5-nitrobenzoic acid furan-2-carboxylic acid-(2-hydroxy-5-chloro-4-nitrophenyl)-amide furan-2-carboxylic acid-(2-methyl-4-nitrophenyl)-amide

-75furan-2-carboxylic acid-(2-methoxy-4-nitrophenyl)-amide N-(2-chloro-4-nitrophenyl)-benzamide

2-methoxy-N-(4-nitrophenyl)acetamide N-(4-nitrophenyl)acrylamide N-(4-nitrophenyl)isobutyramide [(4-acryloylamino)phenyl]carbamic acid tert-butyl ester (4-nitrophenyl)carbamic acid tert-butyl ester

[1,2,3]thiadiazole-4-carboxylic acid-(5-nitro-pyridin-2-yl)-amide furan-2-carboxylic acid-(5-nitro-pyridin-2-yl)-amide 2-fluoro-N-(5-nitro-pyridin-2-yl)-benzamide

N-(2-chloro-4-nitrophenyl)-2-fluorobenzamide furan-2-carboxylic acid-(2,5-dimethoxy-4-nitrophenyl)-amide N-(2-cyano-4-nitrophenyl)-2-fluorobenzamide

2-fluoro-N-(2-methoxy-4-nitrophenyl)-benzamide 2-methyl-N-(5-nitropyridin-2-yl)-benzamide furan-2-carboxylic acid-(2-methoxy-5-methyl-4-nitrophenyl)-amide 2-fluoro-N-(2-methoxy-5-methyl-4-nitrophenyl)-benzamide N-(2-benzoyl-4-nitrophenyl)-acetamide

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

N-(3-methyl-4-nitrophenyl)acetamide

2-fluoro-N-(3-methyl-4-nitrophenyl)-benzamide furan-2-carboxylic acid-(3-methyl-4-nitrophenyl)-amide 2-acetylamino-5-nitro-N-phenylbenzamide

2-[(2-fluorobenzoyl)amino]-5-nitro-N-phenylbenzamide furan-2-carboxylic acid-(4-nitro-2-phenylcarbamoylphenyl)-amide 2-fluoro-N-(4-nitronaphthalen-1-yl)-benzamide furan-2-carboxylic acid-(4-nitronaphthalen-1-yl)-amide

-76N-(5-chloro-2-hydroxy-4-nitrophenyl)acetamide

N-(5-chloro-2-hydroxy-4-nitro-phenyl)-2-fluoro-benzamide furan-2-carboxylic acid-(2-chloro-4-nitro-phenyl)-amide N-(4-nitro-2-trifluoro-methyl-phenyl)-acetamide furan-2-carboxylic acid-(2-cyano-4-nitro-phenyl)-amide 2-fluoro-N-(4-nitro-2-trifluoro-methyl-phenyl)-benzamide furan-2-carboxylic acid-(4-nitro-2-trifluoro-methyl-phenyl)-amide 2-fluoro-N-(2-methyl-4-nitro-phenyl)-benzamide

N-(5-chloro-2-methyl-4-nitro-phenyl)-2-fluoro-benzamide furan-2-carboxylic acid-(5-chloro-2-methyl-4-nitro-phenyl)-amide 2-(2-fluoro-benzoyl-amino)-5-nitro-benzoic acid 2-[(furan-2-carbonyl)-amino)-5-nitro-benzoic acid N-[(3-chloro-4-nitro-phenyl)-2-fluoro-benzamide furan-2-carboxylic acid-(3-chloro-4-nitro-phenyl)-amide 2,5-difluoro-N-(3-methyl-4-nitro-phenyl)-benzamide 2-fluoro-N-(4-nitro-3-trifluoro-methyl-phenyl)-benzamide furan-2-carboxylic acid-(4-nitro-3-trifluoro-methyl-phenyl)-amide 2-chloro-N-(2-chloro-4-nitro-phenyl)-acetamide

N-(2-chloro-4-nitrophenyl)methanesulfonamide furan^-carboxylic acid-[S-methoxy^-^^^-trifluoroacetylamino)phenyl]-amide

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

Example 12. Preparation of {4-[(4-phenyl-[1,2,3]thiadiazole-5-carbonyl)-amino-1-phenyl}-carbamic acid tert-butyl ester

0.8 g of 1-(N-tert-butoxycarbonyl)-1,4-phenylenediamine and

0.7 g of 4-phenyl-[1,2,3]thiadiazole-5-carboxylic acid is dissolved in 10 ml

-77 in methylene chloride, then 1.3 ml of triethylamine and 1.6 g of benztriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate are added. The mixture is stirred at room temperature, then diluted with water and extracted with methylene chloride. The organic phase is washed with 0.5N hydrochloric acid, saturated aqueous sodium bicarbonate and water, then dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The desired product is obtained.

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

{4-[(1H-pyrrole-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester {4-[(pyrazine-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester {4-[(5-methyl-thiophene-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester {4-[(1-methyl-1H-pyrrole-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester {4-[(quinoline-8-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester {4-[(benzofuran-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester {4-[(isoquinoline-1-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester

-78{4-[(quinoline-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester {4-[(pyridine-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester {4-[(isoquinoline-4-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester {4-[([1,2,3]thiadiazole-4-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester {4-[(1 H-[1, 2,3]triazole-4-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester

[4-(2-methylsulfanylbenzoylhydroxylamino)phenyl}-carbamic acid tert-butyl ester {4-[(quinoline-4-carbonyl)amino]phenyl}-carbamic acid tert-butyl ester {4-[(4-methyl-[1,2,3]thiadiazole-5-carbonyl)amino]phenyl}-carbamic acid tert-butyl ester {4-[(4-phenyl-[1,2,3]thiadiazole-5-carbonyl)amino]phenyl}-carbamic acid tert-butyl ester {4-((1 H-indole-2-carbonyl)amino]phenyl}-carbamic acid tert-butyl ester

[1,2,3]thiadiazole-4-carboxylic acid-4-nitro-benzylamide {4-[([ 1,2,3]thiadiazole-4-carbonyl)-amino]-benzyl}-carbamic acid tert-butyl ester Acetic acid 4-(4-tert-butoxycarbonyl-amino-phenylcarbamoyl)-phenyl ester {4-[(quinoline-6-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester

Example 13 (Method 2F) Preparation of acetic acid ((

0.85 g of [3,5-dichloro-4-(2-hydroxyethoxy)phenyl]-carbamic acid tert-butyl ester was dissolved in 14 ml of pyridine, 1.24 ml of acetic anhydride was added, and the mixture was stirred for 15 hours at room temperature. The solvent was distilled off in vacuo and the residue was dissolved in ethyl acetate. The solution was washed twice with 5% hydrochloric acid solution, once with saturated aqueous sodium bicarbonate solution, and then with saturated aqueous sodium chloride solution. The solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off in vacuo to give the desired product as a colorless oil.

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

Phenylsulfanylacetonitrile

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

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

9.5 g of 2,6-dichloro-4-aminophenol are dissolved in 130 ml of tetrahydrofuran, 11.7 g of di-tert-butyl-80-dicarbonate are added, and the reaction mixture is refluxed for about 15 hours. The solution is cooled, concentrated in vacuo, diluted with ethyl acetate, washed three times with 5% aqueous hydrochloric acid and once with saturated aqueous sodium chloride. The solution is dried over anhydrous sodium sulfate, and the solvent is distilled off in vacuo to give the desired product. The residue is triturated with cold methylene chloride to give the product as a white solid.

Using the above procedure, starting from the appropriate starting materials, the following compound was prepared:

(3-amino-5-chlorophenyl)carbamic acid tert-butyl ester

Example 15 (Method 3A)

Preparation of 3,5-dichloro-4-ethoxyphenylamine

To 0.97 g of solid (3,5-dichloro-4-ethoxyphenyl)carbamic acid tert-butyl ester was added 5 ml of trifluoroacetic acid, and the reaction mixture was stirred for about 45 minutes at room temperature. Water was added to the mixture, 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 solution and dried over anhydrous sodium sulfate. The solution was concentrated in vacuo to give

- 81 is evaporated, the residue is recrystallized from hexane, resulting in the desired product in the form of a pale yellow crystalline substance.

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

5-bromo-pyridin-3-yl-amine

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

N-(4-aminophenyl)-2,2,2-trifluoroacetamide

Thiophene-2-carboxylic acid-(4-aminophenyl)-amide

H-pyrrole-2-carboxylic acid (4-aminophenyl)amide

N-(4-aminophenyl)-4-nitrobenzamide

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

N-(4-aminophenyl)-3-dimethylaminobenzamide

N-(4-aminophenyl)-3-methanesulfonylaminobenzamide

- 82 N-(4-aminophenyl)-2-terifluoromethylbenzamide N-(4-aminophenyl)-2,6-difluorobenzamide N-(4-aminophenyl)-2-chlorobenzamide

N-(4-amino-phenyl)-2-brom-benzamide N-(4-amino-phenyl)-2-nitrobenzamide pyrazine-2-carboxylic acid-(4-amino-phenyl)-amide 5-methylthiophene-2-carboxylic acid-(4-amino-phenyl)-amide quinoline-8-carboxylic acid-(4-amino-phenyl)-amide

-methyl-1H-pyrrole-2-carboxylic acid-(4-aminophenyl)-amide benzo[b]thiophene-2-carboxylic acid-(4-aminophenyl)-amide benzofuran-2-carboxylic acid-(4-aminophenyl)-amide

N-(4-Aminophenyl)-Isonicotinamide Naphthalene-2-Carboxylic Acid-(4-Amino-Phenyl)-Amide N aft a I in-1 -Carboxy Acid-(4-Amino-Phenyl)-A Mid Isoquinoline-1-Carboxy Acid-(4-Amino-Phenyl)-Amide Quinolin-2-Carboxy Acid-(4-Amino-Phenyl)-Amide 3,5-Dichloro-4-Ethoxy-Phenyl-Amide

4-Butoxy-3,5-dichlorophenylamine isoquinoline-4-carboxylic acid (4-aminophenyl)amide

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

H-[1,2,3]triazole-4-carboxylic acid-(4-aminophenyl)-amide 3-bromothiophene-2-carboxylic acid-(4-aminophenyl)-amide 4-benzyloxy-3,5-dichlorophenylamine

2-(4-amino-2,6-dichlorophenoxy)acetamide (4-amino-2,6-dichlorophenoxy)acetic acid methyl ester

[3-(4-amino-phenyl-carbamyl)-phenyl]-carbamic acid ethyl ester 2-amino-N-(4-amino-phenyl)-benzamide

- 83 biphenyl-2-carboxylic acid-(4-amino-phenyl)-amide N-(4-amino-phenyl)-2,3-difluoro-benzamide N-(4-amino-phenyl)-2,5-difluoro-benzamide N-(4-amino-phenyl)-2,4-difluoro-benzamide 2-acetyl-amino-N-(4-amino-phenyl)-benzamide N-(4-amino-phenyl)-2-methanesulfonyl-amino-benzamide N-(4-amino-phenyl)-2,3,4-trifluoro-benzamide

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 [S-^-aminophenylcarbamoylphenoxy]-acetic acid ethyl ester Pyridine-2-carboxylic acid-(4-aminophenyl)-amide Quinoline-4-carboxylic acid-(4-aminophenyl)-amide 5-methylfuran-2-carboxylic acid-(4-aminophenyl)-amide 5-Difluoromethylfuran-2-carboxylic acid (4-aminophenyl)-amide 1H-indole-2-carboxylic acid (4-aminophenyl)-amide

4-methyl-[1,2,3]thiadiazole-5-carboxylic acid-(4-amino-phenyl)-amide thiophene-3-carboxylic acid-(4-amino-phenyl)-amide 5-chloro-furan-2-carboxylic acid-(4-amino-phenyl)-amide 5-nitro-furan-2-carboxylic acid-(4-amino-phenyl)-amide N-(4-amino-phenyl)-2-thiophen-2-yl-acetamide

3-methylfuran-2-carboxylic acid-(4-amino-phenyl)-amide 5-bromofuran-2-carboxylic acid-(4-amino-phenyl)-amide 4-bromofuran-2-carboxylic acid-(4-amino-phenyl)-amide

-84N-(4-aminophenyl)nicotinamide

N-(4-aminophenyl)-3-furancarboxamide 4-phenyl-[1,2,3]thiadiazole-5-carboxylic acid-(4-aminophenyl)-amide Acetic acid-3-(4-aminophenylcarbamoyl)-phenyl ester Benzo[1,3]dioxole-4-carboxylic acid-(4-aminophenyl)-amide

N-(4-aminophenyl)-3-(2-dimethylaminoethoxy)-benzamide N-(4-aminophenyl)-(3-trifluoromethoxy)-benzamide N-(4-aminophenyl)-3-(2-morpholin-4-ylethoxy)-benzamide (4-aminophenyl)-carbamic acid hexyl ester furan-2-carboxylic acid-(4-aminophenyl)-amide (4-aminophenyl)-carbamic acid phenyl ester hexanoic acid-(4-aminophenyl)-amide

N-(4-amino-phenyl)-acrylamide

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

5-tert-butylfuran-2-carboxylic acid (4-aminophenyl)amide 3-chloro-4-methanesulfinylphenylamine

5-methyl-[1,2,3]thiadiazole-4-carboxylic acid (4-aminophenyl)-amide 2-(4-amino-2-chlorophenyl)-ethanol (4-amino-2-chlorophenyl)-carbamic acid 2-piperidin-1-yl-ethyl ester

5-chloro-N, N-dimethylbenzene-1,3-di ami η

3-(2-methyl-butyl)-5-trifluoromethyl-phenylamine 3-isobutyl-5-trifluoromethylphenylamine furan-2-carboxylic acid (4-aminomethylphenyl)amide N-(4-aminomethylphenyl)-2-fluorobenzamide

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

-85N-(4-aminomethyl-phenyl)-2,6-difluorobenzamide oxazole-4-carboxylic acid (4-aminomethylphenyl)-amide N-(4-amino-phenyl)-3-chlorobenzamide N-(4-amino-phenyl)-4-chlorobenzamide acetic acid 4-(4-amino-phenylcarbamoyl)-phenyl ester N-(4-aminophenyl)-4-dimethylaminobenzamide 1-(4-aminophenyl)-3-[3,5-bis-(trifluoromethyl)phenyl]thiourea

N-(4-aminophenyl)-2-iodobenzamide N-(4-aminophenyl)-3-trifluoromethylbenzamide

Example 16 (Method 3B) Preparation of 1-(4-amino-2-chlorophenyl)ethanol

5.7 ml of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran was added to 0.5 g of [3-chloro-4-(1-hydroxyethyl)phenyl]carbamic acid 2-trimethylsilanylethyl ester, and the reaction mixture was stirred at room temperature for about 3.5 hours. The solution was evaporated in vacuo, the residue was dissolved in a 1:1 mixture of ethyl acetate and hexane, and then successively with water, saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off in vacuo, and the residue was purified by chromatography using silica gel and 40% ethyl acetate/hexane as eluent. The product was obtained as an amber oil.

Example 17 (Method 3C) Preparation of N-(4-amino-cyano-phenyl)-2-fluoro-benzamide

2.5 g of N-[3-cyano-4-(2,2,2-trifluoroacetylamino)phenyl]-2-fluorobenzamide are dissolved in a mixture of 270 ml of methanol and 16 ml of water, 5.0 g of potassium carbonate are added, and the reaction mixture is refluxed overnight. The solvent is distilled off in vacuo, the residue is taken up in water, and then extracted with methylene dichloride. The organic phases are combined, washed with water and then with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and finally the solvent is distilled off in vacuo. As a result, the product is obtained in the form of a white solid.

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

N-(4-amino-phenyl)-2-methanesulfinyl-benzamide N-(4-amino-3-cyano-phenyl)-2-fluoro-benzamide furan-2-carboxylic acid-(4-amino-3-cyano-phenyl)-amide N-(4-amino-3-cyano-phenyl)-acetamide furan-2-carboxylic acid-(4-amino-3-trifluoromethyl-phenyl)-amide N-(4-amino-3-methoxy-phenyl)-acetamide N-(4-amino-3-methoxy-phenyl)-2-fluoro-benzamide furan-2-carboxylic acid-(4-amino-3-methoxy-phenyl)-amide « ·¥ W Ο** *

Example 17 (Method 4A) Preparation of 2-chloro-1-cyclohexyloxy-4-nitrobenzene

0.9 g of potassium hydride washed three times with hexane is placed in a flask, a solution of 2.9 g of cyclohexanol in 20 ml of dimethyl sulfoxide is slowly added under an argon atmosphere, and the mixture is stirred at room temperature for about 1 hour. A solution of 1 g of 3-chloro-4-fluoronitrobenzene in 10 ml of dimethyl sulfoxide is added to the mixture, and the resulting dark red solution is heated at about 100°C for 3 hours. The reaction mixture is cooled, diluted with 300 ml of diethyl ether, washed successively with saturated aqueous ammonium chloride solution, three times with water, and then with saturated aqueous sodium chloride solution. The organic phase is dried over anhydrous magnesium sulfate, and the solvent is distilled off in vacuo. The residual oil was purified by chromatography using silica gel and 5% ethyl acetate in hexane as eluent to give the product as an orange solid.

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

A mixture of 1.0 g of 3-chloro-4-fluoro-nitrobenzene and 1.72 g of N,N'-dimethyl-S-amino-pyrrolidine was stirred for about 24 hours. The mixture was then diluted with ethyl acetate, washed twice with water, once with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate.

- 88 - ··*· ·.-** **·** -*· * dried. The solvent is distilled off in vacuo and the residue is purified by chromatography using silica gel as the carrier and pure ethyl acetate, then pure methanol as the eluent. As a result, the desired product is obtained in the form of a yellow oil.

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

(2-chloro-4-nitrophenyl)dipropylamine

1-(2-chloro-4-nitro-phenyl)-piperidine 1-(2-chloro-4-nitro-phenyl)-pyrrolidine (2-chloro-4-nitro-phenyl)-cyclohexyl-methyl-amine benzyl-(2-chloro-4-nitro-phenyl)-amine (2-chloro-4-nitro-phenyl)-methyl-(1-methyl-piperidin-4-yl)-amine (2-chloro-4-η i tro-phenyl)-cyclohexyl-ethyl-amine (2-chloro-4--nitro-phenyl)-cyclohexyl-amine (2-chloro-4-η i tro-phenyl)-methyl-( 1 -methyl-pyrrolidin-3-yl)-amine (1 -benzi-pyrrolidin-3-yl)-(2-chloro-4-nitro-phenyl)-methyl-amine (2-chloro-4-nitro-phenyl)-cyclopentyl-methyl-amine 1-(2-chloro-4-nitrophenyl)decahydroquinoline

Allyl-(2-chloro-4-nitrophenyl)cyclohexylamine

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

- ί·.;. · *· - ♦, ·. ·

N-(2-chloro-4-nitrophenyl)-N,N',N'-trimethylpropane-1,3-diamine (1-benzylpiperidin-4-yl)-(2-chloro-4-nitrophenyl)-amine N-(2-chloro-4-nitrophenyl)-N',N'-dimethylethane-1,2-diamine N-(2-chloro-4-nitrophenyl)-N',N'-dimethylpropane-1,3-diamine (2-chloro-4-nitrophenyl)-(2-methoxyethyl)methylamine (1 - benzylpyrrolidin-3-yl)-(2-chloro-4-nitrophenyl)-amine 4-pi per id i n-1-yl-3-trifluoromethylbenzonitrile 4-Dimethylamino-3-trifluoromethylbenzonitrile 4-(4-methylpiperazin-1-yl)-3-trifluoromethylbenzonitrile

Example 19 (Method 4E) Preparation of butyl-(2-chloro-4-nitrophenyl)thioether

5.0 g of 3-chloro-4-fluoro-nitrobenzene and 2.5 g of sodium sulfide were dissolved in 30 ml of N,N-dimethylformamide, stirred at room temperature for 1 hour, and then 12.6 g of butyl iodide were added. The solvent was distilled off in vacuo, and the residue was treated with ethyl acetate and hexane to precipitate the inorganic salts. The solid was filtered off, and the solution was evaporated in vacuo. The residue was purified on a magnesium silicate column using methylene chloride as eluent. The desired product was obtained as a yellow substance.

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

- 90 - ·*?· '»*· *»»* -¾ *«·*

-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

1.0 g of trifluoromethanesulfonic acid 4-chloro-5-methoxy-2-nitrophenyl ester was dissolved in 2.0 ml of tetrahydrofuran, 4.0 ml of 40% aqueous dimethylamine solution was added, and the mixture was stirred for about 15 hours. The solvent was distilled off in vacuo, the residue was dissolved in ethyl acetate, and then washed with water. The aqueous phase was extracted once with ethyl acetate, the combined saturated aqueous sodium chloride solution was washed, and then dried over anhydrous sodium sulfate. The solvent was distilled off in vacuo, and the residue was triturated with hexane. The desired product was obtained as a colorless solid.

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

(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

- 91 1 -(4-chloro-5-methoxy-2-nitro-phenyl)-pyrrolidine benzyl-(4-chloro-5-methoxy-2-nitro-phenyl)-amine (2-chloro-6-nitro-phenyl)-dimethyl-amine

Example 21 (Method 4G) Preparation of (2-chloro-4-nitrophenyl)methylphenylamine

A 2.5M solution of n-butyllithium in hexane (12.3 ml) was added dropwise at 0°C to a solution of 3.0 g of N-methylaniline in 75 ml of tetrahydrofuran. The mixture was allowed to warm slowly to room temperature, cooled to 0°C, and then added via a cannula at -78°C to a solution of 4.9 g of 3-chloro-4-fluorobenzene in 35 ml of tetrahydrofuran. After addition, the reaction mixture was allowed to warm to room temperature over about 1 hour, concentrated in vacuo, quenched with saturated aqueous ammonium chloride, and extracted three times with ethyl acetate. The combined organic phases are 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 anhydrous magnesium sulfate. The solvent is distilled off in vacuo, and the residue is purified by chromatography using a silica gel carrier and a hexane eluent mixture containing 5% by volume diethyl ether. As a result, the desired product is obtained in the form of a clear, colorless oil.

Example 22 (Method 4H)

Preparation of 2,6-dichloro-4-nitrophenol

8.66 g of potassium phenoxide were dissolved in 66 ml of diethylene glycol, 14.86 g of 3,4,5-trichloronitrobenzene were added, 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 phases were washed first with water, then with 10% aqueous sodium hydroxide, and dried over anhydrous magnesium sulfate. The solvent was distilled off in vacuo, and the resulting oil was distilled using a Kugelrohr apparatus. The result was a yellow oil that solidified on standing. The material was recrystallized from ethanol-water to give the desired product as a pale yellow solid.

Example 23 (Method 5A) Preparation of (3,5-dichloro-4-ethoxyphenyl)carbamic acid tert-butyl ester 1.0 g of (3,5-dichloro-4-hydroxyphenyl)carbamic acid tert-butyl ester and 1.0 g of potassium carbonate were dissolved in 100 ml of acetone, followed by the addition of 0.36 g of ethyl iodide, and the mixture was stirred at room temperature for about 15 hours. The solution was filtered, concentrated in vacuo, and partitioned between ethyl acetate and water. The aqueous phase was separated, extracted twice with ethyl acetate, and the combined organic

- 93 phases are washed successively with 10% aqueous sodium hydroxide solution, then with water, and finally dried over anhydrous sodium sulfate. The solvent is distilled off in vacuo to give the desired product as a light brown solid.

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

(3,5-dichloro-4-ethoxyphenyl)carbamic acid tert-butyl ester (4-butoxy-3,5-dichlorophenyl)carbamic acid tert-butyl ester (4-benzyloxy-3,5-dichlorophenyl)carbamic acid tert-butyl ester (4-carbamoylmethoxy-3,5-dichlorophenyl)carbamic acid tert-butyl ester

[3,5-Dichloro-4-(2-cyanoethoxy)phenyl]carbamic acid tert-butyl ester (4-tert-butoxycarbonylamino-2,6-dichlorophenoxy)acetic acid methyl ester

3-Butoxybenzoic acid methyl ester

3-tert-Butoxycarbonylmethoxybenzoic acid methyl ester [4-(3-carbamoylmethoxybenzoylamino)phenyl]carbamic acid tert-butyl ester {4-[3-(2-chloroethoxy)benzoylamino]phenyl}carbamic acid tert-butyl ester

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

2.5 g of 2,6-dichloro-4-nitrophenol and 3.3 g of potassium carbonate are dissolved in 50 ml of N,N-dimethylformamide, 10 ml of bromoacetic acid tert-butyl ester are added, and the reaction mixture is stirred for two days at room temperature. The mixture is then poured into 500 ml of water, extracted three times with hexane, and the combined organic phases are washed with saturated aqueous ammonium chloride solution and dried over anhydrous magnesium sulfate. The solvent is distilled off in vacuo, and the resulting oil is triturated with hexane. The desired product is obtained as a white solid.

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

3-dimethylamino-1-(4-nitrophenyl)propenone 2-chloro-1-isopropoxy-4-nitrobenzene

1,3-dichloro-2-methoxy-4-methyl-5-nitrobenzene

-nitro-4-ethoxy-2-methoxy-5-nitrobenzene

-butoxy-4-kilor-5-methoxy-2-nitrobenzene

-chloro-2-methoxy-5-nitro-4-(phenylmethoxy)-benzene (CA name) 1-chloro-4-methoxy-5-nitro-2-(phenylmethoxy)-benzene (CA name) (2,6-dichloro-4-nitrophenoxy)-acetic acid tere-butyl ester (2,6-dichloro-4-nitrophenoxy)-acetonitrile

- 95 1-chloro-4-methoxy-2-methoxy-5-nitrobenzene

2-(4-chloro-5-methoxy-2-nitrophenoxy)-aceta mid

2-(2-chloro-5-methoxy-4-nitro-phenoxy)-acetamide (4-chloro-5-methoxy-2-nitro-phenoxy)-acetonitrile (2-chloro-5-methoxy-4-nitro-phenoxy)-acetonitrile 4-(2-chloro-5-methoxy-4-nitro-phenoxy)-butyronitrile 2-(4-chloro-5-methoxy-2-nitro-phenoxy)-ethanol

2-(2-chloro-5-methoxy-4-nitro-phenoxy)-ethanol (2-chloro-5-methoxy-4-nitro-phenoxy)-acetic acid tert-butyl ester (2-chloro-5-methoxy-4-nitro-phenoxy)-acetic acid v-methyl ester (4-chloro-5-methoxy-2-nitro-phenoxy)-acetic acid v-methyl ester (4-chloro-5-methoxy-2-nitro-phenoxy)-acetic acid tert-butyl ester (2-chloro-4-nitro-phenoxy)-acetonitrile 1-butoxy-2-chloro-4-nitro-benzene

2-chloro-4-nitro-1-(2,2,2-trifluoroethoxy)benzene

2-chloro-4-nitro-1 - propoxybenzene

2-Chloro-1-ethoxy-4-nitrobenzene

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

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

3-chloro-2,4-dimethoxynitrobenzene

Example 25 (Method 5E)

Preparation of [3,5-dichloro-4-(2-hydroxyethoxy)phenyl]carbamic acid tert-butyl ester

1.0 g of (3,5-dichloro-4-hydroxyphenyl)carbamic acid tert-butyl ester and 0.55 g of potassium carbonate are taken up in 20 ml of toluene, 1.6 g of ethylene carbonate are added, and the mixture is refluxed for 3 hours. The

-96The reaction mixture is cooled and 50 ml of 2.5M aqueous sodium hydroxide solution is added, the organic phase is separated, washed successively with water, saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent is distilled off in vacuo, the residue is purified by chromatography using a silica gel carrier and a hexane eluent mixture containing 30% by volume ethyl acetate. As a result, the desired product is obtained in the form of a white foam.

Example 26 (Method 6) Preparation of 3-(2-chloro-4-nitrophenoxy)-1-methylpyrrolidine

2.0 g of 2-chloro-4-nitrophenol are dissolved in 60 ml of tetrahydrofuran, 2.3 g of 1-methyl-3-pyrrolidinol, 6.0 g of triphenylphosphine and 3.6 g of azodicarboxylic acid diethyl ester are added, and the mixture is stirred at room temperature under an argon atmosphere for 1.5 hours. The solution is concentrated in vacuo, diluted with ethyl acetate, washed successively with 10% by weight aqueous sodium hydroxide solution, water, saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent is distilled off in vacuo, and the residue is purified by chromatography using a silica gel carrier and a methylene dichloride eluent mixture containing 10% by volume methanol. The combined fractions are recrystallized from hexane to give the desired product as a yellow solid.

-97Using the above procedure, starting from the appropriate starting materials, the following compounds were prepared:

4-(2-chloro-4-nitro-phenoxy)-1-methyl-piperidine 3-(2-chloro-4-nitro-phenoxy)-1-methylpyrrolidine [2-(2-chloro-4-nitro-phenoxy)-ethyl]-dimethylamine [3-(2-chloro-4-nitro-phenoxy)-propyl]-dimethylamine

Example 27 (Method 7A) Preparation of 2-chloro-3-methoxy-6-nitrophenol and 2,4-dichloro-3-methoxy-6-nitrophenol

0.5 g of 3-methoxy-6-nitrophenol was placed in a flask, 21 ml of 5.25% aqueous sodium hypochlorite was added, and the mixture was stirred at room temperature for 24 hours. The mixture was cooled in an ice-water bath, acidified with concentrated hydrochloric acid, and extracted twice with ethyl acetate. The organic extracts were dried over anhydrous magnesium sulfate, the solvent was distilled off in vacuo, and the residue was purified by chromatography using silica gel as the carrier and hexane containing 15% by volume acetone as the eluent. As a result, a mixture of mono- and dichlorinated products was obtained as a yellow solid.

- 98 Using the above procedure, the following compounds were prepared from the appropriate starting materials:

3-chloro-2-hydroxy-4-methoxynitrobenzene 3,5-dichloro-2-hydroxy-4-methoxynitrobenzene

Example 28 (Method 7B) Preparation of 2,4-dichloro-3-methyl-6-nitrophenol

5.0 g of 3-methyl-4-nitrophenol were dissolved in 150 ml of water, 230 ml of 5.25% aqueous sodium hypochlorite solution were added, and the mixture was stirred for about 15 hours at room temperature. Another 230 ml of 5.25% aqueous sodium hypochlorite solution was added to the mixture, and the mixture was stirred for another 2.5 days at room temperature. The mixture was then cooled in an ice-water bath, acidified with concentrated hydrochloric acid, and extracted twice with ethyl acetate. The organic extracts were dried over anhydrous magnesium sulfate, the solvent was distilled off in vacuo, and the residue was purified by chromatography using silica gel as the carrier and ethyl acetate as the eluent. The desired product was obtained as a yellow solid. A single recrystallization from chloroform gave an analytically pure sample.

Example 29 (Method 7C) Preparation of 1-bromo-2,4-dimethoxy-5-nitrobenzene

To a solution of 0.50 g of 2,4-dimethoxynitrobenzene in 3 ml of chloroform was added dropwise a solution of 0.23 g of bromine in 1 ml of chloroform, and the mixture was stirred at room temperature for about 15 hours. A further 0.15 g of bromine in 1 ml of chloroform was added and the mixture was stirred for 4 hours. The mixture was poured onto a 5% aqueous sodium bisulfite solution and extracted with chloroform. The combined organic extracts were washed first with a 5% aqueous sodium bisulfite solution and then with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off in vacuo and the residue was recrystallized from toluene. The desired product was obtained as a yellow solid.

Example 30 (Method 7D) Preparation of 4-dibromo-3-methoxy-6-nitrophenol 0.25 g of 5-methoxy-2-nitrophenol and 0.49 g of trifluoroacetate are dissolved in 2 ₁ ml of glacial acetic acid, a solution of 1.42 g of bromine in 3 ml of glacial acetic acid is added dropwise, and the mixture is stirred at room temperature for about 24 hours. The solution is taken up in a mixture of ethyl acetate and water, the organic phase is washed three times with 5% aqueous sodium bisulfite solution and once with saturated aqueous sodium chloride solution. The organic phase is dried over anhydrous magnesium sulfate, and the solvent is distilled off in vacuo. The residue

- Purification by chromatography on silica gel using 20% ethyl acetate/hexane as eluent and recrystallization from chloroform afforded the desired dibrominated product as an orange solid.

Example 31 (Method 7E) Preparation of 1-iodo-2,4-dimethoxy-5-nitrobenzene 1.0 g of 2,4-dimethoxynitrobenzene was dissolved in 10 ml of glacial acetic acid, 1.90 g of benzyltrimethylammonium dichloroiodate and 1.0 g of anhydrous zinc chloride were added, and the mixture was stirred at room temperature under an argon atmosphere. After 5 hours and after 24 hours, another 0.4 g - 0.4 g of benzyltrimethylammonium dichloroiodate were added to the mixture. After 24 hours, another 0.5 g of zinc chloride and 15 ml of glacial acetic acid were added to the mixture. The reaction mixture was stirred at room temperature for three days, filtered, diluted with 5% aqueous sodium bisulfite, and extracted three times with ethyl acetate. The combined organic extracts were washed with 5% aqueous sodium bisulfite, then with saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo and the residue was triturated with hexane to give the desired product as a pale yellow solid.

- 101 -

Example 32 (Method 7F) Preparation of 2,4-diiodo-3-methoxy-6-nitrophenol 0.25 g of 5-methoxy-2-nitrophenol was dissolved in 10 ml of methylene chloride and 6 ml of methanol, followed by the addition of 1.08 g of benzyltrimethylammonium dichloroiodate and 0.85 g of sodium bicarbonate, and the reaction mixture was stirred overnight at room temperature for 24 hours. The solution was filtered, the filtrate was concentrated in vacuo, the residue was dissolved in ethyl acetate, and then washed with 5% aqueous sodium bicarbonate solution, 5% aqueous sodium bisulfite solution, and saturated aqueous sodium chloride solution. The solution was dried over anhydrous magnesium sulfate, the solvent was distilled off in vacuo, and the residue was recrystallized from toluene. As a result, we obtain the desired product in the form of yellow needles.

Example 33 (Method 7G) Preparation of 1-fluoro-2,4-dimethoxy-5-nitrobenzene 1.0 g of 2,4-dimethoxy-nitrobenzene is dissolved in 100 ml of tetrachloroethane, 5.07 g of 3,5-dichloro-1-fluoro-pyridinium-trifluoromethanesulfonic acid (85%) is added, and the mixture is heated at 120 °C for 5 hours. Another 0.25 g of 3,5-dichloro-1-fluoro-pyridinium-trifluoromethanesulfonic acid (85%) is added to the mixture, and heating is continued for another 1 hour. The solution is then cooled to room temperature and the residue is chromatographed on silica gel with hexane and then hexane containing 30% by volume ethyl acetate as eluent.

-102 mixture. The product-containing fractions are combined, concentrated in vacuo, and the residue is recrystallized from hexane to give the desired product as a light brown solid.

Example 34 (Method 8) Preparation of 3-chloro-4-trifluoromethyl-nitrobenzene 2.26 g of 3-chloro-4-iodo-nitrobenzene, 5.68 g of trimethyl-(trifluoromethyl)-silane, 2.28 g of copper(I) iodide and 0.56 g of potassium fluoride are dissolved in 100 ml of Ν,Ν-dimethylformamide, and the mixture is heated in a closed tube at 80 °C for 40 hours. The solution is cooled, diluted with diethyl ether, filtered through diatomaceous earth, the filtrate is washed with water, then with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is distilled off in vacuo and the residue is purified by chromatography on silica gel using 1% by volume diethyl ether in hexane and then 10% by volume ethyl acetate in hexane to give the desired product as a colorless oil.

Example 35 (Method 9) Preparation of 3-chloro-4-methanesulfinylphenyl)carbamic acid tert-butyl ester 0.89 g of (3-chloro-4-methylthiophenyl)carbamic acid tert-butyl ester is dissolved in 100 ml of methylene chloride, then 34 ml of 0.11 M dimethyldioxirane in acetone is added at 0°C.

-103 solution, and the mixture was stirred at 0°C for 1 hour. The solvent was evaporated in vacuo, the residue was dissolved in methylene chloride, washed with aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo to give the desired product as an orange foam.

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

To a solution of 234 mg of 2-methylsulfanyl-N-[4-(2,2,2-trifluoroacetylamino)phenyl]benzamide was added 5 mL of saturated sodium periodate solution and the mixture was stirred for 12 hours. The purple mixture was poured into water, extracted with ethyl acetate, dried over anhydrous potassium carbonate and evaporated to give 101 mg of a red solid.

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

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

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

-104-

Example 37 (Method 10) Preparation of (3-chloro-4-methanesulfonylphenyl)carbamic acid tert-butyl ester 0.90 g of (3-chloro-4-methylthiophenyl)carbamic acid tert-butyl ester is dissolved in 100 ml of methylene chloride, then 80 ml of 0.11M dimethyldioxirane in acetone is added at 0°C, and the mixture is stirred at 0°C for 1 hour. The solvent is distilled off in vacuo, the residue is dissolved in methylene chloride, washed with saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent is distilled off in vacuo, resulting in the desired product as an orange foam.

Example 38 (Method 11)

Preparation of 3-chloro-4-vinylphenylamine

6.95 g of 3-chloro-4-iodoaniline, 0.67 g of triphenylarsine and 0.50 g of tris(dibenzylideneacetone)palladium(O) reagent are dissolved in 120 ml of tetrahydrofuran, the oxygen is blown out of the solution, 10 g of tributylvinyltin are added at 50°C, then the mixture is stirred at 50°C under an argon atmosphere for about 15 hours. The mixture is cooled, filtered through diatomaceous earth and the filtrate is evaporated to dryness in vacuo. The residue is dissolved in hexane and then extracted three times with 5% aqueous hydrochloric acid. The aqueous acid extracts are basified with solid potassium carbonate and then extracted three times with ethyl acetate. The combined organic phases are washed with saturated aqueous

- Wash with 105% sodium chloride solution, dry over anhydrous magnesium sulfate, and remove the solvent in vacuo. The residue is purified by chromatography on silica gel using a mixture of hexane and 10% ethyl acetate as eluent to give the desired product as an amber oil.

Example 39 (Method 12) Preparation of 3-chloro-4-(1-hydroxyethyl)phenylcarbamic acid 2-trimethylsilanylethyl ester

3.48 g of mercury(II) acetate were dissolved in a mixture of 7 ml of water and 5.25 ml of tetrahydrofuran, 2.6 g of (3-chloro-4-vinyl-phenyl]-carbamic acid-2-trimethyl-silylanyl-ethyl ester were added, and the mixture was stirred for about 15 hours. 8.7 ml of 3N aqueous sodium hydroxide solution and 8.7 ml of 0.5M sodium borohydride in 3N aqueous sodium hydroxide were added to the mixture, and the mixture was stirred for 6 hours. The solution was saturated with sodium chloride and extracted with ethyl acetate. The organic extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off in vacuo. The residue was chromatographed on silica gel support. and purified using a mixture of hexane and 20% ethyl acetate by volume to give the desired product as a white solid.

- 106 -

Example 40 (Method 13) Preparation of [3-chloro-4-(2-hydroxyethyl)phenyl]carbamic acid tert-butyl ester

0.45 g of sodium borohydride is suspended in 13 ml of tetrahydrofuran, 0.75 ml of glacial acetic acid is added while stirring at 0°C, and the mixture is then stirred at 0°C for 1 hour. The solution was warmed to room temperature and 1.0 g of (3-chloro-4-vinylphenyl]carbamic acid 2-trimethylsilanylethyl ester was added. The reaction mixture was stirred at room temperature for about 15 hours and then refluxed for about 20 hours. The mixture was cooled and 0.80 ml of 5N aqueous sodium hydroxide solution and 0.56 ml of 30% hydrogen peroxide solution were added. After stirring for another 15 hours, the phases were separated, the aqueous phase was extracted three times with ethyl acetate and the organic phases were dried over anhydrous magnesium sulfate. The solvent was distilled off in vacuo and the residue was purified by chromatography using a silica gel support and a hexane eluent mixture containing 40% by volume ethyl acetate. The result was an amber oil. we get the desired product.

Example 41 (Method 14)

Preparation of Γ4-(1-azidoethyl)-3-chlorophenylcarbamic acid 2-trimethylsilanylethyl ester 1.25 g of [3-chloro-4-(1-hydroxyethyl)phenyl]carbamic acid 2-trimethylsilanylethyl ester is dissolved in 1 ml of tetrahydrofuran, then 2.6 g of triphenylphosphine, approximately 2.5 molar equivalents of HN ₃ prepared according to the method described in Fieser and Fieser, Reagents for Organic Synthesis, 1. Vol. 1, p. 446, Wiley, New York, are added under an argon atmosphere, as well as 1.72 g of azodicarboxylic acid ethyl ester. After about 10 minutes, the solvent is distilled off in vacuo and the residue is purified by chromatography using silica gel as the eluent and hexane containing 5% by volume ethyl acetate to give the desired product as a colorless oil.

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

10.0 g of (3-chloro-4-iodophenyl)carbamic acid tert-butyl ester are dissolved in 120 ml of triethylamine, 2.82 g of 1-dimethylamino-2-propyne, 0.4 g of bis(triphenylphosphine)palladium(II) chloride and 0.054 g of copper(I) iodide are added. The reaction mixture is stirred at room temperature under an argon atmosphere for about 6 hours, then heated briefly (about 10 minutes) to 60°C. The reaction mixture is cooled, filtered through diatomaceous earth, and the solvent is distilled off in vacuo. The residue is dissolved in ethyl acetate, washed three times with water, once with saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent is distilled off in vacuo, and the residue is

- Purification by chromatography on silica gel using 80% ethyl acetate/hexane as eluent gave the desired product as an amber oil which solidified on standing.

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

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

[3-(4-Methoxyphenyl)-prop-2-ynyl]-dimethylamine 4-(3-dimethylamino-prop-1-ynyl)-benzonitrile dimethyl-[3-(4-nitro-phenyl)-prop-2-ynyl]-amine

Example 43 (Method 16) Preparation of 3-chloro-4-(3-dimethylaminoacryloyl)phenylcarbamic acid tert-butyl ester

4.0 g of [3-chloro-4-(3-dimethylaminoprop-1-ynyl)phenyl]carbamic acid tert-butyl ester were dissolved in 30 ml of methylene chloride, the solution was cooled to 0°C, and 2.34 g of 3-chloroperbenzoic acid were added in small portions. The reaction mixture was stirred for 20 minutes at 0°C, then passed through a column filled with 20 weight equivalents of basic alumina support (Brockman Grade I, 150 mesh) and the N-oxide was eluted using a solvent mixture of methylene chloride containing 5% by volume methanol.

- 109 is eluted. The fractions containing the desired N-oxide are combined and evaporated to near dryness in vacuo. The residue is treated three times successively with small portions of methanol (about 50 ml), evaporated to near dryness in vacuo, and the volume of the solution is made up to 250 ml by adding methanol. The methanol solution of the N-oxide is refluxed for about 15 hours, cooled, and the solvent is evaporated to dryness by distillation in vacuo. The residue is purified by chromatography using a silica gel support and a hexane eluent mixture containing 80% by volume ethyl acetate. The desired product is obtained as a pale yellow solid.

Example 44 (Method 17) Preparation of (3-chloro-4-isoxazol-5-ylphenyl)carbamic acid tert-butyl ester

270 mg of [3-chloro-4-(3-dimethylaminoacrylic acid)-phenyl]-carbamic acid tert-butyl ester were dissolved in 3 ml of dioxane, 122 mg of hydroxylamine hydrochloride were added, and the mixture was stirred at room temperature for 10 days. Ethyl acetate was added to the mixture, and the mixture was washed successively with water, 5% sodium bicarbonate, and saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was distilled off in vacuo, and the residue was chromatographed using a silica gel carrier and a hexane eluent mixture containing 33% by volume ethyl acetate.

- 110. The desired product is obtained as a colorless solid.

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

250 mg of [3-chloro-4-(3-dimethylaminoacrylic acid)-phenyl]-carbamic acid tert-butyl ester are dissolved in 1.25 ml of ethanol, 0.25 ml of hydrazine hydrate is added, and the mixture is stirred for 3 hours at room temperature. 30 ml of diethyl ether are added to the mixture, washed three times with water, then once with saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent is distilled off in vacuo, and the residue is purified by chromatography using a silica gel carrier and a hexane eluent mixture containing 67% by volume ethyl acetate. As a result, the desired product is obtained in the form of an oil.

Example 46 (Method 19A) Preparation of N-(2-chloro-4-nitrophenyl)-2-thiomorpholin-4-yl-acetamide 3.80 g of N-(chloro-acetyl)-2-chloro-4-nitroaniline are dissolved in 10 ml of tetrahydrofuran, 10 ml of thiomorpholine are added and the solution is left to stand at room temperature for 1 hour. The reaction mixture is poured into water, the pale yellow product is separated and heated

- 111 is recrystallized from isopropanol. As a result, a pale yellow crystalline product is obtained.

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

(4-{2-[bis-(2-hydroxyethyl)amino]acetylamino}-phenyl)carbamic acid tert-butyl ester

[4-(2-Dimethylaminoacetylamino)phenyl]carbamic acid tert-butyl ester {4-[3-(2-dimethylaminoethoxy)benzoylamino]phenyl}carbamic acid tert-butyl ester {4-[3-(2-morpholin-4-ylethoxy)benzoylamino]phenyl}carbamic acid tert-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-nitro-phenyl)-2-thiomorpholin-4-yl-acetamide N-(2-chloro-4-nitro-phenyl)-2-diethylamino-acetamide N-(2-chloro-4-nitro-phenyl)-2-pyrrolidine-1-yl-acetamide 2-azepan-1 -yl-N-(2-chloro-4-nitro-phenyl)-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

-112-

Example 47 (Method 19B) Preparation of N-(2-chloro-4-nitrophenyl)-2-(2-dimethylaminoethylsulfanyl)acetamide

3.01 g of N-(chloroacetyl)-2-chloro-4-nitro-aniline were dissolved in 100 ml of N,N-dimethylformamide, followed by the addition of 6.0 g of powdered sodium carbonate and 6.0 g of 2-dimethylaminoethanethiol hydrochloride. The mixture was stirred for 1 hour at 25°C, poured into water and extracted with ethyl acetate. The ethyl acetate solution was dried over anhydrous potassium carbonate and evaporated in vacuo to give an oil. The oil was crystallized from a 3:1 toluene-hexane mixture to give pale yellow crystals.

Example 48 (Method 20) Preparation of (4-tert-butoxycarbonylamino-2-chlorophenyl)carbamic acid 2-piperidin-1-ylethyl ester 4.0 g of 1,1-carbonyldi-(1,2,4)-triazole are suspended in 45 ml of methylene chloride, and then a solution of 5.0 g of (4-amino-3-chlorophenyl)carbamic acid tert-butyl ester in 45 ml of methylene chloride is added dropwise over 20 minutes. The reaction mixture is stirred at room temperature for 30 minutes, while a precipitate forms. In order to maintain homogeneity, 6.6 ml of piperidineethanol and 20 ml of tetrahydrofuran are added to the mixture. The mixture was refluxed overnight, poured into water, the organic phase was separated, and then washed with saturated aqueous sodium chloride solution.

-113. The solution is dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a crude oil, which is purified by chromatography using silica gel as the eluent and 5% methanol in methylene chloride as the eluent. The desired product is obtained as a white foam.

Example 49

Preparation of 5-phenyl-n,2,3-thiadiazole-4-carboxylic acid methyl ester 1.1 g of benzoyl acetate ethyl ester is dissolved in ml of acetonitrile, 1.3 g of 4-methylbenzenesulfonyl azide and 1.6 g of triethylamine are added. The mixture is stirred overnight at room temperature, the mixture is concentrated in vacuo, the resulting crude product is dissolved in ethyl acetate, then washed with 1N sodium hydroxide solution. The organic phase is dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give a yellow oil. The oil is taken up in methylene chloride, filtered, eluted through a layer of hydrated magnesium silicate with methylene chloride, resulting in the partially purified diazoketone as a colorless oil. A 1.2 g sample of the diazoketone is dissolved in 25 ml of toluene, 2.8 g of 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide is added, and the mixture is heated to reflux. After 3 hours of boiling, the reaction mixture is cooled to room temperature, a

-114 silica gel and eluted with methylene chloride. After evaporation of the solvent in vacuo, the residual oil is purified by chromatography on silica gel and 30% by volume of diethyl ether in petroleum ether and recrystallized from hexane to give the desired product as pale yellow needles.

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

5-f e η i I-[1,2,3]thiadiazole-4-carboxylic acid ethyl ester 5-methyl-[1,2,3]thiadiazole-4-carboxylic acid methyl ester

Example 50

Preparation of Benzoyl Acetic Acid Semicarbazide Ethyl Ester 5.0 g of benzoyl acetate ethyl ester is dissolved in 130 ml of methanol and then quickly added to a hot solution of 29 g of semicarbazide hydrochloride in 130 ml of water. To the mixture is added 4.1 g of pyridine, heated under reflux for 5 minutes, and then kept at -20°C overnight. The resulting solid semicarbazone is filtered off, washed with water and then with diethyl ether, resulting in the desired product in the form of white crystals.

- 115 Using the above procedure, the following compounds were prepared from the appropriate starting materials:

(Z)-3-[(aminocarbonyl)hydrazono]-4,4,4-trifluorobutyric acid ethyl ester

3-[(Z)-2-[(aminocarbonyl)hydrazono]-3-phenylpropionic acid ethyl ester

3-[(E)-2-[(aminocarbonyl)hydrazono]-3-(3-furyl)propionic acid ethyl ester

Example 51

Preparation of 5-phenyl-[1,2 _{1 3} ]thiadiazole-5-carboxylic acid ethyl ester 2.5 g of benzoylacetic acid ethyl ester semicarbazone are dissolved in 1 ml of thionyl chloride and stirred for 1 hour at 0°C. 25 ml of methylene dichloride are added to the mixture, and the excess thionyl chloride is slowly reacted by adding saturated aqueous sodium hydrogen carbonate solution. The precipitate formed during the reaction is filtered off and the filtrate is extracted with methylene dichloride. The combined organic extracts are dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue is purified by chromatography using a silica gel carrier and a methylene dichloride eluent mixture containing 50% by volume of hexane. As a result, the desired product is obtained in the form of a colorless oil.

- 116 Using the above procedure, the following compounds were prepared from the 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 ethyl ester

Example 52

Preparation of 4-methyl-1,2-trimethyl-thiadiazole-5-carboxylic acid

1.7 g of 4-methyl-[1,2,3]thiadiazole-5-carboxylic acid methyl ester are dissolved in 15 ml of methanol, then 16 ml of 1N sodium hydroxide solution are added. The mixture is stirred for 1 hour at room temperature, 1.5 ml of concentrated hydrochloric acid solution are added, then it is concentrated in vacuo. The resulting cloudy aqueous phase is extracted twice with diethyl ether, then the combined organic phases are dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. As a result, the desired product is obtained in the form of a white powder.

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

3-ethoxycarbonylmethoxybenzoic acid

5-furan-3-yl[1,2,3]thiadiazole-4-carboxylic acid thiazole-4-carboxylic acid

-1174-methyl-[1,2,3]thiadiazole-5-carboxylic acid 5-methyl-[1,2,3]thiadiazole-4-carboxylic acid

Example 53 (Method 25)

Preparation of trifluoromethanesulfonic acid 4-chloro-5-methoxy-2-nitrophenyl ester

6.5 g of 4-chloro-5-methoxy-2-nitrophenol are dissolved in 150 ml of methylene chloride, then 10 g of triethylamine and a solution of 13.5 g of trifluoromethanesulfonic anhydride in 30 ml of methylene chloride are added at 0°C under an argon atmosphere. The solution is stirred for 10 minutes at 0°C, diluted with methylene chloride, and washed successively with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The solution is dried over anhydrous sodium sulfate, the solvent is distilled off in vacuo, and the residue is purified on a short column containing a hydrated magnesium silicate support using a 20% by volume methylene chloride/hexane eluent mixture. The fractions containing the product are combined and the solvent is distilled off in vacuo to give the desired product as a yellow oil.

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

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

Trifluoromethanesulfonic acid 4-chloro-2-nitrophenyl ester Trifluoromethanesulfonic acid 2-chloro-6-nitrophenyl ester

Example 54 (Method 26) Preparation of 4-(3-dimethylaminobenzoylamino)phenyl-Π-carbamic acid tert-butyl ester

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

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

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

-119N-(3-Chloro-5-dimethylaminophenyl)aceta mid

Example 55 (Method 27) Preparation of N-(4-aminophenyl)-2-hydroxybenzamide

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

Example 56 (Method 28) Preparation of (4-(3-hydroxybenzoylamino)phenyl)carbamic acid tert-butyl ester

4.34 g of 3-(4-aminophenylcarbamoyl)phenylacetate were dissolved in 75 ml of methanol, followed by the addition of 25 ml of 0.1N aqueous sodium hydroxide and 25 ml of tetrahydrofuran. The mixture was heated at 40°C for 30 minutes, poured into 1M hydrochloric acid solution, and extracted with ethyl acetate. The ethyl acetate solution was dried over anhydrous sodium sulfate, concentrated in vacuo, and the resulting white solid was further purified by trituration with diethyl ether.

- 120 -

Example 57 (Method 29) Preparation of N-(4-aminophenyl)-2-hydroxymethylbenzamide

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

Example 58 (Method 30) Preparation of (3-chloro-5-dimethylethylaminophenyl)carbamic acid tert-butyl ester

0.32 g of (3-amino-5-chlorophenyl)carbamic acid tert-butyl ester is dissolved in 10 ml of toluene, 1.5 ml of 37% aqueous formaldehyde solution and 0.5 g of 10% palladium on activated carbon are added, and the mixture is stirred under a hydrogen atmosphere for about 15 hours. The solution is filtered through diatomaceous earth and then evaporated in vacuo. The residue is purified by chromatography using a silica gel support and a hexane eluent mixture containing 50% by volume of methylene dichloride. The desired product is obtained as a white solid.

- 121 -

Example 59 (Method 35) Preparation of N-(4-{3-[3,5-dichloro-4-(2-hydroxyethoxy)phenyl]-thioureido}-phenyl)acetamide

0.16 g of 2-{4-[3-(4-acetylaminophenyl)thioureido]-2,6-dichlorophenoxy}acetic acid ethyl ester was dissolved in 2.5 ml of a 1:1 mixture of tetrahydrofuran and methanol, 1 ml of 1N aqueous sodium hydroxide solution was added, and the reaction mixture was stirred at room temperature for about 2 hours. The solution was then poured into 3 ml of 2M aqueous hydrochloric acid solution, extracted with ethyl acetate, and the extracts were dried over anhydrous sodium sulfate. The solvent was distilled off in vacuo, and the residue was triturated with diethyl ether. The desired product was obtained as a white solid.

Example 60 (Method 36) Preparation of {4-[3-(4-acetylaminophenyl)thioureido]-2,6-dichlorophenoxy}acetic acid

0.29 g of {4-[3-(4-acetylaminophenyl)thioureido]-2,6-dichlorophenoxy}acetic acid ethyl ester was dissolved in 4 ml of a 1:1 volume tetrahydrofuran-methanol solvent mixture, 2 ml of 1N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for about 2 hours. Then the solution was poured into 5 ml of 2M aqueous hydrochloric acid solution, extracted with ethyl acetate, and the extracts were dried over anhydrous sodium sulfate. The solvent was distilled off in vacuo, and the residue was extracted with diethyl ether.

- 122 is triturated. The desired product is obtained as a white solid.

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

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

To an ice-cold solution of 0.2 g of N-(4-{3-[3,5-dichloro-4-(2-hydroxyethoxy)phenyl]thioureido}phenyl)acetamide prepared in 2 ml of pyridine and 0.5 ml of tetrahydrofuran, 0.08 g of benzoyl chloride was added, and the mixture was stirred at 0°C for 1.5 hours. The mixture was diluted with ethyl acetate, washed twice with 2% hydrochloric acid solution, then once with saturated aqueous sodium chloride solution, and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by chromatography using a silica gel carrier and a methylene dichloride eluent mixture containing 5% by volume methanol. The

- Fractions containing 123 products are combined, evaporated in vacuo, and the residue is recrystallized from acetone-hexane to obtain the desired product as a white solid.

Example 62 (Method 38) Preparation of methanesulfonic acid 2-{4-[3-(4-acetylaminophenyl)thioureido1-2,6-dichlorophenoxy}-ethyl ester

To an ice-cold solution of 0.2 g of N-(4-{3-[3,5-dichloro-4-(2-hydroxyethoxy)phenyl]thioureido}phenyl)acetamide in 2 ml of pyridine and 0.5 ml of tetrahydrofuran was added 0.11 g of methanesulfonyl chloride, and the mixture was stirred at 0°C for 45 minutes. The mixture was diluted with ethyl acetate, washed twice with 2% hydrochloric acid solution, then once with saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed in vacuo, and the residue was recrystallized from acetone-hexane to give the desired product as a white solid.

Example 63 (Method 39) Preparation of N-(4-{3-[3,5-dichloro-4-(2-dimethylaminoethoxy)phenyl]thioureido}phenyl)acetamide

0.33 g of methanesulfonic acid 2-{4-[3-(4-acetylaminophenyl)thioureido]-2,6-dichlorophenoxy}-ethyl ester was dissolved in 6 ml of tetrahydrofuran, 0.5 ml of 8.8M aqueous dimethylamine solution was added, and the mixture was stirred at room temperature for 5 days. The mixture was extracted with ethyl acetate.

- 124 is diluted, washed with saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off in vacuo and the residue is purified by chromatography using silica gel as the carrier and pure methanol as the eluent. The product-containing fractions are combined, evaporated in vacuo and the residue is recrystallized from acetonitrile to give the desired product as a white solid.

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

N-(4-{3-[3,5-dichloro-4-(2-dimethylaminoethoxy)phenyl]thioureido}-phenyl)acetamide benzoic acid-2-{4-[3-(4-acetylaminophenyl)thioureido]-2,6-

-dichlorophenoxyethyl ester

Example 64 (Method 40)

Preparation of furan-2-carboxylic acid (4-{3-[4-(1-aminoethyl)-3-chlorophenyl]thioureido}-phenyl)amide 0.25 g of (11)-ki-dioxide was dissolved in 100 ml of methanol, 0.22 g of furan-2-carboxylic acid (4-{3-[4-(1-azidoethyl)-3-chlorophenyl]thioureido}-phenyl)amide was added, and the mixture was stirred at room temperature for about 15 hours. The solution was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, then with saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate.

- 125. The solvent is evaporated in vacuo and the residue is purified by chromatography on silica gel using a methylene chloride eluent mixture containing 8% by volume methanol and 1% by weight triethylamine. The desired product is obtained as a yellow solid.

Example 65 (Method 41) Preparation of 1,2,3'-thiadiazole-4-carboxylic acid-(4-isothiocyanatophenyl)amide

7.28 g of 1,1'-thiocarbonyldiimidazole are dissolved in 50 ml of tetrahydrofuran and, while cooling with ice-water, 100 ml of tetrahydrofuran are added.

[1,2,3]thiadiazole-4-carboxylic acid-(4-aminophenyl)-amide. After about one hour, the solvent is distilled off in vacuo and the residue is dissolved in ethyl acetate. The crude product is precipitated by adding diethyl ether, isolated by filtration, dissolved in methylene chloride, and the solution is filtered through a pad of hydrated magnesium silicate. After removal of the solvents, the residue is recrystallized from ethyl acetate-hexane to give the desired product as a slightly yellow solid.

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

2-fluoro-N-(4-isothiocyanatophenyl)benzamide

- 126 furan-2-carboxylic acid-(4-isothiocyanato-phenyl)-amide [1 ^Sjthiadiazole^-carboxylic acid-^-isothiocyanato-phenyl'O-amide thiazole-4-carboxylic acid-(4-isothiocyanato-phenyl)-amide

Example 66 (Method 42) Preparation of N,N-dimethyl-5-trifluoromethylbenzene-1,3-diamine 1.0 g of 3-amino-5-bromotrifluoromethylbenzene is dissolved in 100 ml of tetrahydrofuran, the solution is purged with argon, 0.15 g of bis(tri-o-tolylphosphino)palladium and 4.2 ml of a 2M solution of dimethylamine in tetrahydrofuran are added. The reaction mixture is heated at 100°C in a closed vessel for about 2.5 hours until the reaction is complete. The mixture is cooled to room temperature, reacted with water and diluted with ethyl acetate. The product is extracted three times with 5% aqueous hydrochloric acid solution, and the combined acidic extracts are made alkaline by adding 5N aqueous sodium hydroxide solution while cooling. The alkaline solution is extracted with ethyl acetate, the combined organic extracts are washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and evaporated to dryness in vacuo. The residue is purified by chromatography using silica gel as the carrier and hexane containing 20-30% by volume ethyl acetate as the eluent. As a result, the desired product is obtained as a slightly colored solid.

- 127Using the above procedure, starting from the appropriate starting materials, the following compounds were prepared:

3-(4-methylpiperazin-1-yl)-5-trifluoromethylphenylamine 3-morpholin-4-yl-5-trifluoromethylphenylamine 3-piperidin-1-yl-5-trifluoromethyl-phenylamine 3-pyrrolidin-1-yl-5-trifluoromethylphenylamine N,N-dimethyl-5-trifluoromethylbenzene-1,3-diamine N-isobutyl-N-methyl-5-trifluoromethyl-benzene-1,3-diamine N-buty l-N-methyl-5-trifluoromethylbenzene-1,3-diamine

Example 67 (Method 43) Preparation of (3-isobutyl-5-trifluoromethyl)phenylcarbamic acid tert-butyl ester

Isobutylene was bubbled through 5 ml of tetrahydrofuran placed in a tube cooled in a dry ice-acetone bath and sealed with a rubber septum for about 5 minutes. 11 ml of a 0.5M solution of 9-BBN was added to the solution, the tube was sealed with a Teflon cap, slowly warmed to room temperature and kept at room temperature for about 2.5 hours. The mixture was cooled again in a dry ice-acetone bath, the Teflon cap was replaced with a rubber septum, and argon was bubbled through the mixture while degassing to remove excess isobutylene. To the mixture is added a solution of 1.7 g of (3-bromo-5-trifluoromethylphenyl)carbamic acid tert-butyl ester in 12 ml of tetrahydrofuran, followed by 0.12 g of [1,Γ-128-bis-(diphenylphosphino)ferrocene]palladium(l I) chloride-methylene dichloride complex and 3N aqueous sodium hydroxide solution. The tube is closed again with a Teflon cap and heated at 65°C for about 15 hours. The mixture is cooled to room temperature, diluted with hexane, washed with water, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then evaporated in vacuo. The residual oil is purified by chromatography using silica gel as the carrier and 5% by volume ethyl acetate as the eluent. As a result, the desired product is obtained as a white powder.

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

[3-(2-methylbutyl)-5-trifluoromethylphenyl]carbamic acid tert-butyl ester (3-isobutyl)-5-trifluoromethylphenyl]carbamic acid tert-butyl ester

Example 68 (Method 44) Preparation of 2-(3,5-dichlorophenylsulfanyl)ethylamine

1.2 g of (3,5-dichlorophenylthio)acetonitrile 11 was dissolved in 3.0 ml of ethyl glycol dimethyl ether, then 0.61 ml of 10M borane-dimethylsulfide complex was added, and the mixture was refluxed for 0.5 h. The reaction mixture was cooled in an ice-water bath, then 2.0 ml of water and 2.0 ml of

- 129 concentrated hydrochloric acid solution is added. The mixture is refluxed for 0.5 hour. The clear solution is cooled, basified with 5N sodium hydroxide solution and extracted with diethyl ether. The ether extract is dried over anhydrous potassium carbonate, filtered and concentrated. The desired product is obtained as a colorless oil.

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

2-(3-bromophenylsulfanyl)ethylamine 2-(4-bromophenoxy)ethylamine 2-(4-iodophenoxy)ethylamine 2-(3,4-dichlorophenoxy)ethylamine 2-(3-chlorophenylsulfonyl)ethylamine 2-(3,4-dichlorophenylsulfonyl)ethylamine l-amine 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-feni l-su Ifan il-eti l-am in

2-(2-chlorophenyl)ethylamine

-130-

Example (Method 45)

Preparation of N-(1-naphthalen-2-ylethyl)formamide

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

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

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

N-(1-naphthalin-2-yl-ethyl)-formam id

Example 70 (Method 46) Preparation of 1-(2-naphthyl)ethylamine

A mixture of 1.12 g of N-(1-naphthalen-2-ylethyl)formamide, 10 ml of ethanol and 10 ml of 5N sodium hydroxide was heated under reflux for 1 hour. The solution was cooled, poured into water and extracted with ether. The ether extract was dried over anhydrous potassium carbonate, filtered and evaporated to give 0.95 g of a pale yellow oil.

-131 Using the above procedure, starting from the appropriate starting materials, the following compounds were prepared:

-(3-trifluoromethyl-phenyl)-ethylamine 1-(4-fluorophenyl)-2-methylpropylamine [3-(1-aminoethyl)-phenyl]-dimethylamine 3-(1-aminoethyl)-benzonitrile

Example 71 (Method 47) Preparation of 1-(3-trifluoromethylphenyl)ethanone-O-methyloxime

1.5 g of 3'-(trifluoromethyl)acetophenone are dissolved in a mixture of 20 ml of ethanol and 2 ml of pyridine, then 2.33 g of hydroxylamine hydrochloride are added. The mixture is heated under reflux for 45 minutes. The mixture is cooled, concentrated in vacuo and taken up in a mixture of water and ethyl acetate. The aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and then evaporated to dryness in vacuo. As a result, 1.61 g of the desired product is obtained in the form of a colorless oil.

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

3,5-bis-(trifluoromethyl)benzaldehyde oxime

-1321-(4-fluorophenyl)propan-1-one-O-methyloxime

1-(2-chlorophenyl)ethanone-O-methyloxime

-(2-bromophenyl)ethanone-O-methyloxime

- (3-chlorophenyl)ethanone-O-methyloxime

1-p-tolyl-ethanone-O-methyloxime

- (4-fluorophenyl)-pentan-1-one-O-methyloxime 1-(4-fluorophenyl)-2-phenylethanone-O-methyloxime 1-o-tolyl-ethanone-O-methyloxime

1-m-Tolyl-ethanone-O-methyloxime

1-(2-fluorophenyl)ethanone-O-methyloxime

3-(1-Methoxyiminoethyl)benzonitrile

4-(1-Methoxyiminoethyl)benzonitrile 1-(4-Methoxyphenyl)ethanone-O-methyloxime

-(2-Methoxyphenyl)ethanone-O-methyloxime

-(4-dimethylaminophenyl)ethanone-O-methyloxime

1-(2-trifluoromethylphenyl)ethanone-O-methyloxime

-(3-Methoxyphenyl)ethanone-O-methyloxime

1-(3-trifluoromethylphenyl)ethanone-O-methyloxime

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

1-Furan-2-yl-ethanone-O-methyloxime

1-Pyridin-4-yl-ethanone-O-methyloxime

- (1-Methyl-1H-pyrrol-2-yl)-ethanone-O-methyloxime

-thiophen-3-yl-ethanone-O-methyl-oxime (4-fluoro-phenyl)-phenyl-methanone-O-methyl-oxime

-(4-Methoxyphenyl)ethanone-O-methyloxime

- (3-chloro-4-methoxyphenyl)ethanone-O-methyloxime

4-(1-Methoxyiminoethyl)benzenesulfonam id

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

- 133 1 _[4-(pyridyl η-1-sulfonyl)-phenyl]-eta η ο η-0-methyl-yl-oxime 4-(1-methoxyiminoethyl)-N,N-dipropylbenzenesulfonamide 2-fluoro-N-[4-(1-methoxyiminoethyl)-phenyl]-benzamide

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

-(4-(1 H-imidazo I-1-i I )-pheni I]-1-ethanone-O-methyl-oxime

1-[4-(Trifluoromethyl)phenyl]-1-ethanone-O-methyloxime

1-(1,1'-biphenyl]-4-yl 1-1-ethanone-O-methyloxime

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

1-[4-fluoro-3-(trifluoromethyl)-phenyl]-ethano-O-methyloxime

1-(3,5-bis(trifluoromethyl)-phenyl]-ethane-O-methyloxime

1-[4-Chloro-3-(trifluoromethyl)-phenyl]-ethane-O-methyloxime

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

1-[2-fluoro-4-(trifluoromethyl)-phenyl]-ethane-O-methyloxime

- [2-fluoro-5-(trifluoromethyl)-phenyl]-ethanone-O-methyloxime 1-(2,4-dichlorophenyl)ethanone-O-methyloxime

1-(2,4-dimethyl-phenyl)-ethane-O-methyl-oxime

-[2,4-bis(trifluoromethyl)phenyl]ethanone-O-methyloxime

1-(3-bromophenyl)ethanone-O-methyloxime

1-(3-Methylphenyl)ethanone-O-methyloxime

1-[4-(4-morpholinyl)phenyl]ethanone-O-methyloxime

1-(2-chloro-4-fluorophenyl)ethanone-O-methyloxime

1-(4-bromo-2-fluorophenyl)ethanone-O-methyloxime

1-(3,4-difluorophenyl)ethano n-O-methyloxime

1-[3-(trifluoromethyl)-phenyl]-ethane-O-methyloxime

-[2-(trifluoromethyl)phenyl]ethane-O-methyloxime

1-(2,4-difluorophenyl)ethano n-O-methyloxime

- [3-fluoro-4-(trifluoromethyl)-phenyl]-ethane-O-methyl-oxime 1-(3,4-dichloro-phenyl]-ethanone-O-methyl-oxime

- 134 1-[4-fluoro-2-(trifluoromethyl)-phenyl]-ethanone-O-methyl-oxime 1 ~(3-chloro-4-fluoro-phenyl)-ethanone-O-methyl-oxime 1-(4-chloro-3-fluoro-phenyl)-ethanone-O-methyl-oxime 1-(2,5-difluoro-phenyl)-ethanone-O-methyl-oxime 1-(2-bromo-4-fluoro-phenyl)-ethanone-O-methyl-oxime 1-(3,4-dibromo-phenyl)-ethanone-O-methyl-oxime 1-(2-bromo~phenyl)-ethanone-O-methyl-oxime

Example 72 (Method 48)

Preparation of -(2-trifluoromethylphenyl)ethylamine

1.8 g of zirconium tetrachloride was dissolved in 27 ml of tetrahydrofuran, and then 1.17 g of sodium borohydride was slowly added. A solution of 1.34 g of 1-(2-trifluoromethylpentyl)ethanone-O-methyloxime in 7.7 ml of tetrahydrofuran was added to the mixture, and the reaction mixture was stirred for 12 hours at 25°C. The mixture was cooled to 0°C and 16 ml of water was slowly added. Excess ammonium hydroxide was added, and the solution was extracted twice with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off in vacuo to give the desired product as a pale yellow oil.

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

- 135 1-(3-Methoxyphenyl)ethylamine

1-(4-fluorophenyl)propylamine

1-naphthalen-2-ylethylamine

4-(1-aminoethyl)benzonitrile

- (4-trifluoromethylphenyl)ethylamine

- (4-methoxyphenyl)ethylamine

-prop-2-i n i I-p i rro I i d i n

1-(2-methoxyphenyl)ethylamine

1-m-tolylethylamine

-(2-bromophenyl)propylamine

-m-tolylethylamine

C-(4-fluorophenyl)-C-phenylmethylamine

-(4-fluorophenyl)pentylamine

1-(4-fluorophenyl)-2-phenylethylamine

1-(2-trifluoromethylphenyl)ethylamine

-(3-bromophenyl)ethylamine

-(3-chlorophenyl)ethylamine

[4-(1-aminoethyl)phenyl)]dimethylamine

-(1-Methyl-1H-pyrrol-2-yl)ethylamine

-thiophen-3-ylethylamine

-[3,5-bis(trifluoromethyl)phenyl]propylamine

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

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

-(4-methylphenyl)ethanamine

-(3-trifluoromethylphenyl)ethylamine

- (4-trifluoromethylphenyl)ethylamine

- (3-methylphenyl)ethanamine

-1361 -(3,4-dichlorophenyl)ethanamine

1-(2-bromophenyl)ethylamine

- (2-trifluoromethylphenyl)ethylamine

- (3-bromophenyl)ethylamine

1-(3-chloro-4-methoxyphenyl)ethylamine

4-(1-aminoethyl)-N,N-dimethylbenzenesulfonamide 1-[4-piperidin-1-sulfonyl)phenyl]ethylamine

-ki η ο I i n-6-i l-eti l-am i n

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

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

1-biphenyl-4-ylethylamine

- (4-fluorophenyl)ethylamine

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

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

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

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

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

-[2-fluoro-4-(trifluoromethyl)phenyl]ethylamine

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

-(2,4-dichlorophenyl)ethylamine

-(2,4-dimethylphenyl)ethylamine

-[2,4-bis(trifluoromethyl)phenyl]ethylamine

-(2-chloro-4-fluorophenyl)ethylamine

-1371-(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 1-(4-chloro-3-fluorophenyl)ethylamine 1-(3,4-dibromophenyl)ethylamine 1-(2-bromo-4-fluorophenyl)ethanamine or 1-(2-bromo-4-fluorophenyl)ethylamine

Example 73 (Method 49) Preparation of (2-Fluoro-5-trifluoromethylphenoxy)acetonitrile g 2-fluoro-5-trifluoromethylphenol was dissolved in 550 ml of reagent grade acetone, 7.7 g of potassium carbonate was added, followed immediately by 10 ml of pure bromoacetonitrile. The heterogeneous reaction 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 aqueous sodium chloride solution and dried over anhydrous potassium carbonate. Filtration and evaporation in vacuo gave a pale yellow solid which was purified by chromatography using a silica gel support and methylene dichloride eluent mixture to give 28.3 g of the desired product as a white solid.

- 138 Using the above procedure, the following compounds were prepared from the 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-dichlorophenoxy)acetonitrile (2-fluorophenoxy)acetonitrile (3-fluorophenoxy)acetonitrile (3-chlorophenoxy)acetonitrile (3-bromophenoxy)acetonitrile (2-fluoro-5-trifluoromethylphenoxy)acetonitrile (3-iodophenoxy)acetonitrile (4-bromophenoxy)acetonitrile

Example 74 (Method 50) Preparation of 3-fluoro-5-trifluoromethylphenethylamine tosylate

2.5 g of 3-fluoro-5-trifluoromethylphenylacetonitrile and 2.34 g (12.3 mmol) of p-toluenesulfonic acid were dissolved in 75 ml of ethylene glycol and hydrogenated at room temperature, 40 psi, using 10% palladium on activated carbon (200 mg) for 3 hours. The catalyst was filtered off and the solvent was concentrated to half volume. The desired 3-fluoro-5-trifluoromethylphenethylamine was formed on standing.

The salt of -139β-toluenesulfonic acid crystallizes out. 4.26 g of white crystalline material is isolated by filtration. The yield is 91%.

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

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-bis-trifluoromethylphenyl)ethylamine 2-(4-fluoro-3-trifluoromethylphenyl)ethylamine

Example 75 (Method 51) Preparation of (4-aminomethyl-2-trifluoromethylphenyl)dimethylamine

0.35 g of 4-dimethylamino-3-trifluoromethylbenzonitrile was dissolved in 2 ml of tetrahydrofuran, then at 0°C it was slowly added to a suspension of 0.1 g of lithium aluminum hydride in 2 ml of tetrahydrofuran, and then stirred under an argon atmosphere for 2 hours. Then at 0°C, 0.1 ml of water was slowly added to the reaction mixture, followed by 0.1 ml of 5% sodium hydroxide solution and 0.3 ml of water. The resulting gray solid was filtered and washed with tetrahydrofuran. The filtrates were combined,

The mixture was concentrated in vacuo at -140°C and the resulting oil was purified by chromatography using silica gel as the eluent and 15% methanol in methylene chloride to give 0.164 g of the desired product as a pale yellow oil.

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

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-aminoethyl)-5-trifluoromethylphenyl]dimethylamine [4-(2-Aminoethyl)-2-methylphenyl]-dimethylamine

Example 76 (Method 52) Preparation of 3-Dimethylamino-5-trifluoromethylbenzaldehyde A 1M solution of diisobutylaluminum hydride in methylene dichloride was added dropwise at 0°C to a solution of 1.06 g of 3-dimethylamino-5-trifluoromethylbenzonitrile in 25 ml of methylene dichloride, and the mixture was stirred for 2 hours. A saturated solution of potassium tartrate (8 ml) was slowly added to the mixture at 0°C, and the solution was stirred for 1.5 hours. The reaction mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated in vacuo.

- 141 was evaporated to give 0.97 g of the desired product as a yellow solid.

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

3-dimethylamino-5-trifluoromethylbenzaldehyde 4-dimethylamino-3-methylbenzaldehyde

Example 77 (Method 53)

Preparation of dimethyl-[3-(2-nitro-vinyl)-5-trifluoromethyl-phenyl]-amine

0.885 g of 3-dimethylamino-5-trifluoromethylbenzaldehyde and 0.339 g of ammonium acetate were dissolved in 3.4 ml of acetic acid, 0.473 g of nitromethane were added, and the solution was heated at 110°C for 6 hours. The reaction mixture was cooled to °C, the separated solid was filtered and washed with a 1:1 water-acetic acid mixture. The solid was recrystallized from ethanol to give 0.39 g of the desired product as a red solid.

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

dimethyl-[3-(2-nitrovinyl)-5-trifluoromethylphenyl]amine

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

Example 78 (Method 54)

Preparation of 3-(4-bromophenyl)propionitrile

2.01 g of 4-bromophenethyl alcohol and 7.9 g of triphenylphosphine were dissolved in 16 ml of diethyl ether at 0°C and 5.2 g of azodicarboxylic acid diethyl ester were added dropwise. The reaction mixture was stirred for 10 minutes and then a solution of 2.6 g of acetone cyanohydrin in 10 ml of diethyl ether was added. The clear orange solution was stirred for 5 minutes at 0°C and for 12 hours at 25°C. The reaction mixture was filtered and washed with diethyl ether. The filtrate was concentrated in vacuo and the residue was purified by chromatography using a silica gel support and 10% by volume ethyl acetate in hexane as eluent. As a result, 2.04 g of the desired product was obtained as a pale yellow oil.

Example 79 (Method 55)

Preparation of 3-dimethylamino-2-isocyanoacrylic acid ethyl ester

5.0 g of isocyanoacetic acid ethyl ester was dissolved in 100 ml of ethanol, and 6.5 g of N,N-dimethylformamide dimethylacetal was added dropwise over 10 minutes. The resulting oil was purified by chromatography using a magnesium silicate support and 50% ethyl acetate in hexane as eluent. The solvent was removed and the residual oil was recrystallized from ethyl acetate in hexane to give 3.0 g of light yellow needles.

- 143 «·»»·· »· ♦ ♦ * 4 «4 »* ♦<·

Example 80 (Method 56)

Preparation of thiazole-4-carboxylic acid ethyl ester 1.0 g of 3-dimethylamino-2-isocyanoacrylic acid ethyl ester and 3.0 g of triethylamine are dissolved in 1 ml of tetrahydrofuran, and hydrogen sulfide gas is introduced until all the starting materials are reacted. The mixture is concentrated to an oil and then purified by chromatography using a silica gel carrier and a hexane eluent mixture containing 25% by volume ethyl acetate. As a result, 0.61 g of the purified product is obtained in the form of an oil.

Example 81 (Method 34) Preparation of N-{4-[3-(5-chloro-2,4-dimethoxyphenyl)-ureidolphenyl}-2-fluorobenzamide

0.34 g of N-(4-aminophenyl)-2-fluorobenzamide was suspended in 4 ml of acetonitrile and 0.40 g of 5-chloro-2,4-dimethoxyphenylisocyanate was added. The mixture was allowed to settle for 12 hours. The white solid that separated was filtered. Yield: 0.79 g. [M + H] 444.

Using the above procedure, starting from the appropriate starting materials, the following compounds were prepared (example number, M + H, compound name):

445 N-{4-[3-(5-chloro-2,4-dimethoxyphenyl)ureido]phenyl}-2-fluorobenzamide

- 144 • fi · « 9 ♦ ·

*..* ·.-* . í.

441 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-ureido]-phenyl}-2-methylbenzamide

435 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxyphenyl)-ureido]-phenyl}-amide

443 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(4-chloro-3-trifluoromethylphenyl)ureido]phenyl}-amide

453 N-{4-[3-(4-chlorotrifluoromethylphenyl)ureido]phenyl}-2-fluorobenzamide

409 [1,2,3]thiadiazole-4-carboxylic acid-{4-[3-(3,5-dichlorophenyl)-ureido]-phenyl}-amide

486 N-{4-[3-(3,5-bis-trifluoromethylphenyl)ureido]phenyl}-2-fluorobenzamide

458 furan-2-carboxylic acid-{4-[3-(3,5-bis-trifluoromethylphenyl)-ureido]-phenyl}-amide

476 [1,2,3]thiadiazole-4-carboxylic acid-{4-[3-(3,5-bis-trifluoromethylphenyl)-ureido]-phenyl}-amide

423 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3,4-dichlorobenzyl)ureido]phenyl}-amide

Example 91 (Method 31)

N-(5-(Γ(((1 S)-1-{3,5-bis(trifluoromethyl)phenyl1-ethyl}amino)carbothioyl-amino}-2-pyridinyl)-1,3-thiazole-4-carboxamide

A mixture of 0.36 g of N-(5-isothiocyanato-2-pyridinyl)-1,3-thiazole-4-carboxamide and 0.36 g of (S)-alpha-methyl-3,5-bis(trifluoromethyl)benzenemethanamine was heated with 10 ml of acetonitrile until the solid was completely dissolved. The solution was left to stand for 12 hours, and the resulting white solid was collected by filtration. 0.40 g of the compound was obtained. [M+H] 520.

Using the above procedure, starting from the appropriate starting materials, the following compounds were prepared (example number, M+H, compound name):

506 3-Chloro-5-(3-{4-[([1,2,3]thiadiazol-4-carbonyl)amino]phenyl}thioureido)phenyl]carbamic acid tert-butyl ester

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]phenylsulfanylacetic acid

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

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

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

100 381 N-{3-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}acetamide

101 411 {4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}-carbamic acid ethyl ester

102 319 1-(2,4-dimethoxyphenyl)-3-(4-methoxyphenyl)thiourea

103 346 N-{4-[3-(2,4-dimethoxy-phenyl)-thioureido]-phenyl}-acetamide

104 316 N-{4-[3-(4-Methoxyphenyl)-thioureido]-phenyl}-acetamide

105 316 N-{4-[3-(2-Methoxy-phenyl)-thioureido]-phenyl}-acetamide

106 351 N-{4-[3-(3-chloro-4-methoxyphenyl)thioureido]phenyl}acetamide

107 351 N-{4-[3-(5-chloro-2-methoxyphenyl)thioureido]phenyl}acetamide

108 371 N-{4-[3-(3,5-dichloro-4-hydroxyphenyl)thioureido]phenyl}acetamide

109 385 N-{4-[3-(3,5-dichloro-4-methoxy-phenyl)-thioureido]-phenyl}-acetamide

110 381 N-{4-[3-(4-chloro-2,5-dimethoxyphenyl)thioureido]phenyl}acetamide

111 389 N-{4-[3-(2-chloro-5-trifluoromethylphenyl)thioureido]phenyl}acetamide

112 389 N-{4-[3-(4-chloro-3-trifluoromethylphenyl)thioureido]phenyl}acetamide

113 422 Benzoic acid 4-[3-(4-acetylaminophenyl)thioureido]-3-hydroxyphenyl ester

14 457 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-methylbenzamide

15 501 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-dimethoxyphenyl)-thioureido]-phenyl}-2-fluorobenzamide

119 473 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-methoxy-benzamide

120 473 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3-methoxy-benzamide

121 473 N-{4-[3-(5-chloro-2,4-dimethoxyphenyl)-thioureidophenyl}-4-methoxybenzamide

122 443 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioyl]-phenyl}-benzamide

123 417 N-{4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}methanesulfonamide

124 331 N-{4-[3-(3-nitro-phenyl)-thioureido]-phenyl}-acetamide 125 339 1'(3-chloro-4-methoxy-phenyl)-3-(3-nitro-ferryl)-thiourea

126 337 N-{4-[3-(5-Chloro-2-hydroxypheniol)-thioureido]-pheniol}-acetamide

127 439 {4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}-carbamic acid tert-butyl ester

128 351 N-{4-[3-(3-chloro-4-hydroxy-5-methylphenyl)thioureido]phenyl}-acetamide

129 385 N-{4-[3-(3,5-dichloro-4-hydroxy-2-methylphenyl)thioureido]phenyl}acetamide

- 148 130 318 N-{4-[3-(2,4-dihydroxyphenyl)thioureido]phenyl}-acetamide

131 414 N-{4-[3-(2,4-dimethoxy-5-trifluoromethylphenyl)thioureido]phenyl}acetamide

132 332 N-{4-[3-(2-Hydroxy-4-methoxy-phenyl)-thioureidoJ-phenylj-acetamide

133 465 N-{4-[3-(3,5-dichloro-4-methoxyphenyl)thioureido]phenyl}-4-fluorobenzamide

134 500 3-acetyl-amino-N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-benzamide

135 488 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3-nitro-benzamide

136 486 N-{4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}-3-dimethylaminobenzamide

137 536 N-{4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}-3-methanesulfonylaminobenzamide

138 51 1 N-{4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}-2-trifluoromethylbenzamide

139 459 N-{4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}-2-hydroxybenzamide

140 479 N-{4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}-2,6-difluorobenzamide

141 477 2-chloro-N-{4-[3-(5-chloro-2,4-dimethoxyphenyl)-thioureido]-phenyl}-benzamide

142 522 2-Bromo-N-{4-[3-(5-chloro-2,4-dimethoxyphenyl)-thioureido]-phenyl}-benzamide

143 488 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-nitro-benzamide

- 149 144 445 pyrazine-2-carboxylic acid-{4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}-amide

145 463 5-Methylthiophene-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}-amide

146 494 quinoline-8-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}-amide

147 446 1-Methyl-1H-pyrrole-2-carboxylic acid-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide

148 369 1-(5-chloro-2,4-dimethoxyphenyl)-3-(2-nitrophenyl)thiourea

149 369 1-(5-chloro-2,4-dimethoxyphenyl)-3-(4-nitrophenyl)thiourea

150 425 N-{4-[3-(5-bromo-2,4-dimethoxyphenyl)thioureido]phenyl}acetamide

151 376 N-{4-[3-(3,4,5-trimethoxyphenyl)thioureido]phenyl}acetamide

152 399 N-{4-[3-(3,5-dichloro-2-methoxy-4-methyl-phenyl)-thioureido]-phenyl}-acetamide

153 499 benzo[b]thiophene-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}-amide

154 483 benzofuran-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}-amide

155 444 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-isonicotinamide

156 493 Naphthalene-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}-amide

157 493 naphthalene-1-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}-amide

- 150 158 494 isoquinoline-1-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}-amide

159 494 quinoline-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}-amide

160 444 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl-nicotinamide

161 478 5-Nitrofuran-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}-amide carbamic acid phenyl ester

162 459 {4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}-.....

163 467 5-Chlorofuran-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}-amide

164 439 {4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}-carbamic acid isobutyl ester

165 397 {4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]-

-phenyl}-carbamic acid methyl ester

166 433 furan-3-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}-amide

167 447 3-Methylfuran-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}-amide

168 512 5-Bromofuran-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}-amide

169 512 4-Bromofuran-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}-amide

170 433 furan-2-carboxylic acid-{4-[3-(5-chloro-2,4-dimethoxy-

-f e n i I )-t io u rei do ]-f e n i I }-a rm i d

-151 171 467 {4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureacyclo]phenyl}carbamic acid hexyl ester

172 494 isoquinoline-4-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}-amide

173 451 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}-amide

174 434 1H-[1,2,3]triazole-4-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}-amide

175 528 3-Bromothiophene-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}-amide

176 399 N-{4-[3-(3,5-dichloro-4-ethoxyphenyl)thioureido]phenyl}acetamide

177 427 N-{4-[3-(4-butoxy-3,5-dichlorophenyl)thioureido]phenyl}acetamide

178 461 N-{4-[3-(4-benzyloxy-3,5-dichlorophenyl)thioureido]phenyl}acetamide

179 381 N-{4-[3-(3-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}acetamide

180 530 (3-{4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenylcarbamoyl}phenyl}carbamic acid ethyl ester

181 458 2-amino-N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-benzamide

182 519 biphenyl-2-carboxylic acid-{4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}-amide

183 469 1-(5-chloro-2,4-dimethoxyphenyl)-3-[4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)phenyl]thiourea

184 487 N-{4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}phthalamic acid

- 152 185 473 N-{4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}-2-hydroxymethylbenzamide

186 479 N-{4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}-2,3-difluorobenzamide

187 479 N-{4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}-2,5-difluorobenzamide

188 479 N-{4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}-2,4-difluorobenzamide

189 500 2-acetylamino-N-{4-[3-(5-chloro-2,4-dimethoxyphenyl)-thioureido]-phenyl}-benzamide

190 441 1-(5-chloro-2,4-dimethoxyphenyl)-3-(6-oxo-5,6-dihydrophenanthridin-2-yl)thiourea

191 536 N-{4[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}-2-methanesulfonylaminobenzamide

192 479 N-{4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}-2,3,4-trifluorobenzamide

193 533 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2,3,4,5,6-pentafluorobenzamide

194 489 N-{4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}-2-methylsulfanylbenzamide

195 431 5-methylfuran-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxyphenyl)ureido]phenyl}-amide

196 467 5-Difluoromethylfuran-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxyphenyl)ureido]phenyl}-amide

197 472 N-{4-[3-(5-iodo-2,4-dimethoxyphenyl)thioureido]phenyl}acetamide

198 364 N-{4-[3-(5-fluoro-2,4-dimethoxyphenyl)thioureido]phenyl}acetamide

- 153 199 365 N-{4-[3-(5-chloro-2-methoxy-4-methylphenyl)thioureido]phenyl}-acetamide

200 459 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(4-chloro-3-trifluoromethylphenyl)-amide

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-(cyclohexyl-methyl-amino)-phenyl]-thioureido}-phenyl)-a cetamide

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-dimethoxyphenyl)-3-(3-chloro-4-morpholin-4-ylphenyl)thiourea

207 372 1 -(5-chloro-2,4-dimethoxyphenyl)-3-(5-chloro-2-methylphenyl)thiourea

208 501 N-{4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]-

-phenyl}-isophthalamide acid methyl ester

209 487 N-{4~[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}-isophthalamic acid

210 549 3-Benzyloxy-N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-benzamide

1 434 N-(4-{3-[5-chloro-2-methoxy-4-(4-cyano-butoxy)-phenyl)-thioureido]-phenyl}-acetamide

212 406 N-(4-{3-[5-chloro-2-methoxy-4-(2-cyanoethoxy)-phenyl)-thioureido]-phenyl}-acetamide

- 154 213 406 N-(4-{3-[5-chloro-4-methoxy-2-(2-cyano-ethoxy)-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-methoxyphenyl]thioureido}phenyl)acetamide

216 481 {4-[3-(4-Acetylaminophenyl)thioureido]-2-chloro-5-methoxyphenoxy}acetic acid tert-butyl ester

217 439 {4-[3-(4-Acetylaminophenyl)thioureido]-2-chloro-5-methoxyphenoxy}acetic acid methyl ester

218 481 {2-[3-(4-acetylaminophenyl)thioureido]-4-chloro-5-methoxyphenoxy}acetic acid tert-butyl ester

219 515 3-Butoxy-N-{4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenylbenzamide

220 505 N-{4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}-2-methanesulfinylbenzamide

221 545 (3-{4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]-

-phenylcarbamoyl}-phenoxy)acetic acid ethyl ester

222 517 (3-{4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenylcarbamoyl}phenoxy)acetic acid

223 367 N-{4-[3-(5-chloro-4-hydroxy-2-methoxyphenyl)thioureido]phenyl}acetamide

224 444 pyridine-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}-amide

225 494 quinoline-4-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}-amide

226 436 N-{4-[3-(5-chloro-4-methoxy-2-morpholin-4-yl-phenyl)-thioureido]-phenyl}-acetamide

-155227 394 N-{4-[3-(5-chloro-2-dimethylamino-4-methoxyphenyl)-thioureido]-phenyl}-acetamide

228 420 N-{4-[3-(5-chloro-4-methoxy-2-pyrrolidin-1-yl-phenyl)-thioureido]-phenyl}-acetamide

229 434 N-{4-[3-(5-chloro-4-methoxy-2-piperidin-1-yl-phenyl)-thioureido]-phenyl}-acetamide

230 405 [1 _> 2,3]thiadiazole-4-carboxylic acid {4-[3-(3-chloro-4-methylphenyl)thioureido]phenyl}-amide

231 415 N-{4-[3-(3-chloro-4-methylphenyl)-thioureido]-phenyl}-2-fluorobenzamide

232 427 N-{4-[3-(3-chloro-4-methylphenyl)thioureido]phenyl}-3-methoxybenzamide

233 387 furan-2-carboxylic acid {4-[3-(3-chloro-4-methylphenyl)thioureido]phenyl}-amide

234 411 N-{4-[3-(3-chloro-4-methylphenyl)thioureido]phenyl}-2-methylbenzamide

235 433 N-{4-[3-(3-chloro-4-methylphenyl)thioureido]phenyl}-2,6-difluorobenzamide

236 398 pyridine-2-carboxylic acid-{4-[3-(3-chloro-4-methylphenyl)thioureido]phenyl}-amide

237 502 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[3-chloro-4-(cyclohexylmethylamino)phenyl]thioureido}phenyl)amide

238 512 N-(4-{3-[3-chloro-4-(cyclohexylmethylamino)phenyl]thioureido}phenyl)-2-fluorobenzamide

239 404 N-{4-[3-(3-chloro-4-piperidin-1-yl-phenyl)-thioureido]-phenyl}-acetamide

240 364 N-{4-[3-(3-chloro-4-dimethylaminophenyl)thioureido]phenyl}acetamide

- 156 241 426 N-{4-[3-(4-benzyl-amino-3-chloro-phenyl)-thioureido]-phenyl}-acetamide

242 390 N-{4-[3-(3-chloro-4-pyrrolidin-1-ylphenyl)thioureido]phenyl}acetamide

243 419 N-(4-{3-[3-chloro-4-(4-methylpiperazin-1-yl)phenyl]thioureido}phenyl)acetamide

244 469 N-{4-[3-(4-chloro-3-trifluoromethylphenyl)thioureido]phenyl}-2-fluorobenzamide

245 422 N-{4-[3-(3-benzyl-amino-4-methoxy-phenyl)-thioureido]-phenyl}-acetamide

246 484 furan-2-carboxylic acid (4-{3-[3-chloro-4-(cyclohexylmethylamino)phenyl]thioureido}phenyl)amide

247 508 N-(4-{3-[3-chloro-4-(cyclohexyl-methyl-amino)-phenyl-thioureido}-phenyl)-2-methyl-benzamide

248 530 N-(4-{3-[3-chloro-4-(cyclohexylmethylamino)phenyl]thioureido}phenyl)-2,6-difluorobenzamide

249 495 pyridine-2-carboxylic acid (4-{3-[3-chloro-4-(cyclohexylmethylamino)phenyl]thioureido}phenyl)amide

250 248 N-(4-{3-[3-chloro-4-(cyclohexylmethylamino)phenyl]thioureido}phenyl)-3-methoxybenzamide

251 376 N-(4-{3-[3-chloro-4-(2-cyano-ethoxy)-phenyl]-thioureido}-phenyl)-3-methoxyacetamide

252 393 N-{4-[3-(4-sec-butoxy-3-chlorophenyl)thioureido]phenyl}acetamide

253 501 Acetic acid 3-{4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenylcarbamoyl}-phenyl ester

254 459 N-{4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}-3-hydroxybenzamide

-157- U . -. ? Μ

255 487 Benzo[1,3]dioxole-4-carboxylic acid-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide

256 527 N-{4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}-3-trifluoromethoxybenzamide

257 530 N-{4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}-3-(2-dimethylaminoethoxy)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-dimethoxyphenyl)thioureido]-2-cyanophenyl}-acetamide

260 521 N-{4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]-2,5-dimethoxyphenyl}-2-fluorobenzamide

261 441 N-{4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]-2,5-dimethoxyphenyl}-acetamide

262 527 2-{4-[3-(4-acetylaminophenyl)thioureido]-2-chlorophenoxy}-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-dimethoxyphenyl)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-chlorophenyl)thioureido]phenyl}acetamide

267 446 N-(4-{3-[3-chloro-4-(cyclohexylethylamino)phenyl]thioureido)phenyl)acetamide

268 365 N-{4-[3-(4-ethoxy-3-chlorophenyl)thioureido]phenyl}acetamide

-158269 427 N-{4-[3-(4-benzyloxy-3-chlorophenyl)thioureido]phenyl}acetamide

270 317 {4-[(3-methylfuran-2-carbonyl)amino]phenyl}-

-e cetyl ester of v-tert-butyl ester

271 456 N-{4-[3-(2-benzyl-amino-5-chloro-4-methoxy-phenyl)-thioureido]-phenyl}-acetamide

272 420 N-{4-[3-(4-dipropyl-3-chloroaminophenyl)thioureido]phenyl}-acetamide

273 458 N-(4-{3-[4-allylcyclohexylamino)-3-chlorophenyl]thioureido}phenyl)acetamide

274 41 1 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

276 493 furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]-2,5-dimethoxyphenyl}-amide

277 486 N-{4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]-2-cyanophenyl}-2-fluorobenzamide

278 495 N-{2-chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-fluorobenzamide

279 465 5-methyl-[1,2,3]thiadiazole-4-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}-amide

280 517 5-Furan-3-yl-[1,2,3]thiadiazole-4-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}-amide

281 527 5-phenyl-3-yl-[1,2,3]thiadiazole-4-carboxylic acid “{4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}-amide

282 458 N-(4-{3-[3-chloro-4-(octahydroquinolin-1-yl)phenyl]thioureido}phenyl)acetamide

- 159 283 458 N-[5-[[[(5-chloro-2,4-dimethoxyphenyl)amino]thioxomethyl]amino]-2-pyridinyl]-2-methylbenzamide

284 434 furan-2-carboxylic acid {5-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]pyridin-2-yl)amide

285 425 N-{4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]-2-methoxy-5-methylphenyl}-acetamide

286 505 N-{4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]-2-methoxy-5-methylphenyl}-2-fluorobenzamide

287 477 furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]-2-methoxy-5-methylphenyl}-amide

288 517 4-Furan-3-yl-[1,2,3]thiadiazole-5-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}-amide

289 462 N-{5-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-2-yl}-2-fluorobenzamide

290 384 N-{4-[3-(4-methoxy-3-trifluoromethylphenyl)thioureido]phenyl}acetamide

291 394 N-[4-(3-{3-chloro-4-[(2-hydroxyethyl)methylamino]phenyl}thioureido)phenyl]acetamide

292 485 N-(2-benzoyl-4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}-acetamide

293 565 N-(2-benzoyl-4-[3-(5-chloro-2,4-dimethoxyphenyl)-thioureido]-phenyl}-2-fluorobenzamide

294 537 furan-2-carboxylic acid {2-benzoyl-4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}-amide

295 475 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-methyl-phenyl}-2-fluorobenzamide

296 447 furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]-3-methylphenyl}-amide

- 160 297 395 N-{4-[3-(5-chloro-2,4-dimethoxyphenyl)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-cyclohexylaminophenyl)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 furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]-2-phenylcarbamoylphenyl}-amide

303 491 N-{4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]-2-methoxyphenyl}-2-fluorobenzamide

304 463 furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]-3-methoxyphenyl}-amide

305 449 N-{4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]-2-trifluoromethylphenyl}acetamide

306 458 furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]-2-cyanophenyl}-amide

307 467 furan-2-carboxylic acid {2-chloro-4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}-amide

308 501 furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]-2-trifluoromethylphenyl}-amide

309 395 N-{4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]-2-methylphenyl}-acetamide

- 161 310 475 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methyl-phenyl}-2-fluorobenzamide

311 447 furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]-2-methylphenyl}-amide

312 378 N-{4-[3-(4-acetylaminophenyl)thioureido]-2-chlorophenyl}-acetamide

313 408 {4-[3-(4-acetylaminophenyl)thioureido]-2-chlorophenyl}-carbamic acid ethyl ester

314 382 N-{5-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]pyridin-2-yl}-acetamide

315 509 N-(4-{3-[4-(1-benzyl-piperidin-4-yl-amino)-3-chlorophenyl]-thioureido}-phenyl)-acetamide

316 407 N-(4-{3-[3-chloro-4-(2-dimethylaminoethylamino)phenyl]thioureido}phenyl)acetamide

317 408 N-[4-(3-{3-chloro-4-[(2-methoxyethyl)methylamino]phenyl}-thioureido)phenyl}-acetamide

318 421 N-(4-{3-[3-chloro-4-[(3-dimethylaminopropylamino)phenyl]thioureido}phenyl)acetamide

319 495 N-(4-{3-[4-(1-benzylpyrrolidin-3-ylamino)-3-chlorophenyl]thioureido}-phenyl)acetamide

320 483 furan-2-carboxylic acid {5-chloro-4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]-2-hydroxyphenyl}-amide

321 431 N-{5-chloro-4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]-2-hydroxyphenyl}-acetamide

322 51 1 (5H,11H-benzo[e]pyrrolo[1.2-a][1,4]diazepin-10-yl)-(2-chloro-4-imidazol-1-yl-phenyl)-methanone

323 451 [1,2,3]thiadiazole-5-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}-amide

- 162 324 483 furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]naphthalen-1-yl}-amide

325 51 1 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-naphthalen-1-yl}-2-fluorobenzamide

326 429 N-{5-chloro-4-[3-(5-chloro-2,4-dimethoxyphenyl)-thioureido]-2-methylphenyl}-acetamide

327 509 N-{5-chloro-4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]-2-methylphenyl}-2-fluoroacetamide

328 481 furan-2-carboxylic acid {5-chloro-4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]-2-methylphenyl}-amide

329 431 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-naphthalen-1-yl}-acetamide

330 416 furan-2-carboxylic acid {4-[3-(3-chloro-4-dimethylaminophenyl)thioureido]phenyl}-amide

331 561 furan-2-carboxylic acid [4-(3-{4-[(1-benzylpyrrolidin-3-yl)methylamino]-3-chlorophenyl}-thioureido)phenyl]-amide

332 513 N-[4-(3-{3-chloro-4-[methyl-(1-methyl-pyrrolidin-3-yl)amino]-phenyl}-thioureido)-phenyl]-2-fluorobenzamide

333 463 N-{4-[3-(5-chloro-2-methoxy-4-methylphenyl)thioureido]phenyl}-2,6-difluorobenzamide

334 420 N-(4-{3-[3-chloro-4-(1-methyl-pyrrolidin-3-yloxy)-phenyl]-thioureido}-phenyl)-acetamide

335 434 N-(4-{3-[3-chloro-4-(1-methyl-piperidin-4-yloxy)-phenyl]-thioureido}-phenyl)-acetamide

336 422 N-(4-{3-[3-chloro-4-(dimethylaminopropoxy)phenyl]thioureido}phenyl)acetamide

337 425 2-Acetylamino-5-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]benzoic acid

- 163 338 505 5-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]-2-(2-fluorobenzoylamino)benzoic acid

339 477 5-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]-2-[(furan-2-carbonyl)amino]benzoic acid

340 545 N-[4-(3-{3-chloro-4-[methyl-(1-methyl-piperidin-4-yl)-amino]-phenyl}-thioureido)-phenyl]-2,6-difluoro-benzamide 341 503 [1,2,3]thiadiazole-4-carboxylic acid-[4-(3-{3-chloro-4-[methyl-(1-methyl-pyrrolidin-3-yl)-amino]-phenyl}-thioureido)-phenyl]-amide

342 443 N-{4-[3-(3-chloro-4-methylsulfanylphenyl)thioureido]phenyl}-2-methylbenzamide

343 408 N-(4-{3-[3-chloro-4-(2-dimethylaminoethoxy)phenyl]ticureido}phenyl)acetamide

344 499 furan-2-carboxylic acid [4-(3-{3-chloro-4-[methyl-(1-methylpiperidin-4-yl)amino]phenyl}-thioureido)phenyl]-amide

345 419 N-{4-[3-(3-chloro-4-cyclohexyloxyphenyl)thioureido]phenyl}acetamide

346 440 N-{4-[3-(3-Chloro-4-dimethylaminophenyl)-thioureidoJ-phenyl}-2-methylbenzamide

347 493 N-{4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]-3-methylphenyl}-2,6-difluorobenzamide

348 462 N-{4-[3-(3-chloro-2,4-dimethylamino-phenyl)-thioureido]-phenyl}-2,6-difluorobenzamide

349 531 N-[4-(3-{3-chloro-4-[methyl-(1-methylpyrrolidin-3-yl)amino]phenyl}thioureido)phenyl]-2,6-difluorobenzamide

350 427 pyridine-2-carboxylic acid {4-[3-(3-chloro-4-dimethylaminophenyl)thioureido]phenyl}-amide

- 164 351 430 pyridine-2-carboxylic acid-{4-[3-(3-chloro-4-methylsulfanylphenyl)thioureido]phenyl}-amide

352 428 pyridine-2-carboxylic acid {4-[3-(5-chloro-2-methoxy-4-methylphenyl)thioureido]phenyl}-amide

353 417 furan-2-carboxylic acid {4-[3-(5-chloro-2-methoxy-4-methylphenyl)thioureido]phenyl}-amide

354 496 pyridine-2-carboxylic acid [4-(3-{3-chloro-4-[methyl-(1-methylpyrrolidin-2-yl)amino]phenyl}-thioureido)phenyl]-amide 355 495 N-[3-chloro-4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}-2-fluorobenzamide

356 467 furan-2-carboxylic acid {3-chloro-4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}-amide

357 515 N-{4-[3-(3-Chloro-4-cyclohexylsulfanylphenyl)thioureido]phenyl}-2-fluorobenzamide

358 449 N-{4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]-3-trifluoromethylphenyl}acetamide

359 529 N-{4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]-3-trifluoromethylphenyl}-2-fluorobenzamide

360 421 N-{4-[3-(4-acetyl-amino-phenyl)-thioureido]-2-chloro-phenyl}-2-dimethyl-amino-acetamide

361 473 furan-2-carboxylic acid (4-{3-[3-chloro-4-(2-dimethylaminoacetylamino)phenyl]thioureido}-phenylamide

362 501 N-(4-{3-[3-chloro-4-(2-dimethylamino-acetylamino)-phenyl]-thioureido}-phenyl)-2-fluorobenzamide

363 461 N-{4-[3-(4-acetylaminophenyl)thioureido]-2-chlorophenyl}-2-piperidin-1-ylacetamide

364 541 N-(4-{3-[3-chloro-4-(2-piperidin-1-yl-acetylamino)-phenyl]-thioureido}-phenyl)-2-fluorobenzamide

- 165 365 513 furan-2-carboxylic acid-(4-{3-[3-chloro-4-(2-piperidin-1-yl-acetylamino)-phenyl]-thioureido}-phenylamide

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-yl-acetylamino)-phenyl]-thioureido}-phenyl)-2-fluorobenzamide

368 515 furan-2-carboxylic acid (4-{3-[3-chloro-4-(2-morpholin-4-ylacetylamino)phenyl]thioureido}-phenylamide

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 furan-2-carboxylic acid {4-[3-(3-chloro-4-(methanesulfonylaminophenyl)thioureido]phenyl}-amide

372 481 N-{4-[3-(4-acetylaminophenyl)thioureido]-2-chlorophenyl}-2-(2-dimethylaminoethylsulfanyl)acetamide

373 561 N-[4-(3-{3-chloro-4-[2-(2-dimethylaminoethylsulfanyl)acetylamino]phenyl}thioureido)phenyl]-2-fluorobenzamide

374 585 N-[4-(3-{4-[(1-benzyl-pyrrolidin-3-yl)-methyl-aminops-chloro-phenylj-thioureido-phenylj^-methylbenzamide

375 523 N-[4-(3-{3-chloro-4-[methyl-(1-methylpiperidin-4-yl)-

-amino]-phenyl}-thioureido)-phenyl]-2-methyl

376 510 pyridine-2-carboxylic acid-[4-(3-{3-chloro-4-[methyl-(1-

-methyl-piperidin-4-yl)-amino]-phenyl}-thioureido)-phenyl]-amide

377 347 N-{4-[3-(3-ki ór-4-ν i n i l-phen i l)-t i o u re i d o]-pheni l}-acetamide

- 166 378 441 furan-2-carboxylic acid {4-[3-(4-chloro-3-trifluoromethylphenyl)thioureidophenyl}-amide

379 452 pyridine-2-carboxylic acid {4-[3-(4-chloro-3-trifluoromethylphenyl)thioureidophenyl}-amide

380 487 N-{4-[3-(4-chloro-3-trifluoromethylphenyl)thioureido]phenyl}-2,6-difluorobenzamide

381 486 N-{4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]-3-cyanophenyl}-2-fluorobenzamide

382 458 furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]-3-cyanophenyl}-amide

383 406 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-3-cya no-phenyl}-acetamide

384 395 N-{4-[3-(5-chloro-2,4-dimethoxyphenyl)-2-methylisothioureido]phenyl}-acetamide

385 396 N-{4-[3-(5-chloro-2,4-dimethoxyphenyl)-2-methylisothioureido]phenyl}-acetamide

386 461 N-{4-[3-(4-Ethylsulfanyl-3-chlorophenyl)-thioureido]-phenyl}-2-fluorobenzamide

387 489 N-{4-[3-(4-butylsulfanyl-3-chlorophenyl)thioureido]phenyl}-2-fluorobenzamide

388 41 1 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-methoxy-phenyl}-acetamide

389 491 N-{4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]-3-methoxyphenyl}-2-fluorobenzamide

390 463 furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]-3-methoxyphenyl}-amide

391 531 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[3-chloro-4-[2-piperidin-1-ylacetylamino)phenyl]thioureido}phenyl)amide

- 167 392 481 N-{4-[3-(3-chloro-4-methanesulfinylphenyl)thioureido]phenyl}-2,6-difluorobenzamide

393 497 N-{4-[3-(3-chloro-4-methanesulfonylphenyl)thioureido]phenyl}-2,6-difluorobenzamide

394 459 N-{4-[3-(5-chloro-2-methoxy-4-methylphenyl)thioureido]-2-methylphenyl}-2-fluorobenzamide

395 429 N-{4-[3-(3-chloro-4-methylphenyl)thioureido]-2-methylphenyl}-2-fluorobenzamide

396 533 furan-2-carboxylic acid [4-(3-(3-chloro-4-[2-(2-dimethylaminoethylsulfaniOacetylamino]phenyl]thioureidophenyl]amide

397 458 N-{4-[3-(4-acetyl-amino-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-fluorobenzoylamino)phenyl]thioureido}phenyl)carbamic acid ethyl ester

400 440 N-{4-[3-(4-Acetylaminophenyl)thioureido]-2-chlorophenylj-benzamide

401 520 N-{4-[({[4-(benzoyl-amino)-3-chloro-phenyl]-amino}-thioxomethyl)-amino]-phenyl}-2-fluorobenzamide

402 529 N-{4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]-2-trifluoromethylphenyl}-2-fluorobenzamide

403 492 furan-2-carboxylic acid {4-[3-(4-benzoylamino-3-chlorophenyl)thioureido]phenyl}-amide

404 416 N-{4-[3-(4-amino-3-chlorophenyl)-thioureido]-phenyl}-2-fluorobenzamide

- 168 ···« ··

405 479 N-{4-[3-(4-acetylaminophenyl)thioureido]-2-chlorophenyl}-2-thiomorpholin-4-ylacetamide

406 531 furan-2-carboxylic acid (4-{3-[3-chloro-4-(2-thiomorpholin-4-ylacetylamino)phenyl]thioureido}phenyl)amide

407 559 N-(4-{3-[3-chloro-4-(2-thiomorpholin-4-yl-acetylamino)-phenyl]-thioureido}-phenyl-2-fluorobenzamide

408 461 N-{4-[3-(3-chloro-4-methylsulfanylphenyl)thioureido]-2-methylphenyl}-2-fluorobenzamide

409 430 furan-2-carboxylic acid {4-[3-(4-acetylamino-3-chlorophenyl)thioureido]phenyl}-amide

410 477 N-{4-[3-(4-acetylaminophenyl)thioureido]-2-chlorophenyl}-2-dipropylaminoacetamide

1 529 furan-2-carboxylic acid (4-{3-[3-chloro-4-(2-dipropylaminoacetylamino)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-diethylaminoacetylamino]phenyl]thioureido-amide

414 529 N-(4-{3-[3-chloro-4-(2-diethyl-amino-acetyl-amino)-phenyl]-thioureido}-phenyl)-2-fluorobenzamide

415 447 N-{4-[3-(4-acetylaminophenyl)thioureido]-2-chloro-

-fe n i I }-2-pyr i rro I i d in-1 -yl-acetamide

416 499 furan-2-carboxylic acid-(4-{3-[3-chloro-4-(2-pyrrolidine-

-1-yl-acetylamino)-phenyl]-thioureido}-phenyl)-amide

417 527 N-(4-{3-[3-chloro-4-(2-pyrrolidin-1-yl-acetyl-amino-phenyl]-thioureido}-phenyl)-2-fluorobenzamide

418 475 N-{4-[3-(5-chloro-2-methoxy-4-methylphenyl)thioureido]-3-methoxyphenyl}-2-fluorobenzamide

- 169 419 445 N-{4-[3-(3-chloro-4-methylphenyl)thioureido]-3-methoxyphenyl}-2-fluorobenzamide

420 477 N-{4-[3-(3-chloro-4-methylsulfanylphenyl)thioureido]-3-methoxyphenyl}-2-fluorobenzamide

421 388 furan-2-carboxylic acid {4-[3-(4-amino-3-chlorophenyl)thioureido]phenyl}-amide

422 527 furan-2-carboxylic acid (4-{3-[4-(2-azepan-1-ylacetylamino)-3-chlorophenyl)thioureido]phenyl}-amide

423 555 N-(4-{3-[4-(2-azepan-1-yl)-acetyl-amino)-3-chloro-phenyl]-thioureido}-phenyl)-2-fluorobenzamide

424 527 furan-2-carboxylic acid [4-(3-{3-chloro-4-[2-(2-methyl-piperidin-1-yl)-acetyl-amino]-phenyl}-thioureido)-phenyl]-amide 425 555 N-[4-(3-{3-chloro-4-[2-(2-methyl-piperidin-1-yl)-acetyl-amino]-phenyl}-thioureido)-phenyl]-2-fluoro-benzamide 426 339 furan-2-carboxylic acid [4-(3-pyridin-2-yl-thioureido)-phenyl]-amide

427 339 furan-2-carboxylic acid [4-(3-pyridin-4-yl-thioureido)-phenyl]-amine

428 367 2-Fluoro-N-[4-(3-pyridin-3-yl-thioureido)-phenyl]-benzamide

429 339 furan-2-carboxylic acid [4-(3-pyridin-3-yl-thioureido)-phenyl]-amide

430 353 furan-2-carboxylic acid {4-[3-(3-aminophenyl)thioureido]phenyl}-amide

431 406 furan-2-carboxylic acid {4-[3-(3-trifluoromethylphenyl)thioureido]phenyl}-amide

432 380 2-Fluoro-N-[4-(3-m-tolyl-thioureido)-phenyl]-benzamide

- 170 ·* ♦ ·

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 furan-2-carboxylic acid {4-[3-(3-amino-5-chlorophenyl)thioureido]phenyl}-amide

436 352 furan-2-carboxylic acid [4-[3-m-tolylthioureido)phenyl]amide

437 416 N-{4-[3-(2-amino-5-chlorophenyl)-thioureido]-phenyl}-2-fluorobenzamide

438 571 (2-chloro-4-{3-[4-(2-fluoro-benzoyl-amino)-phenyl]-thioureido}-phenyl)-carbamic acid 2-piperidin-1-yl-ethyl ester 439 543 [2-chloro-4-(3-{4-[(furan-2-carbonyl)-amino]-phenyl}-thioureido)-phenyl]-carbamic acid 2-piperidin-1-yl-ethyl ester 440 388 furan-2-carboxylic acid-{4-[3-(2-amino-5-chloro-phenyl)-thioureido]-phenyl}-amide

441 363 furan-2-carboxylic acid {4-[3-(3-cyanophenyl)thioureido]phenyl}-amide

442 416 N-{4-[3-(3-amino-5-chlorophenyl)-thioureido]-phenyl}-2-fluorobenzamide

443 367 2-fluoro-N-[4-(3-pyridin-2-yl-thioureido)-phenyl]-benzamide

444 367 2-fluoro-N-[4-(3-pyridin-4-yl-thioureido)-phenyl]-benzamide

445 374 furan-2-carboxylic acid {4-[3-(6-chloropyridin-3-yl)thioureido]phenyl}-amide

446 388 furan-2-carboxylic acid {4-[3-(2-amino-3-chlorophenyl)thioureido]phenyl}-amide

- 171 - ··»· ·,*· *,,** *

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

450 399 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3-isopropylphenyl)thioureido]phenyl)amide

451 380 furan-2-carboxylic acid {4-[3-(3-isopropylphenyl)thioureido]phenyl}-amide

452 409 2-Fluoro-N-{4-[3-(3-isopropylphenyl)thioureido]-phenylbenzamide

453 381 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3-cyanophenyl)thioureido]phenyl)amide

454 410 N-{4-[3-(3-Dimethylaminophenyl)thioureido]phenyl}-2-fluorobenzamide

455 381 furan-2-carboxylic acid {4-[3-(3-dimethylaminophenyl)thioureido]phenyl}-amide

456 370 [1,2,3]thiadiazole-4-carboxylic acid [4-(3-m-tolylthioureido)phenyl]-amide

457 424 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3-trifluoromethylphenyl)thioureido]phenyl}-amide

458 479 N-{3-chloro-4-[3-(5-chloro-2-methoxy-4-methylphenyl)thioureido]phenyl}-2-fluorobenzamide

459 449 N-{3-chloro-4-[3-(3-chloro-4-methylphenyl)thioureido]phenyl}-2-fluorobenzamide

460 481 N-{3-chloro-4-[3-(3-chloro-4-methylsulfanylphenyl)thioureido]phenyl}-2-fluorobenzamide

- 172 461 391 N-{4-[3-(3-c i a η o-f e n i I )-t i o u re i d o]-f e n i I }-2-f I uor-benzamide

462 395 furan-2-carboxylic acid {4-[3-(3-acetylaminophenyl)thioureido]phenyl}-amide

463 424 2-Fluoro-N-{4-[3-(3-hydrazinocarbonylphenyl)thioureido]phenylbenzamide

464 400 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[3-(1-hydroxy-ethyl)-phenyl]-thioureid o}-phenyl)-amide

465 434 N-{4-[3-(2-amino-3-chlorophenyl)thioureido]phenyl}-2,6-difluorobenzamide

466 406 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3-amino-5-chlorophenyl)thioureido]phenyl}-amide

467 398 furan-2-carboxylic acid {4-[3-(3,5-dimethoxyphenyl)thioureido]phenyl}-amide

468 416 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3,5-dimethoxyphenyl)thioureido]phenyl}-amide

469 454 5-(3-{4-[(furan-2-carbonyl)-amino]-phenyl}-

-thiourea (isophthalic acid) dimethyl ester

470 434 Isoxazole-5-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]phenyl}-amide

471 392 [1,2,3]thiadiazole-4-carboxylic acid-{4-[3-(6-chloro-

-p i ri d in-3-i l)-t i ou rei d o]-f eni I }-a m i d

472 382 furan-2-carboxylic acid (4-{3-[3-(1-hydroxyethyl)phenyl]thioureido}phenyl)amide

473 368 furan-2-carboxylic acid {4-[3-(3-methoxyphenyl)thioureido]phenyl}-amide

474 354 furan-2-carboxylic acid {4-[3-(3-hydroxyphenyl)thioureido]phenyl}-amide

- 173 475 382 2-fluoro-N-{4-[3-(3-hydroxyphenyl)-thioureido]-phenyl}· -benzamide

476 396 2-Fluoro-N-{4-[3-(3-hydroxymethylphenyl)thioureido]-phenylj-benzamide

477 423 N-{4-[3-(3-Acetylaminophenyl)thioureido]phenyl}-2-fluorobenzamide

478 413 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3-acetylaminophenyl)thioureido]phenyl}-amide

479 400 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3-dimethylaminophenyl)thioureido]phenyl}-amide

480 340 furan-2-carboxylic acid [4-(3-pyrimidin-4-yl-thioureido)-phenyl]-amide

481 378 furan-2-carboxylic acid {4-[3-(1H-indazol-5-yl)-thioureido]-phenyl}-amide

482 395 furan-2-carboxylic acid [4-(3-benzothiazol-5-yl·

-thioureido)-phenyl]-amide

483 406 2-Fluoro-N-{4-[3-(1H-indazol-5-yl)-thioureido]-phenylj-benzamide

484 424 N-[4-(3-Benzthiazol-5-yl-thioureido)-phenyl]-2-fluorobenzamide

485 473 5-(3-{4-[([1,2,3]thiadiazole-4-carbonyl)amino]phenyl}thioureido)isophthalic acid dimethyl ester

486 442 furan-2-carboxylic acid (4-{3-[4-(1-azidoethyl)-3-chlorophenyl]thioureido}-phenyl)amide

487 396 2-Fluoro-N-{4-[3-(3-methoxyphenyl)-thioureido]-phenyl}-benzamide

488 368 furan-2-carboxylic acid {4-[3-[3-hydroxymethylphenyl)thioureido]phenyl}-amide

-174- t«j· J' t,

489 416 furan-2-carboxylic acid {4-[3-(5-chloro-2-dimethylaminophenyl)thioureido]phenyl}-amide

490 444 N-{4-[3-(5-chloro-2-dimethylamino-phenyl)-thioureido]-phenyl}-2-fluorobenzamide

491 506 [3-chloro-5-(3-{4-[([1,2,3]thiadiazole-4-carbonyl)amino]phenyl}thioureido)phenyl]carbamic acid tert-butyl ester

492 470 N-(4-{3-[4-(1-azido-ethyl)-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 furan-2-carboxylic acid-{4-[3-(1H-benzimidazol-5-yl)-thioureido]-phenyl}-amide

495 392 furan-2-carboxylic acid-{4-[3-(2-methyl-1H-benzimidazol-5-yl)-thioureido]-phenyl}-amide

496 406 N-{4-[3-(1H-benzimidazol-5-yl)-thioureido]-phenyl}-2-fluorobenzamide

497 420 2-Fluoro-N-{4-[3-(2-methyl-1H-benzimidazol-5-yl)-thioureido]-phenyl}-benzamide

498 452 [1,2,3]thiadiazole-4-carboxylic acid {5-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]pyridin-2-yl}-amide

499 445 pyridine-2-carboxylic acid-{5-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]pyridin-2-yl}-amide

500 434 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(2-dimethylamino-5-chlorophenyl)thioureido]phenyl}-amide

501 484 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[4-(2-aminopyrimidin-4-yl)-3-chlorophenyl]thioureido}-phenyl)amide

-175- ·/·’»»’·

502 494 N-(4-{3-[4-(2-amino-pyrimidin-4-yl)-3-chlorophenyl]-thioureido}-phenyl)-2-fluorobenzamide

503 434 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3-chloro-2-dimethylaminophenyl)thioureido]phenyl}-amide

504 462 N-{4-[3-(3-Chloro-2-dimethylamino-phenyl)-thioureido]-phenyl}-2,6-difluorobenzamide

505 416 furan-2-carboxylic acid {4-[3-(3-chloro-2-dimethylaminophenyl)thioureido]phenyl}-amide

506 445 pyridine-2-carboxylic acid-{6-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]pyridin-3-yl}-amide

507 462 N-{6-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-3-yl}-2-fluorobenzamide

508 482 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3-iodophenyl)thioureido]phenyl}-amide

509 413 [1,2,3]thiadiazole-4-carboxylic acid-{4-[3-(3-tert-butyl-

-fen i l)-ti ou reid o]-fen i l}-a m id

510 387 furan-2-carboxylic acid {4-[3-(3-chlorobenzyl)thioureido]phenyl}-amide

511 415 N-{4-[3-(3-chlorobenzyl)-thioureido]-phenyl}-2-fluorobenzamide

512 434 furan-2-carboxylic acid-{6-[3-(5-chloro-2,4-dimethoxy-

-f en i l)-t i ou rei d o]-p irid i n-i l}-a m i d

513 435 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3-bromophenyl)thioureido]phenyl}-amide

514 452 [1,2,3]thiadiazole-4-carboxylic acid-{6-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]pyridin-3-yl}-amide

515 426 [1,2,3]thiadiazole-4-carboxylic acid-{5-[3-(3,5-dichlorophenyl!)-thioureido]-pyridin-2-yl}-amide

- 176 516 474 furan-2-carboxylic acid-{4-[3-(3,5-bis-trifluoromethylphenyl)thioureido]phenyl}-amide

517 502 N-{4-[3-(3,5-bis-trifluoromethylphenyl)thioureido]phenyl}-2-fluorobenzamide

518 450 N-{4-[3-(4-amino-3,5-dichlorophenyl)-thioureido]-phenyl}-2-fluorobenzamide

519 539 N-{4-[3-(4-amino-3,5-dibromophenyl)-thioureido]-phenyl}-2-fluorobenzamide

520 392 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(5-chloropyridin-3-yl)thioureido]phenyl}-amide

521 529 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(4-amino-3,5-dibromophenyl)thioureido]phenyl}-amide

522 434 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3-chloro-5-dimethylaminophenyl)thioureido]phenyl}-amide

523 444 N-{4-[3-(3-Chloro-5-dimethylamino-phenyl)-thioureido]-phenyl}-2-fluorobenzamide

524 416 furan-2-carboxylic acid {4-[3-(3-chloro-5-dimethylaminophenyl)thioureido]phenyl}-amide

525 436 [1 _l 2,3]thiadiazole-4-carboxylic acid-{4-[3-(5-bromo-pyridin-3-yl)-thioureido]-phenyl}-amide

526 379 furan-2-carboxylic acid-{4-[3-(1H-benzotriazol-5-yl)-thioureido]-phenyl}-amide

527 425 N-{4-[3-(1H-Benztriazol-5-yl)-thioureido]-phenyl}-2,6-difluorobenzamide

528 388 N-[4-({[2-(3-chlorophenyl)hydrazino]thioxomethyl}amino)phenyl]furan-2-carboxamide

529 416 N-[4-({[2-(3-chlorophenyl)hydrazino]thioxomethyl}arnino)phenyl]-2-fluorobenzamide

- 177 530 456 furan-2-carboxylic acid {4-[3-(2-amino-3-chloro-5-trifluoromethylphenyl)thioureido]phenyl}-amide

531 513 N-{4-[3-(3-bromo-5-trifluoromethylphenyl)thioureido]phenyl}-2-fluorobenzamide

532 503 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3-bromo-5-trifluoromethylphenyl)thioureido]phenyl}-amide

533 374 {4-[(furan-2-carbonyl)amino]phenyl}-thiocarbamic acid O-(3-chlorophenyl) ester

534 474 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(2-amino-3-chloro-5-trifluoromethylphenyl)thioureido]phenyl}-amide

535 508 [1,2,3]thiadiazole-4-carboxylic acid-{4-[3-(3-piperidine-

-1 -il-5-trif I uor-m et i l-fe n i I)-t i o urei do]-f en i I }-a m i d

536 380 N-[4-(3-benzylthioureido)phenyl]-2-fluorobenzamide

537 439 [1 _I 2,3]thiadiazole-4-carboxylic acid {4-[3-(3,4-dichlorobenzyl)thioureido]phenyl}-amide

538 449 N-{4-[3-(3,4-dichlorobenzyl)-thioureido]-phenyl}-2-fluorobenzamide

539 370 [1,2,3]thiadiazole-4-carboxylic acid [4-(3-benzylthioureido)phenyl]-amide

540 424 N-[4-(3-benzo[1,3]dioxol-5-yl-methylthioureido)-phenyl]-2-fluorobenzamide

541 414 [1,2,3]thiadiazole-4-carboxylic acid [4-(3-benzo[1,3]dioxol-5-ylmethylthioureido)phenyl]amide

542 506 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoromethylbenzyl)thioureido]phenyl}-amide

543 516 N-{4-[3-(3,5-bis-trifluoromethylbenzyl)thioureido]phenyl}-2-fluorobenzamide

- 178 544 352 furan-2-carboxylic acid [4-(3-benzylthioureido)phenyl]-amide

545 421 furan-2-carboxylic acid {4-[3-(3,4-dichlorobenzyl)thioureido]phenyl}-amide

546 396 furan-2-carboxylic acid [4-(3-benzo[1,3]dioxol-5-ylmethylthioureido)phenyl]amide

547 488 furan-2-carboxylic acid {4-[3-(3,5-bis-trifluoromethylbenzyl)thioureido]phenyl}-amide

548 503 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(4-bromo-3-trifluoromethylphenyl)thioureido]phenyl}-amide

549 529 N-{4-[3-(3-bromo-4-trifluoromethylphenyl)thioureido]-phenyl}-2-fluorobenzamide

550 519 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3-bromo-4-trifluoromethoxyphenyl)thioureido]phenyl}-amide

551 473 furan-2-carboxylic acid {4-[3-(3-chloro-4-trifluoromethylsulfanylphenyl)thioureido]phenyl}-amide

552 412 2-Fluoro-N-(4-{3-[2-(3-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide

553 412 2-Fluoro-N-(4-{3-[2-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide

554 402 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(3-fluorophenyl)ethyl]thioureido)phenyl)amide

555 402 [1,2,3]thiadiazole-4-carboxylic acid-(4-{3-[2-(4-fluoro-

-f e n i l)-eti l]-t i o u re i d o}-f en i I )-am i d

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-trifluoromethylphenyl)thioureido]phenyl}-amide

- 179 558 523 [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-pyrrolidine-

-1-yl-5-trifluoromethylphenyl)thioureido]phenyl}-amide

561 384 furan-2-carboxylic acid (4-{3-[2-(4-fluorophenyl)ethyl]thioureido}phenyl)amide

562 419 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(3-chlorophenyl)ethyl]thioureido}-phenyl)amide

563 429 N-(4-{3-[2-(3-Chloro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluorobenzamide

564 401 furan-2-carboxylic acid (4-{3-[2-(3-chlorophenyl)ethyl]thioureido}phenyl)amide

565 402 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[1-(4-fluorophenyl)ethyl]thioureido}-phenyl)amide

566 504 2-Fluoro-N-{4-[3-(3-pyrrolidin-1-yl-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-benzamide

567 477 N-{4-[3-(3-dimethylamino-5-trifluoromethylphenyl)thioureido]phenyl}-2-fluorobenzamide

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-trifluoromethyl-phenyl)-thioureido]-phenyl}-benzamide

571 468 ['1,2,3]thiadiazole-4-carboxylic acid-{4-[3-(3-dimethylamino-5-trifluoromethylphenyl)thioureido]phenyl}-amide

-180572 405 [1,2,3]thiadiazole-4-carboxylic acid-{4-[3-(3-chlorobenzyl)thioureido]phenyl}-amide

573 384 furan-2-carboxylic acid (4-{3-[2-(3-fluorophenyl)ethyl]thioureido}phenyl)amide

574 366 furan-2-carboxylic acid [4-(3-phenethylthioureido)phenyl]-amide

575 384 [1,2,3]thiadiazole-4-carboxylic acid [4-(3-phenethylthioureido)phenyl]-amide

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-isobutyl-5-trifluoromethylphenyl)thioureido]phenyl}-benzamide

579 388 furan-2-carboxylic acid {4-[3-(3,5-difluorobenzyl)thioureido]phenyl}-amide

580 416 N-{4-[3-(3,5-difluorobenzyl)thioureido]phenyl}-2-fluorobenzamide

581 406 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3,5-difluorobenzyl)thioureido]phenyl}-amide

582 421 furan-2-carboxylic acid {4-[3-(3,5-dichlorobenzyl)thioureido]phenyl}-amide

583 449 N-{4-[3-(3,5-dichlorobenzyl)-thioureido]-phenyl}-2-fluorobenzamide

584 439 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3,5-dichlorobenzyl)thioureido]phenyl}-amide

585 438 furan-2-carboxylic acid {4-[3-(3-fluoro-5-trifluoromethylbenzyl)thioureido]phenyl}-amide

- 181 586 466 2-fluoro-N-{4-[3-(3-fluoro-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-benzamide

587 456 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3-fluoro-5-trifluoromethylbenzyl)thioureido]phenyl}-amide

588 384 [1,2,3]thiadiazole-4-carboxylic acid-{4-[3-(1-phenylethyl)thioureido]phenyl}-amide

589 394 2-Fluoro-N-{4-[3-(1-phenylethyl)-thioureido]-phenyl}-benzamide

590 366 furan-2-carboxylic acid {4-[3-(1-phenylethyl)thioureido]phenyl}-amide

591 412 2-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide

592 384 furan-2-carboxylic acid (4-{3-[1-(4-fluorophenyl)ethyl]thioureido}-phenyl)amide

593 413 N-{4-[3-(1-tert-butyl-1H-imidazol-2-yl)-thioureido]-phenyl}-2-fluorobenzamide

594 510 [1,2,3]thiadiazole-4-carboxylic acid-(4-{3-[3-(isobutylmethylamino)-5-trifluoromethylphenyl]thioureido}-phenyl)-amide 595 510 [1,2,3]thiadiazole-4-carboxylic acid-(4-{3-[3-(3-hydroxypyrrolidin-1-yl)-5-trifluoromethylphenyl]thioureido}-phenyl)-amide 596 520 2-fluoro-N-(4-{3-[3-(isobutylmethylamino)-5-trifluoromethylphenyl]thioureido}-phenyl)-amide

597 510 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[3-(butylmethylamino)-5-trifluoromethylphenyl]thioureido}-phenyl)-amide 598 520 N-(4-{3-[3-(butylmethylamino)-5-trifluoromethylphenyl]thioureido}-phenyl)-2-fluorobenzamide

599 520 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(3,5-bis-trifluoromethylphenyl)ethyl]thioureido}-phenyl)amide

- 182 600 442 [1,2,3]thiadiazole-4-carboxylic acid-{4-[3-(4-fluoro-3-trifluoromethylphenyl)thioureido]phenyl}-amide

601 522 [ 1,2,3]ti adiazol-4-carbon acid-{4-[3-(4-pi p e rid i n-

- 1-yl-3-trifluoromethyl-benzyl)-thioureido]-phenyl}-amide

602 482 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(4-dimethylamino-3-trifluoromethylbenzyl)thioureido]phenyl}-amide

603 381 furan-2-carboxylic acid (4-{3-[2-(4-aminophenyl)ethyl]thioureido}phenyl)amide

604 445 furan-2-carboxylic acid (4-{3-[2-(4-bromophenyl)ethyl]thioureido}phenyl)amide

605 380 furan-2-carboxylic acid {4-[3-(2-p-tolylethyl)thioureido]phenyl}-amide

606 463 [1,2,3]thiadiazole-4-carboxylic acid-(4-{3-[2-(4-bromo-

- phen i l)-ethyl]-thioure i do}-phen i l)-a mid id

607 396 furan-2-carboxylic acid (4-{3-[2-(3-methoxyphenyl)ethyl]thioureido}phenyl)amide

608 403 [1,2,3]thiadiazole-4-carboxylic acid-{4-[3-(1-tert-butyl·

- 1H-imidazol-2-yl)-thioureido]-phenyl}-amide

609 384 furan-2-carboxylic acid-{4-[3-(1-tert-butyl-1H-imidazol-2-yl)-thioureido]-phenyl}-amide]

610 492 N-{4-[3-Dimethylamino-3-trifluoromethylbenzyl)-thioureido]-phenyl}-2-fluorobenzamide

1 427 furan-2-carboxylic acid (4-{3-[2-(3,4-dimethoxyphenyl)ethyl]thioureido}phenyl)amide

612 380 furan-2-carboxylic acid {4-[3-(3-phenylpropyl)thioureido]phenyl}-amide

613 399 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3-phenylpropyl)thioureido]phenyl}-amide

- 183 614 502 furan-2-carboxylic acid-(4-{3-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-amide

615 550 [1,2,3]thiadiazole-4-carboxylic acid-{4-[3-(4-iodo-3-trifluoromethyl-phenyl)-thioreido]-phenyl}-amide

616 532 2-fluoro-N-{4-[3-(4-piperidin-1-yl-3-trifluoromethylbenzyl)thioureido]phenyl}-benzamide

617 537 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[4-(4-methyl-piperazin-1-yl)-3-trifluoromethyl-benzyl]-thioureido}-phenyl)-amide

618 482 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3-dimethyl-amino-5-trifluoromethylbenzyl)thioureido]phenyl}-amide

619 488 furan-2-carboxylic acid {4-[3-(3,5-bis-trifluoromethylphenyl)thioureidomethyl]phenyl}-amide

620 421 furan-2-carboxylic acid {4-[3-(3,5-dichlorophenyl)thioureidomethyl]phenyl}-amide

621 421 furan-2-carboxylic acid {4-[3-(3,4-dichlorophenyl)thioureidomethyl]phenyl}-amide

622 455 furan-2-carboxylic acid {4-[3-(4-chloro-3-trifluoromethylphenyl)thioureidomethyl]phenyl}-amide

623 466 2-fluoro-N-{4-[3-(4-fluoro-3-trifluoromethyl-benzyl)-thioureido]-phenyl}-benzamide

624 456 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(4-fluoro-3-trifluoromethylbenzyl)thioureido]phenyl}-amide

625 410 2-Fluoro-N-{4-[3-(2-phenoxyethyl)-thioureido]-phenyl}-benzarnide

626 382 furan-2-carboxylic acid {4-[3-(2-phenoxyethyl)thioureido]phenyl}-amide

- 184 627 400 [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 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(5-trifluoromethylpyridin-3-yl)thioureido]phenyl}-amide

630 439 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3,4-dichlorophenyl)thioureidomethyl]phenyl}-amide

631 473 [1,2,3]thiadiazole-4-carboxylic acid-{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-thioureido-methyl]-phenyl}-amide

632 381 2-Fluoro-N-[4-(3-pyridin-3-yl-methylthioureido)-phenyl]-benzamide

633 353 furan-2-carboxylic acid [4-(3-pyridin-3-ylmethylthioureido)phenyl]-amide

634 371 [1,2,3]thiadiazole-4-carboxylic acid-[4-(3-pyridin-3-yl-methyl-thioureido)-phenyl]-amide

635 439 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3,5-dichlorophenyl)thioureidomethyl]phenyl}-amide

636 492 N-{4-[3-(3-dimethylamino-5-trifluoromethylbenzyl)-thioureido]-phenyl}-2-fluorobenzamide

637 415 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(3-methoxy-phenyl)-ethyl]-thioureido}-phenyl)-amide

638 399 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(2-p-tolylethyl)thioureido]phenyl}-amide

639 445 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(3,4-dimethoxy-phenyl)-ethyl]-thioureido}-phenyl)-arnide

640 506 [1,2,3]thiadiazole-4-carboxylic acid-{4-[3-(3,5-bistrifluoromethyl-phenyl)-thioureidomethyl]-phenyl}-amide

- 185 641 516 N-{4-[3-(3,5-bis-trifluoromethylphenyl)thioureidomethyl]phenyl}-2-fluorobenzamide

642 449 N-{4-[3-(3,5-dichlorophenyl)-thioureidomethyl]-phenyl}-2-fluorobenzamide

643 449 N-{4-[3-(3,4-dichlorophenyl)-thioureidomethyl]-phenyl}-2-fluorobenzamide

644 448 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3-acetyl-amino-5-chlorophenyl)thioureido]phenyl}-amide

645 453 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(3,4-dichlorophenyl)ethyl]thioureido}phenyl)amide

646 413 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(1-methyl-3-phenylpropyl)thioureido]phenyl}-amide

647 463 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[1-(4-bromophenyl)ethyl]thioureido}-phenyl)amide

648 413 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(4-phenylbutyl)thioureido]phenyl}-amide

649 397 [1,2,3]thiadiazole-4-carboxylic acid-[4-(3-indan-1-yl-thioureido)-phenyl]-amide

650 400 [1,2,3]thiadiazole-4-carboxylic acid-{4-[3-(2-methoxy-benzyl)-thioureido]-phenyl}-amide

651 415 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(2-methoxy-phenyl)-ethyl]-thioureido}-phenyl)-amide

652 415 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(4-methoxy-phenyl)-ethyl]-thioureido}-phenyl)-amide

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

- 186 655 417 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(2-phenylsulfanylethyl)thioureido]phenyl}-amide

656 427 2-Fluoro-N-{4-[3-(2-phenylsulfanylethyl)-thioureido]-phenylj-benzamide

657 399 furan-2-carboxylic acid {4-[3-(2-phenylsulfanylethyl)thioureido]phenyl}-amide

658 381 2-Fluoro-N-[4-(3-pyridm-4-yl-methylthioureido)-phenylj-benzamide

659 353 Furan-2-carboxylic acid [4-(3-pyridin-4-yl-methylthioureido)-phenyl]-amide

660 371 [1,2,3]thiadiazole-4-carboxylic acid-[4-(3-pyridin-4-yl-methyl-thioureido)-phenyl]-amide

661 506 2-fluoro-N-{4-[3-iodobenzyl)thioureido]phenyl}-benzamide

662 478 furan-2-carboxylic acid {4-[3-(3-iodobenzyl)thioureido]phenyl}-amide

663 496 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3-iodobenzyl)thioureido]phenyl}-amide

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-dichlorophenoxy)ethyl]thioureido}phenyl)amide

666 445 N-(4-{3-[2-(3-chlorophenoxy)ethyl]-thioureido}-phenyl)-2-fluorobenzamide

667 417 furan-2-carboxylic acid (4-{3-[2-(3-chlorophenoxy)ethyl]thioureido}phenyl)amide

668 435 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(3-chlorophenoxy)ethyl]thioureido}-phenyl)amide

- 187 669 466 2-fluoroN-{4-[3-(2-fluoro-5-trifluoromethylbenzyl)thioureido]phenyl}-benzamide

670 438 furan-2-carboxylic acid {4-[3-(2-fluoro-5-trifluoromethylbenzyl)thioureido]phenyl}-amide

671 456 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(2-fluoro-5-trifluoromethylbenzyl)thioureido]phenyl}-amide

672 416 N-{4-[3-(3,4-dif I uor-be nzi l)-t iou reid o]-phen i I I }-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-dimethyl-

- amino-5-trifluoro-methyl-phenyl)-ethyl]-thioureid o}-phenyl)-amide

675 388 furan-2-carboxylic acid {4-[3-(3,4-difluorobenzyl)thioureido]phenyl}-amide

676 406 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3,4-difluorobenzyl)thioureido]phenyl}-amide

677 433 N-{4-[3-(3-chloro-4-fluorobenzyl)-thioureido]-phenyl}-2-fluorobenzamide

678 495 [1,2,3]thiadiazole-4-carboxylic acid-(4-{3-[2-(3-bromo-

- f e n i l-su If a n i l)-et i l]-t i o u re id o}-f en i I )-a m i d

679 477 furan-2-carboxylic acid-(4-{3-[2-(3-bromophenyl-

- su If an i I )-e t i l]-t io u re i d o}-f en i l)-a m id

680 505 N-(4-{3-[2-(3-bromophenylsulfanyl)ethyl]thioureido}phenyl)-2-fluorobenzamide

681 493 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(3-bromo-4-methoxyphenyl)ethyl]thioureido}phenyl)amide

682 493 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(5-bromo-2-methoxyphenyl)ethyl]thioureido}phenyl)amide

- 188 *«-· .·

683 419 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(2-chlorophenyl)ethyl]thioureido}-phenyl)amide

684 402 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(2-fluorophenyl)ethyl]thioureido}-phenyl)amide

685 419 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(4-chlorophenyl)ethyl]thioureido}-phenyl)amide

686 475 [1,2,3]thiadiazole-4-carboxylic acid-{4-[3-(3,3-diphenyl-propyl)-thioureido]-phenyl}-amide

687 547 2-fluoro-N-(4-{3-[4-(4-methylpiperazin-1-yl)-3-trifluoromethylbenzyl]thioureido}-phenyl)benzamide

688 469 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(3,5-dichlorophenoxy)ethyl]thioureido}phenyl)amide

689 423 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3-chloro-4-fluorobenzyl)thioureido]phenyl}-amide

690 427 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(4-tert-butyl· -benzyl)-thioureido]-phenyl}-amide

691 399 [1 ₁ 2,3]thiadiazole-4-carboxylic acid-{4-[3-(3,5-dimethylbenzyl)thioureido]phenyl}-amide

692 442 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(4-dimethylamino-3-methylphenyl)ethyl]thioureido}-phenyl)amide

693 479 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(4-bromophenoxy)ethyl]thioureido}phenyl)amide

694 526 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(4-iodophenoxy)ethyl]thioureido}phenyl)amide

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

-189697 461 furan-2-carboxylic acid-(4-{3-[2-(4-bromophenoxy)ethyl]thioureido}phenyl)amide

698 508 furan-2-carboxylic acid (4-{3-[2-(4-iodophenoxy)ethyl]thioureido}phenyl)amide

699 408 Oxazole-4-carboxylic acid {4-[3-(3,4-dichlorophenyl)thioureido]phenyl}-amide

700 424 thiazole-4-carboxylic acid {4-[3-(3,5-dichlorophenyl)thioureido]phenyl}-amide

701 491 thiazole-4-carboxylic acid-4-[(S-p.S-bis-trifluoromethyl· -phenyl)-thioureido]-phenyl}-amide

702 408 Oxazole-4-carboxylic acid {4-[3-(3,5-dichlorophenyl)thioureido]phenyl}-amide

703 469 [1,2,3]thiadiazole-4-carboxylic acid-(4-{3-[2-(3,4-

-d i ki ór-f en oxi)-eti l]-t io u re id o}-f en i l)-a m id

704 424 thiazole-4-carboxylic acid {4-[3-(3,4-dichlorophenyl)thioureido]phenyl}-amide

705 458 thiazole-4-carboxylic acid {4-[3-(4-chloro-3-trifluoromethylphenyl)thioureido]phenyl}-amide

706 400 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(2-phenyl-aminoethyl)thioureido]phenyl}-amide

707 453 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(2,4-dichlorophenyl)ethyl]thioureido}phenyl)amide

708 452 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(3-trifluoromethylphenyl)ethyl]thioureido}-phenyl)amide

709 453 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(2,6-dichlorophenyl)ethyl]thioureido}phenyl)amide

710 485 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(3,4-dichlorophenylsulfanyl)ethyl]thioureido}phenyl)amide

-19071 1 503 [1,2,3]thiadiazole-4-carboxylic acid-(4-{3-[2-(2-fluoro-5-trifluoromethylphenylsulfanyl)ethyl]thioureido}-phenyl)-amide 712 668 N-(4-{3-[3-chloro-5-(3-{4-[([1,2,3]thiadiazole-4-carbonyl)-amino]-phenyl}-thioureido)-phenyl]-thioureido}-phenyl)-[1,2,3]thiadiazole-4-carboxamide

713 413 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(4-ethylphenyl)ethyl]thioureido}-phenyl)amide

714 442 Oxazole-4-carboxylic acid {4-[3-(4-chloro-3-trifluoromethylphenyl)thioureido]phenyl}-amide

715 475 Oxazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoromethylphenyl)thioureido]phenyl}-amide

716 420 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(3,4-difluorophenyl)ethyl]thioureido}-phenyl)amide

717 452 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(4-trifluoromethylphenyl)ethyl]thioureido}phenyl)amide

718 435 furan-2-carboxylic acid-(4-{3-[2-(3,4-dichlorophenyl)-

-et i l]-t i ou rei d o}-f eni I )-a m i d

719 463 N-(4-{3-[2-(3,4-dichloro-phenyl)-ethyl]-thioureido}-phenyl)-amide

720 420 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(3,5-difluorophenyl)ethyl]thioureido}-phenyl)amide

721 412 2-Fluoro-N-(4-{3-[2-(2-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide

722 429 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(4-nitrophenyl)ethyl]thioureido}-phenyl)amide

723 399 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(1-methyl-2-phenylethyl)thioureido]phenyl}-amide

- 191 724 437 N-{4-[3-(4-Terebutyric acid)-thiourei]-phenyl}-2-fluorobenzamide

725 409 N-{4-[3-(3,5-dimethylbenzyl)thioureido]phenyl}-2-fluorobenzamide

726 400 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(2-hydroxy-1-phenylethyl)thioureido]phenyl}-amide

727 409 2-Fluoro-N-{4-[3-(1-methyl-1-phenylethyl)-thioyl]-phenyl}-benzamide

728 399 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(1-methyl-1-phenylethyl)thioureido]phenyl}-amide

729 405 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(2-chlorobenzyl)thioureido]phenyl}-amide

730 388 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(2-fluorobenzyl)thioureido]phenyl}-amide

731 438 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3-trifluoromethylbenzyl)thioureido]phenyl}-amide

732 388 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3-fluorobenzyl)thioureido]phenyl}-amide

733 435 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(2-chlorophenoxy)ethyl]thioureido}-phenyl)amide

734 479 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(3-bromophenoxy)ethyl]thioureido}phenyl)amide

735 418 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(2-fluorophenoxy)ethyl]thioureido}phenyl)amide

736 418 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(3-fluorophenoxy)ethyl]thioureido}phenyl)amide

737 486 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(2-fluoro-5-trifluoromethylphenoxy)ethyl]thioureido}-phenyl)amide

- 192 738 384 furan-2-carboxylic acid-(4-{3-[2-(2-fluorophenyl)ethyl]thioureido}-phenyl)amide

739 435 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(4-bromophenyl)thioureido]phenyl}-amide

740 374 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(4-fluorophenyl)thioureido]phenyl}-amide

741 388 [1,2,3]thiadiazole-4-carboxylic acid-{4-[3-(4-fluorobenzyl)thioureido]phenyl}-amide

742 405 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(4-chlorobenzyl)thioureido]phenyl}-amide

743 449 [1.2,3]thiadiazole-4-carboxylic acid {4-[3-(4-bromobenzyl)thioureido]phenyl}-amide

744 332 N-(4-{3-[1-(4-fluorophenyl)ethyl]thioureido}phenyl)acetamide

745 438 thiazole-4-carboxylic acid {4-[3-(3,4-dichlorobenzyl)thioureido]phenyl}-amide

746 455 thiazole-4-carboxylic acid {4-[3-(2-fluoro-5-trifluoromethyl· -benzyl)-thioureido]-phenyl}-amide

747 426 thiazole-4-carboxylic acid {4-[3-(tert-butylbenzyl)thioureido]phenyl}-amide

748 374 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(2-fluorophenyl)thioureido]phenyl}-amide

749 374 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3-fluorophenyl)thioureido]phenyl}-amide

750 526 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(3-iodophenoxy)ethyl]thioureido}phenyl)amide

751 409 N-(4-{3-[1-(4-fluorophenyl)ethyl]thioureido}phenyl)-2-phenylacetamide

-193752 425 N - (4-{ 3-[ 1 - (4-f I u or-f e n i I )-et i I ]-t i o u re i d o }-f e η i I )-2-methoxy-benzamide

753 425 N-(4-{3-[1-(4-fluorophenyl)ethyl]-thioureido}-phenyl)-3-methoxybenzamide

754 425 N-(4-{3-[1-(4-fluorophenyl)ethyl]-thioureido}-phenyl)-4-methoxybenzamide

755 429 2-Chloro-N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide

756 429 4-chloro-N-(4-{3-[1-(4-fluorophenyl)ethyl]thioureido}phenyl)benzamide

757 453 Acetic acid 4-(4-{3-[1-(4-fluorophenyl)ethyl]thioureido}phenylcarbamoyl)phenyl ester

758 394 N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide

759 395 N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-isonicotinamide

760 410 N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-4-hydroxybenzamide

761 429 3-Chloro-N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide

762 470 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(3-fluoro-5-trifluoromethylphenyl)ethyl]thioureido}phenyl)amide

763 520 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(2,4-bis-trifluoromethylphenyl)ethyl]thioureido}-phenyl)amide

764 470 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(4-fluoro-3-trifluoromethylphenyl)ethyl]thioureido}-phenyl)amide

765 438 4-Dimethylamino-N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide

- 194 766 470 [1,2,3]thiadiazole-4-carboxylic acid-(4-{3-[2-(2-fluoro-3-trifluoromethylphenyl)ethyl]thioureido}-phenyl)amide

767 470 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(2-fluoro-5-trifluoromethylphenyl)ethyl]thioureido}phenyl)amide

768 510 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(3-iodophenyl)ethyl]thioureido}-phenyl)amide

769 470 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(4-fluoro-2-trifluoromethylphenyl)ethyl]thioureido)phenyl)amide

770 463 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(3-bromophenyl)ethyl]thioureido}phenyl)amide

771 427 2-fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-propyl]-thioureido}-phenyl)-benzamide

772 475 2-Fluoro-N-(4-{3-[(4-fluorophenyl)-phenylmethyl]-thioureido}-phenyl)-benzamide

773 455 2-Fluoro-N-(4-{3-[1-(4-Fluoro-phenyl)-pentyl]-thioureido}-phenyl)-benzamide

774 489 2-fluoro-N-(4-{3-[1-(4-fluorophenyl)-2-phenylethyl]thioureido}-phenyl)benzamide

775 409 2-Fluoro-N-{4-[3-(1-o-tolylethyl)-thioureido]-phenyl}-benzamide

776 409 2-Fluoro-N-{4-[3-(1-m-tolylethyl)-thioureido]-phenyl}-benzamide

777 425 2-Fluoro-N-(4-{3-[1-(4-methoxy-phenyl)-ethyl]-thioureido}-phenyl)-benzamide

778 412 2-Fluoro-N-(4-{3-[1-(2-fluorophenyl)-ethyl]-thioureido}-|

I

-phenyl)benzamide

779 429 N-(4-{3-[1-(3-Chloro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluorobenzamide

- 195 780 473 N-(4-{3-[1-(3-bromo-phenyl)-ethyl]-thioureido}-phenyl)-2-fluorobenzamide

781 429 N - (4-{ 3-[ 1 - (4-chloro-pheniol)-ethyl]-thioureidol}-pheniol)-2-fluorobenzamide

782 409 2-Fluoro-N-{4-[3-(1-p-tolylethyl)-thioureido]-phenyl}-benzamide

783 473 N-(4-{3-[1-(2-bromophenyl)ethyl]thioureido}phenyl)-2-fluorobenzamide

784 4-9 N-(4-{3-[1-(2-chlorophenyl)ethyl]-thioureido}-phenyl)-2-fluorobenzamide

785 462 2-Fluoro-N-(4-{3-[1-(2-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-benzamide

786 462 2-Fluoro-N-(4-{3-[1-(3-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-benzamide

787 462 2-Fluoro-N-(4-{3-[1-(4-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-benzamide

788 425 2-Fluoro-N-(4-{3-[1-(2-methoxy-phenyl)-ethyl]-thioureido}-phenyl)-benzamide

789 425 2-Fluoro-N-(4-{3-[1-(3-methoxy-phenyl)-ethyl]-thioureido}-phenyl)-benzamide

790 441 2-Fluoro-N-(4-{3-[1-(4-Fluoro-phenyl)-2-methyl-propyl]-thioureido}-phenyl)-benzamide

791 419 N-(4-{3-[1-(3-cyano-phenyl)-ethyl]-thioureido}-phenyl)-2-fluorobenzamide

792 419 N-(4-{3-[1-(4-cyano-phenyl)-ethyl]-thioureido}-phenyl)-2-fluorobenzamide

793 438 N-(4-{3-[1-(4-Dimethyl-amino-phenyl)-ethyl]-thioureido}-phenyl)-2-fluorobenzamide

- 196

794 438 N-(4-{3-[ 1 -(3-Dimethylaminophenyl)ethyl]-thioureido}phenyl)-2-fluorobenzamide

795 473 2-Bromo-N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide

796 446 quinoline-2-carboxylic acid (4-{3-[1-(4-fluorophenyl)ethyl]thioureido}-phenyl)amide

797 410 2-Fluoro-N-{4-[3-(2-hydroxy-1-phenylethyl)-thioureido]-phenyl}-benzamide

798 332 2-fluoro-N-[4-(3-isopropylthioureido)phenyl]benzamide

799 445 2-Fluoro-N-{4-[3-(1-natalin-2-yl-ethyl)-thioureido]-phenyl}-benzamide

800 412 3-Fluoro-N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide

801 412 4-Fluoro-N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide

802 384 2-fluoro-N-{4-[3-(1-furan-2-ylethyl)thioureido]phenyl}benzamide

803 395 2-Fluoro-N-{4-[3-(1-pyridin-4-yl-ethyl)-thioureido]-phenylj-benzamide

804 397 2-Fluoro-N-(4-{3-[1-(1-methyl-1H-pyrrol-2-yl)-ethyl]-thioureido}-phenyl)-benzamide

805 401 2-Fluoro-N-{4-[3-(1-thiophen-3-yl-ethyl)-thioureido]-phenyl}-benzamide

806 445 N-{4-[3-(3-chloro-4-ethoxyphenyl)thioureido]phenyl}-2-fluorobenzamide

807 459 N-{4-[3-(3-Chloro-4-propoxy-phenyl)-thioureido]-phenyl}-2-fluorobenzamide

- 197 808 459 N-{4-[3-(3-chloro-4-isopropoxy-phenyl)-thioureido]-phenyl}-2-fluorobenzamide

809 473 N-{4-[3-(4-butoxy-3-chlorophenyl)thioureido]phenyl}-2-fluorobenzamide

810 522 2-fluoro-N-{4-[3-(3-iodo-4-methoxyphenyl)thioureido]phenyl}benzamide

1 475 N-{4-[3-(3-bromo-4-methoxy-phenyl)-thioureido]-phenyl}-2-fluorobenzamide

812 520 N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-iodo-benzamide

813 346 N-(4-{3-[1-(4-fluorophenyl)ethyl]thioureido}phenyl)propionamide

814 286 N-[4-(3-phenylthioureido)phenyl]acetamide

815 463 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[(1S)-1-(4-bromophenyl)ethyl]thioureido}-phenyl)amide,

816 463 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[(1R)-1-(4-bromophenyl)ethyl]thioureido}-phenyl)amide,

818 520 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[1-(3,5-bis-trifluoromethylphenyl)ethyl]thioureido}-phenyl)amide,

820 418 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[(1S)-1-(4-chloro-phenyl)-ethyl]-thioureido}-phenyl)-amide,

821 418 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[(1R)-1-(4-chlorophenyl)-ethyl]-thiored o}-phenyl)-amide,

822 409 N-[4-[[[[1-(4-cyanophenyl)-ethyl]-amino]-thioxomethyl]-amino]-phenyl]-1,2,3-thiadiazole-4-carboxamide,

824 462 thiazole-4-carboxylic acid (3-{3-[1 -(4-bromo-phenyl]-thioureido}-phenyl]-amide,

- 198 825 520 [1,2,3]thiadiazole-4-carboxylic acid-(4-{3-(1 S)-[1 -(3,5-bis-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-amide,

828 470 N-(4-{[({ 1 -[4-fluoro-3-(trifluoromethyl)-phenyl]-ethyl}-amino)-carbothioyl]-amino}-phenyl)-1,2,3-thiadiazole-4-carboxamide,

829 486 N-(4-{[({1-[4-chloro-3-thiadiazole-4-carboxamide, 830 519 N-(4-{[({(1S)-1-[3,5-thiazole-4-carboxamide, 831 469 N-(4-{[({1-[3-fluoro-5-trifluoromethyl)-phenyl]-ethyl}-amino)-carbothioyl]-amino}-phenyl)-1,3-thiazole-4-carboxamide, 832 469 N-(4-{[({1-[2-fluoro-4-trifluoromethyl)-phenyl]-ethyl}-amino)-carbothioyl]-amino}-phenyl)-1,3-thiazole-4-carboxamide, 833 469 N-(4-{[({1-[2-Fluoro-5-trifluoromethyl)-phenyl]-ethyl}-amino)-carbothioyl]-amino}-phenyl)-1,3-thiazole-4-carboxamide, 834 519 N-(4-{[({1 - [ 2,4-bis (t rif I uor m et i1)-phen i I ]) 1}-amino)-carbothioyl]-amino}-phenyl)-1,3-thiazole-4-carboxamide, 834 411 N-{4-[({[1-(2,4-dimethylphenyl)-ethyl]-amino}-carbothioyl)-amino]-phenyl}-1,3-thiazole-4-carboxamide,

836 452 N-{4-[({[1-(2,4-dichlorophenyl)-ethyl]-amino}-carbothioyl)-amino]-phenyl}-1,3-thiazole-4-carboxamide,

837 397 N-{4-[({[1-(3-methylphenyl)ethyl]amino}-carbothioyl)amino]-phenyl}-1,3-thiazole-4-carboxamide,

838 469 N-(4-{[({1-[4-fluoro-3-(trifluoromethyl)phenyl]ethyl}-amino)-carbothioyl]-amino}-phenyl)-1,3-thiazole-4-carboxamide, 839 435 N-{4-[({[1-(2-chloro-4-fluorophenyl)-ethyl]-amino}-carbothioyl)-amino]-phenyl}-1,3-thiazole-4-carboxamide,

840 419 N-{4-[({[1-(3,4-difluorophenyl)ethyl]amino}-carbothioyl)amino]-phenyl}-1,3-thiazole-4-carboxamide,

- 199 841 480 N-{4-[({[1-(4-bromo-2-fluorophenyl)-ethyl]-amino}-carbothioyl)-amino]-phenyl}-1,3-thiazole-4-carboxamide,

842 401 N-{4-[({[1-(3-fluorophenyl)ethyl]amino}-carbothioyl)amino]phenyl}-1,3-thiazole-4-carboxamide,

843 462 N-{4-[({[1-(2-bromophenyl)ethyl]amino]carbothioyl)amino]phenyl}-1,3-thiazole-4-carboxamide,

844 462 N-{4-[({[1-(3-bromophenyl)ethyl]amino}-carbothioyl)amino]phenyl}-1,3-thiazole-4-carboxamide,

845 451 N-(4-{[({1 - [ 2 - (tr if I uormet i I )-phen i I I ]-et i I I }-am i η o )-carbothioyl]-amino}-phenyl)-1,3-thiazole-4-carboxamide,

846 419 N-{4-[({[1-(2,4-difluorophenyl)ethyl]amino}-carbothioyl)amino]phenyl}-1,3-thiazole-4-carboxamide,

847 519 N-(4-{[({( 1 R)-[3,5-bis(trifluoromethyl)phenyl]ethyl}-amino)-carbothioyl]-amino}-phenyl)-1,3-thiazole-4-carboxamide, 848 452 N-{4-[({[1 -(3,4-dichlorophenyl)-ethyl]-amino}-carbothioyl)-amino]-phenyl}-1,3-thiazole-4-carboxamide,

849 469 N-(4-{[({( 1 - [ 3-f I u o r-4-(t r if I u o r m et i I )-phen i i I ]-et i I }-amino)-carbothioyl]-amino}-phenyl)-1,3-thiazole-4-carboxamide, 850 485 N-(4-{[({( 1 -[4-chloro-3-(trifluoromethyl)-phenyl]-ethyl}-amino)-carbothoyl]-amino}-phenyl)-1,3-thiazole-4-carboxamide, 851 435 N-{4-[({[1 -(4-chloro-2-fluorophenyl)-ethyl]-amino}-carbothioyl)-amino]-phenyl}-1,3-thiazole-4-carboxamide,

852 469 N-(4-{[({(1 - [4-f I u o r-2-(t r if I u o rm et i I )-phen i i I ]-et i I I }-amino)-carbothioyl]-amino}-phenyl)-1,3-thiazole-4-carboxamide, 853 435 N-{4-[({[ 1 -(4-chloro-3-fluorophenyl)ethyl]amino}carbothioyl)amino]phenyl}-1,3-thiazole-4-carboxamide,

854 480 N-{4-[({[1-(2-bromo-4-fluorophenyl)-ethyl]-amino}-carbutyl 1)-amino]-phenyl}-1,3-thiazole-4-carboxamide,

- 200 855 541 N-{4-(({[ 1 -(3,4-dibromophenyl)ethyl]amino}-carbothioyl)amino]-phenyl}-1,3-thiazole-4-carboxamide,

856 435 N-{4-[({[1-(3-chloro-4-fluorophenyl)-ethyl]-amino}-carbothioyl)-amino]-phenyl}-1,3-tylazole-4-carboxamide,

857 366 N-(4-{ [({1 -(3,5-b is(trif I uormet i l)-phenyl]-prop i l }-amino)-carbothioyl]-amino}-phenyl)-1,2,3-thiadiazole-4-carboxamide,

858 392 N-(4-{[({1-(3,5-bis(trifluoromethyl)-phenyl]-butyl}-amino)-carbothioyl]-amino}-phenyl)-1,2,3-thiadiazole-4-carboxamide,

859 330 N-(4-{[({1 -[3,5-bis(trifluoromethyl)phenyl]pentyl}-amino)carbothioyl]-amino}-phenyl)-1,2,3-thiadiazole-4-carboxamide,

860 521 N-{4-[({[[3,5-bis(trifluoromethyl)phenyl]-(phenyl)methyl]amino}-carbothioyl)amino]phenyl}-1,2,3-thiadiazole-4-carboxamide,

861 450 N-(4-{(({1-(3,5-bis(trifluoromethyl)phenyl]-1-methylethyl}-amino)carbothioyl]-amino}-phenyl)-1,2,3-thiadiazole-4-carboxamide,

862 433 N-{4-[({[3,5-bis(trifluoromethyl)benzyl]amino}-carbothioyl)amino]phenyl}-1H-imidazole-4-carboxamide,

863 440 N-{4-[({(1-(4-fluorophenyl)-ethyl]-amino}-carbothioyl)-amino]-phenyl}-1 H-imidazole-4-carboxamide,

864 506 N-{4-[({[3,5-bis(trifluoromethyl)benzyl]amino}-carbothioyl)amino]phenyl}-1-methyl-1H-imidazole-4-carboxamide,

865 462 N-(4-{[({1-[3,5-bis(trifluoromethyl)-phenyl]-propyl}-amino)-carbothioyl]-amino}-phenyl)-1,3-thiazole-4-carboxamide

-201 866. Example (Method 32) Preparation of [1 ₁ 2 ₁ 3]thiadiazole-4-carboxylic acid-{4-[3-(2 ₁ 5-dichlorophenyl)thioureido]phenyl}-amide

0.16 g of 2,5-dichloroaniline is dissolved in 20 ml of tetrahydrofuran, 0.2 g of freshly prepared 1,Γ-thiocarbonyldiimidazole is added, and the mixture is stirred for about 30 minutes at room temperature. 0.22 g of [1,2,3]thiadiazole-4-carboxylic acid-(4-aminophenyl)amide is added to the contents of the flask, and the mixture is stirred for about 6 hours. The solvent is evaporated in vacuo and 3 ml of warm acetonitrile is added to the mixture. After 15 hours, the mixture is filtered, the filtered precipitate is washed with acetonitrile, then with diethyl ether and air-dried. The desired product is obtained in the form of a white powder.

Using the above procedure, starting from the appropriate starting materials, the following compounds were prepared (example number, M + H, compound name):

867 321 N-{4-[3-(3-chlorophenyl)thioureido]phenyl}-acetamide 868 413 N-{4-[3-(3-chloro-4-methoxyphenyl)thioureido]phenyl}-benzamide

869 443 N-{4-[3-(3-chloro-4-methoxyphenyl)-thioureido]-phenyl}-2-methoxybenzamide

870 443 N-{4-[3-(3-chloro-4-methoxyphenyl)thioureido]phenyl}-3-methoxybenzamide

-202871 443 N-{4-[3-(3-chloro-4-methoxyphenyl)-thioureido]-phenyl}-4-methoxybenzamide

872 431 N-{4-[3-(3-chloro-4-methoxyphenyl)thioureido]phenyl}-2-methoxybenzamide

873 431 N-{4-[3-(3-chloro-4-methoxyphenyl)thioureido]phenyl}-3-fluorobenzamide

874 431 N-{4-[3-(3-chloro-4-methoxyphenyl)thioureido]phenyl}-4-fluorobenzamide

875 437 furan-2-carboxylic acid-{4-[3-(3,5-dichloro-4-methoxyphenyl)-thioureido]-phenyl}-amide

876 51 1 {4-[3-(5-bromo-2,4-dimethoxyphenyl)thioureido]phenyl}carbamic acid hexyl ester

877 481 caproic acid {4-[3-(5-bromo-2,4-dimethoxyphenyl)thioureido]phenyl}-amide

878 505 N-{4-[3-(5-bromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-fluorobenzamide

879 477 furan-2-carboxylic acid-{4-[3-(5-bromo-2,4-dimethoxy-

-fe n i I )-t io u re i do]-f en i I }-a m id

880 501 N-{4-[3-(5-bromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-methylbenzamide

881 517 N-{4-[3-(5-Bromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-4-methoxy-benzamide

882 395 N-{4-[3-(5-chloro-2-ethoxy-4-methoxyphenyl)thioureido]phenyl}acetamide

883 395 N-{4-[3-(5-chloro-4-ethoxy-2-methoxyphenyl)thioureido]phenyl}acetamide

884 423 N-{4-[3-(2-butoxy-5-chloro-4-methoxyphenyl)thioureido]phenyl}acetamide

- 203 - ’*·· ·,;· .J. J.

885 423 N-{4-[3-(4-butoxy-5-chloro-2-methoxyphenyl)thioureido]phenyl}acetamide

886 457 N-{4-[3-(2-benzyloxy-5-chloro-4-methoxy-phenyl)-thioureido]-phenyl}-acetamide

887 457 N-{4-[3-(4-benzyloxy-5-chloro-2-methoxyphenyl)-

-tiou re id o]-phenyl}-a cetamide

888 421 [1,2,3]-thiadiazole-4-carboxylic acid-{4-[3-(3-chloro-4-methoxyphenyl)thioureido]phenyl}-amide

889 424 2-{4-[3-(4-acetylaminophenyl)thioureido]-2-chloro-5-methoxyphenoxy}-acetamide

890 367 N-{4-[3-(2-hydroxy-5-chloro-4-methoxyphenyl)thioureido]phenyl}acetamide

891 367 N-{4-[3-(3-Chloro-4-methyl-sulfanyl-phenyl)-thioureido]-phenyl}-acetamide

892 447 N-[4-(3-{3-chloro-4-[methyl-(1-methylpiperidin-4-yl)amino]phenyl}thioureido)phenyl]acetamide

893 426 N-(4-{3-[3-chloro-4-(methylphenylamino)phenyl]thioureido}phenyl)acetamide

894 509 N-[4-(3-{4-[(1-benzylpyrrolidin-3-yl)methylamino]-3-chlorophenyl}thioureido)phenyl]acetamide

895 418 N-(4-{3-[3-chloro-4-(cyclopentylmethylamino)phenyl]thioureido}phenyl)acetamide

896 433 N-[4-(3-{3-chloro-4-[methyl-(1-methyl-pyrrolidin-3-yl)-amino]-phenyl}-thioureido)-phenyl]-acetamide

897 419 furan-2-carboxylic acid {4-[3-(3-chloro-4-methylsulfanylphenyl)thioureido]phenyl}-amide

898 447 N-{4-[3-(3-chloro-4-methylsulfanylphenyl)thioureido]phenyl)-2-fluorobenzamide

-204 * *. _β \ · • ♦·* ·«**

899 465 N-{4-[3-(3-chloro-4-methylsulfanylphenyl)thioureido]phenyl}-2,6-difluorobenzamide

900 445 N-{4-[3-(5-chloro-4-methyl-2-methoxyphenyl)thioureido]phenyl}-2-fluorobenzamide

901 441 N-{4-[3-(5-chloro-4-methyl-2-methoxyphenyl)thioureido]phenyl}-2-methylbenzamide

902 434 [1,2 ₎ 3]-thiadiazole-4-carboxylic acid-{4-[3-(4-dimethylamino-3-chlorophenyl)thioureido]phenyl}-amide

903 444 N-{4-[3-(4-dimethylamino-3-chlorophenyl)-thioureido]-phenyl}-2-fluorobenzamide

904 517 [1,2,3]-thiadiazole-4-carboxylic acid [4-(3-{3-chloro-4-[methyl-1-(1-methyl-piperidin-4-yl)-amino]-phenyl}-thioureido)-phenyl]-amide

905 579 [1,2,3]-thiadiazole-4-carboxylic acid [4-(3-{4-[(1-benzylpyrrolidin-3-yl)methylamino]-3-chlorophenyl}-thioureido)phenyl]-amide

906 527 N-[4-(3-{3-chloro-4-[methyl-(1-methyl-piperidin-4-yl)-amino]-phenyl}-thioureido)-phenyl]-2-fluorobenzamide

907 435 [1,2,3]-thiadiazole-4-carboxylic acid {4-[3-(5-chloro-2-methoxy-4-methylphenyl)thioureido]phenyl}-amide

909 589 N - [4-(3-{4-[(1-benziI-pyrroIidin-3-yl)-methyl-amino]-3-chloro-phenyl}-thioureido)-phenyl]-2-fluorobenzamide

909 501 furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxyphenyl)thioureido]-3-trifluoromethylphenyl}-amide

910 366 2-Fluoro-N-[4-(3-phenylthioureido)-phenyl]-benzamide

1 338 furan-2-carboxylic acid [4-(3-phenylthioureido)phenyl]-amide

- 205 - '·$♦<·

912 356 [1,2,3]-thiadiazole-4-carboxylic acid [4-(3-phenylthioureido)phenyl]-amide

913 365 N-(4-{3-[3-chloro-4-(1-hydroxyethyl)phenyl]thioureido}phenyl)acetamide

914 435 [1,2,3]-thiadiazole-4-carboxylic acid (4-{3-[3-chloro-4-(1-hydroxyethylphenyl]thioureido}-phenyl)-amide

915 365 N-(4-{3-[3-chloro-4-(2-hydroxyethyl)phenyl]thioureido}phenyl)acetamide

916 445 N-(4-{3-[3-chloro-4-(1-hydroxyethyl)phenyl]thioureido}phenyl)-2-fluorobenzamide

917 417 furan-2-carboxylic acid (4-{3-[3-chloro-4-(1-hydroxyethylphenyl)phenyl]thioureido}phenyl)amide

918 371 [1,2,3]-thiadiazole-4-carboxylic acid-{4-[3-(3-aminophenyl)thioureido]phenyl}-amide

919 501 furan-2-carboxylic acid {4-[3-(3-bromo-4-trifluoromethoxyphenyl)thioureido]phenyl}-amide

920 423 N-{4-[3-(3-tert-butylphenyl)thioureido]phenyl}-2-fluorobenzamide

1025 440 [1,2,3]-thiadiazole-4-carboxylic acid {4-[3-(3,5-dichloro-4-chlorophenyl)thioureido]phenyl}-amide

1026 485 N-{4-[3-(1-benzofuran-2-ylethyl)thioureido]phenyl}-2-trifluoromethylbenzamide

1027 412 N-(4-fluorophenyl)-4-{3-[ 1 -(4-fluorophenyl)ethyl]-thioureido}-benzamide

1028 446 isoquinoline-1-carboxylic acid (4-{3-[1-(4-fluorophenyl)ethyl]thioureido}-phenyl)amide

1029 468 isoquinoline-1-carboxylic acid {4-[3-(1-benzofuran-2-ylethyl)thioureido]phenyl}-amide

-206 • · >'· Λ ·-’

1030 506 isoquinoline-1-carboxylic acid (4-{3-[1-(4-bromophenyl)ethyl]thioureido}-phenyl)amide

1031 453 isoquinoline-1-carboxylic acid (4-{3-[1-(4-cyano-phenyl)-ethyl]-thioureido}-phenyl)-amide

1032 435 benzofuran-2-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-eth i l]-thioureid o}-phen i I )-amide

1033 457 benzofuran-2-carboxylic acid {4-[3-(1-benzofuran-2-ylethyl)thioureido}phenyl)amide

1034 495 benzofuran-2-carboxylic acid-(4-{3-[1-(4-bromophenyl)ethyl]thioureido}phenyl)amide

1035 442 Benzofuran-2-carboxylic acid (4-{3-[1-(4-cyano-phenyl)ethyl]-thioureido}-phenyl)-amide

1036 446 isoquinoline-3-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide

1037 468 isoquinoline-3-carboxylic acid {4-[3-(1-benzofuran-2-ylethyl)thioureido}-phenyl)amide

1038 453 isoquinoline-3-carboxylic acid (4-{3-[1-(4-cyano-phenyl)-ethyl]-thioureido}-phenyl)-amide

1039 506 isoquinoline-3-carboxylic acid (4-{3-[1-(4-bromophenyl)ethyl]thioureido}phenyl)amide

1040 446 quinoline-3-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide

1041 446 quinoline-4-carboxylic acid (4-{3-[1-(4-fluorophenyl)ethyl]thioureido}-phenyl)amide

1042 446 quinoline-6-carboxylic acid (4-{3-[1-(4-fluorophenyl)ethyl]thioureido}-phenyl)amide

1043 446 quinoline-8-carboxylic acid (4-{3-[1-(4-fluorophenyl)ethyl]thioureido}-phenyl)amide

-207 1044 462 N-(4-{3-[ 1 -(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-trifluoromethylbenzamide

1045 419 2-cyano-N-(4-{3-[1-(4-fluorophenyl)-ethyl]-thioureido}-phenyl)-benzamide

1046 473 N-{4-[3-(3-chloro-4-isobutoxyphenyl)thioureido]phenyl}-2-fluorobenzamide

1047 414 2-fluoro-N-{4-[3-(3-fluoro-4-methoxy-phenyl)-thioureido]-phenyl}-benzamide

1048 475 N-(4-{3-[3-chloro-4-(2-methoxyethoxy)phenyl]thioureido}phenyl)-2-fluorobenzamide

1049 398 2-fluoro-N-{4-[3-(3-fluoro-4-methylphenyl)-thioureido]-phenyl}-benzamide

1050 464 2-fluoro-N-{4-[3-(4-methoxy-3-trifluoromethylphenyl)thioureido]phenyl}-benzamide

1051 449 N-{4-[3-(2-amino-5-trifluoromethylphenyl)thioureido]phenyl}-2-fluorobenzamide

1052 459 N-(4-{3-[1-(3-chloro-4-methoxyphenyl)ethyl]thioureido}phenyl-2-fluorobenzamide

1053 417 N-{4-[3-(2-hydroxy-5-chlorophenyl)thioureido]phenyl}-2-fluorobenzamide

1054 435 N-{4-[3-(1-benzofuran-2-ylethyl)thioureido]phenyl}-2-fluorobenzamide

1055 448 2-fluoro-N-{4-[3-(4-methyl-3-trifluoromethylphenyl)thioureido}phenyl}benzamide

1056 473 (S)-N-(4-{3-[1-(4-bromo-phenyl)-ethyl]-thioureido}-phenyl)-2-fluorobenzamide

1057 473 N-(4-{3-[(1R)-1-(4-bromophenyl)ethyl]thioureido}phenyl)-2-fluorobenzamide

- 208 1058 494 2-fluoro-N-(4-{3-[2-methoxy-4-(2,2,2-trifluoroethoxy)-phenyl]-thioureido}-phenyl)-benzamide

1059 399 N-{4-[3-(2-amino-5-fluorophenyl)-thioureido]-phenyl}-2-fluorobenzamide

1060 502 N-(4-{3-[1-(4-dimethylsulfamoylphenyl)ethyl]thioureido}phenyl)-2-fluorobenzamide

1061 542 2-fluoro-N-[4-(3-{1-[4-(piperidin-1-sulfonyl)-phenyl]-ethyl}-thioureido)-phenyl]-benzamide

1062 562 N-(4-{3-[2,4-bis-(2,2,2-trifluoroethoxy)phenyl]thioureido}phenyl)-2-fluorobenzamide

1063 409 2-Fluoro-N-{4-[3-((1S)-1-p-tolylethyl)-thioureido]-phenylj-benzamide

1064 409 2-Fluoro-N-{4-[3-((1R)-1-p-tolylethyl)-thioureido]-phenylj-benzamide

1065 394 2-fluoro-N-{4-[3-((1S)-1-phenylethyl)-thioureido]-phenylj-benzamide

1066 429 N-(4-{3-[(1R)-1-(4-Chloro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluorobenzamide

1067 429 N-(4-{3-[(1S)-1-(4-Chloro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluorobenzamide

1068 394 2-Fluoro-N-{4-[3-((1R)-1-phenylethyl)-thioureido]-phenylj-benzamide

1069 432 N-(4-{3-[1-(4-cyano-phenyl)-ethyl]-thioureido}-phenyl)-2-methoxybenzamide

1070 447 N-{4-[3-(1-benzofura n-2-i I )-ti o u re i d o]-f e η i I-2-methoxybenzamide

1071 485 N - (4-{ 3-[ 1 - (4-brom-f e η i I) - et i I ]-ti o u r e i d o }-phen i i I) -2-methoxybenzamide

- 209 1072 419 3-cyano-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide

1073 462 N-(4-{3-[ 1 -(4-fluoro-phenyl)ethyl]-thioureido}-phenyl)-4-trifluoromethyl-benzamide

1074 419 4-cyano-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide

1075 469 2-fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2,3,5,6-tetramethyl-phenyl)-benzamide

1076 480 N-(4-{3-[1-(4-cyano-phenyl)-ethyl]-thioureido}-2,5-dimethoxy-phenyl)-2-fluorobenzamide

1077 473 2-Fluoro-N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-2,5,-dimethoxy-phenyl)-benzamide

1078 530 N-{3,5-dichloro-4-[3-(5-chloro-2,4-dimethoxyphenyl)-thioureido]-phenyl}-2-fluorobenzamide

1079 447 N-(3-chloro-4-{3-[1-(4-fluorophenyl)ethyl]thioureido}phenyl)-2-fluorobenzamide

1080 480 2,3,4,5-tetrafluoro-N-(4-{3-[1-(4-fluorophenyl)ethyl]thioureido}-3-methylphenyl)benzamide

1081 462 2,4,5-trifluoro-N-(4-{3-[ 1 -(4-fluorophenyl)ethyl]thioureido}-3-methylphenyl)benzamide

1082 427 2-fluoro-N-(4-{3-[1-(4-fluorophenyl)ethyl]thioureido}-3-methylphenyl)benzamide

1083 457 2-fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-5-triethyl-2-r-ethoxy-phenyl)-benzamide

1084 443 2-Fluoro-N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-3-methoxy-phenyl)-benzamide

1085 570 N-(2,6-dibromo-4-{3-[1-(4-fluorophenyl)ethyl]thioureido}phenyl)-2-fluorobenzamide

210 1086 480 2-fluoro-N-(4-{3-[1-(4-fluorophenyl)ethyl]thioureido}-2-trifluoromethylphenyl)benzamide

1087 541 N-(4-{3-[1-(4-bromophenyl)ethyl]thioureido}-2-trifluoromethyl-phenyl)-2-fluorobenzamide

1088 487 N-(4-{3-[1-(4-cyano-phenyl)-ethyl]-thioureido}-2-trifluoromethyl-phenyl)-2-fluorobenzamide

1089 503 N-{4-[3-(1-benzofuran-2-yl-ethyl)-thioureido]-2-trifluoromethyl-phenyl}-2-fluorobenzamide

1090 447 N-(2-chloro-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide

1091 454 N-(2-Chloro-4-{3-[1-(4-cyano-phenyl)-ethyl]-thioureidoyl)-2-fluorobenzamide

1092 437 N-(2-cyano-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide

1093 498 N-(4-{3-[1-(4-bromophenyl)ethyl]thioureido}-2-cyanophenyl)-2-fluorobenzamide

1094 445 N-(2-cyano-4-{3-[1-(4-cyano-phenyl)-ethyl]-thioureido}-phenyl)-2-fluorobenzamide

1095 460 N-{4-[3-(1-Benzofuran-2-yl-ethyl)-thioureido]-2-cyano-phenyl}-2-fluorobenzamide

1096 517 N-(2-benzoyl-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide

1097 427 2-Fluoro-N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-2-methyl-phenyl)-benzamide

1098 487 N-(4-{3-[1-(4-bromophenyl)ethyl]thioureido}-2-methylphenyl)-2-fluorobenzamide

1099 434 N-(4-{3-[1-(4-cyano-phenyl)-ethyl]-thioureido}-2-methylphenyl)-2-fluorobenzamide

-211 1100 449 N-{4-[3-(1-benzofuran-2-ylethyl)thioureido]-2-methylphenyl}-2-fluorobenzamide

1101 456 N-(2-dimethylamino-4-{3-[1-(4-fluorophenyl)ethyl]-thioureido}-phenyl)-2-fluorobenzamide

1102 526 N-(2-benzyloxy-4-{3-[1-(4-cyano-phenyl)-ethyl]-thioureido}-phenyl)-2-fluorobenzamide

1103 519 N-(2-benzyloxy-4-{3-[1-(4-fluorophenyl)ethyl]thioureido}phenyl)-2-fluorobenzamide

1104 603 N-[4-{3-[1-(4-bromophenyl)ethyl]thioureido}-2-(2-morpholin-4-ylethoxy)phenyl]-2-fluorobenzamide

1105 603 N-[4-{3-[1-(4-bromophenyl)ethyl]thioureido}-2-(2-morpholin-4-ylethoxy)phenyl]-2-fluorobenzamide

1106 542 2-Fluoro-N-[4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-2-(2-morpholin-4-yl-ethoxy)-phenyl]-benzamide

1107 485 N-(2-butoxy-4-{3-[1-(4-fluorophenyl)ethyl]thioureido}phenyl)-2-fluorobenzamide

1108 492 N-(2-butoxy-4-{3-[1-(4-cyano-phenyl)-ethyl]-thioureido}-phenyl)-2-fluorobenzamide

1109 589 N-[4-{3-[1-(4-bromophenyl)ethyl]thioureido}-2-(2-diethylaminoethoxy)phenyl]-2-fluorobenzamide

1100 528 N-(2-(2-diethylaminoethoxy)-4-{3-[1-(4-fluorophenyl)ethyl]thioureido}phenyl)-2-fluorobenzamide

1 11 589 N-[4-{3-[1-(4-bromophenyl)ethyl]thioureido}-2-(2-diethylaminoethoxy)phenyl]-2-fluorobenzamide

12 457 N-(2-ethoxy-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide

13 464 N-(4-{3-[1-(4-cyano-phenyl)-ethyl]-thioureido}-2-ethoxy-phenyl)-2-fluorobenzamide

-212 11 14 468 2-fluoro-N-[4-{3-[ 1 -(4-fluoro-phenyl)-ethyl]-thioureido}-2-(2-cyano-ethoxy)-phenyl]-benzamide

15 475 N-(4-{3-[1-(4-cyano-phenyl)-ethyl]-thioureido}-2-(2-cyano-ethoxy)-phenyl]-2-fluorobenzamide

16 443 2-Fluoro-N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-2-methoxy-phenyl)-benzamide

17 489 2-Fluoro-N-(5-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-biphenyl-2-yl)-benzamide

1118 514 isoquinoline-1-carboxylic acid (4-{3-[1-(4-fluorophenyl)ethyl]thioureido}-2-trifluoromethylphenyl)amide

1119 503 benzofuran-2-carboxylic acid (4-{3-[1-(4-fluorophenyl)ethyl]thioureido}-2-trifluoromethylphenyl)amide

1120 514 isoquinoline-3-carboxylic acid (4-{3-[1-(4-fluorophenyl)ethyl]thioureido}-2-trifluoromethylphenyl)amide

1121 471 isoquinoline-1-carboxylic acid (2-cyano-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide

1122 460 Benzofuran-2-carboxylic acid (2-cyano-(4-{3-[1-(4-fluorophenyl)-ethyl]-thioureido}-phenyl)-arnide

1123 471 Isoquinoline-3-carboxylic acid (2-cyano-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide

1124 460 isoquinoline-1-carboxylic acid (4-{3-[1-(4-fluorophenyl)ethyl]thioureido}-2-methylphenyl)amide

1125 449 benzofuran-2-carboxylic acid (4-{3-[1-(4-fluorophenyl)ethyl]thioureido}-2-methylphenyl)amide

1126 460 isoquinoline-3-carboxylic acid (4-{3-[1-(4-fluorophenyl)ethyl]thioureido}-2-methylphenyl)amide

1127 396 pyrazine-2-carboxylic acid (4-{3-[1-(4-fluorophenyl)ethyl]thioureido}-phenyl)amide

-213 1128 401 thiophene-2-carboxylic acid-(4-{3-[1-(4-fluorophenyl)ethyl]thioureido}phenyl)amide

129 401 thiophene-3-carboxylic acid (4-{3-[1-(4-fluorophenyl)ethyl]thioureido}phenyl)amide

1130 500 2-Isopropylthiazole-4-carboxylic acid {4-[3-(4-chloro-3-trifluoromethylphenyl)thioureido]phenyl}-amide

1131 466 2-Isopropylthiazole-4-carboxylic acid {4-[3-(3,5-dichlorophenyl)thioureido]phenyl}-amide

132 466 2-Isopropylthiazole-4-carboxylic acid {4-[3-(3,4-dichlorophenyl)thioureido]phenyl)amide

1133 534 2-Isopropylthiazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoromethylphenyl)thioureido]phenyl}-amide

134 480 2-Butylthiazole-4-carboxylic acid {4-[3-(3,4-dichlorophenyl)thioureido]phenyl}-amide

135 514 2-Butylthiazole-4-carboxylic acid {4-[3-(4-chloro-3-trifluoromethylphenyl)thioureido]phenyl}-amide

1136 480 2-butylthiazole-4-carboxylic acid {4-[3-(3,5-dichlorophenyl)thioureido]phenyl}-amide

137 548 2-Butylthiazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoromethylphenyl)thioureido]phenyl}-amide

138 438 2-Methylthiazole-4-carboxylic acid {4-[3-(3 _> 5-dichlorophenyl)thioureido]phenyl}-amide

139 438 2-Methylthiazole-4-carboxylic acid {4-[3-(3,4-dichlorophenyl)thioureido]phenyl}-amide

140 505 2-Methylthiazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoromethylphenyl)thioureido]phenyl}-amide

141 534 2-phenylthiazole-4-carboxylic acid {4-[3-(4-chloro-3-trifluoromethylphenyl)thioureido]phenyl}-amide

-214 1142 500 2-phenylthiazole-4-carboxylic acid {4-[3-(3,5-dichlorophenyl)thioureido]phenyl}-amide

1143 500 2-phenylthiazole-4-carboxylic acid {4-[3-(3,4-dichlorophenyl)thioureido]phenyl}-amide

1144 568 2-Phenyl-thiazole-4-carboxylic acid-{4-[3-(3,5-bis-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide

1145 401 2-Fluoro-N-{4-[3-(1-thiazol-2-yl-ethyl)-thioureido]-phenyl}-benzamide

1146 588 2-fluoro-N-[4-(3-{1-[1-toluene-4-sulfonyl)-1H-indol-2-yl]-ethyl}-thioureido)-phenyl]-benzamide

1147 446 2-Fluoro-N-{4-[3-(1-quinolin-2-yl-ethyl)-thioureidoJ-phenylj-benzamide

1148 446 2-Fluoro-N-{4-[3-(1-quinolin-4-yl-ethyl)-thioureido]-phenylj-benzamide

1149 446 2-fluoro-N-{4-[3-(1-isoquinolin-3-yl-ethyl)-thioureido]-phenyl}-benzamide

1150 446 2-Fluoro-N-{4-[3-(1-isoquinolin-1-yl-ethyl)-thioureidoJ-phenyl}-benzamide

151 446 2-fluoro-N-{4-[3-(1-quinolin-6-yl-ethyl)-thioureido]-phenyl}-benzamide

1152 446 2-Fluoro-N-{4-[3-(1-quinolin-3-yl-ethyl)-thioureido]-phenylj-benzamide

153 413 2-Methoxy-N-{4-[3-(1-thiophen-3-yl-ethyl)-thioureido]-phenyl}-benzamide

Example -215921 (Method 33) Preparation of [1,2,31-thiadiazole-4-carboxylic acid-(4-[3-(3,5-dichlorophenyl)thioureidolphenyl]-amide

0.16 g of 2,5-dichloroaniline was dissolved in 20 ml of tetrahydrofuran, 0.20 g of freshly prepared 1,1'-thiocarbonyldi-(1,2,4)-triazole was added, and the mixture was stirred for about 30 minutes at room temperature. 0.22 g of [1,2,3]thiadiazole-4-carboxylic acid (4-aminophenyl)amide was added to the reaction mixture, and the mixture was stirred for about 6 hours. The solvent was evaporated in vacuo and 3 ml of warm acetonitrile was added to the mixture. After 15 hours, the mixture was filtered, the filtered precipitate was washed with acetonitrile, then with diethyl ether, and air-dried. The desired product was obtained as a white powder. [M+H] 424.

Using the above procedure, starting from the appropriate starting materials, the following compounds were prepared (example number, M + H, compound name):

922 465 N-{4-[3-(3,5-dichloro-4-methoxyphenyl)thioureido]phenyl}-3-fluorobenzamide

923 477 N-{4-[3-(3,5-dichloro-4-methoxyphenyl)-thioureido]-phenyl}-2-methoxybenzamide

924 465 N-{4-[3-(3,5-dichloro-4-methoxyphenyl)thioureido]phenyl}-2-fluorobenzamide

925 477 N-{4-[3-(3,5-dichloro-4-methoxyphenyl)-thioureido]-phenyl}-3-methoxybenzamide

-216926 399 N-{4-[3-(3,5-dichloro-2-methoxy-4-methylphenyl)-thioureido]-phenyl}-acetamide

927 365 N-{4-[3-(3-chloro-4-methoxy-5-methylphenyl)thioureido]phenyl}acetamide

928 331 N-{4-[3-(2-nitro-phenyl!)-thioureido]-phenyl}-acetamide

929 331 N-{4-[3-(4-nitro-phenyl)-thioureido]-phenyl}-acetamide 930 477 N-{4-[3-(3,5-dichloro-4-methoxy-phenyl)-thioureido]-phenyl}-4-methoxy-benzamide

931 351 N-{4-[3-(2-chloro-4-methoxyphenyl)thioureido]phenyl}acetamide

932 428 2-{4-[3-(4-acetylaminophenyl)thioureido]-2,6-dichlorophenoxy}-acetamide

933 443 {4-[3-(4-acetylaminophenyl)thioureido]-2,6-dichlorophenoxy}acetic acid methyl ester

934 457 {4-[3-(4-acetylaminophenyl)thioureido]-2,6-dichlorophenoxy}acetic acid ethyl ester

935 447 N-{4-[3-(3,5-dichloro-4-phenoxyphenyl)thioureido]phenyl}acetamide

936 410 N-(4-{3-[3,5-dichloro-4-(2-cyanoethoxy)phenyl]thioureido}phenyl)acetamide

937 485 {4-[3-(4-acetylaminophenyl)thioureido]-2,6-dichlorophenoxy}acetic acid tert-butyl ester

938 469 [1,2,3]thiadiazole-4-carboxylic acid-{4-[3-(3,5-dichloro-2-methoxy-4-methylphenyl)thioureido]phenyl}-amide

939 335 N-{4-[3-(3-chloro-4-methylphenyl)thioureido]phenyl}-acetamide

940 335 N-{4-[3-(5-chloro-2-methylphenyl)thioureido]phenyl}acetamide

- 218 954 400 N-{4-[3-(4-bromo-3-chlorophenyl)thioureido]phenyl}-acetamide

955 424 N-[4-(3-{4-[bis-(2-hydroxyethyl)amino]-3-chlorophenyl}-thioureido)phenyl]acetamide

956 434 N-(4-{3-[3-chloro-4-(hexylmethylaminophenyl]thioureido}phenyl)acetamide

957 406 N-(4-{3-[3-chloro-4-(isobutylmethylaminophenyl]thioureido}phenyl)acetamide

958 389 N-{4-[3-(3-chloro-4-trifluoromethylphenyl)thioureido]phenyl}acetamide

959 441 furan-2-carboxylic acid {4-[3-(3-chloro-4-trifluoromethylphenyl)thioureido]phenyl}-amide

960 459 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3-chloro-4-trifluoromethylphenyl)thioureido]phenyl}-amide

961 469 N-{4-[3-(3-chloro-4-trifluoromethylphenyl)thioureido]phenyl}-2-fluorobenzamide

962 435 N-{4-[3-(3,4-dichlorophenyl)thioureido]phenyl}-2-fluorobenzamide

963 407 furan-2-carboxylic acid {4-[3-(3,4-dichlorophenyl)thioureido]phenyl}-amide

964 425 [1,2,3]thiadiazole·4-carboxylic acid-{4-[3-(3,4-dichloroΓ-phenM)-thioureido]-phenΊ}-amide

965 480 N-{4-[3-(4-bromo-3-chlorophenyl)thioureido]phenyl}-2-fluorobenzamide

966 527 N-{4-[3-(3-chloro-4-iodophenyl)thioureido]phenyl}-2-fluorobenzamide

967 452 furan-2-carboxylic acid {4-[3-(4-bromo-3-chlorophenyl)thioureido]phenyl}-amide

- 219 968 499 furan-2-carboxylic acid-{4-[3-(4-iodo-3-chlorophenyl)thioureido]phenyl}-amide

969 391 furan-2-carboxylic acid {4-[3-(4-fluoro-3-chlorophenyl)thioureido]phenyl}-amide

970 470 [1,2,3]thiadiazole-4-carboxylic acid-{4-[3-(4-bromo-3-chloro-phenyl)-thio]-phenyl}-amide

971 517 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(4-iodo-3-chlorophenyl)thioureido]phenyl}-amide

972 419 N-{4-[3-(3-chloro-4-fluorophenyl)thioureido]phenyl}-2-fluorobenzamide

973 409 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(4-fluoro-3-chlorophenyl)thioureido]phenyl}-amide

974 388 N-{4-[3-(3-chloro-4-isoxazol-5-yl-phenyl)-thioureido]-phenyl}-acetamide

975 387 N-(4-{3-[3-chloro-4-(1H-pyrazol-3-yl)-phenyl]-thioureido}-phenyl)-acetamide

976 355 N-{4-[3-(2,3-dichlorophenyl)thioureido]phenyl}acetamide

977 435 N-{4-[3-(2,3-dichlorophenyl)thioureido]phenyl}-2-fluoroacetamide

978 407 furan-2-carboxylic acid {4-[3-(2,3-dichlorophenyl)thioureido]phenyl}-amide

979 425 [1,2,3]thiadiazole-4-carboxylic acid-{4-[3-(2,3-dichloro-phenyl)-thioureido]-phenyl}-amide

980 355 N-{4-[3-(2,5-dichlorophenyl)thioureido]phenyl}acetamide

981 435 N-{4-[3-(2,5-dichlorophenyl)thioureido]phenyl}-2-fluorobenzamide

-220 982 407 furan-2-carboxylic acid-{4-[3-(2,5-dichlorophenyl)thioureido]phenyl}-amide

983 355 N-{4-[3-(3,5-dichlorophenyl)thioureido]phenyl}acetamide

984 435 N-{4-[3-(3,5-dichlorophenyl)thioureido]phenyl}-2-fluorobenzamide

985 407 furan-2-carboxylic acid {4-[3-(3,5-dichlorophenyl)thioureido]phenyl}-amide

986 390 N-{4-[3-(3,4,5-trichlorophenyl)thioureido]phenyl}acetamide

987 470 2-Fluoro-N-{4-[3-(3,4,5-trichlorophenyl)-thioureido]-phenylj-benzamide

988 442 furan-2-carboxylic acid {4-[3-(3,4,5-trichlorophenyl)thioureido]phenyl}-amide

989 460 [1,2,3]thiadiazole-4-carboxylic acid-{4-[3-(3,4,5-trichlorophenyl)thioureido]phenyl}-amide

990 458 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3-chloro-4-isoxazol-5-yl-phenyl)-thioureido]-phenyl}-amide

991 457 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[3-chloro-4-(1H-pyrazol-3-yl)-phenyl]-thioureido}-phenyl)-amide

992 391 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3-chlorophenyl)thioureido]phenyl}-amide

993 373 furan-2-carboxylic acid {4-[3-(3-chlorophenyl)thioureido]phenyl}-amide

994 401 N-{4-[3-(3-chlorophenyl)thioureido]phenyl}-2-fluorobenzamide

995 373 furan-2-carboxylic acid {4-[3-(4-chlorophenyl)thioureido]phenyl}-amide

-221 996 401 N-{4-[3-(4-chlorophenyl)thioureido]phenyl}-2-fluorobenzamide

997 391 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(4-chlorophenyl)thioureido]phenyl}-amide

998 401 N-{4-[3-(2-chloro-pheniol)-thioureido]-pheniol}-2-fluorobenzamide

999 396 3-(3-{4-[(furan-2-carbonyl)amino]phenyl}thioureido)benzoic acid methyl ester

1000 424 3-{3-[4-(2-fluorobenzoylamino)phenyl]thioureido}benzoic acid methyl ester

1001 414 3-(3-{4-[([1,2,3]thiadiazole-4-carbonyl)amino]phenyl}thioureido)benzoic acid methyl ester

1002 409 N-[4-[[[[3-(aminocarbonyl)phenyl]amino]thioxomethyl]amino]phenyl]-2-fluorobenzamide

1003 373 furan-2-carboxylic acid {4-[3-(2-chlorophenyl)thioureido]phenyl}-amide

1004 381 furan-2-carboxylic acid {4-[3-(3-carbamoylphenyl)thioureido]phenyl}-amide

1005 399 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3-carbamoylphenyl)thioureido]phenyl}-amide

1006 391 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(2-chlorophenyl)thioureido]phenyl)amide

1007 356 furan-2-carboxylic acid {4-[3-(3-fluorophenyl)thioureido]phenyl}-amide

1008 383 furan-2-carboxylic acid {4-[3-(3-nitrophenyl)thioureido]phenyl}-amide

1009 41 1 2-f I u o r-N-{4-[3-(3-n i tro-f e n i I )-t i o u r e i d o]-f e n i I}-benzamide

-222 1010 422 furan-2-carboxylic acid-{4-[3-(3-trifluoromethoxyphenyl)thioureido]phenyl}-amide

101 1 450 2-fluoro-N-{4-[3-(3-trifluoromethoxyphenyl)thioureido]phenyl}-benzamide

1012 384 2-fluoro-N-{4-[3-(3-fluoro-phenyl)-thioureido]-phenyl}-benzamide

1013 410 3-{3-[4-(2-Fluoro-benzoyl-amino)-phenyl]-thioureido-benzoic acid

1014 382 3-(3-{4-[(furan-2-carbonyl)amino]phenyl}thioureido)benzoic acid

1015 408 N-{4-[3-(3-acetylphenyl)thioureido]phenyl}-2-fluorobenzamide

1016 502 N-{4-[3-(3-Butylsulfamoylphenyl)thioureido]phenyl}-2-fluorobenzamide

1017 380 furan-2-carboxylic acid {4-[3-(3-acetylphenyl)thioureido]phenyl}-amide

1018 447 furan-2-carboxylic acid (4-{3-[3-(2-hydroxyethanesulfonyl)phenyl]thioureido}phenyl)amide

1019 475 2-fluoro-N-(4-{3-[3-(2-hydroxyethanesulfonyl)phenyl]thioureido}phenyl)benzamide

1020 474 furan-2-carboxylic acid {4-[3-(3-butylsulfamoylphenyl)thioureido]phenyl}-amide

Example 1021 (Method 57)

Preparation of 1-(4-fluorophenyl)-2-methylpropan-1-ol

2.0 g of 4-fluorobenzaldehyde was dissolved in 40 ml of diethyl ether, and then 9.6 ml of 2.0M isopropylmagnesium bromide was added dropwise at 0°C while stirring. After 1.5 hours

-223 the reaction mixture is reacted with aqueous ammonium chloride solution and then extracted with diethyl ether. The diethyl ether extracts are washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated. The residual oil is purified by chromatography using a silica gel carrier and a hexane eluent mixture containing 10% by volume of methylene dichloride. As a result, 1.76 g of a yellow oil is obtained.

Example 1022 (Method 58) Preparation of 1-(4-fluorophenyl)-2-methylpropan-1-one

1.6 g of 1-(4-fluorophenyl)-2-methylpropan-1-ol were dissolved in 10 ml of acetone, and 20 ml of Jones reagent were added at 0°C while stirring. After 10 minutes, the excess Jones reagent was reacted by adding isopropyl alcohol. Diethyl ether and anhydrous magnesium sulfate were added to the mixture, then filtered and the solvent was evaporated. As a result, 1.2 g of the product was obtained in the form of a yellow oil.

Example 1023 (Method 59) Preparation of 3-dimethylamino-5-trifluoromethylbenzonitrile

7.3 g of 3-dimethylamino-5-trifluoromethyl-bromobenzene were dissolved in 20 ml of N,N-dimethylformamide, 2.7 g of copper(I) chloride were added, and the mixture was refluxed for 12 hours. The reaction mixture was diluted with 40 ml of water and methylene chloride was added. The methylene chloride fraction was extracted with concentrated ammonium hydroxide solution, then

-224 Wash with water. The mixture is dried over anhydrous magnesium sulfate, filtered and evaporated. The remaining yellow solid is recrystallized from hexane to give 4.7 g of a yellow solid.

The herpes virus inhibitory activity of the above compounds was examined using the methods described below.

Human cytomegalovirus

Method used to measure virus yield

Monolayer cultures of human foreskin fibroblasts (HFF) were infected with wild-type human cytomegalovirus (HCMV) in the presence of various concentrations of inhibitor compound at multiple sites 0.508 cm apart. Three days after infection, the total amount of virus produced in the cultures (viral yield) was measured by harvesting the virus and using HFF cultures in 12-well microtiter plates in the absence of inhibitor. Plaques were quantified 2 weeks after infection. Compounds with HCMV inhibitory activity were identified by comparing the reduction in viral yield in the presence of the inhibitor compound with the viral titer in the absence of the compound. In this assay, the relative anti-HCMV activity of the inhibitor is usually expressed as the IC ₅₀ or IC ₉₀ values (the amount of inhibitor required to reduce viral yield by 50% or 90%, respectively).

-225 is determined. Table I shows the IC ₅₀ values of the compounds tested against HCMV.

Microtiter plate method HFF culture placed in a hollow microtiter plate was infected in the presence of the inhibitor compound with a mutant recombinant HCMV containing a prokaryotic β-glucuronidase gene in its genome [Jefferson, RA; Burgess, M. and Hirsch, D. Beta-glucuronidase from Escherichia coli as a gene fusion marker, Proc. Natl. Acad. Sci. USA 83, 8447-8451 (1986)], the expression of which is controlled by a viral promoter. An example of such a virus is RV145 [Jones, TR; Muzithras, VP and Gluzman, Y. Replacement mutagenesis of the human cytomegalovirus genome: US10 and US11 gene products are nonessential, J. Virol. 65., 5860-5872 (1991)]. Since β-glucuronidase is regulated by a viral promoter, its expression in this assay is a direct indicator of HCMV growth and replication. 96 hours after infection, lysates of infected cells are prepared using 0.1% Triton X-100 and 0.1% sarkosyl in 50 mM sodium phosphate (pH 7.0) and β-glucuronidase activity is measured using an enzyme substrate whose cleavage product can be measured colorimetrically in a spectrophotometer or fluorescencely in a microfluorimeter. Such substrates include para-nitrophenyl-β-glucuronide or methyl-226-beta-11-phenyl phenyl glucuronide. The presence of an antiviral compound is indicated by a reduced expression of the β-glucuronidase gene in the HCMV genome compared to the absence of such a compound. In the latter case, the formation of the chromophore or fluorophore product in the assay is proportionally reduced. This assay is suitable for determining the IC ₅₀ value of the inhibitor when varying amounts of inhibitor compound are used.

HSV antiviral (ELISA) test

Beater cells (ATCC #CCL-81) (3.5 x 10 ⁴ cells per 100 μΙ) are plated in 96-well tissue culture plates containing DMEM (Dulbecco's Modified Eagle Medium) supplemented with 2% fetal bovine serum (FBS). The plates are incubated overnight at 37°C in a 5% CO ₂ atmosphere, and then 30 minutes before HSV-1 infection (mean viral load per cell = 0.006), the cells are treated (using multiple concentrations) or left untreated with the test compound or the standard reference compound. Approximately 24 hours after infection, the cells are prepared for ELISA testing after incubation at 37°C in a 5% CO ₂ atmosphere. The primary antibody used is murine anti-HSV glycoprotein D monoclonal primary antibody, and the secondary antibody is goat anti-mouse IgG conjugated to β-galactosidase. The extent of virus replication is determined by measuring the β-galactosidase activity of the

-227 um be 11 ife ri lBDg a I a ctozi dm et i l-ester (Sigma #M1633) is determined by measuring the amount of 4-methyl-umbelliferone cleaved off after the addition of the microfluorimeter method (excitation 365 nm, emission 450 nm). The antiviral activity (IC ₅₀ ) of the test compound is calculated by comparing the fluorescence measured in the absence and presence of the compound. The measured data are shown in Table I.

VZV antiviral (ELISA) test

The VZV culture used in the test is prepared by infecting HFF cells with VZV Ellen strain (ATCC #VR-1367) (mean viral load per cell < 0.1) and incubating the culture overnight at 37°C in an atmosphere containing 5% CO ₂ . After overnight incubation, a mixture of VZV-infected and uninfected cells is harvested and plated in 96-well microtiter plates [3.5 x 10 ⁴ cells per 100 µl of DMEM supplemented with 2% fetal bovine serum (FBS)] containing the test compound or the standard reference compound in 100 µl of DMEM supplemented with 2% fetal bovine serum (FBS) per well. The cells were incubated overnight at 37°C in an atmosphere containing 5% CO ₂ and then prepared for ELISA. The primary antibody used was murine anti-VZV glycoprotein II monoclonal antibody (Applied Biosystems. Inc. #13-145-100), and the secondary antibody was conjugated to β-galactosidase.

-228 -

goat anti-mouse IgG. The extent of virus growth is therefore determined by measuring the activity of β-galactosidase by measuring the amount of 4-methylumbelliferone cleaved after the addition of umbelliferyl-BD-galactoside methyl ester (Sigma #M1633) using a microfluorimeter (excitation 365 nm, emission 450 nm). The antiviral activity (IC ₅₀ ) of the test compound is determined by comparing the fluorescence measured in the presence and absence of the compound. The measured data are shown in Table I.

Table I

IC ₅₀ values of compounds tested against herpes viruses

Example IC50 (pg/ml) HSV (%) inhibition 10 pg/ml VZV IC50 (pg/ml) VZV _IC50 (pg/ml) HCMV 86. >10 32 >10 0.04 88. >10 0.03 0.013 90. >10 0.07 91. >10 6 >10 0.018 144. 7 10 145. 2 51 >15 >10 146. >10 14 >10 >10 147. 10 42 >10 >50 153. 2 8 >10 >10 154. 4 23 >10 10 155. 5 22 >10 5

-229 Table I. continued

Example I IC50 (pg/ml) HSV (%) inhibition 10 pg/ml VZV IC50 (pg/ml) VZV IC50 (pg/ml) HCMV 158. 4 52 >15 >10 159. >10 62 >10 >10 160. 2.5 27 >10 >10 161. 3 113 5 >10 163. 3 30 >10 7 166. 9 30 >10 >10 167. 10 70 3.8 9 168. 3 >10 2.5 169. 3 26 >10 4 170. >10 32 >10 0.2 172. >10 25 >10 >10 173. >10 31 >10 0.08 174. 50 8 >10 6 175. 2 24 >10 >10 200. >10 55 >15 0.02 201. >10 78 8 0.023 224. 3.5 30 >10 0.8 225. 1 30 >10 >10 230. >10 >10 0.015 233. >10 30 >10 0.09 236. >10 40 >10 0.7 237. >10 17 >10 0.02 246. >10 37 4 0.05

- 230 Table I. continued

Example I Tube (pg/ml) HSV (%) inhibition 10 pg/ml VZV IC50 (pg/ml) VZV IC50 (pg/ml) HCMV 249. >10 59 >10 0.4 264. >10 28 >10 >10 279. >10 >10 >10 280. >10 >10 >10 281. >10 31 >10 >10 288. >10 30 >10 4 323. 3 45 >10 0.03 330. >10 29 >10 0.15 331. 1.8 98 5 2 341. 2 50 >10 0.15 344. 4 72 7 0.25 350. >10 50 >10 1 351. 3 90 3.5 0.3 352. 3 51 >10 0.6 353. 0.6 86 7 0.04 354. 0.8 75 7 2 361. 8 26 >10 0.25 365. 10 75 5 0.035 368. >10 20 >10 0.35 371. >10 45 >10 >10 376. 3 83 7 0.8 378. >10 31 >10 0.033

231 Table I. continued

Example IC50 (pg/ml) HSV (%) inhibition 10 pg/ml VZV IC50 (pg/ml) VZV IC50 (pg/ml) HCMV 379. >10 27 >10 >10 391. 8 97 6 0.019 396. >10 26 >10 0.7 398. >10 5 >10 0.13 403. 6 108 >15 0.09 406. >10 28 >10 0.12 409. >10 5 >10 2 411. 8 99 2 0.024 413. 5 103 5 0.081 416. >10 87 >15 0.25 421. 8 >10 0.75 422. 5 69 >10 0.058 424. 3 103 0.7 0.09 430. >10 >10 0.4 431. >10 >10 0.06 435. 10 94 0.9 0.08 436. 10 >10 0.15 438. 5 73 1.5 3 439. 9 46 >10 0.5 440. 1 9 0.3 441. >10 >10 0.17 445. 10 >10 0.15

-232 Table I. continued

Example IC50 (pg/ml) HSV (%) inhibition 10 pg/ml VZV IC50 (pg/ml) VZV IC50 (pg/ml) HCMV 446. 10 >10 0.7 447. >10 >10 >10 449. >10 >10 1.6 450. >10 >10 0.05 451. 8 >10 0.15 453. >10 3 0.07 455. >10 30 >10 0.3 456. >10 12 >10 00.7 457. >10 26 >10 0.019 462. >10 6 >10 1 464. >10 25 >10 0.15 466. >10 93 >10 0.011 467. >10 93 >15 0.12 468 >10 50 >10 0.06 469. >10 54 >10 0.1 470. 0.6 17 >10 0.7 472. >10 31 >10 0.8 473. >10 40 >10 0.3 474. >10 22 >10 1 478. >10 31 >10 0.4 479. >10 30 >10 0.1 481. >10 32 >10 0.5

-233 Table I. continued

Example IC50 (pg/ml) HSV (%) inhibition 10 pg/ml VZV IC50 (pg/ml) VZV IC50 (pg/ml) HCMV 482. 9 33 >10 0.3 485. >10 11 >10 0.03 486. >10 22 >10 0.045 488. >10 13 >10 1.2 489. 5 99 3.5 0.17 494. >10 6 >10 3.5 495. >10 27 >10 3 500. >10 48 >10 0.021 501. >10 10 >10 0.032 503. 8 64 >10 0.053 505. 10 79 8 0.2 508. >10 7 >10 0.013 509. >10 31 >10 0.03 510. 8 19 >10 0.04 513. >10 10 >10 0.01 1 516. >10 7 >10 0.04 521. 10 97 3 0.04 522. >10 32 >10 0.025 524. 4 95 2 0.025 526. >10 22 2.5 3 528. 3.2 107 5 0.25 530. 5 96 6 0.15

-234 Table I. continued

Example IC50 (pg/ml) HSV (%) inhibition 1 0 pg/ml VZV IC50 (pg/ml) VZV IC50 (pg/ml) HCMV 532. >10 6 0.009 534. 7 >10 0.05 535. >10 >10 0.016 537. 9 10 0.003 539. >10 >10 0.036 541. 7 >10 0.017 542. >10 >10 0.0011 544. >10 >10 0.02 545. 3 7 0.012 546. 1.7 7 0.007 547. >10 10 0.006 548. >10 >10 0.008 550. >10 >10 0.013 551. >10 >10 0.043 554. >10 1.5 0.01 555. >10 4 0.008 556. >10 >7.5 0.006 557. >10 >10 0.006 558. 7 >10 0.05 559. >10 >10 0.012 560. >10 >10 0.008 561. >10 8 0.05

- 235 Table I. continued

Example IC50 (pg/ml) HSV (%) inhibition 10 pg/ml VZV _IC50 (pg/ml) VZV IC50 (pg/ml) HCMV 562. >10 8 0.004 564. >10 5 0.027 565. >10 0.22 0.001 571. >10 0.013 572. >10 0.0078 573. >10 0.05 574. >10 0.089 575. 2 0.017 579. 6 0.05 581. >10 0.01 582. 8 0.01 584. >10 0.0026 585. >10 0.015 587. >10 0.005 588. >10 0.36 0.03 590. >10 1 0.12 592. >10 2 0.049 594. >10 >10 0.011 595. >10 3 0.022 597. >10 >10 0.008 599. >10 >10 0.005 600. | >10 >10 0.012

- 236 Table I. continued

Example IC50 (pg/ml) HSV (%) inhibition 10 pg/ml VZV IC50 (pg/ml) VZV IC50 (pg/ml) HCMV 601. >10 >10 0.0011 602. >10 >10 0.0015 603. >10 >10 >0.5 604. >10 10 0.025 605. >10 10 0.062 606. >10 >10 0.0023 607. 8 >10 0.09 61 1. >10 0.5 612. 1 0.049 613. >10 0.01 1 614. 7 0.024 615. >10 0.005 617. >10 0.013 618. >10 0.0016 624. >10 0.002 626. 10 >10 0.07 627. 10 >10 0.014 630, >10 4 0.4 631. 6 6 0.15 635. 10 4 0.15 637. >10 >10 0.014 638. >10 >10 0.01

-237 Table I. continued

Example IC50 (pg/ml) HSV (%) inhibition 10 pg/ml VZV IC50 (pg/ml) VZV IC50 (µg/ml) HCMV 639. >10 >10 0.07 644. >10 8 0.03 645. >10 10 0.003 646. >10 2.5 0.03 647. >10 0.1 0.007 648. >10 0.01 650. >10 0.05 651. >10 0.03 652. >10 0.03 654. >10 0.07 655. >10 0.01 657. 6 0.04 662. >10 0.03 663. >10 0.01 665. 5 0.02 667. 8 0.03 668. >10 0.009 670. >10 0.02 671. >10 0.005 674. >10 0.006 675. >10 0.05 676. >10 0.013

-238 Table I. continued

Example 1 Tube (pg/ml) HSV (%) inhibition 10 pg/ml VZV IC50 (pg/ml) VZV IC50 (pg/ml) HCMV 678. >10 0.005 679. 10 0.01 681. >10 0.02 682. >10 0.006 683. 10 0.02 684. 10 0.005 685. 10 0.006 686. >10 0.007 688. >10 0.006 689. 7 0.007 690. 7 0.004 691. >10 0.008 692. 6 0.04 693. >10 0.03 694. 10 0.04 697. 7 0.04 698. 6 0.04 699. >10 0.016 700. >10 0.004 701. >10 0.008 702. 4 0.01 703. >10 0.007

-239 Table I. continued

Example IC50 (pg/ml) HSV (%) inhibition 10 pg/ml VZV _IC50 (pg/ml) VZV IC50 (μg/ml) HCMV 704. >10 0.006 705. >10 0.006 706. >10 0.04 707. >10 0.005 708. >10 0.005 709. >10 0.05 710. >10 0.006 711. >10 0.004 713. >10 0.009 714. >10 0.02 715. >10 0.03 716. >10 0.01 717. >10 0.003 718. 6 0.02 720. >10 0.01 722. >10 0.015 723. >10 0.03 726. >10 728. 9 729. 0.02 730. 0.033 731. >10 0.007

-240 Table I. continued

Example IC50 (pg/ml) HSV (%) inhibition 10 pg/ml VZV l C50 (pg/ml) VZV IC50 (pg/ml) HCMV 732. 0.022 733. 0.018 734. >10 0.009 735. 0.022 736. 0.012 737. >10 0.005 738. >10 0.11 739. >10 0.02 740. 0.1 741. >10 0.02 742. >10 0.009 743. >10 0.09 745. 9 0.0025 746. >10 0.005 747. >10 0.002 748. >10 0.28 749. >10 0.06 750. >10 0.01 759. >10 2 >10 762. >10 1.5 0.002 763. 5 5 0.004 764. >10 0.004

- 241 Table I. continued

Example IC50 (pg/ml) HSV (%) inhibition 10 pg/ml VZV IC50 (pg/ml) VZV IC50 (pg/ml) HCMV 766. >10 0.006 767. >10 1 0.006 768. >10 0.005 769. >10 0.04 770. >10 0.006 796. >10 >7.5 4 815. 0.27 0.0095 816. >7.5 0.0053 818. >7.5 0.0016 820. >7.5 0.006 821. >7.5 0.005 822. >7.5 0.018 824. 0.17 0.014 825. >7.5 0.0013 828. >7.5 0.002 829. >7.5 0.002 830. >7.5 0.0003 831. >7.5 0.0011 832. >7.5 0.001 833. >7.5 0.0019 834. >7.5 0.002 835. >7.5 0.005

-242 Table I. continued

Example IC50 (pg/ml) HSV (%) inhibition 10 pg/ml VZV IC50 (pg/ml) VZV IC50 (pg/ml) HCMV 836. >7.5 0.004 837. 3.60 0.03 838. >7.5 0.0007 839. >7.5 0.004 840. 0.14 0.0015 841. 0.77 0.0011 842. 1.55 0.02 843. >7.5 0.0031 844. 1.03 0.0008 845. >7.5 0.0060 846. 1.04 0.0130 847. >7.5 0.0008 848. 0.19 0.002 849. 1.82 0.002 850. 2.33 0.0008 851. 1.43 0.017 852. >7.5 0.005 853. 0.062 0.004 854. 0.02 855. 0.02 856. 0.02 857. >7.5 0.0006

-243 Table I. continued

Example IC50 (pg/ml) HSV (%) inhibition 10 pg/ml VZV IC50 (pg/ml) VZV IC50 (pg/ml) HCMV 858. >7.5 0.0007 859. 0.5 0.00001 860. >7.5 0.001 861. >7.5 0.002 862. >7.5 0.1 863. >7.5 2.0 864. >7.5 0.5 865. >7.5 0.0001 866. >10 50 >10 0.035 875. >50 18 >10 >2.2 879. 4 65 10 0.3 888. 6 31 >10 0.06 897. >10 62 >10 0.037 902. >10 10 >10 0.12 904. 12 58 >10 0.4 905. 4 82 2 0.3 907. >10 36 >10 0.009 911. >10 25 >10 0.3 912. >10 0 >10 0.16 913. >10 15 >10 0.056 91 7. 10 >10 0.2 91 8. >10 >10 0.03

-244Table I. continued

Example IC50 (pg/ml) HSV (%) inhibition 10 pg/ml VZV IC50 (pg/ml) VZV IC50 (pg/ml) HCMV 919. >10 >10 0.05 921. 8 85 7 0.05 922. >10 84 7 0.01 939. >10 53 15 0.018 960. >10 58 >10 0.03 961. >10 20 >10 0.006 964. >10 9 >10 0.03 965. >10 36 >10 0.008 966. >10 42 >10 0.02 969. >10 40 >10 0.03 970. >10 16 >10 0.06 971. >10 9 >10 0.013 972. >10 95 >15 0.006 974. >10 14 >10 0.011 979. 8 88 12 0.19 980. >10 56 >10 0.05 983. >10 52 >10 0.12 986. >10 5 >10 0.031 989. >10 21 >10 0.016 990. 8 99 4.5 0.011 991. >10 3 >10 0.022 992. >10 29 >10 0.018

-245 Table I. continued

Example IC50 (pg/ml) HSV (%) inhibition 10 pg/ml VZV IC50 (pg/ml) VZV IC50 (pg/ml) HCMV 993. >10 >10 0.013 994. >10 >10 0.07 996. 10 >10 0.015 998. >10 >10 0.016 1000. >10 >10 0.39 1002. >10 >10 0.07 1004. >10 36 >10 0.5 1005. >10 16 >10 2 1006. >10 13 >10 0.2 1007. >10 18 >10 0.11 1008. >10 15 >10 0.12 1009. 10 22 >10 0.2 1011. >10 20 >10 0.039 1018. >10 2 >10 0.4 1019. >10 2 >10 1.5 1021. 8 68 >10 0.094 1126. >10 0.7 5.8 1127. 9.5 3.7 1 1128. >10 >10 1.3 1129. 1.9 >10 1 1130. 2 5.5 2 1131. 2.2 9 ___1.5

-246 Table I. continued

Example IC50 (pg/ml) HSV (%) inhibition 10 pg/ml VZV IC50 (pg/ml) VZV IC50 (pg/ml) HCMV 1132. 2.6 3.9 1.2 1133. 6 >10 1.5 1134. 2.4 1.6 1 1135. 3.6 7.5 1.3 1136. 2.9 5 1.6 1137. >10 3.5 0.6 1138. >10 >10 0.65 1139. 3.7 6 1.2 1140. 3.5 4 1.6 1141. >10 >10 1.9 1142. >10 >10 1.8 1143. >10 >10 7.5

The compounds of the invention are therefore effective in inhibiting the growth and replication of herpes viruses such as HCMV, VZV and HSV, as they are effective in inhibiting the virus.

Thus, according to the invention, patients suffering from herpes virus infection, such as HCMV, VZV and HSV, can be treated with a compound of the invention in an amount sufficient to inhibit the virus. The compounds of the invention are therefore useful for reducing or eliminating the symptoms caused by the herpes virus in the

-247 in mammals, including but not limited to humans.

The compounds of the invention may be administered to the patient alone or in combination with a suitable pharmaceutical carrier.

Suitable carriers may be one or more substances which may also act as flavouring, lubricating, solubilising, suspending, filling, lubricating, tabletting aid, binder or tablet disintegrating agent or as an encapsulating agent. Powders are mixtures of finely divided solid carrier and finely divided active ingredient. In the case of tablets, the active ingredient is mixed with a carrier in the appropriate proportion and compression properties and compressed into tablets of the desired shape and size. 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, polyvinylpyrrolidine, low melting waxes and ion exchange resins.

Liquid carriers can be used to prepare solutions, suspensions, emulsions, syrups and elixirs. The active ingredient of the invention can be dissolved in a pharmaceutically acceptable liquid carrier, for example water, an organic solvent or a mixture of the two, or a pharmaceutically acceptable oil.

-248 - ^: Λ or fat. The liquid carrier may also contain other suitable pharmaceutically acceptable additives, such as solubilizing agents, emulsifiers, buffers, preservatives, sweeteners, flavorings, suspending agents, thickeners, coloring agents, viscosity-inducing agents, stabilizers and osmotic regulators. Liquid carriers suitable for oral and parenteral use include, for example, water, which may preferably contain the additives listed above, such as cellulose derivatives, preferably the sodium salt of carboxymethylcellulose, alcohols (including mono- and polyalcohols, such as glycols) and their derivatives, and oils (such as fractionated coconut oil and peanut oil). For parenteral administration, oleic acid esters, such as oleic acid ethyl ester and myristic acid isopropyl ester, may be used as carriers. Sterile liquid preparations for parenteral administration may be prepared using sterile liquid carriers. Liquid pharmaceutical preparations in the form of sterile solutions or suspensions may be administered, for example, by intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions may also be administered intravenously. Both liquid and solid preparations are suitable for oral administration.

The pharmaceutical composition is preferably provided in unit dosage form, for example in the form of tablets or capsules. In this case, the composition is

- 249- '··<-„· ^; A' is divided into unit doses containing corresponding quantities of the active ingredient: unit doses may be, for example, packaged preparations, such as packaged powders, vials, ampoules, pre-filled syringes or sachets containing liquids. A unit dose may be the capsule or tablet itself, or a given number of such preparations in packaged form.

The invention also relates to the use of the compounds of the invention of general formula (I) for the inhibition of herpes virus replication and for the preparation of pharmaceutical compositions suitable for the treatment of a patient suffering from herpes virus infection.

The therapeutically effective dose for the treatment of herpes virus infection is determined by the treating physician based on his subjective judgment. In this case, the condition, age and weight of the patient should be taken into account. Treatment of herpes virus infection is carried out by administering to the patient, including humans, a therapeutically effective amount of at least one compound of general formula (I) or a non-toxic, pharmaceutically acceptable salt thereof. The compounds can be administered orally, rectally, parenterally or topically to the skin or mucous membrane. The usual daily dose is 0.01 ·· 1000 mg/kg, preferably 0.5 - 500 mg/kg, and 0.1 - 100 mg/kg, preferably 0.5 - 50 mg/kg, for parenteral administration.

Claims (28)

1. Compounds of general formula (I) and their pharmaceutically acceptable salts, wherein - R ₅ independently represents a hydrogen atom, a C 1-6 alkyl, a C 2-6 alkenyl, a C 2-6 alkynyl, a C 1-6 perhaloalkyl, a C 3-10 cycloalkyl, a C 3-10 heterocycloalkyl, aryl, heteroaryl group, halogen atom, cyano, nitro group, -CO ₂ R ₈ , -COR ₆ , -OR ₈ , -SRe, -SOR ₈ , -SO ₂ R ₆ , -CONR ₇ R ₈ , -NR ₆ N(R ₇ R ₈ ), -N(R ₇ R ₈ ) or a group of the general formula WY-(CH ₂ ) _n -Z, with the proviso that at least one of the Rt - R ₅ groups is not a hydrogen atom; or R ₂ and R ₃ or R ₃ and R ₄ together form a 3-7 membered heterocycloalkyl group or a 3-7 membered heteroaryl group; R ₆ and R ₇ are independently hydrogen, C 1-6 alkyl, C 1-6 perhaloalkyl, or aryl; R ₈ is hydrogen, C 1-6 alkyl, C 1-6 perhaloalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, aryl, heteroaryl, or R ₇ and R ₈ together may form a 3-7 membered heterocycloalkyl group; W is oxygen, -NR ₆ , or absent; -251 Y is -(CO)- or -(CO ₂ )-, or is absent; Z is a group of the general formula -CO ₂ R _6> -COR _6i -conr ₇ r ₈ , -ocor ₆ , -NR ₆ COR ₇ , -OCONR ₆ , -ORe, -SR ₆ , -SOR _6i -SO ₂ R ₆ , SR ₆ N(R ₇ R ₈ ), -N(R ₇ R ₈ ) or a phenyl group; G is a monocyclic heteroaryl group; X is a bond, -NH, C1-6 alkyl, C1-6 alkenyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino or (CH)J; J is C1-6 alkyl, C3-7 cycloalkyl, phenyl or benzyl; and n is 1-6. 2. Compounds according to claim 1, wherein R-, - R ₅ independently represent a hydrogen atom, a C 1-6 alkyl group, a halogen atom, a C 1-6 perhaloalkyl group, -OR ₆ or a group of the general formula -N(R ₇ R ₈ ). 3. Compounds according to claim 1, wherein R _{n ,} R ₂ and R ₃ are hydrogen and R ₄ and R ₅ are independently halogen or -CF ₃ . 4. Compounds according to claim 1, wherein R1, _R2 and _R4 are hydrogen and _R3 and _R5 are independently halogen or _-CF3 . -252 - 5. Compounds according to claim 1, wherein G is a thiazolyl, thiadiazolyl, oxazolyl or furyl or isoquinolyl group. 6. Compounds according to claim 1, wherein G is thiazolyl. 7. Compounds according to claim 1, wherein G is 1,2,3-thiadiazolyl. 8. Compounds according to claim 1, wherein X is a valence bond. 9. Compounds according to claim 1, wherein X is a straight chain alkyl group. 10. Compounds according to claim 1, wherein X is C1-C4 alkyl. 11. Compounds according to claim 1, wherein X is CH(J) and J is C1-C6 alkyl. 12. Compounds according to claim 11, wherein J is methyl. 13. Compounds according to claim 1, wherein X is CH(J) and G is -253 t iazo I i Icso port. 14. Compounds according to claim 1, listed below: [1,2,3]thiadiazole-4-carboxylic acid-{4-[3-(3,5-bis-trifluoromethyl-benzyl)-thioureido]-phenyl}-amide, [1,2,3]thiadiazole-4-carboxylic acid-{4-[3-(4-piperidin-1-yl-3-trifluoromethyl-benzyl)-thioureido]-phenyl}-amide, [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(4-dimethylamino-3-trifluoromethylbenzyl)thioureido]phenyl}-amide, [1,2,3]thiadiazole-4-carboxylate-{4-[3-(3-dimethylamino-5-trifluoromethyl-benzyl)-thioureido]-phenyl}-amide, [1,2,3] ti adiazole-4-carboxylate v-{4-[3-(4-fluoro-3-trifluoromethyl-benzyl)-thioureido]-phenyl}-amide, thiazo I-4-carboxylate v-{4-[3-(4-tert-butyl-benzyl)-thioureido]-phenyl)-amide, [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-(4-bromophenyl)ethyl]thioureido}-phenyl)-amide, thiazole-4-carboxylic acid-{4-[3-(3,4-dichlorobenzyl)thioureido]-phenyl}-amide, [1,2,3]thiadiazole-4-carboxyl-{4-[3-(3,5-dichloro-benzyl)-thioureido]-phenyl}-amide, [1,2,3]thiadiazole-4-carboxylate-{4-[3-(3,4-dichlorobenzyl)-thioureido]-phenyl}-amide, [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(3,4-dichlorophenyl)ethyl]thioureido}phenyl)amide, -254 [ 1,2,3] ti ad i the ο I-4-carb ο ns a v-(4-{3-[ 2-(4-t rif u o rm eti I -phen i l)-eti l]-t iou rei d o}-pheni l)-amide, [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(3-chlorophenyl)ethyl]thioureido}-phenyl)amide, [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(4-tert-butylbenzyl)thioureido]phenyl}-amide, thiazole-4-carboxylic acid {4-[3-(3,5-dichlorophenyl)thioureido]phenyl}-amide, [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(2-fluoro-5-trifluoromethylphenylsulfanyl)ethyl]thioureido}phenyl)amide, [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(2,4-bis-trifluoromethylphenyl)ethyl]thioureido}-phenyl)amide, [1,2.3]thiadiazole-4-carboxylic acid (4-{3-[2-(4-fluoro-3-trifluoromethylphenyl)ethyl]thioureido}-phenyl)amide, [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3-fluoro-5-trifluoromethylbenzyl)thioureido]phenyl}-amide, [1,2,3]thiadiazole-4-carboxylic acid {4-{3-[2-(3,5-bis-trifluoromethylphenyl)ethyl]thioureido}phenyl)amide, [1,2,3]thiadiazole-4-carbonic acid-{4-[3-(4-iodo-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide, [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(2-fluoro-5-trifluoromethylbenzyl)thioureido]phenyl}-amide, [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(3-bromo-phenylsulfonyl)-ethyl]-thioureido}-phenyl)-amide, [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(2-fluorophenyl)ethyl]thioureido}-phenyl)amide, [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(2,4-dichlorophenyl)ethyl]thioureido}-phenyl)amide, -255 [1,2,3]thiadiazole-4-carboxylic acid-(4-{3-[2-(3-trifluoromethylphenyl)ethyl]thioureido}phenyl)amide, [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(2-fluoro-5-trifluoromethyl-phenoxy)-ethyl]-thioureido}-phenyl)-amide, thiazole-4-carboxylic acid {4-[3-(2-fluoro-5-trifluoromethyl-benzyl)-thioureido]-phenyl}-amide, [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(3-iodophenyl)ethyl]thioureido}-phenyl)amide, furan-2-carboxylic acid {4-[3-(3,5-bis-trifluoromethylbenzyl)thioureido]-phenyl}-amide, [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[3-(3-methylbutyl)5-trifluoromethylphenyl]thioureido}-phenyl)amide, [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3-isobutyl-5-trifluoromethylphenyl)thioureido]phenyl}-amide, [1,2,3]thiadiazole-4-carboxylic acid-(4-{3-[2-(3-dimethylamino-5-trifluoromethylphenyl)ethyl]thioureido}-phenyl)amide, [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(5-bromo-2-methoxyphenyl)ethyl]thioureido}phenyl)amide, [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(4-chlorophenyl)ethyl]thioureido}-phenyl)amide, [1,2,3]thiadiazole-4-carboxylic acid-(4-{3-[2-(3,5-dichlorophenoxy)ethyl]thioureido}-phenyl)amide, thiazole-4-carboxylic acid-{4-[3-(3,4-dichlorophenyl)thioureido]-phenyl}-amide, thiazole-4-carboxylic acid-{4-[3-(4-chloro-3-trifluoromethylphenyl)thioureido]-phenyl}-amide, - 256 [1,2,3]thiazol-4-carboxylic acid (4-{3-[2-(3,4-dichlorophenylsulfanyl)ethyl]thioureido}phenyl)amide, [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(2-fluoro-3-trifluoromethylphenyl)ethyl]thioureido}phenyl)amide, [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(2-fluoro-5-trifluoromethylphenyl)ethyl]thioureido}phenyl)amide, [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(3-bromophenyl)ethyl]thioureido}phenyl)amide, [1,2,3]thiadiazole-4-carboxylic acid (4-[3-(3-chloro-4-trifluoromethyl-phenyl)-thiourei do]-phenyl}-amide, [1,2,3]thiadiazole-4-carboxylic acid (4-[3-(3-chloro-4-iodophenyl)thioureido]phenyl}-amide, furan-2-carboxylic acid [4-(3-benzo[1,3]dioxol-5-ylmethylthioureido)phenyl]-amide, [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[1-(4-bromophenyl)ethyl]thioureido}phenyl)amide, [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3,3-diphenylpropyl)thioureido]phenyl}-amide, [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3-chloro-4-fluorobenzyl)thioureido]phenyl}-amide, [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(3,4-dichlorophenoxy)ethyl]thioureido}phenyl)amide, [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3-trifluoromethylbenzyl)thioureido]phenyl}-amide, [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3-chlorobenzyl)thioureido]phenyl}-amide, [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(4-bromo-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide, -257 [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(4-fluorophenyl)ethyl]thioureido}phenyl)amide, [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3-pyrrolidin-1-yl-5-trifluoromethylphenyl)thioureido]phenyl}-amide, [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[3-(butylmethylamino)-5-trifluoromethylphenyl]thioureido}-phenyl]-amide, [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3,5-dimethylbenzyl)thioureido]phenyl}-amide, thiazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoromethylphenyl)thioureido]phenyl}-amide, [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3,4-dichlorophenyl)thioureido]phenyl}-amide, [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3-bromo-5-trifluoromethylphenyl)thioureido]phenyl}-amide, [1,2,3]thiadiazole-4-carboxylic acid-(4-{3-[2-(3-chloro-phenoxy)-ethyl]-thioureido}-phenyl)-amide, [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(4-ethylphenyl)ethyl]thioureido}-phenyl)amide, [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(3-bromophenoxy)ethyl]thioureido}phenyl)amide, [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(4-chlorobenzyl)thioureido]phenyl}-amide, [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(5-chloro-2-methoxy-4-methylphenyl)thioureido]phenyl}-amide, [1,2,3]thiadiazole-4-carboxylic acid {4-{3-[2-(3-fluorophenyl)ethyl]thioureido}phenyl)amide, [1,2,3]thiadiazole-4-carboxylic acid {4-{3-[1-(4-fluorophenyl)ethyl]thioureido)phenyl}amide, - 258 [1, 2,3]thiadiazole-4-carboxylic acid-{4-[3-(3,5-difluorobenzyl)-thioureido]-phenyl}-amide, furan-2-carboxylic acid-{4-[3-(3,5-difluorobenzyl)-thioureido]-phenyl}-amide, [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(2-p-tolylethyl)thioureido]phenyl}-amide, [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(4-phenylbutyl)thioureido]phenyl}-amide, [1,2,3]thiadiazole-4-carboxylic acid-{4-[3-(2-phenylsultanyl-ethyl)-thioureido]-phenyl}-amide, [1,2,3]thiadiazole-4-carboxylic acid-{4-[3-(3-iodo-benzyl)-thioureido]-phenyl}-amide, furan-2-carboxylic acid-(4-{3-[2-(3-bromo-phenylsulfanyl)-ethyl]-thioureido}-phenyl)-amide, oxazole-4-carboxylic acid-}4-[3-(3,5-dichlorophenyl)-thioureido]-phenyl}-amide, [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(3,4-difluorophenyl)ethyl]thioureido}phenyl)amide, [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(3,5-difluorophenyl)ethyl]thioureido}-phenyl)amide, [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(3-iodo-phenoxy)-ethyl]-thioureido}-phenyl)-amide, [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3,5-dichlorophenyl)thioureido]phenyl}-amide, [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3-amino-5-chlorophenyl)thioureido]phenyl}-amide, [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3-bromophenyl)thioureido]phenyl)amide, - 259 [1,2,3]thiadiazole-4-carboxylic acid-(4-{3-[3-(isobutylmethylamino)-5-trifluoromethylphenyl]thioureido}-phenyl)-amide, [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3-phenylpropyl)thioureido]phenyl)amide, [1,2,3]thiadiazole-4-carboxylic acid-{4-[3-(3-chloro-4-fluoropheniI)-thioureido]-pheniI}-amide, [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3,4,5-trichlorophenyl)thioureido]phenyl}-amide, furan-2-carboxylic acid {4-[3-(3,4-dichlorobenzyl)thioureido]phenyl}-amide, [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3-morpholin-4-yl-5-trifluoromethylphenyl)thioureido]phenyl}-amide, [1,2,3]tiadiazole-4-carboxylic acid-{4-[3-(4-fluoro-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide, [1,2,3]thiadiazole-4-carboxylic acid-(4-{3-[2-(3-fluoro-phenoxy)-ethyl]-thioureido}-phenyl)-amide, [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3-iodophenyl)thioureido]phenyl}-amide, [1,2,3]thiadiazole-4-carboxylic acid-{4-[3-(3-bromo-4-trifluoromethoxyphenyl)thioureido]phenyl}-amide, [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3-dimethylamino-5-trifluoromethylphenyl)thioureido]phenyl}-amide, [1,2,3]tiadiazole-4-carboxylic acid (4-{3-[4-(4-methyl-piperazin-1-yl)-3-trifluoromethyl-benzyl]-thioureido}-phenyl)-amide, [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3,4-difluorobenzyl)thioureido]phenyl}-amide, [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(4-bromo-3-chlorophenyl)thioureido]phenyl}-amide, - 260 [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3-chlorophenyl)thioureido]phenyl}-amide, [1,2,3]thiadiazole-4-carboxylic acid-{4-(3-(2-phenoxy-ethyl)-thioureido]-phenyl}-amide, (1,2,3]thiadiazole-4-carboxylic acid-(4-{3-[2-(3-methoxyphenyl)-ethyl]-thioureido}-phenyl)-amide, [1,2,3]thiadiazole-4-carboxylic acid-{4-[3-(3-chloro-4-methyl-phenyl)-thioureido]-phenyl}-amide, furan-2-carboxylic acid-{4-[3-(3-fluoro-5-trifluoromethyl-benzyl)-thioureido]-phenyl}-amide, [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-(3-piperidin-1-yl-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide, oxazole-4-carboxylic acid-{4-[3-(3,4-dichloro-phenyl)-thioureido]-phenyl}-amide, furan-2-carboxylic acid-{4-[3-(3,4,5-trichloro-phenyl)-thioureido]-phenyl}-amide, (1,2,3]thiadiazole-4-carboxylic acid-{4-[3-(4-chloro-phenyl)-thioureido]-phenyl}-amide, [1,2,3]thiadiazole-4-carboxylic acid (4-(3-benzo[1,3]dioxol-5-ylmethylthioureido)phenyl]-amide, [1,2,3]thiadiazole-4-carboxylic acid-[4-(3-phenethylthioureido)phenyl]-amide, [1,2,3]thiadiazole-4-carboxylic acid (4-{3-(2-(2-chlorophenoxy)ethyl]thioureido}-phenyl)amide, (1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoromethylphenyl)thioureido]-phenyl}amide, -261 [1,2,3]thiadiazole-4-carboxylic acid-{4-[3-(3,5-dichloro-2-methoxy-4-methyl-phenyl!)-thioureido]-phenyl}-amide, [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[3-chloro-4-(1H-pyrazol-3-yl)-phenyl]-thioureido}-phenyl)-amide, [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[3-chloro-4-(2-piperidin-1-ylacetylamino)phenyl]thioureido}phenyl)amide, [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(3-trifluoromethylphenyl)thioureido]phenyl}-amide, [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(4-chloro-3-trifluoromethylphenyl)thioureido]phenyl}-amide, [1,2,3]thiadiazole-4-carboxylic acid-(4-{3-[3-chloro-4-(cyclohexylmethylamino)phenyl]thioureido}-phenyl)-amide, furan-2-carboxylic acid-(4-(3-benzylthioureido)-phenyl)-amide, furan-2-carboxylic acid-(4-{3-[2-(3,5-dichlorophenoxy)ethyl]thioureido}-phenyl)-amide, furan-2-carboxylic acid-(4-[3-(2-fluoro-5-trifluoromethylbenzyl)thioureido]-phenyl}-amide, [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(3-bromo-4-methoxyphenyl)ethyl]thioureido}phenyl)amide, [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[2-(2-chlorophenyl)ethyl]thioureido}-phenyl)amide, oxazole-4-carboxylic acid (4-{3-(4-chloro-3-trifluoromethylphenyl)thioureido]-phenyl}-amide, furan-2-carboxylic acid (4-{3-[2-(3,4-dichlorophenyl)ethyl]thioureido}-phenyl)amide, [1,2,3]thiazol-4-carboxylic acid {4-[3-(2-chlorobenzyl)thioureido]phenyl}-amide, -262 [1,2,3]thiadiazole-4-carboxylic acid-{4-[3-(4-bromophenyl)thioureido]phenyl}-amide, [1,2,3]thiadiazole-4-carboxylic acid {4-[3-(4-fluorobenzyl)thioureido]phenyl}-amide, furan-2-carboxylic acid {4-[3-(4-bromo-3-chlorophenyl)thioureido]phenyl}-amide, [1,2,3]thiadiazole-4-carboxylic acid-(4-{3-[(1S)-1-(4-bromienyl)ethyl]thioureido}phenyl)-amide, [1,2,3]thiadiazo I-4-carboxylic acid (4-{3-[(1R)-1-(4-bromienyl)-ethyl]-thioureido}-phenyl)-amide, [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[1-(3,5-bis-trifluoromethylphenyl)ethyl]thioureido}phenyl)amide, [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[(1 S)-1 -(4-chlorophenyl)ethyl]thioureido}-phenyl)amide, [1,2,3]thiadiazole-4-carboxylic acid (4-{3-[(1R)-1-(4-chlorophenyl)ethyl]thioureido}phenyl)amide, N-[4-[[[[1-(4-cyanophenyl)ethyl]amino]thioxomethyl]amino]phenyl]-1,2,3-thiadiazole-4-carboxamide, thiazole-4-carboxylic acid-(3-{3-[1-(4-bromophenyl)ethyl]thioureido}-phenyl]amide, [1,2,3]thiadiazole-4-carboxylic acid (4-{3-(1S)-[1-(3,5-bis-triyl-uormethyl-ien)-ethyl]-thioureido}-phen)-amide, N-(4-{[({ 1 -[4-ylfluoro-3-(triylfluoromethyl)-eneyl]-ethyl}-amino)-carbothioyl]-amino}-enyl)-1,2,3-thiadiazole-4-carboxamide, N-(4-{[({1 -[4-chloro-3-thiadiazole-4-carboxamide, N-(4-{[({(1 S)-1-[3,5-thiazole-4-carboxamide, N-(4-{[({1-[3-fluoro-5-trifluoromethyl)phenyl]ethyl}-amino)-carbothioyl]-amino}-phenyl)-1,3-thiazole-4-carboxamide, - 263 N-(4-{[({1-[2-fluoro-4-trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}phenyl)-1,3-thiazole-4-carboxamide, N-(4-{[({1 -[2-fluoro-5-trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}phenyl)-1,3-thiazole-4-carboxamide, N-(4-{[({1 -[2,4-bis(trifluoromethyl)phenyl]ethyl}-amino)carbothioyl]-amino}-phenyl)-1,3-thiazole-4-carboxamide, N-{4-[({[1-(2,4-dimethylphenyl)-ethyl]-amino}-carbothioyl)-amino]-phenyl}-1,3-thiazole-4-carboxamide, N-{4-[({[ 1 -(2,4-dichlorophenyl)-ethyl]-amino}carboyl)amino]-phenyl}-1,3-thiazole-4-carboxamide, N-{4-[({[1-(3-methylphenyl)ethyl]amino}-carbothioyl)amino]-phenyl}-1,3-thiazole-4-carboxamide, N-(4-{[({ 1 -[4-fluoro-3-(trifluoromethyl)-phenyl]-ethyl}-amino)-carbothioyl]-amino}-phenyl)-1,3-thiazole-4-carboxamide, N-{4-[({[ 1 -(2-Chloro r-4-fluoropheniol)-ethi]-amino}carbothioi)-amino]-phenyl}-1,3-thiazole-4-carboxamide, N-{4-[({[1-(3,4-difluorophenyl)ethyl]amino}-carbothioyl)amino]-phenyl}-1,3-thiazole-4-carboxamide, N-{4-[({[1-(4-bromo-2-fluorophenyl)-ethyl]-amino}-carbotyyl)-amino]-phenyl}-1,3-thiazole-4-carboxamide, N-{4-[({[ 1-(3-fluorophenyl)-ethyl]-amino}-carbothioyl)-amino]-phenyl}-1,3-thiazole-4-carboxamide, N-{4-[({[1-(2-bromophenyl)ethyl]amino}-carbothioyl)amino]phenyl}-1,3-thiazole-4-carboxamide, N-{4-[({[1-(3-bromophenyl)ethyl]amino}-carbothioyl)amino]phenyl}-1,3-thiazole-4-carboxamide, N-(4-{[({1-[2-(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}phenyl)-1,3-thiazole-4-carboxamide, - 264 N-{4-[({[1-(2,4-difluorophenyl)ethyl]amino}-carbothioyl)amino]-phenyl}-1,3-thiazole-4-carboxamide, N-(4-{[({(1 R)-[3,5-bis(trifluoromethyl)phenyl]ethyl}amino)carbonyl]amino}phenyl)-1,3-thiazole-4-carboxamide, N-{4-[({[1-(3,4-Dichlorophenyl)ethyl]-amino}-carbothioyl)-amino]-phenyl}-1,3-thiazole-4-carboxyliide, N-(4-{[({(1-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}phenyl)-1, 3-thiazole-4-carboxamide, N-(4-{[({( 1 -[4-chloro-3-(trifluoromethyl)-phenyl]-ethyl}-amino)-carbothioyl]-amino}-phenyl)-1,3-thiazole-4-carboxamide, N-{4-[({[ 1 -(4-Chloro-2-fluorophenyl)-ethyl]-amino}carbothiol)-amino]-phenyl}-1,3-thiazole-4-carboxamide, N-(4-{[({(1-[4-fluoro-2-(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}phenyl)-1,3-thiazole-4-carboxamide, N-{4-[({[ 1 -(4-Chloro-3-phenyl)ethyl]-amino}carbothiol)-amino]-phenyl}-1,3-thiazole-4-carboxamide, N-{4-[({[1-(2-bromo-4-fluorophenyl)-ethyl]-amino}-carbothioyl)-amino]-phenyl}-1,3-thiazole-4-carboxamide, N-{4-[({[1-(3,4-dibromophenyl)-ethyl]-amino}-carbothioyl)-amino]-phenyl}-1,3-thiazole-4-carboxamide, N-{4-[({[1-(3-chloro-4-fluorophenyl)-ethyl]-amino}-carbothioyl)-amino]-phenyl}-1,3-thiazole-4-carboxamide, N-(4-{[({1-[3,5-bis(trifluoromethyl)phenyl]propyl}amino)carbothioyl]amino}phenyl)-1,2,3-thiadiazole-4-carboxamide, N-(4-{[({1-[3,5-bis(trifluoromethyl)phenyl]butyl}-amino)carbothioyl]amino}-phenyl)-1,2,3-thiadiazole-4-carboxamide, -265 N-(4-{[({ 1 -[3,5-bis(trifluoromethyl)-phenyl]-pentyl}amino)-carbothioyl]-amino}-phenyl)-1,2,3-thiadiazole-4-carboxamide, N-{4-[({[[3,5-bis(trifluoromethyl)phenyl]-(phenyl)methyl]amino}-carbothioyl)amino]phenyl}-1,2,3-thiadiazole-4-carboxamide, N-(4-{[ ({1-[3,5-bis(trifluoromethyl)-phenyl]-1-methyl}-amino)-carbothioyl]-amino}-phenyl)-1,2,3-thiadiazole-4-carboxamide, N-{4-[({[3,5-bis(trifluoromethyl)-benzyl]-amino}-carbothioyl)-amino]-phenyl}-1H-imidazole-4-carboxamide, N-{4-[({[1-(4-fluorophenyl)-ethyl]-amino}-carbothioyl)-amino]-phenyl}-1 H -imidazole-4-carboxamide, N-{4-[({[3,5-bis(trifluoromethyl)benzyl]amino}-carbothioyl)amino]-phenyl}-1-methyl-1H-imidazole-4-carboxamide, N-(4-{[({ 1 -[3,5-bis(trifluoromethyl)-phenyl]-propyl}-amino)-carbothioyl]-amino}-phenyl)-1,3-thiazole-4-carboxamide and their pharmaceutically acceptable salts. 15. [1,2,3]-Thiadiazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoromethylphenyl)thioureido]phenyl}-amide and its pharmaceutically acceptable salts. 16. [1,2,3]-Thiadiazole-4-carboxylic acid {4-[3-(4-chloro-3-trifluoromethylphenyl)thioureido]phenyl}-amide and its pharmaceutically acceptable salts. - 266 - 17. Thiazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide and its pharmaceutically acceptable salts. 18. Pharmaceutical compositions comprising a compound of general formula (I), wherein Ri - R ₅ independently represent a hydrogen atom, a C 1-6 alkyl, a C 2-6 alkenyl, a C 2-6 alkynyl, a C 1-6 perhaloalkyl, a C 3-10 cycloalkyl, a C 3-10 heterocycloalkyl, aryl, heteroaryl group, halogen atom, cyano, nitro group, -CO ₂ R 6> -COR ₆ , -OR ₈ , -SRe, -SOR ₈ , -SO ₂ R ₆ , -CONR ₇ R _8i -NR ₆ N(R ₇ R ₈ ), -N(R ₇ R ₈ ) or a group of the general formula WY-(CH ₂ ) _n -Z, with the proviso that at least one of the R t - R ₅ groups is not a hydrogen atom; or R ₂ and R ₃ or R ₃ and R ₄ together form a 3-7 membered heterocycloalkyl group or a 3-7 membered heteroaryl group; R ₆ and R ₇ are independently hydrogen, C 1-6 alkyl, C 1-6 perhaloalkyl, or aryl; R ₈ is hydrogen, C 1-6 alkyl, C 1-6 perhaloalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, aryl, heteroaryl, or R ₇ and R ₈ together may form a 3-7 membered heterocycloalkyl group; - 267 W represents an oxygen atom, a group of the general formula -NR _S , or is absent; Y is -(CO)- or -(CO ₂ )-, or is absent; Z is a C1-4 alkyl, cyano, -CO2R6, _-cor6 , _-conr7r8 , _-ocor6 , _-NR6COR7 , _-OCONRe , _-OR6 , _-SRe , _{-SOR6 , -SO2R6} , _{SR6N (R7R8 ) ,} -N _{( R7R8 )} or phenyl; G is a monocyclic heteroaryl group; X is a bond, -NH, C1-6 alkyl, C1-6 alkenyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino or (CH)J; J is C1-6 alkyl, C3-7 cycloalkyl, phenyl or benzyl; and n is 1-6. or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent. 19. A method for inhibiting herpes virus replication, comprising treating a herpes virus with a compound of formula (I), wherein r ₁ . R ₅ independently represents a hydrogen atom, a C 1-6 alkyl, a C 2-6 alkenyl, a C 2-6 alkynyl, a C 1-6 perhaloalkyl, a C 3-10 cycloalkyl, a C 3-10 heterocycloalkyl, aryl, heteroaryl group, halogen atom, cyano, nitro group, -CO ₂ R ₆ , -COR ₆ , -OR ₆ , -SR ₆ , -SOR ₆ , -268 - ' “ -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 group, with the proviso that at least one of the R 1 - R ₅ groups is not a hydrogen atom; or R ₂ and R ₃ or R ₃ and R ₄ together form a 3-7 membered heterocycloalkyl group or a 3-7 membered heteroaryl group; R ₆ and R ₇ are independently hydrogen, C 1-6 alkyl, C 1-6 perhaloalkyl, or aryl; R ₈ is hydrogen, C 1-6 alkyl, C 1-6 perhaloalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, aryl, heteroaryl, or R ₇ and R ₈ together may form a 3-7 membered heterocycloalkyl group; W is oxygen, -NR ₆ , or absent; Y is -(CO)- or -(CO ₂ )-, or is absent; Z is a C1-4 alkyl, cyano, _-CO2R6 , _{-cor6 )} , _-conr7r8 , _-ocor6 , _-NR6COR7 , _-OCONR6 , _-OR6 , _-SR6i , _-SOR6 , _-SO2R6 , _{SR6N ( R7R8 )} , _-N ( _{R7R8 ) ,} or a phenyl group; G is a monocyclic heteroaryl group; X is a bond, -NH, C1-6 alkyl, C1-6 alkenyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino or (CH)J; - 269 ···· ·.** Λ -* J is C1-6 alkyl, C3-7 cycloalkyl, phenyl or benzyl; and n is 1-6. or a pharmaceutically acceptable salt thereof. 20. The method of claim 19, wherein the herpes virus is human cytomegalovirus. 21. The method of claim 19, wherein the herpes virus is varicella zoster virus. 22. The process of claim 21, wherein the compound is a substantially pure (S) optical isomer. 23. The method of claim 19, wherein the herpes virus is herpes simplex virus. 24. A compound of general formula (I), wherein R·1 - R ₅ independently represent a hydrogen atom, a C 1-6 alkyl, a C 2-6 alkenyl, a C 2-6 alkynyl, a C 1-6 perhaloalkyl, a C 3-10 cycloalkyl, a C 3-10 heterocycloalkyl, aryl, heteroaryl group, halogen atom, cyano, nitro group, -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 a group of the general formula WY-(CH ₂ ) nZ, with the proviso that that at least one of the groups R-ι - R ₅ is not a hydrogen atom; or R ₂ and R ₃ or R ₃ and R ₄ together form a 3-7 membered heterocycloalkyl group or a 3-7 membered heteroaryl group; R ₆ and R ₇ are independently hydrogen, C 1-6 alkyl, C 1-6 perhaloalkyl, or aryl; R ₈ is hydrogen, C 1-6 alkyl, C 1-6 perhaloalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, aryl, heteroaryl, or R ₇ and R ₈ together may form a 3-7 membered heterocycloalkyl group; W is oxygen, -NR ₆ , or absent; Y is -(CO)- or -(CO ₂ )-, or is absent; _Z is a C1-4 alkyl, _{cyano, -CO2R6, -COR6 ,} -CONR7R8 _{, -OCOR6 , -NR6COR7} , -OCONRs, _-OR6 , _-SR6i , _{-SOR6 , -SO2R6} , _SR6N ( _{R7R8 )} , -N _{( R7R8 )} or a phenyl group; G is a monocyclic heteroaryl group; X is a bond, -NH, C1-6 alkyl, C1-6 alkenyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino or (CH)J; J is C1-6 alkyl, C3-7 cycloalkyl, phenyl or benzyl; and n is 1-6. or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of herpes virus infection. 25. The use of claim 24, wherein the herpes virus is human cytomegalovirus. 26. The use of claim 24, wherein the herpes virus is varicella zoster virus. 27. The use of claim 26, wherein the compound is a substantially pure (S) isomer. 28. The use of claim 24, wherein the herpes virus is herpes simplex virus.