CZ20011956A3 - Thiourea compounds containing heterocyclic carboxamide and phenylene diamine group functioning as inhibitors of herpes virus - Google Patents

Abstract

Compounds having formula (I) wherein R1-R5 are independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10 carbon members, aryl, heteroaryl, halogen, CN, NO2, CO2R6, COR6, OR6, SR6, SOR6, SO2R6, CONR7R8, NR6N(R7R8), N(R7R8) or W-Y-(CH2)n-Z provided that at least one of R1-R5 is not hydrogen; or R2 and R3 or R3 and R4, taken together form a 3 to 7 membered heterocycloalkyl or 3 to 7 membered heteroaryl; R6 and R7 are independently hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, or aryl; R8 is hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10 members, aryl or heteroaryl, or R7 and R8, taken together may form a 3 to 7 membered heterocycloalkyl; W is O, NR6, or is absent; Y is (CO)- or (CO2)-, or is absent; Z is alkyl of 1 to 4 carbon atoms, CN, CO2R6, COR6, CONR7R8, OCOR6, NR6COR7, OCONR6, OR6, SR6, SOR6, SO2R6, SR6N(R7R8), N(R7R8) or phenyl; G is monocyclic heteroaryl; X is a bond, NH, alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, or thioalkyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms, or (CH)J; J is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl or benzyl; and n is an integer from 1 to 6, useful in the treatment of diseases associated with herpes viruses including human cytomegalovirus, herpes simplex viruses, Epstein-Barr virus, varicella-zoster virus, human herpesviruses -6 and -7, and Kaposi herpesvirus.

Description

Thiourea compounds containing a heterocyclic carboxamide and a phenylenediamine group as inhibitors of herpes virus

BACKGROUND OF THE INVENTION

Eight viruses have been identified that are members of the Herpesviridae family (reviewed in Roizman, B. 1996. Herpesviridae, pp. 2221-2230. In BN Fields, DM Knipe, and M. M. Howley (Ed.), Fields Virology, Lippincott-Raven Publishers, Philadelphia, PA). Each member of this family is characterized by a enveloped virus comprising a proteinaceous coat and a nucleocapsid, the latter of which comprises the viral relatively large double-stranded DNA genome (for example, approximately 80 to 250 kilobases). Members of the human alphaherpesvirus subfamily are neurotrophic and include herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) and varicella-zoster virus (VZV). Human betaherpesviruses are cytomegalovirus (HCMV), human herpesvirus 6 (HHV-6) and human herpesvirus 7 (HHV-7). Gammaherpesviruses are lymphotropic and include Epstein-Barr virus (EBV) and Kaposi's herpesvirus (HHV-8). Each of these viruses is causally related to human disease, including herpes labialis and herpes genitalis (HSV-1 and HSV-2 [Whitley, RJ 1996. Herpes Simplex Viruses, pp. 2297-2342. In N. Fields, DM Knipe and M. M. Howley (ed.), Fields Virology, 3rd ed., LippincottRaven Publishers, Philadelphia, PA]; chickenpox and shingles (VZV [Arvin, A. 1996. Varicella-Zoster Virus, pp. 25472585. In N. Fields, DM Knipe and M. Howley (Ed.), Fields Virology, 3rd Ed. Lippincott-Raven Publishers, Philadelphia, PA]; infectious mononucleosis (EBV [Rickinson, A. B. and Kieff, E. 1966. Epstein-Barr Virus, pp. 2397-2446. In N. N. Fields, D. M. Knipe, and L. M. Howley (Ed.), Fields Virology.

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

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

1996. Cytomegalovirus, pp. 2493-2523. B. N. Fields, D. M. Knipe, and P. M. Howley (Ed.) Fields Virology, 3rd Ed. Lippincott-Raven Publishers, Philadelphia, PA]; exanthem subitum (HHV-6 [(Pellet, PE and Black, JB 1996). Human Herpesvirus 6, pp. 2587-2608. In BN Fields, DM Knipe and PM Howley (ed.), Fields Virology. 3rd ed. Lippincott- Raven Publishers, Philadelphia, PA] and HHV-7 [Frenkel, N. and Roffman, E. 1996. Human Herpesvirus 7, pp. 2609-2622. In BN Fields, DM Knipe and PM Howley (Ed.), Fields Virology, Lippincott-Raven Publishers, Philadelphia, PA] and Kaposi's Sarcom (HHV-8 [Neipel, F., Albrecht, JC, and Fleckeinstein, B.

1997. Cell-homologous genes in Kaposi's sarcoma-associated rhadinovirus human herpesvirus 8: determinants of its pathogenicity? J. Virol. 71: 4187-92, 1997]. HCMV is evaluated in more detail below. After a primary infection, herpesvirus creates latency in the infected individual and remains there for the remainder of life. Periodic reactivation of latent virus is clinically relevant. In the case of HSV, reactivated virus can be transmitted to infants during labor and cause skin or eye infection, central nervous system infection or diffuse infection (for example, multiple organs or systems). Shingles is a clinical manifestation of VZV reactivation. Treatment of HSV and VZV is generally performed with antiviral drugs such as acyclovir (Glaxo Welcome), ganciclovir (Roche) and foscarnet (Asta), which target viral encoded DNA polymerase.

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

HCMV is associated with interrupted or incomplete immunity. There are 3 main categories of people with HCMV (reviewed by Britt and Alford, 1996). (1) In patients at risk of AIDS:

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

Some antiviral drugs are commonly marketed (Bron, D., R. Snoeck, and L. Lagneaux. 1996. New insights into the pathogenesis and treatment of cytomegalovirus. Exp. Opin. Invest. Drugs 5: 337-344; Crumpacker, C. 1996. Ganciclovir, New Eng J. Med 335: 721-729, Sachs, S. and F. Alrabiah 1996. Novel herpes treatments: and Review, Exp Opin Invest Drugs 5: 169183). These include: ganciclovir (Roche), a nucleoside analog with haematopoietic cell toxicity; foscarnet (Astra), a pyrophosphate analogue with nephrotoxicity; and cidofovir, Gilead), a nucleoside phosphonate with acute nephrotoxicity. All of these drugs target virally encoded DNA polymerase and are typically administered intravenously due to their low bioavailability and, as mentioned above, are a source of considerable toxicity. Ganciclovir resistant mutants are also often resistant to cidofovir. Therefore, there is a need for a safer (ie, less toxic) orally bioavailable antiviral drug that targets new viruses.

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

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

• · ·

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

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

SUMMARY OF THE INVENTION

The present invention provides compounds of the general formula

where

R 1 -R ₅ are independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms 10 carbon atoms, heterocycloalkyl of 3 to 10 carbon atoms, aryl, heteroaryl, halogen, -CN, -NO ₂ , -co ₂ r ₆ , -or ₆ , -or ₆ , -sr ₆ , -sor ₆ , -so ₂ r ₆ , -CONR ₇ R ₈ , -NR ₆ N (R ₇ R ₈ ), N (R ₇ R ₈ ), or WY- (CH ₂ ) _n -Z, provided that at least one of R 1 -R ₅ is not hydrogen; or R ₂ and R ₃ or R ₃ and R ₄ together form a 3 to 7 membered heterocycloalkyl or a 3 to 7 membered heteroaryl;

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

• ♦ ·

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

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

W is O, NR ₆ or absent;

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

Z is alkyl of 1-4 carbon atoms, -CN, -CO ₂ R _6, -COR, -CONR ₇ R _{8, -OCOR,} -NR ₆ COR _7, -OCONRg, -OR _6, -SR, -SOR ₆ , -SO ₂ R 6 / SR _with N (R ₇ R ₈ ), -N (R ₇ R ₈ ) or phenyl;

G is a monocyclic heteroaryl;

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

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

In a preferred embodiment of the present invention R 1 -R 5 are independently hydrogen, alkyl of 1 to 6 carbon atoms, halogen, perhaloalkyl of 1 to 6 carbon atoms, OR ₆ or N (R ₇ R ₈ ). Preferably 1 to 3 of R 1 -R 5 are not hydrogen. Most preferably, 2 of R 1 -R 5 is not hydrogen. In preferred compounds of the present invention, R 3 and R 5 or R ₄ and R 5 are preferably independently halogen or CF ₃ .

In some embodiments of the present invention G is a monocyclic heteroaryl, preferably thiazolyl, thiadiazolyl, oxazolyl or furyl. G is preferably not substituted.

In some embodiments of the present invention, X is a bond, CH (J) or C 1 -C 4 alkyl. Preferably, when X is C 1 -C 4 alkyl, said alkyl is straight chain. If X is CH (J), then J is preferably methyl.

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

[1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (3,5-bis-trifluoromethyl-benzyl) -thioureido] -phenyl] -amide, {4- [3- (4-Piperidin-1-yl-3-trifluoromethyl-benzyl) -thioureido] -phenyl [1,2,3] Thiadiazole-4-carboxylic acid amide [1,2,3] thiadiazole-4-carboxylic acid {4- [3- (4-Dimethylamino-3-trifluoromethyl-benzyl) -thioureidophenyl) -amide, {4 [1,2,3] thiadiazole-4-carboxylic acid - [3- (3-Dimethylamino-5-trifluoromethyl-benzyl) -thioureido] -phenyl] -amide, {4- [3- (4-Fluoro-3-trifluoromethyl-benzyl) -thioureido] -phenyl] -amide [1,2,3] Thiazole-4-carboxylic acid {4- [3- (4-tert-butylbenzyl) thioureido] phenyl} amide thiazole-4-carboxylic acid (4- {3- [2- (3-Fluoro-5-trifluoromethylphenyl) ethyl] thioureido) phenyl} amide Thiazole-4-carboxylic acid [1,2,3] thiadiazole-4-carboxylic acid, (4- {3- [2- (4-Bromophenyl) ethyl] thioureidophenyl) amide, {4- [3- (3,4-Dichlorobenzyl) thioureido] [1,2,3] Thiadiazole-4-carboxylic acid phenyl] amide, {4- [3- (3,5-Dichlorobenzyl) thioureido] phenyl] amide [1,2] [1,2,3] thiadiazole-4-carboxylic acid, {4- [3- (3,4-Dichlorobenzyl) thioureido] phenyl] amide, (4- {3- [2- (3,4- [1,2.3] Thiadiazole-4-carboxylic acid, dichlorophenyl) ethyl] thioureidophenyl) amide [1,2.3] thiadiazole-4-carboxylic acid, (4- {3- [2- (4-Trifluoromethylphenyl) ethyl] thioureidophenyl) amide, [1,2,3] Thiadiazole-4-carboxylic acid (4- (3- [2- (3-chlorophenyl) ethyl] thioureido} phenyl) amide, (4- [3- (4-tert-butylbenzyl)] thioureido ] Thiazole-4-carboxylic acid {4- (3- (3,5-dichlorophenyl) -thioureido] -phenyl} -amide) -phenyl} -amide [1,2.3] thiazole-4-carboxylic acid {4- (3- [2- [2- [1,2,3] Thiadiazole-4-carboxylic acid-fluoro-5-trifluoromethylphenylsulfanyl) ethyl] thioureido} phenyl) amide, (4- (3- [2- (2,4-Bis-trifluoromethylphenyl) ethyl) thioureido} phenyl) [1,2,3] thiadiazole-4-carboxylic acid amide [1,2,3] thiadiazole-4-carboxylic acid (4- {3- [2- (4-Fluoro-3-trifluoromethyl-phenyl) -ethyl] -thioureido} -phenyl) -amide (4- [3- (3-Fluoro-5-trifluoromethylbenzyl)] thioureido] phenyl] amide [1,2,3] thiadiazole-4-carboxylic acid, (4- (3- [2- (3,5- [1,2,3] Thiadiazole-4-carboxylic acid bis-trifluoromethylphenyl) ethyl] thioureido} phenyl) amide [1,2,3] thiadiazole-4-carboxylic acid [4- [3- (4-iodo-3-trifluoromethylphenyl) thioureido] phenyl} amide [1,2 [1,2,3] thiadiazole-4-carboxylic acid, (4- [3- (2-Fluoro-5-trifluoromethyl-benzyl) -thiomethyl-benzyl) -thioureido] -phenyl} -amide, (4- {3) thiadiazole-4-carboxylic acid; [1,2.3] Thiadiazole-4-carboxylic acid [2- (3-bromophenylsulfanyl) ethyl] thioureido] phenyl} amide, (4- {3- [2- (2-Fluorophenyl) ethyl] thioureido} phenyl) amide [ 1,2,3] Thiadiazole-4-carboxylic acid, [1,2,3] thiadiazole-4-carboxylic acid, (4 - (3- [2- (2,4-Dichlorophenyl) ethyl] thioureido) phenyl) amide, (4 [1,2,3] Thiadiazole-4-carboxylic acid - (3- [2- (3-Trifluoromethyl-phenyl) -ethyl] -thioureido} -phenyl) -amide, (4- {3- [2- (2-Fluoro-5-trifluoromethyl-phenoxy)] [1,2,4,3] thiadiazole-4-carboxylic acid ethyl] thioureido} phenyl) amide Thiazole-4-carboxylic acid {4- [3- (2-Fluoro-5-trifluoromethyl-benzyl) -thiourea] -phenyl} -amide, Furan-2 [1,2,3] thiadiazole-4-carboxylic acid (4- {3- [2- (3-iodophenyl) ethyl] thioureidophenyl) amide, furan-2 {4- [3- (3,5-Bis-trifluoromethylbenzyl) thioureidophenyl} amide [1,2,3] thiadiazole-4-carboxylic acid (4- {3- [3- (2-methylbutyl) -5-trifluoromethylphenyl] thioureido} phenyl) amide, {4- [3- (3-Isobutyl-5) -carboxylic acid, [1,2,3] Thiadiazole-4-carboxylic acid-trifluoromethyl-phenyl) -ethyl] -thioureido} -phenyl) -amide, [1,2,3] -thiadiazole-4 (4- {3- [2- (3-Dimethylamino-5-trifluoromethyl-phenyl) -ethyl} -thioureo-iodophenyl) -amide [1,2,3] thiadiazole-4-carboxylic acid (4- {3- [2- (5-Bromo-2-methoxy-phenyl) -ethyl] -thioureido} -phenyl) -amide, (4- {3- [2- [1,2,3] Thiadiazole-4-carboxylic acid (4-chlorophenyl) ethyl] thioureido} phenyl) amide, [4- {3- [2- (3,5-Dichlorophenoxy) ethyl] thioureido} phenyl] amide [1 2,3,3] thiadiazole-4-carboxylic acid, {4- [3- (3,4-Dichlorophenyl) thioureidophenyl] thiazole-4-carboxylic acid {4- [3- (4-Chloro-3-trifluoromethylphenyl) thioureido] [1,2,3] thiadiazole-4-carboxylic acid (4- {3- [2- (3,4-Dichloro-phenylsulfanyl) -ethyl] -thioureido} -phenyl) -amide; [1,2,3] Thiadiazole-4-carboxylic acid 3- [2- (2-fluoro-3-trifluoromethyl-phenyl) -ethyl] -thioureido} -phenyl) -amide, (4- {3- [2- (2-Fluoro-5-trifluoromethyl-phenyl)) [1,2,3] thiadiazole-4-carboxylic acid ethyl] thioureido} phenyl) amide [1,2,3] thiadiazole-4 (4- {3- [2- (3-Bromophenyl) ethyl] thioureido} phenyl) amide [1,2,3] thiadiazole-4-carboxylic acid [4- [3- (3-Chloro-4-trifluoromethyl-phenyl) -thioureido] -phenyl} -amide, {4- [3- (3-Chloro-carboxylic acid)] [1,2,3] thiadiazole-4-carboxylic acid -4-iodophenyl) thioureido] phenyl} amide furan-2-carboxylic acid [4- (3-Benzo [1,3] dioxol-5-ylmethylthioureido) phenyl] amide acid, (4- [3- [1- (4-Bromophenyl) ethyl] thioureido} phenyl) am id [1,2,3] thiadiazole-4-carboxylic acid [1,2,3] thiadiazole-4-carboxylic acid [4- [3- (3,3-diphenylpropyl) thioureido] phenyl} amide, {4- [1,2,3] Thiadiazole-4-carboxylic acid [3- (3-chloro-4-fluorobenzyl) thioureido] phenyl} amide, (4- [3- [2- (3,4-Dichlorophenoxy) ethyl] thioureido) [1,2,3] thiadiazole-4-carboxylic acid, phenyl) amide, {4- [3- (3-Trifluoromethylbenzyl) thioureido] phenyl} amide [1,2,3] thiadiazole-4-carboxylic acid, {4 [1,2,3] Thiadiazole-4-carboxylic acid - [3- (3-chloro-benzyl) -thioureido] -phenyl} -amide, {4- [3- (4-Bromo-3-trifluoromethyl-phenyl) -thioureido] -phenyl} -amide [1 [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [2- (4-fluoro-phenyl) -ethyl] -thioureido} -phenyl) -amide, 2,3-thiadiazole-4-carboxylic acid, {4- [3- (3-Pyrrolidin-1-yl-5-trifluoromethyl-phenyl) -thio-ureido] -phenyl] -amide [1,2,3] thiadiazole-4-carboxylic acid, (4- {3- [3- (Butylmethylamino) -5] [1,2,3] thiadiazole-4-carboxylic acid-trifluoromethyl-phenyl] -thioureido} -phenyl) -amide, {4- [3- (3,5-Dimethyl-benzyl) -thioureido] -phenyl} -amide [1,2,3] t hiaziazole-4-carboxylic acid, thiazole-4-carboxylic acid {4- [3- (3,5-Bistrifluoromethylphenyl) thioureido] phenyl} amide, {4- [3- (3,4-Dichlorophenyl) thioureido] phenyl] amide [1 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (3-Bromo-5-trifluoromethyl-phenyl) -thioureido] -phenyl} -amide, 2,3] thiadiazole-4-carboxylic acid; 1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [2- (3-chloro-phenoxy) -ethyl] -thioureido} -phenyl) -amide, (4- {3 [1,2,3] Thiadiazole-4-carboxylic acid [2- (4-ethyl-phenyl) -ethyl] -thioureido} -phenyl) -amide, (4- {3- [2- (3-Bromo-phenoxy) -ethyl] -thioureido] -phenyl) [1,2,3] Thiadiazole-4-carboxylic acid amide, {4- [3- (4-Chlorobenzyl) thioureido] phenyl} amide [1,2,3] thiadiazole-4-carboxylic acid, {4- [3 [1,2,3] Thiadiazole-4-carboxylic acid- (5-chloro-2-methoxy-4-methyl-phenyl) -thioureido] -phenyl} -amide, (4- {3- [2- (3-Fluorophenyl) -ethyl) [1,2,3] thiadiazole-4-carboxylic acid [thio-thio} phenyl) amide, [1,2,3] thiadiazole- (4- {3- [1- (4-Fluoro-phenyl) -ethyl] -thioureido} -phenyl) -amide] 4-k [1,2,3] thiadiazole-4-carboxylic acid [4- [3- (3,5-Difluorobenzyl) thioureido] phenyl} amide, {4- [3- (3,5-Dichlorobenzyl) thioureido] phenyl} furan-2-carboxylic acid amide, [4- [3- (2-p-Tolylethyl) thioureido] phenyl] amide [1,2,3] thiadiazole-4-carboxylic acid, {4- [3- (4-Phenylbutyl) (1,2,3) Thiadiazole-4-carboxylic acid, thioureido] phenyl] amide [1,2,3] thiadiazole-4-carboxylic acid, {4- [3- (2-Phenylsulfanylethyl) thioureido] phenyl} amide, {4 [1,2,3] Thiadiazole-4-carboxylic acid - [3- (3-iodo-benzyl) -thioureido] -phenyl} -amide, furan (4- {3- [2- (3-Bromo-phenylsulfanyl) -ethyl] -thioureido} -phenyl) -amide Oxazole-4-carboxylic acid {4- [3- (3,5-Dichlorophenyl) thioureido] phenyl] amide, (4- {3- [2- (3,4-Difluorophenyl) ethyl] thioureido} phenyl) -2-carboxylic acid [1,2,3] Thiadiazole-4-carboxylic acid amide, [1,2,3] thiadiazole-4- (4- {4- [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-Dichloro-phenyl) -thioureido] -phenyl] -amide, [4- [3- (3-Amino-5-chloro-phenyl) -thioureido] -acid [1,2,3] Thiadiazole-4-carboxylic acid [4- [3- (3-bromophenyl) thioureido] phenyl} amide [1,2,3] thiadiazole-4-carboxylic acid phenyl] amide, (4- { [1,2,3] Thiadiazole-4-carboxylic acid 3- [3- (isobutylmethylamino) -5-trifluoromethylphenyl] thioureido] phenyl) amide, [4- [3- (3-Phenylpropyl) thioureido] phenyl] amide [1,2] [1,2,3] thiadiazole-4-carboxylic acid, [4- [3- (3-chloro-4-fluorophenyl) thioureido] phenyl] amide, [4- [3-], [1,2,3] Thiadiazole-4-carboxylic acid (3,4,5-trichlorophenyl) thioureido] phenyl} amide furan-2- [4- [3- (3,4-Dichlorobenzyl) thioureido] phenyl] amide carboxylic acids, {4- [3- (3-Morpholin-4-yl-5-trifluoromethyl-phenyl) -thioureido] -phenyl] -amide [1,2,3] thiadiazole-4-carboxylic acid, [4- [3- (4- Fluoro-3-trifluoromethyl-phenyl) thioureido] phenyl] amide [1,2,3] thiadiazole-4-carboxylic acid, (4- {3- [2- (3-Fluorophenoxy) ethyl] thioureido} [1,2,3] thiadiazole-4-carboxylic acid phenyl] amide, [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] thiadiazole-4-carboxylic acids,

[1,2,3] Thiadiazole-4-carboxylic acid (4- [3- [4- (4-methyl-piperazin-1-yl) -3-trifluoromethyl-benzyl] -thioureido} -phenyl) -amide, [4- [3- (3) [1,2,3] thiadiazole-4-carboxylic acid, 4-difluorobenzyl) thioureido] phenyl] amide [1,2,3] thiadiazole [4- [3- (4-Bromo-3-chlorophenyl) thioureido] phenyl} amide -4-carboxylic acid, [4- [3- (3-Chlorophenyl) thioureido] phenyl] amide [1,2,3] thiadiazole-4-carboxylic acid, [4- [3- (2-phenoxyethyl) thioureido] phenyl} amide [1,2,3] Thiadiazole-4-carboxylic acid [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, [4- [3- (3-Fluoro-5-trifluoromethylbenzyl) thioureido] [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [2- (4-nitrophenyl) -ethyl] -thioureido} -phenyl) -amide, [4- [3- ( [1,2,3] Thiadiazole-4-carboxylic acid 3-piperidin-1-yl-5-trifluoromethyl-phenyl) -thioureido] -phenyl} -amide, [4- [3- (3,4-Dichloro-phenyl) -thioureido] -phenyls oxazole-4-carboxylic acid ljamide, furan-2-carboxylic acid [4- [3- (3,4,5-trichlorophenyl) thioureido] phenyl} amide, {4- [3- (4-Chlorophenyl) thioureido] phenyl} [1,2,3] thiadiazole-4-carboxylic acid 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, (4- {3- [2- (2-Chlorophenoxy) ethyl] thioureido} phenyl) amide [1 2,3,3] thiadiazole-4-carboxylic acid {4- [3- (3,5-Bistrifluoromethylphenyl) thioureido] phenyl] amide [1,2,3] thiadiazole [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (3,5-Dichloro-2-methoxy-4-methyl-phenyl) -thioureido] -phenyl} -amide, (4 - { [1,2,3] Thiadiazole-4-carboxylic acid 3- [3-chloro-4- (1H-pyrazol-3-yl) phenyl] thioureido} phenyl), (4- [3- [3-Chloro- [1,2,3] Thiadiazole-4-carboxylic acid 4- (2-piperidin-1-ylacetylamino) -phenyl] -thioureido} -phenyl) -amide, [4- [3- (3-Trifluoromethyl-phenyl) -thioureido] -phenene [1,2,3] thiadiazole-4-carboxylic acid, {4- [3- (4-Chloro-3-trifluoromethylphenyl) thioureido] phenyl] amide [1,2,3] thiadiazole-4-carboxylic acid, () [1,2,3] Thiadiazole-4-carboxylic acid 4- {3- [3-chloro-4- (cyclohexyl-methyl-amino) -phenyl] -thioureido] -phenyl) -amide furan [4- (3-Benzylthioureido) -phenyl] -amide furan Furan-2-carboxylic acid (4- {3- [2- (3,5-Dichlorophenoxy) ethyl] thioureido] phenyl) amide, (4- [3- (2-Fluoro-5-trifluoromethylbenzyl) -2-carboxylic acid) Thioureido] phenyl} furan-2-carboxylic acid 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-Chloro-phenyl) -ethyl] -thioureido} -phenyl) -amide, [4- [3- (4-Chloro-3- oxazole-4-carboxylic acid trifluoromethylphenyl) thioureido] phenyl} furan-2-carboxylic acid (4- {3- [2- (3,4-dichlorophenyl) ethyl] thioureido] phenyl) amide, [4- [3- [1,2.3] Thiadiazole-4-carboxylic acid (2-chlorobenzyl) thioureido] phenyl} amide, [4- [3- (4-Bromophenyl) thioure] [1,2,3] thiadiazole-4-carboxylic acid {4- [3- (4-Fluorobenzyl) thioureido] phenyl} amide [1,2,3] thiadiazole-4-carboxylic acid, {4- [3] Furan-2-carboxylic acid (4-bromo-3-chlorophenyl) thioureido] phenyl} amide, [4- {3 - [(1S) -1- (4-Bromophenyl) ethyl] thioureido} phenyl] amide [1, [1,2,3] Thiadiazole-4-carboxylic acid (4- {3 - [(IR) -1- (4-bromophenyl) ethyl] thioureido} phenyl) amide, 2,3] thiadiazole-4-carboxylic acid, [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [1- (3,5-Bistrifluoromethyl-phenyl) -ethyl] -thioureido} -phenyl) -amide, (4- {3 - [(1S) -1- [1,2,3] Thiadiazole-4-carboxylic acid (4-chloro-phenyl) -ethyl] -thioureido} -phenyl) -amide, (4- {3 - [(IR) -1- (4-Chloro-phenyl) -ethyl] -thioureido} -phenyl) [1,2,3] thiadiazole-4-carboxylic acid amide,

N- [4 - [[[[1- (4-Cyanophenyl) ethyl] amino] thioxomethyl] amino] phenyl] -1,2,3-thiadiazole-4-carboxamide, (4- {3- [1- (4) Thiazole-4-carboxylic acid -bromophenyl) ethyl] thioureido} phenyl) amide [1,2- (3- (1S) - [1- (3,5-Bis-trifluoromethylphenyl) ethyl] thioureido} phenyl) amide [1,2] 3] thiadiazole-4-carboxylic acids,

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

N- (4 - {[({1- [4-Chloro-3-thiadiazole-4-carboxamide),

N- (4 - {[({(1S) -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) 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} carbothioyl) 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-4-fluorophenyl) ethyl] amino} carbothioyl) 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} 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,

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

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

N- {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} carbothioyl) 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} carbothioyl) 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,

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-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} -1H-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 pharmaceutical salts thereof.

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

Alkyl, as used herein, means a straight or branched chain lower alkyl group containing from 1 to 6 group atoms, including methyl, isobutyl, tert-butyl, pentyl. · · · · · · Uhlíku · Carbon. As examples of alkyl ethyl, propyl, isopropyl, butyl, and hexyl.

Alkenyl as used herein is a branched lower C 2 -C 6 alkyl group containing at least one carbon-carbon double bond. Alkenyl includes vinyl

Alkynyl means a straight or branched lower carbon-carbon bond.

groups of the present or unsubstituted.

is a linear or C 2 -C 6 alkyl group containing at least one triple

The alkyl, alkenyl and alkynyl of the invention may be substituted

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

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

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

Heteroaryl as used herein means an aromatic mono or bicyclic ring of 5 to 10 members having 1 to 3 heteroatoms selected from N, O or S including, but not limited to, thiazolyl, thiadiazolyl, oxazolyl, furyl, indolyl,

A 9 9 benzothiazolyl, benzotriazolyl, benzodioxylolyl, indazolyl and benzofuryl. Preferred heteroaryls include quinolyl, isoquinolyl, naphthalenyl, benzofuranyl, benzothienyl, indolyl, pyridyl, pyrazinyl, thienyl, furyl, pyrrolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, pyrazolyl, triazolyl, thiadiazolyl and imidazolyl. The heteroaryl groups of the present invention may be substituted or unsubstituted.

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

Phenyl as used herein means a 6 membered aromatic ring.

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

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

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

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

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

The compounds of the invention contain a chiral center providing various stereoisomeric forms of the compounds, such as racemic mixtures, as well as the individual optical isomers.

In some preferred embodiments of the present invention, the compounds of the invention are substantially pure optical isomers.

By substantially pure optical isomers is meant a composition containing more than 75% of the desired isomer and may contain no more than 25% of the undesired isomer. In more preferred embodiments, the pure optical isomer contains more than 90% of the desired isomer. The individual isomers may be prepared directly or by asymmetric or stereospecific synthesis or by conventional resolution of optical isomers from racemic mixtures.

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

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

Referring to Methods 31 and 34, the reaction of an appropriately substituted amine 2 wherein R 1 -R 5 and X are as defined above with an appropriately substituted isothiocyanate 3 wherein the substituent G is as described above, either in pure form or in a suitable solvent such as tetrahydrofuran, acetonitrile, ethyl acetate, dichloromethane, or N, N-dimethylformamide, yields the desired thioureas 1. Similarly, by reaction of the appropriately substituted isothiocyanates 4 wherein R 1 -R 5 and X are as defined above with the appropriately substituted anilines 5 wherein substituent G is as described above , in a conventional solvent such as those mentioned above, the desired thioureas 1 are obtained.

• · 0 0

Methods 31 and 34

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

Methods 32, 33

♦ ·· ·

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

Thioureas 1 wherein at least one substituent of R 1 -R 5 is 1-hydroxyethoxy or carboxymethoxy, G is as defined above and X is a bond may be prepared from the corresponding alkyl esters by alkaline hydrolysis with aqueous sodium or potassium hydroxide. »'· • ♦ ··

A in a suitable solvent such as methanol, tetrahydrofuran or mixtures thereof at room temperature according to methods 35 and 36.

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

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

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

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

Method 41

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

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

(a) an iron powder and a strong acid, such as hydrochloric acid (Method 1A), either pure or in an alcoholic solvent, such as methanol or ethanol, at a temperature ranging from room temperature to the solvent reflux temperature, or;

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

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

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

e) when R 1 -R 5 is selected from Cl, Br, I, - (OSO ₂ ) -CF ₃ or - (OSO ₂ ) -ΙΑ 4-methylphenyl), by catalytic reduction, with hydrogen and palladium on carbon (Method 1E) in a suitable solvent such as methanol, ethanol or ethyl acetate under the pressure of one or more atmospheres or;

f) when R 1 -R 5 and R 8 -R _{12 are} selected from Cl, Br, I, - (OSO ₂ ) -CF _3, or

- (0S0 ₂₎ -1- (4 methylphenyl), by catalytic reduction such as with cyclohexene and palladium on carbon (Method 1F) in an appropriate solvent such as methanol or ethanol, at temperatures ranging from room temperature to the reflux temperature of the solvent, or ;

g) aqueous sodium bisulfite in an alcoholic solvent at a temperature ranging from room temperature to the reflux temperature of the solvent (Method 1G).

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

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

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

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

Alternatively, according to Method 11, amines 2, wherein R 1 -R 5 are as defined above and X is as defined above, wherein at least one of the substituents R 1 -R 5 is defined as vinyl, can be prepared by palladium catalyzed coupling of a vinyltrialkyltin reagent such as tributyl vinyl tin. with an appropriately substituted bromo- or iodanilene, for example 3-chloro-4-iodaniline, using a palladium catalyst such as tris (dibenzylideneacetone) bipalladium and ligands such as triphenylarsine in a suitable solvent such as tetrahydrofuran or N-methylpyrrolidinone at temperatures in the range from room temperature to the reflux temperature of the solvent, essentially according to the procedures described by V. Farin and GP Roth in Advances in Metal-Organic Chemistry, Vol. 5, 153, 1996 and references cited therein.

• · · ············

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

Alternatively, according to Method 43, amines 2 wherein R 1 -R 5 are as defined above and X is as defined above and at least one of R ₂ or R ₄ is defined as alkyl may be prepared by palladium catalyzed alkylation of an appropriately substituted 3- or 5-bromo - or iodaniline, for example 3-amino-5-bromobenzotrifluoride, alkenes under conditions which use a palladium catalyst such as [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) chloride-dichloromethane complex and in the presence of 9-borabicyclo [3.3] . Ionane and a suitable base such as aqueous sodium hydroxide in a suitable solvent such as tetrahydrofuran or the like at temperatures ranging from room temperature to the reflux temperature of the solvent.

Acyl and carbamoylamine derivatives used as starting materials in Methods 3A-3C can be prepared by derivatization of the corresponding amines as described in Methods 2A-2G according to various procedures known to those skilled in the art and as described by Greene.

in Protective Groups in Organic Synthesis, Volume 2, Chapter 7, 1991 and references cited therein. Such procedures include:

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

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

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

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

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

f) reacting an appropriately protected aniline, such as arylaminoter-butylcarbamate or the like, wherein at least one of R 1 -R 12 is defined as -WY- (CH ₂ ) _n Z, wherein W, Y and

Z are as defined above, with a carboxylic acid anhydride (Method 2F) in the presence of a suitable base such as pyridine in a suitable solvent such as dichloromethane, dimethylformamide or the like, at temperatures ranging from 0 ° C to room temperature to give the corresponding carboxylic ester ; or;

g) reacting an appropriately substituted aniline in which at least one of R 1 -R 5 is defined as hydroxyl with di-tert-butyl dicarbonate (method 2G) in the presence of one or more molar equivalents of a tertiary amine such as triethylamine or N, N-diisopropylethylamine in a suitable solvent such as acetone, tetrahydrofuran, dimethylformamide, dichloromethane and the like, at temperatures ranging from room temperature to the reflux temperature of the solvent, to give the corresponding arylamino-tert-butyl carbamate.

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

• · · ·

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

(a) reaction of alcohols with appropriately substituted 2- or 4-halo- or sulphonate esters of nitrobenzenes or benzonitriles (Method 4A) either in pure form or in a suitable solvent such as tetrahydrofuran, dioxane, acetonitrile, N, N-dimethylformamide or dimethylsulphoxide in the presence or in the 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 temperatures ranging from room temperature to the reflux temperature of the solvent;

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

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

• · · · · · · · · · · · · ·

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

e) reacting sodium sulphide with an appropriately substituted 2- or 2-carboxylic acid

4-halo- or sulphonate esters of nitrobenzenes or benzonitriles either in pure form or in a suitable solvent such as tetrahydrofuran, dioxane, acetonitrile, N, N-dimethylformamide or dimethylsulfoxide at temperatures ranging from room temperature to the reflux temperature of the solvent, and then addition an alkyl halide directly into the reaction mixture (Method 4E).

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

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

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

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

Alternatively, with reference to Methods 7A-G, nitrobenzene intermediates that ultimately convert to amines 2, R 1 and / or R ₃ is alkoxy, and R ₂ and / or R ₄ is halogen and X is a bond can be prepared by standard halogenation reactions that include the following:

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

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

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

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

e) reaction of 2,4-dimethoxynitrobenzene (Method 7G) with 3,5-dichloro-

1-fluoropyridine triflate in a suitable solvent such as carbon tetrachloride at a temperature ranging from room temperature to the reflux temperature of the solvent.

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

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

Referring to Method 25, nitrobenzene intermediates that are ultimately converted to amines 2, wherein at least one of

R 1 -R 5 is defined as triflate and X is a bond, can be prepared from the corresponding phenol by reaction with trifluoromethanesulfonic anhydride in the presence of tertiary amines such as triethylamine or diisopropylethylamine or the like in the a suitable solvent such as dichloromethane at a temperature of from 0 ° C to room temperature.

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

Referring to Method 12, carbamoylamine derivatives used as starting materials in Methods 3A-3C, which are ultimately converted to amines 2, where R ₄ is defined as

1-hydroxyethyl and R 1 -R 3 and R 5 are as defined above and X is a bond, may be prepared by reacting the corresponding 4-vinylcarbamoylaniline with sodium borohydride in the presence of mercuric acetate in a suitable solvent such as tetrahydrofuran, 1,4-dioxane or the like; room temperature.

Referring to Method 13, carbamoylamine derivatives used as starting materials in Methods 3A-3C, which are ultimately converted to amines 2, where R ₄ is defined as

2-hydroxyethyl and R 1 -R 3 and R ₅ are as defined above and X is a bond, may be prepared by reacting the corresponding 4-vinylcarbamoylaniline with sodium borohydride in the presence of glacial acetic acid in a suitable solvent such as

tetrahydrofuran, 1,4-dioxane or the like; and water at 0 ° C to room temperature.

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

Referring to Method 15, carbamoylamine derivatives used as starting materials in Methods 3A-3C, which are ultimately converted to amines 2, where R ₄ is defined as

3-dimethylaminoprop-1-ynyl and R 1 -R 3 and R 5 are as defined above and X is as defined above may be prepared by reacting the corresponding 4-iodocarbamoylaniline with 1-dimethylamino-2-propyne in a suitable tertiary amine solvent such as triethylamine or diisopropylethylamine in the presence of bis (triphenylphosphine) palladium (II) chloride and cuprous iodide at temperatures ranging from room temperature to the reflux temperature of the solvent.

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

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

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

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

································

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

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

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

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

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

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

··· ·· ·· ·· ··

Unsaturated nitro precursors which are used as starting materials in Method 51 and which are ultimately converted to amines 2, where R 1 -R 5 are as defined above and X is equal to - (CH ₂ ) ₂ - can be prepared by reacting an appropriately substituted benzaldehyde with nitromethane in the presence of ammonium acetate in a suitable solvent, such as acetic acid, at a temperature ranging from room temperature to the reflux temperature of the solvent (method 53). The benzaldehydes used as starting materials in Method 53 can be prepared by reduction of an appropriately substituted benzonitrile with diisobutylaluminum hydride (Method 52). The substituted benzonitriles used as starting materials in method 52 can be prepared from the corresponding aryl bromide by reaction with copper cyanide in a suitable solvent such as N, N-dimethylformamide at a temperature ranging from room temperature to the reflux temperature of the solvent (method 59).

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

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

* · «·

4 · · · *

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

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

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

The amines 2 for which R 1 -R 5 are as defined above and X is equal to -CH (J) -, where J is as defined above, may be:

♦ · ♦ prepared by reduction of an appropriately substituted ketone by the method described above (Methods 45, 47 and 48). These desired ketones, if not commercially available, can be prepared by reacting a suitably substituted benzaldehyde with a suitable organometallic reagent such as phenyllithium, isopropylmagnesium bromide or ethylmagnesium bromide or the like in a suitable solvent such as diethyl ether or tetrahydrofuran at temperatures ranging from -78 ° C to 0 ° C (method 57). The resulting alcohols may be oxidized to the corresponding ketone with a suitable oxidizing agent such as chromium trioxide in aqueous sulfuric acid and acetone or pyridinium chlorochroman or pyridium dichloromethane in a suitable solvent such as dichloromethane or the like at room temperature (method 58).

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

Method 2C, 3A

*; - * “HN

G

O

II NCI H

.CF3CO2H , Γ AND 0 II * h ₂ n — Z i. NaOH \ H —C — G

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

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

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

If the carboxylic acid ester precursors which are then converted to acids 8 are not commercially available, they can be prepared according to methods known in the literature. For example, 5-substituted-1,2,3-thiadiazole-4-carboxylic acid esters can be prepared essentially according to the procedure described by Caron, M. J. Org. Chem. 51, 4075 (1986) and Taber, D. F., Ruckle, R. E. J. Amer. Chem. Soc. 108, 7686 (1986). Thus, according to Method 21, a beta-ketocarboxylic acid ester having a s

4-methylbenzenesulfonylazide or methanesulfonylazide or the like, in the presence of a tertiary amine base such as triethylamine or diisopropylethylamine in a suitable solvent such as acetonitrile yields the corresponding diazo-beta-ketocarboxylic acid ester. Treatment of this compound with 2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphethan-

2,4-disulfide in a suitable solvent such as benzene or toluene or the like at a temperature ranging from room temperature to the reflux temperature of the solvent yields the desired ester

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

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

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

Other appropriately substituted thiazoles can be prepared essentially according to the procedure described by Bredenkamp, Μ. V., Holzafel, C.W., van Zyl, W.J. Synthetic Comm. 20, 2235 (1990). The appropriately substituted oxazoles are prepared essentially according to the procedure described by Henneke, K. H., Schollkopf, U., Neudecker, T. Liebigs Ann. Chem. 1979 (1979). Unsaturated oxazoles can be prepared according to the procedure described by Galeotti, N., Montagne, C., Poncet, J., Jouin, P. Tetrahedron Lett. 33, 2807 (1992) and Shin, C., Okumura, K., Ito, A.

Nakamura, Y. Chemistry Lett. 1305 (1994).

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

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT OF THE INVENTION

Example 1 (Method IA)

4-Methoxy-3-trifluoromethylphenylamine

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

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

2,6-Dichlorobenzene-1,4-diamine

3-Chloro-4-methylsulfanyl-phenylamine

2,6-Dibromobenzene-1,4-diamine

3-Chloro-4-trifluoromethylphenylamine

3-Chloro-4-ethylsulfanyl-phenylamine

4-Methoxy-3-trifluoromethylphenylamine

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

5-Chloro-2-ethoxy-4-methoxyphenylamine 5-Chloro-4-ethoxy-2-methoxyphenylamine

5-Iodo-2,4-dimethoxyphenylamine

3,5-Diodo-2,4-dimethoxyphenylamine

4S ······· *!

! . ········· · · · ···· ·· · ·. . · ·· .....

3,5-Dibromo-2,4-dimethoxyphenylamine

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

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

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

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

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

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

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

-diamin

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

-diamin

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

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

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

2 - [(4-Amino-2-chlorophenyl) - (2-hydroxyethyl) amino] ethanol

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

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

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

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

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

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

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

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

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

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

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

3-Chloro-4- (2-dimethylaminoethoxy) phenylamine

3-Chloro-4- (3-dimethylaminopropoxy) phenylamine

3-Chloro-4- (1-methyl-pyrrolidin-3-yloxy) -phenylamine

3-Chloro-4-cyclohexyloxyphenylamine

Example 2 (Method 1B)

4-Bromo-2,4-dimethoxyphenylamine

A suspension of 4-bromo-2,4-dimethoxynitrobenzene (0.48 g) and iron powder (0.42 g) in acetic acid (10 mL) and ethanol (10 mL) was heated at 120 ° C for about 5 hours. The mixture was then cooled, filtered and concentrated under reduced pressure. Water was added and the mixture was cooled in an ice bath and neutralized with solid potassium carbonate and then extracted with dichloromethane. These organic extracts were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then chromatographed on silica gel (using 20% ethyl acetate in hexanes as eluent) to provide the title compound as an amber oil.

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

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

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

4-Chlorobenzene-1,2-diamine • · · ·

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

(4-Amino-2-chloro-5-methoxy-phenoxy) -acetic acid methyl ester tert -Butyl (4-amino-2-chloro-5-methoxy-phenoxy) -acetic acid tert-butyl ester (2-Amino-4-chloro-5-methoxy-phenoxy) acetic acid

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

N- (4-Amino-2-chlorophenyl) -2- (2-methylpiperidin-1-yl) acetamide

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

3-Chlorobenzene-1,2-diamine

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

Example 4 (ID method)

3,5-Dichloro-4-phenoxyphenylamine

To a slurry of 3,5-dichloro-4-phenoxynitrobenzene (6.1 g) and tin powder (12 g) was added dropwise concentrated hydrochloric acid (60 mL). Ethanol (60 mL) was added and the mixture was heated to reflux for about 1 hour. The mixture was then cooled in an ice bath and basified by addition of solid sodium hydroxide. The resulting suspension was filtered through a pad of diatomaceous earth and extracted three times with ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the desired product as a yellow solid. Recrystallization from ethyl acetate / hexanes gave the product as a pale yellow solid.

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

1- Furan-2-ylethylamine

3-Chloro-4-isopropoxyphenylamine

2-Butoxy-5-chloro-4-methoxyphenylamine

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

2-Benzyloxy-5-chloro-4-methoxyphenylamine

4-Benzyloxy-5-chloro-2-methoxyphenylamine

5-Fluoro-2,4-dimethoxyphenylamine

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

3,5-Dichloro-4-phenoxyphenylamine

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

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

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

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

4-Amino-2-chloro-5-methoxyphenol

2-Amino-4-chloro-5-methoxyphenol

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

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

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

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

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

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

2- (4-Amino-2-chlorophenoxy) ethanol

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

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

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

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

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

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

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

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

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

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

3-Chloro-4-propoxyphenylamine

3-Iodo-4-methoxyphenylamine

3-Chloro-2,4-dimethoxyaniline

3-Bromo-4-methoxyphenylamine

3-Chloro-4-ethoxyphenylamine

Example 5 (IE method)

(4-Aminophenyl) carbamic acid isobutyl ester

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

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

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

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

(4-Aminophenyl) -carbamic acid isobutyl ester

N- (4-Aminophenyl) isobutyramide

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

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

(4-Amino-benzyl) -carbamic acid N- (5-amino-pyridin-2-yl) -2,2,2-trifluoro-acetamide

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

1-tert-Butyl-1H-imidazol-2-ylamine

3- (3-Dimethylaminopropyl) -5-trifluoromethylphenylamine

Example 6 (Method 1F)

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

A mixture of 2-fluoro-N- (2-methyl-4-nitrophenyl) benzamide (4.55 g), cyclohexane (30 mL), ethanol (70 mL), water (30 mL) and 10% palladium on charcoal (3). g) is heated under reflux for 30 minutes. The mixture is filtered through diatomaceous earth and concentrated.

• • • • • • • • • • • • • • _• • • • • • • • • • • • • • • • Under reduced pressure. The resulting oil was dissolved in 50 mL of ethyl acetate and cooled at 4 ° C for 12 hours. Filtration gave the product as a brownish solid.

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

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

2-Methylbenzooxazol-6-ylamine

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

2-Acetylamino-5-aminobenzoic acid

[4- (3-Aminobenzoylamino) phenyl] carbamic acid tert-butyl ester [4- (2-aminobenzoylamino) phenyl] carbamic acid N- (4-aminophenyl) acetamide

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

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

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

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

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

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

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

N- (4-Amino-3-methylphenyl) acetamide

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

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

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

* · ·

Furan-2-carboxylic acid (4-amino-2-cyanophenyl) furan-2-carboxylic acid (4-amino-2-trifluoromethylphenyl) acetamide (4-amino-2-trifluoromethylphenyl) amide

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

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

5-Amino-2 - [(furan-2-carbonyl) amino] benzoic acid

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

N- (4-Amino-3-methylphenyl) -2,6-difluorobenzamide

N- (4-Amino-3-trifluoromethylphenyl) acetamide

N- (4-Amino-3-trifluoromethylphenyl) -2-fluorobenzamide

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

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

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

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

Example 7 (Method 1G)

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

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

• 9 Φ · Φ · · 9 9 9 9 9 9 · ·

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

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

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

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

To a solution of 3-chloro-4-iodoaniline (10 g) in tetrahydrofuran (40 mL) containing diisopropylethylamine (6.9 mL) was added di-tert-butyl bicarbonate (8.6 g) and the mixture was heated to reflux. After about 15 hours, diisopropylethylamine (6.9 mL) and di-tert-butyl bicarbonate (21 g) were added portionwise and heating was continued for another 24 hours.

The solution was then cooled, concentrated under reduced pressure, diluted with ethyl acetate, and washed three times successively with 5% aqueous hydrochloric acid and then once with saturated aqueous sodium chloride. The solution was dried over anhydrous sodium sulfate, then concentrated under reduced pressure to give the desired crude product as a brown oil. Crystallization is induced by the addition of hexanes, and the collected solid is recrystallized from hexanes to give the desired product as a white solid.

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

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

····· ·· · · ·· · tert-butyl acid ester (3-chloro-4-methylsulfanylphenyl) carbamic acid terč.Butylester (4-amino-3-chlorophenyl) carbamic acid terč.Butylester (4-chloro-2-nitrophenyl) carbamic acid terč.Butylester (3-tert-butoxycarbonylamino-5-

chlorophenyl) carbamic acids

terč.Butylester (4-nitrobenzyl) carbamic acid terč.Butylester acid (3-bromo-5-trifluoromethylphenyl) carbamate terč.Butylester (2-Amino-3-chloro-5-

trifluoromethylphenyl) carbamic acids

Example 9 (method 2B)

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

To a solution of 3-chloro-4-vinylphenylamine (3.4 g) in N, N-dimethylformamide (44 mL) containing diisopropylethylamine (5.8 mL) was added 1- [2- (trimethylsilyl) ethoxycarbonyloxy] benzotriazole (7.1 mL). g) and the mixture was stirred at room temperature under argon for three days. The solution was then diluted with water and extracted three times with diethyl ether. The combined organic extracts were washed successively with water, saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue is chromatographed on silica gel (10% ethyl acetate in hexanes is used as eluent) to give the desired product as a yellow oil.

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

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

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

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

N- (4-Aminophenyl) isobutyrylamide

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

2- (4-tert-Butoxycarbonylaminophenylcarbamoyl) phenyl acetic acid tert-butyl [4- (4-Fluorobenzoylamino) phenyl] carbamic acid tert-butyl [4- (3-fluorobenzoylamino) phenyl] carbamate tert -Butyl ester [4- (2-fluorobenzoylamino) [4- (4-Methoxy-benzoylamino) -phenyl] -carbamic acid tert-butyl [4- (2-methoxy-benzoylamino) -phenyl] -carbamic acid [4- (3-methoxy-benzoylamino) -phenyl] -carbamic acid tert-butyl [4- (4-methoxy-benzoylamino) -phenyl] -carbamic acid tert-butyl ester [4- (2) Tert-butyl [4- (2-bromoacetylamino) phenyl] carbamate tert-butyl [4- (2,2,2-trifluoroacetamino) phenyl] carbamate, 2-dimethylpropionylamino) phenylcarbamic acid Tert-butyl (4-benzoylaminophenyl) carbamic acid tert-butyl (4-methanesulfonylaminophenyl) carbamic acid tert-butyl (4-phenylacetylaminophenyl) carbamic acid tert-butyl {4- [(thiophen-2) (carbonyl) aminobiphenyl [4- (3-Nitrobenzoylamino) phenyl] carbamate tert-butyl ester [4- (3-Acetylaminobenzoylamino) phenyl] carbamate tert-butyl [4- (3-methanesulfonylaminobenzoylamino) phenyl] carbamate

Ethyl [3 - [[[4 - [[(1,1-dimethylethoxy) carbonyl] amino] phenyl] carbonyl} phenyl} carbamate tert -Butyl [4- (2-trifluoromethylbenzoylamino) phenyl] carbamate tert-butyl [4- (2,6-difluorobenzoylamino) phenyl] carbamate [4- (2-Bromo-benzoylamino) -phenyl] -carbamic acid tert-butyl [4- (2-bromo-benzoylamino) -phenyl] -carbamic acid tert-butyl {4- [(benzo [b] thiophene-2-carbonyl) - amino] phenylcarbamic acid tert. {4 - [(Pyridine-4-carbonyl) amino] phenyl} carbamate tert-butyl {4 - [(Naphthalene-2-carbonyl) aminobiphenyl] carbamic acid tert-butyl {4 - [(naphthalene-1-carbonyl) aminobiphenyl] carbamate {4 - [(3-Bromo-thiophene-2-carbonyl) -amino] -phenyl} -carbamic acid tert-butyl ester

(4 - [(Biphenyl-2-carbonyl) amino] phenyl} carbanic acid tert-butyl ester

N- (4-tert-Butoxycarbonylaminophenyl) phthalamic acid tert-butyl [4- (2,3-difluorobenzoylamino) phenyl] carbamic acid tert-butyl ester [4- (2,5-difluorobenzoylamino) phenyl] carbamic acid tert-butyl ester [4 - (2,4-difluorobenzoylamino) phenyl] carbamic acid tert-butyl [4- (2-acetylaminobenzoylamino) phenyl] carbamic acid tert-butyl [4- (2-methanesulfonylaminobenzoylamino) phenyl] carbamic acid tert-butyl ester [4- (2 [4- (2,3,4,5,6-Pentafluorobenzoylamino) phenyl] carbamic acid tert -butyl ester, 3,4-trifluobenzoylamino) phenylcarbamic acid

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

2-Methylsulfanyl-N- [4- (2,2,2-trifluoroacetylamino) phenyl] benzamide tert-butyl [4- (3-benzyloxybenzoylamino) phenyl] carbamic acid tert-butyl [4- (3-butoxybenzoylamino) phenyl] carbamate t-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) {4 - [(5-bromofuran-2-carbonyl) amino] phenyl} carbamic acid tert-butyl (4-hexanoylaminophenyl) carbamic acid tert-butyl ester [4- (2-carbonyl) amino] phenyl] carbamate {4 - [(pyridine-3-carbonyl) amino] phenyl} carbamic acid tert -butyl ester {thiophen-2-ylacetylamino) phenyl} carbamate tert. {4 - [(4-Bromofuran-2-carbonyl) amino] phenyl] carbamic acid tert-butyl {4 - [(furan-3-carbonyl) amino] phenyl} carbamic acid tert-butyl ester (4-phenoxycarbonylaminophenyl) ) {4 - [(Benzofl, 3] dioxole-4-carbonyl) amino] phenyl] carbamate tert-butyl ester [4- (3-Trifluoromethoxybenzoylamino) phenyl] carbamate

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

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

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

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

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

N- (4-Acetylamino-2-trifluoromethylphenyl) -2,2,2-trifluoroacetamide 2-Fluoro-N- [4- (2,2,2-trifluoroacetylamino) -3-trifluoromethylphenyl] benzamide [4- (2,2, Furan-2-carboxylic acid 2-trifluoroacetylamino) -3-trifluoromethyl-phenyl-amide

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

4- (2-Fluorobenzoylamino) -2-hydroxybenzoic acid phenyl ester tert -Butyl {4 - [(isoxazole-5-carbonyl) amino] phenyl] carbamate

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

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

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

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

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

Isoxazole-5-carboxylic acid N- (5-chloro-2,4-dinethoxyphenyl) oxalamic acid (4-Aminophenyl) amide • · • ·

2-Fluoro-N- (4-nitrobenzyl) benzamide

Furan-2-carboxylic acid 4-nitrobenzylamide

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

N- (3-Amino-5-chlorophenyl) -2,2,2-trifluoroacetamide

terc.Butylester acid [4- (2-Fluorobenzoylamino) benzyl] carbamate terč.Butylester [4- (2,6-Difluorobenzoylamino) benzyl] carbamate

acid

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

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

terč.Butylester [4- (3-chlorobenzoylamino) phenyl] carbamate

acid

terč.Butylester [4- (4-chlorobenzoylamino) phenyl] carbamate

acid

terc.Butylester [4- (4-dimethylaminobenzoylamino) phenyl] carbamate

acid

terč.Butylester (4-benzenesulfonylaminophenyl) carbamic acid terc.Butylester [4- (3-

trifluoromethylbenzoylamino) phenyl] carbamic acid

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

Example 11 (2D method)

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

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

• · · · · · · · · · · · · · · · · · ·

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

N- (4-Nitro-3-trifluoromethylphenyl) acetamide

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

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

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

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

N- (4-Nitrophenyl) acrylamide

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

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

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

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

N- (2-Cyano-4-nitrophenyl) -2-fluorobenzamide

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

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

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

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

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

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

2-Fluoro-N- (3-methyl-4-nitrophenyl) benzamide

Furan-2-carboxylic acid (3-methyl-4-nitrophenyl) -amide

2-Acetylamino-5-nitro-N-phenylbenzamide

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

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

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

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

Furan-2-carboxylic acid N- (4-nitro-2-trifluoromethylphenyl) acetamide (2-Cyano-4-nitrophenyl) amide 2-Fluoro-N- (4-nitro-2-trifluoromethylphenyl) benzamide (4-Nitro-2) Furan-2-carboxylic acid trifluoromethylphenyl) amide

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

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

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

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

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

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

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

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

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

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

Example 12 λ

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

To a solution of 1- (N-tert-butoxycarbonyl) -1,4-phenylenediamine (0.8 g) and 4-phenyl [1,2,3] thiadiazole-5-carboxylic acid (0.7 g) in dichloromethane (10 ml) was treated with triethylamine (1.3 ml) and benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (1.6 g). After stirring at room temperature, the reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was washed with 0.5 N hydrochloric acid, saturated sodium bicarbonate, and water, then dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the desired product.

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

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

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

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

Example 12 (Method 2F)

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

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

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

Phenylsulfanylacetonitrile

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

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

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

• · · · ·

The following compound was prepared as described above, using appropriate starting materials: (3-Amino-5-chloro-phenyl) -carbamic acid tert-butyl ester Example 15 (Method 3A)

3-5-Dichlo-4-ethoxyphenylamine

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

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

5-Bromopyridin-3-ylamine

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

Acetic acid 2- (4-aminophenylcarbamoyl) phenyl ester

N- (4-Aminophenyl) -4-fluorobenzamide N- (4-Aminophenyl) -3-fluorobenzamide N- (4-Aminophenyl) -2-fluorobenzamide N- (4-Aminophenyl) -2-methoxybenzamide N- (4-Aminophenyl) ) -3-Methoxybenzamide N- (4-Aminophenyl) -4-methoxybenzamide N- (4-Aminophenyl) -2-phenylacetamide

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

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

N- (4-Aminophenyl) -3-nitrobenzamide

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

N- (4-Aminophenyl) -3-dimethylaminobenzamide

N- (4-Aminophenyl) -3-methanesulfonylaminobenzamide

N- (4-Aminophenyl) -2-trifluoromethylbenzamide

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

N- (4-Aminophenyl) -2-chlorobenzamide

N- (4-Aminophenyl) -2-bromobenzamide

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

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

3,5-Dichloro-4-ethoxyphenylamine

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

4-Benzyloxy-3,5-dichlorophenylamine

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

Methyl (4 ^t-amino-2, 6-dichlorophenoxy) acetic acid

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

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

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

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

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

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

N- (4-Aminophenyl) -2-methanesulfonylaminobenzamide

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

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

N- (4-Aminophenyl) -2-methylsulfanylbenzamide

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

N- (4-Aminophenyl) isophthalamic acid methyl ester

N- (4-Aminophenyl) -3-benzyloxybenzamide

N- (4-Aminophenyl) -3-butoxybenzamide

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

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

N- (4-Aminophenyl) nicotinamide

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

Benzo [1,3] dioxole-4-carboxylic acid (4-amino-phenylcarbamoyl) -phenyl acetate

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

N- (4-Aminophenyl) -3-trifluoromethoxybenzamide

N- (4-Aminophenyl) -3- (2-morpholin-4-yl-ethoxy) -benzamide

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

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

N- (4-Aminophenyl) acrylamide

4-Furan-3-yl- [1,2,3] thiadiazole-5-carboxylic acid N- (4-aminophenyl) -2-methoxyacetamide (4-aminophenyl) amide 5-tert-butylfuran- 2-carboxylic acids

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

2- (Amino-2-chlorophenyl) ethanol

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

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

3- (2-Methylbutyl) -5-trifluoromethylphenylamine

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

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

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

N- (4-Aminophenyl) -3-chlorobenzamide

N- (4-Aminophenyl) -4-chlorobenzamide

Acetic acid 4- (4-aminophenylcarbamoyl) phenyl ester

N- (4-Aminophenyl) -4-dimethylaminobenzamide

1- (4-Aminophenyl) -3- (3,5-bistrifluoromethylphenyl) thiourea

N- (4-Aminophenyl) -2-iodobenzamide

N- (4-Aminophenyl) -3-trifluoromethylbenzamide

Example 16 (Method 3B)

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

A solution of 1M tetrabutylammonium fluoride in tetrahydrofuran (5.7 mL) was added to [3-chloro-4- (1-hydroxyethyl) phenyl] carbamic acid 2-trimethylsilanylethyl ester (0.5 g) and the mixture was stirred at room temperature for approximately 3.5 clock. The solution was then concentrated under reduced pressure, dissolved in a 1: 1 mixture of ethyl acetate and hexanes, washed successively with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure followed by silica gel chromatography (40% ethyl acetate in hexanes is used as the eluent) afforded the product as an amber oil.

Example 17 (Method 3C)

N- (4-Amino-3-cyanophenyl) -2-fluorobenzamide

Potassium carbonate (5.0 g) was added to a solution of N- [3-cyano-4- (2,2,2-trifluoroacetylamino) phenyl] -2-fluorobenzamide (2.5 g) in methanol (270 mL) and water (16 mL) and the mixture was heated at reflux overnight. After removal of the solvent under reduced pressure, the residue was suspended in water and extracted with dichloromethane. The organic extracts were combined, washed with water and then saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound as a white solid.

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

• φ

N- (4-Aminophenyl) -2-methanesulfinylbenzamide

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

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

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

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

Example 17 (Method 4A)

2-Chloro-1-cyclohexyloxy-4-nitrobenzene

Cyclohexanol (2.9 g) in dimethylsulfoxide (20 ml) was slowly added to a flask containing potassium hydride (0.90 g, first washed three times with hexanes) under an argon atmosphere, and this solution was then stirred for about 1 hour at room temperature. A solution of 3-chloro-4-fluoronitrobenzene (1 g) in dimethylsulfoxide (10 mL) was added and the resulting solution, now dark red in color, was then heated at about 100 degrees for 3 hours.

The reaction mixture was then cooled, diluted with diethyl ether (300 mL), and washed successively with saturated aqueous ammonium chloride, three times with water, and saturated aqueous sodium chloride. The organic layer was then dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure, and the resulting oil was chromatographed on silica gel (using 5% ethyl acetate in hexanes as eluent) to give the desired product as an orange solid.

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

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

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

(2-Chloro-4-nitrophenyl) dipropylamine

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

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

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

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

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

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

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

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

4-Dimethylamino-3-trifluoromethylbenzonitrile

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

Example 19 (Method 4E)

Butyl (2-chloro-4-nitrophenyl) thioether

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

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

1-Butylsulfanyl-2-chloro-4-nitrobenzene

2-Chloro-1-cyclohexylsulfanyl-4-nitrobenzene

2-Chloro-1-ethylsulfanyl-4-nitrobenzene

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

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

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

(4-Chloro-2-nitrophenyl) dimethylamine

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

1- (4-Chloro-5-methoxy-2-nitrophenyl) piperidine

1- (4-Chloro-5-methoxy-2-nitrophenyl) pyrrolidine

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

Example 21 (Method 4G) (2-Chloro-4-nitrophenyl) methylphenylamine n-Butyl lithium (12.3 mL of a 2.5 M solution in hexanes) was added dropwise to a solution of N-methylaniline (3.0 g) in tetrahydrofuran (75 mL) at 0 ° C. The mixture was slowly warmed to room temperature and then re-cooled to 0 ° C and then added via cannula to a solution of 3-chloro-4-fluoronitrobenzene (4.9 g) in tetrahydrofuran (35 mL) maintained at -78 °. C. The reaction mixture was then allowed to warm

at room temperature for 1 hour and concentrated under reduced pressure, quenched by the addition of saturated aqueous ammonium chloride and extracted three times with ethyl acetate. The combined organic extracts were washed three times with 5% aqueous hydrochloric acid, once with water, once with saturated aqueous sodium bicarbonate, once with saturated aqueous sodium chloride, and then dried over magnesium sulfate. Removal of the solvent under reduced pressure followed by chromatography on silica gel (using 5% diethyl ether in hexanes as eluent) gave the desired product as a clear colorless oil.

Example 22 (Method 4H)

2,6-Dichloro-4-nitrophenol

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

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

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

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

terč.Butylester (3,5-dichloro-4-ethoxyphenyl) carbamic acid terč.Butylester (4-butoxy-3,5-dichlorophenyl) carbamic acid terč.Butylester acid (4-benzyloxy-3,5-dichlorophenyl) carbamate terč.Butylester acid (4-carbamoylmethoxy-3,5-dichlorophenyl) carbamate terč.Butylester acid [3,5-dichloro-4- (2-nitroethoxy) phenyl] carbamate

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

3-Butoxybenzoic acid methyl ester

3-tert-Butoxycarbonylmethoxybenzoic acid methyl ester

3-Carbamoylmethoxybenzoic acid methyl ester tert -Butyl [4- (3-carbamoylmethoxybenzoylamino) phenyl] carbamate t -butyl (4- [3- (2-chloroethoxy) benzoylamino) phenyl] carbamate

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

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

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

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

2-Chloro-1-isopropoxy-4-nitrobenzene

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

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

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

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

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

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

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

(2-Chloro-5-methoxy-4-nitrophenoxy) -acetic acid methyl ester

(4-Chloro-5-methoxy-2-nitrophenoxy) acetic acid methyl ester tert-butyl (4-Chloro-5-methoxy-2-nitrophenoxy) acetic acid (2-Chloro-4-nitrophenoxy) acetonitrile

1-Butoxy-2-chloro-4-nitrobenzene

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

2-Chloro-4-nitro-1-propoxybenzene

2-Chloro-1-ethoxy-4-nitrobenzene

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

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

3-Chloro-2,4-dimethoxynitrobenzene

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

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

Example 26 (method 6)

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

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

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

4- (2-Chloro-4-nitrophenoxy) -1-methylpiperidine

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

Example 27 (Method 7A)

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

To a flask containing 3-methoxy-6-nitrophenol (0.5 g) was added aqueous sodium hypochlorite (5.25% aqueous solution, 21 mL), and the mixture was stirred at room temperature for approximately 24 hours. The mixture was then cooled in an ice bath, acidified by addition of concentrated

hydrochloric acid and then extracted twice with ethyl acetate. These organic extracts were dried over anhydrous magnesium sulfate, the solvent was removed by evaporation under reduced pressure, and the residue was chromatographed on silica gel (using 15% acetone in hexanes as eluent) to give both the mono- and di-chlorinated product as a yellow solid.

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

3-Chloro-2-hydroxy-4-methoxynitrobenzene

3,5-Dichlo-2-hydroxy-4-methoxynitrobenzene

Example 28 (method 7B)

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

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

1-Bromo-2,4-dimethoxy-5-nitrobenzene

Example 29 (Method 7C)

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

Example 30 (method 7D)

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

To a solution of 5-methoxy-2-nitrophenol (0.25 g) and silver trifluoroacetate (0.49 g) in glacial acetic acid (3 mL) was added dropwise a solution of bromine (1.42 g) in glacial acetic acid (3 mL). ml) and the mixture was stirred at room temperature for approximately 24 hours. The solution was then partitioned between ethyl acetate and water, and the organic layer was then washed three times with 5% aqueous sodium bisulfite, three times with saturated aqueous sodium bicarbonate, and once with saturated aqueous sodium chloride. The organic layer was then dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue is chromatographed on silica gel (20% ethyl acetate in hexanes is used as eluent) then recrystallized from chloroform to give the desired dibrominated product as an orange solid.

Example 31 (method 7E) * ♦ metoda 31 31 31 31 31

1-Iodo-2,4-dimethoxy-5-nitrobenzene

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

Example 32 (method 7F)

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

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

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

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

Example 34 (method 8)

3-Chloro-4-trifluoromethylnitrobenzene

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

Example 35 (method 9)

Λ <

• · <* · · · ··· • in * «·» 9 · 85 ·· ·· · »· terc.Butylester acid (3-chloro-4-methanesulfinylphenyl) carbamate

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

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

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

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

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

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

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

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

Example 38 (method 11)

3-Chloro-4-vinylphenylamine

To a deoxygenated solution of 3-chloro-4-iodoaniline (6.95 g), triphenylarsin (0.67 g) and tris (dibenzylideneacetone) palladium (0) (0.50 g) in tetrahydrofuran (120 mL) at 50 ° C was added tributylvinyl tin (10 g) and the mixture was stirred at 50 ° C under argon for about 15 hours. The reaction mixture was then cooled, filtered through diatomaceous earth, and the filtrate was evaporated to dryness under reduced pressure. The residue was dissolved in hexanes and then extracted three times with 5% aqueous hydrochloric acid. The aqueous acid extracts were then basified with solid potassium carbonate and extracted three times with ethyl acetate. The combined organic extracts were then washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The resulting residue is chromatographed on silica gel (hexanes then 10% ethyl acetate in hexanes is used as the eluent) to give the desired product as an amber oil.

Example 39 (method 12)

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

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

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

To a stirred suspension of sodium borohydride (0.45 g) in tetrahydrofuran (13 mL) at 0 ° C was added glacial acetic acid (0.75 mL), and the mixture was stirred at 0 ° C for 1 hour. The solution was then warmed to room temperature and (3-chloro-4-vinylphenyl) carbamic acid 2-trimethylsilanylethyl ester (1.0 g) was added. The reaction mixture was stirred at room temperature for about 15 hours and then heated to reflux for about 20 hours. The mixture was then cooled and solutions of 5N aqueous sodium hydroxide (0.80 mL) and 30% aqueous hydrogen peroxide (0.56 mL) were added. The mixture was stirred for an additional 15 hours and the layers were separated, the aqueous layer was extracted three times with diethyl ether, and these organic extracts were dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure followed by silica gel chromatography (40% ethyl acetate in hexanes was used as eluent) to give the desired product as an amber oil.

Example 41 (method 14)

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

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

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

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

The following compounds were prepared as described above using the appropriate starting materials: [3- (4-Methoxy-phenyl) -propyl- [3-chloro-4- (3-dimethylamino-prop-1-ynyl) -phenyl] -carbamic acid tert-butyl ester. 2-ynyl] dimethylamine

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

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

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

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

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

A solution of [3-chloro-4- (3-dimethylamino-acryloyl) -phenyl] -carbamic acid tert-butyl ester (270 mg) in dioxane (3 mL) was treated with hydroxylamine hydrochloride (122 mg) and the mixture was stirred at room temperature for 10 days. The mixture was diluted with ethyl acetate, washed sequentially with water, 5% aqueous sodium bicarbonate, saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure and the resulting residue was chromatographed on silica gel (using 22% ethyl acetate in hexanes as eluent) to give the desired product as a colorless solid.

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

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

Example 46 (Method 19A)

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

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

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

(4- {2- [Bis- (2-hydroxy-ethyl) -amino-acetylamino} -phenyl) -carbamic acid tert-butyl ester tert-Butyl [4- (2-dimethylamino-acetylamino) -phenyl] -carbamic acid tert-butyl ester {4- [3- (2-Morpholin-4-yl-ethoxy) -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-nitrophenyl) -2-thiomorpholin-4-ylacetamide

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

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

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

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

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

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

Example 47 (method 19B)

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

To a solution of N- (chloroacetyl) -2-chloro-4-nitroaniline (3.01 g) in N, N-dimethylformamide (100 mL) was added powdered sodium carbonate (6.0 g) and 2-dimethylaminoethanthiol hydrochloride (6.0 g) The mixture was stirred at 25 ° C for 1 hour, poured into water and extracted with ethyl acetate. The ethyl acetate solution was dried over anhydrous potassium carbonate and concentrated under reduced pressure to give an oil. The oil was crystallized from toluene-hexanes (3: 1) to give a pale yellow crystalline solid.

Example 48 (method 20)

(4-tert-Butoxycarbonylamino-2-chloro-phenyl) -carbamic acid 2-piperidin-1-yl-ethyl ester

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

Example 49 (method 21)

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

A solution of ethylbenzoylacetate (1.1 g) in acetonitrile (10 mL) was treated with 4-methylbenzenesulfonylazide (1.3 g) and triethylamine (1.6 g). The reaction mixture was stirred at room temperature overnight, then concentrated under reduced pressure and the resulting crude product was dissolved in ethyl acetate and washed with 1N sodium hydroxide. The organic layer was then dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a yellow oil. This oil was taken up in dichloromethane and filtered through a pad of magnesium silicate containing water, eluting with dichloromethane to give a partially pure diazoketone as a colorless oil. A sample of the diazoketone collected above (1.2 g) was dissolved in toluene (25 mL) and treated with 2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetan-2,493

disulfide (2.8 g) and the reaction mixture was heated to reflux. After 3 hours, warm the reaction mixture to room temperature, place it on a pad of silica gel and elute with dichloromethane. After removal of the solvent under reduced pressure, the remaining oil was purified by silica gel chromatography (30% diethyl ether in petroleum ether was used as eluent) and then recrystallized from hexanes to give the desired product as yellow needles.

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

5-Phenyl- [1,2,3] thiadiazole-4-carboxylic acid ethyl ester 5-Methyl- [1,2,3] thiadiazole-4-carboxylic acid ethyl ester Example 50

Ethylbenzoylacetate semicarbazide

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

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

Ethyl (Z) -3 - [(aminocarbonyl) hydrazono] -4,4,4-trifluorobutanoate

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

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

Example 51

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

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

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

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

Example 52

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

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

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

3- Ethoxycarbonylmethoxybenzoic acid

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

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

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

Example 53 (method 25)

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

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

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

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

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

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

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

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

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

N- (3-Chloro-5-dimethylaminophenyl) acetamide λ

Example 55 (method 27)

N- (4-Aminophenyl) -2-hydroxybenzamide

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

Example 56 (method 28)

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

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

Example 57 (method 29)

N- (4-Aminophenyl) -2-hydroxymethylbenzamide

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

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

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

Example 59 (method 35)

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

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

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

To a solution of {4- [3- (4-acetylaminophenyl) thioureido] -2,6-dichloro-phenoxy] -acetic acid ethyl ester (0.29 g) in a mixture of (1: 1) tetrahydrofuran and methanol (4 mL) was added 1 N aqueous sodium hydroxide ( 2 ml) and the mixture was stirred at room temperature for about 2 hours. The solution was then poured into 2M aqueous hydrochloric acid (5 mL), extracted with ethyl acetate, and the extracts dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure and the residue was treated with diethyl ether to give the desired product as a white solid.

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

{4- [3- (4-Acetylaminophenyl) thioureido] -2,6-dichlorophenoxyacetic acid {2- [3- (4-Acetylaminophenyl) thiourido] -4-chloro-5-methoxyphenoxy} acetic acid { 4- [3- (4-Acetylamino-phenyl) -thiourido] -2-chloro-5-methoxy-phenoxy} -acetic acid

Example 61 (Method 37)

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

To an ice-cold solution of N- (4- {3- [3,5-dichloro-4- (2-hydroxyethoxy) phenyl] thioureido} phenyl) acetamide (0.20 g) in pyridine (2

100 • · · * w «« · •. 3 ·· fc ··· 9 •• 4 · 4 »<<<

ml) and tetrahydrofuran (0.5 ml) were added benzoyl chloride (0.08 g) and the mixture was stirred at 0 ° C for 1.5 hours. The mixture was then diluted with ethyl acetate, washed successively twice with 2% aqueous hydrochloric acid, once with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate.

The solvent was removed under reduced pressure and the residue was then chromatographed on silica gel (5% methanol in dichloromethane was used as the eluent) and the product containing fractions were combined, evaporated under reduced pressure, and the residue was recrystallized from acetone-hexanes to give the desired product. as a white powder.

Example 62 (method 38)

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

To an ice-cold solution of N- (4- {3- [3,5-dichloro-4- (2-hydroxyethoxy) phenyl] thioureido} phenyl) acetamide (0.20 g) in pyridine (2 mL) and tetrahydrofuran (0.5 mL) Methanesulfonyl chloride (0.11 g) was added and the solution was stirred at 0 ° C for 45 min. The reaction mixture was then diluted with ethyl acetate, washed successively twice with 2% aqueous hydrochloric acid, once with saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was then recrystallized from acetone-hexanes to give the desired product as a white powder.

Example 63 (method 39)

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

101 φ- *

Κ A solution of 2- (4- (3- (4-acetylaminophenyl) thioureido) -2,6-dichlorophenoxy) ethyl methanesulfonic acid ester (0.33 g) in tetrahydrofuran (6 mL) was treated with aqueous dimethylamine (8.8 M, 0). The reaction mixture was then diluted with ethyl acetate, then washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was then chromatographed on silica gel (as silica gel). The combined product containing the fractions was evaporated under reduced pressure and the residue was recrystallized from acetonitrile to give the desired product as a white powder.

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

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

2- (4- (3- (4-Acetylaminophenyl) thioureido) -2,6-dichlorophenoxy) ethyl benzoate

Example 64 (Method 40) Furan-2-carboxylic acid 4- (3- (4- (1-amino-ethyl) -3-chloro-phenyl) -thioureido] -phenyl) -amide

To a solution of stannous chloride dihydrate (0.25 g) in methanol (2.5 mL) was added furan-2-carboxylic acid (4- (3- (4- (1-azidoethyl) -3-chloro-phenyl) -3-chloro-phenyl) -thioureidophenyl) -amide ( 0.22 g) and the solution was stirred at room temperature for approximately 15 hours, then diluted with ethyl acetate, washed successively with saturated aqueous sodium bicarbonate, then saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate.

··· * · · · · · ·

102

The solvent was removed by evaporation under reduced pressure and the residue was then chromatographed on silica gel (8% methanol in dichloromethane containing 1% triethylamine as eluent) to give the desired product as a yellow solid.

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

To an ice cold solution of 1,1'-thiocarbonyldiimidazole (7.28 g) in tetrahydrofuran (50 mL) was added [1,2,3] thiadiazole-4-carboxylic acid (4-aminophenyl) amide (9.0 g) in tetrahydrofuran (100 mL). After about 1 hour, the solvent was removed by evaporation under reduced pressure and the residue was dissolved in ethyl acetate. Diethyl ether was added to precipitate the crude product, which was then collected by filtration, dissolved in dichloromethane, and passed through a plug of hydrated magnesium silicate. The solvents were removed and the residue was then recrystallized from ethyl acetate / hexanes to give the desired product as a slightly yellow solid.

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

[1,2,3] Thiadiazole-4-carboxylic acid (4-isothiocyanatophenyl) amide [1,2,3] thiadiazole-4-carboxylic acid (4-isothiocyanatophenyl) amide thiazole 2-Fluoro-N- (4-isothiocyanatophenyl) benzamide -4-carboxylic acids

Example 66 (method 42)

N, N-Dimethyl-5-trifluoromethylbenzene-1,3-diamine

103

To a solution of 3-amino-5-bromobenzotrifluoride (1.0 g) in degassed (argon) tetrahydrofuran (2 mL) was added bis (tritolylphosphine) palladium (0.15 g), a solution of dimethylamine in tetrahydrofuran (2M, 4, 2 mL), and a solution of lithium bis (trimethylsilyl) amide in tetrahydrofuran (1M, 10.4 mL). The reaction mixture is stirred in a sealed vessel at 100 ° C for about 2.5 hours to complete the reaction. The mixture was then cooled to room temperature, quenched with water and diluted with ethyl acetate. The product was extracted three times with 5% aqueous hydrochloric acid, and the combined acid extracts were then basified by cooling with 5N aqueous sodium hydroxide while cooling. This basic solution was then extracted with ethyl acetate, and the combined organic extracts were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and evaporated to dryness under reduced pressure. The resulting residue is chromatographed on silica gel (20-30% ethyl acetate in hexanes is used as eluent) to give the desired product as a slightly colored solid.

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

3- (4-Methylpiperazin-1-yl) -5-trifluoromethylphenylamine 3-Morpholin-4-yl-5-trifluoromethylphenylamine 3-Piperidin-1-yl-5-trifluoromethylphenylamine 3-Pyrrolidin-1-yl-5-trifluoromethylphenylamine

N, N-Dimethyl-5-trifluoromethylbenzene-1,3-diamine

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

Example 67 (method 43)

104 (3-Isobutyl-5-trifluoromethyl-phenyl) -carbamic acid tert-butyl ester

Isobutylene was bubbled through a sealed tube containing tetrahydrofuran (5 mL), sealed with a rubber stopper and cooled in a dry ice-acetone bath for approximately 5 minutes. A solution of 9-borabicyclo [3.3.1.0] nonane in tetrahydrofuran (0.5 M, 11 ml) was added, the vessel was sealed with a Teflon stopper and slowly warmed to room temperature, where it was maintained for about 2.5 hours. The mixture is then re-cooled in a dry ice-acetone bath, the Teflon plug is replaced with a rubber plug, and argon is bubbled through the mixture to vent excess isobutylene. A solution of (3-bromo-5-trifluoromethyl-phenyl) -carbamic acid tert-butyl ester (1.7 g) in tetrahydrofuran (12 ml) was added first, followed by [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloromethane / dichloride complex. 12 g), followed by 3N aqueous sodium hydroxide. The vessel was resealed with a Teflon plug and then heated at 65 ° C for approximately 15 hours. The mixture was then cooled to room temperature, diluted with hexanes, washed with water, saturated brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The resulting oil is chromatographed on silica gel (5% ethyl acetate in hexanes is used as eluent) to give the desired product as a white powder.

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

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

Example 68 (method 44)

105 • e · · ·

2- (3,5-Dichlorophenylsulfanyl) ethylamine

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

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

2- (3-Bromophenylsulfanyl) ethylamine

2- (4-Bromophenoxy) ethylamine

2- (4-Iodophenoxy) ethylamine

2- (3,4-Dichlorophenoxy) ethylamine

2- (3-Chlorophenylsulfanyl) ethylamine

2- (3,4-Dichlorophenylsulfanyl) ethylamine

3- (4-Bromophenyl) propylamine

2- (2-Fluorophenoxy) ethylamine

2- (2-Chlorophenoxy) ethylamine

2- (3-Bromophenoxy) ethylamine

2- (3-Fluorophenoxy) ethylamine

2- (3-Iodophenoxy) ethylamine

2- (3,5-Dichlorophenylsulfanyl) ethylamine

2-Phenylsulfanylethylamine

1- (2-Chlorophenyl) ethylamine

Example 69 (method 45)

106 • ······················

N- (1-Naphthalen-2-ylethyl) formamide

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

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

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

N- (1-Naphthalen-2-ylethyl) formamide

Example 70 (method 46)

1- (2-Naphthyl) ethylamine

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

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

1- (3-Trifluoromethylphenyl) ethylamine

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

3- (1-Aminoethyl) benzonitrile

107

Example 71 (Method 47)

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

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

and

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

3,5-Bistrifluoromethylbenzaldehyde oxime

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

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

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

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

O-Methyloxime of 1-p-tolylethanone

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

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

O-Methyloxime of 1-o-tolylethanone

O-Methyloxime of 1-m-tolylethanone

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

3- (1-Methoxyimethyl) benzonitrile

4- (1-Methoxyimethyl) benzonitrile

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

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

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

0

0 0 0 0

108

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

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

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

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

O-Methyloxime of 1-furan-2-ylethanone

O-Methyloxime 1-pyridin-4-ylethanone

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

O-Methyloxime of 1-thiophen-3-ylethanone

O-Methyloxime (4-fluorophenyl) phenylmethanone

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

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

4- (1-Methoxyiminethyl) benzenesulfonamide

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

109 ··· · · ··· ·

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Example 72 (method 48)

2- (2-Trifluoromethylphenyl) ethylamine

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

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

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

1- (3-Methoxyphenyl) ethylamine

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

4- (1-Aminoethyl) benzonitrile

1- (4-Trifluoromethylphenyl) ethylamine

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

1- (2-Methoxyphenyl) ethylamine

1-m-Tolylethylamine

1- (2-Bromophenyl) ethylamine

1-o-Tolylethylamine

C- (4-Fluorophenyl) -C-phenylamine

1- (4-Fluorophenyl) pentylamine

1- (4-Fluorophenyl) -2-phenylethylamine

1- (2-Trifluoromethylphenyl) ethylamine

1- (3-Bromophenyl) ethylamine

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

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

1-Thiophen-3-ylethylamine

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

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

1- (4-Methylphenyl) ethanamine

1- [3- (Trifluoromethyl) phenyl] ethylamine

1- [4- (Trifluoromethyl) phenyl] ethylamine

111

1- (3-Methylphenyl) ethanamine

1- (3,4-Dichlorophenyl) ethanamine

1- (2-Bromophenyl) ethylamine

1- (2-Trifluoromethylphenyl) ethylamine

1- (3-Bromophenyl) ethylamine

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

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

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

1- (3,5-Bistrifluoromethylphenyl) ethylamine

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

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

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

N- [4 - [(1S) -1-aminoethyl] phenyl} -1,2,3-thiadiazole-4-carboxamide 1- [3-Fluoro-5- (trifluoromethyl) phenyl] ethylamine 1- [2-Fluoro-4- (trifluoromethyl) 1- [2-Fluoro-5- (trifluoromethyl) phenyl] ethylamine

1- (2,4-Dichlorophenyl) ethylamine

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

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

1- (3,4-Difluorophenyl) ethylamine

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

1- (3-Fluorophenyl) ethylamine

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

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

112

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

1- (3,4-Dibromophenyl) ethylamine

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

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

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

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

(3-Bromophenylsulfanyl) acetonitrile (3-Chlorophenylsulfanyl) acetonitrile (4-iodophenoxy) acetonitrile (3-Trifluoromethylphenylsulfanyl) acetonitrile (3,5-Dichlorophenylsulfanyl) acetonitrile (3,4-Dichlorophenylsulfanyl) acetonitrile (3,4-Dichlorophenylsulfanyl) -Fluorophenoxy) acetonitrile (3-Fluorophenoxy) acetonitrile (2-Chlorophenoxy) acetonitrile ···············

113 (3-Bromophenoxy) acetonitrile (2-Fluoro-5-trifluoromethylphenoxy) acetonitrile (3-iodophenoxy) acetonitrile (4-Bromophenoxy) acetonitrile

Example 74 (method 50)

3-Fluoro-5-trifluoromethylphenethylamintosylate

A solution of 3-fluoro-5-trifluoromethylphenylacetonitrile and 2.34 g (12.3 mmol) of p-toluenesulfonic acid in 75 ml of ethylene glycol monomethyl ether was hydrogenated at room temperature at 20 psi for 3 hours using 200 mg of 10% palladium on carbon catalyst. The catalyst was filtered off and the solvent was evaporated to half the amount. Upon standing, the p-toluenesulfonic acid salt of the desired 3-fluoro-5-trifluoromethylphenethylamine crystallizes. White crystals, 4.26 g (91%), were collected by filtration.

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

2- (3,5-Difluorophenyl) ethylamine

2- (4-Trifluoromethylphenyl) ethylamine

2- (3,4-Difluorophenyl) ethylamine

2- (2-Fluorophenyl) ethylamine

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

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

2- (2,4-Bistrifluoromethylphenyl) ethylamine

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

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

->

························

114

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

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

4-Piperidin-1-yl-3-trifluoromethylbenzylamine (4-Aminomethyl-2-trifluoromethylphenyl) dimethylamine

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

Example 76 (method 52)

3-Dimethylamino-5-trifluoromethylbenzaldehyde

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

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

3-Dimethylamino-5-trifluoromethylbenzaldehyde

4-Dimethylamino-3-methylbenzaldehyde

Example 77 (method 53)

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

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

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

Dimethyl- [3- (2-nitrophenyl) -5-trifluoromethylphenyl] amine Dimethyl- [2-methyl-4- (2-nitrovinyl) phenyl] amine

Example 78 (method 54)

3- (4-Bromophenyl) propionitrile

116 • ΦΦΦ φ · · · · φ · φ · • • • • «• • · · · · · · · · φ φ φ

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

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

Example 79 (method 55)

3-Dimethylamino-2-isocyanacrylic acid ethyl ester

To a solution of ethyl isocyanate (5.0 g) in ethanol (100 mL) was added dropwise dimethylacetal over 10 minutes with stirring.

Ν, N'-dimethylformamide (6.5 g). The reaction mixture was stirred for 24 hours and then evaporated. The resulting oil was passed over magnesium silicate using 50% ethyl acetate in hexanes as eluent.

The solids were removed and the resulting oil was crystallized from a mixture of ethyl acetate and hexanes to give pale yellow needles, 3.0 g.

Example 80 (method 56)

4-Carboethoxythiazole

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

117 f f f 9 9 9 9 9 · 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9

Ethyl acetate in hexanes as eluent. Pure material (0.61 g) was isolated as an oil.

Example 81 (method 34)

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

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

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

118 · - - - - - - - - - - - - - 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

Ex. C. M + H COMPOUND NAME 81 445 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -ureido] - phenyl} -2-fluorobenzamide 82 441 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -ureido] -phenyl} -2-methyl-benzamide 83 435 {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -ureido] -phenyl) -amide [1,2,3] thiadiazole-4-carboxylic acid 84 443 {4- [3- (4-Chloro-3-trifluoromethyl-phenyl) -ureido] -phenyl] -amide [1,2,3] thiadiazole-4-carboxylic acid 85 453 N- {4- [3- (4-Chloro-3-trifluoromethyl-phenyl) -ureido] -phenyl) -2-fluoro-benzamide 86 409 (4- (3- (3,5-Dichloro-phenyl) -ureido] -phenyl) -amide [1,2,3] thiadiazole-4-carboxylic acid 87 486 N- {4- [3- (3,5-Bistrifluoromethyl-phenyl) -ureido] -phenyl} - -2-fluorobenzamide 88 458 (4- (3- (3,5-Bistrifluoromethylphenyl) ureido] phenyl) amide furan-2-carboxylic acid 89 476 {4- [3- (3,5-Bistrifluoromethyl-phenyl) -ureido] -phenyl} -amide [1,2,3] thiadiazole-4-carboxylic acid 90 Example 91 Method 31 423 [4- (3- (3,4-Dichlorobenzyl) ureido] phenyl} amide [1,2,3] thiadiazole-4-carboxylic acid

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

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

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

· «··

119

Ex. C. M + H COMPOUND NAME 92 506 [3-Chloro-5- (3- {4 - [([1,2,3] thiadiazole-4-carbonyl) -amino] -phenyl} -thioureido) -phenyl] -carbamic acid tert-butyl ester 93 409 1- (5-Chloro-2,4'-dimethoxyphenyl) -3- (4-morpholin-4-ylphenyl) thiourea 94 370 1- (5-Chloro-2,4-dimethoxyphenyl) -3- (4-methylsulfanylphenyl) thiourea 95 338 1- (5-Chloro-2,4-dimethoxyphenyl) -3-p-tolylthiourea 96 414 {4- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] phenylsulfanyl} acetic acid 97 384 1- (5-Chloro-2,4-dimethoxyphenyl) -3- [4-2-hydroxyethoxy) phenyl] thiourea 98 340 1- (5-Chloro-2,4-dimethoxyphenyl) -3- (4-hydroxyphenyl) thiourea 99 395 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -N-methylacetamide 100 ALIGN! 381 N- {3- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -acetamide 101 411 {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -carbamic acid ethyl ester 102 319 1- (2,4-Dimethoxyphenyl) -3- (4-methoxyphenyl) thiourea 103 346 N- {4- [3- (2,4-Dimethoxyphenyl) thioureido] phenyl} acetamide 104 316 N- {4- [3- (4-Methoxyphenyl) thioureido] phenyl} acetamide 105 316 N- {4- [3- (2-Methoxyphenyl) thioureido] phenyl} acetamide 106 351 N- {4- [3- (3-Chloro-4-methoxy-phenyl) -thioureido] -phenyl} -acetamide 107 351 N- {4- [3- (5-Chloro-2-methoxy-phenyl) -thioureido] - phenyl} acetamide 108 371 N- {4- [3- (3,5-Dichloro-4-hydroxy-phenyl) -thioureido] - phenyl} acetamide 109 385 N- {4- [3- (3,5-Dichloro-4-methoxy-phenyl) -thioureido] -phenyl} -acetamide 110 381 N- {4- [3- (4-Chloro-2,5-dimethoxy-phenyl) -thioureido] -phenyl} -acetamide 111 389 N- {4- [3- (2-Chloro-5-trifluoromethyl-phenyl) -thioureido] - ’Phenyl} acetamide 112 389 N- {4- [3- (4-Chloro-3-trifluoromethyl-phenyl) -thioureido] -

• φ · φ • · φ φ

120 phenyl} acetamide

113 422 4- [3- (4-Acetylaminophenyl) thioureido] -3- benzoic acid hydroxyphenyl ester 114 457 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] - phenyl} -2-methylbenzamide 115 501 2- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl)] - thioureido] phenylcarbamoyl} phenylacetate 116 461 N- {4- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] phenyl} -4-fluorobenzamide 117 461 N- {4- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] phenyl} -3-fluorobenzamide 118 461 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] - phenyl} -2-fluorobenzamide 119 473 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] - phenyl) -2-methoxybenzamide 120 473 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -3-methoxy-benzamide 121 474 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -4-methoxy-benzamide 122 443 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -benzamide 123 417 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -methanesulfonamide 124 331 N- {4- [3- (3-Nitrophenyl) thioureido] phenyl} acetamide 125 339 1- (3-Chloro-4-methoxyphenyl) -3- (3-nitrophenyl) thiourea 126 337 N- {4- [3- (5-Chloro-2-hydroxy-phenyl) -thioureido] -phenyl} -acetamide 127 439 (4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl) -carbamic acid tert-butyl ester 128 351 N- {4- [3- (3-Chloro-4-hydroxy-5-methyl-phenyl) -thioureido] -phenyl} -acetamide 129 385 N- {4- (3- (3,5-Dichloro-4-hydroxy-2-methylphenyl) thioureido] phenyl} acetamide 130 318 N- {4- [3- (2,4-Dihydroxyphenyl) thioureido] phenyl} acetamide 131 414 N- {4- [3- (2,4-Dimethoxy-5-trifluoromethyl-phenyl) -thioureido] -phenyl} -acetamide 132 332 N- {4- [3- (2-Hydroxy-4-methoxy-phenyl) -thioureido] - phenyl} acetamide 133 465 N- {4- [3- (3,5-Dichloro-4-methoxy-phenyl) -thioureido] -

• · · · ·

121 phenyl} -4-fluorobenzamide

134 500 3-Acetylamino-N- {4- [3- (5-chloro-2,4-dimethoxyphenyl) thioureido] phenyl} benzamide 135 488 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] - phenyl} -3-nitrobenzamide 136 486 N- {4- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] phenyl} -3-dimethylaminobenzamide 137 536 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -3-methanesulfonylaminobenzamide 138 511 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] - phenyl} -2-trifluoromethylbenzamide 139 459 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -2-hydroxy-benzamide 140 479 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl] -2,6-difluoro-benzamide 141 477 2-Chloro-N- {4- [3- (5-chloro-2,4-dimethoxy-phenyl) -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-dimethoxyphenyl) thioureido] phenyl} -2-nitrobenzamide 144 445 Pyrazine-2-carboxylic acid {4- [3- (5-chloro-2,4-dimethoxyphenyl) thioureido] phenyl) amide 145 463 5-Methyl-thiophene-2-carboxylic acid {4- [3- (5-chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -amide 146 494 Quinoline-8-carboxylic acid {4- [3- (5-chloro-2,4-dimethoxyphenyl) thioureido] phenyl) amide 147 446 {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} - 1-methyl-1H-pyrrole-2-carboxylic acid 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 {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -

benzo [b] thiophene-2-carboxylic acid amide

122 • · ·

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

451 '{4- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] phenyl] amide [1,2,3] thiadiazole-4-carboxylic acid

123

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

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

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

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

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

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

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

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

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

69 1- (5-Chloro-2,4-dimethoxy-phenyl) -3- [4- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -phenyl] -thiourea

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

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

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

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

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

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

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

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

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

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

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

124 phenyl) -2-methylsulfanylbenzamide

195 431 {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -ureido] -phenyl) -amide Of 5-methylfuran-2-carboxylic acid 196 467 {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -ureido] -phenyl} -amide 5-difluoromethylfuran-2-carboxylic acid 197 472 N- {4- [3- (5-Iodo-2,4-dimethoxyphenyl) thioureido) phenyl} acetamide 198 364 N- {4- [3- (5-Fluoro-2,4-dimethoxyphenyl) thioureido] - phenyl} acetamide 199 365 N- {4- [3- (5-Chloro-2-methoxy-4-methyl-phenyl) -thioureido] -phenyl} -acetamide 200 459 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (4-chloro-3-trifluoromethyl-phenyl) -thioureido] -phenyl} -amide 201 455 {4- [3- (3,5-Dichloro-4-methoxy-phenyl) -thioureido] -phenyl} - [1,2,3] thiadiazole-4-carboxylic acid amide 202 392 N- {4- [3- (3-Chloro-4-diethylamino-phenyl) -thioureido] - phenyl} acetamide 203 432 N- (4- {3- [3-Chloro-4- (cyclohexylmethylamino) phenyl] thioureido) phenyl} acetamide 204 506 1-hydroxynaphthalene-2-carboxylic acid {4- [3- (4-acetylaminophenyl) thioureido] -2-chlorophenyl) amide 205 406 N- {4- [3- (3-Chloro-4-morpholin-4-yl-phenyl) -thioureido] - phenyl} acetamide 206 443 1- (5-Chloro-2,4-dimethoxy-phenyl) -3- (3-chloro-4- (morpholin-4-ylphenyl) thiourea 207 372 1- (5-Chloro-2,4-dimethoxyphenyl) -3- (5-chloro-2-methyl- phenyl) thiourea 208 501 N- {4- [3- (5-chloro-2,4-dimethoxyphenyl) thioureido] phenyl} isophthalamic acid methyl ester 209 487 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -isophthalamic acid 210 549 3-Benzyloxy-N- {4- [3- (5-chloro-2,4-dimethoxyphenyl) - thioureido] phenyl] benzamide 211 434 N- (4- {3- [5-Chloro-2-methoxy-4- (4-nitrilobutoxy) phenyl] thioureido} phenyl) acetamide 212 406 N- (4- {3- [5-Chloro-2-methoxy-4- (2-nitroloethoxy) phenyl] thioureido} phenyl) acetamide 213 406 N- (4- {3- [5-Chloro-4-methoxy-2- (2-nitroloethoxy) phenyl] thioureido} phenyl) acetamide 214 411 N- (4- {3- [5-Chloro-2- (2-hydroxyethoxy) -4-methoxy-

phenyl] thioureido) phenyl) acetamide

125 • · ·

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

433 N- {4- [3- (3-Chloro-4-methylphenyl) thioureido] phenyl} 126

236

237

238

239

240

241

242

243

244

245

246

247

248

249

250

251

252

253

-2,6-difluorobenzamide

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

127

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

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

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

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

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

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

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

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

527 2- {4- [3- (4-Acetylaminophenyl) thioureido] -2-chlorophenoxy} -5-chlorobenzenesulfonic acid

562 2- {4- [3- (4-Acetylaminophenyl) thioureido] -2-chlorophenoxy} -4,5-dichlorobenzenesulfonic acid

527 4-Phenyl- [1,2,3] thiadiazole-5-carboxylic acid {4- [3- (5-chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -amide

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

393 N- {4- [3- (4-Butoxy-3-chlorophenyl) thioureido] phenyl} acetamide

446 N- (4- {3- [3-Chloro-4- (cyclohexylethylamino) phenyl] thioureido} phenyl) acetamide

365 N- {4- [3- (3-Chloro-4-ethoxy-phenyl) -thioureido] -phenyl} -acetamide

427 N- {4- [3- (4-Benzyloxy-3-chloro-phenyl) -thioureido] -phenyl} -acetamide

317 {4 - [(3-Methyl-furan-2-carbonyl) -amino] -phenyl} -carbamic acid tert-butyl ester

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

420 N- {4- [3- (3-Chloro-4-dipropylaminophenyl) thioureido] phenyl} acetamide

458 N- (4- {3- [4- (Allylcyclohexylamino) -3-chlorophenyl] thioureido) phenyl} acetamide

411 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] 128

-2-methoxyphenyl} acetamide

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

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

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

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

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

517 5-Furan-3-yl [1,2,3] thiadiazole-4-carboxylic acid {4- [3- (5-chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl] -amide

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

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

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

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

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

505 N- {4- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] -2-methoxy-5-methylphenyl} -2-fluorobenzamide

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

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

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

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

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

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

565 N- [2-Benzoyl-4- [3- (5-chloro-2,4-dimethoxyphenyl) -thioureido] phenyl} -2-fluorobenzamide

294 537 Furan-2-carboxylic acid {2-benzoyl-4- [3- (5-chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl] -amide 295 475 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenylthioureido) -3-] (methylphenyl) -2-fluorobenzamide 296 447 Furan-2-carboxylic acid {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -3-methyl-phenyl-amide 297 395 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -3- -methylphenyl} acetamide 298 435 N- [4- (3- {3-Chloro-4 - [(3-dimethylaminopropyl) methylamino] phenyl} thioureido) phenyl] acetamide 299 418 N- {4- [3- (3-Chloro-4-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 {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -2- Furan-2-carboxylic acid-phenylcarbamoyl-phenyl} -amide 303 491 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] - -2-methoxyphenyl) -2-fluorobenzamide 304 463 {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -2- furan-2-carboxylic acid-methoxyphenyl iamide 305 449 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] - -2-trifluoromethylphenyl} acetamide 306 458 {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -2-cyano- furan-2-carboxylic acid phenyl} amide 307 467 Furan-2-carboxylic acid {2-chloro-4- [3- (5-chloro-2,4-dimethoxyphenyl) thioureido] phenyl} amide 308 501 {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -2- Furan-2-carboxylic acid trifluoromethylphenyl iamide 309 395 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] - -2-methylphenyl} acetamide 310 475 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] - -2-methylphenyl} -2-fluorobenzamide 311 447 {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -2-methyl- furan-2-carboxylic acid phenyljamide 312 378 ’N- {4- [3- (4-Acetylaminophenyl) thioureido] -2-chloro-

phenyl} acetamide

130

313 408 {4- [3- (4-Acetylaminophenyl) thioureido] -2- -chlorophenyl} carbamic acids 314 382 N- {5- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -pyridin-2-yl} -acetamide 315 509 N- (4- {3- [4- (1-Benzylpiperidin-4-ylamino) -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 {5-Chloro-4- [3- (5-chloro-2,4-dimethoxy-phenyl) -thioureido] - Furan-2-carboxylic acid -2-hydroxyphenyl} amide 321 431 N- {5-Chloro-4- [3- (5-chloro-2,4-dimethoxy-phenyl) -thioureido] -2-hydroxy-phenyl} -acetamide 322 511 (5H, HH-Benzo [e] pyrrolo [1,2- a] [1,4] diazepin-10-yl) - - (2-chloro-4-imidazol-1-ylphenyl) methanone 323 451 [1,2,3] Thiadiazole-5-carboxylic acid {4- [3- (5-chloro-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -amide 324 483 Furan-2-carboxylic acid {4- [3- (5-chloro-2,4-dimethoxyphenyl) thioureido] napthalen-1-yl} amide 325 511 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -naphthalen-1-yl} -2-fluoro-benzamide 326 429 N- {5-Chloro-4- [3- (5-chloro-2,4-dimethoxy-phenyl) -thioureido] -2-methyl-phenyl} -acetamide 327 509 N- {5-Chloro-4- [3- (5-chloro-2,4-dimethoxyphenylthioureido) -2-methylphenyl} -2-fluorobenzamide 328 481 {5-Chloro-4- [3- (5-chloro-2,4-dimethoxy-phenyl) -thioureido] - Furan-2-carboxylic acid -2-methylphenyl iamide 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 [4- (3- {4 - [(1-Benzylpyrrolidine- 3-yl) methylamino] -3-chlorophenyl} thioureido) phenyl] furan-2-carboxylic acid amide 332 513 N- [4- (3- {3-Chloro-4- [methyl- (1-methylpyrrolidin-3-yl) amino] phenyl] thioureido) phenyl] -2-fluorobenzamide

in

131 · v v * * * * * * * * * *

463

420

434

422

425

505

477

545

503

443

408

499

419

440

493

462

531

427

430 · β β β β β β

Ν- [4- (3- {5-Chloro-2-methoxy-4-methylphenyl) thioureido] phenyl} -2,6-difluorobenzamide

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

N- (4- (3- [3-Chloro-4- (1-methylpiperidin-4-yloxy) phenyl) thioureido} phenyl) acetamide

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

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

5- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -2- (2-fluoro-benzoylamino) -benzoic acid

5- [3- (5-Chloro-2,4-dimethoxyphenyl) thioureido] -2 - [(furan-2-carbonyl) amino] benzoic acid

N- [4- (3- {3-Chloro-4- [methyl- (1-methylpiperidin-4-yl) amino] phenyl} thioureido) phenyl] -2,6-difluorobenzamide [4- (3- {3- [1,2,3] Thiadiazole-4-carboxylic acid chloro-4- [methyl- (1-methyl-pyrrolidin-3-yl) -amino] -phenyl} -thioureido) -phenyl] -amide

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

N- (4- {3- [3-Chloro-4- (2-dimethylaminoethoxy) phenyl] thioureido] phenyl) acetamide [4- (3- {3-Chloro-4- [methyl (1-methylpiperidin-4-yl)]) (amino) phenyl] thioureido) phenyl] furan-2-carboxylic acid amide

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

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

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

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

N- [4- (3- {3-Chloro-4- [methyl- (1-methylpyrrolidin-3-yl) amino] phenyl} thioureido) phenyl] -2,6-difluorobenzamide {4- [3- (3- Pyridine-2-carboxylic acid {4- [3- (3-Chloro-4-methylsulfanylphenyl) thioureido] phenyl] amide pyridine-2-carboxylic acid chloro-4-dimethylaminophenyl) thioureido

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

132

428 Pyridine-2-carboxylic acid {4- [3- (5-chloro-2-methoxy-4-methyl-phenyl) -thioureido] -phenyl-amide

417 Furan-2-carboxylic acid {4- [3- (5-chloro-2-methoxy-4-methyl-phenyl) -thioureido] -phenyl] -amide

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

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

467 Furan-2-carboxylic acid (3-chloro-4- [3- (5-chloro-2,4-dimethoxyphenyl) thioureido] phenyl] amide

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

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

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

421 N- {4- [3- (4-Acetylaminophenyl) thioureido] -2-chlorophenyl} -2-dimethylaminoacetamide

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

501 N- (4- {3- [3-Chloro-4- (2-dimethylaminoacetylamino) phenyl] thioureido) phenyl} -2-fluorobenzamide

461 N- {4- [3- (4-Acetylaminophenyl) thioureido] -2-chlorophenyl) -2-piperidin-1-yl-acetamide

541 N- (4- {3- [3-Chloro-4- (2-piperidin-1-yl-acetylamino) -phenyl] -thioureido] -phenyl) -2-fluoro-benzamide

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

463 N- {4- [3- (4-Acetylaminophenyl) thioureido] -2-chlorophenyl) -2-morpholin-4-ylacetamide

543 N- (4- {3- [3-Chloro-4- (2-morpholin-4-ylacetylamino) phenyl] thioureido) phenyl} -2-fluorobenzamide

515 Furan-2-carboxylic acid 4- {3- [3-chloro-4- (2-morpholin-4-ylacetylamino) -phenyl] -thioureido] -phenyl) -amide

414 N- {4- [3- (3-Chloro-4-methanesulfonylaminophenyl) thioureido] phenyl} acetamide

494. N- {4- [3- (3-Chloro-4-methanesulfonylaminophenyl) thioureido] phenyl} -2-fluorobenzamide

133

371 466 {4- [3- (3-Chloro-4-methanesulfonylamino-phenyl) -thioureido] - furan-2-carboxylic acid phenyljamide 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-Benzylpyrrolidin-3-yl) methylamino] - -3-chlorophenyl} thioureido) phenyl] -2-methylbenzamide 375 523 N- [4- (3- {3-Chloro-4- [methyl- (1-methyl-piperidin-4-yl)] - amino] phenyl} thioureido) phenyl] -2-methylbenzamide 376 510 Pyridine-2-carboxylic acid [4- (3- {3-chloro-4- [methyl- (1-methylpiperidin-4-yl) amino] phenyl} thioureido) phenyl] amide 377 347 N- {4- [3- (3-Chloro-4-vinyl-phenyl) -thioureido] -phenyl) -acetamide 378 441 {4- [3- (4-Chloro-3-trifluoromethyl-phenyl) -thioureido] - furan-2-carboxylic acid phenyljamide 379 452 {4- [3- (4-Chloro-3-trifluoromethyl-phenyl) -thioureido] - pyridine-2-carboxylic acid phenyljamide 380 487 N- {4- [3- (4-Chloro-3-trifluoromethyl-phenyl) -thioureido] -phenyl) -2,6-difluorobenzamide 381 486 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -3- -cyanophenyl} -2-fluorobenzamide 382 458 Furan-2-carboxylic acid {4- [3- (5-chloro-2,4-dimethoxy-phenyl) -thioureido] -3-cyanophenyl-amide 383 406 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -3- -cyanphenyl} acetamide 384 395 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -2-methyl-isothioureido] -phenyl} -acetamide 385 396 N- {4- (3- (5-Chloro-2,4-dimethoxyphenyl) -2-methylisothioureido] phenyl} acetamide 386 461 N- {4- [3- (3-Chloro-4-ethylsulfanyl-phenyl) -thioureido] -phenyl} -2-fluoro-benzamide 387 489 N- {4- [3- (4-Butylsulfanyl-3-chlorophenyl) thioureido] phenyl} -2-fluorobenzamide 388 411 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] - -3-methoxyphenyl} acetamide 389 491 N- {4- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] - -3-methoxyphenyl} -2-fluorobenzamide

134

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

531 [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [3-chloro-4- (2-piperidin-1-acetylamino) -phenyl] -thioureido} -phenyl) -amide

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

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

459 N- {4- [3- (5-Chloro-2-methoxy-4-methylphenyl) thioureido] -2-methylphenyl) -2-fluorobenzamide

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

533 Furan-2-carboxylic acid [4- (3- {3-chloro-4- [2- (2-dimethylaminoethylsulfanyl) acetylamino] phenyl} thioureido) phenyl] amide

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

460 [2-Chloro-4- (3- {4 - [(furan-2-carbonyl) amino] phenyl] thioureido) phenyl] carbamic acid ethyl ester

488 (2-Chloro-4- {3- [4- (2-fluoro-benzoylamino) -phenyl] -thioureido} -phenyl) -carbamic acid ethyl ester

440 N- {4- [3- (4-Acetylaminophenyl) thioureido] -2-chlorophenyl] benzamide

520 N- {4 - [({[4- (Benzoylamino) -3-chlorophenyl] amino} thioxomethyl) amino] phenyl} -2-fluorobenzamide

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

492 {4- [3- (4-Benzoylamino-3-chloro-phenyl) -thioureido] -phenyl} -furan-2-carboxylic acid

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

479 N- {4- [3- (4-Acetylaminophenyl) thioureido] -2-chlorophenyl} -2-thiomorpholin-4-ylacetamide

531 Furan-2-carboxylic acid 4- {3- [3-chloro-4- (2-thiomorpholin-4-ylacetylamino) -phenyl] -thioureido} -phenyl) -amide

559 N- (4- {3- [3-Chloro-4- (2-thiomorpholin-4-ylacetylamino) phenyl] thioureido} phenyl) -2-fluorobenzamide

461 ’N- {4- [3- (3-Chloro-4-methylsulfanyl-phenyl) -thioureido] -

-2-methylphenyl} -2-fluorobenzamide

135

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

477 N- {4- [3- (4-Acetylaminophenyl) thioureido] -2-chlorophenyl} -2-dipropylaminoacetamide

529 Furan-2-carboxylic acid 4- {3- [3-chloro-4- (2-dipropylamino-acetylamino) -phenyl] -thioureido] -phenyl) -amide

449 N- {4- [3- (4-Acetylaminophenyl) thioureido] -2-chlorophenyl} -2-diethylaminoacetamide

501 Furan-2-carboxylic acid (4- {3- [3-chloro-4- (2-diethylamino-acetylamino) -phenyl] -thioureido] -phenyl) -amide

529 N- (4- {3- [3-Chloro-4- (2-diethylaminoacetylamino) phenyl] thioureido] phenyl) -2-fluorobenzamide

447 N- {4- [3- (4-Acetylaminophenyl) thioureido] -2-chlorophenyl} -2-pyrrolidin-1-ylacetamide

499 Furan-2-carboxylic acid 4- {3- [3-chloro-4- (2-pyrrolidin-1-ylacetylamino) -phenyl] -thioureido] -phenyl) -amide

527 N- (4- {3- [3-Chloro-4- (2-pyrrolidin-1-ylacetylamino) phenyl] thioureido] phenyl) -2-fluorobenzamide

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

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

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

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

527 Furan-2-carboxylic acid 4- (3- (4- (2-Azepan-1-ylacetylamino) -3-chloro-phenyl) -thioureido} -phenyl) -amide

555 N- (4- (3- (4- (2-Azepan-1-ylacetylamino) -3-chlorophenyl) thioureido) phenyl) -2-fluorobenzamide

527 Furan-2-carboxylic acid [4- (3- (3-Chloro-4- [2- (2-methyl-piperidin-1-yl) -acetylamino] -phenyl) -thioureido) -phenyl] -amide

555 N- [4- (3- {3-Chloro-4- [2- (2-methyl-piperidin-1-yl) -acetylamino] -phenyl} -thioureido) -phenyl] -2-fluoro-benzamide

339 Furan-2-carboxylic acid [4- (3-pyridin-2-ylthioureido) phenyl] amide

339 Furan-2-carboxylic acid [4- (3-pyridin-4-ylthioureido) phenyl] amide

367 ’2-Fluoro-N- [4- (3-pyridin-3-ylthioureido) phenyl] benzamide

136

429 339 Furan-2- [4- (3-Pyridin-3-ylthioureido) phenyl] amide -carboxylic acids 430 353 Furan-2- (4- [3- (3-Aminophenyl) thioureido] phenyl) amide -carboxylic acids 431 406 (4- [3- (3-Trifluoromethylphenyl) thioureido] phenyl) amide furan-2-carboxylic acid 432 380 2-Fluoro-N- [4- (3-m-tolylthioureido) phenyl] benzamide 433 434 2-Fluoro-N- {4- [3- (3-trifluoromethylphenyl) thioureido] phenyl} benzamide 434 381 N- {4- [3- (3-Amino-phenyl) -thioureido] -phenyl} - -2-fluorobenzamide 435 388 (4- [3- (3-Amino-5-chloro-phenyl) -thioureido] -phenyl) -amide furan-2-carboxylic acid 436 352 Furan-2-carboxylic acid [4- (3-m-tolyl-thioureido) -phenyl] -amide acid 437 416 N- (4- [3- (2-Amino-5-chloro-phenyl) -thioureido] - phenyl} -2-fluorobenzamide 438 571 2-Piperidin-1-yl-ethyl ester (2-chloro-4- {3- [4- (2-fluoro- benzoylamino) phenyl] thioureido} phenyl) carbamic acid 439 543 2-Piperidin-1-yl-ethyl [2-chloro-4- (3- {4 - [(furan-2- (carbonyl) amino] phenyl} thioureido) phenyl] carbamic acid 440 388 {4- [3- (2-Amino-5-chloro-phenyl) -thioureido] -phenyl} -amide furan-2-carboxylic acid 441 363 Furan-2- {4- [3- (3-Cyanophenyl) thioureido] phenyl} amide -carboxylic acids 442 416 N- {4- [3- (3-Amino-5-chloro-phenyl) -thioureido] -phenyl} - -2-fluorobenzamide 443 367 2-Fluoro-N- [4- (3-pyridin-2-ylthioureido) phenyl] - benzamide 444 367 2-Fluoro-N- [4- (3-pyridin-4-ylthioureido) phenyl] benzamide 445 374 Furan-2-carboxylic acid (4- (3- (6-chloropyridin-3-yl) thioureido) phenyl} amide 446 388 (4- [3- (2-Amino-3-chloro-phenyl) -thioureido] -phenyl) -amide furan-2-carboxylic acid 447 396 Furan-2-carboxylic acid (4- [3- (3-hydrazinocarbonylphenyl) thioureido] phenyl) amide 448 410 2-Fluoro-N- (4- (3- (3- (1-hydroxyethyl) phenyl) thioureido) phenyl) benzamide 449 414 (4- [3- (3-Hydrazinocarbonylphenyl) thioureido] phenyl} amide

• · · ·

137

[1,2,3] thiadiazole-4-carboxylic acid 450 399 (4- [3- (3-Isopropyl-phenyl) -thioureido] -phenyl) -amide [1,2,3] thiadiazole-4-carboxylic acid 451 380 Furan- {4- [3- (3-Isopropyl-phenyl) -thioureido] -phenyl} -amide -2-carboxylic acids 452 409 2-Fluoro-N- {4- [3- (3-isopropylphenyl) thioureido] phenyl} benzamide 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 {4- [3- (3-Dimethylaminophenyl) thioureido] phenyl} amide furan-2-carboxylic acid 456 370 [1,2,3] Thiadiazole-4- [4- (3-m-Tolylthioureido) phenyl] amide -carboxylic acids 457 424 {4- [3- (3-Trifluoromethyl-phenyl) -thioureido) -phenyl} -amide [1,2,3] thiadiazole-4-carboxylic acid 458 479 N- (3-Chloro-4- [3- (5-chloro-2-methoxy-4-methylphenyl) thioureido] phenyl} -2-fluorobenzamide 459 449 N- {3-Chloro-4- [3- (3-chloro-4-methyl-phenyl) -thioureido) -phenyl} -2-fluoro-benzamide 460 481 N- {3-Chloro-4- [3- (3-chloro-4-methylsulfanyl-phenyl) -thioureido) -phenyl} -2-fluoro-benzamide 461 391 N- {4- [3- (3-Cyanophenyl) thioureido) phenyl} -2-fluorobenzamide 462 395 Furan-2-carboxylic acid (4- [3- (3-acetylaminophenyl) thioureido) phenyl) amide 463 424 2-Fluoro-N- {4- [3- (3-hydrazinocarbonylphenyl) thioureido) phenyl} benzamide 464 400 (4- {3- [3- (1-Hydroxyethyl) phenyl) thioureido] phenyl) amide [1,2,3] thiadiazole-4-carboxylic acid 465 434 N- {4- [3- (2-Amino-3-chlorophenyl) thioureido) phenyl} -2,6-difluorobenzamide 466 406 {4- [3- (3-Amino-5-chloro-phenyl) -thioureido) -phenyl} -amide [1,2,3] thiadiazole-4-carboxylic acid 467 398 {4- [3- (3,5-Dimethoxyphenyl) thioureido) phenyl] amide furan-2-carboxylic acid 468 416 (4- (3- (3,5-Dimethoxyphenyl) thioureido) phenyl) amide [1,2,3] thiadiazole-4-carboxylic acid 469 454 5- (3- (4 - ((Furan-2-carbonyl) amino) phenyl) dimethyl ester -

138:.

Thioureido) isophthalic acid

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

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

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

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

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

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

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

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

-2-fluorobenzamide

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

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

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

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

-carboxylic acids

406 2-Fluoro-N- {4- [3- (1H-indazol-5-yl) -thioureido] -phenyl} -benzamide

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

-fluorobenzamide

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

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

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

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

416 {4- [3- (5-Chloro-2-dimethylaminophenyl) thioureido] phenyl} 139

furan-2-carboxylic acid amide

444 N- {4- [3- (5-Chloro-2-dimethylaminophenyl) thioureido] phenyl} -2-fluorobenzamide

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

470 N- (4- {3- [4- (1-Azidoethyl) -3-chlorophenyl] thioureido} phenyl) -2-fluorobenzamide

337 Furan-2-carboxylic acid [4-1H-thiazolo [5,4-b] pyridin-2-ylideneamino) -phenyl] -amide

378 Furan-2-carboxylic acid {4- [3- (1H-Benzoimidazol-5-yl) -thioureido] -phenyl] -amide

392 Furan-2-carboxylic acid {4- [3- (2-methyl-1H-benzoimidazol-5-yl) thioureido] phenyl] amide

406 N- {4- [3- (1H-Benzoimidazol-5-yl) thioureido] phenyl} -2-fluorobenzamide

420 2-Fluoro-N- {4- [3- (2-methyl-1H-benzoimidazol-5-yl) thioureido] phenylbenzamide

452 [1,2,3] Thiadiazole-4-carboxylic acid {5- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -pyridin-2-yl] -amide

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

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

484 [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [4- (2-Aminopyrimidin-4-yl) -3-chloro-phenyl] -thioureido] -phenyl) -amide

494 N- (4- {3- [4- (2-Aminopyrimidin-4-yl) -3-chlorophenyl] thioureido) phenyl} -2-fluorobenzamide

434 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (3-Chloro-2-dimethylaminophenyl) thioureido] phenyl) amide

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

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

445 Pyridine-2-carboxylic acid {6- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -pyridin-3-yl) -amide

462 N- {6- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -pyridin-3-yl} -2-fluoro-benzamide

482 {4- [3- (3-Iodophenyl) thioureido] phenyl] amide [1,2,3] 140

thiadiazole-4-carboxylic acids

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

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

415 N- {4- [3- (3-Chlorobenzyl) thioureido] phenyl} -2-fluorobenzamide

434 Furan-2-carboxylic acid {6- [3- (5-Chloro-2,4-dimethoxy-phenyl) -thioureido] -pyridin-3-yl} -amide

435 [1,2,3] Thiadiazole-4-carboxylic acid (4- [3- (3-bromophenyl) thioureido] phenyl} amide

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

426 [1,2,3] Thiadiazole-4-carboxylic acid {5- [3- (3,5-Dichloro-phenyl) -thioureido] -pyridin-2-yl} -amide

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

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

450 N- {4- [3- (4-Amino-3,5-dichloro-phenyl) -thioureido] -phenyl} -2-fluoro-benzamide

539 N- {4- [3- (4-Amino-3,5-dibromo-phenyl) -thioureido] -phenyl} -2-fluoro-benzamide

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

529 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (4-amino-3,5-dibromo-phenyl) -thioureido] -phenyl} -amide

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

444 N- {4- [3- (3-Chloro-5-dimethylaminophenyl) thioureido] phenyl} -2-fluorobenzamide

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

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

379 Furan-2-carboxylic acid {4- [3- (1H-Benzotriazol-5-yl) -thioureido] -phenyl} -amide

425 N- {4- [3- (1H-Benzotriazol-5-yl) thioureido] phenyl} -

-2,6-difluorobenzamide

388 N- [4 - ({[2- (3-Chloro-phenyl) -hydrazino] thioxomethyl}) -

• ·

amino) phenyl] furan-2-carboxamide

416 N- [4 - ({[2- (3-Chlorophenyl) hydrazino] thioxomethyl} amino) phenyl] -2-fluorobenzamide

456 Furan-2-carboxylic acid {4- [3- (2-Amino-3-chloro-5-trifluoromethyl-phenyl) -thioureido] -phenyl) -amide

513 N- {4- [3- (3-Bromo-5-trifluoromethylphenyl) thioureido] phenyl} -2-fluorobenzamide

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

374 {4 - [(Furan-2-carbonyl) amino] phenyl} thiocarbamic acid O- (3-chlorophenyl) ester

474 1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (2-Amino-3-chloro-5-trifluoromethyl-phenyl) -thioureido] -phenyl) -amide

508 (4- [3- (3-Piperidin-1-yl-5-trifluoromethyl-phenyl) -thioureido] -phenyl] -amide [1,2,3] thiadiazole-4-carboxylic acid

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

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

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

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

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

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

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

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

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

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

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

488 Furan-2-carboxylic acid [4- [3- (3,5-Bistrifluoromethyl-benzyl) -thioureido] -phenyl) -amide w · · · · ·

142

548 503 {4- [3- (4-Bromo-3-trifluoromethyl-phenyl) -thioureido] -phenyl] - [1,2,3] thiadiazole-4-carboxylic acid amide 549 529 N- {4- [3- (3-Bromo-4-trifluoromethoxyphenyl) thioureido] phenyl} -2-fluorobenzamide 550 519 {4- [3- (3-Bromo-4-trifluoromethoxy-phenyl) -thioureido] - [1,2,3] thiadiazole-4-carboxylic acid phenyl iamide 551 473 Furan-2-carboxylic acid {4- [3- (3-chloro-4-trifluoromethylsulfanyl-phenyl) -thioureido] -phenyl} -amide 552 412 2-Fluoro-N- (4- {3- [2- (3-fluorophenyl) ethyl] thioureido} phenyl) benzamide 553 412 2-Fluoro-N- (4- {3- [2- (4-fluorophenyl) ethyl] thioureido} phenyl) benzamide 554 402 (4- {3- [2- (3-Fluorophenyl) ethyl] thioureido] phenyl) amide [1,2,3] thiadiazole-4-carboxylic acid 555 402 (4- {3- [2- (4-Fluorophenyl) ethyl] thioureido] phenyl) amide [1,2,3] thiadiazole-4-carboxylic acid 556 495 [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [3- (2-methylbutyl) -5-trifluoromethylphenyl] thioureido] phenyl) amide 557 481 {4- [3- (3-Isobutyl-5-trifluoromethylphenyl) thioureido] phenyl] amide [1,2,3] thiadiazole-4-carboxylic acid 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 {4- [3- (3-Pyrrolidin-1-yl-5-trifluoromethyl-phenyl) -thioureido] -phenyl] -amide [1,2,3] thiadiazole-4-carboxylic acid 561 384 Furan-2-carboxylic acid (4- {3- [2- (4-fluorophenyl) ethyl] thioureido} phenyl) amide 562 419 (4- {3- [2- (3-Chloro-phenyl) -ethyl] -thioureido} -phenyl) -amide [1,2,3] thiadiazole-4-carboxylic acid 563 429 N- (4- {3- [2- (3-Chloro-phenyl) -ethyl] -thioureido} - phenyl) -2-fluorobenzamide 564 401 (4- {3- [2- (3-Chloro-phenyl) -ethyl] -thioureido) -phenyl} -amide furan-2-carboxylic acid 565 402 (4- {3- [1- (4-Fluoro-phenyl) -ethyl] -thioureido) -phenyl} -amide [1,2,3] thiadiazole-4-carboxylic acid

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

phenyl) furan-2-carboxylic acid amide

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466 2-Fluoro-N- {4- [3- (3-fluoro-5-trifluoromethyl-benzyl) -thioureido] -phenyl} -benzamide

456 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (3-Fluoro-5-trifluoromethyl-benzyl) -thioureido] -phenyl] -amide

384 {4- [3- (1-Phenylethyl) thioureido] phenyl] amide [1,2,3] thiadiazole-4-carboxylic acid

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

366 Furan-2-carboxylic acid {4- [3- (1-phenylethyl) thioureido] phenyl} amide

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

384 Furan-2-carboxylic acid 4- (3- [1- (4-fluorophenyl) ethyl] thioureido] phenyl) amide

413 N- (4- [3- (1-tert-Butyl-1H-imidazol-2-yl) thioureido] phenyl} -2-fluorobenzamide

510 [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [3- (Isobutyl-methylamino) -5-trifluoromethyl-phenyl] -thioureido} -phenyl) -amide

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

520 2-Fluoro-N- (4- {3- [3- (isobutylmethylamino) -5-trifluoromethylphenyl] thioureido} phenyl) benzamide

510 [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [3- (Butylmethylamino) -5-trifluoromethylphenyl] thioureido} phenyl) amide

520 N- (4- {3- [3- (Butylmethylamino) -5-trifluoromethylphenyl] thioureido} phenyl) -2-fluorobenzamide

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

442 {1,2- (4-Fluoro-3-trifluoromethyl-phenyl) -thioureido] -phenyl] -amide [1,2,3] thiadiazole-4-carboxylic acid

522 {1,2- (4-Piperidin-1-yl-3-trifluoromethyl-benzyl) -thioureido] -phenyl] -amide [1,2,3] thiadiazole-4-carboxylic acid

482 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (4-Dimethylamino-3-trifluoromethylbenzyl) • thioureido] phenyl] amide

145

603 381 (4- {3- [2- (4-Aminophenyl) ethyl] thioureido) phenyl} amide furan-2-carboxylic acid 604 445 Furan-2-carboxylic acid (4- {3- [2- (4-bromophenyl) ethyl] thioureido} phenyl) amide 605 380 Furan-2- {4- [3- (2-p-Tolylethyl) thioureido] phenyl) amide -carboxylic acids 606 463 (4- {3- [2- (4-Bromo-phenyl) -ethyl] -thioureido} -phenyl) -amide [1,2,3] thiadiazole-4-carboxylic acid 607 396 Furan-2-carboxylic acid (4- {3- [2- (3-methoxy-phenyl) -ethyl] -thioureido} -phenyl) -amide 608 403 {4- [3- (1-tert-Butyl-1H-imidazol-2-yl) thioureido] phenyl} - [1,2,3] thiadiazole-4-carboxylic acid amide 609 384 Furan-2-carboxylic acid {4- [3- (1-tert-butyl-1H-imidazol-2-yl) -thioureido] -phenyl} -amide 610 492 N- {4- [3- (4-Dimethylamino-3-trifluoromethylbenzyl) thioureido] phenyl} -2-fluorobenzamide 611 427 Furan-2-carboxylic acid (4- {3- [2- (3,4-dimethoxyphenyl) ethyl] thioureido} phenyl) amide 612 380 Furan-2- {4- [3- (3-phenyl-propyl) -thioureido] -phenyl} -amide -carboxylic acids 613 399 {4- [3- (3-Phenyl-propyl) -thioureido] -phenyl} -amide [1,2,3] thiadiazole-4-carboxylic acid 614 502 Furan-2-carboxylic acid (4- (3- [2- (3,5-Bistrifluoromethyl-phenyl) -ethyl] -thioureido) -phenyl) -amide 615 550 {4- [3- (4-Iodo-3-trifluoromethyl-phenyl) -thioureido] -phenyl] - [1,2,3] thiadiazole-4-carboxylic acid amide 616 532 2-Fluoro-N- {4- [3- (4-piperidin-1-yl-3-trifluoromethylbenzyl) thioureido] phenyl} benzamide 617 537 (4- {3- [4- (4-Methyl-piperazin-1-yl) -3-trifluoromethyl- benzyl] thioureido) phenyl) amide [1,2,3] thiadiazole-4- -carboxylic acids 618 482 [1,2,3] Thiadiazole-4-carboxylic acid (4- [3- (3-dimethylamino-5-trifluoromethyl-benzyl) -thioureido] -phenyl} -amide 619 488 (4- (3- (3,5-Bistrifluoromethylphenyl) thioureidomethyl) - phenyl) furan-2-carboxylic acid amide 620 421 (4- [3- (3,5-Dichloro-phenyl) -thioureidomethyl] -phenyl} -amide furan-2-carboxylic acid 621 421 (4- [3- (3,4-Dichlorophenyl) thioureidomethyl] phenyl) amide furan-2-carboxylic acid

146 • ·

455 Furan-2-carboxylic acid {4- [3- (4-chloro-3-trifluoromethyl-phenyl) -thioureidomethyl] -phenyl} -amide

466 2-Fluoro-N- {4- [3- (4-fluoro-3-trifluoromethyl-benzylthioureido) -phenyl] -benzamide

456 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (4-fluoro-3-trifluoromethyl-benzyl) -thioureido] -phenyl] -amide

410 2-Fluoro-N- {4- [3- (2-phenoxyethyl) thioureido] phenyl} benzamide

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

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

09 2-Fluoro-N- {4- [3- (3-phenyl-propyl) -thioureido] -phenyl} -benzamide

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

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

473 1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (4-chloro-trifluoromethyl-benzyl) -phenyl] -thioureidomethyl-phenyl} -amide

381 2-Fluoro-N- [4- (3-pyridin-3-ylmethylthioureido) phenyl] benzamide

353 Furan-2-carboxylic acid [4- (3-pyridin-3-ylmethyl-thioureido) -phenyl] -amide

371 [1,2,3] Thiadiazole-4-carboxylic acid [4- (3-pyridin-3-ylmethyl-thioureido) -phenyl] -amide

439 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (3,5-Dichloro-phenyl) -thioureidomethyl] -phenyl-amide

492 N- {4- [3- (3-Dimethylamino-5-trifluoromethyl-benzyl) -thioureido] -phenyl} -2-fluoro-benzamide

415 [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [2- (3-methoxy-phenyl) -ethyl] -thioureido} -phenyl) -amide

399 {4- [3- (2-p-Tolylethyl) thioureido] phenyl] amide [1,2,3] thiadiazole-4-carboxylic acid

445 [1,2,3] Thiadiazole-4-carboxylic acid (4- (3- (2- (3,4-Dimethoxyphenyl) ethyl) thioureido] phenyl) amide

506 [1,2,3] Thiadiazole-4-carboxylic acid {4- (3- (3,5-bis-trifluoromethyl-phenyl) -thioureidomethyl] -phenyl) -amide

516 N- {4- (3- (3,5-Bis-trifluoromethyl-phenyl) -thioureidomethyl] -phenyl} -2-fluoro-benzamide

147

449 N- {4- [3- (3,5-Dichloro-phenyl) -thioureidomethyl] -phenyl} -2-fluoro-benzamide

449 N- {4- [3,4-Dichloro-phenyl) -thioureidomethyl] -methyl-2-fluoro-benzamide

448 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (3-acetylamino-5-chloro-phenyl) -thioureido] -phenyl} -amide

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

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

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

413 {4- [3- (4-Phenylbutyl) thioureido] phenyl] amide [1,2,3] thiadiazole-4-carboxylic acid

397 [1,2,3] Thiadiazole-4-carboxylic acid [4- (3-indan-1-ylthioureido) phenyl] amide

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

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

415 [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [2- (4-methoxy-phenyl) -ethyl] -thioureido} -phenyl) -amide

506 N- (4- {3- [2- (3-Dimethylamino-5-trifluoromethyl-phenyl) -ethyl] -thioureido] -phenyl) -2-fluoro-benzamide

510 [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [3- (3-Dimethylaminopropyl) -5-trifluoromethylphenyl] thioureido] phenyl) amide

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

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

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

381 2-Fluoro-N- [4- (3-pyridin-4-ylmethylthioureido) phenyl] benzamide

353 Furan-2-carboxylic acid [4- (3-pyridin-4-ylmethyl-thioureido) -phenyl] -amide

371 [1,2,3] Thiadiazole-4-carboxylic acid [4- (3-pyridin-4-ylmethyl-thioureido) -phenyl] -amide

148

506 2-Fluoro-N- {4- [3- (3-iodobenzyl) thioureido] phenyl} benzamide

478 Furan-2-carboxylic acid {4- [3- (3-iodo-benzyl) -thioureido] -phenyl] -amide

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

479 N- (4- {3- [2- (3,5-Dichlorophenoxy) ethyl] thioureido} phenyl) -2-fluorobenzamide

451 Furan-2-carboxylic acid (4- {3- [2- (3,5-Dichloro-phenoxy) -ethyl] -thioureido} -phenyl) -amide

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

417 Furan-2-carboxylic acid (4- {3- [2- (3-chloro-phenoxy) -ethyl] -thioureido} -phenyl) -amide

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

466 2-Fluoro-N- {4- [3- (2-fluoro-5-trifluoromethylbenzyl) thioureido] phenyl} benzamide

438 Furan-2-carboxylic acid {4- [3- (2-Fluoro-5-trifluoromethyl-benzyl) -thioureido] -phenyl) -amide

456 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (2-Fluoro-5-trifluoromethyl-benzyl) -thioureido] -phenyl] -amide

416 N- {4- [3- (3,4-Difluorobenzyl) thioureido] phenyl} -2-fluorobenzamide

452 N- (4- {3- [2- (4-Dimethylamino-3-methylphenyl) ethyl] thioureido} phenyl) -2-fluorobenzamide

496 [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [2- (3-Dimethylamino-5-trifluoromethyl-phenyl) -ethyl] -thioureido] -phenyl) -amide

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

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

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

495 [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [2- (3-Bromo-phenylsulfanyl) -ethyl] -thioureido} -phenyl) -amide

477 Furan-2-carboxylic acid 4- (3- {2- (3-bromo-phenylsulfanyl) -ethyl] -thioureido) -phenyl) -amide

505 N- (4- {3- [2- (3-Bromo-phenylsulfanyl) -ethyl] -thioureido}

149

phenyl) -2-fluorobenzamide

493 [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [2- (3-bromo-4-methoxy-phenyl) -ethyl] -thioureido) -phenyl] -amide

493 [1,2,3] Thiadiazole-4-carboxylic acid 4- {3- [2- (5-bromo-2-methoxy-phenyl) -ethyl] -thioureido} -phenyl) -amide

419 [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [2- (2-chloro-phenyl) -ethyl] -thioureido) -phenyl] -amide

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

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

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

547 2-Fluoro-N- (4- {3- [4- (4-methylpiperazin-1-yl) -3-trifluoromethylbenzyl] thioureido} phenyl) benzamide

469 [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [2- (3,5-Dichloro-phenoxy) -ethyl] -thioureido} -phenyl) -amide

423 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (3-chloro-4-fluoro-benzyl) -thioureido] -phenyl) -amide

427 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (4-tert-butylbenzyl) thioureido] phenyl] amide

399 {4- [3- (3,5-Dimethylbenzyl) thioureido] phenyl] amide [1,2,3] thiadiazole-4-carboxylic acid

442 [1,2,3] Thiadiazole-4-carboxylic acid 4- {3- [2- (4-Dimethylamino-3-methyl-phenyl) -ethyl] -thioureido} -phenyl) -amide

479 [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [2- (4-bromophenoxy) ethyl] thioureido} phenyl) amide

526 [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [2- (4-iodo-phenoxy) -ethyl] -thioureido} -phenyl) -amide

489 N- (4- {3- [2- (4-Bromophenoxy) ethyl] thioureido} phenyl) -2-fluorobenzamide

536 2-Fluoro-N- (4- {3- [2- (4-iphenoxy) ethyl] thioureido} phenyl) benzamide

461 Furan-2-carboxylic acid (4- {3- [2- (4-Bromo-phenoxy) -ethyl] -thioureido) -phenyl} -amide

508-furan-2-carboxylic acid (4- {3- [2- (4-iodo-phenoxy) -ethyl] -thioureido} -phenyl) -amide

408 {4- [3- (3,4-Dichlorophenyl) thioureido] phenyl] amide oxazole

150

4-carboxylic acids

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

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

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

-4-carboxylic acids

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

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

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

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

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

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

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

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

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

668 N- (4- {3- [3-Chloro-5- (3- {4 - [([1,2,3] thiadiazole-4-carbonyl) amino] phenyl} thioureido) phenyl] thioureido) phenyl] [ 1,2,3] thiadiazole-4-carboxamide

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

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

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

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

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

435 (4- {3- [2- (3,4-Dichlorophenyl) ethyl] thioureido) phenyl}

151 furan-2-carboxylic acid amide

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

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

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

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

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

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

-fluorobenzamide

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

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

409 2-Fluoro-N- (4- (3- (1-methyl-1-phenylethyl) thioureido) phenyl} benzamide

399 (4- [3- (1-Methyl-1-phenylethyl) thioureido] phenyl] amide [1,2,3] thiadiazole-4-carboxylic acid

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

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

438 [1,2,3] Thiadiazole-4-carboxylic acid (4- (3- (3-trifluoromethyl-benzyl) -thioureido) -phenyl} -amide

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

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

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

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

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

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

152

acid

384 Furan-2-carboxylic acid 4- (3- [2- (2-fluorophenyl) ethyl] thioureido} phenyl) amide

435 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (4-bromo-phenyl) -thioureido] -phenyl] -amide

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

388 {4- [3- (4-Fluorobenzyl) thioureido] phenyl] amide [1,2,3] thiadiazole-4-carboxylic acid

405 {4- [3- (4-Chlorobenzyl) thioureido] phenyl] amide [1,2,3] thiadiazole-4-carboxylic acid

449 (4- [3- (4-Bromobenzyl) thioureido] phenyl] amide [1,2,3] thiadiazole-4-carboxylic acid

332 N- (4- {3- [1- (4-Fluorophenyl) ethyl] thioureido) phenyl} acetamide

438 Thiazole-4-carboxylic acid {4- [3- (3,4-dichloro-benzyl) -thioureido] -phenyl] -amide

455 Thiazole-4-carboxylic acid {4- [3- (2-fluoro-5-trifluoromethyl-benzyl) -thioureido] -phenyl] -amide

Thiazole-4-carboxylic acid {4- [3- (4-tert-butylbenzyl) thioureido] phenyl} amide

374 {4- [3- (2-Fluorophenyl) thioureido] phenyl] amide [1,2,3] thiadiazole-4-carboxylic acid

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

526 [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [2- (3-iodophenoxy) ethyl] thioureido} phenyl amide

409 N- (4- {3- [1- (4-Fluorophenyl) ethyl] thioureido] phenyl) -2-phenylacetamide

425 N- (4- {3- [1- (4-Fluorophenyl) ethyl] thioureido) phenyl} -

-2-methoxybenzamide

425 N- (4- {3- [1- (4-Fluorophenyl) ethyl] thioureido} phenyl) -3-methoxybenzamide

425 N- (4- {3- [1- (4-Fluorophenyl) ethyl] thioureido) phenyl) -4-methoxybenzamide

429 2-Chloro-N- (4- {3- [1- (4-fluorophenyl) ethyl] thioureido} phenyl) benzamide

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

453 4- (4- (3- (1- (4-Fluorophenyl) ethyl) thioureido} 153-phenylphenylcarbamoyl) phenyl acetic acid ester

394 N- (4- {3- [1- (4-Fluorophenyl) ethyl] thioureido} phenyl) benzamide

395 N- (4- {3- [1- (4-Fluorophenyl) ethyl] thioureido] phenyl) isonicotinamide

410 N- (4- {3- [1- (4-Fluorophenyl) ethyl] thioureido} phenyl) -4-hydroxybenzamide

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

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

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

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

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

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

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

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

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

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

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

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

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

489 2-Fluoro-N- (4- {3- [1- (4-fluorophenyl) -2-phenylethyl] •

154 thioureido} phenyl) benzamide

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

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

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

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

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

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

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

409 2-Fluoro-N- {4- [3- (1-p-tolylethyl) thioureido] phenyl} benzamide

473 N- (4- {3- [1- (2-Bromophenyl) ethyl] thioureido) phenyl} -2-fluorobenzamide

429 N- (4- {3- [1- (2-Chloro-phenyl) -ethyl] -thioureido) -phenyl) -2-fluoro-benzamide

462 2-Fluoro-N- (4- (3- (1- (2-trifluoromethylphenyl) ethyl) thioureido} phenyl) benzamide

462 2-Fluoro-N- (4- (3- (1- (3-trifluoromethylphenyl) ethyl) thioureido} phenyl) benzamide

462 2-Fluoro-N- (4- (3- (1- (4-trifluoromethylphenyl) ethyl) thioureido} phenyl) benzamide

425 2-Fluoro-N- (4- (3- (1- (2-methoxyphenyl) ethyl) thioureido) phenyl) benzamide

425 2-Fluoro-N- (4- (3- (1- (3-methoxyphenyl) ethyl) thioureido) phenyl) benzamide

441 2-Fluoro-N- (4- (3- (1- (4-fluorophenyl) -2-methylpropyl) thioureido} phenyl) benzamide

419 N- (4- (3- (1- (3-Cyanophenyl) ethyl) thioureido) phenyl) -

-2-fluorobenzamide

419 N- (4- {3- [1- (4-Cyanophenyl) ethyl] thioureido) phenyl} -

-2-fluorobenzamide

438 N- (4- (3- [1- (4-Dimethylaminophenyl) ethyl] thioureido} phenyl) -2-fluorobenzamide

N- (4- {3- [1- (3-Dimethylaminophenyl) ethyl] thioureido} phenyl) -2-fluorobenzamide

155 ········ · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

473 2-Bromo-N- (4- {3- [1- (4-fluorophenyl) ethyl] thioureido} phenyl) benzamide

446 Quinoline-2-carboxylic acid (4- {3- [1- (4-fluorophenyl) ethyl] thioureido] phenyl) amide

410 2-Fluoro-N- {4- [3- (2-hydroxy-1-phenylethyl) thioureido] phenyl} benzamide

332 2-Fluoro-N- [4- (3-isopropylthioureido) phenyl] benzamide

445 2-Fluoro-N- {4- [3- (1-naphthalen-2-ylethyl) thioureido] phenyl} benzamide

412 3-Fluoro-N- {4- {3- [1- (4-fluoro-phenyl) -ethyl] -thioureido} -phenyl) -benzamide

412 4-Fluoro-N- (4- {3- [1- (4-fluorophenyl) ethyl] thioureido} phenyl) benzamide

384 2-Fluoro-N- {4- [3- (1-furan-2-ylethyl) thioureido] phenyl} benzamide

395 2-Fluoro-N- {4- [3- (1-pyridin-4-ylethyl) thioureido] phenyl} benzamide

397 2-Fluoro-N- (4- {3- [1- (1-methyl-1H-pyrrol-2-yl) -ethyl] -thioureido} -phenyl) -benzamide

401 2-Fluoro-N- {4- [3- (1-thiophen-3-yl-ethyl) -thioureido] -phenyl} -benzamide

445 N- {4- [3- (3-Chloro-4-ethoxy-phenyl) -thioureido] -phenyl} -2-fluoro-benzamide

459 N- {4- [3- (3-Chloro-4-propoxy-phenyl) -thioureido] -phenyl} -2-fluoro-benzamide

459 N- {4- [3- (3-Chloro-4-isopropoxy-phenyl) -thioureido] -phenyl} -2-fluoro-benzamide

473 N- {4- [3- (4-Butoxy-3-chloro-phenyl) -thioureido] -phenyl} -2-fluoro-benzamide

522 2-Fluoro-N- {4- [3- (3-iodo-4-methoxy-phenyl) -thioureido] -phenyl} -benzamide

475 N- (4- [3- (3-Bromo-4-methoxyphenyl) thioureido] phenyl) -2-fluorobenzamide

520 N- (4- {3- [1- (4-Fluorophenyl) ethyl] thioureido} phenyl) -2-iodobenzamide

346 N- (4- (3- [1- (4-Fluorophenyl) ethyl] thioureido] phenyl) propionamide

286 N- [4- (3-Phenylthioureido) phenyl] acetamide

463 (1,2,3) Thiadiazole-4-carboxylic acid (4- {3 - [(1S) -1- (4-bromophenyl) ethyl] thioureido) phenyl) amide

463 (4- (3 - [(IR) -1- (4-Bromophenyl) ethyl] thioureido) phenyl) amide

• ·

[1,2,3] thiadiazole-4-carboxylic acid

[1,2,3] Thiadiazole-4-carboxylic acid [4- [3- [1- (3,5-Bistrifluoromethyl-phenyl) -ethyl] -thioureido) -phenyl] -amide

418 [1,2,3] Thiadiazole-4-carboxylic acid (4- {3 - [(1S) -1- (4-chloro-phenyl) -ethyl] -thioureido} -phenyl) -amide

[1,2,3] Thiadiazole-4-carboxylic acid (4- {3 - [(IR) -1- (4-chloro-phenyl) -ethyl] -thioureido) -phenyl) -amide

409 N- [4 - [[[[1- (4-Cyanophenyl) ethyl] amino] thioxomethyl] amino] phenyl] -1,2,3-thiadiazole-4-carboxamide

462 Thiazole-4-carboxylic acid (4- {3- [1- (4-bromo-phenyl) -ethyl] -thioureido} -phenyl) -amide

520 (4- {3- (1S) - [1- (3,5-Bistrifluoromethyl-phenyl) -ethyl] -thioureido} -phenylamide [1,2,3] thiadiazole-4-carboxylic acid

470 N- (4 - {[({1- [4-Fluoro-3-trifluoromethyl) phenyl] ethyl} amino) carbothioyl] amino) phenyl) -1,2,3-thiadiazole-4-carboxamide

486 N- (4 - {[({1- [4-Chloro-3-thiadiazole-4-carboxamide)

519 N - (4 - {[({(1S) -1- [3,5-Thiazole-4-carboxamide)

469 N- (4 - {[({1- [3-Fluoro-5-trifluoromethyl) phenyl] ethyl} amino) carbothioyl] amino) phenyl) -1,3-thiazole-4-carboxamide

469 N- (4 - [[([1- [2-Fluoro-4- (trifluoromethyl) phenyl] ethyl} amino) carbothioyl] amino] phenyl] -1,3-thiazole-4-carboxamide

469 N- (4 - {[({1- [2-Fluoro-5-trifluoromethyl) phenyl] ethyl) amino) carbothioyl] amino) phenyl) -1,3-thiazole-4-carboxamide

519 N- (4 - {[({1- [2,4-Bis (trifluoromethyl) phenyl] ethyl} amino) carbothioyl] amino) phenyl) -1,3-thiazole-4-carboxamide

411 N- {4 - [([[1- (2,4-Dimethylphenyl) ethyl] amino} carbothioyl) amino] phenyl} -1,3-thiazole-4-carboxamide

452 N- {4 - [({[1- (2,4-Dichlorophenyl) ethyl] amino) carbothioyl) amino] phenyl} -1,3-thiazole-4-carboxamide

397 N- {4 - [({[1- (3-Methylphenyl) ethyl] amino) carbothioyl) amino] phenyl} -1,3-thiazole-4-carboxamide

469 N- (4 - {[({1- [4-Fluoro-3-trifluoromethyl) phenyl] ethyl) amino) carbothioyl] amino] phenyl) -1,3-thiazole-4-carboxamide

435 N- {4 - [({[1- (2-Chloro-4-fluorophenyl) ethyl] amino} carbothioyl) amino] phenyl] -1,3-thiazole-4-carboxamide

419 N- [4 - [([[1- (3,4-Difluorophenyl) ethyl] amino} carbothioyl) amino] phenyl} -1,3-thiazole-4-carboxamide

480 N- {4 - [({[1- (4-Bromo-2-fluoro-phenyl) -ethyl] -amino) -carbothioyl)

-amino] phenyl} -1,3-thiazole-4-carboxamide

401 N- {4 - [({[1- (3-Fluorophenyl) ethyl] amino} carbothioyl) amino]

157

phenyl} -1,3-thiazole-4-carboxamide 843 4 62 Ν- {4 - [({[1- (2-Bromophenyl) ethyl] amino} carbothioyl) amino] phenyl] -1,3-thiazole-4-carboxamide 844 4 62 N- {4 - [({[1- (3-Bromophenyl) ethyl] amino] carbothioyl) amino] phenyl} -1,3-thiazole-4-carboxamide 845 451 N- (4 - {[({1- [2- (Trifluoromethyl) phenyl] ethyl] amino) 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 - {[({(IR) -1- [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-Fluoro-4-trifluoromethyl) phenyl] ethyl) amino) carbothioyl] amino) phenyl) -1,3-thiazole-4-carboxamide 850 485 N- (4 - {[({1- [4-Chloro-3- (trifluoromethyl) phenyl] ethyl} amino) carbothioyl] 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-Fluoro-2-trifluoromethyl) phenyl] ethyl] 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} carbothioyl) amino] phenyl} -1,3-thiazole-4-carboxamide 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-fluoro-phenyl) -ethyl] -amino) -carbothioyl) -amino] phenyl} -1,3-thiazole-4-carboxamide 857 366 N- (4 - {[({1- (3,5-Bis (trifluoromethyl) phenyl] propyl} 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

158

862

863

864

865

433 N- {4 - [({[3,5-Bis (trifluoromethyl) benzyl] amino] carbothioyl) amino] phenyl) -1H-imidazole-4-carboxamide

440 N- {4 - [({[1- (4-Fluorophenyl) ethyl] amino} carbothioyl) amino] phenyl} -1H-imidazole-4-carboxamide

506 N- {4 - [({[3,5-Bis (trifluoromethyl) benzyl] amino] carbothioyl) amino] phenyl} -1-methyl-1H-imidazole-4-carboxamide

462 N- (4 - {[({1- [3,5-Bis (trifluoromethyl) phenyl] propyl) amino) carbothioyl] amino] phenyl) -1,3-thiazole-4-carboxide

Example 866

Method 32 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (2,5-Dichloro-phenyl) -thioureido] -phenyl} -amide

To a solution of 2,5-dichloroaniline (0.16 g) in tetrahydrofuran (20 mL) was added freshly prepared 1,1'-thiocarbonyldiimidazole (0.20 g) and the mixture was stirred at room temperature for about 30 minutes.

[1,2,3] Thiadiazole-4-carboxylic acid (4-aminophenyl) amide (0.22 g) was added to the reaction flask and the mixture was stirred for about 6 hours. The solvent was then removed by evaporation under reduced pressure and hot acetonitrile (3 mL) was added. After 15 hours the mixture was filtered and the collected precipitate was washed with acetonitrile and then with diethyl ether, air dried to give the desired product as a white powder.

Using the above procedure and appropriate starting materials, the following compounds were prepared:

Ex. Μ + H

COMPOUND NAME

867 321 N- {4- [3- (3-Chloro-phenyl) -thioureido] -phenyl} -acetamide 868 413 N- {4- [3- (3-Chloro-4-methoxy-phenyl) -thioureido] -phenyl] -benzamide 869 443 N- {4- [3- (3-Chloro-4-methoxy-phenyl) -thioureido] -phenyl} -2-methoxy-benzamide 870 443 N- {4- [3- (3-Chloro-4-methoxy-phenyl) -thioureido] -phenyl} - -3-methoxybenzamide 871 443 N- {4- [3- (3-Chloro-4-methoxy-phenyl) -thioureido] -phenyl} -4-methoxy-benzamide

• · • ·

159

431 N- {4- [3- (3-Chloro-4-methoxy-phenyl) -thioureido] -phenyl} -4-methoxy-benzamide

431 N- {4- [3- (3-Chloro-4-methoxy-phenyl) -thioureido] -phenyl) -3-fluoro-benzamide

431 N- {4- [3- (3-Chloro-4-methoxy-phenyl) -thioureido] -phenyl} -4-fluoro-benzamide

437 Furan-2-carboxylic acid {4- [3- (3,5-Dichloro-4-methoxy-phenyl) -thioureido] -phenyl} -amide

511 {4- [3- (5-Bromo-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -carbamic acid hexyl ester

81 Hexanoic acid {4- [3- (5-bromo-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -amide

505 N- {4- [3- (5-Bromo-2,4-dimethoxy-phenyl) -thioureido] -phenyl) -2-fluoro-benzamide

477 Furan-2-carboxylic acid [4- [3- (5-bromo-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -amide

501 N - {4- [3- (5-Bromo-2,4-dimethoxyphenyl) thioureido] phenyl} -2-methylbenzamide

517 N- (4- [3- (5-Bromo-2,4-dimethoxyphenyl) thioureido] phenyl} -4-methoxybenzamide

395 N- {4- [3- (5-Chloro-2-ethoxy-4-methoxy-phenyl) -thioureido] -phenyl} -acetamide

395 N- {4- [3- (5-Chloro-4-ethoxy-2-methoxy-phenyl) -thioureido] -phenyl} -acetamide

423 N- {4- [3- (2-Butoxy-5-chloro-4-methoxy-phenyl) -thioureido] -phenyl} -acetamide

423 N- {4- [3- (4-Butoxy-5-chloro-2-methoxy-phenyl) -thioureido] -phenyl} -acetamide

457 N- {4- [3- (2-Benzyloxy-5-chloro-4-methoxyphenyl) thioureido] phenyl} acetamide

457 N- {4- [3- (4-Benzyloxy-5-chloro-2-methoxyphenyl) thioureido] phenyl} acetamide

421 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (3-chloro-4-methoxyphenyl) thioureido] phenyl] amide

424 2- {4- [3- (4-Acetylaminophenyl) thioureido] -2-chloro-5-methoxyphenoxy) acetamide

367 N- {4- [3- (5-Chloro-2-hydroxy-4-methoxy-phenyl) -thioureido] -phenyl} -acetamide

367 N- {4- [3- (3-Chloro-4-methylsulfanyl-phenyl) -thioureido] -phenyl} -acetamide

447 N- [4- (3- {3-Chloro-4- [methyl- (1-methylpiperidin-4-yl)]] -

160 amino] phenyl) thioureido) phenyl] acetamide

426 N- (4- {3- [3-Chloro-4- (methyl-phenylamino) -phenyl] -thioureido} -phenyl) -acetamide

509 N- [4- (3- {4 - [(1-Benzylpyrrolidin-3-yl) methylamino] -3-chlorophenyl} thioureido) phenyl] acetamide

418 N- (4- {3- [3-Chloro-4- (cyclopentylmethylamino) phenyl] thioureido} phenyl) acetamide

433 N- [4- (3- {3-Chloro-4- [methyl- (1-methyl-pyrrolidin-3-yl) -amino] -phenyl} -thioureido) -phenyl] -acetamide

419 Furan-2-carboxylic acid {4- [3- (3-Chloro-4-methylsulfanyl-phenyl) -thioureido] -phenyl] -amide

447 N- {4- [3- (3-Chloro-4-methylsulfanyl-phenyl) -thioureido] -phenyl} -2-fluoro-benzamide

465 N- {4- [3- (3-Chloro-4-methylsulfanyl-phenyl) -thioureido] -phenyl} -2,6-difluorobenzamide

445 N- {4- [3- (5-Chloro-2-methoxy-4-methyl-phenyl) -thioureido] -phenyl} -2-fluoro-benzamide

441 N- {4- [3- (5-Chloro-2-methoxy-4-methyl-phenyl) -thioureido] -phenyl} -2-methyl-benzamide

434 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (3-Chloro-4-dimethylaminophenyl) thioureido] phenyl) amide

444 N- {4- [3- (3-Chloro-4-dimethylaminophenyl) thioureido] phenyl} -2-fluorobenzamide

517 [1,2,3] Thiadiazole-4-carboxylic acid [4- (3- {3-chloro-4- [methyl- (1-methylpiperidin-4-yl) amino] phenyl} thioureido) phenyl] amide

579 [1,2,3] Thiadiazole-4-carboxylic acid [4- (3- {4 - [(1-Benzylpyrrolidin-3-yl) methylamino] -3-chloro-phenyl] -thioureido) -phenyl] -amide

527 N- [4- (3- {3-Chloro-4- [methyl (1-methylpiperidin-4-yl) amino] phenyl} thioureido) phenyl] -2-fluorobenzamide

435 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (5-Chloro-2-methoxy-4-methyl-phenyl) -thioureido] -phenyl] -amide

589 N- [4- (3- {4 - [(1-Benzylpyrrolidin-3-yl) methylamino] -3-chlorophenyl) thioureido) phenyl] -2-fluorobenzamide

501 Furan-2-carboxylic acid {4- [3- (5-chloro-2,4-dimethoxy-phenyl) -thioureido] -3-trifluoromethyl-phenyl} -amide

366 2-Fluoro-N- [4- (3-phenylthioureido) phenyl] benzamide

338 Furan-2-carboxylic acid [4- (3-phenylthioureido) phenyl] amide

161

912 356 [1,2,3] Thiadiazole-4- [4- (3-phenylthioureido) phenyl] amide -carboxylic acids 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-hydroxyethyl) phenyl] 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-hydroxyethyl) phenyl] thioureido} phenyl) amide 918 371 {4- [3- (3-Aminophenyl) thioureido] phenyl} amide [1,2,3] thiadiazole-4-carboxylic acid 919 501 {4- [3- (3-Bromo-4-trifluoromethoxy-phenyl) -thioureido] - phenyl) furan-2-carboxylic acid amide 920 423 N- {4- [3- (3-tert-Butyl-phenyl) -thioureido] -phenyl- -2-fluorobenzamide 1025 440 {4- [3- (4-Chloro-3,5-dichloro-phenyl) -thioureido] -phenyl] -amide [1,2,3] thiadiazole-4-carboxylic acid 1026 485 N- {4- [3- (1-Benzofuran-2-yl-ethyl) -thioureido] -phenyl) -2-trifluoromethyl-benzamide 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-yl-ethyl) -thioureido] -phenyl} -amide 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-cyanophenyl) ethyl] thioureido} phenyl) amide 1032 435 Benzofuran-2-carboxylic acid (4- (3- (1- (4-fluorophenyl) ethyl) thioureido} phenyl) 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-cyanophenyl) ethyl) thioureido] phenyl) amide 1036 446 (4- (3- (1- (4-Fluorophenyl) ethyl) thioureido] phenyl) amide

• · ♦

162 isoquinoline-3-carboxylic acids

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-cyanophenyl) ethyl] thioureido) phenyl) amide 1039 506 Isoquinoline-3-carboxylic acid (4- {3- [1- (4-bromophenyl) ethyl] thioureido) phenyl} amide 1040 446 (4- {3- [1- (4-Fluorophenyl) ethyl] thioureido] phenyl) amide quinoline-3-carboxylic acids 1041 446 Quinoline-4-carboxylic acid (4- {3- [1- (4-fluorophenyl) ethyl] thioureido] phenyl) amide 1042 446 (4- {3- [1- (4-Fluorophenyl) ethyl] thioureido) phenyl} amide quinoline-6-carboxylic acid 1043 446 Quinoline-8-carboxylic acid (4- {3 - [(4-fluorophenyl) ethyl] thioureido} phenyl) amide 1044 462 N- (4- {3- [1- (4-Fluorophenyl) 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-isobutoxy-phenylthioureido) -phenyl} -2-fluorobenzamide 1047 414 2-Fluoro-N- {4- [3- (3-fluoro-4-methoxyphenyl) 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-trifluoromethyl-phenyl) -thioureido] -phenyl} -benzamide 1051 449 N- {4- [3- (2-Amino-5-trifluoromethyl-phenyl) -thioureido] -phenyl} -2-fluoro-benzamide 1052 459 N- (4- (3- [3- [1- (3-Chloro-4-methoxyphenyl) ethyl] thioureido] phenyl) -2-fluorobenzamide 1053 417 N- {4- [3- (5-Chloro-2-hydroxy-phenyl) -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-trifluoromethyl-phenyl) -thioureido] -phenyl} -benzamide 1056 473 (S) -N- (4- {3- [1- (4-Bromophenyl) ethyl] thioureido} -

phenyl) -2-fluorobenzamide

163

473 N- (4- {3 - [(1R) -1- (4-Bromophenyl) ethyl] thioureido) phenyl} -2-fluorobenzamide

494 2-Fluoro-N- (4- {3- [2-methoxy-4- (2,2,2-trifluoroethoxy) phenyl] thioureido} phenyl) benzamide

399 N- {4- [3- (2-Amino-5-fluorophenyl) thioureido] phenyl} -2-fluorobenzamide

502 N- (4- {3- [1- (4-Dimethylsulfamoylphenyl) ethyl] thioureido] phenyl) -2-fluorobenzamide

542 2-Fluoro-N- [4- (3- {1- [4- (piperidine-1-sulfonyl) phenyl] ethyl} thioureido) phenyl] benzamide

562 N- (4- (3- [2,4-Bis (2,2,2-trifluoroethoxy) phenyl] thioureido] phenyl) -2-fluorobenzamide

409 2-Fluoro-N- {4- [3 - ((1S) -1-p-tolylethyl) thioureido] phenyl} benzamide

409 2-Fluoro-N- {4- [3 - ((IR) -1-p-tolylethyl) thioureido] phenyl} benzamide

394 2-Fluoro-N- {4- [3 - ((1S) -1-phenylethyl) thioureido] phenyl} benzamide

429 N- (4- {3 - [(IR) -1- (4-Chlorophenyl) ethyl] thioureido] phenyl) -2-fluorobenzamide

429 N- (4- {3 - [(1S) -1- (4-Chlorophenyl) ethyl] thioureido} phenyl) -2-fluorobenzamide

394 2-Fluoro-N- {4- [3 - ((IR) -1-phenylethyl) thioureido] phenyl} benzamide

432 N- (4- {3- [1- (4-Cyanophenyl) ethyl] thioureido] phenyl) -2-methoxybenzamide

447 N- (4- (3- (1-Benzofuran-2-ylethyl) thioureido) phenyl} -2-methoxybenzamide

485 N- (4- (3- (1- (4-Bromophenyl) ethyl) thioureido) phenyl) -2-methoxybenzamide

419 3-Cyano-N- (4- (3- (1- (4-fluorophenyl) ethyl) thioureido) phenyl) benzamide

462 N- (4- {3- [1- (4-Fluorophenyl) ethyl] thioureido] phenyl) -4-trifluoromethylbenzamide

419 4-Cyano-N- (4- (3- (1- (4-fluorophenyl) ethyl) thioureido) phenyl) benzamide

469 2-Fluoro-N- (4- {3- [1- (4-fluorophenyl) ethyl] thioureido} -2,3,5,6-tetramethylphenyl} benzamide

480 N- (4- {3- [1- (4-Cyanophenyl) ethyl] thioureido) -2,5'-dimethoxyphenyl) -2-fluorobenzamide

473 2-Fluoro-N- (4- (3- (1- (4-fluorophenyl) ethyl) thioureido))

164

-2,5-dimethoxyphenyl) benzamide

530 N- {3,5-Dichloro-4- [3- (5-chloro-2,4-dimethoxyphenyl) thioureido] phenyl) -2-fluorobenzamide

447 N- (3-Chloro-4- {3- [1- (4-fluoro-phenyl) -ethyl] -thioureido] -phenyl) -2-fluoro-benzamide

480 2,3,4,5-Tetrafluoro-N- (4- {3- [1- (4-fluorophenyl) ethyl] thioureido} -3-methylphenyl) benzamide

462 2,4,5-Trifluoro-N- (4- {3- [1- (4-fluorophenyl) ethyl] thioureido} -3-methylphenyl) benzamide

427 2-Fluoro-N- (4- {3- [1- (4-fluorophenyl) ethyl] thioureido) -3-methylphenyl) benzamide

457 2-Fluoro-N- (4- (3- [1- (4-fluorophenyl) ethyl] thioureido} -2-methoxy-5-methylphenyl) benzamide

443 2-Fluoro-N- (4- {3- [1- (4-fluorophenyl) ethyl] thioureido) -3-methoxyphenyl) benzamide

570 N- (2,6-Dibromo-4- {3- [1- (4-fluorophenyl) ethyl] thioureido} phenyl) -2-fluorobenzamide

480 2-Fluoro-N- (4- {3- [1- (4-fluorophenyl) ethyl] thioureido} -2-trifluoromethylphenyl) benzamide

541 N- (4- {3- [1- (4-Bromophenyl) ethyl] thioureido} -2-trifluoromethylphenyl) -2-fluorobenzamide

487 N- (4- {3- [1- (4-Cyanophenyl) ethyl] thioureido} -2-trifluoromethylphenyl) -2-fluorobenzamide

503 N- {4- [3- (1-Benzofuran-2-ylethyl) thioureido] -2-trifluoromethylphenyl} -2-fluorobenzamide

447 N- (2-Chloro-4- {3- [1- (4-fluoro-phenyl) -ethyl] -thioureido} -phenyl) -2-fluoro-benzamide

454 N- (2-Chloro-4- {3- [1- (4-cyanophenyl) ethyl] thioureido} phenyl) -2-fluorobenzamide

437 N- (2-Cyano-4- {3- [1- (4-fluorophenyl) ethyl] thioureido} phenyl) -2-fluorobenzamide

498 N- (4- {3- [1- (4-Bromophenyl) ethyl] thioureido} -2-cyanophenyl) -2-fluorobenzamide

445 N- (2-Cyano-4- {3- [1- (4-cyanophenyl) ethyl] thioureido} phenyl) -2-fluorobenzamide

460 N- {4- [3- (1-Benzofuran-2-ylethyl) thioureido] -2-cyanophenyl} -2-fluorobenzamide

517 N- (2-Benzoyl-4- {3- [1- (4-fluorophenyl) ethyl] thioureido) phenyl} -2-fluorobenzamide

427 · 2-Fluoro-N- (4- {3- [1- (4-fluorophenyl) ethyl] thioureido} -2-methylphenyl) benzamide

165

1098 487 N- (4- {3- [1- (4-Bromophenyl) ethyl] thioureido} -2-methylphenyl) -2-fluorobenzamide 1099 434 N- (4- {3- [1- (4-Cyanophenyl) ethyl] thioureido) -2-methylphenyl) -2-fluorobenzamide 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-cyanophenyl) 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-Bromo-phenyl) -ethyl] -thioureido} - -2- (2-morpholin-4-ylethoxy) phenyl] -2-fluorobenzamide 1105 603 N- [4- {3- [1- (4-Bromo-phenyl) -ethyl] -thioureido} - -2- (2-morpholin-4-ylethoxy) phenyl] -2-fluorobenzamide 1106 542 2-Fluoro-N- [4- {3- [1- (4-fluorophenyl) ethyl] thioureido} - -2- (2-morpholin-4-ylethoxy) 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-cyanophenyl) ethyl] thioureido} phenyl) -2-fluorobenzamide 1109 589 N- [4- {3- [1- (4-Bromo-phenyl) -ethyl] -thioureido] -2- (2- (diethylaminoethoxy) phenyl] -2-fluorobenzamide 1110 528 N- (2- (2-Diethylaminoethoxy) -4- {3- [1- (4-fluorophenyl) -2-fluorobenzamide] 1111 589 N- [4- {3- [1- (4-Bromo-phenyl) -ethyl] -thioureido} -2- (2- (diethylaminoethoxy) phenyl] -2-fluorobenzamide 1112 457 N- (2-Ethoxy-4- {3- [1- (4-fluorophenyl) ethyl] thioureido} phenyl) -2-fluorobenzamide 1113 464 N- (4- {3- [1- (4-Cyanophenyl) ethyl] thioureido} -2-ethoxyphenyl) -2-fluorobenzamide 1114 468 2-Fluoro-N- [4- {3- [1- (4-fluorophenyl) ethyl] thioureido} -2- - (2-nitriloethoxy) phenyl] benzamide 1115 475 N- [4- {3- [1- (4-Cyanophenyl) ethyl] thioureido} -2- (2-nitriloethoxy) phenyl] -2-fluorobenzamide 1116 443 2-Fluoro-N- (4- {3- [1- (4-fluorophenyl) ethyl] thioureido} -2- (methoxyphenyl) benzamide 1117 489 2-Fluoro-N- (5- {3- [1- (4-fluorophenyl) ethyl] thioureido} - Biphenyl-2-yl) benzamide 1118 514 (4- {3- [1- (4-Fluorophenyl) ethyl] thioureido} -2-

166 · »··

isoquinoline-1-carboxylic acid trifluoromethylphenyl) amide 1119 503 (4- {3- [1- (4-Fluorophenyl) ethyl] thioureido} -2- benzofuran-2-carboxylic acid trifluoromethylphenyl) amide acid 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-fluorophenyl) ethyl] thioureido} phenyl) amide 1122 460 Benzofuran-2-carboxylic acid (2-cyano-4- {3- [1- (4-fluorophenyl) ethyl] thioureido} phenyl) amide 1123 471 Isoquinoline-3-carboxylic acid (2-cyano-4- {3- [1- (4-fluorophenyl) ethyl] thioureido} phenyl) amide 1124 460 (4- (3- (1- (4-Fluorophenyl) ethyl) thioureido) -2-methyl- isoquinoline-1-carboxylic acid phenyljamide 1125 449 (4- (3- (1- (4-Fluorophenyl) ethyl) thioureido) -2-methyl- benzofuran-2-carboxylic acid phenyljamide 1126 460 (4- (3- (1- (4-Fluorophenyl) ethyl) thioureido) -2-methyl- isoquinoline-3-carboxylic acid phenyl) amide 1127 396 Pyrazine-2-carboxylic acid (4- (3- (1- (4-fluorophenyl) ethyl) thioureido) phenyl) amide 1128 401 Thiophene-2-carboxylic acid (4- (3- (1- (4-fluorophenyl) ethyl) thioureido) phenyl) amide 1129 401 (4- (3- (1- (4-Fluorophenyl) ethyl) thioureido) phenyl) amide thiophene-3-carboxylic acids 1130 500 2-Isopropylthiazole-4-carboxylic acid (4- [3- (4-chloro-3-trifluoromethyl-phenyl) -thioureido] -phenyl) -amide 1131 466 (4- (3- (3,5-Dichloro-phenyl) -thioureido] -phenyl) -amide 2-isopropylthiazole-4-carboxylic acid 1132 466 (4- [3- (3,4-Dichloro-phenyl) -thioureido] -phenyl) -amide 2-isopropylthiazole-4-carboxylic acid 1133 534 (4- (3- (3,5-Bistrifluoromethylphenyl) thioureido] phenyl) - 2-Isopropylthiazole-4-carboxylic acid amide 1134 480 (4- [3- (3,4-Dichloro-phenyl) -thioureido] -phenyl) -amide 2-butylthiazole-4-carboxylic acid 1135 514 2-Butylthiazole-4-carboxylic acid (4- [3- (4-chloro-3-trifluoromethyl-phenyl) -thioureido] -phenyl) -amide 1136 480 (4- (3- (3,5-Dichloro-phenyl) -thioureido] -phenyl) -amide 2-butylthiazole-4-carboxylic acids 1137 548 (4- (3- (3,5-Bistrifluoromethylphenyl) thioureido] phenyl) -

167

1138438

1139438

1140505

1141534

1142500

1143500

1144568

1145401

1146588

1147446

1148446

1149446

1150446

1151446

1152446

1153413 2-Butylthiazole-4-carboxylic acid amide {4- [3- (3,5-Dichlorophenyl) thioureido] phenyl] amide

2-methylthiazole-4-carboxylic acid {4- [3- (3,4-Dichlorophenyl) thioureido] phenyl] amide

2-methylthiazole-4-carboxylic acid 2-methylthiazole-4-carboxylic acid {4- (3- (3,5-Bistrifluoromethylphenyl) thioureido] phenyl} amide (4- (3- (4-Chloro-3-trifluoromethylphenyl) thioureido) 2-phenylthiazole-4-carboxylic acid (4- [3- (3,5-Dichlorophenyl) thioureido] phenyl] amide] phenyl] amide

2-phenylthiazole-4-carboxylic acid (4- (3- (3,4-Dichlorophenyl) thioureido) phenyl} amide

2-Phenylthiazole-4-carboxylic acid 2-phenylthiazole-4-carboxylic acid (4- [3- (3,5-Bistrifluoromethylphenyl) thioureido] phenyl} amide

2-Fluoro-N- (4- (3- (1-thiazole-2-ylethyl) thioureido) phenyl} benzamide

2-Fluoro-N- [4- (3- (1- (1- (toluene-4-sulfonyl) -1H-indol-2-yl) ethyl} thioureido) phenyl) benzamide

2-Fluoro-N- (4- (3- (1-quinolin-2-ylethyl) thioureido) phenyl} benzamide

2-Fluoro-N- (4- (3- (1-quinolin-4-ylethyl) thioureido) phenyl} benzamide

2-Fluoro-N- (4- (3- (1-isoquinolin-3-ylethyl) thioureido) phenyl} benzamide

2-Fluoro-N- {4- [3- (1-isoquinolin-1-ylethyl) thioureido] phenyl} benzamide

2-Fluoro-N- (4- (3- (1-quinolin-6-ylethyl) thioureido) phenyl} benzamide

2-Fluoro-N- {4- [3- (1-quinolin-3-ylethyl) thioureido] phenyl} benzamide

2-Methoxy-N- (4- (3- (1-thiophen-3-ylethyl) thioureido) phenyl} benzamide

Example 921

Method 33 [1,2,3] Thiadiazole-4-carboxylic acid 4- (3- (3,5-dichlorophenyl) thioureido] phenyl} amide

T ··· ·· »· € • tf

mixture

168:.:

»·· Φ ·

Κ a solution of 3,5-dichloroaniline (0.16 g) in tetrahydrofuran (20 ml; freshly prepared 1,1'-thiocarbonyl-di- (1,2,4) triazole (0.20 g) is stirred for about 30 minutes at a temperature of [1,2,3] Thiadiazole-4-carboxylic acid (4-aminophenyl) amide (0.22 g) was added to the reaction flask, and the mixture was stirred for about 6 hours, then the solvent was removed by evaporation under reduced pressure. After 15 hours, the mixture was filtered and the collected precipitate was washed with acetonitrile and then with diethyl ether, air-dried to give the desired product as a white powder [M + H] 424.

Using the above procedure and appropriate starting materials, the following compounds were prepared:

··

Ex. C. M + H COMPOUND NUMBER 922 465 N- {4- [3- (3,5-Dichloro-4-methoxy-phenyl) -thioureido] - phenyl} -3-fluorobenzamide 923 477 N- {4- [3- (3,5-Dichloro-4-methoxy-phenyl) -thioureido] - phenyl} -2-methoxybenzamide 924 465 N- {4- [3- (3,5-Dichloro-4-methoxy-phenyl) -thioureido] - phenyl} -2-fluorobenzamide 925 477 N- {4- [3- (3,5-Dichloro-4-methoxy-phenyl) -thioureido] - phenyl} -3-methoxybenzamide 926 399 N- {4- [3- (3,5-Dichloro-2-methoxy-4-methyl-phenyl) -thioureido] -phenyl} -acetamide 927 365 N- {4- [3- (3-Chloro-4-methoxy-5-methyl-phenyl) -thioureido] -phenyl} -acetamide 928 331 N- {4- [3- (2-Nitrophenyl) 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-5-methoxy-phenyl) -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-, ethyl ester (dichlorophenoxy) acetic acid 935 447 ’N- {4- [3- (3,5-Dichloro-4-phenoxyphenyl) thioureido] -

phenyl) acetamide

169

410 N- (4- {3- [3,5-Dichloro-4- (2-nitriloethoxy) phenyl] thioureido} phenyl) acetamide

485 {4- [3- (4-Acetylaminophenyl) thioureido] -2,6-dichlorophenoxy) acetic acid tert-butyl ester

469 [1,2,3] Thiadiazole-4-carboxylic acid 4- (3- (3,5-dichloro-2-methoxy-4-methyl-phenyl) -thioureido] -phenyl] -amide

335 N- {4- [3- (3-Chloro-4-methyl-phenyl) -thioureido] -phenyl) -acetamide

335 N- {4- [3- (5-Chloro-2-methyl-phenyl) -thioureido] -phenyl) -acetamide

703 N- {4- [3- (4- {4- [3- (4-Acetylaminophenyl) thioureido] -2-chlorophenyldisulfanyl] -3-chlorophenyl) thioureido] phenyl} acetamide

369 N- {4- [3- (3,5-Dichloro-4-methyl-phenyl) -thioureido] -phenyl} -acetamide

598 N- {4- [3- (3,5-Diodo-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -acetamide

504 N- {4- [3- (3,5-Dibromo-2,4-dimethoxy-phenyl) -thioureido] -phenyl} -acetamide

317 N- (4- (3- (6-Methoxypyridin-3-yl) thioureido) phenyl} acetamide

347 N- {4- [3- (2,6-Dimethoxypyridin-3-yl) thioureido] phenyl} acetamide

457 2- {4- [3- (4-Acetylaminophenyl) thioureido] -2,6-dichlorophenoxy] acetic acid ethyl ester

365 4- [3- (4-Acetylaminophenyl) thioureido] -2-chlorobenzoic acid

346 N- {4- [3- (3-Chloro-4-cyanophenyl) thioureido] phenyl} acetamide

512 N- (4- {3- [5-Chloro-2- (4-chloro-phenoxy) -4-pyrrol-1-yl-phenyl] -thioureido) -phenyl} -acetamide

355 N- {4- [3- (3,4-Dichloro-phenyl) -thioureido] -phenyl) -acetamide

339 N- {4- [3- (3-Chloro-4-fluoro-phenyl) -thioureido] -phenyl} -acetamide

447 N- {4- [3- (3-Chloro-4-iodo-phenyl) -thioureido] -phenyl} -acetamide

400 N- {4- [3- (4-Bromo-3-chloro-phenyl) -thioureido] -phenyl} -acetamide

424 ´ N- [4- (3- {4- [Bis- (2-hydroxyethyl) amino] -3-chlorophenyl} thioureido) phenyl] acetamide

IN

170

• · φ ·

956 434 Ν- (4- {3- [3-Chloro-4- (hexylmethylamino) phenyl] thioureido} phenyl) acetamide 957 406 N- (4- {3- [3-Chloro-4- (isobutylmethylamino) phenyl] thioureido} phenyl) acetamide 958 389 N- {4- [3- (3-Chloro-4-trifluoromethyl-phenyl) -thioureido] -phenyl} -acetamide 959 441 Furan-2-carboxylic acid {4- [3- (3-chloro-4-trifluoromethyl-phenyl) -thioureido] -phenyl] -amide 960 459 {4- [3- (3-Chloro-4-trifluoromethyl-phenyl) -thioureido] -phenyl] -amide [1,2,3] thiadiazole-4-carboxylic acid 961 469 N- {4- [3- (3-Chloro-4-trifluoromethyl-phenyl) -thioureido] -phenyl} -2-fluoro-benzamide 962 435 N- {4- [3- (3,4-Dichloro-phenyl) -thioureido] -phenyl} -2- -fluorobenzamide 963 407 Furan- {4- [3- (3,4-Dichloro-phenyl) -thioureido] -phenyl} -amide -2-carboxylic acids 964 425 {4- [3- (3,4-Dichloro-phenyl) -thioureido] -phenyl} -amide [1,2,3] thiadiazole-4-carboxylic acid 965 480 N- {4- [3- (4-Bromo-3-chloro-phenyl) -thioureido] -phenyl} -2-fluoro-benzamide 966 527 N- {4- [3- (3-Chloro-4-i-phenyl) -thioureido] -phenyl} -2-fluoro-benzamide 967 452 Furan-2-carboxylic acid {4- [3- (4-bromo-3-chloro-phenyl) -thioureido] -phenyl] -amide 968 499 {4- [3- (3-Chloro-4-i-phenyl) -thioureido] -phenyl} -amide furan-2-carboxylic acid 969 391 {4- [3- (3-Chloro-4-fluoro-phenyl) -thioureido] -phenyl} -amide furan-2-carboxylic acid 970 470 {4- [3- (4-Bromo-3-chloro-phenyl) -thioureido] -phenyl} -amide [1,2,3] thiadiazole-4-carboxylic acid 971 517 {4- [3- (3-Chloro-4-iodo-phenyl) -thioureido] -phenyl} -amide [1,2,3] thiadiazole-4-carboxylic acid 972 419 N- {4- [3- (3-Chloro-4-fluoro-phenyl) -thioureido] -phenyl} -2-fluoro-benzamide 973 409 {4- [3- (3-Chloro-4-fluoro-phenyl) -thioureido] -phenyl] -amide [1,2,3] thiadiazole-4-carboxylic acid 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

«· · · · ·

171 «·

976 355 N- {4- [3- (2,3-Dichloro-phenyl) -thioureido] -phenyl) -acetamide 977 435 N- {4- [3- (2,3-Dichlorophenyl) thioureido] phenyl} -2-fluorobenzamide 978 407 {4- [3- (2,3-Dichloro-phenyl) -thioureido] -phenyl) -amide furan-2-carboxylic acid 979 425 (4- [3- (2,3-Dichloro-phenyl) -thioureido] -phenyl) -amide [1,2,3] thiadiazole-4-carboxylic acid 980 355 N- {4- [3- (2,5-Dichloro-phenyl) -thioureido] -phenyl} -acetamide 981 435 N- {4- [3- (2,5-Dichloro-phenyl) -thioureido] -phenyl) - -2-fluorobenzamide 982 407 {4- [3- (2,5-Dichloro-phenyl) -thioureido] -phenyl) -amide furan-2-carboxylic acid 983 355 N- {4- [3- (3,5-Dichloro-phenyl) -thioureido] -phenyl) -acetamide 984 435 N- {4- [3- (3,5-Dichloro-phenyl) -thioureido] -phenyl} - -2-fluorobenzamide 985 407 {4- [3- (3,5-Dichloro-phenyl) -thioureido] -phenyl} -amide furan-2-carboxylic acid 986 390 N- {4- [3- (3,4,5-Trichlorophenyl) thioureido] phenyl} acetamide 987 470 2-Fluoro-N- {4- [3- (3,4,5-trichlorophenyl) thioureido] phenyl} benzamide 988 442 {4- [3- (3,4,5-Trichloro-phenyl) -thioureido] -phenyl) -amide furan-2-carboxylic acid 989 460 {4- [3- (3,4,5-Trichloro-phenyl) -thioureido] -phenyl} -amide [1,2,3] thiadiazole-4-carboxylic acid 990 458 {4- [3- (3-Chloro-4-isoxazol-5-yl-phenyl) -thioureido] -phenyl] - [1,2,3] thiadiazole-4-carboxylic acid 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 (4- [3- (3-Chloro-phenyl) -thioureido] -phenyl) -amide [1,2,3] thiadiazole-4-carboxylic acid 993 373 Furan- {4- [3- (3-Chloro-phenyl) -thioureido] -phenyl] -amide -2-carboxylic acids 994 401 N- {4- [3- (3-Chloro-phenyl) -thioureido] -phenyl} -2-fluoro-benzamide 995 373 Furan- {4- [3- (4-Chloro-phenyl) -thioureido] -phenyl} -amide -2-carboxylic acids

·· ·· · · · · · · · · · · ·

172

401 N- {4- [3- (4-Chloro-phenyl) -thioureido] -phenyl} -2-fluoro-benzamide

[1,2.3] Thiadizaole-4-carboxylic acid {4- [3- (4-chloro-phenyl) -thioureido] -phenyl) -amide

401 N- {4- [3- (2-Chloro-phenyl) -thioureido] -phenyl} -2-fluoro-benzamide

396 3- (3- {4 - [(Furan-2-carbonyl) amino] phenyl} thioureido) benzoic acid methyl ester

424 3- {3- [4- (2-Fluoro-benzoylamino) -phenyl] -thioureido] -benzoic acid methyl ester

414 3- (3- {4 - [([1,2,3] Thiadiazole-4-carbonyl) amino] phenyl} thioureido) benzoic acid methyl ester

409 N- [4 - [[[[3- (Aminocarbonyl) phenyl] amino] thioxomethyl] amino] phenyl] -2-fluorobenzamide

373 Furan-2-carboxylic acid {4- [3- (2-chloro-phenyl) -thioureido] -phenyl] -amide

381 Furan-2-carboxylic acid {4- [3- (3-carbamoyl-phenyl) -thioureido] -phenyl} -amide

[1,2.3] Thiadiazole-4-carboxylic acid 4- [3- (3-carbamoyl-phenyl) -thioureido] -phenyl) -amide

391 {4- [3- (2-Chloro-phenyl) -thioureido] -phenyl] -amide [1,2,3] thiadiazole-4-carboxylic acid

356 Furan-2-carboxylic acid {4- [3- (3-fluorophenyl) thioureido] phenyl} amide

383 Furan-2- {4- [3- (3-Nitrophenyl) thioureido] phenyl] amide

-carboxylic acids

411 2-Fluoro-N- (4- [3- (3-nitrophenyl) thioureido] phenyl} benzamide

422 Furan-2-carboxylic acid {4- [3- (3-trifluoromethoxy-phenyl) -thioureido] -phenyl} -amide

450 2-Fluoro-N- {4- [3- (3-trifluoromethoxyphenyl) thioureido] phenyl} benzamide

384 2-Fluoro-N- {4- [3- (3-fluoro-phenyl) -thioureido] -phenyl} -benzamide

410 3- (3- [4- (2-Fluorobenzoylamino) phenyl] thioureido] benzoic acid

382 3- (3- (4 - ((Furan-2-carbonyl) amino] phenyl} thioureido) benzoic acid

408. N- {4- [3- (3-Acetylphenyl) thioureido] phenyl} -2-fluorobenzamide

502 N- (4- [3- (3-Butylsulfamoylphenyl) thioureido] phenyl} 173

-2-fluorobenzamide

1017

1018

1019

1020

380 Furan-2-carboxylic acid {4- [3- (3-acetyl-phenyl) -thioureido] -phenyl} -amide

447 Furan-2-carboxylic acid 4- {3- [3- (2-hydroxy-ethanesulfonyl) -phenyl] -thioureido} -phenyl) -amide

475 2-Fluoro-N- (4- {3- [3- (2-hydroxyethanesulfonyl) phenyl] thioureido} phenyl) benzamide

2-Carboxylic acid furan {4- [3- (3-Butylsulfamoyl-phenyl) -thioureido] -phenyl} -amide

Example 1021

Method 57

1- (4-Fluorophenyl) -2-methylpropan-1-ol

To a solution of 4-fluorobenzaldehyde (2.0 g) in diethyl ether (40 mL) at 0 ° C is added dropwise isopropylmagnesium bromide (2.0 M,

9.6 ml). After 1.5 hours, the reaction is quenched by addition of aqueous ammonium chloride and extracted with diethyl ether. The diethyl ether extracts were washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered and evaporated to give an oil. The oil was purified by silica gel chromatography eluting with 10% dichloromethane / hexanes to give the product as a yellow oil (1.76 g).

Example 1022

Method 58

1- (4-Fluorophenyl) -2-methylpropan-1-one

To a solution of 1- (4-fluorophenyl) -2-methylpropan-1-ol (1.6 g) in acetone (10 mL) was added Jones reagent (20 mL) with stirring at 0 ° C. After 10 minutes, excess Jones reagent was removed by addition of isopropyl alcohol. Diethyl ether was added followed by anhydrous magnesium, and the mixture was filtered and evaporated to give the product as a yellow oil (1.2 g).

Example 1023

Method 59

174 · * · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

3-Dimethylamino-5-trifluoromethylbenzonitrile

To a solution of 3-dimethylamino-5-trifluoromethylbromobenzene (7.3 g) in N, N-dimethylformamide (20 ml) was added copper (I) cyanide (2.7 g) and the reaction mixture was heated under reflux for 12 hours. The reaction mixture was diluted with water (40 mL) and dichloromethane was added. The dichloromethane fractions were washed with concentrated ammonium hydroxide and then with water. The solution was dried over anhydrous magnesium sulfate, filtered and concentrated to give a yellow solid which was recrystallized from hexanes to give a yellow solid (4.7 g).

175

The above compounds were tested for activity as inhibitors of herpes virus.

Human cytomegalovirus

Yield test

Single-layer cultures of human foreskin fibroblasts are infected with wild-type HCMW, typically at a multiplicity of infection of up to 0.2 in the presence of inhibitor compound (varying concentrations). On the third day after infection, the total amount of virus produced in these cultures (i.e. virus yield) is examined by harvesting and titrating the virus in 12-well plates with cultured human foreskin fibroblasts (performed in the absence of inhibitor). Slices are quantified 2 weeks after infection. The HCMV inhibitor is identified by reducing the virus yield titer in the presence of the compound with the titer in the absence of the compound. In this assay, the relative anti HCMV activity is typically determined by calculating the IC ₅₀ or ICG _0, ie. an amount of compound that reduces the yield by 50% and 90%, respectively. Table I lists data on the IC ₅ for compounds tested against HCMV.

A microtiter plate assay A well plate with cultures of human foreskin fibroplasts is infected in the presence of an inhibitor compound with HCMV recombinant mutant virus whose genome contains the prokaryotic beta-glucuronidase gene (Jefferspn, RA, SM Burges and D. Hirsh. 1986. Beta-glucuronidase from Escherichia coli) as a gene fusion marker (Proc., Natl. Acad. Sci. USA 83: 8447-8451) whose expression is monitored by a viral promoter. An example of such a virus is RV145 (Jones, T. R., V. P. Muzithras, and Y Gluzman. 1991).

176 of human cytomegalovirus genome: US10 and USU gene products are nonessential. J. Virol. 65: 5860-5872). Since it is regulated by the viral promoter, beta-glucuronidase expression is an indirect indicator of the growth of HCMV replication in this assay. 96 hours after infection, lysates of infected cells (using 50 mM sodium phosphate [pH 7.0] containing 0.1% Triton X100 and 0.1% sarcose) were prepared and assayed for beta-glucuronidase activity using an enzyme substrate that cleavage provides either a product that can be measured colorimetrically in a spectrophotometer or fluorescently in a microfluorimeter. Examples of such substrates are p-nitrophenyl-beta-D-glucuronide and methylumbelliferyl glucuronide. The presence of the antiviral compound is indicated by the reduced expression of the beta-glucuronidase gene resident in the HCMV genome as compared to the absence of inhibitor. Thus, the generation of the chromophore or fluorophore product in this assay is reduced accordingly. Data from this assay generated using different amounts of inhibitor compound is also used to estimate the IC 50 of the inhibitor compound.

HSV Virus Test (ELISA)

Vero cells (ATCC # CCL-81) are coated in 96-well culture plates at 3.5 x 10 ⁴ cells of 100 μΐ tissue culture DMEM (Dublec's Modified Medium Eagle) supplemented with 2% fetal bovine serum (FBS) per well. 30 minutes of incubation at 37 ° C (in 5% CO ₂ ) and 30 minutes prior to HSV-1 infection (multiplicity of infection equals 0.006), cells are not treated or treated with test compound (multiple concentrations) or reference standard drug for control. The cells are subjected to an ELISA approximately 24 hours post-infection (in 5% CO ₂ ) The primary antibody is a mouse anti-HSV glycoprotein D monoclonal primary antibody and the secondary antibody is a goat anti-mouse IgG bound to β / ΊΊ galactosidase. viral replication determined by determining β-galactosidase activity by quantifying the generation of 4-methyl umbelliferone fluorescent cleavage product after addition of methyl umbellifer yl-β-D-galactoside (Sigma # M1633) substrate on a microfluorimeter (365 nm at excitation and 450 nm at emission). The antiviral activity (IC 50) of the test compound is determined by comparing the fluorescence obtained in the absence of the compound to that obtained in the presence of the compound. The data are shown in Table I.

VZV antivirus test (ELISA)

VZV is used to generate inventory in this test. The VZV Ellen strain (ATCC # VR-1367) is used to infect human foreskin fibroblast (HFF) cells at low multiplicity (less than 0.1) and incubated overnight at 37 ° C in 5% CO ₂ . After overnight incubation, a mixture of uninfected and VZV-infected HFF infected cells is collected and added to each well of 96-well plates (3.5 x 10 ⁴ cells in 100 μΐ DMEM supplemented with 2% FBS) containing the test compound or reference standard control. drug (in 100 μΐ DMEM supplemented with 2% FBS per well). these cells are then incubated for three days at 37 ° C in 5% CO ₂ and subjected to ELISA. The primary antibody is a murine anti-VZV glycoprotein II monoclonal antibody (Applied Biosystems, Inc. # 13-145-100) and the secondary antibody is a goat anti-mouse IgG bound to β-galactosidase. Thus, the viral replication rate is determined by determining β-galactosidase activity by quantifying the generation of a 4-methyl umbelliferone fluorescent cleavage product upon addition of methyl umbelliferyl β-D-galactoside (Sigma # M1633) substrate on a microfluorimeter (365 nm at excitation and 450 nm at emission). The antiviral activity (IC ₅₀ ) of the test compound is determined by comparing the fluorescence obtained in the absence of the compound

178 with fluorescence obtained in the presence of the compound. The data are shown in Table I.

Table I gives IC50 data for compounds tested against herpes viruses.

Table I

Example IC 50 (µg / ml) HSV % inhibition 10 µg / ml vz IC50 (µg / ml) VZV IC50 (µg / ml) HCMV 86 > 10 32 > 10 0.04 88 > 10 , 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 22nd > 10 5 158 4 52 "> 15 > 10 159 > 10 62 > 10 > 10 160 2.5 27 Mar: > 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

179

Example 1C50 (µg / ml)% inhibition IC50 (µg / ml) VZV IC50 (µg / ml) HCMV HSV 10ug / ml VZV 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 0.05 249 > 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 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 and 2 361 8 26 > 10 0.25 365 10 75 5 0,035 368 > 10 20 May > 10 0.35 371 > 10 45 > 10 > 10 376 3 83 7 0.8 378 > 10 31 > 10 0,033 379 > 10 27 Mar: > 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

180

Example IC50 (µg / ml · HSV Inhibition: 10 µg / ml vz IC50 (µg / ml) VZV IC 50 (µg / ml) HCMV 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 0.15 446 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 0.07 457 > 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 22nd > 10 1 478 > 10 31 > 10 0.4 479 > 10 30 > 10 0.1 481 > 10 32 > 10 0.5 482 9 33 > 10 0.3 485 > 10 11 > 10 0.03 486 > 10 22nd > 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 Mar: > 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 Dec > 10 0.04

181

'riKiaa IC 50 (µg / ml) HSV % inhibition of 10 µg / ml VZV IC50 (µg / ml) VZV 513 > 10 10 > 10 516 > 10 7 > 10 521 10 97 3 522 > 10 32 > 10 524 4 95 2 526 > 10 22nd 2.5 528 3.2 * 107 4 5 530 5 96 6 532 > 10 6 534 7 > 10 535 > 10 > 10 537 9 10 539 > 10 > 10 541 7 > 10 542 > 10 > 10 544 > 10 > 10 545 3 7 546 IN 7 547 > 10 10 548 > 10 > 10 550 > 10 > 10 551 > 10 > 10 554 > 10 1.5 555 > 10 4 556 > 10 > 7.5 557 > 10 > 10 558 7 > 10 559 > 10 > 10 560 > 10 > 10 561 > 10 8 562 > 10 8 564 > 10 5 565 > 10 0.22 571 > 10 572 Λ > 10 573 > 10 574 > 10 575 2 579 6 581 > 10 582 8 584 > 10 585 > 10 587 > 10 588 > 10 0.36 590 > 10 9 1

IC50 (µg / ml) HCMV

0.011

0.04

0.04

0,025

0,055

0.25

0.15

0.009

0.05

0.016

0.003

0,036

0.017 0.0011

0.02

0,012 0p07

0.006

0.008

0.013

0,043

0.01

0.008

0.006

0.006

0.05

0.012

0.008

0.05

0.004

0,027

0.01

0.013

0.0078

0.05

0,089

0.017

0.05

0.01

0.01

0,0026

0.015

0.005

0.03

0.12 · · · ·

182

Example IC 50 (µg / ml) HSV % inhibition of 10 µg / ml VZV IC50 (µg / ml) VZV IC50 (µg / ml) HCMV 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 0.012 601 > 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 0.09 611 > 10 0.5 612 1 0,049 613 > 10 0.011 614 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 0.01 639 > 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

• · ·

183

Example 671 674 IC 50 (µg / ml) HSV > 10 > 10 % inhibition 10 µg / ml vz IC50 (µg / ml) VZV IC50 (µg / ml) HCMV 0.005 0.006 675 > 10 0.05 676 > 10 0.013 678 > 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 0.007 704 > 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 .4 » 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

184

IC 50 (µg / ml)% inhibition

HSV 10 µg / ml

VZV> 10> 10> 10> 10> 10> 10> 10> 10> 10> 10> 10> 10> 10> 10> 10> 10> 10

IC50 IC50 (µg / ml) (µg / ml) HCMV

VZV

0,033

0.007

0,022

0.018

0.009

0,022

0.012

0.005

0.11

0.02 θ / 1

0.02

0.009

0.09

0,0025

0.005

0,002

0.28

0.06

0.01

2 > 10 1.5 0,002 5 0.004 0004 0.006 1 0.006 0.005 0.04 0.006 > 7.5 4 0.27 0.0095 > 7.5 0.0053 > 7.5 0,0016 > 7.5 0.006 0.005 > 7.5 > 7.5 0.018

0.170.014> 7.5 0.0013> 7.50.002> 7.50.002

185

Example ICSO (µg / ml) % inhibition ICSO ICSO (µg / ml) HSV 10 µg / ml (µg / ml) HCMV VZV VZV 830 > 7.5 > 7.5 0.0003 831 0.0011 832 > 7.5 > 7.5 0.001 0.0019 833 834 > 7.5 0,002 835 > 7.5 0.005 836 > 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 1.55 0.0011 0.02 842 843 > 7.5 1.03 0.0031 844 0.0008 0.0060 845 > 7.5 846 1.04 0.0130 0.0008 847 > 7.5 848 0.19 0,002 849 1.82 2.33 0,002 850 0.0008 851 1.43 0.017 0.005 852 > 7.5 853 0.62 0.004 854 0.02 855 0.02 856 0.02 857 > 7.5 0.0006 0.0007 0.00001 858 > 7.5 859 0.5 860 > 7.5 > 7.5 0.001 861 0,002 862 > 7.5 > 7.5 0.1 2.0 0.5 0.0001 0,035 863 864 Λ > 7.5 865 > 7.5 > 10 866 > 10 50 875 > 50 18 > 10 > 2,2 0.3 879 4 65 10 888 6 31 > 10 0.06 0,037 897 > 10 62 > 10 902 > 10 10 > 10 0.12 904 12 58 > 10 0.4 0.3 905 4 82 2 907 > 10 36 > 10 0.009 0.3 911 > 10 25 > 10

186 β

»·«

Example IC 50 (µg / ml)% inhibition 1C50 (µg / ml) vz IC50 (µg / ml) HCMV HSV l (µg / ml YZV) 912 > 10 0 > 10 0.16 913 > 10 15 Dec > 10 0.056 917 10 > 10 0.2 ’918 > 10 > 10 0.03 919 > 10 > 10 0.05 921 8 85 7 0.05 922 > 10 84 7 0.01 939 > 10 53 15 Dec 0.018 960 > 10 58 > 10 0.03 961 > 10 20 May > 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 0.018 993 > 10 > 10 0.013 994 > 10 > 10 0.07 996 10 > 10 0.15 998 > 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 Dec > 10 0.12 1009 10 22nd > 10 0.2 1011 > 10 20 May > 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 3.7 1 1128 ·> 10 > 10 1.3

187

Example 1C50 (µg / ml)% inhibition 1C50 (µg / ml) VZV IC50 (µg / ml) HCMV HSV 10ug / ml VZV 1129 1.9 > 10 1 1130 2 5.5 2 1131 2.2 9 1.5 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

Thus, the compounds of the present invention are potent inhibitors of herpesvirus growth and replication, including HCMV, VZV and HSV, and effectively inhibit viral yield.

The compounds of the present invention may be administered in accordance with the invention to patients suffering from herpes virus, including HCMV, VZV and HSV in an amount effective to inhibit the virus. Thus, the compounds of the invention are useful for alleviating or eliminating the symptoms of herpes virus infections in mammals, including but not limited to humans.

The compounds of the invention may be administered to the patient either in pure form or with a conventional pharmaceutical carrier.

Suitable solid carriers may include one or more substances which may act as flavorings, lubricants, solvents, suspending agents, binders, glidants, compression aids, binders or tablet disintegrating agents or encapsulating material. In the case of a powder, the carrier is a finely divided substance which is in admixture with the finely divided active component.

In tablets, the active ingredient is mixed with the carrier which it has

188 necessary compression properties in suitable proportions and compressed to 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, polyvinylpyrrolidone, low melting waxes, and ion exchange resins.

Liquid carriers can be used in the preparation of solutions, suspensions, emulsions, syrups and elixirs. The active ingredient of the invention may be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of pharmaceutically acceptable oils or fats. The liquid carrier may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, aromatics, suspending agents, thickeners, colorants, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (especially containing additives as mentioned above, e.g., cellulose derivatives, preferably sodium carboxymethylcellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and derivatives and oils (e.g. fractionated) coconut oil or peanut oil). For parenteral administration, the carrier may also be an oily ester such as ethyl oleate and isopropyl myristate. In sterile liquid compositions for parenteral administration, sterile liquid carriers are employed.

Liquid pharmaceutical compositions which are sterile solutions or suspensions may be used, for example, by intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can be administered intravenously. Oral administration may be in either liquid or solid form.

189

The pharmaceutical compositions are preferably in unit dosage form, such as tablets or capsules. In such form, the composition is subdivided into a unit dosage form containing an appropriate amount of the active ingredient; the unit dosage form may be in packaged form, for example, as packaged powders, vials, ampoules, prefilled syringes or sachets containing liquids. Unit dosage forms may be, for example, capsules or tablets alone, or there may be a suitable number of any such composition in packaged form.

The therapeutically effective dose to be used to treat herpes virus infection is determined by the attending physician. Variables that affect dose include patient condition, age, and weight. The novel methods of the invention for treating herpes virus infection comprise administering to a subject to be treated an effective amount of at least one compound of Formula 1 or a non-toxic pharmaceutically acceptable salt thereof. The compounds may be administered orally, rectally, parenterally or topically to the skin and mucosa. The usual daily dose is dependent on the specific compound, the mode of treatment and the condition of the patient. The usual daily dose is 0.01 to 1000 mg / kg for oral administration, more preferably 0.5 to 500 mg / kg and 0.1 to 100 mg / kg for parenteral administration, preferably 0.5 to 50 mg / kg.

Claims (20)

PATENTOVÉ Claims 1 ,. Compound of formula: where R 1 -R 5 is independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms carbon atoms, heterocycloalkyl of 3 to 10 carbon atoms, aryl, heteroaryl, halogen, -CN, -NO ₂ , -co ₂ r ₆ , -or ₆ , -or ₆ , -sr ₆ , -sor ₆ , -so ₂ r ₆ , -CONR ₇ R ₈ , -NR ₆ N (R ₇ R ₈ ), N (R ₇ R ₈ ) or WY- (CH ₂ ) _n -Z, with the proviso that at least one of R 1 -R 5 is not hydrogen; or _R2 and R3 or R3 and _R4 together form a 3-7 membered heterocycloalkyl or 3-7 membered heteroaryl; R ₆ and R ₇ are independently hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, or aryl; R ₈ is hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10 members, aryl or heteroaryl, or R ₇ and R ₈ together may form a 3 to 7 membered heterocycloalkyl; W is O, NR ₆ or absent; Y is - (CO) - or - (CO ₂ ) - or is absent; Z is C 1 -C 4 alkyl, -CN, -CO ₂ R ₆ , -COR ₆ , -CONR ₇ R ₈ , -ocor ₆ , -nr ₆ cor ₇ , -oconr ₆ , -or ₆ , -sr ₆ , -sor ₆ , -so ₂ r ₆ , SR ₆ N (R ₇ R ₈ ), -N (R ₇ R ₈ ) or phenyl; G is a monocyclic heteroaryl; • · · · · 191 X is a bond, -NH, alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, thioalkyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms, or (CH) J; J is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl or benzyl; and n is an integer from 1 to 6. A compound according to claim 1, wherein R 1 to R 5 are independently hydrogen, alkyl of 1 to 6 carbon atoms, halogen, perhaloalkyl of 1 to 6 carbon atoms, OR ₆ or N (R ₇ R 8). The compound of claim 1, wherein R 1, R ₂ and R ₃ are hydrogen and R ₄ and R 5 are independently halogen or CF ₃ . The compound of claim 1, wherein R 1, R ₂ and R ₄ are hydrogen and R ₃ and R ₅ are independently halogen or CF ₃ . The compound of claim 1, wherein G is thiazolyl, thiadiazolyl, oxazolyl, furyl or isoquinoline. A compound according to claim 1, A compound according to claim 1, A compound according to claim 1, A compound according to claim 1, A compound according to claim 1, carbon. A compound according to claim 1, up to 6 carbon atoms. wherein G is thiazolyl. wherein G is 1,2,3 thiadiazolyl. where X is a bond. wherein X is straight-chain alkyl. wherein X is alkyl of 1 to 4 atoms wherein X is CH (J) aJ is alkyl of 1 192 • · · · · 12. Compound according to claim 11, wherein J is methyl. 13. Compound according to claim 1, wherein X is CH (J) and G is thiazolyl. 14. Compound according to claim 1, which is: [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (3,5-Bistrifluoromethyl-benzyl) -thioureido] -phenyl] -amide, {4- [3- (4-Piperidin-1-yl-3-trifluoromethyl-benzyl) -thioureido] -phenyl] -amide [1,2] [1,2,3] thiadiazole-4-carboxylic acid, {4- [3- (4-Dimethylamino-3-trifluoromethylbenzyl) thioureidophenyl] amide [1,2,3] thiadiazole-4-carboxylic acid, {4- [3- (3-Dimethylamino-5)] [1,2,3] thiadiazole-4-carboxylic acid-trifluoromethylbenzyl) thioureidophenyl iamide, {4- [3- (4-Fluoro-3-trifluoromethylbenzyl) thioureidophenyl] amide [1,2,3] thiadiazole-4-carboxylic acid, { [1,2,3] Thiadiazole-4-carboxylic acid 4- [3- (4-tert-butylbenzyl) thioureidophenyl] amide thiazole-4-carboxylic acid, 4- (3- [2- (3-Fluoro-5-trifluoromethylphenyl) ethyl] thioureidophenyl) amide [1,2,3] thiadiazole-4-carboxylic acid, (4- {3- [2- (4-Bromophenyl) ethyl] thioureido) phenyl] amide, {4- [3- (3,4-Dichlorobenzyl) thioureido] phenyl] amide thiazole- 4-carboxylic acids, {4- [3- (3,5-Dichlorobenzyl) thioureidophene] yl [1,2,3] Thiadiazole-4-carboxylic acid, amide, {4- [3- (3,4-Dichlorobenzyl) thioureidophenyl] [1,2,3] thiadiazole-4-carboxylic acid, amide, (4- {3- [2 - [1,2,3] Thiadiazole-4-carboxylic acid (3,4-dichlorophenyl) ethyl] thioureido (phenyl) amide, 193 [1,2,3] Thiadiazole-4-carboxylic acid 4- {3- [2- (4-trifluoromethyl-phenyl) -ethyl] -thioureido} -phenyl) -amide, (4- {3- [2- (3-Chloro-phenyl) -ethyl] -thioureido} -phenyl) -amide [ 1.2.3] thiadiazole-4-carboxylic acid, (4- [3- (4-tert-butylbenzyl) -thioureido] phenyl] amide [1,2,3] thiadiazole-4-carboxylic acid, {4- [3- (3,5- [1,2,3] Thiadiazole-4-carboxylic acid, (4- {3 - [3- (2- (2-Fluoro-5-trifluoromethyl-phenylsulfanyl) -ethyl] -thioureido} -phenyl) -amide], (4- {3) [1,2,3] Thiadiazole-4-carboxylic acid [2- (2,4-Bis-trifluoromethyl-phenyl) -ethyl] -thioureido} -phenyl) -amide, (4- {3- [2- (4-Fluoro-3-trifluoromethyl-phenyl)) [1,2,3] Thiadiazole-4-carboxylic acid, ethyl [1,2,3] thiadiazole-4-carboxylic acid, (4- [3- (3-Fluoro-5-trifluoromethylbenzyl)] thioureidophenyl) amide [1,2,3] thiadiazole-4-carboxylic acid, (4- ( [1,2,3] Thiadiazole-4-carboxylic acid 3- (2- (3,5-bis-trifluoromethyl-phenyl) -ethyl] -thioureido} -phenyl) -amide, (4- [3- (4-Iodo-3-trifluoromethyl)) [1,2,3] thiadiazole-4-carboxylic acid, (4- [3- (2-Fluoro-5-trifluoromethylbenzyl)] thioureido] phenyl] amide [1,2,3] thiadiazole-4-carboxylic acid, (4- ( [1,2,3] Thiadiazole-4 [1,2,3] thiadiazole-4-carboxylic acid, 3- (2- (3-bromo-phenylsulfanyl) -ethyl] -thioureido) -phenyl] -amide; [1,2,3] thiadiazole-4-carboxylic acid, (4- (3- (2- (2,4-Dichlorophenyl) ethyl) thioureido) phenyl) amide, (4- (3- (2- (3-Trifluoromethylphenyl) ethyl) thioureido) phenyl) ) Thiadiazole-4-carboxylic acid amide [1.2.3], 194 [1,2,3] Thiadiazole-4-carboxylic acid 4- {3- [2- (2-fluoro-5-trifluoromethyl-phenoxy) -ethyl] -thioureido] -phenyl) -amide, (4- [3- (2-Fluoro-5-trifluoromethyl-benzyl)] thiazole-4-carboxylic acid thioureidophenyl iamide, (1,2,3) thiadiazole-4-carboxylic acid (4- (3- (2- (3-iodophenyl) ethyl) thioureidophenyl) amide), (4- [3- (3,5-Bis) [1,2,3] Thiadiazole-4-carboxylic acid, 4- (3- (3- (3- (2-methylbutyl) -5-trifluoromethylphenyl) thioureido) phenyl) amide, (4- (3- (2-methylbutyl) -5-trifluoromethylphenyl) thioureido) phenyl) amide, (4- 1,2,3] Thiadiazole-4-carboxylic acid [3- (3-isobutyl-5-trifluoromethyl-phenyl) -ethyl] -thioureo-iodo-phenyl) -amide, (4- (3- (2- (3-Dimethylamino-5-trifluoromethyl-phenyl) -ethyl) -thioureo-iodo-phenyl) -amide [1,2,3] Thiadiazole-4-carboxylic acid [1,2,3] thiadiazole-4-carboxylic acid, (4- (3- (2- (5-Bromo-2-methoxyphenyl) ethyl) thioureidophenyl) amide), (4- [1,2,3] Thiadiazole-4-carboxylic acid (3- (2- (4-chlorophenyl) ethyl) thioureidophenyl) amide, (4- (3- (2- (3,5-Dichlorophenoxy) ethyl) [1,2,3] Thiadiazole-4-carboxylic acid 1, thioureidophenyl) amide, (4 - [3- (3,4-Dichlorophenyl) thioureidophenyl) thiazole-4-carboxylic acid, (4- [3- (4-Chloro-3-trifluoromethylphenyl)] [1,2,3] Thiadiazole-4-carboxylic acid, thiazole-4-carboxylic acid, (4- (3- (2- (3,4-Dichloro-phenylsulfanyl) -ethyl) -thioureido) -phenyl) -amide, (4- (3- (2) [1,2,3] Thiadiazole-4-carboxylic acid (2-fluoro-3-trifluoromethylphenyl) ethyl] thioureidophenyl) amide [1,2,3] thiadiazole-4-carboxylic acid [4- (3- (2- (2-Fluoro-5-trifluoromethylphenyl) ethyl) thioureidophenyl) amide [1,2] 3-thiadiazole-4-carboxylic acid, [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [2- (3-bromophenyl) ethyl] thioureido] phenyl) amide, {4- [3- (3-Chloro-4-trifluoromethylphenyl) [1,2,3] thiadiazole-4-carboxylic acid thioureido] phenyl} amide [1,2,3] thiadiazole-4 {4- [3- (3-Chloro-4-iodophenyl) thioureido] phenyl] amide furan-2-carboxylic acid [4- (3-Benzo [1,3] dioxol-5-ylmethylthioureido) phenyl] amide, (4- {3- [1- (4-Bromophenyl) ethyl] thioureido} -carboxylic acid [1,2,3] thiadiazole-4-carboxylic acid phenyl) amide, [1,2,3] thiadiazole-4-carboxylic acid {4- [3- (3,3-diphenylpropyl) thioureido] phenyl} amide, ( 4- [3- (3-Chloro-4-fluorobenzyl) thioureido] phenyl] amide [1,2,3] thiadiazole-4-carboxylic acid, (4- {3- [2- (3,4-Dichlorophenoxy) ethyl] thioureido [1,2,3] thiadiazole-4-carboxylic acid, phenyl) amide, {4- [3- (3-Trifluoromethylbenzyl) thioureido] phenyl} amide [1,2,3] thiadiazole-4-carboxylic acid, {4 [1,2,3] Thiadiazole-4-carboxylic acid - [3- (3-chloro-benzyl) -thioureido] -phenyl} -amide, (4- [3- (4-Bromo-3-trifluoromethyl-phenyl) -thioureido] -phenyl] -amide [1, [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [2- (4-fluorophenyl) ethyl] thioureido} phenyl) amide, {4- [2,3] thiadiazole-4-carboxylic acid, 3- (3-Pyrrolidin-1-yl-5-trifluoromethyl-phenyl) -thioureido] -phenyl] -amide [1,2,3] thiadiazole-4-carboxylic acid, (4- {3- [3- (Butylmethylamino) -5-trifluoromethyl-phenyl] -thioureido [1,2,3] thiadiazole-4-carboxylic acid} 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-bistrifluoromethyl-phenyl) -thioureido] -phenyl} -amide, 196 [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (3,4-dichlorophenyl) thioureido] phenyl} amide, {4- [3- (3-Bromo-5-trifluoromethylphenyl) thioureido] [1,2,3] Thiadiazole-4-carboxylic acid phenyljamide, (4- {3- [2- (3-Chlorophenoxy) ethyl] thioureido} phenyl) amide [1,2.3], (4 [1,2.3] Thiadiazole-4-carboxylic acid {3- [2- (4-ethylphenyl) ethyl] thioureido} phenyl) amide, (4- {3- [2- (3-Bromophenoxy) ethyl] thioureido} phenyl) [1,2.3] Thiadiazole-4-carboxylic acid amide, {4- [3- (4-Chlorobenzyl) thioureido] phenyl] amide [1,2,3] thiadiazole-4-carboxylic acid, {4- [3- (5) [1,2,3] thiadiazole-4-carboxylic acid-chloro-2-methoxy-4-methylphenyl) thioureido] phenyl] amide, [4- {3- [2- (3-Fluorophenyl) ethyl] thioureido} phenyl] amide [ 1,2,3] thiadiazole-4-carboxylic acid, [1,2,3] thiadiazole-4-carboxylic acid (4- {3- [1- (4-fluorophenyl) ethyl] thioureido} phenyl) amide, {4 - [3- (3,5-Difluorobenzyl) thioureido] phenyl] amide [1,2,3] thiadiazole-4-carboxylic acid, {4- [3- (3,5-Dichlorobenzyl) thioureido] [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (2-p-tolyl-ethyl) -thioureido] -phenyl} -amide, phenyl- amide, {4- [3- (4- Phenylbutyl) thioureido] phenyljamide [1,2,3] thiadiazole-4-carboxylic acid, {4- [3- (2-Phenylsulfanylethyl) thioureido] phenyl] amide [1,2,3] thiadiazole-4-carboxylic acid, {4- 1,2,3] Thiadiazole-4-carboxylic acid [3- (3-iodo-benzyl) -thioureido] -phenyl] -amide, furan-2- (4- {3- [2- (3-Bromo-phenylsulfanyl) -ethyl] -thioureido} -phenyl) -amide oxazole-4-carboxylic acid {4- [3- (3,5-Dichloro-phenyl) -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 5-difluorophenyl) ethyl] thioureido} phenyl) amide [1,2,3] (4- {3- [2- (3-iodophenoxy) ethyl] thioureido} phenyl) amide [1,2] [1,2,3] thiadiazole-4-carboxylic acid {4- [3- (3,5-Dichloro-phenyl) -thioureido] -phenyl} -amide, [4- [3- (3)] [1,2,3] Thiadiazole-4-carboxylic acid-amino-5-chlorophenyl) thioureido] phenyl} amide [1,2,3] thiadiazole {4- [3- (3-Bromophenyl) thioureido] phenyl} amide [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [3- (isobutylmethylamino) -5-trifluoromethylphenyl] thioureido} phenyl) amide, [4- [3- (3) [1,2,3] thiadiazole-4-carboxylic acid-phenylpropyl) thioureido] phenyljamide, {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 [1,2,3] thiadiazole-4-carboxylic acid, {4- [3- (3,4-Dichlorobenzyl) thioureido] phenyl] amide furan [1,2,3] Thiadiazole-4-carboxylic acid [4- [3- (3-morpholin-4-yl-5-trifluoromethyl-phenyl) -thioureido] -phenyl} -amide, {4- [3- [1,2,3] Thiadiazole-4-carboxylic acid (4-fluoro-3-trifluoromethyl-phenyl) -thioureido] -phenyl] -amide, (4- {3- [2- (3-Fluorophenoxy) -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, 198 {4- [3- (3-Dimethylamino-5-trifluoromethyl-phenyl) -thioureido] -phenyl] -amide [1,2,3] thiadiazole-4-carboxylic acid, (4- [3- [4- (4-Methyl-piperazin-1-yl)] [1,2,3] Thiadiazole-4-carboxylic acid -3-trifluoromethyl-benzyl] -thioureido] -phenyl] -amide, [4- (3- (3,4-Difluoro-benzyl) -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)] [1,2,3] Thiadiazole-4-carboxylic acid thioureido] phenyl] amide [1,2,3] thiadiazole-4-carboxylic acid, (4- [3- (2-Phenoxyethyl) thioureido] phenyl} amide, (4- [1,2,3] Thiadiazole-4-carboxylic acid {3- [2- (3-methoxy-phenyl) -ethyl] -thioureido} -phenyl) -amide, {4- [3- (3-Chloro-4-methyl-phenyl) -thioureido] -phenyl} -amide [1,2,3] Thiadiazole-4-carboxylic acid, {4- [3- (3-Fluoro-5-trifluoromethyl-benzyl) -thioureido] -phenyl] -amide furan-2-carboxylic acid, (4- {3- [2- [1,2,3] Thiadiazole-4-carboxylic acid (4-nitrophenyl) ethyl] thioureido] phenyl) amide, {4- [3- (3-Piperidin-1-yl-5-trif) [1,2,3] thiadiazole-4-carboxylic acid, fluoromethylphenyl) thioureido] phenyl] amide, {4- [3- (3,4-Dichlorophenyl) thioureido] phenyl] amide, oxazole-4-carboxylic acid, {4- [3- (3) [1,2,3] Thiadiazole-4-carboxylic acid {4- [3- (4-chloro-phenyl) -thioureido] -phenyl} -amide, [4,5,3-trichloro-phenyl) -thioureido] -phenyl} -amide, [ [1,2,3] Thiadiazole-4-carboxylic acid 4- (3-benzo [1,3] dioxol-5-yl-methylthioureido) phenyl] amide, [4- (3-Phenethylthioureido) phenyl] amide [1, 2,3] thiadiazole-4-carboxylic acids, [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [2- (2-chloro-phenoxy) -ethyl] -thioureido} -phenyl) -amide, {4- [3- (3,5-Bistrifluoromethyl-phenyl) -thioureido] [1,2,3] thiadiazole-4-carboxylic acid phenyl] amide, {4- [3- (3,5-Dichloro-2-methoxy-4-methylphenyl) thioureido] phenyl] amide [1,2,3] thiadiazole-4 [1,2,3] thiadiazole-4-carboxylic acid (4- {3- [3-Chloro-4- (1H-pyrazol-3-yl) phenyl] -thioureidophenyl) -amide, (4- [3] [1,2,3] Thiadiazole-4-carboxylic acid [3-chloro-4- (2-piperidin-1-ylacetylamino) phenyl] thioureido] phenyl) amide, [4- [3- (3-Trifluoromethylphenyl) thioureido] [1,2,3] thiadiazole-4-carboxylic acid phenyl] amide, {4- [3- (4-Chloro-3-trifluoromethylphenyl) thioureido] phenyl] amide [1,2,3] thiadiazole-4-carboxylic acid, (4 [1,2,3] Thiadiazole-4-carboxylic acid {3- [3-chloro-4- (cyclohexylmethylamino) phenyl] thioureido} phenyl) amide furan-2- [4- (3-Benzylthioureido) phenyl] amide furan-2-carboxylic acid (4- [3- [2- (3,5-Dichlorophenoxy) ethyl] thioureido] phenyl) amide, [4- [3- ( Furan-2-carboxylic acid 2-fluoro-5-trifluoromethylbenzyl) thioureido] phenyl] amide, (4- {3- [2- (3-Bromo-4-methoxyphenyl) ethyl] thioureido} phenyl] amide [1,2,3] thiadiazole- [1,2,3] Thiadiazole-4-carboxylic acid (4- {3- [2- (2-chloro-phenyl) -ethyl] -thioureido} -phenyl) -amide, [4- [3- (4-Chloro)] Oxazole-4-carboxylic acid -3-trifluoromethylphenyl) thioureido] phenyl] amide, furan-2-carboxylic acid (4- {3- [2- (3,4-dichlorophenyl) ethyl] thioureido} phenyl) amide, {4- [3 - 1,2,3] thiadiazole-4-carboxylic acid (2-chlorobenzyl) thioureido] phenyl} amide, 200 [4- [3- (4-Fluorobenzyl) 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-Bromo-3-chlorophenyl) thioureido] phenyl] amide furan-2-carboxylic acid, (4- {3 - [(1S) -1- ( [1,2,3] Thiadiazole-4-carboxylic acid 4-bromophenyl) ethyl] thioureido} phenyl) amide, (4- {3 - [(IR) -1- (4-Bromophenyl) ethyl] thioureido} phenyl) amide [1,2,3] Thiadiazole-4-carboxylic acid [1,2,3] thiadiazole-4-carboxylic acid (4- {3- [1- (3,5-Bistrifluoromethyl-phenyl) -ethyl] -thioureido} -phenyl) -amide [1,2,3] Thiadiazole-4-carboxylic acid (4- {3 - [(1S) -1- (4-chlorophenyl) ethyl] thioureido} phenyl) amide, (4- {3 - [(IR) [1,2,3] Thiadiazole-4-carboxylic acid -1- (4-chlorophenyl) ethyl] thioureido} phenyl) amide, N- [4 - [[[[1- (4-Cyanophenyl) ethyl] amino] thioxomethyl] amino] phenyl] -1,2,3-thiadiazole-4-carboxamide, (4- {3- [1- (4) Thiazole-4-carboxylic acid -bromophenyl) ethyl] thioureido} phenyl) amide [1,2- (3- (1S) - [1- (3,5-Bis-trifluoromethylphenyl) ethyl] thioureido} phenyl) amide 3] thiadiazole-4-carboxylic acids, N- (4 - {[({1- [4-Fluoro-3- (trifluoromethyl) phenyl] ethyl} amino) carbothioyl] amino} phenyl) -1,2,3-thiadiazole-4-carboxamide, N- (4 - {[({1- [4-Chloro-3-thiadiazole-4-carboxamide), N- (4 - {[({(1S) -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) 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, 201 • · · · · · · · · · · · · · · · · · 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] 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-4-fluorophenyl) ethyl] amino} carbothioyl) 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} 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, N- {4 - [({[1- (2,4-Difluorophenyl) ethyl] amino} carbothioyl] amino} phenyl) -1,3-thiazole-4-carboxamide, N- (4 - {[({(IR) -1- [3,5-Bis (trifluoromethyl) phenyl] ethyl} amino) carbothioyl] amino} phenyl) -1,3-thiazole-4-carboxamide, N- {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, 202 · · · · · · · · · · · · · · · · · · · · · · N- {4 - [({[1- (4-Chloro-2-fluorophenyl) ethyl] amino} carbothioyl) 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} carbothioyl) 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, 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-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} -1H-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 pharmaceutical salts thereof. 203 A compound which is {4- [3- (3,5-bistrifluoromethylphenyl) thioureido] phenyl] amide [1,2,3] thiadiazole-4-carboxylic acid; or a salt thereof. A compound which is {4- [3- (4-chloro-3-trifluoromethylphenyl) thioureido] phenyl] amide [1,2,3] thiadiazole-4-carboxylic acid; or a pharmaceutical salt thereof. A compound which is thiazole-4-carboxylic acid {4- [3- (3,5-bistrifluoromethyl-phenyl) -thioureido] -phenyl] -amide; or a pharmaceutical salt thereof. 18. A pharmaceutical composition comprising: s e t í A compound of the formula: R4 Bs / A ΐ R a = X-NH-C-NH- (λ-NH-C-G R2 R1 AND where R 1 -R 5 is independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms carbon atoms, C 3 -C 10 heterocycloalkyl, aryl, heteroaryl, halogen, -CN, -NO ₂ , -co ₂ r ₆ , -or ₆ , -or ₆ , -sr ₆ , -sor ₆ , -so ₂ r _6, -CONR ₇ R _8, -NR ₆ N (R ₇ R _8), N (R ₇ R ₈₎ or WY- (CH _{2) n} -Z provided that at least one of R1-R5 is not hydrogen; or R ₂ and R ₃ or R ₃ and R 4 together form a 3 to 7 membered heterocycloalkyl or a 3 to 7 membered heteroaryl; 204 ····· ·· ·· · * ' R ₆ and R ₇ are independently hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, or aryl; R ₈ is hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10 members, aryl or heteroaryl, or R ₇ and R ₈ together may form a 3 to 7 membered heterocycloalkyl; W is O, NR ₆ or absent; Y is - (CO) - or - (CO ₂ ) - or is absent; Z is C 1 -C 4 alkyl, -CN, -CO ₂ R ₆ , -COR ₆ , -CONR ₇ R ₈ , -OCOR ₈ , -NR ₆ COR ₇ , -OCONR 8, -OR ₆ , "SR ₆ , - SOR ₆ , -SO ₂ R ₆ , SR ₆ N (R ₇ R ₈ ), -N (R ₇ R ₈ ) or phenyl; G is a monocyclic heteroaryl; X is a bond, -NH, alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, thioalkyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms, or (CH) J; J is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl or benzyl; and n is an integer from 1 to 6, or a pharmaceutical salt thereof, and a pharmaceutically acceptable carrier or diluent. 19. A method of inhibiting herpes virus replication, comprising contacting a compound of the formula wherein 205 • · · · · · · · · · R ₁ -R ₅ is independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 atoms carbon, heterocycloalkyl of 3 to 10 carbon atoms, aryl, heteroaryl, halogen, -CN, -NO ₂ , -co ₂ r ₆ , -cor ₆ , -or ₆ , -sr ₆ , -sor ₆ , -so ₂ r ₆ , -CONR ₇ R _8, -NR ₆ N (R ₇ R _8), N (R ₇ R ₈₎ or WY- (CH _{2) n} -Z provided that at least one of R1-R5 is not hydrogen; or R ₂ and R ₃ or R ₃ and R ₄ together form a 3 to 7 membered heterocycloalkyl or a 3 to 7 membered heteroaryl; R ₆ and R ₇ are independently hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, or aryl; R 5 is hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10 members, aryl or heteroaryl, or R ₇ and R ₈ together may form a 3 to 7 membered heterocycloalkyl; W is O, NR ₆ or absent; Y is - (CO) - or - (CO ₂ ) - or is absent; Z is C 1 -C 4 alkyl, -CN, -CO ₂ R ₆ , -COR ₆ , -CONR ₇ R ₈ , -OCOR ₆ , -NR ₆ COR ₇ , -OCONR ₆ , -OR ₆ , -SR ₆ -SOR ₆ , -SO ₂ R ₆ , SR ₆ N (R ₇ R ₈ ), -N (R ₇ R ₈ ) or phenyl; G is a monocyclic heteroaryl; X is a bond, -NH, alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, thioalkyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms, or (CH) J; J is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl or benzyl; and n is an integer from 1 to 6, or a herpes virus pharmaceutical salt thereof. The method of claim 19, wherein the herpes virus is a human cytomegalovirus. > · · «« «« «« «« «« «« «« « 206 The method of claim 19 wherein the herpes virus is varicella zoster virus. 22nd The method of claim 1 optical isomer. 21 wherein the compound is substantially pure 23. The method of claim 19 wherein the herpes virus is herpes simplex virus. 24. A method of treating a patient suffering from a herpes virus infection, comprising administering to the patient a therapeutically effective amount of a compound of the formula: R ₁ -R ₅ is independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 atoms carbon, heterocycloalkyl of 3 to 10 carbon atoms, aryl, heteroaryl, halogen, -CN, -NO ₂ , -co ₂ r ₆ , -cor ₆ , -or ₆ , -sr ₆ , -sor ₆ , -so ₂ r ₆ , -CONR ₇ R _8, -NR ₆ N (R ₇ R _8), N (R ₇ R ₈₎ or WY- (CH _{2) n} -Z provided that at least one of R1-R5 is not hydrogen; or R ₂ and R ₃ or R ₃ and R a together form a 3 to 7 membered heterocycloalkyl or a 3 to 7 membered heteroaryl; R 6 and R ₇ are independently hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, or aryl; * · · · 207 R ₈ is hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10 members, aryl or heteroaryl, or R ₇ and R ₈ together may form a 3 to 7 membered heterocycloalkyl; W is O, NR ₆ or absent; Y is - (CO) - or - (CO ₂ ) - or is absent; Z is C 1 -C 4 alkyl, -CN, -CO ₂ R ₆ , -COR ₆ , -CONR ₇ R ₈ , -OCOR ₆ , -NR ₆ COR ₇ , -OCONR ₆ , -OR ₆ , -SR ₆ -SOR ₆ , -SO ₂ R ₅ , SR ₆ N (R ₇ R ₈ ), -N (R ₇ R ₈ ) or phenyl; G is a monocyclic heteroaryl; X is a bond, -NH, alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, thioalkyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms, or (CH) J; J is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl or benzyl; and n is an integer from 1 to 6, or a pharmaceutically acceptable salt thereof. 25. Way according to claim 24, where herpes virus Yippee human cytomegalovirus. 26. Way according to claim 24, where herpes virus Yippee varicella zoster virus. 27 Mar: Way according to claim 24, where the compound is ! IN basically clean (WITH) optical isomer. 28. Way according to claim 19, where herpes virus Yippee herpes simplex virus.