AU1934700A - Heterocyclic carboxamide-containing thiourea inhibitors of herpes viruses containing phenylenediamine group - Google Patents

Description

WO 00/34258 PCT/US99/28842 HETEROCYCLIC CARBOXAMIDE-CONTAINING THIOUREA INHIBITORS OF HERPES VIRUSES CONTAINING PHENYLENEDIAMINE GROUP 5 Background of the Invention Eight viruses have been identified which are members of the family Herpesviridae (reviewed in Roizman, B. 1996. Herpesviridae, p. 2221-2230. In B. N. Fields, D. M. Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed. Lippincott 10 Raven Publishers, Philadelphia, PA). Each member of this family is characterized by an enveloped virus containing proteinaceous tegument and nucleocapsid, the latter of which houses the viruses' relatively large double-stranded DNA genome (i.e. approximately 80-250 kilobases). Members of the human alphaherpesvirus subfamily are neurotropic and include herpes simplex virus type 1 (HSV-1) and type 15 2 (HSV-2), and varicella-zoster virus (VZV). The human betaherpesviruses are cytomegalovirus (HCMV), human herpesvirus 6 (HHV-6) and human herpesvirus 7 (HHV-7). The gammaherpesviruses are lymphotropic and include Epstein-Barr virus (EBV) and Kaposi's herpesvirus (HHV-8). Each of these herpesviruses is causally related to human disease, including herpes labialis and herpes genitalis (HSV-1 and 20 HSV-2 [Whitley, R.J. 1996. Herpes Simplex Viruses, p. 2297-2342. In B. N. Fields, D. M. Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed. Lippincott-Raven Publishers, Philadelphia, PA]); chicken pox and shingles (VZV [Arvin, A. 1996. Varicella-Zoster Virus, p. 2547-2585. In B. N. Fields, D. M. Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed. Lippincott-Raven Publishers, Philadelphia, 25 PA]); infectious mononucleosis (EBV [Rickinson, A. B. and Kieff, E. 1996. Epstein Barr Virus, p. 2397-2446. In B. N. Fields, D. M. Knipe, and P. 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, p. 2493-2523. In B. N. Fields, D. M. Knipe, and P. M. Howley 30 (ed.), Fields Virology, 3rd ed. Lippincott-Raven Publishers, Philadelphia, PA]); exanthem subitum (HHV-6 [(Pellet, P. E, and Black, J. B. 1996. Human Herpesvirus 6, p. 2587-2608. In B. N. Fields, D. M. Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed. Lippincott-Raven Publishers, Philadelphia, PA] and HHV-7 WO 00/34258 PCT/US99/28842 -2 [Frenkel, N., and Roffman, E. 1996. Human Herpesvirus 7, p. 2609-2622. In B. N. Fields, D. M. Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed. Lippincott Raven Publishers, Philadelphia, PA]); and Kaposi's sarcoma (HHV-8 [Neipel, F., Albrecht, J.C., and Fleckenstein, B. 1997. Cell-homologous genes in the Kaposi's 5 sarcoma-associated rhadinovirus human herpesvirus 8: determinants of its pathogenicity? J. Virol. 71:4187-92, 1997]). HCMV is considered in more detail below. Following the primary infection, herpesviruses establish latency within the infected individual and remain there for the remainder of his/her life. Periodic reactivation of latent virus is clinically relevant. In the case of HSV, reactivated 10 virus can be transmitted to infants during birth, causing either skin or eye infection, central nervous system infection, or disseminated infection (i.e. multiple organs or systems). Shingles is the clinical manifestation of VZV reactivation. Treatment of HSV and VZV is generally with antiviral drugs such as acyclovir (Glaxo Wellcome), ganciclovir (Roche) and foscarnet (Asta) which target viral encoded DNA 15 polymerase. HCMV is a ubiquitous opportunistic pathogen infecting 50-90% of the adult population (Britt, W. J., and Alford, C. A. 1996. Cytomegalovirus, p. 2493-2523. In B. N. Fields, D. M. Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed. 20 Lippincott-Raven Publishers, Philadelphia, Pa.). Primary infection with HCMV is usually asymptomatic, although heterophile negative mononucleosis has been observed. The virus is horizontally transmitted by sexual contact, breast milk, and saliva. Intrauterine transmission of HCMV from the pregnant mother to the fetus occurs and is often the cause of serious clinical consequences. HCMV remains in a 25 latent state within the infected person for the remainder of his/her life. Cell-mediated immunity plays a central role in controlling reactivation from latency. Impaired cellular immunity leads to reactivation of latent HCMV in seropositive persons. HCMV disease is associated with deficient or immature cellular immunity. 30 There are 3 major categories of persons with HCMV disease (reviewed by Britt and Alford, 1996). (1) In immunocompromised (AIDS) patients, HCMV is one of the two most common pathogens causing clinical disease (the other is Pneumocystis). The most common manifestation of HCMV in AIDS is retinitis, although infection of WO 00/34258 PCT/US99/28842 -3 other organs including the adrenal glands, lungs, GI tract, and central nervous system are also reported frequently. 90% of AIDs patients have active HCMV infection; 25 40% (-85,000 patients in the United States) have life- or sight-threatening HCMV disease. HCMV is the cause of death in 10% of persons with AIDs. (2) Due to 5 immune system suppression to reduce the risk of graft rejection, HCMV reactivation or reinfection is common amongst kidney, liver, heart, and allogeneic bone marrow transplant patients. Pneumonia is the most common HCMV disease in these patients, occurring in up to 70% of these transplant patients. (3) Congenital infection due to HCMV occurs in 1% of all births, about 40K per year. Up to 25% of these infants 10 are symptomatic for HCMV disease between ages 0-3 years. HCMV disease is progressive, causing mental retardation and neurological abnormalities, in children. Recent studies suggest that treatment with anti-HCMV drugs may reduce morbidity in these children. Several antiviral drugs are currently being marketed (Bron, D., R. Snoeck, 15 and L. Lagneaux. 1996. New insights into the pathogenesis and treatment of cytomegalovirus. Exp. Opin. Invest. Drugs 5:337-344; Crumpacker, C. 1996. Ganciclovir. New Eng. J. Med. 335:721-729; Sachs, S., and F. Alrabiah. 1996. Novel herpes treatments: a review. Exp. Opin. Invest. Drugs 5:169-183). These include: ganciclovir (Roche), a nucleoside analog with hemopoietic cell toxicity; foscarnet 20 (Astra), a pyrophosphate analog with nephrotoxicity; and cidofovir, Gilead), a nucleoside phosphonate with acute nephrotoxicity. Each of these drugs target the viral-encoded DNA polymerase, are typically administered intravenously due to their low bioavailability, and, as noted above, are the source of significant toxicity. Ganciclovir-resistant mutants which arise clinically are often cross-resistant with 25 cidofovir. Hence, there is a need for safer (i.e. less toxic), orally bioavailable anti viral drugs which are directed against novel viral targets. Phenyl thioureas are disclosed for use in a variety of pharmaceutical applications. Armistead, et al., WO 97/40028, teaches phenyl ureas and thioureas as inhibitors of the inosine monophosphate dehydrogenase (IMPDH) enzyme which is 30 taught to play a role in viral replication diseases such herpes. Widdowson, et al., WO 96/25157, teaches phenyl urea and thiourea compounds of the below formula for treating diseases mediated by the chemokine, interleukin-8.

WO 00/34258 PCT/US99/28842 -4 n(Y)

(R

1 )m H H Morin, Jr., et al., U.S. Patent No. 5,593,993 teaches certain phenyl thiourea compounds for treatment of AIDs and the inhibition of the replication of HIV and 5 related viruses. Therefore, it is an object of this invention to provide compounds, and pharmaceutically acceptable salts thereof, to inhibit and/or treat diseases associated with herpes viruses including human cytomegalovirus, herpes simplex viruses, Epstein-Barr virus, varicella-zoster virus, human herpesviruses-6 and -7, and Kaposi 10 herpesvirus. Description of the Invention In accordance with the present invention are provided compounds having the 15 formula:

R

4 R 5 SO

R

3 X-NH-C-NH NH-C-G 2 1 wherein R-R, 5are independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, 20 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, -NO 2 , -CO 2 R , -COR, -OR, 6SR -SOR, -S0 2 R,, -CONR7R,, -NR 6

N(RR

8 ), -N(RR,) or W-Y-(CI 2 )-Z provided that at 25 least one of R 1

-R

5 is not hydrogen; or R 2 and R 3 or R 3 and R 4 , taken together form a 3 to 7 membered heterocycloalkyl or 3 to 7 membered heteroaryl; WO 00/34258 PCT/US99/28842 -5

R

6 and R, 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 5 members, aryl or heteroaryl, or R, and R 8 , taken together may form a 3 to 7 membered heterocycloalkyl; W is 0, NR 6 , or is absent; Y is -(CO)- or -(CO 2 )-, or is absent; Z is alkyl of 1 to 4 carbon atoms, -CN, -CO 2 R,, COR,, -CONR 7 R,, -OCOR, 10 -NR 6 COR, -OCONR,, -OR , -SR 6 , -SOR 6 , -SO 2 R,, SRN(RR,), -N(R,R) 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, thioalkyl of 1 to 6 carbon 15 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 pharmaceutical salts thereof. 20 In some preferred embodiments of the present invention, R,-R, 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,). Preferably, 1 to 3 of R,-R, is not hydrogen. Most preferably, 2 of R,-R, is not hydrogen. In preferred compounds of the present 25 invention R 3 and R 5 , or R 4 and R, are preferably, independently, halogen or CF,. In some embodiments of the present invention G is 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 Cl-C4 30 alkyl. Preferably, when X is C,-C 4 alkyl, said alkyl is straight chain alkyl. When X is CH(J), J is preferably methyl.

WO 00/34258 PCT/US99/28842 -6 Preferred compounds of the present invention are the following compounds which include pharmaceutical salts thereof. [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl-benzyl) thioureido]-phenyl }-amide, 5 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-piperidin-1-yl-3 trifluoromethyl-benzyl)-thioureido]-phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-dimethylamino-3 trifluoromethyl-benzyl)-thioureido] -phenyl } -amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-dimethylamino-5 10 trifluoromethyl-benzyl)-thioureido]-phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-fluoro-3-trifluoromethyl benzyl)-thioureido]-phenyl }-amide, Thiazole-4-carboxylic acid {4-[3-(4-tert-butyl-benzyl)-thioureido]-phenyl} amide, 15 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-fluoro-5-trifluoromethyl phenyl)-ethyl] -thioureido} -phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4-bromo-phenyl)-ethyl] thioureido}-phenyl)-amide, Thiazole-4-carboxylic acid {4-[3-(3,4-dichloro-benzyl)-thioureido]-phenyl} 20 amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-dichloro-benzyl)-thioureido] phenyl } -amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,4-dichloro-benzyl)-thioureido] phenyl}-amide, 25 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3,4-dichloro-phenyl)-ethyl] thioureido}-phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4-trifluoromethyl-phenyl) ethyl] -thioureido } -phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-chloro-phenyl)-ethyl] 30 thioureido}-phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid f4-[3-(4-tert-butyl-benzyl)-thioureido] phenyl}-amide, WO 00/34258 PCT/US99/28842 -7 Thiazole-4-carboxylic acid {4-[3-(3,5-dichloro-phenyl)-thioureido]-phenyl} amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(2-fluoro-5-trifluoromethyl phenylsulfanyl)-ethyl]-thioureido}-phenyl)-amide, 5 [1,2,3]Thiadiazole-4-carboxylic acid (4-{ 3 -[2-(2,4-bis-trifluoromethyl phenyl)-ethyl] -thioureido } -phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4-fluoro-3-trifluoromethyl phenyl)-ethyl]-thioureido}-phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-fluoro-5-trifluoromethyl 10 benzyl)-thioureido]-phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3,5-bis-trifluoromethyl phenyl)-ethyl] -thioureido} -phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-[3-(4-iodo-3-trifluoromethyl phenyl)-thioureido]-phenyl}-amide, 15 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-fluoro-5-trifluoromethyl benzyl)-thioureido]-phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-bromo-phenylsulfanyl) ethyl] -thioureido }-phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-{ 3- [2-(2-fluoro-phenyl)-ethyl] 20 thioureido}-phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(2,4-dichloro-phenyl)-ethyl] thioureido }-phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-trifluoromethyl-phenyl) ethyl] -thioureido } -phenyl)-amide, 25 [1,2,3]Thiadiazole-4-carboxylic acid (4-f 3-[2-(2-fluoro-5-trifluoromethyl phenoxy)-ethyl]-thioureido}-phenyl)-amide, Thiazole-4-carboxylic acid {4-[ 3

-(

2 -fluoro-5-trifluoromethyl-benzyl) thioureido]-phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-iodo-phenyl)-ethyl] 30 thioureido}-phenyl)-amide, Furan-2-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl-benzyl)-thioureido] phenyl}-amide, WO 00/34258 PCT/US99/28842 -8 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[3-(2-methyl-butyl)-5 trifluoromethyl-phenyl]-thioureido}-phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-isobutyl-5-trifluoromethyl phenyl)-thioureido]-phenyl}-amide, 5 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-dimethylamino-5 trifluoromethyl-phenyl)-ethyl] -thioureido } -phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(5-bromo-2-methoxy-phenyl) ethyl] -thioureido) -phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-(3-[2-(4-chloro-phenyl)-ethyl] 10 thioureido} -phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3,5-dichloro-phenoxy)-ethyl] thioureido } -phenyl)-amide, Thiazole-4-carboxylic acid {4-[3-(3,4-dichloro-phenyl)-thioureido]-phenyl} amide, 15 Thiazole-4-carboxylic acid {4-[ 3

-(

4 -chloro-3-trifluoromethyl-phenyl) thioureido]-phenyl}-amide, [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 (4-{3-[2-(2-fluoro-3-trifluoromethyl 20 phenyl)-ethyl]-thioureido }-phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(2-fluoro-5-trifluoromethyl phenyl)-ethyl]-thioureido }-phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-bromo-phenyl)-ethyl] thioureido } -phenyl)-amide, 25 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-4-trifluoromethyl phenyl)-thioureido]-phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid f 4-[3-(3-chloro-4-iodo-phenyl) thioureido]-phenyl}-amide, Furan-2-carboxylic acid [4-(3-benzo[1,3]dioxol-5-ylmethyl-thioureido) 30 phenyl]-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[1-(4-bromo-phenyl)-ethyl] thioureido }-phenyl)-amide, WO 00/34258 PCT/US99/28842 -9 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,3-diphenyl-propyl)-thioureido] phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-4-fluoro-benzyl) thioureido]-phenyl}-amide, 5 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3,4-dichloro-phenoxy)-ethyl] thioureido}-phenyl)-amide, [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-chloro-benzyl)-thioureido] 10 phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-bromo-3-trifluoromethyl phenyl)-thioureido]-phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-{3- [2- (4-fluoro-phenyl)-ethyl] thioureido } -phenyl)-amide, 15 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-pyrrolidin-l-yl-5 trifluoromethyl-phenyl)-thioureido]-phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[3-(butyl-methyl-amino)-5 trifluoromethyl-phenyll-thioureido}-phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-dimethyl-benzyl)-thioureido] 20 phenyl}-amide, Thiazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl-phenyl) thioureido]-phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,4-dichloro-phenyl)-thioureido] phenyl}-amide, 25 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-bromo-5-trifluoromethyl phenyl)-thioureido]-phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4- {3- [2- (3-chloro-phenoxy)-ethyl] thioureido}-phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4- { 3- [2-(4-ethyl-phenyl)-ethyl] 30 thioureido}-phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-{3- [2-(3-bromo-phenoxy)-ethyl] thioureido} -phenyl)-amide, WO 00/34258 PCT/US99/28842 -10 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-chloro-benzyl)-thioureido] phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(5-chloro-2-methoxy-4-methyl phenyl)-thioureido]-phenyl}-amide, 5 [1,2,3]Thiadiazole-4-carboxylic acid (4-{ 3-[2-(3-fluoro-phenyl)-ethyl] thioureido } -phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4- { 3-[1- (4-fluoro-phenyl)-ethyl] thioureido} -phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-difluoro-benzyl)-thioureido] 10 phenyl}-amide, Furan-2-carboxylic acid {4-[3-(3,5-dichloro-benzyl)-thioureido]-phenyl} amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-p-tolyl-ethyl)-thioureido] phenyl } -amide, 15 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-phenyl-butyl)-thioureido] phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-phenylsulfanyl-ethyl) thioureido]-phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-iodo-benzyl)-thioureido] 20 phenyl}-amide, Furan-2-carboxylic acid (4-{ 3- [2- (3-bromo-phenylsulfanyl)-ethyl] thioureido}-phenyl)-amide, Oxazole-4-carboxylic acid {4-[3-(3,5-dichloro-phenyl)-thioureido]-phenyl} amide, 25 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3- [2-(3,4-difluoro-phenyl)-ethyl] thioureido} -phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-{ 3- [2- (3,5-difluoro-phenyl)-ethyl] thioureido}-phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-iodo-phenoxy)-ethyl] 30 thioureido}-phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-dichloro-phenyl)-thioureido] phenyl } -amide, WO 00/34258 PCT/US99/28842 -11 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-amino-5-chloro-phenyl) thioureido]-phenyl} -amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-bromo-phenyl)-thioureido] phenyl}-amide, 5 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[3-(isobutyl-methyl-amino)-5 trifluoromethyl-phenyl]-thioureido}-phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-[3-(3-phenyl-propyl)-thioureido] phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid { 4-[3-(3-chloro-4-fluoro-phenyl) 10 thioureido]-phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid{ 4 -[3-(3,4,5-trichloro-phenyl) thioureido]-phenyl}-amide, Furan-2-carboxylic acid (4-[3-(3,4-dichloro-benzyl)-thioureido]-phenyl} amide, 15 [1,2,3]Thiadiazole-4-carboxylic acid (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-fluoro-phenoxy)-ethyl] 20 thioureido}-phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-[3-(3-iodo-phenyl)-thioureido] phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-bromo-4-trifluoromethoxy phenyl)-thioureido]-phenyl}-amide, 25 [1,2,3]Thiadiazole-4-carboxylic acid {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)-3 trifluoromethyl-benzyl]-thioureido }-phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,4-difluoro-benzyl)-thioureido] 30 phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-bromo-3-chloro-phenyl) thioureido]-phenyl)-amide, WO 00/34258 PCT/US99/28842 - 12 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-phenyl)-thioureido] phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-phenoxy-ethyl)-thioureido] phenyl}-amide, 5 [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-methyl-phenyl) thioureido]-phenyl}-amide, Furan-2-carboxylic acid {4-[3-(3-fluoro-5-trifluoromethyl-benzyl) 10 thioureido] -phenyl} -amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4-nitro-phenyl)-ethyl] thioureido } -phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-piperidin-1-yl-5-trifluoro methyl-phenyl)-thioureido]-phenyl}-amide, 15 Oxazole-4-carboxylic acid {4-[3-(3,4-dichloro-phenyl)-thioureido]-phenyl} amide, Furan-2-carboxylic acid {4-[3-(3,4,5-trichloro-phenyl)-thioureido]-phenyl} amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-chloro-phenyl)-thioureido] 20 phenyl} -amide, [1,2,3]Thiadiazole-4-carboxylic acid [4-(3-benzo[1,3]dioxol-5-ylmethyl thioureido)-phenyl]-amide, [1,2,3]Thiadiazole-4-carboxylic acid [4-(3-phenethyl-thioureido)-phenyl] amide, 25 [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-(3,5-bis-trifluoromethyl-phenyl) thioureido]-phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-dichloro-2-methoxy-4 30 methyl-phenyl)-thioureido] -phenyl } -amide, [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[3-chloro-4-(1H-pyrazol-3-yl) phenyl]-thioureido}-phenyl)-amide, WO 00/34258 PCT/US99/28842 - 13 [1,2,3]Thiadiazole-4-carboxylic acid (4-{ 3- [3-chloro-4-(2-piperidin- 1-yl acetylamino)-phenyl]-thioureido}-phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-trifluoromethyl-phenyl) thioureido]-phenyl}-amide, 5 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-chloro-3-trifluoromethyl phenyl)-thioureido]-phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[3-chloro-4-(cyclohexyl-methyl amino)-phenyl] -thioureido } -phenyl)-amide, Furan-2-carboxylic acid [4-(3-benzyl-thioureido)-phenyl]-amide, 10 Furan-2-carboxylic acid (4-f{ 3- [2-(3,5-dichloro-phenoxy)-ethyl] -thioureido} phenyl)-amide, Furan-2-carboxylic acid {4-[ 3

-(

2 -fluoro-5-trifluoromethyl-benzyl) thioureido]-phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-bromo-4-methoxy-phenyl) 15 ethyl] -thioureido } -phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-{3- [2- (2-chloro-phenyl)-ethyl] thioureido} -phenyl)-amide, Oxazole-4-carboxylic acid {4-[ 3

-(

4 -chloro-3-trifluoromethyl-phenyl) thioureido]-phenyl}-amide, 20 Furan-2-carboxylic acid (4-{3-[2-(3,4-dichloro-phenyl)-ethyl]-thioureido} phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-chloro-benzyl)-thioureido] phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-bromo-phenyl)-thioureido] 25 phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-fluoro-benzyl)-thioureido] phenyl} -amide, Furan-2-carboxylic acid {4-[3-(4-bromo-3-chloro-phenyl)-thioureido] phenyl}-amide, 30 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[(1S)-1-(4-bromo-phenyl)-ethyl] thioureido}-phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4- {3-(1 R)- 1 -(4-bromo-phenyl)-ethyl] thioureido} -phenyl)-amide, WO 00/34258 PCT/US99/28842 -14 [1,2,3]Thiadiazole-4-carboxylic acid (4- { 3-[i-(3,5-bis-trifluoromethyl phenyl)-ethyl] -thioureido} -phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-{3- [(1 S)- 1-(4-chloro-phenyl)-ethyl] thioureido}-phenyl)-amide, 5 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[(1R)-1-(4-chloro-phenyl)-ethyl] thioureido}-phenyl)-amide, N- [4- [[[[1-(4-Cyanophenyl)ethyl] amino]thioxomethyl] amino]phenyl] -1,2,3 thiadiazole-4-carboxamide, Thiazole-4-carboxylic acid (4-{3- [1- (4-bromo-phenyl)-ethyl] -thioureido} 10 phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-(1S)-[1-(3,5-bis-trifluoromethyl phenyl)-ethyl] -thioureido } -phenyl)-amide, N- (4-{ [({l- [ 4 -fluoro-3-(trifluoromethyl)phenyl] ethyl} amino)carbothioyl] amino } phenyl)- 1,2,3-thiadiazole-4-carboxamide, 15 N-(4-{[({1-[4-chloro-3-hiadiazole-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] 20 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, 25 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 30 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) WO 00/34258 PCT/US99/28842 - 15 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) 5 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 Icarbothioyl)amino]phenyl) -1,3 thiazole-4-carboxamide, 10 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 15 thiazole-4-carboxamide, N-(4- { [({(1 R)- 1- [3,5-bis(trifluoromethyl)phenyl] ethyl) amino) carbothioyl] amino )phenyl)- 1,3-thiazole-4-carboxamide, N- (4-[({[i-(3,4-dichlorophenyl)ethyl] amino) carbothioyl)amino]phenyl -1,3 thiazole-4-carboxamide, 20 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] 25 phenyl} I-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, 30 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, WO 00/34258 PCT/US99/28842 - 16 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, 5 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 } 10 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, 15 N- {4- [({[1-(4-fluorophenyl)ethyl] amino } carbothioyl)amino] phenyl }-1 H imidazole-4-carboxamide, N- {4-( {[3,5-bis(trifluoromethyl)benzyl] amino} carbothioyl)amino]phenyl} 1-methyl-i H-imidazole-4-carboxamide, N-(4-{ [({ 1-[3, 5 -bis(trifluoromethyl)phenyl]propyl} amino)carbothioyl] 20 amino}phenyl)-1,3-thiazole-4-carboxamide; and pharmaceutical salts thereof. Unless otherwise defined, the terms used herein have the following meanings. Alkyl as used herein refers to straight or branched chain lower alkyl of 1 to 6 carbon atoms. Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, 25 isobutyl, t-butyl, pentyl and hexyl. Alkenyl as used herein refers to straight or branched chain lower alkyl of 2 to 6 carbon atoms containing at least one carbon-carbon double bond. Alkenyl includes vinyl groups. Alkynyl as used herein refers to straight or branched chain lower alkyl of 2 to 30 6 carbon atoms containing at least one carbon-carbon triple bond. Alkyl, alkenyl and alkynyl groups of the present invention may be substituted or unsubstituted.

WO 00/34258 PCT/US99/28842 - 17 Cycloalkyl refers to a saturated mono or bicyclic ring system of 3 to 10 carbon atoms. Exemplary cycloalkyl groups include cyclopentyl, cyclohexyl and cycloheptyl. Cycloalkyl groups of the present invention may be substituted or unsubstituted. 5 Heterocycloalkyl refers to a saturated mono or bicyclic ring system of 3 to 10 members having 1 to 3 heteroatoms selected from N, S and 0, including, but not limited to aziridinyl, azetidinyl, imidazolidinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrazolidinyl, piperidinyl, and pyrrolidinyl. Heterocycloalkyl groups of the present invention may be substituted or unsubstituted. 10 Aryl, as used herein refers to an aromatic mono or bicyclic ring of 6 to 10 carbon atoms. Exemplary aryl groups include phenyl, naphthyl, and biphenyl. Aryl groups of the present invention may be substituted or unsubstituted. Heteroaryl as used herein refers to an aromatic mono or bicyclic ring of 5 to 10 members having 1 to 3 heteroatoms selected from N, S or 0 including, but not 15 limited to thiazolyl, thiadiazolyl, oxazolyl, furyl, indolyl, benzothiazolyl, benzotriazolyl, benzodioxyl, indazolyl, and benzofuryl. Preferred heteroaryls include quinolyl, isoquinolyl, napthalenyl, benzofuranyl, benzothienyl, indolyl, pyridyl, pyrazinyl, thienyl, furyl, pyrrolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, pyrazolyl, triazolyl, thiadiazolyl, and imidazolyl. Heteroaryl groups of the 20 present invention may be substituted or unsubstituted. Perhaloalkyl refers to an alkyl group of 1 to 6 carbon atoms in which three or more hydrogens are substituted with halogen. Phenyl as used herein refers to a 6 membered aromatic ring. Halogen, as used herein refers to chlorine, bromine, iodine and fluorine. 25 Unless otherwise limited, substitutents are unsubstituted and may include alkyl of 1 to 6 carbon atoms, cycloalkyl of 1 to 6 carbon atoms, heterocycloalkyl of Ito 6 members, perhaloalkyl of 1 to 6 carbon atoms, amino, azido, hydroxy, alkylamino, dialkylamino, aryl or heteroaryl. Carbon number refers to the number of carbons in the carbon backbone and 30 does not include carbon atoms occurring in substituents such as an alkyl or alkoxy substituents.

WO 00/34258 PCT/US99/28842 - 18 Where terms are used in combination, the definition for each individual part of the combination applies unless defined otherwise. For instance, alkylcycloalkyl is an alkyl-cycloalkyl group in which alkyl and cycloalkyl are as previously described. 5 Pharmaceutically acceptable salts are the acid addition salts which can be formed from a compound of the above general formula and a pharmaceutically acceptable acid such as phosphoric, sulfuric, hydrochloric, hydrobromic, citric, maleic, succinic, fumaric, acetic, lactic, nitric, sulfonic, p-toluene sulfonic, methane sulfonic acid, and the like. 10 The compounds of this invention contain a chiral center, providing for various seteroisomeric 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 present invention are substantially pure optical isomers. By substantially pure optical isomer is meant the composition contains greater than 75% of 15 the desired isomer and may include no more than 25% of the undesired isomer. In more preferred embodiments the pure optical isomer is greater than 90% of the desired isomer. The individual isomers can be prepared directly or by asymmetric or stereospecific synthesis or by conventional separation of optical isomers from the racemic mixture. 20 Compounds of the present invention may be prepared by those skilled in the art of organic synthesis employing methods described below which utilize readily available reagents and starting materials unless otherwise described. Compounds of the present invention are thus prepared in accordance with the following schemes. 25 The novel compounds of the present invention are prepared according to the following reaction schemes. Referring to Methods 31 and 34, reacting appropriately substituted amines 2, wherein the substitutents R,-R,, and X are described as above, with appropriately 30 substituted isothiocyanates 3, wherein the substituent G is described above, either neat or in an appropriate solvent such as tetrahydrofuran, acetonitrile, ethyl acetate, dichloromethane, or N,N-dimethylformamide affords the desired thioureas 1. Similarly, reaction of appropriately substituted isothiocyanates 4, wherein the WO 00/34258 PCT/US99/28842 - 19 substitutents R,-R 5 , and X are described as above with appropriately substituted anilines 5, wherein the substituent G is described above, in a convenient solvent such as those listed above affords the desired thioureas 1. 5 Methods 31 and 34 R 5 1

R

3

NH

2 + S=C=N -G

R

2

R

1

R

11

R

12 2 3 R X+-C- H-G H H 2

R

1

R

11

R

12 1 R X-N=C=S + C-G

R

2

R

1 R 11 R12 4 5 Alternatively, appropriately substituted thioureas 1 can be prepared as described by Methods 32 and 33 by reacting anilines 2 and 5, wherein R,-R,, and G are described as above, in the presence of either one molar equivalent of 1,1' 10 thiocarbonyldiimidazole or 1,1'-carbonyldiimidazole in an appropriate 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 an appropriate solvent such as dichloromethane and tetrahydrofuran or mixtures thereof at room temperature. 15 Methods 32, 33 1) CS(IM) 3 2) ArNH 2 6H H NH32 H 1) CS(Triaz) 2 33 2) ArNH 2 N N H H WO 00/34258 PCT/US99/28842 - 20 In certain instances, subsequent chemical modification of the final thioureas 1 was required. These methods, Methods 35-39, are summarized below. 35 JNO EtOH 0)N:N'O H H H H OAc O : P 1 I N a O H3 6 EtOH & NO 3 0 H 0 H H EtO C HOOC BzCIH3 OH OBz MsCI 38 H H H H HNR2 39 OMs NR2 SnC MeOH -P40 N3 H H N2H H 3

NH

2 5 Thioureas 1 wherein at least one substituent of R 1 -R is 1-hydroxyethoxy or carboxy-methoxy, G is defined as above and X equals a bond, may be prepared from the corresponding alkyl esters by alkaline hydrolysis with aqueous sodium or potassium hydroxide in a suitable solvent such as methanol, tetrahydrofuran or 10 mixtures thereof at room temperature in accordance with Methods 35 and 36.

WO 00/34258 PCT/US99/28842 -21 Thioureas I wherein at least one substituent of R,-R 5 is 1-acyloxyethoxy or methansulfonoxyethoxy, G is defined as above and X equals a bond, may be prepared from the corresponding 1-hydroxyethoxy derivative by acylation with appropriate 5 acylating agents such as benzoic acid chloride or methanesulfonic acid chloride in the presence of a suitable tertiary amine base such as triethylamine or diisopropylethylamine in a suitable solvent such as dichloromethane or the like at room temperature in accordance with Methods 37 and 38. 10 Thioureas 1 wherein at least one substituent of R 1

-R

5 is 1-aminoethoxy, G is defined as above and X equals a bond, may be prepared from the corresponding 1 methanesulfonoxy-ethoxy derivative by reaction with an appropriate secondary amine such as dimethylamine in a suitable solvent mixture such as tetrahydrofuran and water or the like at room temperature in accordance with Method 39. 15 Thioureas 1 wherein at least one substituent of R,-R, is 1-aminoalkyl, G is defined as above and X equals 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 in accordance with Method 40. 20 The intermediate isothiocyanates 3 and 4 shown above in Methods 31 and 34 are prepared in accordance with Method 41 (below) essentially according to the procedures of Staab, H.A. and Walther, G. Justus Liebigs Ann. Chem. 657, 104 (1962)) by reacting appropriately substituted amines 5 or 2, respectively, wherein R 1 25 R 5 and G are described above and X is defined above, with one molar equivalent of 1,1'-thiocarbonyldiimidazole in an appropriate solvent such as dichloromethane and tetrahydrofuran or mixtures thereof.

WO 00/34258 PCT/US99/28842 - 22 Method 41 N

H

2 N / -C-G S=C=N N-G-G H H 5 3 R4 5 NR4 5

R

3

X-NH

2

R

3 \ / X-N=C=S

R

2

R

1

R

2

R

1 2 4 5 The intermediates 2 and 5 may be prepared according to the following protocols: According to Methods 1A-IG, amines 2, wherein R 1

-R

5 are defined above and 10 X is defined above, amines 5 may be prepared by reduction of the appropriately substituted nitrobenzenes according to a variety of procedures known to those skilled in the art and described in R. J. Lindsay, Comprehensive Organic Chemistry (ed. Sutherland), Volume 2, Chapter 6.3.1, Aromatic Amines, 1979. Such procedures include the reduction of nitrobenzenes to form anilines upon exposure to: 15 a) iron powder and a strong acid, such as hydrochloric acid (Methods 1A) either neat or in alcohol solvent such as methanol or ethanol, at temperatures ranging from room temperature to the refluxing temperature of the solvent, or; b) iron powder and glacial acetic acid (Method 1B), either neat or in alcohol solvent such as methanol or ethanol, at temperatures ranging from room temperature to the 20 refluxing temperature of the solvent, or; WO 00/34258 PCT/US99/28842 - 23 c) iron powder and aqueous ammonium chloride (Method IC), either neat or in alcohol solvent such as methanol or ethanol, at temperatures ranging from room temperature to the refluxing temperature of the solvent, or; d) tin and a strong mineral acid, such as hydrochloric acid (Method ID), either neat 5 or in alcohol solvent such as methanol or ethanol, at temperatures ranging from room temperature to the refluxing temperature of the solvent, or; e) when Ri-R. are selected from Cl, Br, I, -(OS0 2 )-CF,, or -(OS02)-l-(4 methylphenyl), by catalytic reduction such as with hydrogen and palladium on carbon (Method 1E) in an appropriate solvent such as methanol, ethanol, or ethyl 10 acetate, under one or more atmospheres of pressure or; f) when R 1

-R

5 and R 9

-R

12 are selected from Cl, Br, I, -(OSO2)-CF,, or -(OSO2)-l-(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 refluxing temperature of the 15 solvent, or; g) aqueous sodium hydrosulfite in alcohol solvent at temperatures ranging from room temperature to the refluxing temperature of the solvent (Method lG). Alternatively, according to Methods 3A-3C, amines 2, wherein R 1

-R

5 are defined 20 above and X is defined above and anilines 5, above may be prepared by the cleavage of the aniline nitrogen-carbon bond of amide and carbamate derivatives of these anilines according to a variety of procedures known to those skilled in the art and described in Greene, Protective Groups in Organic Synthesis volume 2, Chapter 7, 1991, and references therein. Such procedures include: 25 a) the exposure of appropriately substituted arylamino-tert-butyl-carbamates to a strong acid such as trifluoroacetic acid (Method 3A)either neat or in an appropriate solvent such as dichloromethane at temperatures between 0 0 C and room temperature, or; b) the exposure of appropriately substituted arylamino-(2-trimethylsilylethyl) 30 carbamates to a fluoride ion source such as tetrabutylammonium fluoride or potassium fluoride (Method 3B) in aqueous acetonitrile or tetrahydrofuran or mixtures thereof at temperatures ranging from room temperature to the reflux temperature of the solvent, or; WO 00/34258 PCT/US99/28842 - 24 c) the exposure of appropriately substituted arylamino-trifluoroacetamides to a strong base such as sodium or potassium hydroxide or sodium or potassium carbonate in an alcohol solvent such as methanol or ethanol (Method 3C) at temperatures ranging from room temperature to the reflux temperature of the solvent. 5 Alternatively, according to Method 11, amines 2, wherein R,-R 5 are defined above, and X is defined above at least one substituent of R,-R, is defined as vinyl, may be prepared by the palladium catalyzed coupling of a vinyl trialkyltin reagent, such as tributylvinyltin, with an appropriately substituted bromo- or iodo-aniline, for example 3-chloro-4-iodo-aniline, employing a palladium catalyst, such as 10 tris(dibenzylidineacetone)-bipalladium, and a ligand, such as triphenylarsine, in a suitable solvent such as tetrahydrofuran or N-methylpyrrolidinone, at temperatures ranging from room temperature to the reflux temperature of the solvent, essentially according to the procedures of V. Farina and G.P. Roth in Advances in Metal Organic Chemistry, Vol. 5, 1-53, 1996 and references therein. 15 Alternatively, according to Method 42, amines 2, wherein R,-R 5 are defined above and X is defined above and at least one substituent of R 2 or R 4 is defined as dialkylamino, may be prepared by the palladium catalyzed amination of an appropriately substituted 3- or 5-bromo- or iodo-aniline, for example 3-amino-5 bromobenzotrifluoride, by secondary amines under conditions which employ a 20 palladium catalyst, such as bis(dibenzylidineacetone)palladium, and a ligand, such as tri-o-tolylphosphine, and at least two molar equivalents of a strong base, such as lithium bis-(trimethylsilyl)amide in a sealed tube, in a suitable solvent such as tetrahydrofuran or toluene, at temperatures ranging from room temperature to 100 'C, essentially according to the procedures of J.F. Hartwig and J. Louie Tetrahedron 25 Letters 36 (21), 3609 (1995). Alternatively, according to Method 43, amines 2, wherein R,-R 5 are defined above and X is defined above and at least one substituent of R 2 or R 4 is defined as alkyl, may be prepared by the palladium catalyzed alkylation of an appropriately substituted 3- or 5-bromo-or iodo-aniline, for example 3-amino-5 30 bromobenzotrifluoride by alkenes under condiditons which employ a palladium catalyst such as [1,1 '-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex and in the presence of 9-borabicyclo[3.3.1]nonane and a suitable base such as aqueous sodium hydroxide in a suitable solvent such as WO 00/34258 PCT/US99/28842 - 25 tetrahydrofuran or the like at temperatures ranging from room temperature to the reflux temperature of the solvent. The acyl and carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C may be prepared by the derivatization of the corresponding amines 5 as described in Methods 2A-2G according to a variety of procedures known to those skilled in the art and described in Greene, Protective Groups in Organic Synthesis volume 2, Chapter 7, 1991, and references therein. Such procedures include: a) the reaction of an appropriately substituted amine with di-tert-butyl-dicarbonate (Method 2A) in the presence or absence of one or more molar equivalents of a 10 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 produce the corresponding arylamino-tert-butyl carbamate, or; 15 b) the reaction of an appropriately substituted aniline with 1-[2 (trimethylsilyl)ethoxycarbonyl-oxy]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 produce the corresponding arylamino-(2-trimethylsilylethyl)-carbamate, or; 20 c) the reaction of an appropriately substituted aniline with a carboxylic acid chloride or acid anhydride (Method 2C) either neat or in an appropriate solvent such as tetrahydrofuran, dimethylformamide, dichloromethane, pyridine and the like, in the presence of one or more molar equivalents of a teriary amine base such as triethylamine or N,N-diisopropylethyl-amine to produce the corresponding 25 arylaminoamide, or; d) the reaction of an apptopriately substituted nitro aniline with a carboxylic acid chloride (Method 2D) in the absence of one or more molar equivalents of a teriary amine base such as triethylamine or N,N-diisopropylethylamine either neat or in an appropriate solvent such as tetrahydrofuran, 1,4-dioxane and the like at 30 temperatures ranging from room temperature to the reflux temperature of the solvent to produce the corresponding nitro arylaminoamide, or; e) the reaction of an appropiately substituted aniline with a carboxylic acid (Method 2E) in the presence of a coupling agent such as benzotriazole-1-yloxy-tris- WO 00/34258 PCT/US99/28842 - 26 (dimethylamino)-phosphonium hexafluorophosphate, 2-(l H-benzotriazole- 1 yloxy)- 1,1,3,3-tetra-methyluronium hexafluorophosphate, dicyclohexyl carbodiimide and the like and in the presence of a tertiary amine such as triethylamine or diisopropylethylamine in a suitable solvent such as 5 diichloromethane, dimethylformamide and the like, at room temperature to produce the corresponding arylaminoamide, or; f) the reaction of an appropriately protected aniline such as an arylamino-tert-butyl carbamate or the like in which at least one substituent of R 1

-R

12 is defined as -W

Y-(CH

2 ),-Z wherein W, Y, and Z are defined as above, with a carboxylic acid 10 anhydride (Method 2F) in the presence of a suitable base such as pyridine in an appropriate such as dichloromethane, dimethylformamide or the like at temperatures ranging from 0 0 C to room temperature to produce the corresponding carboxylic acid ester, or; g) the reaction of an appropriately substituted aniline in which a t least one 15 substituent of R,-R 5 is defined as hydroxyl with di-tert-butyl-dicarbonate (Method 2G) in the 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 20 solvent to produce the corresponding arylamino-tert-butyl-carbamate. Nitrobenzene intermediates that are ultimately converted to amines 2 and 5 by methods shown above in Methods IA-IG may be prepared in accordance with Methods 4A, 4C, 4E-4F. Referring to Methods 4A, 4C, and 4E-4H, the nitrobenzene intermediates 25 which are ultimately converted into amines 2, R 2 and R 4 are defined above and R,, R, and/or R, are defined as alkoxy, thioalkoxy, alkylsulfenyl, alkylsulfinyl, and dialkylamino may be prepared by the nucleophilic displacement of appropriately substituted 2-, 4-, and/or 6-fluoro-, chloro-, bromo-, iodo-, trifluoromethylsulfonyl-, or (4-methylphenyl)sulfonyl-substituted nitrobenzenes by methods which include the 30 following: a) reaction of alcohols with appropriately substituted 2- or 4- halo- or sulfonate esters of nitrobenzenes or benzonitriles (Method 4A) either neat or in an appropriate solvent such as tetrahydrofuran, dioxane, acetonitrile, N,N-dimethylformamide or WO 00/34258 PCT/US99/28842 - 27 dimethylsulfoxide in the presence or absence of one or more molar equivalents of a base such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, or the like, at temperatures ranging from room temperature to the reflux temperature of the 5 solvent; b) reactions of preformed sodium, lithium, or potassium phenoxides with appropriately substituted 2- or 4- halo- or sulfonate esters of nitrobenzenes or benzonitriles (Method 4H) either neat or in an appropriate solvent such as tetrahydrofuran, dioxane, acetonitrile, N,N-dimethylformamide or 10 dimethylsulfoxide, at temperatures ranging from room temperature to the reflux temperature of the solvent, or; c) reaction of ammonia, primary or secondary amines with appropriately substituted 2- or 4-halo- or sulfonate esters of nitrobenzenes or benzonitriles (Methods 4C,F) either neat or in an appropriate solvent such as tetrahydrofuran, dioxane, 15 acetonitrile, N,N-dimethyl-formamide or dimethylsulfoxide, at temperatures ranging from room temperature to the reflux temperature of the solvent; d) reaction of preformed sodium, lithium, or potassium salts of amines with appropriately substituted 2- or 4- halo- or sulfonate esters of nitrobenzenes or benzonitriles (Method 4G) in an appropriate solvent such as tetrahydrofuran at 20 temperatures ranging from 0 0 C to the reflux temperature of the solvent, or; e) reaction of sodium sulfide with appropriately substituted 2- or 4- halo- or sulfonate esters of nitrobenzenes or benzonitriles either neat or in an appropriate solvent such as tetrahydro-furan, dioxane, acetonitrile, N,N-dimethylformamide or dimethylsulfoxide, at temperatures ranging from room temperature to the reflux 25 temperature of the solvent, followed by the addition of an alkyl halide directly to the reaction mixture (Method 4E). Alternatively, referring to Methods 5C and 6, the nitrobenzene intermediates which are ultimately converted into amines 2, wherein at least one substitutent R 1 -R, is defined as alkoxy may be prepared from the corresponding substituted hydroxy 30 nitrobenzenes by methods which include the following: a) reaction of the hydroxy-nitrobenzene 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 WO 00/34258 PCT/US99/28842 - 28 hydride, in an appropriate solvent such as acetone, N,N-dimethylformamide, tetrahydrofuran or dimethylsulfoxide at temperatures ranging from room temperature to the reflux temperature of the solvent, or; b) reaction of the hydroxy-nitrobenzene with an alkyl alcohol, triphenylphosphine, 5 and a dialkylazadicarboxylate reagent (Method 6), such as diethylazodicarboxylate, in an anhydrous aprotic solvent such as diethyl ether or tetrahydrofuran at temperatures ranging from 0 0 C to the reflux temperature of the solvent, essentially according to methods described in Mitsunobu, 0, Synthesis 1981, 1 and references therein. 10 In addition, referring to Method 5A and 5E, the carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein at least one substituent R,-R 5 is defined as alkoxy may be prepared the corresponding substituted hydroxy arylamino-tert-butyl-carbamate by reaction 15 with alkyl halides, trifluormethane-sulfonates, 4-methylbenzenesulfonates, dialkylsulfonate, ethylene carbonate and the like in the presence of a suitable base such as potassium carbonate in an appropriate solvent such as acetone, toluene, or N,N-dimethylfonnamide at temperatures ranging from room temperature to the reflux temperature of the solvent. 20 Alternatively, referring to Methods 7A-G, the nitrobenzene intermediates which are ultimately converted into amines 2, R, and/or R 3 is alkoxy, and R 2 and/or

R

4 is a halogen, and X equals a bond, may be prepared by standard halogenation reactions which include the following: 25 a) reaction of a 2- or 4- hydroxy-nitrobenzene with aqueous sodium hypochlorite (Methods 7A and 7B), at room temperature or; b) reaction of a 2-hydroxy-4-methoxy or 2

,

4 -dimethoxynitrobenzene (Method 7C and 7D) with bromine in suitable solvent such as chloroform, dichlormethane, glacial acetic acid or the like in the presence or the absence of silver trifluoroacetate at 30 room temperature, or; c) reaction of a 2,4-dimethoxynitrobenzene (Method 7E) with benzyltrimethyl ammonium dichloroiodate in the presence of anhydrous zinc chloride in a suitable solvent such as glacial acetic acid, at room temperature or; WO 00/34258 PCTIUS99/28842 -29 d) reaction of a 2-hydroxy-4-methoxynitrobenzene (Method 7F) with benzyltrimethyl-ammonium dichloroiodate in the presence of sodium bicarbonate in a suitable solvent mixture such as dichloromethane and methanol, at room temperature or; 5 e) reaction of a 2,4-dimethoxynitrobenzene (Method 7G) with 3,5-dichloro-1 fluoropyridine triflate in a suitable solvent such as tetrachloroethane, at a temperature ranging from room temperature to the reflux temperature of the solvent. 10 Referring to Method 8, the nitrobenzene intermediates which are ultimately converted into amines 2, wherein R 4 = -CF,, and R,-R, and R,-R, are defined as above and X equals a bond may be prepared from the corresponding substituted 4 iodo-nitrobenzenes by reaction with trimethyl(trifluoromethyl)silane in the presence of cuprous iodide and potassium fluoride in a suitable solvent such as N,N 15 dimethylformamide or the like at a temperature ranging from room temperature to the reflux temperature of the solvent in a sealed reaction vessel. Referring to Methods 19A and 19B, the nitrobenzene intermediates which are ultimately converted into amines 2, wherein R 4 = -HNCOCH 2 NR.R, or HNCOCH 2

SR

6 , and R,-R, and R, are defined as above and X equals a bond may be 20 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 mixtures at temperatures ranging from room temperature to the reflux temperature of the solvent or by reaction with an appropriate thiol in the presence of a suitable base such as 25 sodium or potassium carbonate or the like in a suitable solvent such as tetrahydrofuran, 1,4-dioxane or the like at temperatures ranging from room temperature to the reflux temperature of the solvent. Referring to Method 25, the nitrobenzene intermediates which are ultimately converted into amines 2, wherein at least one substituent of R 1

-R

5 is defined as triflate 30 and X equals a bond may be prepared from the corresponding phenol by reaction with trifluoromethane-sulfonic anhydride in the presence of a tertiary amines such as triethylamine or diisopropyl-ethylamine or the like in a suitable solvent such as dichloromethane at temperatures ranging from 0 0 C to room temperature.

WO 00/34258 PCT/US99/28842 - 30 Referring to Methods 9, 9B, and 10, the carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein at least one substituent R 1 -R, is defined as either alkylsulfenyl or alkylsulfinyl, may be prepared by reaction of the appropriate 4-alkylthio acyl 5 arylamino or carbamoyl arylamino derivative with an appropriate 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, the carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein 10 R 4 is defined as 1-hydroxyethyl and R,-R, and R, are defined as above and X is a bond may be prepared by reacting the corresponding 4-vinyl carbamoyl aniline with sodium borohydride in the presence of mercuric acetate in a suitable solvent such as tetrahydrofuran, 1,4-dioxane or the like and water at room temperature. Referring to Method 13, the carbamoyl amine derivatives utilized as starting 15 materials in Methods 3A-3C which are ultimately converted into amines 2, wherein

R

4 is defined as 2-hydroxyethyl and R 1 -R, and R, are defined as above and X equals a bond, may be prepared by reacting the corresponding 4-vinyl carbamoyl aniline with sodium borohydride in the presence of glacial acetic acid in a suitable solvent such as tetrahydrofuran, 1,4-dioxane or the like at temperatures ranging from 0 0 C to room 20 temperature. Referring to Method 14, the carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein

R

4 is defined as 1-azidoethyl and R,-R, and R, are defined as above and X is defined above, may be prepared by reacting the corresponding 4-(1-hydroxyethyl) carbamoyl 25 aniline with hydrazoic acid in the presence of a dialkylazodicarboxylate such as diethylazodicarboxylate and triphenylphosphine in a suitable solvent mixture such as tetrahydrofuran and dichloromethane at temperatures ranging from 0 0 C to room temperature. Referring to Method 15, the carbamoyl amine derivatives utilized as starting 30 materials in Methods 3A-3C which are ultimately converted into amines 2, wherein

R

4 is defined as 3-dimethylaminoprop-1-ynyl and R,-R, and R, are defined as above and X is defined above, may be prepared by reacting the corresponding 4 iodocarbamoyl aniline with 1-dimethylamino-2-propyne in a suitable tertiary amine WO 00/34258 PCT/US99/28842 - 31 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, the carbamoyl amine derivatives utilized as starting 5 materials in Methods 3A-3C which are ultimately converted into amines 2, wherein

R

4 is defined as 3-dimethylaminoacryloyl and R 1 -R, and R, are defined as above and X equals a bond, may be prepared by reacting the corresponding 4-(3 dimethylaminoprop-1-ynyl)carbamoyl aniline with a suitable peracid such as 3 chloroperoxybenzoic acid in a suitable solvent mixture such as dichloromethane and 10 methanol at temperatures ranging from 0 0 C to room temperature. Referring toMethods 17 and 18, the carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein R 4 is defined as either 4-isoxazol-5-yl or 4-(1H-pyrazol-3-yl) and R,-R, and RS are defined as above and X equals a bond, may be prepared by reacting the 15 corresponding 4-(3-dimethylamino-acryloyl)carbamoyl aniline with either hydroxylamine hydrochloride or hydrazine hydrate in a suitable solvent such as 1,4 dioxane or ethanol and the like at room temperature. Referring to Method 20, the carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein 20 R 4 = -HNCO 2 Z, and R,-R,, R, and Z are defined as above and X equals a bond, may be prepared by reacting the corresponding 4-aminocarbamoyl aniline with 1,1 carbonyl-di-(1,2,4)-triazole and an appropriately substituted alcohol in a suitable solvent mixture such as tetrahydrofuran and dichloromethane and the like at temperatures ranging from room temperature to the reflux temperature of the solvent. 25 Referring to Methods 26 and 30, the carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein at least one substituent of R 1

-R

5 is defined as dialkylamino and X is defined above may be prepared by reaction of appropriately substituted aldehydes in the presence of either sodium cyanoboro-hydride or hydrogen gas and 10 % palladium on 30 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 substituent of

R

1

-R

5 is defined as hydroxy and X is defined above can be prepared by reaction of the WO 00/34258 PCT/US99/28842 - 32 corresponding ester such as acetate with an appropriate base such as sodium bicarbonate or sodium hydroxide in a suitable solvent mixture such as methanol water mixtures at temperatures ranging from room temperature to the reflux temperature of the solvent. 5 Referring to Method 29, amines 2 wherein at least one substituent of R 1

-R

5 is defined as 2-hydroxybenzamido and X is defined above can be prepared by reaction of the corresponding N-(4-aminophenyl)phthalimide with lithium borohydride in an appropriate solvent such as tetrahydrofuran, diethyl ether, or the like at room temperature. 10 The intermediate amines 2 wherein R 1

-R

5 are defined as above and X equals either -CH 2 - or -(CH 2

)

2 - can be prepared by the following procedures: a) reduction of an appropriately substituted benzo- or phenylacetonitrile with borane-dimethylsulfide complex in a suitable solvent such as ethylene glycol dimethyl ether, tetrahydrofuran or the like a temperatures ranging from room 15 temperature to the reflux temperature of the solvent. (Method 44); b) reduction under one or more atmospheres of hydrogen in the presence of a suitable catalyst such as 5 % or 10 % palladium on carbon and an acid such as 4 methyl-benzenesulfonic acid, hydrochloric acid or the like in a suitable solvent such as ethylene glycol monomethyl ether, ethyl acetate, ethanol or the like at room 20 temperature. (Method 50); c) reduction with lithium aluminum hydride in a suitable solvent such as tetrahydrofuran or diethyl ether at temperatures ranging from 0 0 C to room temperature. (Method 51); The unsaturated nitro precursors which are utilized as starting materials in 25 Method 51 and are ultimately converted to amines 2 wherein R 1

-R

5 are defined as above and X equals -(CH 2

)

2 - can be prepared by reaction of an appropriately substituted benzaldehyde with nitro-methane in the presence of ammonium acetate in a suitable solvent such as acetic acid at temperatures ranging from room temperature to the reflux temperature of the solvent.(Method 53); The benzaldehydes, utilized as 30 starting materials in Method 53, can be prepared by diisobutylaluminum hydride reduction of an appropriately substituted benzonitrile. (Method 52) The substituted benzonitriles, utilized as starting materials in Method 52, can be prepared from the corresponding aryl bromide by reaction with copper cyanide in a suitable solvent WO 00/34258 PCT/US99/28842 - 33 such as N,N-dimethylformamide at temperatures ranging from room temperatture to the reflux temperature of the solvent. (Method 59) For amines 2, wherein R 1

-R

5 is defined as above and X equals either O(CH2)2NH 2 or -S(CH 2

)

2

NH

2 , the requisite nitrile precursors may be prepared by 5 reaction of an appropriately substituted phenol or thiophenol with bromoacetonitrile in the presence of a suitable base such as potassium carbonate in an appropriate solvent such as acetone at room temperature according to Method 49. Alternatively, for amines 2, wherein R,-R, are defined as above and X equals

-(CH

2 ),-, the nitrile precursors can be prepared essentially according to the procedure 10 of Wilk, B. Synthetic Comm. 23, 2481 (1993), by reaction of an appropriately substituted phenethanol with acetone cyanohydrin and triphenylphosphine in the presence of a suitable azodicarboxylate such as diethyl azodicarboxylate in an appropriate solvent such as diethyl ether or tetrahydro-furan or the like at temperatures ranging from OC to room temperature. (Method 54) 15 Alternatively, intermediate amines 2 wherein R,-R, are defined as above and X equals -(CH(CH,))- can be prepared by acid or base catalyzed hydrolysis of the corresponding formamide using an appropriate acid catalyst such as 6N hydrochloric acid or a suitable base catalyst such as 5N sodium or potassium hydroxide in an appropriate solvent mixture such as water and methanol or water and ethanol at 20 temperatures ranging from room temperature to the reflux temperature of the solvent. (Method 46) The formamide precursors utilized as starting materials in Method 46 and which are ultimately converted into amines 2, are prepared according to Method 45 by treatment of an appropriately substituted acetophenone with ammonium formate, 25 formic acid and formamide at temperatures ranging from room temperature to the reflux temperature of the solvent. Alternatively, amines 2 wherein R 1 -R, are defined as above and X equals (CH(CH,))- can be prepared by reduction of an appropriately substituted 0-methyl oxime in the presence of sodium borohydride and zirconium tetrachloride in a 30 suitable solvent such as tetrahydrofuran or diethyl ether at room temperature Method 48 essentially according to the procedure of Itsuno, S., Sakurai, Y., Ito, K. Synthesis 1988, 995. The requisite O-methyl oximes can be prepared from the corresponding acetophenone by reaction with methoxylamine hydrochloride and pyridine in a WO 00/34258 PCT/US99/28842 - 34 suitable solvent such as ethanol or methanol at temperatures ranging from room temperature to the reflux temperature of the solvent. (Method 47) Amines 2 for which R 1 -R, are defined as above and X equals -CH(J)- where J is defined as above, can be prepared by reduction of the appropriately substituted 5 ketone by the methods described above (Methods 45, 47, and 48). These requisite ketones, when not commercially available, can be prepared by reaction of a suitably substituted benzaldehyde with an appropriate 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 10 from -78 "C to 0 0 C. (Method 57) The resulting alcohols can be oxidized to the corresponding ketone with an appropriate oxidizing agent such as chromium trioxide in aqueous sulfuric acid and acetone or pyridinium chlorochromate or pyridium dichromate in an appropriate solvent such as dichloromethane or the like at room temperature. (Method 58) 15 The intermediate anilines 5 may be prepared as previously described Method 3A. Thus treating phenyl carbamic acid tert-butyl ester 6, G is described as above, with neat trifluoroacetic acid at room temperature followed by neutralization with aqueous sodium hydroxide affords the desired anilines 5. The requisite carbamic acid esters 6, wherein G is described as above, are prepared as shown in Method 2C by 20 reaction of substituted acid chlorides, 8, where G is described as above, and 4 aminophenylcarbamic acid tert-butyl esters 7 in the presence of triethylamine in an appropriate 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 25 reaction with oxalyl chloride in a suitable solvent such as dichloromethane at room temperature.

WO 00/34258 PCT/US99/28842 - 35 Method 2C, 3A O,./ 0 L. CF3CO2H O G-COOH /= O ~ of .C301 + HN-- NH 2 0 HNc-G ii. NaOH N-- -G H 8 7 6 5 Alternatively, carbamic acid esters 6, wherein G is described as above, are prepared as shown in Method 2E by reaction of substituted carboxylic acids 8a, 5 wherein G is described as above, and an appropriately substituted 4-aminophenyl carbamic acid tert-butyl esters 7 in the presence of a suitable coupling agent such as benzotriazole-1-yloxy-tris-(dimethylamino)phosphonium hexafluorophosphate, 2 (1H-benzotriazole-1-yloxy)-1,1,3,3-tetramethyluronium hexafluorophosphage, dicyclohexyl carbodiimide or the like and in the presence of a tertiary amine base 10 such as triethylamine or diisopropylethylamine in a suitable solvent such as dichloromethane, dimethylformamide and the like, at room temperature to produce the corresponding arylaminoamide. Carboxylic acids 8a are either commercially available or are prepared according to literature methods. For example, when G is a substituted thiadiazole, 15 the acid is available from the corresponding carboxylic acid ester by reaction with an appropriate base such as sodium or potassium hydroxide in a suitable solvent mixture such as methanol or ethanol and water at room temperature. Similarly, when G is either substituted or unsubstituted thiazole, substituted or unsubstituted oxazole, substituted or unsubstituted isothiazole, or substituted or 20 unsubstituted isoxazole, when not commercially available, the corresponding carboxylic acid 8a is available from the corresponding ethyl or methyl ester by reaction with an appropriate base such as sodium or pottasium 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 literature 25 methods. When the carboxylic acid ester precursors which are ultimately converted to acids 8 are not commmercially available, they may be prepared by methods known in the literature. For example, 5-substituted-1,2,3-thiadiazole-4 carboxylic acid esters WO 00/34258 PCT/US99/28842 - 36 may be prepared essentially according to the procedure of 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, treatment of a beta-keto carboxylic acid ester with 4-methylbenzenesulfonyl azide or methanesulfonyl azide or the like in the 5 presence of a tertiary amine base such triethylamine or diisopropylethylamine in a suitable solvent such as acetonitrile affords the corresponding diazo-beta-keto carboxylic acid ester. Treatment of this compound with 2,4-bis(4-methoxyphenyl) 1,3-dithia-2,4-diphosphetane-2,4-disulfide in a suitable solvent such as benzene or toluene or the like at temperatures ranging from room temperature to the reflux 10 temperature of the solvent gives the desired 5-substituted-1,2,3-thiadiazole-4 carboxylic acid ester. Alternatively, 4-substituted-1,2,3-thiadiazole -5-carboxylic acid esters may be prepared essentially according to the procedure of Shafiee, A., Lalezari, I., Yazdani, S., Shahbazian, F. M., Partovi, T. J. Pharmaceutical Sci. 65, 304 (1976). Thus, 15 according to Method 22 and 23, reaction of an appropriately substituted beta-keto carboxylic acid ester in a suitable alcoholic solvent such as methanol or ethanol with an aqueous solution semicarbazide hydrochloride at temperatures ranging from room temperature to the reflux temperature of the solvent in the presence of a suitable base such as pyridine gives corresponding semicarbazone derivative. Treatment of this 20 compound with neat thionyl chloride at 0 0 C followed by treatment with an excess aqueous solution of sodium bicarbonate affords the corresponding 4-substituted 1,2,3-thiadiazole -5-carboxylic acid esters. 4-carboalkoxythiazoles are prepared essentially according to the procedure of Schullkopf, U., Porsch, P., Lau, H. Liebigs Ann. Chem. 1444 (1979). Thus, 25 according to Method 55 and 56, reaction of ethyl isocyanoacetate with N,N dimethylformamide dimethyl acetal in a suitable alcoholic solvent such as ethanol at room temperature gives the corresponding 3-dimethylamino-2-isocyano-acrylic acid ethyl ester. A solution of this compound in a suitable solvent such as tetrahydrofuran is treated with gaseous hydrogen sulfide in the presence of a suitable tertiary amine 30 base such as triethylamine or diiso-propylethylamine or the like at room temperature to give the corresponding 4-carboethoxy-thiazole. Additional appropriately substituted thiazoles may be prepared essentially according to the procedure of Bredenkamp, M. W., Holzafel, C. W., van Zyl, W. J.

WO 00/34258 PCT/US99/28842 - 37 Synthetic Comm. 20, 2235 (1990). Appropriate unsaturated oxazoles are prepared essentially according to the procedure of Henneke, K. H., Schullkopf, U., Neudecker, T. Liebigs Ann. Chem. 1979 (1979). Substituted oxazoles may be prepared essentially according to the procedures of Galeotti, N., Montagne, C., Poncet, J., 5 Jouin, P. Tetrahedron Lett. 33, 2807, (1992) and Shin, C., Okumura, K., Ito, A., Nakamura, Y. Chemistry Lett. 1305, (1994). The following specific examples are illustrative, but are not meant to be limiting of the present invention. 10 EXAMPLE 1 (METHOD 1A) 4-Methoxy-3-trifluoromethyl- phenylamine A suspension of 4 -methoxy-3-trifluoromethyl-nitrobenzene (2.2 g) and iron powder (1.68 g) in ethanol (35 mL) and water (15 mL) is treated with a solution of 15 concentrated hydrochloric acid (0.42 mL) in ethanol (6 mL) and water (3 mL) and the mixture is heated to reflux for approximately 1 hour. The mixture is then cooled, filtered, and concentrated under reduced pressure. The resulting oil is dissolved in ethyl acetate and extracted three times with 5% aqueous hydrochloric acid. The pooled acidic extracts are then cooled in an ice bath and basified with solid potassium 20 carbonate, then extracted with ethyl acetate. These organic extracts are washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, then passed through a short column of silica gel (ethyl acetate is used as the eluant) to provide the desired compound as an amber oil. 25 Using the above procedure and appropriate starting materials the following compounds were prepared: 2,6-Dichloro-benzene- 1,4-diamine 3-Chloro-4-methylsulfanyl-phenylamine 30 2,6-Dibromo-benzene- 1,4-diamine 3-Chloro-4-trifluoromethyl-phenylamine 3-Chloro-4-ethylsulfanyl-phenylamine 4-Methoxy-3-trifluoromethyl-phenylamine 3,5-Dichloro-4-methoxy-2-methyl-phenylamine WO 00/34258 PCT/US99/28842 - 38 5-Chloro-2-ethoxy-4-methoxy-phenylamine 5-Chloro-4-ethoxy-2-methoxy-phenylamine 5-Iodo-2,4-dimethoxy-phenylamine 3,5-Diiodo-2,4-dimethoxy-phenylamine 5 3,5-Dibromo-2,4-dimethoxy-phenylamine 5-Chloro-2-methoxy-4-methyl-phenylamine 2-Chloro-N(1),N(1)-dimethyl-benzene- 1,4-diamine 3-Chloro-4-piperidin- 1 -yl-phenylamine 3-Chloro-4-pyrrolidin- 1 -yl-phenylamine 10 N(1)-Benzyl-2-chloro-benzene- 1,4-diamine 3-Chloro-4-(4-methyl-piperazin- 1 -yl)-phenylamine 2-Chloro-N(1)-methyl-N(1)-(1 -methyl-piperidin-4-yl)-benzene- 1,4-diamine 2-Chloro-N(1)-methyl-N(1)-(1 -methyl-pyrrolidin-3-yl)-benzene- 1,4-diamine 2-Chloro-N(1)-methyl-N(1)-phenyl-benzene- 1,4-diamine 15 N(1)-(1 -Benzyl-pyrrolidin-3-yl)-2-chloro-N(1)-methyl-benzene- 1,4-diamine 2-Chloro-N(1)-cyclopentyl-N(1)-methyl-benzene- 1,4-diamine 2- [(4-Amino-2-chloro-phenyl)- (2-hydroxy-ethyl)-amino] -ethanol 2-Chloro-N(1)-hexyl-N(1)-methyl-benzene- 1,4-diamine 2-Chloro-N(1)-isobutyl-N(1)-methyl-benzene- 1,4-diamine 20 2- [ (4-Amino-2-chloro-phenyl)-methyl-amino] -ethanol 2-Chloro-N(1)-(3-dimethylamino-propyl)-N(1)-methyl-benzene- 1,4-diamine 2-Chloro-N(1)-(2-dimethylamino-ethyl)-N(1)-methyl-benzene- 1,4-diamine 2-Chloro-N(1)- (2-dimethylamino-ethyl)-benzene- 1,4-diamine N(1)-(1-Benzyl-piperidin-4-yl)-2-chloro-benzene- 1,4-diamine 25 2-Chloro-N(1)-(2-methoxy-ethyl)-N(1)-methyl-benzene- 1,4-diamine 2-Chloro-N(1)-(3-dimethylamino-propyl)-benzene- 1,4-diamine N(1)-(1-Benzyl-pyrrolidin-3-yl)-2-chloro-benzene- 1,4-diamine 3-Chloro-4-(1 -methyl-piperidin-4-yloxy)-phenylamine 3-Chloro-4-(2-dimethylamino-ethoxy)-phenylamine 30 3-Chloro-4-(3-dimethylamino-propoxy)-phenylamine 3-Chloro-4-(1-methyl-pyrrolidin-3-yloxy)-phenylamine 3-Chloro-4-cyclohexyloxy-phenylamine WO 00/34258 PCT/US99/28842 - 39 EXAMPLE 2 (METHOD 1B) 4 -Bromo-2,4-dimethoxy-phenylamine A suspension of 4-bromo-2,4-dimethoxy-nitrobenzene (0.48 g) and iron powder 5 (0.42 g) in acetic acid (10 mL) and ethanol (10 mL) is heated to 120 'C for approximately 5 hours. The mixture is then cooled, filtered, and concentrated under reduced pressure. Water is added and the mixture is cooled in an ice bath and neutralized with solid potassium carbonate and then extracted with dichloromethane. These organic extracts are washed with saturated aqueous sodium chloride, dried over 10 anhydrous sodium sulfate, concentrated under reduced pressure, then chromatographed over silica gel (20% ethyl acetate in hexanes is used as the eluant) to provide the desired compound as an amber oil. EXAMPLE 3 (METHOD 1C) 15 ( 4 -Amino-2,6-dichloro-phenoxy)-acetic acid tert-butyl ester A soution of (4-nitro-2,6-dichloro-phenoxy)-acetic acid tert-butyl ester (I g) in ethanol (17 mL) and water (8.6 mL) is treated with iron powder (0.861 g) and ammonium chloride (86 mg) and the mixture is heated to reflux for approximately 1 20 hour. The mixture is then filtered and concentrated under reduced pressure. The resulting oil is partitioned between water and ethyl acetate, and the organic phase is then washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to provide the desired compound as a pale yellow solid. 25 Using the above procedure and appropriate starting materials the following compounds were prepared: 4-Chloro-benzene- 1,2-diamine 30 N-(4-Amino-2-chloro-phenyl)-acetamide (4-Amino-2,6-dichloro-phenoxy)-acetonitrile (4-Amino-2,6-dichloro-phenoxy)-acetic acid tert-butyl ester WO 00/34258 PCTIUS99/28842 - 40 (2-Amino-4-chloro-5-methoxy-phenoxy)-acetonitrile (4-Amino-2-chloro-5-methoxy-phenoxy)-acetic acid methyl ester (4-Amino-2-chloro-5-methoxy-phenoxy)-acetic acid tert-butyl ester (2-Amino-4-chloro-5-methoxy-phenoxy)-acetic acid tert-butyl ester 5 N(1)-Benzyl-4-chloro-5-methoxy-benzene- 1,2-diamine N-(4-Amino-2-chloro-phenyl)-2-fluoro-benzamide N-(4-Amino-5-chloro-2-hydroxy-phenyl)-acetamide N-(4-Amino-5-chloro-2-hydroxy-phenyl)-2-fluoro-benzamide Furan-2-carboxylic acid (4-amino-2-chloro-phenyl)-amide 10 (4-Amino-2-chloro-phenyl)-carbamic acid ethyl ester N-(4-Amino-5-chloro-2-methyl-phenyl)-acetamide N-(4-Amino-5-chloro-2-methyl-phenyl)-2-fluoro-benzamide Furan-2-carboxylic acid (4-amino-5-chloro-2-methyl-phenyl)amide N-(4-Amino-3-chloro-phenyl)-2-fluoro-benzamide 15 Furan-2-carboxylic acid (4-amino-3-chloro-phenyl)-amide N-(4-Amino-2-chloro-phenyl)-2-dimethylamino-acetamide N-(4-Amino-2-chloro-phenyl)-2-piperidin- 1 -yl-acetamide N-(4-Amino-2-chloro-phenyl)-2-morpholin-4-yl-acetamide N-(4-Amino-2-chloro-phenyl)-methanesulfonamide 20 N-(4-Amino-2-chloro-phenyl)-benzamide N-(4-Amino-2-chloro-phenyl)-2-diethylamino-acetamide N-(4-Amino-2-chloro-phenyl)-2-pyrrolidin- 1 -yl-acetamide N-(4-Amino-2-chloro-phenyl)-2-azepan- 1 -yl-acetamide N-(4-Amino-2-chloro-phenyl)-2-(2-methyl-piperidin- 1 -yl)-acetamide 25 N-(4-Amino-2-chloro-phenyl)-2-(3-methyl-piperidin- 1 -yl)-acetamide 3-Chloro-benzene- 1,2-diamine 4-Chloro-N,N-dimethyl-benzene- 1,2-diamine EXAMPLE 4 (METHOD 1D) 30 3,5-Dichloro-4-phenoxy-phenylamine To a slurry of 3,5-dichloro-4-phenoxy-nitrobenzene (6.1 g) and tin powder (12 g) is added dropwise concentrated hydrochloric acid (60 mL). Ethanol (60mL) is added WO 00/34258 PCTIUS99/28842 - 41 and the mixture is heated to reflux for approximately 1 hour. The mixture is then cooled in an ice bath and basified by addition of solid sodium hydroxide. The resulting suspension is filtered through a pad of diatomaceous earth and extracted three times with ethyl acetate. The combined organic extracts are then washed with 5 saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to provide the desired product as a yellow solid. Recrystallization from ethyl acetate-hexanes provided the product as a pale yellow solid. 10 Using the above procedure and appropriate starting materials the following compounds were prepared: 1 -Furan-2-yl-ethylamine 3-Chloro-4-isopropoxy-phenylamine 15 2-Butoxy-5-chloro-4-methoxy-phenylamine 3,5-Dichloro-2-methoxy-4-methyl-phenylamine 2-Benzyloxy-5-chloro-4-methoxy-phenylamine 4-Benzyloxy-5-chloro-2-methoxy-phenylamine 5-Fluoro-2,4-dimethoxy-phenylamine 20 (4-Amino-2,6-dichloro-phenoxy)-acetic acid ethyl ester 3,5-Dichloro-4-phenoxy-phenylamine 2-(4-Amino-2-chloro-5-methoxy-phenoxy)-acetamide (4-Amino-2-chloro-5-methoxy-phenoxy)-acetonitrile 2-(2-Amino-4-chloro-5-methoxy-phenoxy)-ethanol 25 2-(4-Amino-2-chloro-5-methoxy-phenoxy)-ethanol 4-(4-Amino-2-chloro-5-methoxy-phenoxy)-butyronitrile 4-Amino-2-chloro-5-methoxy-phenol 2-Amino-4-chloro-5-methoxy-phenol 5-Chloro-4-methoxy-2-morpholin-4-yl-phenylamine 30 4-Chloro-5-methoxy-N(1),N(1)-dimethyl-benzene- 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 WO 00/34258 PCTIUS99/28842 - 42 N(2)-Benzyl-4-methoxy-benzene- 1,2-diamine 2- (4-Amino-2-chloro-phenoxy)-ethanol 2-Chloro-N(1)-cyclohexyl-N(1)-ethyl-benzene- 1,4-diamine 4-Butoxy-3-chloro-phenylamine 5 (4-Amino-2-chloro-phenoxy)-acetonitrile 2-Chloro-N(1)-cyclohexyl-benzene- 1,4-diamine 2-Chloro-N(1),N(1)-dipropyl-benzene- 1,4-diamine 3-Chloro-4-(2,2,2-trifluoro-ethoxy)-phenylamine 3-Chloro-4-(octahydro-quinolin- 1 -yl)-phenylamine 10 N(1)-Allyl-2-chloro-N(1)-cyclohexyl-benzene- 1,4-diamine N-(4-Amino-2-methoxy-5-methyl-phenyl)-2-fluoro-benzamide Furan-2-carboxylic acid (4-amino-2-methoxy-5-methyl-phenyl)amide N-(4-Amino-naphthalen- 1-yl)-2-fluoro-benzamide 3-Chloro-N,N-dimethyl-benzene- 1,2-diamine 15 3-Chloro-4-propoxy-phenylamine 3-Iodo-4-methoxy-phenylamine 3-Chloro-2,4-dimethoxy-aniline 3-Bromo-4-methoxy-phenylamine 3-Chloro-4-ethoxy-phenylamine 20 EXAMPLE 5 (Method 1E) (4-Amino-phenyl)-carbamic acid isobutyl ester To a solution of N-(4-Nitro-phenyl)-isobutyrlamide (2.0 g) in 100 mL ethylene 25 glycol monomethyl ether (100 mL) is added 10% palladium on carbon (275 mg). The mixture is hydrogenated for 2 hours at room temperature under 30 psi of hydrogen on a Parr hydrogenation apparatus. The catalyst is then removed by filtration through diatomaceous earth and the filtrate is evaporated to dryness under reduced pressure by azeotroping three times with heptane. Trituration of the residue 30 with heptane provides the desired product as a white solid. Using the above procedure and appropriate starting materials the following compounds were prepared: WO 00/34258 PCTIUS99/28842 - 43 2-Methyl-3H-benzoimidazol-5-ylamine N-(4-Amino-phenyl)-formamide 1H-Benzoimidazol-5-ylamine 5 (4-Amino-phenyl)-carbamic acid isobutyl ester N-(4-Amino-phenyl)-isobutyramide N-(5-Amino-pyridin-2-yl)-2-methyl-benzamide Furan-2-carboxylic acid (5-amino-pyridin-2-yl)-amide N-(5-Amino-pyridin-2-yl)-2-fluoro-benzamide 10 [6-(2,2,2-Trifluoro-acetylamino)-pyridin-3-yl]-carbamic acid tert-butyl ester N-(5-Amino-pyridin-2-yl)-2,2,2-trifluoro-acetamide (4-Amino-benzyl)-carbamic acid tert-butyl ester 2-(3,5-Bis-trifluoromethyl-phenyl)-ethylamine 1-tert-Butyl-1H-imidazol-2-ylamine 15 3-(3-Dimethylamino-propyl)-5-trifluoromethyl-phenylamine EXAMPLE 6 (METHOD 1F) N-(4-Amino-2-methylphenyl)-2-fluorobenzamide 20 A mixture of 2-fluoro-N-(2-methyl-4-nitrophenyl)benzamide (4.55 g), cyclohexene (30 mL), ethanol (70 mL), water (30 mL) and 10% palladium on charcoal (3 g) is heated at reflux for 30 minutes. The mixture is filtered through diatomaceous earth and concentrated under reduced pressure. The resulting oil is dissolved in 50 mL of ethyl acetate and cooled at 4' C for 12 hours. Filtration provides the product as a tan 25 solid. Using the above procedure and appropriate starting materials the following compounds were prepared: 30 N-(4-Amino-2-methyl-phenyl)-acetamide 2-Methyl-benzooxazol-6-ylamine N-(4-Amino-3-methoxy-phenyl)-acetamide WO 00/34258 PCT/US99/28842 - 44 2-Acetylamino-5-amino-benzoic acid N- (4-Amino-phenyl)-acetamide r4- (3-Amino-benzoylamino)-phenyl] -carbamic acid tert-butyl ester [4- (2-Amino-benzoylamino)-phenylj -carbamic acid tert-butyl ester 5 N-(4-Amino-2-cyano-phenyl)-acetamide N-(4-Amino-2,5-dimethoxy-phenyl)-2-fluoro-benzamide Furan-2-carboxylic acid (4-amino-2,5-dimethoxy-phenyl)-amide N- (4-Amino-2-cyano-phenyl)-2-fluoro-benzamide Furan-2-carboxylic acid (4-amino-2-methoxy-phenyl)-amide 10 N-(4-Amino-2-methoxy-phenyl)-2-fluoro-benzamide N- (4-Amino-2-methoxy-5-methyl-phenyl)-acetamide N- (4-Amino-2-benzoyl-phenyl)-acetamide N- (4-Amino-2-benzoyl-phenyl)-2-fluoro-benzamide Furan-2-carboxylic acid (4-amino-2-benzoyl-phenyl)-amide 15 N-(4-Amino-3-methyl-phenyl)-acetamide N- (4-Amino-3-methyl-phenyl)-2-fluoro-benzamide Furan-2-carboxylic acid (4-amino-3-methyl-phenyl)-amide 5-Amino- 2- [ (2-fluorobenzoyl) amino] -N-phenylbenzamide Furan-2-carboxylic acid ( 4 -amino-2-phenylcarbamoyl-phenyl)amide 20 N-(4-Amino-naphthalen- 1 -yl)-acetamide Furan-2-carboxylic acid (4-amino-naphthalen- 1-yl)-amide N-(4-Amino-2-trifluoromethyl-phenyl)-acetamide Furan-2-carboxylic acid (4-amino-2-cyano-phenyl)-amide Furan-2-carboxylic acid ( 4 -amino-2-trifluoromethyl-phenyl)-amide 25 N-(4-Amino-2-methyl-phenyl)-2-fluoro-benzamide Furan-2-carboxylic acid (4-amino-2-methyl-phenyl)-amide 5-Amino-2-(2-fluoro-benzoylamino)-benzoic acid 5 -Amino-2- [ (furan-2-carbonyl)- amino] -benzoic acid N- ( 4 -Amino-2-cyano-phenyl)-2,2,2-trifluoro-acetamide 30 N-(4-Amino-3-methyl-phenyl)-2,6-difluoro-benzamide N-(4-Amino-3-trifluoromethyl-phenyl)-acetamide N-(4-Amino-3-trifluoromethyl-phenyl)-2-fluoro-benzamide N-(4-Amino-2-trifluoromethyl-phenyl)-2,2,2-trifluoro-acetamide WO 00/34258 PCT/US99/28842 - 45 N-( 4 -Amino- 2 -methoxy-phenyl)-2,2,2-trifluoro-acetamide

N-(

4 -Amino- 2 -trifluoromethyl-phenyl)-2-fluoro-N-(2-fluoro-benzoyl)-benzamide

N-(

4 -Amino- 2 -trifluoromethyl-phenyl)-2-fluoro-benzamide 5 EXAMPLE 7 (METHOD 1G)

N-(

4 -Amino- 2 -chlorophenyl)-2-thiomorpholino-4-yl-acetamide A solution of N-( 2 -chloro- 4 -nitrophenyl)-2-thiomorpholino-4-yl-acetamide (3.02 g) in ethanol (200 mL) is added to a solution of sodium thiosulfate (12 g) in water (60 10 mL). The mixture is heated at reflux for 12 hours, cooled and poured into water. The mixture is then extracted with ethyl acetate. The ethyl acetate solution is washed twice with saturated aqueous sodium chloride, dried over anhydrous potassium carbonate, filtered through a pad of diatomaceous earth and concentrated under reduced pressure to give an oil. Toluene is added and the solution chilled to give the 15 desired product as a light orange crystalline solid. Using the above procedure and appropriate starting materials the following compounds were prepared: 20 N-( 4 -Amino- 2 -chloro-phenyl)-2-thiomorpholin-4-yl-acetamide

N-(

4 -Amino- 2 -chloro-phenyl)-2-dipropylamino-acetamide EXAMPLE 8 (METHOD 2A) (3-Chloro-4-iodo-phenyl)-carbamic acid tert-butyl ester 25 To a solution of 3-chloro-4-iodo-aniline (10 g) in tetrahydrofuran (40 mL) containing diiso-propylethylamine (6.9 mL) is added di-tert-butyl-dicarbonate (8.6 g) and the mixture is heated to reflux. After approximately 15 hours additional portions of diisopropylethylamine (6.9 mL) and di-tert-butyl-dicarbonate (21 g) is added and 30 heating is continued for approximately 24 hours. The solution is then cooled, concentrated under reduced pressure, diluted with ethyl acetate, and washed successively three times with 5% aqueous hydrochloric acid then once with saturated WO 00/34258 PCT/US99/28842 - 46 aqueous sodium chloride. The solution is dried over anhydrous sodium sulfate then concentrated under reduced pressure to provide the desired crude product as a brown oil. Crystallization is induced by addition of hexanes, and the collected solid material is recrystallized from hexanes to give the desired product as a white solid. 5 Using the above procedure and appropriate starting materials the following compounds were prepared: N'-(4-Nitro-benzoyl)-hydrazinecarboxylic acid tert-butyl ester 10 (3-Chloro-4-iodo-phenyl)-carbamic acid tert-butyl ester (4-Bromo-3-chloro-phenyl)-carbamic acid tert-butyl ester (3-Chloro-4-vinyl-phenyl)-carbamic acid tert-butyl ester (3-Chloro-4-methylsulfanyl-phenyl)-carbamic acid tert-butyl ester (4-Amino-3-chloro-phenyl)-carbamic acid tert-butyl ester 15 (4-Chloro-2-nitro-phenyl)-carbamic acid tert-butyl ester (3-tert-Butoxycarbonylamino-5-chloro-phenyl)-carbamic acid tert-butyl ester (4-Nitro-benzyl)-carbamic acid tert-butyl ester (3-Bromo-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (2-Amino-3-chloro-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester 20 EXAMPLE 9 (METHOD 2B) (3-Chloro-4-vinyl-phenyl)-carbamic acid2-trimethylsilanyl-ethyl ester To a solution of 3-chloro-4-vinyl-phenylamine (3.4 g) in N,N-dimethylformamide 25 (44 mL) containing diisopropylethylamine (5.8 mL) is added 1-[2-(trimethylsilyl) ethoxycarbonyl-oxy]benzotriazole (7.1 g) and the mixture is stirred at room temperature under an atmosphere of argon for three days. The solution is then diluted with water and extracted three times with diethyl ether. The combined organic extracts are washed successively with water, saturated aqueous sodium 30 chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue is chromatographed over silica gel (10% ethyl acetate in hexanes is used as the eluant) to provide the desired product as a yellow oil.

WO 00/34258 PCT/US99/28842 - 47 EXAMPLE 10 (METHOD 2C) [4-(2-Fluoro-benzoylamino)-phenyll-carbamic acid tert-butyl ester To a solution of mono-N-(t-butoxycarbonyl)-1,4-phenylenediamine (1.58 g) and 5 triethylamine (1.50 mL) in 25 mL of dichloromethane is added o-fluorobenzoyl chloride (1.20 g). A solid formed immediately forms and is filtered and washed with fresh solvent to yield a white solid, 1.90 g. Using the above procedure and appropriate starting materials the following 10 compounds were prepared: N-(3-Methoxy-4-nitro-phenyl)-acetamide N-(4-Amino-phenyl)-isobutyrlamide 2,2,2-Trifluoro-N-(2-methoxy-4-nitro-phenyl)-acetamide 15 [4-(2-Methyl-benzoylamino)-phenyl]-carbamic acid tert-butyl ester Acetic acid 2-(4-tert-butoxycarbonylamino-phenylcarbamoyl)-phenyl ester [4-(4-Fluoro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester [4-(3-Fluoro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester [4-(2-Fluoro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester 20 [4-(2-Methoxy-benzoylamino)-phenyl)-carbamic acid tert-butyl ester [4-(3-Methoxy-benzoylamino)-phenyl]-carbamic acid tert-butyl ester [4-(4-Methoxy-benzoylamino)-phenyl]-carbamic acid tert-butyl ester [4-(2,2-Dimethyl-propionylamino)-phenyl]-carbamic acid tert-butyl ester [4-(2-Bromo-acetylamino)-phenyl]-carbamic acid tert-butyl ester 25 [4-(2,2,2-Trifluoro-acetylamino)-phenyl]-carbamic acid tert-butyl ester (4-Benzoylamino-phenyl)-carbamic acid tert-butyl ester (4-Methanesulfonylamino-phenyl)-carbamic acid tert-butyl ester (4-Phenylacetylamino-phenyl)-carbamic acid tert-butyl ester {4- [(Thiophene-2-carbonyl)-amino] -phenyl}-carbamic acid tert-butyl ester 30 [4-(3-Nitro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester [4-(3-Acetylamino-benzoylamino)-phenyl]-carbamic acid tert-butyl ester [4-(3-Methanesulfonylamino-benzoylamino)-phenyl]-carbamic acid tert-butyl ester WO 00/34258 PCT/US99/28842 - 48 Ethyl [3- [4- [[(1,1 -dimethylethoxy)carbonyl] amino]phenyl] amino] carbonyl] phenyl]carbamate [4-(2-Trifluoromethyl-benzoylamino)-phenyl]-carbamic acid tert-butyl ester [4-(2,6-Difluoro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester 5 [4-(2-Chloro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester [4-(2-Bromo-benzoylamino)-phenyl]-carbamic acid tert-butyl ester [4-(2-Nitro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester (4- [(Benzo [b]thiophene-2-carbonyl)-amino] -phenyl } -carbamic acid tert-butyl ester {4- [(Pyridine-4-carbonyl)-amino] -phenyl} -carbamic acid tert-butyl ester 10 {4- [(Naphthalene-2-carbonyl)-amino] -phenyl -carbamic acid tert-butyl ester {4- [ (Naphthalene- 1 -carbonyl)-amino] -phenyl }-carbamic acid tert-butyl ester {4-[(3-Bromo-thiophene-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester {4- [ (Biphenyl-2-carbonyl)-amino] -phenyl } -carbamic acid tert-butyl ester N-(4-tert-Butoxycarbonylamino-phenyl)-phthalamic acid 15 [4-(2,3-Difluoro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester [4-(2,5-Difluoro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester [4-(2,4-Difluoro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester [4-(2-Acetylamino-benzoylamino)-phenyl]-carbamic acid tert-butyl ester [4-(2-Methanesulfonylamino-benzoylamino)-phenyl]-carbamic acid tert-butyl ester 20 [4-(2,3,4-Trifluoro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester [4-(2,3,4,5,6-Pentafluoro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester N-(4-tert-Butoxycarbonylamino-phenyl)-isophthalamic acid methyl ester 2-Methylsulfanyl-N-[4-(2,2,2-trifluoro-acetylamino)-phenyl]-benzamide [4-(3-Benzyloxy-benzoylamino)-phenyl]-carbamic acid tert-butyl ester 25 [4-(3-Butoxy-benzoylamino)-phenyl]-carbamic acid tert-butyl ester {4-[(5-Difluoromethyl-furan-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester {4- [(Thiophene-3-carbonyl)-amino] -phenyl}-carbamic acid tert-butyl ester {4- [(5-Methyl-furan-2-carbonyl)-amino] -phenyl } -carbamic acid tert-butyl ester 30 {4-[(5-Bromo-furan-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester (4-Hexanoylamino-phenyl)-carbamic acid tert-butyl ester [4-(2-Thiophen-2-yl-acetylamino)-phenyl]-carbamic acid tert-butyl ester (4- [(Pyridine-3-carbonyl)-amino] -phenyl} -carbamic acid tert-butyl ester WO 00/34258 PCT/US99/28842 - 49 { 4-[(4-Bromo-furan-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester { 4- [(Furan-3-carbonyl)-amino] -phenyl }-carbamic acid tert-butyl ester (4-Phenoxycarbonylamino-phenyl)-carbamic acid tert-butyl ester { 4- [(Benzo [1,3] dioxole-4-carbonyl)-amino] -phenyl} -carbamic acid tert-butyl ester 5 [4-(3-Trifluoromethoxy-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

N-(

2 ,5-Dimethoxy-4-nitro-phenyl)-2-fluoro-benzamide {4- [(Furan-2-carbonyl)-amino] -phenyl} -carbamic acid tert-butyl ester [4-(2-Phenoxy-acetylamino)-phenyl]-carbamic acid tert-butyl ester {4- [ (5-Nitro-furan-2-carbonyl)-amino] -phenyl } -carbamic acid tert-butyl ester 10 {4- [(5-Chloro-furan-2-carbonyl)-amino] -phenyl ) -carbamic acid tert-butyl ester {4-[(3-Methyl-furan-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester [4-(2-Methoxy-acetylamino)-phenyl]-carbamic acid tert-butyl ester (4- [(4-Furan-3-yl- [1,2,3]thiadiazole-5-carbonyl)-amino] -phenyl} -carbamic acid tert butyl ester 15 {4- [(5-tert-Butyl-furan-2-carbonyl)-amino] -phenyl} -carbamic acid tert-butyl ester N-[3-Cyano-4-(2,2,2-trifluoro-acetylamino)-phenyl]-2-fluoro-benzamide Furan-2-carboxylic acid [3-cyano-4-( 2 ,2,2-trifluoro-acetylamino)-phenyl]amide

N-(

4 -Acetylamino-2-cyano-phenyl)-2,2,2-trifluoro-acetamide 2,2,2-Trifluoro-N-( 4 -nitro-2-trifluoromethyl-phenyl)-acetamide 20 N-( 4 -Acetylamino-2-trifluoromethyl-phenyl)-2,2,2-trifluoro-acetamide 2-Fluoro-N-[ 4

-(

2

,

2

,

2 -trifluoro-acetylamino)-3-trifluoromethyl-phenyl]benzamide Furan-2-carboxylic acid [4-( 2

,

2

,

2 -trifluoro-acetylamino)-3-trifluoromethyl phenyl]amide 2-Fluoro-N-(2-methyl-benzooxazol-6-yl)-benzamide 25 4

-(

2 -Fluoro-benzoylamino)-2-hydroxy-benzoic acid phenyl ester {4-[(Isoxazole-5-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester

N-(

4 -Acetylamino-2-methoxy-phenyl)-2,2,2-trifluoro-acetamide 2-Fluoro-N-[3-methoxy-4-( 2

,

2

,

2 -trifluoro-acetylamino)-phenyl]benzamide 2-Fluoro-N-( 2 -fluoro-benzoyl)-N-(4-nitro-2-trifluoromethyl-phenyl)benzamide 30 {4-[(1H-Pyrazole-4-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester {4-[(1H-Imidazole-4-carbonyl)-amino]-phenyl} -carbamic acid tert-butyl ester (4- [(5-Methyl-[1,2,3]thiadiazole-4-carbonyl)-amino] -phenyl) -carbamic acid tert butyl ester WO 00/34258 PCTIUS99/28842 - 50 {4- [(5-Furan-3-yl- [ 1,2,3]thiadiazole-4-carbonyl)-amino] -phenyl } -carbamic acid tert butyl ester 2,2,2-Trifluoro-N-(5-nitro-pyridin-2-yl)-acetamide {4- [(1-Methyl-1 H-pyrazole-4-carbonyl)-amino] -phenyl } -carbamic acid tert-butyl 5 ester 4-(2-Fluoro-benzoylamino)-2-hydroxy-benzoic acid methyl ester N-(5-Chloro-2,4-dimethoxy-phenyl)-oxalamic acid Isoxazole-5-carboxylic acid (4-amino-phenyl)-amide 2-Fluoro-N-(4-nitro-benzyl)-benzamide 10 Furan-2-carboxylic acid 4-nitro-benzylamide N-[3-Chloro-5-(2,2,2-trifluoro-acetylamino)-phenyl]-2,2,2-trifluoro-acetamide N-(3-Amino-5-chloro-phenyl)-2,2,2-trifluoro-acetamide [4-(2-Fluoro-benzoylamino)-benzyl]-carbamic acid tert-butyl ester [4-(2,6-Difluoro-benzoylamino)-benzyl]-carbamic acid tert-butyl ester 15 2,6-Difluoro-N-(4-nitro-benzyl)-benzamide { 4- [(Furan-2-carbonyl)-amino] -benzyl } -carbamic acid tert-butyl ester N- (3-Amino-5-chloro-phenyl)-acetamide [4-(3-Chloro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester [4-(4-Chloro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester 20 [4-(4-Dimethylamino-benzoylamino)-phenyl]-carbamic acid tert-butyl ester (4-Benzenesulfonylamino-phenyl)-carbamic acid tert-butyl ester [4-(3-Trifluoromethyl-benzoylamino)-phenyl]-carbamic acid tert-butyl ester 2,2,2-Trifluoro-N-(5-nitro-pyrimidin-2-yl)-acetamide 25 EXAMPLE 11(METHOD 2D) 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) is heated at reflux for 1 hour. The solution is cooled and 30 concentrated under reduced pressure, giving a wet yellow solid. Ether (250 mL) is added and the yellow solid is collected.

WO 00/34258 PCT/US99/28842 -51 Using the above procedure and appropriate starting materias the following compounds were prepared: N-(4-Nitro-3-trifluoromethyl-phenyl)-acetamide 5 (2-Chloro-4-nitro-phenyl)-carbamic acid ethyl ester 2-Acetylamino-5-nitro-benzoic acid Furan-2-carboxylic acid (5-chloro-2-hydroxy-4-nitro-phenyl)-amide Furan-2-carboxylic acid (2-methyl-4-nitro-phenyl)-amide Furan-2-carboxylic acid (2-methoxy-4-nitro-phenyl)-amide 10 N-(2-Chloro-4-nitro-phenyl)-benzamide 2-Methoxy-N-(4-nitro-phenyl)-acetamide N-(4-Nitro-phenyl)-acrylamide N-(4-Nitro-phenyl)-isobutyrlamide [4-)acryloylamino)-phenyl]carbamic acid tert-butyl ester 15 (4-Nitro-phenyl)-carbamic acid isobutyl ester [1,2,3]Thiadiazole-4-carboxylic acid (5-nitro-pyridin-2-yl)-amide Furan-2-carboxylic acid (5-nitro-pyridin-2-yl)-amide 2-Fluoro-N-(5-nitro-pyridin-2-yl)-benzamide N-(2-Chloro-4-nitro-phenyl)-2-fluoro-benzamide 20 Furan-2-carboxylic acid (2,5-dimethoxy-4-nitro-phenyl)-amide N-(2-Cyano-4-nitro-phenyl)-2-fluoro-benzamide 2-Fluoro-N-(2-methoxy-4-nitro-phenyl)-benzamide 2-Methyl-N-(5-nitro-pyridin-2-yl)-benzamide Furan-2-carboxylic acid (2-methoxy-5-methyl-4-nitro-phenyl)-amide 25 2-Fluoro-N-(2-methoxy-5-methyl-4-nitro-phenyl)-benzamide N-(2-Benzoyl-4-nitro-phenyl)-acetamide N-(2-Benzoyl-4-nitro-phenyl)-2-fluoro-benzamide Furan-2-carboxylic acid (2-benzoyl-4-nitro-phenyl)-amide N-(3-Methyl-4-nitro-phenyl)-acetamide 30 2-Fluoro-N-(3-methyl-4-nitro-phenyl)-benzamide Furan-2-carboxylic acid (3-methyl-4-nitro-phenyl)-amide 2-Acetylamino-5-nitro-N-phenyl-benzamide 2- [(2-Fluorobenzoyl)amino] -5-nitro-N-phenylbenzamide WO 00/34258 PCT/US99/28842 - 52 Furan-2-carboxylic acid (4-nitro-2-phenylcarbamoyl-phenyl)-amide 2-Fluoro-N-(4-nitro-naphthalen- 1 -yl)-benzamide Furan-2-carboxylic acid (4-nitro-naphthalen-1-yl)-amide N-(5-Chloro-2-hydroxy-4-nitro-phenyl)-acetamide 5 N-(5-Chloro-2-hydroxy-4-nitro-phenyl)-2-fluoro-benzamide Furan-2-carboxylic acid (2-chloro-4-nitro-phenyl)-amide N-(4-Nitro-2-trifluoromethyl-phenyl)-acetamide Furan-2-carboxylic acid (2-cyano-4-nitro-phenyl)-amide 2-Fluoro-N-(4-nitro-2-trifluoromethyl-phenyl)-benzamide 10 Furan-2-carboxylic acid (4-nitro-2-trifluoromethyl-phenyl)-amide 2-Fluoro-N-(2-methyl-4-nitro-phenyl)-benzamide N-(5-Chloro-2-methyl-4-nitro-phenyl)-2-fluoro-benzamide Furan-2-carboxylic acid (5-chloro-2-methyl-4-nitro-phenyl)-amide 2-(2-Fluoro-benzoylamino)-5-nitro-benzoic acid 15 2- [(Furan-2-carbonyl)-amino] -5-nitro-benzoic acid N-(3-Chloro-4-nitro-phenyl)-2-fluoro-benzamide Furan-2-carboxylic acid (3-chloro-4-nitro-phenyl)-amide 2,6-Difluoro-N-(3-methyl-4-nitro-phenyl)-benzamide 2-Fluoro-N-(4-nitro-3-trifluoromethyl-phenyl)-benzamide 20 Furan-2-carboxylic acid (4-nitro-3-trifluoromethyl-phenyl)-amide 2-Chloro-N-(2-chloro-4-nitro-phenyl)-acetamide N-(2-Chloro-4-nitrophenyl)methanesulfonamide Furan-2-carboxylic acid [3-methoxy-4-(2,2,2-trifluoro-acetylamino)-phenyl]-amide N-(2-Chloro-4-nitro-phenyl)-2,2,2-trifluoro-acetamide 25 EXAMPLE 12 {4-[(4-Phenyl-[1, 2 ,3]thiadiazole-5-carbonyl)-amino]-phenyl} carbamic acid tert-butyl 30 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) is treated with triethylamine (1.3 mL) and benzotriazole-1-yloxy-tris(dimethylamino)- WO 00/34258 PCT/US99/28842 - 53 phosphonium hexa-fluorophosphate (1.6 g). After stirring at room temperature, the reaction is diluted with water and extracted with dichloromethane. The organic layer is washed with 0.5 N hydrochloric acid, saturated sodium bicarbonate, and water then dried over magnesium sulfate, filtered, and concentrated under reduced pressure to 5 give the desired product. Using the above procedure and appropriate starting materials the following compounds were prepared: 10 {4- [(1 H-Pyrrole-2-carbonyl)-amino] -phenyl} -carbamic acid tert-butyl ester {4-[(Pyrazine-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester {4- [(5-Methyl-thiophene-2-carbonyl)-amino] -phenyl } -carbamic acid tert-butyl ester {4- [(1-Methyl-i H-pyrrole-2-carbonyl)-amino] -phenyl} -carbamic acid tert-butyl ester {4-[(Quinoline-8-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester 15 { 4- [(Benzofuran-2-carbonyl)-amino] -phenyl } -carbamic acid tert-butyl ester {4- [(Isoquinoline- 1 -carbonyl)-amino] -phenyl} -carbamic acid tert-butyl ester {4-[(Quinoline-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester {4- [(Pyridine-2-carbonyl)-amino] -phenyl} -carbamic acid tert-butyl ester { 4- [(Isoquinoline-4-carbonyl)-amino] -phenyl }-carbamic acid tert-butyl ester 20 {4- [([1,2,3]Thiadiazole-4-carbonyl)-amino] -phenyl} -carbamic acid tert-butyl ester {4- [(1 H-[ 1,2,3]Triazole-4-carbonyl)-amino] -phenyl } -carbamic acid tert-butyl ester [4-(2-Methylsulfanyl-benzoylamino)-phenyl]-carbamic acid tert-butyl ester {4-[(Quinoline-4-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester {4-[(4-Methyl-[1,2,3]thiadiazole-5-carbonyl)-amino]-phenyl}-carbamic acid tert 25 butyl ester {4-[(4-Phenyl-[1,2,3]thiadiazole-5-carbonyl)-amino]-phenyl}-carbamic acid tert butyl ester {4-[(1H-Indole-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester [1,2,3]Thiadiazole-4-carboxylic acid 4-nitro-benzylamide 30 {4- [([1,2,3]Thiadiazole-4-carbonyl)-amino] -benzyl}-carbamic acid tert-butyl ester Acetic acid 4

-(

4 -tert-butoxycarbonylamino-phenylcarbamoyl)-phenyl ester (4-[(Quinoline-6-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester WO 00/34258 PCT/US99/28842 - 54 EXAMPLE 13 (METHOD 2F) Acetic acid 2 -(4-tert-butoxycarbonylamino 2,6-dichloro-phenoxy)-ethyl ester 5 A solution of [ 3 ,5-dichloro-4-(2-hydroxy-ethoxy)-phenyl]-carbamic acid tert-butyl ester (0.85 g) in pyridine (14 mL) is treated with acetic anhydride (1.24 mL) and the mixture is stirred at room temperature for 15 hours. The solvent is removed under reduced pressure and the residue dissolved in ethyl acetate. This solution is then washed twice with 5% aqueous hydrochloric acid, once with saturated aqueous 10 sodium bicarbonate, and then with saturated aqueous sodium chloride. The solution is dried over anhydrous magnesium sulfate and the solvent is removed under reduced pressure to provide the desired product as a colorless oil. Using the above procedure and appropriate starting materials the following 15 compounds were prepared: Phenylsulfanyl-acetonitrile Acetic acid 2

-(

4 -tert-butoxycarbonylamino-2,6-dichloro-phenoxy)-ethy ester 20 EXAMPLE 14 (METHOD 2G) (3,5-Dichloro-4-hydroxy-phenyl)-carbamic acid tert-butyl ester To a solution of 2,6-dichloro-4-amino phenol (9.5 g) in tetrahydrofuran (130 mL) is added di-tert-butyl-dicarbonate (11.7 g) and the mixture is heated to reflux for 25 approximately 15 hours. The solution is then cooled, concentrated under reduced pressure, diluted with ethyl acetate, and washed successively three times with 5% aqueous hydrochloric acid then once with saturated aqueous sodium chloride. The solution is dried over anhydrous sodium sulfate then concentrated under reduced pressure to provide the desired crude product. This material is then triturated with 30 cold dichloromethane to provide the product as a white solid.

WO 00/34258 PCT/US99/28842 - 55 Using the above procedure and appropriate starting materials the following compound was prepared: (3-Amino-5-chloro-phenyl)-carbamic acid tert-butyl ester 5 EXAMPLE 15 (METHOD 3A) 3,5-Dichloro-4-ethoxy-phenylamine Trifluoroacetic acid (5 mL) is added to solid (3,5-dichloro-4-ethoxy-phenyl) 10 carbamic acid tert-butyl ester (0.97 g) and the mixture is stirred for approximately 45 minutes at room temperature. Water is then added, and the mixture is cooled in an ice bath and basified with solid potassium carbonate. The solution is extracted three times with ethyl acetate and the combined organic phases are washed with saturated aqueous sodium chloride then dried over anhydrous sodium sulfate. Concentration 15 under reduced pressure and recrystallization from hexanes provides the desired product as a pale yellow crystalline solid. Using the above procedure and appropriate starting materials the following compounds were prepared: 20 5-Bromo-pyridin-3-ylamine 3-Chloro-4-methanesulfonyl-phenylamine N-(4-Amino-phenyl)-2-methyl-benzamide Acetic acid 2-(4-amino-phenylcarbamoyl)-phenyl ester 25 N-(4-Amino-phenyl)-4-fluoro-benzamide N-(4-Amino-phenyl)-3-fluoro-benzamide N-(4-Amino-phenyl)-2-fluoro-benzamide N-(4-Amino-phenyl)-2-methoxy-benzamide N-(4-Amino-phenyl)-3-methoxy-benzamide 30 N-(4-Amino-phenyl)-4-methoxy-benzamide N-(4-Amino-phenyl)-2-phenyl-acetamide N-(4-Amino-phenyl)-2,2-dimethyl-propionamide N-(4-Amino-phenyl)-2,2,2-trifluoro-acetamide WO 00/34258 PCT/US99/28842 - 56 Thiophene-2-carboxylic acid (4-amino-phenyl)-amide 1H-Pyrrole-2-carboxylic acid (4-amino-phenyl)-amide N-(4-Amino-phenyl)-3-nitro-benzamide 3-Acetylamino-N-(4-amino-phenyl)-benzamide 5 N-(4-Amino-phenyl)-3-dimethylamino-benzamide N-(4-Amino-phenyl)-3-methanesulfonylamino-benzamide N-(4-Amino-phenyl)-2-trifluoromethyl-benzamide N-(4-Amino-phenyl)-2,6-difluoro-benzamide N-(4-Amino-phenyl)-2-chloro-benzamide 10 N-(4-Amino-phenyl)-2-bromo-benzamide N-(4-Amino-phenyl)-2-nitro-benzamide Pyrazine-2-carboxylic acid (4-amino-phenyl)-amide 5-Methyl-thiophene-2-carboxylic acid (4-amino-phenyl)-amide Quinoline-8-carboxylic acid (4-amino-phenyl)-amide 15 1-Methyl-IH-pyrrole-2-carboxylic acid (4-amino-phenyl)-amide Benzo[b]thiophene-2-carboxylic acid (4-amino-phenyl)-amide Benzofuran-2-carboxylic acid (4-amino-phenyl)-amide N-(4-Amino-phenyl)-isonicotinamide Naphthalene-2-carboxylic acid (4-amino-phenyl)-amide 20 Naphthalene- 1 -carboxylic acid (4-amino-phenyl)-amide Isoquinoline-1-carboxylic acid (4-amino-phenyl)-amide Quinoline-2-carboxylic acid (4-amino-phenyl)-amide 3,5-Dichloro-4-ethoxy-phenylamine 4-Butoxy-3,5-dichloro-phenylamine 25 Isoquinoline-4-carboxylic acid (4-amino-phenyl)-amide [1,2,3]Thiadiazole-4-carboxylic acid (4-amino-phenyl)-amide 1H-[1,2,3]Triazole-4-carboxylic acid (4-amino-phenyl)-amide 3-Bromo-thiophene-2-carboxylic acid (4-amino-phenyl)-amide 4-Benzyloxy-3,5-dichloro-phenylamine 30 2-(4-Amino-2,6-dichloro-phenoxy)-acetamide (4-Amino-2,6-dichloro-phenoxy)-acetic acid methyl ester [3-(4-Amino-phenylcarbamoyl)-phenyl]-carbamic acid ethyl ester 2-Amino-N-(4-amino-phenyl)-benzamide WO 00/34258 PCT/US99/28842 - 57 Biphenyl-2-carboxylic acid (4-amino-phenyl)-amide N-(4-Amino-phenyl)-2,3-difluoro-benzamide N-(4-Amino-phenyl)-2,5-difluoro-benzamide N-(4-Amino-phenyl)-2,4-difluoro-benzamide 5 2-Acetylamino-N-(4-amino-phenyl)-benzamide N-(4-Amino-phenyl)-2-methanesulfonylamino-benzamide N-(4-Amino-phenyl)-2,3,4-trifluoro-benzamide N-(4-Amino-phenyl)-2,3,4,5,6-pentafluoro-benzamide N-(4-Amino-phenyl)-2-methylsulfanyl-benzamide 10 Acetic acid 2-(4-amino-2,6-dichloro-phenoxy)-ethyl ester N-(4-Amino-phenyl)-isophthalamic acid methyl ester N-(4-Amino-phenyl)-3-benzyloxy-benzamide N-(4-Amino-phenyl)-3-butoxy-benzamide [3-(4-Amino-phenylcarbamoyl)-phenoxy] -acetic acid ethyl ester 15 Pyridine-2-carboxylic acid (4-amino-phenyl)-amide Quinoline-4-carboxylic acid (4-amino-phenyl)-amide 5-Methyl-furan-2-carboxylic acid (4-amino-phenyl)-amide 5-Difluoromethyl-furan-2-carboxylic acid (4-amino-phenyl)-amide 1H-Indole-2-carboxylic acid (4-amino-phenyl)-amide 20 4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid (4-amino-phenyl)-amide Thiophene-3-carboxylic acid (4-amino-phenyl)-amide 5-Chloro-furan-2-carboxylic acid (4-amino-phenyl)-amide 5-Nitro-furan-2-carboxylic acid (4-amino-phenyl)-amide N-(4-Amino-phenyl)-2-thiophen-2-yl-acetamide 25 3-Methyl-furan-2-carboxylic acid (4-amino-phenyl)-amide 5-Bromo-furan-2-carboxylic acid (4-amino-phenyl)-amide 4-Bromo-furan-2-carboxylic acid (4-amino-phenyl)-amide N-(4-Amino-phenyl)-nicotinamide N-(4-Aminophenyl)-3-furancarboxamide 30 4-Phenyl-[1,2,3]thiadiazole-5-carboxylic acid (4-amino-phenyl)-amide Acetic acid 3-(4-amino-phenylcarbamoyl)-phenyl ester Benzo[1,3]dioxole-4-carboxylic acid (4-amino-phenyl)-amide N-(4-Amino-phenyl)-3-(2-dimethylamino-ethoxy)-benzamide WO 00/34258 PCTIUS99/28842 - 58 N-(4-Amino-phenyl)-3-trifluoromethoxy-benzamide N-(4-Amino-phenyl)-3-(2-morpholin-4-yl-ethoxy)-benzamide (4-Amino-phenyl)-carbamic acid hexyl ester Furan-2-carboxylic acid (4-amino-phenyl)-amide 5 (4-Amino-phenyl)-carbamic acid phenyl ester Hexanoic acid (4-amino-phenyl)-amide N-(4-Amino-phenyl)-acrylamide N-(4-Amino-phenyl)-2-methoxy-acetamide 4-Furan-3-yl-[1,2,3]thiadiazole-5-carboxylic acid (4-amino-phenyl)-amide 10 5-tert-Butyl-furan-2-carboxylic acid (4-amino-phenyl)-amide 3-Chloro-4-methanesulfinyl-phenylamine 5-Methyl-[1,2,3]thiadiazole-4-carboxylic acid (4-amino-phenyl)-amide 2- (4-Amino-2-chloro-phenyl)-ethanol (4-Amino-2-chloro-phenyl)-carbamic acid 2-piperidin-1-yl-ethyl ester 15 5-Chloro-N,N-dimethyl-benzene- 1,3-diamine 3-(2-Methyl-butyl)-5-trifluoromethyl-phenylamine 3-Isobutyl-5-trifluoromethyl-phenylamine Furan-2-carboxylic acid (4-aminomethyl-phenyl)-amide N-(4-Aminomethyl-phenyl)-2-fluoro-benzamide 20 [1,2,3]Thiadiazole-4-carboxylic acid (4-aminomethyl-phenyl)-amide N-(4-Aminomethyl-phenyl)-2,6-difluoro-benzamide Oxazole-4-carboxylic acid (4-amino-phenyl)-amide N-(4-Amino-phenyl)-3-chloro-benzamide N-(4-Amino-phenyl)-4-chloro-benzamide 25 Acetic acid 4-(4-amino-phenylcarbamoyl)-phenyl ester N-(4-Amino-phenyl)-4-dimethylamino-benzamide 1-(4-Amino-phenyl)-3-(3,5-bis-trifluoromethyl-phenyl)-thiourea N-(4-Amino-phenyl)-2-iodo-benzamide N-(4-Amino-phenyl)-3-trifluoromethyl-benzamide 30 WO 00/34258 PCTIUS99/28842 - 59 EXAMPLE 16 (METHOD 3B) 1-(4-Amino-2-chloro-phenyl)-ethanol A 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (5.7 mL) is added 5 to [3-chloro-4-(1-hydroxy-ethyl)-phenyl]-carbamic acid 2-trimethylsilanyl-ethyl ester (0.5 g) and the mixture is stirred at room temperature for approximately 3.5 hours. The solution is then concentrated under reduced pressure, dissolved in a 1:1 mixture of ethyl acetate and hexanes, washed successively with water then saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. Removal of the 10 solvent under reduced pressure followed by chromatography over silica gel (40% ethyl acetate in hexanes is used as the eluant) provides the product as an amber oil. EXAMPLE 17 (METHOD 3C) N-(4-Amino-3-cyanophenyl)-2-fluoro-benzamide 15 Potassium carbonate (5.0 g) is added to a solution of N-[3-cyano-4-(2,2,2 trifluoroacetyl-amino)-phenyl]-2-fluoro-benzamide (2.5 g) in methanol (270 mL) and water (16 mL) and the mixture is refluxed overnight. After removing the solvent under reduced pressure, the residue is suspended in water and extracted with 20 dichloromethane. The organic extracts are pooled, washed with water and then saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to provide the desired compound as a white solid. 25 Using the above procedure and appropriate starting materials the following compounds were prepared: N-(4-Amino-phenyl)-2-methanesulfinyl-benzamide N-(4-Amino-3-cyano-phenyl)-2-fluoro-benzamide 30 Furan-2-carboxylic acid (4-amino-3-cyano-phenyl)-amide N-(4-Amino-3-cyano-phenyl)-acetamide Furan-2-carboxylic acid (4-amino-3-trifluoromethyl-phenyl)-amide WO 00/34258 PCT/US99/28842 - 60 N-(4-Amino-3-methoxy-phenyl)-acetamide N-(4-Amino-3-methoxy-phenyl)-2-fluoro-benzamide Furan-2-carboxylic acid (4-amino-3-methoxy-phenyl)-amide 5 EXAMPLE 17 (METHOD 4A) 2-Chloro-1-cyclohexyloxy-4-nitro-benzene Cylcohexanol (2.9 g) in dimethylsulfoxide (20 mL) is added slowly to a flask containing potassium hydride (0.90 g, pre-washed three times with hexanes) under an 10 atmosphere of argon and the solution is stirred for about 1 hour at room temperature. A solution of 3-chloro-4-fluoro-nitrobenzene (1 g) in dimethylsulfoxide (10 mL) is added and the resulting dark red colored solution is then heated for three hours to approximately 100 degrees. The reaction mixture is then cooled, diluted with diethyl ether (300 mL), and washed successively with saturated aqueous ammonium 15 chloride, three times with water, then with saturated aqueous sodium chloride. The organic layer is then dried over anhydrous magnesium sulfate, the solvent is removed under reduced pressure, and the resulting oil is chromatographed over silica gel (5% ethyl acetate in hexanes is used as the eluant) to provide the desired product as an orange solid. 20 EXAMPLE 18 (METHOD 4C) (2-Chloro-4-nitro-phenyl)-methyl-(1-methyl-pyrrolidin-3-yl)-amine 3-Chloro-4-fluoronitrobenzene (1.0 g) and N,N'-dimethyl-3-aminopyrrolidine (1.72 25 g) are combined and stirred for approximately 24 hours. The mixture is then diluted with ethyl acetate, washed twice with water and once with saturated sodium chloride, and dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure the residue is chromatographed over silica gel (pure ethyl acetate followed by pure methanol is used as the eluants) to provide the desired product as a yellow 30 oil.

WO 00/34258 PCT/US99/28842 - 61 Using the above procedure and appropriate starting materials the following compounds were prepared: (2-Chloro-4-nitro-phenyl)-dipropyl-amine 5 1-(2-Chloro-4-nitro-phenyl)-piperidine 1-(2-Chloro-4-nitro-phenyl)-pyrrolidine (2-Chloro-4-nitro-phenyl)-cyclohexyl-methyl-amine Benzyl-(2-chloro-4-nitro-phenyl)-amine (2-Chloro-4-nitro-phenyl)-methyl-(1-methyl-piperidin-4-yl)-amine 10 (2-Chloro-4-nitro-phenyl)-cyclohexyl-ethyl-amine (2-Chloro-4-nitro-phenyl)-cyclohexyl-amine (2-Chloro-4-nitro-phenyl)-methyl-(1-methyl-pyrrolidin-3-yl)-amine (1 -Benzyl-pyrrolidin-3-yl)-(2-chloro-4-nitro-phenyl)-methyl-amine (2-Chloro-4-nitro-phenyl)-cyclopentyl-methyl-amine 15 1-(2-Chloro-4-nitro-phenyl)-decahydro-quinoline Allyl-(2-chloro-4-nitro-phenyl)-cyclohexyl-amine 2- [(2-Chloro-4-nitro-phenyl)- (2-hydroxy-ethyl)-amino] -ethanol (2-Chloro-4-nitro-phenyl)-isobutyl-methyl-amine (2-Chloro-4-nitro-phenyl)-hexyl-methyl-amine 20 2-[(2-Chloro-4-nitro-phenyl)-methyl-amino]-ethanol N-(2-Chloro-4-nitro-phenyl)-N,N',N'-trimethyl-ethane- 1,2-diamine N-(2-Chloro-4-nitro-phenyl)-N,N',N'-trimethyl-propane- 1,3-diamine (1-Benzyl-piperidin-4-yl)-(2-chloro-4-nitro-phenyl)-amine N-(2-Chloro-4-nitro-phenyl)-N',N'-dimethyl-ethane- 1,2-diamine 25 N-(2-Chloro-4-nitro-phenyl)-N',N'-dimethyl-propane- 1,3-diamine (2-Chloro-4-nitro-phenyl)-(2-methoxy-ethyl)-methyl-amine (1 -Benzyl-pyrrolidin-3-yl)-(2-chloro-4-nitro-phenyl)-amine 4-Piperidin- 1 -yl-3-trifluoromethyl-benzonitrile 4-Dimethylamino-3-trifluoromethyl-benzonitrile 30 4-(4-Methyl-piperazin- 1 -yl)-3-trifluoromethyl-benzonitrile WO 00/34258 PCT/US99/28842 - 62 EXAMPLE 19 (METHOD 4E) Butyl-(2-chloro-4-nitro-phenyl)thioether A solution of 3-chloro-4-fluoro-nitrobenzene (5.0 g) and sodium sulfide (2.5 g) in 5 N,N-dimethylformamide (30 mL) is stirred at room temperature for 1 hour and then treated with 1-iodobutane (12.6 g). The solvent is then removed under reduced pressure and the resulting residue is treated with ethyl acetate and hexanes to precipitate the inorganic salts. The solids are removed by filtration and the filtrate is reduced under reduced pressure. The resulting residue is then passed through 10 hydrous magnesium silicate using dichloromethane as the eluent to provide the desired compound as a yellow solid. Using the above procedure and appropriate starting materials the following compounds were prepared: 15 1 -Butylsulfanyl-2-chloro-4-nitro-benzene 2-Chloro- 1 -cyclohexylsulfanyl-4-nitro-benzene 2-Chloro- I -ethylsulfanyl-4-nitro-benzene 20 EXAMPLE 20 (METHOD 4F) (4-Chloro-5-methoxy-2-nitro-phenyl)-dimethyl-amine To a solution of trifluoro-methanesulfonic acid 4-chloro-5-methoxy-2-nitro-phenyl ester (1.0 g) in tetrahydrofuran (2.0 mL) is added dimethylamine (4.0 mL of a 40% 25 aqueous solution) and the mixture is stirred at room temperature for approximately 15 hours. The solution is then concentrated under reduced pressure and the residue is dissolved in ethyl acetate and then washed with water. The aqueous layer is extracted once with ethyl acetate and the combined organic layers are washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent is 30 removed by evaporation under reduced pressure and the residue is triturated with hexanes to provide the desired product as a colorless solid.

WO 00/34258 PCT/US99/28842 - 63 Using the above procedure and appropriate starting materials the following compounds were prepared: (4-Chloro-2-nitro-phenyl)-dimethyl-amine 5 4-(4-Chloro-5-methoxy-2-nitro-phenyl)-morpholine (4-Chloro-5-methoxy-2-nitro-phenyl)-dimethyl-amine 1-(4-Chloro-5-methoxy-2-nitro-phenyl)-piperidine 1-(4-Chloro-5-methoxy-2-nitro-phenyl)-pyrrolidine Benzyl-(4-chloro-5-methoxy-2-nitro-phenyl)-amine 10 (2-Chloro-6-nitro-phenyl)-dimethyl-amine EXAMPLE 21 (METHOD 4G)

(

2 -Chloro-4-nitro-phenyl)-methyl-phenyl-amine 15 n-Butyl lithium (12.3 mL of a 2.5 M solution in hexanes) is added dropwise to a solution of N-methyl aniline (3.0 g) in tetrahydrofuran (75 mL) at 0 0 C. The mixture is allowed to warm slowly to room temperature and is then re-cooled to 0 0 C and added by cannula to a solution of 3-chloro-4-fluoronitrobenzene (4.9 g) in tetrahydrofuran (35 mL) that is kept at -78 'C. Following the addition, the reaction 20 mixture is permitted to warm to room temperature over the course of 1 hour, and is then concentrated under reduced pressure, quenched by addition of saturated aqueous ammonium chloride, and extracted three times with ethyl acetate. The pooled organic layers are washed three times with 5% aqueous hydrochloric acid, once with water, once with saturated aqueous sodium bicarbonate, once with saturated aqueous 25 sodium chloride, and then dried over anhydrous magnesium sulfate. Following removal of the solvent under reduced pressure the residue is chromatographed over silica gel (5% diethyl ether in hexanes is used as the eluant) to provide the desired product as a clear colorless oil.

WO 00/34258 PCT/US99/28842 - 64 EXAMPLE 22 (METHOD 4H) 2,6-Dichloro-4-nitrophenol 3,4,5-Trichloronitrobenzene (14.86 g) is added to a solution of potassium phenoxide 5 (8.66 g) in diethylene glycol (66 mL) and the mixture is heated to 160'C for approximately 15 hours. The resulting dark brown solution is cooled to room temperature, poured onto 100 mL cold water, and extracted twice with diethyl ether. The pooled organic extracts are washed with water, 10% aqueous sodium hydroxide, and then dried over anhydrous magnesium sulfate. Following removal of the solvent 10 under reduced pressure the resulting oil is distilled in a Kugelrohr apparatus to provide a yellow oil that solidifies on standing. Recrystallization from ethanol-water provides the desired product as a pale yellow solid. EXAMPLE 23 (METHOD 5A) 15 (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) is added ethyl iodide (0.36 mL) and the mixture is stirred for approximately 15 hours at room temperature. The 20 solution is then filtered, concentrated under reduced pressure, and partitioned between ethyl acetate and water. The separated aqueous layer is further extracted twice with ethyl acetate, and the pooled organic extracts are washed successively with 10% aqueous sodium hydroxide, with water, and then dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure gave the desired product 25 as a tan solid. Using the above procedure and appropriate starting materials the following compounds were prepared: 30 (3,5-Dichloro-4-ethoxy-phenyl)-carbamic acid tert-butyl ester (4-Butoxy-3,5-dichloro-phenyl)-carbamic acid tert-butyl ester (4-Benzyloxy-3,5-dichloro-phenyl)-carbamic acid tert-butyl ester WO 00/34258 PCT/US99/28842 - 65 (4-Carbamoylmethoxy-3,5-dichloro-phenyl)-carbamic acid tert-butyl ester [3,5-Dichloro-4-(2-nitrilo-ethoxy)-phenyl]-carbamic acid tert-butyl ester (4-tert-Butoxycarbonylamino-2,6-dichloro-phenoxy)-acetic acid methyl ester 3-Butoxy-benzoic acid methyl ester 5 3-tert-Butoxycarbonylmethoxy-benzoic acid methyl ester 3-Carbamoylmethoxy-benzoic acid methyl ester [4-(3-Carbamoylmethoxy-benzoylamino)-phenyl]-carbamic acid tert-butyl ester {4-[3-(2-Chloro-ethoxy)-benzoylamino]-phenyl}-carbamic acid tert-butyl ester 10 EXAMPLE 24 (METHOD 5C) (2,6-Dichloro-4-nitro-phenoxy)-acetic acid tert-butyl ester To a solution of 2,6-dichloro-4-nitrophenol (2.5 g) and potassium carbonate (3.3 g) in dimethyl-formamide (50 mL) is added tert-butyl-bromoacetate (10 mL) and the 15 mixture is stirred at room temperature for two days. The solution is then poured into 500 mL water, extracted three times with hexanes, and the pooled organic extracts are washed with saturated aqueous ammonium chloride and then dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure followed by trituration of the resulting oil with hexanes provides the desired product 20 as a white solid. Using the above procedure and starting materials the following compounds were prepared: 25 3-Dimethylamino-1-(4-nitro-phenyl)-propenone 2-Chloro- 1 -isopropoxy-4-nitro-benzene 1,3-Dichloro-2-methoxy-4-methyl-5-nitro-benzene 1 -Chloro-4-ethoxy-2-methoxy-5-nitro-benzene 1 -Butoxy-4-chloro-5-methoxy-2-nitro-benzene 30 1 -Chloro-2-methoxy-5-nitro-4-(phenylmethoxy)benzene (CA name) 1-Chloro-4-methoxy-5-nitro-2-(phenylmethoxy)benzene (CA name) (2,6-Dichloro-4-nitro-phenoxy)-acetic acid tert-butyl ester (2,6-Dichloro-4-nitro-phenoxy)-acetonitrile WO 00/34258 PCTIUS99/28842 - 66 1 -Chloro-4-methoxy-2-methyl-5-nitro-benzene 2-(4-Chloro-5-methoxy-2-nitro-phenoxy)-acetamide 2-(2-Chloro-5-methoxy-4-nitro-phenoxy)-acetamide (4-Chloro-5-methoxy-2-nitro-phenoxy)-acetonitrile 5 (2-Chloro-5-methoxy-4-nitro-phenoxy)-acetonitrile 4-(2-Chloro-5-methoxy-4-nitro-phenoxy)-butyronitrile 2-(4-Chloro-5-methoxy-2-nitro-phenoxy)-ethanol 2-(2-Chloro-5-methoxy-4-nitro-phenoxy)-ethanol (2-Chloro-5-methoxy-4-nitro-phenoxy)-acetic acid tert-butyl ester 10 (2-Chloro-5-methoxy-4-nitro-phenoxy)-acetic acid methyl ester (4-Chloro-5-methoxy-2-nitro-phenoxy)-acetic acid methyl ester (4-Chloro-5-methoxy-2-nitro-phenoxy)-acetic acid tert-butyl ester (2-Chloro-4-nitro-phenoxy)-acetonitrile 1 -Butoxy-2-chloro-4-nitro-benzene 15 2-Chloro-4-nitro- 1- (2,2,2-trifluoro-ethoxy)-benzene 2-Chloro-4-nitro- I -propoxy-benzene 2-Chloro- 1 -ethoxy-4-nitro-benzene 1,3-Diiodo-2,4-dimethoxy-5-nitro-benzene 1,3-Dibromo-2,4-dimethoxy-5-nitro-benzene 20 3-Chloro-2,4-dimethoxy-nitrobenzene EXAMPLE 25 (METHOD 5E) [3,5-Dichloro-4-(2-hydroxy-ethoxy)-phenyl]-carbamic acid tert-butyl ester 25 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) is added ethylene carbonate (1.6 g) and the mixture is heated to reflux for 3 hours. To the cooled reaction mixture is added 2.5 M aqueous sodium hydroxide (50 mL), and the separated 30 organic layer is then washed successively with water, then saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate. The solvent is then removed by evaporation under reduced pressure and the resulting residue is chromatographed WO 00/34258 PCT/US99/28842 - 67 over silica gel (30% ethyl acetate in hexanes is used as the eluant) to provide the desired product as a white foam. EXAMPLE 26 (METHOD 6) 5 3-(2-Chloro-4-nitro-phenoxy)-1-methyl-pyrrolidine To a solution of 2-chloro-4-nitrophenol (2.0 g) in tetrahydrofuran (60 mL) is added 1-methyl-3-pyrrolidinol (2.3 g), triphenyl phosphine (6.0 g), and diethylazodicarboxylate (3.6 mL) and the mixture is stirred at room temperature 10 under an atmosphere of argon for 1.5 hours. The solution is 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 is removed by evaporation under reduced pressure and the residue is chromatographed over silica gel (ethyl acetate then 10% 15 methanol in dichloromethane is used as the eluant). Pooled product fractions are then recrystallized from hexanes to provide the desired product as a yellow solid. Using the above procedure and appropriate starting materials the following compounds were prepared: 20 4-(2-Chloro-4-nitro-phenoxy)- 1 -methyl-piperidine 3-(2-Chloro-4-nitro-phenoxy)- 1 -methyl-pyrrolidine [2-(2-Chloro-4-nitro-phenoxy)-ethyl]-dimethyl-amine [3-(2-Chloro-4-nitro-phenoxy)-propyl]-dimethyl-amine 25 EXAMPLE 27 (METHOD 7A) 2-Chloro-3-methoxy-6-nitro-phenol and 2,4-Dichloro-3-methoxy-6-nitro-phenol 30 To a flask containing 3-methoxy-6-nitro-phenol (0.5 g) is added aqueous sodium hypochlorite (5.25% aqueous solution, 21 mL) and the mixture is stirred at room temperature for approximately 24 hours. The mixture is then cooled in an ice-bath, WO 00/34258 PCT/US99/28842 -68 acidified by addition of concentrated hydrochloric acid, then extracted twice with ethyl acetate. These organic extracts are dried over anhydrous magnesium sulfate, the solvent is removed by evaporation under reduced pressure, and the residue is chromatographed over silca gel (15% acetone in hexanes is used as the eluant) to 5 provide both the mono- and di-chlorinated products as yellow solids. Using the above procedure and appropriate starting materials the following compounds were prepared: 10 3-Chloro-2-hydroxy-4-methoxy-nitrobenzene 3,5-Dichloro-2-hydroxy-4-methoxy-nitrobenzene EXAMPLE 28 (METHOD 7B) 2,4-Dichloro-3-methyl-6-nitro-phenol 15 To a solution of 3-methyl-4-nitro-phenol (5.0 g) in water (150 mL) is added aqueous sodium hypochlorite (5.25% aqueous solution, 230 mL) and the mixture is stirred at room temperature for approximately 15 hours. Additional aqueous sodium hypochlorite (5.25% aqueous solution, 230 mL) is added and the mixture is permitted 20 to stir at room temperature for 2.5 days. The mixture is then cooled in an ice-bath, acidified by addition of concentrated hydrochloric acid, then extracted twice with ethyl acetate. These organic extracts are dried over anhydrous magnesium sulfate, the solvent is removed by evaporation under reduced pressure, and the residue is chromatographed over silca gel (ethyl acetate is used as the eluant) to provide the 25 desired product as a yellow solid. An analytically pure sample is obtained by a single recrystallization from chloroform. EXAMPLE 29 (METHOD 7C) 1-Bromo-2,4-dimethoxy-5-nitro-benzene 30 To a solution of 2,4-dimethoxy-nitrobenzene (0.50 g) in chloroform (3 mL) is added dropwise a solution of bromine (0.23 g) in chloroform (1 mL) and the mixture is allowed to stir at room temperature for approximately 15 hours. Additional bromine WO 00/34258 PCT/US99/28842 - 69 (0.15 g) in chloroform (1 mL) is added and the reaction is stirred for an additional 4 hours. The mixture is then poured onto 5% aqueous sodium bisulfite and then extracted with chloroform. Pooled organic extracts are then washed successively with 5% aqueous sodium bisulfite then saturated sodium chloride, and then dried 5 over anhydrous sodium sulfate. Removal of the solvent under reduced pressure and recrystallization of the residue from toluene provides the desired product as a yellow solid. EXAMPLE 30 (METHOD 7D) 10 2,4-Dibromo-3-methoxy-6-nitro-phenol To a solution of 5-methoxy-2-nitro-phenol (0.25 g) and silver trifluoroacetate (0.49 g) in glacial acetic acid (3 mL) is added dropwise a solution of bromine (1.42 g) in glacial acetic acid (3 mL) and the mixture is stirred at room temperature for 15 approximately 24 hours. The solution is then partitioned between ethyl acetate and water, and the organic layer is washed successively three times with 5% aqueous sodium bisulfite, three times with saturated aqueous sodium bicarbonate, and once with saturated aqueous sodium chloride. The organic layer is then dried over anhydrous magnesium sulfate and the solvent is removed under reduced pressure. 20 The residue is chromatographed over silica gel (20% ethyl acetate in hexanes is used as the eluant) then recrystallized from chloroform to provide the desired dibrominated product as an orange solid. EXAMPLE 31 (METHOD 7E) 25 1-Iodo-2,4-dimethoxy-5-nitro-benzene To a solution of 2,4-dimethoxy-nitrobenzene (1.0 g) in glacial acetic acid (30 mL) is added benzyltrimethylammonium dichloroiodate (1.90 g) and anhydrous zinc chloride (1.0 g) and the mixture is stirred at room temperature under an atmosphere 30 of argon. Additional benzyltrimethylammonium dichloroiodate (0.4 g) is added after 5 hours and again after 24 hours. Additional zinc chloride (0.5 g) and glacial acetic acid (15 mL) is added after 24 hours. The mixture is permitted to stir at room WO 00/34258 PCTIUS99/28842 - 70 temperature for 3 days and is then filtered, diluted with 5% aqueous sodium bisulfite, and extracted three times with ethyl acetate. These pooled organic extracts are washed successively with 5% aqueous sodium bisulfite, saturated aqueous sodium chloride, then dried over anhydrous magnesium sulfate. After removal of the solvent 5 under reduced pressure the residue is triturated with hexanes to provide the desired product as a pale yellow solid. EXAMPLE 32 (METHOD 7F) 2,4-Diiodo-3-methoxy-6-nitro-phenol 10 To a solution of 5-methoxy-2-nitro-phenol (0.25 g) in dichloromethane (15 mL) and methanol (6 mL) is added benzyltrimethylammonium dichloroiodate (1.08 g) and sodium bicarbonate (0.85 g) and the mixture is allowed to stir at room temperature for 24 hours. The solution is then filtered, the filtrate is concentrated under reduced 15 pressure, the residue is dissolved in ethyl acetate and then washed successively with 5% aqueous sodium bicarbonate, 5% aqueous sodium bisulfite, and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate the solvent is removed by evaporation under reduced pressure and the residue is recrystallized from toluene to provide the desired product as yellow needles. 20 EXAMPLE 33 (METHOD 7G) 1-Fluoro-2,4-dimethoxy-5-nitro-benzene To a solution of 2,4-dimethoxy-nitrobenzene (1.0 g) in tetrachloroethane (10 mL) is 25 added 3,5-dichloro-l-fluoro-pyridinium triflate (85%, 5.07 g) and the mixture is heated to 120 'C for 5 hours. Additional 3,5-dichloro-l-fluoro-pyridinium triflate (85%, 0.25 g) is added and heating is continued for 1 hour. The solution is then cooled to room temperature and passed over a column of silica gel (hexanes followed by 30% ethyl acetate in hexanes is used as the eluant). Product containing fractions 30 are combined, evaporated under reduced pressure, and the residue is crystallized from hexanes to provide the desired product as a tan solid.

WO 00/34258 PCT/US99/28842 - 71 EXAMPLE 34 (METHOD 8) 3-Chloro-4-trifluoromethyl-nitrobenzene A solution of 3-chloro-4-iodo-nitrobenzene (2.26 g), trimethyl(trifluoromethyl)silane 5 (5.68 g), copper(I) iodide (2.28 g), and potassium fluoride (0.56 g) in N,N dimethylformamide (8 mL) is heated in a sealed tube to 80 'C for 40 hours. The solution is then cooled, diluted with diethyl ether, filtered through diatomaceous earth, and the filtrate is washed successively with water, saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate. The solvent is removed 10 under reduced pressure and the residue is chromatographed over silica gel (1% diethyl ether in hexanes followed by 10% ethyl acetate in hexanes is used as the eluant) to provided the desired product as a colorless oil. EXAMPLE 35 (METHOD 9) 15 (3-Chloro-4-methanesulfinyl-phenyl)-carbamic acid tert-butyl ester To a solution of (3-chloro-4-thiomethyl-phenyl)-carbamic acid tert-butyl ester (0.89 g) in dichloromethane (15 mL) at 0 0 C is added a solution of dimethyldioxirane (-0.11 M in acetone, 34 mL) and the mixture is stirred at 0 'C for 1 hour. The 20 solvent is removed under reduced pressure and the residue is 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. 25 EXAMPLE 36 (METHOD 9B) [4-(2-Methylsulfinyl-benzoylamino)-phenyl]-carbamic acid tert-butyl ester To a solution of 2-methylsulfanyl-N-[4-(2,2,2-trifluoro-acetylamino)-phenyl] 30 benzamide (234 mg) is added a saturated solution of sodium periodate (5 mL) and the mixture is stirred for 12 hours. The purple mixture is poured into water, extracted WO 00/34258 PCT/US99/28842 - 72 with ethyl acetate, dried over anhydrous potassium carbonate and evaporated to yield a red solid, 101 mg. Using the above procedure and appropriate starting materials the following 5 compounds were prepared: [4-(2-Methanesulfinyl-benzoylamino)-phenyl]-carbamic acid tert-butyl ester 2-Methanesulfinyl-N-[4-( 2

,

2

,

2 -trifluoro-acetylamino)-phenyl]-benzamide 10 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 15 g) in dichloromethane (30 mL) at 0 'C is added a solution of dimethyldioxirane (-0.11 M in acetone, 80 mL) and the mixture is stirred at 0 'C for 1 hour. The solvent is removed under reduced pressure and the residue is dissolved in dichloromethane, washed with saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure 20 gives the desired product as an orange foam. EXAMPLE 38 (METHOD 11) 3-Chloro-4-vinyl-phenylamine 25 To a deoxygenated solution of 3-chloro-4-iodo-aniline (6.95 g), triphenyl arsine (0.67 g), and tris(dibenzylideneacetone)palladium(o) (0.50 g) in tetrahydrofuran (120 mL) at 50 'C is added tributylvinyltin (10 g) and the mixture is stirred for approximately 15 hours at 50 'C under an atmosphere of argon. The reaction is then cooled, filtered through diatomaceous earth, and the filtrate is evaporated to dryness under reduced 30 pressure. The residue is dissolved in hexanes and then extracted three times with 5% aqueous hydrochloric acid. These aqueous acidic extracts are then basified with solid potassium carbonate and extracted three times with ethyl acetate. These pooled WO 00/34258 PCTIUS99/28842 - 73 organic extracts are then washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and the solvent is removed under reduced pressure. The resulting residue is chromatographed over silica gel (hexanes and then 10% ethyl acetate in hexanes is used as the eluant) to provide the desired product as an amber 5 oil. EXAMPLE 39 (METHOD 12) [3-Chloro-4-(1-hydroxy-ethyl)-phenyl]-carbamic acid 2-trimethylsilanyl-ethyl ester 10 (3-Chloro-4-vinyl-phenyl)-carbamic acid 2-trimethylsilanyl-ethyl ester (2.6 g) is added to a solution of mercuric acetate (3.48 g) in water (7 mL) and tetrahydrofuran (5.25 mL) and the mixture is stirred for approximately 15 hours. 3N Aqueous sodium hydroxide (8.7 mL) and a 0.5 M solution of sodium borohydride in 3N 15 aqueous sodium hydroxide (8.7 mL) are then added and stirring is continued for 6 hours. The solution is then saturated with sodium chloride and extracted with ethyl acetate. These organic extracts are then washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. Following removal of the solvent under reduced pressure the residue is chromatographed over silica gel (20% ethyl 20 acetate in hexanes is used as the eluant) to provide the desired product as a white solid. EXAMPLE 40 (METHOD 13) [3-Chloro-4-(2-hydroxy-ethyl)-phenyl]-carbamic acid tert-butyl ester 25 To a stirring suspension of sodium borohydride (0.45 g) in tetrahydrofuran (13 mL) at 0 'C is added glacial acetic acid (0.75 mL) and the mixture is stirred at 0 0 C for 1 hour. The solution is then warmed to room temperature and (3-chloro-4-vinyl phenyl)-carbamic acid 2-trimethylsilanyl-ethyl ester (1.0 g) is added. The reaction is 30 stirred at room temperature for approximately 15 hours and then heated to reflux for approximately 20 hours. The mixture is then cooled and solutions of 5 N aqueous sodium hydroxide (0.80 mL) and 30% aqueous hydrogen peroxide (0.56 mL) are WO 00/34258 PCT/US99/28842 - 74 added. After stirring for an additional 15 hours the layers are separated, the aqueous layer is extracted three times with diethyl ether, and these organic extracts are dried over anhydrous magnesium sulfate. Following removal of the solvent under reduced pressure the residue is chromatographed over silica gel (40% ethyl acetate in hexanes 5 is used as the eluant) to provide the desired product as an amber oil. EXAMPLE 41 (METHOD 14) [4-(1-Azido-ethyl)-3-chloro-phenyl]-carbamic acid 2-trimethylsilanyl-ethyl ester 10 To a solution of [3-chloro-4-(1-hydroxy-ethyl)-phenyl]-carbamic acid 2 trimethylsilanyl-ethyl ester (1.25 g) in tetrahydrofuran (20 mL) at 0 'C under an atmosphere of argon is added triphenyl-phosphine (2.6 g), hydrazoic acid (approximately 2.5 molar equivalents in dichloromethane, prepared by the method of Fieser and Fieser, Reagents for Organic Synthesis, Vol. 1, pg. 446; Wiley, New 15 York) and diethyl azodicarboxylate (1.72 g). After approximately 10 minutes the solvent is removed under reduced pressure and the residue is chromatographed over silica gel (5% ethyl acetate in hexanes is used as the eluant) to provide the desired product as a colorless oil. 20 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-iodo-phenyl)-carbamic acid tert-butyl 25 ester (10.0 g) in triethylamine (120 ml) is added 1-dimethylamino-2-propyne (2.82 g), bis(triphenyl-phosphine)palladium(II) chloride (0.4 g), and cuprous iodide (0.054 g). The mixture is stirred at room temperature under an atmosphere of argon for approximately 6 hours and is then heated briefly (ca. 10 minutes) to 60'C. The reaction mixture is then cooled, filtered through diatomaceous earth, and the solvent 30 is removed by evaporation under reduced pressure. The residue is dissolved in ethyl acetate, washed three times with water, once with saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent is removed by evaporation WO 00/34258 PCT/US99/28842 - 75 under reduced pressure, and the residue is chromatographed over silica gel (80% ethyl acetate in hexanes is used as the eluant) to give the purified product as an amber oil that solidified on standing. 5 Using the above procedure and appropriate starting materials the following compounds were prepared: [3-Chloro-4-(3-dimethylamino-prop-1-ynyl)-phenyl]-carbamic acid tert-butyl ester [3-(4-Methoxy-phenyl)-prop-2-ynyl]-dimethyl-amine 10 4-(3-Dimethylamino-prop- 1 -ynyl)-benzonitrile Dimethyl-[3-(4-nitro-phenyl)-prop-2-ynyl]-amine EXAMPLE 43 (METHOD 16) [3-Chloro-4-(3-dimethylamino-acryloyl)-phenyl]-carbamic acid tert-butyl ester 15 To an ice cold solution of [ 3 -chloro-4-(3-dimethylamino-prop-1-ynyl)-phenyl] carbamic acid tert-butyl ester (4.0 g) in dichloromethane (30 ml) is added in small portions 3-chloroperoxybenzoic acid (2.34 g). After the reaction is stirred at 0 0 C for 20 minutes, the mixture is passed over twenty weight equivalents of basic alumina 20 (Brockmann Grade I, 150 mesh) and the N-oxide is eluted using a solution of 5% methanol in dichloromethane. All fractions containing the desired amine N-oxide were combined and evaporated to near dryness under reduced pressure. The residue is treated successively three times with small portions of methanol (ca. 50 ml) followed by evaporation to near dryness under reduced pressure, and the volume of 25 the solution is adjusted to 250 mL by addition of methanol. The methanolic solution of the N-oxide is then heated to reflux for approximately 15 hours, then cooled, and the solvent is evaporated to dryness under reduced pressure. The residue is purified by chromatography over silica gel (80% ethyl acetate in hexanes is used as the eluant) to give the desired product as a pale yellow solid. 30 WO 00/34258 PCT/US99/28842 - 76 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 5 butyl ester (270 mg) in dioxane (3 ml) is treated with hydroxylamine hydrochloride (122 mg) and the mixture is stirred at room temperature for 10 days. The mixture is diluted with ethyl acetate, washed successively with water, 5% aqueous sodium bicarbonate, saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent is removed by evaporation under reduced pressure 10 and the resulting residue is chromatographed over silica gel (33% ethyl acetate in hexanes is used as the eluant) to provide the desired product as a colorless solid. EXAMPLE 45 (METHOD 18) [3-Chloro-4-(1H-pyrazol-3-yl)-phenyl]-carbamic acid tert-butyl ester 15 A solution of [3-chloro-4-(3-dimethylamino-acryloyl)-phenyl]-carbamic acid tert butyl ester (250 mg) in ethanol (1.25 ml) is treated with hydrazine hydrate (0.25 ml) and the mixture is stirred at room temperature for 3 hours. The mixture is 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. 20 The solvent is removed by evaporation under reduced pressure and the resulting residue is chromatographed over silica gel (67% ethyl acetate in hexanes is used as the eluant) to provide the desired product as an oil. EXAMPLE 46 (METHOD 19A) 25 N-(2-Chloro-4-nitrophenyl)-2-thiomorpholino-4-yI-acetamide To a solution N-(chloroacetyl)-2-chloro-4-nitroaniline (3.80 g) in tetrahydrofuran (50 mL) is added thiomorpholine (10 mL) and the solution allowed to stand for 1 hour. This reaction mixture is poured into water a pale yellow solid is collected and then 30 recrystallized from hot 2-propanol to give a pale yellow crystalline solid.

WO 00/34258 PCT/US99/28842 - 77 Using the above procedure and appropriate starting materials the following compounds were prepared: (4- {2- [Bis-(2-hydroxy-ethyl)-amino] -acetylamino } -phenyl)-carbamic acid tert-butyl 5 ester [4-(2-Dimethylamino-acetylamino)-phenyl]-carbamic acid tert-butyl ester {4-[3-(2-Dimethylamino-ethoxy)-benzoylamino]-phenyl}-carbamic acid tert-butyl ester {4-[3-(2-Morpholin-4-yl-ethoxy)-benzoylamino]-phenyl}-carbamic acid tert-butyl 10 ester N-(2-Chloro-4-nitro-phenyl)-2-dimethylamino-acetamide N-(2-Chloro-4-nitro-phenyl)-2-piperidin-1-yl-acetamide N-(2-Chloro-4-nitro-phenyl)-2-morpholin-4-yl-acetamide N-(2-Chloro-4-nitro-phenyl)-2-dipropylamino-acetamide 15 N-(2-Chloro-4-nitro-phenyl)-2-thiomorpholin-4-yl-acetamide N-(2-Chloro-4-nitro-phenyl)-2-diethylamino-acetamide N-(2-Chloro-4-nitro-phenyl)-2-pyrrolidin- 1 -yl-acetamide 2-Azepan- 1 -yl-N-(2-chloro-4-nitro-phenyl)-acetamide N-(2-Chloro-4-nitro-phenyl)-2-(2-methyl-piperidin- 1 -yl)-acetamide 20 N-(2-Chloro-4-nitro-phenyl)-2-(3-methyl-piperidin- 1 -yl)-acetamide N-(2-Chloro-4-nitro-phenyl)-2-(4-methyl-piperidin- 1 -yl)-acetamide EXAMPLE 47 (METHOD 19B) N-(2-Chloro-4-nitrophenyl)-2-(2-dimethylaminoethylsulfanyl)acetamide 25 To a solution of N-(chloroacetyl)-2-chloro-4-nitroaniline (3.01 g) in N,N dimethylformamide (100 mL) is added powdered sodium carbonate (6.0 g) and 2 dimethylaminoethanethiol hydrochloride (6.0 g). The mixture is stirred for 1 hour at 250 C, poured into water and extracted into ethyl acetate. The ethyl acetate solution 30 is dried over anhydrous potassium carbonate and concentrated under reduced pressure to give an oil. The oil is crystallized from toluene-hexanes (3:1) to yield a pale yellow crystalline solid.

WO 00/34258 PCT/US99/28842 - 78 EXAMPLE 48 (METHOD 20) (4-tert-butoxycarbonylamino-2-chloro-phenyl)-carbamic acid 2 piperidin-1-yl-ethyl ester 5 To a suspension of 1,1-carbonyl-di-(1,2,4)-triazole (4.0 g) in dichloromethane (40 mL) is added a solution of (4-amino-3-chloro-phenyl) carbamic acid tert-butyl ester (5.0 g) in dichloromethane (45 mL) dropwise over 20 minutes. The reaction is stirred at room temperature for 30 minutes at which point a precipitate forms. To this mixture is added piperidineethanol (6.6 mL) and tetra-hydrofuran (20 mL) is 10 added to maintain homogeneity. After heating at reflux overnight the reaction is cooled and then poured into water, the organic layer separated and then washed with saturated aqueous sodium chloride. The solution is dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to a crude oil that is purified by chromatography over silica gel (5% methanol in dichloromethane is used as the 15 eluant) to give the desired product as a white foam. EXAMPLE 49 (METHOD 21) 5-Phenyl-[1,2,3]thiadiazole-4-carboxylic acid methyl ester 20 A solution of ethyl benzoylacetate (1.1 g) in acetonitrile (10 mL) is treated with 4 methylbenzenesulfonyl azide (1.3 g) and triethylamine (1.6 g). After stirring overnight at room temperature, the reaction is concentrated under reduced pressure and the resulting crude product is dissolved in ethyl acetate and washed with 1N sodium hydroxide. The organic layer is then dried over anhydrous magnesium 25 sulfate, filtered and concentrated under reduced pressure to yield a yellow oil. This oil is taken into dichloromethane and filtered through a pad of hydrous magnesium silicate, eluting with dichloromethane to give the partially purified diazoketone as a colorless oil. A sample of the diazoketone from above (1.2 g) is dissolved in toluene (25 mL) and treated with 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 30 2,4-disulfide (2.8 g) and the reaction is heated to reflux. After 3 hours, the reaction is cooled to room temperature, loaded onto a pad of silica gel and eluted with dichloromethane. After removing the solvent under reduced pressure, the resulting WO 00/34258 PCT/US99/28842 - 79 oil is purified by chromatography over silica gel (30% diethyl ether in petroleum ether is used as the eluant) and then recrystallized from hexanes to give the desired product as pale yellow needles. 5 Using the above procedure and appropriate starting materials the following compound was prepared: 5-Phenyl-[1,2,3]thiadiazole-4-carboxylic acid ethyl ester 5-Methyl-[1,2,3]thiadiazole-4-carboxylic acid methyl ester 10 EXAMPLE 50 Ethyl benzoylacetate semicarbazide Ethyl benzoylacetate (5.0 g) is dissolved in methanol (10 mL) and added rapidly to a 15 hot solution of semicarbazide hydrochloride (29 g) in water (130 mL). To this is added pyridine (4.1 g) and after heating to reflux for 5 minutes, the reaction mixture is cooled to -20 'C overnight. The resulting solid semicarbazone is collected by filtration, washed with water and then diethyl ether to give the desired product as white crystals. 20 Using the above procedure and appropriate starting materials the following compound was prepared: Ethyl (Z)-3-[(aminocarbonyl)hydrazono]-4,4,4-trifluorobutanoate 25 3-[(Z)-2-(Aminocarbonyl)hydrazono-3-phenylpropanoic acid ethyl ester 3-[(E)-2-(Aminocarbonyl)hydrazono]-3-(3-furyl)propanoic acid ethyl ster EXAMPLE 51 5-Phenyl-[1,2,3]thiadiazole-5-carboxylic acid ethyl ester 30 A solution of ethyl benzoylacetate semicarbazone (2.5 g) in neat thionyl chloride (5 mL) is stirred at 0 'C for 1 hour. Dichloromethane is then added (25 mL), the excess WO 00/34258 PCT/US99/28842 - 80 thionyl chloride is destroyed slowly with saturated aqueous sodium bicarbonate. The precipitate which forms on quenching is removed by filtration and the filtrate is extracted with dichloromethane. Pooled organic extracts are dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. 5 Chromatography over silica gel (50% hexanes in dichloromethane is used as the eluant) affords the desired product as a colorless oil. Using the above procedure and appropriate starting materials the following compounds were prepared: 10 4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid methyl ester 4-Phenyl-[1,2,3]thiadiazole-5-carboxylic acid ethyl ester 4-Furan-3-yl-[1,2,3]thiadiazole-5-carboxylic acid ethyl ester 15 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) is dissolved in methanol (15 mL) and treated with IN sodium hydroxide (16 mL). After stirring at 20 room temperature for 1 hour, the reaction is treated with concentrated hydrochloric acid (1.5 mL) and concentrated under reduced pressure. The resulting turbid aqueous layer is extracted twice with diethyl ether and the pooled organic layers are dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the desired compound as a white powder. 25 Using the above procedure and appropriate starting materials the following compounds were prepared: 3-Ethoxycarbonylmethoxy-benzoic acid 30 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 WO 00/34258 PCTIUS99/28842 - 81 EXAMPLE 53 (METHOD 25) Trifluoro-methanesulfonic acid 4-chloro-5-methoxy-2-nitro-phenyl ester To a solution of 4-chloro-5-methoxy-2-nitro-phenol (6.5 g) in dichloromethane (150 5 mL) at 0 'C under an atmosphere of argon is added triethylamine (10 g) and then a solution of trifluoro-methanesulfonic anhydride (13.5 g) in dichloromethane (30 mL). The solution is stirred at 0 'C for 10 minutes, and is then diluted with dichloromethane and washed successively with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. After drying over anhydrous sodium sulfate 10 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 hydrous magnesium silicate (20% dichloromethane in hexanes is used as the eluant). Product containing fractions are pooled and the solvents removed by evaporation under reduced pressure to give the desired product as a yellow oil. 15 Using the above procedure and appropriate starting materials the following compounds were prepared: Trifluoro-methanesulfonic acid 4-chloro-5-methoxy-2-nitro-phenyl ester 20 Trifluoro-methanesulfonic acid 4-chloro-2-nitro-phenyl ester Trifluoro-methanesulfonic acid 2-chloro-6-nitro-phenyl ester EXAMPLE 54 (METHOD 26) [4-(3-Dimethylamino-benzoylamino)-phenyl]-carbamic acid t-butyl ester 25 A solution of [4-(3-amino-benzoylamino)-phenyl]-carbamic acid t-butyl ester (505 mg), sodium cyanoborohydride (250 mg), acetic acid (3 drops) and 40 % aqueous formaldehyde (4 mL) in 1:2 tetrahydrofuran-methanol (15 mL) is stirred for 15 minutes, and then poured into saturated aqueous sodium bicarbonate and extracted 30 into ethyl acetate. The ethyl acetate solution is dried over anhydrous potassium carbonate and concentrated under reduced pressure to give a solid which is recrystallized from acetonitrile to provide a pale pink crystalline solid.

WO 00/34258 PCTIUS99/28842 - 82 Using the above procedure and appropriate starting materials the following compounds were prepared: 5 [4-(3-Dimethylamino-benzoylamino)-phenyl]-carbamic acid tert-butyl ester (3-Bromo-5-trifluoromethyl-phenyl)-dimethyl-amine N-(3-Chloro-5-dimethylamino-phenyl)-acetamide EXAMPLE 55 (METHOD 27) 10 N-(4-Aminophenyl)-2-hydroxybenzamide To a solution of 2-(4-aminophenylcarbamoyl) phenyl acetate (580 mg) in methanol (10 mL) is added saturated sodium bicarbonate (2 mL) and water (3 mL). The mixture is heated at 800 C for 30 minutes, then poured into half-saturated aqueous 15 sodium chloride and extracted with ethyl acetate. The ethyl acetate solution is dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an oil which is then triturated with diethyl ether to provide the desired product as a white solid. 20 EXAMPLE 56 (METHOD 28) [4-(3-(Hydroxybenzoylamino)phenyl}carbamic acid t-butyl ester To a solution of of 3-(4-aminophenylcarbamoyl) phenyl acetate (4.34 g) in methanol (75 mL) is added 0.1 N aqueous sodium hydroxide (25 mL) and tetrahydrofuran (25 25 mL). This solution is heated at 400 C for 30 minutes, then cooled, poured into I M hydrochloric acid and extracted with ethyl acetate. The ethyl acetate solution is dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a white solid, which is further purified by trituration with diethyl ether.

WO 00/34258 PCTIUS99/28842 - 83 EXAMPLE 57 (METHOD 29) N-(4-Aminophenyl)-2-hydroxymethylbenzamide To a solution of N-(4-aminophenyl)phthalimide (332 mg) in tetrahydrofuran (4 mL) 5 is added lithium borohydride (1.0 g) and the mixture is stirred for 1 hour at 250 C. The mixture is poured into water and extracted into ethyl acetate. The ethyl acetate solution is dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a white foam, which when triturated with diethyl ether provides the desired product as a white powder. 10 EXAMPLE 58 (METHOD 30) (3-Chloro-5-dimethylamino-phenyl)-carbamic acid tert-butyl ester To a solution of (3-amino-5-chloro-phenyl)-carbamic acid tert-butyl ester (0.32 g) in 15 toluene (10 mL) is added aqueous formaldehyde (37%, 1.5 mL) then 10% palladium on carbon (0.50 g) and the mixture is stirred under an atmosphere of hydrogen for approximately 15 hours. The solution is then filtered through diatomaceous earth and the filtrate is concentrated under reduced pressure. The residue is chromatographed over silica gel (50% dichloromethane in hexanes is used as the eluant) to provide the 20 desired product as a white solid. EXAMPLE 59 (METHOD 35) N-(4-{3-[3,5-Dichloro-4-(2-hydroxy-ethoxy)-phenyl]-thioureido} phenyl)-acetamide 25 To a solution of acetic acid 2-{4-[3-(4-acetylamino-phenyl)-thioureido]-2,6-dichloro phenoxy}-ethyl ester (0.16 g) in a 1:1 mixture of tetrahydrofuran and methanol (2.5 mL) is added 1N aqueous sodium hydroxide (1 mL) and the mixture is stirred for approximately 2 hours at room temperature. The solution is then poured into 2 M 30 aqueous hydrochloric acid (3 mL), extracted into ethyl acetate, and the extracts are dried over anhydrous sodium sulfate. The solvent is removed by evaporation under WO 00/34258 PCT/US99/28842 - 84 reduced pressure and the residue is triturated with diethyl ether to provide the desired product as a white solid. EXAMPLE 60 (METHOD 36) 5 {4- [3-(4-Acetylamino-phenyl)-thioureido] -2,6-dichloro-phenoxy}-acetic acid To a solution of {4-[3-(4-acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy} acetic acid ethyl ester (0.29 g) in a 1:1 mixture of tetrahydrofuran and methanol (4 mL) is added IN aqueous sodium hydroxide (2 mL) and the mixture is stirred for 10 approximately 2 hours at room temperature. The solution is then poured into 2 M aqueous hydrochloric acid (5 mL), extracted into ethyl acetate, and the extracts are dried over anhydrous sodium sulfate. The solvent is removed by evaporation under reduced pressure and the residue is triturated with diethyl ether to provide the desired product as a white solid. 15 Using the above procedure and appropriate starting materials the following compounds were prepared: {4-[3-(4-Acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy} -acetic acid 20 (2- [3-(4-Acetylamino-phenyl)-thioureido]-4-chloro-5-methoxy-phenoxy} -acetic acid {4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-5-methoxy-phenoxy} -acetic acid EXAMPLE 61 (METHOD 37) Benzoic acid 2-{4-[3-(4-acetylamino-phenyl)-thioureido]-2,6-dichloro 25 phenoxy}-ethyl ester To an ice cooled solution of N-(4-{3-[3,5-dichloro-4-(2-hydroxy-ethoxy)-phenyl] thioureido}-phenyl)-acetamide (0.20 g) in pyridine (2 mL) and tetrahydrofuran (0.5 mL) is added benzoyl chloride (0.08 g) and the mixture is stirred at 0 'C for 1.5 30 hours. The mixture is then diluted with ethyl acetate, washed successively two times with 2% aqueous hydrochloric acid, once with saturated aqueous sodium chloride, then dried over anhydrous sodium sulfate. After removal of the solvent under WO 00/34258 PCT/US99/28842 - 85 reduced pressure the residue is chromatographed over silica gel (5% methanol in dichloromethane is used as the eluant) and product containing fractions are combined, evaporated under reduced pressure, and the residue is recrystallized from acetone-hexanes to provide the desired product as a white powder. 5 EXAMPLE 62 (METHOD 38) Methanesulfonic acid 2-{4-[3-(4-acetylamino-phenyl)-thioureido]-2,6-dichloro phenoxy}-ethyl ester 10 To an ice cooled solution of N-(4-{3-[3,5-dichloro-4-(2-hydroxy-ethoxy)-phenyl] thioureido}-phenyl)-acetamide (0.20 g) in pyridine (2 mL) and tetrahydrofuran (0.5 mL) is added methanesulfonyl chloride (0.11 g) and the solution is stirred at 0 'C for 45 minutes. The reaction mixture is then diluted with ethyl acetate, washed successively twice with 2% aqueous hydrochloric acid, once with saturated aqueous 15 sodium chloride, and then dried over anhydrous magnesium sulfate. After removing the solvents by evaporation under reduced pressure the resulting residue is recrystallized from acetone-hexanes to give the desired product as a white powder. EXAMPLE 63 (METHOD 39) 20 N-(4-{3-[3,5-Dichloro-4-(2-dimethylamino-ethoxy)-phenyl]-thioureido}-phenyl) acetamide To a solution of methanesulfonic acid 2-{4-[3-(4-acetylamino-phenyl)-thioureido] 2,6-dichlorophenoxy}-ethyl ester (0.33 g) in tetrahydrofuran (6 mL) is added 25 aqueous dimethyl-amine (8.8 M, 0.5 mL) and the mixture is stirred at room temperature for 5 days. The reaction mixture is then diluted with ethyl acetate, then washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure the residue is chromatographed over silica gel (pure methanol is used as the eluant). Pooled 30 product containing fractions are evaporated under reduced pressure and the residue is recrystallized from acetonitrile to provide the desired product as a white powder.

WO 00/34258 PCTIUS99/28842 - 86 Using the above procedure and appropriate starting materials the following compounds were prepared: N-(4-(3-[3,5-Dichloro-4-(2-dimethylamino-ethoxy)-phenyl]-thioureido}-phenyl) 5 acetamide Benzoic acid 2-{ 4-[3-(4-acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy} ethyl ester EXAMPLE 64 (METHOD 40) 10 Furan-2-carboxylic acid (4-{3-[4-(1-amino-ethyl)-3-chloro-phenyll-thioureido} phenyl)-amide To a solution of tin(II) chloride dihydrate (0.25 g) in methanol (2.5 mL) is added furan-2-carboxylic acid (4-{3-[4-(1-azido-ethyl)-3-chloro-phenyl]-thioureido} 15 phenyl)-amide (0.22 g) and the solution is stirred for approximately 15 hours at room temperature. The solution is then diluted with ethyl acetate, washed successively with saturated aqueous sodium bicarbonate then saturated aqueous sodium chloride, then dried over anhydrous sodium sulfate. After removal of the solvent by evaporation under reduced pressure the residue is chromatographed over silica gel 20 (8% methanol in dichloromethane containing 1% triethylamine is used as the eluant) to provide the desired product as a yellow solid. EXAMPLE 65 (METHOD 41) [1,2,3]Tiadiazole-4-carboxylic acid (4-isothiocyanato-phenyl)-amide 25 To a ice cooled solution of 1,1'-thiocarbonyldiimidazole (7.28 g) in tetrahydrofuran (50 mL) is added [1,2,3]-thiadiazole-4-carboxylic acid (4-amino-phenyl) amide (9.0 g) in tetrahydrofuran (100 mL). After approximately one hour the solvent is removed by evaporation and the residue is dissolved in ethyl acetate. Diethyl ether is 30 added to precipitate the crude product, which is then collected by filtration, dissolved in dichloromethane, and passed through a plug of hydrous magnesium silicate. After WO 00/34258 PCTIUS99/28842 - 87 removal of solvents, the residue is recrystallized from ethyl acetate-hexanes to provide the desired product as a slightly yellow solid. Using the above procedure and appropriate starting materials the following 5 compounds were prepared: 2-Fluoro-N-(4-isothiocyanato-phenyl)-benzamide Furan-2-carboxylic acid (4-isothiocyanato-phenyl)-amide [1,2,3]Thiadiazole-4-carboxylic acid (4-isothiocyanato-phenyl)-amide 10 Thiazole-4-carboxylic acid (4-isothiocyanato-phenyl)-amide EXAMPLE 66 (METHOD 42) N,N-Dimethyl-5-trifluoromethyl-benzene-1,3-diamine 15 To a solution of 3-amino-5-bromo-benzotrifluoride (1.0 g) in degassed (argon) tetrahydrofuran (2 mL) is added bis-(tri-o-tolylphosphino)palladium (0.15 g), a solution of dimethylamine in tetra-hydrofuran (2M, 4.2 mL), and a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (IM, 10.4 mL). The reaction mixture is heated in a sealed vessel to 100 0 C for approximately 2.5 hours to complete 20 the reaction. The mixture is then cooled to room temperature, quenched by addition of water, and diluted with ethyl acetate. The product is extracted three times into 5% aqueous hydrochloric acid, and pooled acidic extracts are then basified with cooling by addition of 5N aqueous sodium hydroxide. This basic solution is then extracted with ethyl acetate, and these pooled organic extracts are washed with saturated 25 aqueous sodium chloride, dried over anhydrous magnesium sulfate, and evaporated to dryness under reduced pressure. The resulting residue is chromatographed over silica gel (20-30% ethyl acetate in hexanes is used as the eluant) to provide the desired product as a slightly tinted solid. 30 Using the above procedure and appropriate starting materials the following compounds were prepared: 3-(4-Methyl-piperazin- 1 -yl)-5-trifluoromethyl-phenylamine 3-Morpholin-4-yl-5-trifluoromethyl-phenylamine WO 00/34258 PCT/US99/28842 - 88 3-Piperidin- 1 -yl-5-trifluoromethyl-phenylamine 3-Pyrrolidin- 1 -yl-5-trifluoromethyl-phenylamine N,N-Dimethyl-5-trifluoromethyl-benzene- 1,3-diamine N-Isobutyl-N-methyl-5-trifluoromethyl-benzene- 1,3-diamine 5 N-Butyl-N-methyl-5-trifluoromethyl-benzene- 1,3-diamine EXAMPLE 67 (METHOD 43) (3-Isobutyl-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester 10 To a sealed tube containing tetrahydrofuran (5 mL) that is capped with a rubber septum and cooled in a dry ice-acetone bath is bubbled isobutylene for about 5 minutes. A solution of 9-borabicyclo[3.3.1]nonane in tetrahydrofuran (0.5 M, 11 mL) is added, the vessel is sealed with a teflon cap, slowly warmed to room temperature and kept at room temperature for approximately 2.5 hours. The mixture 15 is then re-cooled in a dry ice-acetone bath, the teflon cap is replaced by a rubber septum, and argon is bubbled through the mixture with venting to removed the excess isobutylene. A solution of ( 3 -bromo-5-trifluoromethyl-phenyl)-carbamic acid tert butyl ester (1.7 g) in tetrahydrofuran (12 mL) is added, followed by [1,1' bis(diphenylphosphino)-ferrocene]palladium(II) chloride-dichlormethane complex 20 (0.12 g), and then 3N aqueous sodium hydroxide. The vessel is again sealed with the teflon cap and is then heated to 65'C for approximately 15 hours. The mixture is then cooled to room temperature, diluted with hexanes, washed with water, saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The resulting oil is chromatographed over silica gel (5% 25 ethyl acetate in hexanes is used as the eluant) to provide the desired product as a white powder. Using the above procedure and appropriate starting materials the following compounds were prepared: 30 [3-(2-Methyl-butyl)-5-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (3-Isobutyl-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester WO 00/34258 PCT/US99/28842 - 89 EXAMPLE 68 (METHOD 44) 2-(3,5-Dichloro-phenylsulfanyl)-ethylamine 5 To a solution of (3,5-dichlorophenylthio)acetonitrile (1.2g) in 3.0 mL of ethylene glycol dimethyl ether is added 0.61 mL of 1OM borane dimethyl sulfide complex and the mixture heated at reflux for 0.5 hours. The reaction is cooled in an ice bath and 2.0 mL of water and 2.0 mL of concentrated hydrochloric acid is added. This mixture is heated at reflux for 0.5 hr. The clear solution is then cooled and basified with 5N 10 sodium hydroxide and extracted with ether. The ether extract is dried over potassium carbonate, filtered and concentrated to give 1.0g of a colorless oil. Using the above procedure and appropriate starting materials the following compounds were prepared: 15 2-(3-Bromo-phenylsulfanyl)-ethylamine 2-(4-Bromo-phenoxy)-ethylamine 2-(4-Iodo-phenoxy)-ethylamine 2-(3,4-Dichloro-phenoxy)-ethylamine 20 2-(3-Chloro-phenylsulfanyl)-ethylamine 2-(3,4-Dichloro-phenylsulfanyl)-ethylamine 3-(4-Bromo-phenyl)-propylamine 2-(2-Fluoro-phenoxy)-ethylamine 2-(2-Chloro-phenoxy)-ethylamine 25 2-(3-Bromo-phenoxy)-ethylamine 2-(3-Fluoro-phenoxy)-ethylamine 2-(3-Iodo-phenoxy)-ethylamine 2-(3,5-Dichloro-phenylsulfanyl)-ethylamine 2-Phenylsulfanyl-ethylamine 30 1-(2-Chloro-phenyl)-ethylamine WO 00/34258 PCT/US99/28842 - 90 EXAMPLE 69 (METHOD 45) N-(1-Naphthalen-2-yl-ethyl)-formamide A mixture of 2-acetylnaphthylene (3.0 g), ammonium formate (11.0 g), formic acid 5 (3.3 mL), and formamide (3.5 mL) is heated at 190 0 C for 3 hours. The mixture is cooled, poured into water and extracted with ether. The ether extract is dried with anhydrous potassium carbonate, filtered and concentrated to give a yellow oil, which is crystallized from toluene-hexanes to give a white solid, 1.97 g. 10 Using the above procedure and appropriate starting materials the following compounds were prepared: N-[1-(4-Fluoro-phenyl)-2-methyl-propyl]-formamide N-(1-Naphthalen-2-yl-ethyl)-formamide 15 EXAMPLE 70 (METHOD 46) 1-(2-Naphthyl)ethylamine A mixture of N-(1-naphthalen-2-yl-ethyl)-formamide (1.12 g), ethanol (10 mL) and 5 20 N sodium hydroxide (10 mL) is heated at reflux for 1 hour. The solution is cooled, poured into water and extracted with ether. The ether solution is dried with anhydrous potassium carbonate, filtered and concentrated to give the product (0.95 g) as a pale yellow oil. 25 Using the above procedure and appropriate starting materials the following compounds were prepared: 1-(3-Trifluoromethyl-phenyl)-ethylamine 1-(4-Fluoro-phenyl)-2-methyl-propylamine 30 [3-(1-Amino-ethyl)-phenyl]-dimethyl-amine 3-(1-Amino-ethyl)-benzonitrile WO 00/34258 PCT/US99/28842 - 91 EXAMPLE 71 (METHOD 47) 1-(3-Trifluoromethyl-phenyl)-ethanone O-methyl-oxime Methoxylamine hydrochloride (2.33 g) is added to a solution of 3'-(trifluoromethyl) 5 acetophenone (1.5 g) in ethanol (20 mL) and pyridine (2 mL). The solution is heated at reflux for 45 minutes. The reaction mixture is then cooled, concentrated under reduced pressure and partitioned between water and ethyl acetate. The aqueous layer is extracted with ethyl acetate. The combined organic layers are washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and 10 concentrated under reduced pressure to give the desired product as a colorless oil (1.61 g). Using the above procedure and appropriate starting materials the following compounds were prepared: 15 3,5-Bis-trifluoromethyl-benzaldehyde oxime 1-(4-Fluoro-phenyl)-propan- 1-one 0-methyl-oxime 1-(2-Chloro-phenyl)-ethanone 0-methyl-oxime 1-(3-Bromo-phenyl)-ethanone 0-methyl-oxime 20 1-(3-Chloro-phenyl)-ethanone 0-methyl-oxime 1-p-Tolyl-ethanone 0-methyl-oxime 1-(4-Fluoro-phenyl)-pentan- 1-one 0-methyl-oxime 1-(4-Fluoro-phenyl)-2-phenyl-ethanone 0-methyl-oxime 1-o-Tolyl-ethanone 0-methyl-oxime 25 1-m-Tolyl-ethanone 0-methyl-oxime 1-(2-Fluoro-phenyl)-ethanone 0-methyl-oxime 3-(1-Methoxyimino-ethyl)-benzonitrile 4-(1 -Methoxyimino-ethyl)-benzonitrile 1-(4-Methoxy-phenyl)-ethanone 0-methyl-oxime 30 1-(2-Methoxy-phenyl)-ethanone 0-methyl-oxime 1-(4-Dimethylamino-phenyl)-ethanone 0-methyl-oxime 1-(2-Trifluoromethyl-phenyl)-ethanone 0-methyl-oxime 1-(3-Methoxy-phenyl)-ethanone 0-methyl-oxime WO 00/34258 PCT/US99/28842 - 92 1- (3-Trifluoromethyl-phenyl)-ethanone 0-methyl-oxime 1 -(4-Trifluoromethyl-phenyl)-ethanone 0-methyl-oxime 1 -Furan-2-yl-ethanone 0-methyl-oxime 1 -Pyridin-4-yl-ethanone 0-methyl-oxime 5 1 -(1-Methyl-i H-pyrrol-2-yl)-ethanone 0-methyl-oxime 1 -Thiophen-3-yl-ethanone 0-methyl-oxime (4-Fluoro-phenyl)-phenyl-methanone 0-methyl-oxime 1 -(4-methoxyphenyl)ethanone 0-methyloxime 1 -(3-Chloro-4-methoxy-phenyl)-ethanone 0-methyl-oxime 10 4- (1 -Methoxyimino-ethyl)-benzenesulfonamide 4- (1-Methoxyimino-ethyl)-N,N-dimethyl-benzenesulfonamide 1- [4-(Piperidine-l1-sulfonyl)-phenyl]l-ethanone 0-methyl-oxime 4-(l1 -Methoxyimino-ethyl)-N,N-dipropyl-benzenesulfonamide 2-Fluoro-N-[14- (1-methoxyimino-ethyl)-phenylj -benzamide 15 1- (3 ,5-Bis-trifluoromethyl-phenyl)-ethanone 0-methyl-oxime 1- [4-( 1H-Imidazol- 1-yl)phenyl] -1-ethanone, 0-methyloxime 1 -14-(Trifluoromethyl)phenyl]-l1-ethanone, 0-methyloxime 1-Li, 1 -Biphenyl] -4-yl-l -ethanone, 0-methyloxime 1- (4-Methyiphenyl)-l1-ethanone, 0-methyloxime 20 1 -[4-fluoro-3-(trifluoromethyl)phenyllethanone 0-methyloxime 1 -13,5-bis(trifluoromethyl)phenyl]ethanone O-benzyloxime I -[4-chloro-3-(trifluoromethyl)phenyllethanone 0-methyloxime 1- [3-fluoro-5- (trifluoromethyl)phenyl] ethanone 0-methyloxime 1 -[2-fluoro-4-(trifluoromethyl)phenyllethanone 0-methyloxime 25 1 -12-fluoro-5-(trifluoromethyl)phenyl]ethanone 0-methyloxime 1 -(2,4-dichlorophenyl)ethanone 0-methyloxime 1 -(2,4-dimethylphenyl)ethanone 0-methyloxime 1- [2,4-bis(trifluoromethyl)phenyl] ethanone 0-methyloxime 1 -(3-bromophenyl)ethanone 0-methyloxime 30 1 -(3-methylphenyl)ethanone 0-methyloxime 1- [4- (4-morpholinyl)phenyl] ethanone 0-methyloxime 1- (2-chloro-4-fluorophenyl)ethanone 0-methyloxime 1 -(4-bromo-2-fluorophenyl)ethanone 0-methyloxime WO 00/34258 PCT/US99/28842 - 93 1-(3,4-difluorophenyl)ethanone 0-methyloxime 1-[3-(trifluoromethyl)phenyl]ethanone 0-methyloxime 1-[2-(trifluoromethyl)phenyl]ethanone 0-methyloxime 1-(2,4-difluorophenyl)ethanone 0-methyloxime 5 1-[3-fluoro-4-(trifluoromethyl)phenyl]ethanone 0-methyloxime 1-(3,4-dichlorophenyl)ethanone 0-methyloxime 1-[4-fluoro-2-(trifluoromethyl)phenylethanone 0-methyloxime 1-(3-chloro-4-fluorophenyl)ethanone 0-methyloxime 1-(4-chloro-3-fluorophenyl)ethanone 0-methyloxime 10 1-(2,5-difluorophenyl)ethanone 0-methyloxime 1-(2-bromo-4-fluorophenyl)ethanone 0-methyloxime 1-(3,4-dibromophenyl)ethanone 0-methyloxime 1-(2-bromophenyl)ethanone 0-methyloxime 15 EXAMPLE 72 (METHOD 48) 1-(2-Trifluoromethyl-phenyl)-ethylamine Sodium borohydride (1.17 g) is added slowly to a flask containing zirconium tetrachloride (1.8 g) in tetrahydrofuran (27 mL). A solution of 1-(2-trifluoromethyl 20 phenyl)-ethanone 0-methyl-oxime (1.34 g) in tetrahydrofuran (7.7 mL) is added and the resulting solution is stirred at 25 0 C for 12 hours. The reaction mixture is then cooled to 0 'C and water (16 mL) is slowly added. Excess ammonium hydroxide is added and the solution is extracted twice with ethyl acetate. The organic portion is washed twice with 1N hydrochloric acid. The aqueous (acid) layer is basified with 25 sodium hydroxide and extracted twice with ethyl acetate. The organic layer is then washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is removed under reduced pressure to provide the desired product as a yellow oil (0.20 g). 30 Using the above procedure and appropriate starting materials the following compounds were prepared: WO 00/34258 PCT/US99/28842 - 94 1-(3-Methoxy-phenyl)-ethylamine 1-(4-Fluoro-phenyl)-propylamine 1 -Naphthalen-2-yl-ethylamine 4-(1 -Amino-ethyl)-benzonitrile 5 1-(4-Trifluoromethyl-phenyl)-ethylamine 1-(4-Methoxy-phenyl)-ethylamine 1 -Prop-2-ynyl-pyrrolidine 1-(2-Methoxy-phenyl)-ethylamine 1 -m-Tolyl-ethylamine 10 1-(2-Bromo-phenyl)-ethylamine 1-o-Tolyl-ethylamine C-(4-Fluoro-phenyl)-C-phenyl-methylamine 1-(4-Fluoro-phenyl)-pentylamine 1-(4-Fluoro-phenyl)-2-phenyl-ethylamine 15 1-(2-Trifluoromethyl-phenyl)-ethylamine 1-(3-Bromo-phenyl)-ethylamine 1-(3-Chloro-phenyl)-ethylamine [4-(1-Amino-ethyl)-phenyl]-dimethyl-amine 1-(1-Methyl- 1H-pyrrol-2-yl)-ethylamine 20 1-Thiophen-3-yl-ethylamine 1-[3,5-bis(trifluoromethyl)phenyl]propylamine 1-[3,5-bis(trifluoromethyl)phenyl]-1-butanamine or 1-[3,5 bis(trifluoromethyl)phenyl]butylamine 1-[3,5-bis(trifluoromethyl)phenyl]-1-pentanamine 25 1-(4-methylphenyl)ethanamine 1-[3-(trifluoromethyl)phenyl]ethylamine 1-[4-(trifluoromethyl)phenyl]ethylamine 1-(3-methylphenyl)ethanamine 1-(3,4-dichlorophenyl)ethanamine 30 1-(2-Bromo-phenyl)-ethylamine 1-(2-Trifluoromethyl-phenyl)-ethylamine 1-(3-Bromo-phenyl)-ethylamine 1-(3-Chloro-4-methoxy-phenyl)-ethylamine WO 00/34258 PCT/US99/28842 - 95 4-(1 -Amino-ethyl)-N,N-dimethyl-benzenesulfonamide 1-[4-(Piperidine- 1 -sulfonyl)-phenyl]-ethylamine 1 -Quinolin-6-yl-ethylamine 1-(3,5-Bis-trifluoromethyl-phenyl)-ethylamine 5 4- [(1 S)- 1-aminoethyl]benzonitrile (S)-alpha-Methyl-3,5-bis(trifluoromethyl)-benzenemethanamine(S)-alpha-Methyl 3,5-bis(trifluoromethyl)-benzenemethanamine 1 -Biphenyl-4-yl-ethylamine 1-(4-Fluoro-phenyl)-ethylamine 10 1- [4-fluoro-3-(trifluoromethyl)phenyl]ethanamine 1-[4-chloro-3-(trifluoromethyl)phenyl]ethanamine N- {4- [(1R)- 1 -aminoethyl]phenyl }-1,2,3-thiadiazole-4-carboxamide N- {4- [(1 S)- 1 -aminoethyl]phenyl} -1,2,3-thiadiazole-4-carboxamide 1-[3-fluoro-5-(trifluoromethyl)phenyl]ethylamine 15 1-[2-fluoro-4-(trifluoromethyl)phenyl]ethylamine 1- [2-fluoro-5-(trifluoromethyl)phenyl]ethylamine 1-(2,4-dichlorophenyl)ethylamine 1-(2,4-dimethylphenyl)ethylamine 1-[2,4-bis(trifluoromethyl)phenyl]ethylamine 20 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 25 1-[3-fluoro-4-(trifluoromethyl)phenyl]ethylamine 1- [4-fluoro-2-(trifluoromethyl)phenyl]ethylamine 1-(3-chloro-4-fluorophenyl)ethylamine 1-(4-chloro-3-fluorophenyl)ethylamine 1-(3,4-dibromophenyl)ethylamine 30 1-(2-bromo-4-fluorophenyl)ethanamine1 -(2-bromo-4-fluorophenyl)ethylamine WO 00/34258 PCT/US99/28842 - 96 EXAMPLE 73 (METHOD 49) (2-Fluoro-5-trifluoromethyl-phenoxy)-acetonitrile A solution of 2-fluoro-5-trifluoromethylphenol (25 g) in reagent grade acetone (0.55 5 L) is treated with solid potassium carbonate (7.7 g) followed by the rapid addition of neat bromoacetonitrile (10 mL). The heterogenous mixture is stirred vigorously for approximately 20 hours whereupon it is poured into water and extracted into diethyl ether. The combined ether extracts are washed with saturated sodium chloride and dried over anhydrous potassium carbonate. Filtration and concen-tration under 10 reduced pressure gives a pale orange solid which is then chromatographed on silica gel, eluting with dichloromethane, to give the desired product as white solid (28.3 g). Using the above procedure and appropriate starting materials the following compounds were prepared: 15 (3-Bromo-phenylsulfanyl)-acetonitrile (3-Chloro-phenylsulfanyl)-acetonitrile (4-Iodo-phenoxy)-acetonitrile (3-Trifluoromethyl-phenylsulfanyl)-acetonitrile 20 (3,5-Dichloro-phenylsulfanyl)-acetonitrile (3,4-Dichloro-phenylsulfanyl)-acetonitrile (3,4-Dichloro-phenoxy)-acetonitrile (2-Fluoro-phenoxy)-acetonitrile (3-Fluoro-phenoxy)-acetonitrile 25 (2-Chloro-phenoxy)-acetonitrile (3-Bromo-phenoxy)-acetonitrile (2-Fluoro-5-trifluoromethyl-phenoxy)-acetonitrile (3-Iodo-phenoxy)-acetonitrile (4-Bromo-phenoxy)-acetonitrile 30 WO 00/34258 PCT/US99/28842 - 97 EXAMPLE 74 (METHOD 50) 3-Fluoro-5-trifluoromethylphenethylamine tosylate A solution of 2.5 g of 3-fluoro-5-trifluoromethylphenylacetonitrile and 2.34 g (12.3 5 mmol) of p-toluenesulfonic acid in 75 ml of ethylene glycol monomethyl ether is hydrogenated for 3 hours at room temperature at 40 psi, using 200 mg 10% palladium on carbon catalyst. The catalyst is filtered off and the solvent evaporated to half the volume. Upon standing, the p-toluenesulfonic acid salt of the desired 3 fluoro-5-trifluoromethylphenethylamine crystallizes. The white crystals, 4.26g (91%) 10 are collected by filtration. Using the above procedure and appropriate starting materials the following compounds were prepared: 15 2-(3,5-Difluoro-phenyl)-ethylamine 2-(4-Trifluoromethyl-phenyl)-ethylamine 2-(3,4-Difluoro-phenyl)-ethylamine 2-(2-Fluoro-phenyl)-ethylamine 2-(3-Fluoro-5-trifluoromethyl-phenyl)-ethylamine 20 2-(2-Fluoro-3-trifluoromethyl-phenyl)-ethylamine 2-(2,4-Bis-trifluoromethyl-phenyl)-ethylamine 2-(4-Fluoro-3-trifluoromethyl-phenyl)-ethylamine EXAMPLE 75 (METHOD 51) 25 (4-Aminomethyl-2-trifluoromethyl-phenyl)-dimethyl-amine A solution of 4-dimethylamino-3-trifluoromethylbenzonitrile (0.35 g) in tetrahydrofuran (2 mL) is slowly added to a suspension of lithium aluminum hydride (0.1 g) in tetrahydrofuran (2 mL) at 0 'C and stirred under an atmosphere of argon 30 for 2 hours. While at 0 'C water (0.1 mL) is slowly added followed by 5% sodium hydroxide (0.1 mL) and water (0.3 mL). The resulting gray solid is filtered and washed with tetrahydrofuran. The filtrates are collected and concentrated under WO 00/34258 PCT/US99/28842 - 98 reduced pressure and the resulting oil is chromatographed over silica gel (15% methanol in methylene chloride is used as the eluant) to provide the desired product as a pale orange oil (0.164 g). 5 Using the above procedure and appropriate starting materials the following compounds were prepared: 4-Piperidin- 1 -yl-3-trifluoromethyl-benzylamine (4-Aminomethyl-2-trifluoromethyl-phenyl)-dimethyl-amine 10 4-(4-Methyl-piperazin- 1 -yl)-3-trifluoromethyl-benzylamine (3-Aminomethyl-5-trifluoromethyl-phenyl)-dimethyl-amine [3-(2-Amino-ethyl)-5-trifluoromethyl-phenyl]-dimethyl-amine [4-(2-Amino-ethyl)-2-methyl-phenyl]-dimethyl-amine 15 EXAMPLE 76 (METHOD 52) 3-Dimethylamino-5-trifluoromethyl-benzaldehyde Diisobutylaluminum hydride (10 mL of a IM solution in methylene chloride) is added dropwise to a solution of 3-dimethylamino-5-trifluoromethylbenzonitrile (1.06 20 g) in methylene chloride (25 mL) at 0 'C and the mixture stirred for 2 hours. While still at 0 'C a saturated aqueous solution of sodium potassium tartrate (8 mL) is slowly added and the solution is stirred for 1.5 hours. The reaction mixture is then extracted with ethyl acetate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide the desired product as a yellow solid 25 (0.97 g). Using the above procedure and appropriate starting materials the following compounds were prepared: 30 3-Dimethylamino-5-trifluoromethyl-benzaldehyde 4-Dimethylamino-3-methyl-benzaldehyde WO 00/34258 PCT/US99/28842 - 99 EXAMPLE 77 (METHOD 53) Dimethyl-[3-(2-nitro-vinyl)-5-trifluoromethyl-phenyl]-amine Nitromethane (0.473 g) is added to a solution of 3-dimethylamino-5-trifluoromethyl 5 benzaldehyde (0.885 g) and ammonium acetate (0.339 g) in acetic acid (3.4 mL) and the solution is heated at 110 'C for 6 hours. The reaction mixture is cooled to 0 'C and a solid forms which is filtered and washed with 1:1 water-acetic acid. This solid is recrystallized from ethanol to provide the desired product as a red solid (0.39 g). 10 Using the above procedure and appropriate starting materials the following compounds were prepared: Dimethyl-[3-(2-nitro-vinyl)-5-trifluoromethyl-phenyl]-amine Dimethyl-[2-methyl-4-(2-nitro-vinyl)-phenyl]-amine 15 EXAMPLE 78 (METHOD 54) 3-(4-Bromo-phenyl)-propionitrile Diethylazodicarboxylate (5.2 g) is added dropwise to a solution of 4-bromo 20 phenethylalcohol (2.01 g), and triphenylphosphine (7.9 g) in diethyl ether (16 mL) at 0 'C. The reaction mixture is stirred for 10 minutes and a solution of acetone cyanohydrin (2.6 g) in diethyl ether (10 mL) is added. The clear orange solution is stirred for 5 minutes at 0 'C and then at 25 'C for 12 hours. The reaction mixture is then filtered, and washed with diethyl ether. The filtrate is concentrated under 25 reduced pressure and chromatographed over silica gel (10% ethyl acetate-hexanes is used as the eluant) to provide the desired product as a pale yellow oil (2.04 g). EXAMPLE 79 (METHOD 55) 3-Dimethylamino-2-isocyano-acrylic acid ethyl ester 30 To a solution of ethyl isocyanoacetate (5.0 g) in ethanol (100 mL) is added N,N dimethyl-formamide dimethyl acetal (6.5 g) dropwise with stirring over 10 minutes.

WO 00/34258 PCT/US99/28842 - 100 The reaction is stirred for 24 hours and the ethanol is evaporated. The resulting oil is passed through magnesium silicate using 50% ethyl acetate-hexanes as the eluant. The solvents are removed and the resulting oil is crystallized from ethyl acetate hexanes to yield light yellow needles, 3.0 g. 5 EXAMPLE 80 (METHOD 56) 4-Carboethoxythiazole A solution of 3-dimethylamino-2-isocyano-acrylic acid ethyl ester (1.0 g) and 10 triethylamine (3.0 g) in tetrahydrofuran (30 mL) is treated with gaseous hydrogen sulfide until all starting material is consumed. The mixture is concentrated to an oil and purified by column chromatography using silica and 25% ethyl acetate-hexanes as the eluant. The purified material (0.61 g) is isolated as an oil. 15 EXAMPLE 81 (METHOD 34) N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-ureido]-phenyl} 2-fluoro-benzamide A suspension of N-(4-amino-phenyl)-2-fluoro-benzamide (0.43 g) in acetonitrile (4 20 mL) is treated with 5-chloro-2,4-dimethoxyphenylisocyanate (0.40 g). The mixture becomes a solution and is allowed to stand for 12 hours. A white solid forms and is collected by filtration (0.79 g). [M+H] 444. Using the above procedure and appropriate starting materials the following 25 compounds were prepared: EX M+H COMPOUND NAME NO. 81 445 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-ureido]-phenyl}-2-fluoro-benzamide 82 441 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-ureido]-phenyl}-2-methyl-benzamide 83 435 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-ureido] phenyl}-amide 84 443 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-chloro-3-trifluoromethyl-phenyl) ureido]-phenyl} amide WO 00/34258 PCT/US99/28842 - 101 85 453 N-{4-[3-(4-Chloro-3-trifluoromethyl-phenyl)-ureido]-phenyl}-2-fluoro-benzamide 86 409 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-dichloro-phenyl)-ureido]-phenyl} amide 87 486 N-{4-[3-(3,5-Bis-trifluoromethyl-phenyl)-ureido]-phenyl}-2-fluoro-benzamide 88 458 Furan-2-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl-phenyl)-ureido]-phenyl}-amide 89 476 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl-phenyl)-ureido] phenyl}-anide 90 423 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,4-dichloro-benzyl)-ureido]-phenyl} amide EXAMPLE 91 (METHOD 31) N-(5-{[({(iS)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}amino) 5 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)-alpha-methyl-3,5-bis(trifluoromethyl)-benzenemethanamine (0.36 g) is heated with acetonitrile (10 mL) until all solids are dissolved. The solution is allowed 10 to stand for 12 hours. A white solid forms and is collected by filtration (0.40 g). [M+H] 520. Using the above procedure and appropriate starting materials the following compounds were prepared: 15 EX. M+H COMPOUND NAME NO. 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-dimethoxy-phenyl)-3-(4-morpholin-4-yl-phenyl)-thiourea 94 370 1-(5-Chloro-2,4-dimethoxy-phenyl)-3-(4-methylsulfanyl-phenyl)-thiourea 95 338 1-(5-Chloro-2,4-dimethoxy-phenyl)-3-p-tolyl-thiourea 96 414 {4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenylsulfanyl}-acetic acid 97 384 1-(5-Chloro-2,4-dimethoxy-phenyl)-3-[4-(2-hydroxy-ethoxy)-phenyl] thiourea WO 00/34258 PCT/US99/28842 - 102 98 340 1-(5-Chloro-2,4-dimethoxy-phenyl)-3-(4-hydroxy-phenyl)-thiourea 99 395 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-N-methyl acetamide 100 381 N-{3-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-acetamide 101 411 {4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-carbamic acid ethyl ester 102 319 1-(2,4-Dimethoxy-phenyl)-3-(4-methoxy-phenyl)-thiourea 103 346 N-{4-[3-(2,4-Dimethoxy-phenyl)-thioureido]-phenyl}-acetamide 104 316 N-{4-[3-(4-Methoxy-phenyl)-thioureido]-phenyl}-acetamide 105 316 N-{4-[3-(2-Methoxy-phenyl)-thioureido]-phenyl}-acetamide 106 351 N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl}-acetamide 107 351 N-{4-[3-(5-Chloro-2-methoxy-phenyl)-thioureido]-phenyl}-acetamide 108 371 N-{4-[3-(3,5-Dichloro-4-hydroxy-phenyl)-thioureido]-phenyl}-acetamide 109 385 N-{4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]-phenyl}-acetamide 110 381 N-{4-[3-(4-Chloro-2,5-dimethoxy-phenyl)-thioureido]-phenyl}-acetamide 111 389 N-{4-[3-(2-Chloro-5-trifluoromethyl-phenyl)-thioureido]-phenyl} acetamide 112 389 N-{4-[3-(4-Chloro-3-trifluoromethyl-phenyl)-thioureido]-phenyl} acetamide 113 422 Benzoic acid 4-[3-(4-acetylamino-phenyl)-thioureidoj-3-hydroxy phenylester 114 457 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-methyl benzamide 115 501 Acetic acid 2-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl carbainoyl }-phenyl ester 116 461 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-4-fluoro benzamide 117 461 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3-fluoro benzamide 118 461 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-fluoro benzamide 119 473 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-methoxy benzamide 120 473 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3-methoxy benzanide 121 473 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-4-methoxy- WO 00/34258 PCT/US99/28842 - 103 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]-pheny } -methane sulfonamide 124 331 N-{4-[3-(3-Nitro-phenyl)-thioureido]-phenyl}-acetamide 125 339 1-( 3 -Chloro-4-methoxy-phenyl)-3-(3-nitro-phenyl)-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-methyl-phenyl)-thioureido]-phenyl} acetamide 130 318 N-{ 4

-[

3

-(

2

.

4 -Dihydroxy-phenyl)-thioureido]-phenyl}-acetamide 131 414 N-{ 4

-[

3

-(

2

,

4 -Dimethoxy-5-trifluoromethyl-phenyl)-thioureido]-phenyl} acetamide 132 332 N-{ 4

-[

3

-(

2 -Hydroxy-4-methoxy-phenyl)-thioureido]-phenyl}-acetamide 133 465 N-{ 4

-[

3 -(3,5-Dichloro-4-methoxy-phenyl)-thioureido]-phenyl}-4-fluoro benzamide 134 500 3 -Acetylamino-N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido] phenyl)-benzamide 135 488 N-f{ 4 -[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3-nitro benzamide 136 486 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3 dimethylamino-benzanide 137 536 N-{ 4

-[

3

-(

5 -Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3-methane sulfony-amino-benzamide 138 511 N-f{ 4

-[

3

-(

5 -Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-trifluoro methyl-benzamide 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-dimethoxy-phenyl)-thioureido]-phenyl} benzamide WO 00/34258 PCT/US99/28842 - 104 143 488 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-nitro benzamide 144 445 Pyrazine-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl) 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-dimethoxy-phenyl) thioureidol-phenyl } -amide 147 446 1-Methyl-iH-pyrrole-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy phenyl)-thioureido]-phenyl}-amide 148 369 1-(5-Chloro-2,4-dimethoxy-phenyl)-3-(2-nitro-phenyl)-thiourea 149 369 1-(5-Chloro-2,4-dimethoxy-phenyl)-3-(4-nitro-phenyl)-thiourea 150 425 N-{4-[3-(5-Bromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-acetamide 151 376 N-{4-[3-(3,4,5-Trimethoxy-phenyl)-thioureido]-phenyl}-acetanide 152 399 N-{4-[3-(3,5-Dichloro-2-methoxy-4-methyl-phenyl)- thioureido]-phenyl} acetamide 153 499 Benzo[b]thiophene-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy phenyl)-thioureido]-phenyl}-amide 154 483 Benzofuran-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl) thioureido]-phenyl}-amide 155 444 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl} isonicotinamide 156 493 Naphthalene-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl) thioureido]-phenyl}-ainide 157 493 Naphthalene-1-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl) thioureido]- phenyl}-amide 158 494 Isoquinoline-1-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl) thioureido]-phenyl}-amide 159 494 Quinoline-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl) thioureido]-phenyl}-ainide 160 444 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl} nicotinamide 161 478 5-Nitro-furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl) thioureido]-phenyl}-amidecarbamic acid phenyl ester 162 459 {4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl} 163 467 5-Chloro-furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl) thioureido]-phenyl}-anide WO 00/34258 PCT/US99/28842 - 105 164 439 {4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-carbamic acid isobutyl ester 165 397 {4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-carbamic acid methyl ester 166 433 Furan-3-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl) thioureido]-phenyl}-amide 167 447 3-Methyl-furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl) thioureidol-phenyl } -amide 168 512 5-Bromo-furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl) thioureido]-phenyl } -amide 169 512 4-Bromo-furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl) thioureidol-phenyl}-amide 170 433 Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl) thioureido]-phenyl }-amide 171 467 {4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-carbamic acid hexyl ester 172 494 Isoquinoline-4-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl) thioureido]-phenyl}-amide 173 451 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy phenyl)-thioureido]-phenyl}-amide 174 434 1H-[1,2,3]Triazole-4-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy phenyl)- thioureido]-phenyl}-amide 175 528 3-Bromo-thiophene-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy phenyl)- thioureido]-phenyl}-amide 176 399 N-{4-[3-(3,5-Dichloro-4-ethoxy-phenyl)-thioureido]-phenyl}-acetamide 177 427 N-{4-[3-(4-Butoxy-3,5-dichloro-phenyl)-thioureido]-phenyl}-acetamide 178 461 N-{4-[3-(4-Benzyloxy-3,5-dichloro-phenyl)-thioureido]-phenyl} acetamide 179 381 N-{4-[3-(3-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-acetamide 180 530 (3-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenylcarbamoyl} phenyl)-carbamic acid ethyl ester 181 458 2-Amino-N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl} benzamide 182 519 Biphenyl-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl) thioureido]-phenyl}-amide 183 469 1-(5-Chloro-2,4-dimethoxy-phenyl)-3-[4-(1,3-dioxo-1,3-dihydro isoindol-2-yl)-phenyl]-thiourea 184 487 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}- WO 00/34258 PCT/US99/28842 - 106 phthalamic acid 185 473 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2 hydroxy-methyl-benzamide 186 479 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2,3 difluoro-benzamide 187 479 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2,5 difluoro-benzamide 188 479 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2,4 difluoro-benzamide 189 500 2-Acetylamino-N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido] phenyl)-benzamide 190 441 1-(5-Chloro-2,4-dimethoxy-phenyl)-3-(6-oxo-5,6-dihydro phenanthridin-2-yl)-thiourea 191 536 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl} -2 methane-sulfonylamino-benzainide 192 497 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2,3,4 trifluoro-benzamide 193 533 N-{4-[3-(5-cloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl} 2,3,4,5,6-pentafluoro-benzamide 194 489 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2 methyl-sulfanyl-benzamide 195 431 5-Methyl-furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy phenyl)- ureido]-phenyl}-amide 196 467 5-Difluoromethyl-furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy phenyl)-ureido]-phenyl}-amide 197 472 N-{4-[3-(5-Iodo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-acetamide 198 364 N-{4-[3-(5-Fluoro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-acetamide 199 365 N-{4-[3-(5-Chloro-2-methoxy-4-methyl-phenyl)-thioureido]-phenyl} acetamide 200 459 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-chloro-3-trifluoromethyl phenyl)- thioureido]-phenyl}-anide 201 455 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-dichloro-4-methoxy phenyl)- thioureido]-phenyl}-anide 202 392 N-{4-[3-(3-Chloro-4-diethylamino-phenyl)-thioureido-phenyl}-acetamide 203 432 N-(4-{3-[3-Chloro-4-(cyclohexyl-methyl-amino)-phenyl]-thioureido} phenyl)- acetamide 204 506 1-Hydroxy-naphthalene-2-carboxylic acid {4-[3-(4-acetylanino-phenyl) thioureido]-2-chloro-phenyl}-amide WO 00/34258 PCT/US99/28842 - 107 205 406 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-yl-phenyl) thiourea 207 372 1-(5-Chloro-2,4-dimethoxy-phenyl)-3-(5-chloro-2-methyl-phenyl)-thiourea 208 501 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-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-dimethoxy-phenyl)-thioureido] phenyl}-benzamide 211 434 N-(4-{3-[5-Chloro-2-methoxy-4-(4-nitrilo-butoxy)-phenyl]-thioureido} phenyl)-acetamide 212 406 N-(4-{3-[5-Chloro-2-methoxy-4-(2-nitrilo-ethoxy)-phenyl]-thioureido} phenyl)-acetamide 213 406 N-(4-{3-[5-Chloro-4-methoxy-2-(2-nitrilo-ethoxy)-phenyl]-thioureido} phenyl)-acetamide 214 411 N-(4-{3-[5-Chloro-2-(2-hydroxy-ethoxy)-4-methoxy-phenyl]-thioureido} phenyl)-acetamide 215 411 N-(4-{3-[5-Chloro-4-(2-hydroxy-ethoxy)-2-methoxy-phenyl]-thioureido} phenyl)-acetamide 216 481 {4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-5-methoxy-phenoxy} acetic acid tert-butyl ester 217 439 {4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-5-methoxy-phenoxy} acetic acid methyl ester 218 481 { 2-[3-(4-Acetylamino-phenyl)-thioureido]-4-chloro-5-methoxy-phenoxy} acetic acid tert-butyl ester 219 515 3-Butoxy-N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl} benzamide 220 505 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-methane sulfinyl-benzanide 221 545 (3-{4-[3-(5-Chloro-2,4-diinethoxy-phenyl)-thioureido]-phenylcarbamoyl} phenoxy)-acetic acid ethyl ester 222 517 (3-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenylcarbamoyl} phenoxy)-acetic acid 223 367 N-{4-[3-(5-Chloro-4-hydroxy-2-methoxy-phenyl)-thioureido]-phenyl} acetamide 224 444 Pyridine-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)- WO 00/34258 PCT/US99/28842 - 108 thioureido]- phenyl}-amide 225 494 Quinoline-4-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl) thioureido]- phenyl } -amide 226 436 N-{4-[3-(5-Chloro-4-methoxy-2-morpholin-4-yl-phenyl)-thioureido] phenyl}-acetamide 227 394 N-{4-[3-(5-Chloro-2-dimethylamino-4-methoxy-phenyl)-thioureido] phenyl}-acetamide 228 420 N-{4-[3-(5-Chloro-4-methoxy-2-pyrrolidin-1-yl-phenyl)-thioureido] phenyl}-acetamide 229 434 N-{4-[3-(5-Chloro-4-methoxy-2-piperidin-1 -yl-phenyl)-thioureido] phenyl}-acetamide 230 405 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-4-methyl-phenyl) thioureidol-phenyl } -amide 231 415 N- {4-[3-(3-Chloro-4-methyl-phenyl)-thioureido]-phenyl }-2-fluoro benzamide 232 427 N-{4-[3-(3-Chloro-4-methyl-phenyl)-thioureido]-phenyl}-3-methoxy benzamide 233 387 Furan-2-carboxylic acid {4-[3-(3-chloro-4-methyl-phenyl)-thioureido] phenyl}-amide 234 411 N-{4-[3-(3-Chloro-4-methyl-phenyl)-thioureido]-phenyl}-2-methyl benzamide 235 433 N-{4-[3-(3-Chloro-4-methyl-phenyl)-thioureido]-phenyl}-2,6-difluoro benzamide 236 398 Pyridine-2-carboxylic acid {4-[3-(3-chloro-4-methyl-phenyl)-thioureido] phenyl}-amide 237 502 [1,2,3]Thiadiazole-4-carboxylic acid (4-{ 3-[3-chloro-4-(cyclohexyl methyl-amino)-phenyl]-thioureido}-phenyl)-amide 238 512 N-(4-{3-[3-Chloro-4-(cyclohexyl-methyl-anino)-phenyl]-thioureido} phenyl)- 2-fluoro-benzamide 239 404 N-{4-[3-(3-Chloro-4-piperidin-1-yl-phenyl)-thioureido]-phenyl}-acetamide 240 364 N-{4-[3-(3-Chloro-4-dimethylamino-phenyl)-thioureido]-phenyl} acetamide 241 426 N-{4-[3-(4-Benzylamino-3-chloro-phenyl)-thioureido]-phenyl}-acetamide 242 390 N-{4-[3-(3-Chloro-4-pyrrolidin-1-yl-phenyl)-thioureido]-phenyl} acetamide 243 419 N-(4-{3-[3-Chloro-4-(4-methyl-piperazin-1 -yl)-phenyl]-thioureido} phenyl)-acetamide 244 469 N-{4-[3-(4-Chloro-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-2- WO 00/34258 PCT/US99/28842 - 109 fluoro-benzamide 245 422 N-{4-[3-(2-Benzylamino-4-methoxy-phenyl)-thioureido]-phenyl} acetamide 246 484 Furan-2-carboxylic acid (4-{ 3 -[3-chloro-4-(cyclohexyl-methyl-amino) phenyl]-thioureido}-phenyl)-amide 247 508 N-(4-{3-[3-Chloro-4-(cyclohexyl-methyl-amino)-phenyl]-thioureido} phenyl)-2-methyl-benzamide 248 530 N-(4-{3-[3-Chloro-4-(cyclohexyl-methyl-amino)-phenyl]-thioureido} phenyl)-2,6-difluoro-benzamide 249 495 Pyridine-2-carboxylic acid (4-{ 3 -[3-chloro-4-(cyclohexyl-methyl-amino) phenyl]-thioureido}-phenyl)- amide 250 524 N-(4-{3-[3-Chloro-4-(cyclohexyl-methyl-amino)-phenyl]-thioureido} phenyl)-3-methoxy-benzamide 251 376 N-(4-{3-[3-Chloro-4-(2-nitrilo-ethoxy)-phenyl]-thioureido}-phenyl) acetamide 252 393 N-{4-[3-(4-sec-Butoxy-3-chloro-phenyl)-thioureido]-phenyl}-acetamide 253 501 Acetic acid 3-{ 4 -[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl carbamoyl}-phenyl ester 254 459 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3-hydroxy benzamide 255 487 Benzo[1,3]dioxole-4-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy phenyl)-thioureido]-phenyl}-amide 256 527 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3-trifluoro methoxy-benzamide 257 530 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3-(2 dimethylamino-ethoxy)-benzamide 258 572 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3-(2 morpholin-4-yl-ethoxy)-benzamide 259 406 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-cyano-phenyl} acetamide 260 521 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2,5-dimethoxy phenyl}-2-fluoro-benzamide 261 441 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2,5-dimethoxy phenyl}-acetamide 262 527 2

-{

4 -[3-( 4 -Acetylamino-phenyl)-thioureido]-2-chloro-phenoxy}-5-chloro benzenesulfonic acid 263 562 2-{4-[3-(4-Acetylamino-phenyl)-thioureidoj-2-chloro-phenoxy}-4,5 dichloro-benzenesulfonic acid WO 00/34258 PCT/US99/28842 - 110 264 527 4-Phenyl-[1,2,3]thiadiazole-5-carboxylic acid{4-[3-(5-chloro-2,4 dimethoxy-phenyl)-thioureido]-phenyl} -amide 265 381 N-(4-{ 3-[3-Chloro-4-(2-hydroxy-ethoxy)-phenyl]-thioureido}-phenyl) acetamide 266 393 N-{4-[3-(4-Butoxy-3-chloro-phenyl)-thioureido]-phenyl I -acetamide 267 446 N-(4-{3-[3-Chloro-4-(cyclohexyl-ethyl-amino)-phenyl]-thioureido} phenyl)-acetamide 268 365 N-{4-[3-(3-Chloro-4-ethoxy-phenyl)-thioureido]-phenyl } -acetamide 269 427 N-{4-[3-(4-Benzyloxy-3-chloro-phenyl)-thioureido]-phenyl}-acetamide 270 317 {4-[(3-Methyl-furan-2-carbonyl)-amino]-phenyl}-carbamic acidtert-butyl ester 271 456 N-{4-[3-(2-Benzylamino-5-chloro-4-methoxy-phenyl)-thioureido] phenyl}-acetamide 272 420 N-{4-[3-(3-Chloro-4-dipropylamino-phenyl)-thioureido]-phenyl} acetamide 273 458 N-(4-{3-[4-(Allyl-cyclohexyl-amino)-3-chloro-phenyl]-thioureido} phenyl)-acetamide 274 411 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methoxy-phenyl} acetamide 275 415 N-{2-Chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl} acetamide 276 493 Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl) thioureido]-2,5-dimethoxy-phenyl}-ainide 277 486 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-cyano-phenyl}-2 fluoro-benzamide 278 495 N-{2-Chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2 fluoro-benzamide 279 465 5-Methyl-[1,2,3]thiadiazole-4-carboxylic acid{4-[3-(5-chloro-2,4 dimethoxy-phenyl)-thioureido]-phenyl}-amide 280 517 5-Furan-3-yl-[1,2,3]thiadiazole-4-carboxylic acid{4-[3-(5-chloro-2,4 dimethoxy-phenyl)-thioureido]- phenyl amidee 281 527 5-Phenyl-[1,2,3]thiadiazole-4-carboxylic acid{4-[3-(5-chloro-2,4 dimethoxy-phenyl)-thioureido]-phenyl}-amide 282 458 N-(4-{3-[3-Chloro-4-(octahydro-quinolin-1-yl)-phenyl]-thioureido} phenyl)-acetamide 283 458 N-[5-[[[(5-Chloro-2,4-dimethoxyphenyl)amino]thioxomethyl]amino]-2 pyridinyl]-2-methylbenzamide 284 434 Furan-2-carboxylic acid {5-[3-(5-chloro-2,4-dimethoxy-phenyl)- WO 00/34258 PCTIUS99/28842 thioureido]-pyridin-2-yl I}-amide 285 425 N-{4-[3-(5-Ch1oro-2,4-dimethoxy-phel)-tioureido-2-methoxy5 methyl-phenyl I -acetamide 286 505 N- 14-[3 -(5 -Chloro-2,4-dimethoxy-phel)-thioureidoII-2-mehoxy-5 methyl-phenyl I -2-fluoro-benzamide 287 477 Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl) thioureido]-2-methoxy-5-methyl-pheflyl }-amide 288 517 4-Furan-3-yl-[1 ,2,3]thiadiazole-5-carboxylic acid{4-[3-(5-chloro-2,4 dimethoxy-phenyl)-thioureido]-pheflyl }-amide 289 462 N-{ 5-I3-(5-Chloro-2,4-dimethoxy-phenl)-thioureido]-pyridifl 2 -yl }-2 fluoro-benzamide 290 384 N-4[-4Mtoy3tilooety hnl-horio-hnl acetatnide 291 394 N-114-(3-{ Clro4[2hyrx-thl }hy mn]-hnl thioureido)- phenyl]-acetamide 292 485 N-{2-Benzoy1-4-[3-(5-ch1oro-2,4-dimethoxy-pheyl)4hioueidoY-phel} acetamide 293 565 N-12Bnol4[-5cloo24dmtoypeyl horio-hnl 2-fluoro-benzamnide 294 537 Furan-2-carboxylic acid {2-benzoyl-4-[3-(5-chloro-2,4-dimethoxy phenyl)-thioureido]-phenyl}-amfide 295 475 N-{4-[3-(5-Chloro-2,4-dimethoxy-phel)-thioureido]-3-methy1 phenyl}-2-fluoro-benzamide 296 447 Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-pheflyl) thioureido]-3-methyl-phenyl}-amide 297 395 N-{4-[3-(5-Chloro-2,4-dimethoxy-phel)-thioureido]-3-methyl-phel) acetamide 298 435 N-r4-(3-{ 3-Chloro-4-[(3-dimethylainilo-propyl)-methyl-aio]-phel) thioureido)-phenyl]-acetamide 299 418 N-4[-3Clr--ylhxlniopey)tiued]pey} acetamide 300 421 N-[4-(3-{ 3-Chloro-4-[(2-dimethylamfiflo-ethyl)-methyl-amil-phefll thioureido)-phenyl]-acetanide 301 580 5-I[[(5-Chloro-2,4-dimethoxyphel)afifno]thioxomfethy1]amfilo]- 2 [(2-fluorobenzoyl)ainino]-N-phenyl-benzanide 302 552 Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-diunethoxy-phenyl) thioureido]-2-phenylcarbamnoyl-phelyl}-amlide 303 491 N-{4-[3-(5-Ch1oro-2,4-dimethoxy-phel)-thioureidoV-2fethoxy- WO 00/34258 PCT/US99/28842 - 112 phenyl}I-2-fluoro-benzamnide 304 463 Furan-2-carboxylic acid {4-13-(5-chloro-2,4-dimethoxy-phenyl) thioureido]- 2-methoxy-phenyl I -amide 305 449 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureidoJ-2 trifluoromethyl-phenyl I -acetamide 306 458 Furan-2-carboxylic acid {4-13-(5-chloro-2,4-dimethoxy-phenyl) thioureido]- 2-cyano-phenyl I -amide 307 467 Furan-2-carboxylic acid { 2-chloro-4-[3-(5-chloro-2,4-dimethoxy phenyl)- thioureido]-phenyll}-amide 308 501 Furan-2-carboxylic acid { 4-13-(5-chloro-2,4-dimethoxy-phenyl) thioureido]- 2-trifluoromethyl-phenyl) -ainide 309 395 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methyl phenyl}-acetamide 310 475 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methyl phenyl }-2-fluoro-benzamnide 311 447 Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl) thioureido]-2-methyl-phenyl}-amnide 312 378 N-{ 4-13-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl} acetamide 313 408 {4-13-(4-Acetylamnino-phenyl)-thioureido]-2-chloro-phenyl} carbamnic acid ethyl ester 314 382 N-{ 5-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-2-yl

}

acetamnide 315 509 N-(4-{ 3-[4-(1 -Benzyl-piperndin-4-ylainino)-3-chloro-phenyl] thioureido}-phenyl)-acetamnide 316 407 N-(4-{ 3-[3-Chloro-4-(2-dimethylamino-ethylamino)-phenyll thioureido}-phenyl)-acetainide 317 408 N-[4-(3-{ 3-Chloro-4-[(2-methoxy-ethyl)-methyl-amnino]-phenyl} thioureido)-phenyl]-acetamide 318 421 N-(4-{ 3-13-Chloro-4-(3-dimethylamnino-propylamino)-phenyl] thioureido}-phenyl)-acetamide 319 495 N-(4-1{3-[4-(1 -Benzyl-pyrrolidin-3-ylamnino)-3-chloro-phenyl] thioureido}-phenyl)-acetamide 320 483 Furan-2-carboxylic acid { 5-chloro-4-13-(5-chloro-2,4-dimethoxy phenyl)- thioureido]-2-hydroxy-phenyl }-amide 321 431 N-{ 5-Chloro-4-13-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2 hydroxy-phenyl I-acetainide 322 511 (5H, 1H-Benzo[e]pyrrolo[ 1,2-a][1 ,4]diazepin-1O-yl)-(2-chloro-4- WO 00/34258 PCT/US99/28842 - 113 imidazol-1-yl-phenyl)-methanone 323 451 [1,2,3]Thiadiazole-5-carboxylic acid {4-[3-(5-chloro-2,4-dimeth oxy-phenyl)-thioureido]-phenyl}-amide 324 483 Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl) thioureido]-naphthalen-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-dimethoxy-phenyl)-thioureido]-2 methyl-phenyl}-2-fluoro-benzamide 328 481 Furan-2-carboxylic acid { 5-chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl) thioureido]-2-methyl-phenyl} -amide 329 431 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-naphthalen-1-yl} acetamide 330 416 Furan-2-carboxylic acid {4-[3-(3-chloro-4-dimethylanino-phenyl) thioureido]-phenyl}-amide 331 561 Furan-2-carboxylic acid [4-(3-{4-[(1-benzyl-pyrrolidin-3-yl)-methyl amino]-3-chloro-phenyl}-thioureido)- phenyl]-amide 332 513 N-[4-(3-{3-Chloro-4-[methyl-(1-methyl-pyrrolidin-3-yl)-amino] phenyl}-thioureido)-phenyl]-2-fluoro-benzamide 333 463 N-{4-[3-(5-Chloro-2-methoxy-4-methyl-phenyl)-thioureido]-phenyl} 2,6-difluoro-benzamide 334 420 N-(4-{3-[3-Chloro-4-(1-methyl-pyrrolidin-3-yloxy)-phenyl]-thioureido} phenyl)-acetamide 335 434 N-(4-{ 3-[3-Chloro-4-(1-methyl-piperidin-4-yloxy)-phenyl]-thioureido} phenyl)-acetamide 336 422 N-(4-{3-[3-Chloro-4-(3-dimethylamino-propoxy)-phenyl]-thioureido} phenyl)-acetamide 337 425 2-Acetylamino-5-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido] benzoic acid 338 505 5-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-(2-fluoro benzoylamino)- benzoic acid 339 477 5-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-[(furan-2-carbonyl) ainino]-benzoic acid 340 545 N-[4-(3-{ 3-Chloro-4-[methyl-(1-methyl-piperidin-4-yl)-amino]-phenyl} thioureido)-phenyl]-2,6-difluoro-benzamide 341 503 [1,2,3]Thiadiazole-4-carboxylic acid[4-(3-{3-chloro-4-[methyl-(1-methyl- WO 00/34258 PCT/US99/28842 -114 pyrrolidin-3-yl)-amino]-phenyl}-thioureido)-phenyl]-amide 342 443 N-{ 4 -[3-(3-Chloro-4-methylsulfanyl-phenyl)-thioureido]-phenyl}-2 methyl-benzamide 343 408 N-(4-{ 3-[3-Chloro-4-(2-dimethylamino-ethoxy)-phenyl]-thioureido} phenyl)- acetamide 344 499 Furan-2-carboxylic acid [4-(3- { 3-chloro-4-[methyl-(1 -methyl-piperidin 4-yl)- amino]-phenyl}-thioureido)- phenyl]-ainide 345 419 N-{ 4

-[

3

-(

3 -Chloro- 4 -cyclohexyloxy-phenyl)-thioureido]-phenyl} acetamide 346 440 N-{ 4 -[3-(3-Chloro-4-dimethylanino-phenyl)-thioureido]-phenyl}-2 methyl-benzamide 347 493 N-{ 4

-[

3

-(

5 -Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-methyl-phenyl} 2,6-difluoro-benzamide 348 462 N-{ 4 -[3-(3-Chloro-4-dimethylamino-phenyl)-thioureido]-phenyl}-2,6 difluoro-benzamide 349 531 N-[4-(3-{ 3 -Chloro- 4 -[methyl-(1-methyl-pyrrolidin-3-yl)-amino]-phenyl} thioureido)-phenyl]-2,6-difluoro-benzamide 350 427 Pyridine-2-carboxylic acid { 4 -[3-(3-chloro-4-dimethylamino-phenyl) thioureido]-phenyl}-amide 351 430 Pyridine-2-carboxylic acid { 4

-[

3

-(

3 -chloro-4-methylsulfanyl-phenyl) thioureido]-phenyl}-amide 352 428 Pyridine-2-carboxylic acid { 4 -[3-(5-chloro-2-methoxy-4-methyl-phenyl) thioureido]-phenyl}-amide 353 417 Furan-2-carboxylic acid { 4 -[3-(5-chloro-2-methoxy-4-methyl-phenyl) thioureido]-phenyl}-amide 354 496 Pyridine-2-carboxylic acid [4-(3-{3-chloro-4-[methyl-(1-methyl pyrrolidin-3-yl)-amino]-phenyl}-thioureido)- phenyl]-amide 355 495 N-{ 3 -Chloro- 4 -[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido] phenyl } -2-fluoro-benzamide 356 467 Furan-2-carboxylic acid { 3 -chloro- 4 -[3-(5-chloro-2,4-dimethoxy-phenyl) thioureidol-phenyl } -amide 357 515 N-{ 4

-[

3 -(3-Chloro-4-cyclohexylsulfanyl-phenyl)-thioureido]-phenyl}-2 fluoro-benzamide 358 449 N-{ 4

-[

3 -(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-trifluoromethyl phenyl}-acetamide 359 529 N-{ 4

-[

3

-(

5 -Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-trifluoromethyl phenyl}-2-fluoro-benzamide 360 421 N-{ 4

-[

3

-(

4 -Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-2-dimethyl- WO 00/34258 PCT/US99/28842 - 115 amino-acetamide 361 473 Furan-2-carboxylic acid (4-{3-[3-chloro-4-(2-dimethylamino acetylamino) phenyl]-thioureido}-phenyl)-ainide 362 501 N-(4-{3-[3-Chloro-4-(2-dimethylamino-acetylamino)-phenyl]-thioureido} phenyl)-2-fluoro-benzamide 363 461 N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-2 piperidin- 1 -yl-acetamide 364 541 N-(4-{ 3-[3-Chloro-4-(2-piperidin-1-yl-acetylamino)-phenyl]-thioureido} phenyl)-2-fluoro-benzamide 365 513 Furan-2-carboxylic acid (4-{3-[3-chloro-4-(2-piperidin-1-yl-acetylamino) phenyl]-thioureido}-phenyl)- amide 366 463 N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-2 morpholin-4-yl-acetamide 367 543 N-(4-{ 3-[3-Chloro-4-(2-morpholin-4-yl-acetylamino)-phenyl]-thioureido} phenyl)-2-fluoro-benzamide 368 515 Furan-2-carboxylic acid (4-{3-[3-chloro-4-(2-morpholin-4-yl acetylamino)-phenyl]-thioureido}-phenyl)- aide 369 414 N-{4-[3-(3-Chloro-4-methanesulfonylamino-phenyl)-thioureido]-phenyl} acetamide 370 494 N-{4-[3-(3-Chloro-4-methanesulfonylamino-phenyl)-thioureido]-phenyl} 2-fluoro-benzainide 371 466 Furan-2-carboxylic acid {4-[3-(3-chloro-4-methanesulfonylamino-phenyl) thioureido]-phenyl}-amide 372 481 N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-2-(2 dimethy-lamino-ethylsulfanyl)- acetamide 373 561 N-[4-(3-{3-Chloro-4-[2-(2-dimethylamino-ethylsulfanyl)-acetylamino] phenyl}-thioureido)-phenyl]-2-fluoro-benzamide 374 585 N-[4-(3-{4-[(1-Benzyl-pyrrolidin-3-yl)-methyl-amino]-3-chloro-phenyl} thioureido)-phenyl]-2-methyl-benzamide 375 523 N-[4-(3-{3-Chloro-4-[methyl-(1-methyl-piperidin-4-yl)-amino]-phenyl} thioureido)-phenyl]-2-methyl-benzamide 376 510 Pyridine-2-carboxylic acid [4-(3-{ 3-chloro-4-[methyl-(1 -methyl-piperidin 4-yl)-amino]-phenyl}-thioureido)- phenyl]-amide 377 347 N-{4-[3-(3-Chloro-4-vinyl-phenyl)-thioureido]-phenyl}-acetamide 378 441 Furan-2-carboxylic acid {4-[3-(4-chloro-3-trifluoromethyl-phenyl) thioureido]-phenyl}-amide 379 452 Pyridine-2-carboxylic acid {4-[3-(4-chloro-3-trifluoromethyl-phenyl)- WO 00/34258 PCT/US99/28842 - 116 thioureido]-phenyl } -amide 380 487 N-{ 4 -[3-(4-Chloro-3-trifluoromethyl-phenyl)-thioureido]-phenyl }-2.6 difluoro-benzamide 381 486 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido-3 -cyano-phenyl } 2-fluoro-benzamide 382 458 Furan-2-carboxylic acid { 4

-[

3 -(5-chloro-2,4-dimethoxy-phenyl) thioureido]-3-cyano-phenyl }-amide 383 406 N-{4-t3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido-3 -cyano-phenyl } acetamide 384 395 N-{ 4 -[3-(5-Chloro-2,4-dimeffioxypheny2mehylisothioureido] phenyl }-acetamide 385 396 N-{4-r3-(5-Chloro2,4-dimethoxypheny2meffy-isothioureido] phenyl }-acetainide 386 461 N-{ 4 -[3-(3-Chloro-4-ethylsulfanyl-phenyl)-thioureido]-phenyl)}-2-fluioro benzamide 387 489 N-{ 4 -[3-(4-Butylsulfanyl-3-chloro-phenyl).thioureido]-phenyl }-2-fluoro benzamide 388 411 N-{4-[3-(5-Chloro.-2,4-dimethoxy-phenyl)-thioureido-3 -methoxy phenyl }-acetamide 389 491 N-{ 4

-[

3 -(5-Chloro-2,4-dimethoxy-phenyl)-thioureido-3-methoxy phenyl)}-2-fluoro-benzamicle 390 463 Furan-2-carboxylic acid {4-13-(5-chloro-2,4-dimethoxy-phenyl) thioureido]-3-methoxy-phenyl }-amide 391 531 [1 ,2,3]Thiadiazole-4-carboxylic acid (4-f 3-13-chloro-4-(2-pipericlin- 1 yl-acetyl-amnino)-phenyl]-ffiioureido}-phenyl)jaiide 392 481 N- { 4 -[3-(3-Chloro-4-methanesulfiny1-phenyl)-thioureido]-phenylI>2,6 difluoro-benzamnide 393 497 N-{ 4 -[3-(3-Chloro-4-methajnesulfonylphenyl).thioureidoy-phenyl }-2,6 difluoro-benzamicle 394 459 N-{ 4

-[

3 -(5-Chloro-2-methoxy-4-methyl-pheny)thioureido-2-methylp phenyll}-2-fluoro-benzamide 395 429 N-{ 4

-[

3 -(3-Chloro-4-methyl-phenyl)-thioureido-2methylbpheny 1 2 fluoro-benzamide 396 533 Furan-2-carboxylic acid [4-(3-f 3-chloro-4-[2-(2-dimethylwnino ethylsulfanyl)- acetylaniino]-phenyl }-thioureido)-phenyl]-ainide 397 458 N-{ 4 -[3-( 4 -Acetylamino-3-chloro-phenyl)ffioureidoy-phenyl-2-fluoro benzainide 398 460 [ 2 -Chloro- 4 -(3-{4-[(furan-2-carbonyl)-amino]-phenyl }-thioureido)- WO 00/34258 PCTIUS99/28842 - 117 phenyl]- carbamic acid ethyl ester 399 488 (2-Chloro-4-{ 3-j4-(2-fluoro-benzoylainino)-phenyl]-thioureido }-phenyl) carbainic acid ethyl ester 400 440 N-{4-Ii3-(4-Acetylamilo-phel)-thioureido]-2-chloro-pheflyl }-benzamide 401 520 N- {4-[({ [4-(Benzoylamnino)-3-chloro-pheflyli-amino }-thioxomethyl) ainino]-phenyl)4-2-fluoro-benzainide 402 529 N-{4-[3-(5-Chloro-2,4-dimethoxy-phelyl)-thioureido]-2-tffluoromfethylb phenyl 4 -2-fluoro-benzamide 403 492 Furan-2-carboxylic acid {4-L3-(4-benzoylamino-3-chloro-pheflyl) thioureido]-phenyll4-amide 404 416 N-{ 4-[3-(4-Amino-3-chloro-phelyl)-thioureidol-pheflyl 4-2-fluoro benzamnide 405 479 N- {4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phelyl 4-2 thiomorpholin-4-yl-acetainide 406 531 Furan-2-carboxylic acid (4-{ 3-13-chloro-4-(2-thiomorpholin-4-yl-acetyl ainino)-phenyl]-thioureido}-phenyl)-amnide 407 559 N-(4-1{3-[3-Chloro-4-(2-thiomorpholin-4-yl-acetylaiio)-phel] thioureido}-phenyl)-2-fluoro-benzainide 408 461 N-{ 4-[3-(3-Chloro-4-methylsulfalyl-pheyl)-thioureido]-2-methyl phenyl 4 -2-fluoro-benzainide 409 430 Furan-2-carboxylic acid {4-[3-(4-acetylamino-3-chloro-phenyl) thioureido]-phenyl 4-ainide 410 477 N-{4-[3-(4-Acetylamnino-phenyl)-thioureido]-2-chloro-phelyl}-2-dipropyl amino-acetamide 411 529 Furan-2-carboxylic acid (4-{ 3-[3-chloro-4-(2-dipropylamino-acetylainino) phenyl]-thioureido} -phenyl)- amide 412 449 N-{4-[3-(4-Acetylamilo-phenyl)-thioureido-2-chloro-phell -2-diethyl amnino-acetamnide 413 501 Furan-2-carboxylic acid (4- {3-[3-chloro-4-(2-diethylamnino-acetylamino) phenyl]-thioureido}-phenyl)- amide 414 529 N-(4-{ 3-[3-Chloro-4-(2-diethylamino-acetylamino)-phenyll-thioureido} phenyl)-2-fluoro-benzamnide 415 447 N-{4-[3-(4-Acetylamnino-phenyl)-thioureido]-2-chloro-phelyl}-2 pyrrolidin-1 -yl-acetamide 416 499 Furan-2-carboxylic acid (4-{ 3-[3-chloro-4-(2-pyrrolidin-1 -yl-acetylainilo) phenyl]-thioureido}-phenyl)-amide 417 527 N-(4-{ 3-[3-Chloro-4-(2-pyrrolidin-1 -yl-acetylamino)-phenyl]-thioureido} phenyl)-2-fluoro-benzamide WO 00/34258 PCTIUS99/28842 - 118 418 475 N-{4-[3-(5-Chloro-2-methoxy-4-methyl-phenyl)-thioureido]-3-methoxy phenyl I -2-fluoro-benzamnide 419 445 N-{4-r3-(3-Chloro-4-methyl-pheny1)-thioureido]-3-methoxy-pheny }-2 fluoro-benzamide 420 477 N-{4-r3-(3-Chloro-4-mehysufanyl-phenyl)-thioureido-3-mehoxy phenyl } -2-fluoro-benzamide 421 388 Furan-2-carboxylic acid {4-13-(4-amino-3-chloro-phenyl)-thioureido] phenyl }-amide 422 527 Furan-2-carboxylic acid (4-1{3-r4-(2-azepan- 1-yI-acetylamino)-3-chloro phenyl]- thioureido }-phenyl)-amnide 423 555 N-(4-{ 3-14-(2-Azepan-1 -yl-acetylamino)-3-chloro-phenyl]-thioureido} phenyl)- 2-fluoro-benzamide 424 527 Furan-2-carboxylic acid [4-(3-{ 3-chloro-4-[2-(2-methyl-piperidin- l-yl) acetyl-amino]-phenyl }-thioureido)-phenyl]-amide 425 555 N-114-(3-1{3-Chloro-4-[2-(2-methyl-piperidin- 1-yl)-acetylamino]-phenyl } thioureido)-phenyl]-2-fluoro-benzamide 426 339 Furan-2-carboxylic acid [4-(3-pyridin-2-yl-thioureido)-phenyl]-amnide 427 339 Furan-2-carboxylic acid [4-(3-pyridin-4-yl-thioureido)-phenyl]-amide 428 367 2-Fluoro-N-[4-(3-pyridin-3-yl-thioureido)-phenyl]-benzamide 429 339 Furan-2-carboxylic acid [4-(3-pyridin-3-yl-thioureido)-phenyl]-amide 430 353 Furan-2-carboxylic acid {4-[3-(3-amino-phenyl)-thioureido]-phenyl} amaide 431 406 Furan-2-carboxylic acid {4-[3-(3-trifluoromethyl-phenyl)-thioureido] phenyl}-amide 432 380 2-Fluoro-N-[4-(3-m-tolyl-thioureido)-phenyl]-benzamide 433 434 2-Hluoro-N-{4-[3-(3-trifluoromethyl-phenyl)-thioureido]-phenyl } benzamide 434 381 N-f 4-[3-(3-Amino-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 435 388 Furan-2-carboxylic acid {4-[3-(3-amnino-5-chloro-phenyl)-thioureido] phenyll}-amide 436 352 Furan-2-carboxylic acid [4-(3-m-tolyl-thioureido)-phenyl]-wmide 437 416 N-f 4-[3-(2-Amino-5-chloro-phenyl)-thioureido]-phenyl }-2-fluoro benzanide 438 571 (2-Chloro-4-1{3-[ 4 -(2-fluoro-benzoylamino)-phenyl]-thioureido}-phenyl). carbamnic acid 2-piperidin- 1-yl-ethyl ester 439 543 [2-Chloro-4-(3-{ 4-[(furan-2-carbonyl)-ainino]-phenyl }-thioureido) phenyl]-carbamic acid 2-piperidin-1-yl-ethyl ester WO 00/34258 PCT/US99/28842 - 119 440 388 Furan-2-carboxylic acid {4-[3-(2-amino-5-chloro-phenyl)-thioureido] phenyl}-amide 441 363 Furan-2-carboxylic acid {4-[3-(3-cyano-phenyl)-thioureido]-phenyl} amide 442 416 N-{4-[3-(3-Amino-5-chloro-phenyl)-thioureido]-phenyl}-2-fluoro benzamide 443 367 2-Fluoro-N-[4-(3-pyridin-2-yl-thioureido)-phenyl]-benzamide 444 367 2-Fluoro-N-[4-(3-pyridin-4-yl-thioureido)-phenyl]-benzamide 445 374 Furan-2-carboxylic acid {4-[3-(6-chloro-pyridin-3-yl)-thioureido]-phenyl} amide 446 388 Furan-2-carboxylic acid {4-[3-(2-amino-3-chloro-phenyl)-thioureido] phenyl}-amide 447 396 Furan-2-carboxylic acid {4-[3-(3-hydrazinocarbonyl-phenyl)-thioureido] phenyl}-amide 448 410 2-Fluoro-N-(4-{3-[3-(1-hydroxy-ethyl)-phenyl]-thioureido}-phenyl) benzamide 449 414 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-hydrazinocarbonyl-phenyl) thioureido]-phenyll-amide 450 399 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-isopropyl-phenyl) thioureido]-phenyl}-anide 451 380 Furan-2-carboxylic acid {4-[3-(3-isopropyl-phenyl)-thioureido]-phenyl} amide 452 409 2-Fluoro-N-{4-[3-(3-isopropyl-phenyl)-thioureido]-phenyl}-benzamide 453 381 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-cyano-phenyl)-thioureido] phenyl}-anide 454 410 N-{4-[3-(3-Dimethylamino-phenyl)-thioureido]-phenyl}-2-fluoro benzamide 455 381 Furan-2-carboxylic acid {4-[3-(3-dimethylamino-phenyl)-thioureido] phenyl}-amide 456 370 [1,2,3]Thiadiazole-4-carboxylic acid [4-(3-m-tolyl-thioureido)-phenyl] amide 457 424 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-trifluoromethyl-phenyl) thioureido]-phenyl}-ainide 458 479 N-{ 3-Chloro-4-[3-(5-chloro-2-methoxy-4-methyl-phenyl)-thioureido] phenyl}-2-fluoro-benzamide 459 449 N-{ 3-Chloro-4-[3-(3-chloro-4-methyl-phenyl)-thioureido]-phenyl}-2 fluoro-benzamide 460 481 N-{3-Chloro-4-[3-(3-chloro-4-methylsulfanyl-phenyl)-thioureido]- WO 00/34258 PCT/US99/28842 - 120 phenyl I -2-fluoro-benzamide 461 391 N-{ 4-13-(3-Cyano-phenyl)-Lhioureidoj-phenyl } -2-fluoro-benzamide 462 395 Furan-2-carboxylic acid { 4 -13-(3-acetylamino-phenyl)-thioureido] phenyll}-amide 463 424 2-Fluoro-N- { 4 -13-(3-hydrazinocarbonyl-phenyl)-thioureido]-phenyl I benzamide 464 400 [1 ,2,3llThiadiazole-4-carboxylic acid (4-f 3-[3-(l -hydroxy-ethyl)-phenyl] thioureido}I-phenyl)-ainide 465 434 N-{ 4-[3-(2-Amino-3-chloro-phenyl)-thioureido]-phenyI } -2,6-difluoro benzamnide 466 406 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-13-(3-aino-5-chloro-phenyl) thioureido]-phenyl}-amide 467 398 Furan-2-carboxylic acid { 4 -[3-(3,5-dimethoxy-phenyl)-thioureido] phenyll}-amide 468 416 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3 ,5-dimethoxy-phenyl) thioureido]- phenyl I -amnide 469 454 5-(3-{4-[(Furan-2-carbonyl)-amnino]-phenyI }-thioureido)-isophthalic acid dimethyl ester 470 434 Isoxazole-5-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl) thioureido]-phenyl}-amnide 471 392 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(6-chloro-pyridin-3-yl) thioureido]-phenyl }-amnide 472 382 Furan-2-carboxylic acid (4-f 3-[3-( 1-hydroxy-ethyl)-phenyl]-thioureido} phenyl)-amide 473 368 Furan-2-carboxylic acid { 4 -[3-(3-methoxy-phenyl)-thioureido]-phenyl } amnide 474 354 Furan-2-carboxylic acid { 4 -[3-(3-hydroxy-phenyl)-thioureido]-phenyl} amide 475 382 2-Fluoro-N-{4-[3-(3-hydroxy-phenyl)-thioureidoy-phenyl}.benzamide 476 396 2-Fluoro-N-{4-[3-(3-hydroxymethy1-phenyl)-thioureidoy-phenylI> benzamnide 477 423 N-{ 4 -[3-(3-Acetylalnino-phenyl)-thioureido]-phenyl }-2-fluoro benzamide 478 413 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-acetylainino-phenyl) thioureido]- phenyl}-ainide 479 400 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-dimnethylamino-phenyl) thioureidol-phenyl }-amide 480 340 Furan-2-carboxylic acid [ 4 -(3-pyrimidin-4-yl-thioureido)-phenyl]-ainide WO 00/34258 PCTIUS99/28842 - 121 481 378 Furan-2-carboxylic acid {4-[3-(1H-indazol-5-yl)-thioureidol-phenyl} amide 482 395 Furan-2-carboxylic acid [4-(3-benzothiazol-5-yl-thioureido)-phenyl]-amide 483 406 2-Fluoro-N-{4-[3-(1 H-indazol-5-yl)-thioureido]-phenyl }-benzamide 484 424 N-[4-(3-Benzothiazol-5-yl-thioureido)-phenyl]-2-fluoro-belzalfide 485 473 5-(3-{4-[([ 1,2,3]Thiadiazole-4-carbonyl)-amilo]-phelyl }-thioureido) isophthalic acid dimethyl ester 486 442 Furan-2-carboxylic acid (4-{3-[4-(1 -azido-ethyl)-3-chloro-phenyl] thioureido}-phenyl)-wmide 487 396 2-Fluoro-N-{4-[3-(3-methoxy-phenyl)-thioureido]-pheflyl }-benzamide 488 368 Furan-2-carboxylic acid {4-[3-(3-hydroxymethyl-phenyl)-thioureido] phenyll}-amide 489 416 Furan-2-carboxylic acid f{4-[3-(5-chloro-2-dimethylamino-phenyl) thioureido]- phenyl} -ainide 490 444 N- {4-[3-(5-Choro-2-dimethylamino-phenyl)-thioureido]-phel -2 fluoro-benzainide 491 506 [3-Chloro-5-(3-{4-[(L1 ,2,3]thiadiazole-4-carbonyl)-amino]-phenyl

}

thioureido)- phenyl]-carbainic acid tert-butyl ester 492 470 N-(4- {3-[4-(1 -Azido-ethyl)-3-chloro-phenyl]-thioureido }-phenyl)-2-fluoro benzamaide 493 337 Furan-2-carboxylic acid [4-(1 H-thiazololl5,4-b]pyridin-2-ylideneainino) phenyll-amaide 494 378 Furan-2-carboxylic acid f{4-[3-(1 H-benzoimidazol-5-yl)-thioureido] phenyl)-ainide 495 392 Furan-2-carboxylic acid {4-[3-(2-methyl-1H-benzoimidazol-5-yl) thioureido]-phenyl} -amide 496 406 N-{4-[3-(1H-Benzoimidazol-5-yl)-thioureido-pheyl-2-fluoro-belzamfide 497 420 2-Fluoro-N-{4-[3-(2-methyl-H-benzoimidazol-5-y)-thiou-reido]-phelyl} benzainide 498 452 [1,2,3]Thiadiazole-4-carboxylic acid { 5-[3-(5-chloro-2,4-dimethoxy phenyl)-thioureido]-pyridil-2-yl}-wmide 499 445 Pyridine-2-carboxylic acid { 5-[3-(5-chloro-2,4-dimethoxy-phenyl) thioureido]- pyridin-2-yl} -ainide 500 434 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(5-chloro-2-dimethylainino phenyl)-thioureido]-phenyl }-amnide 501 484 [1 ,2,3]Thiadiazole-4-carboxylic acid (4-{ 3-[4-(2-amino-pyrimidin-4-yl) 3-chloro-phenyl]-thioureido} -phenyl)-amide WO 00/34258 PCT/US99/28842 - 122 502 494 N-(4-{3-[4-(2-Amino-pyrimidin-4-yl)-3-chloro-phenyl]-thioureido} phenyl)-2-fluoro-benzamide 503 434 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-2-dimethylamino phenyl)-thioureido]-phenyl } -amide 504 462 N-{4-[3-(3-Chloro-2-dimethylamino-phenyl)-thioureido]-phenyl}-2,6 difluoro-benzamide 505 416 Furan-2-carboxylic acid {4-[3-(3-chloro-2-dimethylamino-phenyl) thioureido]-phenyl } -amide 506 445 Pyridine-2-carboxylic acid {6-[3-(5-chloro-2,4-dimethoxy-phenyl) thioureido]-pyridin-3-yl} -amide 507 462 N-{6-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-3-yl}-2 fluoro-benzamide 508 482 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-iodo-phenyl)-thioureido] phenyl}-amide 509 413 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-tert-butyl-phenyl) thioureido]-phenyl}-amide 510 387 Furan-2-carboxylic acid {4-[3-(3-chloro-benzyl)-thioureido-phenyl} amide 511 415 N-{4-[3-(3-Chloro-benzyl)-thioureido]-phenyl}-2-fluoro-benzamide 512 434 Furan-2-carboxylic acid {6-[3-(5-chloro-2,4-dimethoxy-phenyl) thioureido]-pyridin-3-yl}-amide 513 435 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-bromo-phenyl)-thioureido] phenyl}-amide 514 452 [1,2,3]Thiadiazole-4-carboxylic acid {6-[3-(5-chloro-2,4-dimethoxy phenyl)-thioureido]-pyridin-3-yl}-amide 515 426 [1,2,3]Thiadiazole-4-carboxylic acid {5-[3-(3,5-dichloro-phenyl) thioureido]-pyridin-2-yl}-amide 516 474 Furan-2-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl-phenyl) thioureido]- phenyl}-amide 517 502 N-{4-[3-(3,5-Bis-trifluoromethyl-phenyl)-thioureido]-phenyl}-2 Fluoro-Benzamide 518 450 N-{4-[3-(4-Amino-3,5-dichloro-phenyl)-thioureido]-phenyl}-2-fluoro benzamide 519 539 N-{4-[3-(4-Amino-3,5-dibromo-phenyl)-thioureido]-phenyl}-2-fluoro benzamide 520 392 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(5-chloro-pyridin-3-yl) thioureido]-phenyl}-amide 521 529 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-amino-3,5-dibromo- WO 00/34258 PCTIUS99/28842 - 123 phenyl)-thioureido]-phenyl }-amide 522 434 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-5-dimethylamino phenyl)-thioureido]-phenyl }-amide 523 444 N- {4-[3(3Choro-5-dimethylamiflo-pheiyl)-thioureido]-pheyl}-2 fluoro-benzamide 524 416 Furan-2-carboxylic acid {4-13-(3-chloro-5-dimethylamnino-phenyl) thioureido]- phenyl }-amnide 525 436 [i ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(5-bromo-pyridin-3-yl) thioureido]- phenyll -arnide 526 379 Furan-2-carboxylic acid {4-13-(lH-benzotriazol-5-yl)-thioureido]-phenyl

}

ainide 527 425 N-{4-[3-(1 H-Benzotriazol-5-yl)-thioureido]-phenyl)}-2,6-difluoro benzamide 528 388 N-[4-({ L2-(3-Chloro-phenyl)-hydrazino]-thioxomeffiyl }-amnino)-phenyl] furan-2-carboxainide 529 416 N-[4-({ [2-(3-Chloro-phenyl)-hydrazino]-thioxomethyl }-amino)-phenyl]-2 fluoro-benzamnide 530 456 Furan-2-carboxylic acid {4-[3-(2-amnino-3-chloro-5-trifluoromethyl phenyl)-thioureido]-phenyl}-amide 531 513 N-{4-[3-(3-Bromo-5-trifluoromethyl-phenyl)-thioureido]-phellyl}-2 fluoro-benzamide 532 503 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-bromo-5-trifluoromethyl phenyl)- thioureido]-phenyl}-amnide 533 374 {4-[(Furan-2-carbonyl)-amino]-phenyl} -thiocarbainic acid O-(3-chloro phenyl) ester 534 474 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-amnino-3-chloro-5-trifluoro methyl-phenyl)-thioureido]-phenyl} -amnide 535 508 Li ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-piperidin- 1-yl-5-trifluoro methyl-phenyl)-thioureido]-phenyl}-arnide 536 380 N-{4-(3-Benzyi-thioureido)-phenyl]-2-fluoro-belzalflide 537 439 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,4-dichloro-benzyl) thioureido]-phenyl}-amide 538 449 N- {4-[3-(3,4-Dichloro-benzyi)-thioureido]-phenyl} -2-fluoro-benzainide 539 370 [1 ,2,3]Thiadiazole-4-carboxylic acid [4-(3-benzyl-thioureido)-phenyl] ainide 540 424 N-[4-(3-Benzo[1,3]dioxol-5-ylethyl-thioureido)-phelyl]-2-fluoro benzainide 541 414 [1 ,2,3]Thiadiazole-4-carboxylic acid [4-(3-benzo[1 ,3]dioxol-5-ylmethyl- WO 00/34258 PCTIUS99/28842 - 124 thioureido)-phenyl]-amide 542 506 [1 ,2,3]Thiadiazole-4-carboxylic acid { 4-13-(3.5-bis-trifluoromethyl benzyl)-thioureido]-phenyl I -amide 543 516 N-{(4-[3-(3,5-Bis-trifluoromethyl-benzyl)-thioureido]-phenyl }-2-fluoro benzamnide 544 352 Furan-2-carboxylic acid 14-(3-benzyl-thioureido)-phenyl]-wmide 545 421 Furan-2-carboxylic acid {4-[3-(3,4-dichloro-benzyl)-thioureido]-phenyl } amide 546 396 Furan-2-carboxylic acid [4-(3-benzolll,3]dioxol-5-ylmethyl-thioureido) phenyl]- amnide 547 488 Furan-2-carboxylic acid f{4-13-(3,5-bis-trifluoromethyl-benzyl) thioureido]-phenyl)}-amnide 548 503 [1i,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-bromo-3-trifluoromethyl phenyl)-thioureido]-phenyl }-ainide 549 529 N-{4-13-(3-Bromo-4-trifluoromethoxy-phenyl)-thioureido]-phenyl} -2 fluoro-beuzainide 550 519 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-bromo-4-trifluoromethoxy phenyl)-thioureido]-phenyl} -amide 551 473 Furan-2-carboxylic acid {4-[3-(3-chloro-4-trifluoromethylsulfanyl-phenyl) thioureido]-phenyll}-amide 552 412 2-Fluoro-N-(4-{ 3-[2-(3-fluoro-phenyl)-ethyl]-thioureido }-phenyl) benzamide 553 412 2-Fluoro-N-(4-{ 3-12-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl) benzamnide 554 402 [1 ,2,3]Thiadiazole-4-carboxylic acid (4-f 3-[2-(3-fluoro-phenyl)-ethyl] thioureido}-phenyl)-aniide 555 402 [1 ,2,3]Thiadiazole-4-carboxylic acid (4- {3-12-(4-fluoro-phenyl)-ethyl] thioureido}-phenyl)-ainide 556 495 [1 ,2,3]Thiadiazole-4-carboxylic acid (4-f 3-[3-(2-methyl-butyl)-5-trifluoro methyl-phenyl]-thioureido} -phenyl)-amide 557 481 [1,2,3]Thiadiazoie-4-carboxylic acid {4-[3-(3-isobutyl-5-trifluoromethyl phenyl)- thioureido]-phenyl }-amide 558 523 [1 ,2,3]Thiadiazole-4-carboxylic acid (4-1{3-[3-(4-methyl-piperazin- l-yl)-5 trifluoro-methyl-phenyl]-thioureidol -phenyl)-amide 559 510 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-morpholin-4-yl-5-trifluoro methyl-phenyl)-thioureido]-phenyI I}-amide 560 494 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-pyrrolidin- 1-yl-5-trifluoro methyl-phenyl)-thioureido]-phenyl }-ainide WO 00/34258 PCTIUS99/28842 - 125 561 384 Furan-2-carboxylic acid (4-f 3-12-(4-fluoro-phenyl)-ethyl]-thioureido } phenyl)-amide 562 419 [1 ,2,3]Thiadiazole-4-carboxylic acid (4- (3-12-(3-chloro-phenyl)-ethyl] thioureidol}-phenyl)-aniide 563 429 N-(4-{ 3-12-(3-Chloro-phenyl)-ethyl]-thioureido} -phenyl)-2-fluoro benzamide 564 401 Furan-2-carboxylic acid (4-f 3-12-(3-chloro-phenyl)-ethyl]-thioureido} phenyl)- amide 565 402 [1 ,2,3]Thiadiazole-4-carboxylic acid (4-1{3-[ 1-(4-fluoro-phenyl)-ethyll thioureido I -phenyl)-amnide 566 504 2-Fluoro-N- 14-[3-(3 -pyrrolidin- 1 -yI-5 -trifluoromethyl-phenyl) thioureido] -phenyl I}-benzamnide 567 477 N-{ 4-13-(3-Dimethylamnino-5-trifluoromethyl-phenyl)-thioureido] phenyl I -2-fluoro-benzamide 568 520 2-Fluoro-N- {4-13-(3-morpholin-4-yl-5-trifluoromethyl-phenyl) thioureido]-phenyl}-benzamnide 569 533 2-Fluoro-N-(4-{ 3-[3-(4-methyl-piperazin- 1-yl)-5-trifluoromethyl phenyll-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-trifluoro methyl-phenyl)-thioureido]-phenyl} -amide 572 405 [1 ,2,3IlThiadiazole-4-carboxylic acid {4-[3-(3-chloro-benzyl)-thioureido] phenyl }-amide 573 384 Furan-2-carboxylic acid (4-f 3-[2-(3-fluoro-phenyl)-ethyl]-thioureido} phenyl)- ainide 574 366 Furan-2-carboxylic acid [4-(3-phenethyl-thioureido)-phenyl]-amide 575 384 [1,2,3]Thiadiazole-4-carboxylic acid [4-(3-phenethyl-thioureido) phenyl]-amide 576 394 2-Fluoro-N-[4-(3-phenethyl-thioureido)-phenyl]-benzamide 577 505 2-Fluoro-N-(4- {3-[3-(2-methyl-butyl)-5-trifluoromethyl-phenyl] thioureido} -phenyl)-benzamnide 578 491 2-Fluoro-N- 14-[3-(3 -isobutyl-5 -trifluoromethyl-phenyl) -thioureido] phenyl}I-benzamnide 579 388 Furan-2-carboxylic acid f{4-[3-(3,5-difluoro-benzyl)-thioureido]-phenyl} amide 580 416 N-{4-[3-(3,5-Difluoro-benzyl)-thioureido]-phenyl}-2-fluoro-benzamide 581 406 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-difluoro-benzyl)- WO 00/34258 PCT/US99/28842 - 126 thioureido]-phenyl I -amide 582 421 Furan-2-carboxylic acid {4-[3-(3,5-dichloro-benzyl)-thioureido]-phenyl I amide 583 449 N-{4-[3-(3,5-Dichloro-benzyl)-thioureido]-phenyl)4-2-fluoro-benzamide 584 439 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-dichloro-benzyl) thioureidol-phenyl}I -ainide 585 438 Furan-2-carboxylic acid {4-13-(3-fluoro-5-trifluoromethyl-benzyl) tihioureido]-phenyl I -amnide 586 466 2-Huoro-N-{ 4-113-(3-fluoro-5-trifluoromethyl-benzyl)-thioureido] phenyll4-benzamnide 587 456 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-fluoro-5-trifluoromethyl benzyl)-thioureido]-phenyl 4 -amide 588 384 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-113-( 1-phenyl-ethyl)-thioureido] phenyl} -amide 589 394 2-Fluoro-N- {4-[3-(1 -phenyl-ethyl)-thioureido]-phenyl }-benzamide 590 366 Furan-2-carboxylic acid {4-113-(1 -phenyl-ethyl)-thioureido]-phenyl 4-amide 591 412 2-Fluoro-N-(4-{ 3-[1 -(4-fluoro-phenyl)-ethyl]-thioureidol4-phenyl) benzamide 592 384 Furan-2-carboxylic acid (4-1{3-II-(4-fluoro-phenyl)-ethyl]-thioureido} phenyl)-ainide 593 413 N-{4-[3-(1 -tert-Butyl-1 H-imidazol-2-yl)-thioureido]-phenyl}-2-fluoro benzamide 594 510 [1 ,2,3]Thiadiazole-4-carboxylic acid (4-{ 3-[3-(isobutyl-methyl-amnino)-5 trifluoromethyl-phenyl]-thioureido}-phenyl)-amide 595 510 [1 ,2,3]Thiadiazole-4-carboxylic acid (4- {3-[3-(3-hydroxy-pyrrolidin- l-yl) 5-trifluoromethyl-phenyl]-thioureido}-phenyl)-amide 596 520 2-Fluoro-N-(4-{ 3-[3-(isobutyl-methyl-amnino)-5-trifluoromethyl-phenyll thioureido}-phenyl)-benzamide 597 510 [1 ,2,3]Thiadiazole-4-carboxylic acid (4-{ 3-[3-(butyl-methyl-amnino)-5 trifluoromethyl-phenyl]-thioureido}-phenyl)-amide 598 520 N-(4-{ 3-[3-(Butyl-methyl-amnino)-5-trifluoromethyl-pheflyl]-thioureido} phenyl)-2-fluoro-benzanuide 599 520 [1 ,2,3]Thiadiazole-4-carboxylic acid (4-{ 3-[2-(3,5-bis-trifluoromethyl phenyl)-ethyl]-thioureido}-phenyl)-ainide 600 442 [ 1,2,3]Thiadiazole-4-carboxylic acid f{4-13-(4-fluoro-3-trifluoromethyl phenyl)-thioureido]-phenyl} -ainide 601 522 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-piperidin- 1-yl-3-trifluoro methyl-benzyl)-thioureido]-phenyl}-ainide WO 00/34258 PCTIUS99/28842 - 127 602 482 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-dimethylamino-3-trifluoro methyl-benzyl)-thioureido]-phenyl }-amide 603 381 Furan-2-carboxylic acid (4-1{3-[2-(4-amino-phenyl)-ethyl]-thioureido } phenyl)-amide 604 445 Furan-2-carboxylic acid (4- {3-[2-(4-bromo-phenyl)-ethyl]-thioureido } p-henyl)-amide 605 380 Furan-2-carboxylic acid {4-13-(2-p-tolyl-ethyl)-thioureido]-phenyl }-amide 606 463 [1,2,3]Thiadiazole-4-carboxylic acid (4-f{3-r2-(4-bromo-phenyl)-ethyl] thioureido} -phenyl)-amide 607 396 Furan-2-carboxylic acid (4-{ 3-[2-(3-methoxy-phenyl)-ethyll-thioureido} phenyl)-amnide 608 403 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(1 -tert-butyl-l1H-imidazol-2 yl)-thioureido]-phenyl)}-amide 609 384 Furan-2-carboxylic acid {4-[3-(1 -tert-butyl- 1H-imidazol-2-yl)-thioureido] phenyl } -amide 610 492 N-{4-[3-(4-Dimethylamino-3-trifluoromethyl-benzyl)-thioureido]-phenyl} 2-fluoro-benzainide 611 427 Furan-2-carboxylic acid (4-f{3-[2-(3,4-dimethoxy-phenyl)-ethyl] thioureido}I-phenyl)-amide 612 380 Furan-2-carboxylic acid {4-[3-(3-phenyl-propyl)-thioureido]-phenyl} amide 613 399 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-phenyl-propyl)-thioureido] phenyll}-amnide 614 502 Furan-2-carboxylic acid (4-{ 3-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl] thioureido} -phenyl)-amide 615 550 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-iodo-3-trifluoromethyl phenyl)-thioureido]-phenyl}-amide 616 532 2-Fluoro-N-{4-[3-(4-piperidin-1 -yl-3-trifluoromethyl-benzyl)-thioureido] phenyl}-benzainide 617 537 [1,2,3]Thiadiazole-4-carboxylic acid (4-{ 3-[4-(4-methyl-piperazin-1 -yl)-3 trifluoromethyl-benzyl]-thioureido} -phenyl)-amnide 618 482 [1i,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-dimethylamino-5-trifluoro methyl-benzyl)-thioureido]-phenyl~amide 619 488 Furan-2-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl-phenyl)-thioureido methyl] -phenyl} -amide 620 421 Furan-2-carboxylic acid {4-13-(3,5-dichloro-phenyl)-thioureidomethyl] phenyl}-amide 621 421 Furan-2-carboxylic acid {4-[3-(3,4-dichloro-phenyl)-thioureidomethyl]- WO 00/34258 PCT/US99/28842 - 128 phenyl } -amide 622 455 Furan-2-carboxylic acid {4-[3-(4-chloro-3-trifluoromethyl-phenyl) thioureido-methyl]-phenylI -anide 623 466 2-Fluoro-N-{4-[3-(4-fluoro-3-trifluoromethyl-benzyl)-thioureido]-phenyl} benzamide 624 456 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-fluoro-3-trifluoromethyl benzyl)-thioureido]-phenyl}-amide 625 410 2-Fluoro-N-{4-[3-(2-phenoxy-ethyl)-thioureido]-phenyl} -benzamide 626 382 Furan-2-carboxylic acid {4-[3-(2-phenoxy-ethyl)-thioureido]-phenyl} amide 627 400 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-phenoxy-ethyl)-thioureido] phenyl I -amide 628 409 2-Fluoro-N- {4-[3-(3-phenyl-propyl)-thioureido]-phenyl } -benzamide 629 425 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(5-trifluoromethyl-pyridin-3 yl)-thioureido]-phenyl}-amide 630 439 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,4-dichloro-phenyl) thioureido-methyl]-phenyl}-amide 631 473 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-chloro-3-trifluoromethyl phenyl)-thioureidomethyl]-phenyl}-amide 632 381 2-Fluoro-N-[4-(3-pyridin-3-ylmethyl-thioureido)-phenyl]-benzamide 633 353 Furan-2-carboxylic acid [4-(3-pyridin-3-ylmethyl-thioureido)-phenyl] amide 634 371 [1,2,3]Thiadiazole-4-carboxylic acid [4-(3-pyridin-3-ylmethyl-thioureido) phenyl]-amide 635 439 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-dichloro-phenyl) thioureido-methyl]-phenyl}-amide 636 492 N-{4-[3-(3-Dimethylamino-5-trifluoromethyl-benzyl)-thioureido]-phenyl} 2-fluoro-benzamide 637 415 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-methoxy-phenyl)-ethyl] thioureido}-phenyl)-amide 638 399 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-p-tolyl-ethyl)-thioureido] phenyl}-amide 639 445 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3,4-dimethoxy-phenyl) ethyl]-thioureido}-phenyl)-amide 640 506 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl phenyl)- thioureidomethyl]-phenyl}-amide 641 516 N-{4-[3-(3,5-Bis-trifluoromethyl-phenyl)-thioureidomethyl]-phenyl}-2 fluoro-benzamide WO 00/34258 PCT/US99/28842 - 129 642 449 N-{ 4-[3-(3,5-Dichloro-phenyl)-thioureidomethyly-phenyl }-2-fluoro benzamide 643 449 N-{ 443-(3,4-Dichloro-pheny1)-thioureidomethyl]-pheny1>-2-fuoro benzamide 644 448 [1 ,2,3]Thiadiazole-4-carboxylic acid f{4-[3-(3-acetylainino-5-chloro phenyl)-thioureido]-phenyl }-amide 645 453 [1 ,2,3]Thiadiazole-4-carboxylic acid (4-f 3-[2-(3,4-dichloro-phenyl)-ethyl] thioureido} -phenyl)-ainide 646 413 ri ,2,3]Thiadiazole-4-carboxylic acid {4-[3-( 1-methyl-3-phenyl-propyl) thioureido]-phenyll}-amide 647 463 [1 ,2,3]Thiadiazole-4-carboxylic acid (4-f{ 3-[1 -(4-bromo-phenyl)-ethyl] thioureido } -phenyl)-amide 648 413 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-phenyl-butyl)-thioureido] phenyll}-amnide 649 397 [1 ,2,3llThiadiazole-4-carboxylic acid [4-(3-indan- 1-yl-thioureido)-phenyl] amide 650 400 ri ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-metihoxy-benzyl) thioureido]-phenyl}-amicle 651 415 [1 ,2,3]Thiacliazole-4-carboxylic acid (4-f 3-[2-(2-methoxy-phenyl)-ethyl] thioureido}-phenyl)-ainide 652 415 [1 ,2,3]Thiadiazole-4-carboxylic acid (4-f{ 3-[2-(4-methoxy-phenyl)-ethyl] thioureido}-phenyl)-amide 653 506 N-(4- { 3-[2-(3-Dimethylamnino-5-trifluoromethyl-phenyl)-edhyl] thioureido}-phenyl)-2-fluoro-benzamide 654 510 [1 ,2,3]Thiadiazole-4-carboxylic acid (4-f{ 3-[3-(3-diinethylainino-propyl)-5 trifluoromethyl-phenyl]-thioureido}-phenyl)-amide 655 417 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-phenylsulfanyl-ethyl) thioureido]-phenyl}-ainide 656 427 2-Fluoro-N-{4-[3-(2-phenylsulfanyl-ethyl)-thioureido]-phenyl}-beuzamide 657 399 Furan-2-carboxylic acid {4-[3-(2-phenylsulfanyl-ethyl)-thioureido] phenyl}-amnide 658 381 2 -Fiuoro-N-[ 4 -(3-pyridin-4-ylmethyl-thioureido)-phenyl]-benzamide 659 353 Furan-2-carboxylic acid [4-(3-pyridin-4-ylmethyl-thioureido)-phenyl] amicle 660 371 [1 ,2,3]Thiadiazole-4-carboxylic acid [4-(3-pyridin-4-ylmethyl-thioureido) phenyl]-amide 661 506 2-Fluoro-N-{4-[3-(3-iodo-benzyl)-thioureido]-phenyl }-benzamide 662 478 Furan-2-carboxylic acid {4-[3-(3-iodo-benzyl)-thioureido]-phenyl }-ainide WO 00/34258 PCT/US99/28842 - 130 663 496 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-iodo-benzyl)-thioureido] phenyl}-amide 664 479 N-(4-{3-[2-(3,5-Dichloro-phenoxy)-ethyl]-thioureido}-phenyl)-2-fluoro benzamide 665 451 Furan-2-carboxylic acid (4-{3-[2-(3,5-dichloro-phenoxy)-ethyl] thioureido}-phenyl)-amide 666 445 N-(4-{ 3-[2-(3-Chloro-phenoxy)-ethyl]-thioureido}-phenyl)-2-fluoro benzamide 667 417 Furan-2-carboxylic acid (4-{ 3-[2-(3-chloro-phenoxy)-ethyl]-thioureido} phenyl)-amide 668 435 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-chloro-phenoxy)-ethyl] thioureido}-phenyl)-amide 669 466 2 -Fluoro-N-{ 4 -[3-(2-fluoro-5-trifluoromethyl-benzyl)-thioureido]-phenyl} benzamide 670 438 Furan-2-carboxylic acid {4-[3-(2-fluoro-5-trifluoromethyl-benzyl) thioureido]-phenyl}-amide 671 456 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-fluoro-5-trifluoromethyl benzyl)-thioureido]-phenyl}-amide 672 416 N-{ 4 -[3-(3,4-Difluoro-benzyl)-thioureido]-phenyl}-2-fluoro-benzamide 673 452 N-(4-{3-[ 2 -(4-Dimethylamino-3-methyl-phenyl)-ethyl]-thioureido} phenyl)-2-fluoro-benzamide 674 496 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-dimethylamino-5 trifluoro-methyl-phenyl)-ethyl]-thioureido}-phenyl)-ainide 675 388 Furan-2-carboxylic acid { 4 -[3-(3,4-difluoro-benzyl)-thioureido]-phenyl} amide 676 406 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,4-difluoro-benzyl) thioureido]-phenyl}-amide 677 433 N-{4-[3-(3-Chloro-4-fluoro-benzyl)-thioureido]-phenyl}-2-fluoro benzamide 678 495 [1,2,3]Thiadiazole-4-carboxylic acid (4-{ 3-[2-(3-bromo-phenylsulfanyl) ethyl]-thioureido } -phenyl)-amide 679 477 Furan-2-carboxylic acid (4-{ 3-[2-(3-bromo-phenylsulfanyl)-ethyl] thioureido}-phenyl)-amide 680 505 N-(4-{3-[ 2 -(3-Bromo-phenylsulfanyl)-ethyl]-thioureido}-phenyl)-2-fluoro benzamide 681 493 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-bromo-4-methoxy phenyl)-ethyl]-thioureido}-phenyl)- amide 682 493 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(5-bromo-2-methoxy- WO 00/34258 PCTIUS99/28842 - 131 phenyl)-ethylj-thioureido}-phenyl)- amide 683 419 [1 ,2,3]Thiadiazole-4-carboxylic acid (4-1{3-12-(2-chloro-phenyl)-ethyl] thioureido}-phenyl)-amide 684 402 [1 ,2,3]Thiadiazole-4-carboxylic acid (4-f 3-[2-(2-fluoro-phenyl)-ethyl] thioureido I -phenyl)-amnide 685 419 [1 ,2,3]Thiadiazole-4-carboxylic acid (4-1{3-12-(4-chloro-phenyl)-ethyl] thioureidol}-phenyl)-amide 686 475 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,3-diphenyl-propyl) thioureido]-phenyl} -amide 687 547 2-Fluoro-N-(4-{ 3-[4-(4-methyl-piperazin- 1-yl)-3-trifluoromethyl benzyl]- thioureido} -phenyl)-benzamide 688 469 [1,2,3]Thiadiazole-4-carboxylic acid (4-f 3-[2-(3,5-dichloro-phenoxy) ethyl]-thioureido }-phenyl)-amide 689 423 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-3-(3-chloro-4-fluoro-benzyl) thioureidol-phenyll}-amide 690 427 Li ,2,3]Thiadiazole-4-carboxylic acid {4-13-(4-tert-butyl-benzyl) thioureido]-phenyl }-amide 691 399 [1,2,3]Thiadiazole-4-carboxylic acid {4-13-(3,5-dimethyl-benzyl) thioureido]-phenyl}-amnide 692 442 [1 ,2,3llThiadiazole-4-carboxylic acid (4-f 3-[2-(4-dimethylainino-3-methyl phenyl)-ethyl]-thioureido}-phenyl)-amnide 693 479 [1 ,2,3]Thiadiazole-4-carboxylic acid (4- {3-[2-(4-bromo-phenoxy)-ethyl] thioureido }-phenyl)-ainide 694 526 [1 ,2,3]Thiadiazole-4-carboxylic acid (4-f 3-[2-(4-iodo-phenoxy)-ethyij thioureido }-phenyl)-ainide 695 489 N-(4-{ 3-[2-(4-Bromo-phenoxy)-ethyl]-thioureido-phenyl)-2-fluoro. benzamnide 696 536 2-Fluoro-N-(4-{ 3-[2-(4-iodo-phenoxy)-ethyl]-thioureido }-phenyl) benzamide 697 461 Furan-2-carboxylic acid (4-f 3-[2-(4-bromo-phenoxy)-ethyl]-thioureido} phenyl)-amide 698 508 Furan-2-carboxylic acid (4-{ 3-12-(4-iodo-phenoxy)-ethyl]-thioureido } phenyl)-amide 699 408 Oxazole-4-carboxylic acid { 4 -[3-(3,4-dichloro-phenyl)-thioureido] phenyl }-amide 700 424 Thiazole-4-carboxylic acid {4-13-(3,5-dichloro-phenyl)-thioureido] phenyl}-amnide 701 491 Thiazole-4-carboxylic acid {4-13-(3,5-bis-trifluoromethyl-phenyl).

WO 00/34258 PCTIUS99/28842 - 132 thioureido]-phenyl)}-amide 702 408 Oxazole-4-carboxylic acid {4-r3-(3,5-dichloro-phenyl)-thioureido] phenyl }-ainide 703 469 [1 ,2,3]Thiadiazole-4-carboxylic acid (4-{ 3-[2-(3,4-dichloro-phenoxy) ethyl]-thioureido }-phenyl)-amide 704 424 Thiazole-4-carboxylic acid {4-r3-(3,4-dichloro-phenyl)-thioureido] phenyll}-amnide 705 458 Thiazole-4-carboxylic acid {4-[3-(4-chloro-3-trifluoromethyl-phenyl) thioureido]-phenyl I -amide 706 400 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-phenylamino-etiyl) thioureido]-phenyl I -amnide, 707 453 [1 ,2,3]Thiadiazole-4-carboxylic acid (4-{ 3-[2-(2,4-dichloro-phenyl)-ethyl] thioureido }-phenyl)-ainide 708 452 ri ,2,3]Thiadiazole-4-carboxylic acid (4-{ 3-[2-(3-trifluoromethyl-phenyl) ethyl] -thioureido} -phenyl)-amide 709 453 [1 ,2,3]Thiadiazole-4-carboxylic acid (4-{ 3-[2-(2,6-dichloro-phenyl)-ethyl] thioureido} -phenyl)-amnide 710 485 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3,4-dichloro phenylsulfanyl)-ethyl]-thioureido} -phenyl)-amide 711 503 [1 ,2,3]Thiadiazole-4-carboxylic acid (4-{ 3-[2-(2-fluoro-5-trifluoromethyl phenylsulfanyl)-ethyl]-tiiioureido} -phenyl)-amide 712 668 N-(4-{ 3

-[

3 -Chloro-5-(3-{ 4-[([1,2,3]thiadiazole-4-carbonyl)-amino] phenyl }-thioureido)-phenyl]-thioureido} -phenyl)-[1 ,2,3]thiadiazole-4 carboxamide 713 413 [l,2,3]Thiadiazole-4-carboxylic acid (4-({3-[2-(4-ethyl-phenyl)-ethyl] thioureido I -phenyl)-ainide 714 442 Oxazole-4-carboxylic acid {4-[3-(4-chloro-3-trifluoromethyl-phenyl) thioureidol-phenyl }-amide 715 475 Oxazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl-phenyl) thioureido]-phenyl }-amide 716 420 [1,2,3]Tbiadiazole-4-carboxylic acid (4-f 3-[2-(3,4-difluoro-phenyl)-ethyl] thioureido I -phenyl)-amide 717 452 [1,2,3]Thiadiazole-4-carboxylic acid (4-1{3-12-(4-trifluoromethyl-phenyl) ethyl]-thioureido}-phenyl)-amide 718 435 Furan-2-carboxylic acid (4-f{3-[2-(3,4-dichloro-phenyl)-ethyl]-thioureido} phenyl)-amide 719 463 N-(4-{ 3-[ 2 -(3,4-Dichloro-phenyl)-ethyl]-thioureido I -phenyl)-2-fluoro benzamide WO 00/34258 PCT/US99/28842 - 133 720 420 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3,5-difluoro-phenyl)-ethyl] thioureido } -phenyl)-amide 721 412 2-Fluoro-N-(4-{ 3-[2-(2-fluoro-phenyl)-ethyl]-thioureido } -phenyl) benzamide 722 429 [1,2,3]Thiadiazole-4-carboxylic acid (4-{ 3-[2-(4-nitro-phenyl)-ethyl] thioureido } -phenyl)-amide 723 399 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(1 -methyl-2-phenyl-ethyl) thioureido]-phenyl } -amide 724 437 N- {4-[3-(4-tert-Butyl-benzyl)-thioureido]-phenyl } -2-fluoro-benzamide 725 409 N-{4-[3-(3,5-Dimethyl-benzyl)-thioureido]-phenyl}-2-fluoro-benzamide 726 400 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-hydroxy-1-phenyl-ethyl) thioureido]-phenyl}-amide 727 409 2-Fluoro-N-{4-[3-(i-methyl-1-phenyl-ethyl)-thioureido]-phenyl} benzamide 728 399 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(1-methyl-1-phenyl-ethyl) thioureido]-phenyl}-amide 729 405 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-chloro-benzyl)-thioureido] phenyl }-amide 730 388 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-fluoro-benzyl)-thioureido] phenyl}-amide 731 438 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-trifluoromethyl-benzyl) thioureido]-phenyl}-amide 732 388 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-fluoro-benzyl)-thioureido] phenyl } -amide 733 435 [1,2,3]Thiadiazole-4-carboxylic acid (4-{ 3-[2-(2-chloro-phenoxy)-ethyl] thioureido} -phenyl)-amide 734 479 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-bromo-phenoxy)-ethyl] thioureido}-phenyl)-amide 735 418 [1,2,3]Thiadiazole-4-carboxylic acid (4-{ 3-[2-(2-fluoro-phenoxy)-ethyl] thioureido}-phenyl)-amide 736 418 [1,2,3]Thiadiazole-4-carboxylic acid (4-{ 3-[2-(3-fluoro-phenoxy)-ethyl] thioureido}-phenyl)-amide 737 486 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(2-fluoro-5-trifluoromethyl phenoxy)-ethyl]-thioureido}-phenyl)-amide 738 384 Furan-2-carboxylic acid (4-{ 3-[2-(2-fluoro-phenyl)-ethyl]-thioureido} phenyl)-amide 739 435 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-bromo-phenyl)-thioureido] phenyl} -amide WO 00/34258 PCTIUS99/28842 - 134 740 374 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-L3-(4-fluoro-phenyl)-thioureido] phenyll}-amide 741 388 Li ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-fluoro-benzyl)-thioureido] phenyl)}-amide 742 405 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-chloro-benzyl)-thioureido] phenyll}-amnide 743 449 L1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-bromo-benzyl)-thioureido] phenyll}-ainide 744 332 N-(4- { 3-Li -(4-Fluoro-phenyl)-ethyl]-thioureido)}-phenyl)-acetamide 745 438 Thiazole-4-carboxylic acid {4-[3-(3,4-dichloro-benzyl)-thioureido] phenyl }-amide 746 455 Thiazole-4-carboxylic acid f{4-[3-(2-fluoro-5-trifluoromethyl-benzyl) thioureido]-phenyl}-amide 747 426 Thiazole-4-carboxylic acid {4-[3-(4-tert-butyl-benzyl)-thioureido] phenyl }-amide 748 374 Li ,2,3]Thiadiazole-4-carboxylic acid {4-L3-(2-fluoro-phenyl)-thioureido] phenyl)}-amnide 749 374 [1 ,2,3]Thiadiazoie-4-carboxylic acid {4-L3-(3-fluoro-phenyl)-thioureido] phenyl }-amnide 750 526 Li ,2,3]Thiadiazole-4-carboxylic acid (4-f{ 3-[2-(3-iodo-phenoxy)-ethyl] thioureido}-phenyi)-amide 751 409 N-(4-{ 3-Li -(4-Fiuoro-phenyl)-ethyl]-thioureido I-phenyl)-2-phenyl acetamide 752 425 N-(4-{ 3-[L-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-methoxy benzarnide 753 425 N-(4- { 3-[i -(4-Fluoro-phenyi)-ethyl]-thioureido}-phenyi)-3-methoxy benzamide 754 425 N-(4-{ 3-[L-(4-Fluoro-phenyl)-ethyl]-thioureido }-phenyl)-4-methoxy benzamnide 755 429 2-Chloro-N-(4- f 3-[i -(4-fluoro-phenyi)-ethyl]-thioureido }-phenyl) benzamnide 756 429 4-Chloro-N-(4-{ 3-[l1-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl) benzamnide 757 453 Acetic acid 4-(4-{ 3-Li -(4-fluoro-phenyl)-ethyl]-thioureido} -phenyl carbamoyl)-phenyl ester 758 394 N-(4-{ 3-[i -(4-Fiuoro-phenyi)-ethyl]-thioureido }-phenyl)-benzamnide 759 395 N-(4-{ 3-[L-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyi)-isonicotinainide 760 410 N-(4-{ 3-[i -(4-Fluoro-phenyl)-ethyl]-thioureido }-phenyl)-4-hydroxy- WO 00/34258 PCTIUS99/28842 - 135 benzamide 761 429 3-Chloro-N-(4-1{3-LI -(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl) benzainide 762 470 [1,2,3]Thiadiazole-4-carboxylic acid (4-({3-[2-(3-fluoro-5-trifluoromethyl phenyl)-ethyl]-thioureido }-phenyl)-amnide 763 520 [1 ,2,3]Thiadiazole-4-carboxylic acid (4-1{3-L2-(2,4-bis-trifluoromethyl phenyl)-ethyl]-thioureido }-phenyl)-amnide 764 470 [1 ,2,3]Thiadiazole-4-carboxylic acid (4- {3-[2-(4-fluoro-3-trifluoromethyl phenyl)-ethyl]-thioureido)}-phenyl)-ainide 765 438 4-Dimethylamino-N-(4- {3-LI -(4-fluoro-phenyl)-ethyl]-thioureido} phenyl)-benzamnide 766 470 Li ,2,3]Thiadiazole-4-carboxylic acid (4-f{ 3-[2-(2-fluoro-3-trifluoromethyl phenyl)-ethyl]-thioureido }-phenyl)-amide 767 470 Li ,2,3]Thiadiazole-4-carboxylic acid (4-1{3-L2-(2-fluoro-5-trifluoromethyl phenyl)-ethyl]-thioureido} -phenyl)-aicle 768 510 Li ,2,3]Thiadiazole-4-carboxylic acid (4- {3-L2-(3-iodo-phenyl)-ethyl] thioureidol}-phenyl)-amicle 769 470 Li ,2,3]Thiadiazole-4-carboxylic acid (4- {3-L2-(4-fluoro-2-trifluoromethyl phenyl)-ethyll-thioureido }-phenyl)-amide 770 463 Li ,2,3]Thiadiazole-4-carboxylic acid (4-f 3-[2-(3-bromo-phenyl)-ethyl] thioureido} -phenyl)-amide 771 427 2-Fluoro-N-(4-{ 3-Il-(4-fluoro-phenyl)-propyl]-thioureido }-phenyl) benzainide 772 475 2-Fluoro-N-(4-{ 3-jI(4-fluoro-phenyl)-phenyl-methyi]-thioureido} phenyl)-benzamnide 773 455 2-Fluoro-N-(4-{ 3-[L-(4-fluoro-phenyl)-pentyl]-thioureido }-phenyl) benzamide 774 489 2-Fluoro-N-(4-{ 3-[i-(4-fluoro-phenyl)-2-phenyl-ethyi]-thioureido } phenyl)-benzamnide 775 409 2-Fluoro-N-{ 4-L3-(i -o-tolyl-ethyl)-thioureido]-phenyi}-benzamnide 776 409 2-Fluoro-N-{ 4-L3-(i -m-tolyl-ethyl)-thioureido]-phenyl} -benzamide 777 425 2-Fluoro-N-(4-{ 3-Li -(4-methoxy-phenyl)-ethyl]-thioureil}-phenyl) benzainide 778 412 2-Fluoro-N-(4-{ 3-[l1-(2-fluoro-phenyl)-ethyl]-thioureido I}-phenyl) benzainide 779 429 N-(4-1{3-Li -(3-Chloro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro benzamide 780 473 N-(4-{ 3-[i -(3-Bromo-phenyl)-ethyl]-thioureido }-phenyl)-2-fluoro- WO 00/34258 PCT/US99/28842 - 136 benzamide 781 429 N-(4-{3-[1-(4-Chloro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro benzamide 782 409 2-Fluoro-N-{4-[3-(1-p-tolyl-ethyl)-thioureido]-phenyl}-benzamide 783 473 N-(4-{3-[1-(2-Bromo-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro benzamide 784 429 N-(4-{3-[1-(2-Chloro-phenyl)-ethyll-thioureido}-phenyl)-2-fluoro benzamide 785 462 2-Fluoro-N-(4-{ 3-[1-(2-trifluoromethyl-phenyl)-ethyl]-thioureido } phenyl)-benzamide 786 462 2-Fluoro-N-(4-{3-[1-(3-trifluoromethyl-phenyl)-ethyl]-thioureido} phenyl)-benzamide 787 462 2-Fluoro-N-(4-{ 3-[1-(4-trifluoromethyl-phenyl)-ethyl]-thioureido} phenyl)-benzamide 788 425 2-Fluoro-N-(4-{3-[1-(2-methoxy-phenyl)-ethyl]-thioureido}-phenyl) benzamide 789 425 2-Fluoro-N-(4-{3-[1-(3-methoxy-phenyl)-ethyl]-thioureido}-phenyl) benzamide 790 441 2-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-2-methyl-propyl]-thioureido} phenyl)-benzamide 791 419 N-(4-{3-[1-(3-Cyano-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro benzamide 792 419 N-(4-{3-[1-(4-Cyano-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro benzamide 793 438 N-(4-{3-[l-(4-Dimethylamino-phenyl)-ethyl]-thioureido}-phenyl)-2 fluoro-benzamide 794 438 N-(4-{3-[1-(3-Dimethylamino-phenyl)-ethyl]-thioureido}-phenyl)-2 fluoro-benzamide 795 473 2-Bromo-N-(4-{3-[I-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl) benzamide 796 446 Quinoline-2-carboxylic acid (4-{ 3-[1-(4-fluoro-phenyl)-ethyl]-thioureido} phenyl)-amide 797 410 2-Fluoro-N-{4-[3-(2-hydroxy-1-phenyl-ethyl)-thioureido]-phenyl} benzamide 798 332 2-Fluoro-N-[4-(3-isopropyl-thioureido)-phenyl]-benzamide 799 445 2-Fluoro-N-{4-[3-(1-naphthalen-2-yl-ethyl)-thioureido]-phenyl} benzamide 800 412 3-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)- WO 00/34258 PCT/US99/28842 - 137 benzamide 801 412 4-Fluoro-N-(4-{3-[1 -(4-fluoro-phenyl)-ethyl]-thioureido} -phenyl) benzamide 802 384 2-Fluoro-N- {4-[3-(1 -furan-2-yl-ethyl)-thioureido]-phenyl } -benzamide 803 395 2-Fluoro-N-{4-[3-(1-pyridin-4-yl-ethyl)-thioureido]-phenyl}-benzamide 804 397 2-Fluoro-N-(4-{3-[1 -(1-methyl-1 H-pyrrol-2-yl)-ethyl]-thioureido} phenyl)-benzamide 805 401 2-Fluoro-N- {4-[3-(1 -thiophen-3-yl-ethyl)-thioureido]-phenyl} benzamide 806 445 N-{4-[3-(3-Chloro-4-ethoxy-phenyl)-thioureido]-phenyl} -2-fluoro benzamide 807 459 N- {4-[3-(3-Chloro-4-propoxy-phenyl)-thioureido]-phenyl } -2-fluoro benzamide 808 459 N-{4-[3-(3-Chloro-4-isopropoxy-phenyl)-thioureido]-phenyl } -2-fluoro Benzamide 809 473 N-{4-[3-(4-Butoxy-3-chloro-phenyl)-thioureido]-phenyl} -2-fluoro benzamide 810 522 2-Fluoro-N-{4-[3-(3-iodo-4-methoxy-phenyl)-thioureido]-phenyl} benzainide 811 475 N-{4-[3-(3-Bromo-4-methoxy-phenyl)-thioureido]-phenyl}-2-fluoro benzamide 812 520 N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido } -phenyl)-2-iodo benzamide 813 346 N-(4-{ 3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido} -phenyl)-propionamide 814 286 N-[4-(3-Phenyl-thioureido)-phenyl]-acetamide 815 463 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[(1S)-1-(4-bromo-phenyl) ethyl]-thioureido}-phenyl)-amide 816 463 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[(1R)-1-(4-bromo-phenyl) ethyl]-thioureido}-phenyl)-amide 818 520 [1,2,3]Thiadiazole-4-carboxylic acid (4-{ 3-[1-(3,5-bis-trifluoromethyl phenyl)-ethyl]-thioureido}-phenyl)-amide 820 418 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[(IS)-1-(4-chloro-phenyl) ethyl] -thioureido }-phenyl)-amide 821 418 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[(1R)-1-(4-chloro-phenyl) ethyl]-thioureido}-phenyl)-amide 822 409 N-[4-[[[[1-(4-Cyanophenyl)ethyl]amino]thioxomethyl]amino]phenyl] 1,2,3-thiadiazole-4-carboxamide WO 00/34258 PCTIUS99/28842 - 138 824 462 Thiazole-4-carboxylic acid (4-{3-[I-(4-bromo-phenyl)-ethyl]-thioureido} phenyl)-amide 825 520 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-(1S)-[1-(3,5-bis trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-amide 828 470 N-(4-{[({1-[4-fluoro-3-trifluoromethyl)phenyl]ethyl} amino) carbothioyl]amino}phenyl)-1,2,3-thiadiazole-4-carboxamide 829 486 N-(4-{[({1-[4-chloro-3-hiadiazole-4-carboxamide 830 519 N-(4-{ [({(1S)-1-[3,5-thiazole-4-carboxamide 831 469 N-(4-{[({1- [3-fluoro-5-trifluoromethyl)phenyl]ethyl}amino) carbothioyl]amino}phenyl)-1,3-thiazole-4-carboxamide 832 469 N-(4- { [({ 1-[2-fluoro-4-(trifluoromethyl)phenyl]ethyl I amino) carbothioyl]amino)phenyl)- 1,3-thiazole-4-carboxamide 833 469 N-(4-{[({1- [2-fluoro-5-trifluoromethyl)phenyl]ethyl }amino) carbothioyl]anino}phenyl)- 1,3-thiazole-4-carboxainide 834 519 N-(4-{[({1-[2,4-bis(trifluoromethyl)phenyl]ethyl}amino) carbothioyl]amino}phenyl)- 1,3-thiazole-4-carboxamide 834 411 N-{4-[({[1-(2,4-dimethylphenyl)ethyl]amino}carbothioyl)amino]phenyl} 1,3-thiazole-4-carboxamide 836 452 N-{4-[({[1-(2,4-dichlorophenyl)ethyl]amino}carbothioyl)amino]phenyl} 1,3-thiazole-4-carboxamide 837 397 N-{4-[({[1-(3-methylphenyl)ethyl]amino}carbothioyl)amino]phenyl}-1,3 thiazole-4-carboxamide 838 469 N-(4-{ [({ 1-[4-fluoro-3-trifluoromethyl)phenyl]ethyl }amino) carbothioyl]amino }phenyl)- 1,3-thiazole-4-carboxamide 839 435 N-{4-[({[1-(2-chloro-4 fluorophenyl)ethyl]amino}carbothioyl)amino]phenyl }-1,3 thiazole-4-carboxamide 840 419 N-{4-[({[1-(3,4-difluorophenyl)ethyl]amino}carbothioyl)amino]phenyl} 1,3-thiazole-4-carboxamide 841 480 N-{4-[({[1-(4-bromo-2 fluorophenyl)ethyl]anino }carbothioyl)amino]phenyl }-1,3 thiazole-4-carboxamide 842 401 N-{4-[({[1-(3-fluorophenyl)ethyl]amino}carbothioyl)amino]phenyl}-1,3 thiazole-4-carboxamide 843 462 N-{4-[({[1-(2-bromophenyl)ethyl]amino}carbothioyl)amnino]phenyl}-1,3 thiazole-4-carboxamide 844 462 N-{4-[({[1-(3-bromophenyl)ethyl]amino}carbothioyl)amino]phenyl}-1,3 thiazole-4-carboxamide WO 00/34258 PCT/US99/28842 - 139 845 451 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-{ [({ (1R)-1 -[3,5-bis(trifluoromethyl)phenyl]ethyl }amino) carbothioyl]amino}phenyl)-1,3-thiazole-4-carboxamide 848 452 N-{4-[({[i-(3,4-dichlorophenyl)ethyl]amino}carbothioyl)amino]phenyl} 1,3-thiazole-4-carboxainide 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) carbothioyljamino}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-[({I[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]anino}carbothioyl)amino]phenyl}-1,3 thiazole-4-carboxamide 855 541 N-{4-[({[1-(3,4-dibromophenyl)ethyl]amino}carbothioyl)anino]phenyl} 1,3-thiazole-4-carboxamide 856 435 N-{4-[({[1-(3-chloro-4 fluorophenyl)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)phenyljbutyl}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) WO 00/34258 PCT/US99/28842 - 140 carbothioyl]amino}phenyl)-1,2,3-thiadiazole-4-carboxamide 862 433 N-{4-[({[3,5 bis(trifluoromethyl)benzyl]amino}carbothioyl)amino]phenyl}-1H imidazole-4-carboxamide 863 440 N-{4-[({{1-(4-fluorophenyl)ethyl]amino}carbothioyl)amino]phenyl}-1H imidazole-4-carboxamide 864 506 N-{4-[({[3,5 bis(trifluoromethyl)benzyljamino}carbothioyl)amino]phenyl}-1-methyl 1 H-imidazole-4-carboxamide 865 462 N-(4-{[({ 1-[3,5-bis(trifluoromethyl)phenyl]propyl}amino) carbothioyl]amino }phenyl)- 1 ,3-thiazole-4-carboxamide EXAMPLE 866 (METHOD 32) [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2,5-dichloro-phenyl)-thioureido] phenyl}-amide 5 To a solution of 2,5-dichloroaniline (0.16 g) in tetrahydrofuran (20 mL) is added freshly prepared 1,1'-thiocarbonyldiimidazole (0.20 g) and the mixture is stirred for approximately 30 minutes at room temperature. [1,2,3]-Thiadiazole-4-carboxylic acid (4-amino-phenyl) amide (0.22 g) is added to the reaction flask and the mixture is 10 stirred for approximately 6 hours. The solvent is then removed by evaporation under reduced pressure and warm acetonitrile (3 mL) is added. After 15 hours the mixture is filtered and the collected precipitate is washed with acetonitrile then diethyl ether, and air dried to provide the desired product as a white powder. 15 Using the above procedure and appropriate starting materials the following compounds were prepared: EX. M+H COMPOUND NAME NO. 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-methoxy- WO 00/34258 PCT/US99/28842 benzamnide 871 443 N-{ 4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl }-4-methoxy benzamnide 872 431 N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl }-4-methoxy benzamide 873 431 N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureidol-phenyl }-3-fluoro benzamide 874 431 N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl }-4-fluoro benzamide 875 437 Furan-2-carboxylic acid {4-13-(3,5-dichloro-4-methoxy-phenyl) thioureido]-phenyll}-amnide 876 511 {4-[3-(5-Bromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-carbainic acid hexyl ester 877 481 Hexanoic acid {4-[3-(5-bromo-2,4-dimethoxy-phenyl)-thioureido] phenyl }-amide 878 505 N-{4-[3-(5-Bromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl} -2-fluoro benzamnide, 879 477 Furan-2-carboxylic acid {4-[3-(5-bromo-2,4-dimethoxy-phenyl) thioureido]-phenyll}-amide 880 501 N-{4-[3-(5-Bromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-2 methyl-benzamide 881 517 N-{4-[3-(5-Bromo-2,4-di~methoxy-phenyl)-thioureidol-phenyl }-4 methoxy-benzamide 882 395 N-{4-13-(5-Chloro-2-ethoxy-4-methoxy-phenyl)-thioureido]-phenyl

}

acetamide 883 395 N-{4-[3-(5-Chloro-4-ethoxy-2-methoxy-phenyl)-thioureido]-phenyl

}

acetamide 884 423 N-{ 4-13-(2-Butoxy-5-chloro-4-methoxy-phenyl)-thioureido]-phenyl} acetamide 885 423 N-{ 4-[3-(4-Butoxy-5-chloro-2-methoxy-phenyl)-thioureido]-phenyl

}

acetamide 886 457 N-{4-[3-(2-Benzyloxy-5-chloro-4-methoxy-phenyl)-thioureido]-phenyl} acetainide 887 457 N-{4-[3-(4-Benzyloxy-5-chloro-2-methoxy-phenyl)-thioureido]-phenyl} acetamide 888 421 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-4-methoxy phenyl)-thioureido]-phenyl}-amide 889 424 2-{4-[3-(4-Acetylainino-phenyl)-thioureido]-2-chloro-5-methoxy- WO 00/34258 PCT/US99/28842 - 142 phenoxy}-acetamide 890 367 N-{ 4

-[

3

-(

5 -Chloro-2-hydroxy-4-methoxy-phenyl)-thioureido]-phenyl} acetamide 891 367 N- { 4

-[

3

-(

3 -Chloro-4-methylsulfanyl-phenyl)-thioureido]-phenyl} acetamide 892 447 N-[4-(3-{3-Chloro-4-[methyl-(1-methyl-piperidin-4-yl)-amino]-phenyl} thioureido)-phenyl]-acetamide 893 426 N-(4-{ 3

-[

3 -Chloro-4-(methyl-phenyl-amino)-phenyl]-thioureido} phenyl)-acetamide 894 509 N-[4-(3-{4-[(1-Benzyl-pyrrolidin-3-yl)-methyl-amino]-3-chloro-phenyl} thioureido)-phenyl]-acetamide 895 418 N-(4-{ 3

-[

3 -Chloro- 4 -(cyclopentyl-methyl-amino)-phenyl]-thioureido} phenyl)-acetamide 896 433 N-[4-(3-{ 3-Chloro-4-[methyl-(1-methyl-pyrrolidin-3-yl)-amino] phenyl}-thioureido)-phenyl]-acetamide 897 419 Furan-2-carboxylic acid { 4 -[3-(3-chloro-4-methylsulfanyl-phenyl) thioureido]-phenyl}-amide 898 447 N-{ 4 -[3-(3-Chloro-4-methylsulfanyl-phenyl)-thioureido]-phenyl}-2 fluoro-benzamide 899 465 N-{ 4

-[

3 -(3-Chloro-4-methylsulfanyl-phenyl)-thioureido]-phenyl}-2,6 difluoro-benzamide 900 445 N-{ 4 -[3-(5-Chloro-2-methoxy-4-methyl-phenyl)-thioureido]-phenyl}-2 fluoro-benzamide 901 441 N-f{ 4

-[

3

-(

5 -Chloro-2-methoxy-4-methyl-phenyl)-thioureido]-phenyl}-2 methyl-benzamide 902 434 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-4-dimethylamino phenyl)-thioureido]-phenyl}-amide 903 444 N-{ 4 -[3-(3-Chloro-4-dimethylamino-phenyl)-thioureido]-phenyl}-2 fluoro-benzainide 904 517 [1,2,3]Thiadiazole-4-carboxylic acid [4-(3-{3-chloro-4-[methyl-(1 methyl-piperidin-4-yl)-amino]-phenyl}-thioureido)-phenyl]-amide 905 579 [1,2,3]Thiadiazole-4-carboxylic acid [4-(3-{4-[(1-benzyl-pyrrolidin-3 yl)-methyl-amino]-3-chloro-phenyl}-thioureido)-phenyl]-amide 906 527 N-[4-(3-{3-Chloro-4-[methyl-(1-methyl-piperidin-4-yl)-amino]-phenyl} thioureido)-phenyl]-2-fluoro-benzamide 907 435 [1,2,3]Thiadiazole-4-carboxylic acid { 4 -[3-(5-chloro-2-methoxy-4 methyl-phenyl)-thioureido]-phenyl}-amide 908 589 N-[4-(3-{4-[(1-Benzyl-pyrrolidin-3-yl)-methyl-amino]-3-chloro-phenyl}- WO 00/34258 PCTIUS99/28842 - 143 thioureido)-phenyl]-2-fluoro-benzanide 909 501 Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl) thioureido]-3-trifluoromethyl-phenyl}-amide 910 366 2-Fluoro-N-[4-(3-phenyl-thioureido)-phenyl]-benzamide 911 338 Furan-2-carboxylic acid [4-(3-phenyl-thioureido)-phenyl]-amide 912 356 [1,2,3]Thiadiazole-4-carboxylic acid [4-(3-phenyl-thioureido)-phenyl] amide 913 365 N-(4-{3-[3-Chloro-4-(1-hydroxy-ethyl)-phenyl]-thioureido}-phenyl) acetamide 914 435 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[3-chloro-4-(1-hydroxy ethyl)-phenyl]-thioureido}-phenyl)-amide 915 365 N-(4-{ 3-[3-Chloro-4-(2-hydroxy-ethyl)-phenyl]-thioureido}-phenyl) acetamide 916 445 N-(4-{3-[3-Chloro-4-(1-hydroxy-ethyl)-phenyl]-thioureido}-phenyl)-2 fluoro-benzainide 917 417 Furan-2-carboxylic acid (4-{3-[3-chloro-4-(1-hydroxy-ethyl)-phenyl] thioureido}-phenyl)-amide 918 371 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-amino-phenyl) thioureidol-phenyl}-amide 919 501 Furan-2-carboxylic acid {4-[3-(3-bromo-4-trifluoromethoxy-phenyl) thioureido]-phenyl}-amide 920 423 N-{4-[3-(3-tert-Butyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 1025 440 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-chloro-3,5-dichloro phenyl)-thioureido]-phenyl}-amide 1026 485 N-{4-[3-(1-Benzofuran-2-yl-ethyl)-thioureido]-phenyl}-2 trifluoromethyl-benzainide 1027 412 N-(4-Fluoro-phenyl)-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido} benzamide 1028 446 Isoquinoline-1-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-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-bromo-phenyl)-ethyl] thioureido}-phenyl)-amide 1031 453 Isoquinoline-1-carboxylic acid (4-{ 3-[1-(4-cyano-phenyl)-ethyl] thioureido}-phenyl)-amide 1032 435 Benzofuran-2-carboxylic acid (4-{ 3-[1-(4-fluoro-phenyl)-ethyl] thioureido } -phenyl)-amide WO 00/34258 PCT/US99/28842 - 144 1033 457 Benzofuran-2-carboxylic acid {4-[3-(1-benzofuran-2-yl-ethyl) thioureido]-phenyl} -amide 1034 495 Benzofuran-2-carboxylic acid (4-{3-[1-(4-bromo-phenyl)-ethyl] thioureido } -phenyl)-amide 1035 442 Benzofuran-2-carboxylic acid (4-{3-[1-(4-cyano-phenyl)-ethyl] thioureido}-phenyl)-amide 1036 446 Isoquinoline-3-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl] thioureido }-phenyl)-amide 1037 468 Isoquinoline-3-carboxylic acid {4-[3-(1-benzofuran-2-yl-ethyl) thioureido]-phenyl}-amide 1038 453 Isoquinoline-3-carboxylic acid (4-{3-[1-(4-cyano-phenyl)-ethyl] thioureido}-phenyl)-amide 1039 506 Isoquinoline-3-carboxylic acid (4-{3-[1-(4-bromo-phenyl)-ethyl] thioureido } -phenyl)-anide 1040 446 Quinoline-3-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl] thioureido } -phenyl)-amide 1041 446 Quinoline-4-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl] thioureido}-phenyl)-amide 1042 446 Quinoline-6-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl] thioureido}-phenyl)-amide 1043 446 Quinoline-8-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl] thioureido}-phenyl)-amide 1044 462 N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2 trifluoromethyl-benzamide 1045 419 2-Cyano-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl) benzamide 1046 473 N-{4-[3-(3-Chloro-4-isobutoxy-phenyl)-thioureido]-phenyl}-2-fluoro benzamide 1047 414 2-Fluoro-N-{4-[3-(3-fluoro-4-methoxy-phenyl)-thioureido]-phenyl} benzamide 1048 475 N-(4-{ 3-[3-Chloro-4-(2-methoxy-ethoxy)-phenyl]-thioureido}-phenyl)-2 fluoro-benzamide 1049 398 2-Fluoro-N-{4-[3-(3-fluoro-4-methyl-phenyl)-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 WO 00/34258 PCT/US99/28842 - 145 1052 459 N-(4-{3-[1-(3-Chloro-4-methoxy-phenyl)-ethyl]-thioureido}-phenyl)-2 fluoro-benzamide 1053 417 N-f{4-[3-(5-Chloro-2-hydroxy-phenyl)-thioureido]-phenyl}-2-fluoro benzamide 1054 435 N-{4-[3-(1-Benzofuran-2-yl-ethyl)-thioureido]-phenyl}-2-fluoro benzamide 1055 448 2-Fluoro-N-{ 4 -[3-( 4 -methyl-3-trifluoromethyl-phenyl)-thioureido] phenyl}-benzamide 1056 473 (S)-N-(4-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro benzamide 1057 473 N-(4-{3-[(1R)-1-(4-Bromo-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro benzamide 1058 494 2-Fluoro-N-(4-{3-[ 2 -methoxy-4-(2,2,2-trifluoro-ethoxy)-phenyl] thioureido}-phenyl)-benzamide 1059 399 N-{4-[3-(2-Amino-5-fluoro-phenyl)-thioureido]-phenyl}-2-fluoro benzamide 1060 502 N-(4-{3-[1-(4-Dimethylsulfamoyl-phenyl)-ethyl]-thioureido}-phenyl)-2 fluoro-benzamide 1061 542 2-Fluoro-N-[4-(3-{1-[4-(piperidine-1-sulfonyl)-phenyl]-ethyl} thioureido)-phenyl]-benzamide 1062 562 N-(4-{3-[2,4-Bis-(2,2,2-trifluoro-ethoxy)-phenyl]-thioureido}-phenyl)-2 fluoro-benzamide 1063 409 2-Fluoro-N-{4-[3-((1S)-1-p-tolyl-ethyl)-thioureido]-phenyl}-benzamide 1064 409 2-Fluoro-N-{4-[3-((1R)-1-p-tolyl-ethyl)-thioureido]-phenyl}-benzamide 1065 394 2-Fluoro-N-{4-[3-((1S)-1-phenyl-ethyl)-thioureido]-phenyl}-benzamide 1066 429 N-(4-{3-[(1R)-1-(4-Chloro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro benzamide 1067 429 N-(4-{ 3-[(1 S)- 1 -(4-Chloro-phenyl)-ethyl]-thioureido }-phenyl)-2-fluoro benzamide 1068 394 2-Fluoro-N-{4-[3-((1R)- 1 -phenyl-ethyl)-thioureido]-phenyl }-benzamide 1069 432 N-(4-{ 3-[1-( 4 -Cyano-phenyl)-ethyl]-thioureido}-phenyl)-2-methoxy benzamide 1070 447 N-{4-[3-(l-Benzofuran-2-yl-ethyl)-thioureido]-phenyl}-2-methoxy benzamide 1071 485 N-(4-{ 3-[l-( 4 -Bromo-phenyl)-ethyl]-thioureido}-phenyl)-2-methoxy benzamiide 1072 419 3-Cyano-N-(4-{ 3-[1-( 4 -fluoro-phenyl)-ethyl]-thioureido}-phenyl) benzamide WO 00/34258 PCT/US99/28842 - 146 1073 462 N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-4 trifluoromethyl-benzamide 1074 419 4-Cyano-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl) benzamide 1075 469 2-Fluoro-N-(4-{ 3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2,3,5,6 tetramethyl-phenyl)-benzamide 1076 480 N-(4-{ 3-[l-(4-Cyano-phenyl)-ethyl]-thioureido}-2,5-dimethoxy-phenyl) 2-fluoro-benzamide 1077 473 2-Fluoro-N-(4-{ 3-[I-(4-fluoro-phenyl)-ethyl]-thioureido}-2,5 dimethoxy-phenyl)-benzamide 1078 530 N-{3,5-Dichloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureidoj phenyl }-2-fluoro-benzamide 1079 447 N-(3-Chloro-4-{3-[l-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2 fluoro-benzainide 1080 480 2,3,4,5-Tetrafluoro-N-(4-{ 3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-3 methyl-phenyl)-benzamide 1081 462 2,4,5-Trifluoro-N-(4-{3-[I-(4-fluoro-phenyl)-ethyl]-thioureido}-3 methyl-phenyl)-benzamide 1082 427 2-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-3-methyl phenyl)-benzamide 1083 457 2-Fluoro-N-(4- { 3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-2-methoxy-5 methyl-phenyl)-benzamide 1084 443 2-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-3-methoxy phenyl)-benzamide 1085 570 N-(2,6-Dibromo-4-{ 3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2 fluoro-benzamide 1086 480 2-Fluoro-N-(4-{ 3-[I-(4-fluoro-phenyl)-ethyl]-thioureido}-2 trifluoromethyl-phenyl)-benzamide 1087 541 N-(4-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido}-2-trifluoromethyl phenyl)-2-fluoro-benzamide 1088 487 N-(4-{3-[l1-(4-Cyano-phenyl)-ethyl]-thioureido}-2-trifluoromethyl phenyl)-2-fluoro-benzamide 1089 503 N-{4-[3-(1-Benzofuran-2-yl-ethyl)-thioureido]-2-trifluoromethyl phenyl}-2-fluoro-benzamide 1090 447 N-(2-Chloro-4-{3-[I-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2 fluoro-benzamide 1091 454 N-(2-Chloro-4-{ 3-[I-(4-cyano-phenyl)-ethyl]-thioureido}-phenyl)-2 fluoro-benzamide WO 00/34258 PCT/US99/28842 - 147 1092 437 N-(2-Cyano-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2 fluoro-benzamide 1093 498 N-(4-{3-[i-(4-Bromo-phenyl)-ethyl]-thioureido}-2-cyano-phenyl)-2 fluoro-benzamide 1094 445 N-(2-Cyano-4-{3-[1-(4-cyano-phenyl)-ethyl]-thioureido}-phenyl)-2 fluoro-benzamide 1095 460 N-{4-[3-(1-Benzofuran-2-yl-ethyl)-thioureido]-2-cyano-phenyl}-2 fluoro-benzamide 1096 517 N-(2-Benzoyl-4-{3-[I-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2 fluoro-benzamide 1097 427 2-Fluoro-N-(4- { 3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-2-methyl phenyl)-benzainide 1098 487 N-(4-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido}-2-methyl-phenyl)-2 fluoro-benzamide 1099 434 N-(4-{ 3-[1-(4-Cyano-phenyl)-ethyl]-thioureido}-2-methyl-phenyl)-2 fluoro-benzamide 1100 449 N-{4-[3-(1-Benzofuran-2-yl-ethyl)-thioureido]-2-methyl-phenyl}-2 fluoro-benzamide 1101 456 N-(2-Dimethylamino-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido} phenyl)-2-fluoro-benzanide 1102 526 N-(2-Benzyloxy-4-{3-[1-(4-cyano-phenyl)-ethyl]-thioureido}-phenyl)-2 fluoro-benzamide 1103 519 N-(2-Benzyloxy-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2 fluoro-benzanide 1104 603 N-[4-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido}-2-(2-morpholin-4-yl ethoxy)-phenyl]-2-fluoro-benzamide 1105 603 N-[4-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido}-2-(2-morpholin-4-yl ethoxy)-phenyl]-2-fluoro-benzainide 1106 542 2-Fluoro-N-[4-{3-[l-(4-fluoro-phenyl)-ethyl]-thioureido}-2-(2 morpholin-4-yl-ethoxy)-phenyl]-benzamide 1107 485 N-(2-Butoxy-4-{ 3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2 fluoro-benzamide 1108 492 N-(2-Butoxy-4-{ 3-[1-(4-cyano-phenyl)-ethyl]-thioureido}-phenyl)-2 fluoro-benzamide 1109 589 N-[4-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido}-2-(2-diethylamino ethoxy)-phenyl]-2-fluoro-benzamide 1110 528 N-(2-(2-Diethylamino-ethoxy)-4-{3-[1-(4-fluoro-phenyl)-ethyl] thioureido}-phenyl)-2-fluoro-benzamide WO 00/34258 PCT/US99/28842 - 148 1111 589 N-[4-{3-[i-(4-Bromo-phenyl)-ethyl]-thioureido}-2-(2-diethylamino ethoxy)-phenyl]-2-fluoro-benzamide 1112 457 N-(2-Ethoxy-4-{3-[I1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2 fluoro-benzamide 1113 464 N-(4-{3-[1-(4-Cyano-phenyl)-ethyl]-thioureido}-2-ethoxy-phenyl)-2 fluoro-benzamide 1114 468 2-Fluoro-N-[4-{3-[l-(4-fluoro-phenyl)-ethyl]-thioureido}-2-(2-nitrilo ethoxy)-phenyl]-benzamide 1115 475 N-[4-{3-[i-(4-Cyano-phenyl)-ethyl]-Lhioureido}-2-(2-nitrilo-ethoxy) phenyl]-2-fluoro-benzainide 1116 443 2-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-2-methoxy phenyl)-benzamide 1117 489 2-Fluoro-N-(5-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido } -biphenyl-2-yl) benzamide 1118 514 Isoquinoline-1-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl] thioureido} -2-trifluoromethyl-phenyl)-amide 1119 503 Benzofuran-2-carboxylic acid (4-{3-[i-(4-fluoro-phenyl)-ethyl] thioureido}-2-trifluoromethyl-phenyl)-anide 1120 514 Isoquinoline-3-carboxylic acid (4-{3-[L-(4-fluoro-phenyl)-ethyl] thioureido}-2-trifluoromethyl-phenyl)-amide 1121 471 Isoquinoline-1-carboxylic acid (2-cyano-4-{3-[1-(4-fluoro-phenyl) ethyl]-thioureido}-phenyl)-amide 1122 460 Benzofuran-2-carboxylic acid (2-cyano-4-{3-[I-(4-fluoro-phenyl)-ethyl] thioureido}-phenyl)-amide 1123 471 Isoquinoline-3-carboxylic acid (2-cyano-4-{3-[1-(4-fluoro-phenyl) ethyl]-thioureido}-phenyl)-amide 1124 460 Isoquinoline-1-carboxylic acid (4-{3-[L-(4-fluoro-phenyl)-ethyl] thioureido}-2-methyl-phenyl)-amide 1125 449 Benzofuran-2-carboxylic acid (4-{3-[l-(4-fluoro-phenyl)-ethyl] thioureido}-2-methyl-phenyl)-amide 1126 460 Isoquinoline-3-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl] thioureido}-2-methyl-phenyl)-amide 1127 396 Pyrazine-2-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl] thioureido}-phenyl)-amide 1128 401 Thiophene-2-carboxylic acid (4-{3- [1-(4-fluoro-phenyl)-ethyl] thioureido}-phenyl)-amide 1129 401 Thiophene-3-carboxylic acid (4-{3-[i-(4-fluoro-phenyl)-ethyl] thioureido}-phenyl)-amide WO 00/34258 PCT/US99/28842 - 149 1130 500 2-Isopropyl-thiazole-4-carboxylic acid {4-[3-(4-chloro-3 trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 1131 466 2-Isopropyl-thiazole-4-carboxylic acid {4-[3-(3,5-dichloro-phenyl) thioureido]-phenyl}-amide 1132 466 2-Isopropyl-thiazole-4-carboxylic acid {4-[3-(3,4-dichloro-phenyl) thioureido]-phenyl}-amide 1133 534 2-Isopropyl-thiazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl phenyl)-thioureido]-phenyl}-amide 1134 480 2-Butyl-thiazole-4-carboxylic acid {4-[3-(3,4-dichloro-phenyl) thioureido]-phenyl} -amide 1135 514 2-Butyl-thiazole-4-carboxylic acid {4-[3-(4-chloro-3-trifluoromethyl phenyl)-thioureido]-phenyl} -amide 1136 480 2-Butyl-thiazole-4-carboxylic acid {4-[3-(3,5-dichloro-phenyl) thioureidol-phenyl}-amide 1137 548 2-Butyl-thiazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl phenyl)-thioureido]-phenyl}-amide 1138 438 2-Methyl-thiazole-4-carboxylic acid {4-[3-(3,5-dichloro-phenyl) thioureido]-phenyl} -amide 1139 438 2-Methyl-thiazole-4-carboxylic acid {4-[3-(3,4-dichloro-phenyl) thioureido]-phenyl}-amide 1140 505 2-Methyl-thiazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl phenyl)-thioureido]-phenyl}-amide 1141 534 2-Phenyl-thiazole-4-carboxylic acid {4-[3-(4-chloro-3-trifluoromethyl phenyl)-thioureido]-phenyl}-amide 1142 500 2-Phenyl-thiazole-4-carboxylic acid {4-[3-(3,5-dichloro-phenyl) thioureido]-phenyl}-amide 1143 500 2-Phenyl-thiazole-4-carboxylic acid {4-[3-(3,4-dichloro-phenyl) thioureido]-phenyl}-amide 1144 568 2-Phenyl-thiazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl phenyl)-thioureido]-phenyl}-amide 1145 401 2-Fluoro-N-{4-[3-(1-thiazol-2-yl-ethyl)-thioureido]-phenyl}-benzamide 1146 588 2-Fluoro-N-[4-(3-{1-[i-(toluene-4-sulfonyl)-1H-indol-2-yl]-ethyl} thioureido)-phenyl]-benzanide 1147 446 2-Fluoro-N-{4-[3-(1-quinolin-2-yl-ethyl)-thioureido]-phenyl}-benzamide 1148 446 2-Fluoro-N-{4-[3-(1-quinolin-4-yl-ethyl)-thioureido]-phenyl}-benzamide 1149 446 2-Fluoro-N-{4-[3-(1-isoquinolin-3-yl-ethyl)-thioureido]-phenyl} benzainide 1150 446 2-Fluoro-N-{4-[3-(1-isoquinolin-1-yl-ethyl)-thioureido]-phenyl}- WO 00/34258 PCT/US99/28842 - 150 benzamide 1151 446 2-Fluoro-N- {4-[3-(1 -quinolin-6-yl-ethyl)-thioureido]-phenyl }-benzamide 1152 446 2-Fluoro-N-{4-[3-(1 -quinolin-3-yl-ethyl)-thioureido]-phenyl }-benzamide 1153 413 2-Methoxy-N- {4-[3-(1 -thiophen-3-yl-ethyl)-thioureido] -phenyl} benzamide EXAMPLE 921 (METHOD 33) [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-dichloro-phenyl)-thioureido] phenyl}-amide 5 To a solution of 3,5-dichloroaniline (0.16 g) in tetrahydrofuran (20 mL) is added freshly prepared 1,1'-thiocarbonyl-di-(1,2,4)-triazole (0.20 g) and the mixture is stirred for approximately 30 minutes at room temperature. [1,2,3]-Thiadiazole-4 carboxylic acid (4-amino-phenyl) amide (0.22 g) is added to the reaction flask and 10 the mixture is stirred for approximately 6 hours. The solvent is then removed by evaporation under reduced pressure and warm acetonitrile (3 mL) is added. After 15 hours the mixture is filtered and the collected precipitate is washed with acetonitrile then diethyl ether, and air dried to provide the desired product as a white powder. [M+H] 424. 15 Using the above procedure and appropriate starting materials the following compounds were prepared: EX. M+H COMPOUND NAME NO. 922 465 N-{4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]-phenyl}-3-fluoro benzamide 923 477 N-{4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]-phenyl}-2-methoxy benzamide 924 465 N-{4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido-phenyl}-2-fluoro benzamide 925 477 N-{ 4 -[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]-phenyl}-3-methoxy benzamide 926 399 N-{4-[3-(3,5-Dichloro-2-methoxy-4-methyl-phenyl)-thioureido]-phenyl} -acetamide WO 00/34258 PCT/US99/28842 - 151 927 365 N-{4-[3-(3-Chloro-4-methoxy-5-methyl-phenyl)-thioureido]-phenyl} acetamide 928 331 N-{4-[3-(2-Nitro-phenyl)-thioureido]-phenyl}-acetamide 929 331 N-{4-[3-(4-Nitro-phenyl)-thioureido]-phenyl}-acetamide 930 477 N-{4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]-phenyl}-4-methoxy benzamide 931 351 N-{4-[3-(2-Chloro-5-methoxy-phenyl)-thioureido]-phenyl}-acetamide 932 428 2-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy} acetamide 933 443 {4-[3-(4-Acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy} -acetic acid methyl ester 934 457 {4-[3-(4-Acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy }-acetic acid ethyl ester 935 447 N-{4-[3-(3,5-Dichloro-4-phenoxy-phenyl)-thioureido]-phenyl}-acetamide 936 410 N-(4-{3-[3,5-Dichloro-4-(2-nitrilo-ethoxy)-phenyl]-thioureido}-phenyl) acetamide 937 485 {4-[3-(4-Acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy}-acetic acid tert-butyl ester 938 469 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-dichloro-2-methoxy-4 methyl-phenyl)-thioureido]-phenyl}-amide 939 335 N-{4-[3-(3-Chloro-4-methyl-phenyl)-thioureido]-phenyl}-acetamide 940 335 N-{4-[3-(5-Chloro-2-methyl-phenyl)-thioureido]-phenyl}-acetamide 941 703 N-{4-[3-(4-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro phenyldisulfanyl}-3-chloro-phenyl)-thioureido]-phenyl}-acetamide 942 369 N-{4-[3-(3,5-Dichloro-4-methyl-phenyl)-thioureido]-phenyl}-acetamide 943 598 N-{4-[3-(3,5-Diiodo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-acetamide 944 504 N-{4-[3-(3,5-Dibromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl} acetamide 945 317 N-{4-[3-(6-Methoxy-pyridin-3-yl)-thioureido]-phenyl}-acetamide 946 347 N-{4-[3-(2,6-Dimethoxy-pyridin-3-yl)-thioureido]-phenyl}-acetamide 947 457 Acetic acid 2-{4-[3-(4-acetylamino-phenyl)-thioureido]-2,6-dichloro phenoxy}-ethyl ester 948 365 4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-benzoic acid 949 346 N-{4-[3-(3-Chloro-4-cyano-phenyl)-thioureido]-phenyl}-acetamide 950 512 N-(4-{3-[5-Chloro-2-(4-chloro-phenoxy)-4-pyrrol-1-yl-phenyl]-thioureido} phenyl)-acetamide WO 00/34258 PCT/US99/28842 - 152 951 355 N-{4-[3-(3,4-Dichloro-phenyl)-thioureido]-phenyl } -acetamide 952 339 N-f{4-[3-(3-Chloro-4-fluoro-phenyl)-thioureido]-phenyl } -acetamide 953 447 N-f{4-[3-(3-Chloro-4-iodo-phenyl)-thioureido]-pheny} -acetamide 954 400 N- {4-[3-(4-Bromo-3-chloro-phenyl)-thioureido]-phenyl }-acetamide 955 424 N-[ 4 -(3-{4-[Bis-(2-hydroxy-ethyl)-amino]-3-chloro-phenyl} -thioureido) phenyl]-acetamide 956 434 N-(4- { 3-[3-Chloro-4-(hexyl-methyl-amino)-phenyl]-thioureido }-phenyl) acetamide 957 406 N-(4-{ 3-[3-Chloro-4-(isobutyl-methyl-amino)-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 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-4-trifluoromethyl phenyl)-thioureido]-phenyl}-amide 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-fluoro-benzamide 963 407 Furan-2-carboxylic acid { 4 -[3-(3,4-dichloro-phenyl)-thioureido]-phenyl} amide 964 425 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,4-dichloro-phenyl) thioureido]-phenyl}-amide 965 480 N-{4-[3-(4-Bromo-3-chloro-phenyl)-thioureido]-phenyl}-2-fluoro benzamide 966 527 N-{ 4

-[

3

-(

3 -Chloro-4-iodo-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 967 452 Furan-2-carboxylic acid { 4 -[3-(4-bromo-3-chloro-phenyl)-thioureido] phenyl}-amide 968 499 Furan-2-carboxylic acid {4-[3-(3-chloro-4-iodo-phenyl)-thioureido] phenyl} -amide 969 391 Furan-2-carboxylic acid { 4 -[3-(3-chloro-4-fluoro-phenyl)-thioureido] phenyl}-amide 970 470 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-bromo-3-chloro-phenyl) thioureido]-phenyl}-amide 971 517 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-4-iodo-phenyl) thioureido]-phenyl}-amide 972 419 N-{4-[3-(3-Chloro-4-fluoro-phenyl)-thioureido]-pheny } -2-fluoro benzamide WO 00/34258 PCTIUS99/28842 - 153 973 409 [1 ,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-chloro-4-fluoro-phenyl) thioureidol-phenyl)}-am ide 974 388 N-{4-[3-(3-Chloro-4-isoxazol-5-yl-phenyl)-thioureido]-phenyl }-acetamide 975 387 N-(4-1{3-r3-Chloro-4-(1 H-pyrazol-3-yl)-phenyl]-thioureido }-phenyl) acetaniide 976 355 N-{4-[3-(2,3-Dichloro-phenyl)-thioureido]-phenyl }-acetamide 977 435 N- {4-13-(2,3-Dichloro-phenyl)-thioureido]-phenyl }-2-fluoro-benzamnide 978 407 Furan-2-carboxylic acid {4-[3-(2,3-dichloro-phenyl)-thioureido]-phenyl} amide 979 425 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2,3-dichloro-phenyl) thioureido]-phenyll}-amide 980 355 N-{14-[3-(2,5-Dichloro-phenyl)-thioureido]-phenyl I -acetLamide 981 435 N- {4-13-(2,5-Dichloro-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide 982 407 Furan-2-carboxylic acid { 4 -[3-(2,5-dichloro-phenyl)-thioureido]-phenyl} amide 983 355 N- {4-[3-(3,5-Dichloro-phenyl)-thioureido]-phenyl)}-acetamide 984 435 N-{4-[3-(3,5-Dichloro-phenyl)-thioureido]-phenyl} -2-fluoro-benzamnide 985 407 Furan-2-carboxylic acid {4-[3-(3,5-dichloro-phenyl)-thioureido]-phenyl)} amide 986 390 N-{4-[3-(3,4,5-Trichloro-phenyl)-thioureido]-phenyl }-acetaniide 987 470 2 -Fluoro-N-{4-[3-(3,4,5-trichloro-phenyl)-thioureido]-phenyl 1-beuzainide 988 442 Furan-2-carboxylic acid f{4-[3-(3,4,5-trichloro-phenyl)-thioureido]-phenyl} ainide 989 460 [1 ,2,3llThiadiazole-4-carboxylic acid{4-[3-(3,4,5-tichloro-phenyl) thioureido]-phenyl }-amide 990 458 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-4-isoxazol-5-yl phenyl)-thioureido]-phenyl}-ainide 991 457 [1,2,3]Thiadiazole-4-carboxylic acid(4-{ 3-[3-chloro-4-( 1H-pyrazol-3-yl) phenyl]-thioureido}-phenyl)-amide 992 391 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-13-(3-chloro-phenyl)-thioureido] phenyl}-amide 993 373 Furan-2-carboxylic acid {4-[3-(3-chloro-phenyl)-thioureido]-phenyl }-amide 994 401 N-{4-[3-(3-Chloro-phenyl)-thioureido]-pheny)y2fuoro-benzamide 995 373 Furan-2-carboxylic acid {4-[3-(4-chloro-phenyl)-thioureido]-phenyl }-amide 996 401 N-{4-[3-(4-Chloro-phenyl)-thioureido]-phenyl }-2-fluoro-benzainide 997 391 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-chloro-phenyl)-thioureido]- WO 00/34258 PCT/US99/28842 - 154 phenyl }-ainide 998 401 N- {4-[3-(2-Chloro-phenyl)-thioureido]-phenyl } -2-fluoro-benzamide 999 396 3-(3-{4-r(Furan-2-carbonyl)-amino]-phenyl)}-thioureido)-benzoic acid methyl ester 1000 424 3- { 3 -1 4

-(

2 -Fluoro-benzoylamino)-phenylj-thioureido }-benzoic acid methyl ester 1001 414 3-(3-{4-[([ 1, 2 ,3]Thiadiazole-4-carbonyl)-amino]-phenyl }-thioureido) benzoic acid methyl ester 1002 409 N-[ 4 -[[[r3-(Aminocarbonyl)phenyliamino]thioxomethyl]amino~phenyly2 fluoro-benzamide 1003 373 Furan-2-carboxylic acid { 4

-[

3

-(

2 -chloro-phenyl)-thioureido]-phenyl}-amide 1004 381 Furan-2-carboxylic acid f{ 4

-[

3 -(3-carbamoyl-phenyl)-thioureido]-phenyl

}

amide 1005 399 [1 ,2,3]Thiadiazole-4-carboxylic acid f{ 4 -13-(3-carbamoyl-phenyl) thioureido]-phenyll}-ainide 1006 391 [1 ,2,3]Thiadiazole-4-carboxylic acid { 4 -[3-(2-chloro-phenyl)-thioureido] phenyl }-amide 1007 356 Furan-2-carboxylic acid { 4

-[

3 -(3-fluoro-phenyl)-thioureido]-phenyl }-ainide 1008 383 Furan-2-carboxylic acid { 4

-[

3 -(3-nitro-phenyl)-thioureido]-phenyl}-amide 1009 411 2 -Fluoro-N-{4-[3-(3-nitro-phenyl)thioureido-phenyl-benzamide 1010 422 Furan-2-carboxylic acid {4-[3-(3-trifluoromethoxy-phenyl)-thioureido] phenyl }-amide 1011 450 2 -Fluoro-N-{ 4 -[3-(3-trifluoromethoxy-phenyl)-thioureidoy-phenyl

}

benzamide 1012 384 2-Fluoro-N- { 4 -[3-(3-fluoro-phenyl)-thioureido]-phenyl }-beuzainide 1013 410 3-f 3-[4-(2-Fluoro-benzoylamino)-pheuyl]-thioureido} -benzoic acid 1014 382 3

-(

3

-{

4 -[(Furan-2-carbonyl)-amino]-phenyllthioureido)-enzoic acid 1015 408 N- { 4

-[

3

-(

3 -Acetyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 1016 502 N-{ 4 -[3-(3-Butylsulfamnoyl-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide 1017 380 Furan-2-carboxylic acid { 4 -[3-(3-acetyl-phenyl)-thioureido]-phenyl} -amnide 1018 447 Furan-2-carboxylic acid (4-f 3 -[3-( 2 -hydroxy-ethanesulfonyl)-phenyl] thioureidol}-phenyl)-amide 1019 475 2-Fluoro-N-(4- { 3 -[3-(2-hydroxy-ethanesulfonyl)-phenylj-thioureido} phenyl)-benzamide 1020 474 Furan-2-carboxylic acid { 4 -[3-(3-butylsulfamnoyl-phenyl)-thioureido] phenyl I -ainide WO 00/34258 PCT/US99/28842 - 155 EXAMPLE 1021 (METHOD 57) 1-(4-Fluoro-phenyl)-2-methyl-propan-1-ol 5 To solution of 4-fluorobenzaldehyde (2.0 g) in diethyl ether (40 mL) at 0 'C is added dropwise isopropylmagesium bromide (2.0 M, 9.6 mL) with stirring. After 1.5 hours the reaction is quenched with aqueous ammonium chloride and extracted with diethyl ether. The diethyl ether extracts are washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, flitered and evaporated to give an oil. The 10 oil is purifed by silica gel chromatography eluting with 10% dichloromethane hexanes to give the product, a yellow oil (1.76 g). EXAMPLE 1022 (METHOD 58) 1-(4-Fluoro-phenyl)-2-methyl-propan- 1-one 15 To a solution of 1-(4-Fluoro-phenyl)-2-methyl-propan-l-ol (1.6 g) in acetone (10 mL) at 0 'C is added Jones reagent (20 mL) with stirring. After 10 minutes excess Jones reagent is destroyed by addition of isopropyl alcohol. Diethyl ether is added followed by anhydrous magnesium and the mixture is filtered and evaporated to give 20 the product, a yellow oil (1.2 g). EXAMPLE 1023 (METHOD 59) 3-Dimethylamino-5-trifluoromethyl-benzonitrile 25 To a solution of 3-dimethylamino-5-trifluoromethylbromobenzene (7.3 g) in N,N dimethylformamide (20 mL) is added cuprous cyanide (2.7 g) and the reaction heated at reflux for 12 hours. The reaction is diluted with water (40 mL) and dichloromethane is added. The dichloromethane fraction is washed with concentrated ammonium hydroxide, then water. The solution is dried over anhydrous magnesium 30 sulfate, filtered and concentrated to give a yellow solid which is recrystallized from hexanes to give a yellow solid, (4.7 g).

WO 00/34258 PCT/US99/28842 - 156 The foregoing compounds were tested for activity as herpes virus inhibitors. HUMAN CYTOMEGALOVIRUS Yield assay. Monolayer cultures of human foreskin fibroblasts are infected with 5 HCMV wild-type, typically at a multiplicity of infection equal to 0.2, in the presence of inhibitor compound (varying concentrations). At three days post-infection, total virus produced in these cultures (i.e. virus yield) is assessed by harvesting and titering the virus in 12-well plates of cultured human foreskin fibroblasts (done in the absence of inhibitor). Plaques are quantified at 2 weeks post-infection. An inhibitor 10 of HCMV is identified by the reduction in titer of virus yield in the presence, compared to the titer in the absence of compound. In this assay, the relative anti HCMV activity of an inhibitor is typically determined by calculating the IC50 or IC90 value, that is, the amount of compound required to reduce the virus yield by 50% or 90%, respectively. Table I describes IC 50 data for compounds tested against 15 HCMV. Microtiter plate assay. Ninety-six well plate cultures of human foreskin fibroblasts are infected in the presence of inhibitor compound with a HCMV recombinant mutant virus whose genome contains the prokaryotic beta-glucuronidase 20 gene (Jefferson, R. A., S. M. Burgess, 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 controlled by a viral promoter. An example of such a virus is RV145 (Jones, T. R., V. P. Muzithras, and Y. Gluzman. 1991. Replacement mutagenesis of the human cytomegalovirus genome: US10 and USI 1 gene products 25 are nonessential. J. Virol. 65:5860-5872). Since it is under the control of a viral promoter, beta-glucuronidase expression is an indirect indicator of growth and replication of HCMV in this assay. At 96 hours post-infection, the infected cell lysates are prepared (using 50mM sodium phosphate [pH7.0] containing 0.1% Triton X-100 and 0.1% sarkosyl) and assayed for beta-glucuronidase activity using a 30 substrate for the enzyme which when cleaved yields either a product which can be measured colorimetrically in a spectrophotometer or fluorescently in a microfluorimeter. Examples of such substrates are p-nitrophenyl-beta-D-glucuronide WO 00/34258 PCT/US99/28842 - 157 and methylumbelliferylglucuronide, respectively. The presence of an antiviral compound is indicated by the reduced expression of the HCMV genome resident beta-glucuronidase gene, compared to the absence of inhibitor. Thus, the generation of the chromophore or fluorophore product in this assay is correspondingly reduced. 5 Data from this assay generated using varying amounts of inhibitor compound is also used to estimate the IC50 of an inhibitor compound. HSV antiviral (ELISA) assay 10 Vero cells (ATCC #CCL-81) are plated on 96-well tissue culture plates at 3.5x10 4 cells per 1 0 0 pl tissue culture DMEM (Dulbecco's modified Eagle media) supplemented with 2% fetal bovine serum (FBS) in each well. After overnight incubation @ 37'C (in 5% C0 2 ) and 30 minutes prior to infection with HSV-1 (multiplicity of infection equal to 0.006), cells are either untreated, or treated with 15 test compound (multiple concentrations) or reference standard drug control. After approximately 24 hours post-infection incubation @ 37*C (in 5% C0 2 ), cells are fixed for ELISA assay. The primary antibody is murine anti-HSV glycoprotein D monoclonal primary antibody and the secondary antibody is goat anti-mouse IgG linked to B-galactosidase. Thus the extent of viral replication is determined by 20 assessing B-galactosidase activity by quantifying the generation of the 4-methyl umbelliferone fluorescent cleavage product after addition of the methyl umbelliferyl B-D-galactoside (Sigma #M1633) substrate on a microfluorimeter (365nm for excitation and 450nm for emission). Antiviral activity (IC,,) of the test compound is determined by comparing the flourescence obtained in absence of compound to that 25 obtained in the presence of compound. Data is shown in Table I. VZV antiviral (ELISA) assay For the generation of stock VZV to be used in the assay, VZV strain Ellen (ATCC 30 #VR-1367) is used to infect human foreskin fibroblast (HFF) cells at low multiplicity (less than 0.1) and incubated overnight at 37 0 C in 5% CO 2 . After the overnight incubation, the mixture of uninfected and VZV-infected HFF infected cells are then WO 00/34258 PCT/US99/28842 - 158 harvested and added to each well of 96-well plates (3.5x 10 4 cells in 100 Pl DMEM supplemented with 2% FBS) which contain test compound or the reference standard drug control (in 100p1 DMEM supplemented with 2% FBS per well). These cells are incubated for three days at 37"C in 5% CO 2 , then fixed for ELISA assay. The 5 primary antibody is murine anti-VZV glycoprotein II monoclonal antibody (Applied Biosystems, Inc. #13-145-100) and the secondary antibody is goat anti-mouse IgG linked to B-galactosidase. Thus the extent of viral replication is determined by assessing B-galactosidase activity by quantifying the generation of the 4-methyl umbelliferone fluorescent cleavage product after addition of the methyl umbelliferyl 10 B-D-galactoside (Sigma #M1633) substrate on a microfluorimeter (365nm for excitation and 450nm for emission). Antiviral activity (IC, 0 ) of the test compound is determined by comparing the flourescence obtained in absence of compound to that obtained in the presence of compound. Data is shown in Table I. 15 Table I Example IC50 (ug/ml) % inhibition IC50 IC50 (ug/ml) HSV lOug/ml (ug/ml) HCMV VzV VzV 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 22 >10 5 158 4 52 >15 >10 159 >10 62 >10 >10 160 2.5 27 >10 >10 161 3 113 5 >10 163 3 30 >10 7 166 9 30 >10 >10 167 10 70 3.8 9 168 3 >10 2.5 169 3 26 >10 4 170 >10 32 >10 0.2 172 >10 25 >10 >10 173 >10 31 >10 0.08 WO 00/34258 PCT/US99/28842 - 159 Example IC50 (ug/ml) % inhibition IC50 IC50 (ug/ml) HSV lOug/ml (ug/ml) HCMV vzv 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 1.8 98 5 2 341 2 50 >10 0.15 344 4 72 7 0.25 350 >10 50 >10 1 351 3 90 3.5 0.3 352 3 51 >10 0.6 353 0.6 86 7 0.04 354 0.8 75 7 2 361 8 26 >10 0.25 365 10 75 5 0.035 368 >10 20 >10 0.35 371 >10 45 >10 >10 376 3 83 7 0.8 378 >10 31 >10 0.033 379 >10 27 >10 >10 391 8 97 6 0.019 396 >10 26 >10 0.7 398 >10 5 >10 0.13 403 6 108 >15 0.09 406 >10 28 >10 0.12 409 >10 5 >10 2 411 8 99 2 0.024 413 5 103 5 0.081 416 >10 87 >15 0.25 421 8 >10 0.75 422 5 69 >10 0.058 424 3 103 0.7 0.09 WO 00/34258 PCT/US99/28842 - 160 Example IC50 (ug/ml) % inhibition IC50 IC50 (ug/ml) HSV lOug/ml (ug/ml) HCMV vzv vzv 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 22 >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 22 >10 0.045 488 >10 13 >10 1.2 489 5 99 3.5 0.17 494 >10 6 >10 3.5 495 >10 27 >10 3 500 >10 48 >10 0.021 501 >10 10 >10 0.032 503 8 64 >10 0.053 505 10 79 8 0.2 508 >10 7 >10 0.013 509 >10 31 >10 0.03 510 8 19 >10 0.04 WO 00/34258 PCT/US99/28842 - 161 Example IC50 (ug/ml) % inhibition IC50 IC50 (ug/ml) HSV lOug/ml (ug/ml) HCMV vzv vzv 513 >10 10 >10 0.011 516 >10 7 >10 0.04 521 10 97 3 0.04 522 >10 32 >10 0.025 524 4 95 2 0.055 526 >10 22 2.5 3 528 3.2 107 5 0.25 530 5 96 6 0.15 532 >10 6 0.009 534 7 >10 0.05 535 >10 >10 0.016 537 9 10 0.003 539 >10 >10 0.036 541 7 >10 0.017 542 >10 >10 0.0011 544 >10 >10 0.02 545 3 7 0.012 546 1.7 7 0007 547 >10 10 0.006 548 >10 >10 0.008 550 >10 >10 0.013 551 >10 >10 0.043 554 >10 1.5 0.01 555 >10 4 0.008 556 >10 >7.5 0.006 557 >10 >10 0.006 558 7 >10 0.05 559 >10 >10 0.012 560 >10 >10 0.008 561 >10 8 0.05 562 >10 8 0.004 564 >10 5 0.027 565 >10 0.22 0.01 571 >10 0.013 572 >10 0.0078 573 >10 0.05 574 >10 0.089 575 2 0.017 579 6 0.05 581 >10 0.01 582 8 0.01 584 >10 0.0026 585 >10 0.015 587 >10 0.005 588 >10 0.36 0.03 590 >10 1 0.12 WO 00/34258 PCT/US99/28842 - 162 Example IC50 (ug/ml) % inhibition IC50 IC50 (ug/ml) HSV 10ug/ml (ug/ml) HCMV vzv vzv 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 WO 00/34258 PCT/US99/28842 - 163 Example IC50 (ug/ml) % inhibition IC50 IC50 (ug/ml) HSV 10ug/ml (ug/ml) HCMV vzv vzv 671 >10 0.005 674 >10 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 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 WO 00/34258 PCT/US99/28842 - 164 Example IC50 (ug/ml) % inhibition IC50 IC50 (ug/ml) HSV lOug/ml (ug/mi) HCMV vzv vzv 730 0.033 731 >10 0.007 732 0.022 733 0.018 734 >10 0.009 735 0.022 736 0.012 737 >10 0.005 738 >10 0.11 739 >10 0.02 740 0.1 741 >10 0.02 742 >10 0.009 743 >10 0.09 745 9 0.0025 746 >10 0.005 747 >10 0.002 748 >10 0.28 749 >10 0.06 750 >10 0.01 759 >10 2 >10 762 >10 1.5 0.002 763 5 5 0.004 764 >10 0.004 766 >10 0.006 767 >10 1 0.006 768 >10 0.005 769 >10 0.04 770 >10 0.006 796 >10 >7.5 4 815 0.27 0.0095 816 >7.5 0.0053 818 >7.5 0.0016 820 >7.5 0.006 821 >7.5 0.005 822 >7.5 0.018 824 0.17 0.014 825 >7.5 0.0013 828 >7.5 0.002 829 >7.5 0.002 WO 00/34258 PCT/US99/28842 - 165 Example IC50 (ug/ml) % inhibition IC50 IC50 (ug/ml) HSV 10ug/ml (ug/ml) HCMV vzv vzv 830 >7.5 0.0003 831 >7.5 0.0011 832 >7.5 0.001 833 >7.5 0.0019 834 >7.5 0.002 835 >7.5 0.005 836 >7.5 0.004 837 3.60 0.03 838 >7.5 0.0007 839 >7.5 0.004 840 0.14 0.0015 841 0.77 0.0011 842 1.55 0.02 843 >7.5 0.0031 844 1.03 0.0008 845 >7.5 0.0060 846 1.04 0.0130 847 >7.5 0.0008 848 0.19 0.002 849 1.82 0.002 850 2.33 0.0008 851 1.43 0.017 852 >7.5 0.005 853 0.62 0.004 854 0.02 855 0.02 856 0.02 857 >7.5 0.0006 858 >7.5 0.0007 859 0.5 0.00001 860 >7.5 0.001 861 >7.5 0.002 862 >7.5 0.1 863 >7.5 2.0 864 >7.5 0.5 865 >7.5 0.0001 866 >10 50 >10 0.035 875 >50 18 >10 >2.2 879 4 65 10 0.3 888 6 31 >10 0.06 897 >10 62 >10 0.037 902 >10 10 >10 0.12 904 12 58 >10 0.4 905 4 82 2 0.3 907 >10 36 >10 0.009 911 >10 25 >10 0.3 WO 00/34258 PCT/US99/28842 - 166 Example IC50 (ug/ml) % inhibition IC50 IC50 (ug/ml) HSV lOug/ml (ug/ml) HCMV vzv vzv 912 >10 0 >10 0.16 913 >10 15 >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 0.018 960 >10 58 >10 0.03 961 >10 20 >10 0.006 964 >10 9 >10 0.03 965 >10 36 >10 0.008 966 >10 42 >10 0.02 969 >10 40 >10 0.03 970 >10 16 >10 0.06 971 >10 9 >10 0.013 972 >10 95 >15 0.006 974 >10 14 >10 0.011 979 8 88 12 0.19 980 >10 56 >10 0.05 983 >10 52 >10 0.12 986 >10 5 >10 0.031 989 >10 21 >10 0.016 990 8 99 4.5 0.011 991 >10 3 >10 0.022 992 >10 29 >10 0.018 993 >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 >10 0.12 1009 10 22 >10 0.2 1011 >10 20 >10 0.039 1018 >10 2 >10 0.4 1019 >10 2 >10 1.5 1021 8 68 >10 0.094 1126 >10 0.7 5.8 1127 9.5 3.7 1 1128 >10 >10 1.3 WO 00/34258 PCT/US99/28842 - 167 Example IC50 (ug/ml) % inhibition IC50 IC50 (ug/ml) HSV 10ug/ml (ug/ml) HCMV VZV 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, compounds of the present invention are potent inhibitors of the growth and replication of the herpes viruses, including HCMV, VZV and HSV, effectively 5 inhibiting viral yield. In accordance with the present invention, compounds of the present invention may be administered to a patient suffering from a herpes virus, including HCMV, VZV and HSV in an amount effective to inhibit the virus. Compounds of the present invention are thus useful to ameliorate or eliminate the symptoms of the herpes virus 10 infections in mammals including, but not limited to humans. Compounds of the invention may be administered to a patient either neat or with a convention pharmaceutical carrier. Applicable solid carriers can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, 15 compression aids, binders or tablet-disintegrating agents or an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of 20 the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl WO 00/34258 PCT/US99/28842 - 168 cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins. Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs. The active ingredient of this invention can be dissolved or 5 suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples 10 of liquid carriers for oral and parenteral administration include water (particularly containing additives as above e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil). For parenteral administration the carrier can also be an 15 oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration. Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Oral administration 20 may be either liquid or solid composition form. Preferably the pharmaceutical composition is in unit dosage form, e.g. as tablets or capsules. In such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient; the unit dosage forms can be packaged compositions, for example packeted powders, vials, ampoules, prefilled syringes or 25 sachets containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form. The therapeutically effective dosage to be used in the treatment of herpes virus infection must be subjectively determined by the attending physician. The variables 30 involved include the the condition , age and weight of the patient. The novel method of the invention for treating herpes virus infection comprises administering toa subject, including humans, an effective amount of at least one compound of Formula 1 or a non-toxic, pharmaceutically acceptable salt thereof. The compounds may be WO 00/34258 PCT/US99/28842 - 169 administered orally, rectally, parenterally or topically to the skin and mucosa. The usual daily dose is depending on the specific compound, method of treatment and condition of the patient. The usual daily dose is 0.01 - 1000 mg/Kg for oral application, preferably 0.5 - 500 mg/Kg, and 0.1 - 100 mg/Kg for parenteral 5 application, preferably 0.5 - 50 mg/Kg.

Claims (21)

1. 2. A compound of Claim 1 wherein R, through R, are independently, hydrogen alkyl of 1 to 6 carbon atoms, halogen, perhaloalkyl of 1 to 6 carbon atoms, OR 6 or 10 N(R 7 R 8 ).
2. 3. A compound of Claim 1 wherein R 1 , R 2 and R 3 are hydrogen and R 4 and R, are independently, halogen or CF,. 15 4. A compound of Claim 1 wherein R,, R 2 and R 4 are hydrogen and R, and R, are independently, halogen or CF,.
3. 5. A compound of Claim 1 wherein G is thiazolyl, thiadiazolyl, oxazolyl, furyl or isoquinoline. 20
4. 6. A compound of Claim 1 wherein G is thiazolyl.
5. 7. A compound of Claim 1 wherein G is 1,2,3 thiadiazolyl. 25 8. A compound of Claim 1 wherein X is a bond.
6. 9. A compound of Claim 1 wherein X is straight chain alkyl.
7. 10. A compound of Claim 1 wherein X is alkyl of 1 to 4 carbon atoms. 30
8. 11. A compound of Claim 1 wherein X is CH(J) and J is alkyl of 1 to 6 carbon atoms. WO 00/34258 PCT/US99/28842 - 172 12. A compound of Claim 11 wherein J is methyl.
9. 13. A compound of Claim 1 wherein X is CH(J) and G is thiazolyl. 5 14. A compound of Claim 1 selected from [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl-benzyl)-thioureido]-phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-piperidin-l-yl-3 trifluoromethyl-benzyl)-thioureido]-phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-dimethylamino-3-trifluoro 10 methyl-benzyl)-thioureido]-phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-dimethylamino-5-trifluoro methyl-benzyl)-thioureido]-phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-fluoro-3-trifluoromethyl benzyl)-thioureido]-phenyl}-amide, 15 Thiazole-4-carboxylic acid {4-[3-(4-tert-butyl-benzyl)-thioureido]-phenyl} amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-fluoro-5-trifluoromethyl phenyl)-ethyl]-thioureido} -phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4-bromo-phenyl)-ethyl] 20 thioureido }-phenyl)-amide, Thiazole-4-carboxylic acid {4-[3-(3,4-dichloro-benzyl)-thioureido]-phenyl} amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-dichloro-benzyl)-thioureido] phenyl}-amide, 25 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,4-dichloro-benzyl)-thioureido] phenyl} -amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3,4-dichloro-phenyl)-ethyl] thioureido }-phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4-trifluoromethyl-phenyl) 30 ethyl]-thioureido }-phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4- { 3- [2-(3-chloro-phenyl)-ethyl] thioureido}-phenyl)-amide, WO 00/34258 PCTIUS99/28842 - 173 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-tert-butyl-benzyl)-thioureido] phenyl}-amide, Thiazole-4-carboxylic acid {4-[3-(3,5-dichloro-phenyl)-thioureido]-phenyl} amide, 5 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(2-fluoro-5-trifluoromethyl phenylsulfanyl)-ethyl]-thioureido}-phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(2,4-bis-trifluoromethyl phenyl)-ethyl]-thioureido}-phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4-fluoro-3-trifluoromethyl 10 phenyl)-ethyl] -thioureido } -phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-fluoro-5-trifluoromethyl benzyl)-thioureido]-phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3,5-bis-trifluoromethyl phenyl)-ethyl]-thioureido}-phenyl)-amide, 15 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-iodo-3-trifluoromethyl phenyl)-thioureido]-phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-fluoro-5-trifluoromethyl benzyl)-thioureido]-phenyl }-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-bromo-phenylsulfanyl) 20 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-(2,4-dichloro-phenyl)-ethyl] thioureido } -phenyl)-amide, 25 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-trifluoromethyl-phenyl) ethyl] -thioureido} -phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(2-fluoro-5-trifluoromethyl phenoxy)-ethyl]-thioureido}-phenyl)-amide, Thiazole-4-carboxylic acid {4-[3-(2-fluoro-5-trifluoromethyl-benzyl) 30 thioureido]-phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-iodo-phenyl)-ethyl] thioureido)-phenyl)-amide, WO 00/34258 PCT/US99/28842 - 174 Furan-2-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl-benzyl)-thioureido] phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[3-(2-methyl-butyl)-5 trifluoromethyl-phenyl]-thioureido}-phenyl)-amide, 5 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-isobutyl-5-trifluoromethyl phenyl)-thioureido]-phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-dimethylamino-5 trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(5-bromo-2-methoxy-phenyl) 10 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- [2- (3,5-dichloro-phenoxy)-ethyl] thioureido}-phenyl)-amide, 15 Thiazole-4-carboxylic acid {4-[3-(3,4-dichloro-phenyl)-thioureido]-phenyl} amide, Thiazole-4-carboxylic acid {4-[3-(4-chloro-3-trifluoromethyl-phenyl) thioureido] -phenyl} -amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3,4-dichloro-phenylsulfanyl) 20 ethyl] -thioureido }-phenyl)-amide, [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, 25 [1,2,3]Thiadiazole-4-carboxylic acid (4-(3-[2-(3-bromo-phenyl)-ethyl] thioureido}-phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-[3-(3-chloro-4-trifluoromethyl phenyl)-thioureido]-phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-4-iodo-phenyl) 30 thioureido]-phenyl }-amide, Furan-2-carboxylic acid [4-(3-benzo[1,3]dioxol-5-ylmethyl-thioureido) phenyl]-amide, WO 00/34258 PCT/US99/28842 - 175 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[i-(4-bromo-phenyl)-ethyl] thioureido }-phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,3-diphenyl-propyl)-thioureido] phenyl}-amide, 5 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-4-fluoro-benzyl) thioureido]-phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3,4-dichloro-phenoxy)-ethyl] thioureido}-phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-trifluoromethyl-benzyl) 10 thioureido]-phenyl }-amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-benzyl)-thioureido] phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-bromo-3-trifluoromethyl phenyl)-thioureido)-phenyl}-amide, 15 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4-fluoro-phenyl)-ethyl] thioureido}-phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-pyrrolidin-1-yl-5 trifluoromethyl-phenyl)-thioureido]-phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[3-(butyl-methyl-amino)-5 20 trifluoromethyl-phenyl]-thioureido}-phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-dimethyl-benzyl)-thioureido] phenyl}-amide, Thiazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl-phenyl) thioureido)-phenyl}-amide, 25 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,4-dichloro-phenyl)-thioureido] phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-bromo-5-trifluoromethyl phenyl)-thioureido]-phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-chloro-phenoxy)-ethyl] 30 thioureido }-phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4-ethyl-phenyl)-ethyl] thioureido}-phenyl)-amide, WO 00/34258 PCT/US99/28842 - 176 [1,2,3]Thiadiazole-4-carboxylic acid (4-{ 3-[2-(3-bromo-phenoxy)-ethyl] thioureido}-phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-chloro-benzyl)-thioureido] phenyl}-amide, 5 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(5-chloro-2-methoxy-4-methyl phenyl)-thioureido]-phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-fluoro-phenyl)-ethyl] thioureido}-phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl] 10 thioureido }-phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-difluoro-benzyl)-thioureido] phenyl}-amide, Furan-2-carboxylic acid {4-[3-(3,5-dichloro-benzyl)-thioureido]-phenyl} amide, 15 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-p-tolyl-ethyl)-thioureido] phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-phenyl-butyl)-thioureido] phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-phenylsulfanyl-ethyl) 20 thioureido]-phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-iodo-benzyl)-thioureido] phenyl}-amide, Furan-2-carboxylic acid (4-{3- [2-(3-bromo-phenylsulfanyl)-ethyl] thioureido}-phenyl)-amide, 25 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-difluoro-phenyl)-ethyl] thioureido}-phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3,5-difluoro-phenyl)-ethyl] 30 thioureido}-phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4- { 3- [2- (3-iodo-phenoxy)-ethyl] thioureido } -phenyl)-amide, WO 00/34258 PCTIUS99/28842 - 177 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-dichloro-phenyl)-thioureido] phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid {4- [3-(3-amino-5-chloro-phenyl) thioureido]-phenyl}-amide, 5 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-bromo-phenyl)-thioureido] phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[3-(isobutyl-methyl-amino)-5 trifluoromethyl-phenyl]-thioureido}-phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-phenyl-propyl)-thioureido] 10 phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid {4- [3-(3-chloro-4-fluoro-phenyl) thioureido]-phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,4,5-trichloro-phenyl) thioureido]-phenyl}-amide, 15 Furan-2-carboxylic acid {4-[3-(3,4-dichloro-benzyl)-thioureido]-phenyl} amide, [1,2,3]Thiadiazole-4-carboxylic acid (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 20 phenyl)-thioureido]-phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-fluoro-phenoxy)-ethyl] thioureido}-phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-[3-(3-iodo-phenyl)-thioureido] phenyl } -amide, 25 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-bromo-4-trifluoromethoxy phenyl)-thioureido]-phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid {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)-3 30 trifluoromethyl-benzyl]-thioureido}-phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,4-difluoro-benzyl)-thioureido] phenyl}-amide, WO 00/34258 PCT/US99/28842 - 178 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-bromo-3-chloro-phenyl) thioureido] -phenyl} -amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-phenyl)-thioureido] phenyl}-amide, 5 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-phenoxy-ethyl)-thioureido] phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4- {3- [2- (3-methoxy-phenyl)-ethyl] thioureido}-phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-4-methyl-phenyl) 10 thioureido]-phenyl}-amide, Furan-2-carboxylic acid {4-[3-(3-fluoro-5-trifluoromethyl-benzyl) thioureido] -phenyl} -amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4-nitro-phenyl)-ethyl] thioureido}-phenyl)-amide, 15 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-piperidin-l-yl-5 trifluoromethyl-phenyl)-thioureido]-phenyl}-amide, Oxazole-4-carboxylic acid {4-[3-(3,4-dichloro-phenyl)-thioureido]-phenyl} amide, Furan-2-carboxylic acid {4-[3-(3,4,5-trichloro-phenyl)-thioureido]-phenyl} 20 amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-chloro-phenyl)-thioureido] phenyl }-amide, [1,2,3]Thiadiazole-4-carboxylic acid [4-(3-benzo[1,3]dioxol-5-ylmethyl thioureido)-phenyl]-amide, 25 [1,2,3]Thiadiazole-4-carboxylic acid [4-(3-phenethyl-thioureido)-phenyl] amide, [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-(3,5-bis-trifluoromethyl-phenyl) 30 thioureido]-phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-dichloro-2-methoxy-4 methyl-phenyl)-thioureido]-phenyl}-amide, WO 00/34258 PCT/US99/28842 - 179 [1,2,3]Thiadiazole-4-carboxylic acid(4- (3- [3-chloro-4-(1 H-pyrazol-3-yl) phenyl]-thioureido}-phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[3-chloro-4-(2-piperidin-1-yl acetylamino)-phenyl]-thioureido}-phenyl)-amide, 5 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-trifluoromethyl-phenyl) thioureido]-phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-[3-(4-chloro-3-trifluoromethyl phenyl)-thioureido]-phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-(3-[3-chloro-4-(cyclohexyl-methyl 10 amino)-phenyl] -thioureido} -phenyl)-amide, Furan-2-carboxylic acid [4-(3-benzyl-thioureido)-phenyl]-amide, Furan-2-carboxylic acid (4-{3- [2-(3,5-dichloro-phenoxy)-ethyl] -thioureido} phenyl)-amide, Furan-2-carboxylic acid (4-[3-(2-fluoro-5-trifluoromethyl-benzyl) 15 thioureido]-phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-bromo-4-methoxy-phenyl) ethyl]-thioureido } -phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-(3-[2-(2-chloro-phenyl)-ethyl] thioureido }-phenyl)-amide, 20 Oxazole-4-carboxylic acid (4-[3-(4-chloro-3-trifluoromethyl-phenyl) thioureido]-phenyl}-amide, Furan-2-carboxylic acid (4-{3-[2-(3,4-dichloro-phenyl)-ethyl]-thioureido} phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-chloro-benzyl)-thioureido] 25 phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-[3-(4-bromo-phenyl)-thioureido] phenyl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-fluoro-benzyl)-thioureido] phenyl}-amide, 30 Furan-2-carboxylic acid (4-[3-(4-bromo-3-chloro-phenyl)-thioureido] phenyl ) -amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-(3-[(1S)-1-(4-bromo-phenyl)-ethyl] thioureido } -phenyl)-amide, WO 00/34258 PCT/US99/28842 - 180 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[(iR)-1-(4-bromo-phenyl)-ethyl] thioureido} -phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4- { 3-[1-(3,5-bis-trifluoromethyl phenyl)-ethyl]-thioureido} -phenyl)-amide, 5 [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- [(1 R)- 1-(4-chloro-phenyl)-ethyl] thioureido } -phenyl)-amide, N- [4- [[[[1-(4-Cyanophenyl)ethyl] amino] thioxomethyl] amino]phenyl] -1,2,3 10 thiadiazole-4-carboxamide, Thiazole-4-carboxylic acid (4-{ 3- [1-(4-bromo-phenyl)-ethyl] -thioureido} phenyl)-amide, [1,2,3]Thiadiazole-4-carboxylic acid (4-(3-(1S)-[1-(3,5-bis-trifluoromethyl phenyl)-ethyl]-thioureido}-phenyl)-amide, 15 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-hiadiazole-4-carboxamide, N-(4-{[({(1S)-1-[3,5-thiazole-4-carboxamide; N- (4- { [({1- [3-fluoro-5- (trifluoromethyl)phenyl] ethyl} amino)carbothioyl] 20 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, 25 N-(4-{ [({ 1- [2,4-bis(trifluoromethyl)phenyl] ethyl) amino)carbothioyl] amino Iphenyl)-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 30 thiazole-4-carboxamide, N- {4- [({ [1-(3-methylphenyl)ethyl] amino I carbothioyl)amino]phenyl} -1,3 thiazole-4-carboxamide, WO 00/34258 PCT/US99/28842 - 181 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, 5 N- {4- [({[i-(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 10 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, 15 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}-1,3 thiazole-4-carboxamide, N-(4-{ [({ (1R)- 1- [3,5-bis(trifluoromethyl)phenyl]ethyl } amino)carbothioyl] 20 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, 25 N-(4-{ [((1- [4-chloro-3-(trifluoromethyl)phenyl] ethyl} amino)carbothioyl] amino}phenyl)- 1,3-thiazole-4-carboxamide, N-{4-[({ [I- (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] 30 amino lphenyl)- 1,3-thiazole-4-carboxamide, N- (4- [(([1-(4-chloro-3-fluorophenyl)ethyl] amino } carbothioyl)amino] phenyl} -1,3-thiazole-4-carboxamide WO 00/34258 PCT/US99/28842 - 182 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, 5 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) 10 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 } carbothio yl)amino]phenyl }-1,2,3-thiadiazole-4-carboxamide, 15 N-(4- {[({1-[3,5-bis(trifluoromethyl)phenyl] -1 -methylethyl) amino)carbothio yl] 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 20 imidazole-4-carboxamide, N- (4- [({ [3,5-bis(trifluoromethyl)benzyl] amino) carbothioyl)amino]phenyl} 1-methyl-iH-imidazole-4-carboxamide, and N-(4-{[({1-[3,5-bis(trifluoromethyl)phenyl]propyl)amino)carbothioyl] amino)phenyl)-1,3-thiazole-4-carboxamide; or a pharmaceutical salt thereof. 25
10. 15. A compound which is [1,2,3]-Thiadiazole-4-Carboxylic Acid {4-[3(3,5-bis trifluoromethylphenyl)-thioureido] -phenyl} amide; or a pharmaceutical salt thereof.
11. 16. A compound which is [1,2,3]Thiadiazole-4-carboxylic acid (4-[3-(4-chloro-3 30 trifluoromethyl-phenyl)-thioureido]-phenyl)-amide; or a pharmaceutical salt thereof.
12. 17. A compound which is Thiazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoro methyl-phenyl)-thioureido]-phenyl}-amide; or a pharmaceutical salt thereof. WO 00/34258 PCTIUS99/28842 - 183 18. A pharmaceutical composition comprising a compound of the formula: R4 R 3 - X-NH-C-NH NH-C-G R 2 R 1 5 wherein RIR5 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, 10 halogen, -CN, -NO 2 , -CO 2 R , -COR 6 , -OR6, -SR6, -SOR, -S0 2 R,, -CONR,R, -NR 6 N(R,R,), -N(RR,) or W-Y-(CH 2 )-Z provided that at least one of R 1 -R, is not hydrogen; or R 2 and R 3 or R 3 and R 4 , taken together form a 3 to 7 membered heterocycloalkyl or 3 to 7 membered heteroaryl; 15 R 6 and R, are independently hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of I 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 20 R, and R , taken together may form a 3 to 7 membered heterocycloalkyl; W is 0, NR, or is absent; Y is -(CO)- or -(CO 2 )-, or is absent; Z is alkyl of 1 to 4 carbon atoms, -CN, -CO 2 R , COR 6 , -CONRR 8 , -OCOR 6 , -NR 6 COR,, -OCONR 6 , -OR 6 , -SR, -SOR, -S0 2 R, SR 6 N(RR,), 25 -N(RR.) 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; 30 J is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl or benzyl; and WO 00/34258 PCTIUS99/28842 - 184 n is an integer from 1 to 6, or a pharmaceutical salt thereof, and a pharmaceutically acceptable carrier or diluent.
13. 19. A method of inhibiting the replication of a herpes virus comprising contacting 5 a compound of the formula: R 4 R 5 S 0 R 3 X-NH-C-NH \ / NH-C-G 2 wherein 10 R 1 -R 5 are independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10 carbon members, aryl, heteroaryl, halogen, -CN, -NO 2 , -C0 2 R 6 , -COR, -OR 6 , -SR6, -SOR 6 , -S0 2 R , 15 -CONRR,, -NRN(RR 8 ), -N(RR) or W-Y-(CH 2 )n-Z provided that at least one of R,-R 5 is not hydrogen; or R 2 and R 3 or R a n d R 4 , taken together form a 3 to 7 membered heterocycloalkyl or 3 to 7 membered heteroaryl; R 6 and R, are independently hydrogen, alkyl of 1 to 6 carbon atoms, 20 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, and R 8 , taken together may form a 3 to 7 membered heterocycloalkyl; 25 W is 0, NR , or is absent; Y is -(CO)- or -(CO 2 )-, or is absent; Z is alkyl of 1 to 4 carbon atoms, -CN, -CO 2 R 6 , COR 6 , -CONR 7 R, -OCOR., -NR 6 COR, -OCONR,, -OR , -SR , -SOR, -SO 2 R 6 , SR6N(R7R8), -N(R,R,) or phenyl; 30 G is monocyclic heteroaryl; WO 00/34258 PCT/US99/28842 - 185 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 5 benzyl; and n is an integer from 1 to 6, or a pharmaceutical salt thereof, with a herpes virus.
14. 20. The method of Claim 19 wherein the herpes virus is human 10 cytomegalovirus.
15. 21. The method of Claim 19 wherein the herpes virus is varicella zoster virus.
16. 22. The method of Claim 21 wherein the compound is substantially pure (S) 15 optical isomer.
17. 23. The method of Claim 19 wherein the herpes virus is herpes simplex virus.
18. 24. A method of treating a patient suffering from a herpes virus infection 20 comprising administering to the patient a therapeutically effective amount of a compound having the formula: R4 5 R3 X-NH-C-NHNH-C-G R 2 R 1 25 wherein R 1 -R 5 are independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10 carbon members, aryl, heteroaryl, 30 halogen, -CN, -NO 2 , -CO 2 R , -COR, -OR, -SR, -SOR, -So 2 R 6 , WO 00/34258 PCT/US99/28842 - 186 -CONR,R, -NR 6 N(RR,), -N(RR,) or W-Y-(CH 2 ),-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 , taken together form a 3 to 7 membered heterocycloalkyl or 3 to 7 membered heteroaryl; 5 R 6 and R, 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 10 R, and R,, taken together may form a 3 to 7 membered heterocycloalkyl; W is 0, NR 6 , or is absent; Y is -(CO)- or -(CO 2 )-, or is absent; Z is alkyl of 1 to 4 carbon atoms, -CN, -C0 2 R 6 , COR 6 , -CONRR,, -OCOR 6 , -NR 6 COR,, -OCONR,, -OR,, -SR, -SOR 6 , -SO 2 R 6 , SR6N(R7R8), 15 -N(RR,) 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 I to 6 carbon atoms, or (CH)J; 20 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. 25 25. The method of Claim 24 wherein the herpes virus is human cytomegalovirus.
19. 26. The method of Claim 24 wherein the herpes virus is varicella zoster virus.
20. 27. The method of Claim 26 wherein the compound is substantially pure (S) 30 isomer.
21. 28. The method of Claim 24 wherein the herpes virus is herpes simplex virus.