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AU3112200A - Thiourea inhibitors of herpes viruses - Google Patents

Thiourea inhibitors of herpes viruses Download PDF

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AU3112200A
AU3112200A AU31122/00A AU3112200A AU3112200A AU 3112200 A AU3112200 A AU 3112200A AU 31122/00 A AU31122/00 A AU 31122/00A AU 3112200 A AU3112200 A AU 3112200A AU 3112200 A AU3112200 A AU 3112200A
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Prior art keywords
phenyl
thioureido
chloro
amino
carboxylic acid
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AU756043B2 (en
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Jonathan David Bloom
Martin Joseph Digrandi
Russell George Dushin
Stanley Albert Lang
Bryan Mark O'hara
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Wyeth LLC
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Wyeth LLC
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Priority claimed from PCT/US1999/028892 external-priority patent/WO2000034269A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D307/85—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C335/04—Derivatives of thiourea
    • C07C335/16—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C335/20—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C335/04—Derivatives of thiourea
    • C07C335/16—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C335/22—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Description

WO 00/34269 PCT/US99/28892 THIOUREA INHIBITORS OF HERPES VIRUSES Background of the Invention 5 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 Raven Publishers, Philadelphia, PA). Each member of this family is characterized by an enveloped virus containing proteinaceous tegument and nucleocapsid, the latter of 10 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 2 (HSV-2), and varicella-zoster virus (VZV). The human betaherpesviruses are cytomegalovirus (HCMV), human herpesvirus 6 (HHV-6) and human herpesvirus 7 15 (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 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 20 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, 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.), 25 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 (ed.), Fields Virology, 3rd ed. Lippincott-Raven Publishers, Philadelphia, PA]); exanthem subitum (HHV-6 [(Pellet, P. E, and Black, J. B. 1996. Human Herpesvirus 30 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 [Frenkel, N., and Roffman, E. 1996. Human Herpesvirus 7, p. 2609-2622. In B. N.
WO 00/34269 PCT/US99/28892 -2 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 sarcoma-associated rhadinovirus human herpesvirus 8: determinants of its 5 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 virus can be transmitted to infants during birth, causing either skin or eye infection, 10 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 polymerase. 15 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. Lippincott-Raven Publishers, Philadelphia, Pa.). Primary infection with HCMV is 20 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 latent state within the infected person for the remainder of his/her life. Cell-mediated 25 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. There are 3 major categories of persons with HCMV disease (reviewed by Britt and 30 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 00/34269 PCT/US99/28892 -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. 15 Several antiviral drugs are currently being marketed (Bron, D., R. Snoeck, and L. Lagneaux. 1996. New insights into the pathogenesis and treatment of cytomegalovirus. Exp. Opin. Invest. Drugs 5:337-344; Crumpacker, C. 1996. Ganciclovir. New Eng. J. Med. 335:721-729; Sachs, S., and F. Alrabiah. 1996. Novel herpes treatments: a review. Exp. Opin. Invest. Drugs 5:169-183). These include: 20 ganciclovir (Roche), a nucleoside analog with hemopoietic cell toxicity; foscarnet (Astra), a pyrophosphate analog with nephrotoxicity; and cidofovir, Gilead), a nucleoside phosphonate with acute nephrotoxicity. 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. 25 Ganciclovir-resistant mutants which arise clinically are often cross-resistant with 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 30 applications. Armistead, et al., WO 97/40028, teaches phenyl ureas and thioureas as inhibitors of the inosine monophosphate dehydrogenase (IMPDH) enzyme which is taught to play a role in viral replication diseases such herpes.
WO 00/34269 PCTIUS99/28892 -4 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. n(Y)c (R1) H H 5 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 related viruses. 10 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 herpesvirus. 15 Description of the Invention In accordance with the present invention are provided compounds having the formula: R4 5
R
3 - X-NH-C-NH-A-NH-C-G 20
R
2
R
1 I wherein R1R, 5are 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, 25 perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10 carbon members, aryl, heteroaryl, WO 00/34269 PCT/US99/28892 -5 halogen, -CN, -NO2, -CO 2
R
6 , -COR 6 , 6 -OR, -SR, -SOR, -S0 2 R, CONR,R, -NR 6 N(RR,), -N(RR,) or W-Y-(CH 2 ),-Z; 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 I 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 10 R, and R., taken together may form a 3 to 7 membered heterocycloalkyl; A is heteroaryl; W is 0, NR , or is absent; Y is -(CO)- or -(C0 2 )-, or is absent; Z is alkyl of 1 to 4 carbon atoms, -CN, -CO 2 R , COR , -CONRR, -OCOR, 15 NR 6 COR, -OCONR 6 , -OR 6 , -SR , -SOR 6 , -S0 2
R
6 , SR6N(R7R8), N(RR.) or phenyl; G is aryl or heteroaryl; X is a bond, -NH, alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, thioalkyl of 1 to 6 carbon 20 atoms, alkylamino of 1 to 6 carbon atoms, or (CH)J; J is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl or benzyl; and n is an integer from 1 to 6; or a pharmaceutical salt thereof. 25 In some preferred embodiments of the present invention at least one of R 1
-R
5 is not hydrogen, and preferably one to three of R,-R 5 is not hydrogen. Preferably, R,
R
5 is selected from hydrogen, alkoxy of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, and halogen. 30 Preferably X is (CH)J where J is alkyl of 1 to 6 carbon atoms. More preferably, J is an alkyl of 1 to 3 carbon atoms and most preferably J is methyl.
WO 00/34269 PCTIUS99/28892 -6 In some embodiments of the present invention A may be substituted with at least one of hydrogen, alkyl of 1 to 4 carbon atoms, perhaloalkyl of I to 4 carbon atoms, halogen, alkoxy of 1 to 4 carbon atoms, or cyano. A is most preferably unsubstituted. 5 G is preferably a 5 or 6 membered heteroaryl having 1 or 2 heteroatoms. More preferably, G is oxazoly, furyl, thiazolyl or thiadiazolyl and in more preferred embodiments, G is 1,2,3 thiadiazolyl, 1,3 thiazolyl, or 2-furyl. G is most preferably thiazolyl, and in particular 1,3 thiazolyl. 10 Preferred compounds of the present invention are the following compounds which include pharmaceutical salts thereof: Furan-2-carboxylic acid {5-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido] pyridin-2-yl I -amide, [1,2,3]Thiadiazole-4-carboxylic acid {5-[3-(5-chloro-2,4-dimethoxy-phenyl) 15 thioureido]-pyridin-2-yl}-amide, Pyridine-2-carboxylic acid {5-[3-(5-chloro-2,4-dimethoxy-phenyl) thioureido]-pyridin-2-yl}-amide, Pyridine-2-carboxylic acid (6-[3-(5-chloro-2,4-dimethoxy-phenyl) thioureido]-pyridin-3-yl}-amide, 20 Furan-2-carboxylic acid {6-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido] pyridin-3-yl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid {6-[3-(5-chloro-2,4-dimethoxy-phenyl) thioureido]-pyridin-3-yl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid (5-[3-(3,5-dichloro-phenyl)-thioureido] 25 pyridin-2-yl}-amide, N- [5- [[ [(5-Chloro-2,4-dimethoxyphenyl)amino]thioxomethyl] amino] -2 pyridinyl]-2-methylbenzamide, N-{5-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-2-yl}-2 fluoro-benzamide, 30 N-{6-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-3-yl}-2 fluoro-benzamide, WO 00/34269 PCTIUS99/28892 -7 N-{ 5-[({ [3,5-bis(trifluoromethyl)benzyl] amino) carbothioyl)amino]-2 pyridinyl) -1,2,3-thiadiazole-4-carboxamide, N-(5-{ [((1 S)- I-[3,5-bis(trifluoromethyl)phenyl]ethyl) amino) carbothioyl] amino} -2-pyridinyl)- 1,2,3-thiadiazole-4-carboxamide, 5 N-(5- { [({ (1 S)- 1- [3,5-bis(trifluoromethyl)phenyl]ethyl) amino) carbothioyl] amino) -2-pyridinyl)- 1,3-thiazole-4-carboxamide, N- (5-{ [({1- [2-fluoro-5- (trifluoromethyl)phenyl] ethyl) amino) carbothioyl] amino) -2-pyridinyl)- 1,3-thiazole-4-carboxamide, N-(5- {[({1- [2-fluoro-4-(trifluoromethyl)phenyl ethyl) amino) 10 carbothioyl] amino) -2-pyridinyl)- 1,3-thiazole-4-carboxamide, N-(5-{ [({1- [3-fluoro-5- (trifluoromethyl)phenyl] ethyl) amino) carbothioyl] amino) -2-pyridinyl)- 1,3-thiazole-4-carboxamide, N-(5- { [({ (1 S)- 1-[3,5-bis(trifluoromethyl)phenyl] ethyl) amino) carbonyl] amino) -2-pyridinyl)- 1,3-thiazole-4-carboxamide, 15 N- {5- [(([1- (3-bromophenyl)ethyl] amino} carbothioyl)amino] -2-pyridinyl) 1,3-thiazole-4-carboxamide, N- (5- [(([1-(2-bromophenyl)ethyl] amino I carbothioyl)amino] -2-pyridinyl) 1,3-thiazole-4-carboxamide, N-(5-{ [({ 1- [3- (trifluoromethyl)phenyl] ethyl) amino)carbothioyl] amino) -2 20 pyridinyl)- 1,3-thiazole-4-carboxamide, N-(5- {[({1- [4-chloro-3-(trifluoromethyl)phenyl] ethyl) amino) carbothioyl] amino) -2-pyridinyl)- 1,3-thiazole-4-carboxamide, N- (5- [({[1-(4-chloro-3-fluorophenyl)ethyl] amino) carbothioyl)amino] -2 pyridinyl) -1,3-thiazole-4-carboxamide, 25 N- {5- [({ [1-(4-chloro-2-fluorophenyl)ethyl] amino) carbothioyl)amino] -2 pyridinyl }-1,3-thiazole-4-carboxamide, N- {6- [([1- (4-fluorophenyl)ethyl] amino) carbothioyl)amino] -3-pyridinyl} 1,2,3-thiadiazole-4-carboxamide, N-(6- {[({(1 S)- I -[3,5-bis(trifluoromethyl)phenyl]ethyl) amino) 30 carbothioyl] amino) -3-pyridinyl)- 1,2,3-thiadiazole-4-carboxamide; and pharmaceutical salts thereof.
WO 00/34269 PCTIUS99/28892 -8 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, isobutyl, t-butyl, pentyl and hexyl. Alkenyl as used herein refers to straight or branched chain lower alkyl of 2 to 5 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 6 carbon atoms containing at least one carbon-carbon triple bond. Alkyl, alkenyl and alkynyl groups of the present invention may be substituted 10 or unsubstituted. 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. 15 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. 20 Aryl, as used herein refers to an aromatic mono or bicyclic ring of 5 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 25 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 present 30 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.
WO 00/34269 PCTIUS99/28892 -9 Phenyl as used herein refers to a 6 membered aromatic ring. Halogen, as used herein refers to chlorine, bromine, iodine and fluorine. Unless otherwise limited substitutents are unsubstituted may include alkyl of 1 to 6 carbon atoms, cycloalkyl of 1 to 6 carbon atoms, heterocycloalkyl of lto 6 5 members, perhaloalkyl of 1 to 6 carbon atoms, alkylamino, dialkylamino, aryl or heteroaryl. Carbon number refers to the number of carbons in the carbon backbone and does not include carbon atoms occurring in substituents such as an alkyl or alkoxy 10 substituents. 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. Pharmaceutically acceptable salts are the acid addition salts which can be 15 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. The compounds of this invention contain a chiral center, providing for various 20 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 is meant the composition contains greater than 75% of the desired isomer and may include no more than 25% of the undesired isomer. In more preferred 25 embodiments the pure optical isomer is greater than 90% of the desired isomer. In some preferred embodiments, when the target is VZV, the (S) isomer is preferred. The individual isomers can be prepared directly or by asymmetric or stereospecific synthesis or by conventional separation of optical isomers from the racemic mixture. 30 Compounds of the present invention may be prepared by those skilled in the art of organic synthesis employing methods described below which utilize readily WO 00/34269 PCT/US99/28892 - 10 available reagents and starting materials unless otherwise described. Compounds of the present invention are thus prepared in accordance with the following schemes. The novel compounds of the present invention are prepared according to the 5 following reaction schemes. Referring to Methods 31 (reacting 2 and 3, top) and 34 (reacting 4 and 5, bottom), reacting appropriately substituted amines 2, wherein the substitutents R,-R 5 , and X are described as above, with appropriately substituted isothiocyanates 3, 10 wherein A and G are described above, either neat or in an appropriate solvent such as tetrahydrofuran, acetonitrile, ethyl acetate, dichloro-methane, or N,N dimethylformamide affords the desired thioureas 1. Similarly, reaction of appropriately substituted isothiocyanates 4, wherein the substitutents R,-R,, and X are described as above with appropriately substituted amine 5, wherein A and G are 15 described above, in a convenient solvent such as those listed above affords the desired thioureas 1. Methods 31 and 34 R4 5
R
3 \ / -NH 2 + S=C=N-A-N-C-G 3- H
R
2
R
1 2 3
R
3 \, / C- .A- C--G R2 RI Ra -N=C=S-+ H2N-A- C-G H H H
R
2 R
R
4 5
R
3 N / C3S + H 2 N-A- N-C-G H Rl 2
R,
1 4 5 WO 00/34269 PCT/US99/28892 - 11 Alternatively, appropriately substituted thioureas 1 can be prepared as described by Methods 32 and 33 by reacting amines 2 and 5, wherein R 1 -R,, A and G are described as above, in the presence of either one molar equivalent of 1,1' thiocarbonyl-diimidazole in an appropriate solvent such as dichloromethane and 5 tetrahydrofuran or mixtures thereof or one molar equivalent of 1,1'-thiocarbonyl-di (1,2,4)-triazole in an appropriate solvent such as dichloromethane and tetrahydrofuran or mixtures thereof at room temperature. In certain instances, subsequent chemical modification of the final thioureas 1 10 was required. These methods, Methods 35-39, are summarized below. Thioureas 1 wherein at least one substituent of R 1 -R. is 1-hydroxyethoxy or carboxy-methoxy, A and G are defined as above and X equals a bond, may be prepared from the corresponding alkyl esters by alkaline hydrolysis with aqueous 15 sodium or potassium hydroxide in a suitable solvent such as methanol, tetrahydrofuran or mixtures thereof at room temperature in accordance with Methods 35 and 36. Thioureas 1 wherein at least one substituent of R 1
-R
5 is 1-acyloxyethoxy or 20 methansulfonoxyethoxy, A and G are defined as above and X equals a bond, may be prepared from the corresponding 1-hydroxyethoxy derivative by acylation with appropriate 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 25 room temperature in accordance with Methods 37 and 38. Thioureas 1 wherein at least one substituent of R 1
-R
5 is 1-aminoethoxy, Aand G are defined as above and X equals a bond, may be prepared from the corresponding 1-methanesulfonoxy-ethoxy derivative by reaction with an appropriate secondary 30 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.
WO 00/34269 PCT/US99/28892 - 12 Thioureas 1 wherein at least one substituent of R,-R 5 is 1-aminoalkyl, A and G are 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. 5 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, 10 R, A 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. Method 41 N S O O N S 2 A-X-NH2 A-X-N=C-CS 2 4 15 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 and X are defined 20 above and amines 5, wherein A is defined above, 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 WO 00/34269 PCT/US99/28892 - 13 Organic Chemistry (ed. Sutherland), Volume 2, Chapter 6.3.1, Aromatic Amines, 1979. Such procedures include the reduction of nitrobenzenes to form anilines upon exposure to: a) iron powder and a strong acid, such as hydrochloric acid (Methods 1A) 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; b) iron powder and glacial acetic acid (Method IB), 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; 10 c) iron powder and aqueous ammonium chloride (Method 1C), 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 or in alcohol solvent such as methanol or ethanol, at temperatures ranging from 15 room temperature to the refluxing temperature of the solvent, or; e) when R,-R, and substituents of A are selected from Cl, Br, I, -(OSO)-CF,, or (OSO 2 )-1-(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 acetate, under one or more atmospheres of pressure or; 20 f) when R 1
-R
5 and R 9
-R
12 are selected from Cl, Br, I, -(OS0 2 )-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 solvent, or; 25 g) aqueous sodium hydrosulfite in alcohol solvent at temperatures ranging from room temperature to the refluxing temperature of the solvent (Method 1G). Alternatively, according to Methods 3A-3C, amines 2, wherein R 1 -R, are defined above and X is defined as above and anilines 5, wherein A is defined above, may be prepared by the cleavage of the aniline nitrogen-carbon bond of amide and 30 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 WO 00/34269 PCT/US99/28892 - 14 Synthesis volume 2, Chapter 7, 1991, and references therein. Such procedures include: 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 5 solvent such as dichloromethane at temperatures between 0 0 C and room temperature, or; b) the exposure of appropriately substituted arylamino-(2-trimethylsilylethyl) carbamates to a fluoride ion source such as tetrabutylammonium fluoride or potassium fluoride (Method 3B) in aqueous acetonitrile or tetrahydrofuran or 10 mixtures thereof at temperatures ranging from room temperature to the reflux temperature of the solvent, or; 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 15 ranging from room temperature to the reflux temperature of the solvent. Alternatively, according to Method 11, amines 2, wherein R,-R, are defined above, and X equals a bond and at least one substituent of R,-R 5 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 20 example 3-chloro-4-iodo-aniline, employing a palladium catalyst, such as 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 25 Organic Chemistry, Vol. 5, 1-53, 1996 and references therein. Alternatively, according to Method 42, amines 2, wherein R,-R, are defined above and X is defined as 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 30 bromobenzotrifluoride, by secondary amines under conditions which employ a 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 WO 00/34269 PCT/US99/28892 - 15 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 Letters 36 (21), 3609 (1995). 5 Alternatively, according to Method 43, amines 2, wherein R,-R, are defined above and X is defined as above and at least one substituent of R, 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 bromobenzotrifluoride by alkenes under condiditons which employ a palladium 10 catalyst such as [1,1 '-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex and in the presence of 9-borabicyclo [3.3. 1]nonane and a suitable base such as aqueous sodium hydroxide in a suitable solvent such as tetrahydrofuran or the like at temperatures ranging from room temperature to the reflux temperature of the solvent. 15 The acyl and carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C may be prepared by the derivatization of the corresponding amines 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: 20 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 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 25 temperature of the solvent to produce the corresponding arylamino-tert-butyl carbamate, or; 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 30 solvent such as dimethylformamide at room temperature to produce the corresponding arylamino-(2-trimethylsilylethyl)-carbamate, or; WO 00/34269 PCT/US99/28892 - 16 c) the reaction of an appropriately substituted aniline with a carboxylic acidchloride 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 5 triethylamine or N,N-diisopropylethyl-amine to produce the corresponding arylaminoamide, or; d) the reaction of an appropriately 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 10 or in an appropriate solvent such as tetrahydrofuran, 1,4-dioxane and the like at temperatures ranging from room temperature to the reflux temperature of the solvent to produce the corresponding nitro arylaminoamide, or; e) the reaction of an appropriately substituted aniline with a carboxylic acid (Method 2E) in the presence of a coupling agent such as benzotriazole- I -yloxy 15 tris-(dimethylamino)-phosphonium hexafluorophosphate, 2-(1H-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 diichloromethane, dimethylformamide and the like, at room temperature to 20 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 R5 and substituents of A are defined as -W-Y-(CH 2 )n-Z wherein W, Y, and Z are defined as above, with a carboxylic acid anhydride (Method 2F) in the presence of a suitable base such as 25 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 substituent of R,-R 5 is defined as hydroxyl with di-tert-butyl-dicarbonate (Method 30 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 WO 00/34269 PCTIUS99/28892 - 17 temperatures ranging from room temperature to the reflux temperature of the solvent to produce the corresponding arylamino-tert-butyl-carbamate. Nitrobenzene intermediates that are ultimately converted to amines 2 and 5 by 5 methods shown above in Methods 1 A- 1 G may be prepared in accordance with Methods 4A, 4C, 4E-4F. Referring to Methods 4A, 4C, and 4E-4H, the nitrobenzene intermediates which are ultimately converted into amines 2, R 2 and R 4 are defined above and R 1 , R, and/or R 5 are defined as alkoxy, thioalkoxy, alkylsulfenyl, alkylsulfinyl, and 10 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 following: a) reaction of alcohols with appropriately substituted 2- or 4- halo- or sulfonate esters 15 of nitrobenzenes or benzonitriles (Method 4A) either neat or in an appropriate solvent such as tetrahydrofuran, dioxane, acetonitrile, N,N-dimethylformamide or 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 20 temperatures ranging from room temperature to the reflux temperature of the 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 25 tetrahydrofuran, dioxane, acetonitrile, N,N-dimethylformamide or dimethylsulfoxide, at temperatures ranging from room temperature to the reflux temperature of the solvent, or; c) reaction of ammonia, primary or secondary amines with appropriately substituted 2- or 4-halo- or sulfonate esters of nitrobenzenes or benzonitriles (Methods 4C,F) 30 either neat or in an appropriate solvent such as tetrahydrofuran, dioxane, acetonitrile, N,N-dimethyl-formamide or dimethylsulfoxide, at temperatures ranging from room temperature to the reflux temperature of the solvent; WO 00/34269 PCT/US99/28892 - 18 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 temperatures ranging from 0 0 C to the reflux temperature of the solvent, or; 5 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 temperature of the solvent, followed by the addition of an alkyl halide directly to 10 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,-R, is defined as alkoxy may be prepared from the corresponding substituted hydroxy nitrobenzenes by methods which include the following: 15 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 hydride, in an appropriate solvent such as acetone, N,N-dimethylformamide, tetrahydrofuran or dimethylsulfoxide at temperatures ranging from room 20 temperature to the reflux temperature of the solvent, or; b) reaction of the hydroxy-nitrobenzene with an alkyl alcohol, triphenylphosphine, 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 25 solvent, essentially according to methods described in Mitsunobu, 0, Synthesis 1981, 1 and references therein. 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 30 amines 2, wherein at least one substituent R,-R, is defined as alkoxy may be prepared the corresponding substituted hydroxy arylamino-tert-butyl-carbamate by reaction with alkyl halides, trifluormethane-sulfonates, 4-methylbenzenesulfonates, WO 00/34269 PCTIUS99/28892 - 19 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-dimethyl-formamide at temperatures ranging from room temperature to the reflux temperature of the solvent. 5 Alternatively, referring to Methods 7A-G, the nitrobenzene intermediates which are ultimately converted into amines 2, R, and/or R, is alkoxy, and R, and/or
R
4 is a halogen, and X equals a bond, may be prepared by standard halogenation reactions which include the following: 10 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 15 room temperature, or; c) reaction of a 2,4-dimethoxynitrobenzene (Method 7E) with benzyltrimethylammonium dichloroiodate in the presence of anhydrous zinc chloride in a suitable solvent such as glacial acetic acid, at room temperature or; d) reaction of a 2-hydroxy-4-methoxynitrobenzene (Method 7F) with 20 benzyltrimethyl-ammonium dichloroiodate in the presence of sodium bicarbonate in a suitable solvent mixture such as dichloromethane and methanol, at room temperature or; d) reaction of a 2,4-dimethoxynitrobenzene (Method 7G) with 3,5-dichloro-l fluoropyridine triflate in a suitable solvent such as tetrachloroethane, at a 25 temperature ranging from room temperature to the reflux temperature of the solvent. Referring to Method 8, the nitrobenzene intermediates which are ultimately converted into amines 2, wherein R 4 = -CF, and R,-R 3 and R 5
-R
8 are defined as above 30 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-dimethyl- WO 00/34269 PCT/US99/28892 - 20 formamide 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 NRR, or 5 HNCOCH 2
SR
6 , and R,-R 3 and R,-R 8 are defined as above and X equals a bond may be prepared from the corresponding substituted 4-(N-chloroacetyl)-nitroaniline by reaction with either a suitable secondary amine such as dimethylamine, morpholine or the like in a suitable solvent such as tetrahydrofuran and/or water mixtures at temperatures ranging from room temperature to the reflux temperature of the solvent 10 or by reaction with an appropriate thiol in the presence of a suitable base such as 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 15 converted into amines 2, wherein at least one substituent of R,-R 5 is defined as triflate 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. 20 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
5 is defined as either alkylsulfenyl or alkylsulfinyl, may be prepared by reaction of the appropriate 4-alkylthio acyl arylamino or carbamoyl arylamino derivative with an appropriate oxidizing agent 25 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
R
4 is defined as 1-hydroxyethyl and R,-R 3 and R 5 are defined as above and X equals a 30 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.
WO 00/34269 PCT/US99/28892 - 21 Referring to Method 13, 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 2-hydroxyethyl and R 1
-R
3 and R 5 are defined as above and X equals a bond, may be prepared by reacting the corresponding 4-vinyl carbamoyl aniline with 5 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 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 10 R 4 is defined as 1-azidoethyl and R 1
-R
3 and R 5 are defined as above and X is defined as above, may be prepared by reacting the corresponding 4-(1-hydroxyethyl) carbamoyl 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 15 room temperature. Referring to Method 15, 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 3-dimethylaminoprop-1-ynyl and R 1
-R
3 and R 5 are defined as above and X is defined as above, may be prepared by reacting the corresponding 4 20 iodocarbamoyl aniline with 1-dimethylamino-2-propyne in a suitable tertiary amine solvent such as triethylamine or diisopropylethylamine in the presence of bis(triphenylphosphine)palladium(II) chloride and cuprous iodide at temperatures ranging from room temperature to the reflux temperature of the solvent. Referring to Method 16, the carbamoyl amine derivatives utilized as starting 25 materials in Methods 3A-3C which are ultimately converted into amines 2, wherein
R
4 is defined as 3-dimethylaminoacryloyl and R,-R 3 and R 5 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 30 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, WO 00/34269 PCT/US99/28892 - 22 wherein R 4 is defined as either 4-isoxazol-5-yl or 4-(lH-pyrazol-3-yl) and R,-R, and
R
5 are defined as above and X equals a bond, may be prepared by reacting the corresponding 4-(3-dimethylamino-acryloyl)carbamoyl aniline with either hydroxylamine hydrochloride or hydrazine hydrate in a suitable solvent such as 1,4 5 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 R4 = -HNCO 2 Z, and R 1 -R, Rp, and Z are defined as above and X equals a bond, may be prepared by reacting the corresponding 4-aminocarbamoyl aniline with 1,1 10 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. 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, 15 wherein at least one substituent of R 1
-R
5 is defined as dialkylamino and X is defined as 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 carbon in a suitable solvent such as water, methanol, tetrahydrofuran mixtures or toluene or the like at room temperature. 20 Referring to Methods 27 and 28, amines 2 wherein at least one substituent of R-R 5 is defined as hydroxy and X is defined as above can be prepared by reaction of the 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 25 temperature of the solvent. Referring to Method 29, amines 2 wherein at least one substituent of R,-R, is defined as 2-hydroxybenzamido and X is defined as 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 30 like at room temperature. 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: WO 00/34269 PCT/US99/28892 - 23 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 temperature to the reflux temperature of the solvent. 5 (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, 10 ethanol or the like at room temperature. (Method 50); c) reduction with lithium aluminum hydride in a suitable solvent such as tetrahydrofuran or diethyl ether at temperatures ranging from 0 0 C to room temperature. (Method 51). The unsaturated nitro precursors which are utilized as starting materials in 15 Method 51 and are ultimately converted to amines 2 wherein R,-R, are defined as above and X equals -(CH 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 20 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 such as N,N-dimethylformamide at temperatures ranging from room temperatture to 25 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(CH 2
)
2
NH
2 or -S(CH 2
)
2
NH
2 , the requisite nitrile precursors may be prepared by reaction of an appropriately substituted phenol or thiophenol with bromoacetonitrile in the presence of a suitable base such as potassium carbonate in an appropriate 30 solvent such as acetone at room temperature according to Method 49. Alternatively, for amines 2, wherein RI-R, are defined as above and X equals
-(CH
2
)
3 -, the nitrile precursors can be prepared essentially according to the procedure WO 00/34269 PCT/US99/28892 - 24 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 5 temperatures ranging from 0 0 C to room temperature. (Method 54) Alternatively, intermediate amines 2 wherein R,-R 5 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 10 appropriate solvent mixture such as water and methanol or water and ethanol at temperatures ranging from room temperature to the reflux temperature of the solvent. (Method 46) The formamide precursors utilized as starting materials in Method 46 and which are ultimately converted into amines 2, are prepared according to Method 45 15 by treatment of an appropriately substituted acetophenone with ammonium formate, formic acid and formamide at temperatures ranging from room temperature to the reflux temperature of the solvent. Alternatively, amines 2 wherein R,-R, are defined as above and X equals -(CH(CH,))- can be prepared by reduction of an appropriately substituted 0-methyl 20 oxime in the presence of sodium borohydride and zirconium tetrachloride in a 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 0-methyl oximes can be prepared from the corresponding acetophenone by reaction with methoxylamine hydrochloride and pyridine in a 25 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,-R 5 are defined as above and X equals -CH(J)- where J is defined as above, can be prepared by reduction of the appropriately substituted ketone by the methods described above (Methods 45, 47, and 48). These requisite 30 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 WO 00/34269 PCTIUS99/28892 - 25 in a suitable solvent such as diethyl ether or tetrahydrofuran at temperatures ranging 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 5 dichromate in an appropriate solvent such as dichloromethane or the like at room temperature. (Method 58) The intermediate anilines 5 may be prepared as previously described Method 3A. Thus treating phenyl carbamic acid tert-butyl ester 6 or the corresponding heteroaryl, wherein G is described as above, with neat trifluoroacetic acid at room 10 temperature followed by neutralization with aqueous sodium hydroxide affords the desired anilines 5. The requisite carbamic acid esters 6, wherein A and G are described as above, are prepared as shown in Method 2C by reaction of substituted acid chlorides, 8, where G is described as above, and 4-aminophenyl-carbamic acid tert-butyl esters 7 or the corresponding heteroaryl, wherein A is described above, in 15 the presence of triethylamine in an appropriate solvent such as dichloromethane, dimethylsulfoxide, or dimethylformamide or mixturestthereof. Carboxylic acid chlorides 8 are either commercially available or prepared from the corresponding carboxylic acid by reaction with oxalyl chloride in a suitable solvent such as dichloromethane at room temperature. 20 Method 3A, 2C o -' O i. CF3C02H O GCOOH + HN NH 2 -N HN N C-G ii NaO H 2 N / N-C-G H 8 7 6 5 Alternatively, amines 5 may be prepared as previously described by methods 1A 25 1G. Thus, treating 2-amino-5-nitropyridine (7) with heterocyclic acid chlorides 8 or other activated acid derivatives as described in Methods 2C-2E affords the nitro amide 6, where G is described as above. Subsequent reduction by procedures described in Methods 1A-lG affords amines 5.
WO 00/34269 PCT/US99/28892 - 26 GCOCI 2 N ~Method 2C 0 2 N H 2 N G-COCI + II0 Method 10 Lo N NH 2 N N-C-G N N-C-G 8 H H 76 5 Alternatively, carbamic acid esters 6, wherein A and G are described as 5 above, are prepared as shown in Method 2E by reaction of substituted carboxylic acids 8a, wherein G is described as above, and an appropriately substituted 4 aminophenyl carbamic acid tert-butyl esters 7 or the corresponding heteroaryl in the presence of a suitable coupling agent such as benzotriazole- 1 -yloxy-tris (dimethylamino)-phosphonium hexafluorophosphate, 2-(1H-benzotriazole-1-yloxy) 10 1,1,3,3-tetra-methyluronium hexafluorophosphate, dicyclohexyl carbodiimide or the like and in the presence of a tertiary amine base such as triethylamine or diisopropylethylamine in a suitable solvent such as dichloromethane, dimethylformamide and the like, at room temperature to produce the corresponding heteroaryl or arylaminoamide. 15 Carboxylic acids 8a are either commercially available or are prepared according to literature methods. For example, when G is a substituted thiadiazole, 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 20 such as methanol or ethanol and water at room temperature. Similarly, when G is either substituted or unsubstituted thiazole, substituted or unsubstituted oxazole, substituted or unsubstituted isothiazole or substituted or unsubstituted isoxazole, when not commercially available, the corresponding 25 carboxylic acid 8a is available from the corresponding ethyl or methyl 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. These esters are either commercially available or can be prepared according to literature methods. 30 WO 00/34269 PCT/US99/28892 - 27 When the carboxylic acid ester precursors which are ultimately converted to acids 8a 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 may be prepared essentially according to the procedure of Caron, M J. Org. Chem. 5 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 presence of a tertiary amine base such triethylamine or diisopropylethylamine in a suitable solvent such as acetonitrile affords the corresponding diazo-beta-keto 10 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 temperature of the solvent gives the desired 5-substituted-1,2,3-thiadiazole-4 carboxylic acid ester. 15 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, according to Method 22 and 23, reaction of an appropriately substituted beta-keto 20 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 compound with neat thionyl chloride at 0 0 C followed by treatment with an excess 25 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, 30 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 WO 00/34269 PCT/US99/28892 - 28 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 base such as triethylamine or diiso-propylethylamine or the like at room temperature to give the corresponding 4-carboethoxy-thiazole. 5 Additional appropriately substituted thiazoles may be prepared essentially according to the procedure of Bredenkamp, M. W., Holzafel, C. W., van Zyl, W. J. Synthetic Comm. 20, 2235 (1990). Appropriate unsaturated oxazoles are prepared essentially according to the procedure of Henneke, K. H., Schallkopf, U., Neudecker, 10 T. Liebigs Ann. Chem. 1979 (1979). Substituted oxazoles may be prepared essentially according to the procedures of Galeotti, N., Montagne, C., Poncet, J., Jouin, P. Tetrahedron Lett. 33, 2807, (1992) and Shin, C., Okumura, K., Ito, A., Nakamura, Y. Chemistry Lett. 1305, (1994). 15 The following specific examples are illustrative, but are not meant to be limiting of the present invention. EXAMPLE 1 (METHOD 1A) 4-Methoxy-3-trifluoromethyl- phenylamine 20 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 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, 25 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 carbonate, then extracted with ethyl acetate. These organic extracts are washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, 30 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.
WO 00/34269 PCTIUS99/28892 - 29 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 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 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 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 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 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 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 WO 00/34269 PCT/US99/28892 - 30 2-Chloro-N(1)- (2-dimethylamino-ethyl)-benzene- 1,4-diamine N(1)-(1 -Benzyl-piperidin-4-yl)-2-chloro-benzene- 1,4-diamine 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 3-Chloro-4-(3-dimethylamino-propoxy)-phenylamine 3-Chloro-4-(1 -methyl-pyrrolidin-3-yloxy)-phenylamine 3-Chloro-4-cyclohexyloxy-phenylamine EXAMPLE 2 (METHOD 1B) 4-Bromo-2,4-dimethoxy-phenylamine 5 A suspension of 4-bromo-2,4-dimethoxy-nitrobenzene (0.48 g) and iron powder (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 10 neutralized with solid potassium carbonate and then extracted with dichloromethane. These organic extracts are washed with saturated aqueous sodium chloride, dried over 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. 15 EXAMPLE 3 (METHOD 1C) (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 (1 g) in 20 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 hour. The mixture is then filtered and concentrated under reduced pressure. The WO 00/34269 PCT/US99/28892 - 31 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. 5 Using the above procedure and appropriate starting materials the following compounds were prepared: 4-Chloro-benzene- 1,2-diamine 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 (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 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 (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 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 N-(4-Amino-2-chloro-phenyl)-benzamide WO 00/34269 PCT/US99/28892 - 32 N-( 4 -Amino-2-chloro-phenyl)-2-diethylamino-acetamide N-(4-Amino-2-chloro-phenyl)-2-pyrrolidin- I -yl-acetamide N-(4-Amino-2-chloro-phenyl)-2-azepan- I -yl-acetamide N- (4-Amino-2-chloro-phenyl)-2- (2-methyl-piperidin- 1 -yl)-acetamide
N-(
4 -Amino-2-chloro-phenyl)-2-(3-methyl-piperidin- I -yl)-acetamide 3-Chloro-benzene- 1,2-diamine 4-Chloro-N,N-dimethyl-benzene- 1,2-diamine EXAMPLE 4 (METHOD 1D) 3 ,5-Dichloro-4-phenoxy-phenylamine 5 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 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 10 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 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 15 solid. Using the above procedure and appropriate starting materials the following compounds were prepared: 1-Furan-2-yl-ethylamine 3-Chloro-4-isopropoxy-phenylamine 2 -Butoxy-5-chloro-4-methoxy-phenylamine 3,5-Dichloro-2-methoxy-4-methyl-phenylamine 2 -Benzyloxy-5-chloro-4-methoxy-phenylamine 4 -Benzyloxy-5-chloro-2-methoxy-phenylamine WO 00/34269 PCTIUS99/28892 - 33 5-Fluoro-2,4-dimethoxy-phenylamine (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 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 4-Chloro-5-methoxy-N(1) ,N(l1)-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(l1)-cyclohexyl-N(l1)-methyl-benzene- 1 ,4-diamine N(2)-Benzyl-4-methoxy-benzene- 1 ,2-diamine 2- (4-Amino-2-chloro-phenoxy)-ethanol 2-Chloro-N(l1)-cyclohexyl-N(l1)-ethyl-benzene- 1 ,4-diamine 4-Butoxy-3-chloro-phenylamine (4-Amino-2-chloro-phenoxy)-acetonitrile 2-Chloro-N(l1)-cyclohexyl-benzene- 1 ,4-diamine 2-Chloro-N(l1),N( 1)-dipropyl- benzene- 1 ,4-diamine 3-Chloro-4- (2,2,2-trifluoro-ethoxy)-phenylamine 3-Chloro-4-(octahydro-quinolin- 1 -yl)-phenylamine N(l1)-Allyl-2-chloro-N(l1)-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 3-Chloro-4-propoxy-phenylamine 3-Iodo-4-methoxy-phenylamnine 3 -Chloro-2,4-dimethoxy- aniline WO 00/34269 PCT/US99/28892 - 34 3-Bromo-4-methoxy-phenylamine 3-Chloro-4-ethoxy-phenylamine EXAMPLE 5 (Method 1E) (4-Amino-phenyl)-carbamic acid isobutyl ester 5 To a solution of N-(4-Nitro-phenyl)-isobutyrlamide (2.0 g) in 100 mL ethylene 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 10 filtration through diatomaceous earth and the filtrate is evaporated to dryness under reduced pressure by azeotroping three times with heptane. Trituration of the residue with heptane provides the desired product as a white solid. Using the above procedure and appropriate starting materials the following 15 compounds were prepared: 2-Methyl-3H-benzoimidazol-5-ylamine N-(4-Amino-phenyl)-formamide 1H-Benzoimidazol-5-ylamine (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 [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 3-(3-Dimethylamino-propyl)-5-trifluoromethyl-phenylamine WO 00/34269 PCTIUS99/28892 - 35 EXAMPLE 6 (METHOD 1F) N-(4-Amino-2-methylphenyl)-2-fluorobenzamide A mixture of 2-fluoro-N-(2-methyl-4-nitrophenyl)benzamide (4.55 g), cyclohexene 5 (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 solid. 10 Using the above procedure and appropriate starting materials the following compounds were prepared: N-(4-Amino-2-methyl-phenyl)-acetamide 2-Methyl-benzooxazol-6-ylamine N-(4-Amino-3-methoxy-phenyl)-acetamide 2-Acetylamino-5-amino-benzoic acid N-(4-Amino-phenyl)-acetamide [4-(3-Amino-benzoylamino)-phenyl]-carbamic acid tert-butyl ester [4-(2-Amino-benzoylamino)-phenyl]-carbamic acid tert-butyl ester N-(4-Amino-2-cyano-phenyl)-acetamide N-(4-Amino-2,5-dimethoxy-phenyl)-2-fluoro-benzamide Furan-2-carboxylic acid (4-amino-2,5-dimethoxy-phenyl)-amide N-(4-Amino-2-cyano-phenyl)-2-fluoro-benzamide Furan-2-carboxylic acid (4-amino-2-methoxy-phenyl)-amide N-(4-Amino-2-methoxy-phenyl)-2-fluoro-benzamide N-(4-Amino-2-methoxy-5-methyl-phenyl)-acetamide N-(4-Amino-2-benzoyl-phenyl)-acetamide N-(4-Amino-2-benzoyl-phenyl)-2-fluoro-benzamide Furan-2-carboxylic acid (4-amino-2-benzoyl-phenyl)-amide N-(4-Amino-3-methyl-phenyl)-acetamide WO 00/34269 PCT/US99/28892 - 36 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 N-(4-Amino-naphthalen- 1 -yl)-acetamide Furan-2-carboxylic acid (4-amino-naphthalen-1-yl)-amide N-(4-Amino-2-trifluoromethyl-phenyl)-acetamide Furan-2-carboxylic acid (4-amino-2-cyano-phenyl)-amide Furan-2-carboxylic acid (4-amino-2-trifluoromethyl-phenyl)-amide N-(4-Amino-2-methyl-phenyl)-2-fluoro-benzamide Furan-2-carboxylic acid (4-amino-2-methyl-phenyl)-amide 5-Amino-2-(2-fluoro-benzoylamino)-benzoic acid 5-Amino-2- [(furan-2-carbonyl)-amino] -benzoic acid N-(4-Amino-2-cyano-phenyl)-2,2,2-trifluoro-acetamide 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 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 EXAMPLE 7 (METHOD IG) N-(4-Amino-2-chlorophenyl)-2-thiomorpholino-4-yl-acetamide 5 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 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 WO 00/34269 PCT/US99/28892 - 37 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 desired product as a light orange crystalline solid. 5 Using the above procedure and appropriate starting materials the following compounds were prepared: N-(4-Amino-2-chloro-phenyl)-2-thiomorpholin-4-yl-acetamide N-(4-Amino-2-chloro-phenyl)-2-dipropylamino-acetamide 10 EXAMPLE 8 (METHOD 2A) (3-Chloro-4-iodo-phenyl)-carbamic acid tert-butyl ester To a solution of 3-chloro-4-iodo-aniline (10 g) in tetrahydrofuran (40 mL) containing 15 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 heating is continued for approximately 24 hours. The solution is then cooled, concentrated under reduced pressure, diluted with ethyl acetate, and washed 20 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 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. 25 Using the above procedure and appropriate starting materials the following compounds were prepared: N'-(4-Nitro-benzoyl)-hydrazinecarboxylic acid tert-butyl ester (3-Chloro-4-iodo-phenyl)-carbamic acid tert-butyl ester WO 00/34269 PCT/US99/28892 - 38 (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 (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 EXAMPLE 9 (METHOD 2B) (3-Chloro-4-vinyl-phenyl)-carbamic acid2-trimethylsilanyl-ethyl ester 5 To a solution of 3-chloro-4-vinyl-phenylamine (3.4 g) in N,N-dimethylformamide (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 10 diluted with water and extracted three times with diethyl ether. The combined organic extracts are washed successively with water, saturated aqueous sodium 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. 15 EXAMPLE 10 (METHOD 2C)
[
4
-(
2 -Fluoro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester To a solution of mono-N-(t-butoxycarbonyl)-1,4-phenylenediamine (1.58 g) and 20 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.
WO 00/34269 PCT/US99/28892 - 39 Using the above procedure and appropriate starting materials the following 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 [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 [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 [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 [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 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 [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 WO 00/34269 PCT/US99/28892 - 40 {4- [(Pyridine-4-carbonyl)-amino] -phenyl} -carbamic acid tert-butyl ester {4- [(Naphthalene-2-carbonyl)-amino] -phenyl} -carbamic acid tert-butyl ester {4- [(Naphthalene- 1 -carbonyl)-amino] -phenyl } -carbamic acid tert-butyl ester {4-[(3-Bromo-thiophene-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester {4- [(Biphenyl-2-carbonyl)-amino] -phenyl } -carbamic acid tert-butyl ester N-(4-tert-Butoxycarbonylamino-phenyl)-phthalamic acid [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 [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 [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 {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 {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 [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 WO 00/34269 PCT/US99/28892 - 41 [4-(2-Phenoxy-acetylamino)-phenyl]-carbamic acid tert-butyl ester {4-[(5-Nitro-furan-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester {4- [(5-Chloro-furan-2-carbonyl)-amino] -phenyl } -carbamic acid tert-butyl ester { 4- [(3-Methyl-furan-2-carbonyl)-amino] -phenyl} -carbamic acid tert-butyl ester [4-(2-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 {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 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 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 {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 {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-iH-pyrazole-4-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester 4-(2-Fluoro-benzoylamino)-2-hydroxy-benzoic acid methyl ester WO 00/34269 PCT/US99/28892 - 42 N-(5-Chloro-2,4-dimethoxy-phenyl)-oxalamic acid Isoxazole-5-carboxylic acid (4-amino-phenyl)-amide 2-Fluoro-N-(4-nitro-benzyl)-benzamide 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 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 [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 EXAMPLE 11(METHOD 2D) 2 -Chloro-N-(2-chloro-4-nitrophenyl)acetamide 5 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 concentrated under reduced pressure, giving a wet yellow solid. Ether (250 mL) is added and the yellow solid is collected. 10 Using the above procedure and appropriate starting materias the following compounds were prepared: N-(4-Nitro-3-trifluoromethyl-phenyl)-acetamide (2-Chloro-4-nitro-phenyl)-carbamic acid ethyl ester 2-Acetylamino-5-nitro-benzoic acid WO 00/34269 PCT/US99/28892 - 43 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 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)-phenyljcarbamic acid tert-butyl ester (4-Nitro-phenyl)-carbamic acid isobutyl ester [1 ,2,3]Thiadiazole-4-carboxylic acid (5-nitro-pyridin-2-yI)-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 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 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 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 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-naplithalen- 1-yI)-amide N-(5-Chloro-2-hydroxy-4-nitro-phenyl)-acetamide N- (5-Chloro-2-hydroxy-4-nitro-phenyl)-2-fluoro-benzamjde WO 00/34269 PCT/US99/28892 - 44 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 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 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 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 EXAMPLE 12 {4-[(4-Phenyl-[1,2,3]thiadiazole-5-carbonyl)-amino]-phenyl} carbamic acid tert-butyl 5 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) phosphonium hexa-fluorophosphate (1.6 g). After stirring at room temperature, the 10 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 WO 00/34269 PCT/US99/28892 - 45 dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the desired product. Using the above procedure and appropriate starting materials the following 5 compounds were prepared: {4-[(1H-Pyrrole-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester {4-[(Pyrazine-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester (4- [(5-Methyl-thiophene-2-carbonyl)-amino] -phenyl} -carbamic acid tert-butyl ester {4- [(1-Methyl-i H-pyrrole-2-carbonyl)-amino] -phenyl } -carbamic acid tert-butyl ester { 4- [(Quinoline- 8-carbonyl)-amino] -phenyl} -carbamic acid tert-butyl ester {4- [(Benzofuran-2-carbonyl)-amino] -phenyl } -carbamic acid tert-butyl ester {4-[(Isoquinoline-1-carbonyl)-amino]-phenyl)-carbamic acid tert-butyl ester {4- [(Quinoline-2-carbonyl)-amino] -phenyl} -carbamic acid tert-butyl ester {4- [(Pyridine-2-carbonyl)-amino] -phenyl } -carbamic acid tert-butyl ester {4- [(Isoquinoline-4-carbonyl)-amino] -phenyl } -carbamic acid tert-butyl ester {4-[([1,2,3]Thiadiazole-4-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester (4- [(1 H- [1,2,3]Triazole-4-carbonyl)-amino] -phenyl} -carbamic acid tert-butyl ester [4-(2-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-butyl ester {4-[(4-Phenyl-[1,2,3]thiadiazole-5-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester {4- [(1 H-Indole-2-carbonyl)-amino] -phenyl} -carbamic acid tert-butyl ester [1,2,3]Thiadiazole-4-carboxylic acid 4-nitro-benzylamide (4- [([1,2,3]Thiadiazole-4-carbonyl)-amino] -benzyl } -carbamic acid tert-butyl ester Acetic acid 4-( 4 -tert-butoxycarbonylamino-phenylcarbamoyl)-phenyl ester {4-[(Quinoline-6-carbonyl)-amino]-phenyl)-carbamic acid tert-butyl ester WO 00/34269 PCTIUS99/28892 - 46 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)-ethyl ester EXAMPLE 14 (METHOD 2G) (3,5-Dichloro-4-hydroxy-phenyl)-carbamic acid tert-butyl ester 20 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 approximately 15 hours. The solution is then cooled, concentrated under reduced pressure, diluted with ethyl acetate, and washed successively three times with 5% 25 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 cold dichloromethane to provide the product as a white solid.
WO 00/34269 PCTIUS99/28892 - 47 Using the above procedure and appropriate starting materials the following compound was prepared: (3-Amino-5-chloro-phenyl)-carbamic acid tert-butyl ester EXAMPLE 15 (METHOD 3A) 5 3,5-Dichloro-4-ethoxy-phenylamine Trifluoroacetic acid (5 mL) is added to solid (3,5-dichloro-4-ethoxy-phenyl) 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 10 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 under reduced pressure and recrystallization from hexanes provides the desired product as a pale yellow crystalline solid. 15 Using the above procedure and appropriate starting materials the following compounds were prepared: 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 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 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 00/34269 PCTIUS99/28892 - 48 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 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 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 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 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 Isoquinoline-4-carboxylic acid (4-amino-phenyl)-amide [1,2,3]Thiadiazole-4-carboxylic acid (4-amino-phenyl)-amide IH-[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 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 WO 00/34269 PCT/US99/28892 - 49 2-Amino-N-(4-amino-phenyl)-benzamide Biphenyl-2-carboxylic acid (4-amino-phenyl)-amide N-(4-Amino-phenyl)-2,3-difluoro-benzamide N-(4-Amino-phenyl)-2,5-difluoro-benzamide N-(4-Amino-phenyl)-2,4-difluoro-benzamide 2-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 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 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 4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid (4-amino-phenyl)-amide Thiophene-3-carboxylic acid (4-amino-phenyl)-amide 5-Chloro-furan-2-carboxylic acid (4-amino-phenyl)-amide 5-Nitro-furan-2-carboxylic acid (4-amino-phenyl)-amide
N-(
4 -Amino-phenyl)-2-thiophen-2-yl-acetamide 3-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 4-Phenyl-[1,2,3]thiadiazole-5-carboxylic acid (4-amino-phenyl)-amide Acetic acid 3-(4-amino-phenylcarbamoyl)-phenyl ester WO 00/34269 PCTIUS99/28892 - 50 Benzo[1,3]dioxole-4-carboxylic acid (4-amino-phenyl)-amide N-(4-Amino-phenyl)-3-( 2 -dimethylamino-ethoxy)-benzamide 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 (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 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 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 [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 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 WO 00/34269 PCTIUS99/28892 - 51 EXAMPLE 16 (METHOD 3B) l-(4-Amino-2-chloro-phenyl)-ethanol A IM 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 Furan-2-carboxylic acid ( 4 -amino-3-cyano-phenyl)-amide N-(4-Amino-3-cyano-phenyl)-acetamide WO 00/34269 PCT/US99/28892 - 52 Furan-2-carboxylic acid (4-amino-3-trifluoromethyl-phenyl)-amide N-(4-Amino-3-methoxy-phenyl)-acetamide N-(4-Amino-3-methoxy-phenyl)-2-fluoro-benzamide Furan-2-carboxylic acid (4-amino-3-methoxy-phenyl)-amide EXAMPLE 17 (METHOD 4A) 2-Chloro-1-cyclohexyloxy-4-nitro-benzene 5 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 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 10 approximately 100 degrees. The reaction mixture is then cooled, diluted with diethyl ether (300 mL), and washed successively with saturated aqueous ammonium 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% 15 ethyl acetate in hexanes is used as the eluant) to provide the desired product as an orange solid. EXAMPLE 18 (METHOD 4C) (2-Chloro-4-nitro-phenyl)-methyl-(1-methyl-pyrrolidin-3-yl)-amine 20 3-Chloro-4-fluoronitrobenzene (1.0 g) and N,N'-dimethyl-3-aminopyrrolidine (1.72 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 25 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 oil.
WO 00/34269 PCTIUS99/28892 - 53 Using the above procedure and appropriate starting materials the following compounds were prepared: (2-Chloro-4-nitro-phenyl)-dipropyl-amine 1-(2-Chloro-4-nitro-phenyl)-piperidine 1-(2-Chloro-4-nitro-phenyl)-pyrrolidine (2-Chloro-4-nitro-phenyl)-cyclohexyl-methyl-amine Benzyl-(2-chloro-4-nitro-phenyl)-amine (2-Chloro-4-nitro-phenyl)-methyl-(1 -methyl-piperidin-4-yl)-amine (2-Chloro-4-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 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 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 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 4-(4-Methyl-piperazin- 1 -yl)-3-trifluoromethyl-benzonitrile 5 WO 00/34269 PCT/US99/28892 - 54 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 l-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- 1 -ethylsulfanyl-4-nitro-benzene EXAMPLE 20 (METHOD 4F) (4-Chloro-5-methoxy-2-nitro-phenyl)-dimethyl-amine 20 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% 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 25 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 removed by evaporation under reduced pressure and the residue is triturated with hexanes to provide the desired product as a colorless solid.
WO 00/34269 PCT/US99/28892 - 55 Using the above procedure and appropriate starting materials the following compounds were prepared: (4-Chloro-2-nitro-phenyl)-dimethyl-amine 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 (2-Chloro-6-nitro-phenyl)-dimethyl-amine 5 EXAMPLE 21 (METHOD 4G) (2-Chloro-4-nitro-phenyl)-methyl-phenyl-amine n-Butyl lithium (12.3 mL of a 2.5 M solution in hexanes) is added dropwise to a 10 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 mixture is permitted to warm to room temperature over the course of 1 hour, and is 15 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 sodium chloride, and then dried over anhydrous magnesium sulfate. Following 20 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 00/34269 PCT/US99/28892 - 56 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 0 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:
(
3 ,5-Dichloro-4-ethoxy-phenyl)-carbamic acid tert-butyl ester
(
4 -Butoxy-3,5-dichloro-phenyl)-carbamic acid tert-butyl ester WO 00/34269 PCT/US99/28892 - 57 (4-Benzyloxy-3,5-dichloro-phenyl)-carbamic acid tert-butyl ester (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 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 EXAMPLE 24 (METHOD 5C) (2,6-Dichloro-4-nitro-phenoxy)-acetic acid tert-butyl ester 5 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 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 10 anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure followed by trituration of the resulting oil with hexanes provides the desired product as a white solid. Using the above procedure and starting materials the following compounds were 15 prepared: 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 WO 00/34269 PCT/US99/28892 - 58 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 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 (2-Chloro-5-methoxy-4-nitro-phenoxy)-acetonitrile 4-(2-Chloro-5-methoxy-4-nitro-phenoxy)-butyronitrile 2-(4-Chloro-5-methoxy-2-nitro-phenoxy)-ethanol 2- (2-Chloro-5-methoxy-4-nitro-phenoxy)-ethanol (2-Chloro-5-methoxy-4-nitro-phenoxy)-acetic acid tert-butyl ester (2-Chloro-5-methoxy-4-nitro-phenoxy)-acetic acid 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 2-Chloro-4-nitro- 1- (2,2,2-trifluoro-ethoxy)-benzene 2-Chloro-4-nitro- 1 -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 3-Chloro-2,4-dimethoxy-nitrobenzene EXAMPLE 25 (METHOD 5E) [3,5-Dichloro-4-(2-hydroxy-ethoxy)-phenyl]-carbamic acid tert-butyl ester 5 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 WO 00/34269 PCT/US99/28892 - 59 mixture is added 2.5 M aqueous sodium hydroxide (50 mL), and the separated 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 5 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) 3-(2-Chloro-4-nitro-phenoxy)-1-methyl-pyrrolidine 10 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 under an atmosphere of argon for 1.5 hours. The solution is then concentrated under 15 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% methanol in dichloromethane is used as the eluant). Pooled product fractions are then 20 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: 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 WO 00/34269 PCT/US99/28892 - 60 EXAMPLE 27 (METHOD 7A) 2 -Chloro-3-methoxy-6-nitro-phenol and 2
,
4 -Dichloro-3-methoxy-6-nitro-phenol 5 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, acidified by addition of concentrated hydrochloric acid, then extracted twice with 10 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 provide both the mono- and di-chlorinated products as yellow solids. 15 Using the above procedure and appropriate starting materials the following compounds were prepared: 3-Chloro-2-hydroxy-4-methoxy-nitrobenzene 3 ,5-Dichloro-2-hydroxy-4-methoxy-nitrobenzene EXAMPLE 28 (METHOD 7B) 20 2,4-Dichloro-3-methyl-6-nitro-phenol 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 25 hypochlorite (5.25% aqueous solution, 230 mL) is added and the mixture is permitted 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 30 chromatographed over silca gel (ethyl acetate is used as the eluant) to provide the WO 00/34269 PCTIUS99/28892 - 61 desired product as a yellow solid. An analytically pure sample is obtained by a single recrystallization from chloroform. EXAMPLE 29 (METHOD 7C) 5 1-Bromo-2,4-dimethoxy-5-nitro-benzene 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 10 (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 over anhydrous sodium sulfate. Removal of the solvent under reduced pressure and 15 recrystallization of the residue from toluene provides the desired product as a yellow solid. EXAMPLE 30 (METHOD 7D) 2,4-Dibromo-3-methoxy-6-nitro-phenol 20 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 approximately 24 hours. The solution is then partitioned between ethyl acetate and 25 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. The residue is chromatographed over silica gel (20% ethyl acetate in hexanes is used 30 as the eluant) then recrystallized from chloroform to provide the desired dibrominated product as an orange solid.
WO 00/34269 PCT/US99/28892 - 62 EXAMPLE 31 (METHOD 7E) 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 5 added benzyltrimethylammonium dichloroiodate (1.90 g) and anhydrous zinc chloride (1.0 g) and the mixture is stirred at room temperature under an atmosphere 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 10 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 under reduced pressure the residue is triturated with hexanes to provide the desired 15 product as a pale yellow solid. EXAMPLE 32 (METHOD 7F) 2
,
4 -Diiodo-3-methoxy-6-nitro-phenol 20 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 pressure, the residue is dissolved in ethyl acetate and then washed successively with 25 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.
WO 00/34269 PCTIUS99/28892 - 63 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 5 added 3,5-dichloro-1-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 10 are combined, evaporated under reduced pressure, and the residue is crystallized from hexanes to provide the desired product as a tan solid. EXAMPLE 34 (METHOD 8) 3 -Chloro-4-trifluoromethyl-nitrobenzene 15 A solution of 3-chloro-4-iodo-nitrobenzene (2.26 g), trimethyl(trifluoromethyl)silane (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 20 earth, and the filtrate is washed successively with water, saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate. The solvent is removed 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. 25 EXAMPLE 35 (METHOD 9) (3-Chloro-4-methanesulfinyl-phenyl)-carbamic acid tert-butyl ester To a solution of (3-chloro-4-thiomethyl-phenyl)-carbamic acid tert-butyl ester (0.89 30 g) in dichloromethane (15 mL) at 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 solvent is removed under reduced pressure and the residue is dissolved in WO 00/34269 PCTIUS99/28892 - 64 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. 5 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] 10 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 with ethyl acetate, dried over anhydrous potassium carbonate and evaporated to yield a red solid, 101 mg. 15 Using the above procedure and appropriate starting materials the following compounds were prepared:
[
4
-(
2 -Methanesulfinyl-benzoylamino)-phenyl]-carbamic acid tert-butyl ester 2-Methanesulfinyl-N-[ 4
-(
2
,
2
,
2 -trifluoro-acetylamino)-phenyl]-benzamide EXAMPLE 37 (METHOD 10) 20 (3-Chloro-4-methanesulfonyl-phenyl)-carbamic acid tert-butyl ester To a solution of (3-chloro-4-thiomethyl-phenyl)-carbamic acid tert-butyl ester (0.90 g) in dichloromethane (30 mL) at 0 'C 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 25 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 gives the desired product as an orange foam.
WO 00/34269 PCT/US99/28892 - 65 EXAMPLE 38 (METHOD 11) 3-Chloro-4-vinyl-phenylamine To a deoxygenated solution of 3-chloro-4-iodo-aniline (6.95 g), triphenyl arsine (0.67 5 g), and tris(dibenzylideneacetone)palladium(0) (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 pressure. The residue is dissolved in hexanes and then extracted three times with 5% 10 aqueous hydrochloric acid. These aqueous acidic extracts are then basified with solid potassium carbonate and extracted three times with ethyl acetate. These pooled 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 15 acetate in hexanes is used as the eluant) to provide the desired product as an amber oil. EXAMPLE 39 (METHOD 12) [3-Chloro-4-(1-hydroxy-ethyl)-phenyl]-carbamic acid 20 2-trimethylsilanyl-ethyl ester (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 25 sodium hydroxide (8.7 mL) and a 0.5 M solution of sodium borohydride in 3N 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 30 under reduced pressure the residue is chromatographed over silica gel (20% ethyl acetate in hexanes is used as the eluant) to provide the desired product as a white solid.
WO 00/34269 PCT/US99/28892 - 66 EXAMPLE 40 (METHOD 13) [3-Chloro-4-(2-hydroxy-ethyl)-phenyl]-carbamic acid tert-butyl ester To a stirring suspension of sodium borohydride (0.45 g) in tetrahydrofuran (13 mL) 5 at 0 'C is added glacial acetic acid (0.75 mL) and the mixture is stirred at 0 0 C for I 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 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 10 sodium hydroxide (0.80 mL) and 30% aqueous hydrogen peroxide (0.56 mL) are 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 15 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 20 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 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 25 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.
WO 00/34269 PCT/US99/28892 - 67 EXAMPLE 42 (METHOD 15) [3-Chloro-4-(3-dimethylamino-prop-1-ynyl)-phenyl]-carbamic acid tert-butyl ester 5 To a deoxygenated solution of (3-chloro-4-iodo-phenyl)-carbamic acid tert-butyl 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 10 reaction mixture is then cooled, filtered through diatomaceous earth, and the solvent 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 under reduced pressure, and the residue is chromatographed over silica gel (80% 15 ethyl acetate in hexanes is used as the eluant) to give the purified product as an amber oil that solidified on standing. Using the above procedure and appropriate starting materials the following compounds were prepared: 20 [3-Chloro-4-(3-dimethylamino-prop-1-ynyl)-phenyl]-carbamic acid tert-butyl ester [3-(4-Methoxy-phenyl)-prop-2-ynyl]-dimethyl-amine 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 25 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 WO 00/34269 PCT/US99/28892 - 68 20 minutes, the mixture is passed over twenty weight equivalents of basic alumina (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 5 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 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 10 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. EXAMPLE 44 (METHOD 17) (3-Chloro-4-isoxazol-5-yl-phenyl)-carbamic acid tert-butyl ester 15 A solution of [3-chloro-4-(3-dimethylamino-acryloyl)-phenyl)-carbamic acid tert 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 20 bicarbonate, saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent is removed by evaporation under reduced pressure 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. 25 EXAMPLE 45 (METHOD 18) [3-Chloro-4-(1H-pyrazol-3-yl)-phenyl]-carbamic acid tert-butyl ester A solution of [3-chloro-4-(3-dimethylamino-acryloyl)-phenyl]-carbamic acid tert butyl ester (250 mg) in ethanol (1.25 ml) is treated with hydrazine hydrate (0.25 ml) 30 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.
WO 00/34269 PCTIUS99/28892 - 69 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. 5 EXAMPLE 46 (METHOD 19A)
N-(
2 -Chloro-4-nitrophenyl)-2-thiomorpholino-4-yl-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. 10 This reaction mixture is poured into water a pale yellow solid is collected and then recrystallized from hot 2-propanol to give a pale yellow crystalline solid. Using the above procedure and appropriate starting materials the following compounds were prepared: 15 (4-{2- [Bis-(2-hydroxy-ethyl)-amino] -acetylamino} -phenyl)-carbamic acid tert-butyl 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 ester
N-(
2 -Chloro-4-nitro-phenyl)-2-dimethylamino-acetamide N-(2-Chloro-4-nitro-phenyl)-2-piperidin- I -yl-acetamide
N-(
2 -Chloro-4-nitro-phenyl)-2-morpholin-4-yl-acetamide
N-(
2 -Chloro- 4 -nitro-phenyl)-2-dipropylamino-acetamide
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 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 WO 00/34269 PCT/US99/28892 - 70 EXAMPLE 47 (METHOD 19B) N-(2-Chloro-4-nitrophenyl)-2-(2-dimethylaminoethylsulfanyl)acetamide To a solution of N-(chloroacetyl)-2-chloro-4-nitroaniline (3.01 g) in N,N 5 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 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 10 yellow crystalline solid. EXAMPLE 48 (METHOD 20) (4-tert-butoxycarbonylamino-2-chloro-phenyl)-carbamic acid 2 piperidin-1-yl-ethyl ester 15 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 20 this mixture is added piperidineethanol (6.6 mL) and tetra-hydrofuran (20 mL) is 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 25 by chromatography over silica gel (5% methanol in dichloromethane is used as the eluant) to give the desired product as a white foam. EXAMPLE 49 5-Phenyl-[1,2,3]thiadiazole-4-carboxylic acid methyl ester 30 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 WO 00/34269 PCTIUS99/28892 - 71 overnight at room temperature, the reaction is concentrated under reduced pressure and the resulting crude product is dissolved in ethyl acetate and washed with IN sodium hydroxide. The organic layer is then dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to yield a yellow oil. This 5 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 2,4-disulfide (2.8 g) and the reaction is heated to reflux. After 3 hours, the reaction is 10 cooled to room temperature, loaded onto a pad of silica gel and eluted with dichloromethane. After removing the solvent under reduced pressure, the resulting 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. 15 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 20 EXAMPLE 50 Ethyl benzoylacetate semicarbazide Ethyl benzoylacetate (5.0 g) is dissolved in methanol (10 mL) and added rapidly to a hot solution of semicarbazide hydrochloride (29 g) in water (130 mL). To this is 25 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.
WO 00/34269 PCT/US99/28892 - 72 Using the above procedure and appropriate starting materials the following compound was prepared: Ethyl (Z)-3-[(aminocarbonyl)hydrazono]- 4 ,4,4-trifluorobutanoate 3-[(Z)-2-(Aminocarbonyl)hydrazono]-3-phenylpropanoic acid ethyl ester 3-[(E)-2-(Aminocarbonyl)hydrazono]-3-(3-furyl)propanoic acid ethyl ster EXAMPLE 51 5 5-Phenyl-[1,2,3]thiadiazole-5-carboxylic acid ethyl ester 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 thionyl chloride is destroyed slowly with saturated aqueous sodium bicarbonate. The 10 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. Chromatography over silica gel (50% hexanes in dichloromethane is used as the eluant) affords the desired product as a colorless oil. 15 Using the above procedure and appropriate starting materials the following compounds were prepared: 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 20 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 WO 00/34269 PCT/US99/28892 - 73 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 5 give the desired compound as a white powder. Using the above procedure and appropriate starting materials the following compounds were prepared: 3-Ethoxycarbonylmethoxy-benzoic acid 5-Furan-3-yl-[1,2,3]thiadiazole-4-carboxylic acid Thiazole-4-carboxylic acid 4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid 5-Methyl-[1,2,3]thiadiazole-4-carboxylic acid 10 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 mL) at 0 'C under an atmosphere of argon is added triethylamine (10 g) and then a 15 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 the solvent is removed by evaporation under reduced pressure and the residue is 20 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. 25 Using the above procedure and appropriate starting materials the following compounds were prepared: WO 00/34269 PCT/US99/28892 - 74 Trifluoro-methanesulfonic acid 4-chloro-5-methoxy-2-nitro-phenyl ester 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 5 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 into ethyl acetate. The ethyl acetate solution is dried over anhydrous potassium 10 carbonate and concentrated under reduced pressure to give a solid which is recrystallized from acetonitrile to provide a pale pink crystalline solid. Using the above procedure and appropriate starting materials the following compounds were prepared: 15 [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) N-(4-Aminophenyl)-2-hydroxybenzamide 20 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 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 25 which is then triturated with diethyl ether to provide the desired product as a white solid.
WO 00/34269 PCT/US99/28892 - 75 EXAMPLE 56 (METHOD 28) [4-(3-(Hydroxybenzoylamino)phenyl}carbamic acid t-butyl ester 5 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 mL). This solution is heated at 400 C for 30 minutes, then cooled, poured into 1 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 10 white solid, which is further purified by trituration with diethyl ether. EXAMPLE 57 (METHOD 29) N-(4-Aminophenyl)-2-hydroxymethylbenzamide 15 To a solution of N-(4-aminophenyl)phthalimide (332 mg) in tetrahydrofuran (4 mL) 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 20 desired product as a white powder. EXAMPLE 58 (METHOD 30) (3-Chloro-5-dimethylamino-phenyl)-carbamic acid tert-butyl ester 25 To a solution of (3-amino-5-chloro-phenyl)-carbamic acid tert-butyl ester (0.32 g) in 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 30 over silica gel (50% dichloromethane in hexanes is used as the eluant) to provide the desired product as a white solid.
WO 00/34269 PCT/US99/28892 - 76 EXAMPLE 59 (METHOD 35) N-(4-{3-[3,5-Dichloro-4-(2-hydroxy-ethoxy)-phenyl]-thioureido} phenyl)-acetamide 5 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 aqueous hydrochloric acid (3 mL), extracted into ethyl acetate, and the extracts are 10 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. EXAMPLE 60 (METHOD 36) 15 {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 20 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. 25 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 {2- [3-(4-Acetylamino-phenyl)-thioureido]-4-chloro-5-methoxy-phenoxy) -acetic acid WO 00/34269 PCT/US99/28892 - 77 {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 phenoxy}-ethyl ester 5 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 hours. The mixture is then diluted with ethyl acetate, washed successively two times 10 with 2% aqueous hydrochloric acid, once with saturated aqueous sodium chloride, then dried over anhydrous sodium sulfate. After removal of the solvent under 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 15 acetone-hexanes to provide the desired product as a white powder. EXAMPLE 62 (METHOD 38) Methanesulfonic acid 2
-{
4
-[
3
-(
4 -acetylamino-phenyl)-thioureido]-2,6-dichloro phenoxy}-ethyl ester 20 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 25 successively twice with 2% aqueous hydrochloric acid, once with saturated aqueous 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.
WO 00/34269 PCT/US99/28892 - 78 EXAMPLE 63 (METHOD 39) N-(4-{3-[3,5-Dichloro-4-(2-dimethylamino-ethoxy)-phenyll-thioureido}-phenyl) acetamide 5 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 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 10 sulfate. After removal of the solvent under reduced pressure the residue is chromatographed over silica gel (pure methanol is used as the eluant). Pooled product containing fractions are evaporated under reduced pressure and the residue is recrystallized from acetonitrile to provide the desired product as a white powder. 15 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) acetamide Benzoic acid 2-{4-[3-(4-acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy } ethyl ester EXAMPLE 64 (METHOD 40) 20 Furan-2-carboxylic acid (4-{3-[4-(1-amino-ethyl)-3-chloro-phenyl]-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} 25 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 WO 00/34269 PCT/US99/28892 - 79 evaporation under reduced pressure the residue is chromatographed over silica gel (8% methanol in dichloromethane containing 1% triethylamine is used as the eluant) to provide the desired product as a yellow solid. 5 EXAMPLE 65 (METHOD 41) [1,2,3]Thiadiazole-4-carboxylic acid (4-isothiocyanato-phenyl)-amide 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 10 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 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 removal of solvents, the residue is recrystallized from ethyl acetate-hexanes to 15 provide the desired product as a slightly yellow solid. Using the above procedure and appropriate starting materials the following 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 Thiazole-4-carboxylic acid ( 4 -isothiocyanato-phenyl)-amide 20 EXAMPLE 66 (METHOD 42) N,N-Dimethyl-5-trifluoromethyl-benzene-1,3-diamine To a solution of 3-amino-5-bromo-benzotrifluoride (1.0 g) in degassed (argon) 25 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 WO 00/34269 PCT/US99/28892 - 80 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 5 with ethyl acetate, and these pooled organic extracts are washed with saturated 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. 10 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 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 N-Butyl-N-methyl-5-trifluoromethyl-benzene- 1,3-diamine 15 EXAMPLE 67 (METHOD 43) (3-Isobutyl-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester 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 20 minutes. A solution of 9-borabicyclo[3.3. l]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 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 25 isobutylene. A solution of (3-bromo-5-trifluoromethyl-phenyl)-carbamic acid tert- WO 00/34269 PCTIUS99/28892 - 81 butyl ester (1.7 g) in tetrahydrofuran (12 mL) is added, followed by [1,1' bis(diphenylphosphino)-ferrocene]palladium (II) chloride-dichlormethane complex (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 5 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% ethyl acetate in hexanes is used as the eluant) to provide the desired product as a white powder. 10 Using the above procedure and appropriate starting materials the following compounds were prepared: [3-(2-Methyl-butyl)-5-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (3-Isobutyl-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester 15 EXAMPLE 68 (METHOD 44) 2-(3,5-Dichloro-phenylsulfanyl)-ethylamine 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 20 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 sodium hydroxide and extracted with ether. The ether extract is dried over potassium carbonate, filtered and concentrated to give 1.Og of a colorless oil. 25 Using the above procedure and appropriate starting materials the following compounds were prepared 2-(3-Bromo-phenylsulfanyl)-ethylamine 2(4-Bromo-phenoxy)-ethylamine WO 00/34269 PCT/US99/28892 - 82 2-(4-Iodo-phenoxy)-ethylamine 2-(3,4-Dichloro-phenoxy)-ethylamine 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 2-(3-Bromo-phenoxy)-ethylamine 2-(3-Fluoro-phenoxy)-ethylamine 2-(3-Iodo-phenoxy)-ethylamine 2-(3,5-Dichloro-phenylsulfanyl)-ethylamine 2-Phenylsulfanyl-ethylamine 1-(2-Chloro-phenyl)-ethylamine EXAMPLE 69 (METHOD 45) N-(1-Naphthalen-2-yl-ethyl)-formamide 5 A mixture of 2-acetylnaphthylene (3.0 g), ammonium formate (11.0 g), formic acid (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-[i-(4-Fluoro-phenyl)-2-methyl-propyl]-formamide N-(I -Naphthalen-2-yl-ethyl)-formamide WO 00/34269 PCT/US99/28892 - 83 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 5 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. 10 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 [3-(1-Amino-ethyl)-phenyl]-dimethyl-amine 3-(1-Amino-ethyl)-benzonitrile EXAMPLE 71 (METHOD 47) 15 1-(3-Trifluoromethyl-phenyl)-ethanone O-methyl-oxime Methoxylamine hydrochloride (2.33 g) is added to a solution of 3'-(trifluoromethyl) 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 20 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 concentrated under reduced pressure to give the desired product as a colorless oil (1.61 g). 25 Using the above procedure and appropriate starting materials the following compounds were prepared: WO 00/34269 PCT/US99/28892 - 84 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 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 3-(1-Methoxyimino-ethyl)-benzonitrile 4- (1 -Methoxyimino-ethyl)-benzonitrile 1-(4-Methoxy-phenyl)-ethanone 0-methyl-oxime 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 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 1-(1-Methyl-iH-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 4-(1-Methoxyimino-ethyl)-benzenesulfonamide 4-(1-Methoxyimino-ethyl)-N,N-dimethyl-benzenesulfonamide 1-[4-(Piperidine-1-sulfonyl)-phenyl]-ethanone 0-methyl-oxime 4-(1-Methoxyimino-ethyl)-N,N-dipropyl-benzenesulfonamide 2-Fluoro-N-[4-(1-methoxyimino-ethyl)-phenyl]-benzamide 1-(3,5-Bis-trifluoromethyl-phenyl)-ethanone 0-methyl-oxime 1-[4-(1H-Imidazol-1-yl)phenyl]-1-ethanone, 0-methyloxime WO 00/34269 PCT/US99/28892 - 85 1-[4-(Trifluoromethyl)phenyl]-1-ethanone, 0-methyloxime 1-[1,1'-Biphenyl]-4-yl-1-ethanone, 0-methyloxime 1-(4-Methylphenyl)-1-ethanone, 0-methyloxime 1-[4-fluoro-3-(trifluoromethyl)phenyl]ethanone 0-methyloxime 1-[3,5-bis(trifluoromethyl)phenyl]ethanone O-benzyloxime 1-[4-chloro-3-(trifluoromethyl)phenyl]ethanone 0-methyloxime 1-[3-fluoro-5-(trifluoromethyl)phenyl]ethanone 0-methyloxime 1-[2-fluoro-4-(trifluoromethyl)phenyl]ethanone 0-methyloxime 1-[2-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 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 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 1-[3-fluoro-4-(trifluoromethyl)phenyl]ethanone 0-methyloxime 1-(3,4-dichlorophenyl)ethanone 0-methyloxime 1-[4-fluoro-2-(trifluoromethyl)phenyl]ethanone 0-methyloxime 1-(3-chloro-4-fluorophenyl)ethanone 0-methyloxime 1-(4-chloro-3-fluorophenyl)ethanone 0-methyloxime 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 WO 00/34269 PCT/US99/28892 - 86 EXAMPLE 72 (METHOD 48) 1-(2-Trifluoromethyl-phenyl)-ethylamine Sodium borohydride (1.17 g) is added slowly to a flask containing zirconium 5 tetrachloride (1.8 g) in tetrahydrofuran (27 mL). A solution of 1-(2-trifluoromethyl phenyl)-ethanone 0-methyl-oxime (1.34 g) in tetrahydrofuran (7.7 mL) is added and the resulting solution is stirred at 25 '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 10 washed twice with 1N hydrochloric acid. The aqueous (acid) layer is basified with 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). 15 Using the above procedure and appropriate starting materials the following compounds were prepared: 1-(3-Methoxy-phenyl)-ethylamine 1-(4-Fluoro-phenyl)-propylamine 1 -Naphthalen-2-yl-ethylamine 4-(1 -Amino-ethyl)-benzonitrile 1-(4-Trifluoromethyl-phenyl)-ethylamine 1-(4-Methoxy-phenyl)-ethylamine I -Prop-2-ynyl-pyrrolidine 1-(2-Methoxy-phenyl)-ethylamine 1-m-Tolyl-ethylamine 1-(2-Bromo-phenyl)-ethylamine 1-0-Tolyl-ethylamine C-(4-Fluoro-phenyl)-C-phenyl-methylamine 1-(4-Fluoro-phenyl)-pentylamine 1-(4-Fluoro-phenyl)-2-phenyl-ethylamine WO 00/34269 PCTIUS99/28892 - 87 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-1 H-pyrrol-2-yl)-ethylamine 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 1-(4-methylphenyl)ethanamine 1-[3-(trifluoromethyl)phenyllethylamine 1-[4-(trifluoromethyl)phenyl]ethylamine 1-(3-methylphenyl)ethanamine 1-(3,4-dichlorophenyl)ethanamine 1-(2-Bromo-phenyl)-ethylamine 1-(2-Trifluoromethyl-phenyl)-ethylamine 1-(3-Bromo-phenyl)-ethylamine 1-(3-Chloro-4-methoxy-phenyl)-ethylamine 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 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 1-[4-fluoro-3-(trifluoromethyl)phenyl]ethanamine 1-[ 4 -chloro-3-(trifluoromethyl)phenyl]ethanamine N- { 4- [(1 R)- 1 -aminoethyl]phenyl} -1,2,3-thiadiazole-4-carboxamide N- 4-[(1 S)- 1 -aminoethyl]phenyl} -1,2,3-thiadiazole-4-carboxamide WO 00/34269 PCT/US99/28892 - 88 1- [3-fluoro-5-(trifluoromethyl)phenyl]ethylamine 1-[2-fluoro-4-(trifluoromethyl)phenyl]ethylamine 1-[2-fluoro-5-(trifluoromethyl)phenyl]ethylamine 1-(2,4-dichlorophenyl)ethylamine 1-(2,4-dimethylphenyl)ethylamine 1-[2,4-bis(trifluoromethyl)phenyl]ethylamine 1-(2-chloro-4-fluorophenyl)ethylamine 1-(3,4-difluorophenyl)ethylamine 1-(4-bromo-2-fluorophenyl)ethylamine 1-(3-fluorophenyl)ethylamine 1-(2,4-difluorophenyl)ethylamine 1-[3-fluoro-4-(trifluoromethyl)phenyl]ethylamine 1-[4-fluoro-2-(trifluoromethyl)phenyl]ethylamine 1-(3-chloro-4-fluorophenyl)ethylamine 1-(4-chloro-3-fluorophenyl)ethylamine 1-(3,4-dibromophenyl)ethylamine 1-(2-bromo-4-fluorophenyl)ethanamine 1-(2-bromo-4 fluorophenyl)ethylamine EXAMPLE 73 (METHOD 49) (2-Fluoro-5-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).
WO 00/34269 PCT/US99/28892 - 89 Using the above procedure and appropriate starting materials the following compounds were prepared: (3-Bromo-phenylsulfanyl)-acetonitrile (3-Chloro-phenylsulfanyl)-acetonitrile (4-Iodo-phenoxy)-acetonitrile (3-Trifluoromethyl-phenylsulfanyl)-acetonitrile (3,5-Dichloro-phenylsulfanyl)-acetonitrile (3,4-Dichloro-phenylsulfanyl)-acetonitrile (3,4-Dichloro-phenoxy)-acetonitrile (2-Fluoro-phenoxy)-acetonitrile (3-Fluoro-phenoxy)-acetonitrile (2-Chloro-phenoxy)-acetonitrile (3-Bromo-phenoxy)-acetonitrile (2-Fluoro-5-trifluoromethyl-phenoxy)-acetonitrile (3-Iodo-phenoxy)-acetonitrile (4-Bromo-phenoxy)-acetonitrile 5 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 mmol) of p-toluenesulfonic acid in 75 ml of ethylene glycol monomethyl ether is 10 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%) are collected by filtration. 15 Using the above procedure and appropriate starting materials the following compounds were prepared: WO 00/34269 PCT/US99/28892 - 90 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 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) (4-Aminomethyl-2-trifluoromethyl-phenyl)-dimethyl-amine 5 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 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 10 washed with tetrahydrofuran. The filtrates are collected and concentrated under 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). 15 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 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 WO 00/34269 PCTIUS99/28892 - 91 EXAMPLE 76 (METHOD 52) 3-Dimethylamino-5-trifluoromethyl-benzaldehyde 5 Diisobutylaluminum hydride (10 mL of a IM solution in methylene chloride) is added dropwise to a solution of 3-dimethylamino-5-trifluoromethylbenzonitrile (1.06 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 10 extracted with ethyl acetate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide the desired product as a yellow solid (0.97 g). Using the above procedure and appropriate starting materials the following 15 compounds were prepared: 3-Dimethylamino-5-trifluoromethyl-benzaldehyde 4-Dimethylamino-3-methyl-benzaldehyde EXAMPLE 77 (METHOD 53) Dimethyl-[3-(2-nitro-vinyl)-5-trifluoromethyl-phenyl]-amine 20 Nitromethane (0.473 g) is added to a solution of 3-dimethylamino-5-trifluoromethyl 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 0 C and a solid forms which is filtered and washed with 1:1 water-acetic acid. This solid 25 is recrystallized from ethanol to provide the desired product as a red solid (0.39 g). Using the above procedure and appropriate starting materials the following compounds were prepared: WO 00/34269 PCT/US99/28892 - 92 Dimethyl-[3-( 2 -nitro-vinyl)-5-trifluoromethyl-phenyl]-amine Dimethyl-[2-methyl-4-(2-nitro-vinyl)-phenyl]-amine EXAMPLE 78 (METHOD 54) 3
-(
4 -Bromo-phenyl)-propionitrile 5 Diethylazodicarboxylate (5.2 g) is added dropwise to a solution of 4-bromo 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 10 then filtered, and washed with diethyl ether. The filtrate is concentrated under 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) 15 3 -Dimethylamino-2-isocyano-acrylic acid ethyl ester 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. The reaction is stirred for 24 hours and the ethanol is evaporated. The resulting oil is 20 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. EXAMPLE 80 (METHOD 56) 25 4 -Carboethoxythiazole A solution of 3 -dimethylamino-2-isocyano-acrylic acid ethyl ester (1.0 g) and 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 WO 00/34269 PCT/US99/28892 - 93 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. EXAMPLE 81 (METHOD 34) 5 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 mL) is treated with 5-chloro-2,4-dimethoxyphenylisocyanate (0.40 g). The mixture 10 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 compounds were prepared: 15 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-benzanide 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 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}-amide 90 423 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,4-dichloro-benzyl)-ureido] phenyl}-amide WO 00/34269 PCTIUS99/28892 - 94 EXAMPLE 91(e) N-(5-{[({(1S)- 1-[3,5-bis(trifluoromethyl)phenyl]ethyl}amino) carbothioyl] amino}-2-pyridinyl)- 1,3-thiazole-4-carboxamide 5 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 to stand for 12 hours. A white solid forms and is collected by filtration (0.40 g). [M+H] 520. 10 Using the above procedure and appropriate starting materials the following compounds were prepared: 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 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)-thioureidol-phenyl} -acetanide 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 WO 00/34269 PCT/US99/28892 - 95 105 316 N-{4-[3-(2-Methoxy-phenyl)-thioureido]-phenyl}-acetamide 106 351 N- {4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl}-acetanide 107 351 N-{4-[3-(5-Chloro-2-methoxy-phenyl)-thioureido]-pheny } -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]-phienyl} -acetamide 111 389 N- {4-[3-(2-Chloro-5-trifluoromethyl-phenyl)-thioureido]-phenyl I -acetamide 112 389 N-{4-[3-(4-Chloro-3-trifluoromethyl-phenyl)-thioureido]-phenyl} -acetamide 113 422 Benzoic acid 4-[3-(4-acetylamino-phenyl)-thioureido]-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 carbamoyl } -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 benzamide 121 473 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-4-methoxy benzamide 122 443 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-benzamide 123 417 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl} methanesulfonamide 124 331 N-{4-[3-(3-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 WO 00/34269 PCT/US99/28892 - 96 129 385 N-{ 4 -[3-(3,5-Dichloro-4-hydroxy-2-methyl-phenyl)tjhioureido]-phenyl
}
acetainide 130 318 N- { 4 -13-(2,4-Dihydroxy-phenyl)-thioureido]-phenyl }-acetamnide 131 414 N-{ 4
-[
3
-(
2
,
4 -Dimethoxy-5-trifluoromethylbphenyl)ffiioureido]-phenyl
}
acetamnide 132 332 N- { 4 -[3-(2-Hydroxy-4-methoxy-phenyl)dthioureido]-phenyl)}-acetamide 133 465 N- { 4
-[
3
-(
3
,
5 -Dichloro-4-methoxy-phenyl)-thioureido]-piienyl }-4-iluoro benzamide 134 500 3-Acetylamnino-N-{ 4-[3-(5-chloro-2.4-dimeffioxy-phenyl).ffioureido]. phenyll}-benzamide 135 488 N-f 4 -[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl } -3-nitro benzainide 136 486 N-f 4 -[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-3 dimethylainino-benzamide 137 536 N-f 4 -[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureidoj-pheny } -3-methane sulfony-amino-benzamide 138 511 N- { 4 -[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-2-trifluoro methyl-benzarnide 139 459 N-{ 4-r3-(5-Chloro-2,4-dimethoxy-phenyl).ffioureido]-phenyl }-2-hydroxy benzamnide 140 479 N-{4-[3-(5-Chloro-2,4-dimeffioxy-phenyl)-thioureido]-phenyl } -2,6-difluoro benzainide 141 477 2 -Chloro-N-{ 4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl } beuzamnide 142 522 2 -Bromo-N-{ 4-[3-(5-chloro-2,4-dimethoxy-phenyl)4thioureido]-phenyl } benzamide 143 488 N-{ 4 -[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-2-nitro benzamide 144 445 Pyrazine-2-carboxylic acid {4-13-(5-chloro-2,4-dimethoxy-phenyl) thioureido]-phenyl}-amnide 145 463 5-Methyl-thiophene-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy phenyl)-thioureido]-phenyl }-amnide 146 494 Quinoline-8-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl) thioureido]-phenyl }-amnide 147 446 1-Methyl-1H-pyrrole-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy phenyl)-thioureido]-phenyl }-amide 148 369 1 -( 5 -Chloro- 2 ,4-dimethoxy-phenyl)-3-(2-nitro-phenyl)-thiourea WO 00/34269 PCTIUS99/28892 - 97 149 369 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}-acetamide 152 399 N-{4-[3-(3,5-Dichloro-2-methoxy-4-methyl-phenyl)- thioureido]-phenyl} acetamide 153 499 Benzo[b]thiophene-2-carboxylic acid { 4 -[3-(5-chloro-2,4-dimethoxy-phenyl) thioureidol-phenyl }-amide 154 483 Benzofuran-2-carboxylic acid {4-[3-(5-chloro-2.4-dimethoxy-phenyl) thioureidol-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}-amide 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}-amide 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 }-amide 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) thioureido]-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) thioureido]-phenyl } -amide WO 00/34269 PCT/US99/28892 - 98 170 433 Furan-2-carboxylic acid { 4 -[3-(5-chloro-2.4-dimethoxy-pheny).rjioureido] phenyl }-ainide 171 467 { 4
-[
3
-(
5 -Chloro-2,4-dimethoxy-phenyl).thioureido]-phenyl }-carbainic acid hexyl ester 172 494 Isoquinoline-4-carboxylic acid { 4 -[3-(5-chloro-2,4-dimethoxy-phenyl) thioureidol-phenyl I -amide 173 451 [1 , 2 ,3]Thiadiazole-4-carboxylic acid { 4 -j3-(5-chloro-2,4-dimethoxy-phenyl). thioureidol-phenyl } -amide 174 434 1 H-[ 1,2,3]Triazole-4-carboxylic acid { 4 -[3-(5-chloro-2,4-dimethoxy-phenyl) thioureido]-phenyll}-amnide 175 528 3-Bromo-thiophene-2-carboxylic acid { 4 -[3-(5-chloro-2,4-dimethoxy-phenyl) thioureido]-phenyl)}-amide 176 399 N- { 4 -1 3
-(
3
,
5 -Dichloro-4-ethoxy-phenyl)-thioureido]-phenyl J-acetamide 177 427 N- { 4 -1 3
-(
4 -Butoxy-3.5-dichloro-phenyl)-thioureido]-phenyl I-acetamnide 178 461 N-{ 4
-[
3
-(
4 -Benzyloxy-3,5-dichloro-phenyl)41iioureido] -phenyl)}-acetamide 179 381 N-{ 4
-[
3
-(
3 -Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl I-acetamide 180 530 (3- { 4
-[
3
-(
5 -Chloro- 2 .4-dimeffioxy-phenyl)-thioureidoy-phenylcarbamoy
}
phenyl)-carbamic acid ethyl ester 181 458 2-Amino-N- { 4
-[
3
-(
5 -chloro-2.4-dimethoxy-phenyl)-thioureido]-phenyl
}
benzamnide 182 519 Biphenyl-2-carboxylic acid {4-r3-(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)-phenylj-thiourea 184 487 N-{ 4
-[
3 -(5-Chloro-2,4-dimethoxy-phenyl)ythioureido]-phenyl
}
plithalamic acid 185 473 N- { 4
-[
3
-(
5 -Chloro-2,4-dimethoxy-phenyl)-thioureidoy-phenyl I-2-hydroxy methyl-beuzarnide 186 479 N-{ 4
-[
3 -(5-Chloro-2,4-dimethoxy-phenyl)..thioureido]-phenyl }-2,3 difluoro-benzainide 187 479 N-f 4
-[
3
-(
5 -Chloro-2,4-dimethoxy-phenyl)-thioureidoy-phenyl }-2,5 difluoro-benzamide 188 479 N-{ 4
-[
3
-(
5 -Chloro-2,4-dimethoxy-phenyl)ffiioureido]-phenyl }-2,4 difluoro-benzamide 189 500 2-Acetylamnino-N- { 4
-[
3 -(5-chloro-2,4-dimethoxy-phenyl)-thioureidoj phenyl }-benzamide 190 441 l-( 5 -Chloro- 2
,
4 -dimethoxy-phenyl)3-(6oxo5,6dihydrophenanthridin- WO 00/34269 PCT/US99/28892 - 99 2-yl)-thiourea 191 536 N- { 4
-[
3
-(
5 -Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-methane sulfonylamino-benzamide 192 497 N- { 4
-[
3
-(
5 -Chloro-2,4-dimethoxy-phenyl)-thioureido]-pheny}1 -2.3,4 trifluoro-benzamide 193 533 N-{ 4
-[
3
-(
5 -Chloro-2,4-dimethoxy-phenyl)-thioureido]-pheny1 -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]-pheny } acetamide 200 459 [1, 2 ,3]Thiadiazole-4-carboxylic acid { 4
-[
3 -(4-chloro-3-trifluoromethyl phenyl)-thioureido]-phenyl } -amide 201 455 [1,2,3]Thiadiazole-4-carboxylic acid { 4 -[3-(35-dichloro-4-methoxy-phenyl) thioureido]-phenyl}-amide 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-acetylamino-phenyl) thioureido]-2-chloro-phenyl }-amide 205 406 N- { 4
-[
3
-(
3 -Chloro-4-morpholin-4-yl-phenyl)-thioureido]-phenyl} -acetamide 206 443 1-(5-Chloro- 2
,
4 -dimethoxy-phenyl)-3-(3-chloro-4-morpholin-4-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]-pheny }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 WO 00/34269 PCTIUS99/28892 - 100 211 434 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-benzamide 221 545 ( 3
-{
4
-[
3
-(
5 -Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenylcarbamoyl} phenoxy)-acetic acid ethyl ester 222 517 (3-f{ 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) thioureidol-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 -dimethylanino-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 WO 00/34269 PCT/US99/28892 - 101 230 405 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-4-methyl-phenyl) thioureido]-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 benzainide 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-amino)-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-fluoro benzanide 245 422 N-{4-[3-(2-Benzylamino-4-methoxy-phenyl)-thioureido]-phenyl}-acetanide 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-benzainide 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-ainino)-phenyl]-thioureido} phenyl)-3-methoxy-benzamide WO 00/34269 PCT/US99/28892 - 102 251 376 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]-phenyI }-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-f{ 4
-[
3
-(
5 -Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyI} -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 -Acetylanino-phenyl)-thioureido]-2-chloro-phenoxy}-4,5-dichloro benzenesulfonic acid 264 527 4-Phenyl-[1, 2 ,3]thiadiazole-5-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy phenyl)-thioureido]-phenyl } -amide 265 381 N-(4-{ 3
-[
3 -Chloro-4-(2-hydroxy-ethoxy)-phenyl]-thioureido } -phenyl) acetamide 266 393 N- { 4 -[3-( 4 -Butoxy-3-chloro-phenyl)-thioureido]-phenyl }-acetamide 267 446 N-(4-{ 3
-[
3 -Chloro-4-(cyclohexyl-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]-pheny I -acetamide 270 317 { 4
-[(
3 -Methyl-furan-2-carbonyl)-aminno]-phenyl}-carbamic acidtert-butyl ester 271 456 N-{ 4
-[
3
-(
2 -Benzylamino-5-chloro-4-methoxy-phenyl)-thioureido]-phenyl} acetanide WO 00/34269 PCT/US99/28892 - 103 272 420 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) cetamide 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]-phenyI } acetamide 276 493 Furan-2-carboxylic acid { 4 -[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido] 2,5-dimethoxy-phenyl}-amide 277 486 N-{ 4
-[
3
-(
5 -Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-cyano-pheny}-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}amide 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)-thioureido] pyridin-2-yl}-amide 285 425 N-{ 4
-[
3 -(5-Chloro- 2 ,4-dimethoxy-phenyl)-thioureido]-2-methoxy-5-methyl phenyl}-acetamide 286 505 N-{ 4
-[
3 -(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methoxy-5-methyl phenyl}-2-fluoro-benzamide 287 477 Furan-2-carboxylic acid { 4
-[
3 -(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2 methoxy-5-methyl-phenyl } -amide 288 517 4-Furan-3-yl-[1, 2 ,3]thiadiazole-5-carboxylic acid{4-[3-(5-chloro-2,4 dimethoxy-phenyl)-thioureido]-phenyl} -amide 289 462 N- { 5-[ 3 -(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-2-yl} -2-fluoro benzamide 290 384 N-{ 4
-[
3
-(
4 -Methoxy-3-trifluoromethyl-phenyl)-thioureido]-phenyl } -acetamide 291 394 N-[4-(3-{ 3 -Chloro-4-[(2-hydroxy-ethyl)-methyl-amino]-phenyl}-thioureido)- WO 00/34269 PCTIUS99/28892 - 104 phenyl]-acetamide 292 485 N- {2-Benzoyl-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl } acetamide 293 565 N-{ 2-Benzoyl-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-2 fluoro-benzamide 294 537 Furan-2-carboxylic acid f 2-benzoyl-4-13-(5-chloro-2,4-dimethoxy-phenyl) thioureido]-phenyll}-amide 295 475 N- {4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-methyl-phenyl }-2 fluoro-benzamnide 296 447 Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-3 methyl-phenyl} -amide 297 395 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3 -methyl-phenyl } acetamide 298 435 N-[4-(3-{ 3-Chloro-4-[(3-dimethylamnino-propyl)-methyl-amino]-phenyl } thioureido)-phenyl]-acetamide 299 418 N- {4-[3-(3-Chloro-4-cyclohexylamino-phenyl)-thioureido]-plienyl }-acetamide 300 421 N-[4-(3-{ 3-Chloro-4-[(2-dimethylamino-ethyl)-methyl-amino-phenyl } thioureido)-phenyll-acetainide 301 580 5-[[[(5-Chloro-2,4-dimethoxyphenyl)amino]thioxomethylamino]-2-[(2 fluorobenzoyl)ajmino]-N-phenyl-benzamnide 302 552 Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido] 2-phenylcarbamnoyl-phenyl }-ainide 303 491 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methoxy-phenyl
}
2-fluoro-benzainide 304 463 Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido] 2-methoxy-phenyl }-amnide 305 449 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-trifluoromethyl phenyl}-acetamide 306 458 Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido] 2-cyano-phenyl I}-amnide 307 467 Furan-2-carboxylic acid {2-chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl) thioureido]-phenyl}I -amide 308 501 Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido] 2-trifluoromethyl-phenyll}-amide 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- WO 00/34269 PCT/US99/28892 - 105 fluoro-benzamide 311 447 Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido] 2-methyl-phenyl}-amide 312 378 N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-acetamide 313 408 {4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-carbamic acid ethyl ester 314 382 N-{5-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureidol-pyridin-2-yl} acetamide 315 509 N-(4-{3-[4-(1-Benzyl-piperidin-4-ylamino)-3-chloro-phenyl]-thioureido} phenyl)-acetamide 316 407 N-(4-{3-[3-Chloro-4-(2-dimethylamino-ethylamino)-phenyl]-thioureido} phenyl)-acetamide 317 408 N-[4-(3-{3-Chloro-4-[(2-methoxy-ethyl)-methyl-aminol-phenyl}-thioureido) phenyl]-acetamide 318 421 N-(4-{3-[3-Chloro-4-(3-dimethylamino-propylamino)-phenyl]-thioureido} phenyl)-acetamide 319 495 N-(4-{ 3-[4-(1-Benzyl-pyrrolidin-3-ylamino)-3-chloro-phenyl]-thioureido} phenyl)-acetamide 320 483 Furan-2-carboxylic acid {5-chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl) thioureido]-2-hydroxy-phenyl}-amide 321 431 N-{5-Chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-hydroxy phenyl}-acetamide 322 511 (5H,11 H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-(2-chloro-4-imidazol-1 yl-phenyl)-methanone 323 451 [1,2,3]Thiadiazole-5-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-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}- WO 00/34269 PCT/US99/28892 - 106 acetamide 330 416 Furan-2-carboxylic acid {4-[3-(3-chloro-4-dimethylamino-phenyl) thioureido]-phenyl } -amide 331 561 Furan-2-carboxylic acid [4-(3-{4-[( 1-benzyl-pyrrolidin-3-yl)-methyl-amino] 3-chioro-phenyll}-thioureido)- phenyl]-amide 332 513 N-r4-(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- { 3-13-Chloro-4-(1 -methyl-pyrrolidin-3-yloxy)-phenyl]-thioureido I phenyl)-acetainide 335 434 N-(4-{ 3-[3-Chloro-4-(1 -methyl-piperidin-4-yloxy)-phenyl]-thioureido } phenyl)-acetamide 336 422 N-(4- {3-13-Chloro-4-(3-dimethylamino-propoxy)-phenyl]-thioureido I phenyl)-acetamide 337 425 2-Acetylamino-5-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido] benzoic acid 338 505 5-13-(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) amino] -benzoic acid 340 545 N-[4-(3-1{3-Chloro-4-[methyl-(1 -methyl-piperidin-4-yl)-ainino]-phenyl } thioureido)-phenyl]-2,6-difluoro-benzamide 341 503 [1 ,2,3]Thiadiazole-4-carboxylic acid[4-(3-{ 3-chloro-4-[methyl-(1 -methyl pyrrolidin-3-yl)-amnino]-phenyl }-thioureido)-phenyl]-ainide 342 443 N- {4-[3-(3-Chloro-4-methylsulfanyl-phenyl)-thioureido]-phenyl I-2-methyl benzamide 343 408 N-(4-{ 3-13-Chloro-4-(2-dimethylamino-ethoxy)-phenyl] -thioureido I-phenyl) acetamide 344 499 Furan-2-carboxylic acid 14-(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 I-acetamide 346 440 N-{ 4-[3-(3-Chloro-4-dimethylamino-phenyl)-thioureido]-phenyl 1-2-methyl benzamide 347 493 N-{ 4-r3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido-3-methyl-phenyl)}-2,6 difluoro-benzainide 348 462 N-{4-r3-(3-Chloro-4-dimethylamnino-phenyl)-thioureido]-phenyl }-2,6- WO 00/34269 PCT/US99/28892 - 107 difluoro-benzamide 349 531 N-[4-(3-{3-Chloro-4-[methyl-(1-methyl-pyrrolidin-3-yl)-aminoyphenyl} thioureido)-pheny]-2,6-difluorobenzwnide 350 427 Pyridine-2-carboxylic acid { 4 -[3-(3-chloro-4-dimethylaminophenyl). thioureido]-phenyll}-amide 351 430 Pyndine-2-carboxylic acid { 4
-[
3 -(3-chloro-4-methylsulfanyl-phenyly thioureido]-phenyll}-amide 352 428 Pyridine-2-carboxylic acid { 4 -r3-(5-chloro-2-methoxy-4-methylphenyl) thioureido]-phenyll}-amide 353 417 Furan-2-carboxylic acid { 4
-[
3 -(5-chloro-2-methoxy-4-methylphenyly thioureido]-phenyl }-amide 354 496 Pyridine-2-carboxylic acid [4-(3-{3-chloro-4-[methyl-(1-methyl-pyrrolidin-3 yl)-amino]-phenyl }-thioureido)- phenyl]-aniide 355 495 N-{ 3 -Chloro- 4
-[
3 -(5-chloro-2,4-dimethoxy-phenyI)-thioureidopphenyl}-2 fluoro-benzamide 356 467 Furan-2-carboxylic acid { 3 -chloro-4-[3-(5-chloro-2,4-dimethoxyphenyl) thioureido]-phenyl I -amide 357 515 N }-2 fluoro-benzamnide 358 449 N-{ 4
-[
3
-(
5 -Chloro-2,4dimehoxypheny)thioureidoy3-fluoromety1 phenyl }-acetamnide 359 529 N-{ 4
-[
3 -(5-Chloro-2,4-dimethoxy-phenyl)ffiioureido]3-trifluoromethyl phenyll}-2-fluoro-benzamide 360 421 N-{ 4
-[
3
-(
4 -Acetylamino-phenyl)-tioureidop2chlorophenyl} -2-dimethyl amino-acetamide 361 473 Furan-2-carboxylic acid (4-f 3
-[
3 -chloro-4-(2-dimethylamino-acetylamino> phenyl]-thioureido}-phenyl)-amide 362 501 N-(4-{ 3
-[
3 -Chloro- 4
-(
2 -dimethylainoacetylamino)phenylythioureido} phenyl)-2-fluoro-benzamide 363 461 N-{ 4
-[
3
-(
4 -Acetylamino-phenyl)thioureidoy2chlorophenyl}-2-piperidin 1 -yl-acetamide 364 541 N-(4-3-[3-Chloro-4-(2-pipedin-1-yl-acetyldino)-phenyl]-thioureido} phenyl)-2-fluoro-benzamide 365 513 Furan-2-carboxylic acid (4-{3-[3-chloro-4-(2-piperidin-1-yl-acetylamino) phenyll-thioureido-phenyl)- }aide 366 463 N- 4
-[
3
-(
4 -Acetylamino-phenyl)4hioureidoy2chlorophenylJ-2-morpholin 4-yl-acetamide WO 00/34269 PCT/US99/28892 - 108 367 543 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} acetanide 370 494 N-{4-[3-(3-Chloro-4-methanesulfonylainino-phenyl)-thioureido]-phenyl} 2-fluoro-benzanide 371 466 Furan-2-carboxylic acid {4-[3-(3-chloro-4-methanesulfonylamino-phenyl) thioureido]-phenyl}-anide 372 481 N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-2-(2-dimethy lanino-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) 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}-ainide 383 406 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-cyano-phenyl} acetamide 384 395 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-2-methyl-isothioureido]-phenyl} acetamide 385 396 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-2-methyl-isothioureido]-pheny} acetamide WO 00/34269 PCT/US99/28892 - 109 386 461 N-{ 4 -[3-(3-Chloro-4-ethylsulfanyl-phenyl)-thioureido]-phenyl}-2-fluoro 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} acetanide 389 491 N-{ 4 -[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-methoxy-phenyl}-2 fluoro-benzamide 390 463 Furan-2-carboxylic acid { 4 -[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-3 methoxy-phenyl}-amide 391 531 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[3-chloro-4-(2-piperidin-1-yl acetyl-amino)-phenyl]-thioureido}-phenyl)-amide 392 481 N-{ 4
-[
3 -(3-Chloro-4-methanesulfinyl-phenyl)-thioureido]-phenyl}-2,6 difluoro-benzamide 393 497 N-{ 4
-[
3
-(
3 -Chloro-4-methanesulfonyl-phenyl)-thioureido]-phenyl}-2,6 difluoro-benzamide 394 459 N-{4-[3-(5-Chloro-2-methoxy-4-methyl-phenyl)-thioureido]-2-methyl phenyl}-2-fluoro-benzamide 395 429 N-{ 4 -[3-(3-Chloro-4-methyl-phenyl)-thioureido]-2-methyl-phenyl}-2-fluoro benzamide 396 533 Furan-2-carboxylic acid [4-(3-{3-chloro-4-[2-(2-dimethylamino ethylsulfanyl)-acetylamino]-phenyl}-thioureido)-phenyl]-amide 397 458 N-{ 4
-[
3
-(
4 -Acetylamino-3-chloro-phenyl)-thioureido]-phenyl}-2-fluoro benzamide 398 460 [ 2 -Chloro-4-(3-{4-[(furan-2-carbonyl)-amino]-phenyl}-thioureido)-phenyl] carbamic acid ethyl ester 399 488 (2-Chloro-4-{ 3
-[
4
-(
2 -fluoro-benzoylamino)-phenyl]-thioureido}-phenyl) carbamic acid ethyl ester 400 440 N-{ 4
-[
3
-(
4 -Acetylanino-phenyl)-thioureido]-2-chloro-phenyl}-benzamide 401 520 N-{4-[({ [ 4 -(Benzoylamino)-3-chloro-phenyl]-amino}-thioxomethyl)-amino] phenyl } -2-fluoro-benzanide 402 529 N-{ 4
-[
3
-(
5 -Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-trifluoromethyl phenyl }-2-fluoro-benzamide 403 492 Furan-2-carboxylic acid { 4 -[3-( 4 -benzoylamino-3-chloro-phenyl)-thioureido] phenyl}-amide 404 416 N-{ 4 -[3-(4-Amino-3-chloro-phenyl)-thioureido]-phenyl} -2-fluoro-benzamide 405 479 N-{ 4 -[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-2- WO 00/34269 PCT/US99/28892 -110 thiomorpholin-4-yl-acetamide 406 531 Furan-2-carboxylic acid ( 4 -{3-[3-chloro-4-(2-thiomorpholin-4-yl acetylamino)-phenyl]-thioureido}-phenyl)-amide 407 559 N-(4-{ 3
-[
3 -Chloro- 4 -(2-thiomorpholin-4-yl-acetylamino)-phenyl]-thioureido} phenyl)-2-fluoro-benzamide 408 461 N-{ 4
-[
3
-(
3 -Chloro-4-methylsulfanyl-phenyl)-thioureido]-2-methyl-phenyl} 2-fluoro-benzamide 409 430 Furan-2-carboxylic acid { 4
-[
3
-(
4 -acetylamino-3-chloro-phenyl)-thioureido] phenyl} -amide 410 477 N- { 4
-[
3
-(
4 -Acetylamino-phenyl)-thioureido]-2-chloro-phenyI } -2 dipropylamino-acetamide 411 529 Furan-2-carboxylic acid ( 4
-{
3
-[
3 -chloro-4-(2-dipropylamino-acetylamino) phenyl]-thioureido}-phenyl)- amide 412 449 N-{ 4
-[
3
-(
4 -Acetylamino-phenyl)-thioureido]-2-chloro-pheny} -2-diethyl amino-acetamide 413 501 Furan-2-carboxylic acid (4-{ 3 -[3-chloro-4-(2-diethylamino-acetylamino) phenyl]-thioureido}-phenyl)- amide 414 529 N-(4-{3-[3-Chloro-4-(2-diethylamino-acetylamino)-phenyl]-thioureido} phenyl)-2-fluoro-benzamide 415 447 N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-2-pyrrolidin 1-yl-acetamide 416 499 Furan-2-carboxylic acid (4-{ 3 -[3-chloro-4-(2-pyrrolidin-1-yl-acetylamino) phenyl]-thioureido } -phenyl)-amide 417 527 N-(4-{ 3 -[3-Chloro-4-(2-pyrrolidin- 1 -yl-acetylamino)-phenyl]-thioureido} phenyl)-2-fluoro-benzamide 418 475 N-{ 4
-[
3
-(
5 -Chloro-2-methoxy-4-methyl-phenyl)-thioureido]-3-methoxy phenyl}-2-fluoro-benzamide 419 445 N- 4-[3-(3-Chloro-4-methyl-phenyl)-thioureido]-3-methoxy-phenyI}-2 fluoro-benzamide 420 477 N- 4-[3-(3-Chloro-4-methylsulfanyl-phenyl)-thioureido]-3-methoxy-phenyl} 2-fluoro-benzamide 421 388 Furan-2-carboxylic acid { 4
-[
3
-(
4 -amino-3-chloro-phenyl)-thioureido] phenyl}-amide 422 527 Furan-2-carboxylic acid (4-{ 3
-[
4
-(
2 -azepan-1-yl-acetylamino)-3-chloro phenyl]-thioureido}-phenyl)-amide 423 555 N-(4-{3-[4-(2-Azepan-1-yl-acetylamino)-3-chloro-phenyl]-thioureido} phenyl)-2-fluoro-benzamide WO 00/34269 PCTIUS99/28892 424 527 Furan-2-carboxylic acid [4-(3-f 3-chloro-4-[2-(2-methyl-piperidin- 1-yl)-acetyl aminol-phenyl }-thioureido)-phenyl]-amide 425 555 N-[4-(3-{ 3-Chloro-4-[2-(2-methyl-piperidin-1 -yI)-acetylamino]-phenyl } thioureido)-phenyl]-2-fluoro-benzamnide 426 339 Furan-2-carboxylic acid [4-(3-pyridin-2-yl-thioureido)-phenyl]-amide 427 339 Furan-2-carboxylic acid [4-(3-pyridin-4-yl-thioureido)-phenyl]-amide 428 367 2 -Fluoro-N-114-(3-pyridin-3-yl-thioureido)-phenyl]-benzam-ide 429 339 Furan-2-carboxylic acid [4-(3-pyridin-3-yl-thioureido)-phenyl]-amide 430 353 Furan-2-carboxylic acid f{4-[3-(3-amino-phenyl)-thioureido]-phenyl } -amnide 431 406 Furan-2-carboxylic acid {4-II3-(3-trifluoromethy1-phenyl)-thioureido] phenyll}-amide 432 380 2-Fluoro-N-r4-(3-m-tolyl-thioureido)-phenyl]-benzamide 433 434 2-Fluoro-N- { 4 -13-(3-trifluoromethyl-phenyl)-Lhioureido]-phenyl } benzainide 434 381 N- {4-r3-(3-Amino-phenyl)-thioureido]-phenyl)}-2-fluoro-benzamide 435 388 Furan-2-carboxylic acid {4-[3-(3-amino-5-chloro-phenyl)-thioureido] phenyll}-amide 436 352 Furan-2-carboxylic acid [4-(3-m-tolyl-thioureido)-phenyl]-amnide 437 416 N-{4-13-(2-Amino-5-chloro-phenyl)-thioureido]-phenyl }-2-fluoro-benzamnide 438 571 (2-Chloro-4- {3-[4-(2-fluoro-benzoylamino)-phenyl]-thioureido }-phenyl) carbamic acid 2-piperidin- 1 -yl-ethyl ester 439 543 [2-Chloro-4-(3-{4-[(furan-2-carbonyl)-amino]-phenyl }-thioureido)-phenyl] carbamnic acid 2-piperidin- 1 -yl-ethyl ester 440 388 Furan-2-carboxylic acid {4-[3-(2-amino-5-chloro-phenyl)-thioureido] phenyl }-amnide 441 363 Furan-2-carboxylic acid {4-[3-(3-cyano-phenyl)-thioureido]-phenyl 4 amnide 442 416 N- {4-[3-(3-Aniino-5-chloro-phenyl)-thioureido]-phenyl 4-2-fluoro-benzamnide 443 367 2-Fluoro-N-14-(3-pyridin-2-yl-Lhioureido)-phenyl]-benzainide 444 367 2-Fluoro-N-[4-(3-pyridin-4-yl-thioureido)-phenyl]-benzanide 445 374 Furan-2-carboxylic acid { 4 -t3-(6-chloro-pyridin-3-yl)-thioureidoj-phenyl 4 amide 446 388 Furan-2-carboxylic acid {4-[3-(2-amnino-3-chloro-phenyl)-thioureido] phenyll}-amide 447 396 Furan-2-carboxylic acid {4-13-(3-hydrazinocarbonyl-phenyl)-thioureido]- WO 00/34269 PCTIUS99/28892 - 112 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]-phenyl}-amide 450 399 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-isopropyl-phenyl)-thioureido] phenyl}-amide 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}-amide 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}-amide 458 479 N-{3-Chloro-4-[3-(5-chloro-2-methoxy-4-methyl-phenyl)-thioureido] phenyl}-2-fluoro-benzamide 459 449 N-{ 3-Chloro-4-[3-(3-chloro-4-methyl-phenyl)-thioureido]-phenyl}-2-fluoro benzamide 460 481 N-{3-Chloro-4-[3-(3-chloro-4-methylsulfanyl-phenyl)-thioureido]-phenyl}-2 fluoro-benzamide 461 391 N-{4-[3-(3-Cyano-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 462 395 Furan-2-carboxylic acid {4-[3-(3-acetylamino-phenyl)-thioureido]-phenyl} amide 463 424 2-Fluoro-N-{4-[3-(3-hydrazinocarbonyl-phenyl)-thioureido]-phenyl} benzamide 464 400 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[3-(1-hydroxy-ethyl)-phenyl] thioureido}-phenyl)-amide 465 434 N-{4-[3-(2-Amino-3-chloro-phenyl)-thioureido]-phenyl}-2,6-difluoro benzainide 466 406 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-amino-5-chloro-phenyl) thioureido]-phenyl }-amide 467 398 Furan-2-carboxylic acid {4-[3-(3,5-dimethoxy-phenyl)-thioureido]-phenyl} amide WO 00/34269 PCTIUS99/28892 - 113 468 416 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-dimethoxy-phenyl) thioureido]-phenyl} -amide 469 454 5-(3- {4-[(Furan-2-carbonyl)-aininoj-phenyl }-thioureido)-isophthalic acid dimethyl ester 470 434 Jsoxazole-5-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl) thioureido]-phenyl }-amide 471 392 ri ,2.3]Thiadiazole-4-carboxylic acid {4-[3-(6-chloro-pyridin-3-yI) thioureidol-phenyl } -amide 472 382 Furan-2-carboxylic acid (4- {3-[3-( 1-hydroxy-ethyl)-phenyl]-thioureido } phenyl)-amnide 473 368 Furan-2-carboxylic acid { 4 -13-(3-methoxy-phenyl)-thioureido]-phenyl }-amide 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-Hluoro-N- { 4 -[3-(3-hydroxymethyl-phenyl)-thioureido]-ptienyl }-benzamide 477 423 N- {4-[3-(3-Acetylamino-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide 478 413 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-acetylamino-phenyl) thioureido]-phenyl } -amide 479 400 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-dimethylamino-phenyl) thioureido]-phenyll}-amide 480 340 Furan-2-carboxylic acid 1 4 -(3-pyrimidin-4-yl-thioureido)-phenyl]-ainide 481 378 Furan-2-carboxylic acid {4-[3-(1 H-indazol-5-yl)-thioureidoj-phenyl }-ainide 482 395 Furan-2-carboxylic acid [4-(3-benzothiazol-5-yl-thioureido)-phenyl]-amide 483 406 2-Fluoro-N-{4-[3-(1H-indazol-5-yl)-thioureido]-phenyl)}-benzamide 484 424 N-[ 4 -(3-Benzothiazol-5-yl-thioureido)-phenyl]-2-fluoro-benzamide 485 473 5-(3-f{4-[([ 1,2,3]Thiadiazole-4-carbonyl)-amino]-phenyl)}-thioureido) isophthalic acid dimethyl ester 486 442 Furan-2-carboxylic acid (4-f 3-[4-(1-azido-ethyl)-3-chloro-phenyl] thioureido) -phenyl)-amide 487 396 2-Fluoro-N-{4-[3-(3-methoxy-phenyl)-thioureidoy-phenyl }-benzamnide 488 368 Furan-2-carboxylic acid f{ 4 -13-(3-hydroxymethyl-phenyl)-thioureido]-phenyI amide 489 416 Furan-2-carboxylic acid { 4 -13-(5-chloro-2-dimethylamnino-phenyl) thioureido]-phenyl)}-amide 490 444 N-{4-[3-(5-Chloro-2-dimethylamnino-phenyl)-thioureido]-phenyl -2-fluoro beuzainide WO 00/34269 PCTIUS99/28892 491 506 [3-Chloro-5-(3-{4-L([ 1,2,3]thiadiazole-4-carbonyl)-amino]-phenyl } thioureido)-phenyl]-carbamnic acid tert-butyl ester 492 470 N-(4-{ 3-r4-(l1-Azido-ethyl)-3-chloro-phenyl]-thioureido)}-phenyl)-2-fluoro benzarnide 493 337 Furan-2-carboxylic acid [4-( 1H-thiazolo[5,4-b]pyridin-2-ylideneamino) phenylil-amnide 494 378 Furan-2-carboxylic acid {4-[3-( 1H-benzoimidazol-5-yI)-thioureido]-phenyl 1 amnide 495 392 Furan-2-carboxylic acid {4-[3-(2-methyl-1 H-benzoimidazol-5-yl)-thioureidoj phenyl)}-amide 496 406 N- {4-113-(1 H-Benzoimidazol-5-yl)-thioureido]-phenyl }-2-fluoro-benzamide 497 420 2-Fluoro-N-{4-[3-(2-methyl-1 H-benzoimidazol-5-yl)-thioureido]-phenyl } benzamide 498 452 [1 ,2,3]Thiadiazole-4-carboxylic acid { 5-[3-(5-chloro-2,4-dimethoxy-phenyl) thioureido]-pyridin-2-yl } -aide 499 445 Pyridine-2-carboxylic acid { 5-[3-(5-chloro-2,4-dimethoxy-phenyl) thioureido]-pyridin-2-yl I -amide 500 434 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(5-chloro-2-dimethylamnino phenyl)-thioureido]-phenyl }-ainide 501 484 [1 ,2,3]Thiadiazole-4-carboxylic acid (4- {3-[4-(2-amino-pyrimidin-4-yl)-3 chioro-phenyll-thioureido }-phenyl)-ainide 502 494 N-(4- { 3-[4-(2-Ainino-pyrimidin-4-yl)-3-chloro-phenyl]-thioureido I -phenyl) 2-fluoro-benzamide 503 434 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-2-dimethylamino phenyl)-thioureido]-phenyl I -amide 504 462 N-{f4-1i3-(3-Chloro-2-dimethylamino-phenyl)-thioureido]-pheny 1 -2,6 difluoro-benzamnide 505 416 Furan-2-carboxylic acid {4-[3-(3-chloro-2-dimethylamnino-phenyl) thioureidol-phenyl } -amide 506 445 Pyridine-2-carboxylic acid f 6-[3-(5-chloro-2,4-dimethoxy-phenyl) thioureidoj-pyridin-3-yI}-ainide 507 462 N-{ 6-13-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-3-yl }-2-fluoro benzainide 508 482 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-iodo-phenyl)-thioureidol phenyl }-amide 509 413 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-tert-butyl-phenyl)-thioureidoj phenyl }-amnide WO 00/34269 PCT/US99/28892 - 115 510 387 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-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-(3-Chloro-5-dimethylamino-phenyl)-thioureido]-phenyl} -2-fluoro benzamide 524 416 Furan-2-carboxylic acid {4-[3-(3-chloro-5-dimethylamino-phenyl) thioureido]-phenyl}-amide 525 436 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(5-bromo-pyridin-3-yl) thioureidol-phenyl}-amide 526 379 Furan-2-carboxylic acid {4-[3-(1H-benzotriazol-5-yl)-thioureido]-phenyl} amide 527 425 N-{4-[3-(1H-Benzotriazol-5-yl)-thioureido]-phenyl}-2,6-difluoro-benzamide 528 388 N-[4-({[ 2 -(3-Chloro-phenyl)-hydrazino]-thioxomethyl}-amino)-phenyl]-furan 2-carboxamide 529 416 N-[4-({[ 2
-(
3 -Chloro-phenyl)-hydrazino]-thioxomethyl}-amino)-phenyl]-2 fluoro-benzamide WO 00/34269 PCTIUS99/28892 - 116 530 456 Furan-2-carboxylic acid {4-[3-(2-amino-3-chloro-5-trifluoromethyl-phenyl) thioureidol-phenyllI-amnide 531 513 N- {4-[3-(3-Bromo-5-trifluoromethyl-phenyl)-thioureido]-phenyl }-2-fluoro benzamide 532 503 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-bromo-5-trifluoromethyl phenyl)-thioureido]-phenyl)}-amide 533 374 {4-[(Furan-2-carbonyl)-amnino]-phenyl }-thiocarbamic acid O-(3-chloro phenyl) ester 534 474 Li ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-wmino-3-chloro-5-trifluoro methyl-phenyl)-thioureido]-phenyl }-amnide 535 508 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-piperidin- l-yl-5 trifluoromethyl-phenyl)-thioureido]-phenyl }-amide 536 380 N-[4-(3-Benzyl-thioureido)-phenyl]-2-fluoro-benzamide 537 439 Li ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,4-dichloro-benzyl)-thioureido] phenyll}-amnide 538 449 N- {4-[3-(3,4-Dichloro-benzyl)-thioureido]-phenyl }-2-fluoro-benzainide 539 370 [1 ,2,3]Thiadiazole-4-carboxylic acid [4-(3-benzyl-thioureido)-phenyl]-amide 540 424 N-[4-(3-Benzo[1 ,3]dioxol-5-ylmethyl-thioureido)-phenyl]-2-fluoro-benzanide 541 414 Li ,2,3]Thiadiazole-4-carboxylic acid [4-(3-benzo[l ,3]dioxol-5-ylmethyl thioureido)-phenyl]-amide 542 506 [1 ,2,3]Thiadiazole-4-carboxylic acid f{4-[3-(3,5-bis-trifluoromethyl-benzyl) thioureido]I-phenyl I -amnide 543 516 N-{14- [3-(3,5-Bis-trifluoromethyl-benzyl)-thioureido]-pheny}I -2-fluoro benzaniide 544 352 Furan-2-carboxylic acid [4-(3-benzyl-thioureido)-phenyl]-amide 545 421 Furan-2-carboxylic acid {4-[3-(3,4-dichloro-benzyl)-thioureido]-phenyl)} arnide 546 396 Furan-2-carboxylic acid [4-(3-benzo[i ,3ldioxol-5-ylmethyl-thioureido) phenyl]-amnide 547 488 Furan-2-carboxylic acid f{4-13-(3,5-bis-trifluoromethyl-benzyl)-thioureido] pheuyl} -amnide 548 503 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-bromo-3-trifluoromethyl phenyl)-thioureido]-phenyl}-amide 549 529 N-{4-[3-(3-Bromo-4-trifluoromethoxy-phenyl)-thioureidol-phenyl }-2-fluoro benzamnide 550 519 [1 ,2,3]Tbiadiazole-4-carboxylic acid f{4-[3-(3-bromo-4-trifluoromethoxy phenyl)-thioureido]-phenyl}-amide WO 00/34269 PCT/US99/28892 - 117 551 473 Furan-2-carboxylic acid { 4 -[3-(3-chloro-4-trifluoromethylsulfanyl-phenyl) thioureido]-phenyl}-amide 552 412 2-Fluoro-N-(4-{ 3
-[
2 -(3-fluoro-phenyl)-ethyl]-thioureido } -phenyl)-benzamide 553 412 2-Fluoro-N-(4- { 3
-[
2 -(4-fluoro-phenyl)-ethyl]-thioureido } -phenyl)-benzamide 554 402 [1,2,3]Thiadiazole-4-carboxylic acid (4-{ 3-[2-(3-fluoro-phenyl)-ethyl] thioureido}-phenyl)-amide 555 402 [1,2,3]Thiadiazole-4-carboxylic acid (4-{ 3-[2-(4-fluoro-phenyl)-ethyl] thioureido} -phenyl)-anide 556 495 [1,2,3]Thiadiazole-4-carboxylic acid (4-{ 3 -[3-(2-methyl-butyl)-5-trifluoro methyl-phenyl]-thioureido}-phenyl)-amide 557 481 [1,2,3]Thiadiazole-4-carboxylic acid { 4 -[3-(3-isobutyl-5-trifluoromethyl phenyl)-thioureido]-phenyl}-amide 558 523 [1, 2 ,3]Thiadiazole-4-carboxylic acid (4-{3-[3-(4-methyl-piperazin-1-yl)-5 trifluoro-methyl-phenyl]-thioureido}-phenyl)-amide 559 510 [1,2,3]Thiadiazole-4-carboxylic acid { 4
-[
3 -(3-morpholin-4-yl-5-trifluoro methyl-phenyl)-thioureido]-phenyl} -amide 560 494 [1, 2 ,3]Thiadiazole-4-carboxylic acid {4-[3-(3-pyrrolidin-1-yl-5-trifluoro methyl-phenyl)-thioureido]-phenyl}-amide 561 384 Furan-2-carboxylic acid (4-{ 3-[2-(4-fluoro-phenyl)-ethyl]-thioureido} phenyl)-amide 562 419 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-chloro-phenyl)-ethyl] thioureido}-phenyl)-amide 563 429 N-(4-{ 3
-[
2 -(3-Chloro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 564 401 Furan-2-carboxylic acid (4- { 3
-[
2 -(3-chloro-phenyl)-ethyl]-thioureido} phenyl)-amide 565 402 [1,2,3]Thiadiazole-4-carboxylic acid (4-{ 3-[i-(4-fluoro-phenyl)-ethyl] thioureido}-phenyl)-amide 566 504 2-Fluoro-N-{4-[3-(3-pyrrolidin-1-yl-5-trifluoromethyl-phenyl)-thioureido] phenyl}-benzamide 567 477 N-{ 4
-[
3
-(
3 -Dimethylamino-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-2 fluoro-benzamide 568 520 2-Fluoro-N-{ 4
-[
3
-(
3 -morpholin-4-yl-5-trifluoromethyl-phenyl)-thioureido] phenyl}-benzamide 569 533 2-Fluoro-N-(4-{ 3 -[3-(4-methyl-piperazin-1-yl)-5-trifluoromethyl-phenyl] thioureido}-phenyl)-benzamide 570 518 2-Fluoro-N-{4-[3-(3-piperidin-1 -yl-5-trifluoromethyl-phenyl)-thioureido] phenyl}-benzamide WO 00/34269 PCT1US99/28892 571 468 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-dimethylainino-5-trifluoro methyl-phenyl)-thioureido]-phenyl }-amide 572 405 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-benzyl)-thioureido] phenyl} -ainide 573 384 Furan-2-carboxylic acid (4-1{3-[2-(3-fluoro-phenyl)-ethyl]-thioureido)} phenyl)-amide 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] ainide 576 394 2-Hluoro-N-[4-(3-phenethyl-thioureido)-phenyl]-benzamide 577 505 2-Fluoro-N-(4-({3-[3-(2-methyl-butyl)-5-trifluoromethyl-phenyl-thioureido)} phenyl)-benzamide 578 491 2-Fluoro-N-{ 4-[3-(3-isobutyl-5-trifluoromethyl-phenyl)-thioureido]-phenyl } benzamnide 579 388 Furan-2-carboxylic acid {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)-thioureido] phenyl }-amide 582 421 Furan-2-carboxylic acid {4-[3-(3,5-dichloro-benzyl)-thioureido]-phenyl } amide 583 449 N- {4-[3-(3,5-Dichloro-benzyl)-thioureido]-phenyl}-2-fluoro-benzamide 584 439 [1 ,2,3]Thiadiazole-4-carboxylic acid f{4-[3-(3,5-dichloro-benzyl)-thioureido] phenyl I -ainide 585 438 Furan-2-carboxylic acid {4-[3-(3-fluoro-5-trifluoromethyl-benzyl) thioureido]-phenyl I -amide 586 466 2-Hluoro-N-{14-[3 -(3-fluoro-5-trifluoromethyl-benzyl)-thioureido]-phenyl } benzamide 587 456 iI1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-fluoro-5-trifluoromethyl benzyl)-thioureido]-phenyl }-ainide 588 384 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(1 -phenyl-ethyl)-thioureido] phenyl I}-amnide 589 394 2-Fluoro-N-{4-[3-(l1-phenyl-ethyl)-thioureidoj-phenyl }-beuzamide 590 366 Furan-2-carboxylic acid {4-[3-(1 -phenyl-etihyl)-thioureido]-phenyl)}-amide 591 412 2-Fluoro-N-(4-{ 3-[1 -(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-benzamide 592 384 Furan-2-carboxylic acid (4-{ 3-[l1-(4-fluoro-phenyl)-ethyl]-thioureido }- WO 00/34269 PCT/US99/28892 - 119 phenyl)-amide 593 413 N-{4-[3-(1-tert-Butyl-1H-imidazol-2-yl)-thioureido]-phenyl}-2-fluoro benzamide 594 510 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[3-(isobutyl-methyl-amino)-5 trifluoromethyl-phenyl]-thioureido}-phenyl)-amide 595 510 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[3-(3-hydroxy-pyrrolidin-1-yl)-5 trifluoromethyl-phenyll-thioureido}-phenyl)-amide 596 52() 2-Fluoro-N-(4-{ 3-[3-(isobutyl-methyl-amino)-5-trifluoromethyl-phenyl] thioureido}-phenyl)-benzamide 597 510 [1,2,3]Thiadiazole-4-carboxylic acid (4-{ 3-[3-(butyl-methyl-amino)-5 trifluoromethyl-phenyl]-thioureido}-phenyl)-amide 598 520 N-(4-{3-[3-(Butyl-methyl-amino)-5-trifluoromethyl-phenyl]-thioureido} phenyl)-2-fluoro-benzamide 599 520 [1,2,3]Thiadiazole-4-carboxylic acid (4-{ 3-[2-(3,5-bis-trifluoromethyl phenyl)-ethyl]-thioureido}-phenyl)-amide 600 442 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-fluoro-3-trifluoromethyl phenyl)-thioureido]-phenyl} -amide 601 522 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-piperidin-1-yl-3 trifluoromethyl-benzyl)-thioureido]-phenyl}-amide 602 482 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-dimethylamino-3 trifluoromethyl-benzyl)-thioureido]-phenyl}-amide 603 381 Furan-2-carboxylic acid (4-{3-[2-(4-amino-phenyl)-ethyl]-thioureido} phenyl)-amide 604 445 Furan-2-carboxylic acid (4-{ 3-[2-(4-bromo-phenyl)-ethyl]-thioureido} phenyl)-amide 605 380 Furan-2-carboxylic acid {4-[3-(2-p-tolyl-ethyl)-thioureido]-phenyl}-amide 606 463 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4-bromo-phenyl)-ethyl] thioureido}-phenyl)-amide 607 396 Furan-2-carboxylic acid (4-{ 3-[2-(3-methoxy-phenyl)-ethyl]-thioureido } phenyl)-amide 608 403 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(1-tert-butyl-1H-imidazol-2-yl) thioureido]-phenyl}-amide 609 384 Furan-2-carboxylic acid {4-[3-(1-tert-butyl-1H-imidazol-2-yl)-thioureido] phenyl}-amide 610 492 N-{4-[3-(4-Dimethylamino-3-trifluoromethyl-benzyl)-thioureido]-phenyl}-2 fluoro-benzamide 611 427 Furan-2-carboxylic acid (4-{3-[2-(3,4-dimethoxy-phenyl)-ethyl]-thioureido}- WO 00/34269 PCTIUS99/28892 - 120 phenyl)-ainide 612 380 Furan-2-carboxylic acid { 4 -[3-(3-phenyl-propyl)-thioureido]-phenyl }-aniide 613 399 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-phenyl-propyl)-thioureido] phenyl}-amide 614 502 Furan-2-carboxylic acid (4-{ 3
-[
2 -(3,5-bis-trifluoromethyl-phenyl)-ethyl]y thioureido}-phenyl)-amide 615 550 [1 ,2,3]Thiadiazole-4-carboxylic acid { 4 -[3-( 4 -iodo-3-trifluoroniethyl-phenyl) thioureido]-phenyl)}-aniide 616 532 2-Fluoro-N-{4-[3-(4-piperidin- 1-yl-3-trifluoromethyl-benzyl)-thioureido] phenyll}-beuzamide 617 537 [1 ,2,3]Thiadiazole-4-carboxylic acid (4-f{ 3-[4-(4-methyl-piperazin- 1-yl)-3 trifluoromethyl-benzyl]-thioureido }-phenyl)-amide 618 482 [1 , 2 ,3]Thiadiazole-4-carboxylic acid f{4-[3-(3-dimethylamino-5 trifluoromethyl-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 -[3-(3,5-dichloro-phenyl)-thioureidomethyl.. phenyll}-amide 621 421 Furan-2-carboxylic acid { 4 -13-(3,4-dichloro-phenyl)-thioureidomethyl] phenyl }-amide 622 455 Furan-2-carboxylic acid { 4
-[
3
-(
4 -chloro-3-trifluoromethyl-phenyl)-thioureido methyl] -phenyl }-amide 623 466 2 -Fluoro-N-{ 4 -[3-(4-fluoro-3-trifluoromethyl-benzyl).thioureido]-phenyl
}
benzamnide 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)-tioureido]-phenyl }-benzamide 626 382 Furan-2-carboxylic acid { 4 -13-(2-phenoxy-ethyl)-thioureido]-phenyl }-amide 627 400 [1 ,2,3jThiadiazole-4-carboxylic acid { 4 -[3-(2-phenoxy-ethyl)-thioureido] phenyl} -amide 628 409 2 -Fluoro-N-{ 4 -[3-(3-phenyl-propyl)-thioureidol-phenyl }-benzamide 629 425 [1 ,2,3]Thiadiazole-4-carboxylic acid { 4 -[3-(5-trifluoromethyl-pyridin-3-yl) thioureido]-phenyl}-ainide 630 439 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,4-dichloro-phenyl)-thioureido methyl] -phenyl }-aniide 631 473 [1 ,2,3]Thiadiazole-4-carboxylic acid { 4 -[3-(4-chloro-3-trifluoromethyl phenyl)-thioureidomethyl]-phenyl }-amide WO 00/34269 PCTIUS99/28892 - 121 632 381 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 14-(3-pyridin-3-ylmethyl-thioureido) phenylli-amnide 635 439 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-dichloro-phenyl)-thioureido methyl]-phenyl }-ainide 636 492 N- { 4 -13-(3-Dimethylamino-5-trifluoromethyl-benzyl)-thioureido]-phenyl } 2-fluoro-benzwmide 637 415 [1 ,2,3]Thiadiazole-4-carboxylic acid (4-({3-[2-(3-methoxy-phenyl)-ethyl] thioureido}-phenyl)-amnide 638 399 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-p-tolyl-ethyl)-thioureido] phenyl }-arnide 639 445 [1i,2,3]Thiadiazole-4-carboxylic acid (4-{ 3-[2-(3,4-dimethoxy-phenyl)-ethyl] thioureidol}-phenyl)-ainide 640 506 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl-phenyl) thioureidomethyll-phenyl I -amide 641 516 N- f{ 4 -[3-(3,5 -Bis-trifluoromethyl-phenyl)-thioureidomethyl]-pheny I -2-fluoro benzajnide 642 449 N-{f4-[3-(3,5-Dichloro-phenyl)-thioureidomethyl]-phenyl } -2-fluoro benzamnide 643 449 N-{f 4 -[3 -(3,4-Dichloro-phenyl)-thioureidomethyl] -phenyl}I -2-fluoro beuzainide 644 448 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-acetylamino-5-chloro-phenyl) thioureidol-phenyl) -amide 645 453 [1 ,2,3]Thiadiazole-4-carboxylic acid (4- {3-[2-(3,4-dichloro-phenyl)-ethyl] thioureido } -phenyl)-amide 646 413 [1 ,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)-wmide 648 413 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-r3-(4-phenyl-butyl)-thioureido] phenyl)}-amide 649 397 [1 ,2,3]Thiadiazole-4-carboxylic acid r4-(3-indan-1 -yl-thioureido)-phenyl] arnide 650 400 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-13-(2-methoxy-benzyl)-thioureido] phenyl} -amide 651 415 [1,2,3]Thiadiazole-4-carboxylic acid (4-f 3-[2-(2-methoxy-phenyl)-ethyl]- WO 00/34269 PCT/US99/28892 - 122 thioureido}-phenyl)-amide 652 415 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4-methoxy-phenyl)-ethyl] thioureido}-phenyl)-amide 653 506 N-(4-{3-[ 2 -(3-Dimethylamino-5-trifluoromethyl-phenyl)-ethyl]-thioureido} phenyl)-2-fluoro-benzamide 654 510 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[3-(3-dimethylamino-propyl)-5 trifluoromethyl-phenyl]-thioureido}-phenyl)-amide 655 417 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-phenylsulfanyl-ethyl) thioureido]-phenyl } -amide 656 427 2 -Fluoro-N-{ 4 -[3-(2-phenylsulfanyl-ethyl)-thioureido]-phenyl}-benzamide 657 399 Furan-2-carboxylic acid { 4 -[3-(2-phenylsulfanyl-ethyl)-thioureido]-phenyl} amide 658 381 2 -Fluoro-N-[ 4 -(3-pyridin-4-ylmethyl-thioureido)-phenyl]-benzamide 659 353 Furan-2-carboxylic acid [ 4 -(3-pyridin-4-ylmethyl-thioureido)-phenyl]-amide 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 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 WO 00/34269 PCTIUS99/28892 - 123 672 416 N-{4-[3-(3,4-Difluoro-benzyl)-thioureido]-phenyl }-2-fluoro-benzainide 673 452 N-(4-{ 3
-[
2
-(
4 -Dimethylamino-3-methyl-phenyl)>efiyylioureido }-phenyl)-2 fluoro-benzainide 674 496 [1 , 2 ,3]Thiadiazole-4-carboxylic acid (4-f{ 3-[2-(3-dimethylamTino-5-trifluoro methyl-phenyl)-ethyll-thioureido }-phenyl)-amide 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)ythioureido]-phenyl }-2-fluoro-benzainide 678 495 [1 ,2,3]Thiadiazole-4-carboxylic acid (4-1{3-[2-(3-bromo-phenylsulfanyl) ethyli-thioureido }-phenyl)-amide 679 477 Furan-2-carboxylic acid (4-{ 3-[2-(3-bromo-phenylsulfanyl)-ethyl]y thioureido }-phenyl)-aniide 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-plienyl) ethyllj-thioureido}-phenyl)- amide 682 493 [1 ,2,3]Thiadiazole-4-carboxylic acid (4-1{ 3
-[
2 -(5-bromo-2-methoxy-phenyl) ethyl]-thioureido }-phenyl)- amide 683 419 [1 ,2,3]Thiadiazole-4-carboxylic acid (4-1{3-r2-(2-chloro-phenyl)-ethyl] thioureido}-phenyl)-amide 684 402 [1 ,2,3]Thiadiazole-4-carboxylic acid (4-1{3-[2-(2-fluoro-phenyl)-ethylj thioureido}-phenyl)-ainide 685 419 [1 ,2,3]Thiadiazole-4-carboxylic acid (4-1{3-[2-(4-chloro-phenyl)-ethyl] thioureidol}-phenyl)-amide 686 475 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,3-diphenyl-propyl)-thioureidoj phenyl)I-amide 687 547 2-Fluoro-N-(4-{ 3-j4-(4-methyl-piperazin- 1-yl)-3-trifluoromethyl-benzyl] thioureido }-phenyl)-benzamide 688 469 [1 ,2,3]Thiadiazole-4-carboxylic acid (4-{ 3-[2-(3,5-dichloro-phenoxy)-ethyl]y thioureidol}-phenyl)-amide 689 423 [1i,2,3llThiadiazole-4-carboxylic acid {4-r3-(3-chloro-4-fluoro-benzyl) thioureido]-phenyll}-amnide 690 427 [1 ,2,3llThiadiazole-4-carboxylic acid {4-[3-(4-tert-butyl-benzyl)-thioureido] phenyl }-amide 691 399 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-dimethyl-benzyl)-thioureido]- WO 00/34269 PCTIUS99/28892 - 124 phenyl I -amide 692 442 [1 ,2,3]Thiadiazole-4-carboxylic acid (4- {3-12-(4-dimethylamnino-3-methyl phenyl)-ethyl]-thioureido }-phenyl)-amnide 693 479 [1 ,2,3]Thiadiazole-4-carboxylic acid (4-1{3-[2-(4-bromo-phenoxy)-ethyl] thioureido } -phenyl)-amide 694 526 [1i,2,3]Thiadiazole-4-carboxylic acid (4- {3-[2-(4-iodo-phenoxy)-ethyl] thioureidol}-phenyl)-amide 695 489 N-(4-{ 3-[2-(4-Bromo-phenoxy)-ethyl]-thioureido }-phenyl)-2-fluoro benzainide 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-{ 3-1 2 -(4-iodo-phenoxy)-ethyl]-thioureido I phenyl)-amide 699 408 Oxazole-4-carboxylic acid {4-[3-(3,4-dichloro-phenyl)-thioureido] phenyl)}-amnide 700 424 Thiazole-4-carboxylic acid { 4 -[3-(3,5-dichloro-phenyl)-thioureido]-phenyl } amide 701 491 Thiazole-4-carboxylic acid { 4 -[3-(3,5-bis-trifluoromethyl-phenyl)-thioureido] phenyl)}-amide 702 408 Oxazole-4-carboxylic acid { 4 -[3-(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 -[3-(3,4-dichloro-phenyl)-thioureido]-phenyl} amnide 705 458 Thiazole-4-carboxylic acid { 4 -[3-(4-chloro-3-trifluoromethyl-phenyl) thioureido]-phenyl}-amide 706 400 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-phenylainino-ethyl)-thioureido] phenyl)}-ainide 707 453 [1 ,2,3]Thiadiazole-4-carboxylic acid (4-{ 3-[2-(2,4-dichloro-phenyl)-ethyl] thioureidol}-phenyl)-amide 708 452 [1 ,2,3lThiadiazole-4-carboxylic acid (4-f 3-12-(3-trifluoromethyl-phenyl) ethyl]-thioureido}-phenyl)-aniide 709 453 [1 ,2,3]Thiadiazole-4-carboxylic acid (4-{ 3-[2-(2,6-dichloro-phenyl)-ethyl] thioureido}-phenyl)-amide 710 485 [1 ,2,3]Thiadiazole-4-carboxylic acid (4-{ 3-[2-(3,4-dichloro-phenylsulfanyl)- WO 00/34269 PCT/US99/28892 - 125 ethyl]-thioureido}-phenyl)-amide 711 503 [1,2,3]Thiadiazole-4-carboxylic acid ( 4
-{
3 -[2-(2-fluoro-5-trifluoromethyl phenylsulfanyl)-ethyl]-thioureido}-phenyl)-amide 712 668 N-(4-{3-[3-Chloro-5-(3-{4-[([1,2,3]tiadiazole-4-carbonyl)-amino]-phenyl} thioureido)-phenyl]-thioureido}-phenyl)-[1,2,3]thiadiazole-4-carboxamide 713 413 [1,2,3]Thiadiazole-4-carboxylic acid (4-{ 3-[2-(4-ethyl-phenyl)-ethyl] thioureido}-phenyl)-amide 714 442 Oxazole-4-carboxylic acid { 4 -[3-(4-chloro-3-trifluoromethyl-phenyl) thioureido]-phenyl}-amide 715 475 Oxazole-4-carboxylic acid { 4
-[
3 -(3,5-bis-trifluoromethyl-phenyl)-thioureido] phenyl}-amide 716 420 [1,2,3]Thiadiazole-4-carboxylic acid (4-{ 3-[2-(3,4-difluoro-phenyl)-ethyl] thioureido } -phenyl)-amide 717 452 [1,2,3]Thiadiazole-4-carboxylic acid (4-{ 3 -[2-(4-trifluoromethyl-phenyl) ethyl]-thioureido}-phenyl)-amide 718 435 Furan-2-carboxylic acid (4-{ 3
-[
2 -(3, 4 -dichloro-phenyl)-ethyl]-thioureido} phenyl)-amide 719 463 N-(4-{ 3
-[
2
-(
3
,
4 -Dichloro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro benzamide 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) thioureidol-phenyl}-amide 727 409 2-Fluoro-N-{4-[3-(1-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]- WO 00/34269 PCT/US99/28892 - 126 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 f{4-13-(3-fluoro-benzyl)-thioureido] phenyll}-amide 733 435 [1 ,2,3lThiadiazole-4-carboxylic acid (4-{ 3-[2-(2-chloro-phenoxy)-ethyl] thioureido}-phenyl)-wmide 734 479 [1 ,2,3]Thiadiazole-4-carboxylic acid (4-f 3-[2-(3-bromo-phenoxy)-ethyl] thioureido} -phenyl)-amide 735 418 [1 ,2,3]Thiadiazole-4-carboxylic acid (4-f 3-[2-(2-fluoro-phenoxy)-ethyl] thioureido I -phenyl)-amide 736 418 [1 ,2,3]Thiadiazole-4-carboxylic acid (4-f 3-[2-(3-fluoro-phenoxy)-ethyl] thioureido)}-phenyl)-amide 737 486 [1 ,2,3]Thiadiazole-4-carboxylic acid (4-f 3-[2-(2-fluoro-5-trifluoromethyl pheuoxy)-ethyl]-thioureido} -phenyl)-amide 738 384 Furan-2-carboxylic acid (4-f 3-[2-(2-fluoro-phenyl)-ethyl]-thioureido} phenyl)-amnide 739 435 [1 ,2,3]Thiadiazole-4-carboxylic acid f4-[3-(4-bromo-phenyl)-thioureido] phenyl}-amide 740 374 [1 ,2,3]Thiadiazole-4-carboxylic acid f4-[3-(4-fluoro-phenyl)-thioureido] phenyl} -amide 741 388 [1 ,2,3]Thiadiazole-4-carboxylic acid f4-[3-(4-fluoro-benzyl)-thioureido] phenyl}-amnide 742 405 [1 ,2,3]Thiadiazole-4-carboxylic acid 14-[3-(4-chloro-benzyl)-thioureido] phenyl }-amide 743 449 [1 ,2,3]Thiadiazole-4-carboxylic acid 14-[3-(4-bromo-benzyl)-thioureido] phenyl}-amnide 744 332 N-(4-f 3-[1 -(4-Fluoro-phenyl)-ethyl]-thioureido }-phenyl)-acetamide 745 438 Thiazole-4-carboxylic acid 14-[3-(3,4-dichloro-benzyl)-thioureido-phenyl
}
aniide 746 455 Thiazole-4-carboxylic acid 14-[3-(2-fluoro-5-trifluoromethyl-benzyl) thioureido]-phenyl} -amide 747 426 Thiazole-4-carboxylic acid f 4 -[3-(4-tert-butyl-benzyl)-thioureido]-phenyl} amide 748 374 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-fluoro-phenyl)-thioureido] phenyl } -amide 749 374 [1 ,2,3]Thiadiazole-4-carboxylic acid 14-[3-(3-fluoro-phenyl)-thioureido]- WO 00/34269 PCT/US99/28892 - 127 phenyll-amide 750 526 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-iodo-phenoxy)-ethyl] thioureido} -phenyl)-amide 751 409 N-(4- { 3- [1-(4-Fluoro-phenyl)-ethyl]-thioureido} -phenyl)-2-phenyl acetamide 752 425 N-(4-{3-[l-(4-Fluoro-phenyl)-ethyl]-thioureido }-phenyl)-2-methoxy benzamide 753 425 N-(4- { 3- [1-(4-Fluoro-phenyl)-ethyl]-thioureido -phenyl)-3-methoxy benzamide 754 425 N-(4-{3-[l-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-4-methoxy benzamide 755 429 2-Chloro-N-(4-{3-f1-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-benzamide 756 429 4-Chloro-N-(4-{ 3- [1-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-benzamide 757 453 Acetic acid 4-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido} phenylcarbamoyl)-phenyl ester 758 394 N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide 759 395 N-(4-{3-[l-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-isonicotinamide 760 410 N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-4-hydroxy benzamide 761 429 3-Chloro-N-(4-{3-[l-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-benzamide 762 470 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-fluoro-5-trifluoromethyl phenyl)-ethyl]-thioureido}-phenyl)-anide 763 520 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(2,4-bis-trifluoromethyl phenyl)-ethyl]-thioureido}-phenyl)-amide 764 470 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4-fluoro-3-trifluoromethyl phenyl)-ethyl]-thioureido}-phenyl)-amide 765 438 4-Dimethylamino-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl) benzamide 766 470 [1,2,3]Thiadiazole-4-carboxylic acid (4-{ 3-[2-(2-fluoro-3-trifluoromethyl phenyl)-ethyl]-thioureido}-phenyl)-amide 767 470 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(2-fluoro-5-trifluoromethyl phenyl)-ethyl]-thioureido}-phenyl)-amide 768 510 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-iodo-phenyl)-ethyl] thioureido}-phenyl)-amide 769 470 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4-fluoro-2-trifluoromethyl phenyl)-ethyl]-thioureido}-phenyl)-amide WO 00/34269 PCTIUS99/28892 - 128 770 463 [1,2.3]Thiadiazole-4-carboxylic acid (4-{ 3 -[2-(3-bromo-phenyl)-ethyl] thioureido } -phenyl)-amide 771 427 2-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-propyl]-thioureido}-phenyl) benzamide 772 475 2-Fluoro-N-(4-{ 3
-[(
4 -fluoro-phenyl)-phenyl-methyl]-thioureido}-phenyl) benzamide 773 455 2-Fluoro-N-(4-{ 3-[I-( 4 -fluoro-phenyl)-pentyl]-thioureido}-phenyl) benzamide 774 489 2-Fluoro-N-(4-{3-[1-( 4 -fluoro-phenyl)-2-phenyl-ethyl]-thioureido}-phenyl) benzamide 775 409 2-Fluoro-N-{4-[3-(1-o-tolyl-ethyl)-thioureido]-phenyl}-benzamide 776 409 2-Fluoro-N-{4-[3-(1-m-tolyl-ethyl)-thioureido]-phenyl}-benzamide 777 425 2-Fluoro-N-(4-{3-[1-( 4 -methoxy-phenyl)-ethyl]-thioureido}-phenyl) benzanide 778 412 2-Fluoro-N-(4-{3-[1-( 2 -fluoro-phenyl)-ethyl]-thioureido}-phenyl) benzamide 779 429 N-(4-{3-[1-(3-Chloro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro benzamide 780 473 N-(4-{3-[1-(3-Bromo-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro benzamide 781 429 N-(4-{3-[1-( 4 -Chloro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro benzamide 782 409 2-Fluoro-N-{4-[3-(1-p-tolyl-ethyl)-thioureido]-phenyl}-benzamide 783 473 N-(4-{3-[1-( 2 -Bromo-phenyl)-ethyl]-thioureido} -phenyl)-2-fluoro benzamide 784 429 N-(4-{3-[1-(2-Chloro-phenyl)-ethyl]-thioureido} -phenyl)-2-fluoro benzamide 785 462 2-Fluoro-N-(4- { 3-[1-( 2 -trifluoromethyl-phenyl)-ethyl]-thioureido) -phenyl) benzamide 786 462 2-Fluoro-N-(4-{3-[1-(3-trifluoromethyl-phenyl)-ethyll-thioureido } -phenyl) benzamide 787 462 2-Fluoro-N-(4-{3-[I-(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 WO 00/34269 PCTIUS99/28892 - 129 790 441 2-Fluoro-N-(4-{3-[1-( 4 -fluoro-phenyl)-2-methyl-propyl]-thioureido} phenyl)-benzainide 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-[i-( 4 -Dimethylamino-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro benzamide 794 438 N-(4-{3-[1-(3-Dimethylamino-phenyl)-ethyl]-tiioureido}-phenyl)-2-fluoro benzamide 795 473 2-Bromo-N-(4-{3-[1-( 4 -fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide 796 446 Quinoline-2-carboxylic acid (4-{3-[I-(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)-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-1H-pyrrol-2-yl)-ethyll-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]-pheny} -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}-benzamide 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-benzanide 813 346 N-(4-{3-[1-( 4 -Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-propionamide 814 286 N-[ 4 -(3-Phenyl-thioureido)-phenyl]-acetamide 815 507 N-{5-[({{ 3 ,5-bis(trifluoromethyl)benzyl]amino carbothioyl)amino]-2- WO 00/34269 PCT/US99/28892 - 130 pyridinyl}-1,2,3-thiadiazole-4-carboxamide 816 521 N-(5-{[({(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}amino)carbothioyl] amino }-2-pyridinyl)- 1,2,3-thiadiazole-4-carboxamide 817 520 N-(5-{[({ (1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}amino)carbothioyl] amino}-2-pyridinyl)-1,3-thiazole-4-carboxamide 818 470 N-(5-{[({1-[2-fluoro-5-(trifluoromethyl)phenyl]ethyl}amino)carbothioyl] amino}-2-pyridinyl)- 1,3-thiazole-4-carboxamide 819 470 N-(5-{[({1-[ 2 -fluoro-4-(trifluoromethyl)phenyl]ethyl }amino)carbothioyl] amino}-2-pyridinyl)- 1,3-thiazole-4-carboxamide 820 470 N-(5-{ [( 1-[3-fluoro-5-(trifluoromethyl)phenyl]ethyl }amino)carbothioyl] amino}-2-pyridinyl)- 1,3-thiazole-4-carboxainide 821 504 N-(5-{ [({ (1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}amino)carbonyl] amino}-2-pyridinyl)-1,3-thiazole-4-carboxamide 822 463 N-{5-[({[1-(3-bromophenyl)ethyl]amino}carbothioyl)amino]-2-pyridinyl} 1,3-thiazole-4-carboxamide 823 463 N-{ 5-[({[1-(2-bromophenyl)ethyl]amino}carbothioyl)amino]-2-pyridinyl} 1,3-thiazole-4-carboxamide 824 452 N-(5-{ [({ 1-[3-(trifluoromethyl)phenyl]ethyl}amino)carbothioyljamino} 2-pyridinyl)-1,3-thiazole-4-carboxainide 825 486 N-(5-{[({ 1-[4-chloro-3-(trifluoromethyl)phenyl]ethyl}amino)carbothioyl] amino}-2-pyridinyl)-1,3-thiazole-4-carboxamide 826 436 N-{ 5-[({ [1-( 4 -chloro-3-fluorophenyl)ethyl]amino}carbothioyl)amino]-2 pyridinyl}-1,3-thiazole-4-carboxainide 827 436 N-{5-[({ [1-(4-chloro-2-fluorophenyl)ethyl]amino}carbothioyl)amino]-2 pyridinyl}-1,3-thiazole-4-carboxamide 828 434 N-{6-[({[1-(4-fluorophenyl)ethyl]amino}carbothioyl)amino]-3-pyridinyl} 1,2,3-thiadiazole-4-carboxamide 829 426 N-(6-{ [({(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}amino)carbothioyl] amino }-3-pyridinyl)-1,2,3-thiadiazole-4-carboxamide EXAMPLE 830 (METHOD 32) [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2,5-dichloro-phenyl)-thioureido] 5 phenyl}-amide 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 WO 00/34269 PCT/US99/28892 - 131 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 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 5 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. Using the above procedure and appropriate starting materials the following compounds were prepared: 10 EX. M+H COMPOUND NAME NO. 831 321 N-{4-[3-(3-Chloro-phenyl)-thioureido]-phenyl}-acetamide 832 413 N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl}-benzamide 833 443 N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl}-2-methoxy-benzamide 834 443 N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl}-3-methoxy-benzamide 835 443 N-{ 4 -[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl}-4-methoxy-benzamide 836 431 N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl}-4-methoxy-benzamide 837 431 N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl}-3-fluoro-benzamide 838 431 N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl}-4-fluoro-benzamide 839 437 Furan-2-carboxylic acid { 4 -[3-(3,5-dichloro-4-methoxy-phenyl)-thioureido] phenyl}-amide 840 511 { 4 -[3-(5-Bromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-carbanic acid hexyl ester 841 481 Hexanoic acid { 4 -[3-(5-bromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl} amide 842 505 N-{4-[3-(5-Bromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-fluoro benzamide 843 477 Furan-2-carboxylic acid {4-[3-(5-bromo-2,4-dimethoxy-phenyl)-thioureido] phenyl}-amide 844 501 N-{4-[3-(5-Bromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-methyl benzamide 845 517 N-{ 4 -[3-(5-Bromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-4-methoxy benzamide WO 00/34269 PCT/US99/28892 - 132 846 395 N- {4-[3-(5-Chloro-2-ethoxy-4-methoxy-phenyl)-thioureido]-phenyl }-acetamide 847 395 N-{4-[3-(5-Chloro-4-ethoxy-2-methoxy-phenyl)-thioureido]-phenyl}-acetamide 848 423 N-{4-[3-(2-Butoxy-5-chloro-4-methoxy-phenyl)-thioureido]-phenyl}-acetamide 849 423 N-{4-[3-(4-Butoxy-5-chloro-2-methoxy-phenyl)-thioureido]-phenyl } -acetamide 850 457 N- {4-[3-(2-Benzyloxy-5-chloro-4-methoxy-phenyl)-thioureido]-phenyl} -acetamide 851 457 N- {4-[3-(4-B enzyloxy-5-chloro-2-methoxy-phenyl)-thioureido]-phenyl I -acetamide 852 421 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-4-methoxy-phenyl) thioureido]-phenyl}-amide 853 424 2-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-5-methoxy-phenoxy} acetamide 854 367 N-{4-[3-(5-Chloro-2-hydroxy-4-methoxy-phenyl)-thioureido]-phenyl} -acetamide 855 367 N-f{4-[3-(3-Chloro-4-methylsulfanyl-phenyl)-thioureido]-phenyl } -acetamide 856 447 N-[4-(3-{3-Chloro-4-[methyl-(1 -methyl-piperidin-4-yl)-amino]-phenyl) thioureido) phenyl]-acetamide 857 426 N-(4-{ 3-[3-Chloro-4-(methyl-phenyl-ainino)-phenyl]-thioureido}-phenyl)acetamide 858 509 N-[4-(3-{4-[(1-Benzyl-pyrrolidin-3-yl)-methyl-amino]-3-chloro-phenyl} thioureido)-phenyl]-acetamide 859 418 N-(4-{3-[3-Chloro-4-(cyclopentyl-methyl-ainino)-phenyl]-thioureido}-phenyl) acetamide 860 433 N-[4-(3- {3-Chloro-4-[methyl-(1 -methyl-pyrrolidin-3-yl)-amino]-phenyl} thioureido)-phenyl]-acetamide 861 419 Furan-2-carboxylic acid {4-[3-(3-chloro-4-methylsulfanyl-phenyl)-thioureido] phenyl}-amide 862 447 N-{4-[3-(3-Chloro-4-methylsulfanyl-phenyl)-thioureido]-phenyl}-2-fluoro benzamide 863 465 N-{4-[3-(3-Chloro-4-methylsulfanyl-phenyl)-thioureido]-phenyl}-2,6-difluoro benzamide 864 445 N-{4-[3-(5-Chloro-2-methoxy-4-methyl-phenyl)-thioureido]-phenyl}-2-fluoro benzamide 865 441 N-{4-[3-(5-Chloro-2-methoxy-4-methyl-phenyl)-thioureido]-phenyl}-2-methyl benzamide 866 434 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-4-dimethylamino-phenyl) thioureido]-phenyl}-amide 867 444 N-{4-[3-(3-Chloro-4-dimethylamino-phenyl)-thioureido]-phenyl}-2-fluoro benzamide 868 517 [1,2,3]Thiadiazole-4-carboxylic acid [4-(3-{3-chloro-4-[methyl-(1-methyl- WO 00/34269 PCTIUS99/28892 - 133 piperidin-4-yl)-amino]-phenyl I -thioureido)-phenyl]-ainide 869 579 [ 1,2,3lThiadiazole-4-carboxylic acid [4-(3-f{4+[1 -benzyl-pyrrolidin-3-yl) methyl-amino]-3-chloro-phenyl I}-thioureido)-phenyl]-ainide 870 527 N-[4-(3-{ 3-Chloro-4-[methyl-(1 -methyl-piperidin-4-yl)-amino]-phenyl } thioureido) phenyll-2-fluoro-benzainide 871 435 [1,2,3]Thiadiazole-4-carboxylic acid f{ 4
-[
3 -(5-chloro-2-methoxy-4-methyl phenyl)-thioureido]-phenyl I -amide 872 589 N-[4-(3-{4-[(1 -Benzyl-pyffolidin-3-yl)-meffy-amino]-3-chloro-phenyI thioureido)-phenyl]-2-fluoro-benzamide 873 501 Furan-2-carboxylic acid { 4
-[
3
-(
5 -chloro-2,4-dimethoxy-phenyl)-thioureido] 3-trifluoromethyl-phenyl}-amnide 874 366 2 -Fluoro-N-[ 4 -(3-phenyl-thioureido)phenyl]lbenzamide 875 338 Furan-2-carboxylic acid [ 4
-(
3 -phenyl-thioureido)-phenyl]-amide 876 356 [1 ,2,3]Thiadiazole-4-carboxylic acid 1 4 -(3-phenyl-thioureido)-phenyly-ainide 877 365 N-(4-{ 3-[3-Chloro-4-(1 -hydroxy-ethyl)-phenyl]-thioureido} -phenyl)-acetamide 878 435 [1 ,2,3]Thiadiazole-4-carboxylic acid (4- {3-[3-chloro-4-(lI-hydroxy-ethyl)-phenyl] thioureido }-phenyl)-amide 879 365 N-(4-{ 3
-[
3 -Chloro-4-(2-hydroxy-ethyl)-phenyl].thioureido }-phenyl)-acetamide 880 445 N-(4-{ 3-[3-Chloro-4-(1 -hydroxy-ethyl)-phenyl]-thioureido} -phenyl)-2-fluoro benzwmide 881 417 Furan-2-carboxylic acid (4-{ 3-[3-chloro-4-( 1-hydroxy-ethyl)-phenyl]-thioureido} phenyl)-ainide 882 371 [1 ,2,3]T-hiadiazole-4-carboxylic acid f{ 4 -[3-(3-amino-phenyl)-thioureido]-phenyl } amide 883 501 Furan-2-carboxylic acid { 4
-[
3
-(
3 -bromo-4-trifluoromethoxy-phenyl)-thioureido]y phenyl }-amnide 884 423 N-{4-[3-(3-tert-Butyl-phenyl)-thioureido]-phenyl }-2-fluoro-benzainide 885 440 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-chloro-3,5 -dichioro-phenyl) thioureido]-phenyl}-amide 986 485 N-{ 4-[3-(1 -Benzofuran-2-yl-ethyl)-thioureido]-phenyl }-2-trifluoromethyl benzamide 987 412 N-(4-Fluoro-phenyl)-4-{ 3-[1 -( 4 -fluoro-phenyl)-ethyl]-thioureido}-benzamide 988 446 Isoquinoline-l1-carboxylic acid (4-f 3-[1 -( 4 -fluoro-phenyl)-ethyl]-thioureido
}
phenyl)-amnide 989 468 Isoquinoline-1 -carboxylic acid {4-[3-(1 -benzofuran-2-yl-ethyl)-thioureido] phenyll-ainide WO 00/34269 PCT/US99/28892 - 134 993 506 Isoquinoline-1-carboxylic acid (4-{3-[1-(4-bromo-phenyl)-ethyl]-thioureido} phenyl)-amide 994 453 Isoquinoline-1-carboxylic acid (4-{3-[1-(4-cyano-phenyl)-ethyll-thioureido} phenyl)-amide 995 435 Benzofuran-2-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido} phenyl)-amide 996 457 Benzofuran-2-carboxylic acid {4-[3-(1-benzofuran-2-yl-ethyl)-thioureido]-phenyl} amide 997 495 Benzofuran-2-carboxylic acid (4-{3-[1-(4-bromo-phenyl)-ethyl]-thioureido} phenyl)-amide 998 442 Benzofuran-2-carboxylic acid (4-{3-[1-(4-cyano-phenyl)-ethyl]-thioureido} phenyl)-amide 999 446 Isoquinoline-3-carboxylic acid (4-{ 3-[1-(4-fluoro-phenyl)-ethyl]-thioureido} phenyl)-amide 1000 468 Isoquinoline-3-carboxylic acid {4-[3-(1-benzofuran-2-yl-ethyl)-thioureido] phenyl}-amide 1001 453 Isoquinoline-3-carboxylic acid (4-{3-[1-(4-cyano-phenyl)-ethyl]-thioureido} phenyl)-amide 1002 506 Isoquinoline-3-carboxylic acid (4-{3-[1-(4-bromo-phenyl)-ethyl]-thioureido} phenyl)-amide 1003 446 Quinoline-3-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl) amide 1004 446 Quinoline-4-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl) amide 1005 446 Quinoline-6-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl) amide 1006 446 Quinoline-8-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl) amide 1007 462 N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-trifluoromethyl benzamide 1008 419 2-Cyano-N-(4-{3-[1-(4-fluoro-phenyl)-ethyll-thioureido}-phenyl)-benzamide 1009 473 N-{4-[3-(3-Chloro-4-isobutoxy-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 1010 414 2-Fluoro-N-{4-[3-(3-fluoro-4-methoxy-phenyl)-thioureido]-phenyl}-benzamide 1011 475 N-(4-{3-[3-Chloro-4-(2-methoxy-ethoxy)-phenyl]-thioureido}-phenyl)-2-fluoro benzamide 1012 398 2-Fluoro-N-{4-[3-(3-fluoro-4-methyl-phenyl)-thioureido]-phenyl}-benzamide WO 00/34269 PCT/US99/28892 - 135 1013 464 2 -Fluoro-N-{ 4
-[
3
-(
4 -methoxy-3-trifluoromethyl-phenyl)-thioureido]-phenyl} benzamide 1014 449 N-{ 4
-[
3
-(
2 -Amino-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-2-fluoro benzamide 1015 459 N-(4-{3-[1-( 3 -Chloro- 4 -methoxy-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro benzamide 1016 417 N-f{ 4
-[
3 -(5-Chloro-2-hydroxy-phenyl)-thioureido]-phenyl} -2-fluoro-benzamide 1017 435 N- {4-[3-(1 -Benzofuran-2-yl-ethyl)-thioureido]-phenyl} -2-fluoro-benzamide 1018 448 2-Fluoro-N-f{ 4
-[
3
-(
4 -methyl-3-trifluoromethyl-phenyl)-thioureido]-phenyl} benzamide 1019 473 (S)-N-(4-{3-[i-( 4 -Bromo-phenyl)-ethyl]-thioureido} -phenyl)-2-fluoro-benzamide 1020 473 N-(4-{ 3-[(1R)-1-( 4 -Bromo-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 1021 494 2-Fluoro-N-(4-{ 3
-[
2 -methoxy- 4 -(2,2,2-trifluoro-ethoxy)-phenyl]-thioureido} phenyl)-benzamide 1022 399 N-{ 4 -[3-( 2 -Amino-5-fluoro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 1023 502 N-(4-{3-[l-( 4 -Dimethylsulfamoyl-phenyl)-ethyll-thioureido}-phenyl)-2-fluoro benzamide 1024 542 2-Fluoro-N-[4-(3-{1-[4-(piperidine-1-sulfonyl)-phenyl]-ethyl}-thioureido)-phenyl] benzamide 1025 562 N-(4-{ 3
-[
2
,
4 -Bis-(2,2,2-trifluoro-ethoxy)-phenyl]-thioureido}-phenyl)-2-fluoro benzamide 1026 409 2-Fluoro-N-{4-[3-((1S)-1-p-tolyl-ethyl)-thioureido]-phenyl}-benzamide 1027 409 2-Fluoro-N-{4-[3-((iR)-1-p-tolyl-ethyl)-thioureido]-phenyl}-benzamide 1028 394 2-Fluoro-N-{4-[3-((1S)-1-phenyl-ethyl)-thioureido]-phenyl}-benzamide 1029 429 N-(4-{ 3-[(iR)-1-( 4 -Chloro-phenyl)-ethyll-thioureido}-phenyl)-2-fluoro-benzamide 1030 429 N-(4-{3-[(1S)-1-( 4 -Chloro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 1031 394 2-Fluoro-N-{4-[3-((1R)-1-phenyl-ethyl)-thioureido]-phenyl}-benzamide 1032 432 N-(4-{ 3-[1-(4-Cyano-phenyl)-ethyl]-thioureido}-phenyl)-2-methoxy-benzamide 1033 447 N-{4-[3-(1-Benzofuran- 2 -yl-ethyl)-thioureido]-phenyl}-2-methoxy-benzamide 1034 485 N-(4-{3-[1-( 4 -Bromo-phenyl)-ethyll-thioureido}-phenyl)-2-methoxy-benzamide 1035 419 3-Cyano-N-(4-{3-[1-( 4 -fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide 1036 462 N-(4-{ 3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido } -phenyl)-4-trifluoromethyl benzamide 1037 419 4-Cyano-N-(4-{ 3-[1-( 4 -fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide WO 00/34269 PCTIUS99/28892 - 136 1038 469 2-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2,3,5,6-tetramethyl phenyl)-benzamide 1039 480 N-(4-{3-[i-(4-Cyano-phenyl)-ethyl]-thioureido}-2,5-dimethoxy-phenyl)-2-fluoro benzamide 1040 473 2-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2,5-dimethoxy-phenyl) benzamide 1041 530 N-{3,5-Dichloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2 fluoro-benzamide 1042 447 N-(3-Chloro-4-{3-[i-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro benzamide 1043 480 2,3,4,5-Tetrafluoro-N-(4-{ 3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-3-methyl phenyl)-benzamide 1044 462 2,4,5-Trifluoro-N-(4-{ 3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-3-methyl-phenyl) benzamide 1045 427 2-Fluoro-N-(4-{3-[i-(4-fluoro-phenyl)-ethyll-thioureido}-3-methyl-phenyl) benzamide 1046 457 2-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2-methoxy-5-methyl phenyl)-benzamide 1047 443 2-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-3-methoxy-phenyl) benzamide 1048 570 N-(2,6-Dibromo-4-{ 3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-2-fluoro benzamide 1049 480 2-Fluoro-N-(4-{3-[l-(4-fluoro-phenyl)-ethyl]-thioureido}-2-trifluoromethyl phenyl)-benzamide 1050 541 N-(4-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido}-2-trifluoromethyl-phenyl)-2 fluoro-benzamide 1051 487 N-(4-{3-[1-(4-Cyano-phenyl)-ethyl]-thioureido}-2-trifluoromethyl-phenyl)-2 fluoro-benzamide 1052 503 N-{4-[3-(1-Benzofuran-2-yl-ethyl)-thioureido]-2-trifluoromethyl-phenyl}-2-fluoro benzainide 1053 447 N-(2-Chloro-4-{ 3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro benzamide 1054 454 N-(2-Chloro-4-{3-[i-(4-cyano-phenyl)-ethyl]-thioureido} -phenyl)-2-fluoro benzamide 1055 437 N-(2-Cyano-4-{3-[i-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-2-fluoro benzamide 1056 498 N-(4-{ 3-[i-(4-Bromo-phenyl)-ethyl]-thioureido}-2-cyano-phenyl)-2-fluoro benzamide WO 00/34269 PCT/US99/28892 - 137 1057 445 N-(2-Cyano-4-{3-fl-(4-cyano-phenyl)-ethyl]-thioureido } -phenyl)-2-fluoro benzamide 1058 460 N-{4-[3-(1 -Benzofuran-2-yl-ethyl)-thioureido]-2-cyano-phenyl } -2-fluoro benzamide 1059 517 N-(2-Benzoyl-4- { 3-[1-( 4 -fluoro-phenyl)-ethyl]-thioureido } -phenyl)-2-fluoro benzamide 1060 427 2-Fluoro-N-(4-{3-[i-( 4 -fluoro-phenyl)-ethyl]-thioureido }-2-methyl-phenyl) benzamide 1061 487 N-(4-{ 3-[i-(4-Bromo-phenyl)-ethyl]-thioureido}-2-methyl-phenyl)-2-fluoro benzamide 1062 434 N-(4-{3-[1-( 4 -Cyano-phenyl)-ethyl]-thioureido}-2-methyl-phenyl)-2-fluoro benzamide 1063 449 N-{4-[3-(i-Benzofuran-2-yl-ethyl)-thioureido]-2-methyl-phenyl}-2-fluoro benzamide 1064 456 N-(2-Dimethylamino-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2 fluoro-benzamide 1065 526 N-(2-Benzyloxy-4-{3-[1-( 4 -cyano-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro benzamide 1066 519 N-(2-Benzyloxy-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro benzamide 1067 603 N-[4-{ 3-[i-(4-Bromo-phenyl)-ethyl]-thioureido}-2-(2-morpholin-4-yl-ethoxy) phenyl]-2-fluoro-benzamide 1068 603 N-[4-{3-[i-(4-Bromo-phenyl)-ethyl]-thioureido}-2-(2-morpholin-4-yl-ethoxy) phenyl]-2-fluoro-benzamide 1069 542 2-Fluoro-N-[4-{ 3-[1-( 4 -fluoro-phenyl)-ethyl]-thioureido}-2-(2-morpholin-4-yl ethoxy)-phenyl]-benzamide 1070 485 N-(2-Butoxy-4-{3-[1-( 4 -fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro benzamide 1071 492 N-(2-Butoxy-4-{ 3-[1-(4-cyano-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro benzamide 1072 589 N-[4-{ 3-[i-(4-Bromo-phenyl)-ethyl]-thioureido}-2-(2-diethylamino-ethoxy) phenyl]-2-fluoro-benzamide 1073 528 N-(2-(2-Diethylamino-ethoxy)-4-{ 3-[I-(4-fluoro-phenyl)-ethyl]-thioureido} phenyl)-2-fluoro-benzamide 1074 589 N-[4-{ 3-fl-( 4 -Bromo-phenyl)-ethyl]-thioureido}-2-(2-diethylamino-ethoxy) phenyll-2-fluoro-benzamide 1075 457 N-(2-Ethoxy-4-{3-[i-( 4 -fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro benzamide WO 00/34269 PCT/US99/28892 - 138 1076 464 N-(4-{3-[i-(4-Cyano-phenyl)-ethyl]-thioureido } -2-ethoxy-phenyl)-2-fluoro benzamide 1077 468 2-Fluoro-N-[4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-2-(2-nitrilo-ethoxy) phenyl]-benzamide 1078 475 N-[4-{3-[1-(4-Cyano-phenyl)-ethyl]-thioureido } -2-(2-nitrilo-ethoxy)-phenyl]-2 fluoro-benzamide 1079 443 2-Fluoro-N-(4-{3-[I-(4-fluoro-phenyl)-ethyl]-thioureido }-2-methoxy-phenyl) benzamide 1080 489 2-Fluoro-N-(5-{ 3-[I-(4-fluoro-phenyl)-ethyl]-thioureido } -biphenyl-2-yl)-benzamide 1081 514 Isoquinoline-1-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2 trifluoromethyl-phenyl)-amide 1082 503 Benzofuran-2-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2 trifluoromethyl-phenyl)-anide 1083 514 Isoquinoline-3-carboxylic acid (4-{3-[i-(4-fluoro-phenyl)-ethyl]-thioureido}-2 trifluoromethyl-phenyl)-amide 1084 471 Isoquinoline-1-carboxylic acid (2-cyano-4-{ 3-[I-(4-fluoro-phenyl)-ethyl] thioureido}-phenyl)-amide 1085 460 Benzofuran-2-carboxylic acid (2-cyano-4-{3-[1-(4-fluoro-phenyl)-ethyl] thioureido}-phenyl)-amide 1086 471 Isoquinoline-3-carboxylic acid (2-cyano-4-{3-[1-(4-fluoro-phenyl)-ethyl] thioureido}-phenyl)-amide 1087 460 Isoquinoline-1-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2 methyl-phenyl)-amide 1088 449 Benzofuran-2-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2 methyl-phenyl)-amide 1089 460 Isoquinoline-3-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2 methyl-phenyl)-amide 1090 396 Pyrazine-2-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl) amide 1091 401 Thiophene-2-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl) amide 1092 401 Thiophene-3-carboxylic acid (4-{3-[I-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl) amide 1093 500 2-Isopropyl-thiazole-4-carboxylic acid {4-[3-(4-chloro-3-trifluoromethyl-phenyl) thioureido]-phenyl}-amide 1094 466 2-Isopropyl-thiazole-4-carboxylic acid {4-[3-(3,5-dichloro-phenyl)-thioureido] phenyl}-amide WO 00/34269 PCTIUS99/28892 - 139 1095 466 2-Isopropyl-thiazole-4-carboxylic acid {4-[3-(3,4-dichloro-phenyl)-thioureido] phenyl}-amide 1096 534 2-Isopropyl-thiazole-4-carboxylic acid { 4 -[3-(3,5-bis-trifluoromethyl-phenyl) thioureidol-phenyl}-amide 1097 480 2-Butyl-thiazole-4-carboxylic acid { 4 -[3-(3,4-dichloro-phenyl)-thioureido]-phenyl} amide 1098 514 2-Butyl-thiazole-4-carboxylic acid { 4 -[3-(4-chloro-3-trifluoromethyl-phenyl) thioureido]-phenyl}-amide 1099 480 2-Butyl-thiazole-4-carboxylic acid { 4 -[3-(3,5-dichloro-phenyl)-thioureido]-phenyl} amide 1100 548 2-Butyl-thiazole-4-carboxylic acid { 4 -[3-(3,5-bis-trifluoromethyl-phenyl) thioureido]-phenyl}-amide 1101 438 2-Methyl-thiazole-4-carboxylic acid {4-[3-(3,5-dichloro-phenyl)-thioureido] phenyl}-amide 1102 438 2-Methyl-thiazole-4-carboxylic acid { 4 -[3-(3,4-dichloro-phenyl)-thioureido] phenyl}-amide 1103 505 2-Methyl-thiazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl-phenyl) thioureido]-phenyl}-amide 1104 534 2-Phenyl-thiazole-4-carboxylic acid { 4 -[3-(4-chloro-3-trifluoromethyl-phenyl) thioureido]-phenyl}-amide 1105 500 2-Phenyl-thiazole-4-carboxylic acid { 4 -[3-(3,5-dichloro-phenyl)-thioureido] phenyl}-amide 1106 500 2-Phenyl-thiazole-4-carboxylic acid {4-[3-(3,4-dichloro-phenyl)-thioureido] phenyl}-amide 1107 568 2-Phenyl-thiazole-4-carboxylic acid { 4 -[3-(3,5-bis-trifluoromethyl-phenyl) thioureido]-phenyl}-amide 1108 401 2 -Fluoro-N-{4-[3-(1-thiazol-2-yl-ethyl)-thioureido]-phenyl}-benzamide 1109 588 2-Fluoro-N-[4-(3-{1 -[1-(toluene-4-sulfonyl)-1H-indol-2-yl]-ethyl}-thioureido) phenyll-benzamide 1110 446 2-Fluoro-N-{4-[3-(1-quinolin-2-yl-ethyl)-thioureido]-phenyl}-benzamide 1111 446 2-Fluoro-N-{4-[3-(1-quinolin-4-yl-ethyl)-thioureido]-phenyl}-benzamide 1112 446 2-Fluoro-N-{4-[3-(1-isoquinolin-3-yl-ethyl)-thioureido]-phenyl}-benzamide 1113 446 2-Fluoro-N-{4-[3-(1-isoquinolin-1-yl-ethyl)-thioureido)-phenyl}-benzanide 1114 446 2-Fluoro-N-{4-[3-(1-quinolin-6-yl-ethyl)-thioureido]-phenyl}-benzamide 1115 446 2-Fluoro-N-{4-[3-(1-quinolin-3-yl-ethyl)-thioureido]-phenyl}-benzamide 1116 413 2-Methoxy-N-{4-[3-(1-thiophen-3-yl-ethyl)-thioureido]-phenyl}-benzamide WO 00/34269 PCT/US99/28892 - 140 EXAMPLE 886 (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. 887 465 N-{4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]-phenyl}-3-fluoro-benzamide 888 477 N-{4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]-phenyl}-2-methoxy benzamide 889 465 N-{4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]-phenyl}-2-fluoro benzanide 890 477 N-{4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]-phenyl}-3-methoxy benzamide 891 399 N-{4-[3-(3,5-Dichloro-2-methoxy-4-methyl-phenyl)-thioureido]-phenyl}-acetamide 892 365 N-{4-[3-(3-Chloro-4-methoxy-5-methyl-phenyl)-thioureido]-phenyl}-acetamide 893 331 N-{4-[3-(2-Nitro-phenyl)-thioureido]-phenyl}-acetamide 894 331 N-{4-[3-(4-Nitro-phenyl)-thioureido]-phenyl}-acetamide 895 477 N-{4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]-phenyl}-4-methoxy benzainide WO 00/34269 PCT/US99/28892 - 141 896 351 N-{4-[3-(2-Chloro-5-methoxy-phenyl)-thioureido]-phenyl}-acetamide 897 428 2
-{
4 -[3-( 4 -Acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy}-acetamide 898 443 { 4 -[3-(4-Acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy} -acetic acid methyl ester 899 457 {4-[3-(4-Acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy}-acetic acid ethyl ester 900 447 N-{ 4 -[3-(3,5-Dichloro-4-phenoxy-phenyl)-thioureido]-phenyl}-acetamide 901 410 N-(4-{3-[3,5-Dichloro-4-(2-nitrilo-ethoxy)-phenyl]-thioureido}-phenyl) acetamide 902 485 { 4 -[3-(4-Acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy I-acetic acid tert-butyl ester 903 469 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-dichloro-2-methoxy-4-methyl phenyl)-thioureido]-phenyl} -amide 904 335 N-{4-[3-(3-Chloro-4-methyl-phenyl)-thioureido]-phenyl } -acetamide 905 335 N-{4-[3-(5-Chloro-2-methyl-phenyl)-thioureido]-phenyl}-acetamide 906 703 N-{ 4
-[
3
-(
4
-{
4
-[
3
-(
4 -Acetylamino-phenyl)-thioureido]-2-chloro-phenydisulfanyI} 3-chloro-phenyl)-thioureido]-phenyl}-acetamide 907 369 N-{4-[3-(3,5-Dichloro-4-methyl-phenyl)-thioureido]-phenyl}-acetamide 908 598 N-{ 4
-[
3
-(
3 ,5-Diiodo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-acetamide 909 504 N-{4-[3-(3,5-Dibromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-acetamide 910 317 N-{4-[3-(6-Methoxy-pyridin-3-yl)-thioureido]-phenyl}-acetamide 911 347 N-{4-[3-(2,6-Dimethoxy-pyridin-3-yl)-thioureido]-phenyl}-acetamide 912 457 Acetic acid 2
-{
4 -[3-(4-acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy} ethyl ester 913 365 4-[3-(4-Acetylanino-phenyl)-thioureido]-2-chloro-benzoic acid 914 346 N-{4-[3-(3-Chloro-4-cyano-phenyl)-thioureido]-phenyl}-acetamide 915 512 N-(4-{3-[5-Chloro-2-(4-chloro-phenoxy)-4-pyrrol-1-yl-phenyl]-thioureido} phenyl)-acetamide 916 355 N-{4-[3-(3,4-Dichloro-phenyl)-thioureido]-phenyl} -acetamide 917 339 N-{4-[3-(3-Chloro-4-fluoro-phenyl)-thioureido]-phenyl} -acetamide 918 447 N-{4-[3-(3-Chloro-4-iodo-phenyl)-thioureido]-phenyl }-acetamide 919 400 N-{4-[3-(4-Bromo-3-chloro-phenyl)-thioureido]-phenyl}-acetamide 920 424 N-[4-(3-{4-[Bis-(2-hydroxy-ethyl)-ainino]-3-chloro-phenyl}-thioureido)-phenyl] acetamide WO 00/34269 PCT/US99/28892 - 142 921 434 N.-(4-1{3-[3-Chloro-4-(hexyl-methyl-amino)-phenyl]-thioureido} -phenyl) acetamide 922 406 N-(4-{ 3-13-Chloro-4-(isobutyl-methyl-amnino)-phenyl]-thioureido I}-phenyl) acetamide 923 389 N-{14-[3-(3-Chloro-4-trifluoromethyl-phenyl)-thioureido]-phenyI I -acetamide 924 441 Furan-2-carboxylic acid {4-r3-(3-chloro-4-trifluoromethyl-phenyl)-thioureido] phenyll}-amide 925 459 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-4-trifluoromethyl-phenyl) thioureido]-phenyl I -amide 926 469 N-{ 4-[3-(3-Chloro-4-trifluoromethyl-phenyl)-thioureido]-phenyl }-2-fluoro benzamnide 927 435 N-{4-[3-(3,4-Dichloro-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide 928 407 Furan-2-carboxylic acid {4-13-(3,4-dichloro-phenyl)-thioureido]-phenyl)}-amide 929 425 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,4-dichloro-phenyl)-thioureido] phenyl }-amide 930 480 N-{4-[3-(4-Bromo-3-chloro-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide 931 527 N- {4-r3-(3-Chloro-4-iodo-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide 932 452 Furan-2-carboxylic acid f{4-[3-(4-bromo-3-chloro-phenyl)-thioureido]-phenyl 1 amiide 933 499 Furan-2-carboxylic acid {4-13-(3-chloro-4-iodo-phenyl)-thioureido]-phenyl} amide 934 391 Furan-2-carboxylic acid {4-[3-(3-chloro-4-fluoro-phenyl)-thioureido]-phenyl } amide 935 470 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-13-(4-bromo-3-chloro-phenyl)-thioureido] phenyll}-amide 936 517 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-13-(3-chloro-4-iodo-phenyl)-thioureido] phenyl}-wmide 937 419 N-{4-[3-(3-Chloro-4-fluoro-phenyl)-thioureido]-phenyl) -2-fluoro-benzamide 938 409 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-chloro-4-fluoro-phenyl)-thioureido] phenyl}-amnide 939 388 N-{4-[3-(3-Chloro-4-isoxazol-5-yl-phenyl)-thioureido]-phenyl} -acetainide 940 387 N-(4-{ 3-[3-Chloro-4-(1 H-pyrazol-3-yl)-phenyl]-thioureido} -phenyl)-acetainide 941 355 N- {4-13-(2,3-Dichloro-phenyl)-thioureido]-phenyl)}-acetamide 942 435 N-{ 4-r3-(2,3-Dichloro-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide 943 407 Furan-2-carboxylic acid {4-[3-(2,3-dichloro-phenyl)-thioureido]-phenyl}-ainide WO 00/34269 PCT/US99/28892 - 143 944 425 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2,3-dichloro-phenyl)-thioureido] phenyl}-anide 945 355 N-{ 4 -[3-(2,5-Dichloro-phenyl)-thioureido]-phenyl}-acetamide 946 435 N-{4-[3-(2,5-Dichloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 947 407 Furan-2-carboxylic acid {4-[3-(2,5-dichloro-phenyl)-thioureido]-phenyl}-amide 948 355 N-{4-[3-(3,5-Dichloro-phenyl)-thioureido]-phenyl}-acetamide 949 435 N-{4-[3-(3,5-Dichloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 950 407 Furan-2-carboxylic acid {4-[3-(3,5-dichloro-phenyl)-thioureido]-phenyl}-amide 951 390 N-{4-[3-(3,4,5-Trichloro-phenyl)-thioureido]-phenyl}-acetamide 952 470 2-Fluoro-N-{4-[3-(3,4,5-trichloro-phenyl)-thioureido]-phenyl}-benzamide 953 442 Furan-2-carboxylic acid { 4 -[3-(3,4,5-trichloro-phenyl)-thioureido]-phenyl} amide 954 460 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3,4,5-trichloro-phenyl)-thioureido] phenyl}-amide 955 458 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-4-isoxazol-5-yl-phenyl) thioureido]-phenyl}-amide 956 457 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[3-chloro-4-(1H-pyrazol-3-yl)-phenyl] thioureido}-phenyl)-amide 957 391 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-phenyl)-thioureido]-phenyl} amide 958 373 Furan-2-carboxylic acid {4-[3-(3-chloro-phenyl)-thioureido]-phenyl}-amide 959 401 N-{4-[3-(3-Chloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 960 373 Furan-2-carboxylic acid {4-[3-(4-chloro-phenyl)-thioureido]-phenyl } -amide 961 401 N-{4-[3-(4-Chloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 962 391 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-chloro-phenyl)-thioureido]-phenyl} amide 963 401 N-{4-[3-(2-Chloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 964 396 3
-(
3
-{
4 -[(Furan-2-carbonyl)-amino]-phenyl}-thioureido)-benzoic acid methyl ester 965 424 3-{3-[4-(2-Fluoro-benzoylamino)-phenyl]-thioureido}-benzoic acid methyl ester 966 414 3-(3-{4-[([1, 2 ,3]Thiadiazole-4-carbonyl)-amino]-phenyl}-thioureido)-benzoic acid methyl ester 967 409 N-[ 4 -[[[[3-(Aminocarbonyl)phenyl]amino]thioxomethyl]amino]phenyl]-2-fluoro benzainide WO 00/34269 PCT/US99/28892 - 144 968 373 Furan-2-carboxylic acid { 4
-[
3
-(
2 -chloro-phenyl)-thioureido]-phenyl} -amide 969 381 Furan-2-carboxylic acid { 4
-[
3 -(3-carbamoyl-phenyl)-thioureido]-phenyl}-amide 970 399 [1, 2 ,3]Thiadiazole-4-carboxylic acid { 4 -[3-(3-carbamoyl-phenyl)-thioureido] phenyl}-amide 971 391 [1,2,3]Thiadiazole-4-carboxylic acid { 4 -[3-(2-chloro-phenyl)-thioureido]-phenyl) amide 972 356 Furan-2-carboxylic acid { 4
-[
3 -(3-fluoro-phenyl)-thioureido]-phenyl}-amide 973 383 Furan-2-carboxylic acid { 4
-[
3
-(
3 -nitro-phenyl)-thioureido]-phenyl}-amide 974 411 2-Fluoro-N-{ 4 -[3-(3-nitro-phenyl)-thioureido]-phenyl}-benzamide 975 422 Furan-2-carboxylic acid { 4
-[
3
-(
3 -trifluoromethoxy-phenyl)-thioureido]-phenyl} amide 976 450 2 -Fluoro-N-{ 4 -[3-(3-trifluoromethoxy-phenyl)-thioureido]-phenyl}-benzamide 977 384 2 -Fluoro-N-{4-[3-(3-fluoro-phenyl)-thioureido]-phenyl}-benzamide 978 410 3-{ 3
-[
4
-(
2 -Fluoro-benzoylamino)-phenyl]-thioureido}-benzoic acid 979 382 3 -(3-{4-[(Furan-2-carbonyl)-amino]-phenyl}-thioureido)-benzoic acid 980 408 N-{ 4 -[3-(3-Acetyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 981 502 N-{ 4
-[
3 -(3-Butylsulfamoyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 982 380 Furan-2-carboxylic acid { 4
-[
3
-(
3 -acetyl-phenyl)-thioureido]-phenyl }-amide 983 447 Furan-2-carboxylic acid (4-{ 3-[3-(2-hydroxy-ethanesulfonyl)-phenyl] thioureido}-phenyl)-amide 984 475 2-Fluoro-N-(4-{ 3
-[
3
-(
2 -hydroxy-ethanesulfonyl)-phenyl]-thioureido}-phenyl) benzamide 985 474 Furan-2-carboxylic acid { 4
-[
3
-(
3 -butylsulfamoyl-phenyl)-thioureido]-phenyl} amide EXAMPLE 986 (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, 10 dried over anhydrous magnesium sulfate, flitered and evaporated to give an oil. The WO 00/34269 PCT/US99/28892 - 145 oil is purifed by silica gel chromatography eluting with 10% dichloromethane hexanes to give the product, a yellow oil (1.76 g). EXAMPLE 987 (METHOD 58) 5 1-( 4 -Fluoro-phenyl)-2-methyl-propan- 1-one 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 10 followed by anhydrous magnesium and the mixture is filtered and evaporated to give the product, a yellow oil (1.2 g). EXAMPLE 988 (METHOD 59) 3 -Dimethylamino-5-trifluoromethyl-benzonitrile 15 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 20 ammonium hydroxide, then water. The solution is dried over anhydrous magnesium sulfate, filtered and concentrated to give a yellow solid which is recrystallized from hexanes to give a yellow solid, (4.7 g). The foregoing compounds were tested for activity as herpes virus inhibitors 25 using the following assays. HUMAN CYTOMEGALOVIRUS Yield assay. Monolayer cultures of human foreskin fibroblasts are infected with 30 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 WO 00/34269 PCT/US99/28892 - 146 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 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 5 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 HCMV. 10 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 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) 15 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: US 10 and US 11 gene products 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 20 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 substrate for the enzyme which when cleaved yields either a product which can be measured colorimetrically in a spectrophotometer or fluorescently in a 25 microfluorimeter. Examples of such substrates are p-nitrophenyl-beta-D-glucuronide 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. 30 Data from this assay generated using varying amounts of inhibitor compound is also used to estimate the IC50 of an inhibitor compound.
WO 00/34269 PCT/US99/28892 - 147 HSV antiviral (ELISA) assay Vero cells (ATCC #CCL-81) are plated on 96-well tissue culture plates at 3.5x10 4 cells per l00pl tissue culture DMEM (Dulbecco's modified Eagle media) 5 supplemented with 2% fetal bovine serum (FBS) in each well. After overnight incubation @ 37"C (in 5% CO 2 ) and 30 minutes prior to infection with HSV-1 (multiplicity of infection equal to 0.006), cells are either untreated, or treated with test compound (multiple concentrations) or reference standard drug control. After approximately 24 hours post-infection incubation @ 37'C (in 5% CO 2 ), cells are 10 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 assessing B-galactosidase activity by quantifying the generation of the 4-methyl umbelliferone fluorescent cleavage product after addition of the methyl umbelliferyl 15 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 obtained in the presence of compound. Data is shown in Table I. 20 VZV antiviral (ELISA) assay For the generation of stock VZV to be used in the assay, VZV strain Ellen (ATCC #VR-1367) is used to infect human foreskin fibroblast (HFF) cells at low multiplicity (less than 0.1) and incubated overnight at 37"C in 5% CO 2 . After the overnight 25 incubation, the mixture of uninfected and VZV-infected HFF infected cells are then harvested and added to each well of 96-well plates (3.5x10 4 cells in 100 P1 DMEM supplemented with 2% FBS) which contain test compound or the reference standard drug control (in 100pl 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 30 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 WO 00/34269 PCT/US99/28892 - 148 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, 5 ) of the test compound is 5 determined by comparing the flourescence obtained in absence of compound to that obtained in the presence of compound. Data is shown in Table I. Table I describes IC 5 data for compounds tested against herpes viruses. Example IC50 IC50 % inhibition IC50 (ug/ml) (ug/ml) 10 ug/ml (ug/ml) HCMV HSV VZV VZV 283 7 0.6 17 >10 284 0.4 3 100 >15 289 >10 0.6 30 >10 498 0.14 6 14 >10 499 3 5 25 >10 506 >10 >10 68 >10 507 1.2 10 90 4 512 0.7 0.5 70 4 514 1.2 4 62 >10 515 >10 >10 30 >10 815 0.0024 >7.5 816 0.0015 >7.5 817 0.001 >7.5 818 0.0022 >7.5 819 0.0022 >7.5 820 0.0013 3.4 821 0.014 >7.5 822 0.05 >7.5 823 0.05 >7.5 824 0.004 3.20 825 0.003 6.12 826 0.020 0.86 827 0.026 828 0.45 >7.5 829 0.08 >7.5 10 Thus, in accordance with the present invention, compounds of the present invention may be administered to a patient suffering from herpes virus infections including VZV, HCMV and HSV, in an amount effective to inhibit the virus. Compounds of the present invention are thus useful to ameliorate to eliminate the WO 00/34269 PCTIUS99/28892 - 149 symptoms of herpes virus 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. 5 Applicable solid carriers can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, 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 10 having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes 15 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 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 20 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 of liquid carriers for oral and parenteral administration include water (particularly containing additives as above e.g. cellulose derivatives, preferably 25 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 oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration. 30 Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous WO 00/34269 PCTIUS99/28892 - 150 injection. Sterile solutions can also be administered intravenously. Oral administration 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 5 containing appropriate quantities of the active ingredient; the unit dosage forms can be packaged compositions, for example packeted powders, vials, ampoules, prefilled syringes or 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. 10 The therapeutically effective dosage to be used in the treatment of herpes virus infections including HCMV, VZV and HSV infection must be subjectively determined by the attending physician. The variables involved include the the condition , age and weight of the patient. The novel method of the invention for treating herpes virus infections comprises administering toa subject, including 15 humans, an effective amount of at least one compound of Formula 1 or a non-toxic, pharmaceutically acceptable salt thereof. The compounds may be administered orally, rectally, parenterally or topically to the skin and mucosa. The usual daily dose is 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 20 0.5 - 500 mg/Kg, and 0.1 - 100 mg/Kg for parenteral application, preferably 0.5 - 50 mg/Kg.

Claims (18)

  1. 3. A compound of Claim 1 wherein R,-R 5 are, independently selected from hydrogen, alkoxy of 1 to 6 carbon atoms, perhaloalkyl of I to 6 carbon atoms and halogen. 15
  2. 4. A compound of Claim 1 wherein X is CH(J) and J is alkyl of 1 to 6 carbon atoms.
  3. 5. A compound of Claim 4 wherein J is methyl. 20
  4. 6. A compound of Claim 1 wherein A is unsubstituted.
  5. 7. A compound of Claim 1 wherein A is pyridinyl. 25 8. A compound of Claim 1 wherein G is an unsubstituted 5 or 6 membered heteroaryl.
  6. 9. A compound of Claim 8 wherein G is furyl, thiazoly, or thiadiazolyl. 30 10. A compound of Claim 8 wherein G is 2-furyl.
  7. 11. A compound of Claim 8 wherein G is 1,2,3 thiadiazolyl. WO 00/34269 PCT/US99/28892 - 153 12. A compound of Claim 8 wherein G is 1,3-thiazolyl.
  8. 13. A compound of Claim 1 wherein G is phenyl. 5
  9. 14. A compound of Claim 1 wherein G is substituted phenyl.
  10. 15. A compound of Claim 14 wherein G is substituted with one or more substituents selected from halogen or alkoxy of 1 to 6 carbon atoms. 10
  11. 16. A compound of Claim 1 wherein X is CH(J), J is methyl, A is pyridyl, and G is thiazolyl.
  12. 17. A compound of Claim 1 selected from: 15 Furan-2-carboxylic acid {5-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido] pyridin-2-yl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid {5-[3-(5-chloro-2,4-dimethoxy-phenyl) thioureido]-pyridin-2-yl}-amide, Pyridine-2-carboxylic acid {5-[3-(5-chloro-2,4-dimethoxy-phenyl) 20 thioureido]-pyridin-2-yl}-amide, Pyridine-2-carboxylic acid {6-[3-(5-chloro-2,4-dimethoxy-phenyl) thioureido]-pyridin-3-yl}-amide, Furan-2-carboxylic acid {6-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido] pyridin-3-yl}-amide, 25 [1,2,3]Thiadiazole-4-carboxylic acid {6-[3-(5-chloro-2,4-dimethoxy-phenyl) thioureido]-pyridin-3-yl}-amide, [1,2,3]Thiadiazole-4-carboxylic acid {5-[3-(3,5-dichloro-phenyl)-thioureido] pyridin-2-yl} -amide, N- [5- [ [(5-Chloro-2,4-dimethoxyphenyl)amino]thioxomethyl] amino] -2 30 pyridinyll-2-methylbenzamide, N- { 5- [3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido] -pyridin-2-yl} -2 fluoro-benzamide, WO 00/34269 PCT/US99/28892 - 154 N- { 6-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-3-yl} -2 fluoro-benzamide, Furan-2-carboxylic acid {6-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido] pyridin-3-yl}-amide, 5 [1,2,3]Thiadiazole-4-carboxylic acid {6-[3-(5-chloro-2,4-dimethoxy-phenyl) thioureido]-pyridin-3-yl) -amide, [1,2,3]Thiadiazole-4-carboxylic acid {5-[3-(3,5-dichloro-phenyl)-thioureido] pyridin-2-yl}-amide, N- [5- [ [[(5-Chloro-2,4-dimethoxyphenyl)amino]thioxomethyl] amino] -2 10 pyridinyl]-2-methylbenzamide, N-{5-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-2-yl)-2 fluoro-benzamide, N-{6-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-3-yl}-2 fluoro-benzamide, 15 N- { 5- [({ [3,5-bis(trifluoromethyl)benzyl] amino) carbothioyl)amino] -2 pyridinyl} -1,2,3-thiadiazole-4-carboxamide, N-(5- {[({ (1S)- 1- [3,5-bis(trifluoromethyl)phenyl] ethyl) amino)carbothioyl] amino) -2-pyridinyl)- 1,2,3-thiadiazole-4-carboxamide, N-(5- { [({ (1S)- 1-[3,5-bis(trifluoromethyl)phenyl]ethyl } amino)carbothioyl] 20 amino }-2-pyridinyl)- 1,3-thiazole-4-carboxamide, N- (5-{[({ 1- [2-fluoro-5- (trifluoromethyl)phenyl] ethyl } amino)carbothioyl] amino) -2-pyridinyl)- 1,3-thiazole-4-carboxamide, N-(5-{ [((1- [2-fluoro-4- (trifluoromethyl)phenyl]ethyl} amino)carbothioyl] amino} -2-pyridinyl)- 1,3-thiazole-4-carboxamide, 25 N- (5- { [({1- [3-fluoro-5-(trifluoromethyl)phenyl] ethyl) amino) carbothioyl] amino) -2-pyridinyl)- 1,3-thiazole-4-carboxamide, N-(5- { [({ (IS)- 1- [3,5-bis(trifluoromethyl)phenyl]ethyl } amino)carbonyl] amino) -2-pyridinyl)- 1,3-thiazole-4-carboxamide, N- { 5- [({ [1-(3-bromophenyl)ethyl] amino) carbothioyl)amino] -2-pyridinyl} 30 1,3-thiazole-4-carboxamide, N- (5- [({[1- (2-bromophenyl)ethyl] amino) carbothioyl)amino] -2-pyridinyl } 1,3-thiazole-4-carboxamide, WO 00/34269 PCTIUS99/28892 - 155 N-(5- { [({1-[3-(trifluoromethyl)phenyl]ethyl } amino)carbothioyl]amino }-2 pyridinyl)- 1,3-thiazole-4-carboxamide, N-(5- {[({ 1- [4-chloro-3-(trifluoromethyl)phenyl] ethyl} amino)carbothioyl] amino }-2-pyridinyl)- 1,3-thiazole-4-carboxamide, 5 N- {5-[({ [1-(4-chloro-3-fluorophenyl)ethyl]amino carbothioyl)amino]-2 pyridinyl} -1,3-thiazole-4-carboxamide, N- {5-[({ [1-(4-chloro-2-fluorophenyl)ethyl]amino }carbothioyl)amino]-2 pyridinyl} -1,3-thiazole-4-carboxamide, N- {6-[({ [1-(4-fluorophenyl)ethyl] amino} carbothioyl)amino] -3-pyridinyl} 10 1,2,3-thiadiazole-4-carboxamide, and N-(6- {[({(1 S)- 1 -[3,5-bis(trifluoromethyl)phenyl]ethyl } amino)carbothioyl] amino} -3-pyridinyl)- 1,2,3-thiadiazole-4-carboxamide; and pharmaceutical salts thereof. 15 18. A pharmaceutical composition comprising a compound of the formula R4 5 R3 / X-NH-C-NH-A-NH-C-G R 2 R 1 wherein 20 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, -NO2, -C0 2 R, -COR 6 , -OR 6 , -SR 6 , -SOR, -SO 2 R , 25 -CONRR,, -NR 6 N(R 7 R 8 ), -N(RR 8 ) or W-Y-(CH 2 )n-Z; or R2 and R, or R and 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, perhaloalkyl of 1 to 6 carbon atoms, or aryl; WO 00/34269 PCT/US99/28892 - 156 R. 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, taken together may form a 3 to 7 membered heterocycloalkyl; 5 A is heteroaryl; 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 , -CONR 7 R,, -OCOR , -NR 6 COR, -OCONR 6 , -OR 6 , -SR 6 , -SOR , -S0 2 R 6 , SR6N(R7R8), 10 -N(RR) or phenyl; G is aryl or heteroaryl; X is a bond, -NH, alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, thioalkyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms, or (CH)J; 15 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 or a pharmaceutically acceptable carrier or diluent. 20 19. A method of inhibiting the replication of a herpes virus comprising contacting a compound of the formula 5 R 3 / X-NH-C-NH-A-NH-O-G R 2 R 1 25 wherein R1-R5 are independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10 carbon members, aryl, heteroaryl, WO 00/34269 PCT/US99/28892 - 157 halogen, -CN, -NO2, -CO 2 R , -COR 6 , 6 -OR, 6SR -SOR , -So 2 R , -CONR,R, -NR 6 N(RR,), -N(R 7 R.) or W-Y-(CH 2 )n-Z; or R 2 and R 3 or R, and R, taken together form a 3 to 7 membered heterocycloalkyl or 3 to 7 membered heteroaryl; 5 R and R, are independently hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of I to 6 carbon atoms, or aryl; R, 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; A is heteroaryl; W is O, NR 6 , or is absent; Y is -(CO)- or -(C0 2 )-, or is absent; Z is alkyl of 1 to 4 carbon atoms, -CN, -CO 2 R, COR , -CONRR, -OCOR , 15 -NR 6 COR,, -OCONR 6 , -OR 6 , -SR , -SOR, -SO 2 R , SR6N(R7R8), -N(RR 8 ) or phenyl; G is aryl or heteroaryl; X is a bond, -NH, alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, thioalkyl of 1 to 6 carbon 20 atoms, alkylamino of 1 to 6 carbon atoms, or (CH)J; J is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl or benzyl; and n is an integer from 1 to 6; or a pharmaceutical salt thereof, with a herpes virus. 25
  13. 20. The method of Claim 19 wherein the herpes virus is human cytomegalovirus.
  14. 21. The method of Claim 19 wherein the herpes virus is herpes simplex virus. 30 22. The method of Claim 19 where the herpes virus is varicella zoster virus. WO 00/34269 PCTIUS99/28892 - 158 23. The method of Claim 22 wherein the varicella zoster virus is treated with substantially pure (S) optical isomer.
  15. 24. A method of treating a patient suffering from a herpes virus infection 5 comprising administering to the patient a therapeutically effective amount of a compound having the formula R4 5 R 3 - X-NH-C--NH-A-NH-C-G R 2 R, 10 wherein R,-R 5 are independently selected from hydrogen, alkyl of I 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, 15 halogen, -CN, -NO2, -C0 2 R , -COR 6 , -OR, 6 -SOR 6 , -S0 2 R , CONR,R,, -NR 6 N(RR), -N(RR,) or W-Y-(CH 2 )n-Z; or R 2 and R, or R 3 and R 4 , taken together form a 3 to 7 membered heterocycloalkyl or 3 to 7 membered heteroaryl; R 6 and R 7 are independently hydrogen, alkyl of 1 to 6 carbon atoms, 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 A is heteroaryl; W is 0, NR 6 , or is absent; Y is -(CO)- or -(C0 2 )-, or is absent; WO 00/34269 PCTIUS99/28892 - 159 Z is alkyl of 1 to 4 carbon atoms, -CN, -CO 2 R, COR, -CONRR,, -OCOR, NR 6 COR, -OCONR, -OR 6 , -SR 6 , -SOR, -S0 2 R , SR6N(R7R8), N(RR,) or phenyl; G is aryl or heteroaryl; 5 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 I to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms, or (CH)J; J is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl or benzyl; and 10 n is an integer from 1 to 6; or a pharmaceutical salt thereof.
  16. 25. The method of Claim 24 wherein the herpes virus is human cytomegalovirus. 15 26. The method of Claim 24 wherein the herpes virus is herpes simplex virus.
  17. 27. The method of Claim 24 where the herpes virus is varicella zoster virus.
  18. 28. The method of Claim 27 where the varicella zoster virus is treated with 20 substantially pure (S) optical isomer.
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