AU3111100A - Thiourea inhibitors of herpes viruses - Google Patents

Thiourea inhibitors of herpes viruses Download PDF

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AU3111100A
AU3111100A AU31111/00A AU3111100A AU3111100A AU 3111100 A AU3111100 A AU 3111100A AU 31111/00 A AU31111/00 A AU 31111/00A AU 3111100 A AU3111100 A AU 3111100A AU 3111100 A AU3111100 A AU 3111100A
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Australia
Prior art keywords
phenyl
thioureido
chloro
carboxylic acid
fluoro
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AU31111/00A
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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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American Home Products Corp
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    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
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    • 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
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    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
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    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D233/44—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/28—Radicals substituted by nitrogen atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/06—1,2,3-Thiadiazoles; Hydrogenated 1,2,3-thiadiazoles
    • 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
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
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    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
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    • 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
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    • 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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  • Pyrrole Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
  • Furan Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Hydrogenated Pyridines (AREA)

Description

WO 00/34268 PCT/US99/28838 THIOUREA INHIBITORS OF HERPES VIRUSES 5 Background of the Invention Eight viruses have been identified which are members of the family Herpesviridae (reviewed in Roizman, B. 1996. Herpesviridae, p. 2221-2230. In B. N. Fields, D. M. Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed. Lippincott Raven Publishers, Philadelphia, PA). Each member of this family is characterized by 10 an enveloped virus containing proteinaceous tegument and nucleocapsid, the latter of which houses the viruses' relatively large double-stranded DNA genome (i.e. approximately 80-250 kilobases). Members of the human alphaherpesvirus subfamily are neurotropic and include herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), and varicella-zoster virus (VZV). The human betaherpesviruses are 15 cytomegalovirus (HCMV), human herpesvirus 6 (HHV-6) and human herpesvirus 7 (HHV-7). The gammaherpesviruses are lymphotropic and include Epstein-Barr virus (EBV) and Kaposi's herpesvirus (HHV-8). Each of these herpesviruses is causally related to human disease, including herpes labialis and herpes genitalis (HSV-1 and HSV-2 [Whitley, R.J. 1996. Herpes Simplex Viruses, p. 2297-2342. In B. N. Fields, 20 D. M. Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed. Lippincott-Raven Publishers, Philadelphia, PA]); chicken pox and shingles (VZV [Arvin, A. 1996. Varicella-Zoster Virus, p. 2547-2585. In B. N. Fields, D. M. Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed. Lippincott-Raven Publishers, Philadelphia, PA]); infectious mononucleosis (EBV [Rickinson, A. B. and Kieff, E. 1996. Epstein 25 Barr Virus, p. 2397-2446. In B. N. Fields, D. M. Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed. Lippincott-Raven Publishers, Philadelphia, PA]); pneumonia and retinitis (HCMV [(Britt, W. J., and Alford, C. A. 1996. Cytomegalovirus, p. 2493-2523. In B. N. Fields, D. M. Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed. Lippincott-Raven Publishers, Philadelphia, PA]); 30 exanthem subitum (HHV-6 [(Pellet, P. E, and Black, J. B. 1996. Human Herpesvirus 6, p. 2587-2608. In B. N. Fields, D. M. Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed. Lippincott-Raven Publishers, Philadelphia, PA] and HHV-7 WO 00/34268 PCT/US99/28838 -2 [Frenkel, N., and Roffman, E. 1996. Human Herpesvirus 7, p. 2609-2622. In B. N. Fields, D. M. Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed. Lippincott Raven Publishers, Philadelphia, PA]); and Kaposi's sarcoma (HHV-8 [Neipel, F., Albrecht, J.C., and Fleckenstein, B. 1997. Cell-homologous genes in the Kaposi's 5 sarcoma-associated rhadinovirus human herpesvirus 8: determinants of its pathogenicity? J. Virol. 71:4187-92, 1997]). HCMV is considered in more detail below. Following the primary infection, herpesviruses establish latency within the infected individual and remain there for the remainder of his/her life. Periodic reactivation of latent virus is clinically relevant. In the case of HSV, reactivated 10 virus can be transmitted to infants during birth, causing either skin or eye infection, central nervous system infection, or disseminated infection (i.e. multiple organs or systems). Shingles is the clinical manifestation of VZV reactivation. Treatment of HSV and VZV is generally with antiviral drugs such as acyclovir (Glaxo Wellcome), ganciclovir (Roche) and foscarnet (Asta) which target viral encoded DNA 15 polymerase. HCMV is a ubiquitous opportunistic pathogen infecting 50-90% of the adult population (Britt, W. J., and Alford, C. A. 1996. Cytomegalovirus, p. 2493-2523. In B. N. Fields, D. M. Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed. 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 Alford, 1996). (1) In immunocompromised (AIDS) patients, HCMV is one of the 30 two most common pathogens causing clinical disease (the other is Pneumocystis). The most common manifestation of HCMV in AIDS is retinitis, although infection of other organs including the adrenal glands, lungs, GI tract, and central nervous system are also reported frequently. 90% of AIDs patients have active HCMV infection; 25- WO 00/34268 PCT/US99/28838 -3 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 immune system suppression to reduce the risk of graft rejection, HCMV reactivation or reinfection is common amongst kidney, liver, heart, and allogeneic bone marrow 5 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 are symptomatic for HCMV disease between ages 0-3 years. HCMV disease is progressive, causing mental retardation and neurological abnormalities, in children. 10 Recent studies suggest that treatment with anti-HCMV drugs may reduce morbidity in these children. Several antiviral drugs are currently being marketed (Bron, D., R. Snoeck, and L. Lagneaux. 1996. New insights into the pathogenesis and treatment of cytomegalovirus. Exp. Opin. Invest. Drugs 5:337-344; Crumpacker, C. 1996. 15 Ganciclovir. New Eng. J. Med. 335:721-729; Sachs, S., and F. Alrabiah. 1996. Novel herpes treatments: a review. Exp. Opin. Invest. Drugs 5:169-183). These include: ganciclovir (Roche), a nucleoside analog with hemopoietic cell toxicity; foscarnet (Astra), a pyrophosphate analog with nephrotoxicity; and cidofovir, Gilead), a nucleoside phosphonate with acute nephrotoxicity. Each of these drugs target the 20 viral-encoded DNA polymerase, are typically administered intravenously due to their low bioavailability, and, as noted above, are the source of significant toxicity. Ganciclovir-resistant mutants which arise clinically are often cross-resistant with cidofovir. Hence, there is a need for safer (i.e. less toxic), orally bioavailable anti viral drugs which are directed against novel viral targets. 25 Phenyl thioureas are disclosed for use in a variety of pharmaceutical applications. Armistead, et al., WO 97/40028, teaches phenyl ureas and thioureas as inhibitors of the inosine monophosphate dehydrogenase (IMPDH) enzyme which is taught to play a role in viral replication diseases such herpes.
WO 00/34268 PCT/US99/28838 -4 n (Y) / R~ H H 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. 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:
R
9 Rio S 0 II - II A-X-NH-C-NH NH -C--G
R
11
R
12 20 I wherein A is heteroaryl;
R
9
-R,
2 are independently hydrogen, alkyl of 1 to 4 carbon atoms, perhaloalkyl of 1 to 4 carbon atoms, halogen, alkoxy of 1 to 4 carbon atoms, or 25 cyano, or R 9 and Rio or R 11 ,, and RI 2 may be taken together to form aryl of 5 to 7 carbon atoms; W is O, NR 6 , or is absent; WO 00/34268 PCT/US99/28838 -5 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 5 atoms, alkylamino of 1 to 6 carbon atoms, or (CH)J; and 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. 10 In some preferred embodiments of the present invention A is a 5 or 10 membered mono or bicyclic heteroaryl having 1 or 2 heteroatoms. More preferably, A is pyridyl, furyl, imidazolyl, pyrrolyl, thienyl, or indanyl. Still more preferably, A is 3-pyridyl. 15 In some preferred embodiments of the present invention A is substituted with one or more substitutents selected from 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 -CO 2
R
6 , -COR 6 , -OR6 , -SR6 , -SOR , -SO 2
R
6 , 20 -CONRR , , -NRN(RR,), -N(R 7 R,) or W-Y-(CH 2 )-Z wherein R 6 and R 7 are independently hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, or aryl; R 8 is hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10 members, aryl or heteroaryl, or 25
R
7 and R 8 , taken together may form a 3 to 7 membered heterocycloalkyl; W is O, NR 6 , or is absent; 30 Y is -(CO)- or -(CO 2 )-, or is absent; Z is alkyl of 1 to 4 carbon atoms, -CN, -CO 2
R
6 , COR 6 , -CONR 7 R,, -OCOR 6 ,
-NR
6
COR
7 , -OCONR 6 , -OR 6 , -SR 6,
-SOR
6 , -SO 2
R
6 , SR 6
N(R
7 R,), -N(R 7 R,) or phenyl; and n is 1 to 6.
WO 00/34268 PCT/US99/28838 -6 In still more preferred embodiments A is substituted with one or more substitutents selected from halogen or alkyl of 1-6 carbon atoms. In some embodiments of the present invention, at least 1 of R 9
-R,
2 is not 5 hydrogen. Preferably when one of R 9 -R,2 is not hydrogen, one or more of R 9
-R
2 are selected from halogen, methyl, methoxy, and cyano. More preferably each of R 9
-R
2 is hydrogen. G is preferably a 5 or 6 membered heteroaryl having 1 or 2 heteroatoms. More preferably, G is furyl or thiadiazole and in still more preferred embodiments, G 10 is 1,2,3 thiadiazolyl or 2-furyl. Alternatively, G may be alkyl of 1 to 6 carbon atoms which optionally may be substituted, preferably by a halogen. X is preferably a bond or straight chain lower alkyl group. When X is a lower alkyl group it is preferred that X is methyl or ethyl. 15 Preferred compounds of the present invention are the following compounds which include pharmaceutical salts thereof. Furan-2-carboxylic acid [4-( 3 -pyridin-2-yl-thioureido)-phenyl]-amide; Furan-2-carboxylic acid [ 4
-(
3 -pyridin-4-yl-thioureido)-phenyl]-amide; Furan-2-carboxylic acid [4-( 3 -pyridin-3-yl-thioureido)-phenyl]-amide; 20 [1,2,3]Thiadiazole-4-carboxylic acid { 4-[3-(6-chloro-pyridin-3-yl)-thioureido] phenyl }-amide; Furan-2-carboxylic acid [4-( 3 -pyrimidin-4-yl-thioureido)-phenyl]-amide; [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(5-chloro-pyridin-3-yl)-thioureido] phenyl }-amide; 25 [1,2,3]Thiadiazole-4-carboxylic acid { 4
-[
3 -(5-bromo-pyridin-3-yl)-thioureido] phenyl } -amide; [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(1-tert-butyl-1H-imidazol-2-yl) thioureido]-phenyl}-amide; Furan-2-carboxylic acid {4-[3-(1-tert-butyl- 1H-imidazol-2-yl)-thioureido]-phenyl
}
30 amide; [1,2,3]Thiadiazole-4-carboxylic acid { 4-[3-(5-trifluoromethyl-pyridin-3-yl) thioureido]-phenyl }-amide; Furan-2-carboxylic acid [4-( 3 -pyridin-3-ylmethyl-thioureido)-phenyl]-amide; WO 00/34268 PCT/US99/28838 -7 [1,2,3]Thiadiazole-4-carboxylic acid [4-(3-pyridin-3-ylmethyl-thioureido)-phenyl] amide; [1,2,3]Thiadiazole-4-carboxylic acid [4-(3-indan-1-yl-thioureido)-phenyl]-amide; Furan-2-carboxylic acid [4-(3-pyridin-4-ylmethyl-thioureido)-phenyl]-amide; 5 [1,2,3]Thiadiazole-4-carboxylic acid [4-(3-pyridin-4-ylmethyl-thioureido)-phenyl] amide; 2-Fluoro-N-[4-(3-pyridin-3-yl-thioureido)-phenyl]-benzamide; 2-Fluoro-N-[4-(3-pyridin-2-yl-thioureido)-phenyl]-benzamide; 2-Fluoro-N-[4-(3-pyridin-4-yl-thioureido)-phenyl]-benzamide; 10 2-Fluoro-N-[4-(3-pyridin-3-ylmethyl-thioureido)-phenyl]-benzamide; 2-Fluoro-N- { 4-[3-(1H-indazol-5-yl)-thioureido]-phenyl } -benzamide; N- { 4-[3-( 1 -tert-Butyl- 1H-imidazol-2-yl)-thioureido]-phenyl } -2-fluoro-benzamide; 2-Fluoro-N-[4-(3-pyridin-4-ylmethyl-thioureido)-phenyl]-benzamide; 2-Fluoro-N- { 4-[3-(1 -furan-2-yl-ethyl)-thioureido]-phenyl }-benzamide; 15 2-Fluoro-N- { 4-[3-(1-pyridin-4-yl-ethyl)-thioureido]-phenyl } -benzamide; 2-Fluoro-N-(4- { 3-[ 1 -(1-methyl- 1H-pyrrol-2-yl)-ethyl]-thioureido } -phenyl) benzamide; and 2-Fluoro-N- { 4-[3-(1-thiophen-3-yl-ethyl)-thioureido]-phenyl }-benzamide. 20 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 6 carbon atoms containing at least one carbon-carbon double bond. Alkenyl includes 25 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 or unsubstituted. 30 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.
WO 00/34268 PCT/US99/28838 -8 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 O, including, but not limited to aziridinyl, azetidinyl, imidazolidinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrazolidinyl, piperidinyl, and pyrrolidinyl. Heterocycloalkyl groups of 5 the present invention may be substituted or unsubstituted. 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 10 members having 1 to 3 heteroatoms selected from N, S or O including, but not 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, 15 pyrazolyl, triazolyl, thiadiazolyl, and imidazolyl. Heteroaryl groups of the present invention may be substituted or unsubstituted. Perhaloalkyl refers to an alkyl group of 1 to 6 carbon atoms in which three or more hydrogens are substituted with halogen. Phenyl as used herein refers to a 6 membered aromatic ring. 20 Halogen, as used herein refers to chlorine, bromine, iodine and fluorine. Unless otherwise limited substitutents are unsubstituted and may include alkyl of 1 to 6 carbon atoms, cycloalkyl of 1 to 6 carbon atoms, heterocycloalkyl of lto 6 members, perhaloalkyl of 1 to 6 carbon atoms, alkylamino, dialkylamino, aryl or heteroaryl. 25 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 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 30 alkyl-cycloalkyl group in which alkyl and cycloalkyl are as previously described. Pharmaceutically acceptable salts are the acid addition salts which can be formed from a compound of the above general formula and a pharmaceutically acceptable acid such as phosphoric, sulfuric, hydrochloric, hydrobromic, citric, maleic, WO 00/34268 PCT/US99/28838 -9 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 seteroisomeric forms of the compounds such as racemic mixtures as well as the 5 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 embodiments the pure optical isomer is greater than 90% of the desired isomer. In 10 some preferred emodiments, 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. Compounds of the present invention may be prepared by those skilled in the art of organic synthesis employing methods described below which utilize readily 15 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 following reaction schemes. 20 Referring to Methods 31 and 34, reacting appropriately substituted amines 2, wherein the substitutents of A, and X are described as above, with appropriately substituted isothiocyanates 3, wherein the substituents R 9
-R
2 and G are described above, either neat or in an appropriate solvent such as tetrahydrofuran, acetonitrile, 25 ethyl acetate, dichloromethane, or N,N-dimethylformamide affords the desired thioureas 1. Similarly, reaction of appropriately substituted isothiocyanates 4, wherein the substitutents of A, and X are described as above with appropriately substituted anilines 5, wherein the substituents R,-R 2 and G are described above, in a convenient solvent such as those listed above affords the desired thioureas 1. 30 WO 00/34268 PCT/US99/28838 -10 Methods 31 and 34 R 10 0 - II
A-X--NH
2 + ==C= -G R1 2 3 R 10 H H A-X-NR1C2 A .- S+ H2 @-G
R
11 R12 4 5 Alternatively, appropriately substituted thioureas 1 can be prepared as described by Methods 32 and 33 by reacting amines 2 and 5 in the presence of either 5 one molar equivalent of 1,1'-thiocarbonyl diimidazole in an appropriate solvent such as dichloro-methane and 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. 10 In certain instances, subsequent chemical modification of the final thioureas 1 was required. These methods, Methods 35-39, are summarized below. Thioureas 1 wherein A comprises at least one substituent which is 1 hydroxyethoxy or carboxy-methoxy, R 9
-R
1 2 and G are defined as above and X equals 15 a bond, may be prepared from the corresponding alkyl esters by alkaline hydrolysis with aqueous sodium or potassium hydroxide in a suitable solvent such as methanol, tetrahydrofuran or mixtures thereof at room temperature in accordance with Methods 35 and 36. 20 Thioureas 1 wherein A comprisese at least one substituent which is 1 acyloxyethoxy or methansulfonoxyethoxy, R 9
-R
2 and G are defined as above and X WO 00/34268 PCT/US99/28838 -11 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 5 dichloromethane or the like at room temperature in accordance with Methods 37 and 38. Thioureas 1 wherein A comprises at least one substituent which is 1-amino ethoxy, R 9
-R
2 and G are defined as above and X equals a bond, may be prepared 10 from the corresponding 1-methanesulfonoxy-ethoxy derivative by reaction with an appropriate secondary amine such as dimethylamine in a suitable solvent mixture such as tetrahydrofuran and water or the like at room temperature in accordance with Method 39. 15 Thioureas 1 wherein A comprises at least one substituent which is 1-amino alkyl, R 9 -R 2 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. 20 The intermediate isothiocyanates 3 and 4 shown above in Methods 31 and 34 are prepared in accordance with Method 41 (below) essentially according to the procedures of Staab, H.A. and Walther, G. Justus Liebigs Ann. Chem. 657, 104 (1962)) by reacting appropriately substituted amines 5 or 2, respectively, X is defined 25 above with one molar equivalent of 1,1 '-thiocarbonyldiimidazole in an appropriate solvent such as dichloromethane and tetrahydrofuran or mixtures thereof.
WO 00/34268 PCT/US99/28838 - 12 Method 41 H N - N-C-C ( Y2= 2 2 S=C=N N-C-G HH 5 3 R 5 R 5 -Z 2
R
3 ' / X-NH 2 - - R 3 \ / X-N=C= S
R
2
R
1 R 2
R
1 2 4 The intermediates 2 and 5 may be prepared according to the following 5 protocols: According to Methods 1A-1G, amines 2, wherein A is defined above and X is defined above and amines 5, wherein R 9
-R
2 are defined above, may be prepared by reduction of the appropriately substituted nitrobenzenes and corresponding 10 heteroaryls according to a variety of procedures known to those skilled in the art and described in R. J. Lindsay, Comprehensive Organic Chemistry (ed. Sutherland), Volume 2, Chapter 6.3.1, Aromatic Amines, 1979. Such procedures include the reduction of nitrobenzenes to form anilines upon exposure to: a) iron powder and a strong acid, such as hydrochloric acid (Methods 1A) either neat 15 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; WO 00/34268 PCT/US99/28838 - 13 c) iron powder and aqueous ammonium chloride (Method IC), either neat or in alcohol solvent such as methanol or ethanol, at temperatures ranging from room temperature to the refluxing temperature of the solvent, or; d) tin and a strong mineral acid, such as hydrochloric acid (Method lD), either neat 5 or in alcohol solvent such as methanol or ethanol, at temperatures ranging from room temperature to the refluxing temperature of the solvent, or; e) when substitutents of A and R 9-RI2 are selected from Cl, Br, I, -(OSO 2
)-CF
3 , or (OSO 2 )-l-(4-methylphenyl), by catalytic reduction such as with hydrogen and palladium on carbon (Method lE) in an appropriate solvent such as methanol, 10 ethanol, or ethyl acetate, under one or more atmospheres of pressure or; f) when substituents of A and R 9-R2 are selected from Cl, Br, I, -(OSO 2
)-CF
3 , or (OSO 2 )-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 15 temperature of the solvent, or; 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 A is defined above and X is defined above and anilines 5, wherein R 9 -R 12 are defined above, may 20 be prepared by the cleavage of the aniline nitrogen-carbon bond of amide and carbamate derivatives of these anilines according to a variety of procedures known to those skilled in the art and described in Greene, Protective Groups in Organic Synthesis volume 2, Chapter 7, 1991, and references therein. Such procedures include: 25 a) the exposure of appropriately substituted arylamino-tert-butyl-carbamates to a strong acid such as trifluoroacetic acid (Method 3A)either neat or in an appropriate solvent such as dichloromethane at temperatures between 0OC and room temperature, or; 30 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 WO 00/34268 PCT/US99/28838 -14 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 5 an alcohol solvent such as methanol or ethanol (Method 3C) at temperatures ranging from room temperature to the reflux temperature of the solvent. Alternatively, according to Method 11, amines 2, wherein A is defined above, and X equals a bond and at least one substituent of A is vinyl, may be prepared by the palladium catalyzed coupling of a vinyl trialkyltin reagent, such as tributylvinyltin, 10 with an appropriately substituted bromo- or iodo-aniline, for 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 15 procedures of V. Farina and G.P. Roth in Advances in Metal-Organic Chemistry, Vol. 5, 1-53, 1996 and references therein. Alternatively, according to Method 42, amines 2, wherein A is defined above and X is defined above and at least one substituent of A is defined as dialkylamino, may be prepared by the palladium catalyzed amination of an appropriately substituted 20 3- or 5-bromo- or iodo-aniline, 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 lithium bis-(trimethylsilyl)amide in a sealed tube, in a suitable solvent such as tetrahydrofuran or toluene, at temperatures ranging from room temperature to 100C, 25 essentially according to the procedures of J.F. Hartwig and J. Louie Tetrahedron Letters 36 (21), 3609 (1995). Alternatively, according to Method 43, amines 2, wherein A is defined above and X is defined above and at least one substituent of A is defined as alkyl, may be prepared by the palladium catalyzed alkylation of an appropriately substituted 3- or 30 5-bromo-or iodo-aniline, by alkenes under condiditons which employ a palladium catalyst such as [1,1 '-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex and in the presence of 9-borabicyclo[3.3.1]nonane and a suitable base such as aqueous sodium hydroxide in a suitable solvent such as WO 00/34268 PCT/US99/28838 - 15 tetrahydrofuran or the like at temperatures ranging from room temperature to the reflux temperature of the solvent. The acyl and carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C may be prepared by the derivatization of the corresponding amines 5 as described in Methods 2A-2G according to a variety of procedures known to those skilled in the art and described in Greene, Protective Groups in Organic Synthesis volume 2, Chapter 7, 1991, and references therein. Such procedures include: a) the reaction of an appropriately substituted amine with di-tert-butyl-dicarbonate (Method 2A) in the presence or absence of one or more molar equivalents of a 10 tertiary amine such as triethylamine or N,N-diisopropylethylamine in a suitable solvent such as acetone, tetrahydrofuran, dimethylformamide, dichloromethane, and the like, at temperatures ranging from room temperature to the reflux temperature of the solvent to produce the corresponding arylamino-tert-butyl carbamate, or; 15 b) the reaction of an appropriately substituted aniline with 1-[2 (trimethylsilyl)ethoxycarbonyl-oxy]benzotriazole (Method 2B) in the presence of a tertiary amine such as triethylamine or diisopropylethylamine in a suitable solvent such as dimethylformamide at room temperature to produce the corresponding heteroarylamino-(2-trimethylsilylethyl)-carbamate, or; 20 c) the reaction of an appropriately substituted aniline with a carboxylic acid chloride or acid anhydride (Method 2C) either neat or in an appropriate solvent such as tetrahydrofuran, dimethylformamide, dichloromethane, pyridine and the like, in the presence of one or more molar equivalents of a teriary amine base such as triethylamine or N,N-diisopropylethyl-amine to produce the 25 corresponding arylaminoamide, or; d) the reaction of an apptopriately substituted nitro aniline with a carboxylic acid chloride (Method 2D) in the absence of one or more molar equivalents of a teriary amine base such as triethylamine or N,N-diisopropylethylamine either neat or in an appropriate solvent such as tetrahydrofuran, 1,4-dioxane and the like at 30 temperatures ranging from room temperature to the reflux temperature of the solvent to produce the corresponding nitro arylaminoamide, or; e) the reaction of an appropriately substituted aniline with a carboxylic acid (Method 2E) in the presence of a coupling agent such as benzotriazole-1-yloxy-tris- WO 00/34268 PCT/US99/28838 - 16 (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 5 diichloromethane, dimethylformamide and the like, at room temperature to produce the corresponding arylaminoamide, or; f) the reaction of an appropriately protected aniline such as an heteroarylamino-tert butyl-carbamate or the like in which at least one substituent of A and R 9
-R
1 2 is defined as -W-Y-(CH 2 ),-Z wherein W, Y, and Z are defined as above, with a 10 carboxylic acid anhydride (Method 2F) in the presence of a suitable base such as pyridine in an appropriate such as dichloromethane, dimethylformamide or the like at temperatures ranging from 0oC to room temperature to produce the corresponding carboxylic acid ester, or; g) the reaction of an appropriately substituted aniline in which at least one 15 substituent of A is defined as hydroxyl with di-tert-butyl-dicarbonate (Method 2G) in the absence of one or more molar equivalents of a tertiary amine such as triethylamine or N,N-diisopropylethylamine in a suitable solvent such as acetone, tetrahydrofuran, dimethylformamide, dichloromethane, and the like, at temperatures ranging from room temperature to the reflux temperature of the 20 solvent to produce the corresponding heteroarylamino-tert-butyl-carbamate. Nitrobenzene intermediates that are ultimately converted to amines 2 and 5 by methods shown above in Methods 1A-1G may be prepared in accordance with Methods 4A, 4C, 4E-4F. Referring to Methods 4A, 4C, and 4E-4H, the nitrobenzene intermediates 25 which are ultimately converted into amines 2, where A comprises substituent defined as alkoxy, thioalkoxy, alkylsulfenyl, alkylsulfinyl, and dialkylamino may be prepared by the nucleophilic displacement of appropriately substituted 2-, 4-, and/or 6-fluoro-, chloro-, bromo-, iodo-, trifluoromethylsulfonyl-, or (4-methylphenyl)sulfonyl substituted nitrobenzenes or corresponding heteroaryls by methods which include the 30 following: a) reaction of alcohols with appropriately substituted 2- or 4- halo- or sulfonate esters of nitrobenzenes, benzonitriles or corresponding heteroaryls (Method 4A) either neat or in an appropriate solvent such as tetrahydrofuran, dioxane, WO 00/34268 PCT/US99/28838 - 17 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 temperatures ranging from room temperature to 5 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, benzonitriles or corresponding heteroaryls (Method 4H) either neat or in an appropriate solvent such as tetrahydrofuran, dioxane, acetonitrile, N,N 10 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, benzonitriles or corresponding heteroaryls (Methods 4C,F) either neat or in an appropriate solvent such as 15 tetrahydrofuran, dioxane, acetonitrile, N,N-dimethyl-formamide or dimethylsulfoxide, at temperatures ranging from room temperature to the reflux temperature of the solvent; d) reaction of preformed sodium, lithium, or potassium salts of amines with appropriately substituted 2- or 4- halo- or sulfonate esters of nitrobenzenes or 20 benzonitriles (Method 4G) in an appropriate solvent such as tetrahydrofuran at temperatures ranging from 0OC to the reflux temperature of the solvent, or; e) reaction of sodium sulfide with appropriately substituted 2- or 4- halo- or sulfonate esters of nitrobenzenes or benzonitriles either neat or in an appropriate solvent such as tetrahydro-furan, dioxane, acetonitrile, N,N-dimethylformamide 25 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 the reaction mixture (Method 4E). Alternatively, referring to Methods 5C and 6, the nitrobenzene intermediates and corresponding heteroaryls which are ultimately converted into amines 2, wherein 30 at least one substitutent of A is defined as alkoxy may be prepared from the corresponding substituted hydroxy-nitrobenzenes and corresponding heteroaryls by methods which include the following: WO 00/34268 PCT/US99/28838 - 18 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, 5 tetrahydrofuran or dimethylsulfoxide at temperatures ranging from room temperature to the reflux temperature of the solvent, or; b) reaction of the hydroxy-nitrobenzene or corresponding heteroaryl with an alkyl alcohol, triphenylphosphine, and a dialkylazadicarboxylate reagent (Method 6), such as diethylazodicarboxylate, in an anhydrous aprotic solvent such as diethyl 10 ether or tetrahydrofuran at temperatures ranging from 0OC to the reflux temperature of the solvent, essentially according to methods described in Mitsunobu, O, Synthesis 1981, 1 and references therein. In addition, referring to Method 5A and 5E, the carbamoyl amine derivatives 15 utilized as starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein at least one substituent of A is defined as alkoxy may be prepared the corresponding substituted hydroxy aryl- or heteroarylamino-tert-butyl-carbamate by reaction with alkyl halides, trifluormethane-sulfonates, 4 methylbenzenesulfonates, dialkylsulfonate, ethylene carbonate and the like in the 20 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. Alternatively, referring to Methods 7A-G, the nitrobenzene and corresponding 25 heteroaryls which are ultimately converted into amines 2, comprising at least one alkoxy at least one halogen, and X equals a bond, may be prepared by standard halogenation reactions which include the following: a) reaction of a 2- or 4- hydroxy-nitrobenzene or corresponding heteroaryl with aqueous sodium hypochlorite (Methods 7A and 7B), at room temperature or; 30 b) reaction of a 2-hydroxy-4-methoxy or 2,4-dimethoxynitrobenzene or corresponding heteroaryl (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 room temperature, or; WO 00/34268 PCT/US99/28838 - 19 c) reaction of a 2 ,4-dimethoxynitrobenzene or corresponding heteroaryl (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 or corresponding heteroaryl 5 (Method 7F) with benzyltrimethyl-ammonium dichloroiodate in the presence of sodium bicarbonate in a suitable solvent mixture such as dichloromethane and methanol, at room temperature or; e) reaction of a 2,4-dimethoxynitrobenzene or corresponding heteroaryl (Method 7G) with 3,5-dichloro-1-fluoropyridine triflate in a suitable solvent such as 10 tetrachloroethane, at a temperature ranging from room temperature to the reflux temperature of the solvent. Referring to Method 8, the nitrobenzene intermediates or corresponding heteroaryl which are ultimately converted into amines 2, wherein A is substituted by
CF
3 and X equals a bond may be prepared from the corresponding substituted 4-iodo 15 nitrobenzenes or corresponding heteroaryl by reaction with trimethyl(trifluoromethyl)silane in the presence of cuprous iodide and potassium fluoride in a suitable solvent such as N,N-dimethyl-formamide or the like at a temperature ranging from room temperature to the reflux temperature of the solvent in a sealed reaction vessel. 20 Referring to Methods 19A and 19B, the nitrobenzene intermediates which are ultimately converted into amines 2, wherein A comprises a substituent defined as HNCOCH 2 NR7R or -HNCOCH 2
SR
6 , 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 25 solvent such as tetrahydrofuran and/or water mixtures at temperatures ranging from room temperature to the reflux temperature of the solvent or by reaction with an appropriate thiol in the presence of a suitable base such as 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 30 solvent. Referring to Method 25, the nitrobenzene intermediates or corresponding heteroaryl which are ultimately converted into amines 2, wherein at least one substituent of A is defined as triflate and X equals a bond may be prepared from the WO 00/34268 PCT/US99/28838 - 20 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 0OC to room temperature. 5 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 A is defined as either alkylsulfenyl or alkylsulfinyl, may be prepared by reaction of the appropriate 4-alkylthio acylarylamino or acylheteroarylamino or carbamoylarylamino or carbamoylheteroarylamino derivative 10 with an appropriate oxidizing agent such as dimethyloxirane or sodium periodate in a suitable solvent mixture such as acetone and dichloromethane or water at room temperature. Referring to Method 12, the carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein a 15 substituent of A is defined as 1-hydroxyethyl and X equals a bond may be prepared by reacting the corresponding 4-vinyl carbamoyl aniline with sodium borohydride in the presence of mercuric acetate in a suitable solvent such as tetrahydrofuran, 1,4 dioxane or the like and water at room temperature. Referring to Method 13, the carbamoyl amine derivatives utilized as starting 20 materials in Methods 3A-3C which are ultimately converted into amines 2, wherein a substituent of A is defined as 2-hydroxyethyl and X equals a bond, may be prepared by reacting the corresponding 4-vinyl carbamoyl aniline with sodium borohydride in the presence of glacial acetic acid in a suitable solvent such as tetrahydrofuran, 1,4 dioxane or the like at temperatures ranging from 0OC to room temperature. 25 Referring to Method 14, the carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein a substituent of A is defined as 1-azidoethyl and and X is defined above, may be prepared by reacting the corresponding 4-(1-hydroxyethyl) carbamoyl aniline with hydrazoic acid in the presence of a dialkylazodicarboxylate such as 30 diethylazodicarboxylate and triphenylphosphine in a suitable solvent mixture such as tetrahydrofuran and dichloromethane at temperatures ranging from 0OC to room temperature.
WO 00/34268 PCT/US99/28838 -21 Referring to Method 15, the carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein a substituent of A is defined as 3 -dimethylaminoprop- 1-ynyl and X is defined above, may be prepared by reacting the corresponding 4-iodocarbamoyl aniline with 1 5 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 10 materials in Methods 3A-3C which are ultimately converted into amines 2, wherein a substituent of A is defined as 3 -dimethylaminoacryloyl 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 methanol at temperatures ranging from 15 0OC to room temperature. Referring to Methods 17 and 18, the carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein a substituent of A is defined as either 4-isoxazol-5-yl or 4-(1H-pyrazol-3-yl) and X equals a bond, may be prepared by reacting the corresponding 4-(3 20 dimethylamino-acryloyl)carbamoyl aniline with either hydroxylamine hydrochloride or hydrazine hydrate in a suitable solvent such as 1,4-dioxane or ethanol and the like at room temperature. Referring to Method 20, the carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein a 25 substituent of A is defined as -HNCO 2 Z, Z is defined above and X equals a bond, may be prepared by reacting the corresponding 4-aminocarbamoyl aniline with 1,1 carbonyl-di-(1,2,4)-triazole and an appropriately substituted alcohol in a suitable solvent mixture such as tetrahydrofuran and dichloromethane and the like at temperatures ranging from room temperature to the reflux temperature of the solvent. 30 Referring to Methods 26 and 30, the carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein at least one substituent of A is defined as dialkylamino and X is defined above may be prepared by reaction of appropriately substituted aldehydes in the WO 00/34268 PCT/US99/28838 - 22 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. Referring to Methods 27 and 28, amines 2 wherein at least one substituent of 5 A is defined as hydroxy and X is defined 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 temperature of the solvent. 10 Referring to Method 29, amines 2 wherein at least one substituent of A is defined as 2-hydroxybenzamido and X is defined above can be prepared by reaction of the corresponding N-(4-aminophenyl)phthalimide with lithium borohydride in an appropriate solvent such as tetrahydrofuran, diethyl ether, or the like at room temperature. 15 The intermediate amines 2 wherein X equals either -CH 2 - or -(CH 2
)
2 - can be prepared by the following procedures: a) reduction of an appropriately substituted benzo- phenyl- or corresponding heteroarylacetonitrile with borane-dimethylsulfide complex in a suitable solvent such as ethylene glycol dimethyl ether, tetrahydrofuran or the like 20 a temperatures ranging from room temperature to the reflux temperature of the solvent. (Method 44); b) reduction under one or more atmospheres of hydrogen in the presence of a suitable catalyst such as 5 % or 10 % palladium on carbon and an acid such as 4 -methyl-benzenesulfonic acid, hydrochloric acid or the like in a 25 suitable solvent such as ethylene glycol monomethyl ether, ethyl acetate, ethanol or the like at room temperature. (Method 50); c) reduction with lithium aluminum hydride in a suitable solvent such as tetrahydrofuran or diethyl ether at temperatures ranging from 0OC to room temperature. (Method 51); 30 The unsaturated nitro precursors which are utilized as starting materials in Method 51 and are ultimately converted to amines 2 wherein X equals -(CH 2
)
2 - can be prepared by reaction of an appropriately substituted benzaldehyde or corresponding heteroaryl with nitro-methane in the presence of ammonium acetate in WO 00/34268 PCT/US99/28838 - 23 a suitable solvent such as acetic acid at temperatures ranging from room temperature to the reflux temperature of the solvent.(Method 53); The benzaldehydes or corresponding heteroaryls, utilized as starting materials in Method 53, can be prepared by diisobutylaluminum hydride reduction of an appropriately substituted 5 benzonitrile or corresponding heteroaryl. (Method 52) The substituted benzonitriles or corresponding heteroaryls, utilized as starting materials in Method 52, can be prepared from the corresponding aryl or heteroaryl bromide by reaction with copper cyanide in a suitable solvent such as N,N-dimethylformamide at temperatures ranging from room temperatture to the reflux temperature of the solvent. (Method 59) 10 For amines 2, wherein X equals either -O(CH 2
)
2
NH
2 or -S(CH 2
)
2 NH,, the requisite nitrile precursors may be prepared by reaction of an appropriately substituted phenol, thiophenol or corresponding heteroaryl with bromoacetonitrile in the presence of a suitable base such as potassium carbonate in an appropriate solvent such as acetone at room temperature according to Method 49. 15 Alternatively, for amines 2, wherein X equals -(CH 2
)
3 -, the nitrile precursors can be prepared essentially according to the procedure of Wilk, B. Synthetic Comm. 23, 2481 (1993), by reaction of an appropriately substituted phenethanol or corresponding heteroaryl with acetone cyanohydrin and triphenylphosphine in the presence of a suitable azodicarboxylate such as diethyl azodicarboxylate in an 20 appropriate solvent such as diethyl ether or tetrahydro-furan or the like at temperatures ranging from 0OC to room temperature. (Method 54) Alternatively, intermediate amines 2 wherein X equals -(CH(CH 3 ))- 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 25 such as 5N sodium or potassium hydroxide in an 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 30 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.
WO 00/34268 PCT/US99/28838 - 24 Alternatively, amines 2 wherein X equals -(CH(CH 3 ))- can be prepared by reduction of an appropriately substituted O-methyl 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 5 procedure of Itsuno, S., Sakurai, Y., Ito, K. Synthesis 1988, 995. The requisite O methyl oximes can be prepared from the corresponding acetophenone by reaction with methoxylamine hydrochloride and pyridine in a suitable solvent such as ethanol or methanol at temperatures ranging from room temperature to the reflux temperature of the solvent. (Method 47) 10 Amines 2 for which 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 ketones, when not commercially available, can be prepared by reaction of a suitably substituted benzaldehyde with an appropriate organometallic reagent such as phenyllithium, 15 isopropylmagnesium bromide or ethylmagnesium bromide or the like in a suitable solvent such as diethyl ether or tetrahydrofuran at temperatures ranging from -78 oC to 0oC. (Method 57) The resulting alcohols can be oxidized to the corresponding ketone with an appropriate oxidizing agent such as chromium trioxide in aqueous sulfuric acid and acetone or pyridinium chlorochromate or pyridium dichromate in an 20 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, wherein G is described as above, with neat trifluoroacetic acid at room temperature followed by neutralization 25 with aqueous sodium hydroxide affords the desired anilines 5. The requisite carbamic acid esters 6, wherein R 9
-R
1 2 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-aminophenylcarbamic acid tert-butyl esters 7, wherein R 9
-R
1 2 are described above, in the presence of triethylamine in an appropriate solvent such as 30 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.
WO 00/34268 PCT/US99/28838 - 25 Method 2C, 3A + HN-- NH2-k HN "C-G
H
2 N G-COOH O N H N-QN -. G i. CF3CO2HH2
N-
H ii. NaOH H 8 7 6 5 Alternatively, carbamic acid esters 6, wherein R,-R 1 2 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 in the presence of a suitable coupling agent such as benzotriazole-1-yloxy-tris-(dimethylamino)phosphonium hexafluoro phosphate, 2-(1H-benzotriazole-1-yloxy)-1,1,3,3-tetramethyluronium hexafluoro 10 phosphage, dicyclo-hexyl 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 arylaminoamide. Carboxylic acids 8a are either commercially available or are prepared 15 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 such as methanol or ethanol and water at room temperature. Similarly, when G is either substituted or unsubstituted thiazole, substituted or 20 unsubstituted oxazole, substituted or unsubstituted isothiazole or substituted or unsubstituted isoxazole, when not commercially available, the corresponding carboxylic acid 8a is available from the corresponding ethyl or methyl ester by reaction with an appropriate base such as sodium or potassium hydroxide in a suitable solvent mixture such as methanol or ethanol and water at room temperature. Tbese 25 esters are either commercially available or can be prepared according to literature methods.
WO 00/34268 PCT/US99/28838 - 26 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 carboxylic acid ester in a suitable alcoholic solvent such as methanol or ethanol with 20 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 0OC followed by treatment with an excess aqueous solution of sodium bicarbonate affords the corresponding 4-substituted 25 1,2,3-thiadiazole -5-carboxylic acid esters. 4-carboalkoxythiazoles are prepared essentially according to the procedure of Sch~llkopf, U., Porsch, P., Lau, H. Liebigs Ann. Chem. 1444 (1979). Thus, 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 30 room temperature gives the corresponding 3-dimethylamino-2-isocyano-acrylic acid ethyl ester. A solution of this compound in a suitable solvent such as tetrahydrofuran is treated with gaseous hydrogen sulfide in the presence of a suitable tertiary amine WO 00/34268 PCT/US99/28838 - 27 base such as triethylamine or diiso-propylethylamine or the like at room temperature to give the corresponding 4-carboethoxy-thiazole. Additional appropriately substituted thiazoles may be prepared essentially according to the procedure of Bredenkamp, M. W., Holzafel, C. W., van Zyl, W. J. 5 Synthetic Comm. 20, 2235 (1990). Appropriate unsaturated oxazoles are prepared essentially according to the procedure of Henneke, K. H., Schillkopf, U., Neudecker, T. Liebigs Ann. Chem. 1979 (1979). Substituted oxazoles may be prepared essentially according to the procedures of Galeotti, N., Montagne, C., Poncet, J., Jouin, P. Tetrahedron Lett. 33, 2807, (1992) and Shin, C., Okumura, K., Ito, A., 10 Nakamura, Y. Chemistry Lett. 1305, (1994). The following specific examples are illustrative, but are not meant to be limiting of the present invention. 15 EXAMPLE 1 (METHOD 1A) 4 -Methoxy-3-trifluoromethyl-phenylamine A suspension of 4-methoxy-3-trifluoromethyl-nitrobenzene (2.2 g) and iron powder (1.68 g) in ethanol (35 mL) and water (15 mL) is treated with a solution of 20 concentrated hydrochloric acid (0.42 mL) in ethanol (6 mL) and water (3 mL) and the mixture is heated to reflux for approximately 1 hour. The mixture is then cooled, filtered, and concentrated under reduced pressure. The resulting oil is dissolved in ethyl acetate and extracted three times with 5% aqueous hydrochloric acid. The pooled acidic extracts are then cooled in an ice bath and basified with solid potassium 25 carbonate, then extracted with ethyl acetate. These organic extracts are washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, then passed through a short column of silica gel (ethyl acetate is used as the eluant) to provide the desired compound as an amber oil. 30 Using the above procedure and appropriate starting materials the following compounds were prepared: WO 00/34268 PCT/US99/28838 - 28 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 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 WO 00/34268 PCT/US99/28838 - 29 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 oC for approximately 5 hours. The mixture is then cooled, filtered, and concentrated under reduced pressure. Water is added and the mixture is cooled in an ice bath and neutralized with solid potassium carbonate and then extracted with dichloromethane. 10 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 ethanol (17 mL) and water (8.6 mL) is treated with iron powder (0.861 g) and 20 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 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 25 a pale yellow solid.
WO 00/34268 PCT/US99/28838 - 30 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 N-(4-Amino-2-chloro-phenyl)-2-diethylamino-acetamide N-(4-Amino-2-chloro-phenyl)-2-pyrrolidin- 1 -yl-acetamide N-(4-Amino-2-chloro-phenyl)-2-azepan- 1 -yl-acetamide N-(4-Amino-2-chloro-phenyl)-2-(2-methyl-piperidin- 1 -yl)-acetamide WO 00/34268 PCT/US99/28838 -31 N-(4-Amino-2-chloro-phenyl)-2-(3-methyl-piperidin- 1 -yl)-acetamide 3-Chloro-benzene- 1,2-diamine 4-Chloro-N,N-dimethyl-benzene- 1,2-diamine EXAMPLE 4 (METHOD 1D) 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 resulting suspension is filtered through a pad of diatomaceous earth and extracted 10 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 solid. 15 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 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 WO 00/34268 PCT/US99/28838 - 32 2- (2-Amino-4-chloro-5 -methoxy-phenoxy) -ethanol 2-(4-Amino-2-chloro-5-methoxy-phenoxy)-ethanoI 4- ( 4 -Amino-2-chloro-5-methoxy-phenoxy)-butyronitrile 4-Amino-2-chloro-5-methoxy-phenoI 2-Amino-4-chloro-5-methoxy-phenoI 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( 1)-cyclohexyl-N( 1)-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(1) ,N(l1)-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-phenylamine 3-Chloro-2,4-dimethoxy- aniline 3-Bromo-4-methoxy-phenylamine 3-Chloro-4-ethoxy-phenylamine WO 00/34268 PCT/US99/28838 - 33 EXAMPLE 5 (Method 1E) (4-Amino-phenyl)-carbamic acid isobutyl ester To a solution of N-(4-Nitro-phenyl)-isobutyrlamide (2.0 g) in 100 mL ethylene 5 glycol monomethyl ether (100 mL) is added 10% palladium on carbon (275 mg). The mixture is hydrogenated for 2 hours at room temperature under 30 psi of hydrogen on a Parr hydrogenation apparatus. The catalyst is then removed by filtration through diatomaceous earth and the filtrate is evaporated to dryness under reduced pressure by azeotroping three times with heptane. Trituration of the residue 10 with heptane provides the desired product as a white solid. Using the above procedure and appropriate starting materials the following 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 15 WO 00/34268 PCT/US99/28838 - 34 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 4o 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 N-(4-Amino-3-methyl-phenyl)-2-fluoro-benzamide WO 00/34268 PCT/US99/28838 - 35 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 1G)
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 twice with saturated aqueous sodium chloride, dried over anhydrous potassium 10 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.
WO 00/34268 PCT/US99/28838 - 36 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 5 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 diiso-propylethylamine (6.9 mL) is added di-tert-butyl-dicarbonate (8.6 g) and the 10 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 successively three times with 5% aqueous hydrochloric acid then once with saturated 15 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. 20 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 (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 WO 00/34268 PCT/US99/28838 - 37 (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 diluted with water and extracted three times with diethyl ether. The combined 10 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 triethylamine (1.50 mL) in 25 mL of dichloromethane is added o-fluorobenzoyl 20 chloride (1.20 g). A solid formed immediately forms and is filtered and washed with fresh solvent to yield a white solid, 1.90 g. Using the above procedure and appropriate starting materials the following compounds were prepared: 25 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 WO 00/34268 PCT/US99/28838 -38 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 {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 WO 00/34268 PCT/US99/28838 - 39 [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 [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 WO 00/34268 PCT/US99/28838 - 40 {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 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 WO 00/34268 PCT/US99/28838 - 41 [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 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 WO 00/34268 PCT/US99/28838 - 42 1 4 -)acryloylamino)-phenyllcarbamic acid tert-butyl ester (4-Nitro-phenyl)-carbamic acid isobutyl ester [1 ,2,3]Thiadiazole-4-carboxylic acid ( 5 -nitro-pyridin-2-yl)-amide Furan-2-carboxylic acid ( 5 -nitro-pyridin-2-yl)-amide 2-Fluoro-N- ( 5 -nitro-pyridin-2-yl)-benzamide N- ( 2 -Chloro- 4 -nitro-phenyl)-24tluoro-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)yamide 2 -Fluoro-N-(4-futro-naphthalen-1 -yl)-benzamide Furan-2-carboxylic acid (4-nitro-naplithalen- 1-yl)-amide
N-(
5 -Chloro-2-hydroxy-4-nitro-phenyl)yacetamide N- ( 5 -Chloro- 2 -hydroxy-4-nitrophenyl>2-fluoro-benzamide Furan-2-carboxylic acid ( 2 -chloro-4-nitro-phenyl)-amide N- ( 4 -Nitro-2-trifluoromethyl-phenyl)-acetamide Furan-2-carboxylic acid ( 2 -cyano-4-nitro-phenyl)-amide 2-Fluoro-N- ( 4 -nitro- 2 -trifluoromethyl-phenyl)-benzaniide Furan-2-carboxylic acid ( 4 -nitro-2-trifluoromethyl..phenyl)yamide 2 -Fluoro-N-(2-methy1-4-nitro-phenyl)>benzamide N-5Clr--ehl4ntopey)2fur-ezmd WO 00/34268 PCT/US99/28838 - 43 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 dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the desired product. 15 Using the above procedure and appropriate starting materials the following compounds were prepared: { 4-[(1H-Pyrrole-2-carbonyl)-amino]-phenyl }-carbamic acid tert-butyl ester {4-[(Pyrazine-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester { 4- [(5-Methyl-thiophene-2-carbonyl)-amino]-phenyl I -carbamic acid tert-butyl ester WO 00/34268 PCT/US99/28838 - 44 {4-[(1-Methyl- 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-l1-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-[(1H-[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-[(1H-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 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 10 washed twice with 5% aqueous hydrochloric acid, once with saturated aqueous sodium bicarbonate, and then with saturated aqueous sodium chloride. The solution WO 00/34268 PCT/US99/28838 - 45 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 5 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 10 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% 15 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. 20 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) 25 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 WO 00/34268 PCT/US99/28838 - 46 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 5 product as a pale yellow crystalline solid. 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 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 WO 00/34268 PCT/US99/28838 - 47 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 1H-[1,2,3]Triazole-4-carboxylic acid (4-amino-phenyl)-amide 3-Bromo-thiophene-2-carboxylic acid (4-amino-phenyl)-amide 4-Benzyloxy-3,5-dichloro-phenylamine 2-(4-Amino-2,6-dichloro-phenoxy)-acetamide (4-Amino-2,6-dichloro-phenoxy)-acetic acid methyl ester [3-(4-Amino-phenylcarbamoyl)-phenyl]-carbamic acid ethyl ester 2-Amino-N-(4-amino-phenyl)-benzamide 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 WO 00/34268 PCT/US99/28838 - 48 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 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 WO 00/34268 PCT/US99/28838 - 49 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 EXAMPLE 16 (METHOD 3B) 1-(4-Amino-2-chloro-phenyl)-ethanol 5 A IM solution of tetrabutylammonium fluoride in tetrahydrofuran (5.7 mL) is added 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 10 sodium chloride, and dried over anhydrous magnesium sulfate. Removal of the 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.
WO 00/34268 PCT/US99/28838 - 50 EXAMPLE 17 (METHOD 3C)
N-(
4 -Amino-3-cyanophenyl)-2-fluoro-benzamide 5 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 dichloromethane. The organic extracts are pooled, washed with water and then 10 saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to provide the desired compound as a white solid. Using the above procedure and appropriate starting materials the following 15 compounds were prepared:
N-(
4 -Amino-phenyl)-2-methanesulfinyl-benzamide
N-(
4 -Amino-3-cyano-phenyl)-2-fluoro-benzamide Furan-2-carboxylic acid ( 4 -amino-3-cyano-phenyl)-amide
N-(
4 -Amino-3-cyano-phenyl)-acetamide Furan-2-carboxylic acid ( 4 -amino-3-trifluoromethyl-phenyl)-amide
N-(
4 -Amino-3-methoxy-phenyl)-acetamide
N-(
4 -Amino-3-methoxy-phenyl)-2-fluoro-benzamide Furan-2-carboxylic acid ( 4 -amino-3-methoxy-phenyl)-amide EXAMPLE 17 (METHOD 4A) 2-Chloro- 1-cyclohexyloxy-4-nitro-benzene 20 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 WO 00/34268 PCT/US99/28838 -51 added and the resulting dark red colored solution is then heated for three hours to approximately 100 degrees. The reaction mixture is then cooled, diluted with diethyl ether (300 mL), and washed successively with saturated aqueous ammonium chloride, three times with water, then with saturated aqueous sodium chloride. The 5 organic layer is then dried over anhydrous magnesium sulfate, the solvent is removed under reduced pressure, and the resulting oil is chromatographed over silica gel (5% ethyl acetate in hexanes is used as the eluant) to provide the desired product as an orange solid. 10 EXAMPLE 18 (METHOD 4C) (2-Chloro-4-nitro-phenyl)-methyl-(1-methyl-pyrrolidin-3-yl)-amine 3-Chloro-4-fluoronitrobenzene (1.0 g) and N,N'-dimethyl-3-aminopyrrolidine (1.72 g) are combined and stirred for approximately 24 hours. The mixture is then diluted 15 with ethyl acetate, washed twice with water and once with saturated sodium chloride, and dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure the residue is chromatographed over silica gel (pure ethyl acetate followed by pure methanol is used as the eluants) to provide the desired product as a yellow oil. 20 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 WO 00/34268 PCT/US99/28838 - 52 (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 EXAMPLE 19 (METHOD 4E) Butyl-(2-chloro-4-nitro-phenyl)thioether 5 A solution of 3-chloro-4-fluoro-nitrobenzene (5.0 g) and sodium sulfide (2.5 g) in N,N-dimethylformamide (30 mL) is stirred at room temperature for 1 hour and then treated with 1-iodobutane (12.6 g). The solvent is then removed under reduced pressure and the resulting residue is treated with ethyl acetate and hexanes to precipitate the inorganic salts. The solids are removed by filtration and the filtrate is 10 reduced under reduced pressure. The resulting residue is then passed through 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 15 compounds were prepared: WO 00/34268 PCT/US99/28838 - 53 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 5 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 10 dissolved in ethyl acetate and then washed with water. The aqueous layer is extracted once with ethyl acetate and the combined organic layers are washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent is removed by evaporation under reduced pressure and the residue is triturated with hexanes to provide the desired product as a colorless solid. 15 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 WO 00/34268 PCT/US99/28838 - 54 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 5 solution of N-methyl aniline (3.0 g) in tetrahydrofuran (75 mL) at 0OC. The mixture is allowed to warm slowly to room temperature and is then re-cooled to 0OC and added by cannula to a solution of 3-chloro-4-fluoronitrobenzene (4.9 g) in tetrahydrofuran (35 mL) that is kept at -78 oC. Following the addition, the reaction mixture is permitted to warm to room temperature over the course of 1 hour, and is 10 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 15 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. EXAMPLE 22 (METHOD 4H) 20 2,6-Dichloro-4-nitrophenol 3,4,5-Trichloronitrobenzene (14.86 g) is added to a solution of potassium phenoxide (8.66 g) in diethylene glycol (66 mL) and the mixture is heated to 160oC for approximately 15 hours. The resulting dark brown solution is cooled to room 25 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 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 30 provides the desired product as a pale yellow solid.
WO 00/34268 PCT/US99/28838 - 55 EXAMPLE 23 (METHOD 5A) (3,5-Dichloro-4-ethoxy-phenyl)-carbamic acid tert-butyl ester To a solution of (3,5-dichloro-4-hydroxy-phenyl)-carbamic acid tert-butyl ester (1.0 5 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 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 10% aqueous sodium hydroxide, with water, and then dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure gave the desired product as a tan solid. Using the above procedure and appropriate starting materials the following 15 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 (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 WO 00/34268 PCT/US99/28838 - 56 EXAMPLE 24 (METHOD 5C) (2,6-Dichloro-4-nitro-phenoxy)-acetic acid tert-butyl ester To a solution of 2,6-dichloro-4-nitrophenol (2.5 g) and potassium carbonate (3.3 g) in 5 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 anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure 10 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 prepared: 15 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 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 WO 00/34268 PCT/US99/28838 - 57 (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 SE) [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 mixture is added 2.5 M aqueous sodium hydroxide (50 mL), and the separated 10 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 over silica gel (30% ethyl acetate in hexanes is used as the eluant) to provide the desired product as a white foam. 15 EXAMPLE 26 (METHOD 6) 3-(2-Chloro-4-nitro-phenoxy)- 1-methyl-pyrrolidine To a solution of 2-chloro-4-nitrophenol (2.0 g) in tetrahydrofuran (60 mL) is added 20 1-methyl-3-pyrrolidinol (2.3 g), triphenyl phosphine (6.0 g), and diethylazo- WO 00/34268 PCT/US99/28838 -58 dicarboxylate (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 reduced pressure, diluted with ethyl acetate, washed successively with 10% aqueous sodium hydroxide, water, saturated aqueous sodium chloride, and dried over anhydrous 5 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 recrystallized from hexanes to provide the desired product as a yellow solid. 10 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 EXAMPLE 27 (METHOD 7A) 15 2 -Chloro-3-methoxy-6-nitro-phenol and 2,4-Dichloro-3-methoxy-6-nitro-phenol To a flask containing 3-methoxy-6-nitro-phenol (0.5 g) is added aqueous sodium 20 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 ethyl acetate. These organic extracts are dried over anhydrous magnesium sulfate, the solvent is removed by evaporation under reduced pressure, and the residue is 25 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.
WO 00/34268 PCT/US99/28838 - 59 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 5 EXAMPLE 28 (METHOD 7B) 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 10 room temperature for approximately 15 hours. Additional aqueous sodium 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, 15 the solvent is removed by evaporation under reduced pressure, and the residue is chromatographed over silca gel (ethyl acetate is used as the eluant) to provide the desired product as a yellow solid. An analytically pure sample is obtained by a single recrystallization from chloroform. 20 EXAMPLE 29 (METHOD 7C) 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 25 allowed to stir at room temperature for approximately 15 hours. Additional bromine (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 30 over anhydrous sodium sulfate. Removal of the solvent under reduced pressure and WO 00/34268 PCT/US99/28838 - 60 recrystallization of the residue from toluene provides the desired product as a yellow solid. EXAMPLE 30 (METHOD 7D) 5 2,4-Dibromo-3-methoxy-6-nitro-phenol To a solution of 5-methoxy-2-nitro-phenol (0.25 g) and silver trifluoroacetate (0.49 g) in glacial acetic acid (3 mL) is added dropwise a solution of bromine (1.42 g) in glacial acetic acid (3 mL) and the mixture is stirred at room temperature for 10 approximately 24 hours. The solution is then partitioned between ethyl acetate and water, and the organic layer is washed successively three times with 5% aqueous sodium bisulfite, three times with saturated aqueous sodium bicarbonate, and once with saturated aqueous sodium chloride. The organic layer is then dried over anhydrous magnesium sulfate and the solvent is removed under reduced pressure. 15 The residue is chromatographed over silica gel (20% ethyl acetate in hexanes is used as the eluant) then recrystallized from chloroform to provide the desired dibrominated product as an orange solid. EXAMPLE 31 (METHOD 7E) 20 1-Iodo-2,4-dimethoxy-5-nitro-benzene To a solution of 2,4-dimethoxy-nitrobenzene (1.0 g) in glacial acetic acid (30 mL) is added benzyltrimethylammonium dichloroiodate (1.90 g) and anhydrous zinc chloride (1.0 g) and the mixture is stirred at room temperature under an atmosphere 25 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 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 30 washed successively with 5% aqueous sodium bisulfite, saturated aqueous sodium chloride, then dried over anhydrous magnesium sulfate. After removal of the solvent WO 00/34268 PCT/US99/28838 -61 under reduced pressure the residue is triturated with hexanes to provide the desired product as a pale yellow solid. EXAMPLE 32 (METHOD 7F) 5 2
,
4 -Diiodo-3-methoxy-6-nitro-phenol 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 10 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 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 15 toluene to provide the desired product as yellow needles. EXAMPLE 33 (METHOD 7G) 1-Fluoro-2,4-dimethoxy-5-nitro-benzene 20 To a solution of 2
,
4 -dimethoxy-nitrobenzene (1.0 g) in tetrachloroethane (10 mL) is added 3,5-dichloro-l-fluoro-pyridinium triflate (85%, 5.07 g) and the mixture is heated to 120 oC 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 25 by 30% ethyl acetate in hexanes is used as the eluant). Product containing fractions are combined, evaporated under reduced pressure, and the residue is crystallized from hexanes to provide the desired product as a tan solid.
WO 00/34268 PCT/US99/28838 - 62 EXAMPLE 34 (METHOD 8) 3 -Chloro-4-trifluoromethyl-nitrobenzene A solution of 3-chloro-4-iodo-nitrobenzene (2.26 g), trimethyl(trifluoromethyl)silane 5 (5.68 g), copper(I) iodide (2.28 g), and potassium fluoride (0.56 g) in N,N dimethylformamide (8 mL) is heated in a sealed tube to 80 oC for 40 hours. The solution is then cooled, diluted with diethyl ether, filtered through diatomaceous earth, and the filtrate is washed successively with water, saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate. The solvent is removed 10 under reduced pressure and the residue is chromatographed over silica gel (1% diethyl ether in hexanes followed by 10% ethyl acetate in hexanes is used as the eluant) to provided the desired product as a colorless oil. 15 EXAMPLE 35 (METHOD 9)
(
3 -Chloro-4-methanesulfinyl-phenyl)-carbamic acid tert-butyl ester To a solution of ( 3 -chloro-4-thiomethyl-phenyl)-carbamic acid tert-butyl ester (0.89 g) in dichloromethane (15 mL) at 0 oC is added a solution of dimethyldioxirane 20 (-0.11 M in acetone, 34 mL) and the mixture is stirred at 0 oC for 1 hour. The solvent is removed under reduced pressure and the residue is dissolved in dichloromethane, washed with saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure gave the desired product as an orange foam. 25 EXAMPLE 36 (METHOD 9B)
[
4
-(
2 -Methylsulfinyl-benzoylamino)-phenyl]-carbamic acid tert-butyl ester 30 To a solution of 2-methylsulfanyl-N-[4-( 2
,
2 ,2-trifluoro-acetylamino)-phenyl] benzamide (234 mg) is added a saturated solution of sodium periodate (5 mL) and the mixture is stirred for 12 hours. The purple mixture is poured into water, extracted WO 00/34268 PCT/US99/28838 - 63 with ethyl acetate, dried over anhydrous potassium carbonate and evaporated to yield a red solid, 101 mg. Using the above procedure and appropriate starting materials the following 5 compounds were prepared: [4-( 2 -Methanesulfinyl-benzoylamino)-phenyl]-carbamic acid tert-butyl ester 2-Methanesulfinyl-N-[4-( 2
,
2
,
2 -trifluoro-acetylamino)-phenyl]-benzamide EXAMPLE 37 (METHOD 10)
(
3 -Chloro-4-methanesulfonyl-phenyl)-carbamic acid tert-butyl ester 10 To a solution of ( 3 -chloro- 4 -thiomethyl-phenyl)-carbamic acid tert-butyl ester (0.90 g) in dichloromethane (30 mL) at 0 oC is added a solution of dimethyldioxirane (-0.11 M in acetone, 80 mL) and the mixture is stirred at 0 oC for 1 hour. The solvent is removed under reduced pressure and the residue is dissolved in 15 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. EXAMPLE 38 (METHOD 11) 20 3 -Chloro-4-vinyl-phenylamine To a deoxygenated solution of 3-chloro-4-iodo-aniline (6.95 g), triphenyl arsine (0.67 g), and tris(dibenzylideneacetone)palladium(0) (0.50 g) in tetrahydrofuran (120 mL) at 50 oC is added tributylvinyltin (10 g) and the mixture is stirred for approximately 25 15 hours at 50 oC 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% aqueous hydrochloric acid. These aqueous acidic extracts are then basified with solid potassium carbonate and extracted three times with ethyl acetate. These pooled 30 organic extracts are then washed with saturated aqueous sodium chloride, dried over WO 00/34268 PCT/US99/28838 - 64 anhydrous magnesium sulfate, and the solvent is removed under reduced pressure. The resulting residue is chromatographed over silica gel (hexanes and then 10% ethyl acetate in hexanes is used as the eluant) to provide the desired product as an amber oil. 5 EXAMPLE 39 (METHOD 12) [3-Chloro-4-(1-hydroxy-ethyl)-phenyl]-carbamic acid 2-trimethylsilanyl-ethyl ester 10 (3-Chloro-4-vinyl-phenyl)-carbamic acid 2-trimethylsilanyl-ethyl ester (2.6 g) is added to a solution of mercuric acetate (3.48 g) in water (7 mL) and tetrahydrofuran (5.25 mL) and the mixture is stirred for approximately 15 hours. 3N Aqueous sodium hydroxide (8.7 mL) and a 0.5 M solution of sodium borohydride in 3N aqueous sodium hydroxide (8.7 mL) are then added and stirring is continued for 6 15 hours. The solution is then saturated with sodium chloride and extracted with ethyl acetate. These organic extracts are then washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. Following removal of the solvent under reduced pressure the residue is chromatographed over silica gel (20% ethyl acetate in hexanes is used as the eluant) to provide the desired product as a white 20 solid. EXAMPLE 40 (METHOD 13) [3-Chloro-4-(2-hydroxy-ethyl)-phenyl]-carbamic acid tert-butyl ester 25 To a stirring suspension of sodium borohydride (0.45 g) in tetrahydrofuran (13 mL) at 0 oC is added glacial acetic acid (0.75 mL) and the mixture is stirred at 0OC for 1 hour. The solution is then warmed to room temperature and (3-chloro-4-vinyl phenyl)-carbamic acid 2-trimethylsilanyl-ethyl ester (1.0 g) is added. The reaction is stirred at room temperature for approximately 15 hours and then heated to reflux for 30 approximately 20 hours. The mixture is then cooled and solutions of 5 N aqueous sodium hydroxide (0.80 mL) and 30% aqueous hydrogen peroxide (0.56 mL) are added. After stirring for an additional 15 hours the layers are separated, the aqueous WO 00/34268 PCT/US99/28838 - 65 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 is used as the eluant) to provide the desired product as an amber oil. 5 EXAMPLE 41 (METHOD 14) [4-(1-Azido-ethyl)-3-chloro-phenyl]-carbamic acid 2-trimethylsilanyl-ethyl ester To a solution of [3-chloro-4-(1-hydroxy-ethyl)-phenyl]-carbamic acid 2-trimethyl 10 silanyl-ethyl ester (1.25 g) in tetrahydrofuran (20 mL) at 0 oC 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 York) and diethyl azodicarboxylate (1.72 g). After approximately 10 minutes the solvent is removed 15 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. EXAMPLE 42 (METHOD 15) 20 [3-Chloro-4-(3-dimethylamino-prop-1-ynyl)-phenyl]-carbamic acid tert-butyl ester To a deoxygenated solution of (3-chloro-4-iodo-phenyl)-carbamic acid tert-butyl ester (10.0 g) in triethylamine (120 ml) is added 1-dimethylamino-2-propyne (2.82 25 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 0 C. The 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 30 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% WO 00/34268 PCT/US99/28838 - 66 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 5 compounds were prepared:
[
3 -Chloro-4-(3-dimethylamino-prop-1-ynyl)-phenyl]-carbamic acid tert-butyl ester [3-(4-Methoxy-phenyl)-prop-2-ynyl]-dimethyl-amine 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 10 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 0OC for 20 minutes, the mixture is passed over twenty weight equivalents of basic alumina 15 (Brockmann Grade I, 150 mesh) and the N-oxide is eluted using a solution of 5% methanol in dichloromethane. All fractions containing the desired amine N-oxide were combined and evaporated to near dryness under reduced pressure. The residue is treated successively three times with small portions of methanol (ca. 50 ml) followed by evaporation to near dryness under reduced pressure, and the volume of 20 the solution is adjusted to 250 mL by addition of methanol. The methanolic solution of the N-oxide is then heated to reflux for approximately 15 hours, then cooled, and the solvent is evaporated to dryness under reduced pressure. The residue is purified by chromatography over silica gel (80% ethyl acetate in hexanes is used as the eluant) to give the desired product as a pale yellow solid. 25 WO 00/34268 PCT/US99/28838 - 67 EXAMPLE 44 (METHOD 17) (3-Chloro-4-isoxazol-5-yl-phenyl)-carbamic acid tert-butyl ester A solution of [3-chloro-4-(3-dimethylamino-acryloyl)-phenyl]-carbamic acid tert 5 butyl ester (270 mg) in dioxane (3 ml) is treated with hydroxylamine hydrochloride (122 mg) and the mixture is stirred at room temperature for 10 days. The mixture is diluted with ethyl acetate, washed successively with water, 5% aqueous sodium bicarbonate, saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent is removed by evaporation under reduced pressure 10 and the resulting residue is chromatographed over silica gel (33% ethyl acetate in hexanes is used as the eluant) to provide the desired product as a colorless solid. EXAMPLE 45 (METHOD 18) [3-Chloro-4-(1H-pyrazol-3-yl)-phenyl]-carbamic acid tert-butyl ester 15 A solution of [3-chloro-4-(3-dimethylamino-acryloyl)-phenyl]-carbamic acid tert butyl ester (250 mg) in ethanol (1.25 ml) is treated with hydrazine hydrate (0.25 ml) and the mixture is stirred at room temperature for 3 hours. The mixture is then diluted with 30 mL of diethyl ether, washed three times with water, once with 20 saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. 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. 25 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. 30 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.
WO 00/34268 PCT/US99/28838 - 68 Using the above procedure and appropriate starting materials the following compounds were prepared: (4- { 2-[Bis-(2-hydroxy-ethyl)-amino]-acetylamino }-phenyl)-carbamic acid tert-butyl 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- 1 -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- I -yl)-acetamide N-(2-Chloro-4-nitro-phenyl)-2-(4-methyl-piperidin- 1-yl)-acetamide 5 EXAMPLE 47 (METHOD 19B)
N-(
2 -Chloro- 4 -nitrophenyl)-2-(2-dimethylaminoethylsulfanyl)acetamide To a solution of N-(chloroacetyl)-2-chloro-4-nitroaniline (3.01 g) in N,N dimethylformamide (100 mL) is added powdered sodium carbonate (6.0 g) and 2 10 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 yellow crystalline solid. 15 WO 00/34268 PCT/US99/28838 - 69 EXAMPLE 48 (METHOD 20)
(
4 -tert-butoxycarbonylamino-2-chloro-phenyl)-carbamic acid 2 piperidin-1-yl-ethyl ester 5 To a suspension of 1,1-carbonyl-di-(1,2,4)-triazole (4.0 g) in dichloromethane (40 mL) is added a solution of (4-amino-3-chloro-phenyl) carbamic acid tert-butyl ester (5.0 g) in dichloromethane (45 mL) dropwise over 20 minutes. The reaction is stirred at room temperature for 30 minutes at which point a precipitate forms. To this mixture is added piperidineethanol (6.6 mL) and tetra-hydrofuran (20 mL) is 10 added to maintain homogeneity. After heating at reflux overnight the reaction is cooled and then poured into water, the organic layer separated and then washed with saturated aqueous sodium chloride. The solution is dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to a crude oil that is purified by chromatography over silica gel (5% methanol in dichloromethane is used as the 15 eluant) to give the desired product as a white foam. EXAMPLE 49 5-Phenyl-[1, 2 ,3]thiadiazole-4-carboxylic acid methyl ester 20 A solution of ethyl benzoylacetate (1.1 g) in acetonitrile (10 mL) is treated with 4 methylbenzenesulfonyl azide (1.3 g) and triethylamine (1.6 g). After stirring overnight at room temperature, the reaction is concentrated under reduced pressure and the resulting crude product is dissolved in ethyl acetate and washed with IN sodium hydroxide. The organic layer is then dried over anhydrous magnesium 25 sulfate, filtered and concentrated under reduced pressure to yield a yellow oil. This oil is taken into dichloromethane and filtered through a pad of hydrous magnesium silicate, eluting with dichloromethane to give the partially purified diazoketone as a colorless oil. A sample of the diazoketone from above (1.2 g) is dissolved in toluene (25 mL) and treated with 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 30 2,4-disulfide (2.8 g) and the reaction is heated to reflux. After 3 hours, the reaction is cooled to room temperature, loaded onto a pad of silica gel and eluted with dichloromethane. After removing the solvent under reduced pressure, the resulting WO 00/34268 PCT/US99/28838 - 70 oil is purified by chromatography over silica gel (30% diethyl ether in petroleum ether is used as the eluant) and then recrystallized from hexanes to give the desired product as pale yellow needles. 5 Using the above procedure and appropriate starting materials the following compound was prepared: 5-Phenyl-[1,2,3]thiadiazole-4-carboxylic acid ethyl ester 5-Methyl-[1,2,3]thiadiazole-4-carboxylic acid methyl ester EXAMPLE 50 10 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 added pyridine (4.1 g) and after heating to reflux for 5 minutes, the reaction mixture 15 is cooled to -20 oC overnight. The resulting solid semicarbazone is collected by filtration, washed with water and then diethyl ether to give the desired product as white crystals. Using the above procedure and appropriate starting materials the following 20 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 WO 00/34268 PCT/US99/28838 -71 EXAMPLE 51 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 5 mL) is stirred at 0 oC for 1 hour. Dichloromethane is then added (25 mL), the excess thionyl chloride is destroyed slowly with saturated aqueous sodium bicarbonate. The precipitate which forms on quenching is removed by filtration and the filtrate is extracted with dichloromethane. Pooled organic extracts are dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. 10 Chromatography over silica gel (50% hexanes in dichloromethane is used as the eluant) affords the desired product as a colorless oil. Using the above procedure and appropriate starting materials the following compounds were prepared: 15 4-Methyl-[1, 2 ,3]thiadiazole-5-carboxylic acid methyl ester 4-Phenyl-[1, 2 ,3]thiadiazole-5-carboxylic acid ethyl ester 4-Furan-3-yl-[1, 2 ,3]thiadiazole-5-carboxylic acid ethyl ester EXAMPLE 52 4-Methyl-[1, 2
,
3 ]thiadiazole-5-carboxylic acid 20 4 -Methyl-[1,2,3]thiadiazole-5-carboxylic acid methyl ester (1.7 g) is dissolved in methanol (15 mL) and treated with lN sodium hydroxide (16 mL). After stirring at 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 25 anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the desired compound as a white powder. Using the above procedure and appropriate starting materials the following compounds were prepared: WO 00/34268 PCT/US99/28838 - 72 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 EXAMPLE 53 (METHOD 25) Trifluoro-methanesulfonic acid 4 -chloro-5-methoxy-2-nitro-phenyl ester 5 To a solution of 4 -chloro-5-methoxy-2-nitro-phenol (6.5 g) in dichloromethane (150 mL) at 0 oC under an atmosphere of argon is added triethylamine (10 g) and then a solution of trifluoro-methanesulfonic anhydride (13.5 g) in dichloromethane (30 mL). The solution is stirred at 0 oC for 10 minutes, and is then diluted with 10 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 dissolved in a solution of 20% dichloromethane in hexanes and passed through a short column of hydrous magnesium silicate (20% dichloromethane in hexanes is 15 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. Using the above procedure and appropriate starting materials the following compounds were prepared: 20 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 WO 00/34268 PCT/US99/28838 - 73 EXAMPLE 54 (METHOD 26)
[
4
-(
3 -Dimethylamino-benzoylamino)-phenyl]-carbamic acid t-butyl ester A solution of [ 4
-(
3 -amino-benzoylamino)-phenyl]-carbamic acid t-butyl ester (505 5 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 carbonate and concentrated under reduced pressure to give a solid which is 10 recrystallized from acetonitrile to provide a pale pink crystalline solid. Using the above procedure and appropriate starting materials the following compounds were prepared:
[
4
-(
3 -Dimethylamino-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
(
3 -Bromo-5-trifluoromethyl-phenyl)-dimethyl-amine
N-(
3 -Chloro-5-dimethylamino-phenyl)-acetamide 15 EXAMPLE 55 (METHOD 27)
N-(
4 -Aminophenyl)-2-hydroxybenzamide To a solution of 2
-(
4 -aminophenylcarbamoyl) phenyl acetate (580 mg) in methanol 20 (10 mL) is added saturated sodium bicarbonate (2 mL) and water (3 mL). The mixture is heated at 80o 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 which is then triturated with diethyl ether to provide the desired product as a white 25 solid.
WO 00/34268 PCT/US99/28838 - 74 EXAMPLE 56 (METHOD 28) [4-(3-(Hydroxybenzoylamino)phenyl}carbamic acid t-butyl ester To a solution of of 3
-(
4 -aminophenylcarbamoyl) phenyl acetate (4.34 g) in methanol 5 (75 mL) is added 0.1 N aqueous sodium hydroxide (25 mL) and tetrahydrofuran (25 mL). This solution is heated at 40o 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 white solid, which is further purified by trituration with diethyl ether. 10 EXAMPLE 57 (METHOD 29)
N-(
4 -Aminophenyl)-2-hydroxymethylbenzamide To a solution of N-(4-aminophenyl)phthalimide (332 mg) in tetrahydrofuran (4 mL) 15 is added lithium borohydride (1.0 g) and the mixture is stirred for 1 hour at 250 C. The mixture is poured into water and extracted into ethyl acetate. The ethyl acetate solution is dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a white foam, which when triturated with diethyl ether provides the desired product as a white powder. 20 EXAMPLE 58 (METHOD 30)
(
3 -Chloro-5-dimethylamino-phenyl)-carbamic acid tert-butyl ester To a solution of ( 3 -amino-5-chloro-phenyl)-carbamic acid tert-butyl ester (0.32 g) in 25 toluene (10 mL) is added aqueous formaldehyde (37%, 1.5 mL) then 10% palladium on carbon (0.50 g) and the mixture is stirred under an atmosphere of hydrogen for approximately 15 hours. The solution is then filtered through diatomaceous earth and the filtrate is concentrated under reduced pressure. The residue is chromatographed over silica gel (50% dichloromethane in hexanes is used as the eluant) to provide the 30 desired product as a white solid.
WO 00/34268 PCT/US99/28838 - 75 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 IN 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 {4-[ 3
-(
4 -Acetylamino-phenyl)-thioureido]- 2 -chloro-5-methoxy-phenoxy} -acetic acid WO 00/34268 PCT/US99/28838 - 76 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 oC for 1.5 hours. The mixture is then diluted with ethyl acetate, washed successively two times with 2% aqueous hydrochloric acid, once with saturated aqueous sodium chloride, 10 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 acetone-hexanes to provide the desired product as a white powder. 15 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 oC for 45 minutes. The reaction mixture is then diluted with ethyl acetate, washed successively twice with 2% aqueous hydrochloric acid, once with saturated aqueous 25 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 00/34268 PCT/US99/28838 - 77 EXAMPLE 63 (METHOD 39)
N-(
4
-{
3
-[
3 ,5-Dichloro-4-(2-dimethylamino-ethoxy)-phenyl]-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 00/34268 PCT/US99/28838 - 78 evaporation under reduced pressure the residue is chromatographed over silica gel (8% methanol in dichloro-methane 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 (lM, 10.4 mL). The reaction mixture is heated in a sealed vessel to 100oC for approximately 2.5 hours to complete WO 00/34268 PCT/US99/28838 - 79 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[3.3.1]nonane in tetrahydrofuran (0.5 M, 11 mL) is added, the vessel is sealed with a teflon cap, slowly warmed to room temperature and kept at room temperature for approximately 2.5 hours. The mixture 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 00/34268 PCT/US99/28838 - 80 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 65oC 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 10M 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 1.0g 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 00/34268 PCT/US99/28838 - 81 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 190oC for 3 hours. The mixture is cooled, poured into water and extracted with ether. The ether extract is dried with anhydrous potassium carbonate, filtered and concentrated to give a yellow oil, which is crystallized from toluene-hexanes to give a white solid, 1.97 g. 10 Using the above procedure and appropriate starting materials the following compounds were prepared: N-[1-( 4 -Fluoro-phenyl)-2-methyl-propyl]-formamide N-(1-Naphthalen-2-yl-ethyl)-formamide WO 00/34268 PCT/US99/28838 - 82 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 00/34268 PCT/US99/28838 - 83 3,5-Bis-trifluoromethyl-benzaldehyde oxime 1-(4-Fluoro-phenyl)-propan- 1-one O-methyl-oxime 1-(2-Chloro-phenyl)-ethanone O-methyl-oxime 1-(3-Bromo-phenyl)-ethanone O-methyl-oxime 1-(3-Chloro-phenyl)-ethanone O-methyl-oxime 1-p-Tolyl-ethanone O-methyl-oxime 1-(4-Fluoro-phenyl)-pentan- 1-one O-methyl-oxime 1-( 4 -Fluoro-phenyl)-2-phenyl-ethanone O-methyl-oxime 1-o-Tolyl-ethanone O-methyl-oxime 1-m-Tolyl-ethanone O-methyl-oxime 1-(2-Fluoro-phenyl)-ethanone O-methyl-oxime 3-(1-Methoxyimino-ethyl)-benzonitrile 4-(1-Methoxyimino-ethyl)-benzonitrile 1-(4-Methoxy-phenyl)-ethanone O-methyl-oxime 1-(2-Methoxy-phenyl)-ethanone O-methyl-oxime 1-( 4 -Dimethylamino-phenyl)-ethanone O-methyl-oxime 1-( 2 -Trifluoromethyl-phenyl)-ethanone O-methyl-oxime 1-(3-Methoxy-phenyl)-ethanone O-methyl-oxime 1-(3-Trifluoromethyl-phenyl)-ethanone O-methyl-oxime 1-(4-Trifluoromethyl-phenyl)-ethanone O-methyl-oxime 1-Furan-2-yl-ethanone O-methyl-oxime 1-Pyridin-4-yl-ethanone O-methyl-oxime 1-(1-Methyl-i1H-pyrrol-2-yl)-ethanone O-methyl-oxime 1-Thiophen-3-yl-ethanone O-methyl-oxime
(
4 -Fluoro-phenyl)-phenyl-methanone O-methyl-oxime 1-(4-methoxyphenyl)ethanone O-methyloxime 1-(3-Chloro-4-methoxy-phenyl)-ethanone O-methyl-oxime 4-(1-Methoxyimino-ethyl)-benzenesulfonamide 4-(1-Methoxyimino-ethyl)-N,N-dimethyl-benzenesulfonamide 1-[4-(Piperidine- 1-sulfonyl)-phenyl]-ethanone O-methyl-oxime 4-(1-Methoxyimino-ethyl)-N,N-dipropyl-benzenesulfonamide 2-Fluoro-N-[4-(1-methoxyimino-ethyl)-phenyl]-benzamide WO 00/34268 PCT/US99/28838 - 84 1-( 3 ,5-Bis-trifluoromethyl-phenyl)-ethanone O-methyl-oxime 1-[4-(1H-Imidazol-1-yl)phenyl]-1-ethanone, O-methyloxime 1-[4-(Trifluoromethyl)phenyl]-1-ethanone, O-methyloxime 1- [1,1 '-Biphenyl]-4-yl-1-ethanone, O-methyloxime 1-(4-Methylphenyl)- 1-ethanone, O-methyloxime 1-[ 4 -fluoro-3-(trifluoromethyl)phenyl]ethanone O-methyloxime 1-[3,5-bis(trifluoromethyl)phenyl]ethanone O-benzyloxime 1-[ 4 -chloro-3-(trifluoromethyl)phenyl]ethanone O-methyloxime 1-[3-fluoro-5-(trifluoromethyl)phenyl]ethanone O-methyloxime 1-[2-fluoro-4-(trifluoromethyl)phenyl]ethanone O-methyloxime 1-[2-fluoro-5-(trifluoromethyl)phenyl]ethanone O-methyloxime 1-(2,4-dichlorophenyl)ethanone O-methyloxime 1-(2,4-dimethylphenyl)ethanone O-methyloxime 1-[2,4-bis(trifluoromethyl)phenyl]ethanone O-methyloxime 1-(3-bromophenyl)ethanone O-methyloxime 1-(3-methylphenyl)ethanone O-methyloxime 1-[ 4
-(
4 -morpholinyl)phenyl]ethanone O-methyloxime 1-(2-chloro-4-fluorophenyl)ethanone O-methyloxime 1-(4-bromo-2-fluorophenyl)ethanone O-methyloxime 1-(3,4-difluorophenyl)ethanone O-methyloxime 1-[3-(trifluoromethyl)phenyl]ethanone O-methyloxime 1-[2-(trifluoromethyl)phenyl]ethanone O-methyloxime 1-(2,4-difluorophenyl)ethanone O-methyloxime 1-[ 3 -fluoro-4-(trifluoromethyl)phenyl]ethanone O-methyloxime 1-(3,4-dichlorophenyl)ethanone O-methyloxime 1-[ 4 -fluoro-2-(trifluoromethyl)phenyl]ethanone O-methyloxime 1-(3-chloro-4-fluorophenyl)ethanone O-methyloxime 1-( 4 -chloro-3-fluorophenyl)ethanone O-methyloxime 1-(2,5-difluorophenyl)ethanone O-methyloxime 1-(2-bromo-4-fluorophenyl)ethanone O-methyloxime 1-(3,4-dibromophenyl)ethanone O-methyloxime 1-(2-bromophenyl)ethanone O-methyloxime WO 00/34268 PCT/US99/28838 -85 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 O-methyl-oxime (1.34 g) in tetrahydrofuran (7.7 mL) is added and the resulting solution is stirred at 25 oC for 12 hours. The reaction mixture is then cooled to 0 oC 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 1-Prop-2-ynyl-pyrrolidine 1-(2-Methoxy-phenyl)-ethylamine 1-m-Tolyl-ethylamine 1-(2-Bromo-phenyl)-ethylamine 1-o-Tolyl-ethylamine C-(4-Fluoro-phenyl)-C-phenyl-methylamine 1-(4-Fluoro-phenyl)-pentylamine WO 00/34268 PCT/US99/28838 - 86 1-(4-Fluoro-phenyl)-2-phenyl-ethylamine 1-(2-Trifluoromethyl-phenyl)-ethylamine 1-(3-Bromo-phenyl)-ethylamine 1 -(3-Chloro-phenyl)-ethylamine [4-(1-Amino-ethyl)-phenyl]-dimethyl-amine 1-(1-Methyl- 1H-pyrrol-2-yl)-ethylamine 1-[3,5-bis(trifluoromethyl)phenyl]propylamine 1-[3,5-bis(trifluoromethyl)phenyl]-1l-butanamine or 1-[3,5-bis(trifluoromethyl) phenyl]butylamine 1-[3,5-bis(trifluoromethyl)phenyl]- 1-pentanamine 1-(4-methylphenyl)ethanamine 1 -[3-(trifluoromethyl)phenyl]ethylamine 1-[4-(trifluoromethyl)phenyl]ethylamine 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-[(1R)- 1-aminoethyl]phenyl }-1,2,3-thiadiazole-4-carboxamide N- { 4-[(1S)- 1 -aminoethyl]phenyl } -1,2,3-thiadiazole-4-carboxamide WO 00/34268 PCT/US99/28838 - 87 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]lethylamine 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)ethanaminel-(2-bromo-4-fluorophenyl)ethylamine EXAMPLE 73 (METHOD 49)
(
2 -Fluoro-5-trifluoromethyl-phenoxy)-acetonitrile 5 A solution of 2-fluoro-5-trifluoromethylphenol (25 g) in reagent grade acetone (0.55 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 10 dried over anhydrous potassium carbonate. Filtration and concen-tration under reduced pressure gives a pale orange solid which is then chromatographed on silica gel, eluting with dichloromethane, to give the desired product as white solid (28.3 g). Using the above procedure and appropriate starting materials the following 15 compounds were prepared: WO 00/34268 PCT/US99/28838 - 88 (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 EXAMPLE 74 (METHOD 50) 3-Fluoro-5-trifluoromethylphenethylamine tosylate 5 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 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 10 fluoro-5-trifluoromethylphenethylamine crystallizes. The white crystals, 4.26g (91%) are collected by filtration. Using the above procedure and appropriate starting materials the following compounds were prepared: 15 2-(3,5-Difluoro-phenyl)-ethylamine 2-(4-Trifluoromethyl-phenyl)-ethylamine 2-(3,4-Difluoro-phenyl)-ethylamine WO 00/34268 PCT/US99/28838 - 89 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 oC and stirred under an atmosphere of argon for 2 hours. While at 0 oC 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 00/34268 PCT/US99/28838 - 90 EXAMPLE 76 (METHOD 52) 3-Dimethylamino-5-trifluoromethyl-benzaldehyde Diisobutylaluminum hydride (10 mL of a IM solution in methylene chloride) is 5 added dropwise to a solution of 3-dimethylamino-5-trifluoromethylbenzonitrile (1.06 g) in methylene chloride (25 mL) at 0 oC and the mixture stirred for 2 hours. While still at 0 oC a saturated aqueous solution of sodium potassium tartrate (8 mL) is slowly added and the solution is stirred for 1.5 hours. The reaction mixture is then extracted with ethyl acetate, dried over anhydrous magnesium sulfate and 10 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 compounds were prepared: 15 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 oC for 6 hours. The reaction mixture is cooled to 0 oC and a solid forms which is filtered and washed with 1:1 water-acetic acid. This solid is recrystallized from ethanol to provide the desired product as a red solid (0.39 g). 25 Using the above procedure and appropriate starting materials the following compounds were prepared: Dimethyl-[3-(2-nitro-vinyl)-5-trifluoromethyl-phenyl]-amine Dimethyl-[2-methyl-4-(2-nitro-vinyl)-phenyl]-amine WO 00/34268 PCT/US99/28838 -91 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 oC. 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 oC and then at 25 oC 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 30 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.
WO 00/34268 PCT/US99/28838 - 92 EXAMPLE 81 (METHOD 34)
N-{
4
-[
3 -(5-Chloro-2,4-dimethoxy-phenyl)-ureido]-phenyl} 2-fluoro-benzamide 5 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 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. 10 Using the above procedure and appropriate starting materials the following compounds were prepared: EX M+H COMPOUND NAME NO. 81 445 N- { 4
-[
3
-(
5 -Chloro-2,4-dimethoxy-phenyl)-ureido]-phenyl }-2-fluoro-benzamide 82 441 N- { 4
-[
3 -(5-Chloro-2,4-dimethoxy-phenyl)-ureido]-phenyl }-2-methyl-benzamide 83 435 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl) ureido]-phenyl } -amide 84 443 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-chloro-3-trifluoromethyl-phenyl) ureido]-phenyl} amide 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 00/34268 PCT/US99/28838 - 93 EXAMPLE 91 (METHOD 31) N-(5-{[({(1S)-l-[ 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)-thioureido]-phenyl }-acetamide 101 411 { 4 -[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-carbamic acid ethyl ester 102 319 1-( 2
,
4 -Dimethoxy-phenyl)-3-(4-methoxy-phenyl)-thiourea 103 346 N-{ 4 -[3-(2,4-Dimethoxy-phenyl)-thioureido]-phenyl }-acetamide 104 316 N-{4-[3-(4-Methoxy-phenyl)-thioureido]-phenyl }-acetamide 105 316 N-{4-[3-(2-Methoxy-phenyl)-thioureido]-phenyl }-acetamide WO 00/34268 PCT/US99/28838 - 94 106 351 N- { 4 -[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl }-acetamide 107 351 N- { 4
-[
3 -(5-Chloro-2-methoxy-phenyl)-thioureido]-phenyl } -acetamide 108 371 N- { 4 -[3-(3,5-Dichloro-4-hydroxy-phenyl)-thioureido]-phenyl }-acetamide 109 385 N- { 4 -[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]-phenyl }-acetamide 110 381 N- { 4 -[3-(4-Chloro-2,5-dimethoxy-phenyl)-thioureido]-phenyl }-acetamide 111 389 N- { 4 -[3-(2-Chloro-5-trifluoromethyl-phenyl)-thioureido]-phenyl }-acetamide 112 389 N- { 4
-[
3
-(
4 -Chloro-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-acetamide 113 422 Benzoic acid 4
-[
3
-(
4 -acetylamino-phenyl)-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 benzamnide 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 129 385 N- { 4
-[
3
-(
3
,
5 -Dichloro-4-hydroxy-2-methyl-phenyl)-thioureido]-phenyl } acetamide WO 00/34268 PCTIUS99/28838 - 95 130 318 N-{4-[3-(2,4-Dihydroxy-phenyl)-thioureido]-phenyl)}-acetamide 131 414 N-14- [3 -(2,4-Dimethoxy-5 -trifluoromethyl-phenyl)-thioureido]-phenyI } acetamide 132 332 N-{I4-[3-(2-Hydroxy-4-methoxy-phenyl)-thioureido]-pheny I}-acetamide 133 465 N-{4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]-phenyl }-4-fluoro benzamide 134 500 3-Acetylamino-N- {4-[3-(5-chloro-2.4-dimethoxy-phenyl)-thioureido] phenyl I -benzamide 135 488 N-{ 4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyI J-3-nitro benzamide 136 486 N-{4-[3-(5-Chloro-2.4-dimethoxy-phenyl)-thioureido]-phenyl 1-3 dimethylamino-benzamide 137 536 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyI I -3-methane sulfony-amino-benzamide 138 511 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl I -2-trifluoro methyl-benzamide 139 459 N-f 4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-2-hydroxy benzainide 140 479 N- {4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-pheny } -2,6-difluoro benzamide 141 477 2-Chloro-N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyI I benzamide 142 522 2-B romo-N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pheny } benzamide 143 488 N-{ 4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-pheny }-2-nitro benzamide 144 445 Pyrazine-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl) thioureido]-phenyl }-amide 145 463 5-Methyl-thiophene-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy phenyl)-thioureido]-phenyl)I-amide 146 494 Quinoline-8-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl) thioureido]-phenyl)}-amnide 147 446 1 -Methiyl-lH-pyrrole-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy phenyl)-thioureidol-phenyl }-amide 148 369 1 -(5-Chloro-2,4-dimethoxy-phenyl)-3-(2-nitro-phenyl)-thiourea 149 369 1-(5-Chloro-2,4-dimethoxy-phenyl)-3-(4-nitro-phenyl)-thiourea 150 425 N-{4-[3-(5-Bromo-2,4-dimethoxy-phenyl)-thioureidol-phenyl }-acetamide WO 00/34268 PCT/US99/28838 - 96 151 376 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)-thioureido]-phenyl}-aminide 154 483 Benzofuran-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl) thioureido]-phenyl }-amide 155 444 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl } isonicotinamide 156 493 Naphthalene-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl) thioureido]-phenyl }-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 } -aminide 170 433 Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido] phenyl }-amide 171 467 {4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-carbamic acid WO 00/34268 PCT/US99/28838 - 97 hexyl ester 172 494 Isoquinoline-4-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl) thioureido]-phenyl }-amide 173 451 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl) thioureido]-phenyl } -amide 174 434 1H-[1,2,3]Triazole-4-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy phenyl)-thioureido]-phenyl } -amide 175 528 3-Bromo-thiophene-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy phenyl)-thioureido]-phenyl}-amide 176 399 N- {4-[3-(3,5-Dichloro-4-ethoxy-phenyl)-thioureido]-phenyl }-acetamide 177 427 N-{4-[3-(4-B utoxy-3,5-dichloro-phenyl)-thioureido]-phenyl }-acetamide 178 461 N- {4-[3-(4-Benzyloxy-3,5-dichloro-phenyl)-thioureido]-phenyl }-acetamide 179 381 N- {4-[3-(3-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl } -acetamide 180 530 (3-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenylcarbamoyl } phenyl)-carbamic acid ethyl ester 181 458 2-Amino-N- {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl } benzamide 182 519 Biphenyl-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl) thioureido]-phenyl } -amide 183 469 1-(5-Chloro-2,4-dimethoxy-phenyl)-3-[4-(1,3-dioxo-1,3-dihydro-isoindol 2-yl)-phenyl]-thiourea 184 487 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl } phthalaminic acid 185 473 N- {4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-hioureido]-phenyl }-2-hydroxy methyl-benzamide 186 479 N- {4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-2,3 difluoro-benzamide 187 479 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-2,5 difluoro-benzaminide 188 479 N- {4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-2,4 difluoro-benzaminide 189 500 2-Acetylamino-N- {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido] phenyl }-benzamide 190 441 1-(5-Chloro-2,4-dimethoxy-phenyl)-3-(6-oxo-5,6-dihydro-phenanthridin 2-yl)-thiourea 191 536 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-2-methane sulfonylamino-benzamide WO 00/34268 PCT/US99/28838 - 98 192 497 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-2,3,4 trifluoro-benzamide 193 533 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-2,3,4,5,6 pentafluoro-benzamnide 194 489 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-2-methyl sulfanyl-benzanide 195 431 5-Methyl-furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethioxy-phenyl) ureido]-phenyl } -amnide 196 467 5-Difluoromethyl-furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy phenyl)-ureido]-phenyl I -amnide 197 472 N- f{4-[3-(5-Iodo-2,4-dimethoxy-phenyl)-thioureido]-pheniyl } -acetamide 198 364 N-{4-[3-(5-Fluoro-2,4-dimethoxy-phenyl)4thioureidol-phenyl I -acetamide 199 365 N- { 4 -[3-(5-Chloro-2-methoxy-4-methyl-phenyl)-tiioureido]-pheny I acetamide 200 459 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-chloro-3-trifluoromethyl phenyl)-thioureido]-phenyl } -amnide 201 455 [1 ,2,3]Thiadiazole-4-carboxylic acid f{4-[3-(3,5-dichloro-4-methioxy-phenyl) thioureido]-phenyl I -amnide 202 392 N-{14-[3-(3-Chloro-4-diethylamino-phenyl)-thioureido]-phenyl I -acetamide 203 432 N-(4-{ 3-[3-Chloro-4-(cyclohexyl-methy1-amino)-phenyll-thioureido } phenyl)-acetamide 204 506 1 -Hydroxy-naphthalene-2-carboxylic acid {4-[3-(4-acetylamino-phenyl) thioureidoj-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-morphoin4ylphenyl) thiourea 207 372 1 -(5-Chloro-2,4-dimethoxy-phenyl)-3-(5-chloro-2-methylbphenyl)-thiourea 208 501 N- {4-r3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl } isophthalainic 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)-Lhioureido]-phenyl } beuzamide 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-nitirilo-ethoxy)-phenyl]-thioureidoy phenyl)-acetamide WO 00/34268 PCT/US99/28838 - 99 213 406 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 -Acetylamnino-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
-{
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) thioureido]-phenyl } -amide 225 494 Quinoline-4-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl) thioureido]-phenyl } -amide 226 436 N-{ 4 -[3-(5-Chloro-4-methoxy-2-morpholin-4-yl-phenyl)-thioureido] phenyl } -acetamide 227 394 N- { 4 -[3-(5-Chloro-2-dimethylamino-4-methoxy-phenyl)-thioureido] phenyl }-acetamide 228 420 N-{4-[3-(5-Chloro-4-methoxy-2-pyrrolidin- 1-yl-phenyl)-thioureido]-phenyl } acetamide 229 434 N-{4-[3-(5-Chloro-4-methoxy-2-piperidin- 1-yl-phenyl)-thioureido]-phenyl} acetamide 230 405 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-4-methyl-phenyl) thioureido]-phenyl }-amide 231 415 N- { 4 -[3-(3-Chloro-4-methyl-phenyl)-thioureido]-phenyl } -2-fluoro benzamide WO 00/34268 PCT/US99/28838 - 100 232 427 N-{4-[3-(3-Chloro-4-methyl-phenyl)-thioureido]-phenyl }-3-methoxy benzamide 233 387 Furan-2-carboxylic acid {4-[3-(3-chloro-4-methyl-phenyl)-thioureido] phenyl}-amide 234 411 N- { 4
-[
3 -(3-Chloro-4-methyl-phenyl)-thioureido]-phenyl } -2-methyl benzamide 235 433 N-{4-[3-(3-Chloro-4-methyl-phenyl)-thioureido]-phenyl }-2,6-difluoro benzamide 236 398 Pyridine-2-carboxylic acid {4-[3-(3-chloro-4-methyl-phenyl)-ithioureido] 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 benzamide 245 422 N- { 4 -[3-(2-Benzylamino-4-methoxy-phenyl)-thioureido]-phenyl } -acetamide 246 484 Furan-2-carboxylic acid (4-{3-[3-chloro-4-(cyclohexyl-methyl-amino) phenyl]-thioureido}-phenyl)-amide 247 508 N-(4- { 3 -[3-Chloro-4-(cyclohexyl-methyl-amino)-phenyl]-thioureido } phenyl)-2-methyl-benzamide 248 530 N-(4- { 3-[3-Chloro-4-(cyclohexyl-methyl-amino)-phenyl]-thioureido} phenyl)-2,6-difluoro-benzamide 249 495 Pyridine-2-carboxylic acid (4-{3-[3-chloro-4-(cyclohexyl-methyl-amino) phenyl]-thioureido }-phenyl)- amide 250 524 N-(4-{ 3-[3-Chloro-4-(cyclohexyl-methyl-amnino)-phenyl]-thioureido
}
phenyl)-3-methoxy-benzamide 251 376 N-(4-{ 3-[3-Chloro-4-(2-nitrilo-ethoxy)-phenyl]-thioureido }-phenyl) acetamide 252 393 N- { 4 -[3-(4-sec-Butoxy-3-chloro-phenyl)-thioureido]-phenyl }-acetamide 253 501 Acetic acid 3-{ 4 -[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl- WO 00/34268 PCT/US99/28838 - 101 carbamoyl } -phenyl ester 254 459 N-{ 4
-[
3 -(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3-hydroxy benzamide 255 487 Benzo[1,3]dioxole-4-carboxylic acid { 4 -[3-(5-chloro-2,4-dimethoxy-phenyl) thioureido]-phenyl } -amide 256 527 N-{ 4 -[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3-trifluoro methoxy-benzamide 257 530 N- { 4
-[
3
-(
5 -Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl } -3-(2 dimethylamino-ethoxy)-benzamide 258 572 N- { 4
-[
3
-(
5 -Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl } -3-(2 morpholin-4-yl-ethoxy)-benzamide 259 406 N-{ 4
-[
3
-(
5 -Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-cyano-phenyl} acetamide 260 521 N- { 4
-[
3
-(
5 -Chloro-2,4-dimethoxy-phenyl)-thioureido]-2,5-dimethoxy phenyl }-2-fluoro-benzainide 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 -f{ 4
-[
3
-(
4 -Acetylamino-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)-phenyll-thioureido } -phenyl) acetamide 268 365 N- { 4 -[3-(3-Chloro-4-ethoxy-phenyl)-thioureido]-phenyl } -acetamide 269 427 N-{ 4
-[
3
-(
4 -Benzyloxy-3-chloro-phenyl)-thioureido]-phenyl}-acetamide 270 317 { 4 -[(3-Methyl-furan-2-carbonyl)-amino]-phenyl } -carbamic acidtert-butyl ester 271 456 N-{ 4
-[
3
-(
2 -Benzylamino-5-chloro-4-methoxy-phenyl)-thioureido]-phenyl} acetamide 272 420 N- { 4
-[
3
-(
3 -Chloro-4-dipropylamino-phenyl)-thioureido]-phenyl } -acetamide 273 458 N-(4-{ 3
-[
4 -(Allyl-cyclohexyl-amino)-3-chloro-phenyl]-thioureido}-phenyl) acetamide WO 00/34268 PCT/US99/28838 - 102 274 411 N- {4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methoxy-phenyl } acetamide 275 415 N- {2-Chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl } acetamide 276 493 Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido] 2,5-dimethoxy-phenyl }-amide 277 486 N- {4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-cyano-phenyl } -2 fluoro-benzamide 278 495 N-{2-Chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-2 fluoro-benzamide 279 465 5-Methyl-[1,2,3]thiadiazole-4-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy phenyl)-thioureido]-phenyl } -amide 280 517 5-Furan-3-yl-[1,2,3]thiadiazole-4-carboxylic acid{4-[3-(5-chloro-2,4 dimethoxy-phenyl)-thioureido]- phenyl }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) phenyl]-acetaminide 292 485 N- {2-Benzoyl-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl} acetamide WO 00/34268 PCT/US99/28838 - 103 293 565 N- { 2 -Benzoyl- 4 -[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl } -2 fluoro-benzamide 294 537 Furan-2-carboxylic acid { 2 -benzoyl-4-[3-(5-chloro-2,4-dimethoxy-phenyl) thioureido]-phenyl } -amide 295 475 N-{ 4
-[
3 -(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-methyl-phenyl }-2 fluoro-benzamide 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-dimethylamino-propyl)-methyl-amino]-phenyl
}
thioureido)-phenyl]-acetamide 299 418 N-{ 4
-[
3 -(3-Chloro-4-cyclohexylamino-phenyl)-thioureido]-phenyl
}
acetamide 300 421 N-[4-(3- { 3 -Chloro-4-[(2-dimethylamino-ethyl)-methyl-amino]-phenyl
}
thioureido)-phenyl]-acetamide 301 580 5
-[[[(
5 -Chloro-2,4-dimethoxyphenyl)amino]thioxomethyl]amino]-2-[(2 fluorobenzoyl)amino]-N-phenyl-benzamide 302 552 Furan-2-carboxylic acid { 4 -[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido] 2-phenylcarbamoyl-phenyl } -amide 303 491 N-{ 4
-[
3
-(
5 -Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methoxy-phenyl
}
2-fluoro-benzamide 304 463 Furan-2-carboxylic acid { 4 -[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido] 2-methoxy-phenyl } -amide 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 }-amide 307 467 Furan-2-carboxylic acid { 2 -chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl) thioureido]-phenyl }-amide 308 501 Furan-2-carboxylic acid { 4 -[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido] 2-trifluoromethyl-phenyl }-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 fluoro-benzamide 311 447 Furan-2-carboxylic acid { 4 -[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido] 2-methyl-phenyl } -amide WO 00/34268 PCT/US99/28838 - 104 312 378 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)-thioureido]-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)-acetamnide 317 408 N-[4-(3-{ 3 -Chloro- 4 -[(2-methoxy-ethyl)-methyl-amino]-phenyl } -thioureido) phenyl]-acetamide 318 421 N-(4-{ 3
-[
3 -Chloro- 4 -(3-dimethylamino-propylamino)-phenyl]-thioureido
}
phenyl)-acetamnide 319 495 N-(4- { 3-[4-(1-B enzyl-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, 11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin- 10-yl)-(2-chloro-4-imidazol- 1 yl-phenyl)-methanone 323 451 [1, 2 ,3]Thiadiazole-5-carboxylic acid { 4 -[3-(5-chloro-2,4-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- l-yl } 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]- WO 00/34268 PCT/US99/28838 - 105 3-chloro-phenyl}-thioureido)- phenyl]-amide 332 513 N-[4-(3-{ 3-Chloro-4-[methyl-(1-methyl-pyrrolidin-3-yl)-amino]-phenyl} thioureido)-phenyl]-2-fluoro-benzamide 333 463 N-{ 4 -[3-(5-Chloro-2-methoxy-4-methyl-phenyl)-thioureido]-phenyl}-2,6 difluoro-benzamide 334 420 N-(4- { 3-[3-Chloro-4-(1-methyl-pyrrolidin-3-yloxy)-phenyl]-thioureido } phenyl)-acetamide 335 434 N-(4- { 3-[3-Chloro-4-(1-methyl-piperidin-4-yloxy)-phenyl]-thioureido} phenyl)-acetamide 336 422 N-(4-{ 3-[3-Chloro-4-(3-dimethylamino-propoxy)-phenyl]-thioureido} phenyl)-acetamide 337 425 2 -Acetylamino-5-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido] benzoic acid 338 505 5 -[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-(2-fluoro benzoylamino)-benzoic acid 339 477 5
-[
3 -(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-[(furan-2-carbonyl) amino]-benzoic acid 340 545 N-[4-(3- {3-Chloro-4-[methyl-(I-methyl-piperidin-4-yl)-amino]-phenyl} thioureido)-phenyl]-2,6-difluoro-benzamide 341 503 [1,2,3JThiadiazole-4-carboxylic acid[4-(3-{3-chloro-4-[methyl-(1-methyl pyrrolidin-3-yl)-amino]-phenyl}-thioureido)-phenyl]-amide 342 443 N-{ 4 -[3-(3-Chloro-4-methylsulfanyl-phenyl)-thioureido]-phenyl}-2-methyl benzamide 343 408 N-(4-{3-[3-Chloro-4-(2-dimethylamino-ethoxy)-phenyl]-thioureido} phenyl)-acetamide 344 499 Furan-2-carboxylic acid [4-(3-{3-chloro-4-[methyl-(1-methyl-piperidin-4-yl) amino]-phenyl}-thioureido)- phenyl]-amide 345 419 N-{4-[3-(3-Chloro-4-cyclohexyloxy-phenyl)-thioureido]-phenyl}-acetamide 346 440 N-{4-[3-(3-Chloro-4-dimethylamino-phenyl)-thioureido]-phenyl}-2-methyl benzamide 347 493 N-{ 4 -[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-methyl-phenyl}-2,6 difluoro-benzamide 348 462 N-{4-[3-(3-Chloro-4-dimethylamino-phenyl)-thioureido]-phenyl}-2,6 difluoro-benzamide 349 531 N-[4-(3- {3-Chloro-4-[methyl-(1-methyl-pyrrolidin-3-yl)-amino]-phenyl} thioureido)-phenyl]-2,6-difluoro-benzamide 350 427 Pyridine-2-carboxylic acid {4-[3-(3-chloro-4-dimethylamino-phenyl) thioureido]-phenyl } -amide WO 00/34268 PCT/US99/28838 - 106 351 430 Pyridine-2-carboxylic acid {4-[3-(3-chloro-4-methylsulfanyl-phenyl) thioureido]-phenyl }-amide 352 428 Pyridine-2-carboxylic acid {4-[3-(5-chloro-2-methoxy-4-methyl-phenyl) thioureido]-phenyl }-amide 353 417 Furan-2-carboxylic acid {4-[3-(5-chloro-2-methoxy-4-methyl-phenyl) thioureido]-phenyl } -amide 354 496 Pyridine-2-carboxylic acid [4-(3- { 3-chloro-4-[methyl-(1-methyl-pyrrolidin-3 yl)-amino]-phenyl }-thioureido)- phenyl]-amide 355 495 N-{3-Chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2 fluoro-benzamide 356 467 Furan-2-carboxylic acid {3-chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl) thioureido]-phenyl}-amide 357 515 N-{4-[3-(3-Chloro-4-cyclohexylsulfanyl-phenyl)-thioureido]-phenyl}-2 fluoro-benzamide 358 449 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-trifluoromethyl phenyl } -acetamide 359 529 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-trifluoromethyl phenyl}-2-fluoro-benzamide 360 421 N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-2-dimethyl amino-acetamide 361 473 Furan-2-carboxylic acid (4-{3-[3-chloro-4-(2-dimethylamino-acetylanino) phenyl]-thioureido}-phenyl)-amide 362 501 N-(4- {3-[3-Chloro-4-(2-dimethylamino-acetylamino)-phenyl]-thioureido} phenyl)-2-fluoro-benzamide 363 461 N-f{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-2-piperidin 1-yl-acetamide 364 541 N-(4-{ 3-[3-Chloro-4-(2-piperidin-1-yl-acetylamino)-phenyl]-thioureido} phenyl)-2-fluoro-benzamide 365 513 Furan-2-carboxylic acid (4- { 3-[3-chloro-4-(2-piperidin-1-yl-acetylamino) phenyl]-thioureido}-phenyl)- amide 366 463 N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-2-morpholin 4-yl-acetainide 367 543 N-(4-{3-[3-Chloro-4-(2-morpholin-4-yl-acetylamino)-phenyl]-thioureido} phenyl)-2-fluoro-benzamide 368 515 Furan-2-carboxylic acid (4-{3-[3-chloro-4-(2-morpholin-4-yl-acetylamino) phenyl]-thioureido}-phenyl)- aide 369 414 N- {4-[3-(3-Chloro-4-methanesulfonylamino-phenyl)-thioureido]-phenyl } acetamide WO 00/34268 PCT/US99/28838 - 107 370 494 N- { 4
-[
3
-(
3 -Chloro-4-methanesulfonylamino-phenyl)-thioureido]-phenyl
}
2-fluoro-benzanide 371 466 Furan-2-carboxylic acid { 4
-[
3
-(
3 -chloro-4-methanesulfonylamino-phenyl) thioureidol-phenyl}-amide 372 481 N-{ 4
-[
3
-(
4 -Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-2-(2-dimethy lamino-ethylsulfanyl)- acetamide 373 561 N-[4-(3-{ 3 -Chloro- 4
-[
2
-(
2 -dimethylamino-ethylsulfanyl)-acetylamino] phenyl } -thioureido)-phenyl]-2-fluoro-benzamide 374 585 N-[4-(3-{4-[(1 -B enzyl-pyrrolidin-3-yl)-methyl-amino]-3-chloro-phenyI} 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) thioureidoJ-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]-pheny } -2,6 difluoro-benzamide 381 486 N-{ 4 -[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-cyano-phenyl} 2-fluoro-benzamide 382 458 Furan-2-carboxylic acid { 4
-[
3
-(
5 -chloro-2,4-dimethoxy-phenyl)-thioureido] 3-cyano-phenyl}-amide 383 406 N- { 4
-[
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]-phenyl } acetamide 386 461 N- { 4
-[
3
-(
3 -Chloro-4-ethylsulfanyl-phenyl)-thioureido]-phenyl} -2-fluoro benzainide 387 489 N-{ 4
-[
3
-(
4 -Butylsulfanyl-3-chloro-phenyl)-thioureido]-phenyl } -2-fluoro benzamide 388 411 N-{ 4 -[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido-3 -methoxy-phenyl} acetamide 389 491 N-{ 4
-[
3
-(
5 -Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-methoxy-phenyl}-2- WO 00/34268 PCT/US99/28838 - 108 fluoro-benzamnide 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 (4-1{3-[3-chloro-4-(2-piperidin- l-yl acetyl-amino)-phenyl]-thioureido }-phenyl)-amide 392 481 N- { 4 -[3-(3-Chloro-4-methanesulfinyl-phenyl)-Uhioureidoy-pheny1 }-2,6 difluoro-benzainide 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-benzamnide 395 429 N- { 4 -13-(3-Chloro-4-methyl-phenyl)-thioureido]-2-methyl-phenyI }-2-fluoro benzamide, 396 533 Furan-2-carboxylic acid [4-(3-{ 3-chloro-4-[2-(2-dimethylamino ethylsulfanyl)-acetylamino]-pheny I -thioureido)-phenyl]-amide 397 458 N-{14-[3-(4-Acetylamnino-3-chloro-phenyl)4Lhioureido]-phenyI I -2-fluoro benzamide 398 460 [ 2 -Chloro-4-(3-{4-[(furan-2-carbonyl)-amnino]-phenyI I -thioureido)-phenyl] carbamnic acid ethyl ester 399 488 (2-Chloro-4- {3-[4-(2-fluoro-benzoylamino)-phenyl]-thioureido I -phenyl) carbamnic acid ethyl ester 400 440 N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl }-benzamide 401 520 N-{4-[( [4-(Benzoylwmino)-3-chloro-phenyl]-amino }-thioxomethyl)-ainino] phenyl }-2-fluoro-benzainide 402 529 N-{ 4 -[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-trifluoromethyl phenyl)}-2-fluoro-benzamnide 403 492 Furan-2-carboxylic acid {4-L3-(4-benzoylamino-3-chloro-phenyl) thioureidol-phenyl }-ainide 404 416 N-{4-13-(4-Amino-3-chloro-phenyl)-thioureido]-phenyl)}-2-fluoro-benzaniide 405 479 N- { 4 -[3-(4-Acetylamnino-phenyl)-thioureido]-2-chloro-phenyl }-2 thiomorpholin-4-yl-ace~unide 406 531 Furan-2-carboxylic acid (4-{ 3-[3-chloro-4-(2-thiomorpholin-4-yl acetylamino)-phenylj-thioureido }-phenyl)-ainide 407 559 N-(4-{ 3-[3-Chloro-4-(2-thiomorpholin-4-yl-acetylamino)-phenyl] thioureido I -phenyl)-2-fluoro-benzamnide 408 461 N-{1 4 -[3 -(3-Chloro-4-methylsulfanyl-phenyl)-thioureido]-2-methyl-phenyI I 2-fluoro-benzamnide 409 430 Furan-2-carboxylic acid {4-[3-(4-acetylaimino-3-chloro-phenyl)-thioureido]- WO 00/34268 PCT/US99/28838 - 109 phenyll}-amide 410 477 N-{ 4 -[3-( 4 -Acetylamino-phenyl)-thiioureido-2-chloro-phenyl-2 dipropylamino-acetarmide 411 529 Furan-2-carboxylic acid (4-1{3-[3-chloro-4-(2-dipropylainino-acetylainino) phenyl]-thioureido}-phenyl)- amide 412 449 N-{ 4 -[3-(4-Acetylamino-phenyl)-thioureido-2-chloro.phenyl }-2-diethyl amino-acetainide 413 501 Furan-2-carboxylic acid (4-1{3-[3-clhloro-4-(2-diethylamino-acetylainino) phenyl]-thioureido}-phenyl)- amnide 414 529 N-(4-1{3-[3-Chloro-4-(2-diethylamino-acetylamino)-phenyl]-thioureido
}
phenyl)-2-fluoro-benzamnide 415 447 N-{ 4 -[3-(4-Acetylamnino-phenyl-thioureido-2chloro-phenyl }-2-pyrrolidin 1 -yl-acetamide 416 499 Furan-2-carboxylic acid (4- {3-[3-chloro-4-(2-pyrrolidin- 1-yl-acetylamnino) phenyl]-thioureido)}-phenyl)-amnide 417 527 N-(4-1{3-r3-Chloro-4-(2-pyrrolidin- 1-yl-acetylamino)-phenyl]-thioureido } phenyl)-2-fluoro-benzamnide 418 475 N-{ 4-[3-(5-Chloro-2-methoxy4methyl-phenyl)-thioureido-3-mefioxy phenyl)}-2-fluoro-benzamide 419 445 N-{ 4 -[3-(3-Chloro-4-methyl-phenyl)-thioureido-3-meffioxy-phenyl)}-2 fluoro-benzamide 420 477 N-{ 4 -[3-(3-Chloro-4-methylsulfanyl-phenyl)>thioureido-3-meffioxy phenyl}-2-fluoro-benzamide 421 388 Furan-2-carboxylic acid {4-[3-(4-amino-3-chloro-phenyl)-thioureido] phenyl}-amnide 422 527 Furan-2-carboxylic acid (4- {3-14-(2-azepan- 1-yl-acetylamino)-3-chloro phenyl]-thioureido}-phenyl)-amide 423 555 N-(4-({3-[4-(2-Azepan-1 -yl-acetylainino)-3-chloro-phenyl]-thioureido} phenyl)-2-fluoro-benzamide 424 527 Furan-2-carboxylic acid [4-(3- {3-chloro-4-[2-(2-methyl-piperidin- l-yl) acetyl-aminol-phenyl }-thioureido)-phenyl]-ainide 425 555 N-[4-(3-1{3-Chloro-4-L2-(2-methyl-piperidin- 1-yl)-acetylamino]-phenyl I thioureido)-phenylJ-2-fluoro-benzwmide 426 339 Furan-2-carboxylic acid [ 4 -(3-pyridin-2-yl-thioureido)-phenyl]-ainide 427 339 Furan-2-carboxylic acid 1 4 -(3-pyridin-4-yl-thioureido)-phenyl]-amide 428 367 2 -Fluoro-N-14-(3-pyridin-3-y-thioureido)-phenyl]-benzamide 429 339 Furan-2-carboxylic acid r4-(3-pyridin-3-yl-thioureido)-phenyl]-amnide WO 00/34268 PCTIUS99/28838 - 110 430 353 Furan-2-carboxylic acid {4-[3-(3-amnino-phenyl)-thioureido]-phenyl }-amide 431 406 Furan-2-carboxylic acid {4-r3-(3-trifluoromethyl-phenyl)-thioureido] phenyl)}-amide 432 380 2-Fluoro-N-[4-(3-m-tolyl-thioureido)-phenyl]-benzamnide 433 434 2-Fluoro-N-{4-113-(3-trifluoromethyl-phenyl)-thioureido]-phenyl } benzamide 434 381 N-{4-[3-(3-Amino-phenyl)-thioureido]-phenyl }-2-fluoro-benzamnide 435 388 Furan-2-carboxylic acid {4-[3-(3-amino-5-chloro-phenyl)-thioureido] phenyl } -amnide 436 352 Furan-2-carboxylic acid [4-(3-m-tolyl-Lhioureido)-phenyl]-amnide 437 416 N- {4-[3-(2-Ainino-5-chloro-phenyl)-thioureido]-phenyl)}-2-fluoro-benzamnide 438 571 (2-Chloro-4-{ 3-[4-(2-fluoro-benzoylamino)-phenyl]-thioureido }-phenyl) carbamnic acid 2-piperidin- 1-yl-ethyl ester 439 543 [2-Chloro-4-(3- {4-[(furan-2-carbonyl)-amino]-phenyl)}-thioureido)-phenyl] carbamnic acid 2-piperidin- I-yl-ethyl ester 440 388 Furan-2-carboxylic acid {4-[3-(2-amnino-5-chloro-phenyl)-thioureido] phenyl }-amide 441 363 Furan-2-carboxylic acid {4-[3-(3-cyano-phenyl)-Lhioureido]-phenyl } ainide 442 416 N-{4-[3-(3-Ainino-5-chloro-phenyl)-thioureido]-phenyl I-2-fluoro-benzamnide 443 367 2-Fluoro-N-[4-(3-pyridin-2-yl-thioureido)-phenyl]-benzamide 444 367 2-Fluoro-N-[4-(3-pyridin-4-yl-thioureido)-phenyl]-benzainide 445 374 Furan-2-carboxylic acid { 4-[3-(6-chloro-pyridin-3-yl)-thioureido]-phenyl I amnide 446 388 Furan-2-carboxylic acid {4-[3-(2-amino-3-chloro-phienyl)-thioureido] phenyllI-ainide 447 396 Furan-2-carboxylic acid {4-13-(3-hydrazinocarbonyl-phenyl)-thioureilo] phenyll -amide 448 410 2-Fluoro-N-(4-1{3-[3-(1 -hydroxy-ethyl)-phenyll-thioureido}-phenyl) beuzainide 449 414 ri ,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] phenyllI-amide 451 380 Furan-2-carboxylic acid {4-[3-(3-isopropyl-phenyl)-thioureido]-phenyl}I amide 452 409 2-Fluoro-N-{4-[3-(3-isopropyl-phenyl)-thioureido]-phenyl }-benzainide WO 00/34268 PCT/US99/28838 453 381 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-cyano-phenyl)-thioureido] phenyl }-amide 454 410 N- {47[3-(3-Dimethylamino-phenyl)-thioureido]-phenyl} -2-fluoro-benzamnide 455 381 Furan-2-carboxylic acid {4-[3-(3-dimethylamino-phenyl)-thioureido] phenyll}-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]-phenyll}-amnide 458 479 N-{ 3-Chloro-4-[3-(5-chloro-2-methoxy-4-methyl-phenyl)-thioureido] phenyl }-2-fluoro-benzainide 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-r3-(3-Cyano-phenyl)-thioureido] -phenyl }-2-fluoro-benzamnide 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)} beuzamnide 464 400 [1 ,2,3]Thiadiazole-4-carboxylic acid (4-{ 3-113-(l1-hydroxy-ethyl)-phenyl] thioureidol}-phenyl)-ainide 465 434 N-{4-[3-(2-Amino-3-chloro-phenyl)-thioureido]-phenyl }-2,6-difluoro benzamide 466 406 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-amnino-5-chloro-phenyl) thioureido]-phenyl } -amide 467 398 Furan-2-carboxylic acid {4-[3-(3,5-dimethoxy-phenyl)-thioureido]-phenyl } amide 468 416 [1.2,3]Thiadiazole-4-carboxylic acid f 4-L3-(3,5-dimethoxy-phenyl) thioureido]-phenyll}-amide 469 454 5-(3- {4-[(Furan-2-carbonyl)-amnino]-phenyl}-thioureido)-isophthalic acid dimethyl ester 470 434 Isoxazole-5-carboxylic acid {4-r3-(5-chloro-2,4-dimethoxy-phenyl) thioureido]-phenyl)}-amnide 471 392 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(6-chloro-pyridin-3-yl) thioureido]-phenyl)}-amide 472 382 Furan-2-carboxylic acid (4-1{3-[3-(1 -hydroxy-ethyl)-phenyl]-thioureido} phenyl)-amide WO 00/34268 PCT/US99/28838 - 112 473 368 Furan-2-carboxylic acid { 4 -[3-(3-methoxy-phenyl)-thioureidol-phenyl
}
amnide 474 354 Furan-2-carboxylic acid { 4 -13-(3-hydroxy-phenyl)-thioureido]-phenyl
}
amide 475 382 2 -Fluoro-N-{4-[3-(3-hydroxy-phenyl)-thioureido]-phenyl)}-benzamide 476 396 2 -Fluoro-N-{4-L3-(3-hydroxymethyl-phenyl)-Uhioureidoy-phenyl)}-benzamide 477 423 N-{ 4
-[
3 -(3-Acetylamino-phenyl)-fiioureido].phenyl }-2-fluoro-benzamnide 478 413 [1 , 2 ,3]Thiadiazole-4-carboxylic acid { 4 -[3-(3-acetylamino-phenyl) thioureidol-phenyl)}-ainide 479 400 [1 , 2 ,3]Thiadiazole-4-carboxylic acid {4-[3-(3-dimethylamino-phenyl) thioureido]-phenyl I -amide 480 340 Furan-2-carboxylic acid [ 4
-(
3 -pyrimidin-4-yl-thioureido)..phenyly-amide 481 378 Furan-2-carboxylic acid { 4 -[3-(lH-indazol-5-yl)-thioureido]-phenyI I -amide 482 395 Furan-2-carboxylic acid [ 4
-(
3 -benzothiazol-5-yl-thioureido)-phenyl]yamide 483 406 2 -Fluoro-N-{14-[3-(1H-indazo-5-yl).thioureido]-phenyI I -benzamide 484 424 N-4(-eztizl5y-hored)pey]2fur-ezmd 485 473 5-(3-{f4-[([ 1, 2 ,3]Thiadiazole-4-cartbonyl)-aminoy-phenyI I -thioureido) isophthalic acid dimethyl ester 486 442 Furan-2-carboxylic acid (4-{ 3 -[4-(1-azido-ethyl)-3-chloro-phenyly thioureido}-phenyl)-amnide 487 396 2 -Fluoro-N-{ 4-r3-(3-methoxy-phenyl)-thioureidoy-phenyl }-benzamide 488 368 Furan-2-carboxylic acid { 4 -[3-(3-hydroxymethyl-phenyl)-thioureido] phenyll}-arnide 489 416 Furan-2-carboxylic acid { 4
-[
3 -(5-chloro-2-dimethylainino-phenyl)y thioureidoj-phenyl }-amide 490 444 N-{ 4
-[
3
-(
5 -Chloro-2-dimethylamino-phenyl).tjhioureido]-phenyl }-2-fluoro benzamaide 491 506 [3-Chloro-5-(3- {4-[([1 , 2 ,3]thiadiazole-4-carbonyl)-ainino]-phenyl
}
thioureido)-phenyl]-carbainic acid tert-butyl ester 492 470 N-(4-{ 3-[4-(1 -Azido-ethyl)-3-chloro-phenyl]-thioureido }-phenyl)-2-fluoro benzamide 493 337 Furan-2-carboxylic acid [ 4 -(lH-thiazolo[5,4-bjpyridin-2-ylideneamino). phenyll-ainide 494 378 Furan-2-carboxylic acid { 4 -[3-(lH-benzoimidazol-5-yl)-thioureidoy-phenyl
}
ainide 495 392 Furan-2-carboxylic acid {4-[3-(2-methyl- 1H-benzoimidazol-5-yl) thioureido]-phenyl I -amnide WO 00/34268 PCTIUS99/28838 - 113 496 406 N-{4-[3-( 1H-B enzoimidazol-5-yl)-thioureido]-phenyl }-2-fluoro-benzamide 497 420 2-Fluoro-N-{4-[3-(2-methyl- 1H-benzoimidazol-5-yl)-thioureido]-phenyl
I
benzamide 498 452 [1 ,2,3lThiadiazole-4-carboxylic acid { 5-13-(5-chloro-2,4-dimethoxy-phenyl) thioureido]-pyridin-2-yI }-amide 499 445 Pyridine-2-carboxylic acid f 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-cliloro-2-dimethylamino phenyl)-thioureido]-phenyl)}-amide 501 484 Li ,2,3]Thiadiazole-4-carboxylic acid (4-1{3-[4-(2-amino-pyrimidin-4-yl)-3 chloro-phenyl]-thioureido}-phenyl)-wmide 502 494 N-(4-1{ 3
-[
4
-(
2 -Amino-pyrimidin-4-yl)-3-chloro-phenyl]ythioureido} -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- { 4
-[
3
-(
3 -Chloro-2-dimethylamnino-phenyl)-thiioureidoy-phenyl }-2,6 difluoro-benzainide 505 416 Furan-2-carboxylic acid {4-[3-(3-chloro-2-dimethylamnino-phenyl) thioureido]-phenyl }-amide 506 445 Pyridine-2-carboxylic acid { 6-13-(5-chloro-2,4-dimethoxy-phenyl) thioureido]-pyridin-3-yll}-amide 507 462 N-{ 6-[3-(5-Chloro-2,4-dimeffoxyphenylthioureido-pyridin3yl }-2 fluoro-benzamide 508 482 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-iodo-phenyl)-thioureido] phenyl } -amide 509 413 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-tert-butyl-phenyl)-thioureidoJ phenyll}-amnide 510 387 Furan-2-carboxylic acid {4-13-(3-chloro-benzyl)-thioureido]-phenyl)}-amide 511 415 N-{ 4-[3-(3-Chloro-benzyl)-thioureido]-phenyI I -2-fluoro-benzamnide 512 434 Furan-2-carboxylic acid { 6-[3-(5-chloro-2,4-dimethoxy-pheny1)-uhioureido] pyridin-3-yl }-amide 513 435 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-bromo-phenyl)-thioureido] phenyll}-amide 514 452 II1,2,3]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-yll}-amide 516 474 Furan-2-carboxylic acid { 4 -[3-(3,5-bis-trifluoromethyl-phenyl)-thioureido]- WO 00/34268 PCT/US99/28838 -114 phenyll}-amnide 517 502 N-{4-[3-(3,5-Bis-trifluoromethyl-phenyl)-thioureido]-phenyl }-2-fluoro benzamnide 518 450 N- {4-13-(4-Amino-3,5-dichloro-phenyl)-thioureido]-phenyl }-2-fluoro benzamide 519 539 N-{4-[3-(4-Amino-3,5-dibromo-phenyl)-thioureido]-pheny } -2-fluoro benzamide 520 392 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-r3-(5-chloro-pyridin-3-yl) thioureido]-phenyl } -amide 521 529 [1 ,2,3]Thiadiazole-4-carboxylic acid f{4-[3-(4-amino-3.5 -dibromo-phenyl) thioureido]-phenyll}-amide 522 434 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-5-dimethylainino phenyl)-thioureido]-phenyl } -amnide 523 444 N- {4-[3-(3-Chloro-5-dimethylamnino-phenyl)-thioureido]-phenyl I -2-fluoro benzamide 524 416 Furan-2-carboxylic acid {4-[3-(3-chloro-5-dimethylamino-phenyl) thioureidol-phenyl I -amnide 525 436 [1 ,2,3]Thiadiazole-4-carboxylic acid f 4-[3-(5-bromo-pyridin-3-yl) thioureido]-phenyl)}-amide 526 379 Furan-2-carboxylic acid {4-[3-(1 H-benzotriazol-5-yl)-thioureido]-phenyl} amnide 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 }-amnino)-phenyl]-2 fluoro-benzamide 530 456 Furan-2-carboxylic acid {4-[3-(2-amino-3-chloro-5-trifluoromethyl-phenyl) thioureido]-phenyl I}-amnide 531 513 N-{14- [3-(3 -Bromo-5-trifluoromethyl-phenyl)-thioureido]-phenyl I -2-fluoro benzamnide 532 503 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-bromo-5-trifluoromethyl phenyl)-thioureido]-phenyl }-amnide 533 374 {4-[(Furan-2-carbonyl)-ainino]-phenyl}-thiocarbamnic acid O-(3-chloro phenyl) ester 534 474 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-amino-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 I-amide WO 00/34268 PCT/US99/28838 - 115 536 380 N-[4-(3-Benzyl-thioureido)-phenyl]-2-fluoro-benzamide 537 439 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-13-(3,4-dichloro-benzyl)-thioureido] phenyll}-amnide 538 449 N-f 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-jj4-(3-Benzofl ,3]dioxol-5-ylmethyl-thioureido)-plhenyl]-2-fluoro benzamide 541 414 ri ,2,3]Thiadiazole-4-carboxylic acid [4-(3-benzo[1 ,3]dioxol-5-ylmethyl thioureido)-phenyl]-amnide 542 506 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl-benzyl) thioureido]-phenyl }-amide 543 516 N-f 4 -[3-(3,5-Bis-trifluoromethyl-benzyl)-thioureido]-phenyl }-2-fluoro benzamnide 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} ainide 546 396 Furan-2-carboxylic acid [4-(3-benzorl ,3]dioxol-5-ylmethyl-thioureido) phenyll-amide 547 488 Furan-2-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl-benzyl)-thioureido] phenyl } -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)-thioureido]-phenyl }-2-fluoro benzamide 550 519 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-13-(3-bromo-4-trifluoromethoxy phenyl)-thioureido]-phenyl } -amnide 551 473 Furan-2-carboxylic acid {4-[3-(3-chloro-4-trifluoromethylsulfanyl-phenyl) thioureido] -phenyl I -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-f 3-[2-(3-fluoro-phenyl)-ethyl] thioureido}-phenyl)-amide 555 402 [1 ,2,3lThiadiazole-4-carboxylic acid (4-1{3-L2-(4-fluoro-phenyl)-ethyl] thioureido I -phenyl)-amnide 556 495 ri ,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- WO 00/34268 PCT/US99/28838 - 116 phenyl)-thioureido]-phenyl I -amnide 558 523 [1 ,2,3]Thiadiazole-4-carboxylic acid (4- {3-[3-(4-methyl-piperazin-1 -yl)-5 trifluoro-methyl-phenyl]-thioureido } -phenyl)-ainide 559 510 [1 ,2,3]Thiadiazole-4-carboxylic acid f{4-13-(3-morpholin-4-yl-5 trifluoromethyl-phenyl)-thioureido]-phenyl I}-amide 560 494 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-pyrrolidin-1 -yl-5 trifluoromethyl-phenyl)-thioureido]-phenyl }-amide 561 384 Furan-2-carboxylic acid (4-1{3-[2-(4-fluoro-phenyl)-ethyl]-thioureido } phenyl)-wnide 562 419 [1 ,2,3]Thiadiazole-4-carboxylic acid (4- {3-[2-(3-chloro-phenyl)-ethyl] thioureidol}-phenyl)-amide 563 429 N-(4- {3-[2-(3-Chloro-phenyl)-ethyl]-thioureido }-phenyl)-2-fluoro benzainide 564 401 Furan-2-carboxylic acid (4-{3-[2-(3-chloro-phenyl)-ethyl]-thioureido} phenyl)-amnide 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-1I-yl-5-trifluoromethyl-phenyl)-thioureido] phenyl }-benzamide 567 477 N-{4-[3-(3-Dimethylaniino-5-trifluoromethyl-phenyl)-thioureido]-phenyl }-2 fluoro-benzamide 568 520 2-Fluoro-N- {4-[3-(3-morpholin-4-yl-5-trifluoromethyl-phenyl)-thioureido] phenyl)}-benzamnide 569 533 2-Hluoro-N-(4-{ 3-[3-(4-methyl-piperazin-1I-yl)-5-tiifluoromethyl-phenyl] thioureido }-phenyl)-benzamide 570 518 2-Fluoro-N-{4-113-(3-piperidin- 1-yl-5-trifluoromethyl-phenyl)-thioureido] phenyll}-benzamide 571 468 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-dimethylamino-5 trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 572 405 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-benzyl)-thioureido] phenyl }-amide 573 384 Furan-2-carboxylic acid (4-f 3-[2-(3-fluoro-phenyl)-ethyl]-thioureido } phenyl)-amnide 574 366 Furan-2-carboxylic acid [4-(3-phenethyl-thioureido)-phenyl]-amide 575 384 [1 ,2,3lThiadiazole-4-carboxylic acid [4-(3-phenethyl-thioureido)-phenylj aniide 576 394 2-Fluoro-N-[4-(3-phenethyl-thioureido)-phenyl]-benzamnide 577 505 2-Fluoro-N-(4- {3-13-(2-methyl-butyl)-5-trifluoromethyl-phenyl]-thioureido} - WO 00/34268 PCT/US99/28838 - 117 phenyl)-benzwmide 578 491 2 -Fluoro-N-{4-[3-(3-isobuty1-5-trifluoromethyl-phenyl)>thioureido]-pheny
}
benzamide 579 388 Furan-2-carboxylic acid {4-[3-(3.5-difluoro-benzyl)-thioureido]-phenyl } amide 580 416 N-{4-L3-(3.5-Difluoro-benzy)thioureidop-phenyl }-2-fluoro-benzamide 581 406 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-13-(3,5-difluoro-benzyl)-thioureido] phenyll}-amnide 582 421 Furan-2-carboxylic acid {4-I!3-(3,5-dichloro-benzyl)-thioureido]-phenyl 1 amide 583 449 N-{4-[3-(3,5-Dichloro-benzyl)-thioureido].phenyl I-2-fluoro-benzamnide 584 439 Li ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3.5-dichloro-benzyl)-thioureido] phenyl }-amnide 585 438 Furan-2-carboxylic acid { 4 -[3-(3-fluoro-5-trifluoromethyl-benzyl) thioureido]-phenyl }-amide 586 466 2 -Fluoro-N-{ 4 -[3-(3-fluoro-5-trifluoromethyl..benzyl)4thioureido]-phenyl
}
benzamide 587 456 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-13-(3-fluoro-5-trifluoromethyl benzyl)-thioureido]-phenyl }-ainide 588 384 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(l1-phenyl-ethyl)-thioureido] phenyll}-ainide 589 394 2-Fluoro-N- {4-[3-( 1-phenyl-ethyl)-thioureido]-phenyl }-benzamide 590 366 Furan-2-carboxylic acid {4-[3-(1 -phenyl-ethyl)-thioureido]-phenyl }-amnide 591 412 2-Fluoro-N-(4-1{3-[I -(4-fluoro-phenyl)-ethyl]-ffiioureido }-phenyl)-benzamide 592 384 Furan-2-carboxylic acid (4-{ 3-[1 -(4-fluoro-phenyl)-ethyl]-thioureido} phenyl)-amide 593 413 N-{4-113-( 1-tert-Butyl-1 H-imidazol-2-yl)-thioureido]-phenyl }-2-fluoro benzwmide 594 510 Li ,2,3]Thiadiazole-4-carboxylic acid (4-1{3-[3-(isobutyl-methyl-amino)-5 trifluoromethyl-phenyl]-thioureido }-phenyl)-amide 595 510 [1 ,2,3]Thiadiazole-4-carboxylic acid (4-1{3-[3-(3-hydroxy-pyfrolidin- l-yl)-5 trifluoromethyl-phenyl]-thioureido }-phenyl)-amide 596 520 2-Fluoro-N-(4-{ 3 -[3-(isobutyl-methyl-amino)-5-trifluoromethyl-phenyl]p thioureido I}-phenyl)-benzainide 597 510 Li ,2,3]Thiadiazole-4-carboxylic acid (4- {3-[3-(butyl-methyl-amino)-5 trifluoromethyl-phenyl]-thioureido }-phenyl)-ainide 598 520 N-(4-{ 3-[3-(Butyl-meffiy-amino)-5-rifluoromethyl-phenylyffiioureido}- WO 00/34268 PCT/US99/28838 phenyl)-2-fluoro-benzaniide 599 520 [1 ,2,3]Thiadiazole-4-carboxylic acid (4-{ 3-[2-(3,5-bis-trifluoromethyl phenyl)-ethyl]-thioureido }-phenyl)-ainide 600 442 [1 ,2,3ljThiadiazole-4-carboxylic acid {4-[3-(4-fluoro-3-trifluoromethyl phenyl)-thioureido]-phenyl }-amicle 601 522 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-piperidin- l-yl-3 trifluoromethyl-benzyl)-thioureido]-phenyl I -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)-amnide 604 445 Furan-2-carboxylic acid (4-{ 3-[2-(4-bromo-phenyl)-ethyl]-thioureido} phenyl)-ainide 605 380 Furan-2-carboxylic acid {4-13-(2-p-tolyl-ethyl)-thioureido]-phenyl }-amide 606 463 [1 ,2,3]Thiadiazole-4-carboxylic acid (4-1{3-[2-(4-bromo-phenyl)-ethyl] thioureido I -phenyl)-wmide 607 396 Furan-2-carboxylic acid (4-{ 3-[2-(3-methoxy-phenyl)-ethyl]-thioureido } phenyl)-ainide 608 403 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(1 -tert-butyl-l1H-imidazol-2-yl) thioureido]-phenyl I}-amide 609 384 Furan-2-carboxylic acid {4-[3-(l1-tert-butyl-l1H-imidazol-2-yl)-thioureido] p-henyl }-ainide 610 492 N-{4-[3-(4-Dimethylamnino-3-trifluoromethyl-benzyl)-thioureido]-phenyl }-2 fluoro-benzainide 611 427 Furan-2-carboxylic acid (4-{3-[2-(3,4-dimethoxy-phenyl)-ethyl]-thioureido} phenyl)-amnide 612 380 Furan-2-carboxylic acid {4-[3-(3-phenyl-propyl)-thioureido]-phenyl)4-amide 613 399 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-phenyl-propyl)-thioureido] phenyll4-amide 614 502 Furan-2-carboxylic acid (4-{ 3-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl] thioureidol4-phenyl)-wmide 615 550 [1 ,2,3llThiadiazole-4-carboxylic acid f{4-[3-(4-iodo-3-trifluoromethyl phenyl)-thioureido]-phenyl 4-amide 616 532 2-Fluoro-N- {4-[3-(4-piperidin- 1-yl-3-trifluoromethyl-benzyl)-thioureido] phenyl 4-benzamide 617 537 [1 ,2,3]Thiadiazole-4-carboxylic acid (4-{ 3-14-(4-methyl-piperazin- l-yl)-3 trifluoromethyl-benzyl]-thioureido 4-phenyl)-ainide 618 482 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-dimethylamino-5- WO 00/34268 PCT/US99/28838 -119 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] phenyl}-amide 621 421 Furan-2-carboxylic acid {4-[3-(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
}
benzamide 624 456 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-fluoro-3-trifluoromethyl benzyl)-thioureido]-phenyl } -amide 625 410 2 -Fluoro-N-{4-[3-(2-phenoxy-ethyl)-thioureido]-phenyl } -benzamide 626 382 Furan-2-carboxylic acid {4-[3-(2-phenoxy-ethyl)-thioureido]-phenyl}-amide 627 400 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-phenoxy-ethyl)-thioureido] phenyl } -amide 628 409 2 -Fluoro-N- {4-[3-(3-phenyl-propyl)-thioureido]-phenyl } -benzamide 629 425 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(5-trifluoromethyl-pyridin-3-yl) thioureido]-phenyl } -amide 630 439 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,4-dichloro-phenyl)-thioureido methyl]-phenyl } -amide 631 473 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-chloro-3-trifluoromethyl phenyl)-thioureidomethyl]-phenyl}-amide 632 381 2 -Fluoro-N-[4-(3-pyridin-3-ylmethyl-thioureido)-phenyl]-benzamide 633 353 Furan-2-carboxylic acid [ 4 -(3-pyridin-3-ylmethyl-thioureido)-phenyl]-amide 634 371 [1,2,3]Thiadiazole-4-carboxylic acid [4-(3-pyridin-3-ylmethyl-thioureido) phenyl]-amide 635 439 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-dichloro-phenyl)-thioureido methyl]-phenyl } -amnide 636 492 N-{ 4 -[3-(3-Dimethylamino-5-trifluoromethyl-benzyl)-thioureido]-phenyl
}
2-fluoro-benzamide 637 415 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-methoxy-phenyl)-ethyl] thioureido}-phenyl)-amide 638 399 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-p-tolyl-ethyl)-thioureido] phenyl}-amide 639 445 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3,4-dimethoxy-phenyl)- WO 00/34268 PCT/US99/28838 - 120 ethyl]-thioureido}-phenyl)-amide 640 506 [1,2,3]Thiadiazole-4-carboxylic acid { 4
-[
3
-(
3 ,5-bis-trifluoromethyl-phenyl) thioureidomethyl]-phenyl }-amide 641 516 N-{4-[3-(3,5-Bis-trifluoromethyl-phenyl)-thioureidomethyl]-phenyl }-2 fluoro-benzamide 642 449 N- { 4
-[
3
-(
3
,
5 -Dichloro-phenyl)-thioureidomethyl]-phenyl } -2-fluoro benzamide 643 449 N- { 4
-[
3
-(
3
,
4 -Dichloro-phenyl)-thioureidomethyl]-phenyl }-2-fluoro benzamide 644 448 [1, 2 ,3]Thiadiazole-4-carboxylic acid { 4
-[
3
-(
3 -acetylamino-5-chloro-phenyl) thioureido]-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]-phenyl } -amide 647 463 [1, 2
,
3 ]Thiadiazole-4-carboxylic acid (4-{3-[1-(4-bromo-phenyl)-ethyl] thioureido}-phenyl)-amide 648 413 [1, 2
,
3 ]Thiadiazole-4-carboxylic acid { 4 -[3-(4-phenyl-butyl)-thioureido] phenyl }-amide 649 397 [1, 2 ,3]Thiadiazole-4-carboxylic acid [4-(3-indan-1-yl-thioureido)-phenyl] amide 650 400 [1,2,3]Thiadiazole-4-carboxylic acid { 4 -[3-(2-methoxy-benzyl)-thioureido] phenyl}-amide 651 415 [1, 2 ,3]Thiadiazole-4-carboxylic acid (4-{ 3 -[2-(2-methoxy-phenyl)-ethyl] thioureido}-phenyl)-amide 652 415 [1, 2 ,3]Thiadiazole-4-carboxylic acid (4- {3-[2-(4-methoxy-phenyl)-ethyl] thioureido }-phenyl)-amide 653 506 N-(4-{ 3
-[
2
-(
3 -Dimethylamino-5-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 I -amide 656 427 2 -Fluoro-N-{ 4 -[3-(2-phenylsulfanyl-ethyl)-thioureido]-phenyl I -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 WO 00/34268 PCT/US99/28838 - 121 660 371 [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}-amide 663 496 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-iodo-benzyl)-thioureido] phenyl}-amide 664 479 N-(4- { 3-[2-(3,5-Dichloro-phenoxy)-ethyl]-thioureido } -phenyl)-2-fluoro benzamide 665 451 Furan-2-carboxylic acid (4-{3-[2-(3,5-dichloro-phenoxy)-ethyl]-thioureido} phenyl)-amide 666 445 N-(4-{ 3-[2-(3-Chloro-phenoxy)-ethyl]-thioureido }-phenyl)-2-fluoro benzamide 667 417 Furan-2-carboxylic acid (4- { 3-[2-(3-chloro-phenoxy)-ethyl]-thioureido } phenyl)-amide 668 435 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-chloro-phenoxy)-ethyl] thioureido } -phenyl)-amide 669 466 2-Fluoro-N- {4-[3-(2-fluoro-5-trifluoromethyl-benzyl)-thioureido]-phenyl} benzamide 670 438 Furan-2-carboxylic acid {4-[3-(2-fluoro-5-trifluoromethyl-benzyl) thioureido]-phenyl}-amide 671 456 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-fluoro-5-trifluoromethyl benzyl)-thioureido]-phenyl}-amide 672 416 N- {4-[3-(3,4-Difluoro-benzyl)-thioureido]-phenyl } -2-fluoro-benzamide 673 452 N-(4-{ 3-[2-(4-Dimethylamino-3-methyl-phenyl)-ethyl]-thioureido }-phenyl) 2-fluoro-benzamide 674 496 [1,2,3]Thiadiazole-4-carboxylic acid (4- { 3-[2-(3-dimethylamino-5-trifluoro methyl-phenyl)-ethyl]-thioureido}-phenyl)-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)-thioureido]-phenyl }-2-fluoro-benzamide 678 495 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-bromo-phenylsulfanyl) ethyl]-thioureido}-phenyl)-amide 679 477 Furan-2-carboxylic acid (4-{3-[2-(3-bromo-phenylsulfanyl)-ethyl] thioureido}-phenyl)-amide 680 505 N-(4- {3-[2-(3-Bromo-phenylsulfanyl)-ethyl]-thioureido }-phenyl)-2-fluoro benzamide WO 00/34268 PCT/US99/28838 - 122 681 493 [l, 2 ,3]Thiadiazole-4-carboxylic acid ( 4
-{
3 -[2-(3-bromo-4-methoxy-phenyl) ethyll-thioureido)}-phenyl)- amnide 682 493 [1 , 2 ,3]Thiadiazole-4-carboxylic acid (4-f 3-[ 2 -(5-bromo-2-methoxy-phenyl) ethyl]-thioureidol}-phenyl)- amnide 683 419 [1 , 2 ,3]Thiadiazole-4-carboxylic acid (4-f 3-[2-(2-chloro-phenyl)-ethyl] thioureido}-phenyl)-amide 684 402 [1 , 2 ,3]Thiadiazole-4-carboxylic acid (4- {3-[2-(2-fluoro-phenyl)-ethyl] thioureido } -phenyl)-aniide 685 419 [1 , 2
,
3 ]Thiadiazole-4-carboxylic acid (4-f{ 3-[2-(4-chloro-phenyl)-ethyl] thioureido I -phenyl)-ajnide 686 475 [1 , 2 ,3]Thiadiazole-4-carboxylic acid { 4 -[3-(3,3-diphenyl-propyl) thioureido]-phenyl I -amide 687 547 2-Fluoro-N-(4-1{ 3
-[
4 -(4-methyl-piperazin- 1-yl)-3-trifluoromethyl-benzylj thioureido I -phenyl)-benzamnide 688 469 [1 , 2 ,3]Thiadiazole-4-carboxyuic acid (4- f 3-[2-(3,5-dichloro-phenoxy)-ethyl]y thioureido I -phenyl)-amide 689 423 [1 , 2 ,3]Thiadiazole-4-carboxylic acid { 4-[3-(3-chloro-4-fluoro-benzyl) thioureidol-phenyl I -amnide 690 427 [1 , 2 ,3]Thiadiazole-4-carboxylic acid { 4 -[3-(4-tert-butyl-benzyl)-thioureido] phenyl}-amide 691 399 [1i, 2 ,3]Thiadiazole-4-carboxylic acid {4-[3-(3.5-dimethyl-benzyl) thioureido]-phenyl } -amide 692 442 [1 , 2 ,3]Thiadiazole-4-carboxylic acid (4-1{3-[2-(4-dimethylamino-3-methyl phenyl)-ethyl]-thioureido }-phenyl)-amide 693 479 [1 ,2,3]Thiadiazole-4-carboxyuic acid (4-{ 3-[2-(4-bromo-phenoxy)-ethyly thioureido I}-phenyl)-nide 694 526 [1 ,2,3]Thiadiazole-4-carboxylic acid (4- {3-[2-(4-iodo-phenoxy)-ethyl] thioureido}-phenyl)-amnide 695 489 N-(4-{ 3
-[
2
-(
4 -Bromo-phenoxy)-ethylj-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- { 3
-[
2 -(4-bromo-phenoxy)-ethyl]-thioureido
}
phenyl)-amide 698 508 Furan-2-carboxylic acid (4-1{ 3
-[
2
-(
4 -iodo-phenoxy)-ethyl]-thioureido
}
phenyl)-ainide 699 408 Oxazole-4-carboxylic acid { 4 -[3-(3,4-dichloro-phenyl)-thioureido] phenyl }-ainide 700 424 Thiazole-4-carboxylic acid { 4 -[3-(3,5-dichloro-phenyl)-thioureido]-phenyl)}- WO 00/34268 PCT/US99/28838 - 123 amide 701 491 Thiazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl-phenyl) thioureido]-phenyl} -amide 702 408 Oxazole-4-carboxylic acid f{4-[3-(3,5-dichloro-phenyl)-thioureido]-pheny } amnide 703 469 [1 ,2,3]Thiadiazole-4-carboxylic acid (4-1{3-[2-(3,4-dichloro-phenoxy)-ethyl] thioureido }-phenyl)-amide 704 424 Thiazole-4-carboxylic acid {4-[3-(3,4-dichloro-phenyl)-thioureido]-phenyl } amide 705 458 Thiazole-4-carboxylic acid {4-r3-(4-chloro-3-trifluoromethyl-phenyl) thioureido]-phenyll}-amide 706 400 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-phenylamino-ethyl) thioureido]-phenyl }-amnide 707 453 [1 ,2,3]Thiadiazole-4-carboxylic acid (4-1{3-[2-(2,4-dichloro-phenyl)-ethyll thiioureido }-phenyl)-amide 708 452 [1 ,2,3]Thiadiazole-4-carboxylic acid (4-1{3-r2-(3-trifluoromethyl-phenyl) ethiyl]-thioureido)}-phenyl)-amide 709 453 [1 ,2,3]Thiadiazole-4-carboxylic acid (4- {3-12-(2,6-dichloro-phenyl)-ethyl] thioureido I -phenyl)-ainide 710 485 [1 ,2,3]Thiadiazole-4-carboxylic acid (4-{ 3-[2-(3,4-dichloro-phenylsulfanyl) ethyl]-thioureido } -phenyl)-ainide 711 503 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(2-fluoro-5-trifluoromethyl phenylsulfanyl)-ethyll-thioureido} -phenyl)-amnide 712 668 N-(4-{ 3-jj3-Chloro-5-(3-{ 4-[([1 ,2,3]thiadiazole-4-carbonyl)-amino]-phenyl } thioureido)-phenyl]-thioureido}I-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}-ainide 715 475 Oxazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl-phenyl) thioureido]-phenyl } -amnide 716 420 [1,2,3]Thiadiazole-4-carboxylic acid (4-{ 3-12-(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- WO 00/34268 PCT/US99/28838 - 124 benzamide 720 420 [1 ,2,3]Thiadiazole-4-carboxylic acid (4-f{ 3-[2-(3,5-difluoro-phenyl)-ethyl] thioureido I}-phenyl)-amyide 721 412 2-Fluoro-N-(4- f 3-[2-(2-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-benzamide 722 429 [i,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-( I-methyl-2-phenyl-ethyl) thioureido]-phenyl I -amide 724 437 N-{f 4 -[3-(4-tert-Butyl-benzyl)-thioureido]-phenyl I -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 {4-13-(2-hydroxy-1 -phenyl-ethyl) thioureido]-phenyl } -amnide 727 409 2-Hluoro-N- 14-[3-(l 1-methyl- I -phenyl-ethyl)-thioureido]-phenyl I benzamnide 728 399 [1 , 2 ,3]Thiadiazole-4-carboxylic acid {4-[3-(1 -methyl-I -phenyl-ethyl) thioureido]-phenyl } -amide 729 405 [l, 2 ,3]Thiadiazole-4-caboxylic acid {4-[3-(2-chloro-benzyl)-thioureido] phenyl } -amide 730 388 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-fluoro-benzyl)-thioureido] phenyll}-amide 731 438 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-trifluoromethyl-benzyl) thioureido]-phenyl }-amnide 732 388 [1 , 2 ,3ljThiadiazole-4-carboxylic acid f{4-[3-(3-fluoro-benzyl)-thioureido] phenyll}-ainide 733 435 [1 ,2,3lThiadiazole-4-carboxylic acid (4-1{3-[2-(2-chloro-phenoxy)-ethyl] thioureidol}-phenyl)-ainide 734 479 [1 ,2,3]Thiadiazole-4-carboxylic acid (4-{ 3-[2-(3-bromo-phenoxy)-ethyl] thioureido }-phenyl)-amide 735 418 [1 ,2,3]Thiadiazole-4-carboxylic acid (4-1{3-[2-(2-fluoro-phenoxy)-ethyl] thioureido} -phenyl)-ainide 736 418 ri ,2,3]Thiadiazole-4-carboxylic acid (4-1{3-[2-(3-fluoro-phenoxy)-ethyl] thioureido I -phenyl)-amide 737 486 [1 ,2,3lThiadiazole-4-carboxylic acid (4-1{3-[2-(2-fluoro-5-trifluoromethyl phenoxy)-ethyl]-thioureido)-phenyl)-amide 738 384 Furan-2-carboxylic acid (4-1{3-[2-(2-fluoro-phenyl)-ethyl]-thioureido} phenyl)-ainide 739 435 [1 ,2,3]Thiadiazole-4-carboxylic acid { 4 -[3-(4-bromo-phenyl)-thioureido] phenyl }-amnide WO 00/34268 PCT/US99/28838 - 125 740 374 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-fluoro-phenyl)-thioureido] phenyl}-amide 741 388 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-fluoro-benzyl)-thioureido] phenyl}-amide 742 405 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-chloro-benzyl)-thioureido] phenyl }-amide 743 449 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-bromo-benzyl)-thioureido] phenyl}-amide 744 332 N-(4-{ 3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido }-phenyl)-acetamide 745 438 Thiazole-4-carboxylic acid {4-[3-(3,4-dichloro-benzyl)-thioureido]-phenyl} amide 746 455 Thiazole-4-carboxylic acid {4-[3-(2-fluoro-5-trifluoromethyl-benzyl) thioureido]-phenyl }-amide 747 426 Thiazole-4-carboxylic acid {4-[3-(4-tert-butyl-benzyl)-thioureido]-phenyl} amide 748 374 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-fluoro-phenyl)-thioureido] phenyl } -amide 749 374 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-fluoro-phenyl)-thioureido] phenyl}-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-[1-(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-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-4-methoxy benzamide 755 429 2-Chloro-N-(4- { 3-[ 1-(4-fluoro-phenyl)-ethyl]-thioureido } -phenyl) benzamide 756 429 4-Chloro-N-(4- { 3-[i1-(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-[1-(4-Fluoro-phenyl)-ethyl]-thioureido }-phenyl)-isonicotinamide 760 410 N-(4-{ 3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-4-hydroxy- WO 00/34268 PCT/US99/28838 - 126 benzamide 761 429 3-Chloro-N-(4- { 3-[I-( 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)-amide 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 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-[i-( 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-[1-( 4 -fluoro-phenyl)-pentyl]-thioureido}-phenyl) benzamide 774 489 2-Fluoro-N-(4-{ 3-[i-( 4 -fluoro-phenyl)-2-phenyl-ethyl]-thioureido}-phenyl) benzamide 775 409 2-Fluoro-N-{4-[3-(i-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-[i-(4-methoxy-phenyl)-ethyl]-thioureido}-phenyl) benzainide 778 412 2-Fluoro-N-(4-{3-[i-(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- WO 00/34268 PCT/US99/28838 - 127 benzainide 781 429 N-(4-{ 3-[1 -(4-Chloro-phenyl)-ethyl]-thioureido }-phenyl)-2-fluoro benzamide 782 409 2-Fluoro-N- 14-[3-(l -p-tolyl-ethyl)-thioureido]-phenyl I}-benzamnide 783 473 N-(4-{ 3-[1 -(2-Bromo-phenyl)-ethyl]-thioureido }-phenyl)-2-fluoro benzamide 784 429 N-(4- { 3-[1 -(2-Chloro-phenyl)-ethylJ-thioureido)}-phenyl)-2-fluoro benzamide 785 462 2-Fluoro-N-(4-1{3-[l1-(2-trifluoromethyl-phenyl)-ethyl]-thioureido} -phenyl) benzainide 786 462 2-Fluoro-N-(4- { 3-[l1-(3-trifluoromethyl-phenyl)-ethyl]-thioureido }-phenyl) benzamide 787 462 2-Fluoro-N-(4-1{3-ri -(4-trifluoromethyl-phenyl)-ethyl]-thioureido} -phenyl) benzainide 788 425 2-Fluoro-N-(4- {3-[1 -(2-methoxy-phenyl)-etlhyl]-thioureido }-phenyl) benzamide 789 425 2-Fluoro-N-(4- {3-[1 -(3-methoxy-phenyl)-ethyl]-thioureido)}-phenyl) benzainide 790 441 2-Fluoro-N-(4- { 3-[ 1-(4-fluoro-phenyl)-2-methyl-propyl]-thioureido } phenyl)-benzamide 791 419 N-(4- {3-[1 -(3-Cyano-phenyl)-ethyl]-thioureido }-phenyl)-2-fluoro-benzamide 792 419 N-(4- {3-[1 -(4-Cyano-phenyl)-ethyl]-thioureido }-phenyl)-2-fluoro-benzamide 793 438 N-(4- {3-[i -(4-Dimethylamino-phenyl)-ethyl]-thioureido }-phenyl)-2-fluoro benzamide 794 438 N-(4-({3-[1 -(3-Dimethylamino-phenyl)-ethyl]-thioureido }-phenyl)-2-fluoro benzainide 795 473 2-Bromo-N-(4-{ 3-[ 1-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl) benzamide 796 446 Quinoline-2-carboxylic acid (4-1{3-[l1-(4-fluoro-phenyl)-ethyl]-thioureido} phenyl)-ainide 797 410 2-Fluoro-N-{4-113-(2-hydroxy-1 -phenyl-ethyl)-thioureido]-phenyl } benzainide 798 332 2-Fluoro-N-[4-(3-isopropyl-thioureido)-phenyl-benzamide 799 445 2-Fluoro-N-{4-[3-(l1-naphthalen-2-yl-ethyl)-thioureido]-phenyl} -benzamide 800 412 3-Fluoro-N-(4-{ 3-Il-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-benzainide 801 412 4-Fluoro-N-(4-1{3-[i -(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-benzainide 802 384 2-Fluoro-N-{4-[3-(I -furan-2-yl-ethyl)-thioureido]-phenyl }-benzamide WO 00/34268 PCT/US99/28838 - 128 803 395 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)-ethyl]-thioureido }-phenyl) benzamide 805 401 2-Fluoro-N-{4-[3-(1-thiophen-3-yl-ethyl)-thioureido]-phenyl }-benzamide 806 445 N- { 4
-[
3
-(
3 -Chloro-4-ethoxy-phenyl)-thioureido]-phenyl } -2-fluoro benzamide 807 459 N-{ 4
-[
3
-(
3 -Chloro-4-propoxy-phenyl)-thioureido]-phenyl }-2-fluoro benzamide 808 459 N-{ 4
-[
3
-(
3 -Chloro-4-isopropoxy-phenyl)-thioureido]-phenyl }-2-fluoro benzamide 809 473 N-{4-[3-(4-Butoxy-3-chloro-phenyl)-thioureido]-phenyl }-2-fluoro benzamide 810 522 2-Fluoro-N- { 4
-[
3
-(
3 -iodo-4-methoxy-phenyl)-thioureido]-phenyl
}
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-benzamide 813 346 N-(4- { 3-[1-( 4 -Fluoro-phenyl)-ethyl]-thioureido } -phenyl)-propionamide 814 286 N-[ 4 -(3-Phenyl-thioureido)-phenyl]-acetamnide EXAMPLE 815 (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 approximately 30 minutes at room temperature. [1,2,3]-Thiadiazole-4-carboxylic acid 10 (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 is filtered and the collected precipitate is washed with acetonitrile then diethyl ether, and air dried to provide the desired product as a white powder. 15 WO 00/34268 PCT/US99/28838 - 129 Using the above procedure and appropriate starting materials the following compounds were prepared: EX. M+H COMPOUND NAME NO. 816 321 N-{4-[3-(3-Chloro-phenyl)-thioureido]-phenyl }-acetamide 817 413 N- {4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl } -benzamide 818 443 N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl}-2-methoxy-benzamide 819 443 N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl }-3-methoxy-benzamide 820 443 N- {4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl }-4-methoxy-benzamide 821 431 N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl }-4-methoxy-benzamide 822 431 N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl}-3-fluoro-benzamide 823 431 N- {4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl }-4-fluoro-benzamide 824 437 Furan-2-carboxylic acid {4-[3-(3,5-dichloro-4-methoxy-phenyl)-thioureido] phenyl}-amide 825 511 {4-[3-(5-Bromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-carbamic acid hexyl ester 826 481 Hexanoic acid {4-[3-(5-bromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl} amide 827 505 N- {4-[3-(5-Bromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl } -2-fluoro benzamide 828 477 Furan-2-carboxylic acid {4-[3-(5-bromo-2,4-dimethoxy-phenyl)-thioureido] phenyl }-amide 829 501 N- {4-[3-(5-Bromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl } -2-methyl benzamide 830 517 N-{4-[3-(5-Bromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-4-methoxy benzamide 831 395 N- {4-[3-(5-Chloro-2-ethoxy-4-methoxy-phenyl)-thioureido]-phenyl }-acetamide 832 395 N-{4-[3-(5-Chloro-4-ethoxy-2-methoxy-phenyl)-thioureido]-phenyl }-acetamide 833 423 N- {4-[3-(2-Butoxy-5-chloro-4-methoxy-phenyl)-thioureido]-phenyl}-acetamide 834 423 N- {4-[3-(4-Butoxy-5-chloro-2-methoxy-phenyl)-thioureido]-phenyl } -acetamide 835 457 N- {4-[3-(2-Benzyloxy-5-chloro-4-methoxy-phenyl)-thioureido]-phenyl} acetamide 836 457 N-{4-[3-(4-Benzyloxy-5-chloro-2-methoxy-phenyl)-thioureido]-phenyl } acetamide 837 421 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-4-methoxy-phenyl)- WO 00/34268 PCT/US99/28838 - 130 thioureido]-phenyl}-amide 838 424 2- { 4 -[3-( 4 -Acetylamino-phenyl)-thioureido]-2-chloro-5-methoxy-phenoxy } acetamide 839 367 N- { 4 -[3-(5-Chloro-2-hydroxy-4-methoxy-phenyl)-thioureido]-phenyl }-acetamide 840 367 N-{4-[3-(3-Chloro-4-methylsulfanyl-phenyl)-thioureido]-phenyl }-acetamide 841 447 N-[4-(3-{ 3-Chloro-4-[methyl-(1-methyl-piperidin-4-yl)-amino]-phenyl } thioureido)-phenyl]-acetamide 842 426 N-(4- { 3-[3-Chloro-4-(methyl-phenyl-amino)-phenyl]-thioureido}-phenyl) acetamide 843 509 N-[4-(3-{4-[(1-Benzyl-pyrrolidin-3-yl)-methyl-amino]-3-chloro-phenyl
}
thioureido)-phenyl]-acetamide 844 418 N-(4-{ 3-[3-Chloro-4-(cyclopentyl-methyl-amino)-phenyl]-thioureido }-phenyl) acetamide 845 433 N-[4-(3- { 3-Chloro-4-[methyl-(1-methyl-pyrrolidin-3-yl)-amino]-phenyl } thioureido)-phenyl]-acetamide 846 419 Furan-2-carboxylic acid {4-[3-(3-chloro-4-methylsulfanyl-phenyl)-thioureido] phenyl}-amide 847 447 N- { 4
-[
3 -(3-Chloro-4-methylsulfanyl-phenyl)-thioureido]-phenyl } -2-fluoro benzamide 848 465 N- {4-[3-(3-Chloro-4-methylsulfanyl-phenyl)-thioureido]-phenyl }-2,6-difluoro benzamide 849 445 N- {4-[3-(5-Chloro-2-methoxy-4-methyl-phenyl)-thioureido]-phenyl }-2-fluoro benzamide 850 441 N- { 4 -[3-(5-Chloro-2-methoxy-4-methyl-phenyl)-thioureido]-phenyl }-2-methyl benzamide 851 434 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-4-dimethylamino-phenyl) thioureido]-phenyl }-amide 852 444 N-{4-[3-(3-Chloro-4-dimethylamino-phenyl)-thioureido]-phenyl }-2-fluoro benzamide 853 517 [1,2,3]Thiadiazole-4-carboxylic acid [4-(3-{3-chloro-4-[methyl-(1-methyl piperidin-4-yl)-amino]-phenyl }-thioureido)-phenyl]-amide 854 579 [1,2,3]Thiadiazole-4-carboxylic acid [4-(3- {4-[(1-benzyl-pyrrolidin-3-yl) methyl-amino]-3-chloro-phenyl}-thioureido)-phenyl]-amide 855 527 N-[4-(3- { 3-Chloro-4-[methyl-(1-methyl-piperidin-4-yl)-amino]-phenyl } thioureido)-phenyl]-2-fluoro-benzamide 856 435 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(5-chloro-2-methoxy-4-methyl phenyl)-thioureido]-phenyl }-amide 857 589 N-[4-(3-{4-[(1-Benzyl-pyrrolidin-3-yl)-methyl-amino]-3-chloro-phenyl}- WO 00/34268 PCT/US99/28838 - 131 thioureido)-phenyl]-2-fluoro-benzamide 858 501 Furan-2-carboxylic acid { 4 -[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido] 3-trifluoromethyl-phenyl } -amide 859 366 2 -Fluoro-N-[4-(3-phenyl-thioureido)-phenyl]-benzamide 860 338 Furan-2-carboxylic acid [ 4 -(3-phenyl-thioureido)-phenyl]-amide 861 356 [1,2,3]Thiadiazole-4-carboxylic acid [4-(3-phenyl-thioureido)-phenyl]-amide 862 365 N-(4- { 3-[3-Chloro-4-(1-hydroxy-ethyl)-phenyl]-thioureido }-phenyl)-acetamide 863 435 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[3-chloro-4-(1-hydroxy-ethyl)-phenyl] thioureido }-phenyl)-amide 864 365 N-(4- { 3
-[
3 -Chloro- 4 -(2-hydroxy-ethyl)-phenyl]-thioureido }-phenyl)-acetamnide 865 445 N-(4- { 3-[3-Chloro-4-(1-hydroxy-ethyl)-phenyl]-thioureido }-phenyl)-2-fluoro benzamide 866 417 Furan-2-carboxylic acid (4-{3-[3-chloro-4-(1-hydroxy-ethyl)-phenyl]-thioureido} phenyl)-amide 867 371 [1,2,3]Thiadiazole-4-carboxylic acid { 4 -[3-(3-amino-phenyl)-thioureido]-phenyl} amide 868 501 Furan-2-carboxylic acid { 4
-[
3
-(
3 -bromo-4-trifluoromethoxy-phenyl)-thioureido] phenyl }-amide 869 423 N-{ 4 -[3-(3-tert-Butyl-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide 870 440 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-chloro-3,5-dichloro-phenyl) thioureido]-phenyl} -amide 974 485 N- {4-[3-(1-Benzofuran-2-yl-ethyl)-thioureido]-phenyl } -2-trifluoromethyl benzamnide 975 412 N-(4-Fluoro-phenyl)-4- { 3-[ 1-(4-fluoro-phenyl)-ethyl]-thioureido } -benzamide 976 446 Isoquinoline-1l-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido} phenyl)-amide 977 468 Isoquinoline-l1-carboxylic acid {4-[3-(1-benzofuran-2-yl-ethyl)-thioureido] phenyl}-amide 978 506 Isoquinoline-1l-carboxylic acid (4-{3-[1-(4-bromo-phenyl)-ethyl]-thioureido} phenyl)-amide 979 453 Isoquinoline-l-carboxylic acid (4-{3-[1-(4-cyano-phenyl)-ethyl]-thioureido} phenyl)-amide 980 435 Benzofuran-2-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido} phenyl)-amide 981 457 Benzofuran-2-carboxylic acid {4-[3-(1-benzofuran-2-yl-ethyl)-thioureido]-phenyl} amide 982 495 Benzofuran-2-carboxylic acid (4- {3-[1-(4-bromo-phenyl)-ethyl]-thioureido}- WO 00/34268 PCTIUS99/28838 - 132 phenyl)-amide 983 442 Benzofuran-2-carboxylic acid (4-{ 3-[1 -(4-cyano-phenyl)-ethyl]-thioureido } phenyl)-amide 984 446 Isoquinoline-3-carboxylic acid (4-f 3-[ I-(4-fluoro-phenyl)-ethyl]-thioureido } phenyl)-amide 985 468 Isoquinoline-3-carboxylic acid {4-[3-(1 -benzofuran-2-yl-ethyl)-thioureido phenyl I -amnide 986 453 Isoquinoline-3-carboxylic acid (4- f 3-[l1-(4-cyano-phenyl)-ethyl]-thioureido I phenyl)-amide 987 506 Isoquinoline-3-carboxylic acid (4-f 3-Il-(4-bromo-phenyl)-ethyl]-thioureido I phenyl)-amide 988 446 Quinoline-3-carboxylic acid (4- {3-[ I-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl) amide 989 446 Quinoline-4-carboxylic acid (4-{ 3-[l1-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl) amide 990 446 Quinoline-6-carboxylic acid (4-1{3-[ I-(4-fluoro-phenyl)-ethyl]-thioureido)}-phenyl) ainide 991 446 Quinoline-8-carboxylic acid (4- {3-[ 1-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl) ainide 992 462 N-(4-{ 3-[1 -(4-Fluoro-phenyl)-ethyl]-thioureido)}-phenyl)-2-trifluoromethyl benzamnide 993 419 2-Cyano-N-(4-{ 3-[1 -(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-benzamide 994 473 N-{4-[3-(3-Chloro-4-isobutoxy-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide 995 414 2-Fluoro-N-{4-Il3-(3-fluoro-4-methoxy-phenyl)-thioureido]-phenyl }-benzamide 996 475 N-(4-{ 3-[3-Chloro-4-(2-methoxy-ethoxy)-phenyl]-thioureido }-phenyl)-2-fluoro benzainide 997 398 2-Fluoro-N-{4-[3-(3-fluoro-4-methyl-phenyl)-thioureido]-phenyl }-benzamide 998 464 2-Fluoro-N-{4-[3-(4-methoxy-3-trifluoromethyl-phenyl)-thioureido-phenyl } benzamnide 999 449 N-{4-[3-(2-Ainino-5-trifluoromethyl-phenyl)-thioureido]-phenyl I-2-fluoro benzamnide 1000 459 N-(4-{ 3-[1 -(3-Chloro-4-methoxy-phenyl)-ethyl]-thioureido }-phenyl)-2-fluoro benzamide 1001 417 N-{4-13-(5-Chloro-2-hydroxy-phenyl)-thioureido]-phenyl }-2-fluoro-benzamnide 1002 435 N-{4-[3-(1 -Benzofuran-2-yl-ethyl)-thioureido] -phenyl I-2-fluoro-benzaniide 1003 448 2-Fluoro-N-{4-[3-(4-methyl-3-trifluoromethyl-phenyl)-thioureido]-phenyl benzamide WO 00/34268 PCT/US99/28838 - 133 1004 473 (S)-N-(4-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 1005 473 N-(4-{ 3-[(1R)-l1-(4-Bromo-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 1006 494 2-Fluoro-N-(4-{ 3
-[
2 -methoxy-4-(2,2,2-trifluoro-ethoxy)-phenyl]-thioureido} phenyl)-benzamide 1007 399 N-{ 4 -[3-(2-Amino-5-fluoro-phenyl)-thioureido]-phenyl } -2-fluoro-benzamide 1008 502 N-(4- { 3-[1-( 4 -Dimethylsulfamoyl-phenyl)-ethyl]-thioureido } -phenyl)-2-fluoro benzamide 1009 542 2-Fluoro-N-[4-(3-{ 1-[4-(piperidine-l-sulfonyl)-phenyl]-ethyl}-thioureido)-phenyl] benzamide 1010 562 N-(4-{ 3
-[
2
,
4 -Bis-(2,2,2-trifluoro-ethoxy)-phenyl]-thioureido}-phenyl)-2-fluoro benzamide 1011 409 2-Fluoro-N-{4-[3-((1S)-l1-p-tolyl-ethyl)-thioureido]-phenyl}-benzamide 1012 409 2-Fluoro-N-{4-[3-((1R)-l1-p-tolyl-ethyl)-thioureido]-phenyl}-benzamide 1013 394 2-Fluoro-N-{4-[3-((1S)-1l-phenyl-ethyl)-thioureido]-phenyl } -benzamide 1014 429 N-(4-{3-[(1R)-1-( 4 -Chloro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 1015 429 N-(4-{ 3-[(1S)-1-( 4 -Chloro-phenyl)-ethyl]-thioureido } -phenyl)-2-fluoro-benzamide 1016 394 2-Fluoro-N- {4-[3-((1R)-l-phenyl-ethyl)-thioureido]-phenyl } -benzamide 1017 432 N-(4-{3-[1-(4-Cyano-phenyl)-ethyl]-thioureido}-phenyl)-2-methoxy-benzamide 1018 447 N-{4-[3-(1-Benzofuran-2-yl-ethyl)-thioureido]-phenyl}-2-methoxy-benzamide 1019 485 N-(4-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido}-phenyl)-2-methoxy-benzamide 1020 419 3-Cyano-N-(4-{3-[1l-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide 1021 462 N-(4-{3-[1-( 4 -Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-4-trifluoromethyl benzamide 1022 419 4-Cyano-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido} -phenyl)-benzaminide 1023 469 2-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2,3,5,6-tetramethyl phenyl)-benzamide 1024 480 N-(4-{3-[1-( 4 -Cyano-phenyl)-ethyl]-thioureido}-2,5-dimethoxy-phenyl)-2-fluoro benzamide 1025 473 2-Fluoro-N-(4- { 3-[1-(4-fluoro-phenyl)-ethyl]-thioureido } -2,5-dimethoxy-phenyl) benzamide 1026 530 N-{3,5-Dichloro- 4 -[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2 fluoro-benzamide 1027 447 N-(3-Chloro-4-{ 3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-2-fluoro benzamide 1028 480 2,3,4,5-Tetrafluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-3-methyl phenyl)-benzamide WO 00/34268 PCT/US99/28838 -134 1029 462 2,4.5-Trifluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-3-methyl-phenyl) benzamide 1030 427 2-Fluoro-N-(4-{ 3-[1-(4-fluoro-phenyl)-ethyl]-thioureido } -3-methyl-phenyl) benzamide 1031 457 2-Fluoro-N-(4- { 3-[1-(4-fluoro-phenyl)-ethyl]-thioureido } -2-methoxy-5-methyl phenyl)-benzamide 1032 443 2-Fluoro-N-(4- { 3-[1-(4-fluoro-phenyl)-ethyl]-thioureido } -3-methoxy-phenyl) benzamide 1033 570 N-(2,6-Dibromo-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro benzamide 1034 480 2-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2-trifluoromethyl phenyl)-benzamide 1035 541 N-(4-{ 3-[1-(4-Bromo-phenyl)-ethyl]-thioureido } -2-trifluoromethyl-phenyl)-2 fluoro-benzamide 1036 487 N-(4-{ 3-[1-(4-Cyano-phenyl)-ethyl]-thioureido } -2-trifluoromethyl-phenyl)-2 fluoro-benzaminide 1037 503 N-{4-[3-(1-Benzofuran-2-yl-ethyl)-thioureido]-2-trifluoromethyl-phenyl}-2-fluoro benzamide 1038 447 N-(2-Chloro-4-{ 3-[1-(4-fluoro-phenyl)-ethyl]-thioureido } -phenyl)-2-fluoro benzamide 1039 454 N-(2-Chloro-4- { 3-[1-(4-cyano-phenyl)-ethyl]-thioureido } -phenyl)-2-fluoro benzamide 1040 437 N-(2-Cyano-4-{3-[1l-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro benzamide 1041 498 N-(4-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido}-2-cyano-phenyl)-2-fluoro benzamide 1042 445 N-(2-Cyano-4-{3-[1-(4-cyano-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro benzamide 1043 460 N-{4-[3-(1-Benzofuran-2-yl-ethyl)-thioureido]-2-cyano-phenyl}-2-fluoro benzamide 1044 517 N-(2-Benzoyl-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro benzamide 1045 427 2-Fluoro-N-(4- { 3-[1-(4-fluoro-phenyl)-ethyl]-thioureido } -2-methyl-phenyl) benzamide 1046 487 N-(4- { 3-[1-(4-Bromo-phenyl)-ethyl]-thioureido } -2-methyl-phenyl)-2-fluoro benzamnide 1047 434 N-(4- { 3-[1-(4-Cyano-phenyl)-ethyl]-thioureido } -2-methyl-phenyl)-2-fluoro benzamnide WO 00/34268 PCT/US99/28838 - 135 1048 449 N- {4-[3-(1 -Benzofuran-2-yl-ethyl)-thioureido]-2-methyl-phenyl} -2-fluoro benzamide 1049 456 N-(2-Dimethylamino-4- 3-[1-( 4 -fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2 fluoro-benzamide 1050 526 N-(2-Benzyloxy-4-{ 3-[1-( 4 -cyano-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro benzamide 1051 519 N-(2-B enzyloxy-4-{ 3-[1-( 4 -fluoro-phenyl)-ethyl]-thioureido } -phenyl)-2-fluoro benzamide 1052 603 N-[4-{3-[1-( 4 -Bromo-phenyl)-ethyl]-thioureido}- 2 -(2-morpholin-4-yl-ethoxy) phenyl]-2-fluoro-benzamide 1053 603 N-[4-{3-[1-( 4 -Bromo-phenyl)-ethyl]-thioureido}- 2
-(
2 -morpholin-4-yl-ethoxy) phenyl]-2-fluoro-benzamide 1054 542 2-Fluoro-N-[4-{3-[1-( 4 -fluoro-phenyl)-ethyl]-thioureido}-2-(2-morpholin-4-yl ethoxy)-phenyl]-benzamide 1055 485 N-(2-Butoxy-4-{3-[1-( 4 -fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro benzamide 1056 492 N-(2-Butoxy-4-{ 3-[1-( 4 -cyano-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro benzamide 1057 589 N-[4-{3-[1-( 4 -Bromo-phenyl)-ethyl]-thioureido}-2-(2-diethylamino-ethoxy) phenyl]-2-fluoro-benzamide 1058 528 N-(2-(2-Diethylamino-ethoxy)-4-{3-[I-(4-fluoro-phenyl)-ethyl]-thioureido} phenyl)-2-fluoro-benzamide 1059 589 N-[4-{3-[1-( 4 -Bromo-phenyl)-ethyl]-thioureido}-2-(2-diethylamino-ethoxy) phenyl]-2-fluoro-benzamide 1060 457 N-(2-Ethoxy-4-{ 3-[1-(4-fluoro-phenyl)-ethyl]-thioureido } -phenyl)-2-fluoro benzamiide 1061 464 N-(4-{ 3 -[1-(4-Cyano-phenyl)-ethyl]-thioureido}-2-ethoxy-phenyl)-2-fluoro benzamide 1062 468 2-Fluoro-N-[4- { 3-[l-(4-fluoro-phenyl)-ethyl]-thioureido } - 2 -(2-nitrilo-ethoxy) phenyl]-benzamide 1063 475 N-[4-{ 3-[1-(4-Cyano-phenyl)-ethyl]-thioureido}-2-(2-nitrilo-ethoxy)-phenyl]-2 fluoro-benzanide 1064 443 2-Fluoro-N-(4-{3-[1-( 4 -fluoro-phenyl)-ethyl]-thioureido}-2-methoxy-phenyl) benzamide 1065 489 2-Fluoro-N-(5-{3-[1-( 4 -fluoro-phenyl)-ethyl]-thioureido}-biphenyl-2-yl)-benzamide 1066 514 Isoquinoline-1-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2 trifluoromethyl-phenyl)-amide 1067 503 Benzofuran-2-carboxylic acid (4- {3-[1-( 4 -fluoro-phenyl)-ethyl]-thioureido}-2- WO 00/34268 PCT/US99/28838 - 136 trifluoromethyl-phenyl)-amide 1068 514 Isoquinoline-3-carboxylic acid (4-{3-[1l-(4-fluoro-phenyl)-ethyl]-thioureido}-2 trifluoromethyl-phenyl)-amide 1069 471 Isoquinoline-l1-carboxylic acid (2-cyano-4- { 3-[1-(4-fluoro-phenyl)-ethyl] thioureido } -phenyl)-amide 1070 460 Benzofuran-2-carboxylic acid (2-cyano-4-{3-[1-(4-fluoro-phenyl)-ethyl] thioureido } -phenyl)-amide 1071 471 Isoquinoline-3-carboxylic acid (2-cyano-4-{3-[1-(4-fluoro-phenyl)-ethyl] thioureido}-phenyl)-amide 1072 460 Isoquinoline-1l-carboxylic acid (4-{3-l[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2 methyl-phenyl)-amide 1073 449 Benzofuran-2-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2 methyl-phenyl)-amide 1074 460 Isoquinoline-3-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2 methyl-phenyl)-amide 1075 396 Pyrazine-2-carboxylic acid (4- { 3-[1-(4-fluoro-phenyl)-ethyl]-thioureido } -phenyl) amide 1076 401 Thiophene-2-carboxylic acid (4- {3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl) amide 1077 401 Thiophene-3-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl) aminide 1078 500 2 -Isopropyl-thiazole-4-carboxylic acid {4-[3-(4-chloro-3-trifluoromethyl-phenyl) thioureido]-phenyl } -amide 1079 466 2 -Isopropyl-thiazole-4-carboxylic acid {4-[3-(3,5-dichloro-phenyl)-thioureido] phenyl }-amide 1080 466 2 -Isopropyl-thiazole-4-carboxylic acid {4-[3-(3,4-dichloro-phenyl)-thioureido] phenyl}-amide 1081 534 2 -Isopropyl-thiazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl-phenyl) thioureido]-phenyl}-amide 1082 480 2-Butyl-thiazole-4-carboxylic acid {4-[3-(3,4-dichloro-phenyl)-thioureido]-phenyl} amide 1083 514 2-Butyl-thiazole-4-carboxylic acid {4-[3-(4-chloro-3-trifluoromethyl-phenyl) thioureido]-phenyl}-amide 1084 480 2-Butyl-thiazole-4-carboxylic acid { 4 -[3-(3,5-dichloro-phenyl)-thioureido]-phenyl} amide 1085 548 2-Butyl-thiazole-4-carboxylic acid { 4 -[3-(3,5-bis-trifluoromethyl-phenyl) thioureido]-phenyl }-amide 1086 438 2-Methyl-thiazole-4-carboxylic acid {4-[3-(3,5-dichloro-phenyl)-thioureido]- WO 00/34268 PCT/US99/28838 - 137 phenyl}-amide 1087 438 2-Methyl-thiazole-4-carboxylic acid {4-[3-(3,4-dichloro-phenyl)-thioureido] phenyl}-amide 1088 505 2-Methyl-thiazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl-phenyl) thioureido]-phenyl } -amide 1089 534 2-Phenyl-thiazole-4-carboxylic acid {4-[3-(4-chloro-3-trifluoromethyl-phenyl) thioureido]-phenyl } -amide 1090 500 2-Phenyl-thiazole-4-carboxylic acid {4-[3-(3,5-dichloro-phenyl)-thioureido] phenyl}-amide 1091 500 2-Phenyl-thiazole-4-carboxylic acid {4-[3-(3,4-dichloro-phenyl)-thioureido] phenyl }-aminide 1092 568 2-Phenyl-thiazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl-phenyl) thioureido]-phenyl } -amide 1093 401 2-Fluoro-N-{4-[3-(1-thiazol-2-yl-ethyl)-thioureido]-phenyl }-benzamide 1094 588 2-Fluoro-N-[4-(3- { 1-[1-(toluene-4-sulfonyl)- 1 H-indol-2-yl]-ethyl }-thioureido) phenyl]-benzamide 1095 446 2-Fluoro-N-{4-[3-(1-quinolin-2-yl-ethyl)-thioureido]-phenyl}-benzamide 1096 446 2-Fluoro-N-{4-[3-(1-quinolin-4-yl-ethyl)-thioureido]-phenyl}-benzaminide 1097 446 2-Fluoro-N-{4-[3-(1-isoquinolin-3-yl-ethyl)-thioureido]-phenyl}-benzamide 1098 446 2-Fluoro-N-{4-[3-(1-isoquinolin- 1 -yl-ethyl)-thioureido]-phenyl}-benzamide 1099 446 2-Fluoro-N- {4-[3-(1-quinolin-6-yl-ethyl)-thioureido]-phenyl }-benzamide 1100 446 2-Fluoro-N-{4-[3-(1-quinolin-3-yl-ethyl)-thioureido]-phenyl}-benzamide 1101 413 2-Methoxy-N-{4-[3-(1-thiophen-3-yl-ethyl)-thioureido]-phenyl}-benzamide EXAMPLE 871 (METHOD 33) [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-dichloro-phenyl)-thioureido] 5 phenyl}-amide 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 10 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 WO 00/34268 PCT/US99/28838 - 138 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. 5 Using the above procedure and appropriate starting materials the following compounds were prepared: EX. M+H COMPOUND NAME NO. 872 465 N- {4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]-phenyl }-3-fluoro benzamide 873 477 N- {4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]-phenyl }-2-methoxy benzamide 874 465 N-{ 4 -[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]-phenyl }-2-fluoro benzamide 875 477 N-{ 4 -[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]-phenyl }-3-methoxy benzamide 876 399 N- {4-[3-(3,5-Dichloro-2-methoxy-4-methyl-phenyl)-thioureidol-phenyl } -acetamide 877 365 N- {4-[3-(3-Chloro-4-methoxy-5-methyl-phenyl)-thioureido]-phenyl } acetamide 878 331 N-{4-[3-(2-Nitro-phenyl)-thioureido]-phenyl }-acetamide 879 331 N-{4-[3-(4-Nitro-phenyl)-thioureido]-phenyl }-acetamide 880 477 N-{4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]-phenyl }-4-methoxy benzamide 881 351 N-{4-[3-(2-Chloro-5-methoxy-phenyl)-thioureido]-phenyl }-acetamide 882 428 2-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy } acetamide 883 443 { 4 -[3-( 4 -Acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy}-acetic acid methyl ester 884 457 { 4 -[3-(4-Acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy }-acetic acid ethyl ester 885 447 N- {4-[3-(3,5-Dichloro-4-phenoxy-phenyl)-thioureido]-phenyl }-acetamide 886 410 N-(4- {3-[3,5-Dichloro-4-(2-nitrilo-ethoxy)-phenyl]-thioureido}-phenyl) acetamide 887 485 {4-[3-(4-Acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy }-acetic acid tert-butyl ester WO 00/34268 PCT/US99/28838 - 139 888 469 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-dichloro-2-methoxy-4 methyl-phenyl)-thioureido]-phenyl }-ainide 889 335 N-{4-[3-(3-Chloro-4-methyl-phenyl)-4hioureido]-phenyl }-acetamnide 890 335 N- { 4 -[3-(5-Chloro-2-methyl-phenyl)>uhioureidophenyl }-acetainide 891 703 N-{ 4-[3-(4- { 4
-[
3 -(4-Acetylamino-phenyl)-thioureido]-2-chloro phenyldisulfanyl }-3-chloro-phenyl)-thioureido]-phenyl }-acetainide 892 369 N-{ 4 -[3-(3,5-Dichloro-4-methyb-phenyl)ythioureidoy-phenyl)}-acetamide 893 598 N- { 4
-[
3
-(
3
,
5 -Diiodo-2,4-dimethoxy-phenyl)-thioureidoy-phenyl)I-acetamide 894 504 N- { 4
-[
3
-(
3
,
5 -Dibromo-2,4-dimethoxy-phenyl)-ffiioureidoy-phenyl
}
acetainide 895 317 N-{ 4 -[3-(6-Methoxy-pyridin-3-y1)-ffiioureido]-phenyl }-acetamide 896 347 N- { 4
-[
3
-(
2 ,6-Dimethoxy-pyridin-3-yl)-thioureido]-phenyl)}-acetainide 897 457 Acetic acid 2
-{
4 -1 3
-(
4 -acetylaino-phenyl)-thioureido]-2,6-dichloro phenoxy}I-ethyl ester 898 365 4
-[
3
-(
4 -Acetylamnino-phenyl)-thioureido]-2-chloro-benzoic acid 899 346 N- { 4
-[
3 -(3-Chloro-4-cyano-phenyl)-thioureido]-phenyl)}-acetamide 900 512 N-(4- { 3 -[5-Chloro-2-(4-chloro-phenoxy)-4-pyrrol- 1-yl-phenyl]-thioureido } phenyl)-acetamide 901 355 N-{ 4 -[3-(3,4-Dichloro-phenyl).tjiioureido]-phenyl }-acetamide 902 339 N-{4-[3-(3-Chloro-4-fluoro-phenyl)4thioureido]-phenyl }-acetamide 903 447 N-{4-[3-(3-Chloro-4-iodo-phenyl)..thioureidoy-phenyl }-acetamide 904 400 N-{ 4 -[3-( 4 -Bromo-3-chloro-phenyl)-thioureido]-phenyl }-acetalnide 905 424 N-[ 4 -(3-{4-[Bis-(2-hydroxy-ethyl)-amino]-3-chloro-phenyl }-thioureido) phenyll-acetamide 906 434 N-( 4
-{
3 -[3-Chloro-4-(hexyI-methyl-aino)-pheny].tioureidoy-phenyl) acetamide 907 406 N-(4-1{ 3 -L3-Chloro-4-(isobutyl-methyl-amino)-phenyl]-thioureido }-phenyl) acetainide 908 389 N- { 4
-[
3 -(3-Chloro-4-trifluoromethyl-phenyl)-thioureido]-phenyl }-acetamnide 909 441 Furan-2-carboxylic acid {4-[3-(3-chloro-4-trifluoromethyl-phenyl) thioureido]-phenyl I -amnide 910 459 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-4-trifluoromethyl phenyl)-thioureido]-phenyl }-amnide 911 469 N- { 4
-[
3
-(
3 -Chloro-4-trifluoromethyl-phenyl)-thioureido]-phenyl)}-2-fluoro benzainide 912 435 N-{ 4-[3-(3,4-Dichloro-phenyl)-thioureido]-phenyl }-2-fluoro-benzamnide WO 00/34268 PCT/US99/28838 - 140 913 407 Furan-2-carboxylic acid { 4 -13-(3.4-dichloro-phenyl)-thioureidoj-phenyl
}
amide 914 425 [1 , 2 ,3]Thiadiazole-4-carboxylic acid {4-[3-(3,4-dichloro-phenyl)-thioureido] phenyll}-amnide 915 480 N-{ 4 -[3-(4-Bromo-3-chloro..phenyl).ffiioureidop-phenyl)}-2-fluoro-benzamnide 916 527 N-f 4
-[
3
-(
3 -Chloro-4-iodo-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide 917 452 Furan-2-carboxylic acid { 4 -[3-(4-bromo-3-chloro-phenyl)-thioureidoj. phenyl)}-amide 918 499 Furan-2-carboxylic acid { 4 -[3-(3-chloro-4-iodo-phenyl)-thioureido]-phenyl} amide 919 391 Furan-2-carboxylic acid { 4 -[3-(3-chloro-4-fluoro-phenyl)-thioureido.. phenyll}-amide 920 470 [1 .
2
,
3 ]Thiadiazole-4-carboxylic acid {4-[3-(4-bromo-3-chloro-phenyl) thioureido]-phenyll}-amide 921 517 [1 , 2 ,3]Thiadiazole-4-carboxylic acid {4-13-(3-chloro-4-iodo-phenyl) thioureido]-phenyl)}-amide 922 419 N- { 4
-[
3
-(
3 -Chloro-4-fluoro-phenyl)-thioureido]-phenyl }-2-fluoro-benzamnide 923 409 [1 , 2 ,3]Thiadiazole-4-carboxylic acid{4-[3-(3-chloro-4-fluoro-phenyl)y thioureido]-phenyl I -amide 924 388 N- { 4
-[
3 -(3-Chloro-4-isoxazob5-ylbphenyl).ffioureido]-pheny I -acetamide 925 387 N-(4-{ 3-[3-Chloro-4-(1 H-pyrazol-3-yl)-phenyl]-thioureido }-phenyl) acetamide 926 355 N-{1 4 -[3-(2.3-Dichloro..phenyl)ffiioureidoy-phenyI I -acetamide 927 435 N-{1 4 -1 3
-(
2 .3-Dichloro-phenyl)thioureido]-phenyI I -2-fluoro-benzamide 928 407 Furan-2-carboxylic acid { 4 -[3-(2,3-dichloro-phenyl)-thioureidoy-phenyl}.. amide 929 425 [1 , 2 ,3]Thiadiazole-4-carboxylic acid {4-[3-(2,3-dichloro-phenyl)-thioureido]. phenyl }-amide 930 355 N-{ 4 -[3-(2,5-Dichloro-phenyl)ffiioureidoy-phenyI I -acetaniide 931 435 N-{1 4
-[
3
-(
2 ,5-Dichloro-phenyl)-ffiioureido]-phenyI } -2-fluoro-beuzamide 932 407 Furan-2-carboxylic acid { 4 -[3-(2,5-dichloro-phenyl)-thioureidol-phenyl
}
amide 933 355 N- { 4
-[
3 -(3,5-Dichloro-phenyl)-thioureido]-phenyl }-acetamide 934 435 N-{ 4
-[
3 -(3,5-Dichloro-phenyl)-ffiioureido]-phenyl }-2-fluoro-benzamide 935 407 Furan-2-carboxylic acid {4-r3-(3,5-dichloro-phenyl)-thioureido]-phenyl
}
amide WO 00/34268 PCT/US99/28838 - 141 936 390 N-{1 4
-[
3 -(3,4,5-Trichlorophenyl)-thioureidop-phenyl I -acetamnide 937 470 2-Fluoro-N- { 4
-[
3
-(
3
,
4 ,5-trichloro-phenyl)-thboureido]-phenyI I -benzainide 938 442 Furan-2-carboxylic acid { 4 -r 3
-(
3
,
4 ,5-trichloro-phenyl)-thioureido-phenyl 1 amide 939 460 [i 1, 2
,
3 ]Thiadiazole-4-carboxylic acid{ 4-[3-(3,4,5-trichloro-phenyl) thioureido] -phenyl I -amide 940 458 [1 , 2 ,3]Thiadiazole-4-carboxylic acid { 4
-[
3 -(3-chloro-4-isoxazol-5-yl phenyl)-thioureido]-phenyl I-amide 941 457 [1i, 2 ,3]Thiadiazole-4-carboxylic acid(4-{ 3-13-chloro-4-( 1H-pyrazol-3-yl) phenyl]-thioureido }-phenyl)-amide 942 391 [1 , 2
,
3 ]Thiadiazole-4-carboxylic acid { 4
-[
3 -(3-chloro-phenyl)-thioureido] phenyll}-ainide 943 373 Furan-2-carboxylic acid f{ 4
-[
3
-(
3 -chloro-pheny)-thioureidol-phenyl) -aride 944 401 N-{ 4
-[
3 -(3-Chloro-phenyl)dthioureido]-phenyl }-2-fluoro-benzamide 945 373 Furan-2-carboxylic acid { 4
-[
3
-(
4 -chloro-phenyl)-thioureido]-phenyl)I-amide 946 401 N- { 4
-[
3
-(
4 -Chloro-phenyl)-thioureido]-plenyl I-2-fluoro-benzamide 947 391 [1 , 2
,
3 ilThiadiazole-4-carboxylic acid { 4 -[3-( 4 -chloro-phenyl)-thioureido] phenyl} -amnide 948 401 N-{ 4
-[
3 -(2-Chloro-phenyl)ythioureido]-phenyl I-2-fluoro-benzainide 949 396 3
-(
3
-{
4 -[(Furan-2-carbonyl)amino-pheny I thioureido)-benzoic acid methyl ester 950 424 3-{ 3
-[
4
-(
2 -Fluoro-benzoylamrino)-phenyl]-thioureidoy-benzoic acid methyl ester 951 414 3-(3- {4-II([1 , 2 3 ]Thiadiazole-4-carbonyl)-amino]-phenyl I-thioureido)-benzoic acid methyl ester 952 409 N-[ 4
-[[[[
3 -(Aminocarbonyl)phenyl]aininolthioxomethyl]amino]phenyll-2 fluoro-benzwmide 953 373 Furan-2-carboxyhic acid { 4
-[
3
-(
2 -chloro-phenyl)-thioureido]-phenyl 1-ainide 954 381 Furan-2-carboxylic acid { 4
-[
3
-(
3 -carbamnoyl-phenyl)-thioureido].phenyl
I
amide 955 399 [1 , 2 ,3]Thiadiazole-4-carboxyuic acid { 4 -[3-(3-carbamoyl-phenyl) thioureido]-phenyl)I-amide 956 391 [1 , 2
,
3 llThiadiazole-4-carboxylic acid { 4 -[3-(2-chloro-phenyl)-thioureido] phenyl }-amide 957 356 Furan-2-carboxylic acid { 4
-[
3
-(
3 -fluoro-phenyl)-thioureidoy-phenyl I-amnide 958 383 Furan-2-carboxylic acid { 4
-[
3
-(
3 -nitro-phenyl)-thioureido]-phenyl I-amide WO 00/34268 PCT/US99/28838 - 142 959 411 2-Fluoro-N- {4-[3-(3-nitro-phenyl)-thioureido]-phenyl}-benzamide 960 422 Furan-2-carboxylic acid {4-[3-(3-trifluoromethoxy-phenyl)-thioureido] phenyl}-amide 961 450 2-Fluoro-N- {4-[3-(3-trifluoromethoxy-phenyl)-thioureido]-phenyl } benzamide 962 384 2-Fluoro-N- {4-[3-(3-fluoro-phenyl)-thioureido]-phenyl }-benzamide 963 410 3- {3-[4-(2-Fluoro-benzoylamino)-phenyl]-thioureido}-benzoic acid 964 382 3-(3- {4-[(Furan-2-carbonyl)-amino]-phenyl }-thioureido)-benzoic acid 965 408 N- {4-[3-(3-Acetyl-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide 966 502 N- {4-[3-(3-Butylsulfamoyl-phenyl)-thioureido]-phenyl } -2-fluoro-benzamide 967 380 Furan-2-carboxylic acid {4-[3-(3-acetyl-phenyl)-thioureido]-phenyl}-amide 968 447 Furan-2-carboxylic acid (4-{3-[3-(2-hydroxy-ethanesulfonyl)-phenyl] thioureido }-phenyl)-amide 969 475 2-Fluoro-N-(4- { 3-[3-(2-hydroxy-ethanesulfonyl)-phenyl]-thioureido} phenyl)-benzamide 970 474 Furan-2-carboxylic acid {4-[3-(3-butylsulfamoyl-phenyl)-thioureido] phenyl}-amide EXAMPLE 971 (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 O oC is added dropwise isopropylmagesium bromide (2.0 M, 9.6 mL) with stirring. After 1.5 hours the reaction is quenched with aqueous ammonium chloride and extracted with diethyl ether. The diethyl ether extracts are washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, flitered and evaporated to give an oil. The 10 oil is purifed by silica gel chromatography eluting with 10% dichloromethane hexanes to give the product, a yellow oil (1.76 g). EXAMPLE 972 (METHOD 58) 1-(4-Fluoro-phenyl)-2-methyl-propan- 1-one 15 To a solution of 1-(4-Fluoro-phenyl)-2-methyl-propan-l-ol (1.6 g) in acetone (10 mL) at O oC is added Jones reagent (20 mL) with stirring. After 10 minutes excess WO 00/34268 PCT/US99/28838 - 143 Jones reagent is destroyed by addition of isopropyl alcohol. Diethyl ether is added followed by anhydrous magnesium and the mixture is filtered and evaporated to give the product, a yellow oil (1.2 g). 5 EXAMPLE 973 (METHOD 59) 3-Dimethylamino-5-trifluoromethyl-benzonitrile 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 10 at reflux for 12 hours. The reaction is diluted with water (40 mL) and dichloromethane is added. The dichloromethane fraction is washed with concentrated ammonium hydroxide, then water. The solution is dried over anhydrous magnesium sulfate, filtered and concentrated to give a yellow solid which is recrystallized from hexanes to give a yellow solid, (4.7 g). 15 The foregoing compounds were tested for activity as herpes virus inhibitors using the following assays. HUMAN CYTOMEGALOVIRUS 20 Yield assay. Monolayer cultures of human foreskin fibroblasts are infected with HCMV wild-type, typically at a multiplicity of infection equal to 0.2, in the presence of inhibitor compound (varying concentrations). At three days post-infection, total virus produced in these cultures (i.e. virus yield) is assessed by harvesting and titering the virus in 12-well plates of cultured human foreskin fibroblasts (done in the 25 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 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 30 50% or 90%, respectively. Table I describes IC data for compounds tested against
HCMV.
WO 00/34268 PCT/US99/28838 - 144 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 5 Escherichia coli as a gene fusion marker. Proc. Natl. Acad. Sci. USA 83:8447-8451) whose expression is controlled by a viral promoter. An example of such a virus is RV145 (Jones, T. R., V. P. Muzithras, and Y. Gluzman. 1991. Replacement mutagenesis of the human cytomegalovirus genome: US10 and US 11 gene products are nonessential. J. Virol. 65:5860-5872). Since it is under the control of a viral 10 promoter, beta-glucuronidase expression is an indirect indicator of growth and replication of HCMV in this assay. At 96 hours post-infection, the infected cell lysates are prepared (using 50mM sodium phosphate [pH7.0] containing 0.1% Triton X-100 and 0.1% sarkosyl) and assayed for beta-glucuronidase activity using a substrate for the enzyme which when cleaved yields either a product which can be 15 measured colorimetrically in a spectrophotometer or fluorescently in a 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 20 of the chromophore or fluorophore product in this assay is correspondingly reduced. Data from this assay generated using varying amounts of inhibitor compound is also used to estimate the IC50 of an inhibitor compound. HSV antiviral (ELISA) assay 25 Vero cells (ATCC #CCL-81) are plated on 96-well tissue culture plates at 3.5x10 4 cells per 10 0 1 pl tissue culture DMEM (Dulbecco's modified Eagle media) supplemented with 2% fetal bovine serum (FBS) in each well. After overnight incubation @ 37oC (in 5% CO2) and 30 minutes prior to infection with HSV-1 30 (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 @ 37oC (in 5% CO 2 ), cells are WO 00/34268 PCT/US99/28838 - 145 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 5 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 50 so) 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. 10 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 15 (less than 0.1) and incubated overnight at 37oC in 5% CO 2 . After the overnight 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 pl DMEM supplemented with 2% FBS) which contain test compound or the reference standard drug control (in 100[l DMEM supplemented with 2% FBS per well). These cells are 20 incubated for three days at 37oC in 5% CO 2 then fixed for ELISA assay. The primary antibody is murine anti-VZV glycoprotein II monoclonal antibody (Applied Biosystems, Inc. #13-145-100) and the secondary antibody is goat anti-mouse IgG linked to B-galactosidase. Thus the extent of viral replication is determined by assessing B-galactosidase activity by quantifying the generation of the 4-methyl 25 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 (ICso) 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. 30 WO 00/34268 PCT/US99/28838 - 146 Table I describes ICso 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 426 1.6 >10 2 1.8 427 0.8 >10 21 1.2 428 >10 >10 0 >10 429 1 >10 0 >10 443 >10 >10 0 >10 444 4 8 0 >10 471 0.03 >10 27 >10 480 7 >10 42 >10 483 5 1.2 45 >10 520 0.32 12 38 >10 525 0.018 2.5 39 >10 593 >0.5 10 >10 608 >0.5 9 >10 609 1.5 8 >10 629 0.5 >10 >10 632 >10 >10 >10 633 0.34 >10 >10 634 0.12 >10 >10 649 0.02 >10 0.5 658 >0.5 10 659 >0.5 >10 660 >0.5 10 802 >10 >10 7.3 803 >10 >10 >7.5 804 >10 >10 5.7 805 8 >10 1.6 1093 >10 >10 >10 1094 >10 >10 >7.5 1095 2.4 >10 7.1 1096 5.7 >10 6.7 1097 4 >10 5.50 1098 3.5 9 3.80 1099 5.6 >10 >7.5 1100 4.6 >10 7.3 1101 >10 >10 1 5 Thus, in accordance with the present invention, compounds of the present invention may be administered to a patient suffering from VZV, in an amount effective to inhibit the virus. Compounds of the present invention are thus useful to WO 00/34268 PCT/US99/28838 - 147 ameliorate to eliminate the symptoms of VZV 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 carrier 20 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 sodium 25 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 injection. Sterile solutions can also be administered intravenously. Oral administration may be either liquid or solid composition form.
WO 00/34268 PCT/US99/28838 - 148 Preferably the pharmaceutical composition is in unit dosage form, e.g. as tablets or capsules. In such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient; the unit dosage forms can be packaged compositions, for example packeted powders, vials, ampoules, prefilled syringes or 5 sachets containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form. The therapeutically effective dosage to be used in the treatment of CMV infection must be subjectively determined by the attending physician. The variables 10 involved include the the condition , age and weight of the patient. The novel method of the invention for treating CMV infection comprises administering toa subject, including humans, an effective amount of at least one compound of Formula 1 or a non-toxic, pharmaceutically acceptable salt thereof. The compounds may be administered orally, rectally, parenterally or topically to the skin and mucosa. The 15 usual daily dose is depending on the specific compound, method of treatment and condition of the patient. The usual daily dose is 0.01 - 1000 mg/Kg for oral application, preferably 0.5 - 500 mg/Kg, and 0.1 - 100 mg/Kg for parenteral application, preferably 0.5 - 50 mg/Kg.

Claims (15)

  1. 2. A compound of Claim 1 wherein A is selected from pyridyl, furyl, imidazolyl, pyrrolyl, thienyl or indanyl. 25
  2. 3. A compound of Claim 1 wherein A is 3-pyridyl.
  3. 4. A compound of Claim 1 wherein A is substituted. WO 00/34268 PCT/US99/28838 - 150
  4. 5. A compound of Claim 1 wherein A is substituted with one or more substitutents selected from 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, 5 aryl, heteroaryl, halogen, -CN, -NO2 -CO 2 R 6 , -COR 6 , -OR6, -SR6, -SOR 6 , -SO 2 R 6 , -CONR 7 R 8 , -NR 6 N(RTR.), -N(R 7 R,), or W-Y-(CH 2 )n-Z wherein R 6 and R 7 are independently hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, or aryl; R 8 is hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10 10 members, aryl or heteroaryl, or R, and R 8 , taken together may form a 3 to 7 membered heterocycloalkyl; W is O, NR 6 , or is absent; 15 Y is -(CO)- or -(CO 2 )-, or is absent; Z is alkyl of 1 to 4 carbon atoms, -CN, -CO 2 R 6 , COR 6 , -CONRTR, -OCOR 6 , -NR 6 COR 7 , -OCONR 6 , -OR 6 ,-SR 6 ,-SOR 6 , -SO 2 R 6 , SR 6 N(R 7 R,), -N(R 7 R,) or phenyl; 20 and n is 1 to 6.
  5. 6. A compound of Claim 1 wherein A is substituted with one or more substitutents independently selected from halogen or alkyl of 1 to 6 carbon atoms. 25 7. A compound of Claim 1 wherein one or more of R 9 -R 1 2 is independently selected from halogen, methyl, methoxy, and cyano.
  6. 8. A compound of Claim 1 wherein each of R,-R 9 is hydrogen. 30 9. A compound of Claim 1 wherein G is furyl or thiadiazole.
  7. 10. A compound of Claim 1 wherein G is 1,2,3 thiadiazole. WO 00/34268 PCT/US99/28838 - 151 11. A compound of Claim 1 wherein G is 2-furyl.
  8. 12. A compound of Claim 1 wherein X is a bond. 5 13. A compound of Claim 1 wherein X is lower alkyl.
  9. 14. A compound of Claim 1 selected from: Furan-2-carboxylic acid [ 4 -( 3 -pyridin-2-yl-thioureido)-phenyl]-amide; Furan-2-carboxylic acid [4-(3-pyridin-4-yl-thioureido)-phenyl]-amide; 10 Furan-2-carboxylic acid [4-( 3 -pyridin-3-yl-thioureido)-phenyl]-amide; [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(6-chloro-pyridin-3-yl)-thioureido] phenyl }-amide; Furan-2-carboxylic acid [4-( 3 -pyrimidin-4-yl-thioureido)-phenyl]-amide; [1,2,3]Thiadiazole-4-carboxylic acid { 4-[3-(5-chloro-pyridin-3-yl)-thioureido] 15 phenyl }-amide; [1,2,3]Thiadiazole-4-carboxylic acid {4-[ 3 -(5-bromo-pyridin-3-yl)-thioureido] phenyl }-amide; [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(1-tert-butyl-1H-imidazol-2-yl) thioureido]-phenyl } -amide; 20 Furan-2-carboxylic acid {4-[3-(1-tert-butyl-1H-imidazol-2-yl)-thioureido]-phenyl} amide; [1,2,3]Thiadiazole-4-carboxylic acid {(4-[3-(5-trifluoromethyl-pyridin-3-yl) thioureido]-phenyl }-amide; Furan-2-carboxylic acid [4-(3-pyridin-3-ylmethyl-thioureido)-phenyl]-amide; 25 [1,2,3]Thiadiazole-4-carboxylic acid [4-(3-pyridin-3-ylmethyl-thioureido)-phenyl] amide; [1,2,3]Thiadiazole-4-carboxylic acid [4-(3-indan-1-yl-thioureido)-phenyl]-amide; Furan-2-carboxylic acid [ 4 -( 3 -pyridin-4-ylmethyl-thioureido)-phenyl]-amide; [1,2,3]Thiadiazole-4-carboxylic acid [4-( 3 -pyridin-4-ylmethyl-thioureido)-phenyl] 30 amide; 2-Fluoro-N-[ 4 -(3-pyridin-3-yl-thioureido)-phenyl]-benzamide; 2-Fluoro-N-[ 4 -(3-pyridin-2-yl-thioureido)-phenyl]-benzamide; 2-Fluoro-N-[ 4 -(3-pyridin-4-yl-thioureido)-phenyl]-benzamide; WO 00/34268 PCT/US99/28838 - 152 2-Fluoro-N-[ 4 -( 3 -pyridin-3-ylmethyl-thioureido)-phenyl]-benzamide; 2-Fluoro-N- { 4- [3-( 1H-indazol-5-yl)-thioureido]-phenyl } -benzamide; N- { 4-[3-( 1 -tert-Butyl- 1H-imidazol-2-yl)-thioureido]-phenyl } -2-fluoro-benzamide; 2-Fluoro-N-[4-( 3 -pyridin-4-ylmethyl-thioureido)-phenyl]-benzamide; 5 2-Fluoro-N- (4-[3-(1-furan-2-yl-ethyl)-thioureido]-phenyl }-benzamide; 2-Fluoro-N- { 4-[3-( 1 -pyridin-4-yl-ethyl)-thioureido]-phenyl } -benzamide; 2-Fluoro-N-(4- { 3-[1 -(1-methyl- 1H-pyrrol-2-yl)-ethyl] -thioureido } -phenyl) benzamide; and 2-Fluoro-N- { 4- [3- (1 -thiophen-3-yl-ethyl)-thioureido]-phenyl } -benzamide; 10 and pharmaceutical salts thereof.
  10. 15. A pharmaceutical composition comprising a compound of of the formula: R 9 R 10 o ?I\ W A-X-NH-C-NHO NH-C-G R 11 R 12 15 wherein A is heteroaryl; R 9 -R 12 are independently hydrogen, alkyl of 1 to 4 carbon atoms, perhaloalkyl of 1 to 4 carbon atoms, halogen, alkoxy of 1 to 4 carbon atoms, or cyano, or R 9 and Ro or R u and R 1 2 , may be taken together to form aryl 20 of 5 to 7 carbon atoms; W is O, NR 6 , or is absent; G is aryl or heteroaryl; X is a bond X is a bond, -NH, alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, or thioalkyl of 1 to 6 25 carbon atoms, alkylamino of 1 to 6 carbon atoms, or (CH)J; and J is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl or benzyl, or a pharmaceutical salt thereof; and n is an integer from 1 to 6; and a pharmaceutically acceptable carrier or diluent. WO 00/34268 PCT/US99/28838 - 153 16. A method of inhibiting the replication of a herpes virus comprising contacting a compound of the formula: R 9 R 10 R, RV A-X-NH-C-NH /NH-C-G R 11 R 12 5 wherein A is heteroaryl; R 9 -R 2 are independently hydrogen, alkyl of 1 to 4 carbon atoms, perhaloalkyl of 1 to 4 carbon atoms, halogen, alkoxy of 1 to 4 carbon atoms, or cyano, or R 9 and Rio 0 or RI, and R 12 may be taken together to form aryl 10 of 5 to 7 carbon atoms; W is O, NR 6 , or is absent; G is aryl or heteroaryl; X is a bond X is a bond, -NH, alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, or thioalkyl of 1 to 6 15 carbon atoms, alkylamino of 1 to 6 carbon atoms, or (CH)J; and 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. 20
  11. 17. The method of Claim 16 wherein the herpes virus is human cytomegalovirus.
  12. 18. The method of Claim 16 wherein the herpes virus is herpes simplex virus. 25 19. The method of Claim 16 wherein the herpes virus is varicella zoster virus. WO 00/34268 PCT/US99/28838 - 154
  13. 20. A method of treating a patient suffering from a herpes virus infection comprising administering to the patient a therapeutically effective amount of a compound having the formula: R 9 R 10 R, Ri A-X-NH-C-NH NH-C-G R 11 R 1 2 5 wherein A is heteroaryl; R 9 -R 12 are independently hydrogen, alkyl of 1 to 4 carbon atoms, perhaloalkyl of 1 to 4 carbon atoms, halogen, alkoxy of 1 to 4 carbon atoms, or cyano, or R 9 and Ro or R 1 1 and R 12 may be taken together to form aryl 10 of 5 to 7 carbon atoms; W is O, NR 6 , or is absent; G is aryl or heteroaryl; X is a bond 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 15 carbon atoms, alkylamino of 1 to 6 carbon atoms, or (CH)J; and 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. 20
  14. 21. The method of Claim 20 wherein the herpes virus is human cytomegalovirus.
  15. 22. The method of Claim 20 wherein the herpes virus is herpes simplex virus. 25 23. The method of Claim 20 where the herpes virus is varicella zoster virus.
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