Diaminopuridine-containing thiourea inhibitors of herpes viruses

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 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 alphaherpesviris subfamily are neurotropic and include herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), and varicella-zoster virus (VZV). The human betaherpesviruses are cytomegalovirus (HCMV), human herpesvirus 6 (HHV-6) and human herpesvirus 7 (HHV-7). The gammaherpesviruses are lymphotropic and include Epstein-Barr virus (EBV) and Kaposi's herpesvirus (HHV-8). Each of these herpesviruses is causally-related to human disease, including herpes labialis and herpes genitalis (HSV-1 and HSV-2 [Whitley, R. J. 1996. Herpes Simplex Viruses, p. 2297-2342. In B. N. Fields, D. M. Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed. Lippincott-Raven Publishers, Philadelphia, Pa.]); chicken pox and shingles (VZV [Arvin, A. 1996. Varicella-Zoster Virus, p. 2547-2585. In B. N. Fields, D. M. Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed. Lippincott-Raven Publishers, Philadelphia, Pa.]); infectious mononucleosis (EBV [Rickinson, A. B. and Kieff, E. 1996. Epstein-Barr Virus, p. 2397-2446. In B. N. Fields, D. M. Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed. Lippincott-Raven Publishers, Philadelphia, Pa.]); pneumonia and retinitis (HCMV [(Britt, W. J., and Alford, C. A. 1996. Cytomegalovirus, p. 2493-2523. In B. N. Fields, D. M. Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed. Lippincott-Raven Publishers, Philadelphia, Pa.]); exanthem subitum (HHV-6 [(Pellet, P. E, and Black, J. B. 1996. Human Herpesvirus 6, p. 2587-2608. In B. N. Fields, D. M. Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed. Lippincott-Raven Publishers, Philadelphia, Pa.] and HHV-7 [Frenkel, N., and Roffman, E. 1996. Human Herpesvirus 7, p. 2609-2622. In B. N. Fields, D. M. Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed. Lippincott-Raven Publishers, Philadelphia, Pa.]); and Kaposi's sarcoma (HHV-8 [Neipel, F., Albrecht, J. C., and Fleckenstein, B. 1997. Cell-homologous genes in the Kaposi's sarcoma-associated rhadinovirus human herpesvirus 8: determinants of its pathogenicity? J. Virol. 71:4187-92, 1997]). HCMV is considered in more detail below. Following the primary infection, herpesviruses establish latency within the infected individual and remain there for the remainder of his/her life. Periodic reactivation of latent virus is clinically relevant. In the case of HSV, reactivated virus can be transmitted to infants during birth, causing either skin or eye infection, central nervous system infection, or disseminated infection (i.e. multiple organs or systems). Shingles is the clinical manifestation of VZV reactivation. Treatment of HSV and VZV is generally with antiviral drugs such as acyclovir (Glaxo Wellcome), ganciclovir (Roche) and foscarnet (Asta) which target viral encoded DNA polymerase.
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 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 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 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; 25-40% (.about.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 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. 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. 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 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.
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.
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. ##STR2## Morin, Jr., et al., U.S. Pat. No. 5,593,993 teaches certain phenyl thiourea compounds for treatment of AIDs and the inhibition of the replication of HIV and related viruses.
Therefore, it is an object of this invention to provide compounds, and pharmaceutically acceptable salts thereof, to inhibit and/or treat diseases associated with herpes viruses including human cytomegalovirus, herpes simplex viruses, Epstein-Barr virus, varicella-zoster virus, human herpesviruses-6 and -7, and Kaposi herpesvirus.
DESCRIPTION OF THE INVENTION
In accordance with the present invention are provided compounds having the formula: ##STR3## wherein R.sub.1 -R.sub.5 are independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10 carbon members, aryl, heteroaryl, halogen, --CN, --NO.sub.2, --CO.sub.2 R.sub.6, --COR.sub.6, --OR.sub.6, --SR.sub.6, --SOR.sub.6, --SO.sub.2 R.sub.6, --CONR.sub.7 R.sub.8, --NR.sub.6 N(R.sub.7 R.sub.8), --N(R.sub.7 R.sub.8) or W--Y--(CH.sub.2).sub.n --Z; or R.sub.2 and R.sub.3 or R.sub.3 and R.sub.4, taken together form a 3 to 7 membered heterocycloalkyl or 3 to 7 membered heteroaryl;
R.sub.6 and R.sub.7 are independently hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, or aryl;
R.sub.8 is hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10 members, aryl or heteroaryl, or
R.sub.7 and R.sub.8, taken together may form a 3 to 7 membered heterocycloalkyl;
A is heteroaryl;
W is O, NR.sub.6, or is absent;
Y is --(CO)-- or --(CO.sub.2)--, or is absent;
Z is alkyl of 1 to 4 carbon atoms, --CN, --CO.sub.2 R.sub.6, COR.sub.6, --CONR.sub.7 R.sub.8, --OCOR.sub.6, --NR.sub.6 COR.sub.7, --OCONR.sub.6, --OR.sub.6, --SR.sub.6, --SOR.sub.6, --SO.sub.2 R.sub.6, SR6N(R7R8), --N(R.sub.7 R.sub.8) or phenyl;
G is aryl or heteroaryl;
X is a bond, --NH, alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, thioalkyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms, or (CH)J;
J is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl or benzyl; and
n is an integer from 1 to 6; or a pharmaceutical salt thereof.
In some preferred embodiments of the present invention at least one of R.sub.1 -R.sub.5 is not hydrogen, and preferably one to three of R.sub.1 -R.sub.5 is not hydrogen. Preferably, R.sub.1 -R.sub.5 is selected from hydrogen, alkoxy of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, and halogen.
Preferably X is (CH)J where J is alkyl of 1 to 6 carbon atoms. More preferably, J is an alkyl of 1 to 3 carbon atoms and most preferably J is methyl.
A is most preferably unsubstituted.
In some embodiments of the present invention A may be substituted with at least one of hydrogen, alkyl of 1 to 4 carbon atoms, perhaloalkyl of 1 to 4 carbon atoms, halogen, alkoxy of 1 to 4 carbon atoms, or cyano.
G is preferably a 5 or 6 membered heteroaryl having 1 or 2 heteroatoms. More preferably, G is oxazoly, furyl, thiazolyl or thiadiazolyl and in more preferred embodiments, G is 1,2,3 thiadiazolyl, 1,3 thiazolyl, or 2-furyl. G is most preferably thiazolyl, and in particular 1,3 thiazoly.
Preferred compounds of the present invention are the following compounds which include pharmaceutical salts thereof:
Furan-2-carboxylic acid {5-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-2-yl}-amide,
[1,2,3]Thiadiazole-4-carboxylic acid {5-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-2-yl}-amide,
Pyridine-2-carboxylic acid {5-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-2-yl}-amide,
Pyridine-2-carboxylic acid {6-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-3-yl}-amide,
Furan-2-carboxylic acid {6-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-3-yl}-amide,
[1,2,3]Thiadiazole-4-carboxylic acid {6-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-3-yl}-amide,
[1,2,3]Thiadiazole-4-carboxylic acid {5-[3-(3,5-dichloro-phenyl)-thioureido]-pyridin-2-yl}-amide,
N-[5-[[[(5-Chloro-2,4-dimethoxyphenyl)amino]thioxomethyl]amino]-2-pyridinyl]-2-methylbenzamide,
N-{5-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-2-yl}-2-fluoro-benzamide,
N-{6-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-3-yl}-2-fluoro-benzamide,
N-{5-[({[3,5-bis(trifluoromethyl)benzyl]amino}carbothioyl)amino]-2-pyridinyl}-1,2,3-thiadiazole-4-carboxamide,
N-(5-{[({(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}-2-pyridinyl)-1,2,3-thiadiazole-4-carboxamide,
N-(5-{[({(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}-2-pyridinyl)-1,3-thiazole-4-carboxamide,
N-(5-{[({1-[2-fluoro-5-(trifluoromethyl)phenyl]ethyl}amino) carbothioyl]amino}-2-pyridinyl)-1,3-thiazole-4-carboxamide,
N-(5-{[({1-[2-fluoro-4-(trifluoromethyl)phenyl]ethyl}amino) carbothioyl]amino}-2-pyridinyl)-1,3-thiazole-4-carboxamide,
N-(5-{[({1-[3-fluoro-5-(trifluoromethyl)phenyl]ethyl}amino) carbothioyl]amino}-2-pyridinyl)-1,3-thiazole-4-carboxamide,
N-(5-{[({(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}amino) carbonyl]amino}-2-pyridinyl)-1,3-thiazole-4-carboxamide,
N-{5-[({[1-(3-bromophenyl)ethyl]amino}carbothioyl)amino]-2-pyridinyl}-1,3-thiazole-4-carboxamide,
N-{5-[({[1-(2-bromophenyl)ethyl]amino}carbothioyl)amino]-2-pyridinyl}-1,3-thiazole-4-carboxamide,
N-(5-{[({1-[3-(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}-2-pyridinyl)-1,3-thiazole-4-carboxamide,
N-(5-{[({1-[4-chloro-3-(trifluoromethyl)phenyl]ethyl}amino) carbothioyl]amino}-2-pyridinyl)-1,3-thiazole-4-carboxamide,
N-{5-[({[1-(4-chloro-3-fluorophenyl)ethyl]amino}carbothioyl)amino]-2-pyridinyl}-1,3-thiazole-4-carboxamide,
N-{5-[({[1-(4-chloro-2-fluorophenyl)ethyl]amino}carbothioyl)amino]-2-pyridinyl}-1,3-thiazole-4-carboxamide,
N-{6-[({[1-(4-fluorophenyl)ethyl]amino}carbothioyl)amino]-3-pyridinyl}-1,2,3-thiadiazole-4-carboxamide,
N-(6-{[({(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}amino) carbothioyl]amino}-3-pyridinyl)-1,2,3-thiadiazole-4-carboxamide; and pharmaceutical salts thereof.
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 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.
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.
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 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 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, benzofuraryl, benzothienyl, indolyl, pyridyl, pyrazinyl, thienyl, furyl, pyrrolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, 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.
Halogen, as used herein refers to chlorine, bromine, iodine and fluorine.
Unless otherwise limited substitutents are unsubstituted may include alkyl of 1 to 6 carbon atoms, cycloalkyl of 1 to 6 carbon atoms, heterocycloalkyl of 1 to 6 members, perhaloalkyl of 1 to 6 carbon atoms, alkylamino, dialkylamino, aryl or heteroaryl.
Carbon number refers to the number of carbons in the carbon backbone and does not include carbon atoms occurring in substituents such as an alkyl or alkoxy substituents.
Where terms are used in combination, the definition for each individual part of the combination applies unless defined otherwise. For instance, alkylcycloalkyl is an alkyl-cycloalkyl group in which alkyl and cycloalkyl are as previously described.
Pharmaceutically acceptable salts are the acid addition salts which can be formed from a compound of the above general formula and a pharmaceutically acceptable acid such as phosphoric, sulfuric, hydrochloric, hydrobromic, citric, maleic, succinic, fumaric, acetic, lactic, nitric, sulfonic, p-toluene sulfonic, methane sulfonic acid, and the like.
The compounds of this invention contain a chiral center, providing for various seteroisomeric forms of the compounds such as racemic mixtures as well as the individual optical isomers. In some preferred embodiments of the present invention the compounds of the present invention are substantially pure optical isomers. By substantially pure is meant the composition contains greater than 75% of the desired isomer and may include no more than 25% of the undesired isomer. In more preferred embodiments the pure optical isomer is greater than 90% of the desired isomer. In some preferred embodiments, when the target is VZV, the (S) isomer is preferred. The individual isomers can be prepared directly or by asymmetric or stereospecific synthesis or by conventional separation of optical isomers from the racemic mixture.
Compounds of the present invention may be prepared by those skilled in the art of organic synthesis employing methods described below which utilize readily available reagents and starting materials unless otherwise described. Compounds of the present invention are thus prepared in accordance with the following schemes.
The novel compounds of the present invention are prepared according to the following reaction schemes.
Referring to Methods 31 (reacting 2 and 3, top) and 34 (reacting 4 and 5, bottom), reacting appropriately substituted amines 2, wherein the substitutents R.sub.1 -R.sub.5, and X are described as above, with appropriately substituted isothiocyanates 3, wherein A and G are described above, either neat or in an appropriate solvent such as tetrahydrofuran, acetonitrile, ethyl acetate, dichloro-methane, or N,N-dimethylformamide affords the desired thioureas 1. Similarly, reaction of appropriately substituted isothiocyanates 4, wherein the substitutents R.sub.1 -R.sub.5, and X are described as above with appropriately substituted amine 5, wherein A and G are described above, in a convenient solvent such as those listed above affords the desired thioureas 1. ##STR4##
Alternatively, appropriately substituted thioureas 1 can be prepared as described by Methods 32 and 33 by reacting amines 2 and 5, wherein R.sub.1 -R.sub.5, A and G are described as above, in the presence of either one molar equivalent of 1,1'-thiocarbonyl-diimidazole in an appropriate solvent such as dichloromethane and tetrahydrofuran or mixtures thereof or one molar equivalent of 1,1'-thiocarbonyl-di-(1,2,4)-triazole in an appropriate solvent such as dichloromethane and tetrahydrofuran or mixtures thereof at room temperature.
In certain instances, subsequent chemical modification of the final thioureas 1 was required. These methods, Methods 35-39, are summarized below.
Thioureas 1 wherein at least one substituent of R.sub.1 -R.sub.5 is 1-hydroxyethoxy or carboxy-methoxy, A and G are defined as above and X equals a bond, may be prepared from the corresponding alkyl esters by alkaline hydrolysis with aqueous sodium or potassium hydroxide in a suitable solvent such as methanol, tetrahydrofuran or mixtures thereof at room temperature in accordance with Methods 35 and 36.
Thioureas 1 wherein at least one substituent of R.sub.1 -R.sub.5 is 1-acyloxyethoxy or methansulfonoxyethoxy, A and G are defined as above and X equals a bond, may be prepared from the corresponding l-hydroxyethoxy derivative by acylation with appropriate acylating agents such as benzoic acid chloride or methanesulfonic acid chloride in the presence of a suitable tertiary amine base such as triethylamine or diisopropylethylamine in a suitable solvent such as dichloromethane or the like at room temperature in accordance with Methods 37 and 38.
Thioureas 1 wherein at least one substituent of R.sub.1 -R.sub.5 is 1-aminoethoxy, A and G are defined as above and X equals a bond, may be prepared from the corresponding 1-methanesulfonoxy-ethoxy derivative by reaction with an appropriate secondary 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.
Thioureas 1 wherein at least one substituent of R.sub.1 -R.sub.5 is 1-aminoalkyl, A and G are defined as above and X equals a bond, may be prepared from the corresponding 1-azidoalkyl derivative by reaction with stannous chloride in a suitable solvent such as methanol, ethanol or the like at room temperature in accordance with Method 40.
The intermediate isothiocyanates 3 and 4 shown above in Methods 31 and 34 are prepared in accordance with Method 41 (below) essentially according to the procedures of Staab, H. A. and Walther, G. Justus Liebigs Ann. Chem. 657, 104 (1962)) by reacting appropriately substituted amines 5 or 2, respectively, wherein R.sub.1 -R.sub.5, A and G are described above and X equals a bond, with one molar equivalent of 1,1'-thiocarbonyldiimidazole in an appropriate solvent such as dichloromethane and tetrahydrofuran or mixtures thereof. ##STR5##
The intermediates 2 and 5 may be prepared according to the following protocols:
According to Methods 1A-1G, amines 2, wherein R.sub.1 -R.sub.5 and X are defined above and amines 5, wherein A is defined above, may be prepared by reduction of the appropriately substituted nitrobenzenes according to a variety of procedures known to those skilled in the art and described in R. J. Lindsay, Comprehensive 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 or in alcohol solvent such as methanol or ethanol, at temperatures ranging from room temperature to the refluxing temperature of the solvent, or;
b) iron powder and glacial acetic acid (Method 1B), either neat or in alcohol solvent such as methanol or ethanol, at temperatures ranging from room temperature to the refluxing temperature of the solvent, or;
c) iron powder and aqueous ammonium chloride (Method 1C), either neat or in alcohol solvent such as methanol or ethanol, at temperatures ranging from room temperature to the refluxing temperature of the solvent, or;
d) tin and a strong mineral acid, such as hydrochloric acid (Method 1D), 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;
e) when R.sub.1 -R.sub.5 and substituents of A are selected from Cl, Br, I, --(OSO.sub.2)--CF.sub.3, or --(OSO.sub.2)-1-(4-methylphenyl), by catalytic reduction such as with hydrogen and palladium on carbon (Method 1E) in an appropriate solvent such as methanol, ethanol, or ethyl acetate, under one or more atmospheres of pressure or;
f) when R.sub.1 -R.sub.5 and R.sub.9 -R.sub.12 are selected from Cl, Br, I, --(OSO.sub.2)--CF.sub.3, or --(OSO.sub.2)-1-(4-methylphenyl), by catalytic reduction such as with cyclohexene and palladium on carbon (Method 1F) in an appropriate solvent such as methanol or ethanol, at temperatures ranging from room temperature to the refluxing 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 R.sub.1 -R.sub.5 are defined above and X is defined as above and anilines 5, wherein A is defined above, may be prepared by the cleavage of the aniline nitrogen-carbon bond of amide and 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:
a) the exposure of appropriately substituted arylamino-tert-butyl-carbamates to a strong acid such as trifluoroacetic acid (Method 3A)either neat or in an appropriate solvent such as dichloromethane at temperatures between 0.degree. C. and room temperature, or;
b) the exposure of appropriately substituted arylamino-(2-trimethylsilylethyl)-carbamates to a fluoride ion source such as tetrabutylammonium fluoride or potassium fluoride (Method 3B) in aqueous acetonitrile or tetrahydrofuran or mixtures thereof at temperatures ranging from room temperature to the reflux temperature of the solvent, or;
c) the exposure of appropriately substituted arylamino-trifluoroacetamides to a strong base such as sodium or potassium hydroxide or sodium or potassium carbonate in an alcohol solvent such as methanol or ethanol (Method 3C) at temperatures ranging from room temperature to the reflux temperature of the solvent.
Alternatively, according to Method 11, amines 2, wherein R.sub.1 -R.sub.5 are defined above, and X equals a bond and at least one substituent of R.sub.1 -R.sub.5 is defined as vinyl, may be prepared by the palladium catalyzed coupling of a vinyl trialkyltin reagent, such as tributylvinyltin, with an appropriately substituted bromo- or iodo-aniline, for example 3-chloro-4-iodo-aniline, employing a palladium catalyst, such as tris(dibenzylidineacetone)-bipalladium, and a ligand, such as triphenylarsine, in a suitable solvent such as tetrahydrofuran or N-methylpyrrolidinone, at temperatures ranging from room temperature to the reflux temperature of the solvent, essentially according to the procedures of V. Farina and G. P. Roth in Advances in Metal-Organic Chemistry, Vol. 5, 1-53, 1996 and references therein.
Alternatively, according to Method 42, amines 2, wherein R.sub.1 -R.sub.5 are defined above and X is defined as above and at least one substituent of R.sub.2 or R.sub.4 is defined as dialkylamino, may be prepared by the palladium catalyzed amination of an appropriately substituted 3- or 5-bromo- or iodo-aniline, for example 3-amino-5-bromobenzotrifluoride, by secondary amines under conditions which employ a palladium catalyst, such as bis(dibenzylidineacetone)palladium, and a ligand, such as tri-o-tolylphosphine, and at least two molar equivalents of a strong base, such as lithium bis-(trimethylsilyl)amide in a sealed tube, in a suitable solvent such as tetrahydrofuran or toluene, at temperatures ranging from room temperature to 100.degree. C., 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 R.sub.1 -R.sub.5 are defined above and X is defined as above and at least one substituent of R.sub.2 or R.sub.4 is defined as alkyl, may be prepared by the palladium catalyzed alkylation of an appropriately substituted 3- or 5-bromo-or iodo-aniline, for example 3-amino-5-bromobenzotrifluoride by alkenes under conditions 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 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 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 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;
b) the reaction of an appropriately substituted aniline with 1-[2-(trimethylsilyl)ethoxycarbonyl-oxy]benzotriazole (Method 2B) in the presence of a tertiary amine such as triethylamine or diisopropylethylamine in a suitable solvent such as dimethylformamide at room temperature to produce the corresponding arylamino-(2-trimethylsilylethyl)-carbamate, or;
c) the reaction of an appropriately substituted aniline with a carboxylic acidchloride or acid anhydride (Method 2C) either neat or in an appropriate solvent such as tetrahydrofuran, dimethylformamide, dichloromethane, pyridine and the like, in the presence of one or more molar equivalents of a teriary amine base such as triethylamine or N,N-diisopropylethyl-amine to produce the corresponding arylaminoamide, or;
d) the reaction of an appropriately substituted nitro aniline with a carboxylic acid chloride (Method 2D) in the absence of one or more molar equivalents of a teriary amine base such as triethylamine or N,N-diisopropylethylamine either neat or in an appropriate solvent such as tetrahydrofuran, 1,4-dioxane and the like at temperatures ranging from room temperature to the reflux temperature of the solvent to produce the corresponding nitro arylaminoamide, or;
e) the reaction of an appropriately substituted aniline with a carboxylic acid (Method 2E) in the presence of a coupling agent such as benzotriazole-1-yloxy-tris-(dimethylamino)-phosphonium hexafluorophosphate, 2-(1H-benzotriazole-1-yloxy)-1,1,3,3-tetra-methyluronium hexafluorophosphate, dicyclohexyl carbodiimide and the like and in the presence of a tertiary amine such as triethylamine or diisopropylethylamine in a suitable solvent such as diichloromethane, dimethylformamide and the like, at room temperature to produce the corresponding arylaminoamide, or;
f) the reaction of an appropriately protected aniline such as an arylamino-tert-butyl-carbamate or the like in which at least one substituent of R5 and substituents of A are defined as --W--Y--(CH.sub.2).sub.n --Z wherein W, Y, and Z are defined as above, with, a carboxylic acid anhydride (Method 2F) in the presence of a suitable base such as pyridine in an appropriate such as dichloromethane, dimethylformamide or the like at temperatures ranging from 0.degree. C. to room temperature to produce the corresponding carboxylic acid ester, or;
g) the reaction of an appropriately substituted aniline in which a t least one substituent of R.sub.1 -R.sub.5 is defined as hydroxyl with di-tert-butyl-dicarbonate (Method 2G) in the absence of one or more molar equivalents of a tertiary amine such as triethylamine or N,N-diisopropylethylamine in a suitable solvent such as acetone, tetrahydrofuran, dimethylformamide, dichloromethane, and the like, at temperatures ranging from room temperature to the reflux temperature of the solvent to produce the corresponding arylamino-tert-butyl-carbamate.
Nitrobenzene intermediates that are ultimately converted to amines 2 and 5 by methods shown above in Methods 1A-1G may be prepared in accordance with Methods 4A, 4C, 4E-4F.
Referring to Methods 4A, 4C, and 4E-4H, the nitrobenzene intermediates which are ultimately converted into amines 2, R.sub.2 and R.sub.4 are defined above and R.sub.1, R.sub.3, and/or R.sub.5 are defined as alkoxy, thioalkoxy, alkylsulfenyl, alkylsulfinyl, and dialkylamino may be prepared by the nucleophilic displacement of appropriately substituted 2-, 4-, and/or 6-fluoro-, chloro-, bromo-, iodo-, trifluoromethylsulfonyl-, or (4-methylphenyl)sulfonyl-substituted nitrobenzenes by methods which include the following:
a) reaction of alcohols with appropriately substituted 2- or 4- halo- or sulfonate esters of nitrobenzenes or benzonitriles (Method 4A) either neat or in an appropriate solvent such as tetrahydrofuran, dioxane, acetonitrile, N,N-dimethylformamide or dimethylsulfoxide in the presence or absence of one or more molar equivalents of a base such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, or the like, at temperatures ranging from room temperature to the reflux temperature of the solvent;
b) reactions of preformed sodium, lithium, or potassium phenoxides with appropriately substituted 2- or 4- halo- or sulfonate esters of nitrobenzenes or benzonitriles (Method 4H) either neat or in an appropriate solvent such as tetrahydrofuran, dioxane, acetonitrile, N,N-dimethylformamide or dimethylsulfoxide, at temperatures ranging from room temperature to the reflux temperature of the solvent, or;
c) reaction of ammonia, primary or secondary amines with appropriately substituted 2- or 4-halo- or sulfonate esters of nitrobenzenes or benzonitriles (Methods 4C,F) either neat or in an appropriate solvent such as tetrahydrofuran, dioxane, acetonitrile, N,N-dimethyl-formamide or dimethylsulfoxide, at temperatures ranging from room temperature to the reflux temperature of the solvent;
d) reaction of preformed sodium, lithium, or potassium salts of amines with appropriately substituted 2- or 4 halo- or sulfonate esters of nitrobenzenes or benzonitriles (Method 4G) in an appropriate solvent such as tetrahydrofuran at temperatures ranging from 0.degree. C. to the reflux temperature of the solvent, or;
e) reaction of sodium sulfide with appropriately substituted 2- or 4- halo- or sulfonate esters of nitrobenzenes or benzonitriles either neat or in an appropriate solvent such as tetrahydro-furan, dioxane, acetonitrile, N,N-dimethylformamide or dimethylsulfoxide, at temperatures ranging from room temperature to the reflux temperature of the solvent, followed by the addition of an alkyl halide directly to the reaction mixture (Method 4E).
Alternatively, referring to Methods 5C and 6, the nitrobenzene intermediates which are ultimately converted into amines 2, wherein at least one substitutent R.sub.1 -R.sub.5 is defined as alkoxy may be prepared from the corresponding substituted hydroxy-nitrobenzenes by methods which include the following:
a) reaction of the hydroxy-nitrobenzene with an alkyl halide or dialkyl sulfonate ester (Method 5C) in the presence of a base, such as potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium hydride, or sodium hydride, in an appropriate solvent such as acetone, N,N-dimethylformamide, tetrahydrofuran or dimethylsulfoxide at temperatures ranging from room temperature to the reflux temperature of the solvent, or;
b) reaction of the hydroxy-nitrobenzene with an alkyl alcohol, triphenylphosphine, and a dialkylazadicarboxylate reagent (Method 6), such as diethylazodicarboxylate, in an anhydrous aprotic solvent such as diethyl ether or tetrahydrofuran at temperatures ranging from 0.degree. C. 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 utilized as starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein at least one substituent R.sub.1 -R.sub.5 is defined as alkoxy may be prepared the corresponding substituted hydroxy arylamino-tert-butyl-carbamate by reaction with alkyl halides, trifluormethane-sulfonates, 4-methylbenzenesulfonates, dialkylsulfonate, ethylene carbonate and the like in the presence of a suitable base such as potassium carbonate in an appropriate solvent such as acetone, toluene, or N,N-dimethyl-formamide at temperatures ranging from room temperature to the reflux temperature of the solvent.
Alternatively, referring to Methods 7A-G, the nitrobenzene intermediates which are ultimately converted into amines 2, R.sub.1 and/or R.sub.3 is alkoxy, and R.sub.2 and/or R.sub.4 is a 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 with aqueous sodium hypochlorite (Methods 7A and 7B), at room temperature or;
b) reaction of a 2-hydroxy-4-methoxy or 2,4-dimethoxynitrobenzene (Method 7C and 7D) with bromine in suitable solvent such as chloroform, dichlormethane, glacial acetic acid or the like in the presence or the absence of silver trifluoroacetate at room temperature, or;
c) reaction of a 2,4-dimethoxynitrobenzene (Method 7E) with benzyltrimethylammonium dichloroiodate in the presence of anhydrous zinc chloride in a suitable solvent such as glacial acetic acid, at room temperature or;
d) reaction of a 2-hydroxy-4-methoxynitrobenzene (Method 7F) with benzyltrimethyl-ammonium dichloroiodate in the presence of sodium bicarbonate in a suitable solvent mixture such as dichloromethane and methanol, at room temperature or;
d) reaction of a 2,4-dimethoxynitrobenzene (Method 7G) with 3,5-dichloro-1-fluoropyridine triflate in a suitable solvent such as tetrachloroethane, at a temperature ranging from room temperature to the reflux temperature of the solvent.
Referring to Method 8, the nitrobenzene intermediates which are ultimately converted into amines 2, wherein R.sub.4 =--CF.sub.3, and R.sub.1 -R.sub.3 and R.sub.5 -R.sub.8 are defined as above and X equals a bond may be prepared from the corresponding substituted 4-iodo-nitrobenzenes by reaction with trimethyl(trifluoromethyl)silane in the presence of cuprous iodide and potassium fluoride in a suitable solvent such as N,N-dimethyl-formamide or the like at a temperature ranging from room temperature to the reflux temperature of the solvent in a sealed reaction vessel.
Referring to Methods 19A and 19B, the nitrobenzene intermediates which are ultimately converted into amines 2, wherein R.sub.4 =--HNCOCH.sub.2 NR.sub.7 R.sub.8 or --HNCOCH.sub.2 R.sub.6, and R.sub.1 -R.sub.3 and R.sub.5 -R.sub.8 are defined as above and X equals a bond may be prepared from the corresponding substituted 4-(N-chloroacetyl)-nitroaniline by reaction with either a suitable secondary amine such as dimethylamine, morpholine, or the like in a suitable solvent such as tetrahydrofuran and/or water mixtures at temperatures ranging from room temperature to the reflux temperature of the solvent or by reaction with an appropriate thiol in the presence of a suitable base such as sodium or potassium carbonate or the like in a suitable solvent such as tetrahydrofuran, 1,4-dioxane or the like at temperatures ranging from room temperature to the reflux temperature of the solvent.
Referring to Method 25, the nitrobenzene intermediates which are ultimately converted into amines 2, wherein at least one substituent of R.sub.1 -R.sub.5 is defined as triflate and X equals a bond may be prepared from the corresponding phenol by reaction with trifluoromethane-sulfonic anhydride in the presence of a tertiary amines such as triethylamine or diisopropyl-ethylamine or the like in a suitable solvent such as dichloromethane at temperatures ranging from 0.degree. C. to room temperature.
Referring to Methods 9, 9B, and 10, the carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein at least one substituent R.sub.1 -R.sub.5 is defined as either alkylsulfenyl or alkylsulfinyl, may be prepared by reaction of the appropriate 4-alkylthio acyl-arylamino or carbamoyl arylamino derivative with an appropriate oxidizing agent such as dimethyloxirane or sodium periodate in a suitable solvent mixture such as acetone and dichloromethane or water at room temperature.
Referring to Method 12, the carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein R.sub.4 is defined as 1-hydroxyethyl and R.sub.1 -R.sub.3 and R.sub.5 are defined as above and X equals a bond may be prepared by reacting the corresponding 4-vinyl carbamoyl aniline with sodium borohydride in the presence of 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 materials in Methods 3A-3C which are ultimately converted into amines 2, wherein R.sub.4 is defined as 2-hydroxyethyl and R.sub.1 -R.sub.3 and R.sub.5 are defined as above and X equals a bond, may be prepared by reacting the corresponding 4-vinyl carbamoyl aniline with sodium borohydride in the presence of glacial acetic acid in a suitable solvent such as tetrahydrofuran, 1,4-dioxane or the like at temperatures ranging from 0.degree. C. to room temperature.
Referring to Method 14, the carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein R.sub.4 is defined as 1-azidoethyl and R.sub.1 -R.sub.3 and R.sub.5 are defined as above and X is defined as above, may be prepared by reacting the corresponding 4-(1-hydroxyethyl) carbamoyl aniline with hydrazoic acid in the presence of a dialkylazodicarboxylate such as diethylazodicarboxylate and triphenylphosphine in a suitable solvent mixture such as tetrahydrofuran and dichloromethane at temperatures ranging from 0.degree. C. to room temperature.
Referring to Method 15, the carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein R.sub.4 is defined as 3-dimethylaminoprop-1-ynyl and R.sub.1 -R.sub.3 and R.sub.5 are defined as above and X is defined as above, may be prepared by reacting the corresponding 4-iodocarbamoyl aniline with 1-dimethylamino-2-propyne in a suitable tertiary amine solvent such as triethylamine or diisopropylethylamine in the presence of bis(triphenylphosphine)palladium(II) chloride and cuprous iodide at temperatures ranging from room temperature to the reflux temperature of the solvent.
Referring to Method 16, the carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein R.sub.4 is defined as 3-dimethylaminoacryloyl and R.sub.1 -R.sub.3 and R.sub.5 are defined as above and X equals a bond, may be prepared by reacting the corresponding 4-(3-dimethylaminoprop-1-ynyl)carbamoyl aniline with a suitable peracid such as 3-chloroperoxybenzoic acid in a suitable solvent mixture such as dichloromethane and methanol at temperatures ranging from 0.degree. C. 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 R.sub.4 is defined as either 4-isoxazol-5-yl or 4-(1H-pyrazol-3-yl) and R.sub.1 -R.sub.3 and R.sub.5 are defined as above and X equals a bond, may be prepared by reacting the corresponding 4-(3-dimethylamino-acryloyl)carbamoyl aniline with either hydroxylamine hydrochloride or hydrazine hydrate in a suitable solvent such as 1,4-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 R.sub.4 =--HNCO.sub.2 Z, and R.sub.1 -R.sub.3, R.sub.5, and Z are defined as above and X equals a bond, may be prepared by reacting the corresponding 4-aminocarbamoyl aniline with 1,1-carbonyl-di-(1,2,4)-triazole and an appropriately substituted alcohol in a suitable solvent mixture such as tetrahydrofuran and dichloromethane and the like at temperatures ranging from room temperature to the reflux temperature of the solvent.
Referring to Methods 26 and 30, the carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein at least one substituent of R.sub.1 -R.sub.5 is defined as dialkylamino and X is defined as above, may be prepared by reaction of appropriately substituted aldehydes in the presence of either sodium cyanoboro-hydride or hydrogen gas and 10% palladium on carbon in a suitable solvent such as water, methanol, tetrahydrofuran mixtures or toluene or the like at room temperature.
Referring to Methods 27 and 28, amines 2 wherein at least one substituent of R.sub.1 -R.sub.5 is defined as hydroxy and X is defined as above can be prepared by reaction of the corresponding ester such as acetate with an appropriate base such as sodium bicarbonate or sodium hydroxide in a suitable solvent mixture such as methanol-water mixtures at temperatures ranging from room temperature to the reflux temperature of the solvent.
Referring to Method 29, amines 2 wherein at least one substituent of R.sub.1 -R.sub.5 is defined as 2-hydroxybenzamido and X is defined as above can be prepared by reaction of the corresponding N-(4-aminophenyl)phthalimide with lithium borohydride in an appropriate solvent such as tetrahydrofuran, diethyl ether, or the like at room temperature.
The intermediate amines 2 wherein R.sub.1 -R.sub.5 are defined as above and X equals either --CH.sub.2 -- or --(CH.sub.2).sub.2 -- can be prepared by the following procedures:
a) reduction of an appropriately substituted benzo- or phenylacetonitrile with borane-dimethylsulfide complex in a suitable solvent such as ethylene glycol dimethyl ether, tetrahydrofuran or the like a temperatures ranging from room temperature to the reflux temperature of the solvent. (Method 44);
b) Reduction under one or more atmospheres of hydrogen in the presence of a suitable catalyst such as 5% or 10% palladium on carbon and an acid such as 4-methyl-benzenesulfonic acid, hydrochloric acid or the like in a suitable solvent such as ethylene glycol monomethyl ether, ethyl acetate, ethanol or the like at room temperature. (Method 50);
c) reduction with lithium aluminum hydride in a suitable solvent such as tetrahydrofuran or diethyl ether at temperatures ranging from 0.degree. C. to room temperature. (Method 51);
The unsaturated nitro precursors which are utilized as starting materials in Method 51 and are ultimately converted to amines 2 wherein R.sub.1 -R.sub.5 are defined as above and X equals --(CH.sub.2).sub.2 -- can be prepared by reaction of an appropriately substituted benzaldehyde with nitro-methane in the presence of ammonium acetate in a suitable solvent such as acetic acid at temperatures ranging from room temperature to the reflux temperature of the solvent.(Method 53); The benzaldehydes, utilized as starting materials in Method 53, can be prepared by diisobutylaluminum hydride reduction of an appropriately substituted benzonitrile. (Method 52) The substituted benzonitriles, utilized as starting materials in Method 52, can be prepared from the corresponding aryl bromide by reaction with copper cyanide in a suitable solvent such as N,N-dimethylformamide at temperatures ranging from room temperature to the reflux temperature of the solvent. (Method 59)
For amines 2, wherein R.sub.1 -R.sub.5 is defined as above and X equals either --O(CH.sub.2).sub.2 NH.sub.2 or --S(CH.sub.2).sub.2 NH.sub.2, the requisite nitrile precursors may be prepared by reaction of an appropriately substituted phenol or thiophenol with bromoacetonitrile in the presence of a suitable base such as potassium carbonate in an appropriate solvent such as acetone at room temperature according to Method 49.
Alternatively, for amines 2, wherein R.sub.1 -R.sub.5 are defined as above and X equals --(CH.sub.2).sub.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 with acetone cyanohydrin and triphenylphosphine in the presence of a suitable azodicarboxylate such as diethyl azodicarboxylate in an appropriate solvent such as diethyl ether or tetrahydro-furan or the like at temperatures ranging from 0.degree. C. to room temperature. (Method 54)
Alternatively, intermediate amines 2 wherein R.sub.1 -R.sub.5 are defined as above and X equals --(CH(CH.sub.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 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 by treatment of an appropriately substituted acetophenone with ammonium formate, formic acid and formamide at temperatures ranging from room temperature to the reflux temperature of the solvent.
Alternatively, amines 2 wherein R.sub.1 -R.sub.5 are defined as above and X equals --(CH(CH.sub.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 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)
Amines 2 for which R.sub.1 -R.sub.5 are defined as above and X equals --CH(J)-- where J is defined as above, can be prepared by reduction of the appropriately substituted ketone by the methods described above (Methods 45, 47, and 48). These requisite ketones, when not commercially available, can be prepared by reaction of a suitably substituted benzaldehyde with an appropriate organometallic reagent such as phenyllithium, isopropylmagnesium bromide or ethylmagnesium bromide or the like in a suitable solvent such as diethyl ether or tetrahydrofuran at temperatures ranging from -78.degree. C. to 0.degree. C. (Method 57) The resulting alcohols can be oxidized to the corresponding ketone with an appropriate oxidizing agent such as chromium trioxide in aqueous sulfuric acid and acetone or pyridinium chlorochromate or pyridium dichromate in an appropriate solvent such as dichloromethane or the like at room temperature. (Method 58)
The intermediate anilines 5 may be prepared as previously described Method 3A. Thus treating phenyl carbamic acid tert-butyl ester 6 or the corresponding heteroaryl, wherein X equals a bond and G are described as above, with neat trifluoroacetic acid at room temperature followed by neutralization with aqueous sodium hydroxide affords the desired anilines 5. The requisite carbamic acid esters 6, wherein A and G are described as above, are prepared as shown in Method 2C by reaction of substituted acid chlorides, 8, where G is described as above, and 4-aminophenyl-carbamic acid tert-butyl esters 7 or the corresponding heteroaryl, wherein A is described above, in the presence of triethylamine in an appropriate solvent such as dichloromethane, dimethylsulfoxide, or dimethylformamide or mixtures thereof. Carboxylic acid chlorides 8 are either commercially available or prepared from the corresponding carboxylic acid by reaction with oxalyl chloride in a suitable solvent such as dichloromethane at room temperature. ##STR6##
Alternatively, amines 5 may be prepared as previously described by methods 1A-1G. Thus, treating 2-amino-5-nitropyridine (7) with heterocyclic acid chlorides 8 or other activated acid derivatives as described in Methods 2C-2E affords the nitro amide 6, where G is described as above. Subsequent reduction by procedures described in Methods 1A-1G affords amines 5. ##STR7##
Alternatively, carbamic acid esters 6, wherein A and G are described as above, are prepared as shown in Method 2E by reaction of substituted carboxylic acids 8a, wherein G is described as above, and an appropriately substituted 4-aminophenyl carbamic acid tert-butyl esters 7 or the corresponding heteroaryl in the presence of a suitable coupling agent such as benzotriazole-1-yloxy-tris-(dimethylamino)-phosphonium hexafluorophosphate, 2-(1H-benzotriazole-1-yloxy)-1,1,3,3-tetra-methyluronium hexafluorophosphate, dicyclohexyl carbodiimide or the like and in the presence of a tertiary amine base such as triethylamine or diisopropylethylamine in a suitable solvent such as dichloromethane, dimethylformamide and the like, at room temperature to produce the corresponding heteroaryl or arylaminoamide.
Carboxylic acids 8a are either commercially available or are prepared according to literature methods. For example, when G is a substituted thiadiazole, the acid is available from the corresponding carboxylic acid ester by reaction with ;n appropriate base such as sodium or potassium hydroxide in a suitable solvent mixture such as methanol or ethanol and water at room temperature.
Similarly, when G is either substituted or unsubstituted thiazole, substituted or unsubstituted oxazole, substituted or unsubstituted isothiazole or substituted or 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. These esters are either commercially available or can be prepared according to literature methods.
When the carboxylic acid ester precursors which are ultimately converted to acids 8a are not commercially 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. 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 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.
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 an aqueous solution semicarbazide hydrochloride at temperatures ranging from room temperature to the reflux temperature of the solvent in the presence of a suitable base such as pyridine gives corresponding semicarbazone derivative. Treatment of this compound with neat thionyl chloride at 0.degree. C. followed by treatment with an excess aqueous solution of sodium bicarbonate affords the corresponding 4-substituted-1,2,3-thiadiazole-5-carboxylic acid esters.
4-carboalkoxythiazoles are prepared essentially according to the procedure of Schollkopf, 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 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 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. Synthetic Comm. 20, 2235 (1990). Appropriate unsaturated oxazoles are prepared essentially according to the procedure of Henneke, K. H., Schollkopf, 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., Nakamura, Y. Chemistry Lett. 1305, (1994).
The following specific examples are illustrative, but are not meant to be limiting of the present invention.

EXAMPLE 1 (METHOD 1A)
4-Methoxy-3-trifluoromethyl-phenylamine
A suspension of 4-methoxy-3-trifluoromethyl-nitrobenzene (2.2 g) and iron powder (1.68 g) in ethanol (35 mL) and water (15 mL) is treated with a solution of concentrated hydrochloric acid (0.42 mL) in ethanol (6 mL) and water (3 mL) and the mixture is heated to reflux for approximately 1 hour. The mixture is then cooled, filtered, and concentrated under reduced pressure. The resulting oil is dissolved in ethyl acetate and extracted three times with 5% aqueous hydrochloric acid. The pooled acidic extracts are then cooled in an ice bath and basified with solid potassium carbonate, then extracted with ethyl acetate. These organic extracts are washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, 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.
Using the above procedure and appropriate starting materials the following compounds were prepared:
2,6-Dichloro-benzene-1,4-diamine
3-Chloro-4-methylsulfanyl-phenylamine
2,6-Dibromo-benzene-1,4-diamine
3-Chloro-4-trifluoromethyl-phenylamine
3-Chloro-4-ethylsulfanyl-phenylamine
4-Methoxy-3-trifluoromethyl-phenylamine
3,5-Dichloro-4-methoxy-2-methyl-phenylamine
5-Chloro-2-ethoxy-4-methoxy-phenylamine
5-Chloro-4-ethoxy-2-methoxy-phenylamine
5-Iodo-2,4-dimethoxy-phenylamine
3,5-Diiodo-2,4-dimethoxy-phenylamine
3,5-Dibromo-2,4-dimethoxy-phenylamine
5-Chloro-2-methoxy-4-methyl-phenylamine
2-Chloro-N(1),N(1)-dimethyl-benzene-1,4-diamine
3-Chloro-4-piperidin-1-yl-phenylamine
3-Chloro-4-pyrrolidin-1-yl-phenylamine
N(1)-Benzyl-2-chloro-benzene-1,4-diamine
3-Chloro-4-(4-methyl-piperazin-1-yl)-phenylamine
2-Chloro-N(1)-methyl-N(1)-(1-methyl-piperidin-4-yl)-benzene-1,4-diamine
2-Chloro-N(1)-methyl-N(1)-(1-methyl-pyrrolidin-3-yl)-benzene-1,4-diamine
2-Chloro-N(1)-methyl-N(1)-phenyl-benzene-1,4-diamine
N(1)-(1-Benzyl-pyrrolidin-3-yl)-2-chloro-N(1)-methyl-benzene-1,4-diamine
2-Chloro-N(1)-cyclopentyl-N(1)-methyl-benzene-1,4-diamine
2-[(4-Amino-2-chloro-phenyl)-(2-hydroxy-ethyl)-amino]-ethanol
2-Chloro-N(1)-hexyl-N(1)-methyl-benzene-1,4-diamine
2-Chloro-N(1)-isobutyl-N(1)-methyl-benzene-1,4-diamine
2-[(4-Amino-2-chloro-phenyl)-methyl-amino]-ethanol
2-Chloro-N(1)-(3-dimethylamino-propyl)-N(1)-methyl-benzene-1,4-diamine
2-Chloro-N(1)-(2-dimethylamino-ethyl)-N(1)-methyl-benzene-1,4-diamine
2-Chloro-N(1)-(2-dimethylamino-ethyl)-benzene-1,4-diamine
N(1)-(1-Benzyl-piperidin-4-yl)-2-chloro-benzene-1,4-diamine
2-Chloro-N(1)-(2-methoxy-ethyl)-N(1)-methyl-benzene-1,4-diamine
2-Chloro-N(1)-(3-dimethylamino-propyl)-benzene-1,4-diamine
N(1)-(1-Benzyl-pyrrolidin-3-yl)-2-chloro-benzene-1,4-diamine
3-Chloro-4-(1-methyl-piperidin-4-yloxy)-phenylamine
3-Chloro-(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
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.degree. C. for approximately 5 hours. The mixture is then cooled, filtered, and concentrated under reduced pressure. Water is added and the mixture is cooled in an ice bath and neutralized with solid potassium carbonate and then extracted with dichloromethane. These organic extracts are washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, then chromatographed over silica gel (20% ethyl acetate in hexanes is used as the eluant) to provide the desired compound as an amber oil.
EXAMPLE 3 (METHOD 1C)
(4-Amino-2,6-dichloro-phenoxy)-acetic acid tert-butyl ester
A solution of (4-nitro-2,6-dichloro-phenoxy)-acetic acid tert-butyl ester (1 g) in ethanol (17 mL) and water (8.6 mL) is treated with iron powder (0.861 g) and ammonium chloride (86 mg) and the mixture is heated to reflux for approximately 1 hour. The mixture is then filtered and concentrated under reduced pressure. The resulting oil is partitioned between water and ethyl acetate, and the organic phase is then washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to provide the desired compound as a pale yellow solid.
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
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
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 (60 mL) 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 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.
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
2-(2-Amino-4-chloro-5-methoxy-phenoxy)-ethanol
2-(4-Amino-2-chloro-5-methoxy-phenoxy)-ethanol
4-(4-Amino-2-chloro-5-methoxy-phenoxy)-butyronitrile
4-Amino-2-chloro-5-methoxy-phenol
2-Amino-4-chloro-5-methoxy-phenol
5-Chloro-4-methoxy-2-morpholin-4-yl-phenylamine
4-Chloro-5-methoxy-N(1),N(1)-dimethyl-benzene-1,2-diamine
5-Chloro-4-methoxy-2-piperidin-1-yl-phenylamine
5-Chloro-4-methoxy-2-pyrrolidin-1-yl-phenylamine
2-Chloro-N(1)-cyclohexyl-N(1)-methyl-benzene-1,4-diamine
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(1)-cyclohexyl-benzene-1,4-diamine
2-Chloro-N(1),N(1)-dipropyl-benzene-1,4-diamine
3-Chloro-4-(2,2,2-trifluoro-ethoxy)-phenylamine
3-Chloro-4-(octahydro-quinolin-1-yl)-phenylamine
N(1)-Allyl-2-chloro-N(1)-cyclohexyl-benzene-1,4-diamine
N-(4-Amino-2-methoxy-5-methyl-phenyl)-2-fluoro-benzamide
Furan-2-carboxylic acid (4-amino-2-methoxy-5-methyl-phenyl)amide
N-(4-Amino-naphthalen-1-yl)-2-fluoro-benzamide
3-Chloro-N,N-dimethyl-benzene-1,2-diamine
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
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 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 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)-formnamide
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
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 (30 mL), ethanol (70 mL), water (30 mL) and 10% palladium on charcoal (3 g) is heated at reflux for 30 minutes. The mixture is filtered through diatomaceous earth and concentrated under reduced pressure. The resulting oil is dissolved in 50 mL of ethyl acetate and cooled at 4.degree. C. for 12 hours. Filtration provides the product as a tan solid.
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
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
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 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.
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
EXAMPLE 8 (METHOD 2A)
(3-Chloro-4iodo-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 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 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.
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
(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
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 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.
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 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:
N-(3-Methoxy-4-nitro-phenyl)-acetamide
N-(4-Amino-phenyl)-isobutyrlamide
2,2,2-Trifluoro-N-(2-methoxy-4-nitro-phenyl)-acetamide
[4-(2-Methyl-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
Acetic acid 2-(4-tert-butoxycarbonylamino-phenylcarbamoyl)-phenyl ester
[4-(4-Fluoro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
[4-(3-Fluoro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
[4-(2-Fluoro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
[4-(2-Methoxy-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
[4-(3-Methoxy-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
[4-(4-Methoxy-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
[4-(2,2-Dimethyl-propionylamino)-phenyl]-carbamic acid tert-butyl ester
[4-(2-Bromo-acetylamino)-phenyl]-carbamic acid tert-butyl ester
[4-(2,2,2-Trifluoro-acetylamino)-phenyl]-carbamic acid tert-butyl ester
(4-Benzoylamino-phenyl)-carbamic acid tert-butyl ester
(4-Methanesulfonylamino-phenyl)-carbamic acid tert-butyl ester
(4-Phenylacetylamino-phenyl)-carbamic acid tert-butyl ester
{4-[(Thiophene-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
[4-(3-Nitro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
[4-(3-Acetylamino-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
[4-(3-Methanesulfonylamino-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
Ethyl [3-[[[4-[[(1,1-dimethylethoxy)carbonyl]amino]phenyl]amino]carbonyl]phenyl]carbamate
[4-(2-Trifluoromethyl-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
[4-(2,6-Difluoro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
[4-(2-Chloro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
[4-(2-Bromo-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
[4-(2-Nitro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
{4-[(Benzo[b]thiophene-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
{4-[(Pyridine-4-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
{4-[(Naphthalene-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
{4-[(Naphthalene-1-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
{4-[(3-Bromo-thiophene-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
{4-[(Biphenyl-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
N-(4-tert-Butoxycarbonylamino-phenyl)-phthalamic acid
[4-(2,3-Difluoro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
[4-(2,5-Difluoro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
[4-(2,4-Difluoro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
[4-(2-Acetylamino-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
[4-(2-Methanesulfonylamino-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
[4-(2,3,4-Trifluoro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
[4-(2,3,4,5,6-Pentafluoro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
N-(4-tert-Butoxycarbonylamino-phenyl)-isophthalamic acid methyl ester
2-Methylsulfanyl-N-[4-(2,2,2-trifluoro-acetylamino)-phenyl]-benzamide
[4-(3-Benzyloxy-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
[4-(3-Butoxy-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
{4-[(5-Difluoromethyl-furan-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
{4-[(Thiophene-3-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
{4-[(5-Methyl-furan-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
{4-[(5-Bromo-furan-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
(4-Hexanoylamino-phenyl)-carbamic acid tert-butyl ester
[4-(2-Thiophen-2-yl-acetylamino)-phenyl]-carbamic acid tert-butyl ester
{4-[(Pyridine-3-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
{4-[(4-Bromo-furan-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
{4-[(Furan-3-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
(4-Phenoxycarbonylamino-phenyl)-carbamic acid tert-butyl ester
{4-[(Benzo[1,3]dioxole-4-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
[4-(3-Trifluoromethoxy-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
N-(2,5-Dimethoxy-4-nitro-phenyl)-2-fluoro-benzamide
{4-[(Furan-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
[4-(2-Phenoxy-acetylamino)-phenyl]-carbamic acid tert-butyl ester
{4-[(5-Nitro-furan-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
{4-[(5-Chloro-furan-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
{4-[(3-Methyl-furan-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
[4-(2-Methoxy-acetylamino)-phenyl]-carbamic acid tert-butyl ester
{4-[(4-Furan-3-yl-[1,2,3]thiadiazole-5-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
{4-[(5-tert-Butyl-furan-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
N-[3-Cyano-4-(2,2,2-trifluoro-acetylamino)-phenyl]-2-fluoro-benzamide
Furan-2-carboxylic acid [3-cyano-4-(2,2,2-trifluoro-acetylamino)-phenyl]amide
N-(4-Acetylamino-2-cyano-phenyl)-2,2,2-trifluoro-acetamide
2,2,2-Trifluoro-N-(4-nitro-2-trifluoromethyl-phenyl)-acetamide
N-(4-Acetylamino-2-trifluoromethyl-phenyl)-2,2,2-trifluoro-acetamide
2-Fluoro-N-[4-(2,2,2-trifluoro-acetylamino)-3-trifluoromethyl-phenyl]benzamide
Furan-2-carboxylic acid [4-(2,2,2-trifluoro-acetylamino)-3-trifluoromethyl-phenyl]amide
2-Fluoro-N-(2-methyl-benzooxazol-6-yl)-benzamide
4-(2-Fluoro-benzoylamino)-2-hydroxy-benzoic acid phenyl ester
{4-[(Isoxazole-5-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
N-(4-Acetylamino-2-methoxy-phenyl)-2,2,2-trifluoro-acetamide
2-Fluoro-N-[3-methoxy-4-(2,2,2-trifluoro-acetylamino)-phenyl]benzamide
2-Fluoro-N-(2-fluoro-benzoyl)-N-(4-nitro-2-trifluoromethyl-phenyl)benzamide
{4-[(1H-Pyrazole-4-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
{4-[(1H-Imidazole-4-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
{4-[(5-Methyl-[1,2,3]thiadiazole-4-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
{4-[(5-Furan-3-yl-[1,2,3]thiadiazole-4-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
2,2,2-Trifluoro-N-(5-nitro-pyridin-2-yl)-acetamide
{4-[(1-Methyl-1H-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
[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
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.
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
[4-)acryloylamino)-phenyl]carbamic 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)-2-fluoro-benzamide
Furan-2-carboxylic acid (2,5-dimethoxy-4-nitro-phenyl)-amide
N-(2-Cyano-4-nitro-phenyl)-2-fluoro-benzamide
2-Fluoro-N-(2-methoxy-4-nitro-phenyl)-benzamide
2-Methyl-N-(5-nitro-pyridin-2-yl)-benzamide
Furan-2-carboxylic acid (2-methoxy-5-methyl-4-nitro-phenyl)-amide
2-Fluoro-N-(2-methoxy-5-methyl-4-nitro-phenyl)-benzamide
N-(2-Benzoyl-4-nitro-phenyl)-acetamide
N- (2-Benzoyl-4-nitro-phenyl)-2-fluoro-benzamide
Furan-2-carboxylic acid (2-benzoyl-4-nitro-phenyl)-amide
N-(3-Methyl-4-nitro-phenyl)-acetamide
2-Fluoro-N-(3-methyl-4-nitro-phenyl)-benzamide
Furan-2-carboxylic acid (3-methyl-4-nitro-phenyl)-amide
2-Acetylamino-5-nitro-N-phenyl-benzamide
2-[(2-Fluorobenzoyl)amino]-5-nitro-N-phenylbenzamide
Furan-2-carboxylic acid (4-nitro-2-phenylcarbamoyl-phenyl)-amide
2-Fluoro-N-(4-nitro-naphthalen-1-yl)-benzamide
Furan-2-carboxylic acid (4-nitro-naphthalen-1-yl)-amide
N-(5-Chloro-2-hydroxy-4-nitro-phenyl)-acetamide
N-(5-Chloro-2-hydroxy-4-nitro-phenyl)-2-fluoro-benzamide
Furan-2-carboxylic acid (2-chloro-4-nitro-phenyl)-amide
N- (4-Nitro-2-trifluoromethyl-phenyl)-acetamide
Furan-2-carboxylic acid (2-cyano-4-nitro-phenyl)-amide
2-Fluoro-N-(4-nitro-2-trifluoromethyl-phenyl)-benzamide
Furan-2-carboxylic acid (4-nitro-2-trifluoromethyl-phenyl)-amide
2-Fluoro-N-(2-methyl-4-nitro-phenyl)-benzamide
N-(5-Chloro-2-methyl-4-nitro-phenyl)-2-fluoro-benzamide
Furan-2-carboxylic acid (5-chloro-2-methyl-4-nitro-phenyl)-amide
2-(2-Fluoro-benzoylamino)-5-nitro-benzoic acid
2-[(Furan-2-carbonyl)-amino]-5-nitro-benzoic acid
N-(3-Chloro-4-nitro-phenyl)-2-fluoro-benzamide
Furan-2-carboxylic acid (3-chloro-4-nitro-phenyl)-amide
2,6-Difluoro-N-(3-methyl-4-nitro-phenyl)-benzamide
2-Fluoro-N-(4-nitro-3-trifluoromethyl-phenyl)-benzamide
Furan-2-carboxylic acid (4-nitro-3-trifluoromethyl-phenyl)-amide
2-Chloro-N-(2-chloro-4-nitro-phenyl)-acetamide
N-(2-Chloro-4-nitrophenyl)methanesulfonamide
Furan-2-carboxylic acid [3-methoxy-4-(2,2,2-trifluoro-acetylamino)-phenyl]-amide
N-(2-Chloro-4-nitro-phenyl)-2,2,2-trifluoro-acetamide
EXAMPLE 12
{4-[(4-Phenyl-[1,2,3]thiadiazole-5-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl
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 dichoromethane (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 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.
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}-carbamic acid tert-butyl ester
{4-[(1-Methyl-1H-pyrrole-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
{4-[(Quinoline-8-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
{4-[(Benzofuran-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
{4-[(Isoquinoline-1-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
{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
A solution of [3,5-dichloro-4-(2-hydroxy-ethoxy)-phenyl]-carbamic acid tert-butyl ester (0.85 g) in pyridine (14 mL) is treated with acetic anhydride (1.24 mL) and the mixture is stirred at room temperature for 15 hours. The solvent is removed under reduced pressure and the residue dissolved in ethyl acetate. This solution is then washed twice with 5% aqueous hydrochloric acid, once with saturated aqueous sodium bicarbonate, and then with saturated aqueous sodium chloride. The solution is dried over anhydrous magnesium sulfate and the solvent is removed under reduced pressure to provide the desired product as a colorless oil.
Using the above procedure and appropriate starting materials the following 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
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% 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.
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)
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 ice bath and basified with solid potassium carbonate. The solution is extracted three times with ethyl acetate and the combined organic phases are washed with saturated aqueous sodium chloride then dried over anhydrous sodium sulfate. Concentration under reduced pressure and recrystallization from hexanes provides the desired product as a pale yellow crystalline solid.
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
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-1H-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
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
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
A 1M 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 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.
EXAMPLE 17 (METHOD 3C)
N-(4-Amino-3-cyanophenyl)-2-fluoro-benzamide
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 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 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
Cylcohexanol (2.9 g) in dimethylsulfoxide (20 mL) is added slowly to a flask containing potassium hydride (0.90 g, pre-washed three times with hexanes) under an atmosphere of argon and the solution is stirred for about 1 hour at room temperature. A solution of 3-chloro-4-fluoro-nitrobenzene (1 g) in dimethylsulfoxide (10 mL) is added and the resulting dark red colored solution is then heated for three hours to approximately 100 degrees. The reaction mixture is then cooled, diluted with diethyl ether (300 mL), and washed successively with saturated aqueous ammonium chloride, three times with water, then with saturated aqueous sodium chloride. The organic layer is then dried over anhydrous magnesium sulfate, the solvent is removed under reduced pressure, and the resulting oil is chromatographed over silica gel (5% ethyl acetate in hexanes is used as the eluant) to provide the desired product as an orange solid.
EXAMPLE 18 (METHOD 4C)
(2-Chloro-4-nitro-phenyl)-methyl-(1-methyl-pyrrolidin-3-yl)-amine
3-Chloro-4-fluoronitrobenzene (1.0 g) and N,N'-dimethyl-3-aminopyrrolidine (1.72 g) are combined and stirred for approximately 24 hours. The mixture is then diluted with ethyl acetate, washed twice with water and once with saturated sodium chloride, and dried over anhydrous sodium sulfate. After removal of the solvent under reduced 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.
Using the above procedure and appropriate starting materials the following compounds were prepared:
(2-Chloro-4-nitro-phenyl)-dipropyl-amine
1-(2-Chloro-4-nitro-phenyl)-piperidine
1-(2-Chloro-4-nitro-phenyl)-pyrrolidine
(2-Chloro-4-nitro-phenyl)-cyclohexyl-methyl-amine
Benzyl-(2-chloro-4-nitro-phenyl)-amine
(2-Chloro-4-nitro-phenyl)-methyl-(1-methyl-piperidin-4-yl)-amine
(2-Chloro-4-nitro-phenyl)-cyclohexyl-ethyl-amine
(2-Chloro-4-nitro-phenyl)-cyclohexyl-amine
(2-Chloro-4-nitro-phenyl)-methyl-(1-methyl-pyrrolidin-3-yl)-amine
(1-Benzyl-pyrrolidin-3-yl)-(2-chloro-4-nitro-phenyl)-methyl-amine
(2-Chloro-4-nitro-phenyl)-cyclopentyl-methyl-amine
1-(2-Chloro-4-nitro-phenyl)-decahydro-quinoline
Allyl-(2-chloro-4-nitro-phenyl)-cyclohexyl-amine
2-[(2-Chloro-4-nitro-phenyl)-(2-hydroxy-ethyl)-amino]-ethanol
(2-Chloro-4-nitro-phenyl)-isobutyl-methyl-amine
(2-Chloro-4-nitro-phenyl)-hexyl-methyl-amine
2-[(2-Chloro-4-nitro-phenyl)-methyl-amino]-ethanol
N-(2-Chloro-4-nitro-phenyl)-N,N',N'-trimethyl-ethane-1,2-diamine
N-(2-Chloro-4-nitro-phenyl)-N,N',N'-trimethyl-propane-1,3-diamine
(1-Benzyl-piperidin-4-yl)-(2-chloro-4-nitro-phenyl)-amine
N-(2-Chloro-4-nitro-phenyl)-N',N'-dimethyl-ethane-1,2-diamine
N-(2-Chloro-4-nitro-phenyl)-N',N'-dimethyl-propane-1,3-diamine
(2-Chloro-4-nitro-phenyl)-(2-methoxy-ethyl)-methyl-amine
(1-Benzyl-pyrrolidin-3-yl)-(2-chloro-4-nitro-phenyl)-amine
4-Piperidin-1-yl-3-trifluoromethyl-benzonitrile
4-Dimethylamino-3-trifluoromethyl-benzonitrile
4-(4-Methyl-piperazin-1-yl)-3-trifluoromethyl-benzonitrile
EXAMPLE 19 (METHOD 4E)
Butyl-(2-chloro-4-nitro-phenyl)thioether
A solution of 3-chloro-4-fluoro-nitrobenzene (5.0 g) and sodium sulfide (2.5 g) in N,N-dimethylformamide (30 mL) is stirred at room temperature for 1 hour and then treated with 1-iodobutane (12.6 g). The solvent is then removed under reduced pressure and the resulting residue is treated with ethyl acetate and hexanes to precipitate the inorganic salts. The solids are removed by filtration and the filtrate is reduced under reduced pressure. The resulting residue is then passed through hydrous magnesium silicate using dichloromethane as the eluent to provide the desired compound as a yellow solid.
Using the above procedure and appropriate starting materials the following compounds were prepared:
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
To a solution of trifluoro-methanesulfonic acid 4-chloro-5-methoxy-2-nitro-phenyl ester (1.0 g) in tetrahydrofuran (2.0 mL) is added dimethylamine (4.0 mL of a 40% aqueous solution) and the mixture is stirred at room temperature for approximately 15 hours. The solution is then concentrated under reduced pressure and the residue is dissolved in ethyl acetate and then washed with water. The aqueous layer is extracted 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.
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
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 solution of N-methyl aniline (3.0 g) in tetrahydrofuran (75 mL) at 0.degree. C. The mixture is allowed to warm slowly to room temperature and is then re-cooled to 0.degree. C. and added by cannula to a solution of 3-chloro-4-fluoronitrobenzene (4.9 g) in tetrahydrofuran (35 mL) that is kept at -78.degree. C. Following the addition, the reaction mixture is permitted to warm to room temperature over the course of 1 hour, and is then concentrated under reduced pressure, quenched by addition of saturated aqueous ammonium chloride, and extracted three times with ethyl acetate. The pooled organic layers are washed three times with 5% aqueous hydrochloric acid, once with water, once with saturated aqueous sodium bicarbonate, once with saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. Following removal of the solvent under reduced pressure the residue is chromatographed over silica gel (5% diethyl ether in hexanes is used as the eluant) to provide the desired product as a clear colorless oil.
EXAMPLE 22 (METHOD 4H)
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 160.degree. C. for approximately 15 hours. The resulting dark brown solution is cooled to room temperature, poured onto 100 mL cold water, and extracted twice with diethyl ether. The pooled organic extracts are washed with water, 10% aqueous sodium hydroxide, and then dried over anhydrous magnesium sulfate. Following removal of the solvent under reduced pressure the resulting oil is distilled in a Kugelrohr apparatus to provide a yellow oil that solidifies on standing. Recrystallization from ethanol-water provides the desired product as a pale yellow solid.
EXAMPLE 23 (METHOD 5A)
(3,5-Dichloro-4-ethoxy-phenyl)-carbamic acid tert-butyl ester
To a solution of (3,5-dichloro-4-hydroxy-phenyl)-carbamic acid tert-butyl ester (1.0 g) and potassium carbonate (1.0 g) in acetone (18 mL) is added ethyl iodide (0.36 mL) and the mixture is stirred for approximately 15 hours at room temperature. The solution is then filtered, concentrated under reduced pressure, and partitioned between ethyl acetate and water. The separated aqueous layer is further extracted twice with ethyl acetate, and the pooled organic extracts are washed successively with 10% aqueous sodium hydroxide, with water, and then dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure gave the desired product as a tan solid.
Using the above procedure and appropriate starting materials the following compounds were prepared:
(3,5-Dichloro-4-ethoxy-phenyl)-carbamic acid tert-butyl ester
(4-Butoxy-3,5-dichloro-phenyl)-carbamic acid tert-butyl ester
(4-Benzyloxy-3,5-dichloro-phenyl)-carbamic acid tert-butyl ester
(4-Carbamoylmethoxy-3,5-dichloro-phenyl)-carbamic acid tert-butyl ester
[3,5-Dichloro-4-(2-nitrilo-ethoxy)-phenyl]-carbamic acid tert-butyl ester
(4-tert-Butoxycarbonylamino-2,6-dichloro-phenoxy)-acetic acid methyl ester
3-Butoxy-benzoic acid methyl ester
3-tert-Butoxycarbonylmethoxy-benzoic acid methyl ester
3-Carbamoylmethoxy-benzoic acid methyl ester
[4-(3-Carbamoylmethoxy-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
{4-[3-(2-Chloro-ethoxy)-benzoylamino]-phenyl}-carbamic acid tert-butyl ester
EXAMPLE 24 (METHOD 5C)
(2,6-Dichloro-4-nitro-phenoxy)-acetic acid tert-butyl ester
To a solution of 2,6-dichloro-4-nitrophenol (2.5 g) and potassium carbonate (3.3 g) in dimethyl-formamide (50 mL) is added tert-butyl-bromoacetate (10 mL) and the mixture is stirred at room temperature for two days. The solution is then poured into 500 mL water, extracted three times with hexanes, and the pooled organic extracts are washed with saturated aqueous ammonium chloride and then dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure followed by trituration of the resulting oil with hexanes provides the desired product as a white solid.
Using the above procedure and starting materials the following compounds were prepared:
3-Dimethylamino-1-(4-nitro-phenyl)-propenone
2-Chloro-1-isopropoxy-4-nitro-benzene
1,3-Dichloro-2-methoxy-4-methyl-5-nitro-benzene
1-Chloro-4-ethoxy-2-methoxy-5-nitro-benzene
1-Butoxy-4-chloro-5-methoxy-2-nitro-benzene
1-Chloro-2-methoxy-5-nitro-4-(phenylmethoxy)benzene (CA name)
1-Chloro-4-methoxy-5-nitro-2-(phenylmethoxy)benzene (CA name)
(2,6-Dichloro-4-nitro-phenoxy)-acetic acid tert-butyl ester
(2,6-Dichloro-4-nitro-phenoxy)-acetonitrile
1-Chloro-4-methoxy-2-methyl-5-nitro-benzene
2-(4-Chloro-5-methoxy-2-nitro-phenoxy)-acetamide
2-(2-Chloro-5-methoxy-4-nitro-phenoxy)-acetamide
(4-Chloro-5-methoxy-2-nitro-phenoxy)-acetonitrile
(2-Chloro-5-methoxy-4-nitro-phenoxy)-acetonitrile
4-(2-Chloro-5-methoxy-4-nitro-phenoxy)-butyronitrile
2-(4-Chloro-5-methoxy-2-nitro-phenoxy)-ethanol
2-(2-Chloro-5-methoxy-4-nitro-phenoxy)-ethanol
(2-Chloro-5-methoxy-4-nitro-phenoxy)-acetic acid tert-butyl ester
(2-Chloro-5-methoxy-4-nitro-phenoxy)-acetic acid methyl ester
(4-Chloro-5-methoxy-2-nitro-phenoxy)-acetic acid methyl ester
(4-Chloro-5-methoxy-2-nitro-phenoxy)-acetic acid tert-butyl ester
(2-Chloro-4-nitro-phenoxy)-acetonitrile
1-Butoxy-2-chloro-4-nitro-benzene
2-Chloro-4-nitro-1-(2,2,2-trifluoro-ethoxy)-benzene
2-Chloro-4-nitro-1-propoxy-benzene
2-Chloro-1-ethoxy-4-nitro-benzene
1,3-Diiodo-2,4-dimethoxy-5-nitro-benzene
1,3-Dibromo-2,4-dimethoxy-5-nitro-benzene
3-Chloro-2,4-dimethoxy-nitrobenzene
EXAMPLE 25 (METHOD 5E)
[3,5-Dichloro-4-(2-hydroxy-ethoxy)-phenyl]-carbamic acid tert-butyl ester
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 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.
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 1-methyl-3-pyrrolidinol (2.3 g), triphenyl phosphine (6.0 g), and diethylazodicarboxylate (3.6 mL) and the mixture is stirred at room temperature under an atmosphere of argon for 1.5 hours. The solution is then concentrated under reduced pressure, diluted with ethyl acetate, washed successively with 10% aqueous sodium hydroxide, water, saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent is removed by evaporation under reduced pressure and the residue is chromatographed over silica gel (ethyl acetate then 10% methanol in dichloromethane is used as the eluant). Pooled product fractions are then recrystallized from hexanes to provide the desired product as a yellow solid.
Using the above procedure and appropriate starting materials the following compounds were prepared:
4-(2-Chloro-4-nitro-phenoxy)-1-methyl-piperidine
3-(2-Chloro-4-nitro-phenoxy)-1-methyl-pyrrolidine
[2-(2-Chloro-4-nitro-phenoxy)-ethyl]-dimethyl-amine
[2-(2-Chloro-4-nitro-phenoxy)-propyl]-dimethyl-amine
EXAMPLE 27 (METHOD 7A)
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 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 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.
Using the above procedure and appropriate starting materials the following compounds were prepared:
3-Chloro-2-hydroxy-4-methoxy-nitrobenzene
3,5-Dichloro-2-hydroxy-4-methoxy-nitrobenzene
EXAMPLE 28 (METHOD 7B)
2,4-Dichloro-3-methyl-6-nitro-phenol
To a solution of 3-methyl-4-nitro-phenol (5.0 g) in water (150 mL) is added aqueous sodium hypochlorite (5.25% aqueous solution, 230 mL) and the mixture is stirred at room temperature for approximately 15 hours. Additional aqueous sodium hypochlorite (5.25% aqueous solution, 230 mL) is added and the mixture is permitted to stir at room temperature for 2.5 days. The mixture is then cooled in an ice-bath, acidified by addition of concentrated hydrochloric acid, then extracted twice with ethyl acetate. These organic extracts are dried over anhydrous magnesium sulfate, the solvent is removed by evaporation under reduced pressure, and the residue is 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.
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 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 over anhydrous sodium sulfate. Removal of the solvent under reduced pressure and recrystallization of the residue from toluene provides the desired product as a yellow solid.
EXAMPLE 30 (METHOD 7D)
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 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. 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)
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 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 washed successively with 5% aqueous sodium bisulfite, saturated aqueous sodium chloride, then dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure the residue is triturated with hexanes to provide the desired product as a pale yellow solid.
EXAMPLE 32 (METHOD 7F)
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 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 toluene to provide the desired product as yellow needles.
EXAMPLE 33 (METHOD 7G)
1-Fluoro-2,4dimethoxy-5-nitro-benzene
To a solution of 2,4-dimethoxy-nitrobenzene (1.0 g) in tetrachloroethane (10 mL) is added 3,5-dichloro-1-fluoro-pyridinium triflate (85%, 5.07 g) and the mixture is heated to 120.degree. C. for 5 hours. Additional 3,5-dichloro-1-fluoro-pyridinium triflate (85%, 0.25 g) is added and heating is continued for 1 hour. The solution is then cooled to room temperature and passed over a column of silica gel (hexanes followed by 30% ethyl acetate in hexanes is used as the eluant). Product containing fractions are combined, evaporated under reduced pressure, and the residue is crystallized from hexanes to provide the desired product as a tan solid.
EXAMPLE 34 (METHOD 8)
3-Chloro-4-trifluoromethyl-nitrobenzene
A solution of 3-chloro-4-iodo-nitrobenzene (2.26 g), trimethyl(trifluoromethyl)silane (5.68 g), copper(I) iodide (2.28 g), and potassium fluoride (0.56 g) in N,N-dimethylformamide (8 mL) is heated in a sealed tube to 80.degree. C. for 40 hours. The solution is then cooled, diluted with diethyl ether, filtered through diatomaceous earth, and the filtrate is washed successively with water, saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure and the residue is chromatographed over silica gel (1% diethyl ether in hexanes followed by 10% ethyl acetate in hexanes is used as the eluant) to provided the desired product as a colorless oil.
EXAMPLE 35 (METHOD 9)
(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.degree. C. is added a solution of dimethyldioxirane (.about.0.11 M in acetone, 34 mL) and the mixture is stirred at 0.degree. C. for 1 hour. The solvent is removed under reduced pressure and the residue is dissolved in dichloromethane, washed with saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure gave the desired product as an orange foam.
EXAMPLE 36 (METHOD 9B)
[4-(2-Methylsulfinyl-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
To a solution of 2-methylsulfanyl-N-[4-(2,2,2-trifluoro-acetylamino)-phenyl]-benzamide (234 mg) is added a saturated solution of sodium periodate (5 mL) and the mixture is stirred for 12 hours. The purple mixture is poured into water, extracted with ethyl acetate, dried over anhydrous potassium carbonate and evaporated to yield a red solid, 101 mg.
Using the above procedure and appropriate starting materials the following compounds were prepared:
[4-(2-Methanesulfinyl-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
2-Methanesulfinyl-N-[4-(2,2,2-trifluoro-acetylamino)-phenyl]-benzamide
EXAMPLE 37 (METHOD 10)
(3-Chloro-4-methanesulfonyl-phenyl)-carbamic acid tert-butyl ester
To a solution of (3-chloro-4-thiomethyl-phenyl)-carbamic acid tert-butyl ester (0.90 g) in dichloromethane (30 mL) at 0.degree. C. is added a solution of dimethyldioxirane (.about.0.11 M in acetone, 80 mL) and the mixture is stirred at 0.degree. C. for 1 hour. The solvent is removed under reduced pressure and the residue is dissolved in dichloromethane, washed with saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure gives the desired product as an orange foam.
EXAMPLE 38 (METHOD 11)
3-Chloro-4-vinyl-phenylamine
To a deoxygenated solution of 3-chloro-4-iodo-aniline (6.95 g), triphenyl arsine (0.67 g), and tris(dibenzylideneacetone)palladium(0) (0.50 g) in tetrahydrofuran (120 mL) at 50.degree. C. is added tributylvinyltin (10 g) and the mixture is stirred for approximately 15 hours at 50.degree. C. under an atmosphere of argon. The reaction is then cooled, filtered through diatomaceous earth, and the filtrate is evaporated to dryness under reduced pressure. The residue is dissolved in hexanes and then extracted three times with 5% aqueous hydrochloric acid. These aqueous acidic extracts are then basified with solid potassium carbonate and extracted three times with ethyl acetate. These pooled organic extracts are then washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and the solvent is removed under reduced pressure. The resulting residue is chromatographed over silica gel (hexanes and then 10% ethyl acetate in hexanes is used as the eluant) to provide the desired product as an amber oil.
EXAMPLE 39 (METHOD 12)
[3-Chloro-4-(1-hydroxy-ethyl)-phenyl]-carbamic acid 2-trimethylsilanyl-ethyl ester
(3-Chloro-4-vinyl-phenyl)-carbamic acid 2-trimethylsilanyl-ethyl ester (2.6 g) is added to a solution of mercuric acetate (3.48 g) in water (7 mL) and tetrahydrofuran (5.25 mL) and the mixture is stirred for approximately 15 hours. 3N Aqueous sodium hydroxide (8.7 mL) and a 0.5 M solution of sodium borohydride in 3N aqueous sodium hydroxide (8.7 mL) are then added and stirring is continued for 6 hours. The solution is then saturated with sodium chloride and extracted with ethyl acetate. These organic extracts are then washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. Following removal of the solvent under reduced pressure the residue is chromatographed over silica gel (20% ethyl acetate in hexanes is used as the eluant) to provide the desired product as a white solid.
EXAMPLE 40 (METHOD 13)
[3-Chloro-4-(2-hydroxy-ethyl)-phenyl]-carbamic acid tert-butyl ester
To a stirring suspension of sodium borohydride (0.45 g) in tetrahydrofuran (13 ml) at 0.degree. C. is added glacial acetic acid (0.75 mL) and the mixture is stirred at 0.degree. C. for 1 hour. The solution is then warmed to room temperature and (3-chloro-4-vinyl-phenyl)-carbamic acid 2-trimethylsilanyl-ethyl ester (1.0 g) is added. The reaction is stirred at room temperature for approximately 15 hours and then heated to reflux for approximately 20 hours. The mixture is then cooled and solutions of 5 N aqueous sodium hydroxide (0.80 mL) and 30% aqueous hydrogen peroxide (0.56 mL) are added. After stirring for an additional 15 hours the layers are separated, the aqueous layer is extracted three times with diethyl ether, and these organic extracts are dried over anhydrous magnesium sulfate. Following removal of the solvent under reduced pressure the residue is chromatographed over silica gel (40% ethyl acetate in hexanes is used as the eluant) to provide the desired product as an amber oil.
EXAMPLE 41 (METHOD 14)
[4-(1-Azido-ethyl)-3-chloro-phenyl]-carbamic acid 2-trimethylsilanyl-ethyl ester
To a solution of [3-chloro-4-(1-hydroxy-ethyl)-phenyl]-carbamic acid 2-trimethylsilanyl-ethyl ester (1.25 g) in tetrahydrofuran (20 mL) at 0.degree. C. under an atmosphere of argon is added triphenyl-phosphine (2.6 g), hydrazoic acid (approximately 2.5 molar equivalents in dichloromethane, prepared by the method of Fieser and Fieser, Reagents for Organic Synthesis, Vol. 1, pg. 446; Wiley, New York) and diethyl azodicarboxylate (1.72 g). After approximately 10 minutes the solvent is removed under reduced pressure and the residue is chromatographed over silica gel (5% ethyl acetate in hexanes is used as the eluant) to provide the desired product as a colorless oil.
EXAMPLE 42 (METHOD 15)
[3-Chloro-4-(3-dimethylamino-prop-1-ynyl)-phenyl]-carbamic acid tert-butyl ester
To a deoxygenated solution of (3-chloro-4-iodo-phenyl)-carbamic acid tert-butyl ester (10.0 g) in triethylamine (120 ml) is added 1-dimethylamino-2-propyne (2.82 g), bis(triphenyl-phosphine)palladium(II) chloride (0.4 g), and cuprous iodide (0.054 g). The mixture is stirred at room temperature under an atmosphere of argon for approximately 6 hours and is then heated briefly (ca. 10 minutes) to 60.degree. 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 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% ethyl acetate in hexanes is used as the eluant) to give the purified product as an amber oil that solidified on standing.
Using the above procedure and appropriate starting materials the following compounds were prepared:
[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
To an ice cold solution of [3-chloro-4-(3-dimethylamino-prop-1-ynyl)-phenyl]-carbamic acid tert-butyl ester (4.0 g) in dichloromethane (30 ml) is added in small portions 3-chloroperoxybenzoic acid (2.34 g). After the reaction is stirred at 0.degree. C. for 20 minutes, the mixture is passed over twenty weight equivalents of basic alumina (Brockmann Grade I, 150 mesh) and the N-oxide is eluted using a solution of 5% methanol in dichloromethane. All fractions containing the desired amine N-oxide were combined and evaporated to near dryness under reduced pressure. The residue is treated successively three times with small portions of methanol (ca. 50 ml) followed by evaporation to near dryness under reduced pressure, and the volume of the solution is adjusted to 250 mL by addition of methanol. The methanolic solution of the N-oxide is then heated to reflux for approximately 15 hours, then cooled, and the solvent is evaporated to dryness under reduced pressure. The residue is purified by chromatography over silica gel (80% ethyl acetate in hexanes is used as the eluant) to give the desired product as a pale yellow solid.
EXAMPLE 44 (METHOD 17)
(3-Chloro-4-isoxazol-5-yl-phenyl)-carbamic acid tert-butyl ester
A solution of [3-chloro-4-(3-dimethylamino-acryloyl)-phenyl]-carbamic acid tert-butyl ester (270 mg) in dioxane (3 ml) is treated with hydroxylamine hydrochloride (122 mg) and the mixture is stirred at room temperature for 10 days. The mixture is diluted with ethyl acetate, washed successively with water, 5% aqueous sodium bicarbonate, saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent is removed by evaporation under reduced pressure and the resulting residue is chromatographed over silica gel (33% ethyl acetate in hexanes is used as the eluant) to provide the desired product as a colorless solid.
EXAMPLE 45 (METHOD 18)
[3-Chloro-4-(1H-pyrazol-3-yl)-phenyl]-carbamic acid tert-butyl ester
A solution of [3-chloro-4-(3-dimethylamino-acryloyl)-phenyl]-carbamic acid tert-butyl ester (250 mg) in ethanol (1.25 ml) is treated with hydrazine hydrate (0.2:5 ml) and the mixture is stirred at room temperature for 3 hours. The mixture is then diluted with 30 mL of diethyl ether, washed three times with water, once with saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent is removed by evaporation under reduced pressure and the resulting residue is chromatographed over silica gel (67% ethyl acetate in hexanes is used as the eluant) to provide the desired product as an oil.
EXAMPLE 46 (METHOD 19A)
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. This reaction mixture is poured into water a pale yellow solid is collected and then recrystallized from hot 2-propanol to give a pale yellow crystalline solid.
Using the above procedure and appropriate starting materials the following compounds were prepared:
(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-1-yl)-acetamide
N-(2-Chloro-4-nitro-phenyl)-2-(4-methyl-piperidin-1-yl)-acetamide
EXAMPLE 47 (METHOD 19B)
N-(2-Chloro-4-nitrophenyl)-2-(2-dimethylaminoethylsulfanyl)acetamide
To a solution of N-(chloroacetyl)-2-chloro-4-nitroaniline (3.01 g) in N,N-dimethylformamide (100 mL) is added powdered sodium carbonate (6.0 g) and 2-dimethylaminoethanethiol hydrochloride (6.0 g). The mixture is stirred for 1 hour at 25.degree. 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.
EXAMPLE 48 (METHOD 20)
(4-tert-butoxycarbonylamino-2-chloro-phenyl)-carbamic acid 2-piperidin-1-yl-ethyl ester
To a suspension of 1,1-carbonyl-di-(1,2,4)-triazole (4.0 g) in dichloromethane (40 mL) 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 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 eluant) to give the desired product as a white foam.
EXAMPLE 49
5-Phenyl-[1,2,3]thiadiazole-4-carboxylic acid methyl ester
A solution of ethyl benzoylacetate (1.1 g) in acetonitrile (10 mL) is treated with 4-methylbenzenesulfonyl azide (1.3 g) and triethylamine (1.6 g). After stirring overnight at room temperature, the reaction is concentrated under reduced pressure and the resulting crude product is dissolved in ethyl acetate and washed with 1N sodium hydroxide. The organic layer is then dried over anhydrous magnesium 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-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 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.
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
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 is cooled to -20.degree. C. overnight. The resulting solid semicarbazone is collected by filtration, washed with water and then diethyl ether to give the desired product as white crystals.
Using the above procedure and appropriate starting materials the following compound was prepared:
Ethyl (Z)-3-[(aminocarbonyl)hydrazono]-4,4,4-trifluorobutanoate
3-[(Z)-2-(Aminocarbonyl)hydrazono]-3-phenylpropanoic acid ethyl ester
3-[(E)-2-(Aminocarbonyl)hydrazono]-3-(3-furyl)propanoic acid ethyl ster
EXAMPLE 51
5-Phenyl-[1,2,3]thiadiazole-5-carboxylic acid ethyl ester
A solution of ethyl benzoylacetate semicarbazone (2.5 g) in neat thionyl chloride (5 mL) is stirred at 0.degree. C. 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.
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:
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
4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid methyl ester (1.7 g) is dissolved in methanol (15 mL) and treated with 1N 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 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:
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
To a solution of 4-chloro-5-methoxy-2-nitro-phenol (6.5 g) in dichloromethane (150 mL) at 0.degree. C. under an atmosphere of argon is added triethylamine (10 g) and then a solution of trifluoro-methanesulfonic anhydride (13.5 g) in dichloromethane (30 mL). The solution is stirred at 0.degree. C. for 10 minutes, and is then diluted with dichloromethane and washed successively with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. After drying over anhydrous sodium sulfate the solvent is removed by evaporation under reduced pressure and the residue is dissolved in a solution of 20% dichloromethane in hexanes and passed through a short column of hydrous magnesium silicate (20% dichloromethane in hexanes is used as the eluant). Product containing fractions are pooled and the solvents removed by evaporation under reduced pressure to give the desired product as a yellow oil.
Using the above procedure and appropriate starting materials the following compounds were prepared:
Trifluoro-methanesulfonic acid 4-chloro-5-methoxy-2-nitro-phenyl ester
Trifluoro-methanesulfonic acid 4-chloro-2-nitro-phenyl ester
Trifluoro-methanesulfonic acid 2-chloro-6-nitro-phenyl ester
EXAMPLE 54 (METHOD 26)
[4-(3-Dimethylamino-benzoylamino)-phenyl]-carbamic acid t-butyl ester
A solution of [4-(3-amino-benzoylamino)-phenyl]-carbamic acid t-butyl ester (505 mg), sodium cyanoborohydride (250 mg), acetic acid (3 drops) and 40% aqueous formaldehyde (4 mL) in 1:2 tetrahydrofuran-methanol (15 mL) is stirred for 15 minutes, and then poured into saturated aqueous sodium bicarbonate and extracted into ethyl acetate. The ethyl acetate solution is dried over anhydrous potassium carbonate and concentrated under reduced pressure to give a solid which is recrystallized from acetonitrile to provide a pale pink crystalline solid.
Using the above procedure and appropriate starting materials the following compounds were prepared:
[4-(3-Dimethylamino-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
(3-Bromo-5-trifluoromethyl-phenyl)-dimethyl-amine
N-(3-Chloro-5-dimethylamino-phenyl)-acetamide
EXAMPLE 55 (METHOD 27)
N-(4-Aminophenyl)-2-hydroxybenzamide
To a solution of 2-(4-aminophenylcarbamoyl) phenyl acetate (580 mg) in methanol (10 mL) is added saturated sodium bicarbonate (2 mL) and water (3 mL). The mixture is heated at 80.degree. 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 solid.
EXAMPLE 56 (METHOD 28)
[4-(3-(Hydroxybenzoylamino)phenyl}carbamic acid t-butyl ester
To a solution of 3-(4-aminophenylcarbamoyl) phenyl acetate (4.34 g) in methanol (75 mL) is added 0.1 N aqueous sodium hydroxide (25 mL) and tetrahydrofuran (25 mL). This solution is heated at 40.degree. 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.
EXAMPLE 57 (METHOD 29)
N-(4-Aminophenyl)-2-hydroxymethylbenzamide
To a solution of N-(4-aminophenyl)phthalimide (332 mg) in tetrahydrofuran (4 mL) is added lithium borohydride (1.0 g) and the mixture is stirred for 1 hour at 25.degree. 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.
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 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 desired product as a white solid.
EXAMPLE 59 (METHOD 35)
N-(4-{3-[3,5-Dichloro-4-(2-hydroxy-ethoxy)-phenyl]-thioureido}-phenyl)-acetamide
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 1 N 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 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)
{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 1 N aqueous sodium hydroxide (2 mL) and the mixture is stirred for 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.
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
EXAMPLE 61 (METHOD 37)
Benzoic acid 2-{4-[3-(4-acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy }-ethyl ester
To an ice cooled solution of N-(4-{3-[3,5-dichloro-4-(2-hydroxy-ethoxy)-phenyl]-thioureido}-phenyl)-acetamide (0.20 g) in pyridine (2 mL) and tetrahydrofuran (0.5 mL) is added benzoyl chloride (0.08 g) and the mixture is stirred at 0.degree. C. 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, 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.
EXAMPLE 62 (METHOD 38)
Methanesulfonic acid 2-{4-[3-(4-acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy }-ethyl ester
To an ice cooled solution of N-(4-{3-[3,5-dichloro-4-(2-hydroxy-ethoxy)-phenyl]-thioureido }-phenyl)-acetamide (0.20 g) in pyridine (2 mL) and tetrahydrofuran (0.5 mL) is added methanesulfonyl chloride (0.11 g) and the solution is stirred at 0.degree. C. for 45 minutes. The reaction mixture is then diluted with ethyl acetate, washed successively twice with 2% aqueous hydrochloric acid, once with saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After removing the solvents by evaporation under reduced pressure the resulting residue is recrystallized from acetone-hexanes to give the desired product as a white powder.
EXAMPLE 63 (METHOD 39)
N-(4-{3-[3,5-Dichloro-4-(2-dimethylmanino-ethoxy)-phenyl]-thioureido}-phenyl)-acetamide
To a solution of methanesulfonic acid 2-{4-[3-(4-acetylamino-phenyl)-thioureido]-2, 6-dichlorophenoxy}-ethyl ester (0.33 g) in tetrahydrofuran (6 mL) is added aqueous dimethyl-amine (8.8 M, 0.5 mL) and the mixture is stirred at room temperature for 5 days. The reaction mixture is then diluted with ethyl acetate, then washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure the residue is chromatographed over silica gel (pure methanol is used as the eluant). Pooled product containing fractions are evaporated under reduced pressure and the residue is recrystallized from acetonitrile to provide the desired product as a white powder.
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)
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}-phenyl)-amide (0.22 g) and the solution is stirred for approximately 15 hours at room temperature. The solution is then diluted with ethyl acetate, washed successively with saturated aqueous sodium bicarbonate then saturated aqueous sodium chloride, then dried over anhydrous sodium sulfate. After removal of the solvent by evaporation under reduced pressure the residue is chromatographed over silica gel (8% methanol in dichloromethane containing 1% triethylamine is used as the eluant) to provide the desired product as a yellow solid.
EXAMPLE 65 (METHOD 41)
[1,2,3]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 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 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
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) tetrahydrofuran (2 mL) is added bis-(tri-o-tolylphosphino)palladium (0.15 g), a solution of dimethylamine in tetra-hydrofuran (2 M, 4.2 mL), and a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1 M, 10.4 mL). The reaction mixture is heated in a sealed vessel to 100.degree. C. for approximately 2.5 hours to complete 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 5 N aqueous sodium hydroxide. This basic solution is then extracted 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.
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
EXAMPLE 67 (METHOD 43)
(3-Isobutyl-5-trifluoromethyl-phenyl)-carbaniic 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 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 isobutylene. A solution of (3-bromo-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (1.7 g) in tetrahydrofuran (12 mL) is added, followed by [1,1'-bis (diphenylphosphino)-ferrocene]palladium(II) chloride-dichlormethane complex (0.12 g), and then 3 N aqueous sodium hydroxide. The vessel is again sealed with the teflon cap and is then heated to 65.degree. C. for approximately 15 hours. The mixture is then cooled to room temperature, diluted with hexanes, washed with water, saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The resulting oil is chromatographed over silica gel (5% ethyl acetate in hexanes is used as the eluant) to provide the desired product as a white powder.
Using the above procedure and appropriate starting materials the following compounds were prepared:
[3-(2-Methyl-butyl)-5-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester
(3-Isobutyl-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester
EXAMPLE 68 (METHOD 44)
2-(3,5-Dichloro-phenylsulfanyl)-ethylamine
To a solution of (3,5-dichlorophenylthio)acetonitrile (1.2 g) in 3.0 mL of ethylene glycol dimethyl ether is added 0.61 mL of 10 M borane dimethyl sulfide complex and the mixture heated at reflux for 0.5 hours. The reaction is cooled in an ice bath and 2.0 mL of water and 2.0 mL of concentrated hydrochloric acid is added. This mixture is heated at reflux for 0.5 hr. The clear solution is then cooled and basified with 5 N sodium hydroxide and extracted with ether. The ether extract is dried over potassium carbonate, filtered and concentrated to give 1.0 g of a colorless oil.
Using the above procedure and appropriate starting materials the following compounds were prepared:
2-(3-Bromo-phenylsulfanyl)-ethylamine
2(4-Bromo-phenoxy)-ethylamine
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
A mixture of 2-acetylnaphthylene (3.0 g), ammonium formate (11.0 g), formic acid (3.3 mL), and formamide (3-5 mL) is heated at 190.degree. C. for 3 hours. The mixture is cooled, poured into water and extracted with ether. The ether extract is dried with anhydrous potassium carbonate, filtered and concentrated to give a yellow oil, which is crystallized from toluene-hexanes to give a white solid, 1.97 g.
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
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 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.
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)
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 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).
Using the above procedure and appropriate starting materials the following compounds were prepared:
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-(4Fluoro-phenyl)-pentan-1-one O-methyl-oxime
1-(4-Fluoro-phenyl)-2-phenyl-ethanone O-methyl-oxime
1-o-Tolyl-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-1 H-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
1-(3,5-Bis-trifluoromethyl-phenyl)-ethanone 0-methyl-oxime
1-[4-(1 H-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-(trifluoromethylphenyl]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
EXAMPLE 72 (METHOD 48)
1-(2-Trifluoromethyl-phenyl)-ethylamine
Sodium borohydride (1.17 g) is added slowly to a flask containing zirconium tetrachloride (1.8 g) in tetrahydrofuran (27 mL). A solution of 1-(2-trifluoromethyl-phenyl)-ethanone O-methyl-oxime (1.34 g) in tetrahydrofuran (7.7 mL) is added and the resulting solution is stirred at 25 .degree. C. for 12 hours. The reaction mixture is then cooled to 0 .degree. C. and water (16 mL) is slowly added. Excess ammonium hydroxide is added and the solution is extracted twice with ethyl acetate. The organic portion is washed twice with 1 N 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).
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
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-1 H-pyrrol-2-yl)-ethylamine
1-Thiophen-3-yl-ethylamine
1-[3,5-bis(trifluoromethyl)phenyl]propylamine
1-[3,5-bis(trifluoromethyl)phenyl]-1-butanamine or 1-[3,5-bis (trifluoromethyl)phenyl]butylamine
1-[3,5-bis(trifluoromethyl)phenyl]-1-pentanamine
1-(4-methylphenyl)ethanamine
1-[3-(trifluoromethyl)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-ethylarnine
1-(4-Fluoro-phenyl)-ethylamine
1-[4-fluoro-3-(trifluoromethyl)phenyl]ethanamine
1-[4-chloro-3-(trifluoromethyl)phenyl]ethanamine
N-{4-[(1 R)-1-aminoethyl]phenyl}-1,2,3-thiadiazole-4-carboxamide
N-{4-[(1 S)-1-aminoethyl]phenyl }-1,2,3-thiadiazole-4-carboxamide
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-(4bromo-2-fluorophenyl)ethylamine
1-(3-fluorophenyl)ethylamine
1-(2,4-difluorophenyl)ethylamine
1-[3-fluoro-4-(trifluoromethyl)phenyl]ethylamine
1-[4-fluoro-2-(trifluoromethyl)phenyl]ethylamine
1-(3-chloro-4fluorophenyl)ethylamine
1-(4-chloro-3-fluorophenyl)ethylamine
1-(3,4-dibromophenyl)ethylamine
1-(2-bromo-4-fluorophenyl)ethanamine1-(2-bromo-4-fluorophenyl) ethylamine
EXAMPLE 73 (METHOD 49)
(2-Fluoro-5-trifluoromethyl-phenoxy)-acetonitrile
A solution of 2-fluoro-5-trifluoromethylphenol (25 g) in reagent grade acetone (0.55 L) is treated with solid potassium carbonate (7.7 g) followed by the rapid addition of neat bromoacetonitrile (10 mL). The heterogenous mixture is stirred vigorously for approximately 20 hours whereupon it is poured into water and extracted into diethyl ether. The combined ether extracts are washed with saturated sodium chloride and dried over anhydrous potassium carbonate. Filtration and concen-tration under reduced pressure gives a pale orange solid which is then chromatographed on silica gel, eluting with dichloromethane, to give the desired product as white solid (28.3 g).
Using the above procedure and appropriate starting materials the following compounds were prepared:
(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
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-fluoro-5-trifluoromethylphenethylamine crystallizes. The white crystals, 4.26 g (91%) are collected by filtration.
Using the above procedure and appropriate starting materials the following compounds were prepared:
2-(3,5-Difluoro-phenyl)-ethylamine
2-(4-Trifluoromethyl-phenyl)-ethylamine
2- (3 ,4-Difluoro-phenyl)-ethylamine
2-(2-Fluoro-phenyl)-ethylamine
2-(3-Fluoro-5-trifluoromethyl-phenyl)-ethylamine
2-(2-Fluoro-3-trifluoromethyl-phenyl)-ethylamine
2-(2,4-Bis-trifluoromethyl-phenyl)-ethylamine
2-(4-Fluoro-3-trifluoromethyl-phenyl)-ethylamine
EXAMPLE 75 (METHOD 51)
(4-Aminomethyl-2-trifluoromethyl-phenyl)-dimethyl-amine
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.degree. C. and stirred under an atmosphere of argon for 2 hours. While at 0.degree. C. water (0.1 mL) is slowly added followed by 5% sodium hydroxide (0.1 mL) and water (0.3 mL). The resulting gray solid is filtered and washed with tetrahydrofuran. The filtrates are collected and concentrated under 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).
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
EXAMPLE 76 (METHOD 52)
3-Dimethylamino-5-trifluoromethyl-benzaldehyde
Diisobutylaluminum hydride (10 mL of a 1 M solution in methylene chloride) is added dropwise to a solution of 3-dimethylamino-5-trifluoromethylbenzonitrile (1.06 g) in methylene chloride (25 mL) at 0.degree. C. and the mixture stirred for 2 hours. While still at 0.degree. C. a saturated aqueous solution of sodium potassium tartrate (8 mL) is slowly added and the solution is stirred for 1.5 hours. The reaction mixture is then extracted with ethyl acetate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide the desired product as a yellow solid (0.97 g).
Using the above procedure and appropriate starting materials the following compounds were prepared:
3-Dimethylamino-5-trifluoromethyl-benzaldehyde
4-Dimethylamino-3-methyl-benzaldehyde
EXAMPLE 77 (METHOD 53)
Dimethyl-[3-(2-nitro-vinyl)-5-trifluoromethyl-phenyl]-amine
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.degree. C. for 6 hours. The reaction mixture is cooled to 0.degree. C. and a solid forms which is filtered and washed with 1:1 water-acetic acid. This solid is recrystallized from ethanol to provide the desired product as a red solid (0.39 g).
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
EXAMPLE 78 (METHOD 54)
3-(4-Bromo-phenyl)-propionitrile
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.degree. C. The reaction mixture is stirred for 10 minutes and a solution of acetone cyanohydrin (2.6 g) in diethyl ether (10 mL) is added. The clear orange solution is stirred for 5 minutes at 0.degree. C. and then at 25.degree. C. for 12 hours. The reaction mixture is 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)
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 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)
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 and purified by column chromatography using silica and 25% ethyl acetate-hexanes as the eluant. The purified material (0.61 g) is isolated as an oil.
EXAMPLE 81 (METHOD 34)
N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-ureidol-phenyl}-2-fluoro-benzamide
A suspension of N-(4-amino-phenyl)-2-fluoro-benzamide (0.43 g) in acetonitrile (4 mL) is treated with 5-chloro-2,4-dimethoxyphenylisocyanate (0.40 g). The mixture becomes a solution and is allowed to stand for 12 hours. A white solid forms and is collected by filtration (0.79 g). [M+H] 444.
Using the above procedure and appropriate starting materials the following compounds were prepared:
______________________________________EX NO. M + H COMPOUND NAME______________________________________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______________________________________
EXAMPLE 91(.)
N-(5-{[({(1 S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}-2-pyridinyl)-1,3-thiazole-4-carboxamide
A mixture of N-(5-isothiocyanato-2-pyridinyl)-1,3-thiazole-4-carboxamide (0.36 g) and (S)-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.
Using the above procedure and appropriate starting materials the following compounds were prepared:
______________________________________EX. NO. M + H COMPOUND NAME______________________________________92 506 [3-Chloro-5-(3-{4-[([1,2,3]thiadiazole-4-carbonyl)- amino]-phenyl}-thioureido)-phenyl]-carbamic acid tert- butyl ester 93 409 1-(5-Chloro-2,4-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}-carbarmic acid ethyl ester 102 319 1-(2,4-Dimethoxy-phenyl)-3-(4-methoxy-phenyl)- thiourea 103 346 N-{4-[3-(2,4-Dimethoxy-phenyl)-thioureido]-phenyl}- acetamide 104 316 N-{4-[3-(4-Methoxy-phenyl)-thioureido]-phenyl}- acetamide 105 316 N-{4-[3-(2-Methoxy-phenyl)-thioureido]-phenyl}- acetamide 106 351 N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]- phenyl}-acetamide 107 351 N-{4-[3-(5-Chloro-2-methoxy-phenyl)-thioureido]- phenyl}-acetamide 108 371 N-{4-[3-(3,5-Dichloro-4-hydroxy-phenyl)-thioureido]- phenyl}-acetamide 109 385 N-{4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]- phenyl}-acetamide 110 381 N-{4-[3-(4-Chloro-2,5-dimethoxy-phenyl)-thioureido]- phenyl}-acetamide 111 389 N-{4-[3-(2-Chloro-5-trifluoromethyl-phenyl)-thioureido]- phenyl}-acetamide 112 389 N-{4-[3-(4-Chloro-3-trifluoromethyl-phenyl)-thioureido]- phenyl}-acetamide 113 422 Benzoic acid 4-[3-(4-acetylamino-phenyl)-thioureido]-3- hydroxy-phenylester 114 457 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]- phenyl}-2-methyl-benzamide 115 501 Acetic acid 2-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-phenyl-carbamoyl}-phenyl ester 116 461 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]- phenyl}-4-fluoro-benzamide 117 461 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]- phenyl}-3-fluoro-benzamide 118 461 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]- phenyl}-2-fluoro-benzamide 119 473 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]- phenyl}-2-methoxy-benzamide 120 473 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]- phenyl}-3-methoxy-benzamide 121 473 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]- phenyl}-4-methoxy-benzamide 122 443 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]- phenyl}-benzamide 123 417 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]- phenyl}-methanesulfonamide 124 331 N-{4-[3-(3-Nitro-phenyl)-thioureido]-phenyl}-acetamide 125 339 1-(3-Chloro-4-methoxy-phenyl)-3-(3-nitro-phenyl)- thiourea 126 337 N-{4-[3-(5-Chloro-2-hydroxy-phenyl)-thioureido]- phenyl}-acetamide 127 439 {4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]- phenyl}-carbamic acid tert-butyl ester 128 351 N-{4-[3-(3-Chloro-4-hydroxy-5-methyl-phenyl)- thioureido]-phenyl}-acetamide 129 385 N-{4-[3-(3,5-Dichloro-4-hydroxy-2-methyl-phenyl)- thioureido]-phenyl}-acetamide 130 318 N-{4-[3-(2,4-Dihydroxy-phenyl)-thioureido]-phenyl}- acetamide 131 414 N-{4-[3-(2,4-Dimethoxy-5-trifluoromethyl-phenyl)- thioureido]-phenyl}-acetamide 132 332 N-{4-[3-(2-Hydroxy-4-methoxy-phenyl)-thioureido]- phenyl}-acetamide 133 465 N-{4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]- phenyl}-4-fluoro-benzamide 134 500 3-Acetylamino-N-{4-[3-(5-chloro-2,4-dimethoxy- phenyl)-thioureido]-phenyl}-benzamide 135 488 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]- phenyl}-3-nitro-benzamide 136 486 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]- phenyl}-3-dimethylamino-benzamide 137 536 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]- phenyl}-3-methane-sulfony-amino-benzamide 138 511 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]- phenyl}-2-trifluoro-methyl-benzamide 139 459 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]- phenyl}-2-hydroxy-benzamide 140 479 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]- phenyl}-2,6-difluoro-benzamide 141 477 2-Chloro-N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-phenyl}-benzamide 142 522 2-Bromo-N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-phenyl}-benzamide 143 488 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]- phenyl}-2-nitro-benzamide 144 445 Pyrazine-2-carboxylic acid {4-[3-(5-chloro-2,4- dimethoxy-phenyl)-thioureido]-phenyl}-amide 145 463 5-Methyl-thiophene-2-carboxylic acid {4-[3-(5-chloro- 2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 146 494 Quinoline-8-carboxylic acid {4-[3-(5-chloro-2,4- dimethoxy-phenyl)-thioureido]-phenyl}-amide 147 446 1-Methyl-1H-pyrrole-2-carboxylic acid {4-[3-(5-chloro- 2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 148 369 1-(5-Chloro-2,4-dimethoxy-phenyl)-3-(2-nitro-phenyl)- thiourea 149 369 1-(5-Chloro-2,4-dimethoxy-phenyl)-3-(4-nitro-phenyl)- thiourea 150 425 N-{4-[3-(5-Bromo-2,4-dimethoxy-phenyl)-thioureido]- phenyl}-acetamide 151 376 N-{4-[3-(3,4,5-Trimethoxy-phenyl)-thioureido]-phenyl}- 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}-amide 154 483 Benzofuran-2-carboxylic acid {4-[3-(5-chloro-2,4- dimethoxy-phenyl)-thioureido]-phenyl}-amide 155 444 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]- phenyl}-isonicotinamide 156 493 Naphthalene-2-carboxylic acid {4-[3-(5-chloro-2,4- dimethoxy-phenyl)-thioureido]-phenyl}-amide 157 493 Naphthalene-1-carboxylic acid {4-[3-(5-chloro-2,4- dimethoxy-phenyl)-thioureido]-phenyl}-amide 158 494 Isoquinoline-1-carboxylic acid {4-[3-(5-chloro-2,4- dimethoxy-phenyl)-thioureido]-phenyl}-amide 159 494 Quinoline-2-carboxylic acid {4-[3-(5-chloro-2,4- dimethoxy-phenyl)-thioureido]-phenyl}-amide 160 444 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]- phenyl}-nicotinamide 161 478 5-Nitro-furan-2-carboxylic acid {4-[3-(5-chloro-2,4- dimethoxy-phenyl)-thioureido]-phenyl}-amidecarbamic acid phenyl ester 162 459 {4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]- phenyl}- 163 467 5-Chloro-furan-2-carboxylic acid {4-[3-(5-chloro-2,4- dimethoxy-phenyl)-thioureido]-phenyl}-amide 164 439 {4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]- phenyl}-carbamic acid isobutyl ester 165 397 {4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]- phenyl}-carbamic acid methyl ester 166 433 Furan-3-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy- phenyl)-thioureido]-phenyl}-amide 167 447 3-Methyl-furan-2-carboxylic acid {4-[3-(5-chloro-2,4- dimethoxy-phenyl)-thioureido]-phenyl}-amide 168 512 5-Bromo-furan-2-carboxylic acid {4-[3-(5-chloro-2,4- dimethoxy-phenyl)-thioureido]-phenyl}-amide 169 512 4-Bromo-furan-2-carboxylic acid {4-[3-(5-chloro-2,4- dimethoxy-phenyl)-thioureido]-phenyl}-amide 170 433 Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy- phenyl)-thioureido]-phenyl}-amide 171 467 {4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]- phenyl}-carbamic acid hexyl ester 172 494 Isoquinoline-4-carboxylic acid {4-[3-(5-chloro-2,4- dimethoxy-phenyl)-thioureido]-phenyl}-amide 173 451 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(5-chloro-2,4- dimethoxy-phenyl)-thioureido]-phenyl}-amide 174 434 1H-[1,2,3]Triazole-4-carboxylic acid {4-[3-(5-chloro-2,4- dimethoxy-phenyl)-thioureido]-phenyl}-amide 175 528 3-Bromo-thiophene-2-carboxylic acid {4-[3-(5-chloro- 2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 176 399 N-{4-[3-(3,5-Dichloro-4-ethoxy-phenyl)-thioureido]- phenyl}-acetamide 177 427 N-{4-[3-(4-Butoxy-3,5-dichloro-phenyl)-thioureido]- phenyl}-acetamide 178 461 N-{4-[3-(4-Benzyloxy-3,5-dichloro-phenyl)-thioureido]- phenyl}-acetamide 179 381 N-{4-[3-(3-Chloro-2,4-dimethoxy-phenyl)-thioureido]- phenyl}-acetamide 180 530 (3-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]- phenylcarbamoyl}-phenyl)-carbamic acid ethyl ester 181 458 2-Amino-N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-phenyl}-benzamide 182 519 Biphenyl-2-carboxylic acid {4-[3-(5-chloro-2,4- dimethoxy-phenyl)-thioureido]-phenyl}-amide 183 469 1-(5-Chloro-2,4-dimethoxy-phenyl)-3-[4-(1,3-dioxo-1,3- dihydro-isoindol-2-yl)-phenyl]-thiourea 184 487 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]- phenyl}-phthalamic acid 185 473 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]- phenyl}-2-hydroxy-methyl-benzamide 186 479 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]- phenyl}-2,3-difluoro-benzamide 187 479 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]- phenyl}-2,5-difluoro-benzamide 188 479 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]- phenyl}-2,4-difluoro-benzamide 189 500 2-Acetylamino-N-{4-[3-(5-chloro-2,4-dimethoxy- phenyl)-thioureido]-phenyl}-benzamide 190 441 1-(5-Chloro-2,4-dimethoxy-phenyl)-3-(6-oxo-5,6- dihydro-phenanthridin-2-yl)-thiourea 191 536 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]- phenyl}-2-methane-sulfonylamino-benzamide 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-benzamide 194 489 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]- phenyl}-2-methyl-sulfanyl-benzamide 195 431 5-Methyl-furan-2-carboxylic acid {4-[3-(5-chloro-2,4- dimethoxy-phenyl)-ureido]-phenyl}-amide 196 467 5-Difluoromethyl-furan-2-carboxylic acid {4-[3-(5- chloro-2,4-dimethoxy-phenyl)-ureido]-phenyl}-amide 197 472 N-{4-[3-(5-Iodo-2,4-dimethoxy-phenyl)-thioureido]- phenyl}-acetamide 198 364 N-{4-[3-(5-Fluoro-2,4-dimethoxy-phenyl)-thioureido]- phenyl}-acetamide 199 365 N-{4-[3-(5-Chloro-2-methoxy-4-methyl-phenyl)- thioureido]-phenyl}-acetamide 200 459 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-chloro-3- trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 201 455 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-dich loro- 4-methoxy-phenyl)-thioureido]-phenyl}-amide 202 392 N-{4-[3-(3-Chloro-4-diethylamino-phenyl)-thioureido]- phenyl}-acetamide 203 432 N-(4-{3-[3-Chloro-4-(cyclohexyl-methyl-amino)-phenyl]- thioureido}-phenyl)-acetamide 204 506 1-Hydroxy-naphthalene-2-carboxylic acid {4-[3-(4- acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-amide 205 406 N-{4-[3-(3-Chloro-4-morpholin-4-yl-phenyl)-thioureido]- phenyl}-acetamide 206 443 1-(5-Chloro-2,4-dimethoxy-phenyl)-3-(3-chloro-4- morpholin-4-yl-phenyl)-thiourea 207 372 1-(5-Chloro-2,4-dimethoxy-phenyl)-3-(5-chloro-2- methyl-phenyl)-thiourea 208 501 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]- phenyl}-isophthalamic acid methyl ester 209 487 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]- phenyl}-isophthalamic acid 210 549 3-Benzyloxy-N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-phenyl}-benzamide 211 434 N-(4-{3-[5-Chloro-2-methoxy-4-(4-nitrilo-butoxy)- phenyl]-thioureido}-phenyl)-acetamide 212 406 N-(4-{3-[5-Chloro-2-methoxy-4-(2-nitrilo-ethoxy)- phenyl]-thioureido}-phenyl)-acetamide 213 406 N-(4-{3-[5-Chloro-4-methoxy-2-(2-nitrilo-ethoxy)- phenyl]-thioureido}-phenyl)-acetamide 214 411 N-(4-{3-[5-Chloro-2-(2-hydroxy-ethoxy)-4-methoxy- phenyl]-thioureido}-phenyl)-acetamide 215 411 N-(4-{3-[5-Chloro-4-(2-hydroxy-ethoxy)-2-methoxy- phenyl]-thioureido}-phenyl)-acetamide 216 481 {4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-5- methoxy-phenoxy}-acetic acid tert-butyl ester 217 439 {4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-5- methoxy-phenoxy}-acetic acid methyl ester 218 481 {2-[3-(4-Acetylamino-phenyl)-thioureido]-4-chloro-5- methoxy-phenoxy}-acetic acid tert-butyl ester 219 515 3-Butoxy-N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-phenyl}-benzamide 220 505 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]- phenyl}-2-methane-sulfinyl-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 232 427 N-{4-[3-(3-Chloro-4-methyl-phenyl)-thioureido]- phenyl}-3-methoxy-benzamide 233 387 Furan-2-carboxylic acid {4-[3-(3-chloro-4-methyl- phenyl)-thioureido]-phenyl}-amide 234 411 N-{4-[3-(3-Chloro-4-methyl-phenyl)-thioureido]- phenyl}-2-methyl-benzamide 235 433 N-{4-[3-(3-Chloro-4-methyl-phenyl)-thioureido]- phenyl}-2,6-difluoro-benzamide 236 398 Pyridine-2-carboxylic acid {4-[3-(3-chloro-4-methyl- phenyl)-thioureido]-phenyl}-amide 237 502 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[3-chloro- 4-(cyclohexyl-methyl-amino)-phenyl]-thioureido}- phenyl)-amide 238 512 N-(4-{3-[3-Chloro-4-(cyclohexyl-methyl-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-amino)-phenyl]- thioureido}-phenyl)-3-methoxy-benzamide 251 376 N-(4-{3-[3-Chloro-4-(2-nitrilo-ethoxy)-phenyl]- thioureido}-phenyl)-acetamide 252 393 N-{4-[3-(4-sec-Butoxy-3-chloro-phenyl)-thioureido]- phenyl}-acetamide 253 501 Acetic acid 3-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-phenyl-carbamoyl}-phenyl ester 254 459 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]- phenyl}-3-hydroxy-benzamide 255 487 Benzo[1,3]dioxole-4-carboxylic acid {4-[3-(5-chloro-2,4- dimethoxy-phenyl)-thioureido]-phenyl}-amide 256 527 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]- phenyl}-3-trifluoro-methoxy-benzamide 257 530 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]- phenyl}-3-(2-dimethylamino-ethoxy)-benzamide 258 572 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]- phenyl}-3-(2-morpholin-4-yl-ethoxy)-benzamide 259 406 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2- cyano-phenyl}-acetamide 260 521 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]- 2,5-dimethoxy-phenyl}-2-fluoro-benzamide 261 441 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]- 2,5-dimethoxy-phenyl}-acetamide 262 527 2-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro- phenoxy}-5-chloro-benzenesulfonic acid 263 562 2-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro- phenoxy}-4,5-dichloro-benzenesulfonic acid 264 527 4-Phenyl-[1,2,3]thiadiazole-5-carboxylic acid{4-[3-(5- chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 265 381 N-(4-{3-[3-Chloro-4-(2-hydroxy-ethoxy)-phenyl]- thioureido}-phenyl)-acetamide 266 393 N-{4-[3-(4-Butoxy-3-chloro-phenyl)-thioureido]- phenyl}-acetamide 267 446 N-(4-{3-[3-Chloro-4-(cyclohexyl-ethyl-amino)-phenyl]- thioureido}-phenyl)-acetamide 268 365 N-{4-[3-(3-Chloro-4-ethoxy-phenyl)-thioureido]- phenyl}-acetamide 269 427 N-{4-[3-(4-Benzyloxy-3-chloro-phenyl)-thioureido]- 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)-cetamide 274 411 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]- 2-methoxy-phenyl}-acetamide 275 415 N-{2-Chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-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]-acetamide 292 485 N-{2-Benzoyl-4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-phenyl}-acetamide 293 565 N-{2-Benzoyl-4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-phenyl}-2-fluoro-benzamide 294 537 Furan-2-carboxylic acid {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 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)-acetamide 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)-acetamide 319 495 N-(4-{3-[4-(1-Benzyl-pyrrolidin-3-ylamino)-3-chloro- phenyl]-thioureido}-phenyl)-acetamide 320 483 Furan-2-carboxylic acid {5-chloro-4-[3-(5-chloro-2,4- dimethoxy-phenyl)-thioureido]-2-hydroxy-phenyl}-amide 321 431 N-{5-Chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-2-hydroxy-phenyl}-acetamide 322 511 (5H,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-1-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]-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-(1-methyl-piperidin-4-yl)- amino]-phenyl}-thioureido)-phenyl]-2,6-difluoro- benzamide 341 503 [1,2,3]Thiadiazole-4-carboxylic acid[4-(3-{3-chloro-4- [methyl-(1-methyl-pyrrolidin-3-yl)-amino]-phenyl}- thioureido)-phenyl]-amide 342 443 N-{4-[3-(3-Chloro-4-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 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-acetylamino)-phenyl]-thioureido}- phenyl)-amide 362 501 N-(4-{3-[3-Chloro-4-(2-dimethylamino-acetylamino)- phenyl]-thioureido}-phenyl)-2-fluoro-benzamide 363 461 N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro- phenyl}-2-piperidin-1-yl-acetamide 364 541 N-(4-{3-[3-Chloro-4-(2-piperidin-1-yl-acetylamino)- phenyl]-thioureido}-phenyl)-2-fluoro-benzamide 365 513 Furan-2-carboxylic acid (4-{3-[3-chloro-4-(2-piperidin- 1-yl-acetylamino)-phenyl]-thioureido}-phenyl)-amide 366 463 N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro- phenyl}-2-morpholin-4-yl-acetamide 367 543 N-(4-{3-[3-Chloro-4-(2-morpholin-4-yl-acetylamino)- phenyl]-thioureido}-phenyl)-2-fluoro-benzamide 368 515 Furan-2-carboxylic acid (4-{3-[3-chloro-4-(2-morpholin- 4-yl-acetylamino)-phenyl]-thioureido}-phenyl)-amide 369 414 N-{4-[3-(3-Chloro-4-methanesulfonylamino-phenyl)- thioureido]-phenyl}-acetamide 370 494 N-{4-[3-(3-Chloro-4-methanesulfonylamino-phenyl)- thioureido]-phenyl}-2-fluoro-benzamide 371 466 Furan-2-carboxylic acid {4-[3-(3-chloro-4- methanesulfonylamino-phenyl)-thioureido]-phenyl}- amide 372 481 N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro- phenyl}-2-(2-dimethylamino-ethylsulfanyl)-acetamide 373 561 N-[4-(3-{3-Chloro-4-[2-(2-dimethylamino-ethylsulfanyl)- acetylamino]-phenyl}-thioureido)-phenyl]-2-fluoro- benzamide 374 585 N-[4-(3-{4-[(1-Benzyl-pyrrolidin-3-yl)-methyl-amino]- 3-chloro-phenyl}-thioureido)-phenyl]-2-methyl- benzamide 375 523 N-[4-(3-{3-Chloro-4-[methyl-(1-methyl-piperidin-4-yl)- amino]-phenyl}-thioureido)-phenyl]-2-methyl-benzamide 376 510 Pyridine-2-carboxylic acid [4-(3-{3-chloro-4-[methyl-(1- methyl-piperidin-4-yl)-amino]-phenyl}-thioureido)- phenyl]-amide 377 347 N-{4-[3-(3-Chloro-4-vinyl-phenyl)-thioureido]-phenyl}- acetamide 378 441 Furan-2-carboxylic acid {4-[3-(4-chloro-3- trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 379 452 Pyridine-2-carboxylic acid {4-[3-(4-chloro-3- trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 380 487 N-{4-[3-(4-Chloro-3-trifluoromethyl-phenyl)-thioureido]- phenyl}-2,6-difluoro-benzamide 381 486 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3- cyano-phenyl}-2-fluoro-benzamide 382 458 Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy- phenyl)-thioureido]-3-cyano-phenyl}-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-benzamide 387 489 N-{4-[3-(4-Butylsulfanyl-3-chloro-phenyl)- thioureido]-phenyl}-2-fluoro-benzamide 388 411 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)- thioureido]-3-methoxy-phenyl}-acetamide 389 491 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)- thioureido]-3-methoxy-phenyl}-2-fluoro-benzamide 390 463 Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy- phenyl)-thioureido]-3-methoxy-phenyl}-amide 391 531 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[3-chloro- 4-(2-piperidin-1-yl-acetyl-amino)-phenyl]-thioureido}- phenyl)-amide 392 481 N-{4-[3-(3-Chloro-4-methanesulfinyl-phenyl)- thioureido]-phenyl}-2,6-difluoro-benzamide 393 497 N-{4-[3-(3-Chloro-4-methanesulfonyl-phenyl)- thioureido-phenyl}-2,6-difluoro-benzamide 394 459 N-{4-[3-(5-Chloro-2-methoxy-4-methyl-phenyl)- thioureido]-2-methyl-phenyl}-2-fluoro-benzamide 395 429 N-{4-[3-(3-Chloro-4-methyl-phenyl)-thioureido]-2- methyl-phenyl}-2-fluoro-benzamide 396 533 Furan-2-carboxylic acid [4-(3-{3-chloro-4-[2-(2- dimethylamino-ethylsulfanyl)-acetylamino]-phenyl}- thioureido)-phenyl]-amide 397 458 N-{4-[3-(4-Acetylamino-3-chloro-phenyl)-thioureido]- phenyl}-2-fluoro-benzamide 398 460 [2-Chloro-4-(3-{4-[(furan-2-carbonyl)-amino]-phenyl}- thioureido)-phenyl]-carbamic acid ethyl ester 399 488 (2-Chloro-4-{3-[4-(2-fluoro-benzoylamino)-phenyl]- thioureido}-phenyl)-carbamic acid ethyl ester 400 440 N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro- phenyl}-benzamide 401 520 N-{4-[({[4-(Benzoylamino)-3-chloro-phenyl]-amino}- thioxomethyl)-amino]-phenyl}-2-fluoro-benzamide 402 529 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]- 2-trifluoromethyl-phenyl}-2-fluoro-benzamide 403 492 Furan-2-carboxylic acid {4-[3-(4-benzoylamino-3-chloro- phenyl)-thioureido]-phenyl}-amide 404 416 N-{4-[3-(4-Amino-3-chloro-phenyl)-thioureido]-phenyl}- 2-fluoro-benzamide 405 479 N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro- phenyl}-2-thiomorpholin-4-yl-acetamide 406 531 Furan-2-carboxylic acid (4-{3-[3-chloro-4-(2- thiomorpholin-4-yl-acetylamino)-phenyl]-thioureido}- phenyl)-amide 407 559 N-(4-{3-[3-Chloro-4-(2-thiomorpholin-4-yl-acetylamino)- phenyl]-thioureido}-phenyl)-2-fluoro-benzamide 408 461 N-{4-[3-(3-Chloro-4-methylsulfanyl-phenyl)-thioureido]- 2-methyl-phenyl}-2-fluoro-benzamide 409 430 Furan-2-carboxylic acid {4-[3-(4-acetylamino-3-chloro- phenyl)-thioureido]-phenyl}-amide 410 477 N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro- phenyl}-2-dipropylamino-acetamide 411 529 Furan-2-carboxylic acid (4-{3-[3-chloro-4-(2- dipropylamino-acetylamino)-phenyl]-thioureido}- phenyl)-amide 412 449 N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro- phenyl}-2-diethyl-amino-acetamide 413 501 Furan-2-carboxylic acid (4-{3-[3-chloro-4-(2- diethylamino-acetylamino)-phenyl]-thioureido}-phenyl)- amide 414 529 N-(4-{3-[3-Chloro-4-(2-diethylamino-acetylamino)- phenyl]-thioureido}-phenyl)-2-fluoro-benzamide 415 447 N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro- phenyl}-2-pyrrolidin-1-yl-acetamide 416 499 Furan-2-carboxylic acid (4-{3-[3-chloro-4-(2-pyrrolidin- 1-yl-acetylamino)-phenyl]-thioureido}-phenyl)-amide 417 527 N-(4-{3-[3-Chloro-4-(2-pyrrolidin-1-yl-acetylamino)- phenyl]-thioureido}-phenyl)-2-fluoro-benzamide 418 475 N-{4-[3-(5-Chloro-2-methoxy-4-methyl-phenyl)- thioureido]-3-methoxy-phenyl}-2-fluoro-benzamide 419 445 N-{4-[3-(3-Chloro-4-methyl-phenyl)-thioureido]-3- methoxy-phenyl}-2-fluoro-benzamide 420 477 N-{4-[3-(3-Chloro-4-methylsulfanyl-phenyl)-thioureido]- 3-methoxy-phenyl}-2-fluoro-benzamide 421 388 Furan-2-carboxylic acid {4-[3-(4-amino-3-chloro- phenyl)-thioureido]-phenyl}-amide 422 527 Furan-2-carboxylic acid (4-{3-[4-(2-azepan-1-yl- acetylamino)-3-chloro-phenyl]-thioureido}-phenyl)- amide 423 555 N-(4-{3-[4-(2-Azepan-1-yl-acetylamino)-3-chloro- phenyl]-thioureido}-phenyl)-2-fluoro-benzamide 424 527 Furan-2-carboxylic acid [4-(3-{3-chloro-4-[2-(2-methyl- piperidin-1-yl)-acetyl-amino]-phenyl}-thioureido)- phenyl]-amide 425 555 N-[4-(3-{3-Chloro-4-[2-(2-methyl-piperidin-1-yl)- acetylamino]-phenyl}-thioureido)-phenyl]-2-fluoro- benzamide 426 339 Furan-2-carboxylic acid [4-(3-pyridin-2-yl-thioureido)- phenyl]-amide 427 339 Furan-2-carboxylic acid [4-(3-pyridin-4-yl-thioureido)- phenyl]-amide 428 367 2-Fluoro-N-[4-(3-pyridin-3-yl-thioureido)-phenyl]- benzamide 429 339 Furan-2-carboxylic acid [4-(3-pyridin-3-yl-thioureido)- phenyl]-amide 430 353 Furan-2-carboxylic acid {4-[3-(3-amino-phenyl)- thioureido]-phenyl}-amide 431 406 Furan-2-carboxylic acid {4-[3-(3-trifluoromethyl- phenyl)-thioureido]-phenyl}-amide 432 380 2-Fluoro-N-[4-(3-m-tolyl-thioureido)-phenyl]-benzamide 433 434 2-Fluoro-N-{4-[3-(3-trifluoromethyl-phenyl)-thioureido]- phenyl}-benzamide 434 381 N-{4-[3-(3-Amino-phenyl)-thioureido]-phenyl}-2-fluoro- benzamide 435 388 Furan-2-carboxylic acid {4-[3-(3-amino-5-chloro- phenyl)-thioureido]phenyl}-amide 436 352 Furan-2-carboxylic acid [4-(3-m-tolyl-thioureido)- phenyl]-amide 437 416 N-{4-[3-(2-Amino-5-chloro-phenyl)-thioureido]-phenyl}- 2-fluoro-benzamide 438 571 (2-Chloro-4-{3-[4-(2-fluoro-benzoylamino)-phenyl]- thioureido}-phenyl)-carbamic acid 2-piperidin-1-yl-ethyl ester 439 543 [2-Chloro-4-(3-{4-[(furan-2-carbonyl)-amino]-phenyl}- thioureido)-phenyl]-carbamic acid 2-piperidin-1-yl-ethyl ester 440 388 Furan-2-carboxylic acid {4-[3-(2-amino-5-chloro- phenyl)-thioureido]-phenyl}-amide 441 363 Furan-2-carboxylic acid {4-[3-(3-cyano-phenyl)- thioureido]-phenyl}-amide 442 416 N-{4-[3-(3-Amino-5-chloro-phenyl)-thioureido]-phenyl}- 2-fluoro-benzamide 443 367 2-Fluoro-N-[4-(3-pyridin-2-yl-thioureido)-phenyl]- benzamide 444 367 2-Fluoro-N-[4-(3-pyridin-4-yl-thioureido)-phenyl]- benzamide 445 374 Furan-2-carboxylic acid {4-[3-(6-chloro-pyridin-3-yl)- thioureido]-phenyl}-amide 446 388 Furan-2-carboxylic acid {4-[3-(2-amino-3-chloro- phenyl)-thioureido]-phenyl}-amide 447 396 Furan-2-carboxylic acid {4-[3-(3-hydrazinocarbonyl- phenyl)-thioureido]-phenyl}-amide 448 410 2-Fluoro-N-(4-{3-[3-(1-hydroxy-ethyl)-phenyl]- thioureido}-phenyl)-benzamide 449 414 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3- hydrazinocarbonyl-phenyl)-thioureido]-phenyl}-amide 450 399 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-isopropyl- phenyl)-thioureido]-phenyl}-amide 451 380 Furan-2-carboxylic acid {4-[3-(3-isopropyl-phenyl)- thioureido]-phenyl}-amide 452 409 2-Fluoro-N-{4-[3-(3-isopropyl-phenyl)-thioureido]- phenyl}-benzamide 453 381 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-cyano- phenyl)-thioureido]-phenyl}-amide 454 410 N-{4-[3-(3-Dimethylamino-phenyl)-thioureido]-phenyl}- 2-fluoro-benzamide 455 381 Furan-2-carboxylic acid {4-[3-(3-dimethylamino-phenyl)- thioureido]-phenyl}-amide 456 370 [1,2,3]Thiadiazole-4-carboxylic acid [4-(3-m-tolyl- thioureido)-phenyl]-amide 457 424 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3- trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 458 479 N-{3-Chloro-4-[3-(5-chloro-2-methoxy-4-methyl- phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 459 449 N-{3-Chloro-4-[3-(3-chloro-4-methyl-phenyl)- thioureido]-phenyl}-2-fluoro-benzamide 460 481 N-{3-Chloro-4-[3-(3-chloro-4-methylsulfanyl-phenyl)- thioureido]-phenyl}-2-fluoro-benzamide 461 391 N-{4-[3-(3-Cyano-phenyl)-thioureido]-phenyl}-2-fluoro- benzamide 462 395 Furan-2-carboxylic acid {4-[3-(3-acetylamino-phenyl)- thioureido]-phenyl}-amide 463 424 2-Fluoro-N-{4-[3-(3-hydrazinocarbonyl-phenyl)- thioureido]-phenyl}-benzamide 464 400 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[3-(1- hydroxy-ethyl)-phenyl]-thioureido}-phenyl)-amide 465 434 N-{4-[3-(2-Amino-3-chloro-phenyl)-thioureido]-phenyl}- 2,6-difluoro-benzamide 466 406 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-amino-5- chloro-phenyl)-thioureido]-phenyl}-amide 467 398 Furan-2-carboxylic acid {4-[3-(3,5-dimethoxy-phenyl)- thioureido]-phenyl}-amide 468 416 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5- dimethoxy-phenyl)-thioureido]-phenyl}-amide 469 454 5-(3-{4-[Furan-2-carbonyl)-amino]-phenyl}-thioureido)- isophthalic acid dimethyl ester 470 434 Isoxazole-5-carboxylic acid {4-[3-(5-chloro-2,4- dimethoxy-phenyl)-thioureido]-phenyl}-amide 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-{3-[3-(1-hydroxy-ethyl)- phenyl]-thioureido}-phenyl)-amide 473 368 Furan-2-carboxylic acid {4-[3-(3-methoxy-phenyl)- thioureido]-phenyl}-amide 474 354 Furan-2-carboxylic acid {4-[3-(3-hydroxy-phenyl)- thioureido]-phenyl}-amide 475 382 2-Fluoro-N-{4-[3-(3-hydroxy-phenyl)- thioureido]-phenyl}-benzamide 476 396 2-Fluoro-N-{4-[3-(3-hydroxymethyl-phenyl)-thioureido]- phenyl}-benzamide 477 423 N-{4-[3-(3-Acetylamino-phenyl)-thioureido]- phenyl}-2-fluoro-benzamide 478 413 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3- acetylamino-phenyl)-thioureido]-phenyl}-amide 479 400 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3- dimethylamino-phenyl)-thioureido]-phenyl}-amide 480 340 Furan-2-carboxylic acid [4-(3-pyrimidin-4-yl-thioureido)- phenyl]-amide 481 378 Furan-2-carboxylic acid {4-[3-(1H-indazol-5-yl)- thioureido]-phenyl}-amide 482 395 Furan-2-carboxylic acid [4-(3-benzothiazol-5-yl- thioureido)-phenyl]-amide 483 406 2-Fluoro-N-{4-[3-(1H-indazol-5-yl)-thioureido]- phenyl}-benzamide 484 424 N-[4-(3-Benzothiazol-5-yl-thioureido)-phenyl]-2-fluoro- benzamide 485 473 5-(3-{4-[([1,2,3]Thiadiazole-4-carbonyl)-amino]- phenyl}-thioureido)-isophthalic acid dimethyl ester 486 442 Furan-2-carboxylic acid (4-{3-[4-(1-azido-ethyl)-3- chloro-phenyl]-thioureido}-phenyl)-amide 487 396 2-Fluoro-N-{4-[3-(3-methoxy-phenyl)-thioureido]- phenyl}-benzamide 488 368 Furan-2-carboxylic acid {4-[3-(3-hydroxymethyl- phenyl)-thioureido]-phenyl}-amide 489 416 Furan-2-carboxylic acid {4-[3-(5-chloro-2- dimethylamino-phenyl)-thioureido]-phenyl}-amide 490 444 N-{4-[3-(5-Chloro-2-dimethylamino-phenyl)- thioureido]-phenyl}-2-fluoro-benzamide 491 506 [3-Chloro-5-(3-{4-[([1,2,3]thiadiazole-4-carbonyl)- amino]-phenyl}-thioureido)-phenyl]-carbamic acid tert- butyl ester 492 470 N-(4-{3-[4-(1-Azido-ethyl)-3-chloro-phenyl]-thioureido}- phenyl)-2-fluoro-benzamide 493 337 Furan-2-carboxylic acid [4-(1H-thiazolo[5,4-b]pyridin- 2-ylideneamino)-phenyl]amide 494 378 Furan-2-carboxylic acid {4-[3-(1H-benzoimidazol-5-yl)- thioureido]-phenyl}-amide 495 392 Furan-2-carboxylic acid {4-[3-(2-methyl-1H- benzoimidazol-5-yl)-thioureido]-phenyl}-amide 496 406 N-{4-[3-(1H-Benzoimidazol-5-yl)-thioureido]-phenyl}- 2-fluoro-benzamide 497 420 2-Fluoro-N-{4-[3-(2-methyl-1H-benzoimidazol-5-yl)- thioureido]-phenyl}-benzamide 498 452 [1,2,3]Thiadiazole-4-carboxylic acid {5-[3-(5-chloro- 2,4-dimethoxy-phenyl)-thioureido]-pyridin-2-yl}-amide 499 445 Pyridine-2-carboxylic acid {5-[3-(5-chloro-2,4- dimethoxy-phenyl)-thioureido]-pyridin-2-yl}-amide 500 434 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(5-chloro-2- dimethylamino-phenyl)-thioureido]-phenyl}-amide 501 484 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[4-(2-amino- pyrimidin-4-yl)-3-chloro-phenyl]-thioureido}-phenyl)- amide 502 494 N-(4-{3-[4-(2-Amino-pyrimidin-4-yl)-3-chloro-phenyl]- thioureido}-phenyl)-2-fluoro-benzamide 503 434 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-2- dimethylamino-phenyl)-thioureido]-phenyl}-amide 504 462 N-{4-[3-(3-Chloro-2-dimethylamino-phenyl)-thioureido]- phenyl}-2,6-difluoro-benzamide 505 416 Furan-2-carboxylic acid {4-[3-(3-chloro-2- dimethylamino-phenyl)-thioureido]-phenyl}-amide 506 445 Pyridine-2-carboxylic acid {6-[3-(5-chloro-2,4- dimethoxy-phenyl)-thioureido]-pyridin-3-yl}-amide 507 462 N-{6-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]- pyridin-3-yl}-2-fluoro-benzamide 508 482 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-iodo- phenyl)-thioureido]-phenyl}-amide 509 413 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-tert-butyl- phenyl)-thioureido]-phenyl}-amide 510 387 Furan-2-carboxylic acid {4-[3-(3-chloro-benzyl)- thioureido]-phenyl}-amide 511 415 N-{4-[3-(3-Chloro-benzyl)-thioureido]-phenyl}-2-fluoro- benzamide 512 434 Furan-2-carboxylic acid {6-[3-(5-chloro-2,4-dimethoxy- phenyl)-thioureido]-pyridin-3-yl}-amide 513 435 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-bromo- phenyl)-thioureido]-phenyl}-amide 514 452 [1,2,3]Thiadiazole-4-carboxylic acid {6-[3-(5-chloro-2,4- dimethoxy-phenyl)-thioureido]-pyridin-3-yl}-amide 515 426 [1,2,3]Thiadiazole-4-carboxylic acid {5-[3-(3,5-dich loro- phenyl)-thioureido]-pyridin-2-yl}-amide 516 474 Furan-2-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl- phenyl)-thioureido]-phenyl}-amide 517 502 N-{4-[3-(3,5-Bis-trifluoromethyl-phenyl)-thioureido]- phenyl}-2-fluoro-benzamide 518 450 N-{4-[3-(4-Amino-3,5-dichloro-phenyl)-thioureido]- phenyl}-2-fluoro-benzamide 519 539 N-{4-[3-(4-Amino-3,5-dibromo-phenyl)-thioureido]- phenyl}-2-fluoro-benzamide 520 392 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(5-chloro- pyridin-3-yl)-thioureido]-phenyl}-amide 521 529 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-amino-3,5- dibromo-phenyl)-thioureido]-phenyl}-amide 522 434 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-5- dimethylamino-phenyl)-thioureido]phenyl}-amide 523 444 N-{4-[3-(3-Chloro-5-dimethylamino-phenyl)- thioureido]-phenyl}-2-fluoro-benzamide 524 416 Furan-2-carboxylic acid {4-[3-(3-chloro-5- dimethylamino-phenyl)-thioureido]-phenyl}-amide 525 436 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(5-bromo- pyridin-3-yl)-thioureido]-phenyl}-amide 526 379 Furan-2-carboxylic acid {4-[3-(1H-benzotriazol-5-yl)- thioureido]-phenyl}-amide 527 425 N-{4-[3-(1H-Benzotriazol-5-yl)-thioureido]-phenyl}- 2,6-difluoro-benzamide 528 388 N-[4-({[2-(3-Chloro-phenyl)-hydrazino]-thioxomethyl}- amino)-phenyl]-furan-2-carboxamide 529 416 N-[4-({[2-(3-Chloro-phenyl)-hydrazino]-thioxomethyl}- amino)-phenyl]-2-fluoro-benzamide 530 456 Furan-2-carboxylic acid {4-[3-(2-amino-3-chloro-5- trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 531 513 N-{4-[3-(3-Bromo-5-trifluoromethyl-phenyl)-thioureido]- phenyl}-2-fluoro-benzamide 532 503 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-bromo-5- trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 533 374 {4-[(Furan-2-carbonyl)-amino]-phenyl}-thiocarbamic 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}- amide 535 508 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-piperidin- 1-yl-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 536 380 N-[4-(3-Benzyl-thioureido)-phenyl]-2-fluoro-benzamid e 537 439 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,4-dichloro- benzyl)-thioureido]-phenyl}-amide 538 449 N-{4-[3-(3,4-Dichloro-benzyl)-thioureido]-phenyl}-2- fluoro-benzamide 539 370 [1,2,3]Thiadiazole-4-carboxylic acid [4-(3-benzyl- thioureido)-phenyl]-amide 540 424 N-[4-(3-Benzo[1,3]dioxol-5-ylmethyl-thioureido)- phenyl]-2-fluoro-benzamide 541 414 [1,2,3]Thiadiazole-4-carboxylic acid [4-(3-benzo[1,3] dioxol-5-ylmethyl-thioureido)-phenyl]-amide 542 506 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-bis- trifluoromethyl-benzyl)-thioureido]-phenyl}-amide 543 516 N-{4-[3-(3,5-Bis-trifluoromethyl-benzyl)-thioureido]- phenyl}-2-fluoro-benzamide 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}-amide 546 396 Furan-2-carboxylic acid [4-(3-benzo[1,3]dioxol-5- ylmethyl-thioureido)-phenyl]-amide 547 488 Furan-2-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl- benzyl)-thioureido]-phenyl}-amide 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-[3-(3-bromo-4- trifluoromethoxy-phenyl)-thioureido]-phenyl}-amide 551 473 Furan-2-carboxylic acid {4-[3-(3-chloro-4- trifluoromethylsulfanyl-phenyl)-thioureido]-phenyl}- amide 552 412 2-Fluoro-N-(4-{3-[2-(3-fluoro-phenyl)-ethyl]- thioureido}-phenyl)-benzamide 553 412 2-Fluoro-N-(4-{3-[2-(4-fluoro-phenyl)-ethyl]- thioureido}-phenyl)-benzamide 554 402 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-fluoro- phenyl)-ethyl]-thioureido}-phenyl)-amide 555 402 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4-fluoro- phenyl)-ethyl]-thioureido}-phenyl)-amide 556 495 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[3-(2-methyl- butyl)-5-trifluoro-methyl-phenyl]-thioureido}-phenyl)- amide 557 481 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-isobutyl-5- trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 558 523 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[3-(4-met hyl- piperazin-1-yl)-5-trifluoro-methyl-phenyl]- thioureido}-phenyl)-amide 559 510 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-morpholin- 4-yl-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-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-{3-[2-(4-fluoro-phenyl)- ethyl]-thioureido}-phenyl)-amide 562 419 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-chloro- phenyl)-ethyl]-thioureido}-phenyl)-amide 563 429 N-(4-{3-[2-(3-Chloro-phenyl)-ethyl]-thioureido}- phenyl)-2-fluoro-benzamide 564 401 Furan-2-carboxylic acid (4-{3-[2-(3-chloro-phenyl)- ethyl]-thioureido}-phenyl)-amide 565 402 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[1-(4-fluoro- phenyl)-ethyl]-thioureido}-phenyl)-amide 566 504 2-Fluoro-N-{4-[3-(3-pyrrolidin-1-yl-5-trifluoromethyl- phenyl)-thioureido]-phenyl}-benzamide 567 477 N-{4-[3-(3-Dimethylamino-5-trifluoromethyl-phenyl)- thioureido]-phenyl}-2-fluoro-Benzamide 568 520 2-Fluoro-N-{-4-[3-(3-morpholin-4-yl-5-trifluoromethyl- phenyl)-thioureido]-phenyl}-benzamide 569 533 2-Fluoro-N-(4-{3-[3-(4-methyl-piperazin-1-yl)-5- trifluoromethyl-phenyl]-thioureido}-phenyl)-benzamide 570 518 2-Fluoro-N-{4-[3-(3-piperidin-1-yl-5-trifluoromethyl- phenyl)-thioureido]-phenyl}-benzamide 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-{3-[2-(3-fluoro-phenyl)- ethyl]-thioureido}-phenyl)-amide 574 366 Furan-2-carboxylic acid [4-(3-phenethyl-thioureido)- phenyl]-amide 575 384 [1,2,3]Thiadiazole-4-carboxylic acid [4-(3-phenethyl- thioureido)-phenyl]-amide 576 394 2-Fluoro-N-[4-(3-phenethyl-thioureido)-phenyl]- benzamide 577 505 2-Fluoro-N-(4-{3-[3-(2-methyl-butyl)-5-trifluoromethyl- phenyl]-thioureido}-phenyl)-benzamide 578 491 2-Fluoro-N-{4-[3-(3-isobutyl-5-trifluoromethyl-phenyl)- thioureido]-phenyl}-benzamide 579 388 Furan-2-carboxylic acid {4-[3-(3,5-difluoro-benzyl)- thioureido]-phenyl}-amide 580 416 N-{4-[3-(3,5-Difluoro-benzyl)-thioureido]-phenyl}-2- fluoro-benzamide 581 406 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-difluoro- benzyl)-thioureido]-phenyl}-amide 582 421 Furan-2-carboxylic acid {4-[3-(3,5-dichloro-benzyl)- thioureido]-phenyl}-amide 583 449 N-{4-[3-(3,5-Dichloro-benzyl)-thioureido]-phenyl}-2- fluoro-benzamide 584 439 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-dichloro- benzyl)-thioureido]-phenyl}-amide 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)- thioureido]-phenyl}-benzamide 587 456 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-fluoro- 5-trifluoromethyl-benzyl)-thioureido]-phenyl}-amide 588 384 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(1-phenyl- ethyl)-thioureido]-phenyl}-amide 589 394 2-Fluoro-N-{4-[3-(1-phenyl-ethyl)-thioureido]-phenyl}- benzamide 590 366 Furan-2-carboxylic acid {4-[3-(1-phenyl-ethyl)- thioureido]-phenyl}-amide 591 412 2-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]- thioureido}-phenyl)-benzamide 592 384 Furan-2-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)- ethyl]-thioureido}-phenyl)-amide 593 413 N-{4-[3-(1-tert-Butyl-1H-imidazol-2-yl)-thioureido]- phenyl}-2-fluoro-benzamide 594 510 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[3-(isobutyl- methyl-amino)-5-trifluoromethyl-phenyl]-thioureido}- phenyl)-amide 595 510 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[3-(3- hydroxy-pyrrolidin-1-yl)-5-trifluoromethyl-phenyl]- thioureido}-phenyl)-amide 596 520 2-Fluoro-N-(4-{3-[3-(isobutyl-methyl-amino)-5- trifluoromethyl-phenyl]-thioureido}-phenyl)-benzamide 597 510 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[3-(butyl- methyl-amino)-5-trifluoromethyl-phenyl]-thioureido}- phenyl)-amide 598 520 N-(4-{3-[3-(Butyl-methyl-amino)-5-trifluoromethyl- phenyl]-thioureido}-phenyl)-2-fluoro-benzamide 599 520 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3,5- bis-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)- amide 600 442 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-fluoro- 3-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 601 522 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-piperidin- 1-yl-3-trifluoromethyl-benzyl)-thioureido]-phenyl}-amide 602 482 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4- dimethylamino-3-trifluoromethyl-benzyl)-thioureido]- phenyl}-amide 603 381 Furan-2-carboxylic acid (4-{3-[2-(4-amino-phenyl)- ethyl]-thioureido}-phenyl)-amide 604 445 Furan-2-carboxylic acid (4-{3-[2-(4-bromo-phenyl)- ethyl]-thioureido}-phenyl)-amide 605 380 Furan-2-carboxylic acid {4-[3-(2-p-tolyl- ethyl)-thioureido]-phenyl}-amide 606 463 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4-bromo- phenyl)-ethyl]-thioureido}-phenyl)-amide 607 396 Furan-2-carboxylic acid (4-{3-[2-(3-methoxy-phenyl)- ethyl]-thioureido}-phenyl)-amide 608 403 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(1-tert-butyl- 1H-imidazol-2-yl)-thioureido]-phenyl}-amide 609 384 Furan-2-carboxylic acid {4-[3-(1-tert-butyl-1H-imidazol- 2-yl)-thioureido]-phenyl}-amide 610 492 N-{4-[3-(4-Dimethylamino-3-trifluoromethyl-benzyl)- thioureido]-phenyl}-2-fluoro-benzamide 611 427 Furan-2-carboxylic acid (4-{3-[2-(3,4-dimethoxy- phenyl)-ethyl]-thioureido}-phenyl)-amide 612 380 Furan-2-carboxylic acid {4-[3-(3-phenyl-propyl)- thioureido]-phenyl}-amide 613 399 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-phenyl- propyl)-thioureido]-phenyl}-amide 614 502 Furan-2-carboxylic acid (4-{3-[2-(3,5-bis- trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-amide 615 550 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-iodo-3- trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 616 532 2-Fluoro-N-{4-[3-(4-piperidin-1-yl-3-trifluoromethyl- benzyl)-thioureido]-phenyl}-benzamide 617 537 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[4-(4-methyl- piperazin-1-yl)-3-trifluoromethyl-benzyl]-thioureido}- phenyl)-amide 618 482 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3- dimethylamino-5-trifluoromethyl-benzyl)-thioureido]- phenyl}amide 619 488 Furan-2-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl- phenyl)-thioureido-methyl]-phenyl}-amide 620 421 Furan-2-carboxylic acid {4-[3-(3,5-dichloro-phenyl)- thioureidomethyl]-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)-phen yl]- benzamide 633 353 Furan-2-carboxylic acid [4-(3-pyridin-3-ylmethyl- thioureido)-phenyl]-amide 634 371 [1,2,3]Thiadiazole-4-carboxylic acid [4-(3-pyridin-3- ylmethyl-thioureido)-phenyl]-amide 635 439 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-dichloro- phenyl)-thioureido-methyl]-phenyl}-amide 636 492 N-{4-[3-(3-Dimethylamino-5-trifluoromethyl-benzyl)- thioureido]-phenyl}-2-fluoro-benzamide 637 415 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3- methoxy-phenyl)-ethyl]-thioureido}-phenyl)-amide 638 399 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-p-tolyl- ethyl)-thioureido]-phenyl}-amide 639 445 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3,4- dimethoxy-phenyl)-ethyl]-thioureido}-phenyl)-amide 640 506 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-bis- trifluoromethyl-phenyl)-thioureidomethyl]-phenyl}-amide 641 516 N-{4-[3-(3,5-Bis-trifluoromethyl-phenyl)- thioureidomethyl]-phenyl}-2-fluoro-benzamide 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}-amide 656 427 2-Fluoro-N-{4-[3-(2-phenylsulfanyl-ethyl)-thioureido]- phenyl}-benzamide 657 399 Furan-2-carboxylic acid {4-[3-(2-phenylsulfanyl-ethyl)- thioureido]-phenyl}-amide 658 381 2-Fluoro-N-[4-(3-pyridin-4-ylmethyl-thioureido)- phenyl]-benzamide 659 353 Furan-2-carboxylic acid [4-(3-pyridin-4-ylmethyl- thioureido)-phenyl]-amide 660 371 [1,2,3]Thiadiazole-4-carboxylic acid [4-(3-pyridin-4- ylmethyl-thioureido)-phenyl]-amide 661 506 2-Fluoro-N-{4-[3-(3-iodo-benzyl)-thioureido]-phenyl}- benzamide 662 478 Furan-2-carboxylic acid {4-[3-(3-iodo-benzyl)- thioureido]-phenyl}-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 681 493 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-bromo- 4-methoxy-phenyl)-ethyl]-thioureido}-phenyl)-amide 682 493 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(5-bro mo- 2-methoxy-phenyl)-ethyl]-thioureido}-phenyl)-amide 683 419 [1,2,3]Thiadiazole-4-carboxylic acid (4-{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)-amide 685 419 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4-chloro- phenyl)-ethyl]-thioureido}-phenyl)-amide 686 475 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,3-diphenyl- propyl)-thioureido]-phenyl}-amide 687 547 2-Fluoro-N-(4-{3-[4-(4-methyl-piperazin-1-yl)-3- trifluoromethyl-benzyl]-thioureido}-phenyl)-benzamide 688 469 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3,5- dichloro-phenoxy)-ethyl]-thioureido}-phenyl)-amide 689 423 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro- 4-fluoro-benzyl)-thioureido]-phenyl}-amide 690 427 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-tert-butyl- benzyl)-thioureido]-phenyl}-amide 691 399 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-dimethyl- benzyl)-thioureido]-phenyl}-amide 692 442 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4- dimethylamino-3-methyl-phenyl)-ethyl]-thioureido}- phenyl)-amide 693 479 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4-bromo- phenoxy)-ethyl]-thioureido}-phenyl)-amide 694 526 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4-iodo- phenoxy)-ethyl]-thioureido}-phenyl)-amide 695 489 N-(4-{3-[2-(4-Bromo-phenoxy)-ethyl]-thioureido}- phenyl)-2-fluoro-benzamide 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-{3-[2-(4-iodo-phenoxy)- ethyl]-thioureido}-phenyl)-amide 699 408 Oxazole-4-carboxylic acid {4-[3-(3,4-dichloro-phenyl)- thioureido]-phenyl}-amide 700 424 Thiazole-4-carboxylic acid {4-[3-(3,5-dichloro-phenyl)- thioureido]-phenyl}-amide 701 491 Thiazole-4-carboxylic acid {4-[3-(3,5-bis- trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 702 408 Oxazole-4-carboxylic acid {4-[3-(3,5-dichloro-phenyl)- thioureido]-phenyl}-amide 703 469 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3,4- dichloro-phenoxy)-ethyl]-thioureido}-phenyl)-amide 704 424 Thiazole-4-carboxylic acid {4-[3-(3,4-dichloro-phenyl)- thioureido]-phenyl}-amide 705 458 Thiazole-4-carboxylic acid {4-[3-(4-chloro-3- trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 706 400 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2- phenylamino-ethyl)-thioureido]-phenyl}-amide 707 453 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(2,4- dichloro-phenyl)-ethyl]-thioureido}-phenyl)-amide 708 452 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3- trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-amide 709 453 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(2,6- dichloro-phenyl)-ethyl]-thioureido}-phenyl)-amide 710 485 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3,4- dichloro-phenylsulfanyl)-ethyl]-thioureido}-phenyl)- amide 711 503 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(2- fluoro-5-trifluoromethyl-phenylsulfanyl)-ethyl]- thioureido}-phenyl)-amide 712 668 N-(4-{3-[3-Chloro-5-(3-{4-[([1,2,3]thiadiazole-4- carbonyl)-amino]-phenyl}-thioureido)-phenyl]- thioureido}-phenyl)-[1,2,3]thiadiazole-4-carboxamide 713 413 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4-ethyl- phenyl)-ethyl]-thioureido}-phenyl)-amide 714 442 Oxazole-4-carboxylic acid {4-[3-(4-chloro-3- trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 715 475 Oxazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl- phenyl)-thioureido]-phenyl}-amide 716 420 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3,4- difluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide 717 452 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4- trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-amide 718 435 Furan-2-carboxylic acid (4-{3-[2-(3,4-dichloro-phenyl)- ethyl]-thioureido}-phenyl)-amide 719 463 N-(4-{3-[2-(3,4-Dichloro-phenyl)-ethyl]-thioureido}- phenyl)-2-fluoro-benzamide 720 420 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3,5- difluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide 721 412 2-Fluoro-N-(4-{3-[2-(2-fluoro-phenyl)-ethyl]- thioureido}-phenyl)-benzamide 722 429 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4- nitro-phenyl)-ethyl]-thioureido}-phenyl)-amide 723 399 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(1-methyl-2- phenyl-ethyl)-thioureido]-phenyl}-amide 724 437 N-{4-[3-(4-tert-Butyl-benzyl)-thioureido]-phenyl}-2- fluoro-benzamide 725 409 N-{4-[3-(3,5-Dimethyl-benzyl)-thioureido]-phenyl}-2- fluoro-benzamide 726 400 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-hydroxy- 1-phenyl-ethyl)-thioureido]-phenyl}-amide 727 409 2-Fluoro-N-{4-[3-(1-methyl-1-phenyl-ethyl)-thioureido]- phenyl}-benzamide 728 399 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(1-methyl-1- phenyl-ethyl)-thioureido]-phenyl}-amide 729 405 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-chloro- benzyl)-thioureido]-phenyl}-amide 730 388 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-fluoro- benzyl)-thioureido]-phenyl}-amide 731 438 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3- trifluoromethyl-benzyl)-thioureido]-phenyl}-amide 732 388 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-fluoro- benzyl)-thioureido]-phenyl}-amide 733 435 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(2-chloro- phenoxy)-ethyl]-thioureido}-phenyl)-amide 734 479 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-bromo- phenoxy)-ethyl]-thioureido}-phenyl)-amide 735 418 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(2-fluoro- phenoxy)-ethyl]-thioureido}-phenyl)-amide 736 418 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-fluoro- phenoxy)-ethyl]-thioureido}-phenyl)-amide 737 486 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(2-fluoro- 5-trifluoromethyl-phenoxy)-ethyl]-thioureido}-phenyl)- amide 738 384 Furan-2-carboxylic acid (4-{3-[2-(2-fluoro-phenyl)- ethyl]-thioureido}-phenyl)-amide 739 435 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-bromo- phenyl)-thioureido]-phenyl}-amide 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]-pheny}-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-[1-(4-fluoro-phenyl)-ethyl]- thioureido}-phenyl)-benzamide 757 453 Acetic acid 4-(4-{3-[1-(4-fluoro-phenyl)-ethyl]- thioureido}-phenylcarbamoyl)-phenyl ester 758 394 N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}- phenyl)-benzamide 759 395 N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}- phenyl)-isonicotinamide 760 410 N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}- phenyl)-4-hydroxy-benzamide 761 429 3-Chloro-N-(4-{3-[1-(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-flu oro- 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-[1-(4-fluoro-phenyl)-propyl]- thioureido}-phenyl)-benzamide 772 475 2-Fluoro-N-(4-{3-[(4-fluoro-phenyl)-phenyl-methyl]- thioureido}-phenyl)-benzamide 773 455 2-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-pentyl]- thioureido}-phenyl)-benzamide 774 489 2-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-2-phenyl-ethyl]- thioureido}-phenyl)-benzamide 775 409 2-Fluoro-N-{4-[3-(1-o-tolyl-ethyl)-thioureido]-phenyl}- benzamide 776 409 2-Fluoro-N-{4-[3-(1-m-tolyl-ethyl)-thioureido]-phenyl}- benzamide 777 425 2-Fluoro-N-(4-{3-[1-(4-methoxy-phenyl)-ethyl]- thioureido}-phenyl)-benzamide 778 412 2-Fluoro-N-(4-{3-[1-(2-fluoro-phenyl)-ethyl]- thioureido}-phenyl)-benzamide 779 429 N-(4-{3-[1-(3-Chloro-phenyl)-ethyl]-thioureido}- phenyl)-2-fluoro-benzamide 780 473 N-(4-{3-[1-(3-Bromo-phenyl)-ethyl]-thioureido}- phenyl)-2-fluoro-benzamide 781 429 N-(4-{3-[1-(4-Chloro-phenyl)-ethyl]-thioureido}-phenyl)- 2-fluoro-benzamide 782 409 2-Fluoro-N-{4-[3-(1-p-tolyl-ethyl)-thioureido]-phenyl}- benzamide 783 473 N-(4-{3-[1-(2-Bromo-phenyl)-ethyl]-thioureido}- phenyl)-2-fluoro-benzamide 784 429 N-(4-{3-[1-(2-Chloro-phenyl)-ethyl]-thioureido}-phenyl)- 2-fluoro-benzamide 785 462 2-Fluoro-N-(4-{3-[1-(2-trifluoromethyl-phenyl)-ethyl]- thioureido}-phenyl)-benzamide 786 462 2-Fluoro-N-(4-{3-[1-(3-trifluoromethyl-phenyl)-ethyl]- thioureido}-phenyl)-benzamide 787 462 2-Fluoro-N-(4-{3-[1-(4-trifluoromethyl-phenyl)-ethyl]- thioureido}-phenyl)-benzamide 788 425 2-Fluoro-N-(4-{3-[1-(2-methoxy-phenyl)-ethyl]- thioureido}-phenyl)-benzamide 789 425 2-Fluoro-N-(4-{3-[1-(3-methoxy-phenyl)-ethyl]- thioureido}-phenyl)-benzamide 790 441 2-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-2-methyl-propyl]- thioureido}-phenyl)-benzamide 791 419 N-(4-{3-[1-(3-Cyano-phenyl)-ethyl]-thioureido}-phenyl)- 2-fluoro-benzamide 792 419 N-(4-{3-[1-(4-Cyano-phenyl)-ethyl]-thioureido}-phenyl)- 2-fluoro-benzamide 793 438 N-(4-{3-[1-(4-Dimethylamino-phenyl)-ethyl]- thioureido}-phenyl)-2-fluoro-benzamide 794 438 N-(4-{3-[1-(3-Dimethylamino-phenyl)-ethyl]- thioureido}-phenyl)-2-fluoro-benzamide 795 473 2-Bromo-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]- thioureido}-phenyl)-benzamide 796 446 Quinoline-2-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)- ethyl]-thioureido}-phenyl)-amide 797 410 2-Fluoro-N-{4-[3-(2-hydroxy-1-phenyl-ethyl)- thioureido]-phenyl}-benzamide 798 332 2-Fluoro-N-[4-(3-isopropyl-thioureido)-phenyl]- benzamide 799 445 2-Fluoro-N-{4-[3-(1-naphthalen-2-yl-ethyl)-thioureido]- phenyl}-benzamide 800 412 3-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]- thioureido}-phenyl)-benzamide 801 412 4-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]- thioureido}-phenyl)-benzamide 802 384 2-Fluoro-N-{4-[3-(1-furan-2-yl-ethyl)-thioureido]- phenyl}-benzamide 803 395 2-Fluoro-N-{4-[3-(1-pyridin-4-yl-ethyl)-thioureido]- phenyl}-benzamide 804 397 2-Fluoro-N-(4-{3-[1-(1-methyl-1H-pyrrol-2-yl)-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]-acetamide 815 507 N-{5-[({[3,5-bis(trifluoromethyl)benzyl]amino}- carbothioyl)amino]-2-pyridinyl}-1,2,3-thiadiazole- 4-carboxamide 816 521 N-(5-{[({(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}- amino)carbothioyl]amino}-2-pyridinyl)-1,2,3-thiadiazole- 4-carboxamide 817 520 N-(5-{[({(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}- amino)carbothioyl]amino}-2-pyridinyl)-4,3-thiazole- 4-carboxamide 818 470 N-(5-{[({1-[2-fluoro-5-(trifluoromethyl)phenyl]ethyl}- amino)carbothioyl]amino}-2-pyridinyl)-1,3-thiazole- 4-carboxamide 819 470 N-(5-{[({1-[2-fluoro-4-(trifluoromethyl)phenyl]ethyl}- amino)carbothioyl]amino}-2-pyridinyl)-1,3-thiazole- 4-carboxamide 820 470 N-(5-{[({1-[3-fluoro-5-(trifluoromethyl)phenyl]ethyl}- amino)carbothioyl]amino}-2-pyridinyl)-1,3-thiazole- 4-carboxamide 821 504 N-(5-{[({(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}- amino)carbonyl]amino}-2-pyridinyl)-1,3-thiazole- 4-carboxamide 822 463 N-{5-[({[1-(3-bromophenyl)ethyl]amino}carbothioyl)- amino]-2-pyridinyl}-1,3-thiazole-4-carboxamide 823 463 N-{5-[({[1-(2-bromophenyl)ethyl]amino}carbothioyl)- amino]-2-pyridinyl}-1,3-thiazole-4-carboxamide 824 452 N-(5-{[({1-[3-trifluoromethyl)phenyl]ethyl}amino)- carbothioyl]amino}-2-pyridinyl)-1,3-thiazole- 4-carboxamide 825 486 N-(5-{[({1-[4-chloro-3-(trifluoromethyl)phenyl]ethyl}- amino)carbothioyl]amino}-2-pyridinyl)-1,3-thiazole- 4-carboxamide 826 436 N-{5-[({[1-(4-chloro-3-fluorophenyl)ethyl]amino}- carbothioyl)amino]-2-pyridinyl}-1,3-thiazole- 4-carboxamide 827 436 N-{5-[({[1-(4-chloro-2-fluorophenyl)ethyl]amino}- carbothioyl)amino]-2-pyridinyl}-1,3-thiazole- 4-carboxamide 828 434 N-{6-[({[1-(4-fluorophenyl)ethyl]amino}carbothioyl)- amino]-3-pyridinyl}-1,2,3-thiadiazole- 4-carboxamide 829 426 N-(6-{[({(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}- amino)carbothioyl]amino}-3-pyridinyl)-1,2,3-thiadiazole- 4-carboxamide______________________________________
EXAMPLE 830 (METHOD 32)
[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2,5-dichloro-phenyl)-thioureido]-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 (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.
Using the above procedure and appropriate starting materials the following compounds were prepared:
______________________________________EX. NO. M + H COMPOUND NAME______________________________________831 321 N-{4-[3-(3-Chloro-phenyl)-thioureido]-phenyl}- acetamide 832 413 N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]- phenyl}-benzamide 833 443 N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]- phenyl}-2-methoxy-benzamide 834 443 N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]- phenyl}-3-methoxy-benzamide 835 443 N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]- phenyl}-4-methoxy-benzamide 836 431 N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]- phenyl}-4-methoxy-benzamide 837 431 N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]- phenyl}-3-fluoro-benzamide 838 431 N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]- phenyl}-4-fluoro-benzamide 839 437 Furan-2-carboxylic acid {4-[3-(3,5-dichloro-4-methoxy- phenyl)-thioureido]-phenyl}-amide 840 511 {4-[3-(5-Bromo-2,4-dimethoxy-phenyl)-thioureido]- phenyl}-carbamic acid hexyl ester 841 481 Hexanoic acid {4-[3-(5-bromo-2,4-dimethoxy-phenyl)- thioureido]-phenyl}-amide 842 505 N-{4-[3-(5-Bromo-2,4-dimethoxy-phenyl)-thioureido]- phenyl}-2-fluoro-benzamide 843 477 Furan-2-carboxylic acid {4-[3-(5-bromo-2,4-dimethoxy- phenyl)-thioureido]-phenyl}-amide 844 501 N-{4-[3-(5-Bromo-2,4-dimethoxy-phenyl)-thioureido]- phenyl}-2-methyl-benzamide 845 517 N-{4-[3-(5-Bromo-2,4-dimethoxy-phenyl)-thioureido]- phenyl}-4-methoxy-benzamide 846 395 N-{4-[3-(5-Chloro-2-ethoxy-4-methoxy-phenyl)- thioureido]-phenyl}-acetamide 847 395 N-{4-[3-(5-Chloro-4-ethoxy-2-methoxy-phenyl)- thioureido]-phenyl}-acetamide 848 423 N-{4-[3-(2-Butoxy-5-chloro-4-methoxy-phenyl)- thioureido]-phenyl}-acetamide 849 423 N-{4-[3-(4-Butoxy-5-chloro-2-methoxy-phenyl)- thioureido]-phenyl}-acetamide 850 457 N-{4-[3-(2-Benzyloxy-5-chloro-4-methoxy-phenyl)- thioureido]-phenyl}-acetamide 851 457 N-{4-[3-(4-Benzyloxy-5-chloro-2-methoxy-phenyl)- thioureido]-phenyl}-acetamide 852 421 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro- 4-methoxy-phenyl)-thioureido]-phenyl}-amide 853 424 2-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro- 5-methoxy-phenoxy}-acetamide 854 367 N-{4-[3-(5-Chloro-2-hydroxy-4-methoxy-phenyl)- thioureido]-phenyl}-acetamide 855 367 N-{4-[3-(3-Chloro-4-methylsulfanyl-phenyl)-thioureido]- phenyl}-acetamide 856 447 N-[4-(3-{3-Chloro-4-[methyl-(1-methyl-piperidin-4-yl)- amino]-phenyl}-thioureido)-phenyl]-acetamide 857 426 N-(4-{3-[3-Chloro-4-(methyl-phenyl-amino)-phenyl]- thioureido}-phenyl)-acetamide 858 509 N-[4-(3-{4-[(1-Benzyl-pyrrolidin-3-yl)-methyl-amino]- 3-chloro-phenyl}-thioureido)-phenyl]-acetamide 859 418 N-(4-{3-[3-Chloro-4-(cyclopentyl-methyl-amino)- phenyl]-thioureido}-phenyl)-acetamide 860 433 N-[4-(3-{3-Chloro-4-[methyl-(1-methyl-pyrrolidin-3-yl)- amino]-phenyl}-thioureido)-phenyl]-acetamide 861 419 Furan-2-carboxylic acid {4-[3-(3-chloro-4- methylsulfanyl-phenyl)-thioureido]-phenyl}-amide 862 447 N-{4-[3-(3-Chloro-4-methylsulfanyl-phenyl)-thioureido]- phenyl}-2-fluoro-benzamide 863 465 N-{4-[3-(3-Chloro-4-methylsulfanyl-phenyl)-thioureido]- phenyl}-2,6-difluoro-benzamide 864 445 N-{4-[3-(5-Chloro-2-methoxy-4-methyl-phenyl)- thioureido]-phenyl}-2-fluoro-benzamide 865 441 N-{4-[3-(5-Chloro-2-methoxy-4-methyl-phenyl)- thioureido]-phenyl}-2-methyl-benzamide 866 434 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro- 4-dimethylamino-phenyl)-thioureido]-phenyl}-amide 867 444 N-{4-[3-(3-Chloro-4-dimethylamino-phenyl)-thioureido]- phenyl}-2-fluoro-benzamide 868 517 [1,2,3]Thiadiazole-4-carboxylic acid [4-(3-{3-chloro-4- [methyl-(1-methyl-piperidin-4-yl)-amino]-phenyl}- thioureido)-phenyl]-amide 869 579 [1,2,3]Thiadiazole-4-carboxylic acid [4-(3-{4-[(1-benzyl- pyrrolidin-3-yl)-methyl-amino]-3-chloro-phenyl}- thioureido)-phenyl]-amide 870 527 N-[4-(3-{3-Chloro-4-[methyl-(1-methyl-piperidin-4-yl)- amino]-phenyl}-thioureido)-phenyl]-2-fluoro-benzamide 871 435 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(5-chloro- 2-methoxy-4-methyl-phenyl)-thioureido]-phenyl}-amide 872 589 N-[4-(3-{4-[(1-Benzyl-pyrrolidin-3-yl)-methyl-amino]-3- chloro-phenyl}-thioureido)-phenyl]-2-fluoro-benzamide 873 501 Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethox y- phenyl)-thioureido]-3-trifluoromethyl-phenyl}-amide 874 366 2-Fluoro-N-[4-(3-phenyl-thioureido)-phenyl]-benzamide 875 338 Furan-2-carboxylic acid [4-(3-phenyl-thioureido)- phenyl]-amide 876 356 [1,2,3]Thiadiazole-4-carboxylic acid [4-(3-phenyl- thioureido)-phenyl]-amide 877 365 N-(4-{3-[3-Chloro-4-(1-hydroxy-ethyl)-phenyl]- thioureido}-phenyl)-acetamide 878 435 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[3-chloro-4- (1-hydroxy-ethyl)-phenyl]-thioureido}-phenyl)-amide 879 365 N-(4-{3-[3-Chloro-4-(2-hydroxy-ethyl)-phenyl]- thioureido}-phenyl)-acetamide 880 445 N-(4-{3-[3-Chloro-4-(1-hydroxy-ethyl)-phenyl]- thioureido}-phenyl)-2-fluoro-benzamide 881 417 Furan-2-carboxylic acid (4-{3-[3-chloro-4-(1-hydroxy- ethyl)-phenyl]-thioureido}-phenyl)-amide 882 371 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-amino- phenyl)-thioureido]-phenyl}-amide 883 501 Furan-2-carboxylic acid {4-[3-(3-bromo-4- trifluoromethoxy-phenyl)-thioureido]-phenyl}-amide 884 423 N-{4-[3-(3-tert-Butyl-phenyl)-thioureido]-phenyl}-2- fluoro-benzamide 885 440 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-chloro-3,5- dichloro-phenyl)-thioureido]-phenyl}-amide 986 485 N-{4-[3-(1-Benzofuran-2-yl-ethyl)-thioureido]-phenyl}- 2-trifluoromethyl-benzamide 987 412 N-(4-Fluoro-phenyl)-4-{3-[1-(4-fluoro-phenyl)-ethyl]- thioureido}-benzamide 988 446 Isoquinoline-1-carboxylic acid (4-{3-[1-(4-fluoro- phenyl)-ethyl]-thioureido}-phenyl)-amide 989 468 Isoquinoline-1-carboxylic acid {4-[3-(1-benzofuran-2- yl-ethyl)-thioureido]-phenyl}-amide 993 506 Isoquinoline-1-carboxylic acid (4-{3-[1-(4-bromo- phenyl)-ethyl]-thioureido}-phenyl)-amide 994 453 Isoquinoline-1-carboxylic acid (4-{3-[1-(4-cyano- phenyl)-ethyl]-thioureido}-phenyl)-amide 995 435 Benzofuran-2-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)- ethyl]-thioureido}-phenyl)-amide 996 457 Benzofuran-2-carboxylic acid {4-[3-(1-benzofuran-2-yl- ethyl)-thioureido]-phenyl}-amide 997 495 Benzofuran-2-carboxylic acid (4-{3-[1-(4-bromo- phenyl)-ethyl]-thioureido}-phenyl)-amide 998 442 Benzofuran-2-carboxylic acid (4-{3-[1-(4-cyano-phenyl)- ethyl]-thioureido}-phenyl)-amide 999 446 Isoquinoline-3-carboxylic acid (4-{3-[1-(4-fluoro- phenyl)-ethyl]-thioureido}-phenyl)-amide 1000 468 Isoquinoline-3-carboxylic acid {4-[3-(1-benzofuran-2- yl-ethyl)-thioureido]-phenyl}-amide 1001 453 Isoquinoline-3-carboxylic acid (4-{3-[1-(4-cyano- phenyl)-ethyl]-thioureido}-phenyl)-amide 1002 506 Isoquinoline-3-carboxylic acid (4-{3-[1-(4-bromo- phenyl)-ethyl]-thioureido}-phenyl)-amide 1003 446 Quinoline-3-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)- ethyl]-thioureido}-phenyl)-amide 1004 446 Quinoline-4-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)- ethyl]-thioureido}-phenyl)-amide 1005 446 Quinoline-6-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)- ethyl]-thioureido}-phenyl)-amide 1006 446 Quinoline-8-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)- ethyl]-thioureido}-phenyl)-amide 1007 462 N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)- 2-trifluoromethyl-benzamide 1008 419 2-Cyano-N-(4-{3-[1-(4-fluoro-phenyl)- ethyl]-thioureido}-phenyl)-benzamide 1009 473 N-{4-[3-(3-Chloro-4-isobutoxy-phenyl)-thioureido]- phenyl}-2-fluoro-benzamide 1010 414 2-Fluoro-N-{4-[3-(3-fluoro-4-methoxy-phenyl)- thioureido]-phenyl}-benzamide 1011 475 N-(4-{3-[3-Chloro-4-(2-methoxy-ethoxy)-phenyl]- thioureido}-phenyl)-2-fluoro-benzamide 1012 398 2-Fluoro-N-{4-[3-(3-fluoro-4-methyl-phenyl)- thioureido]-phenyl}-benzamide 1013 464 2-Fluoro-N-{4-[3-(4-methoxy-3-trifluoromethyl-phenyl)- thioureido]-phenyl}-benzamide 1014 449 N-{4-[3-(2-Amino-5-trifluoromethyl-phenyl)-thioureido]- phenyl}-2-fluoro-benzamide 1015 459 N-(4-{3-[1-(3-Chloro-4-methoxy-phenyl)-ethyl]- thioureido}-phenyl)-2-fluoro-benzamide 1016 417 N-{4-[3-(5-Chloro-2-hydroxy-phenyl)-thioureido]- phenyl}-2-fluoro-benzamide 1017 435 N-{4-[3-(1-Benzofuran-2-yl-ethyl)-thioureido]-phenyl}- 2-fluoro-benzamide 1018 448 2-Fluoro-N-{4-[3-(4-methyl-3-trifluoromethyl-phenyl)- thioureido]-phenyl}-benzamide 1019 473 (S)-N-(4-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido}- phenyl)-2-fluoro-benzamide 1020 473 N-(4-{3-[(1R)-1-(4-Bromo-phenyl)-ethyl]-thioureido}- phenyl)-2-fluoro-benzamide 1021 494 2-Fluoro-N-(4-{3-[2-methoxy-4-(2,2,2-trifluoro-ethoxy)- phenyl]-thioureido}-phenyl)-benzamide 1022 399 N-{4-[3-(2-Amino-5-fluoro-phenyl)-thioureido]-phenyl}- 2-fluoro-benzamide 1023 502 N-(4-{3-[1-(4-Dimethylsulfamoyl-phenyl)-ethyl]- thioureido}-phenyl)-2-fluoro-benzamide 1024 542 2-Fluoro-N-[4-(3-{1-[4-(piperidine-1-sulfonyl)-phenyl]- ethyl}-thioureido)-phenyl]-benzamide 1025 562 N-(4-{3-[2,4-Bis-(2,2,2-trifluoro-ethoxy)-phenyl]- thioureido}-phenyl)-2-fluoro-benzamide 1026 409 2-Fluoro-N-{4-[3-((1S)-1-p-tolyl-ethyl)-thioureido]- phenyl}-benzamide 1027 409 2-Fluoro-N-{4-[3-((1R)-1-p-tolyl-ethyl)-thioureido]- phenyl}-benzamide 1028 394 2-Fluoro-N-{4-[3-((1S)-1-phenyl-ethyl)-thioureido]- phenyl}-benzamide 1029 429 N-(4-{3-[(1R)-1-(4-Chloro-phenyl)-ethyl]-thioureido}- phenyl)-2-fluoro-benzamide 1030 429 N-(4-{3-[(1S)-1-(4-Chloro-phenyl)-ethyl]-thioureido}- phenyl)-2-fluoro-benzamide 1031 394 2-Fluoro-N-{4-[3-((1R)-1-phenyl-ethyl)-thioureido]- phenyl}-benzamide 1032 432 N-(4-{3-[1-(4-Cyano-phenyl)-ethyl]-thioureido}-phenyl)- 2-methoxy-benzamide 1033 447 N-{4-[3-(1-Benzofuran-2-yl-ethyl)-thioureido]-phenyl}- 2-methoxy-benzamide 1034 485 N-(4-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido}-phenyl)- 2-methoxy-benzamide 1035 419 3-Cyano-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]- thioureido}-phenyl)-benzamide 1036 462 N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)- 4-trifluoromethyl-benzamide 1037 419 4-Cyano-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]- thioureido}-phenyl)-benzamide 1038 469 2-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]- thioureido}-2,3,5,6-tetramethyl-phenyl)-benzamide 1039 480 N-(4-{3-[1-(4-Cyano-phenyl)-ethyl]-thioureido}-2,5- dimethoxy-phenyl)-2-fluoro-benzamide 1040 473 2-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]- thioureido}-2,5-dimethoxy-phenyl)-benzamide 1041 530 N-{3,5-Dichloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-phenyl}-2-fluoro-benzamide 1042 447 N-(3-Chloro-4-{3-[1-(4-fluoro-phenyl)-ethyl]- thioureido}-phenyl)-2-fluoro-benzamide 1043 480 2,3,4,5-Tetrafluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]- thioureido}-3-methyl-phenyl)-benzamide 1044 462 2,4,5-Trifluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]- thioureido}-3-methyl-phenyl)-benzamide 1045 427 2-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]- thioureido}-3-methyl-phenyl)-benzamide 1046 457 2-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]- thioureido}-2-methoxy-5-methyl-phenyl)-benzamide 1047 443 2-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]- thioureido}-3-methoxy-phenyl)-benzamide 1048 570 N-(2,6-Dibromo-4-{3-[1-(4-fluoro-phenyl)-ethyl]- thioureido}-phenl)-2-fluoro-benzamide 1049 480 2-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]- thioureido}-2-trifiuoromethyl-phenyl)-benzamide 1050 541 N-(4-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido}-2- trifluoromethyl-phenyl)-2-fluoro-benzamide 1051 487 N-(4-{3-[1-(4-Cyano-phenyl)-ethyl]-thioureido}-2- trifluoromethyl-phenyl)-2-fluoro-benzamide 1052 503 N-{4-[3-(1-Benzofuran-2-yl-ethyl)-thioureido]-2- trifluoromethyl-phenyl}-2-fluoro-benzamide 1053 447 N-(2-Chloro-4-{3-[1-(4-fluoro-phenyl)-ethyl]- thioureido}-phenyl)-2-fluoro-benzamide 1054 454 N-(2-Chloro-4-{3-[1-(4-cyano-phenyl)-ethyl]- thioureido}-phenyl)-2-fluoro-benzamide 1055 437 N-(2-Cyano-4-{3-[1-(4-fluoro-phenyl)-ethyl]- thioureido}-phenyl)-2-fluoro-benzamide 1056 498 N-(4-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido}-2- cyano-phenyl)-2-fluoro-benzamide 1057 445 N-(2-Cyano-4-{3-[1-(4-cyano-phenyl)-ethyl]-thioureido}- phenyl)-2-fluoro-benzamide 1058 460 N-{4-[3-(1-Benzofuran-2-yl-ethyl)-thioureido]-2-cyano- phenyl}-2-fluoro-benzamide 1059 517 N-(2-Benzoyl-4-{3-[1-(4-fluoro-phenyl)-ethyl]- thioureido}-phenyl)-2-fluoro-benzamide 1060 427 2-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]- thioureido}-2-methyl-phenyl)-benzamide 1061 487 N-(4-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido{-2- methyl-phenyl)-2-fluoro-benzamide 1062 434 N-(4-{3-[1-(4-Cyano-phenyl)-ethyl]-thioureido}-2- methyl-phenyl)-2-fluoro-benzamide 1063 449 N-{4-[3-(1-Benzofuran-2-yl-ethyl)-thioureido]-2-methyl- phenyl}-2-fluoro-benzamide 1064 456 N-(2-Dimethylamino-4-{3-[1-(4-fluoro-phenyl)-ethyl]- thioureido}-phenyl)-2-fluoro-benzamide 1065 526 N-(2-Benzyloxy-4-{3-[1-(4-cyano-phenyl)-ethyl]- thioureido}-phenyl)-2-fluoro-benzamide 1066 519 N-(2-Benzyloxy-4-{3-[1-(4-fluoro-phenyl)-ethyl]- thioureido}-phenyl)-2-fluoro-benzamide 1067 603 N-[4-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido}-2-(2- morpholin-4-yl-ethoxy)-phenyl]-2-fluoro-benzamide 1068 603 N-[4-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido}-2-(2- morpholin-4-yl-ethoxy)-phenyl]-2-fluoro-benzamide 1069 542 2-Fluoro-N-[4-{3-[1-(4-fluoro-phenyl)-ethyl]- thioureido}-2-(2-morpholin-4-yl-ethoxy)-phenyl]- benzamide 1070 485 N-(2-Butoxy-4-{3-[1-(4-fluoro-phenyl)-ethyl]- thioureido}-phenyl)-2-fluoro-benzamide 1071 492 N-(2-Butoxy-4-{3-[1-(4-cyano-phenyl)-ethyl]- thioureido}-phenyl)-2-fluoro-benzamide 1072 589 N-[4-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido}-2- (2-diethylamino-ethoxy)-phenyl]-2-fluoro-benzamide 1073 528 N-(2-(2-Diethylamino-ethoxy)-4-{3-[1-(4-fluoro-phenyl)- ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 1074 589 N-[4-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido}-2-(2- diethylamino-ethoxy)-phenyl]-2-fluoro-benzamide 1075 457 N-(2-Ethoxy-4-{3-[1-(4-fluoro-phenyl)-ethyl]- thioureido}-phenyl)-2-fluoro-benzamide 1076 464 N-(4-{3-[1-(4-Cyano-phenyl)-ethyl]-thioureido}-2- ethoxy-phenyl)-2-fluoro-benzamide 1077 468 2-Fluoro-N-[4-{3-[1-(4-fluoro-phenyl)-ethyl]- thioureido}-2-(2-nitrilo-ethoxy)-phenyl]-benzamide 1078 475 N-[4-{3-[1-(4-Cyano-phenyl)-ethyl]-thioureido}-2-(2- nitrilo-ethoxy)-phenyl]-2-fluoro-benzamide 1079 443 2-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]- thioureido}-2-methoxy-phenyl)-benzamide 1080 489 2-Fluoro-N-(5-{3-[1-(4-fluoro-phenyl)-ethyl]- thioureido}-biphenyl-2-yl)-benzamide 1081 514 Isoquinoline-1-carboxylic acid (4-{3-[1-(4-fluoro- phenyl)-ethyl]-thioureido}-2-trifluoromethyl-phenyl)- amide 1082 503 Benzofuran-2-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)- ethyl]-thioureido}-2-trifluoromethyl-phenyl)-amide 1083 514 Isoquinoline-3-carboxylic acid (4-{3-[1-(4-fluoro- phenyl)-ethyl]-thioureido}-2-trifluoromethyl-phenyl)- amide 1084 471 Isoquinoline-1-carboxylic acid (2-cyano-4-{3-[1-(4- fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide 1085 460 Benzofuran-2-carboxylic acid (2-cyano-4-{3-[1-(4- fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide 1086 471 Isoquinoline-3-carboxylic acid (2-cyano-4-{3-[1-(4- fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide 1087 460 Isoquinoline-1-carboxylic acid (4-{3-[1-(4-fluoro- phenyl)-ethyl]-thioureido}-2-methyl-phenyl)-amide 1088 449 Benzofuran-2-carboxylic acid (4-{3-[1-(4-fluoro- phenyl)-ethyl]-thioureido}-2-methyl-phenyl)-amide 1089 460 Isoquinoline-3-carboxylic acid (4-{3-[1-(4-fluoro- phenyl)-ethyl]-thioureido}-2-methyl-phenyl)-amide 1090 396 Pyrazine-2-carboxylic acid (4-{3-[1-(4-fluoro- phenyl)-ethyl]-thioureido}-phenyl)-amide 1091 401 Thiophene-2-carboxylic acid (4-{3-[1-(4-fluoro- phenyl)-ethyl]-thioureido}-phenyl)-amide 1092 401 Thiophene-3-carboxylic acid (4-{3-[1-(4-fluoro- phenyl)-ethyl]-thioureido}-phenyl)-amide 1093 500 2-Isopropyl-thiazole-4-carboxylic acid {4-[3-(4-chloro-3- trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 1094 466 2-Isopropyl-thiazole-4-carboxylic acid {4-[3-(3,5- dichloro-phenyl)-thioureido]-phenyl}-amide 1095 466 2-Isopropyl-thiazole-4-carboxylic acid {4-[3-(3,4- dichloro-phenyl)-thioureido]-phenyl}-amide 1096 534 2-Isopropyl-thiazole-4-carboxylic acid {4-[3-(3,5- bis-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 1097 480 2-Butyl-thiazole-4-carboxylic acid {4-[3-(3,4-dichloro- phenyl)-thioureido]-phenyl}-amide 1098 514 2-Butyl-thiazole-4-carboxylic acid {4-[3-(4-chloro-3- trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 1099 480 2-Butyl-thiazole-4-carboxylic acid {4-[3-(3,5-dichloro- phenyl)-thioureido]-phenyl}-amide 1100 548 2-Butyl-thiazole-4-carboxylic acid {4-[3-(3,5-bis- trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 1101 438 2-Methyl-thiazole-4-carboxylic acid {4-[3-(3,5-dichloro- phenyl)-thioureido]-phenyl}-amide 1102 438 2-Methyl-thiazole-4-carboxylic acid {4-[3-(3,4-dichloro- phenyl)-thioureido]-phenyl}-amide 1103 505 2-Methyl-thiazole-4-carboxylic acid {4-[3-(3,5-bis- trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 1104 534 2-Phenyl-thiazole-4-carboxylic acid {4-[3-(4-chloro-3- trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 1105 500 2-Phenyl-thiazole-4-carboxylic acid {4-[3-(3,5-dich loro- phenyl)-thioureido]-phenyl}-amide 1106 500 2-Phenyl-thiazole-4-carboxylic acid {4-[3-(3,4-dichloro- phenyl)-thioureido]-phenyl}-amide 1107 568 2-Phenyl-thiazole-4-carboxylic acid {4-[3-(3,5-bis- trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 1108 401 2-Fluoro-N-{4-[3-(1-thiazol-2-yl-ethyl)-thioureido]- phenyl}-benzamide 1109 588 2-Fluoro-N-[4-(3-{1-[1-(toluene-4-sulfonyl)-1H-indol-2- yl]-ethyl}-thioureido)-phenyl]-benzamide 1110 446 2-Fluoro-N-{4-[3-(1-quinolin-2-yl-ethyl)-thioureido]- phenyl}-benzamide 1111 446 2-Fluoro-N-{4-[3-(1-quinolin-4-yl-ethyl)-thioureido]- phenyl}-benzamide 1112 446 2-Fluoro-N-{4-[3-(1-isoquinolin-3-yl-ethyl)-thioureido]- phenyl}-benzamide 1113 446 2-Fluoro-N-{4-[3-(1-isoquinolin-1-yl-ethyl)-thioureido]- phenyl}-benzamide 1114 446 2-Fluoro-N-{4-[3-(1-quinolin-6-yl-ethyl)-thioureido]- phenyl}-benzamide 1115 446 2-Fluoro-N-{4-[3-(1-quinolin-3-yl-ethyl)-thioureido]- phenyl}-benzamide 1116 413 2-Methoxy-N-{4-[3-(1-thiophen-3-yl-ethyl)-thioureido]- phenyl}-benzamide______________________________________
EXAMPLE 886 (METHOD 33)
[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-dic-loro-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-carboxylic acid (4-amino-phenyl) amide (0.22 g) is added to the reaction flask and the mixture is stirred for approximately 6 hours. The solvent is then removed by evaporation under reduced pressure and warm acetonitrile (3 mL) is added. After 15 hours the mixture 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.
Using the above procedure and appropriate starting materials the following compounds were prepared:
______________________________________EX. NO. M + H COMPOUND NAME______________________________________887 465 N-{4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]- phenyl}-3-fluoro-benzamide 888 477 N-{4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]- phenyl}-2-methoxy-benzamide 889 465 N-{4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]- phenyl}-2-fluoro-benzamide 890 477 N-{4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]- phenyl}-3-methoxy-benzamide 891 399 N-{4-[3-(3,5-Dichloro-2-methoxy-4-methyl-phenyl)- thioureido]-phenyl}-acetamide 892 365 N-{4-[3-(3-Chloro-4-methoxy-5-methyl-phenyl)- thioureido]-phenyl}-acetamide 893 331 N-{4-[3-(2-Nitro-phenyl)-thioureido]-phenyl}-acetamide 894 331 N-{4-[3-(4-Nitro-phenyl)-thioureido]-phenyl}-acetamide 895 477 N-{4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]- phenyl}-4-methoxy-benzamide 896 351 N-{4-[3-(2-Chloro-5-methoxy-phenyl)-thioureido]- phenyl}-acetamide 897 428 2-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2,6- dichloro-phenoxy}-acetamide 898 443 {4-[3-(4-Acetylamino-phenyl)-thioureido]-2,6-dichloro- phenoxy}-acetic acid methyl ester 899 457 {4-[3-(4-Acetylamino-phenyl)-thioureido]-2,6-dichloro- phenoxy}-acetic acid ethyl ester 900 447 N-{4-[3-(3,5-Dichloro-4-phenoxy-phenyl)-thioureido]- phenyl}-acetamide 901 410 N-(4-{3-[3,5-Dichloro-4-(2-nitrilo-ethoxy)-phenyl]- thioureido}-phenyl)-acetamide 902 485 {4-[3-(4-Acetylamino-phenyl)-thioureido]-2,6-dichloro- phenoxy}-acetic acid tert-butyl ester 903 469 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-dichloro- 2-methoxy-4-methyl-phenyl)-thioureido]-phenyl}-amide 904 335 N-{4-[3-(3-Chloro-4-methyl-phenyl)-thioureido]- phenyl}-acetamide 905 335 N-{4-[3-(5-Chloro-2-methyl-phenyl)-thioureido]- phenyl}-acetamide 906 703 N-{4-[3-(4-{4-[3-(4-Acetylamino-phenyl)-thioureido]- 2-chloro-phenyldisulfanyl}-3-chloro-phenyl)-thioureido]- phenyl}-acetamide 907 369 N-{4-[3-(3,5-Dichloro-4-methyl-phenyl)-thioureido]- phenyl}-acetamide 908 598 N-{4-[3-(3,5-Diiodo-2,4-dimethoxy-phenyl)-thioureido]- phenyl}-acetamide 909 504 N-{4-[3-(3,5-Dibromo-2,4-dimethoxy-phenyl)- thioureido]-phenyl}-acetamide 910 317 N-{4-[3-(6-Methoxy-pyridin-3-yl)-thioureido]-phenyl}- acetamide 911 347 N-{4-[3-(2,6-Dimethoxy-pyridin-3-yl)-thioureido]- phenyl}-acetamide 912 457 Acetic acid 2-{4-[3-(4-acetylamino-phenyl)-thioureido]- 2,6-dichloro-phenoxy}-ethyl ester 913 365 4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro- benzoic acid 914 346 N-{4-[3-(3-Chloro-4-cyano-phenyl)-thioureido]-phenyl}- acetamide 915 512 N-(4-{3-[5-Chloro-2-(4-chloro-phenoxy)-4-pyrrol-1-yl- phenyl]-thioureido}-phenyl)-acetamide 916 355 N-{4-[3-(3,4-Dichloro-phenyl)-thioureido]-phenyl}- acetamide 917 339 N-{4-[3-(3-Chloro-4-fluoro-phenyl)-thioureido]-phenyl}- acetamide 918 447 N-{4-[3-(3-Chloro-4-iodo-phenyl)-thioureido]-phenyl}- acetamide 919 400 N-{4-[3-(4-Bromo-3-chloro-phenyl)-thioureido]-phenyl}- acetamide 920 424 N-[4-(3-{4-[Bis-(2-hydroxy-ethyl)-amino]-3-chloro- phenyl}-thioureido)-phenyl]-acetamide 921 434 N-(4-{3-[3-Chloro-4-(hexyl-methyl-amino)-phenyl]- thioureido}-phenyl)-acetamide 922 406 N-(4-{3-[3-Chloro-4-(isobutyl-methyl-amino)-phenyl]- thioureido}-phenyl)-acetamide 923 389 N-{4-[3-(3-Chloro-4-trifluoromethyl-phenyl)-thioureido]- phenyl}-acetamide 924 441 Furan-2-carboxylic acid {4-[3-(3-chloro-4- trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 925 459 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro- 4-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 926 469 N-{4-[3-(3-Chloro-4-trifluoromethyl-phenyl)-thioureido]- phenyl}-2-fluoro-benzamide 927 435 N-{4-[3-(3,4-Dichloro-phenyl)-thioureido]-phenyl}-2- fluoro-benzamide 928 407 Furan-2-carboxylic acid {4-[3-(3,4-dichloro-phenyl)- thioureido]-phenyl}-amide 929 425 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,4-dichloro- phenyl)-thioureido]-phenyl}-amide 930 480 N-{4-[3-(4-Bromo-3-chloro-phenyl)-thioureido]-phenyl}- 2-fluoro-benzamide 931 527 N-{4-[3-(3-Chloro-4-iodo-phenyl)-thioureido]-phenyl}- 2-fluoro-benzamide 932 452 Furan-2-carboxylic acid {4-[3-(4-bromo-3-chloro- phenyl)-thioureido]-phenyl}-amide 933 499 Furan-2-carboxylic acid {4-[3-(3-chloro-4-iodo-phenyl)- thioureido]-phenyl}-amide 934 391 Furan-2-carboxylic acid {4-[3-(3-chloro-4-fluoro- phenyl)-thioureido]-phenyl}-amide 935 470 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-bromo- 3-chloro-phenyl)-thioureido]-phenyl}-amide 936 517 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro- 4-iodo-phenyl)-thioureido]-phenyl}-amide 937 419 N-{4-[3-(3-Chloro-4-fluoro-phenyl)-thioureido]-phenyl}- 2-fluoro-benzamide 938 409 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-chloro-4- fluoro-phenyl)-thioureido]-phenyl}-amide 939 388 N-{4-[3-(3-Chloro-4-isoxazol-5-yl-phenyl)-thioureido]- phenyl}-acetamide 940 387 N-(4-{3-[3-Chloro-4-(1H-pyrazol-3-yl)-phenyl]- thioureido}-phenyl)-acetamide 941 355 N-{4-[3-(2,3-Dichloro-phenyl)-thioureido]-phenyl}- acetamide 942 435 N-{4-[3-(2,3-Dichloro-phenyl)-thioureido]-phenyl}-2- fluoro-benzamide 943 407 Furan-2-carboxylic acid {4-[3-(2,3-dichloro-phenyl)- thioureido]-phenyl}-amide 944 425 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2,3-dichloro- phenyl)-thioureido]-phenyl}-amide 945 355 N-{4-[3-(2,5-Dichloro-phenyl)-thioureido]-phenyl}- acetamide 946 435 N-{4-[3-(2,5-Dichloro-phenyl)-thioureido]-phenyl}-2- fluoro-benzamide 947 407 Furan-2-carboxylic acid {4-[3-(2,5-dichloro-phenyl)- thioureido]-phenyl}-amide 948 355 N-{4-[3-(3,5-Dichloro-phenyl)-thioureido]-phenyl}- acetamide 949 435 N-{4-[3-(3,5-Dichloro-phenyl)-thioureido]-phenyl}- 2-fluoro-benzamide 950 407 Furan-2-carboxylic acid {4-[3-(3,5-dichloro-phenyl)- thioureido]-phenyl}-amide 951 390 N-{4-[3-(3,4,5-Trichloro-phenyl)-thioureido]-phenyl}- acetamide 952 470 2-Fluoro-N-{4-[3-(3,4,5-trichloro-phenyl)-thioureido]- phenyl}-benzamide 953 442 Furan-2-carboxylic acid {4-[3-(3,4,5-trichloro-phenyl)- thioureido]-phenyl}-amide 954 460 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3,4,5- trichloro-phenyl)-thioureido]-phenyl}-amide 955 458 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro- 4-isoxazol-5-yl-phenyl)-thioureido]-phenyl}-amide 956 457 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[3-chloro-4- (1H-pyrazol-3-yl)-phenyl]-thioureido}-phenyl)-amide 957 391 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro- phenyl)-thioureido]-phenyl}-amide 958 373 Furan-2-carboxylic acid {4-[3-(3-chloro-phenyl)- thioureido]-phenyl}-amide 959 401 N-{4-[3-(3-Chloro-phenyl)-thioureido]-phenyl}-2-fluoro- benzamide 960 373 Furan-2-carboxylic acid {4-[3-(4-chloro-phenyl)- thioureido]-phenyl}-amide 961 401 N-{4-[3-(4-Chloro-phenyl)-thioureido]-phenyl}-2-fluoro- benzamide 962 391 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-chloro- phenyl)-thioureido]-phenyl}-amide 963 401 N-{4-[3-(2-Chloro-phenyl)-thioureido]-phenyl}-2- fluoro-benzamide 964 396 3-(3-{4-[(Furan-2-carbonyl)-amino]-phenyl}-thioureido)- benzoic acid methyl ester 965 424 3-{3-[4-(2-Fluoro-benzoylamino)-phenyl]-thioureido}- benzoic acid methyl ester 966 414 3-(3-{4-[([1,2,3]Thiadiazole-4-carbonyl)-amino]- phenyl}-thioureido)-benzoic acid methyl ester 967 409 N-[4-[[[[3-(Aminocarbonyl)phenyl]amino]thioxomethyl] amino]phenyl]-2-fluoro-benzamide 968 373 Furan-2-carboxylic acid {4-[3-(2-chloro-phenyl)- thioureido]-phenyl}-amide 969 381 Furan-2-carboxylic acid {4-[3-(3-carbamoyl-phenyl)- thioureido]-phenyl}-amide 970 399 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-carbamoyl- phenyl)-thioureido]-phenyl}-amide 971 391 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-chloro- phenyl)-thioureido]-phenyl}-amide 972 356 Furan-2-carboxylic acid {4-[3-(3-fluoro-phenyl)- thioureido]-phenyl}-amide 973 383 Furan-2-carboxylic acid {4-[3-(3-nitro-phenyl)- thioureido]-phenyl}-amide 974 411 2-Fluoro-N-{4-[3-(3-nitro-phenyl)-thioureido]-phenyl}- 975 422 Furan-2-carboxylic acid {4-[3-(3-trifluoromethoxy- phenyl)-thioureido]-phenyl}-amide 976 450 2-Fluoro-N-{4-[3-(3-trifluoromethoxy-phenyl)- thioureido]-phenyl}-benzamide 977 384 2-Fluoro-N-{4-[3-(3-fluoro-phenyl)-thioureido]-phenyl}- benzamide 978 410 3-{3-[4-(2-Fluoro-benzoylamino)-phenyl]-thioureido}- benzoic acid 979 382 3-(3-{4-[(Furan-2-carbonyl)-amino]-phenyl}-thioureido)- benzoic acid 980 408 N-{4-[3-(3-Acetyl-phenyl)-thioureido]-phenyl}-2-fluoro- benzamide 981 502 N-{4-[3-(3-Butylsulfamoyl-phenyl)-thioureido]-phenyl}- 2-fluoro-benzamide 982 380 Furan-2-carboxylic acid {4-[3-(3-acetyl-phenyl)- thioureido]-phenyl}-amide 983 447 Furan-2-carboxylic acid (4-{3-[3-(2-hydroxy- ethanesulfonyl)-phenyl]-thioureido}-phenyl)-amide 984 475 2-Fluoro-N-(4-{3-[3-(2-hydroxy-ethanesulfonyl)-phenyl]- thioureido}-phenyl)-benzamide 985 474 Furan-2-carboxylic acid {4-[3-(3-butylsulfamoyl-phenyl)- thioureido]-phenyl}-amide______________________________________
EXAMPLE 986 (METHOD 57)
1-(4-Fluoro-phenyl)-2-methyl-propan-1-ol
To solution of 4-fluorobenzaldehyde (2.0 g) in diethyl ether (40 mL) at 0.degree. C. is added dropwise isopropylmagesium bromide (2.0 M, 9.6 mL) with stirring. After 1.5 hours the reaction is quenched with aqueous ammonium chloride and extracted with diethyl ether. The diethyl ether extracts are washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered and evaporated to give an oil. The oil is purified by silica gel chromatography eluting with 10% dichloromethane-hexanes to give the product, a yellow oil (1.76 g).
EXAMPLE 987 (METHOD 58)
1 -(4-Fluoro-phenyl)-2-methyl-propan-1-one
To a solution of 1-(4-Fluoro-phenyl)-2-methyl-propan-1-ol (1.6 g) in acetone (10 mL) at 0.degree. C. is added Jones reagent (20 mL) with stirring. After 10 minutes excess Jones reagent is destroyed by addition of isopropyl alcohol. Diethyl ether is added followed by anhydrous magnesium and the mixture is filtered and evaporated to give the product, a yellow oil (1.2 g).
EXAMPLE 988 (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 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).
The foregoing compounds were tested for activity as herpes virus inhibitors using the following assays.
HUMAN CYTOMEGALOVIRUS
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 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 IC.sub.50 or IC.sub.90 value, that is, the amount of compound required to reduce the virus yield by 50% or 90%, respectively. Table I describes IC.sub.50 data for compounds tested against HCMV.
Microtiter plate assay. Ninety-six well plate cultures of human foreskin fibroblasts are infected in the presence of inhibitor compound with a HCMV recombinant mutant virus whose genome contains the prokaryotic beta-glucuronidase gene (Jefferson, R. A., S. M. Burgess, and D. Hirsh. 1986. Beta-glucuronidase from Escherichia coli as a gene fusion marker. Proc. Natl. Acad. Sci. USA 83:8447-8451) whose expression is controlled by a viral promoter. An example of such a virus is RV145 (Jones, T. R., V. P. Muzithras, and Y. Gluzman. 1991. Replacement mutagenesis of the human cytomegalovirus genome: US10 and US11 gene products are nonessential. J. Virol. 65:5860-5872). Since it is under the control of a viral promoter, beta-glucuronidase expression is an indirect indicator of growth and replication of HCMV in this assay. At 96 hours post-infection, the infected cell lysates are prepared (using 50 mM sodium phosphate [pH7.0] containing 0.1% Triton X-100 and 0.1% sarkosyl) and assayed for beta-glucuronidase activity using a substrate for the enzyme which when cleaved yields either a product which can be measured calorimetrically 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 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 IC.sub.50 of an inhibitor compound.
HSV antiviral (ELISA) assay
Vero cells (ATCC #CCL-81) are plated on 96-well tissue culture plates at 3.5.times.10.sup.4 cells per 100 .mu.l tissue culture DMEM (Dulbecco's modified Eagle media) supplemented with 2% fetal bovine serum (FBS) in each well. After overnight incubation @ 37.degree. C. (in 5% CO.sub.2) and 30 minutes prior to infection with HSV-1 (multiplicity of infection equal to 0.006), cells are either untreated, or treated with test compound (multiple concentrations) or reference standard drug control. After approximately 24 hours post-infection incubation @ 37.degree. C. (in 5% CO.sub.2), cells are fixed for ELISA assay. The primary antibody is murine anti-HSV glycoprotein D monoclonal primary antibody and the secondary antibody is goat anti-mouse IgG linked to .beta.-galactosidase. Thus the extent of viral replication is determined by assessing .beta.-galactosidase activity by quantifying the generation of the 4-methyl umbelliferone fluorescent cleavage product after addition of the methyl umbelliferyl-.beta.-D-galactoside (Sigma #M1633) substrate on a microfluorimeter (365 nm for excitation and 450 nm for emission). Antiviral activity (IC.sub.50) 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.
VZV Antiviral (ELISA) Assa
For the generation of stock VZV to be used in the assay, VZV strain Ellen (ATCC #VR-1367) is used to infect human foreskin fibroblast (HFF) cells at low multiplicity (less than 0.1) and incubated overnight at 37.degree. C. in 5% CO.sub.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 (3.5.times.10.sup.4 cells in 100 .mu.DMEM supplemented with 2% FBS) which contain test compound or the reference standard drug control (in 100 .mu.l DMEM supplemented with 2% FBS per well). These cells are incubated for three days at 37.degree. C. in 5% CO.sub.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 .beta.-galactosidase. Thus the extent of viral replication is determined by assessing .beta.-galactosidase activity by quantifying the generation of the 4-methyl umbelliferone fluorescent cleavage product after addition of the methyl umbelliferyl-.beta.-D-galactoside (Sigma #M1633) substrate on a microfluorimeter (365 nm for excitation and 450 nm for emission). Antiviral activity (IC.sub.50) 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.
Table I describes IC.sub.50 data for compounds tested against herpes viruses.
______________________________________ IC50 IC50 % inhibition IC50 (ug/ml) (ug/ml) 10 ug/ml (ug/ml) Example HCMV HSV VZV VZV______________________________________283 7 0.6 17 >10 284 0.4 3 100 >15 289 >10 0.6 30 >10 498 0.14 6 14 >10 499 3 5 25 >10 506 >10 >10 68 >10 507 1.2 10 90 4 512 0.7 0.5 70 4 514 1.2 4 62 >10 515 >10 >10 30 >10 815 0.0024 >7.5 816 0.0015 >7.5 817 0.001 >7.5 818 0.0022 >7.5 819 0.0022 >7.5 820 0.0013 3.4 821 0.014 >7.5 822 0.05 >7.5 823 0.05 >7.5 824 0.004 3.20 825 0.003 6.12 826 0.020 0.86 827 0.026 828 0.45 >7.5 829 0.08 >7.5______________________________________
Thus, in accordance with the present invention, compounds of the present invention may be administered to a patient suffering from herpes virus infections including HSV, VZV and HCMV, in an amount effective to inhibit the virus. Compounds of the present invention are thus useful to ameliorate to eliminate the symptoms of herpes virus infections, including HSV, VZV and HCMV, in mammals including, but not limited to humans.
Compounds of the invention may be administered to a patient either neat or with a convention pharmaceutical carrier.
Applicable solid carriers can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents or an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of 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 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 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 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.
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.
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 sachets containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
The therapeutically effective dosage to be used in the treatment of herpes virus infections, including HSV, VZV, and HCMV must be subjectively determined by the attending physician. The variables involved include the the condition , age and weight of the patient. The novel method of the invention for treating herpes virus infection including HSV, VZV and HCMV comprises administering to a 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 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.

Number	Date	Country
WO 965157	Aug 1996	WOX
WO 974002	Oct 1997	WOX
9740028	Oct 1997	WOX
9625157	Oct 1997	WOX

Diaminopuridine-containing thiourea inhibitors of herpes viruses

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Entry
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