CA2351690A1 - Heterocyclic carboxamide-containing thiourea inhibitors of herpes viruses containing a substituted phenylenediamine group - Google Patents

Abstract

Compounds of formula (I) wherein R1-R5 are independently selected from hydrogen, or substituents R9-R12 are independently hydrogen, or substituents provided that at least one of R9-12 is not hydrogen; G is a monocyclic heteroaryl: X is a bond, -NH, alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, or thioalkyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms, or (CH)J; J is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl or benzyl, useful in the treatment of diseases associated with herpes viruses including human cytomegalovirus, herpes simplex viruses, Epstein-Barr virus, varicella-zoste r virus, human herpesviruses-6 and -7, and Kaposi herpesvirus.

Description

HETEROCYCLIC CARBOXAMIDE-CONTAINING THIOUREA
INHIBITORS OF HERPES VIRUSES CONTAINING A SUBSTITUTED
PHENYLENEDIAMINE GROUP
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.
Lipgincott-Raven Publishers, Philadelphia, PA). Each member of this family is characterized by an enveloped virus containing proteinaceous tegumf,nt and nucleocapsid, the latter of which houses the viruses' relatively large double-stranded DNA genome (i.e.
approximately 80-250 kilobases). Members o~f the human alphaherpesvirus subfamily are neurotropic and include herpes simplE:x virus type 1 (HSV-1) and type I5 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-I and HSV-2 [Whitiey, 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, PAJ); 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 Afford, C. A. 1996.
Cytornegalovirus, p. 2493-2523. In B. N. Fields, I7. M. Knipe, and P. M.
Howley 3() {ed:), Fields Virology, 3rd ed. Lippincott-Raven. Publishers, Philadelphia, PA));
exanthem subitum (HHV-6 [(Pellet, P. E, and Black,, J. B. 1996. Human Herpesvirus 5, p. 2587-2608. In B. N. Fields, D. M. Knipe, and P. M. Howley (ed.), Fields _2_ 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, PAS); and Is;aposi's sarcoma (HHV-8 [Neipel, F., 5 Albrecht, J.C., and Fleckenstein, B. 1997. Cell-homologous genes in the Kapasi's sarcoma-associated rhadinovirus human laerpesvirus 8: determinants of its pathogenicity? J. Virol. 71:4187-92, 1997)). HCMV is considered in more detail below. Following the primary infection, hezpesviruses establish latency within the infected individual and remain there for the remainder of his/her life.
Periodic 10 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), 15 ganciclovir (Roche} and foscarnet (Asia) which target viral encoded DNA
polymerase.
HCMV is a ubiquitous opportunistic pathogen infecting 50-90% of the adult population (Brits, W. J., and Alford, C. A. 15>96. Cytomegalovirus, p. 2493-2523. In 20 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 25 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.
30 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 Pheumacystis).

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;

40% (-85,000 patients in the United States) have life- or sight-threatening HCMV
5 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 10 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. T. Med. 335:721-729; Sachs, S., and F. Alrabiah. 1996.
Novel 20 herpes treatments: a review. Exp. Opin. Invest. Drugs 5:169-183). These include:
ganciclovir (Roche), a nucleoside analog with hemopoietic cell toxicity;
foscarnet (Astray, 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 25 low bioavailability, and, as noted above, ~~re 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.
30 Phenyl thioureas are disclosed for use in a variety of pharmaceutical applications. Armistead, et aL, WO 97140028, 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.
x (R~)m H NH-Morin, Jr., et al., U.S. Patent No. 5,593,993 teaches certain phenyl thiourea compounds for treatment of AIDs and the inhibition of the replication of HIV
and related viruses.
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 cytornegalovirus, herpes simplex viruses, Epstein-Barr virus, varicella-zoster virus, human herpesviruses-6 and -7, and Kaposi I S herpesvirus.
Description of the Invention In accordance with the present invention are provided compounds having the formula:
Ra 5 Rs io R3 ANN-C-wNH ~ NH-C-G
R2 R~ R1~ R12 I
wherein R,-RS 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 1 U carbon atoms, heterocycloalkyl of 3 to l0 carbon members, aryl, heteroaryl, halogen, -CN, -NO~, -CO~R6, -CORE, -OR6, -SR6, -SORE, -SO~R6, -CONR7R8, -NR6N(R,R~), -N(R~Rg) or W-Y-(CHZ)~ Z provided that at least one of R,-RS is not hydrogen; or R= and R; or R3 and R4, taken together form a 3 to ? membered heterocycloalkyl or 3 to 7 membered heteroaryl;
5 R6 and R, are independently hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon at~~ms, or aryl;
R$ is hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10 members, aryl or heteroaryl, or 10 R, and R8, taken together may form a 3 to 7 membered heterocycloalkyl;
R~ R,2 are independently hydrogen, alkyl of 1 to 4 carbon atoms, perhaloalkyl of 1 to 4 carbon atoms, halogen, alkoxy of 1 to 4 carbon atoms, or cyano, or R9 and R,o or R" and :R,~ may be taken together to form aryl of 5 to 7 carbon atoms; provided that at least one of R9.,z is not 15 hydrogen;
W is O, NR6, or is absent;
Y is -(CO)- or -(COZ)-, or is absent;
Z is alkyl of l to 4 carbon atoms, -CN, -COzRb, CORE, -CONIt,R&, -OCOR6, -NR6COR,, -OCONR6, -OR6, -SR6, -SORE, -SOZRb, SR6N{R,RB), 20 -N(R,RB) or phenyl;
G is a monocyclic heteroaryl;
X is a bond, -NH, alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, thioalkyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms, or (CH)J;
25 J is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl or benzyl; and n is i to 6, or pharmaceutical salts thereof.
30 In some preferred embodiments of the present invention at least one of R,-RS
is not hydrogen. In other preferred embodiments of the present invention, R,-RS are independently, hydrogen alkyl of 1 to 6 carbon atoms, halogen, perhaloalkyl of 1 to 6 carbon atoms, OR6 or N(R,RB). Preferably, 1 to 3 of R,-RS is not hydrogen.
Most WO 00/34261 PCT/US99l28916 preferably, 2 of R,-RS is not hydrogen. In preferred compounds of the present invention R3 and R5, or Ra and RS are preferably, independently, halogen or CF3.
In some preferred embodiments of the present R9-R12 are selected from halogen, methyl, methoxy and cyano 5 In some embodiments of the present invention G is preferably thiazolyl, thiadiazolyl, oxazolyl or furyl. More preferablly G is furan. G is preferably not substituted.
In some embodiments of the present invention X is a bond or C1-C4 alkyl.
Preferably, when X is C1-C4 alkyl, said alkyl is straight chain alkyl.
10 Preferred compounds of the present invention are the following compounds which include pharmaceutical salts thereof:
Furan-2-carboxylic acid { 4-j3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2,5-dimethoxy-phenyl }-amide, Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-1S 3-trifluoromethyl-phenyl}-amide, Furan-2-carboxylic acid { 3-chloro-4-[:3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-amide, Furan-2-carboxylic acid { 5-chlaro-4-[:3-(5-chloro-2,4-dirnethoxy-phenyi)-thioureido]-2-methyl-phenyl }-amide, 20 Furan-2-carboxylic acid {5-chloro-4-[:3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-hydroxy-phenyl }-amide, Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-3-cyano-phenyl }-amide, Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-25 3-methyl-phenyl }-amide, Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methoxy-5-methyl-phenyl }-amide, Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-3-methoxy-phenyl }-amide, 30 Furan-2-carboxylic acid { 4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-trifluoromethyl-phenyl }-amide, Furan-2-carboxylic acid { 2-chloro-4-[3-(5-chIoro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-amide, WO 00/342b1 PCT/US99/289I6 Furan-2-carboxylic acid {4-[3-(5-chlor~o-2,4-dimethoxy-phenyl)-thiaureido]-2-cyano-phenyl }-amide, 5-[3-(5-Chloro-2,4-dimethoxy-phenyl)~-thioureido]-2-[(furan-2-carbonyl)-amino]-benzoic acid, 5 Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-phenylcarbamoyl-phenyl }-amide, Furan-2-carboxylic acid { 2-benzoyl-4-j[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-amide, Furan-2-carboxylic acid { 4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-10 2-methyl-phenyl }-amide, Furan-2-carboxylic acid {4-[3-{5-chloro-2,4-dimethoxy-phenyl)-thioureido]-naphthalen-1-yl }-amide;
and Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethaxy-phenyl)-thioureido]-15 2-methoxy-phenyl}-amide, and pharmaceutical salts thereof.
Alkyl as used herein refers to straight o~r branched chain lower alkyl of 1 to carbon atoms. Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl.
20 Alkenyl as used herein refers to straight or branched chain lower alkyl of 2 to b 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.
25 Alkyl, aikenyl 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. Cycloalkyh groups of the present invention may be substituted or 30 unsubstituted.
Heterocycloalkyl refers to a saturated r~nono or bicyclic ring system of 3 to members having 1 to 3 heteroatoms selected from N, S and O, including, but not limited to aziridinyl, azetidinyl, imidazolidinyl, morpholinyl, thiomorpholinyl, WO 80/34261 PCT/lJS99128916 _g_ piperazinyl, pyrazolidinyl, piperidinyl, and pywolidinyl. Heterocycloaikyl 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 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 10 quinolyl, isoquinolyl; napthalenyl, benzofuranyl, benzothienyl, indolyl, pyridyl, pyrazinyl, thienyl, furyl, pyrrolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, pyrazolyl, triazolyl, thiadiazolyl, and imidazolyl. Heteroaryl groups of the present 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 we unsubstituted and may include alkyl of 1 to 6 carbon atoms, cycloalkyl of i to 6 carbon atoms, heterocycloalkyl of ito 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 s;ubstituents 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 otherwi;>e. 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, malefic, succinic, fumaric, acetic, lactic, nitric, sulfonic, p-toluene sulfonic, methane sulfonic acid, and the like.

WO 00/34261 PCT/US9912$916 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 5 substantially pure is meant the composition contains greater than 75% of the desired isomer and may include no more than 25% of t:he undesired isomer. In more preferred embodiments the pure optical isomer is greater than 90% of the desired isomer.
In some preferred emodiments, when the target is. VZV, the (S) isomer is preferred. The individual isomers can be prepared directly or by asymmetric or stereospecific synthesis or by conventional separation of optical isomers from the racemic mixture.
Compounds of the present invention may be prepared by those skilled in the art of organic synthesis employing methods described below which utilize readily 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 and 34, reacting appropriately substituted amines 2, wherein the substitutents R,-RS, and X are described as above, with appropriately substituted isothiacyanates 3, wherein the substituents R9-R,= and G are described above, either neat or in an appropriate solvent such as tetrahydrofuran, acetonitrile, ethyl acetate, dichloromethane, or N,N-dimethylformamide affords the desired thioureas 1. Similarly, reaction of appropriately substituted isothiocyanates 4, wherein the substitutents R,-R5, and X are described as above with appropriately substituted anilines 5, wherein the substituents R9 R,~ and G are described above, in a convenient solvent such as those listed above affords the desired thioureas 1.

Methods 31 and 34 2 1 ~1 R ~o Ra s R ~ / ~H G-H ~ / ~ G
R2 Rt R> > R~ 2 R 5 R ~o R3 ~ / ~H2 + S~~ ~ /
R R Rt2 Ra S R ~o R3 ~ / X N=C=S + ~ ~ G
R2 R~ R> > R12 5 Alternatively, appropriately substituted thioureas 1 can be prepared as described by Methods 32 and 33 by reacting amines 2 and 5, wherein R,-R5, R9 R,2 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 dichloro-methane and tetrahydrofuran or mixtures thereof or one molar equivalent of l,l'-thiocarbonyl-di-10 { 1,2,4)-triazole in an appropriate solvent such as dichloromethane and tetrahydrofuran or mixtures thereof at room temperature:
Methods 32, 33 ~ ) cs(im)~ '~ /
2) ArNH2 ~ / ~ ~ 32 i / H H
NHZ ~ ) CS(Tria')2 ! ~ S
I ~ 2) ArNH2 ~ ti H

In certain instances, subsequent chemical modification of the final thioureas was required. These methods, Methods 35-39, axe summarized below.
NaOH
-'-"---i' 35 EtOH
~ ~ ! _NaOH ~ ~ ~ ~ 36 EtOH ~ ~ W
N N
H H ~ H H
Et02C HOOC
BzCI

MsCI

H
HNR2 s O H H
OMs SnCt~
MeOH ~' / ~ ~ ( 40 N N
N ,H H H H
~IH2 Thioureas 1 wherein at least one substit~,zent of R,-R5 is 1-hydroxyethoxy or carboxy-methoxy, Rg-R,~ and G are defined as above and X equals a bond, may be 5 prepared from the corresponding alkyl esters by alkaline hydrolysis with aqueous sodium or potassium hydroxide in a suitable solvent such as methanol, tetrahydro-furan or mixtures thereof at room temperature in accordance with Methods 35 and 36.

Thioureas 1 wherein at least one substituent of R,-RS is 1-acyloxyethoxy or methansulfonoxyethoxy, Rq-Riz and G are defined as above and X equals a bond, may be prepared from the corresponding 1-hydroxyethoxy derivative by acylation with appropriate acylating agents such as benzoic acid chloride or methanesulfonic acid 5 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,-RS is 1-aminoethoxy, R9 R,Z
10 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,-RS is 1-aminoalkyl, R9 R, 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 20 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. Jacs~tacs Liebigs Ann. Chem. 657, 25 (19b2)) by reacting appropriately substituted amines 5 or 2, respectively, wherein R,-R5, R9-R12 and G are described above and X is defined above, with one molar equivalent of 1,1'-thiocarbonyldiimidazole in an appropriate solvent such as dichloromethane and tetrahydrofuran or mixtures thereof.

Method 4.1 N
~N 2 H2N ~ ~ ~-C-G ----= S=C=N ~ ~ l;l-C-G
H ~H

N
R4 5 ~ ~ R4 5 R3 ~ ~ X-NH2 --~ R3 ~ ~ X _ N=C=S
R2 R1 R2 R~

5 The intermediates 2 and 5 may be prepared according to the following protocols:
According to Methods lA-1G, amines :~, wherein R,-RS are defined above and X is defined above and amines 5, wherein R9 Rl= are defined above, rnay he prepared 10 by reduction of the appropriately substituted nitrobenzenes according to a variety of procedures known to those skilled in the art and described in R. J. Lindsay, Comprehensive Organic Chemistry (ed. Sutherland), Volume 2, Chapter 6.3.1, Aromatic Amines, 1979. Such procedures include the reduction of nitrobenzenes to form anilines upon exposure to:
15 a) iron powder and a strong acid, such as hydrochloric acid (Methods lA) 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 temperature;> ranging from room temperature to the 20 refluxing temperature of the solvent, or;

c) iron powder and aqueous ammonium chloride (Method 1 C), 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 5 or in alcohol solvent such as methanol or ethanol, at temperatures ranging from room temperature to the refluxing temperature of the solvent, or;
e) whemR,-RS and Rq-R,Z are selected from Cl, Br, I, -(OSOZ)-CF3, or -(OSOZ)-1-(4-methylphenyl), by catalytic reduction such as with hydrogen and palladium on carbon (Method lE) in an appropriate solvent such as methanol, ethanol, or ethyl lU acetate, under one or more atmospheres of pressure or;
f~ When R~-RS and R~-R,~ are selected from C'.l, Br, I, -(OSO~)-CF3, or -(OSOZ)-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 15 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,-RS are 20 defined above and X is defined above and anilines 5, wherein R9-Rte are 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 25 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°C and room temperature, or;
30 b) the exposure of appropriately substituted arylamino-(2-trimethylsiIylethyl)-carbamates to a fluoride ion source such as tetrabutylammonium fluoride or potassium fluoride (Method 3B) in aqueous acetonitriie or tetrahydrofuran or - 1:5 -mixtures thereof at temperatures ranging from room temperature to the reflux temperature of the solvent, or;
c) the exposure of appropriately substitutef, arylamino-trifluoroacetamides to a strong base such as sodium or potassium hydroxide or sodium or potassium carbonate in 5 an alcohol solvent such as methanol or ethanol (Method 3C) at temperatures ranging from room temperature to the reflux temperature of the solvent:
Alternatively, according to Method 11, amines 2, wherein R,-RS are defined above, and X is defined above and at least one substituent of R,-RS is defined as vinyl, may be prepared by the palladium catalyzed coupling of a vinyl trialkyltin 10 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(dibenzyIidineacetone)-bipalladium, and a ligand, such as triphenylarsine, in a suitable solvent such as tetrahydrofuran o~r N-methylpyrrolidinone, at temperatures ranging from roam temperature to the refl.ux temperature of the solvent, essentially 15 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,-RS are defined above and X equals a bond and at least one substituent of R~ or R, is defined as dialkylamino, may be prepared by the palladium catalyzed amination of an 20 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 25 tetrahydrofuran or toluene; at temperatures ranging from room temperature to 100°C, essentially according to the procedures of J.F. Hartwig and J. Louie Tetrahedron Letters 36 (21), 3609 (1995).
Alternatively, according to Method. 43, amines 2, wherein R,-RS are defined above and X is defined above and at least: one substituent of RZ or R~ is defined as 30 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-brornobenzotrifluoride by alkenes under condiditons which employ a palladium catalyst such as {1,1'-bis(diphenylphosphino)ferrocene)palladium (II) chloride-dichloromethane complex and in the presence of 9-borabicyclo[3.3.1]nonane and a suitable base such as aqueous sodium hydroxide in a suitable solvent such as 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 Or a~ nic Synthesis volume 2, Chapter 7, 1991, and references therein. Such procedures include:
10 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, d.imethylformamide; dichloromethane, and the like, at temperatures ~ ranging from room temperature to the reflux 1 S temperature of the solvent to produce the corresponding arylamino-tert-butyl-carbamate, or;
b) the reaction of an appropriately substituted aniline with l-[2-(txirnethyl-silyl)ethoxycarbonyl-oxy]benzotriazole (Method 2B) in the presence of a tertiary amine such as triethylamine or diisopropylethylamine in a suitable solvent such as 20 dimethylformamide at room temperature to produce the corresponding arylamino-(2-trimethylsilylethyl)-carbamate, or;
c) the reaction of an appropriately substituted aniline with a carboxylic acid chloride or acid anhydride (Method 2C) either neat or in an appropriate solvent such as tetrahydrofuran, dimethylformamide, dichloromethane, pyridine and the like, in 25 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 30 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;

1~ _ e) the reaction of an appropiately substituted aniline with a carboxylic acid (Method 2E) in the presence of a coupling agent such as benzotriazole-1-yloxy-tris-{dimethylamino)-phosphonium hexafluorophosphate, 2-( 1 H-benzotriazole-1-yl-oxy)-1,1,3,3-tetra-methyluronium hexafluorophosphate, dicyclohexyl carbodi-5 imide and the like and in the presence of a. tertiary amine such as triethylamine or diisopropylethylamine in a suitable solvent such as diichloromethane, dimethylfarmamide and the like, at room temperature to produce the corresponding arylaminoamide, or;
t~ the reaction of an appropriately protected aniline such as an arylamino-tent-butyl 10 carbamate ar the like in which at least one substituent of R,-R,, is defined as -W-Y-(CHZ)n-Z wherein W, Y, and Z axe 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 Iike at temperatures ranging from 0°C to room temperature to produce the corresponding 15 carboxylic acid ester, or;
g) the reaction of an appropriately substituted. aniline in which a t least one substituent of R,-RS is defined as hydroxyl with di-tert-butyl-dicaxbonate {Method 2G) in the absence of one or more molar equivalents of a tertiary amine such as triethylarnine or N,N-diisopropylethylamine in a suitable solvent such as acetone, 20 tetrahydrofuran, dimethylformamide, dichloromethane, and the like, at temperatures ranging from room temperature to the reflux temperature of the solvent to produce the correspanding arylamino-tert-butyl-carbamate.
Nitrobenzene intermediates that are ultimately converted to amines 2 and 5 by methods shown above in Methods lA-1G may be prepared in accordance with 25 Methods 4A, 4C, 4E-4F.
Referring to Methods 4A, 4C, and ~lE-4H, the nitrobenzene intermediates which are ultimately converted into amines 2, R, and R~ are defined above and R,, R3, and/or RS are defined as alkoxy, thioalkoxy, alkylsulfenyl, alkylsulfinyl, and dialkylamino rnay be prepared by the nucle;ophilic displacement of appropriately 30 substituted 2-, 4-, and/or 6-fluoro-, chloro-, bromo-, iodo-, trit7uoromethylsulfonyl-, or (4-methylphenyl)sulfonyl-substituted nitrobenzenes by methods which include the following:

WO 00/34261 PCT/US9912891b 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, at:etonitrile, N,N-dimethylformamide ar dimethylsuIfoxide in the presence or absence of one or more molar equivalents of 5 a base such as sodium carbonate, pota;,slum 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 10 appropriately substituted 2- or 4- halo- or sulfonate esters of nitrobenzenes or benzonitriles (Method 4H) either neat o~r in an appropriate solvent such as tetrahydrofuran, dioxane, acetonitrile, N,N-dimethylformamide or dimethyl sulfoxide, at temperatures ranging from room temperature to the retlux temperature of the solvent, or;
IS 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, acetanitrile, N,N-dimethyl-formamide or dimethylsulfoxide, at temperatures ranging from room temperature to the reflux. temperature of the solvent;
20 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°C to the reflux temperature of the solvent, or;
e) reaction of sodium sulfide with appropriately substituted 2- or 4- halo- or sulfonate 25 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).
30 Alternatively, referring to Methods SC arid 6, the nitrobenzene intermediates which are ultimately converted into amines 2, wherein at least one substitutent R,-RS
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 reflex temperature of the solvent, or;
b) reaction of the hydroxy-nitrobenzene with am alkyl alcohol, triphenylphosphine, and a dialkylazadicarbaxylate reagent (Method 6), such as diethylazodi-carboxylate, in an anhydrous aprotic solvent such as diethyl ether or tetrahydrofuran at temperatures ranging from 0°C to the reflex 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,-RS is defined as alkoxy may be prepared the corresponding substituted hydroxy arylamino-tert-butyl-carbamate by reaction with alkyl halides, trifluormethane-sulfonates, 4-methylbenzenesulfonates, dialkyl-sulfonate, 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 reflex temperature of the solvent.
Alternatively, referring to Methods 7A-G, the nitrobenzene intermediates which are ultimately converted into amines 2, R, and/or R3 is ~alkoxy, and RZ
and/or R~ 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 WO 00l3426I PCT/US9912891b acetic acid or the Iike in the presence or the absence of silver trifluoroacetate at room temperature, or;
c) reaction of a 2,4-dimethoxynitrobenzene (Method 7E) with benzyltrimethyl ammonium dichloroiodate in the presence of anhydrous zinc chloride in a suitable solvent such as glacial acetic acid, at room temperature or;
d) reaction of a 2-hydroxy-4-methoxynitrobenzene (Method 7F) with benzyl-trimethyl-ammonium dichloroiodate in the presence of sodium bicarbonate in a suitable solvent mixture such as dichloromethane and methanol, at room temperature or;
1~ e) reaction of a 2,4-dimethoxynitrobenzene {Method 7G) with 3,5-dichloro-1-fluoro-pyridine triflate in a suitable solvent such as tetrachloroethane, at a temperature ranging from room temperature to the reflu~; temperature of the solvent.
Referring to Method 8, the nitrobenzene intermediates which are ultimately converted into amines 2, wherein R4 = -CF3, and R,-R3 and RS-R8 are defined as above and X equals a bond may be prepared from the corresponding substituted 4-iodo nitrobenzenes by reaction with trimethyl(trifl<uoromethyl)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, - -HNCOCHZNR.~R$ or -HNCOCHZSR6, and R~-R3 and RS R$ 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 th,e presence of a suitable base such as sodium or potassium carbonate or the liike 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,-RS 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 ()°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,-R5 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 iin a suitable solvent mixture such as acetone and dichloramethane 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 R4 is defined as 1-hydroxyethyl and RF-R3 and RS 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.
Refernng to Method 13, the carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein R, is defined as 2-hydroxyethyl and R,-R3 and R5 are defined as above and X is defined above may be prepared by reacting the corresponding 4-vinyl carbamoyl aniline with sodium borohydride in the presenace of glacial acetic acid in a suitable solvent such as tetrahydrofuran, 1;4-dioxane or the like at temperatures ranging from 0°C to room temperature.
Refernng to Method 14, the carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein R~ is defined as 1-azidoethyl and R,-R3 and RS are defined as above and X is defined above may be prepared by reacting the corresponding 4-(1-hydroxyethyl) carbamoyl aniline with hydrazoic acid in the presence of a dialkylazodicarboxylate such as diethylazodicarboxylate and triphenylphosphine in a suitable solvent mixture such as tetrahydrofuran and dichloromethane at temperatures ranging from 0°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~ is defined as 3-dimethylaminoprop-1-ynyl and R,-R3 and RS are defined as above and X equals a bond, may be prepared by reacting the corresponding 4-iodo-carbamoyl aniline with I-dimethylamino-2-propyne in a suitable tertiary amine solvent such as triethyiamine 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 i 6, the carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein R~ is defined as 3-dimethylaminoacryloyl and F',,-R3 and RS are defined as above and 1C) X equals a bond, may be prepared by reacting the corresponding 4-(3-dimethylaminoprop-l-ynyl)carbamoyl aniline with a suitable peracid such as 3-chioroperoxybenzoic acid in a suitable solvent mixture such as dichloromethane and methanol at temperatures ranging from 0°C to room temperature.
Referring to Methods I7 and 18; the ca~rbamoyi amine derivatives utilized as i 5 starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein R, is defined as either 4-isoxazol-5-yl or 4-(1H-pyrazol-3-yl) and Rl-R3 and RS are defined as above and X equals a bond, may be prepared by reacting the corresponding 4-(3-dimethylamino-acryloyl)carbamoyl aniline with either hydroxyl-amine hydrochloride or hydrazine hydrate in a suitable solvent such as 1,4-dioxane or 2U ethanol and the like at room temperature.
Referring to Method 2U, the carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein R4 = -HNCO~Z, and R,-R3, R5, and Z are defined as above and X equals a bond, may be prepared by reacting the corresponding 4-aminocarbamoyl aniline with I,I-25 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.
Refernng to Methods 26 and 3U, the carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C which arf: ultimately converted into amines 2, 3U wherein at least one substituent of R,-RS is defined as dialkylamino and X
is defined above may be prepared by reaction of appropriately substituted aidehydes in the presence of either sodium cyanoboro-hydride or hydrogen gas and IU % 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,-RS is defined as hydroxy and X is defined above can be prepared by reaction of the corresponding ester such as acetate with an appropriate base such as sodium bicarbonate or sodium hydroxide in a suitable solvent mixture such as methanol-water mixtures at temperatures ranging from room temperature to the reflux temperature of the solvent.
Referring to Method 29, amines 2 wherein at least one substituent of R,-RS is 1() defined as 2-hydroxybenzamido and X is defined above can be prepared by reaction of the corresponding N-(4-aminophenyl)phthalimide with lithium borohydride in an appropriate solvent such as tetrahydrofuran, dliethyl ether, or the like at room temperature.
' The intermediate amines 2 wherein R,-RS are defined as above and X equals either -CHZ or -(CHZ)Z 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 4.4.);
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 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°C to room temperature. (Method S 1 );
The unsaturated nitro precursors which are utilized as starting materials in Method 51 and are ultimately converted to amines 2 wherein R,-RS are defined as above and X equals -(CHZ)i 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 S3); The benzaldehydes, utilized as WO 00/34261 PCTlUS99128916 starting materials in Method 53, can be prepared by diisobutylaluminum hydride reduction of an appropriately substituted benzonitrile. (Method 52) The substituted benzonitriles, utilized as starting materials in Method 52, can be prepared from the corresponding aryl bromide by reaction with copper cyanide in a suitable solvent such as N,N-dimethylformamide at temperatures ranging from room temperatture to the reflux temperature of the solvent. (Method 59) For amines 2, wherein R,-RS is defined as above and X equals either -4{CH,)~NHZ or -S{CH2)~NH" the requisite nitrite 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,-RS are defined as above and X equals -(CH2)3-, the nitrite 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°C to roam temperature. (Method 54) Alternatively, intermediate amines 2 wherein R,-RS are defined as above and X equals -(CH(CH3))- 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 by treatment of an appropriately substituted acetophenone with ammonium formate, formic acid and formamide at temperatures ranging from room temperature to the retlux temperature of the solvent.
Alternatively, amines 2 wherein R,-RS are defined as above and X equals -(CH(CH3))- 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.
Synthea~is 1988, 995. The requisite O-methyl oximes can be prepared from the corresponding acetophenone by reaction with methoxylamine hydrochloride and pyridine in a 5 suitable solvent such as ethanol or methanol at temperatures ranging from room temperature to the reflux temperature of the sc>lvent. (Method 47) Amines 2 for which R,-RS 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 10 ketones, when not commercially available, ca.n 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 t:etrahydrofuran at temperatures ranging from -78 °C to 0°C. (Method 57) The resulting alcohols can be oxidized to the 15 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 Iike at room temperature. (Method 58) The intermediate anilines 5 may be prepared as previously described Method 20 3A. Thus treating phenyl carbamic acid test-butyl ester 6, wherein G is described as above, with neat trifluoroacetic acid at room temperature followed by neutralization with aqueous sodium hydroxide affords the desired anilines 5. The requisite carbamic acid esters 6, wherein R~-R,~ 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 25 above, and 4-aminophenylcarbamic acid tort-butyl esters 7, wherein R9-R,~
are described above, in the presence of triethylamine in an appropriate solvent such as dichloromethane, dimethylsulfoxide, or dimethylformamide or mixturestthereof.
Carboxylic acid chlorides 8 are either commercially available or prepared from the corresponding carboxylic acid by reaction with oxalyl chloride in a suitable solvent 30 such as dichloromethane ar room temperature.

WO 00134261 i'CT/US99I28916 -z6-Method 2C, 3A
O ~ O
_ ~ _ O i. -f O
+ H ' / NI-~-> H ' / NC G ii. NaOH N-C-G
H ~/
H

Alternatively, carbamic acid esters 6, wfierein R9 R,~ and G are described as above, are prepared as shown in Method 2E by reaction of substituted carboxylic 5 acids 8a, wherein G is described as above, and an appropriately substituted aminophenyl carbamic acid tert-butyl esters 7 :in the presence of a suitable coupling agent such as benzotriazole-1-yloxy-tris-(dimethylamino)phasphonium hexa-fluorophosphate, 2-(1H-benzotriazole-1-yloxy)-1,1,3,3-tetramethyluronium hexa-fluorophosphate, dicyclo-hexyl carbodiimide or the like and in the presence of a 10 tertiary amine base such as triethylamine or diisopropylethylamine in a suitable solvent such as dichloromethane, dimethyl:formamide and the like, at room temperature to produce the corresponding aryla~minoamide.
Carboxylic acids 8a are either commercially available or are prepared according to literature methods. For example, when G is a substituted thiadiazole, IS the acid is available from the corresponding carboxylic acid ester by reaction with an appropriate base such as sodium or potassium hydroxide in a suitable solvent mixture such as methanol or ethanol and water at room temperature:
Similarly, when G is either substituted or unsubstituted thiazole, substituted or unsubstituted oxazole, substituted or unsubstituted isothiazole or substituted or 20 unsubstituted isoxazole, when not commercially available, the corresponding carboxylic acid 8a is available from the corresponding ethyl or methyl ester by reaction with an appropriate base such as sodium or potassium hydroxide in a suitable solvent mixture such as methanol or ethanol a:nd water at room temperature.
These esters are either commercially available or ca.n be prepared according to literature 25 methods.

When the carboxylic acid ester precursors which are ultimately converted to acids 8a are not commmercially available, they may be prepared by methods known in the literature. For example, 5-substituted-1,2,3-thiadiazole-4 carboxylic acid esters may be prepared essentially according to the procedure of Caron, M J. erg.
Chem.
51, 4075 ( 1986) and Taber, D. F., Ruckle, R. E. J. Amer. Chem. Soc. 108, 7686 (1986). Thus, according to Methad 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 acetonitxile affords the corresponding diazo-beta-keto 10 carboxylic acid ester. Treatment of this compound with 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide in a suitable solvent such as benzene or toluene or the like at temperatures ranging Pram room temperature to the reflux temperature of the solvent gives the desired 5-substituted-1,2,3-thiadiazole-4-carboxylic acid ester.
I5 Alternatively, 4-substituted-1,2,3-thiadiazole -5-carboxylic acid esters may be prepared essentially according to the procedure of Shafiee, A., Lalezari, L, Yazdani, S., Shahbazian, F. M., Partovi, T. J. Pharmaceutical Sci. 65, 304 (1976).
Thus, according to Method 22 and 23, reaction of am appropriately substituted beta-keto carboxylic acid ester in a suitable alcoholic solvent such as methanol or ethanol with 20 an aqueous solution semicarbazide hydrochloride at temperatures ranging from room temperature to the reflux temperature of the solvent in the presence of a suitable base such as pyridine gives corresponding semicarbazone derivative. Treatment of this compound with neat thionyl chloride at 0°C followed by treatment with an excess aqueous solution of sodium bicarbonate affords the corresponding 4-substituted-25 1,2,3-thiadiazole -5-carboxylic acid esters.
4-carboalkaxythiazoles 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 30 room temperature gives the corresponding 3-dimethylamino-2-isocyano-acrylic acid ethyl ester. A solution of this compound in a suitable solvent such as tetrahydrofuran is treated with gaseous hydrogen sulfide in the presence of a suitable tertiary amine base such as triethylamine or diiso-propylethylamine or the like at room temperature to give the corresponding 4-carboethoxy-thiaz;ole.
Additional appropriately substituted thiazoles may be prepared essentially according to the procedure of Bredenkamp, M. W., Holzafel, C. W., van Zyl, W.
J.
5 Synthetic Comm. 20, 2235 ( 1990). Appropriate unsaturated oxazoles are prepared essentially according to the procedure of Henneke, K. H., Schollkopf, U., Neudecker, T. Liebigs Ann. Chem. 1979 (1979). Substituted oxazoles may be prepared essentially according to the procedures of CJaleotti, N., Montagne, C., Poncet, J., Jouin, P. Tetrahedron Lett. 33, 2807, (1992) and Shin, C., Okumura, K., Ito, A., 10 Nakamura, Y. Chemistry Lett. 1305, (1994).
The following specific examples are illustrative, but are not meant to be limiting of the present invention.
I5 EXAMPLE 1 (METHOD 1A) 4-Methoxy-3-trifiuoromethyt- phenyiamine A suspension of 4-methoxy-3-trifluoromethyl-nitrobenzene {2.2 g) and iron powder (1.68 g) in ethanol (35 mL) and water {15 mL) is treated with a solution of 20 concentrated hydrochloric acid (0.42 mL) in ethanol (6 mL) and water (3 mL) and the mixture is heated to reflux for approximately I hour. The mixture is then cooled, filtered, and concentrated under reduced pressure. The resulting oil is dissolved in ethyl acetate and extracted three times with 5% aqueous hydrochloric acid. The pooled acidic extracts are then cooled in an ice; bath and basified with solid potassium 25 carbonate, then extracted with ethyl acetate. These organic extracts are washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, then passed through a short column of silica gel (ethyl acetate is used as the eluant) to provide the desired compound as an amber oil.
30 Using the above procedure and appropriate starting materials the following compounds were prepared:
2,6-Dichloro-benzene-1,4-diamine 3-Chloro-4-methylsulfanyl-phenylamine WO 00/34261 PCTlUS99/2891b 2,6-Dibromo-benzene-1,4-diamine 3-Chloro-4-trifluoromethyl-phenylamine 3-Chloro-4-ethylsulfanyl-phenylamine 4-Methoxy-3-trifluoromethyi-phenylamine 3,5-Dichloro-4-methoxy-2-methyl-phenylamin.e 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 10 3,5-Dibromo-2,4-dimethoxy-phenylamine 5-Chloro-2-methoxy-4-methyl-phenylamine 2-Chloro-N( 1 ),N( 1 )-dimethyl-benzene-1,4-dia:mine 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 20 N(1)-(1-Benzyl-pyrrolidin-3-yl)-2-chloro-N(1)-methyl-benzene-1,4-diamine 2-Chloro-N( 1 )-cyciopentyl-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-diamime 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-Ben zyl-piperidin-4-yl)-2-chloro-benzene-1,4-diamine 2-Chloro-N(1)-(2-methoxy-ethyl)-N(1)-methyl-benzene-1,4-diamine 2-Chloro-N( 1 )-(3-dimethylamino-propyl)-benzene-1,4-diamine N( 1 )-{ 1-Benzyl-pyrrolidin-3-yl)-2-chloro-benzene-1,4-diamine 3-Chloro-4-( 1-methyl-piperidin-4-yloxy)-phenylamine 3-Chloro-4-(2-dimethylamino-ethoxy)-phenylamine 3-Chloro-4-(3-dimethylamino-propoxy)-pheny:lamine 3-Chloro-4-( 1-methyl-pyrralidin-3-yloxy)-phenylamine 3-Chloro-4-cyclohexyloxy-phenylamine EXAMPLE 2 (ME'THOD 1B) 4-Bromo-2,4-dimethoxy-phenylamine A suspension of 4-bromo-2,4-dimethoxy-nitrobenzene (().48 g) and iron powder (0.42 g) in acetic acid (10 mL} and ethanol (10 mL) is heated to 120 °C
for approximately 5 hours. The mixture is then cooled, filtered, and concentrated under reduced pressure. Water is added and the mixture is cooled in an ice bath and neutralized with solid potassium carbonate and then extracted with dichloromethane.
These organic extracts are washed with saturated aqueous sodium chloride, dried over 15 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 soution of (4-nitro-2,6-dichloro-phenoxy)-acetic acid tert-butyl ester {1 g) in ethanol ( 17 mL) and water (8.6 mL) is treated with iron powder (0.861 g) and ammonium chloride (8b mg) and the mixture i:> heated to reflux for approximately 1 25 hour. The mixture is then filtered and concentrated under reduced pressure.
The resulting oiI 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:

WO 40/342b1 PCT/US99/28916 4-Chloro-benzene-1,2-diamine N-(4-Amino-2-chloro-phenyl)-acetamide (4-Amino-2,6-dichloro-phenoxy)-acetonitrile 5 (4-Amino-2,6-dichloro-phenoxy)-acetic acid test-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 IO 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)-aceta~mide N-(4-Amino-5-chloro-2-hydroxy-phenyl)-2-fluoro-benzamide Furan-2-carboxylic acid (4-amino-2-chloro-phenyl)-amide 15 (~#-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)arnide N-(4-Amino-3-chloro-phenyl)-2-fluoro-benzamide 20 Furan-2-carboxylic acid (4-amino-3-chloro-phenyl)-amide N-(4-Amino-2-chloro-phenyl)-2-dimethylamind-acetamide N-(4-Amino-2-chloro-phenyl)-2-piperidin- I -yl-acetamide N-(4-Amino-2-chloro-phenyl}-2-morpholin-4-yl-acetamide N-(4-Amino-2-chloro-phenyl}-methanesulfona~nide Z5 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-yI-acetamide N-(4-Amino-2-chloro-phenyl)-2-azepan-I-yl-acetamide N-(4-Amino-2-chloro-phenyl)-2-(2-methyl-piperidin-1-yl)-acetamide 3() N-(4-Amino-2-chloro-phenyl)-2-(3-methyl-piperidin-1-yl)-acetamide 3-Chloro-benzene- I,2-diamine 4-Chloro-N,N-dimethyl-benzene- I ,2-diamine WO 00!34261 PCTlUS99/28916 EXAMPLE 4 (ME;THOD 1D) 3,5-Dichloro-4-phenoxy-phenylamine 5 To a slurry of 3,5-dichloro-4-phenoxy-nitrobenzene (6.1 g) and tin powder ( 12 g) is added dropwise concentrated hydrochloric acid (60 mL). Ethanol (60mL) is added and the mixture is heated to reflux for approximately 1 hour. The mixture is then cooled in an ice bath and basified by addition of solid sodium hydroxide. The resulting suspension is filtered through a pad of diatomaceous earth and extracted 10 three times with ethyl acetate. The combined organic extracts are then washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to provide the desired product as a yellow solid.
Recrystallization from ethyl acetate-hexanes provided the product as a pale yellow solid.

Using the above procedure and appropriate starting materials the following compounds were prepared:
1-Furan-2-yl-ethylamine 3-Chl oro-4-isopropoxy-phenylamine 2-Butoxy-5-chloro-4-methoxy-phenylarnine 3,5-Dichloro-2-methoxy-4-methyl-phenyiamine 2-Benzyloxy-5-chloro-4-methoxy-phenylamine 4-Benzyloxy-5-chloro-2-methoxy-phenylamine 5-Fluoro-2,4-dimetlaoxy-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 WO 00/34261 PCT/US99/2891b 4-Amino-2-chloro-5-methoxy-phenol 2-Amino-4-chloro-5-methoxy-phenol 5-Chloro-4-methoxy-2-morpholin-4-yI-phenylannine 4-Chloro-5-methoxy-N( 1 ),N(1 )-dimethyl-benzene-1,2-diamine 5-Chloro-4-methoxy-2-piperidin-1-yl-phenylamime 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-diarni.ne 3-Chloro-4-(2,2,2-trirluoro-ethoxy)-phenylaminc:
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-benzami~de 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 5 To a solution of N-(4-Nitro-phenyl)-isobutyrlamide (2.0 g) in 100 mL
ethylene glycol monomethyl ether ( 100 mL) is added 10% palladium on carbon (275 mg).
The mixture is hydrogenated for 2 hours at room temperature under 30 psi of hydrogen on a Parr hydrogenation apparatus. The catalyst is then removed by 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 v~rhite solid.
Using the above procedure and appropriate starting materials the following compounds were prepared:
2-Methyl-3H-benzoimidazol-5-ylamine N-{4-Amino-phenyl}-formamide 1 H-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]-c:arbamic acid tert-butyl ester N-(5-Amino-pyridin-2-yl)-2,2,2-trifluoro-acetannide (4-Amino-benzyl)-carbamic acid tert-butyl ester 2-(3,5-Bis-trifluoromethyl-phenyl)-ethylamine 1-tert-Butyl-1 H-imidazol-2-ylamine 3-(3-Dimethylamino-propyl)-5-trifluoromethyl-~phenylamine EXAMPLE 6 (METHOD IF) 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° C for I2 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-b-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-dimetho:Ky-phenyl)-amide N-(4-Amino-2-cyano-phenyl)-2-fluoro-benzam~ide Furan-2-carboxylic acid (4-amino-2-methoxy-phenyl)-amide N-(4-Amino-2-methoxy-phenyl)-2-fluoro-benzainide N-(4-Amino-2-methoxy-5-methyl-phenyl)-acet:amide N-(4-Amino-2-benzoyl-phenyl}-acetamide N-(4-Amino-2-benzoyl-phenyl}-2-fluoro-benzaunide 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-benzarnide 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-txifluoromethyl-phenyl)-amide N-(4-Amino-2-methyl-phenyl)-2-fluoro-benzatnide 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-bf:nzamide N-(4-Amino-3-trifluoromethyl-phenyl)-acetamide N-(4-Amino-3-trifluoromethyl-phenyl)-2-fluoro-benzamide N-(4-Amino-2-tritluoromethyl-phenyl)-2,2,2-irifluoro-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-fluo:ro-benzamide EXAMPLE 7 (M>E;THOD IG}
N-(4-Amino-2-chlorophenyl)-2-thiomorpholino-4-yl-acetamide 5 A solution of N-{2-chloro-4-nitrophenyl)-2-thiomorpholino-4-yl-acetamide (3.02 g) in ethanol (200 mL) is added to a solution of sodium thiosulfate (12 g) in water {60 mL). The mixture is heated at reflex for I2 hours, cooled and poured into water.
The mixture is then extracted with ethyl acetate. The ethyl acetate solution is washed twice with saturated aqueous sodium chloride, dried over anhydrous potassium 10 carbonate, filtered through a pad of diatomiaceous 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 15 compounds were prepared:
N-(4-Amino-2-chloro-phenyl)-2-thiomorpholin-4-yl-acetamide N-(4-Amino-2-chloro-phenyl)-2-dipropylamino-acetamide EXAMPLE $ (ME;TH4D 2A) (3-Chloro-4-iodo-phenyl)-carbamic acid tert-butyl ester To a solution of 3-chloro-4-iodo-aniline ( 10 g) in tetrahydrofuran (40 mL) containing diiso-propylethylamine (6.9 mL) is added di-~tert-butyl-dicarbonate (8.6 g) and the mixture is heated to reflux. After approximately i 5 hours additional portions of diisopropylethylamine (6.9 mL) and di-tert-butyl-dicarbonate (21 g) is added and heating is continued for approximately 24 lhours. 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-ChIoro-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-S-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)-c;arbamic acid tert-butyl ester EXAMPLE 9 (ME'THOD 2B) (3-Chloro-4-vinyl-phenyl)-carbamic aciid2-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%a 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]-c:arbamic 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 (I.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)-a~cetamide [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-benzoylarnino)-phenylJ-carbamic acid tert-butyl ester [4-(2-Methoxy-benzoylamino)-phenyl]-carbamic acid tent-butyl ester [4-(3-Methoxy-benzoylamino)-phenyl]-carbarniic acid tert-butyl ester [4-(4-Methoxy-benzoylamino}-phenyl]-carbamiic 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]-carba~mic acid tert-butyl ester (4-Benzoylamino-phenyl)-carbamic acid tert-butyl ester (4-Methanesulfonylamiino-phenyl)-carbami;c acid tert-butyl ester (4-Phenylacetylamino-phenyl)-carbamic acid tert-butyl ester { 4-[(Thiophene-2-carbonyl)-amino]-phenyl }-caxbamic 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]-carbarnate [4-(2-Trifluoromethyl-benzoylamino}-phenyl]-c:arbamic 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 tort-butyl ester [4-(2-Nitro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester {4-[(Benzo[b]thiophene-2-carbonyl)-amino]-phenyl}-carbamic acid tent-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 tent-butyl ester {4-[(3-Bromo-thiophene-2-carbonyl)-amino]-prienyl}-carbamic acid tert-butyl ester {4-[(Biphenyl-2-carbonyl)-amino]-phenyl}-cart>amic acid tert-butyl ester N-(4-tert-Butoxycarbonylamino-phenyl)-phthaIamic 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]-carbarnic acid tart-butyl ester [4-(2,3,4;5,6-Pentafluoro-benzoylamino)-phenyl]-carbamic acid tart-butyl ester N-(4-tart-Butoxycarbonylamino-phenyl)-isophthalamic acid methyl ester 2-Methylsulfanyl-N-[4-(2,2,2-trifluoro-acetylamino)-phenyl]-benzamide [4-(3-Benzyloxy-benzoylamino)-phenyl]-carbamic acid tart-butyl ester [4-(3-Butoxy-benzoylamino)-phenyl]-carbamic acid tart-butyl ester {4-[(5-Difluoromethyl-furan-2-carbonyl)-amino]-phenyl}-carbamic acid tart-butyl ester {4-[(Thiophene-3-carbonyl)-amino]-phenyl }-carbamic acid test-butyl ester {4-[(5-Methyl-furan-2-carbonyl)-amino]-phenyl}-~carbamic acid tart-butyl ester {4-[(5-Bromo-furan-2-carbonyl)-amino]-phenyl}-carbamic acid tcrt-butyl ester (4-Hexanoylarnino-phenyl)-carbamic acid tart-butyl ester [4-{2-Thiophen-2-yl-acetylamino)-phenyl]-carbamic acid tart-butyl ester {4-[(Pyridine-3-carbonyl)-amino]-phenyl}-carbamic acid tent-butyl ester {4-[{4-Bromo-furan-2-carbonyl)-amino]-phenyl}-carbamic acid tart-butyl ester {4-[(Furan-3-carbonyl)-amino]-phenyl}-carbamic acid tent-butyl ester (4-Phenoxycarbonylamino-phenyl)-carbamic acid tart-butyl ester {4-[{Benzo[1,3]dioxole-4-carbonyl)-amino]-phenyl}-carbamic acid tart-butyl ester [4-(3-Trifluoromethoxy-benzoylamino)-phenyl]-carbamic acid tart-butyl ester N-{2,5-Dimethoxy-4-nitro-phenyl)-2-fluoro-benzaanide { 4-[(Furan-2-carbonyl)-amino]-phenyl }-carbamic acid tart-butyl ester [4-(2-Phenoxy-acetylamino)-phenyl]-carbamic acid tart-butyl ester {4-[(5-Nitro-furan-2-carbonyl)-amino]-phenyl}-carbamic acid tart-butyl ester {4-[(5-Chloro-furan-2-carbonyl)-amino]-phenyl}-carbamic acid tart-butyl ester {4-[{3-Methyl-furan-2-carbonyl)-amino]-phenyl}-carbarnic acid tart-butyl ester [4-(2-Methoxy-acetylamino)-phenyl]-carbamic acid tart-butyl ester {4-[(4-Furan-3-yl-[1,2,3]thiadiazole-5-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester {4-[(5-tart-Butyl-furan-2-carbonyl)-amino]-phenyl}-carbamic acid tart-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-vitro-2-trifluoromethyl-phenyl)-acetamide N-(4-Acetylamino-2-trifluoromethyl-phenyl)-2,2,2-tritluoro-acetamide 2-Fluoro-N-[4-(2,2,2-trifluoro-acetylamino)-3-trilluoromethyl-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-benzoylarnino)-2-hydroxy-benzoic acid phenyl ester {4-[{Isoxa~ole-5-carbonyl)-amino]-phenyl}-carbamic acid test-butyl ester N-(4-Acetylamino-2-methoxy-phenyl)-2,2,2-trifluoro-acetamide 2-Fluoro-N-[3-methoxy-4-(2;2,2-trifluoro-acetyiarnino)-phenyl]benzamide 2-Fluoro-N-(2-fluoro-benzoyl)-N-(4-vitro-2-trifluoromethyl-phenyl)benzamide { 4-[( 1 H-Pyrazole-4-carbonyl)-amino]-phenyl }-carbamic acid tert-butyl ester {4-[(1H-Imidazole-4-carbonyl)-amino]-phenyl}-carbarnic 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-vitro-pyridin-2-yl)-acetamide {4-[(1-Methyl-1H-pyrazole-4-carbonyl)-amino]-phenyl}-carbarnic 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-vitro-benzyl)-benzamide Furan-2-carboxylic acid 4-vitro-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-triflutoro-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-vitro-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 acrid tert-butyl ester [4-(4-Dimethylamino-benzoylamino)-phenyl]-carbamic acid tert-butyl ester (4-Benzenesulfonylamino-phenyl)-carbamic acid tent-butyl ester [4-(3-Trifluoromethyl-benzoylamino)-phenyl]-carbamic acid tert-butyl ester 2, 2,2-Trifluoro-N-(5-nitro-pyrimidin-2-yl )-acetanai de 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 haur. The solution is cooled and concentrated under reduced pressure, giving a wept 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)-carbarnic acid ethyl ester 2-Acetylarnino-5-ni;tro-benzoic acid Furan-2-carboxylic acid (5-chloro-2-hydroxy-4-niitro-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-)acryioylamino)-phenyl]carbamic acid tert-butyl ester (4-Nitro-phenyl)-carbamic acid isobutyl ester [1,2,3]Thiadiazole-4-carboxylic acid {S-nitro-pyridin-2-yl)-amide Furan-2-carboxylic acid (5-nitro-pyridin-2-yl)-amide 2-Fluoro-N-(5-vitro-pyridin-2-yl)-benzamide N-(2-Chloro-4-vitro-phenyl)-2-fluoro-benzamide Furan-2-carboxylic acid (2,5-dimethoxy-4-nitra~-phenyl)-amide N-(2-Cyano-4-vitro-phenyl)-2-fluoro-benzamide 2-Fluoro-N-(2-methoxy-4-vitro-phenyl)-benzannide 2-Methyl-N-{5-vitro-pyridin-2-yl)-benzamide Furan-2-carboxylic acid (2-methoxy-5-methyl-~-vitro-phenyl)-amide 2-Fluoro-N-(2-methoxy-5-methyl-4-vitro-phen'/1)-benzamide N-(2-Benzoyl-4-nitra-phenyl)-acetamide N-(2-Benzoyl-4-vitro-phenyl)-2-fluoro-benzamide Furan-2-carboxylic acid (2-benzoyl-4-vitro-phenyl)-amide N-(3-Methyl-4-vitro-phenyl)-acetamide 2-Fluoro-N-(3-methyl-4-vitro-phenyl)-benzamide Furan-2-carboxylic acid (3-methyl-4-vitro-phenyl)-amide 2-Acetylamino-5-vitro-N-phenyl-benzamide 2-[(2-Fluorobenzoyl)aminoJ-5-vitro-N-phenylbenzamide Furan-2-carboxylic acid (4-vitro-2-phenylcarbamoyl-phenyl)-amide 2-Fluoro-N-{4-vitro-naphthalen- I -yi)-benzamide Furan-2-carboxylic acid (4-vitro-naphthalen-i-yl)-amide N-(5-Chloro-2-hydroxy-4-vitro-phenyl)-acetamide N-(5-Chloro-2-hydroxy-4-vitro-phenyl)-2-~luor~a-benzamide Furan-2-carboxylic acid (2-chloro-4-vitro-phenyl)-amide N-(4-Nitro-2-trifluoromethyl-phenyl)-acetarni de Furan-2-carboxylic acid (2-cyano-4-vitro-phenyl)-amide 2-Fluoro-N-(4-vitro-2-trifluaromethyl-phenyl)-benzamide Furan-2-carboxylic acid (4-vitro-2-trifluoromethyl-phenyl)-amide 2-Fluoro-N-(2-methyl-4-vitro-phenyl)-benzamide N-(5-Chloro-2-methyl-4-vitro-phenyl)-2-fluoro-benzamide Furan-2-carboxylic acid (5-chloro-2-methyl-4-vitro-phenyl)-amide 2-(2-Fluoro-benzoylamino)-5-vitro-benzoic acid 2-[(Furan-2-carbonyl)-amino]-5-vitro-benzoic acid N-{3-Chloro-4-vitro-phenyl)-2-fluora-benzamide Furan-2-carboxylic acid (3-chloro-4-nitro-phenyl)-amide 2,6-Difluoro-N-(3-methyl-4-nitro-phenyl)-benzam~ide 2-Fluora-N-(4-nitro-3-trifluoromethyl-phenyl)-benzamide Furan-2-carboxylic acid (4-vitro-3-trifluoromethyl',-phenyl)-amide 2-Chloro-N-(2-chloro-4-vitro-phenyl)-acetamide N-(2-Chloro-4-nitrophenyl)methanesulfonamide Furan-2-carboxylic acid [3-methoxy-4-{2,2,2-tritluoro-acetylamino)-phenyl]-amide N-(2-Chloro-4-vitro-phenyl)-2,2,2-trifluoro-acetarnide {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 (U.8 g) and 4-phenyl-[I,2,3]thiadiazole-5-carboxylic acid (U.7 g) in dichloromethane (lU mL) is treated with triethylamine (1.3 mL) and benzotriazole-1-y:loxy-tris(dimethylarnino)-phosphonium hexa-fluorophosphate (I.6 g). After stirring at room temperature, the lU reaction is diluted with water and extracted with dichloromethane. The organic layer is washed with 0.5 N hydrochloric acid, saturated ;>odium 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 tent-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-IH-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}-carlbamic 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}-car-bamic acid tert-butyl ester {4-[([I,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 [I,2,3]Thiadiazole-4-carboxylic acid 4-nitro-benzylamide {4-[([1,2,3]Thiadiazole-4-carbonyl)-amino]-benz;yl}-carbamic acid tert-butyl ester Acetic acid 4-(4-tert-butoxycarbonylamino-phenylcarbamoyl}-phenyl ester {4-[(Quinoline-b-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 i 5 hours. The solvent is removed under reduced pressure and the residue dissolved in ethyl acetate. This solution is then IO 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.
I5 Using the above procedure and appropriate starting materials the following compounds were prepared:

PhenylsulfanyI-acetonitrile Acetic acid 2-(4-tert-butoxycarbonylamino-2,6-dichloro-phenoxy)-ethyl ester EXAMPLE 14 (MET'HOD 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 retlux for approximately 15 hours. The solution is then coated, 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 dichloramethane 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,S-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)-phenyli 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-benzarnide 3-Acetylamino-N-(4-amino-phenyl)-benzamide N-(4-Amino-phenyl)-3-dimethylamino-benzamide N-(4-Amino-phenyl)-3-methanesulfonylamirto-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 Quinoiine-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)-annide 3,5-Dichloro-4-ethoxy-phenylamine 4-Butoxy-3,5-dichloro-phenylamine Isoquinoline-4-carboxylic acid (4-amino-phenyl)-amide [I,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)-benzaxnide 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-be~nzamide N-(4-Amino-phenyl)-2,3,4-trifluoro-benzamide N-(4-Amino-phenyl)-2,3,4,5,6-pentalluoro-benza,mide N-(4-Amirio-phenyl)-2-methyisulfanyl-benzamide Acetic acid 2-(4-amino-2,6-dichloro-phenoxy)-ethyl ester N-(4-Amino-phenyl)-isophthalamic acid methyl Eater 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 Quirioline-4-carboxylic acid (4-amino-phenyl)-.amide 5-Methyl-furan-2-carboxylic acid (4-amino-phenyl)-amide 5-Difluoromethyl-furan-2-carboxylic acid (4-annino-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-acetamidc:
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-phe:nyl)-amide N-(4-Amino-phenyl)-nicotinamide N-(4-Aminophenyl)-3-furancarboxamide 4-Phenyl-[1,2,3]thiadiazole-5-carboxylic acid (~l-amino-phenyl)-amide Acetic acid 3-(4-amino-phenylcarbamoyl)-phenyl ester Benzo[1,3]dioxoie-4-carboxylic acid (4-amino-phenyl)-amide N-{4-Amino-phenyl)-3-(2-dimethylamino-ethoxy)-benzamide N-(4-Amino-phenyl)-3-trifluoromethoxy-benza:mide 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)-amidle (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 aciid (4-amino-phenyl)-amide S-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-benzamicle 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 Eater 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-trifluorornethyl-benzamide EXAMPLE 16 (METH:OD 3B) 1-(4-Amino-2-chloro-phenyl)-ethanol A 1 M 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-tritluoroacetyl-amino)-phenyl]-2-fluoro-benzamideA(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-rnethanesulfinyl-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-trifluorometh:yl-phenyl)-amide N-{4-Amino-3-methoxy-phenyl)-acetamide N-(4-Amino-3-methoxy-phenyl)-2-fluoro-benzamiide Furan-2-carboxylic acid (4-amino-3-methoxy-phenyl)-amide EXAMPLE 17 (METHOD 4A) 2-Chloro-1-cyclohexyloxy-4-vitro-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-Chtoro-4-vitro-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 silia~a gel {pure ethyl acetate followed by pure methanol is used as the eluants) to provide the desired product as a yellow oil. XXphysdatXX
Using the above procedure and appropriate starting materials the following compounds were prepared:
(2-Chloro-4-vitro-phenyl)-dipropyl-amine 1-(2-Chloro-4-vitro-phenyl)-piperidine 1-(2-Chloro-4-vitro-phenyl)-pyrrolidine (2-Chloro-4-vitro-phenyl)-cyclohexyl-methyl-amine Benzyl-(2-chloro-4-vitro-phenyl)-amine (2-Chloro-4-vitro-phenyl)-methyl-{ 1-methyl-pipe:ridin-4-yl)-amine (2-Chloro-4-vitro-phenyl)-cyclohexyl-ethyl-amine (2-Chloro-4-vitro-phenyl)-cyclohexyl-amine {2-Chloro-4-vitro-phenyl)-methyl-( 1-methyl-pyrr~olidin-3-yl)-amine ( 1-Benzyl-pyrrolidin-3-yl)-{2-chloro-4-vitro-phenyl)-methyl-amine (2-Chloro-4-nitro-phenyl)-cyclopentyl-methyl-amine I-(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- I ,3-diamine ( 1-Benzyl-piperidin-4-yl)-(2-chloro-4-nitro-phenyl)-amine N-(2-Chloro-4-nitro-phenyl)-N',N'-dimethyl-ethane-I,2-diamine N-(2-Chloro-4-nitro-phenyl)-N',N'-dimethyl-propane- I ,3-diarnine (2-Chloro-4-nitro-phenyl)-(2-methoxy-ethyl)-methyl-amine (1-Benzyi-pyrrolidin-3-yl)-(2-chloro-4-nitro-phenyl)-amine 4-Piperidin- I-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 el:hyl 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 IS compounds were prepared:

WO 00/34261 PCTNS99/2$916 1-Butylsulfanyl-2-chloro-4-vitro-benzene 2-Chloro-1-cyclohexylsulfanyl-4-vitro-benzene 2-Chloro-1-ethylsulfanyl-4-vitro-benzene EXAMPLE 20 (MET1HOD 4F) (4-Chloro-5.methoxy-2.nitro-phenyl)-dimethyl-amine To a solution of trifluoro-methanesulfonic acid 4-chloro-5-methoxy-2-vitro-phenyl ester (1.U 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 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 IU once with ethyl acetate and the combined organic layers are washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent is removed by evaporation under reduced pressure; and the residue is triturated with hexanes to provide the desired product as a colorless solid.
15 Using the above procedure and appropriate starting materials the following compounds were prepared:
(4-Chloro-2-vitro-phenyl)-dimethyl-amine 4-(4-Chloro-5-methoxy-2-vitro-phenyl)-morpholine (4-Chloro-5-methoxy-2-vitro-phenyl)-dimethyl-amine 1-(4-Chloro-5-methoxy-2-vitro-phenyl)-piperidine 1-(4-Chloro-5-methoxy-2-nitra-phenyl)-pyrrolidine Benzyl-(4-chloro-5-methoxy-2-vitro-phenyl)-amine (2-Chloro-6-vitro-phenyl)-dimethyl-amine w0 00/34261 PCT/US99128916 EXAMPLE 21 (ME'THOD 4G) (2-Chloro-4-nitro-phenyl)-methyl-phenyl-amine h-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°C.
The mixture is allowed to warm slowly to room temperature and is then re-cooled to 0°C and added by .cannula to a solution of 3-chloro-4-fluoronitrobenzene (4.9 g) in tetrahydrofuran (35 mL) that is kept at -78 °C. Following the addition, the reaction mixture is permitted to warm to room temperature over the course of 7 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 (ME7CHOD 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°C for approximately 15 hours. The resulting dark brown solution is cooled to room temperature, poured onto 100 mL cold water, a~~d 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 (MET'HOD SA) (3,5-Dichtara-4-ethaxy-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 ( 1 f3 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 f:xtracts 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 tent-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 SC}
(2,6-Dichloro-4-vitro-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-vitro-phenyl)-propenone 2-Chloro-1-isopropoxy-4-vitro-benzene 1,3-Dichloro-2-methoxy-4-methyl-5-vitro-benzene 1-Chloro-4-ethoxy-2-methoxy-5-vitro-benzene 1-Butoxy-4-chloro-5-methoxy-2-vitro-benzene 1-Chloro-2-methoxy-5-vitro-4-(phenylmethoxy)benzene (CA name) 1-Chloro-4-methoxy-5-vitro-2-(phenylmethoxy)benzene (CA name) (2,6-Dichloro-4-vitro-phenoxy)-acetic acid tert-butyl ester (2,6-Dichloro-4-vitro-phenoxy)-acetonitrile 1-Chloro-4-methoxy-2-methyl-5-vitro-benzene 2-(4-Chloro-5-methoxy-2-vitro-phenoxy)-acetamide 2-(2-Chloro-5-methoxy-4-vitro-phenoxy)-acetamide (4-Chloro-5-methoxy-2-vitro-phenoxy)-acetonitrile (2-Chloro-5-methoxy-4-vitro-phenoxy)-acetonitrile 4-(2-Chloro-5-methoxy-4-vitro-phenoxy)-butyronitrile 2-(4-Chloro-5-methoxy-2-vitro-phenoxy)-ethanol 2-(2-Chloro-5-methoxy-4-vitro-phenoxy)-ethanol (2-Chloro-5-methoxy-4-vitro-phenoxy)-acetic acid tert-butyl ester (2-Chloro-5-methoxy-4-vitro-phenoxy)-acetic acid methyl ester (4-Chloro-5-methoxy-2-vitro-phenoxy)-acetic acid methyl ester (4-Chloro-5-methoxy-2-vitro-phenoxy)-acetic acid tert-butyl ester (2-Chloro-4-vitro-phenoxy)-acetonitrile 1-Butoxy-2-chloro-4-vitro-benzene 2-Chloro-4-vitro-1-(2,2,2-trifluoro-ethoxy}-benzene 2-Chloro-4-vitro-1-propoxy-benzene 2-Chloro-1-ethoxy-4-vitro-benzene 1, 3-Dii o do-2,4-dimethoxy-5-vitro-benzene 1,3-Dibromo-2,4-dimethoxy-5-vitro-benzene 3-Chloro-2,4-dimethoxy-nitrobenzene EXAMPLE 25 {ME'THOD SE) [3,5-Dichloro-4-(2-hydroxy-ethoxy)-phenyl]-carbamic acid test-butyl ester To a solution of (3,S-dichloro-4-hydroxy-phenya)-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 lhours. 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-vitro-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 [3-(2-Chloro-4-nitro-phenoxy)-propylJ-dimethyl-amine EXAMPLE 27 (METI~OD 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) andl 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 ovex anhydrous magnesium sulfate, the solvent is removed by evaporation under reduced pressure, and the residue is chromatographed over silca gel (I5% acetone in he;xanes is used as the eluant) to provide both the mono- and di-chlorinated products as yellow solids.

WO OOI342b1 PCT/US99I28916 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-Dichioro-3-methyl-b-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 min;ture 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 (METIEIOD 7C) 1-Bromo-2,4-dimethoxy-5-nitro-benzene To a solution of 2,4-dimethoxy-nitrobenzene (0.5~ g) in chloroform (3 mL) is added dropwise a solution of bromine (0.23 g) in chlorojPorm ~(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 (MET'HOD 7D) 2,4-Dibromo-3-methoxy-G-nitro-phenol To a solution of 5-methoxy-2-nitro-phenol (U.25 g) and silver trifluoroacetate (U.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.
I5 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 (METIHOD 7E) 2U 1-Iodo-2,4-dimethoxy-5-vitro-benzene To a solution of 2,4-dimethoxy-nitrobenzene {1.0 g) in glacial acetic acid (3U
mL) is added benzyltrimethylammonium dichloroiodate (1.9U g) and anhydrous zinc chloride (1.U g) and the mixture is stirred at room temperature under an atmosphere 25 of argon. Additional benzyltrimethylammonium dichloroiodate (U.4 g) is added after 5 hours and again after 24 hours. Additional zinc chloride (U.5 g) and glacial acetic acid ( 15 mL) is added after 24 hours. The mixturE; is permitted to stir at room temperature for 3 days and is then filtered, diluted with 5% aqueous sodium bisulfite, and extracted three times with ethyl acetate. These pooled organic extracts are 30 washed successively with 5% aqueous sodium bisulfate, 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 (MET'HOD 7F) S 2,4-Diiodo-3-methaxy-6-nitro-phenol To a solution of 5-methoxy-2-nitro-phenol (0.25 g) in dichloromethane (IS 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 sodfium bisulfite, and saturated aqueous sadium chloride. After drying over anhydrous magnesium sulfate the solvent is removed by evaporation under reduced pressure a.nd the residue is recrystallized from toluene to provide the desired product as yellow needles.
EXAMPLE 33 (MET130D 7G) 1-Fluoro-2,4-dimethoxy-5-nitro-benzene To a solution of 2,4-dimethoxy-nitrobenzene ( 1.0 g) in tetrachloroethane ( 10 mL) is added 3,5-dichloro-1-fluoro-pyridinium triflate (85%, 5.07 g) and the mixture is heated to I20 °C for S 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 (ME;THOD 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-dimethyl-formamide (8 mL) is heated in a sealed tube to f.0 °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 hexanca 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 dichlorornethane ( 15 mL) at 0 °C is added a solution of dimethyldioxirane 00.11 M in acetone, 34 mL) and the mixture is stirred at 0 °C for 1 hour. The solvent is removed under reduced pressure and tree 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 text-butyl ester To a solution of 2-methylsulfanyl-N-[4-(2,2,2-triifluoro-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-acetylami.no)-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 (U.9U
g) in dichloromethane (30 mL) at U °C is added a :>olution of dimethyldioxirane (--U.11 M in acetone, 8U mL) and the mixture is stirred at 0 °C for 1 hour. The solvent is removed under reduced pressure and the residue is dissolved in dichloromethane, washed with saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure gives the desired product as an orange foam.
EXAMPLE 38 (METPTOD 11) 2U 3-Chloro-4-vinyl-phen;ylamine To a deoxygenated solution of 3-chloro-4-iodo-aniline (6.95 g), triphenyl arsine (U.67 g), and tris(dibenzylideneacetone)palladium(U) (U._'iU g) in tetrahydrofuran (12U mL) at 50 °C is added tributylvinyltin (10 g) and the mixture is stirred for approximately 15 hours at 5U °C under an atmosphere of argon. T'he 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 3U organic extracts are then washed with saturated aqueous sodium chloride, dried over WO 00/34261 PCTlUS99/28916 anhydrous magnesium sulfate, and the solvent is removed under reduced pressure.
The resulting residue is chromatographed over sili~.ca gel (hexanes and then I(?% ethyl acetate in hexanes is used as the eluant) to provide the desired product as an amber oil.
S
EXAMPLE 39 (METI OD 12) [3-Chloro-4-(x-hydroxy-ethyl)-phenyl)-carbarnic acid 2-trimethylsilanyl-ethyl ester I0 (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 I S 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 15 hours. The solution is then saturated with sodium chloride and extracted with ethyl acetate. These organic extracts are then washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. Following removal of the solvent under reduced pressure the residue is chromatographed over silica gel (20%
ethyl acetate in hexanes is used as the eluant) to provide the desired product as a white 20 solid.
EXAMPLE 40 (MET~3~OD 13) [3-Chloro-4-(2-hydroxy-ethyl)-phenyl)-carbamic acid tert-butyl ester 25 To a stirring suspension of sodium borohydride (0.45 g) in tetrahydrofuran (13 mL) at 0 °C is added glacial acetic acid (0.75 mL) and the mixture is stirred at 0°C for I
hour. The solution is then warmed to room temperature and (3-chloro-4-vinyl-phenyl)-carbamic acid 2-trimethylsilanyl-ethyl ester ( 1.0 g) is added. The reaction is stirred at room temperature for approximately 15 hours and then heated to rellux for 30 approximately 20 hours. The mixture is then cooled and solutions of 5 N
aqueous sodium hydroxide (0.80 mL) and 30% aqueous hydrogen peroxide (0.56 mL) are added. After stirring for an additional 15 hours the layers are separated, the aqueous 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-phenyl3-carbamic acid 2-trimethylsilanyl-ethyl ester To a solution of [3-chloro-4-( l-hydroxy-ethyl)-phenyl]-carbamic acid 2-trimethyl-silanyl-ethyl ester (1.25 g) in tetrahydrofuran (20 mL) at 0 °C under an atmosphere of argon is added triphenyl-phosphine (2.6 g), hydrazoic acid (approximately 2.5 molar equivalents in dichloromethane, prepared by the method of Fieser and Fieser, Reagents for Organic Synthesia~, 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-ioda-phenyl}-carbamic acid tert-butyl ester {IU.O g) in triethylamine (12U ml) is added 1-dimethylamino-2-propyne {2.82 g}; bis(triphenyl-phosphine)palladium(TT) 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. IU minutes} to 60°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 {8U%

WO 00/34261 PCT/US99I2891b 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-dimethylarnino-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-vitro-phenyl)-prop-2-ynyl]-amine EXAMPLE 43 (ME'THOD 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°C for minutes, the mixture is passed over twenty weight equivalents of basic alumina 15 (Brockmann Grade I, 150 mesh) and the N-oxide is eluted using a solution of 5%
methanol in dichioromethane. All fractions containing the desired amine N-oxide were combined and evaporated to near dryness under reduced pressure. The residue is treated successively three times with small portions of methanol (ca. 50 ml) followed by evaporation to near dryness under reduced pressure, and the volume of 20 the solution is adjusted to 250 mL by addition of methanol. The methanolic solution of the N-oxide is then heated to reflux for approximately I S 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.

-b8-EXAMPLE 44 (METHOD 17) (3-Chloro-4-isoxazol-5-yl-phenyl)-caribamic 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 mI) is treated with hydrazine hydrate (0.25 ml) and the mixture is stirred at room temperature i.'or 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 geI (67% ethyl acetate in hexanes is used as the eiuant) 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-nitroani:Iine (3.80 g) in tetrahydrofuran (5() mL} is added thiomorpholine (10 mL) and the solution allowed to stand for 1 hour.
This reaction mixture is poured into water a pale yE:llow solid is collected and then recrystallized from hot 2-propanol to give a pale yellow crystalline solid.

Using the above procedure and appropriate startling 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)-benzoylaminoJ-phenyl}-carbamic acid tert-butyl ester { 4-[3-(2-Morpholin-4-yl-ethoxy)-benzoylaminoJ-phenyl }-carbamic acid tert-butyl ester N-(2-Chloro-4-vitro-phenyl)-2-dimethylamino-acetamide N-(2-Chloro-4-vitro-phenyl)-2-piperidin-1-yl-acfaamide N-(2-Chloro-4-vitro-phenyl)-2-morpholin-4-yl-acetamide N-{2-Chloro-4-vitro-phenyl)-2-dipropylamino-ac:etamide N-(2-Chloro-4-vitro-phenyl)-2-thiomorpholin-4-:yl-acetamide N-(2-Chloro-4-vitro-phenyl)-2-diethylamino-acetamide N-(2-Chloro-4-vitro-phenyl)-2-pyrrolidin-1-yl-acetamide 2-Azepan-1-yl-N-(2-chloro-4-vitro-phenyl)-acetamide N-(2-Chloro-4-vitro-phenyl)-2-{2-methyl-piperidin-1-yl)-acetamide N-(2-Chloro-4-vitro-phenyl)-2-(3-methyl-piperidin-1-yl)-acetamide N-(2-Chloro-4-vitro-phenyl)-2-(4-methyl-piperidin-1-yl)-acetamide EXAMPLE 47 (ME1'HUD 19B) N-(2-Chloro-4-nitrophenyl)-2-(2-dimethylaminoethylsulfanyl)acetamide To a solution of N-(chloroacetyl)-2-chloro-4-nitnoaniline (3.01 g) in N,N-dimethyl-formamide {100 mL) is added powdered sodium carbonate (6.0 g) and 2-dimethyl-aminoethanethiol hydrochloride (6.0 g). The mixture is stirred for 1 hour at 25° 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.

WO 00/34261 PCTIUS99/289ib 'j0 _ EXAMPLE 48 (MIE:THOD 2U) {4-tert-butoxycarbonylamino-2-chlo~ro-phenyl)-carbamic acid 2 piperidin-1-yl-etlhyl ester S To a suspension of l,l-carbonyl-di-(1,2,4)-triaz;ole (4.0 g) in dichlorornethane (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 lU added to maintain homogeneity. After heating at reflex 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 1 S eluant) to give the desired product as a white fo~un.
EXAMPLE ~49 5-Phenyl-[1,2,3]thiadiazole-4-carboxylic acid methyl ester 20 A solution of ethyl benzoylacetate ( 1.1 g) in acel:anitriIe ( 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 sodium hydroxide. The organic layer is then driE:d over anhydrous magnesium 25 sulfate, filtered and concentrated under reduced pressure to yield a yellow oil. This oil is taken into dichloromethane and filtered through a pad of hydrous magnesium silicate, eluting with dichloromethane to give the partially purified diazoketone as a colorless oil. A sample of the diazoketone from above (1.2 g) is dissolved in toluene {25 mL) and treated with 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-3U 2,4-disulfide (2.8 g) and the reaction is heated to reflex. 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.
S Using the above procedure and appropriate starting materials the following compound was prepared:
S-Phenyl-[1,2,3)thiadiazole-4-carboxylic acid ethyl ester 5-Methyl-[1,2,3)thiadiazole-4-carboxylic acid methyl ester EXAMPLE ~~0 Ethyl benzoylacetate se~micarbazide 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 reflex for 5 minutes, the reaction mixture is cooled to =20 °C overnight. The resulting solid semicarbazone is collected by filtration, washed with water and then diethyl ethf;r 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-trit~luorobutanoate 3-[(Z)-2-(Aminocarbonyl)hydrazono)-3-phenyipropanoic acid ethyl ester 3-[(E)-2-(Aminocarbonyl)hydrazona)-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 °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 5:.
4-Methyl-j1,2,3]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 1 N 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 pre;~sure. 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 WO 00/34261 pCT/US99J28916 EXAMPLE 53 (MET:HOD 25) Triftuoro-methanesulfonic acid 4-chloro-S..methoxy-2-vitro-phenyl ester To a solution of 4-chloro-5-methoxy-2-vitro-phenol (6.5 g) in dichloromethane (150 mL) at 0 °C under an atmosphere of argon is added triethylamine {10 g) and then a solution of trifluoro-methanesulfonic anhydride (13.5 g) in dichloromethane (30 mL).
The solution is stirred at 0 °C for 10 minutes, and is then diluted with dichloromethane and washed successively with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. After dryiing over anhydrous sodium sulfate 1() 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-methox:y-2-vitro-phenyl ester Trifluoro-methanesulfonic acid 4-chloro-2-vitro-phenyl ester Trifluoro-methanesulfonic acid 2-chloro-6-vitro-ph~.enyl 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 {2S0 mg), acetic acid (3 drops} and 40 % aqueous formaldehyde (4 mL) in 1:2 tetrahydrofuran-methanol (15 mL) is stirred for 1S
minutes, and then poured into saturated aqueous ;odium 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-trifiuoramethyl-phenyl}-dimethyl-annine N-(3-Chloro-5-dimethylamino-phenyl)-acetamide EXAMPLE 55 (MET'HOD 27) N-(4-Aminophenyl)-2-hydroxybenzamide To a solution of 2-(4-aminophenylcarbamoyl) phenyl acetate (58U mg) in methanol l U ( 10 mL) is added saturated sodium bicarbonate; (2 mL) and water (3 mL).
The mixture is heated at 80° 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 (MET130D 28) [4-{3-(Hydroxybenzoylamino)phenyl}carbamic acid t-butyl ester 2U To a solution of of 3-(4-aminophenylcarbamoyl) phenyl acetate (4.34 g) in methanol (75 mL) is added U.1 N aqueous sodium hydroxide (25 mL) and tetrahydrofuran (25 mL). This solution is heated at 40° C for 3() 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.

_~5_ EXAMPLE 57 (ME;THOD 29) N-{4-Aminophenyl)-2-hydro:xymethylbenzamide 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 I hour at 25° C.
The mixture is poured into water and extracted unto ethyl acetate. The ethyl acetate solution is dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a white foam, which when tritu~rated with diethyl ether provides the desired product as a white powder.
EXAMPLE 58 (ME'THOD 3(1) (3-Chloro-5-dimethylamino-phenyl)-c;arbamic 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 (ME7l'HOD 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 l:l 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 rnL), extracted into ethyl acetate, and the extracts are dried over anhydrous sodium sulfate. The solvent is removed by evaporation under _76_ reduced pressure and the residue is triturated with diethyl ether to provide the desired product as a white salid.
EXAMPLE 6(1 (ME'THOD 36) S {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 (~
mL) is added 1N 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 (S 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-ch:(oro-S-methoxy-phenoxy }-acetic acid { 4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chlloro-S-methoxy-phenoxy }-acetic acid EXAMPLE 61 (MET'HOD 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,S-dichloro-4-(2-hydroxy-ethaxy)-phenylj-2S thioureido}-phenyl)-acetamide (0.20 g) in pyridine (2 mL) and tetrahydrofuran (O.S
mL) is added benzoyl chloride (0.08 g) and the mixture is stirred at 0 °C for 1.S
hours. The mixture is then diluted with ethyl acetate, washed successively two times WO 00I342b1 PCTNS99/28916 - 77 _ 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 S combined, evaporated under reduced pressure, a.nd the residue is recrystallized from acetone-hexanes to provide the desired product as a white powder.
EXAMPLE 62 (ME'THOD 38) Methanesulfonic acid 2-{4-[3-(4-acetylamina-phenyl)-thioureida]-2,6-dichlaro-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 °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 b3 (MET'HOD 39) N-(4-{3-[3,5-Dichloro-4-(2-dimethylamino-ethoxy)-phenyl)-thioureido}-phenyl) acetamide To a solution of methanesulfonic acid 2-{4-[3-(4-acetylamino-phenyl)-thioureido)-2,6-dichlorophenoxy }-ethyl ester (0.33 g) in tetrahydrofuran (6 mL) is added aqueous dimethyl-amine (8.8 M, 0.5 mL) and the mixture is stirred at room temperature for S 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 _7g.
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 S compounds were prepared:
N-(4- { 3-[3,S-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 (MET'HUD 40) Furan-2-carboxylic acid (4-{3-(4-(1-amino-ethyl)-3-chloro-phenyl)»thioureido}-phenyl)-amide To a solution of tin(II) chloride dehydrate (U.25 g) in methanol (2.S mL) is added furan-2-carboxylic acid {4-{3-[4-(I-azido-ethyl)-3-chloro-phenyl)-thioureido}-phenyl)-amide (U.22 g) and the solution is stirred for approximately 1 S hours at room 1S 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 dichloro-methane containing 1% triethylamine is used as the eluant) 2U to provide the desired product as a yellow solid.
EXAMPLE 65 (METIHOD 41) (i,2,3)Thiadiazole-4-carboxylic acid (4-isothiocyanato-phenyl)-amide 2S To a ice cooled solution of 1,1'-thiocarbonyldiimidazole (7.28 g) in tetrahydrofuran (SU mL) is added [1,2,3]-thiadiazole-4-carboxylic acid (4-amino-phenyl) amide (9.f1 g) in tetrahydrofuran (IUU 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 startinl3 materials the following compounds were prepared:
2-Fluoro-N-(4-isothiocyanato-phenyl)-benzamide Furan-2-carboxylic acid (4-isothiocyanato-phenyl)-amide [I,2,3]Thiadiazole-4-carboxylic acid (4-isothiocya;nato-phenyl)-amide Thiazole-4-carboxylic acid (4-isothiocyanato-phenyl}-amide IO EXAMPLE 66 (METI~f4D 42) N,N-Dimethyl-5-triflnoromethyt-benzene-1,3-diamine To a solution of 3-amino-5-bromo-benzotr~ifluoride (1.0 g) in degassed (argon) tetrahydrofuran (2 mL) is added bis-(tri-o-tolylphosphino)palladium (0.15 g), a I S solution of dimethylamine in tetra-hydrofuran (:ZM, 4.2 mL), and a solution of lithium bis(trimethylsilyl)amide in. tetrahydrofuran (1M, 10.4 mL). The reaction mixture is heated in a sealed vessel to 100°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%
20 aqueous hydrochloric acid, and pooled acidic extracts are then basified with cooling by addition of SN 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 aver anhydrous malznesium sulfate, and evaporated to dryness under reduced pressure. The resulting residlue is chromatographed over silica 25 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:

WO OOI342b1 PCT/US99128916 _ 8p _ 3-(4-Methyl-piperazin-1-yl)-5-trifluoromethyl-~phenylamine 3-Morpholin-4-yl-5-trifluoromethyl-phenylamine 3-Piperidin-1-yl-5-trifIuoromethyl-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-trifluaromethyl-benzene-1,3-diamine EXAMPLE 67 (ME'THOD 43) (3-Isobutyl-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester To a sealed tube containing tetrahydrofuran (5 mL) that is capped with a rubber septum and cooled in a dry ice-acetone bath is bubbled isobutylene for about 5 minutes. A solution of 9-borabicyclo[3.3.1]non,ane in tetrahydrofuran {0:5 M, 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 te:flon cap is replaced by a rubber septum, and argon is bubbled through the mixture with venting to removed the excess isobutylene. A soIutian 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-dichiormethane complex {0.12 g), and then 3N aqueous sodium hydroxide. The; vessel is again sealed with the teflon cap and is then heated to 65°C for approximately 15 hours. The mixture is 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)-S-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (3-Isobutyl-5-trifluoromethyl-phenyl}-carbamic acid tent-butyl ester EXAMPLE b$ (MET'HOD 44}
2-(3,5-Dichloro-phenylsulfany!)-ethylamine To a solution of (3,5-dichlorophenylthio}acetonitrile (1.2g) in 3.0 mL of ethylene glycol dimethyl ether is added 0.61 mL of IOM 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 SN
sodium hydroxide and extracted with ether. The ether extract is dried over potassium carbonate, filtered and concentrated to give I.Og 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 S A mixture of 2-acetylnaphthylene (3.0 g), ammonium formate (11.0 g), formic acid (3.3 mL), and formamide (3.S mL) is heated at 190°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 ccmcentrated 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-{ I -Naphthalen-2-yl-ethyl)-formamide i S EXAMPLE 70 (ME'THOD 46) 1-(2-Naphthyl)ethylamine A mixture of N-{ 1-naphthalen-2-yl-ethyl}-formamide ( 1.12 g), ethanol { 10 mL) and S
N sodium hydroxide (10 mL} is heated at ret7ux 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 2S compounds were prepared:
I-(3-Trifluoromethyl-phenyl}-ethylamine 1-(4-Fluoro-phenyl)-2-methyl-propylamine [3-(1-Amino-ethyl)-phenyl]-dimethyl-amine 3-(1-Amino-ethyl)-benzonitrile WO 00/34261 PCTlUS99/28916 EXAMPLE 71 (METHOD 47) 1-{3-Trifluoromethyl-phenyl)-ethanone O-methyl-oxime 5 Methoxylamine hydrochloride (2.33 g) is added to a solution of 3'-(tritluoromethyl)-acetaphenone (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 10 saturated aqueous sodium chloride, dried over <~nhydrous magnesium sulfate and concentrated under reduced pressure to give the desired product as a colorless oil (1.6I g).
Using the above procedure and appropriate starting materials the following 15 compounds were prepared:
3,5-Bis-trifluoromethyl-benzaldehyde oxime I-{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 I-p-Tolyl-ethanone O-methyl-oxime I-(4-Fluoro-phenyl)-pentan-I-one O-methyl-oxi.me I-(4-Fluoro-phenyl)-2-phenyl-ethanone O-methyl-oxime 1-o-Tolyl-ethanone O-methyl-oxime I-m-Tolyl-ethanone O-methyl-oxime 1-(2-Fluoro-phenyl)-ethanone O-methyl-oxime 3-{ 1-Methoxyimino-ethyl)-benzonitrile 4-( I -Methaxyimino-ethyl)-benzonitrile l-(4-Methoxy-phenyl)-ethanone O-methyl-axime 1-{2-Methoxy-phenyl)-ethanone O-methyl-oxime 1-(4-Dimethylamino-phenyl)-ethanone O-methyl!-oxime 1-(2-Trifluoromethyl-phenyl)-ethanone O-methyl--axime 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-yI-ethanone O-methyl-oxime 1-(1-Methyl-1H-pyrrol-2-yl)-ethanone O-methyl-oxime l-Thiophen-3-yl-ethanone O-methyl-oxime (4-Fluoro-phenyl)-phenyl-methanone O-methyl-oxime 1-(4-rnethoxyphenyl)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-( I -Methaxyimino-ethyl)-N,N-dipropyl-benzenesulfonamide 2-Fluoro-N-[4-( 1-methoxyimino-ethyl)-phenyl]-benzamide 1-(3,5-Bis-trifluoromethyl-phenyl)-ethanone O-methyl-oxime 1-[4-(1H-Imidazol-1-yl)phenyl]-1-ethanone, O-methyloxime 1-[4-(Trifluoromethyl)phenyl]-1-ethanone, O-meth:yloxime 1-[1,1'-Biphenyl]-4-yl-1-ethanone, O-methyloxime 1-(4-Methylphenyl)-1-ethanone, O-methyloxime 1-[4-fluoro-3-(trif~uoromethyl)phenyl]ethanone O-methyloxime 1-[3,5-bis(trifluoromethyl)phenyl)ethanone O-benzyloxime 1-[4-chloro-3-(trifluoromethyl)phenyl]ethanone O-rnethyloxime 1-[3-fluoro-5-(trifluoromethyi)phenyl]ethanone O-methyloxime 1-[2-tluoro-4-(trifluoromethyl)phenyi)ethanone O-methyloxime i-[2-fluoro-5-(trifluoromethyl)phenyl]ethanone O-methyloxime 1-(2,4-dichlorophenyl)efhanone 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 _8S_ 1-[4-(4-morpholinyl}phenyl]ethanone O-methyloxime 1-(2-chloro-4-fluorophenyl)ethanone O-methyloxime I-(4-bromo-2-fluorophenyl}ethanone O-methyloxime 1-(3,4-difluorophenyl)ethanone O-methyloxime I-[3-(trifluoromethyl)phenyl]ethanone O-methyloxime 1-[2-(trifluoromethyl)phenyl]ethanone O-methyloxime 1-(2,4-difluorophenyl)ethanone O-methyloxime 1-[3-tluoro-4-(trifluoromethyl)phenyl]ethanone O-methyloxime 1-{3,4-dichlorophenyl)ethanone O-methyloxime I-~4-fluoro-2-(trifluoromethyl)phenylJethanonc~ O-rnethyloxime I-(3-chloro-4-fluorophenyl}ethanone O-methyloxime 1-(4-chloro-3-fluorophenyl)ethanone O-methyloxime 1-(2;5-difluorophenyl)ethanone O-rnethyloximc~
1-(2-bromo-4-fluorophenyl)ethanone O-methyloxime 1-(3,4-dibromophenyl)ethanone O-methyloxime I-(2-bromophenyl)ethanone O-methyIoxime EXAMPLE 72 (METHOD 48) 1-(2-Trifluoromethyl-phenyl)-ethylamine Sodium borohydride (1.17 g) is added slowly to a flask containing zirconium tetrachloride (I.8 g) in tetrahydrofuran (27 mL). A solution of I-(2-trifluoromethyl-phenyl)-ethanone O-methyl-oxime (1.34 g) in tEarahydrofuran (7.7 mL) is added and the resulting solution is stirred at 25 °C far i2 hours. The reaction mixture is then cooled to 0 °C and water ( 16 mL) is slowly added. Excess ammonium hydroxide is added and the solution is extracted twice with f~thyl acetate. The organic portion is washed twice with 1N hydrochloric acid. The aqueous (acid) layer is basified with sodium hydroxide and extracted twice with ethyl acetate. The organic layer is then washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is removed under reduced pressure to provide the desired I S product as a yellow oil (0.20 .g).

ss -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-( L-Amino-ethyl)-benzonitrile 1-(4-Tri#luoromethyl-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 o:r 1-[3,5-bis(trifluoromethyl)-phenyl)butylarnine 1-[3,5-bis(trifluoromethyl)phenyl)-1-pentanamine 1-(4-methylphenyl)ethanamine 1-[3-(trifluoromethyl)phenyl)ethylamine 1-[4-(tri#luoromethyl)phenyl]ethylamine 1-(3-methylphenyl)ethanamine 1-(3,4-dichlorophenyl)ethanamine WO 00!34261 PCT/US99128916 _g7_ 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 I-{3,5-Bis-trifluoromethyl-phenyl)-ethylamine 4-[( 1 S)-1-aminoethyl] benzonitrile (S}-alpha-Methyl-3,5-bis(triouoromethyl}-benzenemethanamine(S)-alpha-Methyl-3,5-bis(trifluoromethyl)-benzenemethanamine 1-Biphenyl-4-yl-ethylamine 1-(4-Fluoro-phenyl)-ethylamine 1-[4-fluoro-3-{trifluoromethyl)phenyl]ethanamine 1-[4-chloro-3-(trifluoromethyl)phenyl]ethanamine N-{ 4-[( 1 R)-1-aminoethyl]phenyl }-1,2,3-thiadiazole-4-carboxamide N-{4-[(1 S)-1-aminoethyl]phenyl }-1,2,3-thiadiazole-4-carboxamide 1-[3-fluoro-5-(trifluoromethyl)phenyl]ethylamine 1-[2-fluoro-4-(trifluoromethyI)phenyl]ethylarnine 1-[2-fluoro-5-(trifluoromethyl)phenyl]ethylamine I-(2,4-dichlorophenyl)ethylamine 1-(2,4-dimethylphenyl)ethylamine 1-[2,4-bis(trifluoromethyl)phenyl]ethylamine I-(2-chloro-4-fluorophenyl)ethylarnine 1-(3,4-difluorophenyl)ethylamine 1-(4-bromo-2-fluorophenyl)ethylamine 1-{3-fluorophenyl)ethylamine 1-(2,4-difluorophenyl)ethylamine 1-[3-fluoro-4-(trifluoromethyl}phenyl]ethylamine:
1-[4-t~uoro-2-(trifluoromethyl)phenyl]ethylamine 1-(3-chloro-4-fluorophenyl)ethylamine 1-(4-chloro-3-fluorophenyl)ethylamine _ 88 -1-{3,4-dibromophenyl)ethylamine 1-(2-bromo-4-t7uorophenyl)ethanaminel-(2-bromo-4-tluorophenyl)ethylamine EXAMPLE 73 (ME'THOD 49) (2-Fluoro-5-trifluoromethyl-phenoxy)-acetonitrile S A solution of 2-fiuoro-5-trifluoromeihylphenol {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 (lt) mL). The heterogenous mixture is stirred vigorously for approximately 20 hours whereupon it is poured into water and extracted inta 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-DichIoro-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}-acetonitriie (4-Bromo-phenoxy)-acetonitrile -$9-EXAMPLE 74 (MEZ'HUD 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 4U psi, using 2UU mg l U%
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 fluoro-5-trilluoromethylphenethylamine crystallizes. The white crystals, 4.2bg (91%j lU 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-Tritluoromethyl-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-trifluoromethyi-phenyl)-ethylamine EXAMPLE 75 (METH(fD SI) (4-Aminomethyl-2-trifluoromethyl-phenyl)-dimethyl-amine A solution of 4-dimethylamino-3-trifluoromethylbenzonitrile (U.35 g) in 2U tetrahydrofuran {2 mL) is slowly added to a suspension of lithium aluminum hydride (U.1 g) in tetrahydrofuran (2 mL) at 0 °C and stirred under an atmosphere of argon for 2 hours. While at U °C water (U.l mL) is slowly added followed by 5% sodium hydroxide (U.1 mL) and water (U.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 1M solution in methylene chloride) is added dropwise to a solution of 3-dimethylamino-5-trifluoromethylbenzonitrile ( 1.06 g) in methylene chloride (25 mL) at 0 °C and the; mixture stirred for 2 hours. While still at 0 °C a saturated aqueous solution of sodium potassium tartrate (8 mL) is slowly added and the solution is stirred for 1.5 hours. The reaction mixture is then 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 WO 00!34261 EXAMPLE 77 (M:ETHOD 53) Dimethyl-[3-(2-vitro-vinyl)-5-trifluoromethyl-phenyl)-amine Nitromethane (0.473 g) is added to a solution of 3-dimethy!amino-5-trifluoromethyl-benzaldehyde (0.885 g) and ammonium acetate (0.339 g) in acetic acid (3.4 mL) and the solution is heated at I10 °C for 6 hours. 'rhe reaction mixture is cooled to 0 °C
and a solid forms which is filtered and washed with 1:1 water-acetic acid.
This solid is recrystallized from ethanol to provide the desired product as a red solid (0.39 g).
Using the above procedure and appropriate starting materials the following compounds were prepared:
DimethyI-[3-(2-vitro-vinyl)-5-trifluoromethyl-phenyl]-amine Dimethyl-[2-methyl-4-(2-vitro-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 triphenyIphosphine (7.9 g) in diethyl ether (I6 mL) at 0 °C. The reaction mixture is stirred for 10 minutes and a solution of acetone cyanohydrin (2.6 g) in diethyl ether (IO mL) is added. The clear orange solution is stirred for 5 minutes at 0 °C and then at 25 °C for 12 hours.
The reaction mixture is then filtered, and washed with diethyl ether. The filtrate is concentrated under 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.(?4 g).

EXAMPLE 79 (ME'THOD 55) 3-Dimethylamino-2-isocyano-acrylic acid ethyl ester To a solution of ethyl isocyanoacetate (5.() g) in ethanol {1()0 mL) is added N,N-dimethyl-formamide dimethyl acetal (6.5 g) dropwise with stirring over 1() minutes.
The reaction is stirred for 24 hours and the ethanol is evaporated. The resulting oil is passed through magnesium silicate using SQ% etlhyl 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.() g.
1 () EXAMPLE $0 (MET'HOD 56) 4-Carboethoxythiiazole A solution of 3-dimethylamino-2-isocyano-acrylic acid ethyl ester (l.() g) and triethylamine (3.0 g) in tetrahydrofuran (3() mL) is treated with gaseous hydrogen sulfide until all starting material is consumed. The mixture is concentrated to an oiI
and purified by column chromatography using silica and 25% ethyl acetate-hexanes as the eluant. The purified material (U.bl g} is isolated as an oil.
2U EXAMPLE 8i (METHOD 34) N-{4-[3-(5-Chloro-2;4-dimethoxy-phenyl)-ureido~-phenyl}-2-tluoro-benzamide A suspension of N-(4-amino-phenyl)-2-fluoro-benzamide (().43 g) in acetonitrile (4 mL) is treated with 5-chloro-2,4-dimethoxyphenylisocyanate (().4(> g}. The mixture becomes a solution and is allowed to stand far 12 hours. A white solid forms and is collected by filtration (U.79 g). [M+H]. 444.
Using the above procedure and appropriate starting materials the following 3() compounds were prepared:

Ex M+H COMPOUND NAME
NO.
$1 445 N-{4-[3-(S-Chloro-2,4-dimethoxy-phenyl)-ureidol-phenyl}-2-fluoro-benzamide 82 441 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-ureido]-phenyl}-2-rnethyl-benzamide 83 43S [I,2,3]Thiadiazole-4-carboxylic acid {4G-[3-(S-chloro-2,4-dimetboxy-phenyl)-ureido]-phenyl}-amide 84 443 [1,2,31Thiadiazole-4-carboxylic acid {4~-[3-(4-chloro-3-trifluoromethyl-phenyl)-ureido]-phenyl} amide 85 4S3 N-{4-[3-(4-Chloro-3-trifluoromethyl-phenyl)-ureidoj-phenyl}-2-fluoro-benzamide $6 4U9 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,S-dichloro-phenyl)-ureido]-phenyl }-amide 87 486 N-{4-[3-(3,5-Bis-trifluoromethyl-phenylf)-ureido]-phenyl}-2-lluoro-benzamide $8 458 Fin-2-carboxylic acid {4-[3-(3,5-bis-txifluoromethyl-phenyl)-ureido]-phenyl }-amide 89 476 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl-phenyl)-ureido]-phenyl }-amide 9U 423 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,4-dichloro-benzyl)-ureido]-phenyl }-amide EXAMPLE 91 (METH~DD 31) [1,2,3]-Thiadiazole-4-Carboxylic Acid {4-[3(3,5-bis-trifluoromethylphenyl) thioureido]-phenyl) amide To a solution of [1,2,3]-thiadiazole-4-carboxylic acid {4-amino-phenyl) amide (2.0 g) in acetonitrile (50 mL) is added 1-isothiocyanato-3,S-bis-trifluoramethyl-benzene (2.S g) in acetanitrile (S() mL) drapwise but rapidly and the reaction is stirred at room temperature. After ninety minutes, the solvent is rernoved under reduced pressure and the resulting brown salid is recrystallized from Ethyl acetate/hexanes to give the pure product. [M+H] 492.
Using the above procedure and appropriate starting materials the following compounds were prepared:

EX. M+H COMPOUND NAME
NO.
92 506 [3-Chloro-5-(3-{4-[([I,2,3)thiadiazole-4-carbonyl)-amino]-phenyl}-thioureido)-phenyl]-carbamic acid ten-butyl ester 93 409 1-(5-Chloro-2,4-dimethoxy-phenyl)-3-(4-morpholin-4-yl-phenyl)-thiourea 94 370 1-(S-Chloro-2,4-dimethoxy-phenyl)-3-(4-methylsulfanyl-phenyl)-thiourea 95 338 1-(S-Chloro-2,4-dimethoxy-phenyl)-3-p-tolyl-thiourea 96 414 {4-j3-(S-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenylsulfanyl}-acetic acid 97 384 1-(S-Chloro-2,4-dimethoxy-phenyl)-3-j4-(2-hydroxy-ethoxy)-phenyl)-thiourea 98 340 1-(S-Chloro-2,4-dimethoxy-phenyll)-3-(4-hydroxy-phenyl)-thiourea 99 39S N-{4-j3-(S-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-N-methyl-acetamide 1U0 381 N-{3-[3-(S-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-acetamide 101 41'1 {4-E3-(S-Chloro-2,4-dimethoxy-phenyl)-thiaureido)-phenyl}-carbamic acid ethyl ester 102 319 1-(2,4-Dimethoxy-phenyl)-3-(4-methoxy-phenyl)-thiourea 103 346 N-{4-[3-(2,4-Dimethoxy-phenyl)-thioureido]-phenyl}-acetamide 104 316 N-{4-(3-(4-Methoxy-phenyl)-thioureido]-phenyl}-acetamide 10S 316 N-{4-[3-(2-Methoxy-phenyl)-thiom~eido]-phenyl}-acetamide 106 351 N-{4-j3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl}-acetamide 107 351 N-{4-[3-(S-Chloro-2-methoxy-phenyl)-thioureido)-phenyl}-acetamide 108 371 N-{4-[3-(3,5-Dichloro-4-hydroxy-p;henyl)-thioureido]-phenyl}-acetamide 109 385 N-{4-[3-(3,S-Dichloro-4-methoxy-phenyl)-thioureido]-phenyl}-acetarnide 110 381 N-{4-[3-(4-Chlora-2,S-dimethoxy-phenyl)-thioureido]-phenyl}-acetamide 111 389 N-{4-j3-(2-Chloro-S-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-j3-(S-Chloro-2,4-dimethoxy-phenyl)-ihioureido]-phenyl}-2-methyl-benzamide 11 S SOI Acetic acid 2-{4-[3-(S-chloro-2,4-dimethoxy-phenyl)-thioureido)-phenyl-carbamoyl}-phenyl ester 116 461 N-{4-[3-(5-Chloro-2;4-dimethoxy-phenyl)-Ehioureido]-phenyl}-4-fluoro-benzamide I17 461 N-{4-[3-(5-Chloro-2,4-dimethox;y-phenyl)-thioureido]-phenyl}-3-fluoro-benzamide 118 461 N-{4-[3-(5-Chloro-2,4-dimethox;r-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 I23 417 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-methanesuifonamide 124 331 N-{4-[3-(3-Nitro-phenyl)-thioureido]-phenyl}-acetamide 125 339 1-(3-Chloro-4-rriethoxy-phenyl)-3-(3-vitro-phenyl)-thiourea 126 337 N-{4-[3-(5-Chloro-2-hydroxy-phenyl)-thioureido]-phenyl}-acetamide I27 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)-ihioureido]-phenyl}-acetamide 129 385 N-{4-[3-(3,5-Dichloro-4-hydroxy-:>-methyl-phenyl)-thioureido]-phenyl}-acetamide 130 318 N-{4-[3-(2,4-Dihydroxy-phenyl)-tfiioureidoJ-phenyl}-acetamide I31 414 N-{4-[3-(2,4-Dimethoxy-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-acetamide I32 332 N-{4-[3-(2-Hydroxy-4-methoxy-phenyl)-thioureido]-phenyl}-acetamide 133 465 N-{4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]-h l fl p eny }--ooro-benzamide 134 5p() 3-Acetylamino-N-{4-[3-(~-chloro-Z:,4-dimethoxy-phenyl)-thioureido]-phenyl}-benzamide 135 48$ N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3-vitro-benzamide I36 486 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido)-phenyl}-3-dimethylamino-WO 00/34261 PCT/US99/2$916 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 I42 522 2-Bromo-N-{4-[3-(5-chtoro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-benzamide 143 4$8 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-nitro-benzamide I44 445 Pyrazine-2-carboxylic acid {4-(3-(a-chloro-2,4-dimethoxy-phenyl)-thioureido)-phenyl }-amide 145 463 ~-Methyl-thiophene-2-carboxylic acid {4-(3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-amide 146 494 Quinoline-8-carboxylic acid {4-(3-(5-chloro-2,4-dirnethoxy-phenyt)-thioureido]-phenyl }-amide 147 446 I-Methyl-IH-pyrrole-2-carboxylic;acid {4-[3-(~-c111oro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-amide I4$ 369 1-(5-Chloro-2,4-dimethoxy-phenyl)-3-(2-nitro-phenyl)-thiourea 149 369 1-(5-Chloro-2,4-dimethoxy-phenyt)-3-(4-nitro-phenyl)-thiourea I50 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 I53 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-[~-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-amide _97_ 1S7 493 Naphthalene-1-carhoxylic acid {4-[3-(S-chloro-2,4-dimethoxy-phenyl)-thioureida]- phenyl }-amide 1S8 494 Isoquinoline-1-carboxylic acid {4-[3-(S-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-amide 1 S9 494 Quinoline-2-carboxylic acid {4-[3-(S-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-amide 160 444 N-f4-(3-(S-Chloro-2,4.dimethoxy-phenyl)-thioureido]-phenyl}-nicotinamide 161 478 S-Nitro-furan-2-carboxylic acid {4-[3-(S-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amidecarbamic acid phenyl ester 162 4S9 {4-(3-(S-Chloro-2,4-dimethoxy-pJhenyl)-thioureido]-phenyl}-163 467 S-Chloro-furan-2-carboxylic acid {4-(3-(S-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-amide 164 439 {4-[3-(S-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-carbamic acid isobutyl ester I6S 397 {4-[3-(S-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-carbamic acid methyl ester 166 433 Furan-3-carboxylic acid {4-(3-(S-c:hloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-amide l f 7 447 3-Methyl-furan-2-carboxylic acid {4-(3-(5-chioro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-amide 168 S I S-Bromo-furan-2-carboxylic acid {4-[3-(S-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-amide 169 S I 4-Bromo-furan-2-carboxylic acid {4-[3-(S-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-amide 170 433 Furan-2-carboxylic acid {4-(3-(S-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-amide 171 467 {4-[3-(S-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-carbamic acid hexyl ester 172 494 Isoquinoline-4-carboxylic acid {4-(3-(S-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-amide 173 4S1 (1,2,3]Thiadiazole-4-carboxylic aciid {4-(3-(S-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-amide I74 434 1H-(1,2,3]Triazole-4-carboxylic acid {4-(3-(S-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-amide 17S S28 3-Bromo-thiophene-2-carboxylic acid {4-[3-(S-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-amide 176 399 N-{4-(3-(3,S-Dichloro-4-ethoxy-phenyl)-thioureido]-phenyl}-acetamide 177 427 N-{4-[3-(4-Butoxy-3,S-dichloro-phe;nyl)-thioureido]-phenyl}-acetamide 178 461 N-{4-[3-(4-Benzyloxy-3.S-dichloro-phenyl)-.
thioureido]-phenyl}-acetamide 179 381 N-{4-(3-(3-Chloro-2,4-dimethoxy-p:henyl)-thioureido]-phenyl}-acetaanide 180 S30 (3-{4-[3-(S-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenylcasbamoyl}-phenyl)-carbamic acid ethyl ester 18I 4S8 2-Amino-N-{4-[3-(S-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-benzamide 182 S 19 Biphenyl-2-carboxylic acid {4-(3-(S..chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-amide 183 469 1-(S-Chloro-2,4-dimethoxy-phenyl)-:3-[4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-phenyl]-thiourea 184 487 N-{4-[3-(S-Chloro-2.4-dimethoxy-phenyl)-thioureido]-phenyl}-phthalamic acid 185 473 N-{4-[3-(S-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-hydroxy-methyl-benzamide 186 479 N-{4-[3-(S-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2,3-difluoro-benzamide 187 479 N-{4-(3-(S-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2,S- .
difluoro-benzamide 188 479 N-{4-[3-(S-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2,4-difluoro-benzamide 189 S00 2-Acetylaunino-N-{4-[3-(S-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-benzamide 190 441 1-(S-Chloro-2,4-dimethoxy-phenyl)-3-(6-oxo-S,6-dihydro-phenanthridin-2-yl)-thiourea 191 S36 N-{4-(3-(S-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-methane-sulfonylamino-benaamide 192 497 N-{4-[3-(S-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2,3,4-trifluoro-benzamide 193 S33 N-{4-[3-(S-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2,3,4,5,6-pentalluoro-benzamide 194 4$9 N-{4-[3-(S-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-methyl-sulfanyl-benzaunide 195 431 S-Methyl-furan-2-carboxylic acid {4-[3-(S-chlaro-2,4-dimethoxy-phenyl)-ureido]-phenyl }-amide 196 467 S-Difluoromethyl-furan-2-carboxylic acid {4-[3-(S-chloro-2,4-dimethoxy-phenyl)-ureidd]-phenyl }-amide 197 472 N-{4-[3-(S-Iodo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-acetamide WO 00134261 PCT/US99/2891b 198 364 N-{4-[3-(5-Fluoro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-acetamide 199 365 N-{4-j3-(5-Chloro-2-methoxy-4-methyl-phenyl)-thioureido]-phenyl}-acetamide 200 459 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-chloro-3-triiluoromethyl-phenyl)-thioureido]-phenyl }-amide 201 455 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-{3,5-dichloro-4-methoxy-phenyl)-thioureido]-phenyl.}-amide 202 392 N-{4-[3-(3-Chloro-4-diethylamino-phenyl)-thioureido]-phenyl}-acetamide 203 432 N-(4-{3-[3-Chloro-4-(cyclohexyl-methyl-amino)-phenyl]-thioureido}-phenyl)-acetamide 204 506 1-Hydroxy-naphthalene-2-carboxylic acid {4-[3-(4-acetyiamino-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-morphoIin-4-yl-phenyl)-thiourea 207 372 1-(5-Chloro-2,4-dirnethoxy-phenyl)-3-{5-chloro-2-methyl-phenyl)-thiourea 208 501 N-{4-[3-(5-Chloro-2,4-dimethoxy..phenyl)-thioureido]-phenyl}-isophthalaunic 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 21 i 434 N-{4-{3-[5-Chloro-2-methoxy-4-(4G-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-elhoxy)-4-methoxy-phenyl]-thioureido}-phenyl)-aicetamide 215 411 N-(4-{3-j5-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 ten-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-sullinyl-benzamide 221 545 (3-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureidoJ-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-(:i-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-amide 225 494 Quinoline-4-carboxylic acid {4-(3-(5-chioro-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)-thioureida]-phenyl }-acetamide 230 405 [1,2,3jThiadia2ole-4-carboxylic acid {4-[3-(3-chloro-4-methyl-phenyl)-thioureidoj-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)-thioureidoj-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;l-thioureido]-phenyl }-2,6-dilluoro-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-(cyclohexylamethyl-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-~rl-phenyl)-thioureido]-phenyl}-acetamide 243 419 N-(4-{3-[3-Chloro-4.-(4-methyl-pi~~erazin-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-clzloro-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-chlorcr2,4-dimethoxy-phenyl)-thioureido]-phenyl-carbamoyl}-phenyl ester 254 459 N-{4-[3-(5-Chloro-2,4-dimethoxy-p.henyl)-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-eEhoxy)-benzamide 259 4()6 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)-tlhioureido)-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-j1,2,3)thiadiazole-S-carboxylic acid{4-[3-(5-chloro-2,4 dimethoxy-phenyl)-thioureido)-phenyl }-amide 265 3$1 N-(4-{3-j3-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}
phenyI)-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 27U 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-(S-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-benzatnide 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-(S-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 dirnethoxy-phenyl)-thioureido]-phenyl }-amide 282 458 N-(4-{3-[3-Chloro-4-(octahydro-quinolin-I-yl)-phenyl]-thioureido}-phenyl)-acetamide 283 458 N-[5-[[[(5-Chloro-2,4-dimethoxyphenyl)amino]ihioxomethyl]amino]-2-pyridinyl]-2-methylbenzamide 284 434 Furan-2-carboxylic acid {S-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-2-yl }-amide 285 425 N-{4-j3-(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-(S-c;hloro-2,4-dimethoxy-phenyl)-thioureido]-2-methoxy-5-methyl-phenyl }-amide 288 517 4-Furan-3-y1-[1,2,3]thiadiazole-~-<:arboxylic acid{4-[3-(5-chloro-2,4 dimethoxy-phenyl)-thioureido]-phenyl }-amide 289 462 N-{5-[3-(S-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-eahyl)-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}-fluoro-benzarnide 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-Chioro-2,4-dimethoxy-phenyl)-thioureido]-3-methyl-phenyl}-2-fluoro-benzamide 296 447 Furan-2-carboxylic acid {4-[3-(5-ch~loro-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-dimethyl.amino-propyl)-methyl-amino]-phenyl}-thioureido)-phenyl]-acetamide 299 418 N-{4-[3-(3-Chloro-4-cyclohexyla~nino-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 49I 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-trilluoromethyl-phenyl }-acetamide 306 458 Furan-2-carboxylic acid {4-[3-(5-c.hloro-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-phemyl }-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-AcetyJamino-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 $09 N-(4-{3-[4-(1-J3enzyl-piperidin-4-yJ.amino)-3-chloro-phenyl]-thioureido}-phenyl)-acetamide 316 407 N-(4-{3-(3-Chloro-4-(2-dimethylamino-ethylamino)-phenyl)-thioureido}-phenyl)-acetamide - lOS -3I7 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-dimethylannino-propylamino)-phenyl)-thioureido}-phenyl)-acetamide 319 49S N-(4-{3-[4-(1-Benzyl-pyrrolidin-3-ylarnino)-3-chloro-phenyl]-thioureido}-phenyl)-acetamide 320 483 Furan-2-carboxylic acid {5-chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureidoJ-2-hydraxy-phenyl }-amide 321 431 N-{5-Chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureidoJ-2-hydroxy-phenyl}-acetamide 322 S11 (~H,I1H-Benzo[e]pyrrolo[1,2-aJ[l,4Jdiazepin-10-yl)-(2-chloro-4-imidazol-1-yl-phenyl)-methanone 323 4S1 [1,2,3]Thiadiazole-S-carboxylic acid {4-[3-(S-chloro-2,4-dimethoxy-phenyl)-thioureidoJ-phenyl }-amide 324 483 Furan-2-carboxylic acid {4-[3-(S-chloro-2,4-dimethoxy-phenyl)-thioureido]-naphthalen-1-yl }-amide 325 S11 N-{4-(3-(S-Chloro-2,4-dimethoxy-phenyl)-thioureidoJ-naphthalen-1-yl}-2-fluoro-benzamide 326 429 N-{5-Chlora-4-[3-(S-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methyl-.
phenyl }-acetamide 327 509 N-{S-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)-thioureidoJ-phenyl }-amide 331 S61 Furan-2-carboxylic acid [4-(3-{4-[(l..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-benzam:ide 333 463 N-{4-[3-(S-Chloro-2-methoxy-4-methyl-phenyl)-thioureidoJ-phenyl}-2,C-difluoro-benzamide 334 420 N-(4-{3-[3-Chloro-4-(1-methyl-pyrrolidin-3-yloxy)-phenyl]-thioureido}-phenyl}-acetamide 33S 434 N-(4-{3-[3-Chloro-4-(1-methyl-piperi~din-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 33$ 505 5-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-(2-fluoro-benzoylamino)-benzoic acid 339 477 5-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-[(furan-2-carbonyl)-amino]-benzoic acid 340 545 N-[4-(3-{3-Chloro-4-[methyl-(I-methyl-piperidin-4-yl)-amino]-phenyl}-thioureido)-phenyl]-2,6-difluoro-benzamide 341 503 [1,2,3]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.-methylsulfamyl-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-yl)-amino]-phenyl}-thioureido)- phenyl]-amide 345 419. N-{4-[3-(3-Chloro-4-cyclohexylc~xy-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-Chloxo-4-dimethylamiino-phenyl)-thioureido]-phenyl}-2,6-difluoro-benzamide 349 531 N-[4-(3-{3-Chloro-4-[methyl-(i-nnethyl-pyrrolidin-3-yl)-amino]-phenyl}-thioureido)-phenyl]-2,6-difluoro-benzamide 350 427 Pyridine-2-carboxylic acid {4-[3-(3-chloro-4-dirnethyiamino-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 }-amitde 353 417 Furan-2-carboxylic acid {4-[3-(5-c;hloro-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-di:methoxy-phenyl)-thioureido]-phenyl}-fluoro-benzamide 3S6 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-(S-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-claloro-4-(2-dimethylamino-acetylamino)-phenyl]-thioureido}-phenyl)-amide 362 501 N-(4-{3-[3-Chloro-4-(2-dimethylamino-acety!amino)-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-l..yl-acety!amino)-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)-thiioureido]-2-chloro-phenyl}-2-morpholin-4-yl-acetamide 367 543 N-(4-{3-[3-Chloro-4-(2-morpholin-~E-yl-acety!amino)-phenyl]-thioureido}-phenyl)-2-fluoro-benzamide 368 S1S Furan-2-carboxylic acid (4-{3-[3-chiloro-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-dimethy-!amino-ethylsulfanyl)- acetamide 373 561 N-[4-(3-{3-Chloro-4-j2-(2-dimethylamino-ethylsulfanyl)-acetylamino]
phenyl }-thioureido)-phenyl]-2-fluoro-benzamide 374 585 N-C4-(3-{4-[(1-Benzyl-pyrrolidin-3-yl)-methyl-amino]-3-chloro-phenyl}-thioureido)-phenyl]-2-methyl-ben;samide 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 4$6 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-cl;loro-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 3$5 396 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-2-methyl-isoEhioareido]-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-ChIoro-2,4-dimethoxy-phenyl)-thioureido]-3-methoxy-phenyl}-acetamide 389 491 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-rnethoxy-phenyl}-2-fluoro-benzamide 390 463 Furan-2-carboxylic acid {4-[3-(5-ch):oro-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 }-p.henyl)-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)-thioureidoj-2-methyl-phenyl}-2-fluoro-benzamide 39S 429 N-{4-[3-(3-Chloro-4-methyl-phenyl)-thioureido]-2-methyl-phenyl}-2-fluoro-benzamide 395 533 Furan-2-carboxylic acid [4-(3-{3-chloro-4-[2-(2-dimethylamino-ethylsulfanyl)-acetylaminoj-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-AcetyIamino-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-(S-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-phenylL)-thioureido]-phenyl}-2-fluoro-benzamide 405 479 N-{4-[3-(4-Acetylamino-phenyl)-thioureida]-2-chloro-phenyl}-2-thiomorpholin-4-yl-acetamide 406 531 Furan-2-carboxylic acid (4-{3-[3-chioro-4-(2-thiomorpholin-4-yl-acetylamino)-phenyl]-thioureido }-phenyl)-amide 407 559 N-(4-{3-[3-Chloro-4-(2-thiomorphalin-4-yl-acetylamino)-phenylj-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-ac:etylamino-3-chloro-phenyl)-thioureido]-phenyl }-amide 410 477 N-{4-[3-{4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-2-dipropylamino-acetamide 41 I 529 Furan-2-carboxylic acid (4-{ 3-(3-chloro-4-(2-dipropylamino-acetylamino)-phenyl)-thioureido}-phenyl)- amide 412 44.9 N-{4-[3-(4-Acetylamino-phenyl)-thiioureido]-2-chloro-phenyl}-2-diethyl-amino-acetamide 413 501 Furan-2-carboxylic acid (4-{3-[3-chloro-4-(2-diethylamino-acetylamino)-WO 00/34261 PCT/US9912$916 - 1 I (> -phenyl]-thioureido}-phenyl)- amide 414 529 N-(4-{3-[3-Chloro-4-(2-diethyla~mino-acetylamino)-phenyl]-thioureido}-phenyl)-2-fluoro-benzamide 41S 447 N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-2-pyrroiidin-I-yl-acetamide 416 499 Furan-2-carboxylic acid (4-{3-[3-chloro-4-(2-pyrrolidin-1-yl-acetylamino)-phenylJ-thioureido}-phenyl)-amide 417 527 N-(4-{3-[3-Chloro-4-(2-pyrrolidi:n-I-yl-acetylamino)-phenyl]-thioureido}-phenyl)-2-lluoro-benzamide 418 475 N-{4-[3-(5-Chloro-2-methoxy-4amethyl-phenyl)-thioureido]-3-methoxy-phenyl}-2-fluoro-benzamide ,419 445 N-{4-(3-(3-Chloro-4-methyl-phenyl)-thioureidoJ-3-methoxy-phenyl}-2-fluoro-benzamide 42() 477 N-{4-[3-(3-Chloro-4-methylsulfanyl-phenyl)-thioureidoJ-3-methoxy-phenyl } -2-fluoro-benzamide 421 3$8 Furan-2-carboxylic acid {4-[3-(4-amino-3-chloro-phenyl)-thioureidoJ-phenyl }-amide 422 527 Furan-2-carboxylic acid (4-{3-[4-(2-azepan-1-yl-acetylamino)-3-chloro-phenyl]-thioureido}-phenyl)-amide 423 555 N-(4-{3-(4-(2-Azepan-I-yl-acetylamino)-3-chioro-phenyl]-thioureido}-phenyl)-2-fluoro-benzamide 424 527 Furan-2-carboxylic acid [4-(3-{3-c;hloro-4-[2-(2-methyl-piperidin-1-yl)-acetyl-amino]-phenyl }-thioureido)-phenyl]-amide 425 555 N-[4-(3-{3-Chioro-4-[2-(2-methyl-piperidin-1-yl)-acetylamino]-phenyl}-thioureido)-phenyl]-2-fluoro-benzarnide 426 339 Furan-2-carboxylic acid [4-(3-pyridin-2-yl-thioureido)-phenyl)-amide 427 339 Furan-2-carboxylic acid (4-(3-pyridin-4-yl-thioureido)-phenyl]-amide 428 367 2-Fiuoro-N-(4-(3-pyridin-3-yl-thiowreido)-phenyl]-benzamide 429 . 339 Furan-2-carboxylic acid [4-(3-pyridin-3-yl-thioureido)-phenyl]-amide 430 353 Furan-2-carboxylic acid {4-[3-(3-amino-phenyl)-thioureido]-phenyl}-amide 431 406 Furan-2-carboxylic acid {4-[3-(3-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 432 380 2-Fluoro-N-[4-(3-m-tolyl-thioureido)-phenyl]-benzamide 433 434 2-Fluoro-N-{4-[3-(3-trifluoromethyl-phenyl)-thioureido]-phenyl}-benzamide 434 381 N-{4-[3-(3-Amino-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 435 38$ Furan-2-carboxylic acid {4-[3-(3-annino-5-chioro-phenyl)-thioureido]

- Ill -phenyl }-amide 436 352 Furan-2-carboxylic acid [4-(3-nn-tolyl-thioureido)-phenyl]-amide 437 416 N-{4-[3-(2-Amine-5-chloro-phenyl)-thioureido]-hen l}

fl p y --uoro-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-carlbonyl)-amino]-phenyl}-thioureido)-phenyl]-carbamic acid 2-piperidin-1-yl-a;thyl ester 440 388 Furan-2-carboxylic acid {4-[3-(2-amino-5-chloro-phenyl)-thioureido]-phenyl }-amide 44l 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-th:ioureido)-phenylJ-benzamide 445 374 Furan-2-carboxylic acid {4-j3-(6-chloro-pyridin-3-yl)-thioureido]-phenyl}-amide 446 388 Furan-2-carboxylic acid {4-[3-(2-amino-3-chloro-phenyl)-thioureidoJ-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-cahyl)-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 3$0 Furan-2-carboxylic acid {4-[3-(3-iisopropyl-phenyl)-thioureidoJ-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-phenyll)-thioureido]-phenyl}-2-tluoro-benzamide 455 381 Furan-2-carboxylic acid {4-[3-(3-dlimethylamino-phenyl)-thioureido]-phenyl}-amide 456 370 [1,2,3jThiadiazole-4-carboxylic acid [4-(3-m-tolyl-thioureido)-phenylJ-amide 457 424 [1,2,3]Thiadiazole-4-carboxylic acid {4-(3-(3-tryfluoromeWyl-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 46I 39I 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)-thioureidoJ-phenyl}-amide 467 398 Furan-2-carboxylic acid {4-[3-(3,5-dimethoxy-phenyl)-thioureido]-phenyl}-amide 468 416 [1.2,3JThiadiazole-4-carboxylic: acid {4-[3-(3,5-dimethoxy-phenyl)-thiaureido)-phenyl }-amide 469 454 5-(3-{4-[(Furan-2-carbonyl)-amino]-phenyl}-thioureido)-isaphthalic 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)-thioureidoJ-phenyl}-amide 475 382 2-Fiuoro-N-{4-[3-(3-hydroxy-phenyl)-thioureido)-phenyl}-benzamide 476 396 2-Fluoro-N-{4-[3-(3-hydroxymethyl-phenyl)-thioureidoj-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)-thioureidoj-phenyl }-amide 479 400 [1,2>3jThiadiazole-4-carboxylic acid {4-[3-(3-dimethylamino-phenyl)-thioureidoj-phenyl }-amide ' 4$0 340 Furan-2-carboxylic acid [4-(3-pyrimidin-4-yl-thioureido)-phenyl]-amide 481 378 Furan-2-carboxylic acid {4-[3-(1H-indazol-5-yl)-thioureido]-phenyl}-amide 482 395 Furan-2-carboxylic acid [4-(3-benzothiazol-5-yl-thioureido)-phenyl]-amide 483 406 2-Fluoro-N-{4-[3-(1H-indazol-5-yl)-thioureido]-phenyl}-benzamide 484 424 N-[4-(3-Benzothiazol-5-yl-thioureido)-phenyl]-2-fluoro-benzamide 485 473 5-(3-{4-[([1,2,3jThiadiazole-4-carbonyl)-amino]-phenyl}-thioureido)-isophthalic acid dimethyl ester 486 442 Furan-2-carboxylic acid (4-{3-[4-(1-azido~ethyl)-3-chloro-phenyl]-thioureido}-phenyl)-amide 487 396 2-Fluoro-N-{4-[3-(3-methoxy-phenyl)-thioureidoj-phenyl}-benzamide 488 36$ 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-dimethylamiino-phenyl)-thioureido]-phenyl}-2-lluoro-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-(1Hf-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-benzarnide 497 420 2-Fluoro-N-{4-[3-(2-methyl-1H-be;nzoimidazol-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-chIoro-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-yI)-3-chloro-phenyl]-thioureido}-phenyl)-2-fluoro-benzaunide 503 434 [1,2,3]Thiadiazole-4-caxboxyIic .acid {4-[3-(3-chloro-2-dimethylaanino-phenyl)-ihioureido]-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 4$2 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-iodo-phenyl)-thioureido]-phenyl }-amide 509 413 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-tert-butyl-phenyl)-thioureido]-phenyl }-amide 510 387 Furan-2-carboxylic acid {4-[3-(3-chloro-benzyl)-thioureido]-phenyl}-amide 511 4i$ 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 }-aunide 513 435 11,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-bromo-phenyl)-thioureido]-phenyl}-amide 514 452 [I,2,3]Thiadiazole-4-carboxylic acid {6-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-3-yl }-amide 515 426 [1,2,3]Thiadiazole-4-carboxylic acid {5-[3-(3,5-dichloro-phenyl)-thioureido]-pyridin-2-yl }-amide 516 474 Furan-2-carboxylic acid {4-[3-(3,5-his-trifluoromethyl-phenyl)-thioureido]-phenyl }-annide 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 [I,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-amino-3,5-dibromo-phenyl)-thioureido]-phenyl}-amide 522 434 [I,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-5-dimethylamino-phenyl)-thioureido]-phenyl }-ami.de 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-y1)-thioureido]-phenyl }-amide 526 379 Furan-2-carboxylic acid {4-[3-(1:13-benzotriazol-S-yl)-thioureido]-phenyl}-amide 527 425 N-{4-[3-(IH-Benzotriazol-S-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]-pheny:l }-amide 535 508 [1,2,3]Thiadiazole-4-carboxylic acid {4-j3-(3-piperidin-I-yl-5-trifluoromethyl-phenyl)-thioureidaJ-phenyl }-amide 536 380 N-[4-(3-Benzyl-thioureido)-phenyl]-2-fluoro-benzamide 537 439 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,4-dichloro-benzyl)-thioureido]-phenyl }-amide WO 00/34261 iPCT/US99/28916 538 449 N-{4-[3-(3,4-Dichloro-benzyl)-thioureido]-phenyl}-2-fluoro-benzamide 539 370 [1,2,3]Thiadiazole-4-carboxyIi.c acid [4-(3-benzyl-thioureido)-phenyl]-amide 540 424 N-[4-(3-Benzo(l,3jdioxol-5-ylmethyl-thioureido)-phenylj-2-fluoro-benzamide S41 4I4 [1,2,3]Thiadiazole-4-carboxylic acid [4-(3-benzo[1,3]dioxol-5-ylmethyl-ihioureido)-phenyl]-amide 542 506 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3;5-bis-trifluorornethyl-benzyl)-thioureido]-phenyl}-amide 543 516 N-{4-[3-(3,5-Bis-trifluorometh;yl-benzyl)-thioureido]-phenyl}-2-fluoro-benzamide 544 352 Furan-2-carboxylic acid [4-(3-benzyl-thioureido)-phenylj-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[l,3Jdioxol-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-trifluaromethyl-phenyl)-thioureido]-phenyl )-amide 549 529 N-{4-[3-(3-Bromo-4-trifluoromeEhoxy-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 550 519 [1,2,3JThiadiazole-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)-thioureidoJ-phenyl}-amide 552 412 2-Fluoro-N-(4-{3-(2-(3-fluoro-pl'amyl)-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 [1,2,3jThiadiazole-4-carboxylic ;acid (4-{3-[2-(4-fluoro-phenyl)-ethylj-thioureido } -phenyl)-amide 556 495 [1,2,3JThiadiazole-4-carboxylic acid (4-{3-[3-(2-methyl-butyl)-5-trifluoro-methyl-phenyl]-thioureido }-phenyl)-amide 557 48I [1,2,3]Thiadiazole-4-carboxylic acid {4-(3-(3-isobutyl-5-trifluoromethyl-phenyl)-thioureidoJ-phenyl }-amide 55$ 523 [1,2,3jThiadiazole-4-carboxylic acid (4-{3-[3-(4-methyl-piperazin-1-yl)-5-trifluoro-methyl-phenyl]-thioureido }-phenyl)-amide 559 510 (1,2,3jThiadiazole-4-carboxylic acid {4-[3-(3-morpholin-4-yl-5-trifluoromethyl-phenyl)-thioureidoj-phenyl }-amide 560 494 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-pyrrolidin-1-yl-5-trifluoromethyl-phenyl)-thioureidoj-phenyl }-amide 561 384 Furan-2-carboxylic acid (4-{3-[2-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide 562 419 [I>2,3jThiadiazole-4-carboxylic acid (4-(3-[2-(3-chloro-phenyl)-ethylj-thioureido}-phenyl)-amide 563 429 N-(4-{3-[2-(3-Chloro-phenyl)-edhylj-thioureido}-phenyl)-2-fluoro-benzamide 564 401 Furan-2-carboxylic acid (4-{3-[2-(3-chIoro-phenyl)-ethyl]-thioureido}-phenyl)-amide 565 402 (1,2,3jThiadiazole-4-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl)-thioureido}-phenyl)-amide 566 504 2-Fluoro-N-{4-[3-(3-pyrroIidin-1-yl-5-trifluoromethyl-phenyl)-thioureidoj-phenyl }-benzamide 567 477 N-(4-[3-(3-Dimethylamino-5-triffuoromethyl-phenyl)-thioureidoj-phenyl}-2-fluoro-benzamide 568 520 2-Fluoro-N-{4-[3-(3-morpholin-4-yl-5-trifluoromethyl-phenyl)-thioureidoj-phenyl }-benzamide 569 533 2-Fluoro-N-(4-{3-[3-(4-methyl-piperazin-1-yl)-~-trifluoromethyl-phenylj-thioureido}-phenyl)-benzamide 570 518 2-Fluoro-N-{4-[3-(3-piperidin-1-y~l-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-benzamide 571 468 [1,2,3jThiadiazole-4-carboxylic aoid {4-[3-(3-dimethylarnino-5-trifluoromethyl-phenyl}-thioureidoj-phenyl }-amide 572 405 (1,2,3JThiadiazole-4-carboxylic a~;id {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 [1,2,3jThiadiazole-4-carboxylic acid [4-(3-phenethyl-thioureido)-phenylj-amide 5?6 394 2-Fluoro-N-[4-(3-phenethyl-thioureido)-phenyl]-benzamide 577 505 2-F7uoro-N-(4-{3-[3-(2-methyl-butyl)-5-trifluoromethyl-phenylj-thioureido }-phenyl)-benzamide 578 , 491 2-Fluoro-N-{4-[3-(3-isobutyl-5-trifluoromethyl-phenyl)-thioureido)-phenyl}-benzamide 579 38$ Furan-2-carboxylic acid {4-[3-(;3,5-dilluoro-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-j3-(3,5-dichloro-benzyl)-thioureido]-phenyl }-amide 585 438 Furan-2-carboxylic acid {4-[3-(3-fluoro-5-trilluoromethyl-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-(I-phenyl-ethyl)-thioureido]-phenyl}-benzamide 590 366 Furan-2-carboxylic acid {4-[3-(I-;phenyl-ethyl)-tllioureido)-phenyl}-amide 591 4I2 2-Fluoro-N-(4-{3-[1-(4-fluoro-phf;nyl)-ethyl)-thioureido}-phenyl)-benzamide 592 384 Furan-2-carboxylic acid (4-{3-[I-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide 593 413 N-{4-[3-(1-test-Butyl-IH-imidazol-2-y1)-thioureido]-phenyl}-2-fluoro-benzamide 594 510 [I,2,3)Thiadiazole-4-carboxylic acid (4-{3-[3-(isobutyl-methyl-amino)-LrifluoromethyI-phenyl]-thioureido}-phenyl)-amide 595 510 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[3-(3-hydroxy-pyrrolidin-I-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)-:i-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 b00 442 [12,3]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)-thioureiido]-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)-aanide 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-tent-butyl-1H-imidazol-2-yl)-thioureido]-phenyl }-amide 609 384 Furam-2-carboxylic acid {4-[3-(1-tent-butyl-IH-imidazol-2-yl)-thioureido]-phenyl }-amide 610 492 N-{4-[3-(4-Dimethylaunino-3-trifluoromethyl-benzyl)-thioureido]-phenyl}-2-fluoro-benzarnide 611 427 Furan-2-carboxylic acid (4-{3-[2-(3,4-dimethoxy-phenyl)-ethyl]-thioureido}-phenyl)-amide 612 3$0 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 $02 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-I-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 4$2 [1,2,3]Thiadiazole-4-carboxylic a~,id {4-[3-(3-dimethylamino-5-trifluoromethyl-benzyl)-thioureido]-phenyl}amide 619 488 Furan-2-carboxylic acid {4-[3-(3,5-bis-trilluoromethyl-phenyl)-thioureido-methyl]-phenyl }-amide 62U 421 Furan-2-carboxylic acid {4-[3-(3.5-dichloro-phenyl)-thioureidomethyl]-phenyl }-amide 621 421 Furan-2-carboxylic acid {4-[3-(?~,4-dichloro-phenyl)-thioureidomethyl]-phenyl }-amide 622 455 Furan-2-carboxylic acid {4-[3-(4.-chloro-3-trifluoromethyl-phenyl)-thioureido-methyl]-phenyi }-amide 623 466 2-Fluoro-N-{4-[3-(4-fluoro-3-trilluoromethyl-benzyl)-thioureido]-phenyl}-benzamide 624 456 [1,2,3]Thiadiazole-4-carboxylic acid {4-(3-(4-lluoro-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-prop;yl)-thioureido]-phenyl }-benzamide 629 425 [1,2,3)Thiadiazole-4-carboxylic acid {4-[3-(5-trifluoromethyl-pyridin-3-yl)-thioureido]-phenyl }-amide 630 439 [1,2,3)Thiadiazole-4-carboxylic acid {4-[3-(3,4-dichloro-phenyl)-thioureido-methyl)-phenyl }-amide 631 473 [1,2,3)Thiadiazole-4-carboxylic acid {4-[3-(4-chloro-3-trifluoromethyl-phenyl)-thioureidomethyl]-phenyl }-amide 632 381 2-Fluoro-N-[4-(3-pyridin-3-ylmethyl-thioureido)-phenyl]-benzamide 633 353 Furan-2-carboxylic acid [4-(3-pyriidin-3-yImethyl-thioureido)-phenyl]-amide 634 371 [1,2,3]Thiadiazole-4-carboxylic acid [4-(3-pyridin-3-ylmethyl-thioureido)-phenyl]-amide 635 439 11,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-dichloro-phenyl)-thioureido-methyl]-phenyl }-amide 636 492 N-{4-[3-(3-Dimethylamino-5-trilluoromethyl-benzyl)-thioureido]-phenyl}-2-fluoro-benzarnide 637 415 [I>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)-thiaureido)-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]-thioureida}-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 [12.3]Thiadiazole-4-carboxylic acid (4-{3-[2-(2-methoxy-phenyl)-ethyl]-thioureido }-phenyl)-amide 652 415 [1,2,3]Thiadiazole-4-carboxylic arid (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-Iluoro-benzamide 654 510 [I,2,3]Thiadiazole-4-carboxylic acid (4-{3-[3-(3-dimethylamino-propyl)-trifluoromethyl-phenyl)-thioureido }-phenyl)-amide 655 417 [I,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-pyrinin-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}-benzarnide 662 478 Furan-2-carboxylic acid {4-[3-(3-iodo-benzyl)-thioureido]-phenyl }-amide 663 496 (1,2,3jThiadiazole-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-trafluoromethyl-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-3amethyl-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]-thiaureido }-phenyl)-amide 675 38$ 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)-Ehioureido]-phenyl }-2-fluoro-benzamide 678 495 [1,2,3]Thiadiazole-4.carboxyIic 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--123~-benzamide 681 493 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-bromo-4-methoxy-phenyl)-ethyl]-thioureido}-phenyl)- amide 682 493 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(5-bromo-2-methoxy-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-Biphenyl-propyl)-thioureido]-phenyl }-amide 687 547 2-Fluoro-N-(4-{3-[4-(4-methyl-piperazin-1-yl)-3-trifluoromethyl-benzyl)-thioureido}-phenyl)-benzamide 68$ 469 [1>2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3,5-dichloro-phenoxy)-ethyl]-thioureido}-phenyl)-auricle 689 423 [?>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-phenyi)-ethyl]-thioureido }-phemyl)-amide 693 479 [l>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)-Nthyl]-thioureido}-phenyl)-2-fluoro-benzamide 696 536 2-F7uoro-N-(4-{3-[2-(4-iodo-phenoxy)-ethyl]-thioureido}-phenyl)-henzamide 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 70I 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 a<;id (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 11,2,3]Thiadiazole-4-carboxylic aciid (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 }-iphenyl)-amide 712 66$ 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 acidl (4-{3-[2-(4-trifluoromethyl-phenyt)-ethyl]-thioureido}-phenyl)-amide WO 00/34261 PCT/US99/2891ti - 125 ~-718 435 Puran-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 42U [1,2,3jThiadiazole-4-carboxylic acid (4-{3-[2-(3,5-difluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide 72I 412 2-Fluoro-N-(4-{3-[2-(2-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide 722 429 CI,2,3jThiadiazole-4-carboxylic acid (4-{3-[2-(4-nitro-phenyl)-ethyl]-thioureido }-phenyl)-amide 723 399 [1,2,3jThiadiazole-4-carboxylic; acid {4-[3-(1-methyl-2-phenyl-ethyl)-thioureido]-phenyl }-amide 724 437 N-{4-[3-(4-ten-Butyl-benzyl)-thioureidoj-phenyl}-2-fluoro-benzamide 725 409 N-{4-[3-(3,5-Dimethyl-benzyl)..thioureidoj-phenyl}-2-fluoro-benzamide 726 400 [1,2,3jThiadiazole-4-carboxylic acid {4-[3-(2-hydroxy-1-phenyl-ethyI)-thioureidoj-phenyl }-amide 727 409 2-Fluoro-N-{4-[3-(1-methyl-I-phenyl-ethyl)-thioureidoj-phenyl}-benzamide 728 399 [1,2,3jThiadiazole-4-carboxylic acid {4-[3-(1-methyl-I-phenyl-ethyl)-thioureidoj-phenyl }-amide 729 405 [1,2,3jThiadiazole-4-carboxylic acid {4-[3-(2-chloro-benzyl)-thioureidoj-phenyl }-amide 730 388 [1,2,3jThiadiazole-4-carboxylic acid {4-[3-(2-fluoro-benzyl)-thioureidoj-phenyl }-amide 731 438 [1,2,3jThiadiazole-4-carboxylic acid {4-[3-(3-trifluoromethyl-benzyl)-thioureidoj-phenyl}-amide 732 388 [1,2,3jThiadiazole-4-carboxylic acid {4-[3-(3-fluoro-benzyl)-thioureidoj-phenyl}-amide 733 435 [1,2,3jThiadiazole-4-carboxylic acid (4-{3-[2-(2-chloro-phenoxy)-ethylj-thioureido }-phenyl)-amide 734 479 [1,2,3jThiadiazole-4-carboxylic acid (4-{3-[2-(3-bromo-phenoxy)-ethylj-thioureido }-phenyl)-amide 735 418 [1,2,3jThiadiazole-4-carboxylic acid (4-{3-[2-(2-fluora-phenoxy)-ethylj-thioureido}-phenyl)-amide 736 418 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-fluoro-phenoxy)-ethylj-thioureido }-phenyl)-amide 737 486 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(2-fluoro-5-trifluoromethyl-phenoxy)-ethylj-thioureido}-phenyl)-amide WO 00/342b1 PCT/US99/28916 -126~-738 384 Furan-2-carboxylic acid (4-{3-(2-(2-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide 739 435 [I,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)-eithyl]-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-tort-butyl-benzyl)-thioureido]-phenyl}-amide 748 374 [1,2,3]Thiadiazole-4-carboxylic acid {4-(3-(2-tluoro-phenyl)-thioureido]-phenyl }-amide 749 374 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-fluoro-phenyl)-thioureido]-phenyl }-amide 750 526 [I,2,3)Thiadiazole-4-carboxylic acid (4-{3-[2-(3-iodo-phenoxy)-ethyl]-thioureido}-phenyl)-amide 751 409 N-E4-{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-methaxy-benzamide 755 429 2-Chloro-N-(4-{3-[1-(4-lluoro-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 41 () N-(4-{3-[1-(4-FIuoro-phenyl)-ethyl]-thioureido}-phenyl)-4-hydroxy-benzamide 761 429 3-Chloro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide 762 47U [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-fluoro-5-trifluoromethyI-phenyl)-ethyl]-thioureido }-phenyl)-amide 763 520 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(2,4-bis-trifluaromethyl-phenyl)-ethyl]-thioureido }-phenyl)-amide 764 47U [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4-fluoro-3-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-amide 765 438 4-Dimethylamino-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido)-phenyl)-benzamide 766 47U [1,2,3)Thiadiazole-4-carboxylic acid (4-{3-[2-(2-fluoro-3-trifluoromethyl-phenyl)-ethyl)-thioureido}-phen;yl)-amide 767 470 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(2-fluoro-5-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-amide 768 51U [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-triflaaromethyl-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-fluora-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 4U9 2-Fluoro-N-{4-[3-(I-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 7$0 473 N-(4-{3-[I-(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-(I-(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-[I-(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-[I-(3-methoxy--phenyl)-ethyl)-thioureido}-phenyl)-benzamide 790 441 2-FIuoro-N-(4-{3-[1-(4-fluoro-phenyl).-2-methyl-propyl]-thioureido}-phenyl)-benzamide 791 419 N-(4-{3-[I-(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-pl:ienyl-ethyl)-thioureido)-phenyl}-WO 00/34261 PCT/US99/2891b benzamide 798 332 2-Fluoro-N-[4-(3-isopropyl-thiaureido)-phenyl]-benzamide 799 445 2-Fluoro-N-{4-[3-(1-naphthalen :2-yl-ethyl)-thioureida]-phenyl}-benzamide 800 412 3-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide 801 412 4-Fluoro-N-(4-{3-[I-(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-[I-(1-methyl-IH-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-fiuoro-benzamide 807 459 N-{4-[3-(3-Chloro-4-propaxy-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 808 459 N-{4-[3-(3-Chloro-4-isopropoxy-phenyl)-thioureido]-phenyl}-2-fluaro-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-phe:nyl)-thioureido]-phenyl}-2-fluoro-benzamide 812 520 N-(4-{3-[1-(4-Fluoro-phenyl)-ethy:l]-thioureido}-phenyl)-2-ioda-benzamide 813 346 N-(4-{3-[I-(4-Fluoro-phenyl)-ethylf]-thioureido}-phenyl)-propionamide 814 286 N-[4-(3-Phenyl-thioureido)-phenyl]-acetamide EXAMPLE $1S (MET'HOD 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 (0.2U g) and the mixture is stirred for approximately 30 minutes at room temperature. [1,2,3]-Thiadiazole-4-carboxylic acid - 13(> -(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 1 S hours the mixture is filtered and the collected precipitate is washed with acetonitrile then diethyl ether, 5 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. M+H COMPOUND NAME
NO.
816 321 N-{4-[3-(3-Chloro-phenyl)-thioureido]-phenyl}-acetamide 817 413 N-{4-[3-(3-Chloro.-4-methoxy-phenyl)-thioureidoJ-phenyl}-benzamide 818 443 N-{4-[3-(3-Chloro-4-methoxy-phenyl)-tJhioureido]-phenyl}-2-methoxy-benzamide 819 443 N-{4-[3-(3-Chloro-4.-methoxy-phenyl)-tlzioureidoJ-phenyl}-3-methoxy-benzamide 82() 443 N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-ghenyl}-4-methoxy-benzamide 821 431 N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl}-4-methoxy-benzamide 822 431 N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioUreido]-phenyl}-3-fluoro-benzamide $23 431 N-{4-[3-(3-Chloro-4-methoxy-phenyl)-tlnioureido]-phenyl}-4-fluoro-benzamide 824 437 Furan-2-carboxylic acid {4-[3-(3>S-dichloro-4-methoxy-phenyl)-thioureido]-phenyl }-amide 82S Sll {4-[3-(S-Bromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-carbamicacid hexyI ester 826 481 Hexanoic acid {4-[3-(S-bromo-2,4-dimethoxy-phenyl}-thioureido]-phenyl}-amide 827 SUS N-{4-[3-(S-Bromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-tluoro-benzamide 828 477 Furan-2-carboxylic acid {4-[3-(S-bromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide $29 SUl N-{4-[3-(S-Bromo-2,4-dimethoxy-phenyl;~-thioureidoJ-phenyl}-2-methyl-benzamide 83() 517 N-{4-[3-(S-Bromo-2,4-dimethoxy-phenyl)~-thioureido]-phenyl}-4-methoxy-benzamide 831 395 N-{4-[3-(S-Chloro-2-ethoxy-4-rnethoxy-phenyl)-thioureido]-phenyl}-acetamide 832 39S N-{4-[3-(S-Chloro-4-ethoxy-2-methoxy-phenyl)-thioureido]-phenyl}-acetamide 833 423 N-{4-[3-(2-Butoxy-S-chloro-4-methoxy-phenyl)-thioureido]-phenyl}-acetamide 834 423 N-{4-[3-(4-Butoxy-~-chloro-2-methoxy-phenyl)-thioureido]-phenyl}-acetamide 835 457 N-{4-[3-(2-Benzyloxy-5-chloro-4-methoxy-phenyl}-thiaureido]-phenyl}-acetamide $36 457 N-{4-[3-(4-Benzyloxy-5-chloro-2-met~hoxy-phenyl)-thioureido]-phenyl }-acetamide 837 421 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chlaro-4-methoxy-phenyl)-thioureido]-phenyl }-amide 838 424 2-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-5-methoxy-phenoxy}-acetamide 839 367 N-{4-[3-(5-Chloro-2-hydroxy-4-methoxy-phenyl)-thioureido]-phenyl}-acetamide 840 367 N-{4-[3-(3-Chloro-4-methylsulfanyl-phenyl)-thioureido]-phenyl }-acetamide 841 447 N-[4-(3-{3-Chloro-4-[methyl-(1-methyl-piperidin-4-yl)-amino]=phenyl}-thioureido)-phenyl]-acetamide 842 426 N-(4-{3-[3-Chloro-4-(methyl-phenyl-amino)-phenyl]-thioureido}-phenyl)-acetamide 843 509 N-[4-(3-{4-[(1-Benzyl-pyrrolidin-3-yl)-methyl-amino]-3-chloro-phenyl}-thioureido)-phenyl]-acetamide 844 418 N-(4-{3-[3-Chloro-4-(cyclopentyl-methyl-amino)-phenyl]-thioureido}-phenyl)-acetamide 845 433 N-[4-(3-{3-Chloro-4-[methyl-(1-methyl-pyrrolidin-3-yl)-amino]-phenyl}-thioureido}-phenyl]-acetamide 846 4I9 Furan-2-carboxylic acid {4-[3-(3-chlora-4-methylsulfanyl-phenyl)-thioureido]-phenyl }-amide $47 447 N-{4-[3-(3-Chloro-4-methylsulfanyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 848 465 N-{4-[3-(3-Chloro-4 methylsulfanyl-phenyl)-thioureido]-phenyl}-2,6-difluoro-benzamide 849 445 N-{4-[3-(5-Chloro-2-methoxy-4-methyl: phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 850 441 N-{4-[3-(5-Chloro-2-methoxy-4-methyl-phenyl)-thioureido]-phenyl}-2-methyl-benzamide 851 434 (1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chlora-4-dimethylamino-phenyl)-thioureido]-phenyl }-amide 852 444 N-{4-[3-(3-Chloro-4-dirnethylamino-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 853 517 [1,2,3]Thiadiazole-4-carboxylic acid [4-(3-{3-chloro-4-[methyl-(1-methyl piperidin-4-yl)-amino]-phenyl }-thioureido)-phenyl]-amide 854 579 [1,2,3)Thiadiazole-4.-carboxylic acid [4-(3-{4-[(1-benzyl-pyrrolidin-3-yl)-methyl-amino]-3-chloro-phenyl }-thioureido)-phenyl]-amide 855 527 N-[4-(3-{3-Chloro-9.-[methyl-(I-methyl-piperidin-4-yI}-amino]-phenyl}-thioureido)-phenyl)-2-fluoro-benzamide 856 435 [I,2,3]Thiadiazole-4-carboxylic acid {4-[3-(5-chloro-2-methoxy-4-methyl-phenyl)-thioureido]-phenyl }-amide 857 589 N-[4-(3-{4-[(1-Benzyl-pyrrolidin-3-yl)~-methyl-amino)-3-chloro-phenyl}-thioureido)-phenyl)-2-fluoro-benzamide 858 501 Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-ihioureido]-3-trifluoromethyl-phenyl }-amide 859 366 2-Fluoro-N-(4-(3-phenyl-thioureido)-phenyl]-benzamide 860 338 Furan-2-carboxylic acid [4-(3-phenyl-thioureido)-phenyl]-amide 861 356 [I,2,3]Thiadiazole-4-carboxylic acid [4-(3-phenyl-chioureido)-phenyl)-amide 862 365 N-(4-{3-[3-Chloro-4-(1-hydroxy-ethyl)-.phenyl]-thioureido}-phenyl)-acetamide 863 435 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[3-chioro-4-(1-hydroxy-ethyl)-phenylJ-thioureido}-phenyl)-amide $64 365 N-(4-{3-[3-Chloro-4-(2-hydroxy-ethyl)-phenyl]-thioureido}-phenyl)-acetamide 865 445 N-(4-{3-[3-Chloro-4-(1-hydroxy-ethyl)-phenyl]-thioureido}-phenyl)-2-fluoro-benzamide 866 417 Furan-2-carboxylic acid (4-{3-[3-chloro.-4-(1-hydroxy-ethyl)-phenyl]-thioureido}-phenyl)-amide 867 371 [1,2,3)Thiadiazole-4-carboxylic acid {4-[3-(3-amino-phenyl)-thioureido)-phenyl}-amide 868 501 Furan-2-carboxylic acid {4-[3-(3-bromo-4-trifluoromethoxy-phenyl)-thioureido)-phenyl }-amide $69 423 N-{4-[3-(3-test-Butyl-phenyl)-thioureido)-phenyl}-2-fluoro-benzamide 870 440 [1,2,3)Thiadiazole-4-carboxylic acid {4-~[3-(4-chloro-3,5-dichloro-phenyl)-thioureidoJ-phenyl }-amide 974 4$5 N-{4-[3-(I-Benzofuran-2-yl-ethyl)-thioureidoJ-phenyl}-2-trifluoromethyl-benzamide 975 4I2 N-(4-Fluoro-phenyl)-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-benzamide 976 446 lsoquinoline-1-carboxylic acid (4-{3-[I-(.4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide 977 46$ lsoquinoline-1-carboxylic acid {4-[3-(I-benzofuran-2-yl-ethyl)-thioureido)-- phenyl }-amide 978 506 Isoquinoline-I-carboxylic acid (4-{3-[1-(4-bromo-phenyl)-ethyl]-thioureido}-phenyl)-amide 979 453 Isoquinoline-I-carboxylic acid (4-{3-[1-(4-cyano-phenyl)-ethyl)-thioureido}-phenyl)-amide 98() 435 Benzofuran-2-carboxylic acid (4-{3-(I-(4.-fluoro-phenyl)-ethyl)-ti~ioureido}-phenyl)-amide 981 457 Benzofuran-2-carboxylic acid {4-(3-(I-bt;nzofuran-2-yi-ethyl)-thioureido]-phenyl}-amide 982 495 Benzofuran-2-carboxylic acid (4-{3-[I-(4-bromo-phenyl)-ethyl)-thioureido}-phenyl)-amide 983 442 Benzofuran-2-carboxylic acid (4-{3-[1-(4-cyano-phenyl)-ethyl)-thioureido}-phenyl)-amide 984 446 lso9uinoline-3-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide 985 468 Isoquinoline-3-carboxylic acid {4-[3-(I-be:nzofuran-?-yl-ethyl)-thioureido)-phenyl }-amide 986 453 Isoquinoline-3-carboxylic acid (4-{3-[1-(4.-cyano-phenyl)-ethyl)-thioureido}-phenyl)-amide 987 506 lsoquinoline-3-carboxylic acid (4-{3-(1-(4-bromo-phenyl)-ethyl)-chioureido}-phenyl)-amide 988 446 Quinoline-3-carboxylic acid (4-{3-[I-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide 989 446 Quinoline-4-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide 990 446 Quinoline-b-carboxylic acid (4-{3-[I-(4-fluoro-phenyl)-ethyl)-thioureido}-phenyl)-amide 991 446 Quinoline-8-carboxylic acid (4-{3-[I-(4-fluoro-phenyl)-ethyl)-thioureido}-phenyl)-amide 992 462 N-(4-{3-[I-(4-Fluoro-phenyl)-ethyl]-thioure ido}-phenyl)-2-trifluoromethyl-benzamide 993 419 2-Cyano-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl)-thioureido}-phenyl)-benzamide 994 473 N-{4-[3-(3-Chloro-4-isobutoxy-phenyl)-thioureido)-phenyl}-2-lluoro-benzamide 995 414 2-Fdoro-N-{4-j3-(3-lluoro-4-methoxy-phenyl)-thioureido]-phenyl}-benzamide 996 475 N-(4-{3-[3-Chloro-4-(2-methoxy-ethoxy)-p.henyl]-thioureido}-phenyl)-2-fluoro-benzamide 997 398 2-Fluoro-N-{4-[3-(3-fluoro-4-methyl-phenyl)-thioureido]-phenyl}-benzamide 998 464 2-Fluoro-N-{4-[3-(4-methoxy-3-trifluoromethyl-pheny)-thioureido]-phenyl}
benzamide 999 449 N-{4-[3-(2-Amino-S-trifluoromethyl-phenyl.)-thioureido]-phenyl}-2-lluoro-benzamide 1(X)0 459 N-(4-{3-[1-(3-Chloro-4-methoxy-phenyl)-ethyl]-thioureido}-phenyl)-2-tluoro-benzamide 1001 417 N-{4-[3-(~-Chloro-2-hydroxy-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 1()02 435 N-{4-[3-(1-Benzofuran-2-yl-ethyl)-thioureido)-phenyl}-2-lluc~ro-benzamide 1003 448 2-Fluoro-N-{4-[3-(4-methyl-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-benzamide 1()04 473 (S)-N-(4-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido}-phenyl)-2-tluoro-benzamide 1()05 473 N-(4-{3-[(1R)-1-(4-Bromo-phenyl)-ethyl]-thioureido}-phenyl)-2-tluoro-benzamide IO()6 494 2-Fluoro-N-(4-{3-[2-methoxy-4-(2,2,2-trifluoro-ethoxy)-phenyl]-thioureido}-phenyl)-benzamide 1()07 399 N-{4-(3-(2-.~nino-5-tluoro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 1008 502 N-(4-{3-(1-(4-Dimethylsulfamoyl-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 1(X)9 542 2-Fhoro-N-[4-(3-{1-[4-(piperidine-1-sulfonyl)-phenyl]-ethyl}-thioureido)-phenyl]-benzamide 1010 562 N-(4-{3-[2,4-Bis-(2,2,2-trifluoro-ethoxy)-phenyl]-thioureido}-phenyl)-2-fluoro-benzamide 1011 409 2-Fluoro-N-{4-[3-((1S)-1-p-tolyl-ethyl)-thioureido]-phenyl}-benzamide 1()12 409 2-Fluoro-N-{4-[3-((1R)-1-p-tolyl-ethyl)-thioureido]-phenyl}-benzamide 1()13 394 2-Fluoro-N-{4-[3-((1S)-1-phenyl-ethyl)-thioureido]-phenyl}-benzamide 1014 429 N-(4-{3-((1R)-1-(4-Chloro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzarnide 1015 429 N-(4-{3-[(1S)-1-(4-Chloro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 1016 394 2-Fluoro-N-{4-[3-((IR)-1-phenyl-ethyl)-thioureido]-phenyl}-benzamide 1017 432 N-(4-{3-[1-(4-Cyano-phenyl)-ethyl]-thioureido}-phenyl)-2-methoxy-benzamide 101$ 447 N-{4-[3-(1-Benzofuran-2-yl-ethyl)-thioureido]-phenyl}-2-methoxy-benzamide 1019 485 N-(4-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido}-phenyl)-2-methoxy-benzamide 1020 419 3-Cyano-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide 1021 462 N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-4-trifluoromethyl-benzamide 1022 419 4-Cyano-N-(4-{3-[1-(4-tluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide 1023 469 2-Fluoro-N-(4-{3-[1-(4-tluoro-phenyl)-ethyl]-thioureido}-2,3,5.6-tetramethyl phenyl)-henzamide 1024 480 N-(4-{3-[1-(4-Cyano-phenyl)-ethyl)-thioureido}-2,5-dimethoxy-phenyl)-2-fluoro-benzamide 102$ 473 2-Fluoro-N-(4-{3-[1-(4-tluoro-phenyl)-ethyl]-thioureido}-2,5-dimethoxy-phenyl)-benzamide 1026 530 N-{3,5-Dichloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-fluora-benzamide 1027 447 N-(=~-Chloro-4-{3-[I-(4-fluaro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluaro-benzamide 1028 480 2>3,4,5-Tetrafluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-3-methyl-phenyl)-benzamide 1029 462 2,4,~-Trifluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-3-methyl-phenyl)-benzamide I03() 427 2-Ftuoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-3-methyl-phenyl)-benzamide 1()31 457 2-Fluaro-N-(4-{3-[1-(4-fluaro-phenyl)-ethyl]-thioureido}-Z-methoxy-~-methyl-phenyl)-benzamide 1032 443 2-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethylJ-thioureido}-3-methoxy-phenyl)-benzamide 1()33 570 N-(2,6-Dibromo-4-{3-[I-(4-fluoro-phenyl)-ethyl]-thioureida}-phenyl)-2-fluoro-benzamide I()34 480 2-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethylJ-thioureido}-2-trifluoromethyl-phenyl)-benzamide 1035 541 N-(4-{3-[I-(4-Bromo-phenyl)-ethyl]-thiaureido}-2-trifluaromethyl-phenyl)-2-fluoro-benzamide 1036 48? N-(4-{3-[I-(4-Cyano-phenyl)-ethyl]-thioureido}-2-trifluoromethyl-phenyl)-2-fluoro-benzamide 1037 5()3 N-{4-[3-(I-Benzofuran-2-yl-ethyl)-thioureidoJ-2-trifluoromethyl-phenyl}-2-fluoro-benzamide 1038 447 N-(2-Chloro-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 1039 454 N-(2-Chloro-4-{3-[1-(4-cyana-phenyl)-ethyl]-thioureida}-phenyl)-2-fluoro-benzamide 1040 437 N-(2-Cyana-4-{3-[I-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 1()41 498 N-(4-{3-[I-(4-Bromo-phenyl)-ethyl]-thioureida}-2-cyano-phenyl)-2-fluoro-benzamide 1042 445 N-(2-C.yano-4-{3-[1-(4-cyano-phenyl)-ethyl]-thioureido}-phenyl)-2-fluora-benzamide 1043 46() N-{4-(3-(I-Benzofuran-2-yl-ethyl)-thioureido]-2-cyano-phenyl}-2-fluoro-benzamide 1044 SI7 N-(2-Benzoyl-4-{3-(I-(4-fluaro-phenyl)-ethyl]-thiaureido}-phenyl)-2-tiuaro-henzamide 1()45 427 ~-~ur~ro-N-(4-{3-(1-(4-fluoro-phenyl)-ethyl]-thioureido}-2-methyl-phenyl)-henzamide 1046 487 N-(4-{3-[I-(4-Bromo-phenyl)-ed~yR]-thioureido}-2-methyl-phenyl)-2-f7uoro-benzamide 1047 434 N-(4-{3-[1-(4-Cyano-phenyl)-ethyl:}-thioureido}-2-methyl-phenyl)-2-fluoro-benzamide 1048 449 N-{4-[3-(I-Benzofuran-2-yl-ethyl)-thioureido]-2-methyl-phenyl}-2-fluoro-henzamide 1049 456 N-(2-Dimethylamino-4-{3-[I-(4-fluoro-phenyl)-ethyl]-thiaureido}-phenyl)-2-tluoro-benzamide 105() 526 N-(2-Benzyloxy-4-{3-(1-(4-cyano-phenyl)-ethyl]-thiaureido}-phenyl)-2-fluoro-benzamide 1051 5I9 N-(2-Benzyloxy-4-{3-(I-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)=2-fluoro-benzamide 1052 603 N-[4-{3-[I-(4-Bromo-phenyl)-ethyl]-thioureido}-2-(2-morpholin-~l-yl-ethoxy)-phenyl]-2-fluoro-benzamide 1053 603 N-[4-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido}-2-(2-morpholin-4-yl-ethoxy)-phenyl]-2-fluoro-benzamide 1054 542 2-Fluoro-N-[4-{3-[I-(4-fluoro-phenyl)-ethyl]-thioureido}-2-(2-morpholin-4-yl-ethoxy)-phenyl]-benzamide 1055 485 N-(2-Butoxy-4-{3-[1-{4-fluoro-phen;yl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 1056 492 N-(2-Butoxy-4-{3-[1-(4-cyano-phen3rl)-ethyl]-thioureido}-phenyl)-2-tluoro-benzamide 1057 589 N-[4-{3-[I-(4-Bromo-phenyl)-ethyl]-thioureido}-2-{2-diethylamino-ethoxy)-phenyl]-2-tluoro-benzamide 1058 528 N-(2-(2-Diethylamino-ethoxy)-4-{3-[1-(4-t7uoro-phenyl)-ethyl]-thioureido}-phenyl)-2-tluoro-benzamide 1059 589 N-[4-{3-II-(4-Bromo-phenyl)-ethyl]-thioureido}-2-(2-diethylamino-etiroxy)-phenyl]-2-tluoro-benzamide 106() 457 N-(2-Ethoxy-4-{3-[1-{4-fluoro-phenyl}-ethyl]-thioureido}-phenyl)-2-tluoro-benzamide 1061 464 N-(4-{3-[1-(4-Cyano-phenyl)-ethyl]-thioureido}-2-ethoxy-phenyl)-2-fluoro-benzamide 1062 468 2-Fluoro-N-[4-{3-[1-(4-fluoro-phenyl)-ethyl)-thioureido}-2-(2-nitrilo-ethoxy)-phenyl]-henzamide 1063 475 N-[4-{3-[I-(4-Cyano-phenyl)-ethyl]-duoureida}-2-(2-nitrilo-ethoxy)-phenyl]-2-WO OU/342G1 PCTlUS99/28916 -137_ fluora-benzamide.
1()64 443 2-Fluoxo-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2-methoxy-phenyl)-benzamide 1065 489 2-Fluoro-N-(5-{3-[1-(4~fluoro-phenyl)-ethyl]-thioureida}-biphenyl-2-yl)-benzamide 1066 514 lsoquinoIine-1-carboxylic acid (4-{3-(1-(4-tluoro-phenyl)-ethyl]-thioureido}-2-trifluoromethyl-phenyl)-amide 1067 503 Benzofuran-2-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2-trifluoromethyl-phenyl)-amide 1()68 514 lsoquinoline-3-carboxylic acid (4-{3-[1-(4-fluaro-phenyl)-ethyl]-thioureido}-2-trifluoromethyl-phenyl)-amide 1069 471 Isoquinoline-1-carboxylic acid (2-cyano-4-{3-[1-(4-tluoro-phenyl)-ethyl]-thioureido }-phenyl)-amide 107() 460 Benzofuran-2-carboxylic acid (2-cyano-4={3-(1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide 1071 471 lsoquinoline-3-carboxylic acid (2-cyano-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-amide 1072 460 Isoquinoline-i-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2-methyl-phenyl)-amide 1073 449 lienzofuran-2-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2-methyl-phenyl)-amide 1074 46(1 Isoquinoline-3-carboxylic acid (4-{:3-(1-(4-fluora-phenyl}-ethyl]-thioureido}-2-methyl-phenyl)-amide 1075 396 PYr~ine-2-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide 1076 4()1 Thiophene-2-carboxylic acid (4-{3-[1~(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide 1077 401 Thiophene-3-carboxylic acid (4-{3-(1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide 1078 500 2-Isopropyl-thiazale-4-carboxylic acid {4-(3-(4-chloro-3-trifluoromethyl-phenyl)-thioureido]-phenyl }-amide 1079 466 2-Isopropyl-thiazole-4-carboxylic acid {4-(3-(3,~-dichloro-phenyl)-thioureido]-phenyl }-amide 10$0 466 2-Isopropyl-thiazole-4-carboxylic acid {4-[3-(3,4-dichioro-phenyl)-thioureido]-phenyl }-amide 1081 534 2-Isopropyl-thiazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl-phenyl)-thioureido]-phenyl }-amide 1082 480 2-$utyl-thiazole-4-carboxylic acid {4-[3-(3.4-dichloro-phenyl)-.
thioureido]-phenyl}-amide WO 00134261 PCT/US99l28916 1()83 514 2-Butyl-thiazole-4-carboxylic acid {4-(3-(4-chloro-3-tril7uoromethyl-phenyl)-thioureido]-phenyl }-amide 1084 480 2-Butyl-thiazole-d-carboxylic acid {4-[3-(3,5-dichIoro-phenyl)-thioureido]-phenyl}-amide 1085 548 2-Butyl-thiazole-4-carboxylic acid {4-[3-(3,~-his-trifluoromethyl-phenyl)-thioureido]-phenyl }-amide 1086 438 2-Methyl-thiazole-4-carboxylic acid {4-[3-(3,~-dichloro-phenyl)-thioureido]-phenyl }-amide 1087 438 2-Methyl-thiazole-4.-carboxylic acid {4-(3-(3,4-dichloro-phenyl)-thioureido]-phenyl }-amide 1()88 505 2-Methyl-thiazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl-phenyl)-thioureido]-phenyl }-amide 1089 534 2-Phenyl-thiazole-4-carboxylic acid {4-(3-(4-chloro-3-tril7uoromethyl-phenyl)-thioureido]-phenyl}-amide 109(1 500 2-Phenyl-thiazole-4-carboxylic acid {4-[3-(3,5-dichloro-phenyl)-chiaureido]-phenyl }-amide 1091 500 2-Phenyl-thiazole-4-carboxylic acid {4-[3-(3,4-dichloro-phenyl)-thioureido]-phenyl }-amide 1092 568 2-Phenyl-thiazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl-phenyl)-thioureido]-phenyl }-amide 1093 401 2-Fluoro-N-{4-[3-(1-thiazol-2-yl-ethyl)-thioureido]-phenyl}-benzamide 1094 588 2-Fluoro-N-[4-(3-{1-[1-(toluene-4-sul.fonyl)-1H-indol-2-yl]-ethyl}-thioureido)-phenyl]-benzamide 1095 446 2-Fluora-N-{4-[3-(1-quinolin-2-yl-ethyl)-thioureido]-phenyl}-benzamide 1096 446 2-Fluaro-N-{4-[3-(1-quinolin-4-yl-eth;yl)-thioureido]-phenyl}-benzamide 1()97 446 2-Fluoro-N-{4-[3-(1-isoquinolin-3-yl-ethyl)-thioureido]-phenyl}-benzamide 109$ 446 2-Fluoro-N-{4-[3-(1-isoquinolin-1-yl-ethyl)-thioureido]-phenyl}-benzamide 1099 446 2-Fluoro-N-{4-[3-(1-quinoiin-6-yl-ethyl)-thioureido]-phenyl}-benzamide 11()0 446 2-Fluoro-N-{4-[3-(1-quinolin-3-yl-ethyl)-thioureido]-phenyl}-benzamide 1101 413 2-Methoxy-N-{4-[3-(1-thiophen-3-yl-ethyl)-thioureido]-phenyl}-benzamide EXAMPLE 871 {METHOD 33}
[1,2,3]Thiadiazole-4-carboxylic acid {~.[3.{3,5-dichloro-phenyl)-thioureido]
phenyl }-amide 5 To a solution of 3,5-dichloroaniline ((>.16 ~) in tetrahydrofuran (2() mL) is added freshly prepared 1,1'-thiocarbonyl-di-(1,2,4'.)-triazole (().2() g) and the mixture is stirred for approximately 30 minutes at room temperature. [1,2,3]-Thiadiazole-carboxylic acid (4-amino-phenyl) amide (0.22 ~) is added to the reaction flask and the mixture is stirred for approximately 6 hours. The solvent is then removed by 10 evaporation under reduced pressure and warm acetonitriIe {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.
[1V1+H] 424.
15 Using the above procedure and appropriate starting materials the following compounds were prepared:
EX. M+H COMPOUND NAME

NO.

872 465 N-{4-[3-(3,S-Dichloro-4-metJhoxy-phenyl)-thioureido]-phenyl}-3-fluoro-benzamide 873 477 N-{4-[3-(3,S-Dichloro-4-methoxy-phenyl)-thioureido]-phenyl }-2-methoxy-benzamide 874 46S N-{4-[3-(3,S-Dichloro-4-medioxy-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 875 477 N-{4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]-phenyl}-3-methoxy-benzamide 876 399 N-{4-I3-(3,S-Dichloro-2-metlnoxy-4-methyl-phenyl)-thioureido]-phenyl}

-acetamide 877 365 N-{4-[3-(3-Chloro-4-methoxy-S-methyl-phenyl)-thioureido]-phenyl}-acetamide 878 331 N-{4-[3-(2-Nitro-phenyl)-thioureido]-phenyl}-acetamide 879 331 N-{4-[3-(4-Nitro-phenyl)-thiou~reido]-phenyl}-acetamide 8$0 477 N-{4-I3-(3,S-Dichloro-4-methoxy-phenyl)-thioureido]-phenyl}-4-methoxy-benzamide - 14() -881 351 N-{4-[3-(2-Chloro-~-methoxy-phenyl)-thioureido]-phenyl}-acetamide 882 428 2-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy}-acetamide 883 443 {4-[3-(4-Acetylamino-phenyl)-t:hioureido]-2,6-dichloro-phenoxy}-acetic acid methyl ester 884 457 {4-[3-(4-Acetylamino-phenyi)-thioureido]-2,fi-dichloro-phenoxy}-acetic acid ethyl ester 885 447 N-{4-[3-(3,5-Dichloro-4-phenoxy-phenyl)-thioureido]-phenyl}-acetamide 886 41U N-(4-{3-[3,5-Dichloro-4-(2-nitrilo-ethoxy)-phenyl]-thioureido}-phenyl)-Acetamide 887 485 {4-[3-(4-Acetylamino-phenyl)-tJhioureido]-2,6-dichloro-phenoxy}-acetic acid tert-butyl ester 88$ 469 [1,2.3]Thiadiazole-4-carboxylic acid {4-[3-(3,~-dichloro-2-methoxy-4-methyl-phenyl)-thioureido]-phenyl }-amide 889 335 N-{4-[3-(3-Chloro-4-methyl-phe:nyl)-thioureido]-phenyl}-acetamide 890 335 N-{4-[3-(5-Chioro-2-methyl-phenyl)-thioureido]-phenyl}-acetamide 891 7U3 N-{4-[3-(4-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyldisulfanyl }-3-chloro-phenyl)-thi oureido]-phenyl } -acetamide 892 369 N-{4-[3-(3,5-Dichloro-4-methyl-.phenyl)-thioureido]-phenyl}-acetamide 893 598 N-{4-(3-(3,5-Diiodo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-acetamide 894 SU4 N-{4-[3-(3,5-Dibrorno-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-acetamide 895 317 N-{4-(3-(b-Methoxy-pyridin-3-yl)-thioureido]-phenyl}-acetamide 896 347 N-{4-[3-(2,b-Dimethoxy-pyridin--3-yl)-thioureido]-phenyl}-acetamide 897 457 Acetic acid 2-{4-[3-(4-acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy}-ethyl ester 898 365 4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-benzoic acid 899 346 N-{4-f3-(3-Chloro-4-cyano-phenyl)-thioureido]-phenyl}-acetamide 9UU 512 N-(4-{3-[5-Chloro-2-(4-chloro-phenoxy)-4-pyrrol-1-yl-phenyl]-thioureido}-phenyl)-acetamide 9U1 355 N-{4-[3-(3,4-Dichloro-phenyl)-thioureido]-phenyl}-acetamide 9U2 339 N-{4-(3-(3-Chloro-4-Iluoro-phenyl)-thioureido]-phenyl}-acetamide 9U3 447 N-{4-[3-(3-Chloro-4-iodo-phenyl)-tliioureido]-phenyl}-acetamide 9U4 4UU 1'1-{4-[3-(4-Bromo-3-chloro-phen.yJ)-thioureido]-phenyl}-acetamide 905 424 N-[4-(3-{4-[Bis-(2-hydroxy-ethyl)-amino]-3-chloro-phenyl}-thioureido)-phenyl]-acetamide - 141 ~-9()6 434 N-(4-{3-[3-Chloro-4-(hexyl-m<ahyl-amino)-phenyl]-thioureido}-phenyl)-acetamide 907 406 N-(4-{3-[3-Chloro-4-(isobutyl-.methyl-amino)-phenyl)-thioureido}-phenyl)-acetamide 9()8 389 N-{4-[3-(3-Chloro-4-trif7uorom~ethyl-phenyl)-thioureido]-phenyl}-acetamide 909 441 Furan-2-carboxylic acid {4-(3-(3-chloro-4-trifluoromethyl-phenyl)-thioureido]-phenyl }-amide 910 459 [7,2,3]Thiadiazole-4-carboxylic, acid {4-[3-(3-chloro-4-trilluoromethyl-phenyl)-thioureido]-phenyl }-amide 911 469 N-{4-[3-(3-Chloro-4-trifluoromethyl-phenyl)-thioureido]-phenyl}-2-Iluoro-benzamide 912 435 N-{4-[3-(3,4-Dichioro-phenyl)-rhioureido]-phenyl}-2-tluoro-benzamide 913 4()7 Furan-2-carboxylic acid {4-(3-(3.4-dichloro-phenyl)-tbioureido]-phenyl}-amide 914 425 [I,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,4-dichloro-phenyl)-thioureido]-phenyl }-amide 915 480 N-{4-[3-(4-Bromo-3-chioro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 916 527 N-{4-[3-(3-Chloro-4-iodo-phenyl)-thioureido]-phenyl}-2-Iluoro-ben a id m z e 917 452 Furan-2-carboxylic acid {4-[3-(4-bromo-3-chloro-phenyl)-thioureido]-phenyl }-amide 918 499 Furan-2-carboxylic acid {4-[3-(3-chloro-4-iodo-phenyl)-thioureido]-phenyl }-amide 919 391 Furan-2-carboxylic acid {4-[3-(3-chloro-4-lluoro-phenyl)-thioureido]-phenyl }-amide 920 470 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-promo-3-chloro-phenyl)-thioureido]-phenyl }-amide 921 517 E7-2~3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-4-iodo-phenyl)-thioureido]-phenyl }-amide 922 419 N-{4-[3-(3-Chloro-4-Iluoro-phenyt)-thioureido]-phenyl }-2-f7uoro-benzamide 923 409 [1,2,3]Thiadiazole-4-carboxylic a.cid{4-[3-(3-chloro-4-fluoro-phenyl)-thioureido]-phenyl }-amide 924 388 N-{4-[3-(3-Chloro-4-isoxazol-5-yl-phenyl)-thioureido]-phenyl}-acetamide 925 387 N-(4-{3-[3-Chloro-4-(7H-pyrazol-3-yl)-phenyl]-thioureido}-phenyl)-acetamide WO 00/34261 PCTlUS99/28916 92b 355 N-{4-(3-(2,3-Dichloro-phenyl)-thioureido]-phenyl)-acetarnide 927 435 N-{4-[3-(2.3-Dichloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 928 407 Furan-2-carboxylic acid {4-[3-(2,3-dichloro-phenyl)-thioureido]-phenyl}-amide 929 425 [1~2,3JThiadiazole-4-carboxylic acid {4-[3-(2,3-dichloro-phenyl)-thioureido]-phenyl }-amide 93() 355 N-{4-[3-(2,S-Dichloro-phenyl)-thioureido]-phenyl}-acetamide 931 435 N-{4-[3-(2,S-Dichloro-phenyl}-thioureido]-phenyl}-2-fluoro-benzamide 932 4()7 Furan-2-carboxylic acid {4-[3-(2,5-dichIoro-phenyl)-thioureido]-phenyl}-amide 933 355 N-{4-[3-(3,5-DichIoro-phenyl)-thioureido]-phenyl}-acetamide 934 435 N-{4-[3-(3,S-Dichloro-phenyl)-thioureido]-phenyl}-2-lluoro-benzamide 935 4()7 Furan-2-carboxylic acid {4-[3-(:3,~-dichloro-phenyl)-thioureido]-phenyl}-amide 936 39U N-{4-[3-(3,4,5-Trichloro-phenyl!)-thioureido]-phenyl }-acetamide 937 470 2-Fluoro-N-{4-[3-(3,4,~-trichloro-phenyl)-thioureido]-phenyl}-benzamide 938 442 Furan-2-carboxylic acid {4-[3-(3,4,~-trichloro-phenyl)-thioureido]-phenyl}-amide 939 460 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3,4,5-trichloro-phenyl)-thioureido]-phenyl }-amide 940 458 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-4-isoxazol-5-yl-phenyl)-thioureido]-phenyl }-amide 941 457 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[3-chloro-4-(1H-pyrazol-3-yl)-phenyl]-thioureido )-phenyl)-amide 942 391 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-phenyl)-thioureido]-phenyl }-amide 943 373 Furan-2-carboxylic acid {4-[3-(3~-chloro-phenyl)-thioureido]-phenyl}-amide 944 4U1 N-{4-[3-(3-Chloro-phenyl)-thioureido]-phenyl}-2-Fluoro-benzamide 945 373 Furan-2-carboxylic acid {4-[3-(4..chloro-phenyl)-thioureido]-phenyl}-amide 946 40I N-{4-[3-(4-Chioro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 947 391 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-chloro-phenyl)-thioureido]-phenyl }-amide 948 401 N-{4-[3-(2-Chloro-phenyl)-thioureido]-phenyl}-2-lluoro-benzamide 949 396 3-(3-{4-[(Furan-2-carbonyl)-amino]-phenyl}-thioureido)-benzoic acid methyl ester 950 424 3-{3-[4-(2-Fluoro-benzoylamino)..phenyl]-thioureido}-benzoic acid methyl PCTlUS99/28916 ester 951 414 3-(3-{4-[([1,2,3JTl~iadiazole-4-carbonyl)-amino]-phenyl}-thioureido)-benzoic acid methyl ester 952 4U9 N-(4-[[([3-(Aminocarbonyl)phenyl]amino]thioxomethyl]amino]phenyl)-2-fluoro-benzamide 953 373 Furan-2-carboxylic~acid {4-[3-(:Z-chloro-phenyl)-thioureido]-phenyl}-amide 954 381 Furan-2-carboxylic acid {4-[3-(3-carbamoyl-phenyl)-thioureido)-phenyl}-amide 955 399 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-carbamoyl-phenyl)-thioureidoJ-phenyl }-amide 956 391 (1,2,3)Thiadiazole-4-carboxylic acid {4-[3-(2-chloro-phenyl)-thioureida]-phenyl }-amide 957 356 Furan-2-carboxylic acid {4-[3-(3-fluoro-phenyl)-thioureido}-phenyl}-amide 958 383 Furan-2-carboxylic acid {4-(3-(3-nitro-phenyl)-thioureidoJ-phenyl}-amide 959 411 2-Fluoro-N-{4-[3-(3-nitra-phenyl)-thioureido]-phenyl}-benzamide 960 422 Furan-2-carboxylic acid {4-[3-(3-trifluoromethoxy-phenyl)-thioureidol-phenyl }-amide 961 450 2-Fluoro-N-{4-[3-(3-trifluoromethoxy-phenyl)-thioureido)-phenyl}-benzamide 962 384 2-Fluoro-N-{4-(3-(3-fluoro-phenyl}-thioureido]-phenyl}-benzamide 963 41U 3-{3-[4-(2-Fluoro-benzoylamino)-phenyl]-thioureido}-benzoic acid 964 382 3-(3-{4-[(Furan-2-carbonyl)-amino]-phenyl}-thioureido)-benzoic acid 965 4()8 N-{4-j3-(3-Acetyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 966 5U2 N-{4-[3-(3-Butylsulfamoyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 967 380 Furan-2-carboxylic acid {4-[3-(3-acetyl-phenyl)-thioureidoj-phenyl}-amide 968 447 Furan-2-carboxylic acid (4-{3-[3-(2-hydroxy-ethanesulfonyl)-phenyl]-thioureido }-phenyl)-amide 969 475 2-Fluoro-N-(4-{3-[3-(2-hydroxy-ethanesulfanyl)-phenyl)-thioureido}-phenyl)-benzamide 970 474 Furan-2-carboxylic acid {4-[3-(3-butylsulfamoyl-phenyl)-thioureido)-phenyl}-amide EXAMPLE 971 (M;ETHOD 57) 1-(4-Fluoro-phenyl)-2-methyl-propan-1-of To solution of 4-fluorobenzaldehyde {2.() g) in diethyl ether (4() mL) at O
°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, tliter~ed and evaporated to give an oil. The nil is purifed by silica gel chromatography eluting with 1()x/0 dichloromethane-hexanes to give the product, a yellow oil {1.76 ~!).
EXAMPLE 972 (METHOD S8) 1-(4-Fluoro-phenyl)-2-metlhyl-propan-1-one To a solution of 1-(4-Fluoro-phenyl)-2-methyl!-propan-1-of ( 1.6 g) in acetone ( 1 (>
mL) at O °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 973 (ME'THOD 59) 3-Dimethytamina-5-trifluoramethyl-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 retlux for I2 hours. The reaction is diluted with water (4() 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 CYTOMEG.ALOVIRUS
Yield assay. Monolayer cultures of human foreskin fibroblasts are infected with HCMV wild-type, typically at a multiplicity of infection equal to U.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 lU the virus in 12-well plates of cultured human foreskin libroblasts (done in the absence of inhibitor). Plaques are quantified at 2 weeks post-infection. An inhibitor of HCMV is identified by the reduction in tiiter 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 ICSp or IC9U value, that is, the amount of compound required to reduce the virus yield by 5U% or 90/0, respectively. Table I describes IC,~ data for compounds tested against HCMV.
Microtiter plate assay. Ninety-six well plate cultures of human foreskin 2U 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. Harsh. 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 RV 145 (Jones, T. R.; V. P. Muzithras, and Y. Gluzman. 1991. Replacement mutagenesis of the human cytomegalovirus genome: US 1 (> and US I 1 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 3() Iysates are prepared {usin= SUmM sodium phosphate [pH7.()] containing U.1 % Triton X-lUU and U.1~/~ sarkosyl) and assayed for beta-glucuronidase activity using a substrate far the enzyme which when cleaved yields either a product which can be measured colorimetrically in a spectrophotometer or tluorescently in a WO 00/34261 pCT/US99/289i6 microtluorimeter. Examples of such substrates are p-nitrophenyl-beta-D-glucuronide and methylumbeIliferylglucuronide, 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 tluorophore product in this assay is correspondingly reduced.
Data from this assay generated using varying amounts of inhibitor compound is also used to estimate the ICSp of an inhibitor compound.
HSV antiviral (ELISA} assay 1 (?
Vero cells (ATCC #CCL-81) are plated on 96--well tissue culture plates at 3.5x10' cells per 1()()pl tissue culture DMEM {Dulbecco's moditied Eagle media) supplemented with 2% fetal bovine serum (FIBS} in each well. After overnight incubation C> 37°C (in 5°l~ COz) and 30 minutes prior to infection with HSV-1 (multiplicity of infection equal to 0.()()6), cells are either untreated, or treated with test compound (multiple concentrations} or reference standard drug control.
After approximately 24 hours post-infection incubation C> 37°C (in 5~7o CO,), 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 13-galactosidase. Thus the extent of viral replication is determined by assessing 1~-galactosidase activity by quantifying the generation of the 4-methyl umbelliferone fluorescent cleavage product after addition of the methyl umbelliferyl-li-D-galactoside {Sigma #M1633} substrate on a microtluorimeter (365nm for excitation and 45Unrn for emission). Antiviral activity (ICso) of the test compound is determined by comparing the flourescence obtained in absence of compound to that obtained in the presence of compound: Data is shown in Table I.
VZV antiviral (ELISA) assay 3Q For the generation of stock VZV to be used in the assay, VZV strain Ellen (ATCC
#VR-1367) is used to infect human foreskin fibrolalast (HFF) cells at low multiplicity {less than ().1) and incubated overnight at 37°C in 5~/o CO~. After the overnight incubation, the mixture of uninfected and VZV-iinfected HFF infected cells are then harvested and added to each well of 96-well plates (3.Sx 1 ()' cells in 1 (H) lal DMEM
supplemented with 2% FBS) which contain test compound or the reference standard drug control (in 1()()pl DMEM supplemented with 2% FBS per well). These cells are incubated for three days at 37°C in 5% CO~, 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 13-galactosidase. Thus the extent of viral replication is determined by assessing f3-galactosidase activity by quantifying the generation of the 4-methyl umbelliferone fluorescent cleavage product after addition of the methyl umbelliferyl-l;-D-galactoside (Sigma #M1633) substrate on a microfluorimeter (365nm for excitation and 450nm for emission). Antiviral activity (ICS,) 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 ICso data for compounds tested against herpes viruses.
Example ICS(! IC5(1 % IC50 {ug/ml) (ug/ml} inhibittion(ug/ml) HCMV HSV 1() ug/ml VZV

VZV

276 >10 >10 75 4 287 >50 8 5 >10 294 > 1 () >SO 0 > 10 296 8 1.2 48 >10 302 > 1 () 10 5 > 10 306 2.5 >10 33 >10 3t)7 5 >10 30 >10 311 6 12 13 >10 320 8 8 50 > 1 () 324 8 4 24 >10 328 >10 >10 44 >10 339 50 >50 11 >10 356 0.4 0.5 72 1.9 382 >1() >10 46 >10 390 >10 0.5 61 >10 858 2 2.5 26 >1() Thus, in accordance with the present invention, compounds of the present invention may be administered to a patient :suffering from VZV, in an amount effective to inhibit the virus. Compounds of tile present invention are thus useful to ameliorate to eliminate the symptoms of VZV infections in mammals including, but not limited to humans.
Compounds of the invention may be administered to a patient either neat or with a conventional pharmaceutical carrier.
Applicable solid carriers can include one or more substances which may also 1(> act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents or an encapsulating material.
Tn 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 talblets 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.
2() 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, (favoring 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 3U 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 snit dosage form, e.g. as tablets or capsules. Tn 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 pocketed 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 CMV
infection must be subjectively determined by the attending physician. The variables involved include the the condition , age and weight of the patient. The novel method of the invention for treating CMV infection comprises administering too subject, including humans, an effective amount of at least one compound of Formula 1 'or a non-toxic, pharmaceutically acceptable salt tl'~ereof. 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 2U condition of the patient. The usual daily dose is O.UI - 1(K)() mg/Kg for oral application, preferably 0:5 - 500 mg/Kg, and G.1 - 10() mg/Kg for parenteral application, preferably 0.5 - SU mg/Kg.

Claims (20)

What is claimed:

1. A compound of the formula:

wherein R1-R5 are independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10 carbon members, aryl, heteroaryl, halogen, -CN, -NO3, -CO3R6, -CO3R6, -OR6, -SR6, -SOR6, -SO2R6, -CONR7R8, -NR6N(R7R8), -N(R7R80) or W-Y-(CH2)n-Z provided that at least one of R1-R5 is not hydrogen; or R2 and R3 or R3 and R4, taken together form a 3 to 7 membered heterocycloalkyl or 3 to 7 membered heteroaryl;
R6 and R7 are independently hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, or aryl;
R8 is hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10 members, aryl or heteroaryl, or R7 and R8, taken together may form a 3 to 7 membered heterocycloalkyl;
R9-R12 are independently hydrogen, alkyl of 1 to 4 carbon atoms, perhaloalkyl of 1 to 4 carbon atoms, halogen, alkoxy of 1 to 4 carbon atoms, or cyano, or R9 and R10 or R11 and R12 may be taken together to form aryl of 5 to 7 carbon atoms; provided that at least one of R9-12 is not hydrogen;
W is O, NR6, or is absent;

Y is -(CO)- or -(CO2)-, or is absent;
Z is alkyl of 1 to 4 carbon atoms. -CN, -CO2R6, COR6, -CONR7R8, -OCOR6, -NR6COR7, -OCONR6, -OR6, -SR6, -SOR6, -SO2R6, SR6N(R7R8), -N(R7R8) or phenyl;
G is a monocyclic heteroaryl;
X is a bond, -NH, alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, or thioalkyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms, or (CH)J;
J is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl or benzyl; and n is an integer from 1 to 6, or pharmaceutical salts thereof.

2. A compound of Claim 1 wherein R1 through R5 are independently, hydrogen alkyl of 1 to 6 carbon atoms, halogen, perhaloalkyl of 1 to 6 carbon atoms, OR6 or N(R7R8).

3. A compound of Claim 1 wherein R1, R2 and R3 are hydrogen and R4 and R5 are independently, halogen or CF3.

4. A compound of Claim 1 wherein R1, R2 and R4 are hydrogen and R3 and R5 are independently, halogen or CF3.

5. A compound of Claim 1 wherein G is thiazolyl, thiadiazolyl, oxazolyl or furyl.

6. A compound of Claim 1 wherein G is furyl.

7. A compound of Claim 1 wherein R9-R12 are independently, hydrogen, halogen, methyl, methoxy and cyano.

8. A compound of Claim 1 wherein X is a bond.

9. A compound of Claim 1 wherein X is straight chain alkyl.

10. A compound of Claim 1 wherein X is alkyl of 1 to 4 carbon atoms.

11. A compound of Claim 1 selected from:
Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2,5-dimethoxy-phenyl}-amide, Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-3-trifluoromethyl-phenyl}-amide, Furan-2-carboxylic acid {3-chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide, Furan-2-carboxylic acid {5-chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methyl-phenyl}-amide, Furan-2-carboxylic acid {5-chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-hydroxy-phenyl}-amide, Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-3-cyano-phenyl}-amide, Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-3-methyl-phenyl}-amide, Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methoxy-5-methyl-phenyl}-amide, Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-3-methoxy-phenyl}-amide, Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-trifluoromethyl-phenyl}-amide, Furan-2-carboxylic acid {2-chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide, Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-cyano-phenyl}-amide, 5-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-[(furan-2-carbonyl)-amino]-benzoic acid, Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-phenylcarbamoyl-phenyl}-amide, Furan-2-carboxylic acid {2-benzoyl-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide, Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methyl-phenyl}-amide, Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-naphthalen-1-yl}-amide;
and Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methoxy-phenyl}-amide, or a pharmaceutical salt thereof.

12. A pharmaceutical composition comprising a compound of the formula:

wherein R1-R5 are independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10 carbon members, aryl, heteroaryl, halogen, -CN, -NO~, -CO2R6, -COR6, -OR6, -SR6, -SOR6, -SO2R6, -CONR7R8, -NR6N(R7R8), -N(R7R8) or W-Y-(CH2)n-Z provided that at least one of R1-R5 is not hydrogen; or R2 and R3 or R3 and R4, taken together form a 3 to 7 membered heterocycloalkyl or 3 to 7 membered heteroaryl;
R6 and R7 are independently hydrogen, alkyl of 7 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, or aryl;
A monocyclicR8 is hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10 members, aryl or heteroaryl, or R7 and R8, taken together may form a 3 to 7 membered heterocycloalkyl;

R9-R12 are independently hydrogen, alkyl of 1 to 4 carbon atoms, perhaloalkyl of 1 to 4 carbon atoms, halogen, alkoxy of 1 to 4 carbon atoms, or cyano, or R9 and R10 or R11 and R12 may be taken together to form aryl of 5 to 7 carbon atoms; provided that at least one of R9-12 is not hydrogen;
W is O, NR6, or is absent;
Y is -(CO)- or -(CO2)-, or is absent;
Z is alkyl of 1 to 4 carbon atoms, -CN, -CO2R6, COR6, -CONR7R8, -OCOR6, -NR6COR7, -OCONR6, -OR6, -SR6, -SOR6, -SO2R6, SR6N(R7R8), -N(R7R8) or phenyl;
G is a monocyclic heteroaryl;
X is a bond, -NH, alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, or thioalkyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms, or (CH)J;
J is alkyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl or benzyl; and n is an integer from 1 to 6, or pharmaceutical salts thereof; and a pharmaceutically acceptable carrier or diluent.

13. A method of inhibiting the replication of a herpes virus comprising contacting a compound of the formula:
wherein R1-R5 are independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10 carbon members, aryl, heteroaryl, halogen, -CN, -NO2, -CO2R6, -COR6, -OR6, -SR6, -SOR6, -SO2R6, -CONR7R8, -NR6N(R7R8), -N(R7R8) or W-Y-(CH2)n-Z provided that at least one of R1-R5 is not hydrogen; or R2 and R3 or R3 and R4, taken together form a 3 to 7 membered heterocycloalkyl or 3 to 7 membered heteroaryl;
R6 and R7 are independently hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, or aryl;
R8 is hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10 members, aryl or heteroaryl, or R7 and R8, taken together may form a 3 to 7 membered heterocycloalkyl;
R9-R12 are independently hydrogen, alkyl of 1 to 4 carbon atoms, perhaloalkyl of 1 to 4 carbon atoms, halogen, alkoxy of 1 to 4 carbon atoms, or cyano, or R9 and R10 or R11 and R12 may be taken together to form aryl of 5 to 7 carbon atoms; provided that at least one of R9-13 is not hydrogen;
W is O, NR6, or is absent;
Y is -(CO)- or -(CO2)-, or is absent;
Z is alkyl of 1 to 4 carbon atoms, -CN, -CO2R6, COR6, -CONR7R8, -OCOR6, -NR6COR7, -OCONR6, -OR6, -SR6, -SOR6, -SO2R6, SR6N(R7R8), -N(R7R8) or phenyl;
G is a monocyclic heteroaryl;
X is a bond, -NH, alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, or thioalkyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms, or (CH)J;
J is alkyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl or benzyl; and n is an integer from 1 to 6, or pharmaceutical salts thereof, with a herpes virus.

14. The method of Claim 13 wherein the herpes virus is human cytomegalovirus.

15. The method of Claim 13 wherein the herpes virus is herpes simplex virus.

16. The method of Claim 13 where the herpes virus is varicella zoster virus.

17. A method of treating a patient suffering from a herpes virus infection comprising administering to the patient in need thereof a therapeutically effective amount of a compound having the formula:
wherein R1-R5 are independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10 carbon members, aryl, heteroaryl, halogen, -CN, -NO2, -CO2R6, -COR6, -OR6, -SR6, -SOR6, -SO2R6, -CONR7R8, -NR6N(R7R8), -N(R7R8) or W-Y-(CH2)n-Z provided that at least one of R4-R5 is not hydrogen; or R2 and R3 or R3 and R4, taken together form a 3 to 7 membered heterocycloalkyl or 3 to 7 membered heteroaryl;
R6 and R7 are independently hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, or aryl;
R8 is hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10 members, aryl or heteroaryl, or R7 and R8, taken together may form a 3 to 7 membered heterocycloalkyl;
R9-R12 are independently hydrogen, alkyl of 1 to 4 carbon atoms, perhaloalkyl of 1 to 4 carbon atoms, halogen, alkoxy of 1 to 4 carbon atoms, or cyano, or R9 and R10 or R11 and R12 may be taken together to form aryl of 5 to 7 carbon atoms; provided that at least one of R9-12 is not hydrogen;
W is O, NR6, or is absent:

Y is -(CO)- or -(CO2)-, or is absent;
Z is alkyl of 1 to 4 carbon atoms, -CN, -CO2R6, COR6, -CONR7R8, -OCOR6, -NR6COR7, -OCONR6, -OR6, -SR6, -SOR6, -SO2R6, SR6N(R7R8), -N(R7R8) or phenyl;
G is a monocyclic heteroaryl;
X is a bond, -NH, alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, or thioalkyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms, or (CH)J;
J is alkyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl or benzyl; and n is an integer from 1 to 6, or pharmaceutical salts thereof.

18. The method of Claim 17 wherein the herpes virus is human cytomegalovirus.

19. The method of Claim 17 wherein the herpes virus is herpes simplex virus.

20. The method of Claim 17 where the herpes virus is varicella zoster virus.