Note: Descriptions are shown in the official language in which they were submitted.
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HETEROCYCLIC CARBOXAMIDE-CONTAINING THIOUREA
INHIBITORS OF HERPES VIRUSES CONTAINING 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.
Lippincott-
Raven Publishers, Philadelphia, PA). Each member of this family is
characterized by
an enveloped virus containing proteinaceous tegument and nucleocapsid, the
latter of
which houses the viruses' relatively large double-stranded DNA genome (i.e.
approximately 80-250 kilobases). Members of the human alphaherpesvirus
subfamily are neurotropic and include herpes simplex virus type 1 (HSV-1) and
type
2 (HSV-2), and varicella-zoster virus (VZV). The human betaherpesviruses are
cytomegalovirus (HCMV), human herpesvirus 6 (HHV-6) and human herpesvirus 7
{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-
l and
HSV-2 [Whitley, R.J. 1996. Herpes Simplex Viruses, p. 2297-2342. In B. N.
Fields,
D. M. Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed. Lippincott-Raven
Publishers, Philadelphia, PA]); chicken pox and shingles (VZV [Arvin, A. 1996.
Varicella-Zoster Virus, p. 2547-2585. In B. N. Fields, D. M. Knipe, and P. M.
Howley (ed.), Fields Virology, 3rd ed. Lippincott-Raven Publishers,
Philadelphia,
PA]); infectious mononucleosis (EBV [Rickinson, A. B. and Kieff, E. 1996.
Epstein-
Barr Virus, p: 2397-2446. In B. N. Fields, D. M. Knipe, and P. M. Howley
(ed.),
Fields Virology, 3rd ed. Lippincott-Raven Publishers, Philadelphia, PA]);
pneumonia and retinitis (HCMV [(Britt, W. J., and Alford, C. A. 1996.
Cytomegalovirus, p. 2493-2523. In B. N. Fields, D. M. Knipe, and F. M. Howley
(ed.), Fields Virology, 3rd ed. Lippincott-Raven Publishers, Philadelphia,
PA]);
exanthem subitum {HHV-6 [(Pellet, P. E, and Black, J. B. 1996. Human
Herpesvirus
6, p. 2587-2608. In B. N. Fields, D. M. Knipe, and P. M. Howley (ed.), Fields
Virology, 3rd ed. Lippincott-Raven Publishers, Philadelphia, PA] and HHV-7
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[Frenkel, N., and Raffman, E. 1996. Human Herpesvirus 7, p. 2609-2622. In B.
N.
Fields, D. M. Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed.
Lippincott-
Raven Publishers, Philadelphia, PA]); and Kaposi's sarcoma (HHV-8 [Neipel, F.,
Albrecht, J.C., and Fleckenstein, B. 199'7. Cell-homologous genes in the
Kaposi's
sarcoma-associated rhadinovirus human herpesvirus 8: determinants of its
pathogenicity? J. Virol. 71:4I8'7-92, 19971). HCMV is considered in more
detail
below. Following the primary infection, herpesviruses establish latency within
the
infected individual and remain there for the remainder of hislher life.
Periodic
reactivation of latent virus is clinically relevant. In the case of HSV,
reactivated
virus can be transmitted to infants during birth, causing either skin or eye
infection,
central nervous system infection, or disseminated infection (i.e. multiple
organs or
systems). Shingles is the clinical manifestation of VZV reactivation.
Treatment of
HSV and VZV is generally with antiviraI drugs such as acyclovir (Glaxo
Wellcome),
ganciclovir (Roche) and fascarnet (Asta) which target viral encoded DNA
polymerase:
HCMV is a ubiquitous opportunistic pathogen infecting 50-90°l0 of
the adult
population (Britt, W. J., and Alford, C. A. 1996. Cytomegalovirus, p. 2493-
2523. In
B. N. Fields, D. M. Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed.
Lippincott-Raven Publishers, Philadelphia, Pa.). Primary infection with HCMV
is
usually asymptomatic, although heterophile negative mononucleosis has been
observed. The virus is horizontally transmitted by sexual contact, breast
milk, and
saliva. Intrauterine transmission of HCMV from the pregnant mother to the
fetus
occurs and is often the cause of serious clinical consequences. HCMV remains
in a
latent state within the infected person for the remainder of his/her life.
Cell-mediated
immunity plays a central role in controlling reactivation from latency.
Impaired
cellular immunity leads to reactivation of latent HCMV in seropositive
persons.
HCMV disease is associated with deficient or immature cellular immunity.
There are 3 major categories of persons with HCMV disease (reviewed by Britt
and
Alford, I996). (1) In immunocompromised {AIDS) patients, HCMV is one of the
two most common pathogens causing clinical disease (the other is
Pnea~mocystis).
The most common manifestation of HCMV in AIDS is retinitis, although infection
of
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other organs including the adrenal glands, lungs, GI tract, and central
nervous system
are also reported frequently. 90% of AIDs patients have active HCMV infection;
25-
40% (85,000 patients in the United States) have life- or sight-threatening
HCMV
disease. HCMV is the cause of death in 10% of persons with AIDS. (2) Due to
immune system suppression to reduce the risk of graft rejection, HCMV
reactivation
or reinfection is common amongst kidney, liver, heart, and allogeneic bone
marrow
transplant patients. Pneumonia is the most common HCMV disease in these
patients,
occurring in up to 70% of these transplant patients. (3) Congenital infection
due to
HCMV occurs in 1% of all births, about 40K per year. Up to 25% of these
infants
are symptomatic for HCMV disease between ages 0-3 years. HCMV disease is
progressive, causing mental retardation and neurological abnormalities, in
children.
Recent studies suggest that treatment with anti-HCMV drugs may reduce
morbidity
in these children.
Several antiviral drugs are currently being marketed (Bron, D., R. Snoeck,
and L. Lagneaux. 1996. New insights into the pathogenesis and treatment of
cytomegalovirus. Exp. Opin. Invest. Drugs 5:337-344.; Crumpacker, C. 1996.
Ganciclovir. New Eng. J. Med. 335:721-729; Sachs, S., and F. Alrabiah. 1996.
Novel
herpes treatments: a review. Exp. Opin. Invest. Drugs 5:169-183). These
include:
ganciclovir (Roche), a nucleoside analog with hemopoietic cell toxicity;
foscarnet
(Astray, a pyrophosphate analog with nephrotoxicity; and cidofovir, Gilead), a
nucleoside phosphonate with acute nephrotoxicity. Each of these drugs target
the
viral-encoded DNA polymerise, are typically administered intravenously due to
their
low bioavailability, and, as noted above, are the source of significant
toxicity.
Ganciclovir-resistant mutants which arise clinically are often cross-resistant
with
cidofovir. Hence, there is a need for safer (i.e. less toxic), orally
bioavailable anti-
viral drugs which are directed against novel viral targets.
Phenyl thioureas are disclosed for use in a variety of pharmaceutical
applications. Armistead, et al., WO 97/40028, teaches phenyl areas 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.
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hm ./~ %(R~ )m
H H
Morin, Jr., et al., U.S. Patent No. 5,593,993 teaches certain phenyl thiourea
compounds for treatment of AIDS and the inhibition of the replication of HIV
and
related viruses.
Therefore, it is an object of this invention to provide compounds, and
pharmaceutically acceptable salts thereof, to inhibit and/or treat diseases
associated
with herpes viruses including human cytomegalovirus, herpes simplex viruses,
Epstein-Barr virus, varicella-zoster virus, human herpesviruses-6 and -7, and
Kaposi
herpesvirus.
Description of the Invention
In accordance with the present invention are provided compounds having the
formula:
Ra Rs
S _ O
R3 ~ X-NH-C-NH ~ NH-C-O
2 R,
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, cycloaIkyl of 3 to 10 carbon
atoms, heterocycloalkyl of 3 to 10 carbon members, aryl, heteroaryl,
halogen, -CN, -NO2, -C02R6, -CORE, -OR6, -SR6, -SORE, -SOZR6,
-CONR,RB, -NR6N(R7R8), -N(R,RB) or W-Y-{CH2)n Z provided that at
least one of Rl-RS is not hydrogen; or RZ and R3 or R3 and R4, taken
together form a 3 to 7 membered heterocycloalkyl or 3 to 7 membered
heteroaryl;
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R6 and R, are independently hydrogen, alkyl of 1 to 6 carbon atoms,
perhaloalkyl of 1 to 6 carbon atoms, or aryl;
R8 is hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon
atoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10
members, aryl or heteroaryl, or
R~ and R8, taken together may form a 3 to 7 membered heterocycloalkyl;
W is O, NR6, or is absent;
Y is -(CO)- or -(COZ)-, or is absent;
Z is alkyl of 1 to 4 carbon atoms, -CN, -C02R6, CORE, -CONR7R8, -OCOR6,
-NR6COR,, -OCONR6, -OR6, -SR6, -SORE, -SOZR6, SR6N{R,RB),
-N(R,R$) or phenyl;
G is monocyclic heteroaryl;
X is a bond, -NH, alkyl of 1 to b carbon atoms, alkenyl of 1 to 6 carbon
atoms, alkoxy of 1 to 6 carbon atoms, thioalkyl of 1 to 6 carbon
atoms, alkylamino of 1 to 6 carbon atoms, or (CH)J;
J is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl
or
benzyl; and
n is an integer from 1 to 6,
or pharmaceutical salts thereof.
In some preferred embodiments of the present invention, R,-RS are
independently, hydrogen alkyl of ,1 to 6 carbon atoms, halogen, perhaloalkyl
of 1 to 6
carbon atoms, OR6 or N(R7Rg). Preferably, 1 to 3 of R,-R$ is not hydrogen.
Most
preferably, 2 of R,-RS is not hydrogen. In preferred compounds of the present
invention R3 and R5, or R4 and RS are preferably, independently, halogen or
CF3.
In some embodiments of the present invention G is monocyclic heteroaryl,
preferably thiazolyl, thiadiazolyl, oxazolyl or furyl. G is preferably not
substituted.
In some embodiments of the present invention X is a bond, CH(J) or C,-C,
alkyl. Preferably, when X is C,-C4 alkyl, said alkyl is straight chain alkyl.
When X
is CH(J), J is preferably methyl.
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Preferred compounds of the present invention are the following compounds
which include pharmaceutical salts thereof.
[ 1,2,3)Thiadiazole-4-carboxylic acid { 4-[3-(3,5-bis-trifluoromethyl-benzyl)-
thioureido)-phenyl }-amide,
[ 1,2,3)Thiadiazole-4-carboxylic acid { 4-[3-(4-piperidin-1-yI-3-
trifluoromethyl-benzyl)-thioureido]-phenyl }-amide,
[1,2,3)Thiadiazole-4-carboxylic acid {4-[3-(4-dimethylamino-3-
trifluoromethyl-benzyl)-thioureido)-phenyl }-amide,
[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-dimethylamino-5-
trifluoromethyl-benzyl)-thioureido]-phenyl }-amide,
[1,2,3)Thiadiazole-4-carboxylic acid {4-[3-(4-fluoro-3-trifluoromethyl-
benzyl)-thioureido)-phenyl }-amide,
Thiazole-4-carboxylic acid {4-[3-(4-tent-butyl-benzyl)-thioureido]-phenyl}-
amide,
[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-fluoro-5-trifluoromethyl-
phenyl)-ethyl]-thioureido } -phenyl)-amide,
[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4-bromo-phenyl)-ethyl]-
thioureido }-phenyl)-amide,
Thiazole-4-carboxylic acid {4-[3-(3,4-dichloro-benzyl)-thioureido]-phenyl}-
amide,
[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-dichloro-benzyl)-thioureido]-
phenyl }-amide,
[1,2,3)Thiadiazole-4-carboxylic acid {4-[3-(3,4-dichloro-benzyl)-thioureido]-
phenyl }-amide,
[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3,4-dichloro-phenyl)-ethyl)-
thioureido }-phenyl)-amide,
[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4-trifluoromethyl-phenyl)-
ethyl)-thioureido }-phenyl)-amide,
[ 1,2,3]Thiadiazole-4-carboxylic acid (4-{ 3-[2-(3-chloro-phenyl)-ethyl]-
thioureido }-phenyl)-amide,
[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-tert-butyl-benzyl)-thioureido]-
phenyl }-amide,
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Thiazole-4-carbaxylic acid {4-(3-(3,5-dichloro-phenyl)-thioureido]-phenyl }-
amide,
[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(2-fluoro-5-trifiuoromethyl-
phenylsulfanyl)-ethyl]-thioureido }-phenyl)-amide,
(1,2,3]Thiadiazoie-4-carboxylic acid {4-{3-(2-{2,4-bis-trifluoromethyl-
phenyl)-ethyl]-thioureida }-phenyl)-amide,
[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4-fluoro-3-trifluoromethyl-
phenyl)-ethyl)-thioureido }-phenyl)-amide,
(1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-fluoro-5-trifluorornethyl-
benzyl)-thioureido]-phenyl}-amide,
[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3,5-bis-trifluoromethyl-
phenyl)-ethyl]-thiaureido }-phenyl)-amide,
[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-iodo-3-trifluoromethyl-
phenyl)-thioureida]-phenyl }-amide,
[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-fluoro-5-trifluoromethyl-
benzyl)-thioureido]-phenyl }-amide,
[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-bromo-phenylsulfanyl)-
ethyl]-thioureido }-phenyl)-amide,
[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(2-fluaro-phenyl)-ethyl]-
thioureido}-phenyl)-amide,
[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(2,4-dichloro-phenyl)-ethyl]-
thioureido }-phenyl)-amide,
[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-trifluoromethyl-phenyl)-
ethyl]-thioureido } -phenyl)-amide,
[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(2-fluoro-5-trifluorornethyl-
phenoxy)-ethyl]-thioureido }-phenyl)-amide,
Thiazole-4-carboxylic acid {4-[3-(2-fluoro-5-trifluoramethyl-benzyl)-
thiaureido]-phenyl }-amide,
[ 1,2,3]Thiadiazole-4-carboxylic acid (4-{ 3-[2-(3-iodo-phenyl)-ethyl]-
thioureido}-phenyl)-amide,
Furan-2-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl-benzyl)-thioureido]-
phenyl }-amide,
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[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[3-(2-methyl-butyl)-5-
trifluoromethyl-phenyl]-thioureido }-phenyl)-amide,
[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-isobutyl-5-tritluoromethyl-
phenyl)-thioureido]-phenyl }-amide,
[I,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-dimethylamino-5-
trifluoromethyl-phenyl)-ethyl]-thioureido }-phenyl)-amide,
[I,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(5-bromo-2-methoxy-phenyl)-
ethyl]-thioureido }-phenyl)-amide,
[x,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4-chloro-phenyl)-ethyl]-
thioureido }-phenyl)-amide,
[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3,5-dichloro-phenoxy)-ethyl]-
thioureido }-phenyl)-amide,
Thiazole-4-carboxylic acid {4-[3-(3,4-dichloro-phenyl)-thioureido]-phenyl}-
amide,
Thiazole-4-carboxylic acid { 4-[3-(4-chloro-3-trifluoromethyl-phenyl)-
thioureido]-phenyl }-amide,
[I,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3,4-dichloro-phenylsulfanyl)-
ethyl]-thioureido }-phenyl)-amide,
[ I,2,3]Thiadiazole-4-carboxylic acid (4- { 3-[2-(2-fluoro-3-trifluoromethyl-
phenyl)-ethyl]-thioureido}-phenyl)-amide,
[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(2-fluoro-5-trifluoromethyl-
phenyl)-ethyl]-thioureido }-phenyl)-amide,
[ 1,2,3]Thiadiazole-4-carboxylic acid (4-{ 3-[2-(3-bromo-phenyl)-ethyl]-
thioureido }-phenyl)-amide,
[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-4-trifluoromethyl-
phenyl)-thioureido]-phenyl }-amide,
[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-4-iodo-phenyl)-
thioureido]-phenyl }-amide,
Furan-2-carboxylic acid [4-(3-benzo[1,3]dioxol-5-ylmethyl-thioureido)-
phenyl]-amide,
[1,2,3]Thiadiazole-4--carboxylic acid (4-{3-[1-(4-bromo-phenyl)-ethyl]-
thioureido }-phenyl)-amide,
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[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,3-diphenyl-propyl)-thioureido]-
phenyl }-amide,
[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-{3-chloro-4-ftuoro-benzyl)-
thioureido]-phenyl }-amide,
[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3,4-dichloro-phenoxy)-ethyl]-
thioureido }-phenyl)-amide,
[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-trifluoromethyl-benzyl)-
thioureidol-phenyl }-amide,
[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-benzyl)-thioureido]-
phenyl }-amide,
[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-bromo-3-trifluoromethyl-
phenyl)-thioureido]-phenyl }-amide,
[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4-fluoro-phenyl)-ethyl]-
thioureido }-phenyl)-amide,
[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-{3-pyrrolidin-1-yl-5-
trifluoromethyl-phenyl)-thioureido]-phenyl }-amide,
[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[3-(butyl-methyl-amino)-5-
trifluoromethyl-phenyl]-thioureido }-phenyl)-amide,
[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-dimethyl-benzyl)-thioureido]-
phenyl}-amide,
Thiazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl-phenyl)-
thioureido]-phenyl }-amide,
[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,4-dichloro-phenyl)-thioureido]-
phenyl }-amide,
[I,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-bromo-5-trifluoromethyl-
phenyl)-thioureido]-phenyl }-amide,
[1,2,3]Thiadiazole-4-carboxylic acid {4-{3-[2-(3-chloro-phenoxy)-ethyl]-
thioureido }-phenyl)-amide,
[1,2,3]Thiadiazole-4-carboxylic acid {4-{3-[2-(4-ethyl-phenyl)-ethyl]-
thioureido }-phenyl)-amide,
[1,2,3]Thiadiazole-4-carboxylic acid {4-{3-[2-(3-bromo-phenoxy)-ethyl]-
thioureido }-phenyl)-amide,
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[ 1,2,3]Thiadiazole-4-carboxylic acid { 4-[3-(4-chloro-benzyl)-thioureido]-
phenyl }-amide,
[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(5-chloro-2-methoxy-4-methyl-
phenyl)-thioureido]-phenyl }-amide,
[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-(2-(3-fluoro-phenyl)-ethyl]-
thioureido }-phenyl)-amide,
j1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-
thioureido }-phenyl)-amide,
[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-difluoro-benzyl)-thioureido]-
phenyl }-amide,
Furan-2-carboxylic acid {4-j3-(3,5-dichloro-benzyl)-thioureido]-phenyl}-
amide,
(1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-p-tolyl-ethyl)-thioureido]-
phenyl }-amide,
[1,2,3]Thiadiazole-4-carboxylic acid {4-(3-(4-phenyl-butyl)-thioureido]-
phenyl }-amide,
[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-phenylsulfanyl-ethyl)-
thioureido]-phenyl }-amide,
[1,2,3]Thiadiazole-4-carboxylic acid {4-(3-(3-iodo-benzyl)-thioureido]-
phenyl }-amide,
Furan-2-carboxylic acid (4-{3-[2-(3-bromo-phenylsulfanyl)-ethyl]-
thioureido }-phenyl)-amide,
Oxazole-4-carboxylic acid {4-[3-(3,5-dichioro-phenyl)-thioureido]-phenyl}-
amide,
(1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3,4-difluoro-phenyl)-ethyl}-
thioureido } -phenyl)-amide,
[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3,5-difluoro-phenyl)-ethyl]-
thioureido }-phenyl)-amide,
[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-iodo-phenoxy)-ethyl]-
thioureido }-phenyl)-amide,
[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-dichloro-phenyl)-thioureido]-
phenyl }-amide,
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[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-amino-5-chloro-phenyl)-
thioureido]-phenyl }-amide,
[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-bromo-phenyl)-thioureido]-
phenyl }-amide,
[I,2,3]Thiadiazole-4-carboxylic acid (4-{3-[3-(isobutyl-methyl-amino)-5-
trifluoromethyl-phenyl]-thioureido }-phenyl)-amide,
[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-phenyl-propyl)-thioureido]-
phenyl }-amide,
[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-chloro-4-fluoro-phenyl)-
thioureido]-phenyl}-amide,
[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3,4,5-trichloro-phenyl)-
thioureido]-phenyl }-amide,
Furan-2-carboxylic acid { 4-[3-(3,4-dichToro-benzyl)-thioureido]-phenyl }-
amide,
[1,2,3]Thiadiazoie-4-carboxylic acid {4-[3-(3-morpholin-4-yl-5-
trifluoromethyl-phenyl)-thioureido]-phenyl }-amide,
[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-fluoro-3-trifluoromethyl-
phenyl)-thioureido]-phenyl }-amide,
[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-fluoro-phenoxy)-ethyl]-
thioureido }-phenyl)-amide,
[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-iodo-phenyl)-thioureido]-
phenyl }-amide,
[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-bromo-4-trifluoromethoxy-
phenyl)-thioureido]-phenyl }-amide,
[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-dimethylamino-5-
trifluoromethyl-phenyl)-thioureido]-phenyl }-amide,
[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[4-(4-methyl-piperazin-1-yl)-3-
trifluoromethyl-benzyl]-thioureido }-phenyl)-amide,
[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,4-difluoro-benzyl)-thioureido]-
phenyl }-amide,
[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-bromo-3-chloro-phenyl)-
thioureido]-phenyl }-amide,
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[ 1,2,3]Thiadiazole-4-carboxylic acid { 4-[3-(3-chloro-phenyl)-thioureido]-
phenyl }-amide,
[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-phenoxy-ethyl)-thioureitlo]-
phenyl }-amide,
[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-methoxy-phenyl)-ethyl]-
thioureido }-phenyl)-amide,
[1;2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-4-methyl-phenyl)-
thioureido]-phenyl }-amide,
Furan-2-carboxylic acid {4-[3-(3-fluoro-5-trifluoromethyl-benzyl)-
thioureido]-phenyl }-amide,
[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4-nitro-phenyl)-ethyl]-
thioureido }-phenyl)-amide,
[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-piperidin-1-yl-5-trifluoro-
methyl-phenyl}-thioureido]-phenyl }-amide,
Oxazole-4-carboxylic acid {4-[3-(3,4-dichloro-phenyl)-thioureido]-phenyl}-
amide,
Furan-2-carboxylic acid {4-[3-(3,4,5-trichloro-phenyl)-thioureido]-phenyl}-
amide,
[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-chloro-phenyl)-thioureido]-
phenyl }-amide,
[1,2,3]Thiadiazole-4-carboxylic acid [4-(3-benzo[1,3]dioxol-5-ylmethyl-
thioureido)-phenyl]-amide,
[1,2,3]Thiadiazole-4-carboxylic acid [4-(3-phenethyl-thioureido)-phenyl]-
amide,
[ 1,2,3]Thiadiazole-4-carboxylic acid (4-{ 3-[2-(2-chloro-phenoxy)-ethyl]-
thioureido }-phenyl)-amide,
[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl-phenyl)-
thioureido]-phenyl }-amide,
[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-dichloro-2-methoxy-4-
methyl-phenyl)-thioureido]-phenyl}-amide,
[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[3-chloro-4-(1H-pyrazol-3-yl)-
phenyl]-thioureido }-phenyl)-amide,
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[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[3-chloro-4-(2-piperidin-1-yl-
acetylamino)-phenyl]-thioureido }-phenyl)-amide,
[1,2,3]Thiadiazole-4-carboxylic acid {4-(3-(3-trifluoromethyl-phenyl)-
thioureido]-phenyl }-amide,
[1,2,3]Thiadiazole-4--carboxylic acid {4-[3-{4-chloro-3-trifluoromethyl-
phenyl)-thioureido]-phenyl }-amide,
[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[3-chloro-4-(cyclahexyl-methyl-
amino)-phenyl]-thioureido }-phenyl)-amide,
Furan-2-carboxylic acid [4-(3-benzyl-thioureido)-phenyl]-amide,
IO Furan-2-carboxylic acid (4-{3-[2-(3,5-dichloro-phenoxy)-ethyl]-thiaureida}-
phenyl)-amide,
Furan-2-carboxylic acid {4-[3-(2-fluoro-5-trifluoromethyl-benzyl)-
thioureido]-phenyl }-amide,
[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-bromo-4-methoxy-phenyl)-
ethyl]-thioureido}-phenyl)-amide,
[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(2-chloro-phenyl)-ethyl]-
thioureido }-phenyl)-amide,
Oxazole-4-carboxylic acid {4-[3-{4-chloro-3-trifluoramethyl-phenyl)-
thioureido]-phenyl }-amide,
Furan-2-carboxylic acid (4-{3-[2-(3,4-dichlaro-phenyl)-ethyl}-thioureido}-
phenyl)-amide,
[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-chloro-benzyl)-thioureido]-
phenyl }-amide,
[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-broma-phenyl)-thiaureido]-
phenyl }-amide,
[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-fluoro-benzyl)-thioureido]-
phenyl }-amide,
Furan-2-carboxylic acid {4-[3-(4-bromo-3-chlora-phenyl)-thioureida]-
phenyl }-amide,
(1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[(1S)-I-(4-bromo-phenyl)-ethyl]-
thioureido }-phenyl)-amide,
[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-((1R)-1-(4-bromo-phenyl)-ethyl]-
thioureido } -phenyl)-amide,
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[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[1-(3,5-bis-trifluoromethyl-
phenyl)-ethyl]-thioureido }-phenyl)-amide,
[1,2,3]Thiadiazole-4-carboxylic acid {4-{3-[(1S)-1-(4-chloro-phenyl)-ethyl]-
thioureido }-phenyl)-amide,
[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[(1R)-1-(4-chloro-phenyl)-ethyl]-
thioureido }-phenyl)-amide,
N-[4-[[[[1-(4-Cyanophenyl)ethyl]amino]thioxomethyl]amino]phenyl]-1,2,3-
thiadiazole-4-carboxamide,
Thiazole-4-carboxylic acid (4-{ 3-[ 1-(4-bromo-phenyl)-ethyl]-thioureido }-
phenyl)-amide,
[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-(1S)-[1-(3,5-bis-trifluoroinethyl-
phenyl)-ethyl]-thioureido }-phenyl)-amide,
N-(4-{ [({ 1-[4-fluoro-3-(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]-
amino }phenyl)-1,2,3-thiadiazole-4-carboxamide,
N-(4-{[({ 1-[4-chloro-3-hiadiazole-4-carboxarnide,
N-(4- { [( { ( 1 S)-1-[3,5-thiazole-4-carboxamide,
N-(4-{ [( { 1-[3-fluoro-5-(trifluoromethyl)phenyl]ethyl } amino)carbothioyl]
amino } phenyl)-1,3-thi azole-4-carboxamide,
N-(4-{[({ 1-[2-fluoro-4-(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]-
amino}phenyl)-1,3-thiazole-4-carboxamide,
N-(4-{ [({ i-[2-fluoro-5-trifluoromethyl)phenyl]ethyl } amino)carbothioyl]-
amino }phenyl)-1,3-thiazole-4-carboxamide,
N-(4-{[({ 1-[2,4-bis(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}-
phenyl)-1,3-thiazole-4-carboxamide,
N-{4-[({[1-(2,4-dimethylphenyl)ethyl]amino}carbothioyl)amino]phenyl}-1,3-
thiazole-4-carboxamide, .
N-{ 4-[({ [ 1-(2,4-dichlorophenyl)ethyl] amino }carbothioyl)amino]phenyl }-1,3-
thiazole-4-carboxarnide,
N-{ 4-[({ [ 1-(3-methylphenyl)ethyl]amino }carbothioyl)amino]phenyl }-1,3-
thiazole-4-carboxamide,
N-(4-{ [({ 1-[4-fluoro-3-(trifluoromethyl)phenyl)ethyl}amino)
carbothioyl]amino } phenyl)-1,3-thiazole-4-carboxamide,
N- { 4-[{ { [ 1-(2-chloro-4-fluorophenyl)ethyl] amino } carbothioyl)
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amino]phenyl }-1,3-thiazole-4-carboxamide,
N-{4-[{{ [ 1-(3,4-difluorophenyl)ethyl]amino }caxbothioyl)aminoJphenyl }-1,3-
thiazole-4-carboxamide,
N-{ 4-[{ { [ 1-(4-bromo-2-fluorophenyl)ethyl]amino }carbothioyl)
amino]phenyl }-1,3-thiazole-4-carboxamide,
N-{ 4-[( { [ 1-{3-fluorophenyl)ethyl] amino } caxbothioyl)amino]phenyl }-1,3-
thiazole-4-carboxamide,
N-{ 4-[( { [ 1-(2-bromophenyl)ethyl] amino } carbothioyl)amino]phenyl }-1,3-
thiazole-4-carboxamide,
N-{4-[{{[1-(3-bromophenyl)ethyl]amino}carbothioyl)amino]phenyl}-1,3-
thiazole-4-carboxamide,
N-(4-{ j({ 1-[2-(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}-
phenyl)-1,3-thiazole-4-carboxamide,
N-{ 4-[({ [1-(2,4-difluorophenyl)ethyl]amino }carbothioyl)amino]phenyl }-1,3-
IS thiazole-4-carboxamide,
N-{4- { [{ { ( 1 R)-1-[3,S-bis(trifluoromethyl)phenyl]ethyl } amino)-
carbothioyl]amino }phenyl)-1,3-thiazole-4-carboxamide,
N-{ 4-[{{ [ 1-(3,4-dichlorophenyl)ethyl]amino }caxbothioyl)amino]phenyl }-1,3-
thiazole-4-carboxarnide,
N-(4-{ j({ 1-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]-
amino } phenyl)-1, 3-thiazole-4-carboxamide,
N-(4-{[({ 1-j4-chloro-3-(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]-
amino } phenyl)-1,3-thiazole-4-carboxamide,
N-{4-[({ [1-(4-chloro-2-fluorophenyl)ethyl]amino}carbothioyl)amino]-
phenyl}-1,3-thiazole-4-carboxamide,
N-(4-{ [({ 1-[4-fluoro-2-(trifluoromethyl)phenyl]ethyl }amino)carbothioyl]-
amino }phenyl)-1,3-thiazole-4-carboxamide,
N-{ 4-[({ [ 1-(4-chloro-3-fluorophenyl)ethyl]amino }carbothioyl)amino]-
phenyl }-1,3-thiazole-4-carboxamide,
N-{4-[({ j1-(2-bromo-4-fluorophenyl)ethyl]amino}carbothioyl)amino]-
phenyl }-1,3-thiazole-4-carboxamide,
N- { 4-[{{ [ 1-(3,4-dibromophenyi)ethyl] amino }carbothioyl)amino]phenyl }-1,3-
thiazole-4-carboxamide,
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N-{ 4-[({ [ 1-(3-chloro-4-fluorophenyl)ethyl]amino }carbothioyl)amino]-
phenyl }-1,3-thiazole-4-carboxamide,
N-(4-{ [({ 1-[3,5-bis(trifluoromethyl)phenyl]propyl}amino)carbothioyl]-
amino}phenyl)-1,2,3-thiadiazole-4-carboxamide,
N-(4-{[({ 1-[3,5-bis(trifluoromethyl)phenyl]butyl}amino)carbothioyl]-
amino }phenyl)-1,2,3-thiadiazole-4-carboxamide,
N-(4-{[({ 1-[3,5-bis(trifluoromethyl)phenyl]pentyl}amino)carbothioyl]-
amino }phenyl)-I,2,3-thiadiazole-4-carboxamide,
N-{4-[({ [[3,5-bis(trifluoramethyl)phenyl](phenyl)methyl]amino }-
carbothioyl)amino]phenyl}-1,2,3-thiadiazale-4-carboxamide,
N-(4-{ [({ 1-[3,5-bis(trifluoromethyl)phenyl]-I-methylethyl }amino)-
carbothioyl] amino } phenyl)-1,2,3-thiadiazole-4-carboxamide,
N-{ 4-[({ [3,5-bis(trifluoromethyl)benzyl]amino }carbothioyl)amino]phenyl }-
1H-imidazole-4-carboxarnide,
N-{4-[({[1-(4-fluorophenyl)ethyl]amino}carbothioyI)amino]phenyl}-1H-
imidazole-4-carboxamide,
N- { 4-[ ( { [3,5-bis(trifluoromethyl)benzyl]amino } carbothioyl)amino]phenyl
}-
1-methyl-1 H-imidazole-4-carboxarilide,
N-(4-{ [({ 1-[3,5-bis(trifluoromethyl)phenyl]propyl}amino)carbothioyl]-
amino}phenyl)-1,3-thiazole-4-carboxamide; and pharmaceutical salts thereof.
Unless otherwise defined, the terms used herein have the following meanings.
Alkyl as used herein refers to straight or branched chain lower alkyl of 1 to
fi
carbon atoms. Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl,
butyl,
isobutyl, t-butyl, pentyl and hexyl.
Alkenyl as used herein refers to straight ar branched chain lower alkyl of 2
to 6
carbon atoms containing at least one carbon-carbon double bond. Aikenyl
includes
vinyl groups.
Alkynyi as used herein refers to straight or branched chain lower alkyl of 2
to
6 carbon atoms containing at least one carbon-carbon triple bond.
Alkyl, alkenyl and alkynyl groups of the present invention may be substituted
or unsubstituted.
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Cycloalkyl refers to a saturated mono or bicyclic ring system of 3 to 10
carbon atoms. Exemplary cycloalkyl groups include cyclopentyl, cyclohexyl and
cycloheptyl. Cycloalkyl groups of the present invention may be substituted or
unsubstituted.
Heterocycloalkyl refers to a saturated mono or bicyclic ring system of 3 to
members having 1 to 3 heteroatoms selected from N, S and O, including, but not
limited to aziridinyl, azetidinyl, imidazolidinyl, morpholinyl,
thiomorpholinyl,
piperazinyl, pyrazolidinyl, piperidinyl, and pyrrolidinyl. Heterocycloalkyl
groups of
the present invention may be substituted or unsubstituted.
10 Aryl, as used herein refers to an aromatic mono or bicyclic ring of 6 to 10
carbon atoms. Exemplary aryl groups include phenyl, naphthyl, and biphenyl.
Aryl
groups of the present invention may be substituted or unsubstituted.
Heteroaryl as used herein refers to an aromatic mono or bicyclic ring of 5 to
10 members having 1 to 3 heteroatoms selected from N, S or O including, but
not
limited to thiazolyl, thiadiazolyl, oxazolyi, furyl, indolyl, benzothiazolyl,
benzotriazolyl, benzodioxyl, indazolyl, and benzofuryl. Preferred heteroaryls
include quinolyl, isoquinolyl, napthalenyl, benzofuranyl, benzothienyl,
indolyl,
pyridyl, pyrazinyl, thienyl, furyl, pyrrolyl, isoxazolyl, oxazolyl,
isothiazolyl,
thiazolyl, pyrazolyl, triazolyl, thiadiazolyl, and imidazolyl. Heteroaryl
groups of the
present 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 mernbered aromatic ring.
Halogen, as used herein refers to chlorine, bromine, iodine and fluorine.
Unless otherwise limited, substitutents are unsubstituted and may include
alkyl of 1 to 6 carbon atoms, cycloalkyl of 1 to 6 carbon atoms,
heterocycloalkyl of
lto b members, perhaloalkyl of 1 to 6 carbon atoms, amino, azido, hydroxy,
alkylamino, dialkylamino, aryl or heteroaryl.
Carbon number refers to the number of carbons in the carbon backbone and
does not include carbon atoms occurring in substituents such as an alkyl or
alkoxy
substituents.
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Where terms are used in combination, the definition for each individual part
of
the combination applies unless defined otherwise. For instance,
alkylcycloalkyl is an
alkyl-cycloalkyl group in which alkyl and cycloalkyl are as previously
described.
S 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.
The compounds of this invention contain a chiral center, providing for various
seteroisomeric forms of the compounds such as racemic mixtures as well as the
individual optical isomers. In some preferred embodiments of the present
invention the
compounds of the present invention are substantially pure optical isomers. By
substantially pure optical isomer is meant the composition contains greater
than 75% of
the desired isomer and may include no more than 25% of the undesired isomer.
In
more preferred embodiments the pure optical isomer is greater than 90% of the
desired
isomer. The individual isomers can be prepared directly or by asymmetric or
stereospecific synthesis or by conventional separation of optical isomers from
the
racemic mixture.
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,-R5, and X are described as above, with
appropriately
substituted isothiocyanates 3, wherein the substituent G is described above,
either
neat or in an appropriate solvent such as tetrahydrofuran, acetonitrile, ethyl
acetate,
dichloromethane, or N,N-dimethylformamide affords the desired thioureas 1.
Similarly, reaction of appropriately substituted isothiocyanates 4, wherein
the
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substitutents R,-R5, and X are described as above with appropriately
substituted
anilines 5, wherein the substituent G is described above, in a convenient
solvent such
as those listed above affords the desired thioureas 1.
Methods 31 and 34
R 5 R ,o
R3 ~ I NH2 + S=C' ~ I C--G
R2 Ri R » R,2
2 3
R ,o
RQ 5 ,
R ~ I ~-W G,-H ~ I GSh'-G
R2 R, R" R, 2
1
R4 5 R ,o
R ~ I X-fV~C~S + HZ ' I C-G
R2 Ri R" R12
a
Alternatively, appropriately substituted thioureas 1 can be prepared as
described by Methods 32 and 33 by reacting anilines 2 and 5, wherein R,-RS,
and G
are described as above, in the presence of either one molar equivalent of 1,1'-
thiocarbonyldiimidazole or I,1'-carbonyldiimidazole in an appropriate solvent
such
as dichloromethane and tetrahydrofuran or mixtures thereof or one molar
equivalent
of 1,1'-thiocarbonyl-di-(1,2,4)-triazole or 1,1'-carbonyl-di-(1,2,4)-triazole
in an
appropriate solvent such as dichlararnethane and tetrahydrofuran or mixtures
thereof
at room temperature.
Methods 32, 33
1} CS(Im}~ ~ ~ 32
2) ArNH2
H H
NHZ ~} CS(Tria~)2 ~ S ~ 33
2) ArNH2 I / N~N
H H
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In certain instances, subsequent chemical modification of the final thioureas
1
was required. These methods, Methods 35-39, are summarized below.
NaOH
EtOH ~ 35
I ~ ~ ~ ( NaOH ~ ' \
/ N N ~' EtOH ~ ,~ I 36
H H O' M H
Et
HOOC
\ / I BzCI
I / N'"' ~ / ~ \ I 37
N N
H H H
OBz
\ ~ MsCI
\ I ' 38
H
HNRz
,.. I ' I ~ ~ ~ I 39
O N N ~N
H H H H
OMs N~2
SnCtz
I MeOH ' ,/ _ ~ ~ I 40
N N
H H ~ N
N3 H H
2
Thioureas 1 wherein at least one substituent of R,-RS is 1-hydroxyethoxy or
carboxy-methoxy, G is defined as above and X equals a bond, may be prepared
from
the corresponding alkyl esters by alkaline hydrolysis with aqueous sodium or
potassium hydroxide in a suitable solvent such as methanol, tetrahydrofuran or
mixtures thereof at room temperature in accordance with Methods 35 and 36.
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Thioureas .1 wherein at least one substituent of R,-RS is 1-acyloxyethoxy or
methansulfonoxyethoxy, G is defined as above and X equals a bond, may be
prepared
from the corresponding 1-hydroxyethoxy derivative by acylation with
appropriate
acylating agents such as benzoic acid chloride or methanesulfonic acid
chloride in the
presence of a suitable tertiary amine base such as triethylamine or
diisopropylethylamine in a suitable solvent such as dichloromethane or the
like at
room temperature in accordance with Methods 37 and 38.
Thioureas 1 wherein at least one substituent of R,-RS is 1-aminoethoxy, G is
defined as above and X equals a bond, may be prepared from the corresponding I-
methanesuifonoxy-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 R1-RS is 1-arninoalkyl, G is
defined as above and X equals a bond, may be prepared from the corresponding 1-
azidoalkyl derivative by reaction with stannous chloride in a suitable solvent
such as
methanol, ethanol or the like at room temperature in accordance with Method
40.
2a
The intermediate isothiocyanates 3 and 4 shown above in Methods 31 and 34
are prepared in accordance with Method 41 (below), essentially according to
the
procedures of Staab, H.A. and Walther, G. Justus Liebigs Ann. Chem. 657, I04
(1962)) by reacting appropriately substituted amines 5 or 2, respectively,
wherein R,-
RS 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.
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Method 41
N
~N z
H2N ~ ~ i-C-G -~ S=C=N ~ ~ H-C-G
3
N=~
R4 5 / R4 5
2
R3 ~ ~ X-N H2 --s R3 ~ ~ X-N=C=S
R2 R1 R~ Rj
2 4
5
The intermediates 2 and 5 may be prepared according to the following
protocols:
According to Methods lA-1G, amines 2, wherein R1-RS are defined above and
i 0 X is defined above, amines 5 may be prepared by reductian 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, I979. Such procedures
include the reduction of nitrobenzenes to form anilines upon exposure to:
a) iron powder and a strong acid, such as hydrochloric acid (Methods lA)
either neat
or in alcohol solvent such as methanal or ethanol, at temperatures ranging
from
room temperature to the refluxing temperature of the solvent, or;
b) iron powder and glacial acetic acid (Method IB), either neat or in alcohol
solvent
such as methanol or ethanol, at temperatures ranging from room temperature to
the
refluxing temperature of the solvent, or;
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c) iron powder and aqueous ammonium chloride (Method 1C), either neat or in
alcohol solvent such as methanol or ethanol, at temperatures ranging from room
temperature to the refluxing temperature of the solvent, or;
d) tin and a strong mineral acid, such as hydrochloric acid (Method 1D),
either neat
or in alcohol solvent such as methanol or ethanol, at temperatures ranging
from
room temperature to the refluxing temperature of the solvent, or;
e) when R,-RS are selected from Cl, Br, I, -(OSOZ)-CF3, or -(OS02)-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
acetate, under one ar more atmospheres of pressure or;
f) when R,-RS and R9 R,Z are selected from Cl, Br, I, -(OSOZ}-CF3, ar -(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 roam temperature to the refluxing temperature of the
solvent, or;
g) aqueous sodium hydrosulfite in alcohol solvent at temperatures ranging from
room
temperature to the refluxing temperature of the solvent (Method 1G).
Alternatively, according to Methods 3A-3C, amines 2, wherein R,-RS are defined
above and X is defined above and anilines 5, above may be prepared by the
cleavage
of the aniline nitrogen-carbon bond of amide and carbamate derivatives of
these
anilines according to a variety of procedures known to those skilled in the
art and
described in Greene, Protective Groups in Or ang is Synthesis volume 2,
Chapter 7,
1991, and references therein. Such procedures include:
a) the exposure of appropriately substituted arylamino-tent-butyl-carbamates
to a
strong acid such as trifluoraacetic acid (Method 3A)either neat ar in an
appropriate
solvent such as dichloromethane at temperatures between 0°C and room
temperature, or;
b) the exposure of appropriately substituted arylamino-(2-trimethylsilylethyl)-
carbamates to a fluoride ion source such as tetrabutylammonium fluoride or
potassium fluoride (Method 3B) in aqueous acetonitrile or tetrahydrofuran or
mixtures thereof at temperatures ranging from room temperature to the reflux
temperature of the solvent, ar;
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c) the exposure of appropriately substituted arylamino-trifluoroacetamides to
a strong
base such as sodium or potassium hydroxide or sodium or potassium carbonate in
an alcohol solvent such as methanol or ethanol (Method 3C) at temperatures
ranging from room temperature to the reflex temperature of the solvent.
Alternatively, according to Method 11, amines 2, wherein R,-RS are defined
above, and X is defined above at least one substituent of R,-RS is defined as
vinyl,
may be prepared by the palladium catalyzed coupling of a vinyl trialkyltin
reagent,
such as tributylvinyltin, with an appropriately substituted bromo- or iodo-
aniline, for
example 3-chloro-4-iodo-aniline, employing a palladium catalyst, such as
tris(dibenzylidineacetone)-bipalladium, and a ligand, such as triphenylarsine,
in a
suitable solvent such as tetrahydrofuran or N-methylpyrrolidinone, at
temperatures
ranging from room temperature to the reflex temperature of the solvent,
essentially
according to the procedures of V. Farina and G:P. Roth in Advances in Metal-
Org_anic Chemistry, Vol. 5, 1-53, 1996 and references therein.
Alternatively, according to Method 42, amines 2, wherein R,-RS are defined
above and X is defined above and at least one substituent of R2 or R4 is
defined as
dialkylamino, may be prepared by the palladium catalyzed amination of an
appropriately substituted 3- or 5-bromo- or iodo-aniline, for example 3-amino-
5-
bromobenzotrifluoride, by secondary amines under conditions which employ a
palladium catalyst, such as bis(dibenzylidineacetone)palladium, and a ligand,
such as
tri-o-tolylphosphine, and at least two molar equivalents of a strong base,
such as
lithium bis-(trimethylsilyl)amide in a sealed tube, in a suitable solvent such
as
tetrahydrofuran or toluene, at temperatures ranging from room temperature to
100
°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 RQ is
defined as
alkyl, may be prepared by the palladium catalyzed alkylation of an
appropriately
substituted 3- or 5-bromo-or iodo-aniline, far 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
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tetrahydrofuran or the like at temperatures ranging from room temperature to
the
reflex 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
S 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 anic
Synthesis
volume 2, Chapter 7, 1991, and references therein. Such procedures include:
a) the reaction of an appropriately substituted amine with di-tert-butyl-
dicarbonate
{Method 2A) in the presence or absence of one or more molar equivalents of a
tertiary amine such as triethylamine or N,N-diisopropylethylarnine in a
suitable
solvent such as acetone, tetrahydrofuran, dimethylformamide, dichloromethane,
and the like, at temperatures ranging from room temperature to the reflex
temperature of the solvent to produce the corresponding arylamino-tert-butyl-
carbamate, or;
b) the reaction of an appropriately substituted aniline with 1-[2-
(trimethylsilyl)ethoxycarbonyl-oxy]benzotriazole (Method 2B) in the presence
of a
tertiary amine such as triethylamine or diisopropylethylarnine in a suitable
solvent
such as dimethylformamide at room temperature to produce the corresponding
arylamino-(2-trimethylsilylethyl)-carbamate, or;
c) the reaction of an appropriately substituted aniline with a carboxylic acid
chloride
or acid anhydride (Method 2C) either neat or in an appropriate solvent such as
tetrahydrofuran, dimethylforrnamide, dichlorornethane, pyridine and the like,
in
the presence of one or more molar equivalents of a teriary amine base such as
triethylarnine or N,N-diisopropylethyl-amine to produce the corresponding
arylaminoamide, or;
d) the reaction of an apptopriately substituted nitro aniline with a
carboxylic acid
chloride (Method 2D) in the absence of one or more molar equivalents of a
teriary amine base such as triethylamine or N,N-diisopropylethylamine either
neat
or in an appropriate solvent such as tetrahydrofuran, 1,4-dioxane and the like
at
temperatures ranging from room temperature to the reflex temperature of the
solvent to produce the corresponding nitro arylaminoamide, or;
e) the reaction of an appropiately substituted aniline with a carboxylic acid
{Method
2E) in the presence of a coupling agent such as benzotriazole-1-yloxy-tris-
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(dimethylamino}-phosphoniurn hexafluorophosphate, 2-(1H-benzotriazole-1-
yloxy)-1,I,3,3-tetra-methyluronium hexafluorophosphate, dicyclohexyl
carbodiimide and the like and in the presence of a tertiary amine such as
triethylamine or diisopropylethylamine in a suitable solvent such as
diichloromethane, dimethylformamide and the like, at room temperature to
produce the corresponding arylaminoamide, or;
f) the reaction of an appropriately protected aniline such as an arylamino-
tert-butyl-
carbarnate or the like in which at least one substituent of R,-RI~ is defined
as -W-
Y-(CHZ)n-Z wherein W, Y, and Z are defined as above, with a carboxylic acid
anhydride (Method 2F} in the presence of a suitable base such as pyridine in
an
appropriate such as dichloromethane, dimethylformamide or the like at
temperatures ranging from 0°C to room temperature to produce the
corresponding
carboxylic acid ester, or;
g) the reaction of an appropriately substituted aniline in which a t least one
substituent of R,-RS is defined as hydroxyl with di-tert-butyl-dicarbonate
(Method
2G) in the absence of one or more molar equivalents of a tertiary amine such
as
triethylamine or N,N-diisopropylethylamine in a suitable solvent such as
acetone,
tetrahydrofuran, dimethylformamide, dichloromethane, and the like, at
temperatures ranging from room temperature to the reflux temperature of the
solvent to produce the corresponding arylamino-tert-butyl-carbamate.
Nitrobenzene intermediates that are ultimately converted to amines 2 and 5 by
methods shown above in Methods lA-1G may be prepared in accordance with
Methods 4A, 4C, 4E-4F.
Referring to Methods 4A, 4C, and 4E-4H, the nitrobenzene intermediates
which are ultimately converted into amines 2, RZ and R4 are defined above and
R,, R3,
and/or RS are defined as alkoxy, thioalkoxy, alkylsulfenyl, alkylsulfinyl, and
dialkylamino may be prepared by the nucleophilic displacement of appropriately
substituted 2-, 4-, and/or 6-fluoro-, chloro-, bromo-, iodo-,
trifluoromethylsulfonyl-,
or (4-methylphenyl)sulfonyl-substituted nitrobenzenes by methods which include
the
following:
a) reaction of alcohois with appropriately substituted 2- or 4- halo- or
sulfonate esters
of nitrobenzenes or benzonitriles (Method 4A} either neat or in an appropriate
solvent such as tetrahydrofuran, dioxane, acetonitrile, N,N-dimethylformamide
or
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dimethylsulfoxide in the presence or absence of one or more molar equivalents
of
a base such as sodium carbonate, potassium carbonate, sodium hydroxide,
potassium hydroxide, sodium hydride, potassium hydride, or the like, at
temperatures ranging from room temperature to the reflux temperature of the
solvent;
b) reactions of preformed sodium, lithium, or potassium phenoxides with
appropriately substituted 2- or 4- halo- or sulfonate esters of nitrobenzenes
or
benzonitriles (Method 4H) either neat or in an appropriate solvent such as
tetrahydrofuran, dioxane, acetonitrile, N,N-dimethylformamide or
dimethylsulfoxide, at temperatures ranging from room temperature to the reflux
temperature of the solvent, or;
c) reaction of ammonia, primary or secondary amines with appropriately
substituted
2- or 4-halo- or sulfonate esters of nitrobenzenes or benzonitriles (Methods
4C,F)
either neat or in an appropriate solvent such as tetrahydrofuran, dioxane,
acetonitrile, N,N-dimethyl-formamide or dimethylsulfoxide, at temperatures
ranging from room temperature to the reflux temperature of the solvent;
d) reaction of preformed sodium, lithium, or potassium salts of amines with
appropriately substituted 2- or 4- halo- or sulfonate esters of nitrobenzenes
or
benzonitriles {Method 4G) in an appropriate solvent such as tetrahydrofuran at
temperatures ranging from 0°C to the reflux temperature of the solvent,
or;
e} reaction of sodium sulfide with appropriately substituted 2- or 4- halo- or
sulfonate
esters of nitrobenzenes or benzonitriles either neat or in an appropriate
solvent
such as tetrahydro-furan, dioxane, acetonitrile, N,N-dimethylformamide or
dimethylsulfoxide, at temperatures ranging from room temperature to the reflux
temperature of the solvent, followed by the addition of an alkyl halide
directly to
the reaction mixture (Method 4E).
Alternatively, referring to Methods SC and 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 SC) in the presence of a base, such as potassium carbonate, sodium
carbonate, potassium hydroxide, sodium hydroxide, potassium hydride, or sodium
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hydride, in an appropriate solvent such as acetone, N,N-dimethylformamide,
tetrahydrofuran or dimethylsulfoxide at temperatures ran~ina from room
temperature to the reflux temperature of the solvent, or;
b) reaction of the hydroxy-nitrobenzene with an alkyl alcohol,
triphenylphosphine,
and a dialkylazadicarboxylate reagent {Method 6), such as
diethylazodicarboxylate, in an anhydrous aprotic solvent such as diethyl ether
or
tetrahydrofuran at temperatures ranging from 0°C to the reflux
temperature of the
solvent, essentially according to methods described in Mitsunobu, O, Synthesis
1981, I 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,
dialkylsulfonate, ethylene carbonate and the like in the presence of a
suitable base
such as potassium carbonate in an appropriate solvent such as acetone,
toluene, or
N,N-dimethylformamide at temperatures ranging from room temperature to the
reflux temperature of the solvent.
Alternatively, referring to Methods 7A-G, the nitrobenzene intermediates
which are ultimately converted into amines 2, R~ and/or R3 is alkoxy, and R2
and/or
R4 is a halogen, and X equals a bond, may be prepared by standard halogenation
reactions which include the following:
a) reaction of a 2- or 4- hydroxy-nitrobenzene with aqueous sodium
hypochlorite
{Methods 7A and 7B), at room temperature or;
b} reaction of a 2-hydroxy-4-methoxy or 2,4-dimethoxynitrobenzene {Method 7C
and
7D) with bromine in suitable solvent such as chloroform, dichlormethane,
glacial
acetic acid or the like in the presence or the absence of silver
trifluoroacetate at
room temperature, or;
c) reaction of a 2,4-dimethoxynitrobenzene (Method 7E) with benzyltrimethyl-
ammonium dichloroiodate in the presence of anhydrous zinc chloride in a
suitable
solvent such as glacial acetic acid, at room temperature or;
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d) reaction of a 2-hydroxy-4-methoxynitrobenzene (Method 7F) with
benzyltrimethyl-ammonium dichloroiodate in the presence of sodium bicarbonate
in a suitable solvent mixture such as dichloromethane and methanol, at room
temperature or;
e) reaction of a 2,4-dimethoxynitrobenzene {Method 7G) with 3,5-dichloro-1-
fiuoropyridine triflate in a suitable solvent such as tetrachloroethane, at a
temperature ranging from room temperature to the reflex 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(trifluoromethyl)silane in the
presence
of cuprous iodide and potassium fluoride in a suitable solvent such as N,N-
dimethylformamide or the like at a temperature ranging from room temperature
to
the reflex 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, - -HNCOCH2NR,R8 or -
HNCOCH2SR6, and R,-R3 and RS 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 reflex temperature of the
solvent
or by reaction with an appropriate thiol in the presence of a suitable base
such as
sodium or potassium carbonate or the like in a suitable solvent such as
tetrahydrofuran, 1,4-dioxane or the like at temperatures ranging from room
temperature to the reflex 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 0°C to morn temperature.
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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,-RS is defined as either alkylsulfenyl or
alkylsulfinyl, may be prepared by reaction of the appropriate 4-alkylthio acyl-
arylamino or carbamoyl arylamino derivative with an appropriate oxidizing
agent
such as dimethyloxirane or sodium periodate in a suitable solvent mixture such
as
acetone and dichloromethane or water at room temperature.
Referring to Methad 12, the carbamoyl amine derivatives utilized as starting
materials in Methods 3A-3C which are ultimately converted into amines 2,
wherein
Ra is defined as 1-hydroxyethyl and R,-R3 and RS are defined as above and X is
a
bond may be prepared by reacting the corresponding 4-vinyl carbamoyl aniline
with
sodium borohydride in the presence of mercuric acetate in a suitable solvent
such as
tetrahydrofuran, 1,4-dioxane or the like and water at room temperature.
Referring to Method 13, the carbamoyl amine derivatives utilized as starting
materials in Methods 3A-3C which are ultimately converted into amines 2,
wherein
R4 is defined as 2-hydroxyethyl and R,-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 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.
Referring to Method 14, 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-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
diethylazadicarboxylate 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 Rl-R3 and RS are defined as
above
and X is defined above, may be prepared by reacting the corresponding 4-
iodocarbamoyl aniline with 1-dimethylamino-2-propyne in a suitable tertiary
amine
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solvent such as triethylamine or diisopropylethylamine in the presence of
bis(triphenylphosphine)-palladium{II) chloride and cuprous iodide at
temperatures
ranging from room temperature to the reflux temperature of the solvent.
Referring to Method 16, the carbamoyl amine derivatives utilized as starting
materials in Methods 3A-3C which are ultimately converted into amines 2,
wherein
R4 is defined as 3-dimethylaminoacryloyl and R,-R3 and RS are defined as above
and
X equals a bond, may be prepared by reacting the corresponding 4-(3-
dimethylaminoprap-I-ynyl)carbamoyl aniline with a suitable peracid such as 3-
chloroperoxybenzoic acid in a suitable solvent mixture such as dichloromethane
and
IO methanol at temperatures ranging from 0°C to room temperature.
Referring toMethods I7 and 18, the carbamoyl amine derivatives utilized as
starting materials in Methods 3A-3C which are ultimately converted into amines
2,
wherein RQ is defined as either 4-isoxazol-5-yl or 4-( 1 H-pyrazol-3-yl) and
R,-R3 and
RS are defined as above and X equals a bond, may be prepared by reacting the
IS corresponding 4-(3-dimethylamino-acryloyl)carbamoyl aniline with either
hydroxylamine hydrochloride or hydrazine hydrate in a suitable solvent such as
1,4-
dioxane or ethanol and the like at room temperature.
Referring to Method 20, the carbamoyl amine derivatives utilized as starting
materials in Methods 3A-3C which are ultimately converted into amines 2,
wherein
20 R4 = -HNCOZZ, and Rl-R3, R5, and Z are defined as above and X equals a
bond, may
be prepared by reacting the corresponding 4-aminocarbamoyl aniline with 1,1-
carbonyl-di-(1,2,4)-triazole and an appropriately substituted alcohol in a
suitable
solvent mixture such as tetrahydrofuran and dichloromethane and the like at
temperatures ranging from room temperature to the reflux temperature of the
solvent.
25 Referring to Methods 26 and 30, the carbamoyl amine derivatives utilized as
starting materials in Methods 3A-3C which are ultimately converted into amines
2,
wherein at least one substituent of R,-RS is defined as dialkylamino and X is
defined
above may be prepared by reaction of appropriately substituted aldehydes in
the
presence of either sodium cyanoboro-hydride or hydrogen gas and 10 °lo
palladium on
30 carbon in a suitable solvent such as water, methanol, tetrahydrofuran
mixtures or
toluene or the like at room temperature.
Referring to Methods 27 and 28, amines 2 wherein at least one substituent of
R,-RS is defined as hydroxy and X is defined above can be prepared by reaction
of the
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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
defined as 2-hydroxybenzamido and X is defined above can be prepared by
reaction
of the corresponding N-(4-aminophenyl)phthalimide with lithium borohydride in
an
appropriate solvent such as tetrahydrofuran, diethyl ether, or the like at
room
temperature.
The intermediate amines 2 wherein R,-RS are defined as above and X equals
either -CHZ or -(CHz),- can be prepared by the following procedures:
a) reduction of an appropriately substituted benzo- or phenylacetonitrile with
borane-dimethylsulfide complex in a suitable solvent such as ethylene glycol
dimethyl ether, tetrahydrofuran or the like a temperatures ranging from room
temperature to the reflux temperature of the solvent. (Method 44);
b) reduction under one or more atmospheres of hydrogen in the presence of a
suitable catalyst such as 5 % ar 10 % palladium on carbon and an acid such as
4
methyl-benzenesulfonic acid, hydrochloric acid or the like in a suitable
solvent such
as ethylene glycol monomethyl ether, ethyl acetate, ethanol or the like at
room
temperature. (Method 50};
c) reduction with lithium aluminum hydride in a suitable solvent such as
tetrahydrofuran or diethyl ether . at temperatures ranging from 0°C to
room
temperature. (Method 51 );
The unsaturated nitro precursors which are utilized as starting materials in
Method 51 and are ultimately converted to amines 2 wherein R,-RS are defined
as
above and X equals -(CHZ}2 can be prepared by reaction of an appropriately
substituted benzaldehyde with vitro-methane in the presence of ammonium
acetate in
a suitable solvent such as acetic acid at temperatures ranging from room
temperature
to the reflux temperature of the solvent. (Method 53); The benzaldehydes,
utilized as
starting materials in Method 53, can be prepared by diisobutylaluminum hydride
reduction of an appropriately substituted benzonitrile. (Method 52} The
substituted
benzonitriles, utilized as starting materials in Method 52, can be prepared
from the
corresponding aryl bromide by reaction with copper cyanide in a suitable
solvent
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such as N,N-dimethylformamide at temperatures ranging from room temperatture
to
the reftux temperature of the solvent. (Method 59)
For amines 2, wherein R,-RS is defined as above and X equals either
O{CHZ),NHZ or -S(CHZ)~NH2, 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,-R$ are defined as above and X equals
-(CHZ)3-, the nitrite precursors can be prepared essentially according to the
procedure
IO of Wilk, B. Synthetic Comm. 23, 2481 (1993), by reaction of an
appropriately
substituted phenethanol with acetone cyanohydrin and triphenylphospliine in
the
presence of a suitable azodicarboxyiate such as diethyl azodicarboxylate in an
appropriate solvent such as diethyl ether or tetrahydro-furan or the like at
temperatures ranging from OC to room temperature. (Method 54)
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
45
by treatment of an appropriately substituted acetophenone with ammonium
formate,
formic acid and formamide at temperatures ranging from room temperature to the
reflux temperature of the solvent.
Alternatively, amines 2 wherein R,-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.
Synthesis
1988, 995. The requisite O-methyl oxirnes can be prepared from the
corresponding
acetophenone by reaction with methoxylamine hydrochloride and pyridine in a
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suitable solvent such as ethanol or methanol at temperatures ranging from room
temperature to the reflux temperature of the solvent. (Method 47)
Amines 2 for which R,-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
ketones, when not commercially available, can be prepared by reaction of a
suitably
substituted benzaldehyde with an appropriate organometallic reagent such as
phenyllithium, isopropylmagnesium bromide or ethylmagnesium bromide or the
like
in a suitable solvent such as diethyl ether or tetrahydrofuran at temperatures
ranging
from -78 °C to 0°C. (Method 57) The resulting alcohols can be
oxidized to the
corresponding ketone with an appropriate oxidizing agent such as chromium
trioxide
in aqueous sulfuric acid and acetone or pyridinium chlorochromate or pyridium
dichromate in an appropriate solvent such as dichloromethane or the like at
room
temperature. (Method 58)
The intermediate anilines 5 may be prepared as previously described Method
3A. Thus treating phenyl carbamic acid tert-butyl ester 6, G is described as
above,
with neat trifluoroacetic acid at room temperature followed by neutralization
with
aqueous sodium hydroxide affords the desired anilines 5. The requisite
carbamic acid
esters 6, wherein G is described as above, are prepared as shown in Method 2C
by
reaction of substituted acid chlorides, 8, where G is described as above, and
4-
aminophenylcarbamic acid tert-butyl esters 7 in the presence of triethylamine
in an
appropriate solvent such as dichloromethane, dimethylsulfoxide, or
dimethylformamide or mixtures thereof. Carboxylic acid chlorides 8 are either
commercially available or prepared from the corresponding carboxylic acid by
reaction with oxalyl chloride in a suitable solvent such as dichloromethane at
room
temperature.
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Method 2C, 3A
x O
~O~p _ 4 _ O i. CF3C02H p
G-COOH + HN ~ ~ NH2-~ HN ~ ~ N~C-G ~--~ Hz ~ ~ N-IC-G
ii. NaOH
H
7 g
Alternatively, carbamic acid esters 6, wherein G is described as above, are
prepared as shown in Method 2E by reaction of substituted carboxylic acids 8a,
wherein G is described as above, and an appropriately substituted 4-
aminophenyl
carbamic acid tent-butyl esters 7 in the presence of a suitable coupling agent
such as
benzotriazole-1-yloxy-tris-(dimethylamino)phosphonium hexafluorophosphate, 2-
{1H-benzotriazole-1-yloxy)-1,1,3,3-tetramethyluronium hexafluorophosphage,
dicyclohexyl carbodiimide or the like and in the presence of a tertiary amine
base
such as triethylamine or diisopropylethylamine in a suitable solvent such as
dichloromethane, dimethylformamide and the Like, at room temperature to
produce
the corresponding arylaminoamide.
Carboxylic acids 8a are either commercially available or are prepared
according to literature methods. For example, when G is a substituted
thiadiazole,
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
unsubstituted isoxazole, when not commercially available, the corresponding
carboxylic acid 8a is available from the corresponding ethyl or methyl ester
by
reaction with an appropriate base such as sodium or pottasium hydroxide in a
suitable
solvent mixture such as methanol or ethanol and water at room temperature.
These
esters are either commercially available or can be prepared according to
literature
methods.
When the carboxylic acid ester precursors which are ultimately converted to
acids 8 are not commmercially available, they may be prepared by methods known
in
the literature. For example, 5-substituted-1,2,3-thiadiazole-4 carboxylic acid
esters
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may be prepared essentially according to the procedure of Caron, M J. Org.
Chem.
51, 4075 (1986) and Taber, D. F., Ruckle, R. E. J. Amer. Chem. Soc. 108, 7686
(1986). Thus, according to Method 21, treatment of a beta-keto carboxylic acid
ester
with 4-methylbenzenesulfonyl azide or methanesulfonyl azide or the like in the
S presence of a tertiary amine base such triethyiamine or
diisopropylethylamine in a
suitable solvent such as acetonitrile affords the corresponding diazo-beta-
keto
carboxylic acid ester. Treatment of this compound with 2,4-bis(4-
methoxyphenyl)-
1,3-dithia-2,4-diphosphetane-2,4-disulfide in a suitable solvent such as
benzene or
toluene or the like at temperatures ranging from room temperature to the
reflux
temperature of the solvent gives the desired 5-substituted-1,2,3-thiadiazole-4-
carboxylic acid ester.
Alternatively, 4-substituted-1,2,3-thiadiazole -5-carboxylic acid esters may
be
prepared essentially according to the procedure of Shafiee, A., Lalezari, L,
Yazdani,
S., Shahbazian, F. M., Partovi, T. J. Pharmaceutical Sci. 65, 304 (I976).
Thus,
according to Method 22 and 23, reaction of an appropriately substituted beta-
keta
carboxylic acid ester in a suitable alcoholic solvent such as methanol or
ethanol with
an aqueous solution semicarbazide hydrochloride at temperatures ranging from
room
temperature to the reflux temperature of the solvent in the presence of a
suitable base
such as pyridine gives corresponding semicarbazone derivative. Treatment of
this
compound with neat thionyl chloride at 0°C followed by treatment with
an excess
aqueous solution of sodium bicarbonate affords the corresponding 4-substituted-
1,2,3-thiadiazole -5-carboxylic acid esters.
4-carboalkoxythiazoles are prepared essentially according to the procedure of
Schollkopf, U., Parsch, P., Lau, H. Liebigs Ann. Chem. 1444 (1979). Thus,
according to Method 55 and 56, reaction of ethyl isocyanoacetate with N,N-
dimethylformamide dimethyl acetal in a suitable alcoholic solvent such as
ethanol at
room temperature gives the corresponding 3-dimethylamino-2-isocyano-acrylic
acid
ethyl ester. A solution of this compound in a suitable solvent such as
tetrahydrofuran
is treated with gaseous hydrogen sulfide in the presence of a suitable
tertiary amine
base such as triethylamine or diiso-propylethylamine or the like at room
temperature
to give the corresponding 4-carboethoxy-thiazole.
Additional appropriately substituted thiazoles may be prepared essentially
according to the procedure of Bredenkamp, M. W., Halzafel, C. W., van Zyl, W.
J.
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Synthetic Comm. 20, 2235 (1990). Appropriate unsaturated oxazoles are prepared
essentially according to the procedure of Henneke, K. H., Schollkopf, U.,
Neudecker,
T. Liebigs~Anr~. Chem. 1979 {1979). Substituted oxazoles may be prepared
essentially according to the procedures of Galeotti, N., Montagne, C., Poncet,
J.,
Jouin, P. Tetrahedron Lett 33, 2807, ( 1992) and Shin, C., Okumura, K., Ito,
A.,
Nakamura, Y. Chemistry Lett. 1305, (1994).
The following specific examples are illustrative, but are not meant to be
limiting of the present invention.
EXAMPLE 1 (METHOD 1A)
4-Methoxy-3-trifluoromethyI- phenylamine
A suspension of 4-methoxy-3-trifluoromethyl-nitrobenzene {2.2 g) and iron
powder
( 1.68 g) in ethanol (35 mL) and water ( 15 mL) is treated with a solution of
concentrated hydrochloric acid (0.42 mL) in ethanol (6 mL) and water (3 mL)
and
the mixture is heated to reflux for approximately 1 hour. The mixture is then
cooled,
filtered, and concentrated under reduced pressure. The resulting oil is
dissolved in
ethyl acetate and extracted three times with 5% aqueous hydrochloric acid. The
pooled acidic extracts are then cooled in an ice bath and basified with solid
potassium
carbonate, then extracted with ethyl acetate. These organic extracts are
washed with
saturated aqueous sodium chloride, dried over anhydrous sodium sulfate,
concentrated under reduced pressure, then passed through a short column of
silica gel
(ethyl acetate is used as the eluant) to provide the desired compound as an
amber oil.
Using the above procedure and appropriate starting materials the following
compounds were prepared:
2,6-Dichloro-benzene-1,4-diarnine
3-Chloro-4-methylsulfanyl-phenylamine
2,6-Dihromo-benzene-1,4-diamine
3-Chloro-4-trifluoromethyl-phenylamine
3-Chloro-4-ethylsulfanyl-phenylarnine
4-Methoxy-3-trifluoromethyl-phenylamine
3,5-Dichloro-4-methoxy-2-methyl-phenylamine
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5-Chloro-2-ethoxy-4-methoxy-phenylamine
5-Chloro-4-ethoxy-2-methoxy-phenylarnine
5-Iodo-2,4-dimethoxy-phenylamine
3,5-Diiodo-2,4-dimethoxy-phenylamine
3,5-Dibromo-2,4-dimethoxy-phenylamine
5-Chloro-2-methoxy-4-methyl-phenylamine
2-Chloro-N( 1 ),N( 1 )-dimethyl-benzene-1,4-diamine
3-Chlaro-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-pyrrvlidin-3-yl)-benzene-1,4-diamine
2-Chloro-N( 1 )-methyl-N( 1 )-phenyl-benzene-1,4-diamine
N( 1 }-( 1-Benzyl-pyrrolidin-3-yl)-2-chloro-N( 1 )-methyl-benzene-1,4-diamine
2-Chloro-N( i )-cyclopentyl-N( 1 )-methyl-benzene-1,4-diamine
2-[(4-Amino-2-chloro-phenyl)-(2-hydroxy-ethyl)-amino]-ethanol
2-Chloro-N( 1 )-hexyl-N( 1 )-methyl-benzene-1,4-diamine
2-Chloro-N( 1 )-isobutyl-N( 1 )-methyl-benzene-1,4-diamine
2-[(4-Amino-2-chloro-phenyl)-methyl-amino}-ethanol
2-Chloro-N( 1 )-(3-dimethylamino-propyl)-N( 1 )-methyl-benzene-1,4-diamine
2-Chloro-N{ 1 )-(2-dimethylamino-ethyl)-N( 1 )-methyl-benzene-1,4-diamine
2-Chloro-N( 1 }-(2-dimethylamino-ethyl)-benzene-1,4-diamine
N( 1 )-( 1-Benzyl-piperidin-4-yl)-2-chloro-benzene-1,4-diamine
2-Chloro-N(1)-(2-methoxy-ethyl)-N(1)-methyl-benzene-1,4-diamine
2-Chloro-N( 1 )-(3-dimethylamino-propyl}-benzene-1,4-diamine
N{ 1 )-( 1-Benzyl-pyrrolidin-3-yl)-2-chloro-benzene-1,4-diamine
3-Chloro-4-( 1-methyl-piperidin-4-yloxy)-phenylamine
3-Chlorv-4-(2-dimethylamino-ethoxy)-phenylamine
3-Chloro-4-(3-dimethylamino-propoxy)-phenylamine
3-Chloro-4-{ 1-methyl-pyrrolidin-3-yloxy)-phenylamine
3-Chloro-4-cyclohexyloxy-phenylamine
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EXAMPLE 2 (METHOD 1B)
4-Bromo-2,4-dimethoxy-phenylamine
A suspension of 4-bromo-2,4-dimethoxy-nitrobenzene (0.48 g) and iron powder
(0.42 g} in acetic acid (10 mL) and ethanol (10 mL) is heated to 120 °C
for
approximately 5 hours. The mixture is then cooled, filtered, and concentrated
under
reduced pressure. Water is added and the mixture is cooled in an ice bath and
neutralized with solid potassium carbonate and then extracted with
dichloromethane.
These organic extracts are washed with saturated aqueous sodium chloride,
dried over
anhydrous sodium sulfate, concentrated under reduced pressure, then
chromatographed over silica gel (20% ethyl acetate in hexanes is used as the
eluant)
to provide the desired compound as an amber oil.
EXAMPLE 3 (METHOD 1 C)
(4-Amino-2,6-dichloro-phenoxy)-acetic acid tert-butyl ester
A soution of {4-nitro-2,6-dichloro-phenoxy)-acetic acid tent-butyl ester (1 g)
in
ethanol (17 rnL) and water (8.6 mL) is treated with iron powder (0.861 g) and
ammonium chloride {86 mg) and the mixture is heated to reflux for
approximately 1
hour. The mixture is then filtered and concentrated under reduced pressure.
The
resulting oil is partitioned between water and ethyl acetate, and the organic
phase is
then washed with saturated aqueous sodium chloride, dried over anhydrous
sodium
sulfate, and concentrated under reduced pressure to provide the desired
compound as
a pale yellow solid.
Using the above procedure and appropriate starting materials the following
compounds were prepared:
4-Chloro-benzene-1,2-diamine
N-{4-Amino-2-chloro-phenyl)-acetarnide
(4-Amino-2,6-dichloro-phenoxy)-acetonitxile
{4-Amino-2,6-dichloro-phenoxy)-acetic acid tert-butyl ester
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{2-Amino-4-chloro-5-methoxy-phenoxy)-acetonitrile
(4-Amino-2-chloro-5-methoxy-phenoxy)-acetic acid methyl ester
(4-Amino-2-chloro-5-methoxy-phenoxy}-acetic acid tert-butyl ester
(2-Amino-4-chloro-5-methoxy-phenoxy)-acetic acid tert-butyl ester
N(1)-Benzyl-4-chloro-5-methoxy-benzene-I,2-diamine
N-(4-Amino-2-chloro-phenyl)-2-fluoro-benzamide
N-{4-Amino-5-chloro-2-hydroxy-phenyl)-acetamide
N-(4-Amino-S-chloro-2-hydroxy-phenyl)-2-fluoro-benzamide
Furan-2-carboxylic acid (4-amino-2-chloro-phenyl)-amide
{4-Amino-2-chloro-phenyl)-carbamic acid ethyl ester
N-(4-Amino-5-chloro-2-methyl-phenyl)-acetamide
N-(4-Amino-5-chloro-2-methyl-phenyl)-2-fluoro-benzamide
Furan-2-carboxylic acid (4-amino-5-chioro-2-methyl-phenyl}amide
N-(4-Amino-3-chloro-phenyl)-2-fluoro-benzamide
Furan-2-carboxylic acid (4-amino-3-chloro-phenyl)-amide
N-(4-Amino-2-chloro-phenyl)-2-dimethylamino-acetamide
N-(4-Amino-2-chloro-phenyl)-2-piperidin-1-yl-acetamide
N-(4-Amino-2-chloro-phenyl)-2-morpholin-4-yl-acetamide
N-(4-Amino-2-chloro-phenyl)-methanesulfonamide
N-(4-Amino-2-chloro-phenyl)-benzamide
N-(4-Amino-2-chloro-phenyl}-2-diethylamino-acetamide
N-(4-Amino-2-chloro-phenyl)-2-pyrrolidin-1-yl-acetamide
N-(4-Amino-2-chloro-phenyl)-2-azepan-1-yl-acetamide
N-(4-Amino-2-chloro-phenyl)-2-(2-methyl-piperidin-1-yl)-acetamide
N-(4-Amino-2-chloro-phenyl)-2-(3-methyl-piperidin-1-yl)-acetamide
3-Chloro-benzene-1,2-diamine
4-Chloro-N,N-dimethyl-benzene-I,2-diamine
EXAMPLE 4 (METHOD 1D)
3,S-Dichloro-4-phenoxy-phenylamine
To a slurry of 3,5-dichloro-4-phenoxy-nitrobenzene (b. l g) and tin powder (
12 g) is
added dropwise concentrated hydrochloric acid (60 mL). Ethanol (60mL) is added
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and the mixture is heated to reflux for approximately 1 hour. The mixture is
then
cooled in an ice bath and basified by addition of solid sodium hydroxide. The
resulting suspension is filtered through a pad of diatomaceous earth and
extracted
three times with ethyl acetate. The combined organic extracts are then washed
with
saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure to provide the desired product as a yellow
solid.
Recrystallization from ethyl acetate-hexanes provided the product as a pale
yellow
solid.
Using the above procedure and appropriate starting materials the following
compounds were prepared:
1-Furan-2-yl-ethylamine
3-Chloro-4-isopropoxy-phenylamine
2-Butoxy-5-chloro-4-methoxy-phenylamine
3,5-Dichloro-2-methoxy-4-methyl-phenylamine
2-Benzyloxy-5-chloro-4-methoxy-phenylamine
4-Benzyloxy-5-chloro-2-methoxy-phenylamine
5-Fluoro-2,4-dimethoxy-phenylamine
(4-Amino-2,6-dichloro-phenoxy)-acetic acid ethyl ester
3,5-Dichloro-4-phenoxy-phenylamine
2-(4-Amino-2-chloro-5-methoxy-phenoxy)-acetamide
(4-Amino-2-chloro-5-methoxy-phenoxy)-acetonitrile
2-(2-Amino-4-chloro-5-methoxy-phenoxy)-ethanol
2-(4-Amino-2-chloro-5-methoxy-phenoxy)-ethanol
4-(4-Amino-2-chloro-5-methoxy-phenoxy)-butyronitrile
4-Amino-2-chloro-5-methoxy-phenol
2-Amino-4-chloro-5-methoxy-phenol
5-Chloro-4-methoxy-2-morpholin-4-yl-phenylamine
4-Chloro-5-methoxy-N(1),N(1)-dimethyl-benzene-1,2-diamine
5-Chloro-4-methoxy-2-piperidin-1-yl-phenylamine
5-Chloro-4-methoxy-2-pyrrolidm-1-yl-phenylamine
2-Chloro-N( 1 )-cyclohexyl-N{ 1 )-methyl-benzene-1,4-diamine
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N(2)-Benzyl-4-methoxy-benzene-1,2-diamine
2-(4-Amino-2-chioro-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-diarnine
2-Chloro-N( 1 ),N( 1 )-dipropyl-benzene-1,4-diamine
3-Chloro-4-(2,2,2-trifluoro-ethoxy)-phenylamine
3-Chloro-4-(octahydro-quinolin-1-yl)-phenylamine
N(1)-Allyl-2-chlaro-N(1}-cyclohexyl-benzene-1,4-diamine
N-(4-Amino-2-methoxy-5-methyl-phenyl)-2-fluoro-benzamide
Furan-2-carboxylic acid {4-amino-2-methoxy-5-methyl-phenyl)amide
N-(4-Amino-naphthalen-1-yl)-2-fluoro-benzamide
3-Chloro-N,N-dimethyl-benzene-1,2-diamine
3-Chloro-4-propoxy-phenylamine
3-Iodo-4-methoxy-phenylamine
3-Chloro-2,4-dimethoxy-aniline
3-Bromo-4-methoxy-phenylamine
3-Chloro-4-cthoxy-phenylamine
EXAMPLE 5 (Method lE)
(4-Amino-phenyl)-carbamic acid isobutyl ester
To a solution of N-(4-Nitro-phenyl)-isobutyrlamide (2.0 g) in 100 mL ethylene
glycol monomethyl ether {100 mL) is added 10% palladium on carbon (275 mg).
The mixture is hydrogenated for 2 hours at room temperature under 30 psi of
hydrogen on a Parr hydrogenation apparatus. The catalyst is then removed by
filtration through diatomaceous earth and the filtrate is evaporated to
dryness under
reduced pressure by azeotroping three times with heptane. Trituration of the
residue
with heptane provides the desired product as a white solid.
Using the above procedure and appropriate starting materials the following
compounds were prepared:
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2-Methyl-3H-benzoimidazol-5-ylamine
N-(4-Amino-phenyl)-formamide
1H-Benzoimidazol-5-ylarnine
(4-Amino-phenyl)-carbamic acid isobutyl ester
N-(4-Amino-phenyl)-isobutyramide
N-(5-Amino-pyridin-2-yl)-2-methyl-benzamide
Furan-2-carboxylic acid (5-amino-pyridin-2-yl}-amide
N-(5-Amino-pyridin-2-yl}-2-fluoro-benzamide
[6-(2,2,2-Trifluoro-acetylamino)-pyridin-3-yl]-carbamic acid tert-butyl ester
N-(5-Amino-pyridin-2-yl)-2,2,2-trifluoro-acetamide
(4-Amino-benzyl)-carbamic acid tert-butyl ester
2-(3,5-Bis-trifluoromethyl-phenyl}-ethylamine
I -tert-Butyl-1 H-imidazol-2-ylamine
3-(3-Dimethylamino-propyi)-5-trifiuoromethyl-phenylamine
EXAMPLE 6 (METHOD 1F)
N-(4-Amino-2-methylphenyl)-2-fluorobenzamide
A mixture of 2-fluoro-N-(2-methyl-4-nitrophenyl)benzamide (4.55 g),
cyclohexene
(30 mL), ethanol (70 mL), water (30 mL) and I0% palladium on charcoal (3 g) is
heated at reflux for 30 minutes. The mixture is filtered through diatomaceous
earth
and concentrated under reduced pressure. The resulting oil is dissolved in 50
mL of
ethyl acetate and cooled at 4° C for 12 hours. Filtration provides the
product as a tan
solid.
Using the above procedure and appropriate starting materials the following
compounds were prepared:
N-(4-Amino-2-methyl-phenyl)-acetamide
2-Methyl-benzooxazol-6-ylamine
N-(4-Amino-3-methoxy-phenyl}-acetamide
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2-Acetylamino-5-amino-benzoic acid
N-(4-Amino-phenyl)-acetamide
[4-(3-Amino-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
[4-{2-Amino-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
N-(4-Amino-2-cyano-phenyl)-acetamide
N-(4-Amino-2,5-dimethoxy-phenyl)-2-fluoro-benzamide
Furan-2-carboxylic acid (4-amino-2,5-dimethoxy-phenyl)-amide
N-{4-Amino-2-cyano-phenyl}-2-fluoro-benzamide
Furan-2-carboxylic acid (4-amino-2-methoxy-phenyl)-amide
N-(4-Amino-2-methoxy-phenyl)-2-fluoro-benzamide
N-(4-Amino-2-methoxy-5-methyl-phenyl)-acetamide
N-(4-Amino-2-benzoyl-phenyl)-acetamide
N-(4-Amino-2-benzoyl-phenyl)-2-fluoro-benzamide
Furan-2-carboxylic acid (4-amino-2-benzoyl-phenyl)-amide
N-(4-Amino-3-methyl-phenyl)-acetamide
N-(4-Amino-3-methyl-phenyl)-2-fluoro-benzamide
Furan-2-carboxylic acid {4-amino-3-methyl-phenyl)-amide
5-Amino-2-[(2-fluorobenzoyl)amino]-N-phenylbenzamide
Furan-2-carboxylic acid (4-amino-2-phenylcarbamoyl-phenyl)amide
N-(4-Amino-naphthalen-1-yl)-acetamide
Furan-2-carboxylic acid (4-amino-naphthalen-1-yI}-amide
N-(4-Amino-2-trifluoromethyl-phenyl)-acetamide
Furan-2-carboxylic acid (4-amino-2-cyano-phenyl)-amide
Furan-2-carboxylic acid {4-amino-2-trifluoromethyl-phenyl)-amide
N-(4-Amino-2-methyl-phenyl)-2-fluoro-benzamide
Furan-2-carboxylic acid (4-amino-2-methyl-phenyl)-amide
5-Amino-2-{2-fluoro-benzoylamino}-benzoic acid
5-Amino-2-[(furan-2-carbonyl}-amino]-benzoic acid
N-(4-Amino-2-cyano-phenyl)-2,2,2-trifluoro-acetamide
N-(4-Amino-3-methyl-phenyl)-2,6-difluoro-benzamide
N-(4-Amino-3-trifluoromethyl-phenyl)-acetamide
N-(4-Arnino-3-trifluoromethyl-phenyl}-2-fluoro-benzamide
N-(4-Amino-2-trifluoromethyl-phenyl)-2,2,2-trifluoro-acetamide
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N-(4-Amino-2-methoxy-phenyl)-2,2,2-trifluoro-acetamide
N-(4-Amino-2-trifluoromethyl-phenyl)-2-fluoro-N-(2-fluoro-benzoyl)-benzamide
N-(4-Amino-2-trifluoromethyl-phenyl)-2-fluoro-benzamide
EXAMPLE 7 (METHOD 1G)
N-(4-Amino-2-chlorophenyl)-2-thiomorpholino-4-yl-acetamide
A solution of N-(2-chloro-4-nitrophenyl}-2-thiomorpholino-4-yl-acetamide (3.02
g)
in ethanol (200 mL) is added to a solution of sodium thiosulfate (12 g) in
water (60
mL). The mixture is heated at reflux for 12 hours, cooled and poured into
water.
The mixture is then extracted with ethyl acetate. The ethyl acetate solution
is washed
twice with saturated aqueous sodium chloride, dried over anhydrous potassium
carbonate, filtered through a pad of diatomaceous earth and concentrated under
reduced pressure to give an oii. Toluene is added and the solution chilled to
give the
desired product as a light orange crystalline solid.
Using the above procedure and appropriate starting materials the following
compounds were prepared:
N-(4-Arnino-2-chloro-phenyl}-2-thiomorpholin-4-yl-acetamide
N-(4-Amino-2-chloro-phenyl)-2-dipropylamino-acetamide
EXAMPLE 8 (METHOD 2A)
(3-Chloro-4-iodo-phenyl)-carbamic acid tert-butyl ester
To a solution of 3-chloro-4-iodo-aniline ( 10 g) in tetrahydrofuran {40 mL)
containing
diiso-propylethylamine (6.9 mL) is added di-tert-butyl-dicarbonate (8.6 g) and
the
mixture is heated to reflux. After approximately 15 hours additional portions
of
diisopropylethylamine (6.9 mL) and di-tert-butyl-dicarbonate (21 g) is added
and
heating is continued for approximately 24 hours. The solution is then cooled,
concentrated under reduced pressure, diluted with ethyl acetate, and washed
successively three times with 5% aqueous hydrochloric acid then once with
saturated
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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 text-butyl ester
(3-Chloro-4-vinyl-phenyl)-carbamic acid tert-butyl ester
(3-Chloro-4-methylsulfanyl-phenyl)-carbamic acid tert-butyl ester
(4-Amino-3-chloro-phenyl)-carbamic acid tert-butyl ester
(4-Chloro-2-nitro-phenyl)-carbamic acid tert-butyl ester
(3-tert-Butoxycarbonylamino-5-chloro-phenyl)-carbamic acid tert-butyl ester
(4-Nitro-benzyl)-carbamic acid tert-butyl ester
(3-Bromo-5-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester
(2-Amino-3-chloro-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester
EXAMPLE 9 (METHOD 2B)
(3-Chloro-4-vinyl-phenyl)-carbamic acid2-trimethylsilanyl-ethyl ester
To a solution of 3-chloro-4-vinyl-phenylamine {3.4 g) in N,N-dimethylformamide
(44 mL) containing diisopropylethylamine (5.8 rnL) is added 1-j2-
(trimethylsilyl)-
ethoxycarbonyl-oxy]benzotriazole (7.1 g) and the mixture is stirred at room
temperature under an atmosphere of argon for three days. The solution is then
diluted with water and extracted three times with diethyl ether. The combined
organic extracts are washed successively with water, saturated aqueous sodium
chloride, dried over anhydrous magnesium sulfate, and concentrated under
reduced
pressure. The resulting residue is chromatographed over silica gel { 10% ethyl
acetate
in hexanes is used as the eluant) to provide the desired product as a yellow
oil.
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EXAMPLE ld (METHOD 2C)
[4-(2-Fluoro-benzoyiamino)-phenyl]-carbamic acid tert-butyl ester
To a solution of mono-N-(t-butoxycarbonyl)-1,4-phenylenediarnine (1.58 g) and
triethylamine (1.50 mL) in 25 mL of dichloromethane is added o-fluorobenzoyl
chloride (1.20 g). A solid formed immediately forms and is filtered and washed
with
fresh solvent to yield a white solid, 1.90 g.
Using the above procedure and appropriate starting materials the following
compounds were prepared:
N-(3-Methoxy-4-nitro-phenyl)-acetamide
N-(4-Amino-phenyl)-isobutyrlamide
2;2,2-Trifluoro-N-(2-methoxy-4-nitro-phenyl)-acetamide
[4-(2-Methyl-benzoylamino)-phenyl]-carbamic acid tent-butyl ester
Acetic acid 2-(4-tent-butoxycarbonylamino-phenylcarbamoyl)-phenyl ester
[4-(4-Fluoro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
[4-(3-Fluoro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
[4-(2-Fluoro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
[4-(2-Methoxy-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
[4-(3-Methoxy-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
[4-(4-Methoxy-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
[4-(2,2-Dimethyl-propionylamino)-phenyl]-carbamic acid tert-butyl ester
[4-(2-Bromo-acetylamino)-phenyl]-carbamic acid tert-butyl ester
[4-(2,2,2-Trifluoro-acetylamino)-phenyl]-carbamic acid tert-butyl ester
(4-Benzoylamino-phenyl)-carbamic acid tert-butyl ester
(4-Methanesulfonylamino-phenyl)-carbamic acid tert-butyl ester
(4-Phenylacetylamino-phenyl)-carbamic acid tert-butyl ester
{4-[(Thiophene-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
[4-(3-Nitro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
[4-(3-Acetylamino-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
{4-(3-Methanesulfonylamino-benzoylamino)-phenyl]-carbamic acid tert-butyl
ester
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Ethyl [3-[[[4-[((1,1-dimethylethoxy)carbonyl]amino]phenyl]amino)carbonyl)-
phenyl] carbamate
[4-(2-Trifluoromethyl-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
[4-(2,6-Difluoro-benzoylamino)-phenyl)-carbamic acid tert-butyl ester
[4-(2-Chloro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
[4-(2-Bromo-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
(4-(2-Nitro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
{4-[(Benzo[b]thiophene-2-carbonyl)-amino)-phenyl}-carbamic acid tert-butyl
ester
{4-((Pyridine-4-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
{4-[(Naphthalene-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
{ 4-[(Naphthalene-1-carbonyl)-amino]-phenyl }-carbamic acid tert-butyl ester
{4-((3-Bromo-thiophene-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl
ester
{4-((Biphenyl-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
N-(4-tert-Butoxycarbonylamino-phenyl)-phthalamic acid
[4-(2,3-Difluoro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
[4-(2,5-Difluoro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
[4-(2,4-Difluoro-benzoylamino)-phenyl)-carbamic acid tent-butyl ester
(4-(2-Acetylarnino-benzoyiamino)-phenyl]-carbamic acid tert-butyl ester
[4-(2-Methanesulfonylamino-benzoylamino)-phenyl)-carbamic acid tert-butyl
ester
[4-(2,3,4-Trifluoro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
[4-(2,3,4,5,6-Pentafluoro-benzoylamino)-phenyl)-carbamic acid tert-butyl ester
N-(4-tert-Butoxycarbonylamino-phenyl)-isophthalamic acid methyl ester
2-Methylsulfanyl-N-[4-(2,2,2-trifluoro-acetylamino)-phenyl)-benzamide
(4-(3-Benzyloxy-benzoylamino)-phenyl)-carbamic acid tert-butyl ester
[4-(3-Butoxy-benzoylamino)-phenyl)-carbamic acid tert-butyl ester
{ 4-[(5-Difluoromethyl-furan-2-carbonyl)-amino]-phenyl }-carbamic acid tert-
butyl
ester
{ 4-[(Thiophene-3-carbonyl)-amino]-phenyl }-carbamic acid tent-butyl ester
{4-[(5-Methyl-furan-2-carbonyl)-amino)-phenyl}-carbamic acid tert-butyl ester
{4-((5-Bromo-furan-2-carbonyl)-amino]-phenyl}-carbamic acid tent-butyl ester
(4-Hexanoylamino-phenyl)-carbamic acid tert-butyl ester
[4-(2-Thiophen-2-yl-acetylamino)-phenyl]-carbamic acid tert-butyl ester
{4-[(Pyridine-3-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
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{4-[(4-Bromo-furan-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
{4-[(Furan-3-carbonyl}-amino]-phenyl}-carbamic acid tert-butyl ester
(4-Phenoxycarbonylamino-phenyl)-carbamic acid tert-butyl ester
{4-[(Benzo[1,3)dioxole-4-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl
ester
S [4-(3-Trifluoromethoxy-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
N-(2,S-Dimethoxy-4-nitro-phenyl)-2-fluoro-benzamide
{4-[{Furan-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
[4-(2-Phenoxy-acetylamino)-phenyl]-carbamic acid tert-butyl ester
{4-[(S-Nitro-furan-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
{4-[(S-Chloro-furan-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
{ 4-[(3-Methyl-furan-2-carbonyl)-amino]-phenyl }-carbamic acid tert-butyl
ester
j4-(2-Methoxy-acetylamino)-phenyl]-carbamic acid tert-butyl ester
{4-[(4-Furan-3-yl-[1,2,3]thiadiazole-S-carbonyl)-amino]-phenyl}-carbamic acid
tert-
butyl ester
1 S { 4-[(S-tert-Butyl-furan-2-carbonyl)-amino]-phenyl }-carbamic acid tert-
butyl ester
N-[3-Cyano-4-(2,2,2-trifluoro-acetylamino)-phenyl]-2-fluoro-benzamide
Furan-2-carboxylic acid [3-cyano-4-(2,2,2-trifluoro-acetylamino)-phenyl]amide
N-(4-Acetylamino-2-cyano-phenyl)-2,2,2-trifluoro-acetamide
2,2,2-Trifiuoro-N-(4-nitro-2-trifluoromethyl-phenyl)-acetamide
N-(4-Acetylamino-2-trifluoromethyl-phenyl)-2,2,2-trifluoro-acetamide
2-Fluoro-N-[4-(2,2,2-trifluoro-acetylamino)-3-trifluoromethyl-phenyl)
benzamide
Furan-2-carboxylic acid [4-(2,2,2-trifluoro-acetylamino)-3-trifluoromethyl-
phenyl] amide
2-Fluoro-N-(2-methyl-benzooxazol-6-yl)-benzamide
2S 4-(2-Fluoro-benzoylamino)-2-hydroxy-benzoic acid phenyl ester
{4-[(Isoxazole-S-carbonyl}-amino]-phenyl}-carbamic acid tert-butyl ester
N-(4-Acetylamino-2-methoxy-phenyl)-2,2,2-trifluoro-acetamide
2-Fluoro-N-[3-methoxy-4-(2,2,2-trifluoro-acetylamino)-phenyl] benzamide
2-Fluoro-N-(2-fluoro-benzoyl)-N-(4-nitro-2-trifluoromethyl-phenyl)benzamide
{4-[(IH-Pyrazole-4-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
{4-[(1H-Imidazole-4-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
{4-[(S-Methyl-[1,2,3]thiadiazole-4-carbonyl)-amino]-phenyl}-carbamic acid tert-
butyl ester
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{4-[(5-Furan-3-yl-[1,2,3]thiadiazole-4-carbonyl)-amino]-phenyl}-carbamic acid
tert-
butyl ester
2,2,2-Trifluoro-N-(5-nitro-pyridin-2-yl)-acetamide
{4-[(1-Methyl-1H-pyrazole-4-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl
ester
4-(2-Fluoro-benzoylamino)-2-hydroxy-benzoic acid methyl ester
N-(5-Chloro-2,4-dimethoxy-phenyl)-oxalamic acid
Isoxazole-5-carboxylic acid (4-amino-phenyl)-amide
2-Fluoro-N-(4-nitro-benzyl)-benzarnide
Furan-2-carboxylic acid 4-nitro-benzylamide
N-[3-Chloro-5-{2,2,2-trifluoro-acetylamino)-phenyl]-2,2,2-trifluoro-acetamide
N-(3-Amino-5-chloro-phenyl)-2,2,2-trifluoro-acetamide
[4-{2-Fluoro-benzoylamino)-benzyl]-carbamic acid tert-butyl ester
[4-(2,6-Difluoro-benzoylamino)-benzyl]-carbamic acid tert-butyl ester
IS 2,6-Difluoro-N-(4-nitro-benzyl)-benzamide
{4-[(Furan-2-carbonyl)-amino]-benzyl}-carbamic acid tert-butyl ester
N-(3-Amino-5-chloro-phenyl)-acetamide
[4-(3-Chloro-benzoylamino)-phenyl]-carbamic acid tent-butyl ester
[4-(4-Chloro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
[4-(4-Dimethylamino-benzoylamino)-phenyl]-carbarnic acid tert-butyl ester
(4-Benzenesulfonylamino-phenyl)-carbamic acid tert-butyl ester
[4-(3-Trifluoromethyl-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
2,2,2-Trifluoro-N-(S-nitro-pyrimidin-2-yl)-acetamide
2S EXAMPLE 11(METHOD 2D)
2-Chloro-N-(2-chloro-4-nitrophenyl)acetamide
A solution of 2-chloro-4-nitroaniline ( 19.0 g) and chloroacetyl chloride (30
mL) in
tetrahydrofuran ( 150 mL) is heated at reflux for 1 hour. The solution is
cooled and
concentrated under reduced pressure, giving a wet yellow solid. Ether (250 mL)
is
added and the yellow solid is collected.
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Using the above procedure and appropriate starting material the following
compounds were prepared:
N-(4-Nitro-3-trifluoromethyl-phenyl)-acetamide
(2-Chloro-4-vitro-phenyl)-carbamic acid ethyl ester
2-Acetylamino-5-vitro-benzoic acid
Furan-2-carboxylic acid (5-chloro-2-hydroxy-4-vitro-phenyl)-amide
Furan-2-carboxylic acid (2-methyl-4-vitro-phenyl)-amide
Furan-2-carboxylic acid (2-methoxy-4-vitro-phenyl)-amide
N-(2-Chloro-4-vitro-phenyl)-benzamide
2-Methoxy-N-(4-vitro-phenyl)-acetamide
N-(4-Nitro-phenyl)-acrylamide
N-(4-Nitro-phenyl)-isobutyrlamide
[4-)acryloylamino)-phenyl]carbamic acid tert-butyl ester
(4-Nitro-phenyl)-carbamic acid isobutyl ester
[1,2,3]Thiadiazole-4-carboxylic acid (5-vitro-pyridin-2-yl)-amide
Furan-2-carboxylic acid (5-vitro-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-vitro-phenyl)-amide
N-(2-Cyano-4-vitro-phenyl)-2-fluoro-benzamide
2-Fluoro-N-(2-methoxy-4-vitro-phenyl)-benzamide
2-Methyl-N-(5-vitro-pyridin-2-yl)-benzamide
Furan-2-carboxylic acid (2-methoxy-5-methyl-4-vitro-phenyl}-amide
2-Fluoro-N-(2-methoxy-5-methyl-4-vitro-phenyl)-benzamide
N-(2-Benzoyl-4-vitro-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}amino]-5-vitro-N-phenylbenzamide
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Furan-2-carboxylic acid (4-vitro-2-phenylcarbamoyl-phenyl)-amide
2-Flu oro-N-(4-vitro-naphthalen-1-yi)-benzamide
Furan-2-carboxylic acid (4-vitro-naphthalen-1-yl)-amide
N-(S-Chloro-2-hydroxy-4-vitro-phenyl)-acetamide
S N-(S-Chloro-2-hydroxy-4-vitro-phenyl)-2-fluoro-benzamide
Furan-2-carboxylic acid (2-chloro-4-vitro-phenyl)-amide
N-(4-Nitro-2-trifluoromethyl-phenyl)-acetamide
Furan-2-carboxylic acid (2-cyano-4-vitro-phenyl)-amide
2-Fluoro-N-(4-vitro-2-trifluoromethyl-phenyl)-benzamide
Furan-2-carboxylic acid (4-vitro-2-trifluoromethyl-phenyl)-amide
2-Fluoro-N-(2-methyl-4-vitro-phenyl)-benzamide
N-(S-Chloro-2-methyl-4-vitro-phenyl)-2-fluoro-benzamide
Furan-2-carboxylic acid (S-chloro-2-methyl-4-vitro-phenyl)-amide
2-(2-Fluoro-benzoylamino)-S-vitro-benzoic acid
1S 2-[(Furan-2-carbonyl)-amino]-S-vitro-benzoic acid
N-(3-Chloro-4-vitro-phenyl)-2-fluoro-benzamide
Furan-2-carboxylic acid (3-chloro-4-vitro-phenyl)-amide
2,6-Difluoro-N-{3-methyl-4-vitro-phenyl)-benzamide
2-Fluoro-N-(4-vitro-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-trifluoro-acetylamino)-phenyl]-
amide
N-(2-Chloro-4-vitro-phenyl)-2,2,2-trifluoro-acetamide
2S
EXAMPLE 12
{4-[(4-Phenyl-[1,2,3]thiadiazole-S-carbonyl)-amino]-phenyl}
carbamic acid tert-butyl
A solution of 1-(N-tert-butoxycarbonyl)-1,4-phenylenediamine (0.8 g) and 4-
phenyl-
[1,2,3]thiadiazole-S-carboxylic acid (0.7 g) in dichloromethane (10 mL) is
treated
with triethylamine (1.3 mL) and benzotriazole-1-yloxy-tris(dimethylamino}-
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phosphonium hexa-fluorophosphate (1:6 g). After stirring at room temperature,
the
reaction is diluted with water and extracted with dichloromethane. The organic
layer
is washed with O.S N hydrochloric acid, saturated sodium bicarbonate, and
water then
dried over magnesium sulfate, filtered, and concentrated under reduced
pressure to
give the desired product.
Using the above procedure and appropriate starting materials the following
compounds were prepared:
{4-[(1H-Pyrrole-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
{4-[(Pyrazine-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
{4-[(5-Methyl-thiophene-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl
ester
{4-[(1-Methyl-1H-pyrrole-2-carbonyl)-amino]-phenyl}-carbamic acid tent-butyl
ester
{4-[(Quinoline-$-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
{4-[(Benzofuran-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
{4-[(Isoquinoline-1-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
{4-[(Quinoline-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
{4-[(Pyridine-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
{4-[(Isoquinoline-4-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
{4-[([1,2,3]Thiadiazole-4-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl
ester
{4-[(1H-[1,2,3]Triazole-4-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl
ester
[4-(2-Methylsulfanyl-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
{4-[(Quinoline-4-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
{4-[(4-Methyl-[1,2,3]thiadiazole-S-carbonyl)-amino]-phenyl}-carbamic acid tert-
butyl ester
{4-[(4-Phenyl-[1,2,3]thiadiazole-5-carbonyl)-amino]-phenyl}-carbamic acid tert-
butyl ester
{4-[(1H-Indole-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
[1,2,3]Thiadiazole-4-carboxylic acid 4-nitro-benzylamide
{4-[([1,2,3]Thiadiazole-4-carbonyl)-amino]-benzyl}-carbamic acid tert-butyl
ester
Acetic acid 4-(4-tert-butoxycarbonylamino-phenylcarbamoyl)-phenyl ester
{4-[(Quinoline-6-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
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EXAMPLE 13 (METHOD 2F)
Acetic acid 2-(4-tert-butoxycarbonylamino-
2,6-dichloro-phenoxy)-ethyl ester
A solution of [3,5-dichloro-4-(2-hydroxy-ethoxy)-phenyl]-carbamic acid tert-
butyl
ester (0.85 g) in pyridine (14 mL) is treated with acetic anhydride (1.24 mL)
and the
mixture is stirred at room temperature for 15 hours. The solvent is removed
under
reduced pressure and the residue dissolved in ethyl acetate. This solution is
then
washed twice with 5% aqueous hydrochloric acid, once with saturated aqueous
sodium bicarbonate, and then with saturated aqueous sodium chloride. The
solution
is dried over anhydrous magnesium sulfate and the solvent is removed under
reduced
pressure to provide the desired product as a colorless oil.
Using the above procedure and appropriate starting materials the following
compounds were prepared:
Phenylsulfanyl-acetonitrile
Acetic acid 2-(4-tent-butoxycarbonylamino-2,6-dichloro-phenoxy}-ethyl ester
EXAMPLE 14 (METHOD 2G)
(3,5-Dichloro-4-hydroxy-phenyl)-carbamic acid tert-butyl ester
To a solution of 2,6-dichloro-4-amino phenol (9.5 g) in tetrahydrofuran (130
mL) is
added di-tert-butyl-dicarbonate (11.7 g) and the mixture is heated to reflux
for
approximately 15 hours. The solution is then cooled, concentrated under
reduced
pressure, diluted with ethyl acetate, and washed successively three times with
5%
aqueous hydrochloric acid then once with saturated aqueous sodium chloride.
The
solution is dried over anhydrous sodium sulfate then concentrated under
reduced
pressure to provide the desired crude product. This material is then
triturated with
cold dichloromethane to provide the product as a white solid.
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Using the above procedure and appropriate starting materials the following
compound was prepared:
(3-Amino-5-chloro-phenyl)-carbamic acid tert-butyl ester
EXAMPLE 1S (METHOD 3A)
3,S-Dichloro-4-ethoxy-phenylamine
Trifluoroacetic acid (5 mL) is added to solid (3,5-dichloro-4-ethoxy-phenyl)-
carbamic acid tort-butyl ester (0.97 g) and the mixture is stirred for
approximately 45
minutes at room temperature. Water is then added, and the mixture is cooled in
an'
ice bath and basified with solid potassium carbonate. The solution is
extracted three
times with ethyl acetate and the combined organic phases are washed with
saturated
aqueous sodium chloride then dried over anhydrous sodium sulfate.
Concentration
under reduced pressure and recrystallization from hexanes provides the desired
product as a pale yellow crystalline solid.
Using the above procedure and appropriate starting materials the following
compounds were prepared:
5-Bromo-pyridin-3-ylamine
3-Chloro-4-methanesulfonyl-phenylamine
N-(4-Amino-phenyl)-2-methyl-benzamide
Acetic acid 2-(4-amino-phenylcarbamoyl)-phenyl ester
N-(4-Amino-phenyl)-4-fluoro-benzamide
N-(4-Amino-phenyl)-3-fluoro-benzamide
N-{4-Amino-phenyl)-2-fluoro-benzamide
N-{4-Amino-phenyl)-2-methoxy-benzamide
N-(4-Amino-phenyl)-3-methoxy-benzamide
N-(4-Amino-phenyl)-4-methoxy-benzamide
N-(4-Amino-phenyl)-2-phenyl-acetarnide
N-(4-Amino-phenyl)-2,2-dimethyl-propionamide
N-(4-Amino-phenyl)-2,2,2-trifluoro-acetamide
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Thiophene-2-carboxylic acid (4-amino-phenyl)-amide
1H-Pyrrole-2-carboxylic acid (4-amino-phenyl)-amide
N-(4-Amino-phenyl)-3-nitro-benzamide
3-Acetylamino-N-(4-amino-phenyl)-benzamide
N-(4-Amino-phenyl}-3-dimethylamino-benzamide
N-(4-Amino-phenyl)-3-methanesulfonylamino-benzamide
N-(4-Amino-phenyl)-2-trifluoromethyl-benzamide
N-(4-Amino-phenyl)-2,6-difluoro-benzamide
N-{4-Amino-phenyl)-2-chloro-benzamide
N-(4-Amino-phenyl)-2-bromo-benzamide
N-(4-Amino-phenyl)-2-nitro-benzamide
Pyrazine-2-carboxylic acid {4-amino-phenyl)-amide
5-Methyl-thiophene-2-carboxylic acid (4-amino-phenyl)-amide
Quinoline-8-carboxylic acid (4-amino-phenyl)-amide
1-Methyl-1H-pyrrole-2-carboxylic acid {4-amino-phenyl)-amide
Benzo[b]thiophene-2-carboxylic acid (4-amino-phenyl)-amide
Benzofuran-2-carboxylic acid (4-amino-phenyl)-amide
N-(4-Amino-phenyl)-isonicotinamide
Naphthalene-2-carboxylic acid (4-amino-phenyl)-amide
Naphthalene-1-carboxylic acid (4-amino-phenyl)-amide
Isoquinaline-1-carboxylic acid (4-amino-phenyl)-amide
Quinoline-2-carboxylic acid (4-amino-phenyl)-amide
3,5-Dichloro-4-ethoxy-phenyla.mine
4-Butoxy-3,5-dichloro-phenylamine
Isoquinoline-4-carboxylic acid (4-amino-phenyl)-amide
[1,2,3]Thiadiazole-4-carboxylic acid (4-amino-phenyl)-amide
1H-[1,2,3]Triazole-4-carboxylic acid (4-amino-phenyl)-amide
3-Bromo-thiophene-2-carboxylic acid (4-amino-phenyl)-amide
4-Benzyloxy-3,5-dichloro-phenylamine
2-(4-Amino-2,6-dichloro-phenoxy)-acetamide
(4-Amino-2,6-dichloro-phenoxy)-acetic acid methyl ester
[3-(4-Amino-phenylcarbamoyi)-phenyl]-carbarnic acid ethyl ester
2-Amino-N-(4-amino-phenyl)-benzamide
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Biphenyl-2-carboxylic acid (4-amino-phenyl)-amide
N-(4-Amino-phenyl)-2,3-difluoro-benzamide
N-(4-Amino-phenyl)-2, 5-difluoro-benzamide
N-(4-Amino-phenyl)-2,4-difluoro-benzamide
2-Acetylamino-N-{4-amino-phenyl)-benzamide
N-(4-Amino-phenyl)-2-methanesulfonylamino-benzamide
N-(4-Amino-phenyl)-2,3,4-trifluoro-benzamide
N-(4-Amino-phenyl)-2,3,4,5,6-pentafluoro-benzamide
N-(4-Amino-phenyl)-2-methylsulfanyl-benzamide
Acetic acid 2-(4-amino-2,b-dichloro-phenoxy)-ethyl ester
N-(4-Amino-phenyl)-isophthalamic acid methyl ester
N-(4-Amino-phenyl)-3-benzyloxy-benzamide
N-(4-Amino-phenyl)-3-butoxy-benzamide
[3-(4-Amino-phenylcarbarnoyl)-phenoxy]-acetic acid ethyl ester
Pyridine-2-carboxylic acid (4-amino-phenyl)-amide
Quinoline-4-carboxylic acid (4-amino-phenyl)-amide
5-Methyl-furan-2-carboxylic acid (4-amino-phenyl)-amide
5-Difluoromethyl-furan-2-carboxylic acid (4-amino-phenyl)-amide
1H-Indole-2-carboxylic acid (4-amino-phenyl)-amide
4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid (4-amino-phenyl)-amide
Thiophene-3-carboxylic acid {4-amino-phenyl)-amide
5-Chloro-furan-2-carboxylic acid {4-amino-phenyl}-amide
5-Nitro-furan-2-carboxylic acid (4-amino-phenyl)-amide
N-(4-Amino-phenyl)-2-thiophen-2-yl-acetamide
3-Methyl-furan-2-carboxylic acid {4-amino-phenyl)-amide
5-Bromo-furan-2-carboxylic acid (4-amino-phenyl)-amide
4-Bromo-furan-2-carboxylic acid (4-amino-phenyl)-amide
N-(4-Amino-phenyl)-nicotinamide
N-(4-Aminophenyl}-3-furancarboxamide
4-Phenyl-[1,2,3]thiadiazole-5-carboxylic acid {4-amino-phenyl)-amide
Acetic acid 3-(4-amino-phenylcarbamoyl)-phenyl ester
Benzo[1,3]dioxole-4-carboxylic acid (4-amino-phenyl)-amide
N-(4-Amino-phenyl).-3-{2-dimethylamino-ethoxy)-benzamide
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N-(4-Amino-phenyl)-3-trifluoromethoxy-benzamide
N-(4-Amino-phenyl)-3-{2-morpholin-4-yl-ethoxy)-benzamide
(4-Amino-phenyl)-carbamic acid hexyl ester
Furan-2-carboxylic acid (4-amino-phenyl)-amide
(4-Amino-phenyl)-carbamic acid phenyl ester
Hexanoic acid (4-amino-phenyl)-amide
N-(4-Amino-phenyl)-acrylamide
N-(4-Amino-phenyl)-2-methoxy-acetamide
4-Furan-3-yl-[1,2,3]thiadiazole-5-carboxylic acid (4-amino-phenyl)-amide
5-tert-Butyl-furan-2-carboxylic acid (4-amino-phenyl)-amide
3-Chloro-4-rnethanesulfinyl-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,b-difluoro-benzarnide
Oxazole-4-carboxylic acid {4-amino-phenyl)-amide
N-(4-Amino-phenyl)-3-chloro-benzamide
N-(4-Amino-phenyl)-4-chloro-benzamide
Acetic acid 4-(4-amino-phenylcarbamoyl)-phenyl ester
N-(4-Amino-phenyl)-4-dimethylamino-benzamide
1-(4-Amino-phenyl)-3-(3,5-bis-trifluoromethyl-phenyl)-thiourea
N-(4-Amino-phenyl)-2-iodo-benzamide
N-(4-Amino-phenyl)-3-trifluoromethyl-benzamide
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EXAMPLE 16 (METHOD 3B)
1-(4-Amino-2-chloro-phenyl)-ethanol
A 1M solution of tetrabutylammonium fluoride in tetrahydrafuran (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
i5
Potassium carbonate (5.0 g) is added to a solution of N-[3-cyano-4-{2,2,2-
trifluoroacetyl-amino)-phenyl]-2-fluoro-benzamide (2.5 g) in methanol (270 mL)
and
water (ib mL) and the mixture is refluxed overnight. After removing the
solvent
under reduced pressure, the residue is suspended in water and extracted with
dichloromethane. The organic extracts are pooled, washed with water and then
saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate,
filtered
and concentrated under reduced pressure to provide the desired compound as a
white
solid.
Using the above procedure and appropriate starting materials the following
compounds were prepared:
N-{4-Amino-phenyl)-2-methanesulfinyl-benzamide
N-{4-Amino-3-cyano-phenyl)-2-fluoro-benzamide
Furan-2-carboxylic acid (4-amino-3-cyano-phenyl)-amide
N-{4-Amino-3-cyano-phenyl)-acetamide
Furan-2-carboxylic acid (4-amino-3-trifluoromethyl-phenyl}-amide
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N-(4-Amino-3-methoxy-phenyl)-acetamide
N-(4-Amino-3-methoxy-phenyl)-2-fluoro-benzamide
Furan-2-carboxylic acid (4-amino-3-methoxy-phenyl)-amide
EXAMPLE 17 {METHOD 4A)
2-Chloro-1-cyclohexyloxy-4-nitro-benzene
Cylcohexanol (2.9 g) in dimethylsulfoxide (20 mL) is added slowly to a flask
containing potassium hydride (0.90 g, pre-washed three times with hexanes)
under an
atmosphere of argon and the solution is stirred for about 1 hour at room
temperature.
A solution of 3-chloro-4-fluoro-nitrobenzene ( I 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 (S%
ethyl acetate in hexanes is used as the eluant) to provide the desired product
as an
orange solid.
EXAMPLE 18 (METHOD 4C)
(2-Chloro-4-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 silica gel (pure ethyl acetate
followed
by pure methanol is used as the eluants) to provide the desired product as a
yellow
oil.
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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-piperidin-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-pyrrolidin-3-yl)-amine
( 1-Benzyl-pyrrolidin-3-yl}-(2-chloro-4-vitro-phenyl}-methyl-amine
(2-Chloro-4-vitro-phenyl)-cyclopentyl-methyl-amine
1-(2-Chloro-4-vitro-phenyl)-decahydro-quinoline
Allyl-(2-chloro-4-vitro-phenyl)-cyclohexyl-amine
2-[(2-Chloro-4-vitro-phenyl)-(2-hydroxy-ethyl)-amino]-ethanol
(2-Chloro-4-vitro-phenyl)-isobutyl-methyl-amine
(2-Chloro-4-vitro-phenyl)-hexyl-methyl-amine
2-[(2-Chloro-4-vitro-phenyl)-methyl-amino]-ethanol
N-(2-Chloro-4-vitro-phenyl)-N,N',N'-trimethyl-ethane- I,2-diamine
N-(2-Chloro-4-vitro-phenyl)-N,N',N'-trimethyl-propane-1,3-diamine
{ 1-Benzyl-piperidin-4-yl)-(2-chloro-4-vitro-phenyl)-amine
N-{2-Chloro-4-vitro-phenyl)-N',N'-dimethyl-ethane-1,2-diamine
N-{2-Chloro-4-vitro-phenyl)-N',N'-dimethyl-propane-1,3-diamine
(2-Chloro-4-vitro-phenyl)-(2-methoxy-ethyl)-methyl-amine
( I-Benzyl-pyrrolidin-3-yl)-(2-chlaro-4-vitro-phenyl)-amine
4-Piperidin-1-yl-3-trifluoromethyl-benzonitrile
4-Dimethylamino-3-trifluorornethyl-benzonitrile
4-(4-Methyl-piperazin-1-yl)-3-trifluoromethyl-benzonitrile
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EXAMPLE 19 {METHOD 4E)
Butyl-(2-chloro-4-vitro-phenyl)thioether
A solution of 3-chloro-4-fluoro-nitrobenzene (5.0 g) and sodium sulfide (2.5
g) in
N,N-dimethylformamide (30 mL) is stirred at room temperature for 1 hour and
then
treated with 1-iodobutane (12.6 g). The solvent is then removed under reduced
pressure and the resulting residue is treated with ethyl acetate and hexanes
to
precipitate the inorganic salts. The solids are removed by filtration and the
filtrate is
reduced under reduced pressure. The resulting residue is then passed through
hydrous magnesium silicate using dichloromethane as the eiuent to provide the
desired compound as a yellow solid.
Using the above procedure and appropriate starting materials the following
compounds were prepared:
1-Butylsulfanyl-2-chloro-4-vitro-benzene
2-Chloro-1-cyclohexylsulfanyl-4-vitro-benzene
2-Chloro-1-ethylsulfanyl-4-vitro-benzene
EXAMPLE 20 {METHOD 4F)
(4-Chloro-5-methoxy-2-vitro-phenyl)-dimethyI-amine
To a solution of trifluoro-methanesulfonic acid 4-chloro-5-methoxy-2-vitro-
phenyl
ester {1.0 g) in tetrahydrofuran (2.0 mL) is added dimethylamine (4.0 mL of a
40%
aqueous solution) and the mixture is stirred at room temperature for
approximately
15 hours. The solution is then concentrated under reduced pressure and the
residue is
dissolved in ethyl acetate and then washed with water. The aqueous layer is
extracted
once with ethyl acetate and the combined organic layers are washed with
saturated
aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent
is
removed by evaporation under reduced pressure and the residue is triturated
with
hexanes to provide the desired product as a colorless solid.
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Using the above procedure and appropriate starting materials the following
compounds were prepared:
(4-Chloro-2-nitro-phenyl)-dimethyl-amine
4-(4-Chloro-5-methoxy-2-nitro-phenyl)-morpholine
(4-Chloro-5-methoxy-2-nitro-phenyl)-dimethyl-amine
1-(4-Chloro-5-methoxy-2-nitro-phenyl)-piperidine
1-(4-Chloro-5-methoxy-2-nitro-phenyl)-pyrrolidine
B enzyl-(4-chloro-5-methoxy-2-nitro-phenyl)-amine
(2-Chloro-6-nitro-phenyl)-dimethyl-amine
EXAMPLE 21 (METHOD 4G)
(2-Chloro-4-nitro-phenyl)-methyl-phenyl-amine
n-Butyl lithium (12.3 mL of a 2.5 M solution in hexanes) is added dropwise to
a
solution of N-methyl aniline (3.0 g) in tetrahydrofuran (75 mL) at 0°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 roam temperature over the course of 1 hour,
and is
then concentrated under reduced pressure, quenched by addition of saturated
aqueous
ammonium chloride; and extracted three times with ethyl acetate. The pooled
organic layers are washed three times with 5% aqueous hydrochloric acid, once
with
water, once with saturated aqueous sodium bicarbonate, once with saturated
aqueous
sodium chloride, and then dried over anhydrous magnesium sulfate. Following
removal of the solvent under reduced pressure the residue is chromatographed
over
silica gel {5% diethyl ether in hexanes is used as the eluant) to provide the
desired
product as a clear colorless oil.
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EXAMPLE 22 (METHOD 4H)
2,6-Dichloro-4-nitrophenol
3,4,5-Trichloronitrobenzene (14.86 g) is added to a solution of potassium
phenoxide
(8.66 g) in diethylene glycol (66 mL) and the mixture is heated to
160°C for
approximately 15 hours. The resulting dark brown solution is cooled to room
temperature, poured onto 100 mL cold water, and extracted twice with diethyl
ether.
The pooled organic extracts are washed with water, 10°lo aqueous sodium
hydroxide,
and then dried over anhydrous magnesium sulfate. Following removal of the
solvent
under reduced pressure the resulting oil is distilled in a Kugelrohr apparatus
to
provide a yellow oil that solidifies on standing. Recrystallization from
ethanol-water
provides the desired product as a pale yellow solid.
EXAMPLE 23 (METHOD 5A)
{3,5-Dichloro-4-ethoxy-phenyl)-carbamic acid tert-butyl ester
To a solution of (3,5-dichloro-4-hydroxy-phenyl)-carbamic acid tert-butyl
ester (1.0
g) and potassium carbonate (1.0 g) in acetone (18 mL) is added ethyl iodide
{0.36
mL) and the mixture is stirred for approximately 15 hours at room temperature.
The
solution is then filtered, concentrated under reduced pressure, and
partitioned
between ethyl acetate and water. The separated aqueous layer is further
extracted
twice with ethyl acetate, and the pooled organic extracts are washed
successively with
10% aqueous sodium hydroxide, with water, and then dried over anhydrous sodium
sulfate. Evaporation of the solvent under reduced pressure gave the desired
product
as a tan solid.
Using the above procedure and appropriate starting materials the following
compounds were prepared:
(3,5-Dichloro-4-ethoxy-phenyl)-carbamic acid tert-butyl ester
(4-Butoxy-3,5-dichloro-phenyl)-carbamic acid tert-butyl ester
(4-Benzyloxy-3,5-dichloro-phenyl)-carbamic acid tert-butyl ester
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(4-Carbamoylmethoxy-3,5-dichloro-phenyl)-carbamic acid tert-butyl ester
[3,5-Dichloro-4-(2-nitrilo-ethoxy)-phenyl]-carbamic acid tert-butyl ester
(4-tert-Butoxycarbonylamino-2,6-dichloro-phenoxy)-acetic acid methyl ester
3-Butoxy-benzoic acid methyl ester
3-tert-Butoxycarbonylmethoxy-benzoic acid methyl ester
3-Carbamoylmethoxy-benzoic acid methyl ester
[4-(3-Carbamoylmethoxy-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
{ 4-[3-(2-Chloro-ethoxy)-benzoylamino]-phenyl }-carbamic acid tert-butyl ester
EXAMPLE 24 (METHOD 5C)
(2,6-Dichloro-4-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 tent-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
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1-ChIoro-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 tent-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-Diiodo-2,4-dimethoxy-5-vitro-benzene
1,3-Dibromo-2,4-dimethoxy-5-vitro-benzene
3-Chloro-2,4-dimethoxy-nitrobenzene
EXAMPLE 25 (METHOD 5E)
[3,5-Dichioro-4-(2-hydroxy-ethoxy)-phenyl]-carbamic acid
tert-butyl ester
To a solution of (3,5-dichloro-4-hydroxy-ghenyl)-carbamic acid tert-butyl
ester (1.0
g) and potassium carbonate (0.55 g) in toluene {20 mL) is added ethylene
carbonate
(l.f g) and the mixture is heated to reflux for 3 hours. To the cooled
reaction
mixture is added 2.5 M aqueous sodium hydroxide (50 mL), and the separated
organic layer is then washed successively with water, then saturated aqueous
sodium
chloride, and then dried over anhydrous sodium sulfate. The solvent is then
removed
by evaporation under reduced pressure and the resulting residue is
chromatographed
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over silica gel (30% ethyl acetate in hexanes is used as the eluant) to
provide the
desired product as a white foam.
EXAMPLE 2b (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-vitro-phenoxy)-1-methyl-piperidine
3-(2-Chloro-4-vitro-phenoxy)-1-methyl-pyrrolidine
[2-(2-Chloro-4-vitro-phenoxy)-ethylj-dimethyl-amine
[3-(2-Chloro-4-vitro-phenoxy)-propyl]-dimethyl-amine
EXAMPLE 27 (METHOD 7A)
2-Chloro-3-methoxy-b-vitro-phenol
and
2,4-Dichtoro-3-methoxy-b-vitro-phenol
To a flask containing 3-methoxy-6-vitro-phenol (0.5 g) is added aqueous sodium
hypochlorite (5.25% aqueous solution, 21 mL) and the mixture is stirred at
room
temperature for approximately 24 hours. The mixture is then cooled in an ice-
bath,
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acidified by addition of concentrated hydrochloric acid, then extracted twice
with
ethyl acetate. These organic extracts are dried over anhydrous magnesium
sulfate,
the solvent is removed by evaporation under reduced pressure, and the residue
is
chromatographed over silca gel (15% acetone in hexanes is used as the eluant)
to
provide both the mono- and di-chlorinated products as yellow solids.
Using the above procedure and appropriate starting materials the following
compounds were prepared:
3-Chloro-2-hydroxy-4-methoxy-nitrobenzene
3,5-Dichloro-2-hydroxy-4-methoxy-nitrobenzene
EXAMPLE 28 (METHOD 7B}
2,4-Dichloro-3-methyl-b-nitro-phenol
To a solution of 3-methyl-4-nitro-phenol (S.O g) in water (150 mL) is added
aqueous
sodium hypochlorite (5.25% aqueous solution, 230 mL) and the mixture is
stirred at
room temperature for approximately 15 hours. Additional aqueous sodium
hypochlorite (5.25% aqueous solution, 230 mL) is added and the mixture is
permitted
to stir at room temperature for 2.5 days. The mixture is then cooled in an ice-
bath,
acidified by addition of concentrated hydrochloric acid, then extracted twice
with
ethyl acetate. These organic extracts are dried over anhydrous magnesium
sulfate,
the solvent is removed by evaporation under reduced pressure, and the residue
is
chromatographed over silca gel (ethyl acetate is used as the eluant) to
provide the
desired product as a yellow solid. An analytically pure sample is obtained by
a single
recrystallization from chloroform.
EXAMPLE 29 {METHOD 7C)
1-Bromo-2,4-dimethoxy-5-nitro-benzene
To a solution of 2,4-dimethoxy-nitrobenzene (0.50 g) in chloroform (3 mL) is
added
dropwise a solution of bromine (0.23 g) in chloroform (1 mL) and the mixture
is
allowed to stir at room temperature for approximately 15 hours. Additional
bromine
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(0.15 g) in chloroform (1 mL) is added and the reaction is stirred for an
additional 4
hours. The mixture is then poured onto 5% aqueous sodium bisulfite and then
extracted with chloroform. Pooled organic extracts are then washed
successively
with 5% aqueous sodium bisulfite then saturated sodium chloride; and then
dried
over anhydrous sodium sulfate. Removal of the solvent under reduced pressure
and
recrystallization of the residue from toluene provides the desired product as
a yellow
solid.
EXAMPLE 30 (METHOD 7D)
2,4-Dibromo-3-methoxy-6-nitro-phenol
To a solution of 5-methoxy-2-nitro-phenol (0.25 g) and silver trifluoroacetate
(0.49
g) in glacial acetic acid (3 mL) is added dropwise a solution of bromine (
1.42 g} in
glacial acetic acid (3 mL) and the mixture is stirred at room temperature for
approximately 24 hours. The solution is then partitioned between ethyl acetate
and
water, and the organic layer is washed successively three times with 5%
aqueous
sodium bisulfate, three times with saturated aqueous sodium bicarbonate, and
once
with saturated aqueous sodium chloride. The organic layer is then dried over
anhydrous magnesium sulfate and the solvent is removed under reduced pressure.
The residue is chromatographed over silica gel (20% ethyl acetate in hexanes
is used
as the eluant) then recrystallized from chloroform to provide the desired
dibrominated product as an orange solid.
EXAMPLE 31 (METHOD 7E)
1-Iodo-2,4-dimethoxy-5-nitro-benzene
To a solution of 2,4-dirnethoxy-nitrobenzene (1.0 g) in glacial acetic acid
{30 rnL) is
added benzyltrimethylammonium dichloroiodate {1.90 g) and anhydrous zinc
chloride ( 1.0 g) and the mixture is stirred at room temperature under an
atmosphere
of argon. Additional benzyltrimethylammonium dichloroiodate (0.4 g) is added
after
5 hours and again after 24 hours. Additional zinc chloride (0.5 g) and glacial
acetic
acid (15 mL) is added after 24 hours. The mixture is permitted to stir at room
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temperature for 3 days and is then filtered, diluted with 5% aqueous sodium
bisulfate,
and extracted three times with ethyl acetate. These pooled organic extracts
are
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 (METHOD 7F)
2,4-Diiodo-3-methoxy-6-vitro-phenol
To a solution of 5-methoxy-2-vitro-phenol (0.25 g) in dichloromethane (15 mL)
and
methanol (6 mL) is added benzyltrimethylammonium dichloroiodate (1.08 g) and
sodium bicarbonate (0.85 g) and the mixture is allowed to stir at room
temperature
for 24 hours. The solution is then filtered, the filtrate is concentrated
under reduced
pressure, the residue is dissolved in ethyl acetate and then washed
successively with
5% aqueous sodium bicarbonate, 5% aqueous sodium bisulfate, and saturated
aqueous
sodium chloride. After drying over anhydrous magnesium sulfate the solvent is
removed by evaporation under reduced pressure and the residue is
recrystallized from
toluene to provide the desired product as yellow needles.
EXAMPLE 33 (METHOD 7G)
1-Fluoro-2,4-dimethoxy-5-vitro-benzene
To a solution of 2,4-dimethoxy-nitrobenzene (1.0 g) in tetrachloroethane (10
mL) is
added 3,5-dichloro-1-fluoro-pyridinium triflate (85%, 5.07 g) and the mixture
is
heated to 120 °C for 5 hours. Additional 3,5-dichloro-1-fluoro-
pyridinium triflate
(85%; 0.25 g) is added and heating is continued for 1 hour. The solution is
then
cooled to room temperature and passed over a column of silica gel (hexanes
followed
by 30% ethyl acetate in hexanes is used as the eluant). Product containing
fractions
are combined, evaporated under reduced pressure, and the residue is
crystallized from
hexanes to provide the desired product as a tan solid.
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EXAMPLE 34 (METHOD 8)
3-Chloro-4-trifluoromethyl-nitrobenzene
A solution of 3-chloro-4-iodo-nitrobenzene (2.26 g),
trimethyl{trifluoromethyl)silane
(5.68 g), copger(I) iodide (2.28 g), and potassium fluoride (0.56 g) in N,N-
dimethylformamide (8 rnL) is heated in a sealed tube to 80 °C for 40
hours. The
solution is then cooled, diluted with diethyl ether, filtered through
diatomaceous
earth, and the filtrate is washed successively with water; saturated aqueous
sodium
chloride, and then dried over anhydrous sodium sulfate. The solvent is removed
under reduced pressure and the residue is chromatographed over silica gel (1%
diethyl ether in hexanes followed by 10% ethyl acetate in hexanes is used as
the
eluant) to provided the desired product as a colorless oil.
EXAMPLE 35 (METHOD 9)
(3-Chloro-4-methanesulfinyl-phenyl)-carbamic acid tert-butyl ester
To a solution of (3-chloro-4-thiomethyl-phenyl)-carbamic acid tert-butyl ester
(0.89
g) in dichloromethane (15 mL) at 0 °C is added a solution of
dimethyldioxirane
(-0.11 M in acetone, 34 mL) and the mixture is stirred at 0 °C for 1
hour. The
solvent is removed under reduced pressure and the residue is dissolved in
dichloromethane, washed with saturated aqueous sodium chloride, and then dried
over anhydrous magnesium sulfate. Removal of the solvent under reduced
pressure
gave the desired product as an orange foam.
EXAMPLE 36 (METHOD 9B}
[4-(2-Methylsulfinyl-benzoylamino)-phenyl]-carbamic acid
tert-butyl ester
To a solution of 2-methylsulfanyl-N-[4-(2,2,2-trifluoro-acetylarnino)-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
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with ethyl acetate, dried over anhydrous potassium carbonate and evaporated to
yield
a red solid, 101 mg.
Using the above procedure and appropriate starting materials the following
compounds were prepared:
[4-{2-Methanesulfinyl-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
2-Methanesulfinyl-N-[4-(2,2,2-trifluoro-acetylamino)-phenyl)-benzamide
EXAMPLE 37 (METHOD 10)
(3-Chloro-4-methanesulfonyl-phenyl)-carbamic acid text-butyl ester
To a solution of (3-chloro-4-thiomethyl-phenyl)-carbamic acid tert-butyl ester
(0.90
g) in dichloromethane {30 mL) ai 0 °C is added a solution of
dimethyldioxirane
00.11 M in acetone, 80 mL) and the mixture is stirred at 0 °C for 1
hour. The
solvent is removed under reduced pressure and the residue is dissolved in
dichloromethane, washed with saturated aqueous sodium chloride, and then dried
over anhydrous magnesium sulfate. Removal of the solvent under reduced
pressure
gives the desired product as an orange foam.
EXAMPLE 38 {METHOD 11)
3-Chioro-4-vinyl-phenylamine
To a deoxygenated solution of 3-chloro-4-iodo-aniline {6.95 g), triphenyl
arsine (0.67
g), and tris(dibenzylideneacetone}palladium(0) (0.50 g) in tetrahydrofuran
(120 mL)
at SO °C is added tributylvinyltin (10 g) and the mixture is stirred
for approximately
15 hours at 50 °C under an atmosphere of argon. The reaction is then
cooled, filtered
through diatomaceous earth, and the filtrate is evaporated to dryness under
reduced
pressure. The residue is dissolved in hexanes and then extracted three times
with 5°l0
aqueous hydrochloric acid. These aqueous acidic extracts are then basified
with solid
potassium carbonate and extracted three times with ethyl acetate. These pooled
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organic extracts are then washed with saturated aqueous sodium chloride, dried
over
anhydrous magnesium sulfate, and the solvent is removed under reduced
pressure.
The resulting residue is chromatographed over silica gel (hexanes and then 10%
ethyl
acetate in hexanes is used as the eluant) to provide the desired product as an
amber
oil.
EXAMPLE 39 (METHOD 12)
[3-Chloro-4-(1-hydroxy-ethyl)-phenyl]-carbamic acid
2-trimethylsilanyl-ethyl ester
(3-Chloro-4-vinyl-phenyl)-carbamic acid 2-trimethylsilanyl-ethyl ester (2.6 g}
is
added to a solution of mercuric acetate (3.48 g) in water (7 mL) and
tetrahydrofuran
(5.25 mL) and the mixture is stirred for approximately 15 hours. 3N Aqueous
sodium hydroxide (8.7 mL) and a 0.5 M solution of sodium borohydride in 3N
aqueous sodium hydroxide (8.7 rnL) are then added and stirring is continued
for 6
hours. The solution is then saturated with sodium chloride and extracted with
ethyl
acetate. These organic extracts are then washed with saturated aqueous sodium
chloride and dried over anhydrous sodium sulfate. Following removal of the
solvent
under reduced pressure the residue is chromatographed over silica gel {20%
ethyl
acetate in hexanes is used as the eluant) to provide the desired product as a
white
solid.
EXAMPLE 40 (METHOD 13)
[3-ChIoro-4-(2-hydroxy-ethyl)-phenyl]-carbamic acid tert-butyl ester
To a stirnng 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 1
hour. The solution is then warmed to room temperature and (3-chloro-4-vinyl-
phenyl)-carbamic acid 2-trimethylsilanyl-ethyl ester ( I .0 g) is added. The
reaction is
stirred at room temperature for approximately 15 hours and then heated to
reflux for
approximately 20 hours. The mixture is then cooled and solutions of 5 N
aqueous
sodium hydroxide (0.80 mL) and 30% aqueous hydrogen peroxide (0.56 mL) are
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added. After stirring for an additional 15 hours the layers are separated, the
aqueous
layer is extracted three times with diethyl ether, and these organic extracts
are dried
over anhydrous magnesium sulfate. Following removal of the solvent under
reduced
pressure the residue is chromatographed over silica gel (40% ethyl acetate in
hexanes
is used as the eluant} to provide the desired product as an amber oil.
EXAMPLE 41 (METHOD 14)
[4-(1-Azido-ethyl)-3-chloro-phenyl]-carbamic acid 2-trimethylsilanyl-ethyl
ester
To a solution of [3-chlora-4-(1-hydroxy-ethyl)-phenyl]-carbamic acid 2-
trimethylsilanyl-ethyl ester ( 1.25 g) in tetrahydrofuran (20 mL) at 0
°C under an
atmosphere of argon is added triphenyl-phosphine (2.6 g), hydrazoic acid
(approximately 2.5 molar equivalents in dichloromethane, prepared by the
method of
Fieser and Fieser, Reagents for Organic Synthesis, Vol. 1, pg. 446; Wiley, New
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 arid
tert-butyl ester
To a deoxygenated solution of {3-chloro-4-iodo-phenyl)-carbamic acid tort-
butyl
ester ( 10.0 g) in triethylamine ( 120 ml} is added 1-dimethylamino-2-propyne
(2.82
g}; bis(triphenyl-phosphine)palladium(II) chloride (0.4 g), and cuprous iodide
(0.054
g). The mixture is stirred at room temperature under an atmosphere of argon
for
approximately 6 hours and is then heated briefly (ca. 10 minutes) to
60°C. The
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
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under reduced pressure, and the residue is chromatographed over silica gel
(80%
ethyl acetate in hexanes is used as the eluant) to give the purified product
as an amber
oil that solidified on standing.
Using the above procedure and appropriate starting materials the following
compounds were prepared:
[3-Chloro-4-(3-dimethylamino-prop-1-ynyl)-phenyl]-carbamic acid tert-butyl
ester
[3-(4-Methoxy-phenyl)-prop-2-ynyl]-dimethyl-amine
4-(3-Dimethylamino-prop-1-ynyl)-benzonitrile
Dimethyl-[3-(4-nitro-phenyl)-prop-2-ynyl]-amine
EXAMPLE 43 (METHOD 16)
[3-Chloro-4-(3-dimethylamino-acryloyl)-phenyl]-carbamic acid tent-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
20 {Brockmann Grade I, 150 mesh) and the N-oxide is eluted using a solution of
5%
methanol in dichloromethane. AlI fractions containing the desired amine N-
oxide
were combined and evaporated to near dryness under reduced pressure. The
residue
is treated successively three times with small portions of methanol (ca. 50
ml)
followed by evaporation to near dryness under reduced pressure, and the volume
of
the solution is adjusted to 250 mL by addition of methanol. The methanolic
solution
of the N-oxide is then heated to reflux for approximately 15 hours, then
cooled, and
the solvent is evaporated to dryness under reduced pressure. The residue is
purified
by chromatography over silica gel (80% ethyl acetate in hexanes is used as the
eluant) to give the desired product as a pale yellow solid.
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EXAMPLE 44 (METHOD 17)
(3-Chloro-4-isoxazol-S-yl-phenyl)-carbamic acid tert-butyl ester
A solution of [3-chloro-4-(3-dimethylamino-acryloyl)-phenyl]-carbamic acid
tert-
butyl ester (270 mg) in dioxane (3 ml) is treated with hydroxylamine
hydrochloride
( 122 mg) and the mixture is stirred at room temperature for 10 days. The
mixture is
diluted with ethyl acetate, washed successively with water, 5~/o 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 tent-butyl ester
A solution of [3-chloro-4-(3-dimethylamino-acryloyl)-phenyl]-carbamic acid
tert-
butyl ester (250 mg} in ethanol ( 1.25 ml) is treated with hydrazine hydrate
(0.25 ml)
and the mixture is stirred at room temperature for 3 hours. The mixture is
then
diluted with 30 mL of diethyl ether, washed three times with water, once with
saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate.
The solvent is removed by evaporation under reduced pressure and the resulting
residue is chromatographed over silica gel (67% ethyl acetate in hexanes is
used as
the 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-nitroaniline (3.80 g} in
tetrahydrofuran (50
mL) is added thiomorpholine (10 mL} and the solution allowed to stand for 1
hour.
This reaction mixture is poured into water a pale yellow solid is collected
and then
recrystallized from hot 2-propanol to give a pale yellow crystalline solid.
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Using the above procedure and appropriate starting materials the following
compounds were prepared:
{4-{ 2-[Bis-(2-hydroxy-ethyl}-amino]-acetylamino }-phenyl)-carbamic acid tert-
butyl
ester
[4-(2-Dimethylamino-acetylamino}-phenyl]-carbamic acid tert-butyl ester
{4-[3-(2-Dimethylamino-ethoxy)-benzoylamino]-phenyl}-carbamic acid test-butyl
ester
{4-[3-(2-Morpholin-4-yl-ethoxy)-benzoylamino]-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-acetamide
N-(2-Chloro-4-vitro-phenyl)-2-morpholin-4-yl-acetamide
N-(2-Chloro-4-vitro-phenyl}-2-dipropylamino-acetamide
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 (METHOD 19B)
N-(2-Chloro-4-nitrophenyl)-2-(2-dimethylaminoethylsulfanyl)acetamide
To a solution of N-(chloroacetyl}-2-chloro-4-nitroaniline (3.01 g) in N,N-
dimethylformamide (100 mL) is added powdered sodium carbonate (6.0 g) and 2-
dimethylaminoethanethiol hydrochloride (b.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.
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EXAMPLE 48 (METHOD 20)
(4-tart-butoxycarbonylamino-2-chloro-phenyl)-carbamic acid 2-
piperidin-1-yl-ethyl ester
Ta a suspension of I,l-carbonyl-di-(1,2,4)-triazole {4.0 g) in dichloromethane
(40
mL) is added a solution of (4-amino-3-chloro-phenyl) carbamic acid tart-butyl
ester
(5.0 g) in dichioromethane (45 mL) dropwise over 20 minutes. The reaction is
stirred at room temperature for 30 minutes at which point a precipitate forms.
To
this mixture is added piperidineethanol (6.6 mL) and tetra-hydrofuran (20 mL)
is
added to maintain homogeneity. After heating at reflux overnight the reaction
is
cooled and then poured into water, the organic layer separated and then washed
with
saturated aqueous sodium chloride. The solution is dried over anhydrous sodium
sulfate, filtered and concentrated under reduced pressure to a crude oil that
is purified
by chromatography over silica gel {5% methanol in dichloromethane is used as
the
eluant) to give the desired product as a white foam.
EXAMPLE 49 (METHOD 21)
5-Phenyl-[1,2,3]thiadiazole-4-carboxylic acid methyl ester
A solution of ethyl benzoylacetate (1.1 g) in acetonitrile {10 mL) is treated
with 4-
methylbenzenesulfonyl azide ( 1.3 g) and triethylamine ( 1.6 g). After
stirring
overnight at room temperature, the reaction is concentrated under reduced
pressure
and the resulting crude product is dissolved in ethyl acetate and washed with
1N
sodium hydroxide. The organic layer is then dried over anhydrous magnesium
sulfate, filtered and concentrated under reduced pressure to yield a yellow
oil. This
oil is taken into dichloromethane and filtered through a pad of hydrous
magnesium
silicate, eluting with dichloromethane to give the partially purified
diazoketone as a
colorless oil. A sample of the diazoketone from above ( 1.2 g) is dissolved in
toluene
(25 mL) and treated with 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-
2,4-disulfide (2.8 g) and the reaction is heated to reflux. After 3 hours, the
reaction is
cooled to room temperature, loaded onto a pad of silica gel and eluted with
dichloromethane. After removing the solvent under reduced pressure, the
resulting
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oil is purified by chromatography over silica gel (30% diethyl ether in
petroleum
ether is used as the eluant) and then recrystallized from hexanes to give the
desired
product as pale yellow needles.
Using the above procedure and appropriate starting materials the following
compound was prepared:
5-Phenyl-[I,2,3]thiadiazole-4-carboxylic acid ethyl ester
5-Methyl-[ 1,2,3]thiadiazole-4-carboxylic acid methyl ester
EXAMPLE 50
Ethyl benzoylacetate semicarbazide
Ethyl benzoylacetate {5.0 g) is dissolved in methanol ( 10 mL) and added
rapidly to a
hot solution of semicarbazide hydrochloride (29 g) in water (130 mL). To this
is
added pyridine (4.1 g) and after heating to reflux for 5 minutes, the reaction
mixture
is cooled to -20 °C overnight. The resulting solid semicarbazone is
collected by
filtration, washed with water and then diethyl ether to give the desired
product as
white crystals.
Using the above procedure and appropriate starting materials the following
compound was prepared:
Ethyl (Z)-3-[(aminocarbonyl)hydrazono]-4,4,4-trifluorobutanoate
3-[{Z)-2-(Aminocarbonyl)hydrazono]-3-phenylpropanoic acid ethyl ester
3-[(E)-2-(Aminocarbonyl)hydrazono]-3-(3-furyl)propanoic acid ethyl ster
EXAMPLE 51
5-Phenyl-[1,2,3]thiadiazole-5-carboxylic acid ethyl ester
A solution of ethyl benzoylacetate semicarbazone (2.5 g) in neat thionyl
chloride (5
mL) is stirred at 0 °C for 1 hour. Dichloromethane is then added (25
mL), the excess
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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°lo 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-S-carboxylic acid methyl ester
4-Phenyl-[1,2,3]thiadiazole-S-carboxylic acid ethyl ester
4-Furan-3-yl-[1,2,3]thiadiazole-S-carboxylic acid ethyl ester
1 S EXAMPLE 52
4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid
4-Methyl-[1,2,3]thiadiazole-S-carboxylic acid methyl ester (1.7 g) is
dissolved in
methanol (1S mL) and treated with 1N sodium hydroxide (16 mL). After stirring
at
room temperature for 1 hour, the reaction is treated with concentrated
hydrochloric
acid (l.S mL) and concentrated under reduced pressure. The resulting turbid
aqueous
layer is extracted twice with diethyl ether and the pooled organic layers are
dried over
anhydrous magnesium sulfate, filtered and concentrated under reduced pressure
to
give the desired compound as a white powder.
2S
Using the above procedure and appropriate starting materials the following
compounds were prepared:
3-Ethoxycarbonylmethoxy-benzoic acid
S-Furan-3-yl-[1,2,3]thiadiazole-4-carboxylic acid
Thiazole-4-carboxylic acid
4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid
S-Methyl-[1,2,3]thiadiazole-4-carboxylic acid
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EXAMPLE S3 (METHOD 2S)
Trifluoro-methanesulfonic acid 4-chloro-S-methoxy-2-nitro-phenyl ester
To a solution of 4-chloro-5-methoxy-2-nitro-phenol (6.5 g) in dichloromethane
{I50
mL) at 0 °C under an atmosphere of argon is added triethylamine { 10 g)
and then a
solution of trifluoro-methanesulfonic anhydride (13.5 g) in dichloromethane
{30 mL).
The solution is stirred at 0 °C for 10 minutes, and is then
diluted with
dichloromethane and washed successively with saturated aqueous sodium
bicarbonate
and saturated aqueous sodium chloride. After drying over anhydrous sodium
sulfate
the solvent is removed by evaporation under reduced pressure and the residue
is
dissolved in, a solution of 20% dichloromethane in hexanes and passed through
a
short column of hydrous magnesium silicate (20% dichloromethane in hexanes is
used as the eluant}. Product containing fractions are pooled and the solvents
removed
by evaporation under reduced pressure to give the desired product as a yellow
oil.
Using the above procedure and appropriate starting materials the following
compounds were prepared:
Trifluoro-methanesulfonic acid 4-chloro-5-methoxy-2-nitro-phenyl ester
Trifluoro-methanesulfonic acid 4-chloro-2-vitro-phenyl ester
Trifluoro-methanesulfonic acid 2-chloro-6-vitro-phenyl ester
EXAMPLE S4 (METHOD 26)
[4-(3-Dimethylamino-benzoylamino)-phenyl]-carbamic acid t-butyl ester
A solution of [4-(3-amino-benzoylamino)-phenyl]-carbamic acid t-butyl ester
{505
mg), sodium cyanoborohydride (250 mg), acetic acid (3 drops) and 40 % aqueous
formaldehyde (4 mL) in 1:2 tetrahydrofuran-methanol (15 mL) is stirred for 15
minutes, and then poured into saturated aqueous sodium bicarbonate and
extracted
into ethyl acetate. The ethyl acetate solution is dried over anhydrous
potassium
carbonate and concentrated under reduced pressure to give a solid which is
recrystallized from acetonitrile to provide a pale pink crystalline solid.
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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-trifiuoromethyl-phenyl)-dimethyl-amine
N-(3-Chloro-5-dimethylamino-phenyl)-acetamide
EXAMPLE 55 (METHOD 27)
N-(4-Aminophenyl)-2-hydroxybenzamide
To a solution of 2-(4-aminophenylcarbamoyl) phenyl acetate (580 mg) in
methanol
( 10 mL) is added saturated sodium bicarbonate (2 mL) and water (3 mL). The
mixture is heated at 80° C for 30 minutes, then poured into half-
saturated aqueous
sodium chloride and extracted with ethyl acetate. The ethyl acetate solution
is dried
over anhydrous sodium sulfate and concentrated under reduced pressure to give
an oil
which is then triturated with diethyl ether to provide the desired product as
a white
solid.
EXAMPLE 56 (METHOD 28)
[4-(3-(Hydroxybenzoylamino)phenyl}carbamic acid t-butyl ester
To a solution of of 3-(4-aminophenylcarbamoyl) phenyl acetate (4.34 g) in
methanol
(75 mL) is added 0.1 N aqueous sodium hydroxide (25 mL) and tetrahydrofuran
(25
mL). This solution is heated at 40° C for 30 minutes, then cooled,
poured into 1 M
hydrochloric acid and extracted with ethyl acetate. The ethyl acetate solution
is dried
over anhydrous sodium sulfate and concentrated under reduced pressure to give
a
white solid, which is further purified by trituration with diethyl ether.
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EXAMPLE 57 (METHOD 29}
N-(4-Aminophenyl)-2-hydroxymethylbenzamide
To a solution of N-(4-aminophenyl)phthalimide (332 mg) in tetrahydrofuran (4
mL)
is added lithium borohydride ( I .0 g) and the mixture is stirred for 1 hour
at 25° C.
The mixture is poured into water and extracted into ethyl acetate. The ethyl
acetate
solution is dried over anhydrous sodium sulfate and concentrated under reduced
pressure to give a white foam, which when triturated with diethyl ether
provides the
desired product as a white powder.
EXAMPLE 58 (METHOD 30}
(3-Chloro-5-dimethylamino-phenyl)-carbamic acid tert-butyl ester
To a solution of (3-amino-5-chloro-phenyl)-carbamic acid tert-butyl ester
(0.32 g} in
toluene (10 mL) is added aqueous formaldehyde (37%, 1.5 mL) then 10% palladium
on carbon (0.50 g) and the mixture is stirred under an atmosphere of hydrogen
for
approximately 15 hours. The solution is then filtered through diatomaceous
earth and
the filtrate is concentrated under reduced pressure. The residue is
chromatographed
over silica gel (50% dichloromethane in hexanes is used as the eluant) to
provide the
desired product as a white solid.
EXAMPLE S9 (METHOD 3S)
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. I6 g) in a 1:1 mixture of tetrahydrofuran and
methanol (2.5
mL) is added 1 N aqueous sodium hydroxide ( 1 mL) and the mixture is stirred
for
approximately 2 hours at room temperature. The solution is then poured into 2
M
aqueous hydrochloric acid (3 mL), extracted into ethyl acetate, and the
extracts are
dried over anhydrous sodium sulfate. The solvent is removed by evaporation
under
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reduced pressure and the residue is triturated with diethyl ether to provide
the desired
product as a white solid.
EXAMPLE 60 (METHOD 36)
{4-[3-(4-Acetylamino-phenyl)-thioureido]-2,6-dichtoro-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 I:1 mixture of tetrahydrofuran and
methanol (4
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 (5 mL), extracted into ethyl acetate, and the
extracts are
dried over anhydrous sodium sulfate. The solvent is removed by evaporation
under
reduced pressure and the residue is triturated with diethyl ether to provide
the desired
product as a white solid.
Using the above procedure and appropriate starting materials the following
compounds were prepared:
{ 4-[3-(4-Acetylamino-phenyl)-thioureido}-2,6-dichloro-phenoxy }-acetic acid
{ 2-[3-(4-Acetylamino-phenyl)-thioureido]-4-chloro-5-methoxy-phenoxy }-acetic
acid
{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-5-methoxy-phenoxy}-acetic
acid
EXAMPLE 61 {METHOD 37)
Benzoic acid 2-{4-[3-(4-acetytamino-phenyl)-thioureido]-2,6-dichtoro-
phenoxy}-ethyl ester
To an ice cooled solution of N-(4-{3-[3,5-dichloro-4-(2-hydroxy-ethoxy)-
phenyl]-
thioureido }-phenyl)-acetamide (0.20 g) in pyridine (2 mL) and tetrahydrofuran
(0.5
mL) is added benzoyl chloride (0.0$ g) and the mixture is stirred at 0
°C for 1.5
hours. The mixture is then diluted with ethyl acetate, washed successively two
times
with 2% aqueous hydrochloric acid, once with saturated aqueous sodium
chloride,
then dried over anhydrous sodium sulfate. After removal of the solvent under
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reduced pressure the residue is chromatographed over silica gel (5% methanol
in
dichloromethane is used as the eluant) and product containing fractions are
combined, evaporated under reduced pressure, and the residue is recrystallized
from
acetone-hexanes to provide the desired product as a white powder.
EXAMPLE 62 (METHOD 38)
Methanesulfonic acid 2-{4-[3-(4-acetylamino-phenyl)-thioureido]-2,6-dichloro-
phenoxy)-ethyl ester
To an ice cooled solution of N-(4-{3-[3,5-dichloro-4-(2-hydroxy-ethoxy)-
phenyl]-
thioureido}-phenyl)-acetamide (0.20 g) in pyridine (2 mL) and tetrahydrofuran
(0.5
mL) is added methanesulfonyl chloride (0.11 g) and the solution is stirred at
0 °C for
45 minutes. The reaction mixture is then diluted with ethyl acetate, washed
successively twice with 2% aqueous hydrochloric acid, once with saturated
aqueous
sodium chloride, and then dried over anhydrous magnesium sulfate. After
removing
the solvents by evaporation under reduced pressure the resulting residue is
recrystallized from acetone-hexanes to give the desired product as a white
powder.
EXAMPLE 63 (METHOD 39)
N-(4-{3-[3,5-DichIoro-4-(2-dimethylamino-ethoxy)-phenyl]-thioureido}-phenyl)-
acetamide
To a solution of methanesulfonic acid 2-{4-[3-(4-acetylamino-phenyl)-
thioureido]-
2,b-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
product containing fractions are evaporated under reduced pressure and the
residue is
recrystallized from acetonitrile to provide the desired product as a white
powder.
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Using the above procedure and appropriate starting materials the following
compounds were prepared:
N-(4-{ 3-j3,5-Dichloro-4-(2-dimethylamino-ethoxy)-phenyl]-thioureido }-phenyl)-
acetamide
Benzoic acid 2-{4-[3-(4-acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy}-
ethyl ester
EXAMPLE 64 (METHOD 40)
Furan-2-carboxylic acid (4-{3-[4-(1-amino-ethyl)-3-chloro-phenyl]-thioureido}-
phenyl)-amide
To a solution of tin(II) chloride dehydrate (0.25 g) in methanol (2.5 mL) is
added
furan-2-carboxylic acid (4-{3-[4-(1-azido-ethyl)-3-chloro-phenyl]-thioureido}-
phenyl)-amide (0.22 g) and the solution is stirred for approximately 15 hours
at room
temperature. The solution is then diluted with ethyl acetate, washed
successively
with saturated aqueous sodium bicarbonate then saturated aqueous sodium
chloride,
then dried over anhydrous sodium sulfate. After removal of the solvent by
evaporation under reduced pressure the residue is chromatographed over silica
gel
(8% methanol in dichloromethane containing 1 % triethylamine is used as the
eluant)
to provide the desired product as a yellow solid.
EXAMPLE 65 (METHOD 41)
[1,2,3]Thiadiazole-4-carboxylic acid (4-isothiocyanato-phenyl)-amide
To a ice cooled solution of 1,1'-thiocarbonyldiimidazole (7.28 g) in
tetrahydrofuran
(50 mL) is added [1,2,3]-thiadiazole-4-carboxylic acid (4-amino-phenyl) amide
(9.0
g) in tetrahydrofuran {100 mL). After approximately one hour the solvent is
removed by evaporation and the residue is dissolved in ethyl acetate. Diethyl
ether is
added to precipitate the crude product, which is then collected by filtration,
dissolved
in dichlorornethane, and passed through a plug of hydrous magnesium silicate.
After
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removal of solvents, the residue is recrystallized from ethyl acetate-hexanes
to
provide the desired product as a slightly yellow solid.
Using the above procedure and appropriate starting materials the following
compounds were prepared:
2-Fluoro-N-(4-isothiocyanato-phenyl)-benzamide
Furan-2-carboxylic acid (4-isothiocyanato-phenyl}-amide
[1,2,3]Thiadiazole-4-carboxylic acid {4-isothiocyanato-phenyl)-amide
Thiazole-4-carboxylic acid (4-isothiocyanato-phenyl)-amide
EXAMPLE 66 (METHOD 42)
N,N-Dimethyl-5-trifluoromethyl-benzene-1,3-diamine
To a solution of 3-amino-5-bromo-benzotrifluoride (1.0 g) in degassed (argon}
tetrahydrofuran (2 mL} is added bis-(tri-o-tolylphosphino)palladium {0.15 g},
a
solution of dimethylamine in tetra-hydrofuran (2M, 4.2 mL), and a solution of
lithium bis(trimethylsilyl)amide in tetrahydrofuran ( i M, 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%
aqueous hydrochloric acid, and pooled acidic extracts are then basified with
cooling
by addition of 5N aqueous sodium hydroxide. This basic solution is then
extracted
with ethyl acetate, and these pooled organic extracts are washed with
saturated
aqueous sodium chloride, dried over anhydrous magnesium sulfate, and
evaporated to
dryness under reduced pressure. The resulting residue is chromatographed over
silica
gel (20-30% ethyl acetate in hexanes is used as the eluant) to provide the
desired
product as a slightly tinted solid.
Using the above procedure and appropriate starting materials the following
compounds were prepared:
3-(4-Methyl-piperazin-1-yl)-5-trifluoromethyl-phenylamine
3-Morpholin-4-yl-5-trifluoromethyl-phenylamine
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3-Piperidin-I-yl-5-trifluoromethyl-phenylamine
3-Pyrrolidin-1-yl-5-trifluoromethyl-phenylamine
N,N-Dimethyl-5-trifluoromethyl-benzene-I,3-diamine
N-Isobutyl-N-methyl-5-trifluoromethyl-benzene-2,3-diamine
N-Butyl-N-methyl-5-trifluoromethyl-benzene-1,3-diamine
EXAMPLE b7 (METHOD 43)
(3-Isobutyl-S-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 S
minutes. A solution of 9-borabicyclo[3.3.1]nonane in tetrahydrofuran {0.5 M,
11
mL) is added, the vessel is sealed with a teflon cap, slowly warmed to room
temperature and kept at room temperature for approximately 2.5 hours. The
mixture
is then re-cooled in a dry ice-acetone bath, the teflon cap is replaced by a
rubber
septum, and argon is bubbled through the mixture with venting to removed the
excess
isobutylene. A solution of (3-bromo-5-trifluoromethyl-phenyl)-carbamic acid
tert-
butyl ester { 1.7 g) in tetrahydrofuran ( 12 mL) is added, followed by [ l, I'
-
bis{diphenylphosphino)-ferrocene]palladium(II) chloride-dichlormethane complex
(0.12 g), and then 3N aqueous sodium hydroxide. The vessel is again sealed
with the
teflon cap and is then heated to 65°C for approximately 15 hours. The
mixture is
then cooled to room temperature, diluted with hexanes, washed with water,
saturated
aqueous sodium chloride, dried over anhydrous magnesium sulfate, and
evaporated
under reduced pressure. The resulting oil is chromatographed over silica gel
(5%
ethyl acetate in hexanes is used as the eluant) to provide the desired product
as a
white powder.
Using the above procedure and appropriate starting materials the following
compounds were prepared:
[3-(2-Methyl-butyl)-5-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester
3-Isobutyl-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester
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EXAMPLE 6$ (METHOD 44)
2-(3,5-Dichloro-phenyIsulfanyl)-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 lOM 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 1.0g 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-Brorno-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-Phanylsulfanyl-ethylamine
1-(2-Chloro-phenyl)-ethylamine
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EXAMPLE 69 (METHOD 45)
N-(1-Naphthalen-2-yl-ethyl)-formamide
.~1 mixture of 2-acetylnaphthylene (3.0 g), ammonium formate (11.0 g), formic
acid
{3.3 mL), and formamide (3.5 mL} is heated at 190°C for 3 hours. The
mixture is
cooled, poured into water and extracted with ether. The ether extract is dried
with
anhydrous potassium carbonate, filtered and concentrated to give a yellow oil,
which
is crystallized from toluene-hexanes to give a white solid, 1.97 g.
Using the above procedure and appropriate starting materials the following
compounds were prepared:
N-[ 1-(4-Fluoro-phenyl)-2-methyl-propyl]-formamide
N-{ 1-Naphthalen-2-yl-ethyl)-formamide
EXAMPLE '70 (METHOD 46)
1-(2-Naphthyl)ethylamine
A mixture of N-(1-naphthalen-2-yl-ethyl)-formarnide (1.12 g), ethanol (10 mL)
and 5
N sodium hydroxide (10 mL) is heated at reflux for 1 hour. The solution is
cooled,
poured into water and extracted with ether. The ether solution is dried with
anhydrous potassium carbonate, filtered and concentrated to give the product
(0.95 g)
as a pale yellow oil.
Using the above procedure and appropriate starting materials the following
compounds were prepared:
1-(3-Trifluoromethyl-phenyl)-ethylamine
1-(4-Fluoro-phenyl)-2-methyl-propylamine
[3-(1-Amino-ethyl)-phenyl]-dimethyl-amine
3-( i -Amino-ethyl)-benzonitrile
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EXAMPLE 71 (METHOD 47)
1-(3-Trifluoromethyl-phenyl)-ethanone O-methyl-oxime
Methoxylamine hydrochloride (2.33 g) is added to a solution of 3'-
(trifluoromethyl)-
acetophenone (1.5 g) in ethanol (20 mL) and pyridine (2 rnL). The solution is
heated
at reflex for 45 minutes. The reaction mixture is then cooled, concentrated
under
reduced pressure and partitioned between water and ethyl acetate. The aqueous
layer
is extracted with ethyl acetate. The combined organic layers are washed with
saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and
concentrated under reduced pressure to give the desired product as a colorless
oil
(1.61 g).
Using the above procedure and appropriate starting materials the following
compounds were prepared:
1S
3,5-Bis-trifluoromethyl-benzaldehyde oxime
1-(4-Fluoro-phenyl)-propan-1-one O-methyl-oxime
1-(2-Chloro-phenyl)-ethanone O-methyl-oxime
1-(3-Bromo-phenyl)-ethanone O-methyl-oxime
1-(3-Chloro-phenyl)-ethanone O-methyl-oxirne
1-p-Tolyl-ethanone O-methyl-oxime
1-(4-Fluoro-phenyl)-pentan-1-one O-methyl-oxime
1-(4-Fluoro-phenyl}-2-phenyl-ethanone O-methyl-oxime
1-o-Tolyl-ethanone O-methyl-oxime
1-m-Tolyl-ethanone O-methyl-oxime
1-(2-Fluoro-phenyl)-ethanone O-methyl-oxime
3-( 1-Methoxyimino-ethyl)-benzonitrile
4-( 1-Methoxyimino-ethyl)-benzonitrile
1-(4-Methoxy-phenyl)-ethanone O-methyl-oxime
1-(2-Methoxy-phenyl)-ethanone O-methyl-oxime
1-(4-Dimethylamino-phenyl)-ethanone O-methyl-oxirne
1-(2-Trifluoromethyl-phenyl)-ethanone O-methyl-oxime
1-(3-Methoxy-phenyl}-ethanone O-methyl-oxime
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I-(3-Tri#luoromethyl-phenyl}-ethanone O-methyl-oxime
1-(4-Trifluoromethyl-phenyl)-ethanone O-methyl-oxime
1-Furan-2-yl-ethanone O-methyl-oxime
1-Pyridin-4-yl-ethanone O-methyl-oxime
1-(1-Methyl-1H-pyrrol-2-yl)-ethanone O-methyl-oxime
1-Thiophen-3-yl-ethanone O-methyl-oxime
(4-Fluoro-phenyl)-phenyl-methanone O-methyl-oxime
I-(4-methoxyphenyl)ethanone O-methyloxime
1-(3-Chloro-4-methoxy-phenyl)-ethanone O-methyl-oxime
IO 4-(1-Methoxyimino-ethyl)-benzenesulfonamide
4-( 1-Methoxyimino-ethyl)-N,N-dimethyl-benzenesulfonamide
1-j4-(Piperidine-1-sulfonyl)-phenyl)-ethanone O-methyl-oxime
4-( 1-Methoxyimino-ethyl)-N,N-dipropyl-benzenesulfonamide
2-Fluoro-N-[4-( I-methoxyimino-ethyl)-phenyl]-benzamide
IS I-(3,5-Bis-trifluoromethyl-phenyl)-ethanone O-methyl-oxime
1-[4-(1H-Imidazol-1-yl)phenyl]-1-ethanone, O-methyloxime
1-[4-(Trifluoromethyl)phenyl]-1-ethanone, O-methyloxime
1-[1,1'-Biphenyl]-4-yl-I-ethanone, O-methyloxime
1-(4-Methylphenyl)-1-ethanone, O-methyloxime
20 1-[4-fluoro-3-(trifluoromethyl)phenyl]ethanone O-methyloxime
I-[3,5-bis(trifluoromethyl)phenyl]ethanone O-benzyloxime
1-[4-chloro-3-(trifluoromethyl)phenyl]ethanone O-methyloxime
1- j3-fluoro-5-(trifluoromethyl)phenyl]ethanone O-methyloxime
I-[2-fluoro-4-(trifluoromethyl)phenyl]ethanone O-methyloxime
25 1-[2-fluoro-5-(trifluoromethyl)phenyl]ethanone O-methyloxime
1-(2,4-dichlorophenyl)ethanone O-methyloxime
1-(2,4-dimethylphenyl)ethanone O-methyloxime
1-j2,4-bis(trifluoromethyl)phenyl]ethanone O-methyloxime
I-(3-bromophenyl}ethanone O-methyloxime
30 1-(3-methylphenyl)ethanone O-methyloxime
1-[4-(4-morpholinyl)phenyl]ethanone O-methyloxime
1-(2-chloro-4-fluorophenyl)ethanone O-methyloxime
1-(4-bromo-2-fluorophenyl)ethanone O-methyloxime
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1-(3,4-difluorophenyl)ethanone O-methyloxime
1-[3-(trifluoromethyl)phenyl]ethanone O-methyloxime
1-[2-(trifluoromethyl)phenyl]ethanone O-methyloxime
1-(2,4-difluorophenyl)ethanone O-methyloxime
1-[3-fluoro-4-{trifluoromethyl)phenyl]ethanone O-methyloxime
1-(3,4-dichlorophenyl)ethanone O-methyloxime
1-[4-fluoro-2-(trifluoromethyl)phenyl]ethanone O-methyloxime
1-(3-chloro-4-fluorophenyl)ethanone O-methyloxime
1-(4-chloro-3-fluorophenyl)ethanone O-methyloxime
1-(2,5-difluorophenyl)ethanone O-methyloxirne
1-{2-bromo-4-fluorophenyl}ethanone O-methyloxime
1-(3,4-dibromophenyl)ethanone O-methyloxirne
1-(2-bromophenyl)ethanone O-methyloxime
EXAMPLE 72 (METHOD 48)
1-(2-Trifluoromethyl-phenyl)-ethylamine
Sodium borohydride {1.17 g) is added slowly to a flask containing zirconium
tetrachloride (1.8 g) in tetrahydrofura.n (27 mL). A solution of 1-{2-
trifluoromethyl-
phenyl)-ethanone O-methyl-oxime {1.34 g) in tetrahydrofuran (7.7 mL) is added
and
the resulting solution is stirred at 25 °C for 12 hours. The reaction
mixture is then
cooled to 0 °C and water (16 mL} is slowly added. Excess ammonium
hydroxide is
added and the solution is extracted twice with ethyl acetate. The organic
portion is
washed twice with 1N hydrochloric acid. The aqueous (acid) layer is basified
with
sodium hydroxide and extracted twice with ethyl acetate. The organic layer is
then
washed with saturated aqueous sodium chloride and dried over anhydrous
magnesium
sulfate. The solvent is removed under reduced pressure to provide the desired
product as a yellow oil (0.20 g).
Using the above procedure arid appropriate starting materials the following
compounds were prepared:
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1-(3-Methoxy-phenyl)-ethylamine
1-(4-Fluoro-phenyl)-propylamine
1-Naphthalen-2-yl-ethylamine
4-{ 1-Amino-ethyl)-benzonitrile
1-(4-Trifluoromethyl-phenyl)-ethylamine
1-(4-Methoxy-phenyl)-ethylamine
1-Prop-2-ynyl-pyrrolidine
1-(2-Methoxy-phenyl)-ethylamine
1-m-Tolyl-ethylamine
1-{2-Bromo-phenyl)-ethylamine
1-o-Tolyl-ethylamine
C-(4-Fluoro-phenyl}-C-phenyl-methylamine
1-(4-Fluoro-phenyl)-pentylamine
1-(4-Fluoro-phenyl)-2-phenyl-ethylamine
1-(2-Trifluoromethyl-phenyl)-ethylamine
1-{3-Bromo-phenyl)-ethylamine
1-(3-Chloro-phenyl)-ethylamine
[4-( 1-Amino-ethyl)-phenyl]-dimethyl-amine
1-( 1-Methyl-1 H-pyrrol-2-yl)-ethylamine
1-Thiophen-3-yl-ethylamine
1-[3,5-bis(trifluoromethyl)phenyl]propylamine
1-[3;5-bis(trifluoromethyl}phenyl]-1-butanamine or 1-[3,5-
bis(trifluoromethyl)phenyl]butylamine
1- [3,5-bis(trifluoromethyl)phenyl]-1-pentanamine
1-(4-methylphenyl)ethanamine
1-[3-(trifluoromethyl)phenyl]ethylamine
1-[4-(trifluoromethyl)phenyl]ethylamine
1-(3-methylphenyl)ethanamine
1-(3,4-dichlorophenyl)ethanamine
1-(2-Bromo-phenyl)-ethylamine
1-{2-Trifluoromethyl-phenyl)-ethylamine
1-{3-Bromo-phenyl)-ethylamine
1-{3-Chloro-4-methoxy-phenyl)-ethylamine
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4-( 1-Amino-ethyl)-N,N-dimethyl-benzenesulfonamide
1-[4-(Piperidine-1-sulfonyl)-phenyl]-ethylamine
1-Quinolin-b-yl-ethylamine
1-(3,5-Bis-trifluoromethyl-phenyl)-ethylamine
4-[(1S)-1-aminoethyl]benzonitrile
(S)-alpha-Methyl-3,5-bis{trifluoromethyl)-benzenemethanamine(S)-alpha-Methyl-
3,5-bis(trifluoromethyl)-benzenemethanamine
1-Biphenyl-4-yl-ethylamine
1-(4-Fluoro-phenyl)-ethylamine
1-[4-fluoro-3-(trifluoromethyl)phenyl]ethanamine
1-[4-chloro-3-{trifluoromethyl)phenyl]ethanamine
N- { 4- [ ( 1 R)-1-aminoethyl] phenyl } -1, 2,3-thiadiazole-4-carb oxarnide
N- { 4-[( 1 S)-1-aminoethyl]phenyl }-1,2,3-thiadiazole-4-carboxarnide
1-[3-fluoro-5-(trifluoromethyl)phenyl]ethylamine
1-[2-fluoro-4-{trifluoromethyl)phenyl]ethylamine
1-[2-fluoro-5-(trifluoromethyl)phenyl]ethylamine
1-(2,4-dichlorophenyl)ethylamine
1-(2,4-dimethylphenyl)ethylamine
1-[2,4-bis (trifluoromethyl)phenyl] ethylamine
1-(2-chloro-4-fluorophenyl)ethylamine
1-(3,4-difluorophenyl)ethylamine
1-(4-bromo-2-fluorophenyl)ethylamine
1-(3-fluorophenyl)ethylamine
1-(2,4-difluorophenyl)ethylamine
1-[3-fluoro-4-(trifluoromethyl)phenyl]ethylamine
1- [4-fluoro-2-(trifluoromethyl)phenyl] ethylamine
1-(3-chloro-4-fluorophenyl)ethylamine
1-(4-chloro-3-fluorophenyl)ethylamine
1-(3,4-dibromophenyl)ethylamine
I-(2-bromo-4-fluorophenyl)ethanaminel-(2-bromo-4-fluorophenyl)ethylamine
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EXAMPLE 73 (METHOD 49)
(2-Fluoro-5-trifluoromethyl-phenoxy)-acetonitrile
A solution of 2-tluoro-5-trifluoromethylphenol (25 g) in reagent grade acetone
(0.55
L) is treated with solid potassium carbonate (7.7 g) followed by the rapid
addition of
neat bromoacetonitrile (10 mL). The heterogenous mixture is stirred vigorously
for
approximately 20 hours whereupon it is poured into water and extracted into
diethyl
ether. The combined ether extracts are washed with saturated sodium chloride
and
dried over anhydrous potassium carbonate. Filtration and concen-tration under
reduced pressure gives a pale orange solid which is then chromatographed on
silica
gel, eluting with dichloromethane, to give the desired product as white solid
(28.3 g).
Using the above procedure and appropriate starting materials the following
compounds were prepared:
(3-Bromo-phenylsulfanyl)-acetonitrile
(3-Chloro-phenylsulfanyI)-acetonitrile
(4-Iodo-phenoxy)-acetonitrile
{3-Trifluoromethyl-phenylsulfanyl)-acetonitrile
(3,5-Dichloro-phenylsulfanyl)-acetonitrile
(3,4-Dichloro-phenylsulfanyl)-acetonitrile
(3,4-Dichloro-phenoxy)-acetonitrile
(2-Fluoro-phenoxy)-acetonitrile
(3-Fluoro-phenoxy)-acetonitrile
{2-Chloro-phenoxy)-acetonitrile
(3-Bromo-phenoxy)-acetonitrile
(2-Fluoro-5-trifluoromethyl-phenoxy)-acetonitrile
{3-Iodo-phenoxy)-acetonitriie
(4-Bromo-phenoxy)-acetonitrile
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EXAMPLE 74 {METHOD 50)
3-Fluoro-5-trifluoromethylphenethylamine tosylate
,.
A solution of 2.5 g of 3-fluoro-5-trifluoromethylphenylacetonitrile and 2.34 g
(12.3
mmol) of p-toluenesulfonic acid in ?5 ml of ethylene glycol monomethyl ether
is
hydrogenated for 3 hours at room temperature at 40 psi, using 200 mg 10%
palladium on carbon catalyst. The catalyst is filtered off and the solvent
evaporated to
half the volume. Upon standing, the p-toluenesulfonic acid salt of the desired
3-
fluoro-5-trifluoromethylphenethylamine crystallizes. The white crystals, 4.268
(91%)
are collected by filtration.
Using the above procedure and appropriate starting materials the following
compounds were prepared:
2-(3,5-Difluoro-phenyl)-ethylamine
2-{4-Trifluoromethyl-phenyl)-ethylamine
2-{3,4-Difluoro-phenyl)-ethylamine
2-{2-Fluoro-phenyl)-ethylamine
2-(3-Fluoro-5-trifluoromethyl-phenyl)-ethylamine
2-(2-Fluoro-3-trifluoromethyl-phenyl)-ethylarnine
2-(2,4-B is-trifluoromethyl-phenyl)-ethylamine
2-(4-Fluoro-3-trifluoromethyl-phenyl)-ethylamine
EXAMPLE 75 (METHOD 5i)
(4-Aminomethyl-2-trifluoromethyl-phenyl)-dimethyl-amine
A solution of 4-dimethylamino-3-trifluorornethylbenzonitrile (0.35 g) in
tetrahydrofuran (2 mL) is slowly added to a suspension of lithium aluminum
hydride
{0.1 g) in tetrahydrofuran {2 mL) at 0 °C and stirred under an
atmosphere of argon
for 2 hours. While at 0 °C water (0.1 mL) is slowly added followed by
5% sodium
hydroxide (0.1 mL) and water {0.3 mL). The resulting gray solid is filtered
and
washed with tetrahydrofuran. The filtrates are collected and concentrated
under
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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-Arnino-ethyl)-2-methyl-phenyl]-dimethyl-amine
EXAMPLE 76 (METHOD S2)
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-trifluaromethylbenzonitrile
( 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
saiid
(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
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EXAMPLE 77 {METHOD 53)
Dimethyl-[3-{2-vitro-vinyl)-S-trifluoromethyl-phenyl]-amine
Nitromethane (0.473 g) is added to a solution of 3-dimethylamino-5-
trifluoromethyl-
benzaldehyde (0.885 g) and ammonium acetate (0.339 g) in acetic acid (3.4 mL)
and
the solution is heated at 110 °C for 6 hours. The reaction mixture is
cooled to 0 °C
and a solid forms which is filtered and washed with 1:1 water-acetic acid.
This solid
is recrystallized from ethanol to provide the desired product as a red solid
(0.39 g).
Using the above procedure and appropriate starting materials the following
compounds were prepared:
Dimethyl-[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 triphenylphosphine (7:9 g) in diethyl ether (16
mL) at
0 °C. The reaction mixture is stirred for 10 minutes and a solution of
acetone
cyanohydrin (2.6 g) in diethyl ether (10 mL) is added. The clear orange
solution is
stirred for 5 minutes at 0 °C and then at 25 °C for 12 hours.
The reaction mixture is
then filtered, and washed with diethyl ether. The filtrate is concentrated
under
reduced pressure and chromatographed over silica gel ( 10°lo ethyl
acetate-hexanes is
used as the eluant) to provide the desired product as a pale yellow oil (2.04
g).
EXAMPLE 79 (METHOD 55)
3-Dimethylamino-2-isocyano-acrylic acid ethyl ester
To a solution of ethyl isocyanoacetate (5.0 g) in ethanol (100 mL) is added
N,N-
dimethyl-formamide dimethyl acetal (6.5 g) dropwise with stirnng over 10
minutes.
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The reaction is stirred for 24 hours and the ethanol is evaporated. The
resulting oil is
passed through magnesium silicate using 50% ethyl acetate-hexanes as the
eluant.
The solvents are removed and the resulting oil is crystallized from ethyl
acetate-
hexanes to yield light yellow needles, 3.0 g.
EXAMPLE 80 (METHOD S5)
4-Carboethoxythiazole
A solution of 3-dimethylamino-2-isocyano-acrylic acid ethyl ester ( 1.0 g} and
triethylamine (3.0 g) in tetrahydrofuran (30 mL) is treated with gaseous
hydrogen
sulfide until all starting material is consumed. The mixture is concentrated
to an oil
and purified by column chromatography using silica and 25% ethyl acetate-
hexanes
as the eluant. The purified material (0.61 g) is isolated as an oil.
EXAMPLE 81 {METHOD 34)
N-{4-[3-{S-Chloro-2,4-dimethoxy-phenyl}-ureido]-phenyl}-
2-fluoro-benzamide
A suspension of N-(4-amino-phenyl)-2-fluoro-benzamide (0.43 g) in acetonitrile
{4
mL) is treated with 5-chloro-2,4-dimethoxyphenylisocyanate (0.40 g). The
mixture
becomes a solution and is allowed to stand for 12 hours. A white solid forms
and is
collected by filtration (0.79 g). [M+H] 444.
Using the above procedure and appropriate starting materials the following
compounds were prepared:
Ex M+H COMPOUND NAME
No.
81 445 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-ureido]-phenyl}-2-fluoro-
benzamide
82 441 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-ureido]-phenyl}-2-methyl-
benzamide
$3 435 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-
phenyl)-ureido]-
phenyl }-amide
$4 443 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-chloro-3-tritluoromethyl-
phenyl)-
ureido]-phenyl} amide
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85 453 N-{4-[3-(4-Chloro-3-trifluoromethyl-phenyl)-ureido]-phenyl}-2-fluoro-
benzamide
86 409 11,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-dichloro-phenyl)-
ureido]-phenyl}-
amide
87 486 N-{4-[3-(3,5-Bis-trifluoromethyl-phenyl)-ureido]-phenyl}-2-fluoro-
benzamide
$$ 45$ Furan-2-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl-phenyl)-ureido]-
phenyl}-amide
89 476 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl-
phenyl)-ureido]-
phenyl }-amide
90 423 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,4-dichloro-benzyl)-
ureido]-phenyl}-
amide
EXAMPLE 91 (METHOD 31)
N-(S-{[({(1S)-1-[3,S-bis(trifluoromethyl)phenylJethyl}amino)-
carbothioyl] amino}-2-pyridinyl)-1,3-thiazole-4-carboxamide
A mixture of N-(5-isothiocyanato-2-pyridinyl)-1,3-thiazole-4-carboxamide (0.36
g)
and (S)-alpha-methyl-3,5-bis(trifluoromethyl)-benzenemethanamine (0.36 g) is
heated with acetonitrile ( 10 mL) until all solids are dissolved. The solution
is allowed
to stand for 12 hours. A white solid forms and is collected by filtration
(0.40 g).
[M+H] 520.
Using the above procedure and appropriate starting materials the following
compounds were prepared:
EX. M+H COMPOUND NAME
NO.
92 506 [3-Chloro-5-(3-{4-[([1,2,3]thiadiazole-4-carbonyl)-amino]-phenyl}-
thioureido)phenyl]-carbamic acid tert-butyl
ester
93 409 1-(5-Chloro-2,4-dimethoxy-phenyl)-3-(4-morpholin-4-y1-phenyl)-
thiourea
94 370 1-(5-Chloro-2,4-dimethoxy-phenyl)-3-(4-methylsulfanyl-phenyl)-
thiourea
95 338 1-(5-Chloro-2,4-dimethoxy-phenyl)-3-p-tolyl-thiourea
96 4I4 {4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenylsulfanyl}-
acetic
acid
97 384 1-(5-Chloro-2,4-dimethoxy-phenyl)-3-[4-(2-hydroxy-ethoxy)-phenyl]-
thiourea
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98 340 1-(5-Chloro-2,4-dirnethoxy-phenyl)-3-(4-hydroxy-phenyl)-thiourea
99 395 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-N-
methyl-
acetamide
100 381 N-{3-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-
acetamide
101 411 {4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-carbamic
acid
ethyl ester
102 319 1-(2,4-Dimethoxy-phenyl)-3-(4-methoxy-phenyl)-thiourea
103 346 N-{4-[3-(2,4-Dimethoxy-phenyl)-thioureido]-phenyl}-acetamide
104 316 N-{4-I3-(4-Methoxy-phenyl)-thioureido]-phenyl}-acetamide
105 316 N-{4-[3-(2-Methoxy-phenyl)-thioureido]-phenyl}-acetamide
106 351 N-{4-[3-(3-Chloro-4-methoxy-phenyl}-thioureido]-phenyl}-acetamide
107 351 N-{4-[3-(5-Chloro-2-methoxy-phenyl)-thioureido]-phenyl}-acetamide
108 371 N-{4-[3-(3,5-Dichloro-4-hydroxy-phenyl)-thioureido]-phenyl}-
acetamide
109 385 N-{4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]-phenyl}-
acetamide
110 381 N-{4-[3-(4-Chloro-2,5-dimethoxy-phenyl)-thioureido]-phenyl}-
acetamide
11I 389 N-{4-[3-(2-Chloro-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-
acetamide
112 389 N-{4-[3-(4-Chloro-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-
acetamide
113 422 Benzoic acid 4-[3-(4-acetylamino-phenyl)-thioureido]-3-hydroxy-
phenylester
114 457 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-
methyl-
benzamide
115 501 Acetic acid 2-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-
phenyl-
carbamoyl }-phenyl ester
116 461 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-4-
fluoro-
benzamide
117 461 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3-
fluoro-
benzarnide
I18 461 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-
fluoro..
benzamide
119 473 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-
methoxy-
benzamide
120 473 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3-
methoxy-
benzamide
121 473 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-4.-
methoxy-
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benzamide
122 443 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-
benzamide
123 417 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-methane-
suIfonamide
124 331 N-{4-[3-(3-Nitro-phenyl)-thioureido]-phenyl}-acetamide
125 339 1-(3-Chloro-4-rnethoxy-phenyl)-3-(3-vitro-phenyl)-thiourea
126 337 N-{4-[3-(5-Chloro-2-hydroxy-phenyl)-thioureido]-phenyl}-acetamide
127 439 {4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-carbamic
acid
tert-butyl ester
128 351 N-{4-[3-(3-Chloro-4-hydroxy-5-methyl-phenyl)-thioureido]-phenyl}-
acetamide
129 385 N-{4-[3-(3,5-Dichloro-4-hydroxy-2-methyl-phenyl)-thioureido]-
phenyl}-
acetamide
130 3I8 N-{4-[3-(2,4-Dihydroxy-phenyl)-thioureido]-phenyl}-acetamide
13I 414 N-{4-[3-(2,4-Dimethoxy-5-trifluoromethyl-phenyl)-thioureido]-
phenyl}-
acetamide
132 332 N-{4-[3-(2-Hydroxy-4-methoxy-phenyl)-thioureido]-phenyl}-acetamide
133 465 N-{4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]-phenyl}-4-
fluoro-
benzamide
134 500 3-Acetylamino-N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-
phenyl}-benzamide
135 48$ N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3-nitro-
benzamide-
136 486 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3-
dimethylamino-benzamide
137 536 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3-
methane-
sulfony-amino-benzamide
138 511 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-
trifluoro-
methyl-benzamide
139 459 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-
hydroxy-
benzamide
140 479 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2,6-
difluoro-benzamide
141 477 2-Chloro-N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-
phenyl}-
benzamide
142 522 2-Bromo-N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-
benzamide
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143 4$8 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-nitro-
benzamide
144 445 Pyrazine-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-
thioureido]- phenyl}-amide
145 463 5-Methyl-thiophene-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-
phenyl)-thioureido]-phenyl }-amide
146 494 Quinoline-$-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-
thioureido]-phenyl }-amide
147 446 1-Methyl-1H-pyrrole-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-
phenyl)-thioureido]-phenyl }-amide
14$ 369 1-(5-Chloro-2,~.-dimethoxy-phenyl)-3-(2-vitro-phenyl)-thiourea
149 369 I-(~-C~oro-2,4-dimethoxy-phenyl)-3-(4-vitro-phenyl)-thiourea
150 425 N-{4-[3-(5-Bromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-acetamide
151 376 N-{4-[3-(3,4,5-Trimethoxy-phenyl)-thioureido]-phenyl}-acetamide
152 399 N-{4-[3-(3,5-Dichloro-2-methoxy-4-methyl-phenyl)- thioureido]-phenyl}-
acetamide
153 499 Benzo[b]thiophene-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-
phenyl)-thioureido]-phenyl }-amide
154 483 Benzofuran-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-
thioureido]-phenyl}-amide
155 444 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-
isonicotinamide
i56 493 Naphthalene-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-
thioureido]-phenyl }-amide
I57 493 Naphthalene-1-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl}-
thioureido]- phenyl}-amide
158 494 Isoquinoline-1-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-
Wioureido]-phenyl }-amide
159 494 Quinoline-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-
thioureido]-phenyl }-amide
160 444 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-
nicotinamide
161 478 5-Nitro-furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dirnethoxy-phenyl)-
thioureido]-phenyl}-amidecarbarnic acid phenyl ester
162 459 {4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}- .
163 467 5-Chloro-furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimetboxy-phenyl)-
thioureido]-phenyl }-amide
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164 439 {4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-carbamic
acid
isobutyl ester
I65 397 {4-[3-(S-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-carbamic
acid
methyl ester
166 433 Furan-3-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-
thioureido]-phenyl }-amide
167 447 3-Methyl-furan-2-carboxylic acid {4-[3-(S-chloro-2,4-dimethoxy-phenyl)-
thioureido]-phenyl }-amide
I68 S I2 5-Bromo-furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-
thioureido]-phenyl }-amide
169 512 4-Bromo-furan-2-carboxylic acid {4-[3-(S-chloro-2,4-dimethoxy-phenyl)-
thioureido]-phenyl }-amide
170 433 Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-
thioureido]-phenyl }-amide
171 467 {4-E3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-carbamic
acid
hexyl ester
172 494 lsoduinoline-4-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-
thioureido]-phenyl}-amide
173 451 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(S-chloro-2,4-dimethoxy-
phenyl)-thioureido]-phenyl }-amide
174 434 1H-[1,2,3]Triazole-4-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-
phenyl)- thioureido]-phenyl}-amide
175 528 3-Bromo-thiophene-2-carboxylic acid {4-[3-{5-chloro-2,4-dimethoxy-
phenyl)- thioureido]-phenyl}-amide
176 399 N-{4-[3-(3,S-Dichloro-4-ethoxy-phenyl)-thioureido]-phenyl}-acetamide
177 427 N-{4-[3-(4-Butoxy-3,5-dichloro-phenyl)-thioureido]-phenyl}-acetamide
178 461 N-{4-[3-(4-Benzyloxy-3,5-dichloro-phenyl)-thioureido]-phenyl}-
acetamide
179 3$1 N-{4-[3-(3-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-acetamide
180 530 (3-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenylcarbamoyl}-
phenyl)-carbamic acid ethyl ester
1$1 458 2-Amino-N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-
benzamide
182 5I9 Biphenyl-2-carboxylic acid {4-[3-(S-chloro-2,4-dimethoxy-phenyl)-
thioureido]-phenyl }-amide
183 469 1-(5-Chloro-2,4-dimethoxy-phenyl)-3-[4-(1,3-dioxo-1,3-dihydro-
isoindol-2-yl)-phenyl]-thiourea
184 4$7 N-{4-[3-(S-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-
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phthalamic acid
1$S 473 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-
hydroxy-methyl-benzamide
186 479 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2,3-
difluoro-benzamide
187 479 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2,5-
difluoro-benzamide
188 479 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl}-thioureido]-phenyl}-2,4-
difluoro-benzamide
1$9 500 2-Acetylamino-N-{4-[3-(S-chloro-2,4-dimethoxy-phenyl)-thioureido]-
phenyl }-benzamide
190 441 1-(5-Chloro-2,4-dimethoxy-phenyl)-3-(6-oxo-5,6-dihydro-
phenanthridin-2-yl)-thiourea
191 536 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2
methane-sulfonylamino-benzamide
192 497 N-{4-[3-(5-Chioro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2,3,4-
trifluoro-benzamide
193 533 N-{4-[3-(5-cloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-
2,3,4,5,6-pentafluoro-benzamide
194 489 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-
methyl-sulfanyl-benzamide
195 431 S-Methyl-furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-
phenyl)- ureido]-phenyl}-amide
196 4s7 5-Difluoromethyl-furan-2-carboxylic acid {4-j3-(5-chloro-2,4-
dimethoxy-
phenyl)-ureido]-phenyl}-amide
197 472 N-{4-[3-(5-Ioda-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-acetamide
198 364 N-{4-[3-(5-Fluoro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-
acetamide
199 365 N-{4-I3-(5-Chloro-2-methoxy-4-methyl-phenyl)-thioureido]-phenyl}-
acetamide
200 459 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-chloro-3-
trifluoromethyl-
phenyl)- thioureido]-phenyl}-amide
201 455 [I~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
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205 406 N-{4-[3-(3-Chloro-4-morpholin-4-yI-phenyl)-thioureido]-phenyl}-
acetamide
206 443 1-(5-Chloro-2;4-dimethoxy-phenyl)-3-(3-chloro-4-morpholin-4-yl-phenyl)-
thiourea
207 372 1-(5-Chloro-2,4-dimethoxy-phenyl)-3-(5-chloro-2-methyl-phenyl)-
thiourea
208 501 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-
isophthalamic acid methyl ester
209 487 N-{4-[3-(5-Cbloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-
isophthalamic acid
210 549 3-Benzyloxy-N-{4-[3-(S-chloro-2,4-dimethoxy-phenyl)-thioureido]-
phenyl}-benzamide
211 434 N-(4-{3-[5-Chloro-2-rnethoxy-4-(4-nitrilo-butoxy)-phenyl]-
thioureido}-
phenyl)-acetamide
212 406 N-(4-{3-[5-Chloro-2-methoxy-4-(2-nitrilo-ethoxy)-phenyl]-
thioureido}-
phenyl)-acetamide
213 406 N-(4-{3-[5-Chloro-4-methoxy-2-(2-nitrilo-ethoxy)-phenyl]-
thioureido}-
phenyl)-acetamide
214 411 N-(4-{3-[5-Chloro-2-(2-hydroxy-ethoxy)-4-methoxy-phenyl]-
thioureido}-
phenyl)-acetamide
215 411 N-(4-{3-[5-Chloro-4-(2-hydroxy-ethoxy)-2-methoxy-phenyl]-
thioureido}-
phenyl)-acetamide
216 481 {4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-5-methoxy-
phenoxy}-
acetic acid tent-butyl ester
217 439 {4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-5-methoxy-
phenoxy}-
acetic acid methyl ester
21$ 481 {2-[3-(4-Acetylamino-phenyl)-thioureido]-4-chloro-5-methoxy-
phenoxy}-
acetic acid tert-butyl ester
219 515 3-Butoxy-N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-
phenyl}-
benzamide
220 505 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-
methane-
sulfinyl-benzamide
221 545 (3-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-
phenylcarbamoyl}-
phenoxy)-acetic acid ethyl ester
222 517 (3-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-
phenylcarbamoyl}-
phenoxy)-acetic acid
223 367 N-{4-[3-(5-Chloro-4-hydroxy-2-methoxy-phenyl)-thioureido]-phenyl}-
acetamide
224 444 Pyridine-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-
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thioureido]- phenyl}-amide
225 494 Quinoline-4-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-
thioureido]- phenyl }-amide
226 436 N-{4-[3-(5-Chloro-4-methoxy-2-morpholin-4-yl-phenyl)-thioureido]-
phenyl}-acetamide
227 394 N-{4-[3-(5-Chloro-2-dimethylamino-4-rnethoxy-phenyl)-thioureido]-
phenyl }-acetamide
228 420 N-{4-[3-(5-Chloro-4-methoxy-2-pyrrolidin-1-yl-phenyl)-thioureido]-
phenyl }-acetamide
229 434 N-{4-(3-(5-Chloro-4-methoxy-2-piperidin-1-yl-phenyl)-thioureido]-
phenyl }-acetamide
230 405 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-4-methyl-
phenyl)-
thioureido]-phenyl }-amide
231 415 N-{4-[3-(3-Chloro-4-methyl-phenyl)-thioureido]-phenyl}-2-fluoio-:
benzamide
232 427 N-{4-[3-(3-Chioro-4-methyl-phenyl)-thioureido]-phenyl}-3-methoxy-
benzamide
233 387 Furan-2-carboxylic acid {4-[3-(3-chloro-4-methyl-phenyl)-
thioureido]-
phenyl }-amide
234. 411 N-{4-[3-(3-Chloro-4-methyl-phenyl)-thioureido]-phenyl}-2-methyl-
benzamide
235 433 N-{4-[3-(3-Chloro-4-methyl-phenyl)-thioureido]-phenyl}-2,6-difluoro-
benzamide
236 398 Pyridine-2-carboxylic acid {4-[3-(3-chloro-4-methyl-phenyl)-
thioureido]-
phenyl }-amide
237 502 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[3-chloro-4-(cyclohexyl-
methyl-amino)-phenyl]-thioureido}-phenyl)-amide
238 512 N-(4-{3-[3-Chloro-4-(cyclohexyl-methyl-amino)-phenyl]-thioureido}-
phenyl)- 2-fluoro-benzamide
239 404 N-{4-[3-(3-Chloro-4-piperidin-1-yl-phenyl)-thioureido]-phenyl}-
acetamide
240 364 N-{4-[3-(3-Chloro-4-dimethylamino-phenyl)-thioureido]-phenyl}-
acetarnide
241 426 N-{4-[3-(4-Benzylamino-3-chlaro-phenyl)-thioureido]-phenyl}-
acetamide
242 390 N-{4-[3-(3-Chloro-4-pyrrolidin-1-yl-phenyl)-thioureido]-phenyl}-
acetamide
243 419 N-(4-{3-[3-Chloro-4-(4-methyl-piperazin-1-yl)-phenyl]-thioureido}-
phenyl)-acetamide
244 469 N-{4-[3-(4-Chloro-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-2-
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fluoro-benzamide
245 422 N-{4-[3-(2-Benzylamino-4-methoxy-phenyl)-thioureido]-phenyl}-
acetamide
246 484 Furan-2-carboxylic acid.(4-{3-[3-chloro-4-(cyclohexyl-methyl-
amino)-
phenyl]-thioureido }-phenyl)-amide
247 508 N-(4-{3-[3-Chloro-4-(cyclohexyl-methyl-amino)-phenyl]-thioureido}-
phenyl)-2-methyl-benzarnide
248 530 N-(4-{3-[3-Chloro-4-(cyclohexyl-methyl-amino)-phenyl]-thioureido}-
phenyl)-2,6-difluoro-benzamide
249 495 Pyridine-2-carboxylic acid (4-{ 3-[3-chloro-4-(cyclohexyl-methyl-
amino)-
phenyl]-thioureido}-phenyl)- amide
250 524 N-(4-{3-[3-Chloro-4-(cyclohexyl-methyl-amino)-phenyl]-thioureido}-
phenyl)-3-methoxy-benzamide
251 376 N-(4-{3-[3-Chloro-4-{2-nitrilo-ethoxy)-phenyl]-thioureido}-phenyl)-
acetamide
252 393 N-{4-[3-(4-sec-Butoxy-3-chloro-phenyl)-thioureido]-phenyl}-
acetamide
253 501 Acetic acid 3-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-
phenyl-
carbamoyl}-phenyl ester
254 459 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3-
hydroxy-
benzamide
255 487 Benzo[I,3]dioxole-4-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-
phenyl)-thioureido]-phenyl }-amide
256 527 N-{4-[3-(5=Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3-
trifluoro-
methoxy-benzamide
257 530 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3-(2-
dimethylamino-ethoxy)-benzamide
258 572 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3-(2-
morpholin-4-yl-ethoxy)-benzamide
259 406 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-cyano-
phenyl}-
acetamide
260 521 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2,5-dimethoxy-
phenyl}-2-fluoro-benzamide
261 441 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2,5-dimethoxy-
phenyl}-acetamide
262 527 2-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenoxy}-5-chloro-
benzenesulfonic acid
263 562 2-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenoxy}-4,5-
dichloro-benzenesulfonic acid
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264 527 4-Phenyl-[1,2,3]thiadiazole-5-carboxylic acid{4-[3-(5-chloro-2,4-
dimethoxy-phenyl)-thioureido)-phenyl}-amide
265 381 N-{4-{3-f3-Chloro-4-(2-hydroxy-ethoxy)-phenyl]-thioureido}-phenyl)-
acetamide
266 393 N-{4-[3-(4-Butoxy-3-chloro-phenyl)-thioureida]-phenyl}-acetamide
267 446 N-{4-{3-[3-Chloro-4-{cyclohexyl-ethyl-amino)-phenyl]-thioureido}-
phenyl)-acetamide
268 365 N-{4-[3-(3-Chloro-4-ethoxy-phenyl)-thioureido]-phenyl}-acetamide
269 427 N-{4-[3-(4-Benzyloxy-3-chloro-phenyl)-thioureidoJ-phenyl}-acetamide
270 3I7 {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)-thioureidoJ-phenyl}-
acetamide
273 458 N-(4-{3-[4-(Allyl-cyclohexyl-amino}-3-chloro-phenyl]-thioureido}-
phenyl)-acetamide
274 411 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methoxy-
phenyl}-.
acetamide
275 415 N-{2-Chloro-4-[3-{5-chloro-2,4-dimethoxy-phenyl)-thioureido]-
phenyl}-
acetamide
276 493 Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-
thiaureido]-2,5-dimethoxy-phenyl }-amide
277 486 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-cyano-phenyl}-
2-
fluoro-benzamide
278 495 N-{2-Chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-
phenyl}-2-
fluoro-benzamide
279 465 5-Methyl-[1,2,3]thiadiazole-4-carboxylic acid{4-[3-(5-chloro-2,4-
dimethoxy-phenyl)-thioureido]-phenyl }-amide
280 517 5-Furan-3-yl-[1,2,3]thiadiazole-4-carboxylic
acid{4-[3-{5-chloro-2,4-
dimethoxy-phenyl)-thioureido]- phenyl}amide
281 527 5-Phenyl-[1,2,3]thiadiazale-4-carboxylic acid{4-[3-(5-chloro-2,4-
dimethoxy-phenyl)-thioureido]-phenyl}-amide
282 458 N-(4-{3-[3-Chloro-4-(octahydro-quinolin-1-yl)-phenyl]-thioureido}-
phenyl)-acetamide
283 458 N-[5-[[[(5-Chloro-2,4-dimethoxyphenyl)amino]thioxomethyl]amino)-2-
pyridinyl]-2-methylbenzamide
284 434 Furan-2-carboxylic acid {5-[3-(5-chloro-2,4-dimethoxy-phenyl)-
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thioureido]-pyridin-2-yl}-amide
285 425 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methoxy-5-
methyl-phenyl }-acetamide
286 505 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methoxy-5-
methyl-phenyl }-2-fluoro-benzamide
287 477 Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-
thioureido]-2-methoxy-5-methyl-phenyl}-amide
288 517 4-Furan-3-yl-[1,2,3]thiadiazole-5-carboxylic acid{4-[3-(5-chloro-2,4-
dimethoxy-phenyl)-thioureido]-phenyl }-amide
289 462 N-{S-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-2-yl}-2-
fluoro-benzamide
290 384 N-{4-[3-(4-Methoxy-3-irifluoromethyl-phenyl)-thioureido]-phenyl}-
acetamide
291 394 N-[4-(3-{3-Chloro-4-[(2-hydroxy-ethyl)-methyl-amino]-phenyl}-
thioureido)- phenyl]-acetamide
292 485 N-{2-Benzoyl-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-
acetamide
293 565 N-{2-Benzayl-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-
2-fluoro-benzamide
294 537 Furan-2-carbaxyiic acid {2-benzoyl-4-[3-(5-chloro-2,4-dimethoxy-
phenyl)-thioureido]-phenyl }-amide
295 475 N-{4-[3-(S-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-methyl-
phenyl}-2-fluoro-benzamide
296 447 Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-
ihioureido]-3-methyl-phenyl }-amide
297 395 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-methyl-phenyl}-
acetamide
298 435 N-[4-(3-{3-Chloro-4-[(3-dimethylamino-propyl)-methyl-amino]-phenyl}-
thioureido)-phenyl]-acetamide
299 418 N-{4-[3-(3-Chloro-4-cyclohexylamino-phenyl)-thioureido]-phenyl}-
acetamide
300 421 N-[4-(3-{3-Chloro-4-[(2-dimethylamino-ethyl)-methyl-amino]-phenyl}-
thiaureido)-phenyl]-acetamide
301 580 5-[[[(5-Chloro-2,4-dimethoxyphenyl)amino]thioxomethyl]amino]-2-
((2-fluorobenzoyl)amino]-N-phenyl-benzamide
302 552 Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-
thioureido]-2-phenylcarbamoyl-phenyl}-amide
303 491 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methoxy-
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phenyl}-2-fluoro-benzamide
304 463 Furan-2-carboxylic acid {4-[3-(5-chlora-2,4-dimethoxy-phenyl)-
thioureido]- 2-methoxy-phenyl}-amide
305 449 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2
trifluoromethyl-phenyl }-acetamide
306 458 Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-
thioureido]- 2-cyano-phenyl}-amide
307 467 Furan-2-carboxylic acid {2-chloro-4-[3-(5-chloro-2,4-dimethoxy-
phenyl)- thioureida]-phenyl}-amide
308 501 Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-
thioureido]- 2-trifluoromethyI-phenyl}-amide
309 395 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methyl-
phenyl }-acetamide
310 475 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methyl-
phenyl }-2-fluoro-benzamide
311 447 Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-
thioureido]-2-methyl-phenyl }-amide
312 378 N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-
acetamide
313 408 {4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-
carbamic acid ethyl ester
314 382 N-{5-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureida]-pyridin-2-yl}-
acetamide
315 509 N-(4-{3-[4-(1-Benzyl-piperidin-4-ylamino)-3-chloro-phenyl]-
thiaureido}-phenyl)-acetamide
316 407 N-(4-{3-[3-Chloxa-4-(2-dimethylamino-ethylamino)-phenyl]-
thioureido}-phenyl)-acetamide
3I7 408 N-[4-(3-{3-Chloro-4-j(2-methoxy-ethyl)-methyl-amino]-phenyl}-
thioureido)-phenyl]-acetamide
318 421 N-(4-{3-[3-Chloro-4-(3-dimethylamino-propylamino)-phenyl]-
thioureido}-phenyl)-acetamide
319 495 N-(4-{3-[4-(1-Benzyl-pyrrolidin-3-ylamino)-3-chloro-phenyl]-
thioureido}-phenyl)-acetarnide
320 4$3 Furan-2-carboxylic acid {5-chloro-4-[3-(5-chloro-2,4-dimethoxy-
phenyl)- thioureido]-2-hydroxy-phenyl}-amide
32I 431 N-{5-Chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-
hydroxy-phenyl}-acetamide
322 511 (5H,11H-Benzo[e]pyrxalo[1,2-a][1,4]diazepin-10-yl)-(2-chloro-4-
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imidazol-1-yl-phenyl)-methanone
323 451 (1,2,3]Thiadiazole-5-carboxylic acid {4-[3-(5-chloro-2,4-dimeth-
oxy-phenyl)-thioureido]-phenyl }-amide
324 483 Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-
thioureido]-naphthalen-I-yl}-amide
325 511 N-{4-[3-(5-Chloro-2;4-dimethoxy-phenyl)-thioureido]-naphthalen-1-
yl}-2-fluoro-benzamide
326 429 N-{5-Chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-
methyl-phenyl}-acetamide
327 509 N-{5-Chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-
methyl-phenyl}-2-fluoro-benzamide
328 4$ I Furan-2-carboxylic acid {5-chloro-4-(3-(5-chlora-2,4-dimethoxy-
phenyl)-
thioureido]-2-methyl-phenyl}-amide
329 431 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-naphthalen-1-
yl}-
acetamide
330 416 Furan-2-carboxylic acid {4-[3-(3-chloro-4-dimethylamino-phenyl)-
thioureido]-phenyl}-amide
331 561 Furan-2-carboxylic acid [4-(3-{4-[(I-benzyl-pyrroIidin-3-yl)-methyl-
amino]-3-chloro-phenyl}-thioureido)- phenyl]-amide
332 513 N-[4-(3-{3-Chloro-4-[methyl-(1-methyl-pyrrolidin-3-yl)-amino]-
phenyl}-thioureido)-phenyl]-2-fluoro-benzamide
333 463 N-{4-[3-(5-Chloro-2-methoxy-4-methyl-phenyl)-thioureido]-phenyl}-
2,G-difluoro-benzamide
334 420 N-(4-{3-[3-Chloro-4-(1-methyl-pyrrolidin-3-yioxy)-phenyl]-
thioureido}-
phenyl)-acetamide
335 434 N-(4_{3-[3-Chloro-4-(1-methyl-piperidin-4-yloxy)-phenyl]-
thioureido}-
phenyl)-acetamide
336 422 N-(4-{3-[3-Chloro-4-{3-dimethylamino-propoxy)-phenyl]-thioureido}-
phenyl)-acetamide
337 425 2-Acetylamino-5-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-
benzoic acid
338 505 5-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-(2-fluoro-
benzoylamino)- benzoic acid
339 477 5-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-[(furan-2-
carbonyl)-
amino]-benzoic acid
340 545 N-[4-(3-{3-Chloro-4-[methyl-(1-methyl-piperidin-4-yl)-amino]-
phenyl}-
thioureido)-phenyl]-2,6-difluoro-benzamide
341 503 [1,2,3]Thiadiazole-4-carboxylic acid[4-(3-{3-chloro-4-[methyl-(1-
methyl-
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pyrrolidin-3-yl)-amino]-phenyl }-thioureido)-phenyl]-amide
342 443 N-{4-[3-(3-Chloro-4-methylsulfanyl-phenyl)-thioureido]-phenyl}-2-
methyl-benzamide
343 408 N-(4-{3-[3-Chloro-4-(2-dimethylamino-ethoxy)-phenyl]-thioureido}-
phenyl)- acetamide
344 499 Furan-2-carboxylic acid [4-(3-{3-chloro-4-[methyl-(1-methyl-
piperidin-
4-yI)- amino]-phenyl}-thioureido)- phenyl]-amide
345 419 N-{4-[3-(3-Chloro-4-cyclohexyloxy-phenyl)-thioureido]-phenyl}-
acetamide
346 440 N-{4-[3-(3-Chloro-4-dimethylamino-phenyl)-thioureido]-phenyl}-2-
methyl-benzamide
347 493 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-methyl-
phenyl}-
2,6-difluoro-benzamide
348 462 N-{4-[3-(3-Chloro-4-dimethylamino-phenyl)-thioureidoJ-phenyl}-2,6-
difluoro-benzamide
349 531 N-[4-(3-{3-Chloro-4-[methyl-(1-methyl-pyrrolidin-3-yl)-amino]-
phenyl}-
thioureido)-phenyl]-2,6-difluoro-benzamide
350 427 Pyridine-2-carboxylic acid {4-[3-(3-chloro-4-dimethylamino-phenyl)-
thioureido]-phenyl }-amide
351 430 Pyridine-2-carboxylic acid {4-[3-(3-chloro-4-methylsulfanyl-
phenyl)-
thioureido]-phenyl }-amide
352 428 Pyridine-2-carboxylic acid {4-[3-(5-chloro-2-methoxy-4-methyl-
phenyl)-
thioureido]-phenyl }-amide
353 417 Fm'an-2-carboxylic acid {4-[3-(5-chloro-2-methoxy-4-methyl-phenyI)-
thioureido]-phenyl }-amide
354 496 Pyridine-2-carboxylic acid [4-(3-{3-chloro-4-[methyl-(1-methyl-
pyrrolidin-3-yl)-amino]-phenyl}-thioureido)-
phenyl]-amide
355 495 N-{3-Chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-
phenyl }-2-fluoro-benzamide
356 467 Furan-2-carboxylic acid {3-chloro-4-[3-(5-chloro-2,4-dimethoxy-
phenyl)-
thioureido]-phenyl }-amide
357 515 N-{4-(3-(3-Chloro-4-cyclohexylsulfanyl-phenyl)-thioureido]-phenyl}-
2-
fluoro-benzamide
358 449 N-{4-j3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-trifluoromethyl-
phenyl }-acetamide
359 529 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-trifluoromethyl-
phenyl}-2-fluoro-benzamide
360 421 N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-2-dimethyl-
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amino-acetamide
361 473 Furan-2-carboxylic acid (4-{3-(3-chloro-4-(2-dimethylamino-
acetylamino)-
phenyl]-thioureido }-phenyl)-amide
362 SO1 N-(4-{3-[3-Chloro-4-(2-dimethylamino-acetylamino)-phenyl]-thioureido}-
phenyl)-2-fluoro-benzamide
363 461 N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-2-
piperidin-1-yl-acetamide
364 541 N-{4-{3-[3-Chloro-4-(2-piperidin-1-yl-acetylamino)-phenyl]-thioureido}-
phenyl)-2-fiuoro-benzamide
365 SI3 Furan-2-carboxylic acid (4-{3-[3-chloro-4-(2-giperidin-1-yl-
acetylamino)-
phenyl]-ihioureido}-phenyl)- amide
366 463 N-{4-(3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-2-
morpholin-4-yl-acetamide
367 543 N-(4-{3-[3-Chloro-4-(2-morpholin-4-y1-acetylamino)-phenyl]-thioureido}-
phenyl)-2-fluoro-benzamide
368 515 Furan-2-carboxylic acid (4-{3-[3-chloro-4-(2-morpholin-4-yl-
acetylamino)-phenyl]-thioureido}-phenyl)- amide
369 414 N-{4-[3-(3-Chloro-4-methanesulfonylamino-phenyl)-thioureido]-phenyl}-
acetamide
370 494 N-{4-[3-(3-Chloro-4.-methanesulfonylamino-phenyl)-thioureido]-phenyl}-
2-fluaro-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-
dirnethy-lamino-ethylsulfanyl)- acetamide
373 561 N-[4-(3-{3=Chloro-4-[2-(2-dimethylamino-ethylsuifanyl)-acetylarnino]
phenyl}-thioureido)-phenyl]-2-fluoro-benzamide
374 585 N-[4-(3-{4-[(1-Benzyl-pyrrolidin-3-yl)-methyl-amino]-3-chloro-phenyl}
thioureido)-phenyl]-2-methyl-benzamide
375 523 N-[4-(3-{3-Chloro-4-[methyl-(1-methyl-piperidin-4-yl)-amino]-phenyl}-
thioureido)-phenyl]-2-methyl-benzamide
376 510 Pyridine-2-carboxylic acid [4-(3-{3-chlaro-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)-
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thioureido]-phenyl }-amide
380 487 N-{4-[3-(4-Chloro-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-2,6-
difluoro-benzamide
381 486 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-cyano-phenyl}-
2-fluoro-benzamide
382 45$ Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-
thioureido]-3-cyano-phenyl }-amide
383 406 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-cyano-phenyl}-
acetamide
384 395 N-{4-[3-(5-Chloro-2,4-dimethoxy..phenyl)-2-methyl-isothioureido]-
phenyl }-acetamide
385 396 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-2-methyl-isothioureido]-
phenyl }-acetamide
3$6 461 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
38$ 411 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-methoxy-
phenyl }-acetarnide
389 491 N-{4-[3-{5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-methoxy-
phenyl }-2-fluoro-benzamide
390 463 Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-
thioureido]-3-methoxy-phenyl }-amide
391 S3I [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[3-chloro-4-(2-piperidin-
1-
yl-acetyl-amino)-phenyl]-thioureido }-phenyl)-amide
392 481 N-{4-[3-(3-Chloro-4-methanesulfinyl-phenyl)-thioureido]-phenyl}-2,6-
difluaro-benzamide
393 497 N-{4-C3-(3-Chloro-4-methanesulfonyl-phenyl)-thioureido]-phenyl}-2,6-
difluoro-benzamide
394 459 N-{4-[3-(5-Chloro-2-methoxy-4-methyl-phenyl)-thioureido]-2-methyl-
phenyl}-2-fluoro-benzamide
39S 429 N-{4-[3-(3-Chloro-4-methyl-phenyl)-thioureido]-2-methyl-phenyl}-2-
fluoro-benzamide
396 533 Furan-2-carboxylic acid [4-(3-{3-chloro-4-[2-(2-dimethylamino-
ethylsulfanyl)- acetylamino]-phenyl}-thioureido)-phenyl]-amide
397 4S8 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)-
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- 117 -
phenyl]- carbamic acid ethyl ester
399 488 (2-Chloro-4-{3-[4-(2-fluoro-benzoylamino)-phenyl]-thioureido}-phenyl)-
carbamic acid ethyl ester
400 440 N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chlora-phenyl}-benzamide
401 520 N-{4-[({[4-(Benzoylamino)-3-chloro-phenyl]-amino}-thioxomethyl)-
amino]-phenyl }-2-fluoro-benzamide
402 529 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-
trifluoromethyl-
phenyl}-2-fluora-benzamide
403 492 Furan-2-carboxylic acid {4-[3-(4-benzoylarnino-3-chloro-phenyl)-
thioureido]-phenyl }-amide
404 416 N-{4-[3-(4-Amino-3-chloro-phenyl)-thioureido]-phenyl}-2-fluoro-
benzamide
405 479 N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-2-
thiamorpholin-4-yl-acetamide
406 531 Furan-2-carboxylic acid (4-{3-[3-chloro-4-(2-thiomorpholin-4-yl-
acetyl-
amino)-phenyl]-thioureido }-phenyl)-amide
407 559 N-(4-{3-[3-Chloro-4-(2-thiomorphoiin-4-yl-acetylamino)-phenyl]-
thioureido }-phenyl)-2-fluoro-benzamide
408 461 N-{4-[3-(3-Chloro-4-methylsulfanyl-phenyl)-thioureido]-2-methyl-
phenyl }-2-fluoro-benzamide
409 430 Furan-2-carboxylic acid {4-[3-(4-acetylamino-3-chloro-phenyl)-
thioureido]-phenyl }-amide
410 477 N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-2-
dipropyl-
amino-acetamide
411 529 Furan-2-carboxylic acid (4-{3-[3-chloro-4-(2-dipropylamino-
acetylamino)-
phenyl]-thioure'ido}-phenyl)- amide
412 449 N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-2-diethyl-
amino-acetamide
413 501 F~-2-c~'boxylie acid (4-{3-[3-chloro-4-(2-diethylamino-acetylamino)-
phenyl]-thioureido}-phenyl)- amide
414 529 N-(4-{3-[3-Chloro-4-(2-diethylamino-acetylamino)-phenyl]-
thioureido}-
phenyl)-2-fluoro-benzamide
415 447 N-{4-[3-(4-Acetylamina-phenyl)-thioureido]-2-chloro-phenyl}-2-
pyrrolidin-1-yl-acetamide
416 499 Furan-2-carboxylic acid (4-{3-[3-chloro-4-(2-gyrrolidin-1-yl-
acetylamino)-
phenyl]-thioureido}-phenyl)-amide
417 527 N-(4-{3-[3-Chloro-4-(2-pyrrolidin-1-yl-acetylamino)-phenyl]-
thioureido}-
phenyl)-2-fluoro-benzamide
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41$ 475 N-{4-[3-(5-Chioro-2-methoxy-4-methyl-phenyl)-thioureido]-3-methoxy-
phenyl}-2-fiuoro-benzamide
419 445 N-{4-[3-(3-Chloro-4-methyl-phenyl)-thioureido]-3-methoxy-phenyl}-2-
fluoro-benzamide
420 477 N-{4-[3-(3-Chloro-4-methylsulfanyl-phenyl)-thioureido]-3-methoxy-
phenyl }-2-fluoro-benzamide
421 388 Furan-2-carboxylic acid {4-[3-(4-amino-3-chloro-phenyl)-thioureido]-
phenyl }-amide
422 527 Furan-2-carboxylic acid (4-{3-[4-(2-azepan-1-yl-acetylamino)-3-chloro-
phenyl]- thioureido}-phenyl)-amide
423 555 N-(4-{3-[4-(2-Azepan-1-y1-acetylamino)-3-chloro-phenyl]-thioureido}-
phenyl)- 2-fluoro-benzamide
424 527 Furan-2-carboxylic acid [4-(3-{3-chloro-4-[2-(2-methyl-piperidin-1-yl)
acetyl-amino]-phenyl}-thioureido)-phenyl]-amide
425 555 N-[4-(3-{3-Chloro-4-[2-(2-methyl-piperidin-1-yl)-acetyiamino]-phenyl}
thioureido)-phenyl]-2-fluoro-benzamide
426 339 Furan-2-carboxylic acid [4-(3-pyridin-2-yl-thioureido)-phenyl]-amide
427 339 Furan-2-carboxylic acid [4-(3-pyridin-4-yl-thioureido)-phenyl]-amide
428 367 2-Fluoro-N-[4-(3-pyridin-3-yl-thioureido)-phenyl]-benzamide
429 339 Furan-2-carboxylic acid [4-(3-pyridin-3-yl-thioureido)-phenyl]-amide
430 353 Furan-2-carboxylic acid {4-(3-(3-amino-phenyl)-thioureido]-phenyl}-
amide
431 406 Furan-2-carboxylic acid {4-[3-(3-trifluoromethyl-phenyl)-thioureido]-
phenyl}-amide
432 380 2-Fluoro-N-[4-(3-m-tolyl-thioureido)-phenyl]~benzamide
433 434 2-Fluoro-N-{4-(3-(3-trifluoromethyl-phenyl)-thioureido]-phenyl}-
benzamide
434 381 N-{4-[3-(3-Amino-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide
435 388 Furan-2-carboxylic acid {4-[3-(3..amino-5-chloro-phenyl)-thioureido)-
phenyl }-amide
436 352 Furan-2-carboxylic acid [4-(3-m-tolyl-thioureido)-phenyl]-amide
437 416 N-{4-[3-(2-Amino-5-chloro-phenyl)-thioureido]-phenyl }-2-fiuoro-
benzamide
438 571 (2-Chloro-4-{3-j4-(2-fluoro-benzoylamino)-phenyl]-thioureido}-phenyl)-
carbamic acid 2-piperidin-1-yl-ethyl ester
439 543 [2-Chloro-4-(3-{4-[(furan-2-carbonyl)-amino]-phenyl}-thioureido)-
phenyl]-carbamic acid 2-piperidin-1-yl-ethyl ester
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440 388 Furan-2-carboxylic acid {4-[3-(2-amino-5-chloro-phenyl)-thioureido]-
phenyl }-amide
441 363 Furan-2-carboxylic acid {4-[3-(3-cyano-phenyl)-thioureido]-phenyl}-
amide
442 416 N-{4-[3-(3-Amino-5-chloro-phenyl)-thioureido]-phenyl}-2-fluoro-
benzamide
443 367 2-Fluoro-N-[4-(3-pyridin-2-yl-thioureido)-phenyl]-benzamide
444 367 2-Fluoro-N-[4-(3-pyridin-4-yl-thioureido)-phenyl]-benzamide
445 374 Furan-2-carboxylic acid {4-(3-(6-chloro-pyridin-3-yl)-thiaureido]-
phenyl}-
amide
446 388 Furan-2-carboxylic acid {4-[3-(2-amino-3-chloro-phenyl)-thioureido]-
phenyl }-amide
447 396 Furan-2-carboxylic acid {4-[3-(3-hydrazinocarbonyl-phenyl)-thioureido]-
phenyl}-amide
44$ 410 2-Fluoro-N-(4-{3-[3-(1-hydroxy-ethyl)-phenyl]-thioureido}-phenyl)-
benzamide
449 414 (1,2,3]Thiadiazole-4-carboxylic acid {4-(3-(3-hydrazinocarbonyl-
phenyl)-
thioureido]-phenyl}-amide
450 399 [1,2,3]Thiadiazole~4-carboxylic acid {4-[3-(3-isopropyl-phenyl)-
thioureido]-phenyl }-amide
451 380 Furan-2-carboxylic acid {4-[3-(3-isopropyl-phenyl)-thiaureido]-phenyl}-
amide
452 409 2-Fluoro-N-{4-[3-(3-isopropyl-phenyl)-thioureido]-phenyl}-benzamide
453 381 [I,2,3]Thiadiazole-4- carboxylic acid {4-[3-(3-cyano-phenyl)-
thioureido]-
phenyl }-amide
454 410 N-{4-(3-(3-Dimethylamino-phenyl)-thioureido]-phenyl}-2-fluora-
benzamide
455 381 Furan-2-carboxylic acid {4-[3-(3-dimethylamino-phenyl)-thioureido]-
phenyl }-amide
456 370 [1,2,3]Thiadiazole-4-carboxylic acid [4-(3-m-tolyl-thioureido)-phenyl]-
amide
457 424 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-trifluoromethyl-phenyl)-
thioureido]-phenyl}-amide
458 479 N-{3-Chloro-4-[3-(5-chloro-2-methoxy-4-methyl-phenyl)-thioureido]-
phenyl}-2-fluoro-benzamide
459 449 N-{3-Chloro-4-[3-(3-chloro-4-methyl-phenyl)-thioureido]-phenyl}-2-
fluoro-benzamide
460 481 N-{3-Chloro-4-[3-(3-chloro-4-methylsulfanyl-phenyl}-thioureido]-
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phenyl }-2-fluoro-benzamide
461 391 N-{4-[3-(3-Cyano-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide
462 395 Furan-2-carboxylic acid {4-[3-(3-acetylamino-phenyl)-thioureido]
phenyl }-amide
463 424 2-Fluoro-N-{4-[3-(3-hydrazinocarbonyl-phenyl)-thioureido]-phenyl}-
benzamide
464 400 [2,2,3]Thiadiazole-4-carboxylic acid (4-{3-[3-(1-hydroxy-ethyl)-
phenyl]-
thioureido}-phenyl)-amide
465 434 N-{4-I3-(2-.4mino-3-chloro-phenyl)-thioureido]-phenyl}-2,6-difluoro-
benzamide
466 406 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-amino-5-chloro-phenyl)-
thioureido]-phenyl }-amide
467 398 Furan-2-carboxylic acid {4-[3-(3,5-dirnethoxy-phenyl)-thioureido]-
phenyl }-amide
468 416 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-dimethoxy-phenyl)-
thioureido]- phenyl }-amide
469 454 5-(3-{4-[(Furan-2-carbonyl)-amino]-phenyl }-thioureido)-isophthalic
acid dimethyl ester
470 434 Isoxazole-5-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-
thioureido]-phenyl}-amide
471 392 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(6-chloro-pyridin-3-yl)-
thioureido]-phenyl }-amide
472 382 Furan-2-carboxylic acid (4-{3-[3-(1-hydroxy-ethyl)-phenyl]-thioureido}-
phenyl)-amide
473 368 Furan-2-carboxylic acid {4-[3-(3-methoxy-phenyl}-thioureido]-phenyl}-
amide
474 354 Furan-2-carboxylic acid {4-[3-(3-hydroxy-phenyl}-thioureido]-phenyl}-
amide
475 382 2-Fluoro-N-{4-[3-(3-hydroxy-phenyl)-thioureido]-phenyl}-benzamide
476 396 2-Fluoro-N-{4-[3-(3-hydroxymethyl-phenyl)-thioureido]-phenyl}-
benzamide
477 423 N-{4-[3-(3-Acetylamino-phenyl)-thioureido]-phenyl}-2-fluoro-
benzamide
478 413 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-{3-acetylamino-phenyl)-
thioureido]- phenyl}-amide
479 400 [1,2,3]Thiadiazole-4.-carboxylic acid {4-[3-(3-dimethylamino-phenyl)-
thioureido]-phenyl}-amide
480 340 Furan-2-carboxylic acid [4-(3-pyrimidin-4-yl-thioureido)-phenyl]-amide
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481 37$ 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-ihioureido)-phenyl]-2-fluoro-benzamide
485 473 5-(3-{4-[([1,2,3]Thiadiazole-4-carbonyl)-amino]-phenyl}-thioureido)-
isophthalic acid dimethyl ester
486 442 Furan-2-carboxylic acid (4-{3-[4-(1-azido-ethyl)-3-chloro-phenyl]-
thioureido}-phenyl)-amide
487 396 2-Fluoro-N-{4-[3-(3-methoxy-phenyl)-thioureido]-phenyl}-benzamide
488 368 Furan-2-carboxylic acid {4-[3-(3-hydroxymethyl-phenyl)-thioureido]-
phenyl }-amide
489 416 Furan-2-carboxylic acid {4-[3-(5-chloro-2-dimethylamino-phenyl)-
thioureido]- phenyl}-amide
490 444 N-{4-[3-(5-Chloro-2-dimethylamino-phenyl)-thioureido]-phenyl}-2-
fluoro-benzamide
491 506 [3-Chloro-5-(3-{4-[([I,2,3]thiadiazole-4-carbonyl)-amino]-phenyl}-
thioureido)- phenyl]-carbamic acid tert-butyl
ester
492 470 N-(4-{3-[4-(1-Azido-ethyl)-3-chloro-phenyl]-thioureido}-phenyl)-2-
fluoro-
benzamide
493 337 Furan-2-carboxylic acid [4-(1H-thiazolo[5,4-b]pyridin-2-
ylideneamino)-
phenyl]-amide
494 378 Furan-2-carboxylic acid {4-[3-(1H-benzoimidazoi-5-yl)-thioureido]-
phenyl}-amide
495 392 Furan-2-carboxylic acid {4-[3-(2-methyl-1H-benzoimidazol-5-yl)-
thioureido]-phenyl}-amide
496 406 N-{4-[3-(1H-Benzoimidazol-5-yl)-thioureido]-phenyl}-2-fluoro-
benzamide
497 420 2-Fluoro-N-{4-[3-(2-methyl-1H-benzoimidazol-5-yl)-thioureido]-
phenyl}-
benzamide
498 452 [1,2,3]Thiadiazole-4.-carboxylic acid {5-[3-(5-chloro-2,4-dimethoxy-
phenyl)-thioureido]-pyridin-2-yl}-amide
499 445 Pyridine-2-carboxylic acid {5-[3-(5-chloro-2,4-dimethoxy-phenyl)-
thioureido]- pyridin-2-yl}-amide
500 434 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(5-chloro-2-
dimethylamino-
phenyl)-thioureido]-phenyl }-amide
501 484 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[4-(2-amino-pyrimidin-4-
yl)-
3-chloro-phenyl]-thioureido}-phenyl)-amide
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502 494 N-(4-{3-(4-(2-Amino-pyrimidin-4-yl)-3-chloro-phenyl]-thioureido}-
phenyl)-2-fluoro-benzamide
503 434 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-2-dimethylamino-
phenyl)-thioureido]-phenyl }-amide
504 462 N-{4-[3-(3-Chloro-2-dimethylamino-phenyl)-thioureido]-phenyl}-2,b-
difluoro-benzamide
505 416 Furan-2-carboxylic acid {4-[3-(3-chloro-2-dimethylamino-phenyl)-
thioureido]-phenyl }-amide
506 445 Pyridine-2-carboxylic acid {t-[3-(5-chloro-2,4-dimethoxy-phenyl)-
thioureido]-pyridin-3-yl }-amide
507 462 N-{6-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-3-yl}-2-
fluoro-benzamide
508 482 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-iodo-phenyl)-thioureido]-
phenyl}-amide
509 413 (1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-tert-butyl-phenyl)-
thioureido]-phenyl }-amide
510 387 Furan-2-carboxylic acid {4-[3-(3-chloro-benzyl)-thioureido]-phenyl}-
amide
511 415 N-{4-[3-(3-Chloro-benzyl)-thioureido]-phenyl}-2-fluoro-benzamide
512 434 Furan-2-carboxylic acid { 6-[3-(5-chloro-2,4-dimethoxy-phenyl)-
thioureido]-pyridin-3-yl }-amide
513 435 (1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-bromo-phenyl)-
thioureido]-
phenyl }-amide
514 452 [1,2,3]Thiadiazole-4-cazboxylic acid {6-[3-(5-chloro-2,4-dimethoxy-
phenyl)-thioureido]-pyridin-3-yl}-amide
515 426 [1,2,3]Thiadiazole-4-carboxylic acid {5-(3-(3,5-dichloro-phenyl)-
thioureido]-pyridin-2-yl}-amide
516 474 Furan-2-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl-phenyl)-
thioureido]- phenyl}-amide
517 502 N-{4-I3-(3,5-Bis-trifluoromethyl-phenyl)-thioureido]-phenyl}-2-
Fluoro-Benzamide
5I8 450 N-{4-[3-(4-Amino-3,S-dichloro-phenyl)-thioureido]-phenyl}-2-fluoro-
benzamide
519 539 N-{4-[3-(4-Amino-3,5-dibromo-phenyl)-thioureido]-phenyl}-2-fluoro-
benzamide
520 392 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(5-chloro-pyridin-3-yl)-
thioureido]-phenyl }-amide
521 529 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-amino-3,5-dibromo-
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phenyl)-thioureido]-phenyl }-amide
522 434 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-S-dimethylamino-
phenyl)-thioureido]-phenyl }-amide
523 444 N-{4-[3-(3-Chloro-S-dimethylarnino-phenyl)-thioureido]-phenyl}-2-
fluoro-benzamide
524 416 Furan-2-carboxylic acid {4-[3-(3-chloro-S-dimethylamino-phenyl)-
thioureido]- phenyl}-amide
525 436 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(S-bromo-pyridin-3-yl)-
thioureido]- phenyl}-amide
526 379 Furan-2-carboxylic acid {4-[3-(1H-benzotriazol-S-yl)-thioureido]-
phenyl}-
amide
527 425 N-{4-[3-(1H-Benzotriazol-5-yl)-thioureido]-phenyl}-2,6-diftuoro-
benzamide
528 388 N-[4-({C2-(3-Chloro-phenyl)-hydrazino]-thioxomethyl}-amino)-phenyl]-
furan-2-carboxamide
529 416 N-I4-({ [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-S-trifluoromethyl-
phenyl)- thioureido]-phenyl}-amide
533 374 {4-[(Furan-2-carbonyl)-amino]-phenyl}-thiocarbamic acid O-(3-chloro-
phenyl) ester
534 474 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-amino-3-chloro-5-
trifluoro-
methyl-phenyl)-thioureido]-phenyl}-amide
535 508 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-piperidin-1-yl-5-
trifluoro-
methyl-phenyl)-thioureido]-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
53$ 449 N-{4-[3-(3,4-Dichloro-benzyl)-thioureido]-phenyl}-2-fluoro-
benzamide
539 370 [1,2,3]Thiadiazole-4-carboxylic acid [4-(3-benzyl-thioureido)-
phenyl]-
amide
540 424 N-[4-(3-Benzo[1,3]dioxol-S-ylmethyl-thioureido)-phenyl]-2-fluoro-
benzamide
541 414 [1,2,3]Thiadiazole-4-carboxylic acid [4-(3-benzo[1,3]dioxol-5-
ylmethyl-
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thioureido)-phenyl]-amide
542 506 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl-
benzyl}-thioureido]-phenyl }-amide
543 516 N-{4-[3-(3,5-Bis-trifluoromethyl-benzyl)-thioureido]-phenyl}-2-
fluoro-
benzamide
544 352 Furan-2-carboxylic acid [4-(3-benzyl-thioureido)-phenyl]-amide
545 421 Furan-2-carboxylic acid {4-[3-(3,4-dichloro-benzyl)-thioureido]-
phenyl}-
amide
546 396 Furan-2-carboxylic acid [4-(3-benzo[1,3]dioxol-5-yhnethyl-
thioureido)-
phenyl]- amide
547 488 Furan-2-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl-benzyl)-
thioureido]-phenyl}-amide
548 503 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-bromo-3-
trifluoromethyl-
phenyl)-thioureido]-phenyl }-amide
549 529 N-{4-[3-(3-Bromo-4-trifiuoromethoxy-phenyl)-thioureido]-phenyl}-2-
fluoro-benzamide
550 519 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-bromo-4-
trifluoromethoxy-
phenyl)-thioureido]-phenyl}-amide
551 473 Furan-2-carboxylic acid {4-[3-(3-chloro-4-trifluoromethylsulfanyl-
phenyl)-
thioureido]-phenyl }-amide
552 412 2-Fluoro-N-(4-{3-[2-(3-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-
benzamide
553 412 2-Fluoro-N-(4-{3-[2-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-
benzamide
554 402 11,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-fluoro-phenyl)-
ethyl]-
thioureido}-phenyl)-amide
555 402 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4-fluoro-phenyl)-
ethyl]-
thioureido}-phenyl)-amide
556 495 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[3-(2-methyl-butyl)-5-
trifluoro-
methyl-phenyl]-thioureido}-phenyl}-amide
557 481 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-isobutyl-5-
trifluoromethyl-
phenyl)- thioureido]-phenyl}-amide
558 523 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[3-(4-methyl-piperazin-1-
yl)-5-
trifluoro-methyl-phenyl]-thioureido}-phenyl)-amide
559 510 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-morpholin-4-yl-5-
triflaoro-
methyl-phenyl)-thioureido]-phenyl }-amide
560 494 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-pyrrolidin-1-yl-5-
trifluoro-
methyl-phenyl)-thioureido]-phenyl }-amide
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561 384 Furan-2-carboxylic acid (4-{3-[2-(4-fluoro-phenyl)-ethyl]-
thioureido}-
phenyl)-amide
562 419 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-chloro-phenyl)-
ethyl]-
thioureido }-phenyl)-amide
563 429 N-(4-{3-[2-(3-Chloro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-
benzamide
564 40I Furan-2-carboxylic acid (4-{3-[2-(3-chloro-phenyl}-ethyl]-
thioureido}-
phenyl)- amide
565 402 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-
ethyl]-
thioureido }-phenyl)-amide
566 504 2-Fluoro-N-{4-[3-(3-pyrrolidin-1-yl-5-trifluoromethyl-phenyl)-
thioureido]-phenyl }-benzamide
567 477 N-{4-[3-(3-Dimethylamino-5-trifluoromethyl-phenyl)-thioureido]-
phenyl}-2-fluoro-benzamide
568 $20 2-~uoro-N-{4-[3-(3-morpholin-4-yl-5-trifluoromethyl-phenyl)-
thioureido]-phenyl}-benzamide
569 533 2-Fluoro-N-(4-{3-[3-(4-methyl-piperazin-1-yl)-5-trifluoromethyl-
phenyl]-thioureido }-phenyl)-benzamide
570 518 2-Fluoro-N-{4-[3-(3-piperidin-1-yl-5-trifluoromethyl-phenyl)-
thioureido]-phenyl}-benzamide
571 468 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-dimethylamino-5-
trifluoro-
methyl-phenyl)-thioureido]-phenyl}-amide
572 405 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-benzyl)-
thioureido]-
phenyl }-amide
573 384 Furan-2-carboxylic acid (4-{3-[2-(3-fluoro-phenyl)-ethyl]-
thioureido}-
phenyl)- amide .
574 366 Fm'an-2-carboxylic acid [4-(3-phenethyl-thioureido)-phenyl]-amide
575 384 [1,2,3]Thiadiazole-4-carboxylic acid [4-(3-phenethyl-thioureido)-
phenyl]-amide
S76 394 2-Fluoro-N-[4-(3-phenethyl-thioureido)-phenyl]-benzamide
577 505 2-Fluoro-N-(4-{3-[3-(2-methyl-butyl)-5-trifluoromethyl-phenyl]-
thioureido}-phenyl)-benzamide
578 491 2-Fluoro-N-{4-[3-(3-isabutyl-5-trifluoromethyl-phenyl)-thioureido]-
phenyl}-benzamide
579 388 Furan-2-carboxylic acid {4-[3-(3,5-difluoro-benzyl)-thioureido]-
phenyl}-
amide
580 416 N-{4-[3-(3,5-Difluoro-benzyl)-thioureido]-phenyl}-2-fluoro-
benzamide
581 406 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-difluoro-benzyl)-
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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
S$4 439 [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-trifluoromethyl-benzyl)-
thioureido]-phenyl }-amide
586 466 2-Fluoro-N-{4-[3-(3-fluoro-5-trifluoromethyl-benzyl)-thioureido]-
phenyl }-benzamide
587 456 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-fluoro-5-trifluoromethyl-
benzyl)-thioureido]-phenyl }-amide
588 384 [i,2,3]Thiadiazole-4.-carboxylic acid {4-[3-(1-phenyl-ethyl)-
thioureido]-
phenyl}-amide
589 394 2-Fluoro-N-{4-[3-(1-phenyl-ethyl)-thioureido]-phenyl}-benzamide
590 366 Furan-2-carboxylic acid {4-[3-(1-phenyl-ethyl)-thioureido]-phenyl}-
amide
591 412 2-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-
benzamide
592 384 Furan-2-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-
phenyl)-amide
593 413 N-{4-[3-(1-tent-Butyl-1H-imidazol-2-yl)-thioureido]-phenyl}-2-fluoro-
benzamide
594 510 I1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[3-(isobutyl-methyl-amino)-
5
trifluoromethyl-phenyl]-thioureido}-phenyl)-amide
595 510 f 1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[3-(3-hydraxy-pyrrolidin-1-
yl)
5-trifluoromethyl-phenyl]-thioureido}-phenyl)-amide
596 S20 2-Fluoro-N-(4-{3-[3-(isobutyl-methyl-amino)-5-trifluoromethyl-phenyl]-
thioureido}-phenyl)-benzamide
597 S 10 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[3-(butyl-methyl-amino)-5-
trifluoromethyl-phenyl]-thioureido}-phenyl)-amide
598 520 N-(4-{3-(3-(Butyl-methyl-amino)-5-trifluoromethyl-phenyl]-thioureido}-
phenyl)-2-fluoro-benzamide
599 520 E1.2.3]Thiadiazole-4-carboxylic acid {4-{3-[2-(3,5-bis-trifluoromethyl-
phenyl)-ethyl]-thioureido}-phenyl)-amide
600 442 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-fluoro-3-trifluoromethyl-
- phenyl)-thioureido]-phenyl}-amide
601 522 [1,2,3]Thiadiazole-4-carboxylic acid {4-(3-(4-piperidin-1-yI-3-
trifluoro-
methyl-benzyl)-thioureido]-phenyl}-amide
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602 482 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-dimethylamino-3-
trifiuoro-
methyl-benzyl)-thioureido]-phenyl}-amide
603 381 Furan-2-carboxylic acid (4-{3-[2-(4-amino-phenyl)-ethyl]-
thioureido}-
phenyl)-amide
604 445 Furan-2-carboxylic acid (4-{3-[2-(4-bromo-phenyl)-ethyl]-
thioureido}-
phenyl)-amide
605 380 Furan-2-carboxylic acid {4-[3-(2-p-tolyl-ethyl)-thioureido]-phenyl}-
amide
606 463 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4-bromo-phenyl)-
ethyl]-
thioureido}-phenyl)-amide
607 396 Furan-2-carboxylic acid (4-{3-[2-(3-methoxy-phenyl)-ethyl)-
thioureido}-
phenyl)-amide
1
403 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(1-tert-butyl-1H-
imidazol-2-
60$
yl)-thioureido]-phenyl}-amide
609 384 Furan-2-carboxylic acid {4-[3-(1-tert-butyl-1H-imidazal-2-y1)-
thioureido]-
phenyl}-amide
610 492 N-{4-[3-(4-Dimethylamino-3-trifiuoromethyl-benzyl)-thioureido]-
phenyl}-
2-fiuoro-benzamide
611 427 Furan-2-carboxylic acid (4-{3-[2-(3,4-dimethoxy-phenyl)-ethyl]-
thioureido}-phenyl)-amide
612 380 Furazx-2-carboxylic acid {4-[3-(3-phenyl-propyl)-thioureido]-
phenyl}-
amide
613 399 E1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-phenyl-propyl)-
thioureido]-
phenyl }-amide
614 502 Furan-2-carboxylic acid (4-{3-[2-(3,5-bis-trifiuoromethyl-phenyl)-
ethyl]-
thioureido}-phenyl)-amide
615 550 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-iado-3-
trifiuoromethyl-
phenyl)-thioureido]-phenyl }-amide
616 532 2-Fluoro-N-{4-[3-(4-piperidin-1-y1-3-trifiuoromethyl-benzyl)-
thioureido)-
phenyl}-benzamide
617 537 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[4-(4-methyl-piperazin-1-
yl)-3-
trifiuoromethyl-benzyl]-thioureido}-phenyl)-amide
618 482 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-dimethylamino-5-
trifluoro-
methyl-benzyl)-thioureido]-phenyl}amide
619 488 Furan-2-carboxylic acid {4-[3-(3,5-bis-trifiuoromethyl-phenyl)-
thioureido-
methyl]-phenyl }-amide
620 421 Furan-2-carboxylic acid {4-[3-(3,5-dichloro-phenyl)-
thioureidomethyl]-
phenyl}-amide
621 421 Furan-2-carboxylic acid {4-[3-(3,4-dichloro-phenyl)-
thioureidomethyl]-
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phenyl }-amide
622 455 Furan-2-carboxylic acid {4-[3-(4-chloro-3-trifluoromethyl-
phenyl)-
thioureido-methyl]-phenyl }-amide
623 466 2-Fluoro-N-{4-[3-(4-fluoro-3-trifluorometlnyl-benzyl)-
thioureido]-phenyl}-
benzamide
624 456 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-fluoro-3-
trifluoromethyl-
benzyl)-thioureida]-phenyl }-amide
625 410 2-Fluoro-N-{4-[3-(2-phenoxy-ethyl)-thioureido]-phenyl}-benzamide
626 382 Furan-2-carboxylic acid {4-[3-(2-phenoxy-ethyl)-thioureido]-
phenyl}-
amide
627 400 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-phenoxy-ethyl)-
thioureido]-
phenyl }-amide
628 409 2-Fluoro-N-{4-[3-(3-phenyl-propyl)-thioureido]-phenyl}-benzamide
629 425 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(5-trifluoromethyl-
pyridin-3-
yl)-thioureido]-phenyl }-amide
630 439 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,4-dichloro-phenyl)-
thioureido-methyl]-phenyl}-amide
631 473 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-chloro-3-
trifluoromethyl-
phenyl)-thioureidomethyl]-phenyl }-amide
632 381 2-~uoro-N-[4-(3-pyridin-3-ylmethyl-thioureido)-phenyl]-benzamide
633 353 Furan-2-carboxylic acid [4-(3-pyridin-3-ylmethyl-thioureido)-
phenyl]-
amide
634 371 [2,2,3]Thiadiazole-4-carboxylic acid [4-(3-pyridin-3-ylmethyl-
thioureido)-
phenyl]-amide
635 439 [1,2,3]Thiadiazale-4-carboxylic acid {4-[3-(3,5-dichloro-phenyl)-
thioureido-methyl]-phenyl }-amide
636 492 N-{4-[3-(3-Dimethylamino-5-trifluoromethyl-benzyl)-thioureido]-
phenyl}-
2-fluoro-benzamide
637 415 [2,2,3]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 5D6 [1,2,3]Thiadiazole-4.-carboxylic acid {4-[3-(3,5-bis-
trifluoromethyl-
phenyi)- thioureidomethyl]-phenyl}-amide
641 516 N-{4-[3-(3,5-Bis-trifluoromethyl-phenyl)-thioureidomethyl]-
phenyl}-2-
fluoro-benzamide
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642 449 N-{4-[3-(3,S-Dichloro-phenyl)-thioureidomethyl]-phenyl}-2-fluoro-
benzamide
643 449 N-{4-[3-(3,4-Dichloro-phenyl)-thioureidomethyl]-phenyl}-2-fluoro-
benzamide
644 448 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-acetylamino-5-chloro-
phenyl)-thioureido]-phenyl }-amide
645 453 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3,4-dichloro-phenyl)-
ethyl]-
thioureido}-phenyl)-amide
646 413 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(1-methyl-3-phenyl-propyl)-
thioureido]-phenyl}-amide
647 463 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[1-(4-bromo-phenyl)-ethyl]-
thioureido }-phenyl)-amide
648 413 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-phenyl-butyl)-
thioureido]-
phenyl }-amide
649 397 [x,2,3]Thiadiazole-4-carboxylic acid [4-(3-indan-1-yI-thioureido)-
phenyl]-
amide
650 400 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-methoxy-benzyl)-
thioureido]-phenyl}-amide
65i 415 [1,2,3]ThiadiazoIe-4-carboxylic acid (4-{3-[2-(2-methoxy-phenyl)-
ethyl]-
thioureido }-phenyl)-amide
652 415 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4-methoxy-phenyl)-
ethyl]-
thioureido }-phenyl)-amide
653 506 N-(4-{3-[2-(3-Dimethylamino-5-trifluoromethyl-phenyl)-ethyl]-
thioureido}-phenyl)-2-fluoro-benzamide
654 510 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[3-(3-dimethylamino-propyl)-
5-
trifluoromethyl-phenyl]-thioureido}-phenyl)-amide
655 417 [1,2;3]Thiadiazole-4.-carboxylic acid {4-j3-(2-phenylsulfanyl-ethyl)-
thioureido]-phenyl}-amide
656 427 2-Fluoro-N-{4-[3-{2-phenylsulfanyl-ethyl)-thioureido]-phenyl}-
benzamide
657 399 Furan-2-carboxylic acid {4-[3-(2-phenylsulfanyl-ethyl)-thioureido]-
phenyl}-amide
658 381 2-Fluoro-N-[4-{3-pyridin-4-ylmethyl-thioureido)-phenyl]-benzamide
659 353 Furan-2-carboxylic acid [4-(3-pyridin-4-ylrnethyl-thioureido)-phenyl]-
amide
660 371 [1,2,3]Thiadiazole-4-carboxylic acid [4-(3-pyridin-4-ylmethyl-
thioureido)-
phenyl]-amide
661 506 2-Fluoro-N-{4-[3-(3-iodo-benzyl)-thioureido]-phenyl}-benzamide
662 478 Furan-2-carboxylic acid {4-[3-(3-iodo-benzyl)-thioureido]-phenyl}-
amide
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663 496 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-iodo-benzyl)-thioureido]-
phenyl }-amide
664 479 N-(4-{3-[2-(3,5-Dichloro-phenoxy)-ethyl]-thioureido}-phenyl)-2-fluoro-
benzamide
665 451 Furan-2-carboxylic acid (4-{3-[2-(3,5-dichloro-phenoxy)-ethyl}-
thioureido}-phenyl)-amide
666 445 N-(4-{3-[2-(3-Chloro-phenoxy)-ethyl]-thioureido}-phenyl)-2-fluoro-
benzamide
667 417 Furan-2-carboxylic acid (4-{ 3-[2-(3-chloro-phenoxy}-ethyl]-
thioureido}-
phenyl)-amide
66$ 435 [1,2,3JThiadiazole-4-carboxylic acid (4-{3-[2-(3-chloro-phenoxy)-
ethyl]-
thioureido }-phenyl}-amide
669 466 2-Fluoro-N-{4-[3-(2-fluoro-5-trifluoromethyl-benzyl)-thioureido]-
phenyl}-
benzamide
670 438 Furan-2-carboxylic acid {4-[3-(2-fluoro-5-trifluoromethyl-benzyl}-
thioureido]-phenyl}-amide
671 456 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-fluoro-5-trifluoromethyl-
benzyl)-thioureido]-phenyl }-amide
672 416 N-{4-[3-(3,4-Difluoro-benzyl)-thioureido]-phenyl}-2-fluoro-benzamide
673 452 N-(4-{3-[2-(4-Dimethylamino-3-methyl-phenyl)-ethyl]-thioureido}-
phenyl)-2-fluoro-benzamide
674 496 [1,2,3JThiadiazole-4-carboxylic acid (4-{3-[2-(3-dirnethylamino-5-
trifluoro-methyl-phenyl)-ethyl]-thioureido}-phenyl)-amide
675 388 Furan-2-carboxylic acid {4-[3-(3,4-difluoro-benzyl)-thioureidoJ-
phenyl}-
amide
676 406 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,4-difluoro-benzyl)-
thioureido]-phenyl}-amide
677 433 N-{4-[3-(3-Chloro-4-fluoro-benzyl)-thioureido]-phenyl}-2-fluoro-
benzamide
678 495 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-bromo-phenylsulfanyl)-
ethyl]-thioureido }-phenyl)-amide
679 477 F-2-carboxylic acid (4-{ 3-[2-(3-bromo-phenylsulfanyl)-ethyl]-
thioureido}-phenyl)-amide
680 505 N-(4-{3-[2-(3-Bromo-phenylsulfanyl)-ethyl]-thioureido}-phenyl)-2-
fluoro-
benzamide
681 493 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-bromo-4-methoxy-
phenyl)-ethyl]-thioureido}-phenyl)- amide
682 493 [1>2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(5-bromo-2-methoxy-
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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]ThiadiazoIe-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-j4-(4-methyl-piperazin-1-yl)-3-trifluoromethyl-
benzyl]- thioureido}-phenyl)-benzamide
688 469 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3,5-dichloro-phenoxy)-
ethyl]-thioureido }-phenyl)-amide
689 423 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-4-fluoro-benzyl)-
thioureido]-phenyl }-amide
690 427 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-tert-butyL.benzyl)-
thioureido]-phenyl }-amide
691 399 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-dimethyl-benzyl)-
thioureido]-phenyl}-amide
692 442 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4-dimethylamino-3-
methyl-
phenyl)-ethyl]-thioureido }-phenyl)-amide
693 479 [1,2,3]Thiadiazole-4.-carboxylic acid (4-{3-[2-(4-bromo-phenoxy)-
ethyl]-
thioureido }-phenyl)-amide
694 526 [1,2,3]Thiadiazole-4.-carboxylic acid (4-{3-[2-(4-iodo-phenoxy)-ethyl]-
thioureido }-phenyl)-amide
695 489 N-(4-{3-[2-(4-Bromo-phenoxy)-ethyl]-thioureido}-phenyl)-2-fluoro-
benzamide
696 536 2-Fluoro-N-(4-{3-[2-(4-iado-phenoxy)-ethyl]-thioureida}-phenyl)-
benzarnide
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,S-dichloro-phenyl)-thioureido]-
phenyl}-amide
701 491 Thiazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl-phenyl)-
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thioureido]-phenyl }-amide
702 408 Oxazole-4-carboxylic acid {4-[3-(3,5-dichloro-phenyl)-thioureido]-
phenyl }-amide
703 469 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[Z-(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-
phenyI)-
thioureido]-phenyl }-amide
706 400 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-phenylannino-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 [I,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-trifluoromethyl-
phenyl)-
ethyl]-thioureido}-phenyl)-amide
709 453 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(2,6-dichloro-phenyl)-
ethyl]-
thioureido}-phenyl)-amide
710 485 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-{3,4-dichloro-
phenylsulfanyl)-ethyl]-thioureido}-phenyl)-amide
711 503 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(2-fluoro-5-
trifluoromethyl-
phenylsulfanyl)-ethyl]-thioureido}-phenyl)-amide
712 668 N-(4-{3-[3-Chioro-5-(3-{4-[([1,2,3]thiadiazole-4-carbonyl)-amino]-
phenyl}-thioureido)-phenyl]-thioureido}-phenyl)-[1,2,3]thiadiazole-4-
carboxamide
7i3 413 [I,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
726 420 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3,4-difluoro-
phenyl)-ethyl]-
thioureido }-phenyl)-amide
717 452 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4-
trifluoromethyl-phenyl)-
ethyl]-thioureido}-phenyl)-amide
718 435 Furan-2-carboxylic acid (4-{3-[2-(3,4-dichloro-phenyl)-ethyl]-
thioureido}-
phenyl)-amide
719 463 N-(4-{3-[2-(3,4-Dichloro-phenyl)-ethyl]-thioureido}-phenyl)-2-
fluoro-
benzamide
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720 420 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3,5-difluoro-
phenyl)-ethyl]-
thioureido}-phenyl)-amide
721 412 2-Fluoro-N-(4-{3-[2-(2-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-
benzamide
722 429 [I,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4-nitro-phenyl)-
ethyl]-
thioureido }-phenyl)-amide
723 399 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(1-methyl-2-phenyl-
ethyl)-
thioureido]-phenyl}-amide
724 437 N-{4-[3-(4-tert-Butyl-benzyl)-thioureido]-phenyl}-2-fluoro-
benzamide
725 409 N-{4-[3-(3,5-Dirnethyl-benzyl)-thioureido]-phenyl}-2-fluoro-
benzamide
726 400 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-hydroxy-1-phenyl-
ethyl)-
thioureido]-phenyl }-amide
727 409 2-Fluoro-N-{4-[3-(1-methyl-1-phenyl-ethyl)-thioureido]-phenyl}-
benzamide
728 399 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(1-methyl-1-phenyl-
ethyl)-
thioureido]-phenyl }-amide
729 405 I1>2>3]Thiadiazole-4-carboxylic acid {4-[3-(2-chloro-benzyl)-
thioureido]-
phenyl }-amide
730 388 (1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-fluoro-benzyl)-
thioureido]-
phenyl}-amide
731 438 (1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-trifluoromethyl-
benzyl)-
thioureido]-phenyl}-amide
732 388 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-fluoro-benzyl)-
thioureido]-
phenyl}-amide
733 435 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(2-chloro-phenoxy)-
ethyl]-
thioureido }-phemyl)-amide
734 479 (1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-bromo-phenoxy)-
ethyl]-
thioureido}-phenyl)-amide
735 41$ [1,2,3]Thiadiazole-4.-carboxylic acid (4-{3-[2-(2-fluoro-phenoxy)-
ethyl]-
thioureido}-phenyl)-amide
736 41$ [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-fluoro-phenoxy}-
ethyl]-
thioureido}-phenyl)-amide
737 486 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(2-fluoro-5-
trifluoromethyl-
phenoxy)-ethyl]-thioureido }-phenyl)-amide
738 384 Furan-2-carboxylic acid (4-{3-[2-(2-fluoro-phenyl)-ethyl]-
thioureido}-
phenyl)-amide
739 435 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-bromo-phenyl)-
thioureido}-
phenyl }-amide
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740 374 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-fluoro-phenyl)-
thioureido]-
phenyl }-amide
74I 388 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-fluoro-benzyl)-
thioureido]-
phenyl }-amide
742 405 [1;2,3JThiadiazole-4-carboxylic acid {4-[3-(4-chloro-benzyl)-
thioureido]-
phenyl }-amide
743 449 [1,2,3]Thiadiazoie-4.-carboxylic acid {4-[3-(4-bromo-benzyl)-
thioureido]-
phenyl}-amide
744 332 N-(4-{3-[1-(4-Fluoro-phenyl)-ethylJ-thioureido}-phenyl)-acetamide
745 438 Thiazole-4-carboxylic acid {4-[3-(3,4-dichloro-benzyl)-thioureido]-
phenyl }-amide
746 455 Thiazole-4-carboxylic acid {4-[3-(2-fluoro-5-trifluoromethyl-
benzyl)-
thioureido]-phenyl}-amide
747 426 Thiazole-4-carboxylic acid {4-[3-(4-tert-butyl-benzyl)-thioureidoJ-
phenyl }-amide
748 374 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-fluoro-phenyl)-
thioureido]-
phenyl }-amide
749 374 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-fluoro-phenyl)-
thioureido]-
phenyl }-amide
750 526 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-iodo-phenoxy)-
ethyl]-
thioureido}-phenyl)-amide
751 409 N-(4-{3-[~-(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
?54 425 N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-4-methoxy-
benzamide
755 429 2-Chloro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-
benzamide
756 429 4-Toro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-
benzamide
757 453 Acetic acid 4-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl-
carbamoyl)-phenyl ester
758 394 N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide
759 395 N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-
isonicotinamide
760 410 N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-4-hydroxy-
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benzamide
761 429 3-Chloro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-tttioureido}-phenyl}-
benzamide
762 470 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-fluoro-5-
trifluoromethyl-
phenyl)-ethyl]-thioureido }-phenyl)-amide
763 520 [i,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(2,4-bis-triflnoromethyl-
phenyl)-ethyl]-thioureido }-phenyl)-amide
764 470 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4-fluoro-3-
trifluoromethyl-
phenyl)-ethyl]-thioureido }-phenyl)-amide
765 438 4-Dimethylamino-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-
phenyl)-benzamide
766 470 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(2-fluoro-3-
trifluoromethyl-
phenyl)-ethyl]-thiaureido }-phenyl}-amide
767 470 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(2-fluoro-5-
trifluoromethyl-
phenyl)-ethyl]-thioureido}-phenyl)-amide
768 510 [1,2,3]Thiadiazole-4-carboxylic acid {4-{3-[2-(3-iodo-phenyl)-ethyl]-
thioureido }-phenyl)-amide
769 470 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4-fluoro-2-
trifluoromethyl-
phenyl)-ethyl]-thioureido }-phenyl}-amide
770 463 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-bromo-phenyl)-ethyl]-
thioureido}-phenyl)-amide
771 427 2-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-propyl]-thioureido}-phenyl)-
benzamide
772 475 2-Fluaro-N-(4-{3-[(4-fluoro-phenyl}-phenyl-methyl]-thioureido}-
phenyl)-benzamide
773 455 2-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-pentyl]-thioureido}-phenyl)-
benzamide
774 489 2-~uoro-N-(4-{3-[1-(4-fluoro-phenyl)-2-phenyl-ethyl]-thioureido}-
phenyl)-benzamide
775 409 2-Fluoro-N-{4-[3-(1-o-tolyl-ethyl)-thioureido]-phenyl}-benzamide
776 409 2-Fluoro-N-{4-[3-(1-m-tolyl-ethyl)-thioureido]-phenyl}-benzamide
777 425 2-Fluoro-N-(4-{3-[I-(4-methoxy-phenyl)-ethyl]-thioureido}-phenyl)-
benzamide
778 412 2-Fluoro-N-(4-{3-[1-(2-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-
benzamide
'7'79 42g N-(4-{3-[1-(3-Chloro-phenyl}-ethyl]-thioureido}-phenyl)-2-fluoro-
benzamide
780 473 N-(4-{3-[1-(3-l3romo-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-
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benzamide
781 429 N-(4-{3-[I-(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-jl-(2-Bromo-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro
benzamide
784 429 N-(4-{3-[1-(2-Chloro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-
benzamide
785 462 2-Fluoro-N-(4-{3-[1-(2-trifluoromethyl-phenyl)-ethyl]-thioureido}-
phenyl)-benzamide
786 462 2-Fluoro-N-(4-{3-[1-(3-trifluorometbyl-phenyl)-ethyl]-thioureido}-
phenyl)-benzarnide
787 462 2-Fluoro-N-(4-{3-[1-(4-trifluoromethyl-phenyl)-ethyl]-thioureido}-
phenyl)-benzamide
788 425 2-Fluoro-N-(4-{3-[1-(2-methoxy-phenyl)-ethyl]-thioureido}-phenyl)-
benzamide
789 425 2-Fluoro-N-(4-{3-[1-(3-methoxy-phenyl)-ethyl]-thioureido}-phenyl)-
benzamide
790 441 2-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-2-methyl-propyl]-thioureido}-
phenyl)-benzamide
791 419 N-(4-{3-[1-(3-Cyano-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-
benzamide
792 419 N-(4-{3-[1-(4-Cyano-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-
benzamide
793 438 N-(4-{3-[1-(4-Dimethylamino-phenyl)-ethyl]-thioureido}-phenyl)-2-
fluoro-benzamide
794 438 N-(4-{3-[1-(3-Dimethylamino-phenyl)-ethyl]-thioureido}-phenyl)-2-
fluoro-benzamide
795 473 2-Bromo-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-
benzarnide
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-I-phenyl-ethyl)-thioureido]-phenyl}-
benzamide
798 332 2-Fluoro-N-[4-(3-isopropyl-thioureido)-phenyl]-benzamide
799 445 2-Fluoro-N-{4-[3-(1-naphthalen-2-yl-ethyl)-thioureido]-phenyl}-
benzamide
800 412 3-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl}-thioureido}-phenyl)-
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benzamide
801 412 4-Fluoro-N-(4-{3-[1-.(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-
benzamide
802 384 2-Fluoro-N-{4-(3-(1-furan-2-yl-ethyl)-thioureido]-phenyl}-benzamide
803 395 2-Fluoro-N-{4-[3-(1-pyridin-4-yl-ethyl)-thioureido]-phenyl}-
benzarnide
$04 397 2-~uoro-N-(4-{3-[1-(1-methyl-1H-pyrrol-2-yl)-ethyl]-thioureido}-
phenyl)-benzamide
$05 401 2-Fluoro-N-{4-[3-(1-thiophen-3-yl-ethyl)-thioureido]-phenyl}-
benzamide
806 445 N-{4-[3-(3-Chloro-4-ethoxy-phenyl)-chioureido]-phenyl
}-2-fluoro-
benzamide
807 459 N-{4-[3-(3-Chloro-4-propoxy-phenyl)-thioureido]-phenyl}-2-fluoro-
benzamide
808 459 N-{4-[3-{3-Chloro-4-isopropoxy-phenyl)-thioureido]-phenyl}-2-fluoro-
l3enzamide
809 473 N-{4-[3-(4-Butoxy-3-chloro-phenyl)-thioureido]-phenyl}-2-fluoro-
benzamide
810 522 2-~uoro-N-{4-[3-(3-iodo-4-methoxy-phenyl)-thioureido]-phenyl}-
benzamide
811 475 N-{4-[3-{3-Bromo-4-methoxy-phenyl)-thioureido]-phenyl}-2-fluoro-
benzamide
812 520 N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-iodo-
benzamide
813 346 N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-
propionamide
814 286 N-[4-(3-Phenyl-thioureido)-phenyl]-acetamide
$15 463 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[(2S)-1-(4-bromo-phenyl)-
ethyl]-thioureido}-phenyl)-amide
816 463 [1,2,3]Thiadiazole-4-carboxylic acid {4-{3-[(1R)-1-(4-bromo-phenyl)-
ethyl]-thioureido }-phenyl)-amide
818 520 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[1-(3,5-bis-
trifluoromethyl-
phenyl)-ethyl]-thioureido}-phenyl)-amide
820 418 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[(1S)-1-(4-chloro-
phenyl)-
ethyl]-thioureido }-phenyl)-amide
821 418 [1,2,3)Thiadiazole-4-carboxylic acid (4-{3-[{1R)-1-(4-chloro-
phenyl)-
ethyl]-thioureido}-phenyl)-amide
822 409 N-I4-[E[[1-(4-Cyanophenyl)ethyl]amino]thioxomethyl]amino]phenyl]-
1,2,3-thiadiazole-4-carboxamide
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824 462 Thiazole-4-carboxylic acid (4-{3-[I-(4-bromo-phenyl)-ethyl]-
thioureido}-
phenyl)-amide
825 520 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-(1S)-[1-(3,5-bis-
trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-amide
828 470 N-(4-{[({1-[4-fluoro-3-trifluoramethyl)phenyl]ethyl}amino)
carbothioyl]amino}phenyl)-1,2,3-thiadiazole-4-carboxamide
829 486 N-(4-{ [({ 1-[4-chloro-3-hiadiazole-4-carboxamide
830 519 N-(4-{[({(IS)-1-[3,5-thiazole-4-carboxamide
831 469 N-(4-{[({1-[3-fluoro-5-trifluoromethyl)phenyl]ethyl}amino)
carbothioyl]amino}phenyl)-1,3-thiazole-4-carboxamide
832 469 N-(4-{[({1-[2-fluoro-4-(trifluoromethyl)phenyl]ethyl}amino)
carbothioyl]amino}phenyl)-1,3-thiazole-4-carboxamide
833 469 N-(4-{C({1-[2-fluoro-5-trifluoromethyl)phenyl]ethyl}amino)
carbothioyl]amino}phenyl)-1,3-thiazole-4-carboxamide
834 519 N-(4-{ [({ 1-[2,4-bis(trifluoromethyl)phenyl]ethyl}amino)
carbothioyl]amino}phenyl)-1,3-thiazole-4-carboxamide
834 411 N-{4-[({[1-(2,4-
dimethylphenyl)ethyl]amino}carbothioyl)amino]phenyl}-
1,3-thiazole-4-carboxamide
$36 452 N-{4-[({[1-(2,4-
dichlorophenyl)ethyl]amino}carbothioyl)amino]phenyl}-
1,3-thiazole-4-carboxamide
837 397 N-{4-[({[1-(3-methylphenyl)ethyl]amino}carbothioyl)amino]phenyl}-
1,3-
thiazole-4-carboxamide
838 469 N-(4-{[({1-[4-fluoro-3-trifluoromethyl)phenyl]ethyl}amino)
carbothioyl]amino }phenyl)-1,3-thiazole-4-carboxamide
839 435 N-{4-f({[1-(2-chloro-4-
fluorophenyl)ethyl]amino}carbothioyl)amino]phenyl}-1,3-
thiazole-4-carboxarnide
$40 419 N-{4-[({[1-(3,4-
difluorophenyl)ethyl]amino}carbothioyl)amino]phenyl}-
1,3-ihiazole-4-caxboxamide
841 480 N-{4-[({[1-(4-promo-2-
fluorophenyl)ethyl]amino } carbothioyl)amino]phenyl
}-1,3-
thiazole-4-carboxamide
842 401 N-{4-[({[1-(3-fluorophenyl)ethyl]amino}carbothioyl)amino]phenyl}-
1,3-
thiazole-4-carboxamide
843 462 N-{4-[({[1-(2-bromophenyl)ethyl]amino}carbothioyl)amino]phenyl}-1,3-
thiazole-4-carboxamide
844 462 N-{4-[({[1-(3-bromophenyl)ethyl]amino}carbothioyl)amino]phenyl}-1,3-
thiazole-4-carboxamide
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845 451 N-(4-{[({1-[2-
(trifluorornethyl)phenyl]ethyl } amino)carbothioyl]amino
} phenyl)-1,3-
thiazole-4-carboXamide
846 419 N-{4-[({[1-(2,4-
difluorophenyl)ethyl]amino}carbothioyl)amino]phenyl}-
1,3-thiazole-4-carboxamide
847 519 N-(4-{[({(1R)-1-[3,5-bis(trifluoromethyi)phenyl]ethyl}amino)
carbothioyl]amino}phenyl)-1,3-thiazole-4-carboxamide
848 452 N-{4-[({[1-(3,4-
dichlorophenyl)ethyl]amino}carbothioyl)amino]phenyl}-
1,3-thiazole-4.-carboxamide
849 469 N-(4-{[({1-[3-fluoro-4-trifluoromethyl)phenyl]ethyl}amino)
carbothioyl]amino}phenyl)-1,3-thiazole-4-carboxamide
850 485 N-(4-{[({1-[4-chloro-3-(trifluoromethyl)phenyl]ethyl}amino)
carbothioyl]amino}phenyl)-1,3-thiazole-4-carboxamide
851 435 N-{4-[({[I-(4-chloro-2-
fluorophenyl)ethyl]amino}carbothioyl)amino]phenyl}-1,3-
thiazole-4-carboxamide
852 469 N-(4-{[({1-[4-fluoro-2-trifluoromethyl)phenyl]ethyl}amino)
carbothioyl]amino}phenyl)-1,3-thiazole-4-carboxamide
853 435 N-{4-[({[1-(4-chloro-3-
fluorophenyl)ethyl]amino}carbothioyl)amino]phenyl}-1,3-
thiazole-4-carboxamide
854 480 N-{4-[({[1-(2-bromo-4-
fluorophenyl)ethyl]amino } carbothioyl)amino]phenyl
}-1,3-
thiazole-4-carboxamide
855 541 N-{4-[({[1-(3,4-dibromophenyl)ethyljamino}carbothioyl)amino]phenyl}-
1,3-thiazole-4-carboxamide
856 435 N-{4-[({E1-(3-chioro-4-
fluorophenyl)ethyl]amino}carbothioyl)amino]phenyl}-1,3-
thiazole-4-carboxamide
857 366 N-(4-{[({1-[3,5-bis(trifluoromethyl)phenyl]propyl}amino)
carbothioyl]amino }phenyl)-1,2,3-thiadiazole-4-carboxamide
$58 392 N-(4-{[({1-[3,5-bis(trifluoromethyl)phenyl]butyl}amino)
carbothioyl]amino}phenyl)-1,2,3-thiadiazole-4-carboxamide
859 330 N-(4-{[({1-[3,5-his(trifluoromethyl)phenyl]pentyl}amino)
carbothioyl]amino}phenyl)-1,2,3-thiadiazole-4-carboxamide
860 521 N-{4-I({[[3,5-bis(trifluoromethyl)phenyl](phenyl)methyl]
amino }carbothioyl)amino]phenyl }-1,2,3-thiadiazole-4-carboxamide
861 450 N-(4-{[({1-[3,5-bis(trifluoromethyl)phenyl]-1-methyiethyl}amino)
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carbothioyl]amino}phenyl)-1,2,3-thiadiazole-4.-carboxamide
862 433 N-{4-[({[3,5-
bis(trifluoromethyl)benzyl)amino } carbotllioyl)amino)phenyl }-1 H-
imidazole-4-carboxamide
863 440 N-{4-[({[1-(4-fluorophenyl)ethyl]amino}carbothioyl)amino]phenyl}-1H-
imidazole-4-carboxamide
864 506 N-{4-[({[3,5-
bis(trifluoromethyl)benzyl)amino}carbothioyl)amino]phenyl}-1-methyl-
1 H-imidazole-4-carboxamide
865 462 N-(4-{[({1-[3,5-bis(trifluoromethyl)phenyl]propyl}amino)
carbothioyl]amino}phenyl)-1,3-thiazole-4-carboxamide
EXAMPLE $66 (METHOD 32)
[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2,5-dichloro-phenyl)-thioureido]
phenyl}-amide
To a solution of 2,5-dichloroaniline (0.16 g) in tetrahydrofuran (20 mL) is
added
freshly prepared 1,1'-thiocarbonyldiimidazole (0.20 g) and the mixture is
stirred for
approximately 30 minutes at room temperature. [1,2,3]-Thiadiazole-4-carboxylic
acid
(4-amino-phenyl) amide (0.22 g) is added to the reaction flask and the mixture
is
IO stirred for approximately 6 hours. The solvent is then removed by
evaporation under
reduced pressure and warm acetonitrile (3 mL) is added. After 15 hours the
mixture
is filtered and the collected precipitate is washed with acetonitrile then
diethyl ether,
and air dried to provide the desired product as a white powder.
Using the above procedure and appropriate starting materials the following
compounds were prepared:
EX.M+H COMPOUND NAME
NO.
867321 N-{4-[3-(3-Chloro-phenyl)-thioureido]-phenyl}-acetamide
868413 N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl}-benzamide
869443 N-{4-[3-(3..Chloro-4-methoxy-phenyl)-thioureido]-phenyl}-2-methoxy-
benzamide
870443 N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl}-3-methoxy-
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benzamide
871 443 N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl}-4-methoxy-
benzamide
872 431 N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl}-4-methoxy-
benzamide
873 431 N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl}-3-flaoro-
benzamide
874 431 N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl}-4-fluoro-
benzamide
875 437 Furan-2-carboxylic acid {4-[3-(3,5-dichloro-4-methoxy-phenyl)-
thioureido]-phenyl}-amide
87b 511 {4-[3-(S-Bromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-carbamic
acid hexyl ester
877 481 Hexanoic acid {4-[3-(5-bromo-2,4-dimethoxy-phenyl)-thioureido]-
phenyl }-amide
878 505 N-{4-[3-(5-Bromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-fluoro-
benzamide
$79 477 Furan-2-carboxylic acid {4-[3-(5-bromo-2,4-dimethoxy-phenyl)-
thioureido]-phenyl }-amide
880 501 N-{4-[3-(S~Bromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-
methyl-benzamide
88I 517 N-{4-[3-(5-Bromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-4-
methoxy-benzamide
882 395 N-{4-[3-(5-Chloro-2-ethoxy-4-methoxy-phenyl)-thioureido]-phenyl}-
acetamide
883 395 N-{4-[3-(S-Chioro-4-ethoxy-2-methoxy-phenyl)-thioureido]-phenyl}-
acetamide
884 423 N-{4-[3-(2-Butoxy-S-chloro-4-methoxy-phenyl)-thioureidoJ-phenyl}-
acetamide
885 423 N-{4-[3-(4-Butoxy-S-chloro-2-methoxy-phenyl)-thioureido]-phenyl}-
acetamide
886 457 N-{4-[3-(2-Benzyloxy-S-chloro-4-methoxy-phenyl)-thioureido]-phenyl}-
acetamide
887 457 N-{4-[3-(4-Benzyloxy-S-chloro-2-methoxy-phenyl)-thioureido]-phenyl}-
acetamide
888 421 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-4-methoxy-
phenyl)-thioureido]-phenyl }-amide
$89 424 2-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-5-methoxy-
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phenoxy }-acetamide
890 367 N-{4-[3-(5-Chloro-2-hydroxy-4-methoxy-phenyl)-thioureido]-phenyl}-
acetamide
891 367 N-{4-[3-(3-Chloro-4-methylsulfanyl-phenyl)-thioureido]-phenyl}-
acetamide
$92 4q.7 N-[4-(3-{3-Chloro-4-[methyl-(1-methyl-piperidin-4-yl)-amino]-phenyl}-
thioureido)-phenyl]-acetamide
893 426 N-(4-{3-[3-Chloro-4-(methyl-phenyl-amino)-phenyl]-thioureido}-
phenyl)-acetamide
894 509 N-['~-(3-{4-[(I-Benzyl-pyrrolidin-3-yl)-methyl-amino]-3-chloro-phenyl}-
thioureido)-phenyl]-acetamide
895 418 N-(4-{3-[3-Chloro-4-(cyclopentyl-methyl-amino)-phenyl]-thioureido}-
phenyl)-acetamide
896 433 N-[4-(3-{3-Chloro-4-[methyl-(1-methyl-pyrrolidin-3-yl)-amino]-
phenyi }-thioureido)-phenyl]-acetamide
$97 419 Furan-2-carboxylic acid {4-[3-(3-chloro-4-methylsulfanyl-phenyl)-
thioureido]-phenyl }-amide
898 447 N-{4-[3-(3-Chlora-4-methylsulfanyl-phenyl)-thioureido]-phenyl}-2-
fluoro-benzamide
899 465 N-{4-[3-(3-Chloro-4-methylsulfanyl-phenyl)-thioureido]-phenyl}-2,6-
difluoro-benzamide
900 445 N-{4-[3-(5-Chloro-2-methoxy-4-methyl-phenyl)-thioureido]-phenyl}-2-
fluoro-benzamide
901 441 N-{4-[3-(5-Chloro-2-methoxy-4-methyl-phenyl)-thioureido]-phenyl}-2-
methyl-benzamide
902 434 I1~2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-4-dimethylamino-
phenyl)-thioureido]-phenyl }-amide
903 444 N-{4-[3-(3-Chloro-4-dimethylamino-phenyl)-thioureido]-phenyl}-2-
fluoro-benzamide
904 517 [1,2,3]Thiadiazole-4-carboxylic acid [4-(3-{3-chloro-4-[methyl-(1
methyl-piperidin-4-yI)-amino]-phenyl}-thioureido)-phenyl]-amide
905 579 [I,2,3]Thiadiazole-4-carboxylic acid [4-(3-{4-[(I-benzyl-pyrrolidin-3
yl)-methyl-amino]-3-chloro-phenyl }-thioureido)-phenyl]-amide
906 527 N-C4-(3-{3-Chloro-4-[methyl-(I-methyl-piperidin-4-y1)-amino]-phenyl}-
thioureido)-phenyl]-2-fluoro-benzamide
907 435 [I,2,3]Thiadiazole-4-carboxylic acid {4-[3-(5-chloro-2-methoxy-4-
methyl-phenyl)-thioureido]-phenyl }-amide
90$ 589 N-[4-(3-{4-[(I-Benzyl-pyrrolidin-3-yl)-methyl-amino]-3-chloro-phenyl}-
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thioureido)-phenyl]-2-fluoro-benzamide
909 501 Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-
thioureido]-3-trifluoromethyl-phenyl }-amide
910 366 2-Fluoro-N-[4-(3-phenyl-thioureido}-phenyl]-benzamide
911 338 Furan-2-carboxylic acid [4-(3-phenyl-thioureido)-phenyl]-amide
912 356 [1,2,3]Thiadiazole-4-carboxylic acid [4-(3-phenyl-thioureido)-phenyl]-
amide
913 365 N-(4-{3-[3-Chloro-4-(1-hydroxy-ethyl)-phenyl]-thioureido}-phenyl)-
acetamide
914 435 [1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[3-chloro-4-(1-hydroxy-
ethyl)-phenyl]-thioureido}-phenyl)-amide
915 365 N-(4-{3-[3-Chloro-4-(2-hydroxy-ethyl)-phenyl]-thioureido}-phenyl)-
acetamide
916 445 N-(4-{3-[3-Chloro-4-(1-hydroxy-ethyl)-phenyl]-thioureido}-phenyl)-2-
fluoro-benzamide
917 417 Fui'an-2-carboxylic acid (4-{3-[3-chloro-4-(1-hydroxy-ethyl)-phenyl]-
thioureido }-phenyl)-amide
918 371 [1.2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-amino-phenyl)-
thioureido]-phenyl }-amide
919 501 Fui'an-2-c~boxylic acid {4-[3-(3-bromo-4-trifluoromethoxy-phenyl)-
thioureido]-phenyl }-amide
920 423 N-{4-[3-(3-tert-Butyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide
1025 440 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-chloro-3,5-dichloro-
phenyl)-thioureido]-phenyl }-amide
1026 485 N-{4-[3-(1-Benzofuran-2-yl-ethyl)-thioureido]-phenyl}-2-
trifluoromethyl-benzamide
1027 412 N-(4-Fluoro-phenyl)-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-
benzamide
1028 446 Isoquinoline-1-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-
thioureido }-phenyl)-amide
1029 468 Isoquinoline-1-carboxylic acid {4-[3-(1-benzofuran-2-yl-ethyl)-
thioureido]-phenyl }-amide
1030 506 Isoquinoline-1-carboxylic acid (4-{3-jl-(4-bromo-phenyl)-ethyl]-
thioureido}-phenyl)-amide
1031 453 Isoquinoline-1-carboxylic acid (4-{3-[1-(4-cyano-phenyl)-ethyl]-
thioureido}-phenyl)-amide
1032 435 Benzofuran-2-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-
thioureido }-phenyl)-amide
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1033 457 Benzofuran-2-carboxylic acid {4-[3-(1-benzofuran-2-yl-ethyl)-
thioureido]-phenyl }-amide
1034 495 Benzofuran-2-carboxylic acid (4-{3-jl-(4-bromo-phenyl)-ethyl]-
thioureido}-phenyl)-amide
1035 442 Benzofuran-2-carboxylic acid (4-{3-[1-(4-cyano-phenyl)-ethyl]-
thioureido}-phenyl)-amide
1036 446 Isoquinoline-3-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-
thioureido }-phenyl)-amide
1037 468 lsoquinoline-3-carboxylic acid {4-[3-(1-benzofuran-2-yl-ethyl)-
thioureido]-phenyl }-amide
1038 453 Isoquinoline-3-carboxylic acid (4-{3-[1-(4-cyano-phenyl)-ethyl]-
thioureido }-phenyl)-amide
1039 506 Isoquinoline-3-carboxylic acid (4-{3-(1-(4-bramo-phenyl)-ethyl]-
thioureido}-phenyl)-amide
1040 446 Quinaline-3-carboxylic acid (4-{3-[1-(4-fluora-phenyl)-ethyl]-
thioureido }-phenyl)-amide
1041 446 Quinoline-4-carboxylic acid (4-{3-(1-(4-fluora-phenyl)-ethyl]-
thioureido}-phenyl)-amide
1042 446 Quinoline-G-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-
thioureido }-phenyl)-amide
1043 44.6 Quinoline-8-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-
thioureido}-phenyl)-amide
1044 462 N-(4-{3-(1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-
trifluoromethyl-benzamide
1045 419 2-Cyana-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-
benzamide
1046 473 N-{4-[3-(3-Chloro-4-isobutoxy-phenyl)-thioureido]-phenyl}-2-fluoro-
benzamide
1047 414 2-~uoro-N-{4-[3-(3-fluoro-4-methoxy-phenyl)-thioureido]-phenyl}-
benzamide
1048 475 N-(4-{3-[3-Chloro-4-(2-methoxy-ethoxy)-phenyl]-thioureido}-phenyl)-2-
fluoro-benzamide
1049 398 2-~uoro-N-{4-(3-(3-fluaro-4-methyl-phenyl)-thioureido]-phenyl}-
benzamide
1050 464 2-~uoro-N-{4-[3-(4-methoxy-3-trifluoromethyl-phenyl)-thioureido]-
phenyl}-benzamide
1051 449 N-{4-[3-(2-Amino-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-2-
fluoro-benzamide
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1052 459 N-(4-{3-[I-(3-Chloro-4-methoxy-phenyl}-ethyl]-thioureido}-phenyl)-2-
fluoro-benzamide
1053 417 N-{4-[3-(5-Chloro-2-hydroxy-phenyl)-thioureido]-phenyl}-2-fluoro-
benzamide
1054 435 N-{4-[3-(1-Benzofuran-2-yl-ethyl)-thioureido]-phenyl}-2-fluoro-
benzamide
1055 448 2-Fluoro-N-{4-[3-(4-methyl-3-trifluoromethyl-phenyl)-thioureido]-
phenyl }-benzamide
1056 473 (S)-N-(4-{3-[I-(4-Bromo-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-
benzamide
1057 473 N-(4-{3-j(1R)-1-(4-Bromo-phenyl}-ethyl]-thioureidoy-phenyl)-2-fluoro-
benzamide
1058 494 2-Fluoro-N-(4-{3-j2-methoxy-4-(2,2,2-trifluoro-ethoxy)-phenyl]-
thioureido}-phenyl)-benzamide
1059 399 N-{4-[3-(2-Amino-5-fluoro-phenyl)-thioureido]-phenyl}-2-fluoro-
benzamide
1060 502 N-(4-{3-[1-(4-Dimethylsulfamoyl-phenyl)-ethyl]-thioureido}-phenyl)-2-
fluoro-benzamide
1061 542 2-Fluoro-N-[4-(3-{1-[4-(piperidine-1-sulfonyl)-phenyl]-ethyl}-
thioureido)-phenyl]-benzamide
1062 562 N-(4-{3-[2,4-Bis-(2,2,2-trifluoro-ethoxy)-phenyl]-thioureido}-phenyl)-
2-
fluoro-benzamide
1063 409 2-~uoro-N-{4-[3-((1S)-1-p-tolyl-ethyl)-thioureido]-phenyl}-benzamide
1064 409 2-Fluoro-N-{4-[3-((1R)-I-p-tolyl-ethyl)-thioureido]-phenyl}-benzamide
1065 394 2-~uoro-N-{4-[3-((IS)-1-phenyl-ethyl)-thioureido]-phenyl}-benzamide
1066 429 N-(4-{3-[(1R)-1-(4-Chloro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-
benzamide
1067 429 N-(4-{3-[(1S)-I-(4-Chloro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-
benzamide
1068 394 2-Fluoro-N-{4-[3-((1R)-I-phenyl-ethyl)-thioureido]-phenyl}-benzamide
1069 432 N-(4-{3-[1-(4-Cyano-phenyl)-ethyl]-thioureido}-phenyl)-2-methoxy-
benzannide
1070 447 N-{4-[3-(1-Benzofuran-2-yl-ethyl)-thioureido]-phenyl}-2-methoxy-
benzamide
1071 4$5 N-(4-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido}-phenyl)-2-methoxy-
benzamide
1072 419 3-Cyano-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-
benzarnide
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1073 N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-4-
462
trifluoromethyl-benzamide
1074 4-Cyano-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-
419
benzamide
1075 2-Fluaro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2,3,5,6-
469
tetramethyl-phenyl)-benzamide
1076 N-(4-{3-[1-(4-Cyano-phenyl)-ethylJ-thioureido}-2,5-dimethoxy-phenyl)-
480
2-fluoro-benzamide
10177 2-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2,5-
473
dimethoxy-phenyl)-benzamide
1078 N-{3,5-Dichloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-
530
phenyl}-2-fluoro-benzamide
1079 N-(3-Chloro-4-{3-[1-{4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-
447
fluoro-benzamide
1080 2,3,4,5-Tetrafluoro-N-{4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-3-
4$0
methyl-phenyl)-benzamide
10$1 2,4,5-Trifluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-3-
462
methyl-phenyl)-benzamide
1082 2-~uoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-3-methyl-
427
phenyl)-benzamide
1083 2-~uoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2-methoxy-5-
457
methyl-phenyl)-benzamide
1084 2-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-3-methoxy-
443
phenyl)-benzamide
1085 N-(2,6-Dibromo-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-
570
fluoro-benzamide
1086 2-~uoro-N-(4-{3-[i-(4-fluoro-phenyl)-ethyl]-thioureido}-2-
480
trifluoromethyl-phenyl)-benzamide
1087 N-(4-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido}-2-trifluoromethyl-
541
phenyl)-2-fluoro-benzamide
1088 N-(4-{3-[1-(4-Cyano-phenyl)-ethyl]-thioureido}-2-trifluoromethyl-
487
phenyl)-2-fluoro-benzamide
1089 N-{4-[3-(1-Benzofuran-2-yl-ethyl)-thioureido]-2-trifluoromethyl-
503
phenyl}-2-fluoro-benzamide
1090 N-(2-Chloro-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-
447
fluoro-benzamide
1091 N-{2-Chloro-4-{3-[1-(4-cyano-phenyl)-ethyl]-thioureido}-phenyl)-2-
454
fluoro-benzamide
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1092 437 N-(2-Cyano-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-
fluoro-benzamide
1093 498 N-(4-{3-[1-(4-Bromo-phenyl}-ethyl]-thioureido}-2-cyano-phenyl)-2-
fluoro-benzamide
1094 445 N-(2-Cyano-4-{3-[1-(4-cyano-phenyl)-ethyl]-thioureido}-phenyl)-2-
fluoro-benzamide
1095 460 N-{4-[3-(I-Benzofuran-2-yl-ethyl)-thioureido]-2-cyano-phenyl}-2-
fluoro-benzamide
1096 517 N-(Z-Benzoyl-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-
fluoro-benzamide
1097 427 2-~uoro-N-(4-{3-[1-(4-fluoro-phenyl}-ethyl]-thioureido}-2-methyl-
phenyl)-benzamide
1098 487 N-(4-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido}-2-methyl-phenyl)-2-
fluoro-benzamide
1099 434 N-(4-{3-[1-(4-Cyano-phenyl)-ethyl]-thioureido}-2-methyl-phenyl)-2-
fluoro-benzamide
1100 449 N-{4-[3-(1-Benzofuran-2-yl-ethyl)-thioureido]-2-methyl-phenyl}-2-
fluoro-benzamide
1101 456 N-(2-Dimethylamino-4-{3-[l-(4-fluoro-phenyl)-ethyl]-thioureido}-
phenyl)-2-fluoro-benzamide
1102 526 N-(2-Benzyloxy-4-{3-[1-(4-cyano-phenyl)-ethyl]-thioureido}-phenyl)-2-
fluoro-benzamide
1103 519 N-(2-Benzyloxy-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-
fluoro-benzamide
1104 603 N-[4-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido}-2-(2-morpholin-4-yl-
ethoxy)-phenyl]-2-fluoro-benzamide
1105 603 N-[4-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido}-2-(2-morpholin-4-yl-
ethoxy)-phenyl]-2-fluoro-benzamide
1106 542 2-~uoro-N-[4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2-(2-
morpholin-4-yl-ethoxy)-phenyl]-benzamide
1107 485 N-(2-Butoxy-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-
fluoro-benzamide
1108 492 N-(2-Butoxy-4-{3-[l-(4-cyano-phenyl)-ethyl]-thioureido}-phenyl)-2-
fluoro-benzamide
1109 589 N-[4-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido}-2-(2-diethylamino-
ethoxy)-phenyl]-2-fluoro-benzamide
1110 528 N-(2-(2-Diethylamino-ethoxy)-4-{3-[1-(4-fluoro-phenyl)-ethyl]-
thioureido }-phenyl)-2-fluoro-benzamide
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1111 589 N-[~-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido}-2-(2-diethylamino-
ethoxy)-phenyl]-2-fluoro-benzamide
1112 457 N-(2-Ethoxy-4-{3-[1-(4-fluora-phenyl)-ethyl]-thioureido}-phenyl)-2-
fluoro-benzamide
1113 464 N-(~-{3-[1-(4-Cyano-phenyl)-ethyl]-thioureido}-2-ethoxy-phenyl)-2-
fluoro-benzamide
1114 468 2-Fluoro-N-j4-{3-jl-(4-fluoro-phenyl)-ethyl]-thioureido}-2-(2-nitrilo-
ethoxy)-phenylJ-benzamide
1115 475 N-j4-{3-[I-(4-Cyano-phenyl)-ethyl]-thioureido}-2-(2-nitrilo-ethaxy)-
phenyl]-2-fluoro-benzamide .
1116 443 2-~uoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2-methoxy-
phenyl)-benzamide
1117 489 2-Fluoro-N-(5-{3-[1-(4-fluoro-phenyl)-ethylJ-thioureido}-biphenyl-2-
yl)-
benzamide
1118 514 Isoquinoline-1-carboxylic acid (4-{3-[1-(4-fluoro-phenyl}-ethylJ-
thioureido }-2-trifluoromethyl-phenyl)-amide
1119 Benzofuran-2-carboxylic acid (4-{3-[1-(4.-fluoro-phenyl)-ethyl]-
503
thioureido }-2-trifluoromethyl-phenyl)-amide
1120 Isoquinoline-3-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl}-
514
thioureido}-2-trifluoromethyl-phenyl)-amide
1121 Isoquinoline-1-carboxylic acid (2-cyano-4-{3-[1-(4-fluoro-phenyl)-
471
ethyl]-thioureido}-phenyl)-amide
1122 Benzofuran-2-carboxylic acid (2-cyano-4-{3-[1-(4-fluoro-phenyl)-ethyl]-
460
thioureido}-phenyl)-amide
1123 Isoquinoline-3-carboxylic acid (2-cyano-4-{3-j1-(4-fluoro-phenyl)-
471
ethyl]-thioureido}-phenyl)-amide
1124 Isoquinoline-1-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-
460
thioureido}-2-methyl-phenyl)-amide
1125 Benzofuran-2-carboxylic acid (4-{3-[l-(4-fluoro-phenyl)-ethyl]-
449
thioureido}-2-methyl-phenyl)-amide
1126 Isoquinoline-3-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-
460
thioureido}-2-methyl-phenyl)-amide
1127 PYI'~ine-2-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-
396
thioureido}-phenyl)-amide
1128 Thiophene-2-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-
401
thioureido }-phenyl)-amide
1129 Thiophene-3-carboxylic acid (4-{3-[1-(~-fluoro-phenyl)-ethyl]-
401
thioureido}-phenyl)-amide
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1130 500 2-Isopropyl-thiazole-4-carboxylic acid {4-[3-(4-chloro-3-
trifluoromethyl-phenyl)-thioureido]-phenyl
}-amide
1131 2-Isopropyl-thiazole-4-carboxylic acid
466 {4-[3-(3,5-dichloro-phenyl)-
thioureido]-phenyl}-amide
1132 2-Isopropyl-thiazole-4-carboxylic acid
466 {4-[3-(3,4-dichloro-phenyl)-
thioureido]-phenyl }-amide
1133 2-Isopropyl-thiazole-4-carboxylic acid
534 {4-[3-(3,5-bis-trifluoromethyl-
phenyl)-thioureido]-phenyl}-amide
1134 2-Butyl-thiazole-4-carboxylic acid {4-[3-(3,4-dichloro-phenyl)-
480
thioureido]-phenyl}-amide
1135 2-Butyl-thiazole-4-carboxylic acid {4-[3-(4-chloro-3-trifluoromethyl-
514
phenyl)-thioureido]-phenyl }-amide
1136 2-Butyl-thiazole-4-carboxylic acid {4-[3-(3,5-dichloro-phenyl)-
480
thioureido]-phenyl}-amide
1137 2-Butyl-thiazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl-
548
phenyl)-thioureido]-phenyl }-amide
1138 2-Methyl-thiazole-4-carboxylic acid {4-[3-(3,S-dichloro-phenyl)-
438
thioureido]-phenyl}-amide
1139 2-Methyl-thiazole-4-carboxylic acid {4-[3-(3,4-dichloro-phenyl)-
438
thioureido]-phenyl}-amide
1140 z-Methyl-thiazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl-
505
phenyl)-thioureido]-phenyl }-amide
1141 2-1'henyl-thiazole-4-carboxylic acid {4-[3-(4-chloro-3-trifluoromethyl-
534
phenyl)-thioureido]-phenyl}-amide
1142 2-Phenyl-thiazole-4-carboxylic acid {4-[3-(3,5-dichloro-phenyl)-
500
thioureido]-phenyl}-amide
1143 2-phenyl-thiazole-4-carboxylic acid {4-[3-(3,4-dichloro-phenyl)-
500
thioureido]-phenyl }-amide
1144 2-Phenyl-thiazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl-
568
phenyl)-thioureido]-phenyl}-amide
1145 2-Fluoro-N-{4-[3-(1-thiazol-2-yl-ethyl)-thioureido]-phenyl}-benzamide
401
1146 5$8 2-~uoro-N-[4-(3-{1-[Z-(toluene-4-sulfonyl)-1H-indol-2-yl]-eWyl}-
thioureido)-phenyl]-benzamide
1147 446 2-~uoro-N-{4-[3-(1-quinolin-2-yl-ethyl)-thioureido]-phenyl}-benzamide
1148 446 2-~uoro-N-{4-[3-(1-quinolin-4-yl-ethyl)-thioureido]-phenyl}-benzamide
1149 446 2-~uoro-N-{4-[3-(1-isoquinolin-3-yl-ethyl)-thioureido]-phenyl}-
benzamide
1150 446 2-Fluoro-N-{4-[3-(1-isoquinolin-1-yl-ethyl)-thioureido]-phenyl}-
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benzamide
1151 446 2-~uoro-N-{4-[3-(1-quinolin-b-yl-ethyl)-thioureido]-phenyl}-benzamide
1152 446 2-~uoro-N-{4-[3-(1-quinolin-3-yl-ethyl)-thioureidoJ-phenyl}-
benzarnide
1153 413 2-Methoxy-N-{4-[3-(1-thiophen-3-yl-ethyl)-thioureido]-phenyl}-
benzamide
EXAMPLE 921 (METHOD 33)
[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-{3,S-dichloro-phenyl)-thioureido]-
phenyl}-amide
To a solution of 3,5-dichloroaniline (0.16 g) in tetrahydrofuran (20 mL) is
added
freshly prepared 1,1'-thiocarbonyl-di-(1,2,4)-triazole (0.20 g) and the
mixture is
stirred for approximately 30 minutes at room temperature. [1,2,3]-Thiadiazole-
4-
carboxylic acid (4-amino-phenyl) amide (0.22 g) is added to the reaction flask
and
the mixture is stirred for approximately 6 hours. The solvent is then removed
by
evaporation under reduced pressure and warm acetonitrile (3 mL) is added.
After 15
hours the mixture is filtered and the collected precipitate is washed with
acetonitrile
then diethyl ether, and air dried to provide the desired product as a white
powder.
[M+H] 424.
Using the above procedure and appropriate starting materials the following
compounds were prepared:
EX. M+H COMPOUND NAME
NO.
922 465 N-{4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]-phenyl}-3-
fluoro-
benzamide
923 477 N-{4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]-phenyl}-2-
methoxy-
benzamide
924 465 N-{4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]-phenyl}-2-
lluoro-
benzamide
925 477 N-{4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]-phenyl}-3-
methoxy-
benzamide
926 399 N-{~-[3-(3,5-Dichloro-2-methoxy-4-methyl-phenyl)-thioureido]-
phenyl}
-acetamide
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927 365 N-{4-[3-{3-Chloro-4-methoxy-5-methyl-phenyl)-thioureido]-phenyl}-
acetamide
928 331 N-{4-[3-(2-Nitro-phenyl)-thioureido]-phenyl}-acetamide
929 331 N-{4-[3-{4-Nitro-phenyl)-thioureido]-phenyl}-acetamide
930 477 N-{4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]-phenyl}-4-methoxy-
benzamide
931 351 N-{4-[3-(2-Chloro-5-methoxy-phenyl)-thioureido]-phenyl}-acetamide
932 428 2-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy}-
acetamide
933 443 {4-[3-(4-Acetylamino-phenyl)-thioureido]-2,6-dichioro-phenoxy}-acetic
acid methyl ester
934 457 {4-[3-(4-Acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy}-acetic
acid ethyl ester
935 447 N-{4-[3-(3,5-Dichloro-4-phenoxy-phenyl)-thioureido]-phenyl}-acetarnide
936 410 N-(4-{3-[3,5-Dichloro-4-(2-nitrilo-ethoxy)-phenyl]-thioureido}-phenyl)-
acetamide
937 485 {4-I3-(4-Acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy}-acetic
acid tert-butyl ester
93$ 469 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-dichloro-2-methoxy-4-
methyl-phenyl)-thioureido]-phenyl }-amide
939 335 N-{4-[3-(3-Chloro-4.-methyl-phenyl)-thioureido]-phenyl}-acetamide
940 335 N-{4-[3-(5-Chloro-2-methyl-phenyl)-thioureido]-phenyl}-acetamide
941 703 N-{4-[3-(4-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-
phenyldisulfanyl}-3-chloro-phenyl)-thioureido]-phenyl}-acetamide
942 369 N-{4-[3-(3,5-Dichloro-4-methyl-phenyl)-thioureido]-phenyl}-acetamide
943 598 N-{4-[3-(3,5-Diiodo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-
acetamide
944 504 N-{4-[3-(3,5-Dibromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-
acetamide
945 317 N-{4-[3-(6-Methoxy-pyridin-3-yl)-thioureido]-phenyl}-acetamide
946 347 N-{4-[3-(2,6-Dimethoxy-pyridin-3-yl)-thioureido]-phenyl}-acetamide
947 457 Acetic acid 2-{4-[3-(4-acetylamino-phenyl)-thioureido]-2,6-dichloro-
phenoxy}-ethyl ester
948 365 4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-benzoic acid
949 346 N-{4-[3-(3-Chloro-4-cyano-phenyl)-thioureido]-phenyl}-acetamide
950 512 N-(4-{3-[5-Chloro-2-(4-chloro-phenoxy)-4-pyrrol-1-yl-phenyl]-
thioureido}-
phenyl)-acetamide
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951 355 N-{4-[3-(3,4-Dichloro-phenyl)-thioureido]-phenyl}-acetamide
952 339 N-{4-[3-(3-Chloro-4-fluoro-phenyl)-thioureido]-phenyl}-acetamide
953 447 N-{4-[3-(3-Chloro-4-iodo-phenyl)-thioureido]-phenyl}-acetamide
954 400 N-{4-[3-(4-Bromo-3-chloro-phenyl)-thioureido]-phenyl}-acetarnide
955 424 N-[4-(3-{4-[Bis-(2-hydroxy-ethyl)-amino]-3-chloro-phenyl}-thioureido)-
phenyl]-acetamide
956 434 N-(4-{3-[3-Chloro-4-(hexyl-methyl-amino)-phenyl]-thioureido}-phenyl)-
acetamide
957 406 N-(4-{3-[3-Chioro-4-(isobutyl-methyl-amino)-phenyl]-thioureido}-
phenyl)-
acetamide
958 389 N-{4-[3-(3-Chloro-4-trifluoromethyl-phenyl)-thioureido]-phenyl}-
acetamide
959 441 Furan-2-carboxylic acid {4-[3-(3-chloro-4-trifluoromethyl-phenyl=
thioureido]-phenyl}-amide
960 459 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-4-trifluoromethyl-
phenyl)-thioureido]-phenyl}-amide
961 469 N-{4-[3-(3-Chloro-4-trifluoromethyl-phenyl)-thioureido]-phenyl}-2-
fluoro-
benzamide
962 435 N-{4-[3-(3,4-Dichloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide
963 407 Furan-2-carboxylic acid {4-[3-(3,4-dichloro-phenyl)-thioureido]-
phenyl}-
amide
964 425 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,4-dichloro-phenyl)-
thioureido]-phenyl}-amide
965 480 N-{4-[3-(4-Bromo-3-chloro-phenyl)-thioureido]-phenyl}-2-fluoro-
benzamide
966 527 N-{4-[3-(3-Chlora-4-iodo-phenyl)-thioureido]-phenyl}-2-fiuoro-
benzamide
967 452 Furan-2-carboxylic acid {4-[3-(4-bromo-3-chloro-phenyl)-thioureido]-
phenyl }-amide
968 499 Furan-2-carboxylic acid {4-[3-(3-chloro-4-iodo-phenyl)-thioureido]-
phenyl}-amide
969 391 Furan-2-carboxylic acid {4-[3-(3-chloro-4-fluoro-phenyl)-thioureido]-
phenyl}-amide
970 470 [I,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-bromo-3-chloro-phenyl)-
thioureido]-phenyl}-amide
971 517 C1~2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-4-iodo-phenyl)-
thioureido]-phenyl }-amide
972 419 N-{4-[3-(3-Chloro-4-fluora-phenyl)-thioureido]-phenyl}-2-fluoro-
benzamide
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973 409 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-chloro-4-fluoro-phenyl)-
thioureido]-phenyl }-amide
974 388 N-{4-[3-(3-Chloro-4-isoxazol-5-yl-phenyl)-thioureido]-phenyl}-
acetamide
975 387 N-(4-{3-[3-Chloro-4.-(1H-pyrazol-3-yi)-phenyl]-thioureido}-phenyl)-
acetamide
976 355 N-{4-[3-(2,3-Dichloro-phenyl)-thioureido]-phenyl}-acetamide
977 435 N-f 4-[3-(2,3-Dichloro-phenyl)-thioureido]-phenyl}-2-lluoro-benzamide
978 407 Furan-2-carboxylic acid {4-[3-(2,3-dichloro-phenyl)-thioureido]-
phenyl}-
amide
979 425 (1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2,3-dichloro-phenyl)-
thioureido]-phenyl }-amide
980 355 N-{4-[3-(2,5-Dichloro-phenyl)-thioureido]-phenyl}-acetamide
981 435 N-{4-[3-(2,5-Dichloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide
982 407 Furan-2-carboxylic acid {4-[3-(2,5-dichloro-phenyl)-thioureido]-
phenyl}-
amide
983 355 N-{4-[3-(3,5-Dichloro-phenyl)-thioureido]-phenyl}-acetamide
984 435 N-{4-[3-(3,5-Dichloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide
985 407 Furan-2-carboxylic acid {4-[3-(3,5-dichloro-phenyl)-thioureido]-
phenyl}-
amide
986 390 N-{4-[3-(3,4,5-Trichloro-phenyl)-thioureido]-phenyl}-acetamide
9$7 470 2-Fluoro-N-{4-[3-(3,4,5-trichloro-phenyl)-thioureido]-phenyl}-
benzamide
9$$ q.q.2 Furan-2-carboxylic acid {4-[3-(3,4,5-trichloro-phenyl)-thioureido]-
phenyl}-
amide
989 460 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3,4,5-trichloro-phenyl)-
thioureido]-phenyl}-amide
990 458 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-4-isoxazol-5-y1-
phenyl)-thioureido]-phenyl }-amide
991 457 [1,2,3]Thiadiazole-4.-carboxylic acid(4-{3-[3-chloro-4-(1H-pyrazol-3-
yl)-
phenyl]-thioureido}-phenyl)-amide
992 391 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-phenyl)-
thioureido]-
phenyl}-amide
993 373 Furan-2-carboxylic acid {4-[3-(3-chloro-phenyl)-thioureido]-phenyl}-
amide
994 401 N-{4-j3-(3-Chloro-phenyl)-thioureido]-phenyl}-2-lluoro-benzamide
995 373 Furan-2-carboxylic acid {4-[3-(4-chloro-phenyl)-thioureido]-phenyl}-
amide
996 401 N-{4-[3-(4-Chloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide
997 391 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-chloro-phenyl)-
thioureido]-
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phenyl }-amide
998 401 N-{4-[3-(2-Chloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide
999 396 3-(3-{4-[(Furan-2-carbonyl)-amino]-phenyl}-thioureido)-benzoic acid
methyl ester
1000 424 3-{3-[4-(2-Fluoro-benzoylamino)-phenyl]-thioureido}-benzoic acid
methyl
ester
1001 414 3-(3-{4-[([1,2,3]Thiadiazole-4-caxbonyl)-amino]-phenyl}-thioureido)-
benzoic acid methyl ester
1002 409 N-[4-[[[[3-(Aminocarbonyl)phenyl]amino]thioxomethyl]amino]phenyl]-2-
fluoro-benzamide
I003 373 Furan-2-carboxylic acid {4-[3-(2-chloro-phenyl)-thioureido]-phenyl}-
amide
1004 381 Furan-2-carboxylic acid {4-[3-(3-carbamoyl-phenyl)-thioureido]-
phenyl}-
amide
1005 399 (1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-carbamoyl-phenyl)-
thioureido]-phenyl}-amide
1006 391 (1,2,3)Thiadiazole-4-carboxylic acid {4-[3-(2-chloro-phenyl)-
thioureido]-
phenyl }-amide
1007 356 Furan-2-carboxylic acid {4-[3-(3-fluoro-phenyl)-thioureido]-phenyl}-
amide
1008 383 Furan-2-carboxylic acid {4-[3-(3-vitro-phenyl)-thioureido]-phenyl}-
amide
1009 411 2-Fluoro-N-{4-[3-(3-vitro-phenyl)-thioureido]-phenyl}-benzamide
1010 422 Furan-2-carboxylic acid {4-[3-(3-trifluoromethoxy-phenyl)-thioureido]-
phenyl}-amide
1011 450 2-Fluoro-N-{4-[3-(3-trifluoromethoxy-phenyl)-thioureido]-phenyl}-
benzamide
1012 3$4 2-Fluoro-N-{4-[3-(3-fluoro-phenyl)-thioureido]-phenyl}-benzamide
1013 410 3-{3-[4-(2-Fluoro-benzoylamino)-phenyl]-thioureido}-benzoic acid
1014 382 3-(3-{4-[(Furan-2-carbonyl)-amino]-phenyl}-thioureido)-benzoic acid
1015 408 N-{4-[3-(3-Acetyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide
1016 502 N-{4-[3-(3-Butylsulfamoyl-phenyl)-thioureido]-phenyl}-2-fluoro-
benzamide
1017 3$0 Fui'~-2-carboxylic acid {4-[3-(3-acetyl-phenyl)-thioureido]-phenyl}-
amide
1018 447 Furan-2-carboxylic acid (4-{ 3-[3-(2-hydroxy-ethanesulfonyl)-phenyl]-
thioureido}-phenyl)-amide
1019 475 2-Fluoro-N-(4-{3-[3-(2-hydroxy-ethanesulfonyl)-phenyl]-thioureido}-
phenyl)-benzamide
1020 474 Furan-2-carboxylic acid {4-[3-(3-butylsulfamoyl-phenyl)-thioureido]-
phenyl }-amide
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EXAMPLE 1021 (METHOD 57)
1-(4-Fluoro-phenyl)-2-methyl-propan-1-0l
To solution of 4-fluorobenzaldehyde (2.0 g} in diethyl ether (40 mL) at O
°C is
added dropwise isopropylmagesium bromide {2.0 M, 9.6 mL) with stirnng. After
1.5
hours the reaction is quenched with aqueous ammonium chloride and extracted
with
diethyl ether. The diethyl ether extracts are washed with saturated sodium
chloride,
dried over anhydrous magnesium sulfate, flitered and evaporated to give an
oil. The
oil is purifed by silica gel chromatography eluting with 10% dichloromethane-
hexanes to give the product, a yellow oil ( 1.76 g}.
EXAMPLE 1022 (METHOD 58)
1-(4-Fluoro-phenyl)-2-methyl-propan-1-one
To a solution of 1-(4-Fluoro-phenyl)-2-methyl-propan-1-of (1.6 g) in acetone
(10
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 1023 (METHOD 59)
3-Dimethylamino-S-trifiuoromethyl-benzonitrile
To a solution of 3-dimethylamino-5-trifluoromethylbromobenzene (7.3 g) in N,N-
dimethylformamide (20 mL} is added cuprous cyanide (2.7 g) and the reaction
heated
at reflux for 12 hours. The reaction is diluted with water (40 mL) and
dichloromethane is added. The dichloromethane fraction is washed with
concentrated
ammonium hydroxide, then water. The solution is dried over anhydrous magnesium
sulfate, filtered and concentrated to give a yellow solid which is
recrystallized from
hexanes to give a yellow solid, {4.7 g).
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The foregoing compounds were tested for activity as herpes virus inhibitors.
HUMAN CYTOMEGALOVIRUS
Yield assay. Monolayer cultures of human foreskin fibroblasts are infected
with
HCMV wild-type, typically at a multiplicity of infection equal to 0.2, in the
presence
of inhibitor compound (varying concentrations). At three days post-infection,
total
virus produced in these cultures (i.e. virus yield) is assessed by harvesting
and titering
the virus in 12-well plates of cultured human foreskin fibroblasts (done in
the
absence of inhibitor). Plaques are quantified at 2 weeks post-infection. An
inhibitor
of HCMV is identified by the reduction in titer of virus yield in the
presence,
compared to the titer in the absence of compound. In this assay, the relative
anti
HCMV activity of an inhibitor is typically determined by calculating the IC50
or
IC90 value, that is, the amount of compound required to reduce the virus yield
by
50% or 90%, respectively. Table I describes ICso data for compounds tested
against
HCMV.
Microtiter plate assay. Ninety-six well plate cultures of human foreskin
fibroblasts are infected in the presence of inhibitor compound with a HCMV
recombinant mutant virus whose genome contains the prokaryotic beta-
glucuronidase
gene (Jefferson, R. A., S. M. Burgess, and D. Hirsh. 1986. Beta-glucuronidase
from
Escherichia coli as a gene fusion marker. Proc. Natl. Acad. Sci. USA 83:8447-
8451)
whose expression is controlled by a viral promoter. An example of such a virus
is
RV 145 {Jones, T. R., V. P. Muzithras, and Y. Gluzman. 1991. Replacement
mutagenesis of the human cytomegalovirus genome: US 10 and US 11 gene products
are nonessential. J. Viroi. 65:5860-5872). Since it is under the control of a
viral
promoter, beta-glucuronidase expression is an indirect indicator of growth and
replication of HCMV in this assay. At 96 hours post-infection, the infected
cell
lysates are prepared (using 50mM sodium phosphate [pH7.0] containing 0.1 %
Triton
X-100 and 0.1% sarkosyl) and assayed for beta-glucuronidase activity using a
substrate for the enzyme which when cleaved yields either a product which can
be
measured colorimetrically in a spectrophotometer or fluorescently in a
microfluorimeter. Examples of such substrates are p-nitrophenyl-beta-D-
glucuronide
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and methylumbelliferylglucuronide, respectively. The presence of an antiviral
compound is indicated by the reduced expression of the HCMV genome resident
beta-glucuronidase gene, compared to the absence of inhibitor. Thus, the
generation
of the chromophore or fluorophore product in this assay is correspondingly
reduced.
Data from this assay generated using varying amounts of inhibitor compound is
also
used to estimate the ICSO of an inhibitor compound.
HSV antiviral (ELISA) assay
Vero cells (ATCC #CCL-81) are plated on 96-well tissue culture plates at
3.5x104
cells per 100p1 tissue culture DMEM (Dulbecco's modified Eagle media)
supplemented with 2% fetal bovine serum (FBS) in each well. After overnight
incubation @ 37°C (in 5% COZ) and 30 minutes prior to infection with
HSV-1
(multiplicity of infection equal to 0.006), cells are either untreated, or
treated with
I S test compound (multiple concentrations) or reference standard drug
control. After
approximately 24 hours post-infection incubation C 37°C (in S% C02),
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 f3-galactosidase activity by quantifying the generation of the 4-
methyl
umbelliferone fluorescent cleavage product after addition of the methyl
umbelliferyl-
!3-D-galactaside (Sigma #M1633) substrate on a microfluorimeter (365nm for
excitation and 450nm for emission). Antiviral activity (ICso) of the test
compound is
determined by comparing the flourescence obtained in absence of compound to
that
obtained in the presence of compound. Data is shown in Table I.
VZV antiviral (ELISA) assay
For the generation of stock VZV to be used in the assay, VZV strain Ellen
(ATCC
#VR-1367) is used to infect human foreskin fibroblast (HFF) cells at low
multiplicity
(less than 0.1) and incubated overnight at 37°C in 5% C02. After the
overnight
incubation, the mixture of uninfected and VZV-infected HFF infected cells are
then
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harvested and added to each well of 96-well plates (3.5x10' cells in 100 pl
DMEM
supplemented with 2% FBS) which contain test compound or the reference
standard
drug control (in 100pI DMEM supplemented with 2% FBS per well). These cells
are
incubated for three days at 37°C in 5°lo CO2, then fixed for
ELISA assay. The
primary antibody is marine anti-VZV glycoprotein II monoclonal antibody
(Applied
Biosystems, Inc. #13-I45-100) and the secondary antibody is goat anti-mouse
IgG
linked to 13-galactosidase. Thus the extent of viral replication is determined
by
assessing 13-galactosidase activity by quantifying the generation of the 4-
methyl
umbelliferone fluorescent cleavage product after addition of the methyl
umbelliferyl-
13-D-galactoside (Sigma #M1633) substrate on a microfluorimeter (365nm for
excitation and 450nm for emission). Antiviral activity (ICso) of the test
compound is
determined by comparing the flourescence obtained in absence of compound to
that
obtained in the presence of compound. Data is shown in Table I.
Table I
ExampleIC50 (ug/ml) ICSO IC50 (ug/ml)
% inhibition
HSV l0uglml (ug/ml)HCMV
VZV VZV
86 >10 32 >10 0.04
88 >10 .03 0.013
90 >10 0.07
91 >10 6 >10 0.018
144. 7 10
145 2 51 >I5 >10
146 >IO 14 >10 >10
I47 10 42 >10 >50
153 2 8 >10 >10
154 4 23 >10 10
155 5 22 >10 5
158 4 52 >15 >IO
159 >10 62 >10 >10
160 2.5 27 >IO >10
16I 3 113 5 >10
163 3 30 >10 7
166 9 30 >10 >10
167 2 0 70 3.8 9
168 3 >10 2.5
169 3 26 >10 4
170 >10 32 >10 0.2
172 >10 25 >10 >10
173 >10 31 >10 0.08
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Example iC50 (ug/ml) IC50 ICSO (uglml)
% inhibition
HSV lOugJm1 (ug/ml) HCMV
VZV VZV
174 50 8 >10 6
175 2 24 >10 >10
200 >10 SS >1S 0.02
201 >10 78 8 0.023
224 3.5 30 > I0 0. 8
22S 1 30 >10 >10
230 >10 >10 0.015
233 >10 30 >10 0.09
236 >IO 40 >10 0.7
237 >10 I7 >10 0.02
246 > 10 37 4 0.05
249 > 10 59 > 10 0.4
264 >I0 28 >10 >10
279 >10 >10 >10
280 >10 >10 >10
281 >10 3I >10 >10
288 >10 30 >10 4
323 3 4S >10 0.03
330 >20 29 >10 0.15
331 1.8 98 5 2
341 2 50 >10 0.15
344 4 72 7 0.25
350 >10 50 >10 1
351 3 90 3.S 0.3
352 3 51 >10 0.6
353 0.6 86 7 0.04
354 0.8 75 7 2
361 8 26 >10 0.25
365 10 75 5 0.035
368 >10 20 >10 0.35
371 >10 45 >10 >10
376 3 83 7 0. g
378 >10 31 >10 0.033
379 >10 27 >10 >10
391 8 97 6 0.019
396 >10 26 >10 0.7
398 >10 5 >10 0.13
403 6 108 > 15 0.09
406 >10 28 >10 0.12
409 >10 5 >10 2
411 8 99 2 0.024
413 5 103 S 0.081
416 >10 87 >15 0.25
421 8 >10 0.75
422 5 69 >10 0.058
424 3 103 0.7 0.09
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Example ICSO (ug/ml) IC50 ICSO (ug/ml)
% inhibition
HSV l0ug/ml (uglml)HCMV
VZV VZV
430 >10 >10 0.4
431 >10 >10 0.06
435 10 94 0.9 0.08
436 10 >10 0.15
438 5 73 1.5 3
439 9 46 >10 0.5
440 1 9 0.3
441 >I0 >10 0.17
445 10 >10 0.I5
446 10 >10 0.7
447 >10 >10 >10
449 >10 >10 1.6
450 >10 >10 0.05
451 8 >10 0.15
453 >10 3 0.07
455 >10 30 >10 0.3
456 >10 12 >10 0.07
457 >10 26 >10 0.019
462 >10 6 >10 1
464 >10 25 >10 0.15
466 >10 93 >I0 0.0I1
467 >10 93 >15 0.12
468 >10 50 >10 0.06
469 >10 54 >10 0.1
470 0.6 I7 >10 0.7
472 >10 31 >10 0.8
473 >10 40 >10 0.3
474 >10 22 >l0 1
478 >10 31 >10 0:4
479 >10 30 >10 0.1
481 >10 32 >10 0.5
482 9 33 >10 0.3
485 >10 11 >10 0.03
486 >10 22 >10 0.045
488 >10 13 >10 I.2.
489 5 99 3.5 0.17
494 >10 6 >10 3.5
495 >10 27 >10 3
500 >10 48 >10 0.021
501 >IO 10 >10 0.032
503 8 64 >10 0.053
505 10 79 8 0.2
508 >10 7 >10 O.OI3
509 >10 31 >10 0.03
510 8 19 >10 0.04
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Example IC50 (ug/ml)% inhibitionICSO IC50 (ug/ml)
HSV l0ug/ml (ug/ml) HCMV
VZV VZV
513 >10 10 >10 0.011
516 >IO 7 >10 0.04
521 10 97 3 0.04
522 >10 32 >10 0.025
524 4 95 2 O.OSS
526 >10 22 2.5 3
528 3.2 107 5 0.25
530 5 9d 6 0.15
532 >i0 6 0.009
534 7 >10 0.05
535 >10 >10 0.016
537 9 10 0.003
539 >10 >10 0.036
541 7 >10 0.017
542 >10 >10 0.0011
544 >10 >10 0.02
545 3 7 O.OI2
546 1.7 7 0007
547 >10 10 0.006
548 >10 >10 0.008
550 >10 >10 0.013
551 >10 >10 0.043
554 >10 I.5 0.01
555 ' >10 4 0.008
556 >10 >7.5 0.006
557 >10 >10 0.006
558 7 >10 0.05
559 >10 >10 O.OI2
560 >10 >10 0.008
561 >10 8 0.05
562 >10 8 0.004
564 >10 S 0.027
565 >10 0.22 0.01
571 >10 0.013
572 >10 0.0078
573 >10 0.05
574 >10 0.089
575 2 0.017
579 6 0.05
581 >10 0.01
582 8 0.01
584 >10 0.0026
585 >10 0.015
587 >10 0.005
588 >10 0.36 0.03
590 >10 1 0.12
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ExampleICSO (uglml) ~o inhibitionIC50 ICSO (ug/ml}
HSV l0ug/ml (uglml) HCMV
VZV VZV
592 >10 2 0.049
594 >10 >lU 0.011
595 >10 3 0.022
597 >10 >10 0.008
599 > 10 > 10 0.005
6~ >10 >10 0.012
601 >10 >10 0.0011
602 > I 0 > 10 0.0015
603 > 10 > 10 >0.5
604 > 10 10 0.025
605 > 10 10 0.062
606 >10 >I0 0.0023
607 8 > 10 0.09
611 >10 0.5
612 1 0.049
613 >10 0.011
614 7 0.024
615 >10 0.005
617 >10 0.013
618 >10 0.0016
624 >10 0.002
626 10 >10 0.07
627 10 >10 0.014
630 >10 4 0.4
631 6 6 0.15
635 10 4 0.15
637 >10 >10 0.014
638 >10 >10 0.01
639 >10 >10 0:07
644 >10 8 0.03
645 >10 10 0.003
646 >10 2.5 0.03
647 > 10 0.1 0.007
648 >I0 0.01
650 > 10 0.05
651 >10 0.03
652 >10 0.03
654 >10 0.07
655 >10 0.01
657 6 0.04
662 > 10 0.03
663 >10 0.01
665 5 0.02
667 8 0.03
668 >10 0.009
670 > 10 0.02
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ExampleICSO (ug/ml) % inhibition IC50 (ug/ml)
IC50
HSV l0ug/ml (ug/ml) HCMV
VZV VZV
671 > 10 0.005
674 >10 0.006
675 > 10 0.05
676 >10 0.013
678 >10 0.005
679 10 0.01
681 >10 0.02
682 >10 0.006
683 10 0.02
684 10 0.005
685 10 0.006
686 >10 0.007
688 >10 0.006
689 7 0.007
690 7 0.004
691 > 10 0.008
692 6 0.04
693 > 10 0.03
694 10 0.04
697 ? 0.04
698 6 0.04
699 >10 0.016
700 > 10 0.004
701 > 10 0.008
702 4 0.01
703 > 10 0.007
704 >10 0.006
705 >10 0.006
706 > 10 0.04
707 > 10 0.005
708 >IO 0.005
709 >10 0.05
710 >10 0.006
711 >10 0.004
713 >10 0.009
714 >10 0.02
715 >10 0.03
716 >10 0.01
717 >10 0.003
718 6 0.02
720 >10 0.01
722 >10 0.015
723 >10 0.03
726 >10
728 9
729 0.02
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ExampleIC50 (ug/ml) % inhibitionIC50 IC50 (ug/ml)
HSV l0uglml (ug/ml) HCMV
VZV VZV
730 0.033
731 >10 0.007
732 0.022
733 0.018
734 >10 0.009
735 0.022
736 0.012
737 > 10 0.005
738 >10 0.11
739 >10 0.02
740 0.1
741 >10 0.02
742 >10 0.009
743 >10 0.09
745 9 0.0025
746 > 10 0.005
747 > 10 0.002
748 >10 0.28
749 >10 0.06
750 >10 0.01
759 >10 2 >20
762 >10 1.5 0.002
763 5 5 0.004
764 >10 0.004
766 >10 0.006
767 >10 ~ 1 0.006
768 >10 0.005
769 >10 0.04
770 > 10 0.006
796 >10 >7.5 4
815 0.27 0.0095
816 >7.5 0.0053
818 >7.5 0.0016
820 >7.5 0.006
821 >7.5 0.005
822 >7.5 O.OI8
824 0.17 0.014
825 >7.5 0.0013
828 >7.5 0.002
829 >7.5 0.002
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ExampleIC50 (ug/ml)% inhibitionIC50 IC50 {ug/ml)
HSV l0uglml (ug/ml}HCMV
VZV VZV
830 >7.5 0.0003
831 >7.5 0.0011
832 >7.5 0.001
833 >7.5 0.0019
834 >7.5 0.002
835 >7.5 0.005
836 >7.5 0.004
837 3.60 0.03
838 >7.5 0.0007
839 >7.5 0.004
840 0.14 0.0015
841 0.77 0.0011
842 1.55 0.02
843 >7.5 0.0031
844 1.03 0.0008
845 >7.5 0.0060
846 1.04 0.0130
847 >7.5 0.0008
848 0.19 0.002
849 1.82 0.002
850 2.33 0.0008
851 1.43 0.017
852 >7.5 0.005
853 0.62 0.004
854 0.02
855 0.02
856 0.02
857 >7.5 0.0006
858 >7.5 0.0007
859 0.5 0.00001
860 >7.5 0.001
861 >7.5 0.002
862 >7.5 0.1
863 >7.5 2.0
864 >7.5 0.5
865 >7.5 0.0001
866 >10 50 >10 0.035
875 >50 18 >10 >2.2
879 4 65 10 0.3
888 6 31 >10 0.06
897 >10 62 >10 0.037
902 >10 10 >10 0.12
904 12 58 >10 0.4
905 4 82 2 0.3
907 >10 36 >10 0.009
9i 1 >10 25 >10 0.3
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Example IC50 (ug/ml) ICSO IC50 (ug/ml)
% inhibition
HSV l0ug/ml (ug/ml) HCMV
VZV VZV
912 >10 0 >10 0.16
913 >10 15 >10 0.056
917 10 >10 0.2
918 >10 >10 0.03
919 >10 >10 0.05
921 8 85 7 0.05
922 > 10 84 7 0.01
939 >10 53 15 0.018
960 >10 58 >10 0.03
961 > 10 20 > 10 0.006
964 >10 9 >10 0.03
965 >10 36 >10 0.008
966 >10 42 >10 0.02
969 > 10 40 > 10 0.03
970 > 10 16 > 10 0.06
971 >10 9 >10 0.013
972 >10 95 >15 0.006
974 >10 14 >10 0.011
979 8 $8 12 0.19
980 >10 56 >10 0.05
983 >10 52 >10 0.12
986 >10 5 >10 0.031
989 >10 21 >10 0.016
990 8 99 4.5 0.011
991 >10 3 >10 0.022
992 >10 29 >10 0.018
993 > 10 > 10 0.013
994 >10 >10 0.07
996 10 >10 0.15
998 >10 >10 0.016
1000 >10 >10 0.39
1002 >10 >10 0.07
1004 >10 36 >10 0.5
1005 >10 16 >10 2
1006 >10 13 >10 0.2
1007 >10 18 >10 0.11
1008 >10 15 >10 0.12
1009 10 22 >10 0.2
1011 >10 20 >10 0.039
1018 >10 2 >10 0.4
1019 >10 2 >10 1.5
1021 8 68 >10 0.094
1126 >10 0.7 5.8
1127 9.5 3.7 1
1128 >10 >i0 1.3
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ExampleIC50 (uglml} % inhibitionIC50 IC50 (ug/ml)
HSV IOug/ml (ug/ml) HCMV
VZV VZV
1129 1.9 >10 1
1130 2 5.5 2
1131 2.2 9 1.5
I132 2.6 3.9 1.2
1133 6 >10 1.5
1134 2.4 1.6 1
I 135 3.6 7.5 1.3
1136 2.9 5 1.6
1137 >10 3.5 0.6
I138 >10 >10 0.65
I 139 3.7 6 1.2
I 140 3.5 4 1.6
1141 >10 >10 1.9
1142 >10 >10 1.8
1143 >10 >10 7.5
Thus, compounds of the present invention are potent inhibitors of the growth
and replication of the herpes viruses, including HCMV, VZV and HSV,
effectively
inhibiting viral yield.
In accordance with the present invention, compounds of the present invention
may be administered to a patient suffering from a herpes virus, including
HCMV,
VZV and HSV in an amount effective to inhibit the virus. Compounds of the
present
invention are thus useful to ameliorate or eliminate the symptoms of the
herpes virus
infections in mammals including, but not limited to humans.
Compounds of the invention may be administered to a patient either neat or
with a convention pharmaceutical carrier.
Applicable solid carriers can include one or more substances which may also
act
as flavoring agents, lubricants, solubilizers, suspending agents, fillers,
glidants,
compression aids, binders or tablet-disintegrating agents or an encapsulating
material.
In powders, the carrier is a finely divided solid which is in admixture with
the finely
divided active ingredient. In tablets, the active ingredient is mixed with a
carrier
having the necessary compression properties in suitable proportions and
compacted in
the shape and size desired. The powders and tablets preferably contain up to
99°Io of
the active ingredient. Suitable solid carriers include, for example, calcium
phosphate,
magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin,
cellulose, methyl
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cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting
waxes
and ion exchange resins.
Liquid carriers may be used in preparing solutions, suspensions, emulsions,
syrups and elixirs. The active ingredient of this invention can be dissolved
or
suspended in a pharmaceutically acceptable liquid Garner such as water, an
organic
solvent, a mixture of both or pharmaceutically acceptable oils or fat. The
liquid carrier
can contain other suitable pharmaceutical additives such as solubilizers,
emulsifiers,
buffers, preservatives, sweeteners, flavoring agents, suspending agents,
thickening
agents, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable
examples
of liquid carriers for oral and parenterai administration include water
(particularly
containing additives as above e.g. cellulose derivatives, preferably sodium
carboxymethyl cellulose solution), alcohols (including monohydric alcohols and
polyhydric alcohols e.g. glycols) and their derivatives, and oils (e.g.
fractionated
coconut oil and arachis oil). For parenteral administration the carrier can
also be an
oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid
carriers are used
in sterile liquid form compositions for parenteral administration.
Liquid pharmaceutical compositions which are sterile solutions or suspensions
can be utilized by, for example, intramuscular, intraperitoneal or
subcutaneous
injection. Sterile solutions can also be administered intravenously. Oral
administration
may be either liquid or solid composition form.
Preferably the pharmaceutical composition is in unit dosage form, e.g. as
tablets
or capsules. In such form, the composition is sub-divided in unit dose
containing
appropriate quantities of the active ingredient; the unit dosage forms can be
packaged
compositions, for example packeted powders, vials, ampoules, prefilled
syringes or
sachets containing liquids. The unit dosage form can be, for example, a
capsule or
tablet itself, or it can be the appropriate number of any such compositions in
package
form.
The therapeutically effective dosage to be used in the treatment of herpes
virus
infection must be subjectively determined by the attending physician. The
variables
involved include the the condition , age and weight of the patient. The novel
method
of the invention for treating herpes virus infection comprises administering
toa subject,
including humans, an effective amount of at least one compound of Formula 1 or
a
non-toxic, pharmaceutically acceptable salt thereof. The compounds may be
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administered orally, rectally, parenterally or topically to the skin and
mucosa. The
usual daily dose is depending on the specific compound, method of treatment
and
condition of the patient. The usual daily dose is 0.01 - 1000 mg/Kg for oral
application, preferably 0.5 - 500 mg/Kg, and 0.1 - 100 mg/Kg for parenteral
application, preferably 0.5 - 50 mg/Kg.
