CN1335843A - Thiourea inhibitors of herpes viruses - Google Patents

Thiourea inhibitors of herpes viruses Download PDF

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CN1335843A
CN1335843A CN99815807A CN99815807A CN1335843A CN 1335843 A CN1335843 A CN 1335843A CN 99815807 A CN99815807 A CN 99815807A CN 99815807 A CN99815807 A CN 99815807A CN 1335843 A CN1335843 A CN 1335843A
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phenyl
chloro
amino
carbon atom
thioureido
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J·D·布卢姆
M·J·迪格安迪
R·G·杜什
S·A·兰格
B·M·奥哈拉
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Wyeth LLC
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American Home Products Corp
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D307/85—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C335/04—Derivatives of thiourea
    • C07C335/16—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C335/20—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C335/04—Derivatives of thiourea
    • C07C335/16—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C335/22—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by carboxyl groups
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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  • Pyridine Compounds (AREA)

Abstract

Compounds of formula (1) wherein, R1-R5 are independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10 carbon members, aryl, heteroaryl, halogen, -CN, -NO2, -CO2R6,-COR6, -OR6, -SR6, - SOR6, -SO2R6, -CONR7R8, -NR6N(R7R8), -N(R7R8) or W-Y-(CH2)n-Z; or R2 and R3 or R3 and R4, taken together from a 3 to 7 membered heterocycloalkyl or 3 to 7 membered heteroaryl; R6 and R7 are independently hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, or aryl; R8 is hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalky l of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10 members, aryl or heteroaryl, or R7 and R8, taken together may form a 3 to 7 membered heterocycloalkyl; A is heteroaryl; W is O, NR6, or is absent; Y is -(CO)- or - (CO2)-, or is absent; Z is alkyl of 1 to 4 carbon atoms, -CN, -CO2R6, COR6, - CONR7R8, -OCOR6, -NR6COR7, -OCONR6, -OR6, -SR6, -SOR6, -SO2R6, SR6N(R7R8), - N(R7R8) or phenyl; G is aryl or heteroaryl; X is a bond, -NH, alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, thioalkyl of 1 to 6 carbon atoms, alkylaminoof 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; useful in the treatment of diseases associated with herpes viruses including human cytomegalovirus, herpes simplex viruses, Epstein-Barr virus, varicella-zoster virus, human herpes viruses -6 and -7, and Kaposi herpesvirus.

Description

The thiourea inhibitors of simplexvirus
Background of invention
Identified the viral member (Roizman of 8 kinds of herpetoviridaes, B.1996, Herpesviridae, p.2221-2230, B.N.Fields, D.M.Knipe, and P.M.Howley (volume), Fields Virology, the third edition, Lippincott-Raven Publishers, Philadelphia summarizes among the PA).Each member's of this section feature is the envelope virus that contains outer quilt of protein and nucleocapsid, carries the relatively large double-stranded DNA genome (promptly about 80-250 does base) of virus in the nucleocapsid.The member of people's Alphaherpesviridae is neurotropic, comprises herpes simplex types 1 virus (HSV-1) and 2 types (HSV-2) and varicella zoster virus (VZV).People β-simplexvirus is cytomegalovirus (HCMV), herpes virus hominis 6 (HHV-6) and herpes virus hominis 7 (HHV-7).Gamma herpes viruses is that the parent is lymphatic, comprises Epstein-Barr virus (EBV) and Kaposi herpesvirus (HHV-8).Each all has cause-effect relationship with human diseases these simplexviruss, comprise herpes labialis and genital herpes (HSV-1 and HSV-2[Whitley, R.J.1996.Herpes Simplex Viruses, p.2297-2342, in B.N.Fields, D.M.Knipe, and P.M.Howley (volume) Fields Virology, the third edition, Lippincott-Raven Publishers, Philadelphia, PA]); Chicken pox and zoster (VZV[Arvin.A.1996.Varicella-Zoster Virus, p.2547-2585, in B.N.Fields, D.M.Knipe, and P.M.Howley (volume), Fields Virology, the third edition, Lippincott-RavenPublishers, Philadelphia, PA]); Infectious monocytosis (EBV[Rickinson, A.B. and Kieff, Virus E.1996.Epstein-Barr, p.2397-2446, in B.N.Fields, D.M.Knipe, and P.M.Howley (volume), Fields Virology, the third edition, Lippincott-Raven Publishers, Philadelphia, PA]); Pneumonia and the retinitis (HCMV[(Britt, W.J. and Alford, C.A.1996.Cytomegalovirus, p.2493-2523, in B.N.Fields, D.M.Knipe, and P.M.Howley (volume), Fields Virology, the third edition, Lippincott-Raven Publishers, Philadelphia, PA)]); Roseola infantum (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 (volume), Fields Virology, the third edition, Lippincott-Raven Publishers, Philadelphia, PA)] and HHV-7[Frenkel, N., and Roffman, E.1996.Human Herpesvirus 7, p.2609-2622, in B.N.Fields, D.M.Knipe, and P.M.Howley (volume), Fields Virology, the third edition, Lippincott-Raven Publishers, Philadelphia, PA]); And Kaposi (HHV-8[Neipel, F., Albrecht, J.C., and Fleckenstein, B.1997, the cell homologous genes of the rhadinovirus human herpes virus 8 that Kaposi is relevant: its pathogenicity bo determinant? J.Virol.71:4187-92,1997]).Considered HCMV hereinafter in more detail.After the primary infection, simplexvirus is set up in infected individuality and hides, and will have the remaining time in all one's life in his body.Regularly reactivating of latent virus is clinical relevant.With regard to HSV, the virus that reactivates can pass to fetus at birth, causes skin or ocular infection, central nervous system infection, or disseminated infections (being a plurality of organs or whole body).Zoster is the clinical manifestation that VZV reactivates.Antiviral is used in the treatment of HSV and VZV usually, and as acyclovir (Glaxo Wellcome), ganciclovir (Roche) and phosphine formic acid (foscamet) (Astra), their target is the archaeal dna polymerase of encoding viral.
HCMV is a kind of ubiquitous opportunistic pathogen, infects the crowd's of growing up 50-90% (Britt, W.J. and Alford, C.A.1996. cytomegalovirus, p.2493-2523, in B.N.Fields, D.M.Knipe, and P.M.Howley (volume), open-air virusology, the third edition, Lippincott-Raven Publishers, Philadelphia, PA).The primary infection of HCMV usually is asymptomatic, though observe the monocytosis of heterophil feminine gender.Pass through sexual intercourse, breast milk and saliva that virus is horizontal are transmitted.The intrauterine HCMV of existence from pregnant woman to the fetus transmits, and it usually is the reason of serious clinical consequences.HCMV is in infected human body, and its residue is all kept latent state throughout one's life eventually.Cell-mediated immunity is hidden in control and played central role in being brought back to life.The impaired HCMV that causes the seropositivity philtrum to be hidden of cellular immunity brings back to life.
The HCMV disease is relevant with defective or jejune cellular immunization.The people who suffers from the HCMV disease mainly contains three classes (Britt and Alford summary, 1996).(1) at immunocompromised host (AIDS) philtrum, HCMV is one of two kinds of modal pathogenic agent that cause clinical disease (another kind is the lung sac worm).HCMV modal performance in patient AIDS is the retinitis, though other organ comprises that the infection of suprarenal gland, lung, gi tract and central nervous system also often is in the news.90% patient AIDS suffers from active HCMV and infects; 25-40% (about～85,000 patient of the U.S.) suffers from the HCMV disease of threat to life or vision.HCMV is patient's 10%AIDS the cause of death.(2) owing to for the danger that suppresses transplant rejection suppresses immunity system, HCMV bring back to life or again subinfection be common among the patient of kidney, liver, heart and simplified marrow transplanting.Pneumonia is a modal HCMV disease among these patients, reaches 70% in these transplant patients.(3) because the congenital infection that causes of HCMV takes place approximately annual 40,000 in neonatal 1% at all.Reach 25% among these babies and have the symptom of HCMV disease between year at 0-3.The HCMV disease is progressive, causes children's backwardness and dysautonomia.Recent research prompting can reduce these children's sickness rate with anti-HCMV pharmacological agent.
That sells at present has several antiviral (Bron, D., R.Snoeck and L.Lagneaux, 1996, the new viewpoint of cytomegalovirus pathogeny and treatment, an Exp.Opin.Invest.Drugs 5:337-344; Crumpacker, C.1996. treating herpes: summary, Exp.Opin.Invest.Drugs 5:169-183).These comprise: ganciclovir (Roche), the toxic nucleosides congener of a kind of tool hematopoietic cell; Phosphine formic acid (Asta), a kind of tetra-sodium congener of tool Toxicity of Kidney; And Xi Duofuwei (cidofovir) (Gilead), the toxic nucleoside phosphonate of a kind of tool acute renal.Each target of these medicines all is the archaeal dna polymerase of encoding viral, because their low biological effectiveness, usually intravenously is used, and as mentioned above, is the source of serious toxicity.The ganciclovir resistant mutants of clinical generation usually has crossed resistance to Xi Duofuwei.Therefore, need safer (being that toxicity is less), oral biology effectively at the antiviral of new virus target.
Disclose and be used for the phenylthiourea that various pharmacology are used.Armistead etc., WO 97/40028 have explained phenylurea or the thiocarbamide as the inhibitor of xanthoglobulin monophosphate dehydrogenase (IMPDH) enzyme (it is in the virus replication disease, as working in the bleb).
Widdowson etc., WO96/25157 have explained the phenylurea and the thiourea compound of following formula, are used for the treatment of the disease of chemokine interleukin 8 mediation.
Figure A9981580700111
Morin, Jr. etc., U.S. Patent number 5,593,993 have explained some phenylthiourea compound, are used for the treatment of AIDS and suppress duplicating of HIV and correlated virus.
Therefore, an object of the present invention is to provide acceptable salt on compound and the pharmacology thereof, suppress and/or treatment and simplexvirus, as human cytomegalic inclusion disease virus, hsv, Epstein-Barr virus, varicella zoster virus, herpes virus hominis-6 and-7, the disease relevant with Kaposi herpesvirus.
Invention is described
According to the invention provides compound with following formula: Wherein
R 1-R 5Be selected from respectively cycloalkyl, a 3-10 carbon atom of perhaloalkyl radical, a 3-10 carbon atom of alkynyl, a 1-6 carbon atom of alkenyl, a 2-6 carbon atom of alkyl, a 2-6 carbon atom of hydrogen, a 1-6 carbon atom Heterocyclylalkyl, aryl, heteroaryl, halogen ,-CN ,-NO 2,-CO 2R 6,-COR 6,-OR 6,-SR 6,-SOR 6,-SO 2R 6,-CONR 7R 8,-NR 6N (R 7R 8) ,-N (R 7R 8) or W-Y-(CH 2) n-Z; Or R 2And R 3, or R 3And R 4Form 3-7 unit's Heterocyclylalkyl or 3-7 unit heteroaryl altogether;
R 6And R 7Be respectively the alkyl of hydrogen, a 1-6 carbon atom, the perhaloalkyl radical of a 1-6 carbon atom, or aryl;
R 8Be the alkyl of hydrogen, a 1-6 carbon atom, the perhaloalkyl radical of a 1-6 carbon atom, cycloalkyl, 3-10 unit Heterocyclylalkyl, aryl or the heteroaryl of a 3-10 carbon atom, or
R 7And R 8Can form 3-7 unit Heterocyclylalkyl altogether;
A is a heteroaryl;
W is O, NR 6, or do not exist;
Y is-(CO)-or-(CO 2)-, or do not exist;
Z be 1-4 carbon atom alkyl ,-CN ,-CO 2R 6, COR 6,-CONR 7R 8,-OCOR 6,-NR 6COR 7,-OCONR 6,-OR 6,-SR 6,-SOR 6,-SO 2R 6, SR 6N (R 7R 8) ,-N (R 7R 8) or phenyl;
G is aryl or heteroaryl;
X be a key ,-alkylamino of the alkoxyl group of the alkyl of NH, a 1-6 carbon atom, the alkenyl of a 1-6 carbon atom, a 1-6 carbon atom, the alkylthio of a 1-6 carbon atom, a 1-6 carbon atom or (CH) J;
J is the alkyl of 1-6 carbon atom, cycloalkyl, phenyl or the benzyl of a 3-7 carbon atom; With
N is the integer of 1-6;
Or the salt on the pharmacology.
In preferences more of the present invention, R 1-R 5In at least one is not a hydrogen, preferred R 1-R 5Middle 1-3 is not hydrogen.Preferred R 1-R 5Be selected from the alkoxyl group of hydrogen, a 1-6 carbon atom, the perhaloalkyl radical and the halogen of a 1-6 carbon atom.
Preferred X is (CH) J, and wherein J is the alkyl of 1-6 carbon atom.Preferred J is the alkyl of 1-3 carbon atom, and most preferably J is a methyl.
In some embodiments of the invention, A can be by the alkoxyl group of the perhaloalkyl radical of the alkyl of hydrogen, a 1-4 carbon atom, a 1-4 carbon atom, halogen, a 1-4 carbon atom or at least one replacement in the cyano group.A most preferably is not substituted.
G is the heteroaryl of 5-6 unit preferably, has 1 or 2 heteroatoms.Most preferred G Shi oxazolyl, furyl, thiazolyl or thiadiazolyl group, in most preferred embodiment, G is 1,2,3 thiadiazolyl groups, 1,3-thiazoles base or 2-furyl.G most preferably is a thiazolyl, particularly the 1,3-thiazoles base.
Preferred compounds of the invention are following compounds, comprise the salt on its pharmacology:
Furans-2-carboxylic acid 5-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridine-2-yl }-acid amides
[1,2,3] thiadiazoles-4-carboxylic acid 5-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridine-2-yl }-acid amides
Pyridine-2-carboxylic acids 5-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridine-2-yl }-acid amides
Pyridine-2-carboxylic acids 6-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-3-yl }-acid amides
Furans-2-carboxylic acid 6-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-3-yl }-acid amides
[1,2,3] thiadiazoles-4-carboxylic acid 6-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-3-yl }-acid amides
[1,2,3] thiadiazoles-4-carboxylic acid 5-[3-(3,5-two chloro-phenyl)-thioureido]-pyridine-2-yl }-acid amides
N-[5-[[[(5-chloro-2, the 4-Dimethoxyphenyl) amino] sulphomethyl] amino]-the 2-pyridyl]-the 2-methyl benzamide
N-{5-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridine-2-yl }-2-fluoro-benzamide
N-{6-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-3-yl }-2-fluoro-benzamide
N-{5-[({[3,5-two (trifluoromethyl) benzyl] amino } thiocarbonyl (carbothioyl)) amino]-the 2-pyridyl }-1,2,3-thiadiazoles-4-carboxylic acid amides
N-(5-{[({ (1S)-1-[3,5-two (trifluoromethyl) phenyl] ethyl } amino) thiocarbonyl] amino }-the 2-pyridyl)-1,2,3-thiadiazoles-4-carboxylic acid amides
N-(5-{[({ (1S)-1-[3,5-two (trifluoromethyl) phenyl] ethyl } amino) thiocarbonyl] amino }-the 2-pyridyl)-1,3-thiazoles-4-carboxylic acid amides
N-(5-{[({1-[2-fluoro-5-(trifluoromethyl) phenyl] ethyl } amino) thiocarbonyl] amino }-the 2-pyridyl)-1,3-thiazoles-4-carboxylic acid amides
N-(5-{[({1-[2-fluoro-4-(trifluoromethyl) phenyl] ethyl } amino) thiocarbonyl] amino }-the 2-pyridyl)-1,3-thiazoles-4-carboxylic acid amides
N-(5-{[({1-[3-fluoro-5-(trifluoromethyl) phenyl] ethyl } amino) thiocarbonyl] amino }-the 2-pyridyl)-1,3-thiazoles-4-carboxylic acid amides
N-(5-{[({ (1S)-1-[3,5-two (trifluoromethyl) phenyl] ethyl } amino) carbonyl] amino }-the 2-pyridyl)-1,3-thiazoles-4-carboxylic acid amides
N-{5-[({[1-(3-bromophenyl) ethyl] amino } thiocarboxyl group) amino]-the 2-pyridyl }-1,3-thiazoles-4-carboxylic acid amides
N-{5-[({[1-(2-bromophenyl) ethyl] amino } thiocarboxyl group) amino]-the 2-pyridyl }-1,3-thiazoles-4-carboxylic acid amides
N-(5-{[({1-[3-(trifluoromethyl) phenyl] ethyl } amino) thiocarbonyl] amino }-the 2-pyridyl)-1,3-thiazoles-4-carboxylic acid amides
N-(5-{[({1-[4-chloro-3-(trifluoromethyl) phenyl] ethyl } amino) thiocarbonyl] amino }-the 2-pyridyl)-1,3-thiazoles-4-carboxylic acid amides
N-{5-[({[1-(4-chloro-3-fluorophenyl) ethyl] amino } thiocarbonyl) amino]-the 2-pyridyl }-1,3-thiazoles-4-carboxylic acid amides
N-{5-[({[1-(4-chloro-2-fluorophenyl) ethyl] amino } thiocarbonyl) amino]-the 2-pyridyl }-1,3-thiazoles-4-carboxylic acid amides
N-{6-[({[1-(4-fluorophenyl) ethyl] amino } thiocarbonyl) amino]-the 3-pyridyl }-1,2,3-thiadiazoles-4-carboxylic acid amides
N-(6-{[({1S)-1-[3,5-two (trifluoromethyl) phenyl] ethyl } amino) thiocarbonyl] amino }-the 3-pyridyl)-1,2,3-thiadiazoles-4-carboxylic acid amides; With the salt on its pharmacology.
Alkyl used herein refers to the straight or branched low alkyl group of 1-6 carbon atom.Exemplary alkyl comprises methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group and hexyl.
Alkenyl used herein refers to the straight or branched of 2-6 carbon atom, contains the low alkyl group of at least one carbon-carbon double bond.Alkenyl comprises vinyl.
Alkynyl used herein refers to 2-6 carbon atom, contains at least one carbon carbon triple-linked straight or branched low alkyl group.
Alkyl of the present invention, alkenyl and alkynyl can be that replace or unsubstituted.
Cycloalkyl refers to the saturated monocycle or the bicyclic system of 3-10 carbon atom.Exemplary cycloalkyl comprises cyclopentyl, cyclohexyl and suberyl.Cycloalkyl of the present invention can be that replace or unsubstituted.
Heterocyclylalkyl refers to 3-10 unit, have 1-3 heteroatomic saturated monocycle or bicyclic system that is selected from N, S and O, include but not limited to: '-aziridino, azetidinyl, imidazolidyl, morpholinyl, thio-morpholinyl, piperazinyl, pyrazolidyl, piperidyl and pyrrolidyl.Heterocyclylalkyl of the present invention can be that replace or unsubstituted.
Aryl used herein refers to the aromatic monocyclic or the dicyclo of 5-10 carbon atom.Exemplary aryl comprises phenyl, naphthyl and xenyl.Aryl of the present invention can be that replace or unsubstituted.
Heteroaryl used herein refers to 5-10 unit, has 1-3 heteroatomic aromatic monocyclic or dicyclo that is selected from N, S or O, includes but not limited to: thiazolyl, thiadiazolyl group, oxazolyl, furyl, indyl, benzothiazolyl, benzotriazole base, benzo dioxy base (benzodioxyl), indazolyl and benzofuryl.Preferred heteroaryl comprises quinolyl, isoquinolyl, naphthyl (napthalenyl), benzofuryl, benzothienyl, indyl, pyridyl, pyrazinyl, thienyl, furyl, pyrryl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, pyrazolyl, triazolyl, thiadiazolyl group and imidazolyl.Heteroaryl of the present invention can be that replace or unsubstituted.
Perhaloalkyl radical refers to the alkyl of 1-6 carbon atom, and a wherein three or more hydrogen are replaced by halogen.
Phenyl used herein refers to 6 yuan of aromatic rings.
Halogen used herein refers to chlorine, bromine, iodine and fluorine.
Unless otherwise defined, substituting group is unsubstituted, and can comprise cycloalkyl, the 1-6 unit Heterocyclylalkyl of alkyl, a 1-6 carbon atom of 1-6 carbon atom, perhaloalkyl radical, alkylamino, dialkyl amido, aryl or the heteroaryl of a 1-6 carbon atom.
Carbon number refers to the carbonatoms in the carbon skeleton, does not comprise being present in substituting group, as the carbon atom in alkyl or the alkoxy substituent.
When uniting the use term, the definition of this combination each several part is all worked, unless otherwise defined.For example, alkyl-cycloalkyl is an alkyl-group of naphthene base, and wherein alkyl and cycloalkyl are all as previously mentioned.
Acceptable salt is acid salt on the pharmacology, it can form as acid such as phosphoric acid, sulfuric acid, hydrochloric acid, Hydrogen bromide, citric acid, toxilic acid, succsinic acid, fumaric acid, acetate, lactic acid, nitric acid, sulfonic acid, tosic acid, methylsulfonic acids from acceptable acid on the compound of above-mentioned general formula and a kind of pharmacology.
Compound of the present invention contains chiral centre, and the various stereoisomeric forms in any ratio of compound are provided, as racemic mixture and each other optical isomer.In preferences more of the present invention, compound of the present invention is pure optical isomer on substantially.Substantially the pure composition that means contains desired isomer more than 75%, and can comprise and be lower than 25% unwanted isomer.In preferred embodiment, pure optical isomer is a desired isomer more than 90%.In some preferences, when target was VZV, (S) isomer was preferred.Can be directly with asymmetric or stereospecificity synthetic, or from racemic mixture conventional separating optical isomeric body, prepare various isomer.
Unless describe in addition, can use following method by the technician in organic synthesis field, utilize the reagent and the parent material that obtain easily, prepare compound of the present invention.Therefore, according to following flow preparation compound of the present invention.
Prepared compounds of the present invention according to following reaction process.
According to method 31 (2 and 3, the top) and 34 (4 and 5, the bottom), make suitable replacement amine 2 (substituent R wherein 1-R 5With X as mentioned above) and the lsothiocyanates 3 (wherein A and G are as mentioned above) of suitable replacement under solvent-free condition or at suitable solvent (as tetrahydrofuran (THF), acetonitrile, ethyl acetate, methylene dichloride or N, dinethylformamide) reaction obtains desired thiocarbamide 1 in.Similarly, as mentioned above, make the lsothiocyanates 4 (substituent R wherein of suitable replacement 1-R 5With X as mentioned above) and the aniline 5 (wherein A and G are as mentioned above) of suitable replacement in solvent (as above listing) reaction easily, obtain desired thiocarbamide 1.
Method 31 and 34
Figure A9981580700161
In addition, can be as the thiocarbamide 1 of the suitable replacement of preparation as described in method 32 and 33, by making amine 2 and 5 (R wherein 1-R 5, A and G as mentioned above) at 1 of 1 molar equivalent, 1 '-existence of thio-carbonyldiimidazole under, in suitable solvent, in methylene dichloride and tetrahydrofuran (THF) or its mixture, or 1,1 of 1 molar equivalent '-thiocarbonyl-two-(1,2,4)-existence of triazole under in suitable solvent (as methylene dichloride and tetrahydrofuran (THF) or its mixture) solution, reaction at room temperature.
In some example, need subsequently final thiocarbamide 1 to be carried out chemically modified.These methods have hereinafter been summed up, method 35-39.
Can be from corresponding alkyl ester, by with sodium hydroxide or potassium hydroxide aqueous solution in suitable solvent (as methyl alcohol, tetrahydrofuran (THF) or its mixture), according to method 35 and 36 basic hydrolysis at room temperature, preparation thiocarbamide 1 (at least one R wherein 1-R 5Substituting group is that 1-hydroxyl-oxethyl or carboxyl-methoxyl group, A and G as above define, and X as above defines).
Can be from corresponding 1-'-hydroxyethoxy radical derivative; by with suitable acylating agent (as Benzoyl chloride or methylsulfonyl chloride) in the presence of suitable tertiary amine base (as triethylamine or diisopropyl ethyl amine); in suitable solvent (as methylene dichloride etc.); according to method 37 and 38 acidylate at room temperature, preparation thiocarbamide 1 (at least one R wherein 1-R 5Substituting group is 1-acyloxy oxyethyl group or mesyloxy oxyethyl group, and A and G as above define, and X is a key).
Can be from corresponding 1-mesyloxy oxyethyl group derivative, by with suitable secondary amine (as dimethyl amine) at suitable solvent mixture (as tetrahydrofuran (THF) and water etc.), at room temperature react preparation thiocarbamide 1 (R wherein according to method 39 1-R 5In at least one substituting group be the 1-amino ethoxy, A and G as above define, X is a key).
Can be from corresponding 1-alkyl azide derivative, by with tin protochloride in suitable solvent (as methyl alcohol, ethanol etc.), at room temperature react preparation thiocarbamide 1 (R wherein according to method 40 1-R 5In at least one substituting group be the 1-aminoalkyl group, A and G as above define, X is a key).
According to method 41 (hereinafter),, H.A. and Walther, G.Justus Liebigs Ann.Chem.657,104 (1962) mainly according to Staab) program, (the R wherein of the amine 5 or 2 by making suitable replacement respectively 1-R 5, A and G as mentioned above, X as above defines) and 1 molar equivalent 1,1 '-thio-carbonyldiimidazole reacts in suitable solvent (as methylene dichloride and tetrahydrofuran (THF) or its mixture etc.), prepared the intermediate lsothiocyanates 3 and 4 shown in the method 31 and 34.
Method 41
Figure A9981580700181
Can prepare intermediate 2 and 5 according to following scheme:
According to method 1A-1G, can pass through according to various programs well known by persons skilled in the art, and R.J.Lindsay, Comprehensive Organic Chemistry (Sutherland volume), volume 2,6.3.1 chapter, aromatic amine, 1979 is described, and the oil of mirbane of suitable replacement of reducing prepares amine 2 (R wherein 1-R 5As above definition, X as above defines) and amine 5 (wherein A as above defines).These programs comprise reduction oil of mirbane, behind the following material of contact, form aniline:
A) in room temperature arrives the temperature range of solvent refluxing temperature, solvent-free or iron powder in alcoholic solvent (as methyl alcohol or ethanol) and strong acid (example hydrochloric acid) (method 1A), or;
B) in room temperature arrives the temperature range of solvent refluxing temperature, solvent-free or iron powder in alcoholic solvent (as methyl alcohol or ethanol) and Glacial acetic acid (method 1B), or;
C) in room temperature arrives the temperature range of solvent refluxing temperature, solvent-free or iron powder in alcoholic solvent (as methyl alcohol or ethanol) and aqueous ammonium chloride solution (method 1C), or;
D) in room temperature arrives the temperature range of solvent refluxing temperature, solvent-free or tin in alcoholic solvent (as methyl alcohol or ethanol) and strong mineral acid (example hydrochloric acid) (method 1D), or;
E) work as R 1-R 5With the substituting group of A be selected from Cl, Br, I ,-(OSO 2)-CF 3, or-(OSO 2During)-1-(4-aminomethyl phenyl),, in the atmosphere of one or more barometric points, use hydrogen and palladium carbon catalytic reduction (method 1E) by in suitable solvent (as methyl alcohol, ethanol or ethyl acetate), or;
F) work as R 1-R 5And R 9-R 12Be selected from Cl, Br, I ,-(OSO 2)-CF 3, or-(OSO 2During)-1-(4-aminomethyl phenyl),, in the scope of solvent refluxing temperature, use tetrahydrobenzene and palladium carbon catalytic reduction (method 1F) in room temperature by in suitable solvent (as methyl alcohol or ethanol), or;
G) in room temperature arrives the scope of solvent refluxing temperature, the sodium pyrosulfate aqueous solution (method 1G) in alcoholic solvent.
In addition, according to method 3A-3C, can pass through according to various programs well known by persons skilled in the art, and Greene, Protective Groups in Organic Synthesis, volume 2, chapter 7,1991 described and reference wherein, cut the acid amides of these aniline and the aniline nitrogen-carbon bond of carbamate derivatives, prepare amine 2 (R wherein 1-R 5As above definition, X as above defines) and aniline 5 (wherein A as above defines).These programs comprise:
A) solvent-free or in suitable solvent (as methylene dichloride), between 0 ℃ and room temperature, make suitable substituted aryl amino-t-butyl carbamate contact (method 3A) with strong acid (as trifluoroacetic acid), or;
B) in acetonitrile solution or tetrahydrofuran (THF) or its mixture, in the temperature range of room temperature between the solvent refluxing temperature, make arylamino-(2-trimethyl silyl ethyl) carbamate of suitable replacement contact (method 3B) with fluoride sources (as tetrabutyl ammonium fluoride or Potassium monofluoride), or;
C) in alcoholic solvent (as methyl alcohol or ethanol), in the temperature range of room temperature between the solvent refluxing temperature, make the arylamino-trifluoroacetamide of suitable replacement and highly basic (as sodium hydroxide or potassium hydroxide, or yellow soda ash or salt of wormwood) contact (method 3C).
In addition, according to method 11, can be mainly according to V.Farina and G.P.Roth in Advances in Metal-Organic Chemistry, volume 5,1-53,1996 and reference wherein, by using palladium catalyst (as three (dibenzalacetone)-two palladiums) and part (as triphenylarsine), in suitable solvent (as tetrahydrofuran (THF) or N-Methyl pyrrolidone), in room temperature arrives the scope of solvent refluxing temperature, make the bromo-or the iodo-aniline (as 3-chloro-4-iodo-aniline) of a kind of vinyl trialkyltin reagent (as tributylvinyl tin) and a kind of suitable replacement carry out the palladium catalytic coupling, prepare amine 2 (R wherein 1-R 5As above definition, X is a key, R 1-R 5In at least one substituting group be vinyl).
In addition, according to method 42, can be mainly according to J.F.Hartwig and J.Louie Tetrahedron Letters36 (21), 3609 (1995) program, by in the temperature range of room temperature to 100 ℃, in suitable solvent (as tetrahydrofuran (THF) or toluene), using palladium catalyst (as two (dibenzalacetone) palladium) and part (as three-o-tolylphosphine), the highly basic of at least 2 molar equivalents is (under the condition of two (trimethyl silyl) lithamide in tube sealing, with 3-bromine or 5-bromo-or the iodo-aniline (as 3-amino-5-5 bromine benzotrifluoride) of secondary amine, prepare amine 2 (R wherein by the suitable replacement of palladium catalytic ammoniation 1-R 5As above definition, X as above defines, R 2Or R 4In at least one substituting group be defined as dialkyl amido).
In addition, according to method 43, can be by in room temperature arrives the temperature range of solvent refluxing temperature, in suitable solvent (as tetrahydrofuran (THF) etc.), using palladium catalyst (as 1,1 '-two (diphenylphosphino) ferrocene] Palladous chloride (II)-methylene dichloride mixture, under the condition that exists at assorted two ring [3.3.1] nonanes of 9-boron and suitable alkali (as aqueous sodium hydroxide solution), pass through palladium catalysis with alkene, the 3-of the replacement that alkylation is suitable or 5-bromo-or iodo-aniline (as 3-amino-5-5 bromine benzotrifluoride) prepare amine 2 (R wherein 1-R 5As above definition, X equals key, R 2Or R 4In at least one substituting group be defined as alkyl).
2A-2G is described as method; according to various well known by persons skilled in the art and at Greene; Protective Groups in Organic Synthesis; volume 2; chapter 7; 1991 and the described program of reference, by the derivatize of corresponding amine, preparation is used as the acyl group and the carbamyl sulfonamide derivatives of parent material in method 3A-3C.These programs comprise:
A) one or the tertiary amine of several molar equivalents (as triethylamine or N, the N-diisopropylethylamine) under existence or the non-existent condition, in suitable solvent (as acetone, tetrahydrofuran (THF), dimethyl formamide, methylene dichloride etc.), in room temperature arrives the scope of solvent refluxing temperature, make the amine and the Di-tert butyl pyrocarbonate reaction (method 2A) of suitable replacement, produce corresponding arylamino-t-butyl carbamate, or;
B) in the presence of tertiary amine (as triethylamine or diisopropylethylamine), in suitable solvent (as dimethyl formamide), at room temperature make the aniline and 1-[2-(trimethyl silyl) ethoxy carbonyl-oxygen base of suitable replacement] benzotriazole reaction (method 2B), produce corresponding arylamino-(2-trimethyl silyl ethyl) carbamate, or;
C) solvent-free or in suitable solvent (as tetrahydrofuran (THF), dimethyl formamide, methylene dichloride, pyridine etc.), one or the tertiary amine base of several molar equivalents (as triethylamine or N, the N-diisopropylethylamine) exists down, make aniline and the carboxylic acid chloride or the anhydride reaction (method 2C) of suitable replacement, produce corresponding arylamino acid amides, or;
D) one or the tertiary amine base of several molar equivalents (as triethylamine or N, the N-diisopropylethylamine) do not exist down, solvent-free or at suitable solvent (as tetrahydrofuran (THF), 1,4-diox etc.) in, in room temperature arrives the scope of solvent refluxing temperature, make the N-methyl-p-nitroaniline and the carboxylic acid chloride reaction (method 2D) of suitable replacement, produce corresponding nitro arylamino acid amides, or;
E) at coupling agent (as benzotriazole-1-base oxygen base-three-(dimethylamino)-phosphorus phosphofluoric acid, 2-(1H-benzotriazole-1-base oxygen base)-1,1,3,3-tetramethyl- phosphofluoric acid, dicyclohexylcarbodiimide etc.) existence under and in the presence of tertiary amine (as triethylamine or diisopropylethylamine), in suitable solvent (as methylene dichloride, dimethyl formamide etc.), at room temperature make the aniline and the carboxylic acid reaction (method 2E) of suitable replacement, produce corresponding arylamino acid amides, or;
F) in the presence of suitable alkali (as pyridine); in suitable solvent (as methylene dichloride, dimethyl formamide etc.); in 0C arrives the temperature range of room temperature; (as arylamino-tertiary butyl-carbamate etc., wherein the substituting group of at least one substituting group of R5 and A is defined as-W-Y-(CH to make the aniline of suitable protection 2) n-Z, wherein W, X and Z as above define) and carboxylic acid anhydride reaction (method 2F), produce the corresponding carboxylic acid ester, or;
G) one or the tertiary amine of several molar equivalents (as triethylamine or N, the N-diisopropylethylamine) under the non-existent condition, in suitable solvent (as acetone, tetrahydrofuran (THF), dimethyl formamide, methylene dichloride etc.), in the scope of solvent refluxing temperature, make the aniline (R wherein of suitable replacement in room temperature 1-R 5In at least one substituting group be defined as hydroxyl) and Di-tert butyl pyrocarbonate reaction (method 2G), produce corresponding arylamino-tertiary butyl one carbamate.
Can be according to method 4A, 4C, 4E-4F, preparation finally is converted into the oil of mirbane intermediate of amine 2 and 5 by the method that shows among the method 1A-1G.
According to method 4A, 4C and 4E-4H; available following method; 2-, 4-by making suitable replacement and/or 6-fluoro-, chloro-, bromo-, iodo-, trifluoromethyl sulfonyl-or the oil of mirbane generation nucleophilic substitution of (4-aminomethyl phenyl) alkylsulfonyl-replacement, prepare the oil of mirbane intermediate (R that finally changes into amine 2 2And R 4As above definition, R 1, R 3And/or R 5Be defined as alkoxyl group, thio alkoxy, alkyl sulphinyl, alkyl sulfinyl and dialkyl amido):
A) solvent-free or at suitable solvent (as tetrahydrofuran (THF), diox, acetonitrile, N, dinethylformamide or dimethyl sulfoxide (DMSO)) in, one the alkali (as yellow soda ash, salt of wormwood, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride KH etc.) of several molar equivalents exists or not in the presence of, in the scope of solvent refluxing temperature, make the oil of mirbane of pure and mild suitable replacement or 2-or the 4-halides or the sulphonate reaction (method 4A) of benzonitrile in room temperature;
B) solvent-free or at suitable solvent (as tetrahydrofuran (THF), diox, acetonitrile, N, dinethylformamide or dimethyl sulfoxide (DMSO)) in, in room temperature arrives the scope of solvent refluxing temperature, make 2-or the 4-halides or the sulphonate reaction (method 4H) of the oil of mirbane or the benzonitrile of ready-formed phenoxy group sodium, lithium or potassium and suitable replacement, or;
C) solvent-free or at suitable solvent (as tetrahydrofuran (THF), diox, acetonitrile, N, dinethylformamide or dimethyl sulfoxide (DMSO)) in, in the scope of solvent refluxing temperature, make the oil of mirbane of ammonia, primary amine or secondary amine and suitable replacement or 2-or the 4-halides or the sulphonate reaction (method 4C, F) of benzonitrile in room temperature;
D) in suitable solvent (as tetrahydrofuran (THF)), 0 ℃ in the scope of solvent refluxing temperature, make sodium, lithium or sylvite and the oil of mirbane of suitable replacement or 2-or the 4-halides or sulphonate reaction (method 4G) reaction of benzonitrile of ready-formed amine, or;
E) solvent-free or at suitable solvent (as tetrahydrofuran (THF), diox, acetonitrile, N, dinethylformamide or dimethyl sulfoxide (DMSO)) in, in room temperature arrives the scope of solvent refluxing temperature, make 2-or the 4-halides or the sulphonate reaction of the oil of mirbane or the benzonitrile of sodium sulphite and suitable replacement, then direct direct adding alkyl halide (method 4E) in reaction mixture.
In addition, according to method 5C and 6, available following method finally changes into amine 2 (R wherein from the hydroxyl of corresponding replacement-oil of mirbane preparation 1-R 5In at least one substituting group be defined as alkoxyl group) the oil of mirbane intermediate:
A) at suitable solvent (as acetone, N, dinethylformamide, tetrahydrofuran (THF) or dimethyl sulfoxide (DMSO)) in, in the presence of alkali (as salt of wormwood, yellow soda ash, potassium hydroxide, sodium hydroxide, potassium hydride KH or sodium hydride etc.), in room temperature arrives the scope of solvent refluxing temperature, make hydroxyl-oil of mirbane and alkyl halide or sulfonic acid dialkyl reaction (method 5C), or;
B) in anhydrous aprotonic solvent (as ether or tetrahydrofuran (THF)), arrive in the scope of solvent refluxing temperature at 0 ℃, mainly according to Mitsunobu, O, Synthesis 1981,1 and reference, make hydroxyl-oil of mirbane and alkyl alcohol, triphenyl phosphine and azo-2-carboxylic acid's dialkyl reagent (as the diethylazodicarboxylate) reaction (method 6).
In addition, according to method 5A and 5E, can be at suitable solvent (acetone, toluene or N, dinethylformamide) in, in room temperature arrives the scope of solvent refluxing temperature, in the presence of suitable alkali (as salt of wormwood), reaction such as hydroxyaryl amino-tertiary butyl-carbamate by making corresponding replacement and halogenated alkyl thing, trifluoromethane-sulphonate, 4-toluene sulfonic acide ester, sulfonic acid dialkyl, ethylene carbonate prepares and finally changes into amine 2 (R wherein 1-R 5Be defined as alkoxyl group) the carbamyl sulfonamide derivatives as the parent material of method 3A-3C.
In addition, according to method 7A-G, can finally change into amine 2, R by the standard halogenating reaction preparation that comprises following reaction 1And/or R 3Be alkoxyl group, R 2And/or R 4Be halogen, X equals the oil of mirbane intermediate of key:
A) at room temperature make 2-or 4-hydroxyl oil of mirbane and aqueous sodium hypochlorite solution reaction (method 7A and 7B), or;
B) in suitable solvent (as chloroform, methylene dichloride, Glacial acetic acid etc.),, at room temperature make 2-hydroxyl-4-methoxyl group or 2 in the existence of trifluoroacetic acid silver or not, 4-dimethoxy oil of mirbane and bromine reaction (method 7C and 7D), or;
C) in the presence of Zinc Chloride Anhydrous, in suitable solvent (as Glacial acetic acid), at room temperature make 2,4-dimethoxy oil of mirbane and phenmethyl trimethylammonium dichloro ammonium iodate reaction (method 7E), or;
D) in the presence of sodium bicarbonate, in suitable solvent mixture (as methylene dichloride and methyl alcohol), at room temperature make 2-hydroxyl-4-methoxy nitrobenzene and phenmethyl trimethylammonium dichloro ammonium iodate reaction (method 7F), or;
E) in suitable solvent (as tetrachloroethane), in the scope of solvent refluxing temperature, make 2 in room temperature, 4-dimethoxy oil of mirbane and 3,5-two chloro-1-fluorine pyridine fluoroform sulphonates (triflate) reactions (method 7G).
According to method 8, can be at suitable solvent (as N, dinethylformamide etc.) in, in room temperature arrives the scope of solvent refluxing temperature, in sealed reaction vessel, react in the presence of cuprous iodide and Potassium monofluoride by 4-iodo-oil of mirbane and trimethylammonium (trifluoromethyl) silane that makes corresponding replacement, prepare and finally change into amine 2 (R wherein 4=-CF 3, R 1-R 3And R 5-R 8As above the definition, X equals key) the oil of mirbane intermediate.
According to method 19A and 19B; 4-(N-the chloracetyl)-N-methyl-p-nitroaniline that can make corresponding replacement is in suitable solvent (as tetrahydrofuran (THF) and/or water mixture); in room temperature arrives the scope of solvent refluxing temperature; with suitable secondary amine (as dimethyl amine, morpholine etc.) reaction; or at suitable solvent (as tetrahydrofuran (THF), 1; 4-diox etc.) in; in the presence of suitable alkali (as yellow soda ash or salt of wormwood etc.); in room temperature arrives the scope of solvent refluxing temperature; with suitable thiol reactant, prepare and finally change into amine 2 (R wherein 4=-HNCOCH 2NR 7R 8Or-HNCOCH 2SR 6, R 1-R 3And R 5As above the definition, X equals key) the oil of mirbane intermediate.
According to method 25, can in suitable solvent (as methylene dichloride), arrive in the temperature range of room temperature, in the presence of tertiary amine (triethylamine or diisopropyl ethyl amine etc.) at 0 ℃, finally change into amine 2 (R wherein by making the reaction of corresponding phenol and trifluoromethane-sulphonic acid anhydride, preparing 1-R 5In at least one substituting group be defined as the trifluoromethanesulfonic acid base, X equals key) the oil of mirbane intermediate.
According to method 9; 9B and 10; can be in suitable solvent mixture (as acetone and methylene dichloride or water); at room temperature; make the reaction of suitable 4-alkylthio acyl group-arylamino or formamyl arylamino derivative and suitable oxygenant (as dimethyl ethylene oxide (dimethyloxirane) or sodium periodate), prepare and finally change into amine 2 (R wherein 1-R 5At least one substituting group is defined as alkyl sulphinyl or alkyl sulfinyl) the carbamyl sulfonamide derivatives as the parent material of method 3A-3C.
According to method 12, can be in suitable solvent (as tetrahydrofuran (THF), diox etc. and water), at room temperature, in the presence of mercuric acetate, finally change into amine 2 (R wherein by making the reaction of corresponding 4-vinyl formamyl aniline and sodium borohydride, preparing 4Be defined by the 1-hydroxyethyl, and R 1-R 3And R 5As above the definition, X equals key) the carbamyl sulfonamide derivatives as method 3A-3C parent material.
According to method 13, can be in suitable solvent (as tetrahydrofuran (THF), 1,4-diox etc.), 0 ℃ under room temperature, in the presence of Glacial acetic acid, finally change into amine 2 (R wherein by making the reaction of corresponding 4-vinyl formamyl aniline and sodium borohydride, preparing 4Be defined by the 2-hydroxyethyl, and R 1-R 3And R 5As above the definition, X equals key) the carbamyl sulfonamide derivatives as method 3A-3C parent material.
According to method 14; can be in suitable solvent mixture (as tetrahydrofuran (THF) and methylene dichloride); at 0 ℃ under room temperature; in the presence of azo-2-carboxylic acid's dialkyl (as the diethylazodicarboxylate) and triphenyl phosphine; finally change into amine 2 (R wherein by making the reaction of corresponding 4-(1-hydroxyethyl) formamyl aniline and hydrazoic acid, preparing 4Be defined by the 1-azidoethyl, and R 1-R 3And R 5As above the definition, X as above defines) the carbamyl sulfonamide derivatives as method 3A-3C parent material.
According to method 15; can be in suitable tertiary amine solvent (as triethylamine or diisopropyl ethyl amine); in temperature range from room temperature to the solvent refluxing temperature; in the presence of two (triphenyl phosphine) Palladous chloride (II) and cuprous iodide; finally change into amine 2 (R wherein by making the reaction of corresponding 4-iodo formamyl aniline and 1-dimethylamino-2-propine, preparing 4Be defined by 3-dimethylamino third-1-alkynyl, and R 1-R 3And R 5As above the definition, X as above defines) the carbamyl sulfonamide derivatives as method 3A-3C parent material.
According to method 16; can be in suitable solvent mixture (as methylene dichloride and methyl alcohol); at 0 ℃ under the temperature between the room temperature; make the reaction of corresponding 4-(3-dimethylamino third-1-alkynyl) formamyl aniline and suitable peracid (as the 3-chloroperoxybenzoic acid), prepare and finally change into amine 2 (R wherein 4Be defined by 3-dimethylamino acryl, and R 1-R 3And R 5As above the definition, X equals key) the carbamyl sulfonamide derivatives as method 3A-3C parent material.
According to method 17 and 18; can be in suitable solvent (as 1,4-diox or ethanol etc.), at room temperature; make the reaction of corresponding 4-(3-dimethylamino-acryl) formamyl aniline and hydroxylamine hydrochloride or hydrazine hydrate, prepare and finally change into amine 2 (R wherein 4Be defined by 4-isoxazole-5-base or 4-(1H-pyrazole-3-yl), and R 1-R 3And R 5As above the definition, X equals key) the carbamyl sulfonamide derivatives as method 3A-3C parent material.
According to method 20; can be in suitable solvent mixture (as tetrahydrofuran (THF) and methylene dichloride etc.); under the temperature in room temperature arrives the solvent refluxing temperature range; make the amino formamyl aniline and 1 of corresponding 4-; 1-carbonyl-two-(1; 2,4)-and the alcohol reaction of triazole and suitable replacement, prepare and finally change into amine 2 (R wherein 4Be defined by-HNCO 2Z, and R 1-R 3, R 5As above define with Z, X equals key) the carbamyl sulfonamide derivatives as method 3A-3C parent material.
According to method 26 and 30, can be in suitable solvent (as water, methyl alcohol, tetrahydrofuran compound or toluene etc.), at room temperature, in the presence of sodium cyanoborohydride or hydrogen and 10% palladium carbon, by making the aldehyde reaction of suitable replacement, prepare and finally change into amine 2 (R wherein 1-R 5At least one substituting group is defined as dialkyl amido, and X as above defines) the carbamyl sulfonamide derivatives as method 3A-3C parent material.
According to method 27 and 28, can be in suitable solvent mixture (as methanol-water mixtures), under the temperature of room temperature between the solvent refluxing temperature, corresponding ester (as acetic ester) and suitable alkali (as sodium bicarbonate or sodium hydroxide) are reacted, prepare amine 2 (R wherein 1-R 5At least one substituting group be defined as hydroxyl, X as above defines).
According to method 29, can be in suitable solvent (as tetrahydrofuran (THF), ether etc.), at room temperature, make the reaction of corresponding N-(4-aminophenyl) phthalic imidine and lithium borohydride, prepare amine 2 (R wherein 1-R 5In at least one substituting group be defined as 2-hydroxybenzene amido, X as above defines).
Can prepare intermediate amine 2 (R wherein according to following process 1-R 5As above definition, X equals-CH 2Or-(CH 2) 2):
A) with borine-dimethyl thioether mixture in suitable solvent (as glycol dimethyl ether, tetrahydrofuran (THF) etc.), under the temperature of room temperature in the solvent refluxing temperature, reduce the benzonitrile or the phenylacetonitrile of suitable replacement.(method 44);
B) in suitable solvent (as methyl glycol, ethyl acetate, ethanol etc.), at room temperature, appropriate catalyst (palladium carbon) as 5% or 10% and acid (4-methyl-Phenylsulfonic acid, hydrochloric acid etc.)) in the presence of, under one or more normal atmosphere hydrogen atmosphere, reduce.(method 50);
C) in suitable solvent (as tetrahydrofuran (THF) or ether), under 0 ℃ of temperature in the room temperature, use lithium aluminium hydride reduction.(method 51);
Can be in suitable solvent (as acetate), under the temperature of room temperature in the solvent refluxing temperature, in the presence of ammonium acetate, react by phenyl aldehyde and the Nitromethane 99Min. that makes suitable replacement, prepare and finally change into amine 2 (R wherein 1-R 5As above definition, X equals-(CH 2) 2-) the unsaturated nitro precursor as method 51 parent materials.(method 53); Can reduce the benzonitrile of suitable replacement by diisobutyl aluminium hydride, come the phenyl aldehyde of preparation method's 53 parent materials.(method 52); Can be in suitable solvent (as N, dinethylformamide), under the temperature in room temperature arrives the solvent refluxing temperature, from corresponding aryl bromide and cupric cyanide reaction, preparation is as the benzonitrile of the replacement of method 52 parent materials.(method 59).
According to method 49, for amine 2 (R wherein 1-R 5As above definition, X equals-O (CH 2) 2NH 2Or-S (CH 2) 2NH 2), can be in suitable solvent (as acetone), at room temperature, in the presence of suitable alkali (as salt of wormwood), phenol or thiophenol and bromination acetonitrile reaction by making suitable replacement prepare essential nitrile precursor.
In addition, according to Wilk, B., Synthetic Comm., 23,2481 (1993), for amine 2 (R wherein 1-R 5As above definition, X equals-(CH 2) 3-), can be in suitable solvent (as ether or tetrahydrofuran (THF) etc.), at 0 ℃ under the temperature between the room temperature, in the presence of suitable azodicarboxylate (as azodicarboxylate's diethyl ester), phenylethyl alcohol and acetone cyanohydrin and triphenyl phosphine reaction by making suitable replacement prepare the nitrile precursor.(method 54)
In addition, can be in suitable solvent mixture (as water and methyl alcohol or water and ethanol), in room temperature under the temperature between the solvent degree of rising again, with suitable acid catalyst (as 6N hydrochloric acid) or suitable alkaline catalysts (as 5N sodium hydroxide or potassium hydroxide) acid or the corresponding methane amide of alkali catalyzed hydrolysis, prepare intermediate amine 2 (R wherein 1-R 5As above definition, X equals-(CH (CH 3))-).(method 46)
According to method 45, can be under the temperature between the solvent refluxing temperature in room temperature, the phenyl methyl ketone with the suitable replacement of ammonium formiate, formic acid and methane amide processing prepares the parent material as method 46, and finally changes into the methane amide precursor of amine 2.
In addition, method 48 is basically according to Itsuno, S., Sakurai, Y., Ito, K., Synthesis, 1988,995 program, can be in suitable solvent (as tetrahydrofuran (THF) or ether), at room temperature, in the presence of sodium borohydride and zirconium tetrachloride, by reducing the O-methyloxime of suitable replacement, prepare amine 2 (R wherein 1-R 5As above definition, X equals-(CH (CH 3))-).Can in suitable solvent (as ethanol or methyl alcohol), under the temperature between the solvent refluxing temperature, make the reaction of corresponding phenyl methyl ketone and methoxy amine hydrochlorate and pyridine, prepare essential O-methyloxime in room temperature.(method 47)
Available aforesaid method (method 45,47 and 48) prepares amine 2 (R wherein by reducing the ketone of suitable replacement 1-R 5As above definition, X equals-CH (J)-, wherein J as above defines).When can not commodity buying, phenyl aldehyde that can be by making suitable replacement and suitable organometallic reagent (as phenyl lithium, sec.-propyl bromination magnesium or ethylmagnesium bromide etc.) are in suitable solvent (as ether or tetrahydrofuran (THF) etc.), under the temperature between-78 ℃-0 ℃, react, prepare these ketone.(method 57).Available suitable oxygenant (as chromium trioxide in aqueous sulfuric acid and acetone or pyridinium chlorochromate or dichromic acid pyridine) in appropriate solution such as methylene dichloride, the alcohol that oxidation at room temperature obtains makes corresponding ketone.(method 58).
Available preceding method 3A prepares intermediate aniline 5.Use pure trifluoroacetic acid, at room temperature handle the phenylcarbamic acid tert-butyl ester 6 (wherein G as mentioned above), with the aqueous sodium hydroxide solution neutralization, obtain desired aniline 5 then.Shown in method 2C, isoxazolecarboxylic acid 8 (wherein G as mentioned above) by making replacement and 4-aminophenyl t-butyl carbamate 7 or corresponding heteroaryl (wherein A as above defines) have prepared required carbamate 6 (wherein A and G are as mentioned above) in suitable solvent (as methylene dichloride, dimethyl sulfoxide (DMSO) or dimethyl formamide or its mixture) in the presence of triethylamine.Carboxyl acyl chloride 8 can be used as commodity and buys, or passes through suitable solvent (as methylene dichloride) from corresponding carboxylic acid, and at room temperature reaction makes with oxalyl chloride.
Method 3A, 2C
Figure A9981580700271
In addition, can prepare amine 5 as described before according to method 1A-1G.Like this, handle 2-amino-5-nitropyridine (7) with heterocyclic acids acyl chlorides 8 or other activated acid derivative (as described in method 2C-2E), obtain nitro acid amides 6, wherein G as mentioned above.With the method reduction of describing among the method 1A-1G, obtain amine 5 then.
Figure A9981580700272
In addition, shown in method 2E, can be at suitable solvent (as methylene dichloride, dimethyl formamide etc.) in, at room temperature, in suitable coupling agents (as benzotriazole-1-base oxygen base-three-(dimethylamino) Phosphonium phosphofluoric acid, 2-(1H-benzotriazole-1-base oxygen base)-1,1,3,3-tetramethyl- phosphofluoric acid, dicyclohexylcarbodiimide etc.) under the existence, and tertiary amine base (as triethylamine or diisopropyl ethyl amine etc.) exists down, by the carboxylic acid 8a (wherein G as mentioned above) that makes replacement, 4-aminophenyl t-butyl carbamate 7 reactions with suitable replacement, prepare carbamate 6 (wherein A and G are as mentioned above), produce corresponding heteroaryl or arylamino acid amides.
Commodity are buied or are prepared carboxylic acid 8a according to literature method.For example, when G is the thiadiazoles that replaces, can at room temperature make corresponding carboxylic acid ester and suitable alkali (as sodium hydroxide or potassium hydroxide) reaction, preparation acid by in suitable solvent mixture (as methyl alcohol or second alcohol and water).
Similarly, when G replaces or unsubstituted thiazole, replacement or do not replace De oxazole, replacement or during for the isothiazole that replaces or replacement or unsubstituted isoxazole, when can not commodity buying, can be from corresponding ethyl ester or methyl esters by at room temperature reacting preparation corresponding carboxylic acid 8a at suitable solvent mixture (as methyl alcohol or second alcohol and water) with suitable alkali (as sodium hydroxide or potassium hydroxide).These esters can be that commodity are buied or prepare according to literature method.When can not commodity buying the carboxylicesters precursor that finally changes into acid 8, they can be according to known method preparation in the document.For example, can be basically according to Caron, M.J.Org.Chem., 51,4075 (1986) and Taber, D.F., Ruckle, R.E.J.Amer.Chem., 108,7686 (1986) program prepares 5-and replaces 1,2,3-thiadiazoles-4 carboxylicesters.Therefore,, in the presence of tertiary amine base (as triethylamine or diisopropyl ethyl amine), in suitable solvent (as acetonitrile), handle β-esters of keto-carboxylic acid, obtain corresponding two azos-β-esters of keto-carboxylic acid with 4-Methyl benzenesulfonyl nitrine or methylsulfonyl nitrine according to method 21.In suitable solvent (as benzene or toluene etc.), under the temperature in room temperature arrives the scope of solvent refluxing temperature, with 2,4-two (4-p-methoxy-phenyl)-1,3-two thiophenes-2,4-two phospha butane-2, the 4-disulfide is handled this compound, obtain desired 5-and replace-1,2,3-thiadiazoles-4-carboxylicesters.
In addition, can be substantially according to Shafiee, A., Lalezari, I., Yazdami, S., Shahbazian, F.M., Patovi, the program of T.J.Pharmaceutical Sci.65.304 (1976), preparation 4-replaces-1,2,3-thiadiazoles-5-carboxylicesters.Therefore, according to method 22 and 23, in suitable alcoholic solvent (as methyl alcohol or ethanol), make the β-esters of keto-carboxylic acid of suitable replacement and the carbamylhydrazine hydrochloride aqueous solution in room temperature under the temperature between the solvent refluxing temperature, reaction obtains corresponding semicarbazide derivative in the presence of suitable alkali (as pyridine).Handle this compound at 0 ℃ with pure thionyl chloride, handle with the excess bicarbonate aqueous solution then, obtain corresponding 4-and replace-1,2,3-thiadiazoles-5-carboxylicesters.
Can be substantially according to Sch llkopf, U., Porsch, P., Lau, H., the program of Liebigs Ann.Chem 1444 (1979), preparation 4-carbalkoxy thiazole.Therefore,, make isocyano acid B ester in suitable alcoholic solvent (as ethanol) according to method 55 and 56, at room temperature, and N, the reaction of dinethylformamide dimethyl acetal obtains corresponding 3-dimethylamino-2-isocyano--ethyl propenoate.In the presence of suitable tertiary amine base (as triethylamine or diisopropyl ethyl amine etc.), at room temperature handle the solution that this compound is dissolved in suitable solvent (as tetrahydrofuran (THF)) with hydrogen sulfide, obtain corresponding 4-ethoxycarbonyl-thiazole.
Can be substantially according to Bredenkamp, M.W., Holzafel, C.W., van Zyl, W.J.Synthetic Comm.20,2235 (1990) program prepares the thiazole of other suitable replacement.Basically according to Henneke, K.H., Sch llkopf, U., Neudecker, the program of T.Liebigs Ann.Chem1979 (1979) prepares suitable unsaturated De oxazole.Can be substantially according to Galeotti, N., Montagene, C., Poncet, J., Jouin, P.Tetrahedron Lett.33,2807 (1992) and Shin, C., Okumura, K., Ito, A., Nakamura, Y.Chemistry Lett.1305, (1994) preparation replaces the De oxazole.
Following specific embodiment is illustrative, and does not mean that and will limit the present invention.
Embodiment 1 (method 1A)
4-methoxyl group-3-trifluoromethyl-phenyl amine
The suspension in ethanol (35 milliliters) and water (15 milliliters) with concentrated hydrochloric acid (0.42 milliliter) solution-treated 4-methoxyl group-3-trifluoromethyl-oil of mirbane that is dissolved in ethanol (6 milliliters) and water (3 milliliters) (2.2 gram) and iron powder (1.68 restrain), then with mixture heating up to refluxing about 1 hour.Cooling mixture and filtration then, concentrating under reduced pressure.The oil that obtains is dissolved in ethyl acetate also with 5% aqueous hydrochloric acid extraction 3 times.In ice bath, cool off the acid extraction thing that merges then, and, use ethyl acetate extraction then with solid-state carbonic acid potashization.Wash these organic extracts with saturated sodium-chloride water solution, use anhydrous sodium sulfate drying, concentrating under reduced pressure by short silicagel column (using ethyl acetate as elutriant), obtains desired amber oily compound then.
Use said procedure and suitable parent material to prepare following compounds:
2,6-two chloro-benzene-1,4-diamines
3-chloro-4-methylthio group (sulfanyl)-aniline
2,6-two bromo-benzene-1,4-diamines
3-chloro-4-trifluoromethyl-phenyl amine
3-chloro-4-ethylmercapto group-phenyl amine
4-methoxyl group-3-trifluoromethyl-phenyl amine
3,5-two chloro-4-methoxyl group-2-methyl-phenyl amine
5-chloro-2-oxyethyl group-4-methoxyl group-phenyl amine
5-chloro-4-oxyethyl group-2-methoxyl group-phenyl amine
5-iodo-2,4-dimethoxy-phenyl amine
3,5-two iodo-2,4-dimethoxy-phenyl amine
3,5-two bromo-2,4-dimethoxy-phenyl amine
5-chloro-2-methoxyl group-4-methyl-phenyl amine
2-chloro-N (1), N (1)-dimethyl-benzene-1,4-diamines
3-chloro-4-piperidines-1-base-phenyl amine
3-chloro-4-tetramethyleneimine-1-base-phenyl amine
N (1)-benzyl-2-chloro-benzene-1, the 4-diamines
3-chloro-4-(4-methyl-piperazine-1-yl)-aniline
2-chloro-N (1)-methyl-N (1)-(1-methyl-piperidin-4-yl)-benzene-1, the 4-diamines
2-chloro-N (1)-methyl-N (1)-(1-methyl-tetramethyleneimine-3-yl)-benzene-1, the 4-diamines
2-chloro-N (1)-methyl-N (1)-phenyl-benzene-1, the 4-diamines
N (1)-(1-benzyl-tetramethyleneimine-3-yl)-2-chloro-N (1)-methyl-benzene-1, the 4-diamines
2-chloro-N (1)-cyclopentyl-N (1)-methyl-benzene-1, the 4-diamines
2-[(4-amino-2-chloro-phenyl)-(2-hydroxyethyl)-amino]-ethanol
2-chloro-N (1)-hexyl-N (1)-methyl-benzene-1, the 4-diamines
2-chloro-N (1)-isobutyl--N (1)-methyl-benzene-1, the 4-diamines
2-[(4-amino-2-chloro-phenyl)-methyl-amino]-ethanol
2-chloro-N (1)-(3-dimethylamino-propyl group)-N (1)-methyl-benzene-1, the 4-diamines
2-chloro-N (1)-(2-dimethylamino-ethyl)-N (1)-methyl-benzene-1, the 4-diamines
2-chloro-N (1)-(2-dimethylamino-ethyl)-benzene-1, the 4-diamines
N (1)-(1-benzyl-piperidin-4-yl)-2-chloro-benzene-1, the 4-diamines
2-chloro-N (1)-(2-methoxyl group-ethyl)-N (1)-methyl-benzene-1, the 4-diamines
2-chloro-N (1)-(3-dimethylamino-propyl group)-benzene-1, the 4-diamines
N (1)-(1-benzyl-tetramethyleneimine-3-yl)-2-chloro-benzene-1, the 4-diamines
3-chloro-4-(1-methyl-piperidin-4-yl oxygen base)-phenyl amine
3-chloro-4-(2-dimethylamino-oxyethyl group)-phenyl amine
3-chloro-4-(3-dimethylamino-propoxy-)-phenyl amine
3-chloro-4-(1-methyl-tetramethyleneimine-3-base oxygen base)-phenyl amine
3-chloro-4-cyclohexyloxy-phenyl amine
Embodiment 2 (method B)
4-bromo-2,4-dimethoxy-phenyl amine
With 4-bromo-2,4-dimethoxy-oil of mirbane (0.48 gram) and iron powder (0.42 restrains) suspension in acetate (10 milliliters) and ethanol (10 milliliters) be heated to 120 ℃ about 5 hours.Cooling mixture and filtration then, concentrating under reduced pressure.Add entry, cooling mixture in ice bath, and, use dichloromethane extraction then with solid-state carbonic acid potashization.Wash these organic extracts with saturated sodium-chloride water solution, use anhydrous sodium sulfate drying, concentrating under reduced pressure is used silica gel (hexane solution of 20% ethyl acetate is as elutriant) chromatography then, obtains desired amber oily compound.
Embodiment 3 (method 1C)
(4-amino-2,6-two chloro-phenoxy groups)-tert.-butyl acetate
Handle the ethanol (17 milliliters) of (4-nitro-2,6-two chloro-phenoxy groups)-tert.-butyl acetate (1 gram) and the solution of water (8.6 milliliters) with iron powder (0.861 gram) and ammonium chloride (86 milligrams).With mixture heating up to refluxing about 1 hour.Mixture filters and concentrating under reduced pressure then.Distribute the oil that obtains between water and ethyl acetate, wash organic phase with saturated sodium-chloride water solution then, use anhydrous sodium sulfate drying, concentrating under reduced pressure obtains desired faint yellow solid-state compound.
Use said procedure and suitable parent material to prepare following compounds:
4-chloro-benzene-1, the 2-diamines
N-(4-amino-2-chloro-phenyl)-ethanamide
(4-amino-2,6-two chloro-phenoxy groups)-acetonitrile
(4-amino-2,6-two chloro-phenoxy groups)-tert.-butyl acetate
(2-amino-4-chloro-5-methoxyl group-phenoxy group)-acetonitrile
(4-amino-2-chloro-5-methoxyl group-phenoxy group)-methyl acetate
(4-amino-2-chloro-5-methoxyl group-phenoxy group)-tert.-butyl acetate
(2-amino-4-chloro-5-methoxyl group-phenoxy group)-tert.-butyl acetate
N (1)-benzyl-4-chloro-5-methoxyl group-benzene-1, the 2-diamines
N-(4-amino-2-chloro-phenyl)-2-fluoro-benzamide
N-(4-amino-5-chloro-2-hydroxyl-phenyl)-ethanamide
N-(4-amino-5-chloro-2-hydroxyl-phenyl)-2-fluoro-benzamide
Furans-2-carboxylic acid (4-amino-2-chloro-phenyl)-acid amides
(4-amino-2-chloro-phenyl) urethanum
N-(4-amino-5-chloro-2-methyl-phenyl)-ethanamide
N-(4-amino-5-chloro-2-methyl-phenyl)-2-fluoro-benzamide
Furans-2-carboxylic acid (4-amino-5-chloro-2-methyl-phenyl)-acid amides
N-(4-amino-3-chloro-phenyl)-2-fluoro-benzamide
Furans-2-carboxylic acid (4-amino-3-chloro-phenyl)-acid amides
N-(4-amino-2-chloro-phenyl)-2-dimethylamino-ethanamide
N-(4-amino-2-chloro-phenyl)-2-piperidines-1-base-ethanamide
N-(4-amino-2-chloro-phenyl)-2-morpholine-4-base-ethanamide
N-(4-amino-2-chloro-phenyl)-Toluidrin
N-(4-amino-2-chloro-phenyl)-benzamide
N-(4-amino-2-chloro-phenyl)-2-diethylamino-ethanamide
N-(4-amino-2-chloro-phenyl)-2-tetramethyleneimine-1-base-ethanamide
N-(4-amino-2-chloro-phenyl)-2-nitrogen heterocyclic heptan (azepanyl)-1-base-ethanamide
N-(4-amino-2-chloro-phenyl)-2-(2-methyl-piperidines-1-yl)-ethanamide
N-(4-amino-2-chloro-phenyl)-2-(3-methyl-piperidines-1-yl)-ethanamide
3-chloro-benzene-1, the 2-diamines
4-chloro-N, N-dimethyl-benzene-1,2-diamines
Embodiment 4 (method 1D)
3,5-two chloro-4-phenoxy group-phenyl amine
3, drip concentrated hydrochloric acid (60 milliliters) in the slurries of 5-two chloro-4-phenoxy group-oil of mirbane (6.1 gram) and glass putty (12 gram).Add ethanol (60 milliliters), and heated mixt is to refluxing about 1 hour.The alkalization of the solid sodium hydroxide of cooling mixture in ice bath, and adding then.With the suspension filtration over celite pad that obtains, and with ethyl acetate extraction 3 times.The organic extract that merges with the saturated sodium-chloride water solution washing is used anhydrous magnesium sulfate drying then, and concentrating under reduced pressure, obtains desired yellow solid product.Recrystallization obtains faint yellow solid-state product from ethyl acetate-hexane.
Use said procedure and suitable parent material to prepare following compounds:
1-furans-2-base-ethylamine
3-chloro-4-isopropoxy-phenyl amine
2-butoxy-5-chloro-4-methoxyl group-phenyl amine
3,5-two chloro-2-methoxyl group-4-methyl-phenyl amine
2-benzyloxy-5-chloro-2-methoxyl group-phenyl amine
4-benzyloxy-5-chloro-2-methoxyl group-phenyl amine
5-fluoro-2,4-dimethoxy-phenyl amine
(4-amino-2,6-two chloro-phenoxy groups)-ethyl acetate
3,5-two chloro-4-phenoxy group-phenyl amine
2-(4-amino-2-chloro-5-methoxyl group-phenoxy group)-ethanamide
(4-amino-2-chloro-5-methoxyl group-phenoxy group)-acetonitrile
2-(2-amino-4-chloro-5-methoxyl group-phenoxy group)-ethanol
2-(4-amino-2-chloro-5-methoxyl group-phenoxy group)-ethanol
4-(4-amino-2-chloro-5-methoxyl group-phenoxy group)-butyronitrile
4-amino-2-chloro-5-methoxyl group-phenol
2-amino-4-chloro-5-methoxyl group-phenol
5-chloro-4-methoxyl group-2-morpholine-4-base-phenyl amine
4-chloro-5-methoxyl group-N (1), N (1)-dimethyl-benzene-1,2-diamines
5-chloro-4-methoxyl group-2-piperidines-1-base-phenyl amine
5-chloro-4-methoxyl group-2-tetramethyleneimine-1-base-phenyl amine
2-chloro-N (1)-cyclohexyl-N (1)-methyl-benzene-1, the 4-diamines
N (2)-benzyl-4-methoxyl group-benzene-1, the 2-diamines
2-(4-amino-2-chloro-phenoxy group)-ethanol
2-chloro-N (1)-cyclohexyl-N (1)-ethyl-benzene-1, the 4-diamines
4-butoxy-3-chloro-phenyl amine
(4-amino-2-chloro-phenoxy group)-acetonitrile
2-chloro-N (1)-cyclohexyl-benzene-1, the 4-diamines
2-chloro-N (1), N (1)-dipropyl-benzene-1,4-diamines
3-chloro-4-(2,2,2-three fluoro-oxyethyl groups)-phenyl amine
3-chloro-4-(octahydro-quinoline-1-yl)-phenyl amine
N (1)-allyl group-2-chloro-N (1)-cyclohexyl-benzene-1, the 4-diamines
N-(4-amino-2-methoxyl group-5-methyl-phenyl)-2-fluoro-benzamide
Furans-2-carboxylic acid (4-amino-2-methoxyl group-5-methyl-phenyl) acid amides
N-(4-amino-naphthalene-1-yl)-2-fluoro-benzamide
3-chloro-N, N-dimethyl-benzene-1,2-diamines
3-chloro-4-propoxy--phenyl amine
3-iodo-4-methoxyl group-phenyl amine
3-chloro-2,4-dimethoxy-aniline
3-bromo-4-methoxyl group-phenyl amine
3-chloro-4-oxyethyl group-phenyl amine
Embodiment 5 (method 1E)
(4-amino-phenyl)-isobutyl carbamate
In 100 milliliters of methyl glycols (100ml) solution of N-(4-nitro-phenyl)-isobutyramide (2.0 gram), add 10% palladium carbon (275 milligrams).Hydrogenated mixture is 2 hours under the hydrogen at 30psi on the Parr hydrogenation instrument.Filtration over celite is removed catalyzer then, and decompression is extremely done with 3 evaporated filtrates of heptane azeotropic.Grind residuum with heptane and obtain desired white solid product.
Prepared following compounds with said procedure and suitable parent material:
2-methyl-3H-benzoglyoxaline-5-base amine
N-(4-amino-phenyl)-methane amide
1H-benzoglyoxaline-5-base amine
(4-amino-phenyl)-isobutyl carbamate
N-(4-amino-phenyl)-isobutyramide
N-(5-amino-pyridine-2-yl)-2-methyl-benzamide
Furans-2-carboxylic acid (5-amino-pyridine-2-yl)-acid amides
N-(5-amino-pyridine-2-yl)-2-fluoro-benzamide
[6-(2,2,2-three fluoro-acetylamino)-pyridin-3-yl]-t-butyl carbamate
N-(5-amino-pyridine-2-yl)-2,2,2-three fluoro-ethanamides
(4-amino-benzyl) t-butyl carbamate
2-(3,5-di-trifluoromethyl-phenyl)-ethamine
The 1-tertiary butyl-1H-imidazoles-2-base amine
3-(3-dimethylamino-propyl group)-5-trifluoromethyl-phenyl amine
Embodiment 6 (method 1F)
N-(4-amino-2-methyl phenyl)-2-fluorobenzamide
The mixture heating up of heating 2-fluoro-N-(2-methyl-4-nitrophenyl) benzamide (4.55 gram), tetrahydrobenzene (30 milliliters), ethanol (70 milliliters), water (30 milliliters) and 10% palladium carbon (3 gram) is to refluxing 30 minutes.With the mixture filtration over celite, and concentrating under reduced pressure.The oil that obtains is dissolved in 50 milliliters of ethyl acetate, and 4 ℃ were cooled off 12 hours.Filtration obtains the tawny solid product.
Use said procedure and suitable parent material to prepare following compounds:
N-(4-amino-2-methyl-phenyl)-ethanamide
2-methyl-benzoxazoles-6-base amine
N-(4-amino-3-methoxyl group-phenyl)-ethanamide
2-acetylamino-5-amino-phenylformic acid
N-(4-amino-phenyl)-ethanamide
[4-(3-amino-benzoyl-amido)-phenyl]-t-butyl carbamate
[4-(2-amino-benzoyl-amido)-phenyl]-t-butyl carbamate
N-(4-amino-2-cyano group-phenyl)-ethanamide
N-(4-amino-2,5-dimethoxy-phenyl)-2-fluoro-benzamide
Furans-2-carboxylic acid (4-amino-2,5-dimethoxy-phenyl)-acid amides
N-(4-amino-2-cyano group-phenyl)-2-fluoro-benzamide
Furans-2-carboxylic acid (4-amino-2-methoxyl group-phenyl)-acid amides
N-(4-amino-2-methoxyl group-phenyl)-2-fluoro-benzamide
N-(4-amino-2-methoxyl group-5-methyl-phenyl)-ethanamide
N-(4-amino-2-benzoyl-phenyl)-ethanamide
N-(4-amino-2-benzoyl-phenyl)-2-fluoro-benzamide
Furans-2-carboxylic acid (4-amino-2-benzoyl-phenyl)-acid amides
N-(4-amino-3-methyl-phenyl)-ethanamide
N-(4-amino-3-methyl-phenyl)-2-fluoro-benzamide
Furans-2-carboxylic acid (4-amino-3-methyl-phenyl)-acid amides
5-amino-2-[(2-fluoro benzoyl) amino]-the N-phenylbenzamaide
Furans-2-carboxylic acid (4-amino-2-phenyl amino formyl radical-phenyl) acid amides
N-(4-amino-naphthalene-1-yl)-ethanamide
Furans-2-carboxylic acid (4-amino-naphthalene-1-yl)-acid amides
N-(4-amino-2-trifluoromethyl-phenyl)-ethanamide
Furans-2-carboxylic acid (4-amino-2-cyano group-phenyl)-acid amides
Furans-2-carboxylic acid (4-amino-2-trifluoromethyl-phenyl)-acid amides
N-(4-amino-2-methyl-phenyl)-2-fluoro-benzamide
Furans-2-carboxylic acid (4-amino-2-methyl-phenyl)-acid amides
5-amino-2-(2-fluoro-benzoyl-amido)-phenylformic acid
5-amino-2-[(furans-2-carbonyl)-amino]-phenylformic acid
N-(4-amino-2-cyano group-phenyl)-2,2,2-three fluoro-ethanamides
N-(4-amino-3-methyl-phenyl)-2,6-two fluoro-benzamide
N-(4-amino-3-trifluoromethyl-phenyl)-ethanamide
N-(4-amino-3-trifluoromethyl-phenyl)-2-fluoro-benzamide
N-(4-amino-2-trifluoromethyl-phenyl)-2,2,2-three fluoro-ethanamides
N-(4-amino-2-methoxyl group-phenyl)-2,2,2-three fluoro-ethanamides
N-(4-amino-2-trifluoromethyl-phenyl)-2-fluoro-N-(2-fluoro-benzoyl)-benzamide
N-(4-amino-2-trifluoromethyl-phenyl)-2-fluoro-benzamide
Embodiment 7 (method 1G)
N-(4-amino-2-chloro-phenyl-)-2-thiomorpholine-4-base-ethanamide
Ethanol (200 milliliters) solution of N-(2-chloro-4-nitrophenyl)-2-thiomorpholine-4-base-ethanamide (3.02 gram) is added in water (60 milliliters) solution of Sulfothiorine (12 gram).Reflux mixture 12 hours cools off and pours in the water.Use the ethyl acetate extraction mixture then.Wash ethyl acetate solution 2 times with saturated nacl aqueous solution, use the Anhydrous potassium carbonate drying, filtration over celite plate, and concentrating under reduced pressure obtain oil.Add toluene, frozen soln obtains desired greenish orange look lenticular solid product.
Use said procedure and suitable parent material to prepare following compounds:
N-(4-amino-2-chloro-phenyl)-2-thiomorpholine-4-base-ethanamide
N-(4-amino-2-chloro-phenyl)-2-dipropyl amino-ethanamide
Embodiment 8 (method 2A)
(3-chloro-4-iodo-phenyl)-t-butyl carbamate
Add Di-tert butyl pyrocarbonate (8.6 gram) in the solution of the tetrahydrofuran (THF) (40 milliliters) (containing diisopropyl ethyl amine (6.9ml)) of 3-chloro-4-iodo-aniline (10 gram), heated mixt is to refluxing.Add another part diisopropyl ethyl amine (6.9 milliliters) and Di-tert butyl pyrocarbonate (21 gram) after about 15 hours, continue about 24 hours of heating.Cooling solution then, concentrating under reduced pressure with the ethyl acetate dilution, and is used 5% salt acid elution 3 times continuously, with saturated sodium-chloride washing 1 time.Use anhydrous sodium sulfate drying solution, concentrating under reduced pressure obtains desired brown oily crude product then.Cause crystallization by adding hexane, the solid matter that recrystallization is collected from hexane obtains desired white solid state product.
Use said procedure and suitable parent material to prepare following compounds:
N '-(4-nitro-benzoyl)-hydrazine carboxylic acid's tert-butyl ester
(3-chloro-4-iodo-phenyl)-t-butyl carbamate
(4-bromo-3-chloro-phenyl)-t-butyl carbamate
(3-chloro-4-vinyl-phenyl)-t-butyl carbamate
(3-chloro-4-methylthio group-phenyl)-t-butyl carbamate
(4-amino-3-chloro-phenyl)-t-butyl carbamate
(4-chloro-2-nitro-phenyl)-t-butyl carbamate
(3-tert-butoxycarbonyl amino-5-chloro-phenyl)-t-butyl carbamate
(4-nitro-benzyl)-t-butyl carbamate
(3-bromo-5-trifluoromethyl-phenyl)-t-butyl carbamate
(2-amino-3-chloro-5-trifluoromethyl-phenyl)-t-butyl carbamate
Embodiment 9 (method 2B)
(3-chloro-4-vinyl-phenyl)-carboxylamine 2-TMS ethyl ester
N at 3-chloro-4-vinyl-phenyl amine (3-4 gram), in the solution of dinethylformamide (44 milliliters) (containing diisopropyl ethyl amine (5.8 milliliters)), add 1-[2-(TMS)-ethoxy carbonyl-oxygen base] benzotriazole (7.1 gram), under the room temperature, under argon gas, stirred the mixture 3.Dilute with water solution is used ethyl acetate extraction 3 times then.The organic extract that water, saturated sodium-chloride water solution continuous washing merge is used anhydrous magnesium sulfate drying, concentrating under reduced pressure.With silica gel (hexane solution of 10% ethyl acetate is as the elutriant) residuum that chromatography obtains, provide desired yellow oil product.
Embodiment 10 (method 2C)
[4-(2-fluoro-benzoyl-amido)-phenyl]-t-butyl carbamate
At one-N-(tert-butoxycarbonyl)-1, add fluorobenzoyl chloride (1.20 gram) in 25 milliliters of dichloromethane solutions of 4-phenylenediamine (1.58 gram) and triethylamine (1.50 milliliters).Form solid immediately, filter and wash, obtain white solid 1.90 grams with fresh solvent.
Use said procedure and suitable parent material to prepare following compounds:
N-(3-methoxyl group-4-nitro-phenyl)-ethanamide
N-(4-aminophenyl)-isobutyramide
2,2,2-three fluoro-N-(2-methoxyl group-4-nitro-phenyl)-ethanamide
[4-(2-methyl-benzoyl-amido)-phenyl]-t-butyl carbamate
Acetate 2-(4-tert-butoxycarbonyl amino-phenyl amino formyl radical)-phenyl ester
[4-(4-fluoro-benzoyl-amido)-phenyl]-t-butyl carbamate
[4-(3-fluoro-benzoyl-amido)-phenyl]-t-butyl carbamate
[4-(2-fluoro-benzoyl-amido)-phenyl]-t-butyl carbamate
[4-(2-methoxyl group-benzoyl-amido)-phenyl]-t-butyl carbamate
[4-(3-methoxyl group-benzoyl-amido)-phenyl]-t-butyl carbamate
[4-(4-methoxyl group-benzoyl-amido)-phenyl]-t-butyl carbamate
[4-(2,2-dimethyl-propionyl amino)-phenyl]-t-butyl carbamate
[4-(2-bromo-acetylamino)-phenyl]-t-butyl carbamate
[4-(2,2,2-three fluoro-acetylamino)-phenyl]-t-butyl carbamate
(4-benzoyl-amido-phenyl)-t-butyl carbamate
(4-methylsulfonyl amino-phenyl)-t-butyl carbamate
(4-phenyl acetyl amino-phenyl)-t-butyl carbamate
4-[(thiophene-2-carbonyl)-amino]-phenyl }-t-butyl carbamate
[4-(3-nitro-benzoyl-amido)-phenyl]-t-butyl carbamate
[4-(3-acetylamino-benzoyl-amido)-phenyl]-t-butyl carbamate
[4-(3-methylsulfonyl amino-benzoyl-amido)-phenyl]-t-butyl carbamate
[3-[[[4-[[(1,1-dimethyl oxyethyl group) carbonyl] amino] phenyl] amino] carbonyl]-phenyl] urethanum
[4-(2-trifluoromethyl-benzoyl-amido)-phenyl]-t-butyl carbamate
[4-(2,6-two fluoro-benzoyl-amidos)-phenyl]-t-butyl carbamate
[4-(2-chloro-benzoyl-amido)-phenyl]-t-butyl carbamate
[4-(2-bromo-benzoyl-amido)-phenyl]-t-butyl carbamate
[4-(2-nitro-benzoyl-amido)-phenyl]-t-butyl carbamate
4-[(benzo [b] thiophene-2-carbonyl)-amino]-phenyl }-t-butyl carbamate
4-[(pyridine-4-carbonyl)-amino]-phenyl }-t-butyl carbamate
4-[(naphthalene-2-carbonyl)-amino]-phenyl }-t-butyl carbamate
4-[(naphthalene-1-carbonyl)-amino]-phenyl }-t-butyl carbamate
4-[(3-bromo-thiophene-2-carbonyl)-amino]-phenyl }-t-butyl carbamate
4-[(xenyl-2-carbonyl)-amino]-phenyl }-t-butyl carbamate
N-(4-tert-butoxycarbonyl amino-phenyl)-phthalamic acid
[4-(2,3-two fluoro-benzoyl-amidos)-phenyl]-t-butyl carbamate
[4-(2,5-two fluoro-benzoyl-amidos)-phenyl]-t-butyl carbamate
[4-(2,4-two fluoro-benzoyl-amidos)-phenyl]-t-butyl carbamate
[4-(2-acetylamino-benzoyl-amido)-phenyl]-t-butyl carbamate
[4-(2-methylsulfonyl amino-benzoyl-amido)-phenyl]-t-butyl carbamate
[4-(2,3,4-three fluoro-benzoyl-amidos)-phenyl]-t-butyl carbamate
[4-(2,3,4,5,6-five fluoro-benzoyl-amidos)-phenyl]-t-butyl carbamate
N-(4-tert-butoxycarbonyl amino-phenyl)-isophthalamic acid methyl esters
2-methylthio group-N-[4-(2,2,2-three fluoro-acetylamino)-phenyl]-benzamide
[4-(3-benzyloxy-benzoyl-amido)-phenyl]-t-butyl carbamate
[4-(3-butoxy-benzoyl-amido)-phenyl]-t-butyl carbamate
4-[(5-difluoromethyl-furans-2-carbonyl)-amino]-phenyl }-t-butyl carbamate
4-[(thiophene-3-carbonyl)-amino]-phenyl }-t-butyl carbamate
4-[(5-methyl-furans-2-carbonyl)-amino]-phenyl }-t-butyl carbamate
4-[(5-bromo-furans-2-carbonyl)-amino]-phenyl }-t-butyl carbamate
(4-caproyl amino-phenyl)-t-butyl carbamate
[4-(2-thiophene-2-base-acetylamino)-phenyl]-t-butyl carbamate
4-[(pyridine-3-carbonyl)-amino]-phenyl }-t-butyl carbamate
4-[(4-bromo-furans-2-carbonyl)-amino]-phenyl }-t-butyl carbamate
4-[(furans-3-carbonyl)-amino]-phenyl }-t-butyl carbamate
(4-phenyloxycarbonyl amino-phenyl)-t-butyl carbamate
4-[(benzo [1,3] dioxole-4-carbonyl)-amino]-phenyl }-t-butyl carbamate
[4-(3-trifluoromethoxy-benzoyl-amido)-phenyl]-t-butyl carbamate
N-(2,5-dimethoxy-4 '-nitro-phenyl)-2-fluoro-benzamide
4-[(furans-2-carbonyl)-amino]-phenyl }-t-butyl carbamate
[4-(2-phenoxy group-acetylamino)-phenyl]-t-butyl carbamate
4-[(5-nitro-furans-2-carbonyl)-amino]-phenyl }-t-butyl carbamate
4-[(5-chloro-furans-2-carbonyl)-amino]-phenyl }-t-butyl carbamate
4-[(3-methyl-furans-2-carbonyl)-amino]-phenyl }-t-butyl carbamate
[4-(2-methoxyl group-acetylamino)-phenyl]-t-butyl carbamate
4-[(4-furans-3-base-[1,2,3] thiadiazoles-5-carbonyl)-amino]-phenyl }-t-butyl carbamate
The 4-[(5-tertiary butyl-furans-2-carbonyl)-amino]-phenyl }-t-butyl carbamate
N-[3-cyano group-4-(2,2,2-three fluoro-acetylamino)-phenyl]-2-fluoro-benzamide
Furans-2-carboxylic acid [3-cyano group-4-(2,2,2-three fluoro-acetylamino)-phenyl] acid amides
N-(4-acetylamino-2-cyano group-phenyl)-2,2,2-three fluoro-ethanamides
2,2,2-three fluoro-N-(4-nitro-2-trifluoromethyl-phenyl)-ethanamide
N-(4-acetylamino-2-trifluoromethyl-phenyl)-2,2,2-three fluoro-ethanamides
2-fluoro-N-[4-(2,2,2-three fluoro-acetylamino)-3-trifluoromethyl-phenyl] benzamide
Furans-2-carboxylic acid [4-(2,2,2-three fluoro-acetylamino)-3-trifluoromethyl-phenyl] acid amides
2-fluoro-N-(2-methyl-benzoxazoles-6-yl)-benzamide
4-(2-fluoro-benzoyl-amido)-2-hydroxy-benzoic acid phenyl ester
4-[(isoxazole-5-carbonyl)-amino]-phenyl }-t-butyl carbamate
N-(4-acetylamino-2-methoxyl group-phenyl)-2,2,2-three fluoro-ethanamides
2-fluoro-N-[3-methoxyl group-4-(2,2,2-three fluoro-acetylamino)-phenyl] benzamide
2-fluoro-N-(2-fluoro-benzoyl)-N-(4-nitro-2-trifluoromethyl-phenyl) benzamide
4-[(1H-pyrazoles-4-carbonyl)-amino]-phenyl }-t-butyl carbamate
4-[(1H-imidazoles-4-carbonyl)-amino]-phenyl }-t-butyl carbamate
4-[(5-methyl-[1,2,3] thiadiazoles-4-carbonyl)-amino]-phenyl }-t-butyl carbamate
4-[(5-furans-3-base-[1,2,3] thiadiazoles-4-carbonyl)-amino]-phenyl }-t-butyl carbamate
2,2,2-three fluoro-N-(5-nitro-pyridine-2-yl)-ethanamide
4-[(1-methyl isophthalic acid H-pyrazoles-4-carbonyl)-amino]-phenyl }-t-butyl carbamate
4-(2-fluoro-benzoyl-amido)-2-hydroxy-benzoic acid methyl esters
N-(5-chloro-2,4-dimethoxy-phenyl)-oxalyl amino acid
Isoxazole-5-carboxylic acid (4-amino-phenyl)-acid amides
2-fluoro-N-(4-nitro-benzyl)-benzamide
Furans-2-carboxylic acid 4-nitrobenzyl acid amides
N-[3-chloro-5-(2,2,2-three fluoro-acetylamino)-phenyl]-2,2,2-three fluoro-ethanamides
N-(3-amino-5-chloro-phenyl)-2,2,2-three fluoro-ethanamides
[4-(2-fluoro-benzoyl-amido)-benzyl]-t-butyl carbamate
[4-(2,6-two fluoro-benzoyl-amidos)-benzyl]-t-butyl carbamate
2,6-two fluoro-N-(4-nitro-benzyl)-benzamide
4-[(furans-2-carbonyl)-amino]-benzyl }-t-butyl carbamate
N-(3-amino-5-chloro-phenyl)-ethanamide
[4-(3-chloro-benzoyl-amido)-phenyl]-t-butyl carbamate
[4-(4-chloro-benzoyl-amido)-phenyl]-t-butyl carbamate
[4-(4-dimethylamino-benzoyl-amido)-phenyl]-t-butyl carbamate
(4-benzenesulfonyl amino-phenyl)-t-butyl carbamate
[4-(3-trifluoromethyl-benzoyl-amido)-phenyl]-t-butyl carbamate
2,2,2-three fluoro-N-(5-nitro-pyrimidine-2-base)-ethanamide
Embodiment 11 (method 2D)
2-chloro-N-(2-chloro-4-nitrophenyl) ethanamide
Tetrahydrofuran (THF) (150 milliliters) solution of reflux 2-chloro-4-N-methyl-p-nitroaniline (19.0 gram) and chloroacetyl chloride (30 milliliters) 1 hour.Cooling solution and concentrating under reduced pressure obtain wet yellow solid.Add ether (250 milliliters), and collect yellow solid.
Use said procedure and suitable parent material to prepare following compounds:
N-(4-nitro-3-trifluoromethyl-phenyl)-ethanamide
(2-chloro-4-nitro-phenyl)-urethanum
2-acetylamino-5-nitro-phenylformic acid
Furans-2-carboxyl (5-chloro-2-hydroxyl-4-nitro-phenyl)-acid amides
Furans-2-carboxylic acid (2-methyl-4-nitro-phenyl)-acid amides
Furans-2-carboxylic acid (2-methoxyl group-4-nitro-phenyl)-acid amides
N-(2-chloro-4-nitro-phenyl)-benzamide
2-methoxyl group-N-(4-nitro-phenyl)-ethanamide
N-(4-nitro-phenyl)-acrylamide
N-(4-nitro-phenyl)-isobutyramide
[4-(acryl amino)-phenyl] t-butyl carbamate
(4-nitro-phenyl)-isobutyl carbamate
[1,2,3] thiadiazoles-4-carboxylic acid (5-nitro-pyridine-2-yl)-acid amides
Furans-2-carboxylic acid (5-nitro-pyridine-2-yl)-acid amides
2-fluoro-N-(5-nitro-pyridine-2-yl)-benzamide
N-(2-chloro-4-nitro-phenyl)-2-fluoro-benzamide
Furans-2-carboxylic acid (2,5-dimethoxy-4 '-nitro-phenyl)-acid amides
N-(2-cyano group-4-nitro-phenyl)-2-fluoro-benzamide
2-fluoro-N-(2-methoxyl group-4-nitro-phenyl)-benzamide
2-methyl-N-(5-nitro-pyridine-2-yl)-benzamide
Furans-2-carboxylic acid (2-methoxyl group-5-methyl-4-nitro-phenyl)-acid amides
2-furans-N-(2-methoxyl group-5-methyl-4-nitro-phenyl)-benzamide
N-(2-benzoyl-4-nitro-phenyl)-ethanamide
N-(2-benzoyl-4-nitro-phenyl)-2-fluoro-benzamide
Furans-2-carboxylic acid (2-benzoyl-4-nitro-phenyl)-acid amides
N-(3-methyl-4-nitro-phenyl)-ethanamide
2-fluoro-N-(3-methyl-4-nitro-phenyl)-benzamide
Furans-2-carboxylic acid (3-methyl-4-nitro-phenyl)-acid amides
2-acetylamino-5-nitro-N-phenyl-benzamide
The 2-[(2-fluoro benzoyl) amino]-5-nitro-N-phenylbenzamaide
Furans-2-carboxylic acid (4-nitro-2-phenyl amino formyl radical-phenyl)-acid amides
2-fluoro-N-(4-nitro-naphthalene-1-yl)-benzamide
Furans-2-carboxylic acid (4-nitro-naphthalene-1-yl)-acid amides
N-(5-chloro-2-hydroxyl-4-nitro-phenyl)-ethanamide
N-(5-chloro-2-hydroxyl-4-nitro-phenyl)-2-fluoro-benzamide
Furans-2-carboxylic acid (2-chloro-4-nitro-phenyl)-acid amides
N-(4-nitro-2-trifluoromethyl-phenyl)-ethanamide
Furans-2-carboxylic acid (2-cyano group-4-nitro-phenyl)-acid amides
2-fluoro-N-(4-nitro-2-trifluoromethyl-phenyl)-benzamide
Furans-2-carboxylic acid (4-nitro-2-trifluoromethyl-phenyl)-acid amides
2-fluoro-N-(2-methyl-4-nitro-phenyl)-benzamide
N-(5-chloro-2-methyl-4-nitro-phenyl)-2-fluoro-benzamide
Furans-2-carboxylic acid (5-chloro-2-methyl-4-nitro-phenyl)-acid amides
2-(2-fluoro-benzoyl-amido)-5-nitro-phenylformic acid
2-[(furans-2-carbonyl)-amino]-5-nitro-phenylformic acid
N-(3-chloro-4-nitro-phenyl)-2-fluoro-benzamide
Furans-2-carboxylic acid (3-chloro-4-nitro-phenyl)-acid amides
2,6-two fluoro-N-(3-methyl-4-nitro-phenyl)-benzamide
2-fluoro-N-(4-nitro-3-trifluoromethyl-phenyl)-benzamide
Furans-2-carboxylic acid (4-nitro-3-trifluoromethyl-phenyl)-acid amides
2-chloro-N-(2-chloro-4-nitro-phenyl)-ethanamide
N-(2-chloro-4-nitrophenyl) Toluidrin
Furans-2-carboxylic acid [3-methoxyl group-4-(2,2,2-three fluoro-acetylamino)-phenyl]-acid amides
N-(2-chloro-4-nitro-phenyl)-2,2,2-three fluoro-ethanamides
Embodiment 12
4-[(4-phenyl-[1,2,3] thiadiazoles-5-carbonyl)-amino]-phenyl }-t-butyl carbamate
Handle 1-(N-tert-butoxycarbonyl)-1 with triethylamine (1.3 milliliters) and benzotriazole-1-base oxygen base-three (dimethylamino)-phosphorus hexafluorophosphate (1.6 gram), 4-phenylenediamine (0.8 gram) and 4-phenyl-[1,2,3] methylene dichloride (10 milliliters) solution of thiadiazoles-5-carboxylic acid (0.7 gram).After at room temperature stirring, the dilute with water reactant, and use dichloromethane extraction.Organic layer is used dried over mgso then with 0.5N hydrochloric acid, saturated sodium bicarbonate and water washing, filters, and concentrating under reduced pressure, obtain desired product.
Use said procedure and suitable parent material to prepare following compounds:
4-[(1H-pyrroles-2-carbonyl)-amino]-phenyl }-t-butyl carbamate
4-[(pyrazine-2-carbonyl)-amino]-phenyl }-t-butyl carbamate
4-[(5-methyl-thiophene-2-carbonyl)-amino]-phenyl }-t-butyl carbamate
4-[(1-methyl isophthalic acid H-pyrroles-2-carbonyl)-amino]-phenyl }-t-butyl carbamate
4-[(quinoline-8-carbonyl)-amino]-phenyl }-t-butyl carbamate
4-[(cumarone-2-carbonyl)-amino]-phenyl }-t-butyl carbamate
4-[(isoquinoline 99.9-1-carbonyl)-amino]-phenyl }-t-butyl carbamate
4-[(quinoline-2-carbonyl)-amino]-phenyl }-t-butyl carbamate
4-[(pyridine-2-carbonyl)-amino]-phenyl }-t-butyl carbamate
4-[(isoquinoline 99.9-4-carbonyl)-amino]-phenyl }-t-butyl carbamate
4-[([1,2,3] thiadiazoles-4-carbonyl)-amino]-phenyl }-t-butyl carbamate
4-[(1H-[1,2,3] triazole-4-carbonyl)-amino]-phenyl }-t-butyl carbamate
[4-(2-methylthio group-benzoyl-amido)-phenyl]-t-butyl carbamate
4-[(quinoline-4-carbonyl)-amino]-phenyl }-t-butyl carbamate
4-[(4-methyl-[1,2,3] thiadiazoles-5-carbonyl)-amino]-phenyl }-t-butyl carbamate
4-[(4-phenyl-[1,2,3] thiadiazoles-5-carbonyl)-amino]-phenyl }-t-butyl carbamate
The 4-[(1H-indole-2-carbonyl)-amino]-phenyl }-t-butyl carbamate
[1,2,3] thiadiazoles-4-carboxylic acid 4-nitrobenzyl acid amides
4-[([1,2,3] thiadiazoles-4-carbonyl)-amino]-phenyl }-t-butyl carbamate
Acetate 4-(4-tert-butoxycarbonyl amino-phenyl amino formyl radical)-phenyl ester
4-[(quinoline-6-carbonyl)-amino]-phenyl }-t-butyl carbamate
Embodiment 13 (method 2F)
Acetate 2-(4-tert-butoxycarbonyl amino-2,6-two chloro-phenoxy groups)-ethyl ester
Handle pyridine (14 milliliters) solution of [3,5-two chloro-4-(2-hydroxyl-oxyethyl group)-phenyl]-t-butyl carbamate (0.85 restrains), stirring at room mixture 15 hours with diacetyl oxide (1.24 milliliters).Removal of solvent under reduced pressure is dissolved in ethyl acetate with residuum.Use 5% salt acid elution 2 times then, with saturated sodium bicarbonate aqueous solution washing 1 time, then with saturated sodium-chloride water solution washing 1 time.Use anhydrous magnesium sulfate drying solution, removal of solvent under reduced pressure obtains desired colorless oil product.
Use said procedure and suitable parent material to prepare following compounds:
Thiophenyl-acetonitrile
Acetate 2-(4-tert-butoxycarbonyl amino-2,6-two chloro-phenoxy groups)-ethyl ester
Embodiment 14 (method 2G)
(3,5-two chloro-4-hydroxyl-phenyl)-t-butyl carbamate
2, add Di-tert butyl pyrocarbonate (11.7 gram) in tetrahydrofuran (THF) (130 milliliters) solution of 6-two chloro-4-amino-phenols (9.5 gram), and with mixture heating up to refluxing about 15 hours.Cooling mixture then, concentrating under reduced pressure with the ethyl acetate dilution, and with 5% hydrochloric acid continuous washing 3 times, washs 1 time with saturated sodium-chloride water solution.Use anhydrous sodium sulfate drying solution, concentrating under reduced pressure obtains desired crude product then.Then this material is ground with cold methylene dichloride, obtain the white solid state product.
Use said procedure and suitable parent material to prepare following compounds:
(3-amino-5-chloro-phenyl)-t-butyl carbamate
Embodiment 15 (method 3A)
3,5-two chloro-4-oxyethyl group-phenyl amine
In solid (3,5-two chloro-4-oxyethyl group-phenyl)-t-butyl carbamate (0.97 gram), add trifluoroacetic acid (5 milliliters), stirred the mixture under the room temperature about 45 minutes.Add entry then, cooling mixture in ice bath, and with solid carbonic acid potashization.With this solution of ethyl acetate extraction 3 times,, use anhydrous sodium sulfate drying then with the organic phase that the saturated sodium-chloride water solution washing merges.Concentrating under reduced pressure, recrystallization from hexane obtains desired faint yellow crystalline solid-state product.
Use said procedure and suitable parent material to prepare following compounds:
5-bromo-pyridin-3-yl amine
3-chloro-4-methylsulfonyl-phenyl amine
N-(4-amino-phenyl)-2-methyl-benzamide
Acetate 2-(4-amino-phenyl amino formyl radical)-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-methoxyl group-benzamide
N-(4-amino-phenyl)-3-methoxyl group-benzamide
N-(4-amino-phenyl)-4-methoxyl group-benzamide
N-(4-amino-phenyl)-2-phenyl-ethanamide
N-(4-amino-phenyl)-2,2-dimethyl-propionic acid amide
N-(4-amino-phenyl)-2,2,2-three fluoro-ethanamides
Thiophene-2-carboxylic acid (4-amino-phenyl)-acid amides
1H-pyrroles-2-carboxylic acid (4-amino-phenyl)-acid amides
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-methylsulfonyl amino-benzamide
N-(4-amino-phenyl)-2-trifluoromethyl-benzamide
N-(4-amino-phenyl)-2,6-two fluoro-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)-acid amides
5-methyl-thiophene-2-carboxylic acid (4-amino-phenyl)-acid amides
Quinoline-8-carboxylic acid (4-amino-phenyl)-acid amides
1-methyl isophthalic acid H-pyrroles-2-carboxylic acid (4-amino-phenyl)-acid amides
Benzo [b] thiophene-2-carboxylic acid (4-amino-phenyl)-acid amides
Cumarone-2-carboxylic acid (4-amino-phenyl)-acid amides
N-(4-amino-phenyl)-Isonicotinamide
Naphthalene-2-carboxylic acid (4-amino-phenyl)-acid amides
Naphthalene-1-carboxylic acid (4-amino-phenyl)-acid amides
Isoquinoline 99.9-1-carboxylic acid (4-amino-phenyl)-acid amides
Quinaldic acid's (4-amino-phenyl)-acid amides
3,5-two chloro-4-oxyethyl group-phenyl amine
4-butoxy-3,5-two chloro-phenyl amine
Isoquinoline 99.9-4-carboxylic acid (4-amino-phenyl)-acid amides
[1,2,3] thiadiazoles-4-carboxylic acid (4-amino-phenyl)-acid amides
1H-[1,2,3] triazole-4-carboxylic acid (4-amino-phenyl)-acid amides
3-bromo-thiophene-2-carboxylic acid (4-amino-phenyl)-acid amides
4-benzyloxy-3,5-two chloro-phenyl amine
2-(4-amino-2,6-two chloro-phenoxy groups)-ethanamide
(4-amino-2,6-two chloro-phenoxy groups)-methyl acetate
[3-(4-amino-phenyl amino formyl radical)-phenyl]-urethanum
2-amino-N-(4-amino-phenyl)-benzamide
Xenyl-2-carboxylic acid (4-amino-phenyl)-acid amides
N-(4-amino-phenyl)-2,3-two fluoro-benzamide
N-(4-amino-phenyl)-2,5-two fluoro-benzamide
N-(4-amino-phenyl)-2,4-two fluoro-benzamide
2-acetylamino-N-(4-amino-phenyl)-benzamide
N-(4-amino-phenyl)-2-methylsulfonyl amino-benzamide
N-(4-amino-phenyl)-2,3,4-three fluoro-benzamide
N-(4-amino-phenyl)-2,3,4,5,6-five fluoro-benzamide
N-(4-amino-phenyl)-2-methylthio group-benzamide
Acetate 2-(4-amino-2,6-two chloro-phenoxy groups)-ethyl ester
N-(4-amino-phenyl)-isophthalamic acid methyl esters
N-(4-amino-phenyl)-3-benzyloxy-benzamide
N-(4-amino-phenyl)-3-butoxy-benzamide
[3-(4-amino-phenyl amino formyl radical)-phenoxy group]-ethyl acetate
Pyridine-2-carboxylic acids (4-amino-phenyl)-acid amides
Cinchonic Acid's (4-amino-phenyl)-acid amides
5-methyl-furans-2-carboxylic acid (4-amino-phenyl)-acid amides
5-difluoromethyl-furans-2-carboxylic acid (4-amino-phenyl)-acid amides
1H-Indoline-2-carboxylic acid (4-amino-phenyl)-acid amides
4-methyl-[1,2,3] thiadiazoles-5-carboxylic acid (4-amino-phenyl)-acid amides
Thiophene-3-carboxylic acid (4-amino-phenyl)-acid amides
5-chloro-furans-2-carboxylic acid (4-amino-phenyl)-acid amides
5-nitro-furans-2-carboxylic acid (4-amino-phenyl)-acid amides
N-(4-amino-phenyl)-2-benzene sulphur (thiophen)-2-base-ethanamide
3-methyl-furans-2-carboxylic acid (4-amino-phenyl)-acid amides
5-bromo-furans-2-carboxylic acid (4-amino-phenyl)-acid amides
4-bromo-furans-2-carboxylic acid (4-amino-phenyl)-acid amides
N-(4-amino-phenyl)-niacinamide
N-(4-amino-phenyl)-3-furans carboxylic acid amides
4-phenyl-[1,2,3] thiadiazoles-5-carboxylic acid (4-amino-phenyl)-acid amides
Acetate 3-(4-amino-phenyl amino formyl radical)-phenyl ester
Two oxa-s pentane-4-carboxylic acid (4-amino-phenyl)-acid amides between benzo [1,3]
N-(4-amino-phenyl)-3-(2-dimethylamino-oxyethyl group)-benzamide
N-(4-amino-phenyl)-3-trifluoromethoxy-benzamide
N-(4-amino-phenyl)-3-(2-morpholine-4-base-oxyethyl group)-benzamide
The own ester of (4-amino-phenyl)-carboxylamine
Furans-2-carboxylic acid (4-amino-phenyl)-acid amides
(4-amino-phenyl)-phenyl carbamate
Caproic acid (4-amino-phenyl)-acid amides
N-(4-amino-phenyl)-acrylamide
N-(4-amino-phenyl)-2-methoxyl group-ethanamide
4-furans-3-base-[1,2,3] thiadiazoles-5-carboxylic acid (4-amino-phenyl)-acid amides
The 5-tertiary butyl-furans-2-carboxylic acid (4-amino-phenyl)-acid amides
3-chloro-4-methanesulfinyl-phenyl amine
5-methyl-[1,2,3] thiadiazoles-4-carboxylic acid (4-amino-phenyl)-acid amides
2-(4-amino-2-chloro-phenyl)-ethanol
(4-amino-2-chloro-phenyl)-carboxylamine 2-piperidines-1-base-ethyl ester
5-chloro-N, N-dimethyl-benzene-1,3-diamines
3-(2-methyl-butyl)-5-trifluoromethyl-phenyl amine
3-isobutyl--5-trifluoromethyl-phenyl amine
Furans-2-carboxylic acid (4-amino methyl-phenyl)-acid amides
N-(4-amino methyl-phenyl)-2-fluoro-benzamide
[1,2,3] thiadiazoles-4-carboxylic acid (4-amino methyl-phenyl)-acid amides
N-(4-amino methyl-phenyl)-2,6-two fluoro-benzamide
Oxazole-4-carboxylic acid (4-amino-phenyl)-acid amides
N-(4-amino-phenyl)-3-chloro-benzamide
N-(4-amino-phenyl)-4-chloro-benzamide
Acetate 4-(4-amino-phenyl amino formyl radical)-phenyl ester
N-(4-amino-phenyl)-4-dimethylamino-benzamide
1-(4-amino-phenyl)-3-(3,5-di-trifluoromethyl-phenyl)-thiocarbamide
N-(4-amino-phenyl)-2-iodo-benzamide
N-(4-amino-phenyl)-3-trifluoromethyl-benzamide
Embodiment 16 (method 3B)
1-(4-amino-2-chloro-phenyl)-ethanol
Tetrahydrofuran (THF) (5.7 milliliters) solution of 1M tetrabutyl ammonium fluoride is added in [3-chloro-4-(1-hydroxyl-ethyl)-phenyl]-carboxylamine 2-TMS ethyl ester (0.5 gram) about 3.5 hours of stirring at room mixture.Concentrating under reduced pressure mixture then is dissolved in 1: 1 the ethyl acetate and hexanes mixtures, water continuously, and the saturated sodium-chloride water solution washing, and use anhydrous magnesium sulfate drying.Removal of solvent under reduced pressure is used silica gel (with the hexane solution of 45% ethyl acetate as elutriant) chromatography then, obtains amber oily product.
Embodiment 17 (method 3C)
N-(4-amino-3-cyano-phenyl)-2-fluoro-benzamide
Salt of wormwood (5.0 gram) is added to N-[3-cyano group-4-(2,2,2-trifluoroacetyl group-amino)-phenyl]-methyl alcohol (270 milliliters) of 2-fluoro-benzamide (2.5 gram) and the solution of water (16 milliliters) in, the backflow mixture overnight.After the removal of solvent under reduced pressure, residuum is suspended in water, use dichloromethane extraction.Merge organic extract, water with the saturated sodium-chloride water solution washing, is used anhydrous magnesium sulfate drying then, filters and concentrating under reduced pressure, obtains desired white solid state compound.
Use said procedure and suitable parent material to prepare following compounds:
N-(4-amino-phenyl)-2-methanesulfinyl-benzamide
N-(4-amino-3-cyano group-phenyl)-2-fluoro-benzamide
Furans-2-carboxylic acid (4-amino-3-cyano group-phenyl)-acid amides
N-(4-amino-3-cyano group-phenyl)-ethanamide
Furans-2-carboxylic acid (4-amino-3-trifluoromethyl-phenyl)-acid amides
N-(4-amino-3-methoxyl group-phenyl)-ethanamide
N-(4-amino-3-methoxyl group-phenyl)-2-fluoro-benzamide
Furans-2-carboxylic acid (4-amino-3-methoxyl group-phenyl)-acid amides
Embodiment 17 (method 4A)
2-chloro-1-cyclohexyl oxygen base-4-oil of mirbane
Under the argon gas, slowly dimethyl sulfoxide (DMSO) (20 milliliters) solution with hexalin (2.9 gram) is added in the flask that contains potassium hydride KH (0.90 gram washs 3 times in advance with hexane) stirring at room solution 1 hour.Add dimethyl sulfoxide (DMSO) (10 milliliters) solution of 3-chloro-4-fluoro-oil of mirbane (1 gram), then about 100 degree were arrived in the dark red solution heating that obtains in 3 hours.Reaction mixture with ether (300 milliliters) dilution, and with saturated aqueous ammonium chloride, water (3 times), is the saturated sodium-chloride water solution washing then then.Use the anhydrous magnesium sulfate drying organic layer then, removal of solvent under reduced pressure with silica gel (with the hexane solution of 5% ethyl acetate as the elutriant) oil that chromatography obtains, obtains desired orange solid product.
Embodiment 18 (method 4C)
(2-chloro-4-nitro-phenyl)-methyl-(1-methyl-tetramethyleneimine-3-yl)-amine
Merge 3-chloro-4-fluoronitrobenzene (1.0 gram) and N, N '-dimethyl-3-amino-pyrrolidine (1.72 gram), stir about 24 hours.Use ethyl acetate diluted mixture thing then, wash with water 2 times,, use anhydrous sodium sulfate drying with saturated sodium-chloride washing 1 time.After removal of solvent under reduced pressure,, obtain desired yellow oil product with silica gel column chromatography residuum (is that pure methyl alcohol is as elutriant then with pure ethyl acetate).
Use said procedure and suitable parent material to prepare following compounds:
(2-chloro-4-nitro-phenyl)-dipropyl-amine
1-(2-chloro-4-nitro-phenyl)-piperidines
1-(2-chloro-4-nitro-phenyl)-tetramethyleneimine
(2-chloro-4-nitro-phenyl)-cyclohexyl-methylamine
Benzyl-(2-chloro-4-nitro-phenyl)-amine
(2-chloro-4-nitro-phenyl)-methyl-(1-methyl-piperidin-4-yl)-amine
(2-chloro-4-nitro-phenyl)-cyclohexyl-ethyl-amine
(2-chloro-4-nitro-phenyl)-cyclohexyl-amine
(2-chloro-4-nitro-phenyl)-methyl-(1-methyl-tetramethyleneimine-3-yl)-amine
(1-benzyl-tetramethyleneimine-3-yl)-(2-chloro-4-nitro-phenyl)-methyl-amine
(2-chloro-4-nitro-phenyl)-cyclopentyl-methyl-amine
1-(2-chloro-4-nitro-phenyl)-decahydro-quinoline
Allyl group-(2-chloro-4-nitro-phenyl)-cyclohexyl-amine
2-[(2-chloro-4-nitro-phenyl)-(2-hydroxyl-ethyl)-amino]-ethanol
(2-chloro-4-nitro-phenyl)-isobutyl--methyl-amine
(2-chloro-4-nitro-phenyl)-hexyl-methyl-amine
2-[(2-chloro-4-nitro-phenyl)-methyl-amino]-ethanol
N-(2-chloro-4-nitro-phenyl)-N, N ', N '-trimethylammonium-ethane-1,2-diamines
N-(2-chloro-4-nitro-phenyl)-N, N ', N '-trimethylammonium-propane-1,3-diamines
(1-benzyl-piperidin-4-yl)-(2-chloro-4-nitro-phenyl)-amine
N-(2-chloro-4-nitro-phenyl)-N, N '-dimethyl-ethane-1,2-diamines
N-(2-chloro-4-nitro-phenyl)-N ', N '-dimethyl-propane-1,3-diamines
(2-chloro-4-nitro-phenyl)-(2-methoxyl group-ethyl)-methyl-amine
(1-benzyl-tetramethyleneimine-3-yl)-(2-chloro-4-nitro-phenyl)-amine
4-piperidines-1-base-3-trifluoromethyl-benzonitrile
4-dimethylamino-3-trifluoromethyl-benzonitrile
4-(4-methyl-piperazine-1-yl)-3-trifluoromethyl-benzonitrile
Embodiment 19 (method 4E)
Butyl-(2-chloro-4-nitro-phenyl) thioether
At room temperature stir the N of 3-chloro-4-fluoro-oil of mirbane (5.0 gram) and sodium sulphite (2.5 gram), dinethylformamide (30 milliliters) solution 1 hour uses 1-iodate butane (12.6 gram) to handle then.Removal of solvent under reduced pressure is handled the residuum that obtains with ethyl acetate and hexane then, precipitates inorganic salt.Solids removed by filtration, concentrating under reduced pressure filtrate.Make the residuum that obtains by hydrous magnesium silicate then, as elutriant, obtain desired yellow solid compounds with methylene dichloride.
Use said procedure and suitable parent material to prepare following compounds:
1-butylthio-2-chloro-4-oil of mirbane
2-chloro-1-hexamethylene sulfenyl-4-oil of mirbane
2-chloro-1-ethylmercapto group-4-oil of mirbane
Embodiment 20 (method 4F)
(4-chloro-5-methoxyl group-2-nitro-phenyl)-dimethyl-amine
In tetrahydrofuran (THF) (2.0 milliliters) solution of trifluoromethanesulfonic acid 4-chloro-5-methoxyl group-2-nitro-phenyl ester (1.0 gram), add dimethyl amine (40% aqueous solution, 4 milliliters), at room temperature stirred the mixture about 15 hours.Decompression concentrated solution is dissolved in ethyl acetate with residuum then, washes with water then.With ethyl acetate extraction water layer 1 time,, use anhydrous sodium sulfate drying with the organic layer that the saturated sodium-chloride water solution washing merges.Solvent removed by evaporation at reduced pressure is ground residuum and hexane altogether, obtains desired colourless solid product.
Use said procedure and suitable parent material to prepare following compounds:
(4-chloro-2-nitro-phenyl)-dimethyl-amine
4-(4-chloro-5-methoxyl group-2-nitro-phenyl)-morpholine
(4-chloro-5-methoxyl group-2-nitro-phenyl)-dimethyl-amine
1-(4-chloro-5-methoxyl group-2-nitro-phenyl)-piperidines
1-(4-chloro-5-methoxyl group-2-nitro-phenyl)-tetramethyleneimine
Benzyl-(4-chloro-5-methoxyl group-2-nitro-phenyl)-amine
(2-chloro-6-nitro-phenyl)-dimethyl-amine
Embodiment 21 (method 4G)
(2-chloro-4-nitro-phenyl)-methyl-phenyl-amine
At 0 ℃, in tetrahydrofuran (THF) (75 milliliters) solution of methylphenylamine (3.0 gram), drip n-Butyl Lithium (12.3 milliliters 2.5M hexane solutions).Make mixture be slowly to warm to room temperature, be cooled to 0 ℃ then again, and be added to intubate in tetrahydrofuran (THF) (35 milliliters) solution of the 3-chloro-4-fluoronitrobenzene (4.9 gram) that remains on-78 ℃.After adding, make mixture warm to room temperature in 1 hour, concentrating under reduced pressure by adding the saturated aqueous ammonium chloride cancellation, is used ethyl acetate extraction 3 times then.With 5% hydrochloric acid (3 times), water (1 time), usefulness saturated sodium bicarbonate aqueous solution (1 time), the organic layer of using saturated sodium-chloride water solution (1 time) washing to merge is again used anhydrous magnesium sulfate drying then.After the removal of solvent under reduced pressure,, obtain desired clear colorless oil shape product with silica gel (with the hexane solution of 5% ether as elutriant) chromatography residuum.
Embodiment 22 (method 4H)
2,6-two chloro-4-nitrophenolss
With 3,4,5-trichloronitrobenzene (14.86 gram) is added in ethylene glycol (66 milliliters) solution of phenoxy group potassium (8.66 gram), heated mixt to 160 ℃ about 15 hours.The dark brown solution that obtains is chilled to room temperature, pours in 100 milliliters of cold water, use extracted with diethyl ether 2 times.Water, 10% aqueous sodium hydroxide washes are washed the organic extract of merging, use anhydrous magnesium sulfate drying then.After the removal of solvent under reduced pressure, in the Kugelrohr device, distill, solidify when the yellow oil that obtains is placed.Recrystallization obtains desired faint yellow solid-state product from alcohol-water.
Embodiment 23 (method 5A)
(3,5-two chloro-4-oxyethyl group-phenyl)-t-butyl carbamate
In acetone (18 milliliters) solution of (3,5-two chloro-4-hydroxyl-phenyl)-t-butyl carbamate (1.0 gram) and salt of wormwood (1.0 gram), add ethyl iodide (0.36 milliliter), about 15 hours of stirring at room mixture.Filtering solution then, concentrating under reduced pressure, and between ethyl acetate and water, distribute.Then use the isolating water layer of ethyl acetate extraction 2 times again, the organic extract that merges with 10% aqueous sodium hydroxide solution, water washing is used anhydrous sodium sulfate drying then continuously.Solvent evaporated under reduced pressure obtains desired brown solid product.
Use said procedure and suitable parent material to prepare following compounds:
(3,5-two chloro-4-oxyethyl group-phenyl)-t-butyl carbamate
(4-butoxy-3,5-two chloro-phenyl)-t-butyl carbamate
(4-benzyloxy-3,5-two chloro-phenyl)-t-butyl carbamate
(4-carbamyl ylmethoxy-3,5-two chloro-phenyl)-t-butyl carbamate
[3,5-two chloro-4-(2-nitrilo oxyethyl group)-phenyl]-t-butyl carbamate
(4-tert-butoxycarbonyl amino-2,6-two chloro-phenoxy groups)-methyl acetate
3-butoxy-methyl benzoate
3-tert-butoxycarbonyl methoxyl group-methyl benzoate
3-carbamyl ylmethoxy-methyl benzoate
[4-(3-carbamyl ylmethoxy-benzoyl-amido)-phenyl]-t-butyl carbamate
4-[3-(2-chloro-oxyethyl group)-benzoyl-amido]-phenyl }-t-butyl carbamate
Embodiment 24 (method 5C)
(2,6-two chloro-4-nitro-phenoxy groups)-tert.-butyl acetate
2, in dimethyl formamide (50 milliliters) solution of 6-two chloro-4-nitrophenolss (2.5 gram) and salt of wormwood (3.3 gram), add bromo-acetic acid tert-butyl (10 milliliters), stirring at room mixture 2 days.Then solution is poured in 500 ml waters, used hexane extraction 3 times,, use anhydrous magnesium sulfate drying then with the organic extract that the saturated aqueous ammonium chloride washing merges.Solvent evaporated under reduced pressure makes the oil and the hexane that obtain grind altogether then, obtains desired white solid state product.
Use said procedure and suitable parent material to prepare following compounds:
3-dimethylamino-1-(4-nitro-phenyl)-acrylketone
2-chloro-1-isopropoxy-4-oil of mirbane
1,3-two chloro-2-methoxyl groups-4-methyl-5-nitro benzene
1-chloro-4-oxyethyl group-2-methoxyl group-5-nitro-benzene
1-butoxy-4-chloro-5-methoxyl group-2-nitro-benzene
1-chloro-2-methoxyl group-5-nitro-4-(phenyl methoxyl group) benzene (CA title)
1-chloro-4-methoxyl group-5-nitro-2-(phenyl methoxyl group) benzene (CA title)
(2,6-two chloro-4-nitro-phenoxy groups)-tert.-butyl acetate
(2,6-two chloro-4-nitro-phenoxy groups)-acetonitrile
1-chloro-4-methoxyl group-2-methyl-5-nitro-benzene
2-(4-chloro-5-methoxyl group-2-nitro-phenoxy group)-ethanamide
2-(2-chloro-5-methoxyl group-4-nitro-phenoxy group)-ethanamide
(4-chloro-5-methoxyl group-2-nitro-phenoxy group)-acetonitrile
(2-chloro-5-methoxyl group-4-nitro-phenoxy group)-acetonitrile
4-(2-chloro-5-methoxyl group-4-nitro-phenoxy group)-butyronitrile
2-(4-chloro-5-methoxyl group-2-nitro-phenoxy group)-ethanol
2-(2-chloro-5-methoxyl group-4-nitro-phenoxy group)-ethanol
(2-chloro-5-methoxyl group-4-nitro-phenoxy group)-tert.-butyl acetate
(2-chloro-5-methoxyl group-4-nitro-phenoxy group)-methyl acetate
(4-chloro-5-methoxyl group-2-nitro-phenoxy group)-methyl acetate
(4-chloro-5-methoxyl group-2-nitro-phenoxy group)-tert.-butyl acetate
(2-chloro-4-nitro-phenoxy group)-acetonitrile
1-butoxy-2-chloro-4-nitro-benzene
2-chloro-4-nitro-1-(2,2,2-three fluoro-oxyethyl groups)-benzene
2-chloro-4-nitro-1-propoxy--benzene
2-chloro-1-oxyethyl group-4-nitro-benzene
1,3-two iodo-2,4-dimethoxy-5-nitro-benzene
1,3-two bromo-2,4-dimethoxy-5-nitro-benzene
3-chloro-2,4-dimethoxy-oil of mirbane
Embodiment 25 (method 5E)
[3,5-two chloro-4-(2-hydroxyl-oxyethyl group)-phenyl]-t-butyl carbamate
In toluene (20 milliliters) solution of (3,5-two chloro-5-hydroxyl-phenyl)-t-butyl carbamate (1.0 gram) and salt of wormwood (0.55 gram), add ethylene carbonate (1.6 gram), heated mixt is to refluxing 3 hours.Add 2.5M aqueous sodium hydroxide solution (50 milliliters) in the refrigerative reaction mixture, water, the saturated isolating organic layer of sodium chloride aqueous solution continuous washing are used anhydrous sodium sulfate drying then then.Solvent removed by evaporation at reduced pressure then with silica gel (with the hexane solution of 30% ethyl acetate as the elutriant) residuum that chromatography obtains, obtains desired white foam shape product.
Embodiment 26 (method 6)
3-(2-chloro-4-nitro-phenoxy group)-1-methyl-tetramethyleneimine
In tetrahydrofuran (THF) (60 milliliters) solution of 2-chloro-4-nitrophenols (2.0 gram), add 1-methyl-3-pyrrolidinol (2.3 gram), triphenyl phosphine (6.0 gram) and diethylazodicarboxylate's (3.6 milliliters), in argon gas atmosphere, at room temperature stirred the mixture 1.5 hours.Decompression concentrated solution then with the ethyl acetate dilution, is used 10% saturated aqueous sodium hydroxide solution, water, saturated sodium chloride aqueous solution continuous washing then, uses anhydrous sodium sulfate drying.Solvent removed by evaporation at reduced pressure then, the residuum that obtains with silica gel (use ethyl acetate earlier, the dichloromethane solution of using 10% methyl alcohol again is as elutriant) chromatography.The product component that recrystallization goes out to merge from hexane obtains desired yellow solid product then.
Use said procedure and suitable parent material to prepare following compounds:
4-(2-chloro-4-nitro-phenoxy group)-1-methyl-piperidines
3-(2-chloro-4-nitro-phenoxy group)-1-methyl-tetramethyleneimine
[2-(2-chloro-4-nitro-phenoxy group)-ethyl]-dimethyl-amine
[3-(2-chloro-4-nitro-phenoxy group)-propyl group]-dimethyl-amine
Embodiment 27 (method 7A)
2-chloro-3-methoxyl group-6-nitro-phenol and 2,4-two chloro-3-methoxyl group-6-nitro-phenol
In the flask that contains 3-methoxyl group-6-nitro-phenol (0.5 gram), add aqueous sodium hypochlorite solution (5.25% aqueous solution, 21 milliliters), about 24 hours of stirring at room mixture.Cooling mixture in ice bath is used the concentrated hydrochloric acid acidifying then, then uses ethyl acetate extraction 2 times.Use the anhydrous magnesium sulfate drying organic extract.Solvent removed by evaporation at reduced pressure with silica gel (with the hexane solution of 15% acetone as elutriant) chromatography residuum, provides one solid-state-or two-chlorating product of yellow.
Use said procedure and suitable parent material to prepare following compounds:
3-chloro-2-hydroxyl-4-methoxyl group-oil of mirbane
3,5-two chloro-2-hydroxyl-4-methoxyl group-oil of mirbane
Embodiment 28 (method 7B)
2,4-two chloro-3-methyl-6-nitro-phenol
In water (150 milliliters) solution of 3-methyl-4-nitro-phenol (5.0 gram), add aqueous sodium hypochlorite solution (5.25% aqueous solution, 230 milliliters), about 15 hours of stirring at room mixture.Add aqueous sodium hypochlorite solution (5.25% aqueous solution, 230 milliliters) once more, stirring at room mixture 2.5 days.Cooling mixture in ice bath is used the concentrated hydrochloric acid acidifying then, then uses ethyl acetate extraction 2 times.With these organic extracts of dried over mgso, solvent removed by evaporation at reduced pressure,, obtain desired yellow solid product with silica gel (using ethyl acetate) chromatography residuum as elutriant.Recrystallization obtains analytically pure sample 1 time from chloroform.
Embodiment 29 (method 7C)
1-bromo-2,4-dimethoxy-5-nitro-benzene
2, chloroform (1 milliliter) solution of dripping bromine (0.23 gram) in chloroform (3 milliliters) solution of 4-dimethoxy-oil of mirbane (0.50 gram), about 15 hours of stirring at room mixture.Chloroform (1 milliliter) solution that adds bromine (0.15 gram) once more, restir mixture 4 hours.Mixture is poured in 5% aqueous solution of sodium bisulfite then, then used chloroform extraction.Use 5% aqueous solution of sodium bisulfite then continuously, the organic extract that merges with the saturated sodium-chloride washing is used anhydrous sodium sulfate drying then then.Removal of solvent under reduced pressure, recrystallization from toluene obtains desired yellow solid product.
Embodiment 30 (method 7D)
2,4-two bromo-3-methoxyl group-6-nitro-phenol
Glacial acetic acid (3 milliliters) solution of dripping bromine (1.42 gram) in Glacial acetic acid (3 milliliters) solution of 5-methoxyl group-2-nitro-phenol (0.25 gram) and trifluoroacetic acid silver (0.49 gram), about 24 hours of stirring at room mixture.Then solution is distributed between ethyl acetate and water, organic layer is continuously with 5% aqueous solution of sodium bisulfite washing 3 times, with saturated sodium bicarbonate aqueous solution washing 3 times, with saturated sodium-chloride water solution washing 1 time.Use the anhydrous magnesium sulfate drying organic layer then, removal of solvent under reduced pressure.With silica gel (with the hexane solution of 20% ethyl acetate as elutriant) chromatography residuum, recrystallization from chloroform obtains desired orange solid-state dibrominated product then.
Embodiment 31 (method 7E)
1-iodo-2,4-dimethoxy-5-nitro-benzene
2, add two chloriodic acid benzyltrimethylammon.um (1.90 gram) and Zinc Chloride Anhydrous (1.0 gram) in Glacial acetic acid (30 milliliters) solution of 4-dimethoxy-oil of mirbane (1.0 gram), stirring at room mixture under one deck argon gas.After 5 hours, add two chloriodic acid benzyltrimethylammon.um (0.4 gram) once more, add again 1 time after 24 hours.After 24 hours, add zinc chloride (0.5 gram) and Glacial acetic acid (1 5 milliliters) once more.Stirring at room mixture 3 days filters then, with the dilution of 5% aqueous solution of sodium bisulfite, uses ethyl acetate extraction 3 times.Wash the organic extract of these merging with 5% sulfurous hydracid sodium water solution, saturated sodium-chloride water solution, use anhydrous magnesium sulfate drying then.Removal of solvent under reduced pressure, residuum and hexane grind altogether, obtain desired faint yellow solid-state product.
Embodiment 32 (method 7F)
2,4-two iodo-3-methoxyl group-6-nitro-phenol
In the solution of the methylene dichloride (15 milliliters) of 5-methoxyl group-2-nitro-phenol (0.25 gram) and methyl alcohol (6 milliliters), add two chloriodic acid benzyltrimethylammon.um (1.08 gram) and sodium bicarbonate (0.85 restrains), stirring at room mixture 24 hours.Filtering solution then, concentrating under reduced pressure filtrate is dissolved in ethyl acetate with residuum, then with 5% sodium bicarbonate aqueous solution, 5% sulfurous hydracid sodium water solution and saturated sodium-chloride water solution continuous washing.Behind anhydrous magnesium sulfate drying, solvent removed by evaporation at reduced pressure, recrystallization residuum from toluene obtains the acicular product of desired yellow.
Embodiment 33 (method 7G)
1-fluoro-2,4-dimethoxy-5-nitro-benzene
2, add 3 in tetrachloroethane (10 milliliters) solution of 4-dimethoxy-oil of mirbane (1.0 gram), 5-two chloro-1-fluoro-pyridine fluoroform sulphonates (85%, 5.07 gram), heated mixt to 120 ℃ 5 hours.Add 3 again, 5-two chloro-1-fluorine pyridine fluoroform sulphonates (85%, 0.25 gram) continue to stir 1 hour.Then solution is cooled to room temperature, by silicagel column (is that the hexane solution of 30% ethyl acetate is as elutriant then with hexane).Merge the product that contains component, reduction vaporization, recrystallization from hexane obtains desired brown solid product.
Embodiment 34 (method 8)
3-chloro-4-trifluoromethyl-oil of mirbane
With the N of 3-chloro-4-iodo-oil of mirbane (2.26 gram), trimethylammonium (trifluoromethyl) silane (5.68 gram), cupric iodide (I) (2.28 gram) and Potassium monofluoride (0.56 gram), dinethylformamide (8 milliliters) solution was tube sealing internal heating to 80 ℃ 40 hours.Cooling solution dilutes with ether then, filtration over celite, and water, saturated sodium-chloride water solution wash filtrate are used anhydrous sodium sulfate drying then continuously.Removal of solvent under reduced pressure with silica gel (with the hexane solution of 1% ether, the hexane solution of using 10% ethyl acetate then is as elutriant) chromatography residuum, obtains desired colorless oil product.
Embodiment 35 (method 9)
(3-chloro-4-methanesulfinyl-phenyl)-t-butyl carbamate
In methylene dichloride (15 milliliters) solution of (3-chloro-4-methylthio group-phenyl)-t-butyl carbamate (0.89 gram), add dimethyl ethylene oxide (the dimethyldioxirane) (acetone soln of～0.11M at 0 ℃, 34 milliliters), 0 ℃ stirred the mixture 1 hour.Removal of solvent under reduced pressure is dissolved in methylene dichloride with residuum, with the saturated sodium-chloride water solution washing, uses colourless dried over mgso then.Removal of solvent under reduced pressure obtains desired orange spumescence product.
Embodiment 36 (method 9B)
[4-(2-methylsulfinyl-benzoyl-amido)-phenyl]-t-butyl carbamate
At 2-methylthio group-N-[4-(2,2,2-three fluoro-acetylamino)-phenyl]-add the saturated solution (5 milliliters) of sodium periodate in the solution of benzamide (234 milligrams), stirred the mixture 12 hours.The purple mixture is poured in the water, used ethyl acetate extraction, use the Anhydrous potassium carbonate drying, evaporation obtains 101 milligrams of red solid.
Use said procedure and suitable parent material to prepare following compounds:
[4-(2-methanesulfinyl-benzoyl-amido)-phenyl]-t-butyl carbamate
2-methanesulfinyl-N-[4-(2,2,2-three fluoro-acetylamino)-phenyl]-benzamide
Embodiment 37 (method 10)
(3-chloro-4-methylsulfonyl-phenyl)-t-butyl carbamate
In methylene dichloride (30 milliliters) solution of (3-chloro-4-methylthio group-phenyl)-t-butyl carbamate (0.90 gram), add dimethyl ethylene oxide (acetone soln of～0.11M, 80 milliliters) at 0 ℃, 0 ℃ stirred the mixture 1 hour.Removal of solvent under reduced pressure is dissolved in methylene dichloride with residuum, with the saturated sodium-chloride water solution washing, uses anhydrous magnesium sulfate drying then.Removal of solvent under reduced pressure obtains desired orange spumescence product.
Embodiment 38 (method 11)
3-chloro-4-vinyl-phenyl amine
In tetrahydrofuran (THF) (120 milliliters) solution of 3-chloro-4-iodo-aniline (6.95 gram), triphenylarsine (0.67 gram) and three (dibenzalacetone) palladium (0) (0.50 gram), add tributylvinyl tin (10 gram) at 50 ℃, 50 ℃ stirred the mixture under argon gas about 15 hours.Cool off reactant then, filtration over celite, reduction vaporization filtrate is to doing.Residuum is dissolved in hexane, then with 5% aqueous hydrochloric acid extraction 3 times.Use these acid extraction thing aqueous solution of solid-state carbonic acid potashization then, and with ethyl acetate extraction 3 times.Wash the organic extract of these merging then with saturated sodium-chloride water solution, use anhydrous magnesium sulfate drying, removal of solvent under reduced pressure.Residuum with silica gel (hexane, the hexane solution that is 10% ethyl acetate then is as elutriant) chromatography obtains obtains desired amber oily product.
Embodiment 39 (method 12)
[3-chloro-4-(1-hydroxyl-ethyl)-phenyl]-carboxylamine 2-TMS-ethyl ester
(3-chloro-4-vinyl-phenyl)-carboxylamine 2-TMS-ethyl ester (2.6 gram) is added in the water (7 milliliters) and tetrahydrofuran (THF) (5.25 milliliters) solution of mercuric acetate (3.48 gram), stirred the mixture about 15 hours.Add the solution of the 3N aqueous sodium hydroxide solution (8.7 milliliters) of 3N aqueous sodium hydroxide solution (8.7 milliliters) and 0.5M sodium borohydride then, then stirred 6 hours.Use sodium chloride saturated solution then, use ethyl acetate extraction.Wash these organic extracts with saturated sodium-chloride water solution then, and use anhydrous sodium sulfate drying.Removal of solvent under reduced pressure with silica gel (with the hexane solution of 20% ethyl acetate as elutriant) chromatography residuum, obtains desired white solid state product.
Embodiment 40 (method 13)
[3-chloro-4-(2-hydroxyl-ethyl)-phenyl]-t-butyl carbamate
In the stirring suspension of the tetrahydrofuran (THF) (13 milliliters) of sodium borohydride (0.45 gram),, stirred the mixture 1 hour at 0 ℃ at 0 ℃ of adding Glacial acetic acid (0.75 milliliter).Then with the solution temperature to room temperature, add (3-chloro-4-vinyl-phenyl)-carboxylamine 2-TMS-ethyl ester (1.0 gram).About 15 hours of stirring at room reactant is heated to then and refluxed about 20 hours.Cooling mixture then adds the solution of 5N aqueous sodium hydroxide solution (0.80 milliliter) and 30% aqueous hydrogen peroxide solution (0.56 milliliter).After stirring 15 hours once more, separating layer is used extracted with diethyl ether water layer 3 times, uses the anhydrous magnesium sulfate drying organic extract.After the removal of solvent under reduced pressure,, obtain desired amber oily product with silica gel (with the hexane of 40% ethyl acetate as elutriant) chromatography residuum.
Embodiment 41 (method 14)
[4-(1-azido--ethyl)-3-chloro-phenyl]-carboxylamine 2-TMS-ethyl ester
In tetrahydrofuran (THF) (20 milliliters) solution of [3-chloro-4-(1-hydroxyl-ethyl)-phenyl]-carboxylamine 2-TMS-ethyl ester (1.25 gram), at 0 ℃, under one deck argon gas, add triphenyl phosphine (2.6 gram), the hydrazoic acid (dichloromethane solution of about 2.5 molar equivalents, according to Fieser and Fierser, Reagents for Organic Synthesis, Vol.1, pg.446; Wiley, the method preparation of New York) and diethylazodicarboxylate's (1.72 gram).After about 10 minutes, removal of solvent under reduced pressure with silica gel (with the hexane solution of 5% ethyl acetate as elutriant) chromatography residuum, obtains desired colorless oil product.
Embodiment 42 (method 15)
[3-chloro-4-(3-dimethylamino-third-1-alkynyl)-phenyl]-t-butyl carbamate
In the deoxidation solution of the triethylamine (120 milliliters) of (3-chloro-4-iodo-phenyl)-t-butyl carbamate (10.0 gram), add 1-dimethylamino-2-propine (2.82 gram), chlorination two (triphenyl phosphine) palladium (II) (0.4 gram) and cuprous iodide (0.054 gram).Under the argon gas, about 6 hours of stirring at room mixture, short period of time heating (about 10 minutes) is to 60 ℃ then.Reaction mixture then, filtration over celite, solvent removed by evaporation at reduced pressure.Residuum is dissolved in ethyl acetate, washes with water 3 times,, use colourless dried over mgso with saturated sodium-chloride water solution washing 1 time.Solvent removed by evaporation at reduced pressure with silica gel (with the hexane solution of 80% ethyl acetate as elutriant) chromatography residuum, obtains the amber oily product of purifying, and it solidifies in placement.
Use said procedure and suitable parent material to prepare following compounds:
[3-chloro-4-(3-dimethylamino-third-1-alkynyl)-phenyl]-t-butyl carbamate
[3-(4-methoxyl group-phenyl)-Propargyl]-dimethyl-amine
4-(3-dimethylamino-third-1-alkynyl)-benzonitrile
Dimethyl-[3-(4-nitro-phenyl)-Propargyl]-amine
Benzonitrile
Embodiment 43 (method 16)
[3-chloro-4-(3-dimethylamino-acryl)-phenyl]-t-butyl carbamate
In the freezing solution of the methylene dichloride (30 milliliters) of [3-chloro-4-(3-dimethylamino-third-1-alkynyl)-phenyl]-t-butyl carbamate (4.0 gram), divide and add 3-chlorine peroxybenzoic acid (2.34 gram) in a small amount.0 ℃ of reaction stirred is after 20 minutes, with the alkali alumina (Brockmann Grade I, 150 orders) of mixture by 20 weight equivalents, with the dichloromethane solution wash-out N-oxide compound of 5% methyl alcohol.Merge the component that all contain desired amine n-oxide, reduction vaporization is to approaching dry.Handle 3 times with small portion methyl alcohol (about 50 milliliters) continuously, reduction vaporization is adjusted to 250 milliliter by adding methyl alcohol with liquor capacity near dry then.Methanol solution with the N-oxide compound is heated to about 15 hours of backflow then, cooling then, and solvent evaporated under reduced pressure is to doing.With silica gel (with the hexane solution of 80% ethyl acetate as elutriant) chromatography residuum, obtain desired faint yellow solid-state product.
Embodiment 44 (method 17)
(3-chloro-4-isoxazole-5-base-phenyl)-t-butyl carbamate
Handle [3-chloro-4-(3-dimethylamino-acryl-phenyl]-t-butyl carbamate (270 milligrams of) De dioxs (3 milliliters) solution, stirring at room mixture 10 days with oxammonium hydrochloride (122 milligrams).With ethyl acetate diluted mixture thing, water, 5% sodium bicarbonate aqueous solution, saturated sodium-chloride water solution continuous washing are used anhydrous magnesium sulfate drying.Solvent removed by evaporation at reduced pressure with silica gel (with the hexane solution of 33% ethyl acetate as the elutriant) residuum that chromatography obtains, obtains desired colourless solid product.
Embodiment 45 (method 18)
[3-chloro-4-(1H-pyrazole-3-yl)-phenyl]-t-butyl carbamate
With ethanol (1.25 milliliters) solution of hydrazine hydrate (0.25 milliliter) processing [3-chloro-4-(3-dimethylamino-acryl)-phenyl]-t-butyl carbamate (250 milligrams), stirring at room mixture 3 hours.Use 30 milliliters of ether diluted mixture things then, wash with water 3 times,, use anhydrous magnesium sulfate drying with saturated sodium-chloride water solution washing 1 time.Solvent removed by evaporation at reduced pressure with silica gel (with the hexane solution of 67% ethyl acetate as the elutriant) residuum that chromatography obtains, obtains desired oily product.
Embodiment 46 (method 19A)
N-(2-chloro-4-nitrophenyl)-2-thiomorpholine-4-base-ethanamide
In tetrahydrofuran (THF) (50 milliliters) solution of N-(chloracetyl)-2-chloro-4-N-methyl-p-nitroaniline (3.80 gram), add thiomorpholine (10 milliliters), placed solution 1 hour.Reaction mixture is poured in the water, collected faint yellow solid, recrystallization from the 2-propyl alcohol of heat obtains faint yellow crystalline solid then.
Use said procedure and suitable parent material to prepare following compounds:
(4-{2-[two-(2-hydroxyl-ethyl)-amino]-acetylamino }-phenyl)-t-butyl carbamate
[4-(2-dimethylamino-acetylamino)-phenyl]-t-butyl carbamate
4-[3-(2-dimethylamino-oxyethyl group)-benzoyl-amido]-phenyl }-t-butyl carbamate
4-[3-(2-morpholine-4-base-oxyethyl group)-benzoyl-amido]-phenyl }-t-butyl carbamate
N-(2-chloro-4-nitro-phenyl)-2-dimethylamino-ethanamide
N-(2-chloro-4-nitro-phenyl)-2-piperidines-1-base-ethanamide
N-(2-chloro-4-nitro-phenyl)-2-morpholine-4-base-ethanamide
N-(2-chloro-4-nitro-phenyl)-2-dipropyl amino-ethanamide
N-(2-chloro-4-nitro-phenyl)-2-thiomorpholine-4-base-ethanamide
N-(2-chloro-4-nitro-phenyl)-2-diethylamino-ethanamide
N-(2-chloro-4-nitro-phenyl)-2-tetramethyleneimine-1-base-ethanamide
2-nitrogen heterocyclic heptan-1-base-N-(2-chloro-4-nitro-phenyl)-ethanamide
N-(2-chloro-4-nitro-phenyl)-2-(2-methyl-piperidines-1-yl)-ethanamide
N-(2-chloro-4-nitro-phenyl)-2-(3-methyl-piperidines-1-yl)-ethanamide
N-(2-chloro-4-nitro-phenyl)-2-(4-methyl-piperidines-1-yl)-ethanamide
Embodiment 47 (method 19B)
N-(2-chloro-4-nitrophenyl)-2-(2-dimethylamino ethylmercapto group) ethanamide
At the N of N-(acetyl chloride base)-2-chloro-4-N-methyl-p-nitroaniline (3.01 gram), add powdered sodium carbonate (6.0 gram) and 2-dimethylaminoethyl thiolate hydrochlorate (6.0 gram) in the solution of dinethylformamide (100 milliliters).25 ℃ stirred the mixture 1 hour, poured in the water, used ethyl acetate extraction.With the dry ethyl acetate solution of Anhydrous potassium carbonate, concentrating under reduced pressure obtains oil.From toluene-hexane (3: 1) recrystallization, obtain faint yellow solid-state crystalline solid.
Embodiment 48 (method 20)
(4-tert-butoxycarbonyl amino-2-chloro-phenyl)-carboxylamine 2-piperidines-1-base-ethyl ester
1, in methylene dichloride (40 milliliters) suspension of 1-carbonyl-two-(1,2,4)-triazole (4.0 gram) with methylene dichloride (45 milliliters) solution that was added dropwise to (4-amino-3-chloro-phenyl) t-butyl carbamate (5.0 restrain) in 20 minutes.Stirring at room mixture 30 minutes forms precipitation at this time point.In this mixture, add piperidines ethanol (6.6 milliliters) and tetrahydrofuran (THF) (20 milliliters), to keep homogeneous phase.After reflux was spent the night, the cooling reactant was poured in the water then, separates organic layer, washs with saturated sodium-chloride water solution then.Use anhydrous sodium sulfate drying solution, filter and concentrating under reduced pressure, obtain thick oil,, obtain desired white foam shape product with silica gel (with the dichloromethane solution of 5% methyl alcohol as elutriant) chromatography purification.
Embodiment 49 (method 21)
5-phenyl-[1,2,3] thiadiazoles-4-carboxylate methyl ester
Handle acetonitrile (10 milliliters) solution of ethyl benzoylacetate (1.1 gram) with 4-Methyl benzenesulfonyl nitrine (1.3 gram) and triethylamine (1.6 gram).After the stirred overnight at room temperature, the concentrating under reduced pressure reactant, the crude product that obtains with acetic acid ethyl dissolution, and wash with 1N sodium hydroxide.Use the anhydrous magnesium sulfate drying organic layer then, filter and concentrating under reduced pressure, obtain yellow oil.Dissolve this oil with methylene dichloride, filter hydrated magnesium silicate, use the methylene dichloride wash-out, obtain partially purified colorless oil diazo-ketones.To be dissolved in toluene (25 milliliters) from the diazo-ketones sample (1.2 gram) that obtains, with 2,4-two (4-p-methoxy-phenyl)-1,3-dithia-2,4-two phosphorus heterocycle butane-2,4-disulphide (2.8 gram) is handled, and the reacting by heating thing is to refluxing.After 3 hours, reactant is cooled to room temperature, is added on the silicagel pad, use the methylene dichloride wash-out.After the removal of solvent under reduced pressure, with silica gel (with the petroleum ether solution of 30% ether as elutriant) chromatography, the oil that purifying obtains, recrystallization from hexane obtains desired faint yellow needle-like product then.
Use said procedure and suitable parent material to prepare following compounds:
5-phenyl-[1,2,3] thiadiazoles-4-carboxylic acid, ethyl ester
5-methyl-[1,2,3] thiadiazoles-4-carboxylate methyl ester
Embodiment 50
The ethyl benzoylacetate Urea,amino-
Ethyl benzoylacetate (5.0 gram) is dissolved in methyl alcohol (10 milliliters), is added to rapidly in water (130 milliliters) solution of hot carbamylhydrazine hydrochloride (29 gram).In this solution, add pyridine (4.1 gram), be heated to then and refluxed 5 minutes, reaction mixture is cooled to-20 ℃ and spends the night.Filter and collect the solid semicarbazone that obtains, wash with water, with the ether washing, obtain desired white crystalline product then.
Use said procedure and suitable parent material to prepare following compounds:
(Z)-and the 3-[(aminocarboxyl) hydrazone group]-4,4,4-trifluoroacetic acid ethyl ester
3-[(Z)-2-(aminocarboxyl) hydrazone group]-3-phenylpropionic acid ethyl ester
3-[(E)-2-(aminocarboxyl) hydrazone group]-3-(3-furyl) ethyl propionate
Embodiment 51
5-phenyl-[1,2,3] thiadiazoles-5-carboxylic acid, ethyl ester
0 ℃ of pure thionyl chloride (5 milliliters) solution that stirs ethyl benzoylacetate semicarbazone (2.5 gram) 1 hour.Add methylene dichloride (25 milliliters) then, slowly destroy excessive thionyl chloride with saturated sodium bicarbonate.The precipitation that forms when removing by filter cancellation is used dichloromethane extraction filtrate.Organic extract with anhydrous magnesium sulfate drying merges filters and concentrating under reduced pressure.With silica gel (with the dichloromethane solution of 50% hexane as elutriant) chromatography, obtain desired colorless oil product.
Use said procedure and suitable parent material to prepare following compounds:
4-methyl-[1,2,3] thiadiazoles-5-carboxylate methyl ester
4-phenyl-[1,2,3] thiadiazoles-5-carboxylic acid, ethyl ester
4-furans-3-base-[1,2,3] thiadiazoles-5-carboxylic acid, ethyl ester
Embodiment 52
4-methyl-[1,2,3] thiadiazoles-5-carboxylic acid
4-methyl-[1,2,3] thiadiazoles-5-carboxylate methyl ester (1.7 gram) is dissolved in methyl alcohol (15 milliliters), and handles with 1N sodium hydroxide (16 milliliters).After the stirring at room 1 hour, with concentrated hydrochloric acid (1.5 milliliters) processing reaction thing, and concentrating under reduced pressure.The muddy water layer that obtains with extracted with diethyl ether 2 times, the organic layer with anhydrous magnesium sulfate drying merges filters, and concentrating under reduced pressure, obtains desired white powder compound.
Use said procedure and suitable parent material to prepare following compounds:
3-ethoxycarbonyl methoxy-phenylformic acid
5-furans-3-base-[1,2,3] thiadiazoles-4-carboxylic acid
The thiazole-4-carboxylic acid
4-methyl-[1,2,3] thiadiazoles-5-carboxylic acid
5-methyl-[1,2,3] thiadiazoles-4-carboxylic acid
Embodiment 53 (method 25)
Three fluoro-methylsulfonic acid 4-chloro-5-methoxyl group-2-nitro phenyl esters
In the solution of the methylene dichloride (150 milliliters) of 4-chloro-5-methoxyl group-2-nitrophenols (6.5 gram), at 0 ℃, under argon gas, add triethylamine (10 gram), add methylene dichloride (30 milliliters) solution of trifluoromethanesulfanhydride anhydride (13.5 gram) then.0 ℃ of stirred solution 10 minutes is then with the methylene dichloride dilution, with saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution washing.Behind anhydrous sodium sulfate drying, solvent removed by evaporation at reduced pressure is dissolved in the hexane solution of 20% methylene dichloride with residuum, and by magnesium silicate hydrate short column (with the hexane solution of 20% methylene dichloride as elutriant).Merge the product that contains component, solvent removed by evaporation at reduced pressure obtains desired yellow oil product.
Use said procedure and suitable parent material to prepare following compounds:
Three fluoro-methylsulfonic acid 4-chloro-5-methoxyl group-2-nitro-phenyl esters
Three fluoro-methylsulfonic acid 4-chloro-2-nitro-phenyl esters
Three fluoro-methylsulfonic acid 2-chloro-6-nitro-phenyl esters
Embodiment 54 (method 26)
[4-(3-dimethylamino-benzoyl-amido)-phenyl]-t-butyl carbamate
1: 2 tetrahydrofuran (THF)-methyl alcohol (15 milliliters) solution of stirring [4-(3-amino-benzoyl-amido)-phenyl]-t-butyl carbamate (505 milligrams), sodium cyanoborohydride (250 milligrams), acetate (3) and 40% formalin (4 milliliters) 15 minutes; pour into then in the saturated sodium bicarbonate aqueous solution, be extracted into ethyl acetate.With the dry ethyl acetate solution of Anhydrous potassium carbonate, concentrating under reduced pressure obtains solid, uses the acetonitrile recrystallization, obtains rose pink crystalline solid.
Use said procedure and suitable parent material to prepare following compounds:
[4-(3-dimethylamino-benzoyl-amido)-phenyl]-t-butyl carbamate
(3-bromo-5-trifluoromethyl-phenyl)-dimethyl-amine
N-(3-chloro-5-dimethylamino-phenyl)-ethanamide
Embodiment 55 (method 27)
N-(4-aminophenyl)-2-hydroxybenzamide
In methyl alcohol (10 milliliters) solution of acetate 2-(4-aminophenyl formamyl) phenyl ester (580 milligrams), add saturated sodium bicarbonate (2 milliliters) and water (3 milliliters).Mixture 80 ℃ of heating 30 minutes, is poured in the half saturated sodium chloride aqueous solution then, used ethyl acetate extraction.Use the anhydrous sodium sulfate drying ethyl acetate solution, concentrating under reduced pressure obtains oil, then should oil and ether grind altogether, obtain desired white solid state product.
Embodiment 56 (method 28)
[4-(3-(hydroxy benzoyl amino) phenyl) } t-butyl carbamate
In methyl alcohol (75 milliliters) solution of acetate 3-(4-aminophenyl formamyl) phenyl ester (4.34 gram), add 0.1N aqueous sodium hydroxide solution (25 milliliters) and tetrahydrofuran (THF) (25 milliliters).40 ℃ were heated this solution 30 minutes, and cooling is poured in the 1M hydrochloric acid, and used ethyl acetate extraction then.Use the anhydrous sodium sulfate drying ethyl acetate solution, concentrating under reduced pressure obtains white solid, and it is further by grinding purifying altogether with ether.
Embodiment 57 (method 29)
N-(4-aminophenyl)-2-hydroxymethyl benzamide
Add lithium borohydride (1.0 gram) in tetrahydrofuran (THF) (4 milliliters) solution of N-(4-aminophenyl) phthalic imidine (332 milligrams), 25 ℃ were stirred this mixture 1 hour.Mixture is poured in the water, used ethyl acetate extraction.Use the anhydrous sodium sulfate drying ethyl acetate solution, concentrating under reduced pressure obtains white foam, when it and ether grind altogether, obtains desired white powder product.
Embodiment 58 (method 30)
(3-chloro-5-dimethylamino-phenyl)-t-butyl carbamate
In toluene (10 milliliters) solution of (3-amino-5-chloro-phenyl)-t-butyl carbamate (0.32 gram), add formalin (37%, 1.5 milliliter), add 10% palladium carbon (0.50 gram) then, under hydrogen, stirred the mixture about 15 hours.Then with the solution filtration over celite, concentrating under reduced pressure filtrate.With silica gel (with the hexane solution of 50% methylene dichloride as elutriant) chromatography residuum, obtain desired white solid state product.
Embodiment 59 (method 35)
N-(4-{3-[3,5-two chloro-4-(2-hydroxyl-oxyethyl group)-phenyl]-thioureido }-phenyl)-ethanamide
At acetate 2-{4-[3-(4-acetylamino-phenyl)-thioureido]-2; 6-two chloro-phenoxy groups }-add 1N aqueous sodium hydroxide solution (1 milliliter), about 2 hours of stirring at room mixture in 1: 1 tetrahydrofuran (THF) of ethyl ester (0.16 gram) and the mixture solution of methyl alcohol (2.5 milliliters).Then solution is poured in the 2M aqueous hydrochloric acid (3 milliliters), be extracted into ethyl acetate, use anhydrous sodium sulfate drying.Solvent removed by evaporation at reduced pressure is ground residuum and ether altogether, obtains desired white solid state product.
Embodiment 60 (method 36)
4-[3-(4-acetylamino-phenyl)-thioureido] and-2,6-two chloro-phenoxy groups }-acetate
In the mixture solution of 1: 1 tetrahydrofuran (THF) of { 4-[3-(4-acetylamino-phenyl)-thioureido]-2,6-two chloro-phenoxy groups }-ethyl acetate (0.29 gram) and methyl alcohol (4 milliliters), add 1N sodium hydroxide (2 milliliters), about 2 hours of stirring at room mixture.Then solution is poured in the 2M aqueous hydrochloric acid (5 milliliters), be extracted into ethyl acetate, use the anhydrous sodium sulfate drying extract.Solvent removed by evaporation at reduced pressure is ground residuum and ether altogether, obtains desired white solid state product.
Use said procedure and suitable parent material to prepare following compounds:
4-[3-(4-acetylamino-phenyl) thioureido] and-2,6-two chloro-phenoxy groups }-acetate
2-[3-(4-acetylamino-phenyl) thioureido]-4-chloro-5-methoxyl group-phenoxy group }-acetate
4-[3-(4-acetylamino-phenyl) thioureido]-2-chloro-5-methoxyl group-phenoxy group }-acetate
Embodiment 61 (method 37)
Phenylformic acid 2-{4-[3-(4-acetylamino-phenyl)-thioureido]-2, the 6-dichlorophenoxy }-ethyl ester
At N-(4-{3-[3,5-two chloro-4-(2-hydroxyl-oxyethyl group)-phenyl]-thioureido }-phenyl)-add Benzoyl chloride (0.08 restrains) in the pyridine (2 milliliters) of ethanamide (0.20 gram) and the ice-cold solution of tetrahydrofuran (THF) (0.5 milliliter), 0 ℃ stirred the mixture 1.5 hours.Use ethyl acetate diluted mixture thing then,,, use anhydrous sodium sulfate drying then with saturated sodium-chloride water solution washing 1 time with 2% salt acid elution 2 times.After the removal of solvent under reduced pressure, with silica gel (with the dichloromethane solution of 5% methyl alcohol as elutriant) chromatography residuum, merging contains the branch that washes out of product, reduction vaporization, and recrystallization residuum from acetone-hexane obtains desired white powder product.
Embodiment 62 (method 38)
Methylsulfonic acid 2-{4-[3-(4-acetylamino-phenyl)-thioureido]-2,6-two chloro-phenoxy groups }-ethyl ester
At N-(4-{3-[3,5-two chloro-4-(2-hydroxyl-oxyethyl group)-phenyl]-thioureido }-phenyl)-add methylsulfonyl chloride (0.11 restrains) in the pyridine (2 milliliters) of ethanamide (0.20 gram) and the ice-cold solution of tetrahydrofuran (THF) (0.5 milliliter), 0 ℃ stirred the mixture 45 minutes.Use ethyl acetate diluted mixture thing then,,, use anhydrous magnesium sulfate drying then with saturated sodium-chloride water solution washing 1 time with 2% salt acid elution 2 times.After the solvent removed by evaporation at reduced pressure, recrystallization residuum from acetone-hexane obtains desired white powder product.
Embodiment 63 (method 39)
N-(4-{3-[3,5-two chloro-4-(2-dimethylamino-oxyethyl group)-phenyl]-thioureido }-phenyl)-ethanamide
At methylsulfonic acid 2-{4-[3-(4-acetylamino-phenyl)-thioureido]-2, the 6-dichlorophenoxy }-add dimethylamine agueous solution (8.8M, 0.5 milliliter), stirring at room mixture 5 days in tetrahydrofuran (THF) (6 milliliters) solution of ethyl ester (0.33 gram).Use ethyl acetate diluted mixture thing then,, use anhydrous magnesium sulfate drying with the saturated sodium-chloride water solution washing.After the removal of solvent under reduced pressure, with silica gel (with pure methyl alcohol as elutriant) chromatography residuum.The branch that washes out that contains product that reduction vaporization merges, recrystallization residuum from acetonitrile obtains desired white powder product.
Use said procedure and suitable parent material to prepare following compounds:
N-(4-{3-[3,5-two chloro-4-(2-dimethylamino-oxyethyl group)-phenyl]-thioureido }-phenyl)-ethanamide
Phenylformic acid 2-{4-[3-(4-acetylamino-phenyl)-thioureido]-2,6-two chloro-phenoxy groups }-ethyl ester
Embodiment 64 (method 40)
Furans-2-carboxylic acid (4-{3-[4-(1-amino-ethyl)-3-chloro-phenyl]-thioureido }-phenyl)-acid amides
In methyl alcohol (2.5 milliliters) solution of two hydration tin chlorides (II) (0.25 gram), add furans-2-carboxylic acid (4-{3-[4-(1-azido--ethyl)-3-chloro-phenyl]-thioureido-phenyl)-acid amides (0.22 gram), stirred solution is about 15 hours under the room temperature.Use the ethyl acetate diluting soln, with saturated sodium bicarbonate aqueous solution, saturated sodium-chloride water solution washing, use anhydrous sodium sulfate drying then continuously.After the solvent removed by evaporation at reduced pressure,, obtain desired yellow solid product with silica gel (with the dichloromethane solution that contains 1% triethylamine of 8% methyl alcohol as elutriant) chromatography residuum.
Embodiment 65 (method 41)
[1,2,3] thiadiazoles-4-carboxylic acid (4-isothiocyanic acid base-phenyl)-acid amides
1,1 '-add tetrahydrofuran (THF) (100 milliliters) solution of [1,2,3]-thiadiazoles-4-carboxylic acid (4-amino-phenyl) acid amides (9.0 gram) in the freezing solution of the tetrahydrofuran (THF) (50 milliliters) of thio-carbonyldiimidazole (7.28 gram).After about 1 hour, evaporation removes and desolvates, and residuum is dissolved in ethyl acetate.Add ether and precipitate crude product, collect crude product by filtering then, be dissolved in methylene dichloride, by the hydrated magnesium silicate pad.Except that after desolvating, go out residuum with ethyl acetate-hexane recrystallization, obtain desired faint yellow solid-state product.
Use said procedure and suitable parent material to prepare following compounds:
2-fluoro-N-(4-isothiocyanic acid base-phenyl)-benzamide
Furans-2-carboxylic acid (4-isothiocyanic acid base-phenyl)-acid amides
[1,2,3] thiadiazoles-4-carboxylic acid (4-isothiocyanic acid base-phenyl)-acid amides
Thiazole-4-carboxylic acid's (4-isothiocyanic acid base-phenyl)-acid amides
Embodiment 66 (method 42)
N, N-dimethyl-5-trifluoromethyl-benzene-1,3-diamines
Tetrahydrofuran solution (the 2M that in tetrahydrofuran (THF) (2 milliliters) solution of degas (argon) of 3-amino-5-bromo-phenylfluoroform (1.0 gram), adds two-(three-adjacent toluene phosphino-) palladiums (0.15 gram), dimethyl amine, 4.2 milliliter) and the tetrahydrofuran solution (1M, 10.4 milliliters) of two (TMS) lithamide.In sealed vessel, reaction mixture is heated to 100 ℃, about 2.5 hours, finishes reaction.Cooling mixture adds entry and comes the cancellation reaction to room temperature then, dilutes with ethyl acetate.Extraction product 3 times, in 5% hydrochloric acid, cooling on one side then is Yi Bian add the acid extraction thing that the alkalization of 5N aqueous sodium hydroxide solution merges.With this basic solution of ethyl acetate extraction, with the organic extract that the saturated sodium-chloride water solution washing merges, use anhydrous magnesium sulfate drying then, reduction vaporization is to doing.With silica gel (with the hexane solution of 20-30% ethyl acetate as the elutriant) residuum that chromatography obtains, obtain desired light brown solid product.
Use said procedure and suitable parent material to prepare following compounds:
3-(4-methyl-piperazine-1-yl)-5-trifluoromethyl-aniline
3-morpholine-4-base-5-trifluoromethyl-aniline
3-piperidines-1-base-5-trifluoromethyl-aniline
3-tetramethyleneimine-1-base-5-trifluoromethyl-aniline
N, N-dimethyl-5-trifluoromethyl-benzene-1,3-diamines
N-isobutyl--N-methyl-5-trifluoromethyl-benzene-1, the 3-diamines
N-butyl-N-methyl-5-trifluoromethyl-benzene-1, the 3-diamines
Embodiment 67 (method 43)
(3-isobutyl--5-trifluoromethyl-phenyl)-t-butyl carbamate
Bubbling fed iso-butylene about 5 minutes in the sealing test tube that contains tetrahydrofuran (THF) (5 milliliters) (envelope has the rubber diaphragm separator plug, and cools off in dry ice acetone bath).The tetrahydrofuran solution (0.5M, 11 milliliters) that adds assorted two ring [3.3.1] nonanes of 9-boron with tetrafluoroethylene cap closure container, is slowly to warm to room temperature, at room temperature is incubated about 2.5 hours.Again cooling mixture in dry ice-propanone is bathed replaces the tetrafluoroethylene cap with the diaphragm of rubber plug then, on one side exhaust, the argon gas bubbling is fed mixture on one side, remove excessive iso-butylene.Tetrahydrofuran (THF) (12 milliliters) solution that adds (3-bromo-5-trifluoromethyl-phenyl)-t-butyl carbamate (1.7 gram), add [1 then, 1 '-two (diphenylphosphino)-ferrocene] Palladous chloride (II)-methylene dichloride mixture (0.12 gram), add the 3N aqueous sodium hydroxide solution then.Use tetrafluoroethylene cap sealed vessel once more, be heated to then 65 ℃ about 15 hours.Then mixture is cooled to room temperature, with the hexane dilution, anhydrous magnesium sulfate drying is used in water, saturated sodium-chloride water solution washing, and reduction vaporization.With silica gel (with the hexane solution of 5% ethyl acetate as the elutriant) oil that chromatography obtains, obtain desired white powder product.
Use said procedure and suitable parent material to prepare following compounds:
[3-(2-methyl-butyl)-5-trifluoromethyl-phenyl]-t-butyl carbamate
(3-isobutyl--5-trifluoromethyl-phenyl)-t-butyl carbamate
Embodiment 68 (method 44)
2-(3,5-two chloro-thiophenyls)-ethylamine
Add 0.61 milliliter of 10M dimethyl thioether borane complexes in 3.0 milliliters of ethylene glycol dimethyl ether solutions of (3,5-dichlorobenzene sulfenyl) acetonitrile (1.2 gram), heated mixt is to refluxing 0.5 hour.In ice bath, cool off reactant, add 2.0 ml waters and 2.0 milliliters of concentrated hydrochloric acids.Heat this compound to refluxing 0.5 hour.Cool off then and, use extracted with diethyl ether with 5N sodium hydroxide alkalization settled solution.With the dry ether extract of salt of wormwood, filter and concentrate, obtain 1.0 gram water white oils.
Use said procedure and suitable parent material to prepare following compounds:
2-(3-bromo-thiophenyl)-ethylamine
2-(4-bromo-phenoxy group)-ethylamine
2-(4-iodo-phenoxy group)-ethylamine
2-(3,4-two chloro-phenoxy groups)-ethylamine
2-(3-chloro-thiophenyl)-ethylamine
2-(3,4-two chloro-thiophenyls)-ethylamine
3-(4-bromo-phenyl)-propyl group amine
2-(2-fluoro-phenoxy group)-ethylamine
2-(2-chloro-phenoxy group)-ethylamine
2-(3-bromo-phenoxy group)-ethylamine
2-(3-fluoro-phenoxy group)-ethylamine
2-(3-iodo-phenoxy group)-ethylamine
2-(3,5-two chloro-thiophenyls)-ethylamine
2-thiophenyl-ethylamine
1-(2-chloro-phenyl)-ethylamine
Embodiment 69 (method 45)
N-(1-naphthalene-2-base-ethyl)-methane amide
In the mixture of 190 ℃ of heating 2 acetyl naphthalenes (3.0 gram), ammonium formiate (11.0 gram), formic acid (3.3 milliliters) and methane amide (3.5 milliliters) 3 hours.Cooling mixture is poured in the water, uses extracted with diethyl ether.With the dry ether extract of Anhydrous potassium carbonate, filter, concentrate, obtain yellow oil, it obtains white solid from toluene-hexane recrystallization, 1.97 grams.
Use said procedure and suitable parent material to prepare following compounds:
N-[1-(4-fluoro-phenyl)-2-methyl-propyl group]-methane amide
N-(1-naphthalene-2-base-ethyl)-methane amide
Embodiment 70 (method 46)
1-(2-naphthyl) ethylamine
The mixture of heating N-(1-naphthalene-2-base-ethyl)-methane amide (1.12 gram), ethanol (10 milliliters) and 5N sodium hydroxide (10 milliliters) is to refluxing 1 hour.Cooling mixture is poured in the water, uses extracted with diethyl ether.With the dry ethereal solution of Anhydrous potassium carbonate, filter and concentrate, obtain faint yellow oily product (0.95 gram).
Use said procedure and suitable parent material to prepare following compounds:
1-(3-trifluoromethyl-phenyl)-ethylamine
1-(4-fluoro-phenyl)-2-methyl-propyl group amine
[3-(1-amino-ethyl)-phenyl]-dimethyl-amine
3-(1-amino-ethyl)-benzonitrile
Embodiment 71 (method 47)
1-(3-trifluoromethyl-phenyl)-ethyl ketone (ethenone) O-methyl-oxime
Methoxy-amine hydrochloride (2.33 gram) is added to 3 '-ethanol (20 milliliters) and pyridine (2 milliliters) solution of (trifluoromethyl)-acetylbenzene (1.5 gram).Heated solution is to refluxing 45 minutes, reaction mixture then, and concentrating under reduced pressure distributes between water and ethyl acetate.Use the ethyl acetate extraction water layer.With the organic layer that the saturated sodium-chloride water solution washing merges, use anhydrous magnesium sulfate drying, and concentrating under reduced pressure, obtain desired colorless oil product (1.61 gram).
Use said procedure and suitable parent material to prepare following compounds:
3,5-di-trifluoromethyl-benzaldoxime
1-(4-fluoro-phenyl)-third-1-ketone O-methyloxime
1-(2-chloro-phenyl)-ethyl ketone O-methyloxime
1-(3-bromo-phenyl)-ethyl ketone O-methyloxime
1-(3-chloro-phenyl)-ethyl ketone O-methyloxime
1-p-methylphenyl-ethyl ketone O-methyloxime
1-(4-fluoro-phenyl)-penta-1-ketone O-methyloxime
1-(4-fluoro-phenyl)-2-phenyl-ethyl ketone O-methyloxime
1-o-tolyl-ethyl ketone O-methyloxime
3-(1-methoxyimino-ethyl)-benzonitrile
4-(1-methoxyimino-ethyl)-benzonitrile
1-(4-methoxyl group-phenyl)-ethyl ketone O-methyloxime
1-(2-methoxyl group-phenyl)-ethyl ketone O-methyloxime
1-(4-dimethylamino-phenyl)-ethyl ketone O-methyloxime
1-(2-trifluoromethyl-phenyl)-ethyl ketone O-methyloxime
1-(3-methoxyl group-phenyl)-ethyl ketone O-methyloxime
1-(3-trifluoromethyl-phenyl)-ethyl ketone O-methyloxime
1-(4-trifluoromethyl-phenyl)-ethyl ketone O-methyloxime
1-furans-2-base-ethyl ketone O-methyloxime
1-pyridin-4-yl-ethyl ketone O-methyloxime
1-(1-methyl isophthalic acid H-pyrroles-2-yl)-ethyl ketone O-methyloxime
1-thiene-3-yl-ethyl ketone O-methyloxime
(4-fluoro-phenyl)-phenyl-ketone O-methyloxime
1-(4-p-methoxy-phenyl) ethyl ketone O-methyloxime
1-(3-chloro-4-methoxyl group-phenyl)-ethyl ketone O-methyloxime
4-(1-methoxyimino-ethyl)-benzsulfamide
4-(1-methoxyimino-ethyl)-N, N-dimethyl-benzsulfamide
1-[4-(piperidines-1-alkylsulfonyl)-phenyl]-ethyl ketone O-methyloxime
4-(1-methoxyimino-ethyl)-N, N-dipropyl-benzsulfamide
2-fluoro-N-[4-(1-methoxyimino-ethyl)-phenyl]-benzamide
1-(3,5-di-trifluoromethyl-phenyl)-ethyl ketone O-methyloxime
1-[4-(1H-imidazoles-1-yl)-phenyl]-1-ethyl ketone O-methyloxime
1-[4-(trifluoromethyl)-phenyl]-1-ethyl ketone O-methyloxime
1-[1,1 '-xenyl]-4-base-1-ethyl ketone O-methyloxime
1-(4-aminomethyl phenyl)-1-ethyl ketone O-methyloxime
1-[4-fluoro-3-(trifluoromethyl) phenyl] ethyl ketone O-methyloxime
1-[3,5-two (trifluoromethyl) phenyl] ethyl ketone O-methyloxime
1-[4-chloro-3-(trifluoromethyl) phenyl] ethyl ketone O-methyloxime
1-[3-fluoro-5-(trifluoromethyl) phenyl] ethyl ketone O-methyloxime
1-[2-fluoro-4-(trifluoromethyl) phenyl] ethyl ketone O-methyloxime
1-[2-fluoro-5-(trifluoromethyl) phenyl] ethyl ketone O-methyloxime
1-(2,4 dichloro benzene base) ethyl ketone O-methyloxime
1-(2, the 4-3,5-dimethylphenyl) ethyl ketone O-methyloxime
1-[2,4-two (trifluoromethyl) phenyl] ethyl ketone O-methyloxime
1-(3-bromophenyl) ethyl ketone O-methyloxime
1-(3-aminomethyl phenyl) ethyl ketone O-methyloxime
1-[4-(4-morpholinyl) phenyl] ethyl ketone O-methyloxime
1-(2-chloro-4-fluorophenyl) ethyl ketone O-methyloxime
1-(4-bromo-2-fluorophenyl) ethyl ketone O-methyloxime
1-(3, the 4-difluorophenyl) ethyl ketone O-methyloxime
1-[3-(trifluoromethyl) phenyl] ethyl ketone O-methyloxime
1-[2-(trifluoromethyl) phenyl] ethyl ketone O-methyloxime
1-(2,4 difluorobenzene base) ethyl ketone O-methyloxime
1-[3-fluoro-4-(trifluoromethyl) phenyl] ethyl ketone O-methyloxime
1-(3, the 4-dichlorophenyl) ethyl ketone O-methyloxime
1-[4-fluoro-2-(trifluoromethyl) phenyl] ethyl ketone O-methyloxime
1-(3-chloro-4-fluorophenyl) ethyl ketone O-methyloxime
1-(4-chloro-3-fluorophenyl) ethyl ketone O-methyloxime
1-(2, the 5-difluorophenyl) ethyl ketone O-methyloxime
1-(2-bromo-4-fluorophenyl) ethyl ketone O-methyloxime
1-(3, the 4-dibromo phenyl) ethyl ketone O-methyloxime
1-(2-bromophenyl) ethyl ketone O-methyloxime
Embodiment 72 (method 48)
1-(2-trifluoromethyl-phenyl)-ethylamine
Sodium borohydride (1.17 gram) slowly is added in the flask of tetrahydrofuran (THF) (27 milliliters) solution that contains zirconium tetrachloride (1.8 gram).The solution that tetrahydrofuran (THF) (7.7 milliliters) solution that adds 1-(2-trifluoromethyl-phenyl)-ethyl ketone O-methyloxime (1.34 gram), 25 ℃ of stirrings obtain 12 hours.Reaction mixture is chilled to 0 ℃ then, slowly adds entry (16 milliliters).Add the excessive hydrogen ammonium oxide, use ethyl acetate extraction solution 2 times.With 1N salt acid elution organic layer 2 times.With alkalize water (acid) layer of sodium hydroxide, with ethyl acetate extraction 2 times.Wash organic layer with saturated sodium-chloride water solution then, and use anhydrous magnesium sulfate drying.Removal of solvent under reduced pressure obtains desired yellow oil product (0.20 gram).
Use said procedure and suitable parent material to prepare following compounds:
1-(3-methoxyl group-phenyl)-ethylamine
1-(4-fluoro-phenyl)-propyl group amine
1-naphthalene-2-base-ethylamine
4-(1-amino-ethyl)-benzonitrile
1-(4-trifluoromethyl-phenyl)-ethylamine
1-(4-methoxyl group-phenyl)-ethylamine
1-propine-2-base-tetramethyleneimine
1-(2-methoxyl group-phenyl)-ethylamine
Tolyl-ethylamine between 1-
1-(2-bromo-phenyl)-ethylamine
1-o-tolyl-ethylamine
C-(4-fluoro-phenyl)-C-phenyl-methylamine
1-(4-fluoro-phenyl)-amylamine
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 isophthalic acid H-pyrroles-2-yl)-ethylamine
1-[3,5-two (trifluoromethyl) phenyl] propyl group amine
1-[3,5-two (trifluoromethyl) phenyl]-1-butylamine or 1-[3,5-two (trifluoromethyl)-phenyl] butylamine
1-[3,5-two (trifluoromethyl) phenyl]-the 1-amylamine
1-(4-aminomethyl phenyl) ethamine
1-[3-(trifluoromethyl) phenyl] ethylamine
1-[4-(trifluoromethyl) phenyl] ethylamine
1-(3-aminomethyl phenyl) ethamine
1-(3, the 4-dichlorophenyl) ethamine
1-(2-bromo-phenyl)-ethylamine
1-(2-trifluoromethyl-phenyl)-ethylamine
1-(3-bromo-phenyl)-ethylamine
1-(3-chloro-4-methoxyl group-phenyl)-ethylamine
4-(1-amino-ethyl)-N, N-dimethyl-benzsulfamide
1-[4-(piperidines-1-alkylsulfonyl)-phenyl]-ethylamine
1-quinoline-6-base-ethylamine
1-(3,5-di-trifluoromethyl-phenyl)-ethylamine
4-[(1S)-and the 1-amino-ethyl] benzonitrile
(S)-and Alpha-Methyl-3,5-two (trifluoromethyl)-benzene methanamine (S)-Alpha-Methyl-3,5-two (trifluoromethyl)-benzene methanamine
1-biphenyl-4-base-ethylamine
1-(4-fluoro-phenyl)-ethylamine
1-[4-fluoro-3-(trifluoromethyl) phenyl] ethamine
1-[4-chloro-3-(trifluoromethyl) phenyl] ethamine
N-{4-[(1R)-and the 1-amino-ethyl] phenyl }-1,2,3-thiadiazoles-4-carboxylic acid amides
N-{4-[(1S)-and the 1-amino-ethyl] phenyl }-1,2,3-thiadiazoles-4-carboxylic acid amides
1-[3-fluoro-5-(trifluoromethyl) phenyl] ethylamine
1-[2-fluoro-4-(trifluoromethyl) phenyl] ethylamine
1-[2-fluoro-5-(trifluoromethyl) phenyl] ethylamine
1-(2,4 dichloro benzene base) ethylamine
1-(2, the 4-3,5-dimethylphenyl) ethylamine
1-[2,4-two (trifluoromethyl) phenyl] ethylamine
1-(2-chloro-4-fluorophenyl) ethylamine
1-(3, the 4-difluorophenyl) ethylamine
1-(4-bromo-2-fluorophenyl) ethylamine
1-(3-fluorophenyl) ethylamine
1-(2,4 difluorobenzene base) 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, the 4-dibromo phenyl) ethylamine
1-(2-bromo-4-fluorophenyl) ethamine
1-(2-bromo-4-fluorophenyl) ethylamine
Embodiment 73 (method 49)
(2-fluoro-5-trifluoromethyl-phenoxy group)-acetonitrile
Reagent grade acetone (0.55L) solution with solid carbonic acid potassium (7.7 gram) processing 2-fluoro-5-trifloro methyl phenol (25 gram) adds pure bromoacetonitrile (10 milliliters) then rapidly.About 20 hours of vigorous stirring heterogeneous mixture is poured in the water then, is extracted into ether.With the ether extract of saturated sodium-chloride washing merging, and use the Anhydrous potassium carbonate drying.Filter and concentrating under reduced pressure, obtain greenish orange look solid, use silica gel column chromatography then, use the methylene dichloride wash-out, obtain desired white solid state product (28.3 gram).
Use said procedure and suitable parent material to prepare following compounds:
(3-bromo-thiophenyl)-acetonitrile
(3-chloro-thiophenyl)-acetonitrile
(4-iodo-phenoxy group)-acetonitrile
(3-trifluoromethyl-thiophenyl)-acetonitrile
(3,5-two chloro-thiophenyls)-acetonitrile
(3,4-two chloro-thiophenyls)-acetonitrile
(3,4-two chloro-phenoxy groups)-acetonitrile
(2-fluoro-phenoxy group)-acetonitrile
(3-fluoro-phenoxy group)-acetonitrile
(2-chloro-phenoxy group)-acetonitrile
(3-bromo-phenoxy group)-acetonitrile
(2-fluoro-5-trifluoromethyl-phenoxy group)-acetonitrile
(3-iodo-phenoxy group)-acetonitrile
(4-bromo-phenoxy group)-acetonitrile
Embodiment 74 (method 50)
Toluenesulphonic acids 3-fluoro-5-trifluoromethylbenzene ethylamine
At room temperature,, use 200 milligram of 10% palladium-carbon catalyst, 75 milliliters of methyl glycol solution of hydrogenation 2.5 gram 3-fluoro-5-trifluoromethyl acetonitriles and 2.34 gram (12.3 mmole) tosic acid 3 hours with 40psi.The elimination catalyzer, evaporating solvent to volume half.After the placement, the tosilate crystallization of desired 3-fluoro-5-trifluoromethylbenzene ethylamine.Filter and collect white crystal 4.26 grams (91%).
Use said procedure and suitable parent material to prepare following compounds:
2-(3,5-two fluoro-phenyl)-ethylamine
2-(4-trifluoromethyl-phenyl)-ethylamine
2-(3,4-two fluoro-phenyl)-ethylamine
2-(2-fluoro-phenyl)-ethylamine
2-(3-fluoro-5-trifluoromethyl-phenyl)-ethylamine
2-(2-fluoro-3-trifluoromethyl-phenyl)-ethylamine
2-(2,4-di-trifluoromethyl-phenyl)-ethylamine
2-(4-fluoro-3-trifluoromethyl-phenyl)-ethylamine
Embodiment 75 (method 51)
(4-amino methyl-2-trifluoromethyl-phenyl)-dimethyl-amine
Tetrahydrofuran (THF) (2 milliliters) solution of 4-dimethylamino-3-trifluoromethyl benzonitrile (0.35 gram) in 0 ℃ of tetrahydrofuran (THF) (2 milliliters) suspension that slowly is added to lithium aluminium hydride (0.1 gram), and was stirred 2 hours under argon gas.Slowly adding entry (0.1 milliliter) at 0 ℃, is 5% sodium hydroxide (0.1 milliliter) and water (0.3 milliliter) then.The gray solid that filtration obtains is washed with tetrahydrofuran (THF).Collect filtrate, concentrating under reduced pressure with silica gel (with the dichloromethane solution of 15% methyl alcohol as the elutriant) oil that chromatography obtains, obtains desired greenish orange look oily product (0.164 restrains).
Use said procedure and suitable parent material to prepare following compounds:
4-piperidines-1-base-3-trifluoromethyl-benzyl amine
(4-amino methyl-2-trifluoromethyl-phenyl)-dimethyl-amine
4-(4-methyl-piperazine-1-yl)-3-trifluoromethyl-benzyl amine
(3-amino methyl-5-trifluoromethyl-phenyl)-dimethyl-amine
[3-(2-amino-ethyl)-5-trifluoromethyl-phenyl]-dimethyl-amine
[4-(2-amino-ethyl)-2-methyl-phenyl]-dimethyl-amine
Embodiment 76 (method 52)
3-dimethylamino-5-trifluoromethyl-phenyl aldehyde
Diisobutyl aluminium hydride (10 milliliters of 1M dichloromethane solutions) in 0 ℃ of methylene dichloride (25 milliliters) solution that is added drop-wise to 3-dimethylamino-5-trifluoromethyl benzonitrile (1.06 gram), was stirred the mixture 2 hours.At 0 ℃, slowly add saturated sodium tartrate aqueous solutions of potassium (8 milliliters), stirred solution 1.5 hours.Use the ethyl acetate extraction reaction mixture then, use anhydrous magnesium sulfate drying, concentrating under reduced pressure obtains desired yellow solid product (0.97 gram).
Use said procedure and suitable parent material to prepare following compounds:
3-dimethylamino-5-trifluoromethyl-phenyl aldehyde
4-dimethylamino-3-methyl-phenyl aldehyde
Embodiment 77 (method 53)
Dimethyl-[3-(2-nitro-vinyl)-5-trifluoromethyl-phenyl]-amine
Nitromethane 99Min. (0.473 gram) is added in acetate (3.4 milliliters) solution of 3-dimethylamino-5-trifluoromethyl-phenyl aldehyde (0.885 gram) and ammonium acetate (0.339 restrains) 110 ℃ of heated solutions 6 hours.Reaction mixture is cooled to 0 ℃, leaches the solid of formation, with water-acetate washing in 1: 1.This solid recrystallization from ethanol obtains desired red solid product (0.39 gram).
Use said procedure and suitable parent material to prepare following compounds:
Dimethyl-[3-(2-nitro-vinyl)-5-trifluoromethyl-phenyl]-amine
Dimethyl-[2-methyl-4-(2-nitro-vinyl)-phenyl]-amine
Embodiment 78 (method 54)
3-(4-bromo-phenyl)-propionitrile
With diethylazodicarboxylate (5.2 gram) in the solution of 0 ℃ of ether (16 milliliters) that is added drop-wise to 4-bromo-styroyl alcohol (2.01 gram) and triphenyl phosphine (7.9 restrain).Stirred reaction mixture 10 minutes, ether (10 milliliters) solution of adding acetone cyanohydrin (2.6 gram).0 ℃ was stirred clear orange solution 5 minutes, stirred 12 hours at 25 ℃ then.Filter reaction mixture washs with ether then.Concentrating under reduced pressure filtrate with silica gel (with 10% ethyl acetate-hexane as elutriant) chromatography, obtains desired faint yellow oily product (2.04 restrain).
Embodiment 79 (method 55)
3-dimethylamino-2-isocyano--ethyl propenoate
Drip N in ethanol (100 milliliters) solution of isocyano acid B ester (5.0 gram), N-dimethyl-methane amide dimethylacetal (6.5 gram) stirs more than 10 minutes.Reaction stirred 24 hours, ethanol evaporation.The oil that obtains uses 50% ethyl acetate-hexane as eluent by Magnesium Silicate q-agent.Remove and desolvate, the oil that recrystallization obtains from ethyl acetate-hexane obtains faint yellow spicule, 3.0 grams.
Embodiment 80 (method 56)
4-ethoxy carbonyl thiazole
Tetrahydrofuran (THF) (30 milliliters) solution with hydrogen sulfide processing 3-dimethylamino-2-isocyano--ethyl propenoate (1.0 gram) and triethylamine (3.0 gram) has been consumed up to parent material.Enriched mixture is used column chromatography purification to oily, uses silicon-dioxide and 25% ethyl acetate-hexane as elutriant.The material (0.61 gram) that separates the buttery purifying.
Embodiment 81 (method 34)
N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-urea groups]-phenyl }-2-fluoro-benzamide
With 5-chloro-2,4-dimethoxy benzene based isocyanate (0.40 gram) is handled acetonitrile (4 milliliters) suspension of N-(4-amino-phenyl)-2-fluoro-benzamide (0.43 gram).Mixture becomes solution, places 12 hours.Form white solid, filter and collect (0.79 gram).[M＋H]444。
Use said procedure and suitable parent material to prepare following compounds:
Embodiment number M＋H The compound title
81 445 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-urea groups]-phenyl }-2-fluoro-benzamide
82 441 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-urea groups]-phenyl }-2-methyl-benzamide
83 435 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(5-chloro-2,4-dimethoxy-phenyl)-urea groups]-phenyl }-acid amides
84 443 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(4-chloro-3-trifluoromethyl-phenyl)-urea groups]-phenyl }-acid amides
85 453 N-{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-urea groups]-phenyl }-2-fluoro-benzamide
86 409 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(3,5-two chloro-phenyl)-urea groups]-phenyl }-acid amides
87 486 N-{4-[3-(3,5-di-trifluoromethyl-phenyl)-urea groups]-phenyl }-2-fluoro-benzamide
88 458 Furans-2-carboxylic acid { 4-[3-(3,5-di-trifluoromethyl-phenyl)-urea groups }-phenyl }-acid amides
89 476 [1,2,3] thiadiazoles-4-carboxylic acid { 4-[3-(3,5-di-trifluoromethyl-phenyl)-urea groups }-phenyl }-acid amides
90 423 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(3,4-two chloro-benzyls)-urea groups]-phenyl }-acid amides
Embodiment 91 (method 31)
N-(5-{[({ (1S)-1-[3,5-two (trifluoromethyl) phenyl] ethyl } amino) sulfo-carboxylic acyl group]-amino }-the 2-pyridyl)-1,3-thiazoles-4-carboxylic acid amides
With N-(5-isothiocyanic acid base-2-pyridyl)-1,3-thiazoles-4-carboxylic acid amides (0.36 gram) and (S)-and Alpha-Methyl-3, mixture and the acetonitrile (10 milliliters) of 5-two (trifluoromethyl)-benzene methanamine (0.36 restrains) heat together, dissolve up to all solids.Placed solution 12 hours.Form white solid, filter and collect (0.40 gram).[M＋H]520。
Use said procedure and suitable parent material to prepare following compounds:
Embodiment number M＋H The compound title
92 506 [3-chloro-5-(3-{4-([1,2,3] thiadiazoles-4-carbonyl)-amino]-phenyl }-thioureido)-phenyl]-t-butyl carbamate
93 409 1-(5-chloro-2,4-dimethoxy-phenyl)-3-(4-morpholine-4-base-phenyl)-thiocarbamide
94 370 1-(5-chloro-2,4-dimethoxy-phenyl)-3-(4-methylthio group-phenyl)-thiocarbamide
95 338 1-(5-chloro-2,4-dimethoxy-phenyl)-3-p-methylphenyl-thiocarbamide
96 414 4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-thiophenyl }-acetate
97 384 1-(5-chloro-2,4-dimethoxy-phenyl)-3-[4-(2-hydroxyl-oxyethyl group)-phenyl]-thiocarbamide
98 340 1-(5-chloro-2,4-dimethoxy-phenyl)-3-(4-hydroxyl-phenyl)-thiocarbamide
99 395 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-N-methyl-ethanamide
100 381 N-{3-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-ethanamide
101 411 4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-urethanum
102 319 1-(2,4-dimethoxy-phenyl)-3-(4-methoxyl group-phenyl)-thiocarbamide
103 346 N-{4-[3-(2,4-dimethoxy-phenyl)-thioureido]-phenyl }-ethanamide
104 316 N-{4-[3-(4-methoxyl group-phenyl)-thioureido]-phenyl }-ethanamide
105 316 N-{4-[3-(2-methoxyl group-phenyl)-thioureido]-phenyl }-ethanamide
106 351 N-{4-[3-(3-chloro-4-methoxyl group-phenyl)-thioureido]-phenyl }-ethanamide
107 351 N-{4-[3-(5-chloro-2-methoxyl group-phenyl)-thioureido]-phenyl }-ethanamide
108 371 N-{4-[3-(3,5-two chloro-4-hydroxyl-phenyl)-thioureido]-phenyl }-ethanamide
109 385 N-{4-[3-(3,5-two chloro-4-methoxyl group-phenyl)-thioureido]-phenyl }-ethanamide
110 381 N-{4-[3-(4-chloro-2,5-dimethoxy-phenyl)-thioureido]-phenyl }-ethanamide
111 389 N-{4-[3-(2-chloro-5-trifluoromethyl-phenyl)-thioureido]-phenyl }-ethanamide
112 389 N-{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-thioureido]-phenyl }-ethanamide
113 422 Phenylformic acid 4-[3-(4-acetylamino-phenyl)-thioureido]-3-hydroxyl-phenyl ester
114 457 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-2-methyl-benzamide
115 501 Acetate 2-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl-formamyl }-phenyl ester
116 461 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-4-fluoro-benzamide
117 461 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-3-fluoro-benzamide
118 461 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide
119 473 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-2-methoxyl group-benzamide
120 473 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-3-methoxyl group-benzamide
121 473 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-4-methoxyl group-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 }-Toluidrin
124 331 N-{4-[3-(3-nitro-phenyl)-thioureido]-phenyl }-ethanamide
??125 ??339 1-(3-chloro-4-methoxyl group-phenyl)-3-(3-nitro-phenyl)-thiocarbamide
??126 ??337 N-{4-[3-(5-chloro-2-hydroxyl-phenyl)-thioureido]-phenyl }-ethanamide
??127 ??439 4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-t-butyl carbamate
??128 ??351 N-{4-[3-(3-chloro-4-hydroxy-5-methyl base-phenyl)-thioureido]-phenyl }-ethanamide
??129 ??385 N-{4-[3-(3,5-two chloro-4-hydroxy-2-methyl-phenyl)-thioureido]-phenyl }-ethanamide
??130 ??318 N-{4-[3-(2,4-dihydroxyl-phenyl)-thioureido]-phenyl }-ethanamide
??131 ??414 N-{4-[3-(2,4-dimethoxy-5-trifluoromethyl-phenyl)-thioureido]-phenyl }-ethanamide
??132 ??332 N-{4-[3-(2-hydroxyl-4-methoxyl group-phenyl)-thioureido]-phenyl }-ethanamide
??133 ??465 N-{4-[3-(3,5-two chloro-4-methoxyl group-phenyl)-thioureido]-phenyl }-4-fluoro-benzamide
??134 ??500 3-acetylamino-N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-benzamide
??135 ??488 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-3-nitro-benzamide
??136 ??486 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-3-dimethylamino-benzamide
??137 ??536 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-3-methylsulfonyl-amino-benzamide
??138 ??511 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-2-three fluoro-methyl-benzamide
??139 ??459 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-2-hydroxyl-benzamide
??140 ??479 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-2,6-two fluoro-benzamide
??141 ??477 2-chloro-N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-benzamide
??142 ??522 2-bromo-N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-benzamide
??143 ??488 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-2-nitro-benzamide
??144 ??445 Pyrazine-2-carboxylic acid 4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-acid amides
??145 ??463 5-methyl-thiophene-2-carboxylic acid 4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-acid amides
??146 ??494 Quinoline-8-carboxylic acid 4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-acid amides
??147 ??446 1-methyl isophthalic acid H-pyrroles-2-carboxylic acid 4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-acid amides
??148 ??369 1-(5-chloro-2,4-dimethoxy-phenyl)-3-(2-nitro-phenyl)-thiocarbamide
??149 ??369 1-(5-chloro-2,4-dimethoxy-phenyl)-3-(4-nitro-phenyl)-thiocarbamide
??150 ??425 N-{4-[3-(5-bromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-ethanamide
??151 ??376 N-{4-[3-(3,4,5-trimethoxy-phenyl)-thioureido]-phenyl }-ethanamide
??152 ??399 N-{4-[3-(3,5-two chloro-2-methoxyl group-4-methyl-phenyl)-thioureido]-phenyl }-ethanamide
??153 ??499 Benzo [b] thiophene-2-carboxylic acid 4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-acid amides
????154 ??483 Cumarone-2-carboxylic acid 4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-acid amides
????155 ??444 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-Isonicotinamide
????156 ??493 Naphthalene-2-carboxylic acid 4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-acid amides
????157 ??493 Naphthalene-1-carboxylic acid 4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-acid amides
????158 ??494 Isoquinoline 99.9-1-carboxylic acid 4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-acid amides
????159 ??494 The quinaldic acid 4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-acid amides
????160 ??444 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl)-niacinamide
????161 ??478 5-nitro-furans-2-carboxylic acid 4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-acyl ammonia
????162 ??459 4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-phenyl carbamate
????163 ??467 5-chloro-furans-2-carboxylic acid 4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-acid amides
????164 ??439 4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-isobutyl carbamate
????165 ??397 4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-Urethylane
????166 ??433 Furans-3-carboxylic acid 4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-acid amides
????167 ??447 3-methyl-furans-2-carboxylic acid 4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-acid amides
????168 ??512 5-bromo-furans-2-carboxylic acid 4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-acid amides
????169 ??512 4-bromo-furans-2-carboxylic acid 4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-acid amides
????170 ??433 Furans-2-carboxylic acid 4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-acid amides
????171 ??467 4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-the own ester of carboxylamine
????172 ??494 Isoquinoline 99.9-4-carboxylic acid 4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-acid amides
????173 ??451 [1,2,3] thiadiazoles-4-carboxylic acid 4-(3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-acid amides
????174 ??434 1H-[1,2,3] triazole-4-carboxylic acid 4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-acid amides
????175 ??528 3-bromo-thiophene-2-carboxylic acid 4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-acid amides
????176 ??399 N-{4-[3-(3,5-two chloro-4-oxyethyl group-phenyl)-thioureido]-phenyl }-ethanamide
????177 ??427 N-{4-[3-(4-butoxy-3,5-two chloro-phenyl)-thioureido]-phenyl }-ethanamide
????178 ??461 N-{4-[3-(4-benzyloxy-3,5-two chloro-phenyl)-thioureido]-phenyl }-ethanamide
????179 ??381 N-{4-[3-(3-chloro-2,4-dimethoxy-phenyl)-thioureido }-phenyl }-ethanamide
????180 ??530 (3-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido }-the phenyl amino formyl radical }-phenyl)-urethanum
????181 ??458 2-amino-N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-benzamide
????182 ??519 Diphenyl-2-carboxylic acid 4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-acid amides
183 ??469 1-(5-chloro-2,4-dimethoxy-phenyl)-3-[4-(1,3-dioxy-1,3-dihydro-isoindole-2-yl)-phenyl]-thiocarbamide
184 ??487 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-phthalamic acid
185 ??473 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-2-hydroxyl-methyl-benzamide
186 ??479 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-2,3-two fluoro-benzamide
187 ??479 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-2,5-two fluoro-benzamide
188 ??479 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-2,4-two fluoro-benzamide
189 ??500 2-acetylamino-N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-benzamide
190 ??441 1-(5-chloro-2,4-dimethoxy-phenyl)-3-(6-oxo-5,6-dihydro-phenanthridines-2-yl)-thiocarbamide
191 ??536 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-2-methylsulfonyl amino-benzamide
192 ??497 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-2,3,4-three fluoro-benzamide
193 ??533 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-2,3,4,5,6-five fluoro-benzamide
194 ??489 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-2-methylthio group-benzamide
195 ??431 5-methyl-furans-2-carboxylic acid 4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-acid amides
196 ??467 5-difluoromethyl-furans-2-carboxylic acid 4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-acid amides
197 ??472 N-{4-[3-(5-iodo-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-ethanamide
198 ??364 N-{4-[3-(5-fluoro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-ethanamide
199 ??365 N-{4-[3-(5-chloro-2-methoxyl group-4-methyl-phenyl)-thioureido]-phenyl }-ethanamide
200 ??459 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(4-chloro-3-trifluoromethyl-phenyl)-thioureido]-phenyl }-acid amides
201 ??455 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(3,5-two chloro-4-methoxyl group-phenyl)-thioureido]-phenyl }-acid amides
202 ??392 N-{4-[3-(3-chloro-4-diethylamino-phenyl)-thioureido]-phenyl }-ethanamide
203 ??432 N-(4-{3-[3-chloro-4-(cyclohexyl-methyl-amino)-phenyl]-thioureido }-phenyl)-ethanamide
204 ??506 1-hydroxyl-naphthalene-2-carboxylic acid 4-[3-(4-acetylamino-phenyl)-thioureido]-2-chloro-phenyl }-acid amides
205 ??406 N-{4-[3-(3-chloro-4-morpholine-4-base-phenyl)-thioureido]-phenyl }-ethanamide
206 ??443 1-(5-chloro-2,4-dimethoxy-phenyl)-3-(3-chloro-4-morpholine-4-base-phenyl)-thiocarbamide
207 ??372 1-(5-chloro-2,4-dimethoxy-phenyl)-3-(5-chloro-2-methyl-phenyl)-thiocarbamide
208 ??501 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-the isophthalamic acid methyl esters
209 ??487 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-isophthalamic acid
210 ??549 3-benzyloxy-N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-benzamide
211 ??434 N-(4-{3-[5-chloro-2-methoxyl group-4-(4-nitrilo-butoxy)-phenyl]-thioureido }-phenyl)-ethanamide
212 406 N-(4-{3-[5-chloro-2-methoxyl group-4-(2-nitrilo-oxyethyl group)-phenyl]-thioureido }-phenyl)-ethanamide
213 406 N-(4-{3-[5-chloro-4-methoxyl group-2-(2-nitrilo-oxyethyl group)-phenyl]-thioureido }-phenyl)-ethanamide
214 411 N-(4-{3-[5-chloro-2-(2-hydroxyl-oxyethyl group)-4-methoxyl group-phenyl]-thioureido }-phenyl)-ethanamide
215 411 N-(4-{3-[5-chloro-4-(2-hydroxyl-oxyethyl group)-2-methoxyl group-phenyl]-thioureido]-phenyl)-ethanamide
216 481 4-[3-(4-acetylamino-phenyl)-thioureido]-2-chloro-5-methoxyl group-phenoxy group }-tert.-butyl acetate
217 439 4-[3-(4-acetylamino-phenyl)-thioureido]-2-chloro-5-methoxyl group-phenoxy group]-methyl acetate
218 481 2-[3-(4-acetylamino-phenyl)-thioureido]-4-chloro-5-methoxyl group-phenoxy group }-tert.-butyl acetate
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-methanesulfinyl-benzamide
221 545 (3-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-the phenyl amino formyl radical }-phenoxy group)-ethyl acetate
222 517 (3-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-the phenyl amino formyl radical }-phenoxy group)-acetate
223 367 N-{4-[3-(5-chloro-4-hydroxyl-2-methoxyl group-phenyl)-thioureido]-phenyl }-ethanamide
224 444 Pyridine-2-carboxylic acids 4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-acid amides
225 494 The Cinchonic Acid 4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-acid amides
226 436 N-{4-[3-(5-chloro-4-methoxyl group-2-morpholine-4-base-phenyl)-thioureido]-phenyl }-ethanamide
227 394 N-{4-[3-(5-chloro-2-methylamino-4-methoxyl group-phenyl)-thioureido]-phenyl }-ethanamide
228 420 N-{4-[3-(5-chloro-4-methoxyl group-2-tetramethyleneimine-1-base-phenyl)-thioureido]-phenyl }-ethanamide
229 434 N-{4-[3-(5-chloro-4-methoxyl group-2-piperidines-1-base-phenyl)-thioureido]-phenyl }-ethanamide
230 405 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(3-chloro-4-methyl-phenyl)-thioureido]-phenyl }-acid amides
231 415 N-{4-[3-(3-chloro-4-methyl-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide
232 427 N-{4-[3-(3-chloro-4-methyl-phenyl)-thioureido]-phenyl }-3-methoxyl group-benzamide
233 387 Furans-2-carboxylic acid 4-[3-(3-chloro-4-methyl-phenyl)-thioureido]-phenyl }-acid amides
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-two fluoro-benzamide
236 398 Pyridine-2-carboxylic acids 4-[3-(3-chloro-4-methyl-phenyl)-thioureido]-phenyl }-acid amides
237 502 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[3-chloro-4-(cyclohexyl-methyl-amino)-phenyl]-thioureido }-phenyl)-acid amides
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-piperidines-1-base-phenyl)-thioureido]-phenyl }-ethanamide
240 364 N-{4-[3-(3-chloro-4-dimethylamino-phenyl)-thioureido]-phenyl }-ethanamide
241 426 N-{4-[3-(4-benzylamino-3-chloro-phenyl)-thioureido]-phenyl }-ethanamide
242 390 N-{4-[3-(3-chloro-4-tetramethyleneimine-1-base-phenyl)-thioureido]-phenyl]-ethanamide
243 419 N-(4-{3-[3-chloro-4-(4-methyl-piperazine-1-yl)-phenyl]-thioureido }-phenyl)-ethanamide
244 469 N-{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-thioureido]-phenyl]-2-fluoro-benzamide
245 422 N-{4-[3-(2-benzylamino-4-methoxyl group-phenyl)-thioureido]-phenyl }-ethanamide
246 484 Furans-2-carboxylic acid (4-{3-[3-chloro-4-(cyclohexyl-methyl-amino)-phenyl]-thioureido }-phenyl)-acid amides
247 508 N-(4-{3-[3-chloro-4-(cyclohexyl-methyl-amino)-phenyl]-thioureido }-phenyl)-2-methyl-benzamide
248 530 N-(4-{3-[3-chloro-4-(cyclohexyl-methyl-amino)-phenyl]-thioureido }-phenyl)-2,6-two fluoro-benzamide
249 495 Pyridine-2-carboxylic acids (4-{3-[3-chloro-4-(cyclohexyl-methyl-amino)-phenyl]-thioureido }-phenyl)-acid amides
250 524 N-(4-{3-[3-chloro-4-(cyclohexyl-methyl-amino)-phenyl]-thioureido }-phenyl)-3-methoxyl group-benzamide
251 376 N-(4-{3-[3-chloro-4-(2-nitrilo-oxyethyl group)-phenyl]-thioureido }-phenyl)-ethanamide
252 393 N-{4-[3-(4-sec-butoxy-3-chloro-phenyl)-thioureido]-phenyl }-ethanamide
253 501 Acetate 3-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl-formamyl }-phenyl ester
254 459 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-3-hydroxyl-benzamide
255 487 Benzo [1,3] dioxole-4-carboxylic acid 4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-acid amides
256 527 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-3-fluoro-methoxyl group-benzamide
257 530 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-3-(2-dimethylamino-oxyethyl group)-benzamide
258 572 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-3-(2-morpholine-4-base-oxyethyl group)-benzamide
259 406 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-cyano group-phenyl }-ethanamide
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 }-ethanamide
262 527 2-{4-[3-(4-acetylamino-phenyl)-thioureido]-2-chloro-phenoxy group }-5-chloro-Phenylsulfonic acid
263 562 2-{4-[3-(4-acetylamino-phenyl)-thioureido]-2-chloro-phenoxy group }-4,5-two chloro-Phenylsulfonic acids
264 527 4-phenyl-[1.2,3] thiadiazoles-5-carboxylic acid 4-[3-(5-chloro-2,4-methoxyl group-phenyl)-thioureido]-phenyl }-acid amides
265 381 N-(4-{3-[3-chloro-4-(2-hydroxyl-oxyethyl group)-phenyl]-thioureido }-phenyl)-ethanamide
266 393 N-{4-[3-(4-butoxy-3-chloro-phenyl)-thioureido]-phenyl }-ethanamide
267 446 N-(4-{3-[3-chloro-4-(cyclohexyl-ethyl-amino)-phenyl]-thioureido }-phenyl)-ethanamide
268 365 N-{4-[3-(3-chloro-4-oxyethyl group-phenyl)-thioureido]-phenyl }-ethanamide
269 427 N-{4-[3-(4-benzyloxy-3-chloro-phenyl)-thioureido]-phenyl }-ethanamide
270 317 4-[(3-methyl-furans-2-carbonyl)-amino }-phenyl }-t-butyl carbamate
271 456 N-{4-[3-(2-benzylamino-5-chloro-4-methoxyl group-phenyl)-thioureido]-phenyl }-ethanamide
272 420 N-{4-[3-(3-chloro-4-dipropyl amino-phenyl)-thioureido]-phenyl }-ethanamide
273 458 N-(4-{3-[4-(allyl group-cyclohexyl-amino)-3-chloro-phenyl]-thioureido }-phenyl)-ethanamide
274 411 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-the 2-p-methoxy-phenyl }-ethanamide
275 415 N-{2-chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-ethanamide
276 493 Furans-2-carboxylic acid 4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido] and-2,5-dimethoxy-phenyl }-acid amides
277 486 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-cyano group-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] thiadiazoles-4-carboxylic acid 4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-acid amides
280 517 5-furans-3-base-[1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-acid amides
281 527 5-phenyl-[1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-acid amides
282 458 N-(4-{3-[3-chloro-4-(octahydro quinoline-1-yl)-phenyl]-thioureido }-phenyl)-ethanamide
283 458 N-[5-[[[(5-chloro-2,4-dimethoxy-phenyl) amino] sulphomethyl] amino]-the 2-pyridyl]-the 2-methyl benzamide
284 434 Furans-2-carboxylic acid 5-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridine-2-yl }-acid amides
285 425 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methoxyl group-5-methyl-phenyl }-ethanamide
286 505 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methoxyl group-5-methyl-phenyl }-2-fluoro-benzamide
287 477 Furans-2-carboxylic acid 4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methoxyl group-5-methyl-phenyl }-acid amides
288 517 4-furans-3-base-[1,2,3] thiadiazoles-5-carboxylic acid 4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-acid amides
289 462 N-{5-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridine-2-yl }-2-fluoro-benzamide
290 384 N-{4-[3-(4-methoxyl group-3-trifluoromethyl-phenyl)-thioureido]-phenyl }-ethanamide
291 394 N-[4-(3-{3-chloro-4-[(2-hydroxyl-ethyl)-methyl-amino]-phenyl }-thioureido)-phenyl]-ethanamide
292 485 N-{2-benzoyl-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-ethanamide
293 565 N-{2-benzoyl-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide
294 537 Furans-2-carboxylic acid 2-benzoyl-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-acid amides
295 475 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-3-methyl-phenyl }-2-fluoro-benzamide
296 447 Furans-2-carboxylic acid 4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-3-methyl-phenyl }-acid amides
297 395 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-3-methyl-phenyl }-ethanamide
298 435 N-[4-(3-{3-chloro-4-[(3-dimethylamino-propyl group)-methyl-amino]-phenyl }-thioureido)-phenyl]-ethanamide
299 418 N-{4-[3-(3-chloro-4-cyclohexyl amino-phenyl)-thioureido]-phenyl }-ethanamide
300 421 N-[4-(3-{3-chloro-4-[(2-dimethylamino-ethyl)-methyl-amino]-phenyl }-thioureido)-phenyl]-ethanamide
301 580 5-[[[(5-chloro-2, the 4-Dimethoxyphenyl) amino] sulphomethyl] amino]-the 2-[(2-fluoro benzoyl) amino]-N-phenyl-benzamide
302 552 Furans-2-carboxylic acid 4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-phenyl amino formyl radical-phenyl }-acid amides
303 491 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-the 2-p-methoxy-phenyl }-2-fluoro-benzamide
304 463 Furans-2-carboxylic acid 4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methoxyl group-phenyl }-acid amides
305 449 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-trifluoromethyl-phenyl }-ethanamide
306 458 Furans-2-carboxylic acid 4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-cyano group-phenyl }-acid amides
307 467 Furans-2-carboxylic acid 2-chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-acid amides
308 501 Furans-2-carboxylic acid 4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-trifluoromethyl-phenyl }-acid amides
309 395 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methyl-phenyl }-ethanamide
310 475 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methyl-phenyl }-2-fluoro-benzamide
311 447 Furans-2-carboxylic acid 4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methyl-phenyl }-acid amides
312 378 N-{4-[3-(4-acetylamino-phenyl)-thioureido]-2-chloro-phenyl }-ethanamide
313 408 4-[3-(4-acetylamino-phenyl)-thioureido]-2-chloro-phenyl }-urethanum
314 382 N-{5-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridine-2-yl }-ethanamide
315 509 N-(4-{3-[4-(1-benzyl-piperidin-4-yl amino)-3-chloro-phenyl]-thioureido }-phenyl)-ethanamide
316 407 N-(4-{3-[3-chloro-4-(2-dimethylamino-ethylamino)-phenyl]-thioureido }-phenyl)-ethanamide
317 408 N-[4-(3-{3-chloro-4-[(2-methoxyl group-ethyl)-methyl-amino]-phenyl }-thioureido)-phenyl]-ethanamide
318 421 N-(4-{3-[3-chloro-4-(3-dimethylamino-propyl group amino)-phenyl]-thioureido }-phenyl)-ethanamide
319 495 N-(4-{3-[4-(1-benzyl-tetramethyleneimine-3-base is amino)-3-chloro-phenyl]-thioureido }-phenyl)-ethanamide
320 483 Furans-2-carboxylic acid 5-chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-hydroxyl-phenyl }-acid amides
321 431 N-{5-chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-hydroxyl-phenyl }-ethanamide
322 511 (5H, 11H-benzo [e] pyrrolo-[1,2-a] [1,4] two azepines-10-yl)-(2-chloro-4-imidazoles-1-base-phenyl)-ketone
323 451 [1,2,3] thiadiazoles-5-carboxylic acid 4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-acid amides
324 483 Furans-2-carboxylic acid 4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-naphthalene-1-yl }-acid amides
325 511 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-naphthalene-1-yl }-2-fluoro-benzamide
326 429 N-{5-chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methyl-phenyl }-ethanamide
327 509 N-{5-chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methyl-phenyl }-2-fluoro-benzamide
328 481 Furans-2-carboxylic acid 5-chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methyl-phenyl }-acid amides
329 431 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-naphthalene-1-yl }-ethanamide
330 416 Furans-2-carboxylic acid 4-[3-(5-chloro-4-dimethylamino-phenyl)-thioureido]-phenyl }-acid amides
331 561 Furans-2-carboxylic acid [4-(3-{4-[(1-benzyl-tetramethyleneimine-3-yl)-methyl-amino]-3-chloro-phenyl }-thioureido)-phenyl]-acid amides
332 513 N-[4-(3-{3-chloro-4-[methyl-(1-methyl-tetramethyleneimine-3-yl)-amino]-phenyl }-thioureido)-phenyl]-2-fluoro-benzamide
333 463 N-{4-[3-(5-chloro-2-methoxyl group-4-methyl-phenyl)-thioureido]-phenyl }-2,6-two fluoro-benzamide
334 420 N-(4-{3-[3-chloro-4-(1-methyl-tetramethyleneimine-3-base oxygen base)-phenyl]-thioureido }-phenyl)-ethanamide
335 434 N-(4-{3-[3-chloro-4-(1-methyl-piperidin-4-yl oxygen base)-phenyl]-thioureido }-phenyl)-ethanamide
336 422 N-(4-{3-[3-chloro-4-(3-dimethylamino-propoxy-)-phenyl]-thioureido }-phenyl)-ethanamide
337 425 2-acetylamino-5-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenylformic acid
338 505 5-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-(2-fluoro-benzoyl-amido)-phenylformic acid
339 477 5-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-[(furans-2-carbonyl)-amino]-phenylformic acid
340 545 N-[4-(3-{3-chloro-4-[methyl-(1-methyl-piperidin-4-yl)-amino]-phenyl }-thioureido)-phenyl]-2,6-two fluoro-benzamide
341 503 [1,2,3] thiadiazoles-4-carboxylic acid [4-(3-{3-chloro-4-[methyl-(1-methylpyrrolidin-3-yl)-amino]-phenyl }-thioureido)-phenyl]-acid amides
342 443 N-{4-[3-(3-chloro-4-methylthio group-phenyl)-thioureido]-phenyl }-2-methyl-benzamide
343 408 N-(4-{3-[3-chloro-4-(2-dimethylamino-oxyethyl group)-phenyl]-thioureido }-phenyl)-ethanamide
344 499 Furans-2-carboxylic acid [4-(3-{3-chloro-4-[methyl-(1-methyl-piperidin-4-yl)-amino]-phenyl }-thioureido)-phenyl]-acid amides
345 419 N-{4-[3-(3-chloro-4-cyclohexyl oxygen base-phenyl)-thioureido]-phenyl }-ethanamide
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-two fluoro-benzamide
348 462 N-{4-[3-(3-chloro-4-dimethylamino-phenyl)-thioureido]-phenyl }-2,6-two fluoro-benzamide
349 531 N-[4-(3-{3-chloro-4-[methyl-(1-methyl-tetramethyleneimine-3-yl)-amino]-phenyl }-thioureido)-phenyl]-2,6-two fluoro-benzamide
350 427 Pyridine-2-carboxylic acids 4-[3-(3-chloro-4-dimethylamino-phenyl }-thioureido)-phenyl }-acid amides
351 430 Pyridine-2-carboxylic acids 4-[3-(3-chloro-4-methylthio group-phenyl }-thioureido)-phenyl }-acid amides
352 428 Pyridine-2-carboxylic acids 4-[3-(5-chloro-2-methoxyl group-4-methyl-phenyl }-thioureido)-phenyl }-acid amides
353 417 Furans-2-carboxylic acid 4-[3-(5-chloro-2-methoxyl group-4-methyl-phenyl }-thioureido)-phenyl }-acid amides
354 496 Pyridine-2-carboxylic acids [4-(3-{3-chloro-4-[methyl-(1-methyl-tetramethyleneimine-3-yl)-amino]-phenyl }-thioureido)-phenyl]-acid amides
355 495 N-{3-chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide
356 467 Furans-2-carboxylic acid 3-chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-acid amides
357 515 N-{4-[3-(3-chloro-4-hexamethylene sulfenyl-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide
358 449 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-3-trifluoromethyl-phenyl }-ethanamide
359 529 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-3-trifluoromethyl-phenyl }-2-fluoro-benzamide
360 421 N-{4-[3-(4-acetylamino-phenyl)-thioureido]-2-chloro-phenyl }-2-dimethyl-amino-ethanamide
361 473 Furans-2-carboxylic acid (4-{3-[3-chloro-4-(2-dimethylamino-acetylamino)-phenyl]-thioureido }-phenyl)-acid amides
362 501 N-(4-{3-[3-chloro-4-(2-dimethylamino-acetylamino)-phenyl }-thioureido }-phenyl)-2-fluoro-benzamide
363 461 N-{4-[3-(4-acetylamino-phenyl)-thioureido]-2-chloro-phenyl }-2-piperidines-1-base-ethanamide
364 541 N-(4-{3-[3-chloro-4-(2-piperidines-1-base-acetylamino)-phenyl]-thioureido }-phenyl)-2-fluoro-benzamide
365 513 Furans-2-carboxylic acid (4-{3-[3-chloro-4-(2-piperidines-1-base-acetylamino)-phenyl]-thioureido }-phenyl)-acid amides
366 463 N-{4-[3-(4-acetylamino-phenyl)-thioureido]-2-chloro-phenyl }-2-morpholine-4-base-ethanamide
367 543 N-(4-{3-[3-chloro-4-(2-morpholine-4-base-acetylamino)-phenyl]-thioureido }-phenyl)-2-fluoro-benzamide
368 515 Furans-2-carboxylic acid (4-{3-[3-chloro-4-(2-morpholine-4-base-acetylamino)-phenyl]-thioureido }-phenyl)-acid amides
369 414 N-{4-[3-(3-chloro-4-methylsulfonyl amino-phenyl)-thioureido]-phenyl }-ethanamide
370 494 N-{4-[3-(3-chloro-4-methylsulfonyl amino-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide
371 466 Furans-2-carboxylic acid 4-[3-(3-chloro-4-methylsulfonyl amino-phenyl)-thioureido]-phenyl }-ethanamide
372 481 N-{4-[3-(4-acetylamino-phenyl)-thioureido]-2-chloro-phenyl }-2-(2-dimethylamino-ethylmercapto group)-ethanamide
373 561 N-[4-(3-{3-chloro-4-[2-(2-dimethylamino-ethylmercapto group)-acetylamino]-phenyl }-thioureido)-phenyl]-2-fluoro-benzamide
374 585 N-[4-(3-{4-[(1-benzyl-tetramethyleneimine-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 acids [4-(3-{3-chloro-4-[methyl-(1-methyl-piperidin-4-yl)-amino]-phenyl }-thioureido)-phenyl]-acid amides
377 347 N-{4-[3-(3-chloro-4-vinyl-phenyl)-thioureido]-phenyl }-ethanamide
378 441 Furans-2-carboxylic acid 4-[3-(4-chloro-3-trifluoromethyl-phenyl)-thioureido]-phenyl }-acid amides
379 452 Pyridine-2-carboxylic acids 4-[3-(4-chloro-3-trifluoromethyl-phenyl)-thioureido]-phenyl }-acid amides
380 487 N-{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-thioureido]-phenyl }-2,6-two fluoro-benzamide
381 486 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-3-cyano group-phenyl }-2-fluoro-benzamide
382 458 Furans-2-carboxylic acid 4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-3-cyano group-phenyl }-acid amides
383 406 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-3-cyano group-phenyl }-ethanamide
384 395 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-2-methyl-isothioureido]-phenyl }-ethanamide
385 396 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-2-methyl-isothioureido]-phenyl }-ethanamide
386 461 N-{4-[3-(3-chloro-4-ethylmercapto group-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide
387 489 N-{4-[3-(4-butylthio-3-chloro-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide
388 411 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-3-methoxyl group-phenyl }-ethanamide
389 491 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-3-methoxyl group-phenyl }-2-fluoro-benzamide
390 463 Furans-2-carboxylic acid 4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-3-methoxyl group-phenyl }-acid amides
391 531 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[3-chloro-4-(2-piperidines-1-base-ethanoyl-amino)-phenyl]-thioureido } phenyl)-acid amides
392 481 N-{4-[3-(3-chloro-4-methanesulfinyl-phenyl)-thioureido]-phenyl }-2,6-two fluoro-benzamide
393 497 N-{4-[3-(3-chloro-4-methylsulfonyl-phenyl)-thioureido]-phenyl }-2,6-two fluoro-benzamide
394 459 N-{4-[3-(5-chloro-2-methoxyl group-4-methyl-phenyl)-thioureido]-2-methyl-phenyl }-2-fluoro-benzamide
395 429 N-{4-[3-(3-chloro-4-methyl-phenyl)-thioureido]-2-methyl-phenyl }-2-fluoro-benzamide
396 533 Furans-2-carboxylic acid [4-(3-{3-chloro-4-[2-(2-dimethylamino-ethylmercapto group)-acetylamino]-phenyl }-thioureido)-phenyl]-acid amides
397 458 N-{4-[3-(4-acetylamino-3-chloro-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide
398 460 [2-chloro-4-(3-{4-[(furans-2-carbonyl)-amino]-phenyl }-thioureido)-phenyl]-urethanum
390 488 [2-chloro-4-{3-[4-(2-fluoro-benzoyl-amido)-phenyl]-thioureido }-phenyl]-urethanum
400 440 N-{4-[3-(4-acetylamino-phenyl)-thioureido]-2-chloro-phenyl }-benzamide
401 520 N-{4-[({[4-(benzoyl-amido)-3-chloro-phenyl]-amino }-sulphomethyl)-amino]-phenyl }-2-fluoro-benzamide
402 529 N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-trifluoromethyl-phenyl }-2-fluoro-benzamide
403 492 Furans-2-carboxylic acid 4-[3-(4-benzoyl-amido-3-chloro-phenyl)-thioureido]-phenyl }-acid amides
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-thiomorpholine-4-base-ethanamide
406 531 Furans-2-carboxylic acid (4-{3-[3-chloro-4-(2-thiomorpholine-4-base-acetylamino)-phenyl]-thioureido }-phenyl)-acid amides
407 559 N-(4-{3-[3-chloro-4-(2-thiomorpholine-4-base-acetylamino)-phenyl]-thioureido }-phenyl)-2-fluoro-benzamide
408 461 N-{4-[3-(3-chloro-4-methylthio group-phenyl)-thioureido]-2-methyl-phenyl }-2-fluoro-benzamide
409 430 Furans-2-carboxylic acid 4-[3-(4-acetylamino-3-chloro-phenyl)-thioureido]-phenyl }-acid amides
410 477 N-{4-[3-(4-acetylamino-phenyl)-thioureido]-2-chloro-phenyl }-2-dipropyl amino-ethanamide
411 529 Furans-2-carboxylic acid (4-{3-[3-chloro-4-(2-dipropyl amino-acetylamino)-phenyl]-thioureido }-phenyl)-acid amides
412 449 N-{4-[3-(4-acetylamino-phenyl)-thioureido]-2-chloro-phenyl }-2-diethylamino-ethanamide
413 501 Furans-2-carboxylic acid (4-{3-[3-chloro-4-(2-diethylamino-acetylamino)-phenyl]-thioureido }-phenyl)-acid amides
414 529 N-(4-{3-[3-chloro-4-(2-diethylamino-acetylamino)-phenyl]-thioureido }-phenyl)-2-fluoro-benzamide
415 447 N-{4-[3-(4-acetylamino-phenyl)-thioureido]-2-chloro-phenyl }-2-tetramethyleneimine-1-base-ethanamide
416 499 Furans-2-carboxylic acid (4-{3-[3-chloro-4-(2-tetramethyleneimine-1-base-acetylamino)-phenyl]-thioureido }-phenyl)-acid amides
417 527 N-(4-{3-[3-chloro-4-(2-tetramethyleneimine-1-base-acetylamino)-phenyl]-thioureido }-phenyl)-2-fluoro-benzamide
418 475 N-{4-[3-(5-chloro-2-methoxyl group-4-methyl-phenyl)-thioureido]-3-methoxyl group-phenyl }-2-fluoro-benzamide
419 445 N-{4-[3-(3-chloro-4-methyl-phenyl)-thioureido]-3-methoxyl group-phenyl }-2-fluoro-benzamide
420 477 N-{4-[3-(3-chloro-4-methylthio group-phenyl)-thioureido]-3-methoxyl group-phenyl }-2-fluoro-benzamide
421 388 Furans-2-carboxylic acid 4-[3-(4-amino-3-chloro-phenyl)-thioureido]-phenyl }-acid amides
422 527 Furans-2-carboxylic acid (4-{3-[4-(2-nitrogen heterocyclic heptan-1-base-acetylamino)-3-chloro-phenyl]-thioureido }-phenyl)-acid amides
423 555 N-(4-{3-[4-(2-nitrogen heterocyclic heptan-1-base-acetylamino)-3-chloro-phenyl]-thioureido }-phenyl)-2-fluoro-benzamide
424 527 Furans-2-carboxylic acid [4-(3-{3-chloro-4-[2-(2-methyl-piperidines-1-yl)-ethanoyl-amino]-phenyl }-thioureido)-phenyl]-acid amides
425 555 N-[4-(3-{3-chloro-4-[2-(2-methyl-piperidines-1-yl)-ethanoyl-amino]-phenyl }-thioureido)-phenyl]-2-fluoro-benzamide
426 339 Furans-2-carboxylic acid [4-(3-pyridine-2-base-thioureido)-phenyl]-acid amides
427 339 Furans-2-carboxylic acid [4-(3-pyridin-4-yl-thioureido)-phenyl]-acid amides
428 367 2-fluoro-N-[4-(3-pyridin-3-yl-thioureido)-phenyl]-benzamide
429 339 Furans-2-carboxylic acid [4-(3-pyridin-3-yl-thioureido)-phenyl]-acid amides
430 353 Furans-2-carboxylic acid 4-[3-(3-amino-phenyl)-thioureido]-phenyl }-acid amides
431 406 Furans-2-carboxylic acid 4-[3-(3-trifluoromethyl-phenyl)-thioureido]-phenyl }-acid amides
432 380 2-fluoro-N-[4-(tolyl-thioureido between 3-)-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 Furans-2-carboxylic acid 4-[3-(3-amino-5-chloro-phenyl)-thioureido]-phenyl }-acid amides
436 352 Furans-2-carboxylic acid [4-(tolyl-thioureido between 3-)-phenyl]-acid amides
437 416 N-{4-[3-(2-amino-5-chloro-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide
438 571 (2-chloro-4-{3-[4-(2-fluoro-benzoyl-amido)-phenyl]-thioureido }-phenyl)-carboxylamine 2-piperidines-1-base-ethyl ester
439 543 [2-chloro-4-(3-{4-[(furans-2-carbonyl)-amino]-phenyl }-thioureido)-phenyl]-carboxylamine 2-piperidines-1-base-ethyl ester
440 388 Furans-2-carboxylic acid 4-[3-(2-amino-5-chloro-phenyl)-thioureido]-phenyl }-acid amides
441 363 Furans-2-carboxylic acid 4-[3-(3-cyano group-phenyl)-thioureido]-phenyl }-acid amides
442 416 N-{4-[3-(3-amino-5-chloro-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide
????443 ????367 2-fluoro-N-[4-(3-pyridine-2-base-thioureido)-phenyl]-benzamide
????444 ????367 2-fluoro-N-[4-(3-pyridin-4-yl-thioureido)-phenyl]-benzamide
????445 ????374 Furans-2-carboxylic acid 4-[3-(6-chloro-pyridin-3-yl)-thioureido]-phenyl }-acid amides
????446 ????388 Furans-2-carboxylic acid 4-[3-(2-amino-3-chloro-phenyl)-thioureido]-phenyl }-acid amides
????447 ????396 Furans-2-carboxylic acid 4-[3-(3-diazanyl carbonyl-phenyl)-thioureido]-phenyl }-acid amides
????448 ????410 2-fluoro-N-(4-{3-[3-(1-hydroxyl-ethyl)-phenyl]-thioureido }-phenyl)-benzamide
????449 ????414 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(3-diazanyl carbonyl-phenyl)-thioureido]-phenyl }-acid amides
????450 ????399 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(3-sec.-propyl-phenyl)-thioureido]-phenyl }-acid amides
????451 ????380 Furans-2-carboxylic acid 4-[3-(3-sec.-propyl-phenyl)-thioureido]-phenyl }-acid amides
????452 ????409 2-fluoro-N-{4-[3-(3-sec.-propyl-phenyl)-thioureido]-phenyl }-benzamide
????453 ????381 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(3-cyano group-phenyl)-thioureido]-phenyl }-acid amides
????454 ????410 N-{4-[3-(3-dimethylamino-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide
????455 ????381 Furans-2-carboxylic acid 4-[3-(3-dimethylamino-phenyl)-thioureido]-phenyl }-acid amides
????456 ????370 [1,2,3] thiadiazoles-4-carboxylic acid [4-(tolyl-thioureido between 3-)-phenyl]-acid amides
????457 ????424 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(3-trifluoromethyl-phenyl)-thioureido]-phenyl }-acid amides
????458 ????479 N-{3-chloro-4-[3-(5-chloro-2-methoxyl group-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-methylthio group-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide
????461 ????391 N-{4-[3-(3-cyano group-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide
????462 ????395 Furans-2-carboxylic acid 4-[3-(3-acetylamino-phenyl)-thioureido]-phenyl }-acid amides
????463 ????424 2-fluoro-N-{4-[3-(3-diazanyl carbonyl-phenyl)-thioureido]-phenyl }-benzamide
????464 ????400 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[3-(1-hydroxyl-ethyl)-phenyl]-thioureido }-phenyl)-acid amides
????465 ????434 N-{4-[3-(2-amino-3-chloro-phenyl)-thioureido]-phenyl }-2,6-two fluoro-benzamide
????466 ????406 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(3-amino-5-chloro-phenyl)-thioureido]-phenyl }-acid amides
????467 ????398 Furans-2-carboxylic acid 4-[3-(3,5-dimethoxy-phenyl)-thioureido]-phenyl }-acid amides
????468 ????416 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(3,5-dimethoxy-phenyl)-thioureido]-phenyl }-acid amides
????469 ????454 5-(3-{4-[(furans-2-carbonyl)-amino]-phenyl }-thioureido)-dimethyl isophthalate
????470 ????434 Isoxazole-5-carboxylic acid { 4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido }-phenyl }-acid amides
????471 ????392 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(6-chloro-pyridin-3-yl)-thioureido]-phenyl }-acid amides
472 382 Furans-2-carboxylic acid (4-{3-[3-(1-hydroxyl-ethyl)-phenyl]-thioureido }-phenyl)-acid amides
473 368 Furans-2-carboxylic acid 4-[3-(3-methoxyl group-phenyl)-thioureido]-phenyl }-acid amides
474 354 Furans-2-carboxylic acid 4-[3-(3-hydroxyl-phenyl)-thioureido]-phenyl }-acid amides
475 382 2-fluoro-N-{4-[3-(3-hydroxyl-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] thiadiazoles-4-carboxylic acid 4-[3-(3-acetylamino-phenyl)-thioureido]-phenyl }-acid amides
479 400 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(3-dimethylamino-phenyl)-thioureido]-phenyl }-acid amides
480 340 Furans-2-carboxylic acid [4-(3-pyrimidine-4-base-thioureido)-phenyl]-acid amides
481 378 Furans-2-carboxylic acid 4-[3-(1H-indazole-5-yl)-thioureido]-phenyl }-acid amides
482 395 Furans-2-carboxylic acid [4-(3-benzothiazole-5-base-thioureido)-phenyl]-acid amides
483 406 2-fluoro-N-{4-[3-(1H-indazole-5-yl)-thioureido]-phenyl }-benzamide
484 424 N-[4-(3-benzothiazole-5-base-thioureido)-phenyl]-2-fluoro-benzamide
485 473 5-(3-{4-[([1,2,3] thiadiazoles-4-carbonyl)-amino]-phenyl }-thioureido)-dimethyl isophthalate
486 442 Furans-2-carboxylic acid (4-{3-[4-(1-azido-ethyl)-3-chloro-phenyl]-thioureido }-phenyl)-acid amides
487 396 2-fluoro-N-{4-[3-(3-methoxyl group-phenyl)-thioureido]-phenyl }-benzamide
488 368 Furans-2-carboxylic acid 4-[3-(3-hydroxymethyl-phenyl)-thioureido]-phenyl }-acid amides
489 416 Furans-2-carboxylic acid 4-[3-(5-chloro-2-dimethylamino-phenyl)-thioureido]-phenyl }-acid amides
490 444 N-{4-[3-(5-chloro-2-dimethylamino-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide
491 506 [3-chloro-5-(3-{4-[([1,2,3] thiadiazoles-4-carbonyl)-amino]-phenyl }-thioureido)-phenyl]-t-butyl carbamate
492 506 N-(4-{3-[4-(1-azido-ethyl)-3-chloro-phenyl]-thioureido }-phenyl)-2-fluoro-benzamide
493 337 Furans-2-carboxylic acid [4-(the 1H-thiazole is [5,4-b] pyridine-2-alkenyl amino also)-phenyl]-acid amides
494 378 Furans-2-carboxylic acid 4-[3-(1H-benzoglyoxaline-5-yl)-thioureido]-phenyl }-acid amides
495 392 Furans-2-carboxylic acid 4-[3-(2-methyl isophthalic acid H-benzoglyoxaline-5-yl)-thioureido]-phenyl }-acid amides
496 406 N-{4-[3-(1H-benzoglyoxaline-5-yl)-thioureido]-phenyl }-2-fluoro-benzamide
497 420 2-fluoro-N-{4-[3-(2-methyl isophthalic acid H-benzoglyoxaline-5-yl)-thioureido]-phenyl }-benzamide
498 452 [1,2,3] thiadiazoles-4-carboxylic acid 5-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridine-2-yl }-acid amides
499 445 Pyridine-2-carboxylic acids 5-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridine-2-yl }-acid amides
500 434 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-acid amides
501 484 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[4-(2-amino-pyrimidine-4-yl)-3-chloro-phenyl]-thioureido }-phenyl)-acid amides
502 494 N-(4-{3-[4-(2-amino-pyrimidine-4-yl)-3-chloro-phenyl]-thioureido }-phenyl)-2-fluoro-benzamide
503 434 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(3-chloro-2-dimethylamino-phenyl)-thioureido]-phenyl }-acid amides
504 462 N-{4-[3-(3-chloro-2-dimethylamino-phenyl)-thioureido]-phenyl }-2,6-two fluoro-benzamide
505 416 Furans-2-carboxylic acid 4-[3-(3-chloro-2-dimethylamino-phenyl)-thioureido]-phenyl }-acid amides
506 445 Pyridine-2-carboxylic acids 6-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-3-yl }-acid amides
507 462 N-{6-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-3-yl }-2-fluoro-benzamide
508 482 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(3-iodo-phenyl)-thioureido]-phenyl }-acid amides
509 413 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(the 3-tertiary butyl-phenyl)-thioureido]-phenyl }-acid amides
510 387 Furans-2-carboxylic acid 4-[3-(3-chloro-benzyl)-thioureido]-phenyl }-acid amides
511 415 N-{4-[3-(3-chloro-benzyl)-thioureido]-phenyl }-2-fluoro-benzamide
512 434 Furans-2-carboxylic acid 6-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-3-yl }-acid amides
513 435 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(3-bromo-phenyl)-thioureido]-phenyl }-acid amides
514 452 [1,2,3] thiadiazoles-4-carboxylic acid 6-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-3-yl }-acid amides
515 426 [1,2,3] thiadiazoles-4-carboxylic acid 5-[3-(3,5-two chloro-phenyl)-thioureido]-pyridine-2-yl }-acid amides
516 474 Furans-2-carboxylic acid 4-[3-(3,5-di-trifluoromethyl-phenyl)-thioureido]-phenyl }-acid amides
517 502 N-{4-[3-(3,5-di-trifluoromethyl-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide
518 450 N-{4-[3-(4-amino-3,5-two chloro-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide
519 539 N-{4-[3-(4-amino-3,5-two bromo-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide
520 392 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(5-chloro-pyridin-3-yl)-thioureido]-phenyl }-acid amides
521 529 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(4-amino-3,5-two bromo-phenyl)-thioureido]-phenyl }-acid amides
522 434 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(3-chloro-5-dimethylamino-phenyl)-thioureido]-phenyl }-acid amides
523 444 N-{4-[3-(3-chloro-5-dimethylamino-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide
524 416 Furans-2-carboxylic acid 4-[3-(3-chloro-5-dimethylamino-phenyl)-thioureido]-phenyl }-acid amides
525 436 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(5-bromo-pyridin-3-yl)-thioureido]-phenyl }-acid amides
526 379 Furans-2-carboxylic acid 4-[3-(1H-benzotriazole-5-yl)-thioureido]-phenyl }-acid amides
527 425 N-{4-[3-(1H-benzotriazole-5-yl)-thioureido]-phenyl }-2,6-two fluoro-benzamide
528 388 N-[4-({ [2-(3-chloro-phenyl)-diazanyl]-sulphomethyl }-amino)-phenyl]-furans-2-carboxylic acid amides
529 416 N-[4-({ [2-(3-chloro-phenyl)-diazanyl]-sulphomethyl }-amino)-phenyl]-2-fluoro-benzamide
530 456 Furans-2-carboxylic acid 4-[3-(2-amino-3-chloro-5-trifluoromethyl-phenyl)-thioureido]-phenyl }-acid amides
531 513 N-{4-[3-(3-bromo-5-trifluoromethyl-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide
532 503 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(3-bromo-5-trifluoromethyl-phenyl)-thioureido]-phenyl }-acid amides
533 374 4-[(furans-2-carbonyl)-amino]-phenyl }-thiocarbamate O-(3-chloro-phenyl) ester
534 474 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(2-amino-3-chloro-5-trifluoromethyl-phenyl)-thioureido]-phenyl }-acid amides
535 508 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(3-piperidines-1-base-5-trifluoromethyl-phenyl)-thioureido]-phenyl }-acid amides
536 380 N-[4-(3-benzyl-thioureido)-phenyl]-2-fluoro-benzamide
537 439 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(3,4-two chloro-benzyls)-thioureido]-phenyl }-acid amides
538 449 N-{4-[3-(3,4-two chloro-benzyls)-thioureido]-phenyl }-2-fluoro-benzamide
539 370 [1,2,3] thiadiazoles-4-carboxylic acid [4-(3 benzyls-thioureido)-phenyl]-acid amides
540 424 N-[4-(3-benzo [1,3] dioxole-5-ylmethyl-thioureido)-phenyl]-2-fluoro-benzamide
541 414 [1,2,3] thiadiazoles-4-carboxylic acid [4-(3-benzo [1,3] dioxole-5-ylmethyl-thioureido)-phenyl]-acid amides
542 506 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(3,5-di-trifluoromethyl-benzyl)-thioureido]-phenyl }-acid amides
543 516 N-{4-[3-(3,5-di-trifluoromethyl-benzyl)-thioureido]-phenyl }-2-fluoro-benzamide
544 352 Furans-2-carboxylic acid [4-(3-benzyl-thioureido)-phenyl]-acid amides
545 421 Furans-2-carboxylic acid 4-[3-(3,4-two chloro-benzyls)-thioureido]-phenyl }-acid amides
546 396 Furans-2-carboxylic acid [4-(3-benzo [1,3] dioxole-5-ylmethyl-thioureido)-phenyl]-acid amides
547 488 Furans-2-carboxylic acid { 4-[3-(3,5-di-trifluoromethyl-benzyl)-thioureido }-phenyl }-acid amides
548 503 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(4-bromo-3-trifluoromethyl-phenyl)-thioureido]-phenyl }-acid amides
549 529 N-{4-[3-(3-bromo-4-trifluoromethoxy-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide
550 519 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(3-bromo-4-trifluoromethoxy-phenyl)-thioureido]-phenyl }-acid amides
551 473 Furans-2-carboxylic acid 4-[3-(3-chloro-4-trifluoromethylthio-phenyl)-thioureido]-phenyl }-acid amides
552 412 2-fluoro-N-(4-{3-[2-(3-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-benzamide
553 412 2-fluoro-N-(4-{3-[2-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-benzamide
554 402 [1,2,3]-thiadiazoles-4-carboxylic acid (4-{3-[2-(3-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
555 402 [1,2,3]-thiadiazoles-4-carboxylic acid (4-{3-[2-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
556 495 [1,2,3]-thiadiazoles-4-carboxylic acid (4-{3-[2-(2-methyl-butyl)-5-trifluoromethyl-phenyl]-thioureido }-phenyl)-acid amides
557 481 [1,2,3]-thiadiazoles-4-carboxylic acid 4-[3-(3-isobutyl--5-trifluoromethyl-phenyl)-thioureido]-phenyl }-acid amides
558 523 [1,2,3]-thiadiazoles-4-carboxylic acid (4-{3-[3-(4-methyl-piperazine-1 base)-5-trifluoromethyl-phenyl]-thioureido }-phenyl)-acid amides
559 510 [1,2,3]-thiadiazoles-4-carboxylic acid 4-[3-(3-morpholine-4-base-5-trifluoromethyl-phenyl)-thioureido]-phenyl }-acid amides
560 494 [1,2,3]-thiadiazoles-4-carboxylic acid 4-[3-(3-tetramethyleneimine-1-base-5-trifluoromethyl-phenyl)-thioureido]-phenyl }-acid amides
561 384 Furans-2-carboxylic acid (4-{3-[2-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
562 419 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[2-(3-chloro-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
563 429 N-(4-{3-[2-(3-chloro-phenyl)-ethyl]-thioureido }-phenyl)-2-fluoro-benzamide
564 401 Furans-2-carboxylic acid (4-{3-[2-(3-chloro-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
565 402 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
566 504 2-fluoro-N-{4-[3-(3-tetramethyleneimine-1-base-5-trifluoromethyl-phenyl)-thioureido]-phenyl }-benzamide
567 477 N-{4-[3-(3-dimethylamino-5-trifluoromethyl-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide
568 520 2-fluoro-N-{4-[3-(3-morpholine-4-base-5-trifluoromethyl-phenyl)-thioureido]-phenyl }-benzamide
569 533 2-fluoro-N-(4-{3-[3-(4-methyl-piperazine-1-yl)-5-trifluoromethyl-phenyl]-thioureido }-phenyl)-benzamide
570 518 2-fluoro-N-{4-[3-(3-piperidines-1-base-5-trifluoromethyl-phenyl)-thioureido]-phenyl }-benzamide
571 468 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(3-dimethylamino-5-trifluoromethyl-phenyl)-thioureido]-phenyl }-acid amides
572 405 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(3-chloro-benzyl)-thioureido]-phenyl }-acid amides
573 384 Furans-2-carboxylic acid (4-{3-[2-(3-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
574 366 Furans-2-carboxylic acid [4-(3-styroyl-thioureido)-phenyl]-acid amides
575 384 [1,2,3] thiadiazoles-4-carboxylic acid [4-(3-styroyl-thioureido)-phenyl]-acid amides
576 394 2-fluoro-N-[4-(3-styroyl-thioureido)-phenyl]-benzamide
577 505 2-fluoro-N-(4-{3-[3-(2-methyl-butyl)-5-trifluoromethyl-phenyl]-thioureido }-phenyl)-benzamide
578 491 2-fluoro-N-{4-[3-(3-isobutyl--5-trifluoromethyl-phenyl)-thioureido]-phenyl }-benzamide
579 388 Furans-2-carboxylic acid 4-[3-(3,5-two fluoro-benzyls)-thioureido]-phenyl }-acid amides
580 416 N-{4-[3-(3,5-two fluoro-benzyls)-thioureido]-phenyl }-2-fluoro-benzamide
581 406 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(3,5-two fluoro-benzyls)-thioureido]-phenyl }-acid amides
582 421 Furans-2-carboxylic acid 4-[3-(3,5-two chloro-benzyls)-thioureido]-phenyl }-acid amides
583 449 N-{4-[3-(3,5-two chloro-benzyls)-thioureido]-phenyl }-2-fluoro-benzamide
584 439 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(3,5-two chloro-benzyls)-thioureido]-phenyl }-acid amides
585 438 Furans-2-carboxylic acid 4-[3-(3-fluoro-5-trifluoromethyl-benzyl)-thioureido]-phenyl }-acid amides
586 466 2-fluoro-N-{4-[3-(3-fluoro-5-trifluoromethyl-benzyl)-thioureido]-phenyl }-benzamide
587 456 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(3-fluoro-5-trifluoromethyl-benzyl)-thioureido]-phenyl }-acid amides
??588 ??384 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(1-phenylethyl)-thioureido]-phenyl }-acid amides
??589 ??394 2-fluoro-N-{4-[3-(1-phenyl-ethyl)-thioureido]-phenyl }-benzamide
??590 ??366 Furans-2-carboxylic acid 4-[3-(1-phenyl-ethyl)-thioureido]-phenyl }-benzamide
??591 ??412 2-fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-benzamide
??592 ??384 Furans-2-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
??593 ??413 N-{4-[3-(the 1-tertiary butyl-1H-imidazoles-2-yl)-thioureido]-phenyl }-2-fluoro-benzamide
??594 ??510 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[3-(isobutyl--methyl-amino)-5-trifluoromethyl-phenyl]-thioureido }-phenyl)-acid amides
??595 ??510 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[3-(3-hydroxyl-tetramethyleneimine-1-yl)-5-trifluoromethyl-phenyl]-thioureido }-phenyl)-acid amides
??596 ??520 2-fluoro-N-(4-{3-[3-(isobutyl--methyl-amino)-5-trifluoromethyl-phenyl]-thioureido }-phenyl)-benzamide
??597 ??510 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[3-(butyl-methyl-amino)-5-trifluoromethyl-phenyl]-thioureido }-phenyl)-acid amides
??598 ??520 N-(4-{3-[3-(butyl-methyl-amino)-5-trifluoromethyl-phenyl]-thioureido }-phenyl)-2-fluoro-benzamide
??599 ??520 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[2-(3,5-di-trifluoromethyl-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
??600 ??442 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(4-fluoro-3-trifluoromethyl-phenyl)-thioureido]-phenyl }-acid amides
??601 ??522 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(4-piperidines-1-base-3-trifluoromethyl-benzyl)-thioureido]-phenyl }-acid amides
??602 ??482 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(4-dimethylamino-3-trifluoromethyl-benzyl)-thioureido]-phenyl }-acid amides
??603 ??381 Furans-2-carboxylic acid (4-{3-[2-(4-amino-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
??604 ??445 Furans-2-carboxylic acid (4-{3-[2-(4-bromo-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
??605 ??380 Furans-2-carboxylic acid 4-[3-(2-p-methylphenyl-ethyl)-thioureido]-phenyl }-acid amides
??606 ??463 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[2-(4-bromo-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
??607 ??396 Furans-2-carboxylic acid (4-{3-[2-(3-methoxyl group-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
??608 ??403 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(the 1-tertiary butyl-1H-imidazoles-2-yl)-thioureido]-phenyl }-acid amides
??609 ??384 Furans-2-carboxylic acid 4-[3-(the 1-tertiary butyl-1H-imidazoles-2-yl)-thioureido]-phenyl }-acid amides
??610 ??492 N-{4-[3-(4 dimethylaminos-3-trifluoromethyl-benzyl)-thioureido]-phenyl }-2-fluoro-benzamide
??611 ??427 Furans-2-carboxylic acid (4-{3-[2-(3,4-dimethoxy-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
??612 ??380 Furans-2-carboxylic acid 4-[3-(3-phenyl-propyl group)-thioureido]-phenyl }-acid amides
??613 ??399 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(3-phenyl-propyl group)-thioureido]-phenyl }-acid amides
??614 ??502 Furans-2-carboxylic acid (4-{3-[2-(3,5-di-trifluoromethyl-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
??615 ??550 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(4-iodo-3-trifluoromethyl-phenyl)-thioureido]-phenyl }-acid amides
??616 ??532 2-fluoro-N-{4-[3-(4-piperidines-1-base-3-trifluoromethyl-benzyl)-thioureido]-phenyl }-benzamide
617 537 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[4-(4-methyl-piperazine-1-yl)-3-trifluoromethyl-benzyl]-the thioureido methyl }-phenyl)-acid amides
618 482 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(3-dimethylamino-5-trifluoromethyl-benzyl)-thioureido methyl]-phenyl }-acid amides
619 488 Furans-2-carboxylic acid 4-[3-(3,5-di-trifluoromethyl-phenyl)-thioureido methyl]-phenyl }-acid amides
620 421 Furans-2-carboxylic acid 4-[3-(3,5-two chloro-phenyl)-thioureido methyl]-phenyl }-acid amides
621 421 Furans-2-carboxylic acid 4-[3-(3,4-two chloro-phenyl)-thioureido methyl]-phenyl }-acid amides
622 455 Furans-2-carboxylic acid 4-[3-(4-chloro-3-trifluoromethyl-phenyl)-thioureido methyl]-phenyl }-acid amides
623 466 2-fluoro-N-{4-[3-(4-fluoro-3-trifluoromethyl-benzyl)-thioureido]-phenyl }-benzamide
624 456 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(4-fluoro-3-trifluoromethyl-benzyl)-thioureido]-phenyl }-acid amides
625 410 2-fluoro-N-{4-[3-(2-phenoxy group-ethyl)-thioureido]-phenyl }-benzamide
626 382 Furans-2-carboxylic acid 4-[3-(2-phenoxy group-ethyl)-thioureido]-phenyl }-acid amides
627 400 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(2-phenoxy group-ethyl)-thioureido]-phenyl }-acid amides
628 409 2-fluoro-N-{4-[3-(3-phenyl-propyl group)-thioureido]-phenyl }-benzamide
629 425 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(5-trifluoromethyl-pyridin-3-yl)-thioureido]-phenyl }-acid amides
630 439 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(3,4-two chloro-phenyl)-thioureido methyl]-phenyl }-acid amides
631 473 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(4-chloro-3-trifluoromethyl-phenyl)-thioureido methyl]-phenyl }-acid amides
632 381 2-fluoro-N-[4-(3-pyridin-3-yl methyl-thioureido)-phenyl]-benzamide
633 353 Furans-2-carboxylic acid [4-(3-pyridin-3-yl methyl-thioureido)-phenyl]-acid amides
634 371 [1,2,3] thiadiazoles-4-carboxylic acid [4-(3-pyridin-3-yl methyl-thioureido)-phenyl]-acid amides
635 439 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(3,5-two chloro-phenyl)-thioureido methyl]-phenyl }-acid amides
636 492 N-{4-[3-(3-dimethylamino-5-trifluoromethyl-benzyl)-thioureido]-phenyl }-2-fluoro-benzamide
637 415 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[2-(3-methoxyl group-phenyl)-ethyl] thioureido }-phenyl)-acid amides
638 399 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(2-p-methylphenyl-ethyl)-thioureido]-phenyl }-acid amides
639 445 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[2-(3,4-dimethoxy-phenyl)-ethyl] thioureido }-phenyl)-acid amides
640 506 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(3,5-di-trifluoromethyl-phenyl)-thioureido methyl]-phenyl }-acid amides
641 516 N-{4-[3-(3,5-di-trifluoromethyl-phenyl)-thioureido methyl]-phenyl }-2-fluoro-benzamide
642 449 N-{4-[3-(3,5-two chloro-phenyl)-thioureido methyl]-phenyl }-2-fluoro-benzamide
643 449 N-{4-[3-(3,4-two chloro-phenyl)-thioureido methyl]-phenyl }-2-fluoro-benzamide
644 448 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(3-acetylamino-5-chloro-phenyl)-thioureido]-phenyl }-acid amides
645 453 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[2-(3,4-two chloro-phenyl)-ethyl] thioureido }-phenyl)-acid amides
646 413 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(1-methyl-3-phenyl-propyl group)-thioureido]-phenyl }-acid amides
647 463 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[1-(4-bromo-phenyl)-ethyl] thioureido }-phenyl)-acid amides
648 413 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(4-phenyl-butyl)-thioureido]-phenyl }-acid amides
649 397 [1,2,3] thiadiazoles-4-carboxylic acid [4-(3-indane-1-base-thioureido)-phenyl]-acid amides
650 400 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(2-methoxyl group-benzyl)-thioureido]-phenyl }-acid amides
651 415 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[2-(2-methoxyl group-phenyl)-ethyl] thioureido }-phenyl)-acid amides
652 415 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[2-(4-methoxyl group-phenyl)-ethyl] thioureido }-phenyl)-acid amides
653 506 N-(4-{3-[2-(3-dimethylamino-5-trifluoromethyl-phenyl)-ethyl]-thioureido }-phenyl)-2-fluoro-benzamide
654 510 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[3-(3-dimethylamino-propyl group)-5-trifluoromethyl-phenyl]-thioureido }-phenyl)-acid amides
655 417 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(2-thiophenyl-ethyl)-thioureido]-phenyl }-acid amides
656 427 2-fluoro-N-{4-[3-(2-thiophenyl-ethyl)-thioureido]-phenyl }-benzamide
657 399 Furans-2-carboxylic acid 4-[3-(2-thiophenyl-ethyl)-thioureido]-phenyl }-benzamide
658 381 2-fluoro-N-[4-(3-pyridin-4-yl methyl-thioureido)-phenyl]-benzamide
659 353 Furans-2-carboxylic acid [4-(3-pyridin-4-yl methyl-thioureido)-phenyl]-acid amides
660 371 [1,2,3] thiadiazoles-4-carboxylic acid [4-(3-pyridin-4-yl methyl-thioureido)-phenyl]-acid amides
661 506 2-fluoro-N-{4-[3-(3-iodo-benzyl)-thioureido]-phenyl }-benzamide
662 478 Furans-2-carboxylic acid 4-[3-(3-iodo-benzyl)-thioureido]-phenyl }-acid amides
663 496 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(3-iodo-benzyl)-thioureido]-phenyl }-acid amides
664 479 N-(4-{3-[2-(3,5-two chloro-phenoxy groups)-ethyl]-thioureido }-phenyl)-2-fluoro-benzamide
665 451 Furans-2-carboxylic acid (4-{3-[2-(3,5-two chloro-phenoxy groups)-ethyl]-thioureido }-phenyl)-acid amides
666 445 N-(4-{3-[2-(3-chloro-phenoxy group)-ethyl]-thioureido }-phenyl)-2-fluoro-benzamide
667 417 Furans-2-carboxylic acid (4-{3-[2-(3-chloro-phenoxy group)-ethyl]-thioureido }-phenyl)-acid amides
668 435 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[2-(3-chloro-phenoxy group)-ethyl]-thioureido }-phenyl)-acid amides
669 466 2-fluoro-N-{4-[3-(2-fluoro-5-trifluoromethyl-benzyl)-thioureido]-phenyl }-benzamide
670 438 Furans-2-carboxylic acid 4-[3-(2-fluoro-5-trifluoromethyl-benzyl)-thioureido]-phenyl }-acid amides
671 456 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(2-fluoro-5-trifluoromethyl-benzyl)-thioureido]-phenyl }-acid amides
672 416 N-{4-[3-(3,4-two fluoro-benzyls)-thioureido]-phenyl }-2-fluoro-benzamide
673 452 N-(4-{3-[2-(4-dimethylamino-3-methyl-phenyl)-ethyl]-thioureido }-phenyl)-2-fluoro-benzamide
674 496 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[2-(3-dimethylamino-5-trifluoromethyl-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
675 388 Furans-2-carboxylic acid 4-[3-(3,4-two fluoro-benzyls)-thioureido]-phenyl }-acid amides
676 406 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(3,4-two fluoro-benzyls)-thioureido]-phenyl }-acid amides
677 433 N-{4-[3-(3-chloro-4-fluoro-benzyl)-thioureido]-phenyl }-2-fluoro-benzamide
678 495 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[2-(3-bromo-thiophenyl)-ethyl]-thioureido }-phenyl)-acid amides
679 477 Furans-2-carboxylic acid (4-{3-[2-(3-bromo-thiophenyl)-ethyl]-thioureido }-phenyl)-acid amides
680 505 N-(4-{3-[2-(3-bromo-thiophenyl)-ethyl]-thioureido }--phenyl)-2-fluoro-benzamide
681 493 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[2-(3-bromo-4-methoxyl group-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
682 493 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[2-(5-bromo-4-methoxyl group-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
683 419 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[2-(2-chloro-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
684 402 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[2-(2-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
685 419 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[2-(4-chloro-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
686 475 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(3,3-phenylbenzene-propyl group)-thioureido]-phenyl }-acid amides
687 547 2-fluoro-N-(4-{3-[4-(4-methyl-piperazine-1-yl)-3-trifluoromethyl-benzyl]-thioureido }-phenyl)-benzamide
688 469 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[2-(3,5-two chloro-phenoxy groups)-ethyl]-thioureido }-phenyl)-acid amides
689 423 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(3-chloro-4-fluoro-benzyl)-thioureido]-phenyl }-acid amides
690 427 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(the 4-tertiary butyl-benzyl)-thioureido]-phenyl }-acid amides
691 399 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(3,5-dimethyl-benzyl)-thioureido]-phenyl }-acid amides
692 442 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[2-(4-dimethylamino-3-methyl-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
693 479 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[2-(4-bromo-phenoxy group)-ethyl]-thioureido }-phenyl)-acid amides
694 526 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[2-(4-iodo-phenoxy group)-ethyl]-thioureido }-phenyl)-acid amides
695 489 N-(4-{3-[2-(4-bromo-phenoxy group)-ethyl]-thioureido }-phenyl)-2-fluoro-benzamide
696 536 2-fluoro-N-(4-{3-[2-(4-iodo-phenoxy group)-ethyl]-thioureido }-phenyl)-benzamide
697 461 Furans-2-carboxylic acid (4-{3-[2-(4-bromo-phenoxy group)-ethyl]-thioureido }-phenyl)-acid amides
698 508 Furans-2-carboxylic acid (4-{3-[2-(4-iodo-phenoxy group)-ethyl]-thioureido }-phenyl)-acid amides
699 408 Oxazole-4-carboxylic acid 4-[3-(3,4-two chloro-phenyl)-thioureido]-phenyl }-acid amides
700 424 The thiazole-4-carboxylic acid 4-[3-(3,5-two chloro-phenyl)-thioureido]-phenyl }-acid amides
701 491 The thiazole-4-carboxylic acid 4-[3-(3,5-di-trifluoromethyl-phenyl)-thioureido]-phenyl }-acid amides
702 408 Oxazole-4-carboxylic acid 4-[3-(3,5-two chloro-phenyl)-thioureido]-phenyl }-acid amides
703 469 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[2-(3,4-two chloro-phenoxy groups)-ethyl]-thioureido }-phenyl)-acid amides
704 424 The thiazole-4-carboxylic acid 4-[3-(3,4-two chloro-phenyl)-thioureido]-phenyl }-acid amides
705 458 The thiazole-4-carboxylic acid 4-[3-(4-chloro-3-trifluoromethyl-phenyl)-thioureido]-phenyl }-acid amides
706 400 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(2-phenyl amino-ethyl)-thioureido]-phenyl }-acid amides
707 453 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[2-(2,4-two chloro-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
708 452 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[2-(3-trifluoromethyl-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
709 453 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[2-(2,6-two chloro-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
710 485 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[2-(3,4-two chloro-thiophenyls)-ethyl]-thioureido }-phenyl)-acid amides
711 503 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[2-(2-fluoro-5-trifluoromethyl-thiophenyl)-ethyl]-thioureido }-phenyl)-acid amides
712 668 N-(4-{3-[3-chloro-5-(3-{4-[([1,2,3] thiadiazoles-4-carbonyl)-amino]-phenyl }-thioureido)-phenyl]-thioureido }-phenyl)-[1,2,3] thiadiazoles-4-carboxylic acid amides
713 413 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[2-(4-ethyl-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
714 442 Oxazole-4-carboxylic acid 4-[3-(4-chloro-3-trifluoromethyl-phenyl)-thioureido]-phenyl }-acid amides
715 475 Oxazole-4-carboxylic acid 4-[3-(3,5-di-trifluoromethyl-phenyl)-thioureido]-phenyl }-acid amides
716 420 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[2-(3,4-two fluoro-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
717 452 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[2-(4-trifluoromethyl-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
718 435 Furans-2-carboxylic acid (4-{3-[2-(3,4-two chloro-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
719 463 N-(4-{3-[2-(3,4-two chloro-phenyl)-ethyl]-thioureido }-phenyl)-2-fluoro-benzamide
720 420 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[2-(3,5-two fluoro-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
721 412 2-fluoro-N-(4-{3-[2-(2-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-benzamide
722 429 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[2-(4-nitro-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
723 399 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(1-methyl-2-phenyl-ethyl)-thioureido]-phenyl }-acid amides
724 437 N-{4-[3-(the 4-tertiary butyl-benzyl)-thioureido]-phenyl }-2-fluoro-benzamide
725 409 N-{4-[3-(3,5-dimethyl-benzyl)-thioureido]-phenyl }-2-fluoro-benzamide
726 400 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(2-hydroxyl-1-phenyl-ethyl)-thioureido]-phenyl }-acid amides
727 409 2-fluoro-N-{4-[3-(1-methyl isophthalic acid-phenyl-ethyl)-thioureido]-phenyl }-benzamide
728 399 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(1-methyl isophthalic acid-phenyl-ethyl)-thioureido]-phenyl }-acid amides
729 405 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(2-chloro-benzyl)-thioureido]-phenyl }-acid amides
730 388 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(2-fluoro-benzyl)-thioureido]-phenyl }-acid amides
731 438 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(3-trifluoromethyl-benzyl)-thioureido]-phenyl }-acid amides
732 388 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(3-fluoro-benzyl)-thioureido]-phenyl }-acid amides
733 435 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[2-(2-chloro-phenoxy group)-ethyl]-thioureido }-phenyl)-acid amides
734 479 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[2-(3-bromo-phenoxy group)-ethyl]-thioureido }-phenyl)-acid amides
735 418 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[2-(2-fluoro-phenoxy group)-ethyl]-thioureido }-phenyl)-acid amides
736 418 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[2-(3-chloro-phenoxy group)-ethyl]-thioureido }-phenyl)-acid amides
737 486 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[2-(2-fluoro-5-trifluoromethyl-phenoxy group)-ethyl]-thioureido }-phenyl)-acid amides
738 384 Furans-2-carboxylic acid (4-{3-[2-(2-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
739 435 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(4-bromo-phenyl)-thioureido]-phenyl }-acid amides
740 374 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(4-fluoro-phenyl)-thioureido]-phenyl }-acid amides
741 388 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(4-fluoro-benzyl)-thioureido]-phenyl }-acid amides
742 405 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(4-chloro-benzyl)-thioureido]-phenyl }-acid amides
743 449 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(4-bromo-benzyl)-thioureido]-phenyl }-acid amides
744 332 N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-ethanamide
745 438 The thiazole-4-carboxylic acid 4-[3-(3,4-two chloro-benzyls)-thioureido]-phenyl }-acid amides
746 455 The thiazole-4-carboxylic acid 4-[3-(2-fluoro-5-trifluoromethyl-benzyl)-thioureido]-phenyl }-acid amides
747 426 The thiazole-4-carboxylic acid 4-[3-(the 4-tertiary butyl-benzyl)-thioureido]-phenyl }-acid amides
748 374 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(2-fluoro-phenyl)-thioureido]-phenyl }-acid amides
749 374 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(3-fluoro-phenyl)-thioureido]-phenyl }-acid amides
750 526 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[2-(3-iodo-phenoxy group)-ethyl]-thioureido }-phenyl)-acid amides
751 409 N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-2-phenyl-ethanamide
752 425 N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-2-methoxyl group-benzamide
753 425 N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-3-methoxyl group-benzamide
754 425 N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-4-methoxyl group-benzamide
755 429 2-chloro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-benzamide
756 429 4-chloro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-benzamide
757 453 Acetate 4-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-the phenyl amino formyl radical)-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-hydroxyl-benzamide
761 429 3-chloro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-benzamide
762 470 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[2-(3-fluoro-5-trifluoromethyl-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
763 520 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[2-(2,4-di-trifluoromethyl-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
764 470 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[2-(4-fluoro-3-trifluoromethyl-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
765 438 4-dimethylamino-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-benzamide
766 470 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[2-(2-fluoro-3-trifluoromethyl-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
767 470 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[2-(2-fluoro-5-trifluoromethyl-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
768 510 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[2-(3-iodo-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
769 470 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[2-(4-fluoro-2-trifluoromethyl-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
770 463 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[2-(3-bromo-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
771 427 2-fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-propyl group]-thioureido }-phenyl)-benzamide
772 475 2-fluoro-N-(4-{3-[(4-fluoro-phenyl)-phenyl-methyl]-thioureido }-phenyl)-benzamide
773 455 2-fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-amyl group]-thioureido }-phenyl)-benzamide
774 489 2-fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-2-phenyl-ethyl]-thioureido }-phenyl)-benzamide
775 409 2-fluoro-N-{4-[3-(1-o-tolyl-ethyl)-thioureido]-phenyl }-benzamide
776 409 2-fluoro-N-{4-[3-(tolyl-ethyl between 1-)-thioureido]-phenyl }-benzamide
777 425 2-fluoro-N-(4-{3-[1-(4-methoxyl group-phenyl)-ethyl]-thioureido }-phenyl)-benzamide
778 412 2-fluoro-N-(4-{3-[1-(2-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-benzamide
779 429 N-(4-{3-[1-(3-chloro-phenyl)-ethyl]-thioureido }-phenyl)-2-fluoro-benzamide
780 473 N-(4-{3-[1-(3-bromo-phenyl)-ethyl]-thioureido }-phenyl)-2-fluoro-benzamide
781 429 N-(4-{3-[1-(4-chloro-phenyl)-ethyl]-thioureido }-phenyl)-2-fluoro-benzamide
782 409 2-fluoro-N-{4-[3-(1-p-methylphenyl-ethyl)-thioureido]-phenyl }-benzamide
783 473 N-(4-{3-[1-(2-bromo-phenyl)-ethyl]-thioureido }-phenyl)-2-fluoro-benzamide
784 429 N-(4-{3-[1-(2-chloro-phenyl)-ethyl]-thioureido }-phenyl)-2-fluoro-benzamide
785 462 2-fluoro-N-(4-{3-[1-(2-trifluoromethyl-phenyl)-ethyl]-thioureido }-phenyl)-benzamide
786 462 2-fluoro-N-(4-{3-[1-(3-trifluoromethyl-phenyl)-ethyl]-thioureido }-phenyl)-benzamide
787 462 2-fluoro-N-(4-{3-[1-(4-trifluoromethyl-phenyl)-ethyl]-thioureido }-phenyl)-benzamide
788 425 2-fluoro-N-(4-{3-[1-(2-methoxyl group-phenyl)-ethyl]-thioureido }-phenyl)-benzamide
789 425 2-fluoro-N-(4-{3-[1-(3-methoxyl group-phenyl)-ethyl]-thioureido }-phenyl)-benzamide
790 441 2-fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-2-methyl-propyl group]-thioureido }-phenyl)-benzamide
791 419 N-(4-{3-[1-(3-cyano group-phenyl)-ethyl]-thioureido }-phenyl)-2-fluoro-benzamide
792 419 N-(4-{3-[1-(4-cyano group-phenyl)-ethyl]-thioureido }-phenyl)-2-fluoro-benzamide
793 438 N-(4-{3-[1-(4-dimethylamino-phenyl)-ethyl]-thioureido }-phenyl)-2-fluoro-benzamide
794 438 N-(4-{3-[1-(3-dimethylamino-phenyl)-ethyl]-thioureido }-phenyl)-2-fluoro-benzamide
795 473 2-bromo-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-benzamide
796 446 The quinaldic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
797 410 2-fluoro-N-{4-[3-(2-hydroxyl-1-phenyl-ethyl)-thioureido]-phenyl }-benzamide
798 332 2-fluoro-N-[4-(3-sec.-propyl-thioureido)-phenyl]-benzamide
799 445 2-fluoro-N-{4-[3-(1-naphthalene-2-base-ethyl)-thioureido]-phenyl }-benzamide
800 412 3-fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-benzamide
801 412 4-fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-benzamide
802 384 2-fluoro-N-{4-[3-(1-furans-2-base-ethyl)-thioureido]-phenyl }-benzamide
803 395 2-fluoro-N-{4-[3-(1-pyridin-4-yl-ethyl)-thioureido]-phenyl }-benzamide
804 397 2-fluoro-N-(4-{3-[1-(1-methyl isophthalic acid H-pyrroles-2-yl)-ethyl]-thioureido }-phenyl)-benzamide
805 401 2-fluoro-N-{4-[3-(1-benzene sulphur-3-base-ethyl)-thioureido]-phenyl }-benzamide
806 445 N-{4-[3-(3-chloro-4-oxyethyl group-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide
807 459 N-{4-[3-(3-chloro-4-propoxy--phenyl)-thioureido]-phenyl }-2-fluoro-benzamide
808 459 N-{4-[3-(3-chloro-4-isopropoxy-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide
809 473 N-{4-[3-(4-butoxy-3-chloro-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide
810 522 2-fluoro-N-{4-[3-(3-iodo-4-methoxyl group-phenyl)-thioureido]-phenyl }-benzamide
811 475 N-{4-[3-(3-bromo-4-methoxyl group-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)-propionic acid amide
814 286 N-[4-(3-phenyl-thioureido)-phenyl]-ethanamide
815 507 N-{5-({ [3,5-two (trifluoromethyl) benzyl] amino } thiocarbonyl) amino]-2-pyridyl-1,2,3-thiadiazoles-4-carboxylic acid amides
816 521 N-(5-{[({ (1S)-1-[3,5-two (trifluoromethyl) phenyl] ethyl } amino) thiocarbonyl]-amino }-the 2-pyridyl)-1,2,3-thiadiazoles-4-carboxylic acid amides
817 520 N-(5-{[({ (1S)-1-[3,5-two (trifluoromethyl) phenyl] ethyl } amino) thiocarbonyl]-amino }-the 2-pyridyl)-1,3-thiazoles-4-
Carboxylic acid amides
818 470 N-(5-{[({1-[2-fluoro-5-(trifluoromethyl) phenyl] ethyl } amino) thiocarbonyl]-amino }-the 2-pyridyl)-1,3-thiadiazoles-4-carboxylic acid amides
819 470 N-(5-{[({1-[2-fluoro-4-(trifluoromethyl) phenyl] ethyl } amino) thiocarbonyl]-amino }-the 2-pyridyl)-1,3-thiazoles-4-carboxylic acid amides
820 470 N-(5-{[({1-[3-fluoro-5-(trifluoromethyl) phenyl] ethyl } amino) thiocarbonyl]-amino }-the 2-pyridyl)-1,3-thiazoles-4-carboxylic acid amides
821 504 N-(5-{[({ (1S)-1-[3,5-two (trifluoromethyl) phenyl] ethyl } amino) carbonyl]-amino }-the 2-pyridine)-1,3-thiazoles-4-carboxylic acid amides
822 463 N-{5-[({ (1-(3-bromophenyl) ethyl] amino } thiocarbonyl) amino]-the 2-pyridyl }-1,3-thiazoles-4-carboxylic acid amides
823 463 N-{5-[({ (1-(2-bromophenyl) ethyl] amino } thiocarbonyl) amino]-the 2-pyridyl }-1,3-thiazoles-4-carboxylic acid amides
824 452 N-(5-{[({1-[3-(trifluoromethyl) phenyl] ethyl } amino) carbonyl] amino }-the 2-pyridine)-1,3-thiazoles-4-carboxylic acid amides
825 486 N-(5-{[({1-[4-chloro-3-(trifluoromethyl) phenyl] ethyl } amino) carbonyl]-amino }-the 2-pyridine)-1,3-thiazoles-4-carboxylic acid amides
826 436 N-{5-[({[1-(4-chloro-3-fluorophenyl) ethyl] amino } thiocarbonyl) amino]-the 2-pyridyl }-1,3-thiazoles-4-carboxylic acid amides
827 436 N-{5-[({[1-(4-chloro-2-fluorophenyl) ethyl] amino } thiocarbonyl) amino]-the 2-pyridyl }-1,3-thiazoles-4-carboxylic acid amides
828 434 N-{6-[({[1-(4-fluorophenyl) ethyl] amino } thiocarbonyl) amino]-the 3-pyridyl }-1,2,3-thiadiazoles-4-carboxylic acid amides
829 426 N-(6-{[({[1S)-1-[3,5-two (trifluoromethyl) phenyl] ethyl } amino) carbonyl]-amino }-the 3-pyridine)-1,2,3-thiadiazoles-4-carboxylic acid amides
Embodiment 830 (method 32)
[1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(2,5-two chloro-phenyl)-thioureido]-phenyl }-acid amides
2, add in tetrahydrofuran (THF) (20 milliliters) solution of 5-dichlorphenamide bulk powder (0.16 gram) 1,1 of prepared fresh '-thio-carbonyldiimidazole (0.20 gram), about 30 minutes of stirring at room mixture.In reaction flask, add [1,2,3]-thiadiazoles-4-carboxylic acid (4-amino-phenyl) acid amides (0.22 gram), stirred the mixture about 6 hours.Solvent removed by evaporation at reduced pressure adds warm acetonitrile (3 milliliters) then.After 15 hours, filtering mixt is used acetonitrile, and the precipitation of collecting with the ether washing is air-dry then, obtains desired white powder product.
Use said procedure and suitable parent material to prepare following compounds:
Embodiment number M＋H The compound title
??831 ??321 N-{4-[3-(3-chloro-phenyl)-thioureido]-phenyl }-ethanamide
??832 ??413 N-{4-[3-(3-chloro-4-methoxyl group-phenyl)-thioureido]-phenyl }-benzamide
??833 ??443 N-{4-[3-(3-chloro-4-methoxyl group-phenyl)-thioureido]-phenyl }-2-methoxyl group-benzamide
??834 ??443 N-{4-[3-(3-chloro-4-methoxyl group-phenyl)-thioureido]-phenyl }-3-methoxyl group-benzamide
??835 ??443 N-{4-[3-(3-chloro-4-methoxyl group-phenyl)-thioureido]-phenyl }-4-methoxyl group-benzamide
??836 ??431 N-{4-[3-(3-chloro-4-methoxyl group-phenyl)-thioureido]-phenyl }-4-methoxyl group-benzamide
??837 ??431 N-{4-[3-(3-chloro-4-methoxyl group-phenyl)-thioureido]-phenyl }-3-fluoro-benzamide
??838 ??431 N-{4-[3-(3-chloro-4-methoxyl group-phenyl)-thioureido]-phenyl }-4-fluoro-benzamide
??839 ??437 Furans-2-carboxylic acid 4-[3-(3,5-two chloro-4-methoxyl group-phenyl)-thioureido]-phenyl }-acid amides
??840 ??511 4-[3-(5-bromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-the own ester of carboxylamine
??841 ??481 Caproic acid 4-[3-(5-bromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-acid amides
??842 ??505 N-{4-[3-(5-bromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide
??843 ??477 Furans-2-carboxylic acid 4-[3-(5-bromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-acid amides
??844 ??501 N-{4-[3-(5-bromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-2 methyl-benzamide
??845 ??517 N-{4-[3-(5-bromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-4-methoxyl group-benzamide
??846 ??395 N-{4-[3-(5-chloro-2-oxyethyl group-4-methoxyl group-phenyl)-thioureido]-phenyl }-ethanamide
??847 ??395 N-{4-[3-(5-chloro-4-oxyethyl group-2-methoxyl group-phenyl)-thioureido]-phenyl }-ethanamide
??848 ??423 N-{4-[3-(2-butoxy-5-chloro-4-methoxyl group-phenyl)-thioureido]-phenyl }-ethanamide
??849 ??423 N-{4-[3-(2-butoxy-5-chloro-2-methoxyl group-phenyl)-thioureido]-phenyl }-ethanamide
??850 ??457 N-{4-[3-(2-benzyloxy-5-chloro-4-methoxyl group-phenyl)-thioureido]-phenyl }-ethanamide
??851 ??457 N-{4-[3-(4-benzyloxy-5-chloro-2-methoxyl group-phenyl)-thioureido]-phenyl }-ethanamide
??852 ??421 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(3-chloro-4-methoxyl group-phenyl)-thioureido]-phenyl }-acid amides
??853 ??424 2-{4-[3-(4-acetylamino-phenyl)-thioureido]-2-chloro-5-methoxyl group-phenoxy group }-ethanamide
??854 ??367 N-{4-[3-(5-chloro-2-hydroxyl-4-methoxyl group-phenyl)-thioureido]-phenyl }-ethanamide
??855 ??367 N-{4-[3-(3-chloro-4-methylthio group-phenyl)-thioureido]-phenyl }-ethanamide
??856 ??447 N-[4-(3-{3-chloro-4-[methyl-(1-methyl-piperidin-4-yl)-amino]-phenyl }-thioureido)-phenyl]-ethanamide
??857 ??426 N-(4-{3-[3-chloro-4-(methyl-phenyl-amino)-phenyl]-thioureido }-phenyl)-ethanamide
??858 ??509 N-[4-(3-{4-[(1-benzyl-tetramethyleneimine-3-yl)-methyl-amino]-3-chloro-phenyl }-thioureido)-phenyl]-ethanamide
??859 ??418 N-(4-{3-[3-chloro-4-(cyclopentyl-methyl-amino)-phenyl]-thioureido }-phenyl)-ethanamide
??860 ??433 N-[4-(3-{3-chloro-4-[methyl-(1-methyl-tetramethyleneimine-3-yl)-amino]-phenyl }-thioureido)-phenyl]-ethanamide
??861 ??419 Furans-2-carboxylic acid 4-[3-(3-chloro-4-methylthio group-phenyl)-thioureido]-phenyl }-acid amides
??862 ??447 N-{4-[3-(3-chloro-4-methylthio group-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide
??863 ??465 N-{4-[3-(3-chloro-4-methylthio group-phenyl)-thioureido]-phenyl }-2,6-two fluoro-benzamide
??864 ??445 N-{4-[3-(5-chloro-2-methoxyl group-4-methyl-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide
??865 ??441 N-{4-[3-(5-chloro-2-methoxyl group-4-methyl-phenyl)-thioureido]-phenyl }-2-methyl-benzamide
??866 ??434 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(3-chloro-4-dimethylamino-phenyl)-thioureido]-phenyl }-acid amides
??867 ??444 N-{4-[3-(3-chloro-4-dimethylamino-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide
??868 ??517 [1,2,3] thiadiazoles-4-carboxylic acid [4-(3-{3-chloro-4-[methyl-(1-methyl-piperidin-4-yl)-amino]-phenyl }-thioureido)-phenyl]-acid amides
??869 ??579 [1,2,3] thiadiazoles-4-carboxylic acid [4-(3-{4[(1-benzyl-tetramethyleneimine-3-yl)-methyl-amino]-3-chloro-phenyl }-thioureido)-phenyl]-acid amides
??870 ??527 N-[4-(3-{3-chloro-4-[methyl-(1-methyl-piperidin-4-yl)-amino]-phenyl }-thioureido)-phenyl]-2-fluoro-benzamide
??871 ??435 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(5-chloro-2-methoxyl group-4-methyl-phenyl)-thioureido]-phenyl }-acid amides
??872 ??589 N-[4-(3-{4-[(1-benzyl-tetramethyleneimine-3-yl)-methyl-amino]-3-chloro-phenyl }-thioureido)-phenyl]-2-fluoro-benzamide
??873 ??501 Furans-2-carboxylic acid 4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-3-trifluoromethyl-phenyl }-acid amides
??874 ??366 2-fluoro-N-[4-(3-phenyl-thioureido)-phenyl]-benzamide
??875 ??338 Furans-2-carboxylic acid [4-(3-phenyl-thioureido)-phenyl]-acid amides
??876 ??356 [1,2,3] thiadiazoles-4-carboxylic acid [4-(3-phenyl-thioureido)-phenyl]-acid amides
??877 ??365 N-(4-{3-[3-chloro-4-(1-hydroxyl-ethyl)-phenyl]-thioureido }-phenyl)-ethanamide
??878 ??435 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[3-chloro-4-(1-hydroxyl-ethyl)-phenyl]-thioureido }-phenyl)-acid amides
??879 ??365 N-(4-{3-[3-chloro-4-(2-hydroxyl-ethyl)-phenyl]-thioureido }-phenyl)-ethanamide
??880 ??445 N-(4-{3-[3-chloro-4-(1-hydroxyl-ethyl)-phenyl]-thioureido }-phenyl)-2-fluoro-benzamide
??881 ??417 Furans-2-carboxylic acid (4-{3-[3-chloro-4-(1-hydroxyl-ethyl)-phenyl]-thioureido }-phenyl)-acid amides
??882 ??371 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(3-amino-phenyl)-thioureido]-phenyl }-acid amides
??883 ??501 Furans-2-carboxylic acid 4-[3-(3-bromo-4-trifluoromethoxy-phenyl)-thioureido]-phenyl }-acid amides
??884 ??423 N-{4-[3-(the 3-tertiary butyl-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide
??885 ??440 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(4-chloro-3,5-two chloro-phenyl)-thioureido]-phenyl }-acid amides
??986 ??485 N-{4-[3-(1-cumarone-2-base-ethyl)-thioureido]-phenyl }-2-trifluoromethyl-benzamide
??987 ??412 N-(4-fluoro-phenyl)-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-benzamide
??988 ??446 Isoquinoline 99.9-1-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
??989 ??468 Isoquinoline 99.9-1-carboxylic acid 4-[3-(1-cumarone-2-base-ethyl)-thioureido]-phenyl }-acid amides
??993 ??506 Isoquinoline 99.9-1-carboxylic acid (4-{3-[1-(4-bromo-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
??994 ??453 Isoquinoline 99.9-1-carboxylic acid (4-{3-[1-(4-cyano group-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
??995 ??435 Cumarone-2-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
??996 ??457 Cumarone-2-carboxylic acid 4-[3-(1-cumarone-2-base-ethyl)-thioureido]-phenyl }-acid amides
??997 ??495 Cumarone-2-carboxylic acid (4-{3-[1-(4-bromo-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
??998 ??442 Cumarone-2-carboxylic acid (4-{3-[1-(4-cyano group-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
??999 ??446 Isoquinoline 99.9-3-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
??1000 ??468 Isoquinoline 99.9-3-carboxylic acid 4-[3-(1-cumarone-2-base-ethyl)-thioureido]-phenyl }-acid amides
??1001 ??453 Isoquinoline 99.9-3-carboxylic acid (4-{3-[1-(4-cyano group-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
??1002 ??506 Isoquinoline 99.9-3-carboxylic acid (4-{3-[1-(4-bromo-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
??1003 ??446 Quinoline-3-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
??1004 ??446 The Cinchonic Acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
??1005 ??446 QUINOLINE-6-CARBOXYLIC ACID (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
??1006 ??446 Quinoline-8-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
??1007 ??462 N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-2-methyl fluoride-benzamide
??1008 ??419 2-cyano group-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-benzamide
??1009 ??473 N-{4-[3-(3-chloro-4-isobutoxy-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide
??1010 ??414 2-fluoro-N-{4-[3-(3-fluoro-4-methoxyl group-phenyl)-thioureido]-phenyl }-benzamide
??1011 ??475 N-(4-{3-[3-chloro-4-(2-methoxyl group-oxyethyl group)-phenyl]-thioureido }-phenyl)-2-fluoro-benzamide
??1012 ??398 2-fluoro-N-{4-[3-(3-fluoro-4-methyl-phenyl)-thioureido]-phenyl }-benzamide
??1013 ??464 2-fluoro-N-{4-[3-(4-methyl-3-trifluoromethyl-phenyl)-thioureido]-phenyl }-benzamide
??1014 ??449 N-{4-[3-(2-amino-5-trifluoromethyl-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide
??1015 ??459 N-(4-{3-[1-(3-chloro-4-methoxyl group-phenyl)-ethyl]-thioureido }-phenyl)-2-fluoro-benzamide
??1016 ??417 N-{4-[3-(5-chloro-2-hydroxyl-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide
??1017 ??435 N-{4-[3-(1-cumarone-2-base-ethyl)-thioureido]-phenyl }-2-fluoro-benzamide
??1018 ??448 2-fluoro-N-{4-[3-(4-methyl-3-trifluoromethyl-phenyl)-thioureido]-phenyl }-benzamide
??1019 ??473 (S)-N-(4-{3-[1-(4-bromo-phenyl)-ethyl]-thioureido }-phenyl)-2-fluoro-benzamide
??1020 473 N-(4-{3-[(1R)-1-(4-bromo-phenyl)-ethyl]-thioureido }-phenyl)-2-fluoro-benzamide
??1021 494 2-fluoro-N-(4-{3-[2-methoxyl group-4-(2,2,2-three fluoro-oxyethyl groups)-phenyl]-thioureido }-phenyl)-benzamide
??1022 399 N-{4-[3-(2-amino-5-fluoro-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide
??1023 502 N-(4-{3-[1-(4-dimethylamino alkylsulfonyl phenyl)-ethyl]-thioureido }-phenyl)-2-fluoro-benzamide
??1024 542 2-fluoro-N-[4-(3-{1-[4-(piperidines-1-alkylsulfonyl)-phenyl]-ethyl }-thioureido)-phenyl]-benzamide
??1025 562 N-(4-{3-[2,4-two (2,2,2-three fluoro-oxyethyl groups)-phenyl]-thioureido }-phenyl)-2-fluoro-benzamide
??1026 409 2-fluoro-N-{4-[3-((1S)-1-p-methylphenyl-ethyl)-thioureido]-phenyl }-benzamide
??1027 409 2-fluoro-N-{4-[3-((1R)-1-p-methylphenyl-ethyl)-thioureido]-phenyl }-benzamide
??1028 394 2-fluoro-N-{4-[3-((1S)-1-phenyl-ethyl)-thioureido]-phenyl }-benzamide
??1029 429 N-(4-{3-[(1R)-1-(4-chloro-phenyl)-ethyl]-thioureido }-phenyl)-2-fluoro-benzamide
??1030 429 N-(4-{3-[(1S)-1-(4-chloro-phenyl)-ethyl]-thioureido }-phenyl)-2-fluoro-benzamide
??1031 394 2-fluoro-N-{4-[3-((1R)-1-phenyl-ethyl)-thioureido]-phenyl }-benzamide
??1032 432 N-(4-{3-[1-(4-cyano group-phenyl)-ethyl]-thioureido }-phenyl)-2-methoxyl group-benzamide
??1033 447 N-{4-[3-(1-cumarone-2-base-ethyl)-thioureido]-phenyl }-2-methoxyl group-benzamide
??1034 485 N-(4-{3-[1-(4-bromo-phenyl)-ethyl]-thioureido }-phenyl)-2-methoxyl group-benzamide
??1035 419 3-cyano group-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-benzamide
??1036 462 N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-4-trifluoromethyl-benzamide
??1037 419 4-cyano group-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-benzamide
??1038 469 2-fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-2,3,5,6-tetramethyl--phenyl)-benzamide
??1039 480 N-(4-{3-[1-(4-cyano group-phenyl)-ethyl]-thioureido }-2,5-dimethoxy-phenyl)-2-fluoro-benzamide
??1040 473 2-fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-2,5-dimethoxy-phenyl)-benzamide
??1041 530 N-{3,5-two chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide
??1042 447 N-(3-chloro-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-2,5-dimethoxy-phenyl)-2-fluoro-benzamide
??1043 480 2,3,4,5-tetrafluoro-N-(3-chloro-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-3-methyl-phenyl)-benzamide
??1044 462 2,4,5-three fluoro-N-(3-chloro-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-3-methyl-phenyl)-benzamide
??1045 427 2-fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-3-methyl-phenyl)-benzamide
??1046 457 2-fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-2-methoxyl group-5-methyl-phenyl)-benzamide
??1047 443 2-fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-3-methoxyl group-phenyl)-benzamide
??1048 570 N-(2,6-two bromo-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-3-methyl-phenyl)-2-fluoro-benzamide
??1049 ??480 2-fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-2-trifluoromethyl-phenyl)-benzamide
??1050 ??541 N-(4-{3-[1-(4-bromo-phenyl)-ethyl]-thioureido }-2-trifluoromethyl-phenyl)-2-fluoro-benzamide
??1051 ??487 N-(4-{3-[1-(4-cyano group-phenyl)-ethyl]-thioureido }-2-trifluoromethyl-phenyl)-2-fluoro-benzamide
??1052 ??503 N-{4-[3-(1-cumarone-2-base-ethyl)-thioureido]-2-trifluoromethyl-phenyl }-2-fluoro-benzamide
??1053 ??447 N-(2-chloro-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-2-fluoro-benzamide
??1054 ??454 N-(2-chloro-4-{3-[1-(4-cyano group-phenyl)-ethyl]-thioureido }-phenyl)-2-fluoro-benzamide
??1055 ??437 N-(2-cyano group-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-2-fluoro-benzamide
??1056 ??498 N-(4-{3-[1-(4-bromo-phenyl)-ethyl]-thioureido }-the 2-cyano-phenyl)-2-fluoro-benzamide
??1057 ??445 N-(2-cyano group-4-{3-[1-(4-cyano group-phenyl)-ethyl]-thioureido }-phenyl)-2-fluoro-benzamide
??1058 ??460 N-{4-[3-(1-cumarone-2-base-ethyl)-thioureido]-2-cyano group-phenyl }-2-fluoro-benzamide
??1059 ??517 N-(2-benzoyl-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-2-fluoro-benzamide
??1060 ??427 2-fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-2-methyl-phenyl)-benzamide
??1061 ??487 N-(4-{3-[1-(4-bromo-phenyl)-ethyl]-thioureido }-2-methyl-phenyl)-2-fluoro-benzamide
??1062 ??434 N-(4-{3-[1-(4-cyano group-phenyl)-ethyl]-thioureido }-2-methyl-phenyl)-2-fluoro-benzamide
??1063 ??449 N-{4-[3-(1-cumarone-2-base-ethyl)-thioureido]-2-methyl-phenyl }-2-fluoro-benzamide
??1064 ??456 N-(2-dimethylamino-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-2-fluoro-benzamide
??1065 ??526 N-(2-benzyloxy-4-{3-[1-(4-cyano group-phenyl)-ethyl]-thioureido }-phenyl)-2-fluoro-benzamide
??1066 ??519 N-(2-benzyloxy-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-2-fluoro-benzamide
??1067 ??603 N-[4-{3-[1-(4-bromo-phenyl)-ethyl]-thioureido }-2-(2-morpholine-4-base-oxyethyl group)-phenyl]-2-fluoro-benzamide
??1068 ??603 N-[4-{3-[1-(4-bromo-phenyl)-ethyl]-thioureido }-2-(2-morpholine-4-base-oxyethyl group)-phenyl]-2-fluoro-benzamide
??1069 ??542 2-fluoro-N-[4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-2-(2-morpholine-4-base-oxyethyl group)-phenyl]-benzamide
??1070 ??485 N-(2-butoxy-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-2-fluoro-benzamide
??1071 ??492 N-(2-butoxy-4-{3-[1-(4-cyano group-phenyl)-ethyl]-thioureido }-phenyl)-2-fluoro-benzamide
??1072 ??589 N-[4-{3-[1-(4-bromo-phenyl)-ethyl]-thioureido }-2-(2-diethylamino-oxyethyl group)-phenyl]-2-fluoro-benzamide
??1073 ??528 N-(2-(2-diethylamino-oxyethyl group)-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-2-fluoro-benzamide
??1074 ??589 N-[4-{3-[1-(4-bromo-phenyl)-ethyl]-thioureido }-2-(2-diethylamino-oxyethyl group)-phenyl]-2-fluoro-benzamide
??1075 ??457 N-(2-oxyethyl group-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-2-fluoro-benzamide
??1076 ??464 N-(4-{3-[1-(4-cyano group-phenyl)-ethyl]-thioureido }-2-oxyethyl group-phenyl)-2-fluoro-benzamide
??1077 ??468 2-fluoro-N-[4-{3-[1-(4-bromo-phenyl)-ethyl]-thioureido }-2-(2-nitrilo-oxyethyl group)-phenyl]-benzamide
??1078 ??475 N-[4-{3-[1-(4-cyano group-phenyl)-ethyl]-thioureido }-2-(2-nitrilo-oxyethyl group)-phenyl]-2-fluoro-benzamide
??1079 ??443 2-fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-2-methoxyl group-phenyl)-benzamide
??1080 ??489 2-fluoro-N-(5-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-biphenyl-2-yl)-benzamide
??1081 ??514 Isoquinoline 99.9-1-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-2-trifluoromethyl-phenyl)-acid amides
??1082 ??503 Cumarone-2-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-2-trifluoromethyl-phenyl)-acid amides
??1083 ??514 Isoquinoline 99.9-3-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-2-trifluoromethyl-phenyl)-acid amides
??1084 ??471 Isoquinoline 99.9-1-carboxylic acid (2-cyano group-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
??1085 ??460 Cumarone-2-carboxylic acid (2-cyano group-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
??1086 ??471 Isoquinoline 99.9-3-carboxylic acid (2-cyano group-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
??1087 ??460 Isoquinoline 99.9-1-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-2-methyl-phenyl)-acid amides
??1088 ??449 Cumarone-2-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-2-methyl-phenyl)-acid amides
??1089 ??460 Isoquinoline 99.9-3-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-2-methyl-phenyl)-acid amides
??1090 ??396 Pyrazine-2-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
??1091 ??401 Thiophene-2-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
??1092 ??401 Thiophene-3-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido }-phenyl)-acid amides
??1093 ??500 2-sec.-propyl-thiazole-4-carboxylic acid 4-[3-(4-chloro-3-trifluoromethyl-phenyl)-thioureido]-phenyl }-acid amides
??1094 ??466 2-sec.-propyl-thiazole-4-carboxylic acid 4-[3-(3,5-two chloro-phenyl)-thioureido]-phenyl }-acid amides
??1095 ??466 2-sec.-propyl-thiazole-4-carboxylic acid 4-[3-(3,4-two chloro-phenyl)-thioureido]-phenyl }-acid amides
??1096 ??534 2-sec.-propyl-thiazole-4-carboxylic acid 4-[3-(3,5-di-trifluoromethyl-phenyl)-thioureido]-phenyl }-acid amides
??1097 ??480 2-butyl-thiazole-4-carboxylic acid 4-[3-(3,4-two chloro-phenyl)-thioureido]-phenyl }-acid amides
??1098 ??514 2-butyl-thiazole-4-carboxylic acid 4-[3-(4-chloro-3-trifluoromethyl-phenyl)-thioureido]-phenyl }-acid amides
??1099 ??480 2-butyl-thiazole-4-carboxylic acid 4-[3-(3,5-two chloro-phenyl)-thioureido]-phenyl }-acid amides
??1100 ??548 2-butyl-thiazole-4-carboxylic acid 4-[3-(3,4-di-trifluoromethyl-phenyl)-thioureido]-phenyl }-acid amides
??1101 ??438 2-methyl-thiazole-4-carboxylic acid 4-[3-(3,5-two chloro-phenyl)-thioureido]-phenyl }-acid amides
??1102 ??438 2-methyl-thiazole-4-carboxylic acid 4-[3-(3,4-two chloro-phenyl)-thioureido]-phenyl }-acid amides
??1103 ??505 2-methyl-thiazole-4-carboxylic acid 4-[3-(3,5-di-trifluoromethyl-phenyl)-thioureido]-phenyl }-acid amides
??1104 ??534 2-phenyl-thiazole-4-carboxylic acid 4-[3-(4-chloro-3-trifluoromethyl-phenyl)-thioureido]-phenyl }-acid amides
??1105 ??500 2-phenyl-thiazole-4-carboxylic acid 4-[3-(3,5-two chloro-phenyl)-thioureido]-phenyl }-acid amides
??1106 ??500 2-phenyl-thiazole-4-carboxylic acid 4-[3-(3,4-two chloro-phenyl)-thioureido]-phenyl }-acid amides
1107 568 2-phenyl-thiazole-4-carboxylic acid 4-[3-(3,5-di-trifluoromethyl-phenyl)-thioureido]-phenyl }-acid amides
1108 401 2-fluoro-N-{4-[3-(1-thiazol-2-yl-ethyl)-thioureido }-phenyl }-benzamide
1109 588 2-fluoro-N-[4-(3-{1-[1-(toluene-4-alkylsulfonyl)-1H-indoles-2-yl]-ethyl }-thioureido)-phenyl]-benzamide
1110 446 2-fluoro-N-{4-[3-(1-quinoline-2-base-ethyl)-thioureido]-phenyl }-benzamide
11?11 446 2-fluoro-N-{4-[3-(1-quinolyl-4-ethyl)-thioureido]-phenyl }-benzamide
1112 446 2-fluoro-N-{4-[3-(1-isoquinoline 99.9-3-base-ethyl)-thioureido]-phenyl }-benzamide
1113 446 2-fluoro-N-{4-[3-(1-isoquinolyl-1-ethyl)-thioureido]-phenyl }-benzamide
1114 446 2-fluoro-N-{4-[3-(1-quinoline-6-base-ethyl)-thioureido]-phenyl }-benzamide
1115 446 2-fluoro-N-{4-[3-(1-quinoline-3-base-ethyl)-thioureido]-phenyl }-benzamide
1116 413 2-methoxyl group-N-{4-[3-(1-thiene-3-yl--ethyl)-thioureido]-phenyl }-benzamide
Embodiment 886 (method 33)
[1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(3,5-two chloro-phenyl)-thioureido]-phenyl }-acid amides
3, add in tetrahydrofuran (THF) (20 milliliters) solution of 5-dichlorphenamide bulk powder (0.16 gram) 1,1 of prepared fresh '-thiocarbonyl-two-(1,2,4)-triazole (0.20 gram), about 30 minutes of stirring at room mixture.In reaction flask, add [1,2,3]-thiadiazoles-4-carboxylic acid (4-amino-phenyl) acid amides (0.22 gram), stirred the mixture about 6 hours.Solvent removed by evaporation at reduced pressure adds hot acetonitrile (3 milliliters) then.15 hours after-filtration mixtures are used acetonitrile, and the precipitation of collecting with the ether washing is air-dry then, obtains desired white powder product.[M＋H]424。
Use said procedure and suitable parent material to prepare following compounds:
Embodiment number ??M＋H The compound title
887 465 N-{4-[3-(3,5-two chloro-4-methoxyl group-phenyl)-thioureido]-phenyl }-3-fluoro-benzamide
888 477 N-{4-[3-(3,5-two chloro-4-methoxyl group-phenyl)-thioureido]-phenyl }-2-methoxyl group-benzamide
889 465 N-{4-[3-(3,5-two chloro-4-methoxyl group-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide
890 477 N-{4-[3-(3,5-two chloro-4-methoxyl group-phenyl)-thioureido]-phenyl }-3-methoxyl group-benzamide
891 399 N-{4-[3-(3,5-two chloro-2-methoxyl group-4-methyl-phenyl)-thioureido]-phenyl }-ethanamide
892 365 N-{4-[3-(3-chloro-4-methoxyl group-5-methyl-phenyl)-thioureido]-phenyl }-ethanamide
893 331 N-{4-[3-(2-nitro-phenyl)-thioureido]-phenyl }-ethanamide
894 331 N-{4-[3-(4-nitro-phenyl)-thioureido]-phenyl }-ethanamide
??895 ??477 N-{4-[3-(3,5-two chloro-4-methoxyl group-phenyl)-thioureido]-phenyl }-4-methoxyl group-benzamide
??896 ??351 N-{4-[3-(2-chloro-5-methoxyl group-phenyl)-thioureido]-phenyl }-ethanamide
??897 ??428 2-{4-[3-(4-acetylamino-phenyl)-thioureido]-2,6-two chloro-phenoxy groups }-ethanamide
??898 ??443 4-[3-(4-acetylamino-phenyl)-thioureido] and-2,6-two chloro-phenoxy groups }-methyl acetate
??899 ??457 4-[3-(4-acetylamino-phenyl)-thioureido] and-2,6-two chloro-phenoxy groups }-ethyl acetate
??900 ??447 N-{4-[3-(3,5-two chloro-4-phenoxy group-phenyl)-thioureido]-2,6-two chloro-phenoxy groups }-ethanamide
??901 ??410 N-(4-{3-[3,5-two chloro-4-(2-nitrilo-oxyethyl group)-phenyl]-thioureido }-phenyl-ethanamide
??902 ??485 4-[3-(4-acetylamino-phenyl)-thioureido] and-2,6-two chloro-phenoxy groups }-tert.-butyl acetate
??903 ??469 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(3,5-two chloro-2-methoxyl group-4-methyl-phenyl)-thioureido]-phenyl }-acid amides
??904 ??335 N-{4-[3-(3-chloro-4-methyl-phenyl)-thioureido]-phenyl }-ethanamide
??905 ??335 N-{4-[3-(5-chloro-2-methyl-phenyl)-thioureido]-phenyl }-ethanamide
??906 ??703 N-{4-[3-(4-{4-[3-(4-acetylamino-phenyl)-thioureido]-2-chloro-diphenyl disulfide base }-3-chloro-phenyl)-thioureido]-phenyl }-ethanamide
??907 ??369 N-{4-[3-(3,5-two chloro-4-methyl-phenyl)-thioureido]-phenyl }-ethanamide
??908 ??598 N-{4-[3-(3,5-two iodo-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-ethanamide
??909 ??504 N-{4-[3-(3,5-two bromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl }-ethanamide
??910 ??317 N-{4-[3-(6-methoxyl group-pyridin-3-yl)-thioureido]-phenyl }-ethanamide
??911 ??347 N-{4-[3-(2,6-dimethoxy-pyridin-3-yl)-thioureido]-phenyl }-ethanamide
??912 ??457 Acetate 2-{4-[3-(4-acetylamino-phenyl)-thioureido]-2,6-two chloro-phenoxy groups }-ethyl ester
??913 ??365 4-[3-(4-acetylamino-phenyl)-thioureido]-2-chloro-phenylformic acid
??914 ??346 N-{4-[3-(3-chloro-4-cyano group-phenyl)-thioureido]-phenyl }-ethanamide
??915 ??512 N-(4-{3-[5-chloro-2-(4-chloro-phenoxy group)-4-pyrroles-1-base-phenyl]-thioureido }-phenyl)-ethanamide
??916 ??355 N-{4-[3-(3,4-two chloro-phenyl)-thioureido]-phenyl }-ethanamide
??917 ??339 N-{4-[3-(3-chloro-4-fluoro-phenyl)-thioureido }-phenyl }-ethanamide
??918 ??447 N-{4-[3-(3-chloro-4-iodo-phenyl)-thioureido]-phenyl }-ethanamide
??919 ??400 N-{4-[3-(4-bromo-3-chloro-phenyl)-thioureido]-phenyl }-ethanamide
??920 ??424 N-[4-(3-{4-[two-(2-hydroxyl-ethyl)-amino]-3-chloro-phenyl }-thioureido)-phenyl]-ethanamide
??921 ??434 N-(4-{3-[3-chloro-4-(hexyl-methyl-amino)-phenyl]-thioureido }-phenyl)-ethanamide
??922 ??406 N-(4-{3-[3-chloro-4-(isobutyl--methyl-amino)-phenyl]-thioureido }-phenyl)-ethanamide
923 389 N-{4-[3-(3-chloro-4-trifluoromethyl-phenyl)-thioureido]-phenyl }-ethanamide
924 441 Furans-2-carboxylic acid 4-[3-(3-bromo-4-trifluoromethyl-phenyl)-thioureido]-phenyl }-acid amides
925 459 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(3-chloro-4-trifluoromethyl-phenyl)-thioureido]-phenyl }-acid amides
926 469 N-{4-[3-(3-chloro-4-trifluoromethyl-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide
927 435 N-{4-[3-(3,4-dichlor-4-trifluoromethyl-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide
928 407 Furans-2-carboxylic acid 4-[3-(3,4-two chloro-phenyl)-thioureido]-phenyl }-acid amides
929 425 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(3,4-two chloro-phenyl)-thioureido]-phenyl }-acid amides
930 480 N-{4-[3-(4-bromo-3-chloro-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide
931 527 N-{4-[3-(3-chloro-4-iodo-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide
932 452 Furans-2-carboxylic acid 4-[3-(4-bromo-3-chloro-phenyl)-thioureido]-phenyl }-acid amides
933 499 Furans-2-carboxylic acid { 4-[3-(3-chloro-4-iodo-phenyl)-thioureido }-phenyl }-acid amides
934 391 Furans-2-carboxylic acid 4-[3-(3-chloro-4-fluoro-phenyl)-thioureido]-phenyl }-acid amides
935 470 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(4-bromo-3-chloro-phenyl)-thioureido]-phenyl }-acid amides
936 517 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(3-chloro-4-iodo-phenyl)-thioureido]-phenyl }-acid amides
937 419 N-{4-[3-(3-chloro-4-f fluoro-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide
938 409 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(3-chloro-4-fluoro-phenyl)-thioureido]-phenyl }-acid amides
939 388 N-{4-[3-(3-chloro-4-isoxazole-5-base-phenyl)-thioureido]-phenyl }-ethanamide
940 387 N-(4-{3-[3-chloro-4-(1H-pyrazole-3-yl)-phenyl]-thioureido]-phenyl)-ethanamide
941 355 N-{4-[3-(2,3-two chloro-phenyl)-thioureido]-phenyl }-ethanamide
942 435 N-{4-[3-(2,3-two chloro-phenyl)-thioureido]-phenyl }-2-fluoro-ethanamide
943 407 Furans-2-carboxylic acid 4-[3-(2,3-two chloro-phenyl)-thioureido]-phenyl }-acid amides
944 425 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(2,3-two chloro-phenyl)-thioureido]-phenyl }-acid amides
945 355 N-{4-[3-(2,5-two chloro-phenyl)-thioureido]-phenyl }-ethanamide
946 435 N-{4-[3-(2,5-two chloro-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide
947 407 Furans-2-carboxylic acid 4-[3-(2,5-two chloro-phenyl)-thioureido]-benzene }-the Ji acid amides
948 355 N-{4-[3-(3,5-two chloro-phenyl)-thioureido]-phenyl }-ethanamide
949 435 N-{4-[3-(2,5-two chloro-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide
950 407 Furans-2-carboxylic acid 4-[3-(3,5-two chloro-phenyl)-thioureido]-phenyl }-acid amides
951 390 N-{4-[3-(3,4,5-three chloro-phenyl)-thioureido]-phenyl }-ethanamide
952 470 2-fluoro-N-{4-[3-(3,4,5-three chloro-phenyl)-thioureido]-phenyl }-benzamide
953 442 Furans-2-carboxylic acid 4-[3-(3,4,5-three chloro-phenyl)-thioureido]-phenyl }-acid amides
954 460 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(3,4,5-three chloro-phenyl)-thioureido]-phenyl }-acid amides
955 458 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(3-chloro-4-isoxazole-5-base-phenyl)-thioureido]-phenyl }-acid amides
956 457 [1,2,3] thiadiazoles-4-carboxylic acid (4-{3-[3-chloro-4-(1H-pyrazole-3-yl)-phenyl]-thioureido }-phenyl)-acid amides
957 391 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(3-chloro-phenyl)-thioureido]-phenyl }-acid amides
958 373 Furans-2-carboxylic acid 4-[3-(3-chloro-phenyl)-thioureido]-phenyl }-acid amides
959 401 N-{4-[3-(3-chloro-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide
960 373 Furans-2-carboxylic acid 4-[3-(4-chloro-phenyl)-thioureido]-phenyl }-acid amides
961 401 N-{4-[3-(4-chloro-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide
962 391 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(4-chloro-phenyl)-thioureido]-phenyl }-acid amides
963 401 N-{4-[3-(2-chloro-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide
964 396 3-(3-{4-[(4-furans-2-carbonyl)-amino]-phenyl }-thioureido)-methyl benzoate
965 424 3-{3-[4-(2-fluoro-benzoyl-amido)-phenyl]-thioureido }-methyl benzoate
966 414 3-(3-{4-[([1,2,3] thiadiazoles-4-carbonyl)-amino]-phenyl }-thioureido)-methyl benzoate
967 409 N-[4-[[[[3-(aminocarboxyl)-phenyl] amino] sulphomethyl] amino] phenyl]-2-fluoro-benzamide
968 373 Furans-2-carboxylic acid 4-[3-(2-chloro-phenyl)-thioureido]-phenyl }-acid amides
969 381 Furans-2-carboxylic acid 4-[3-(3-formamyl-phenyl)-thioureido]-phenyl }-acid amides
970 399 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(3-formamyl-phenyl)-thioureido]-phenyl }-acid amides
971 391 [1,2,3] thiadiazoles-4-carboxylic acid 4-[3-(2-chloro-phenyl)-thioureido]-phenyl }-acid amides
972 356 Furans-2-carboxylic acid 4-[3-(3-fluoro-phenyl)-thioureido]-phenyl }-acid amides
973 383 Furans-2-carboxylic acid 4-[3-(3-nitro-phenyl)-thioureido]-phenyl }-acid amides
974 411 2-fluoro-N-{4-[3-(3-nitro-phenyl)-thioureido]-phenyl }-benzamide
975 422 Furans-2-carboxylic acid 4-[3-(3-trifluoromethoxy-phenyl)-thioureido]-phenyl }-acid amides
976 450 2-fluoro-N-{4-[3-(3-trifluoromethoxy-phenyl)-thioureido]-phenyl }-benzamide
977 384 2-fluoro-N-{4-[3-(3-fluoro-phenyl)-thioureido]-phenyl }-benzamide
978 410 3-{3-[4-(2-fluoro-benzoyl-amido)-thioureido]-phenyl]-phenylformic acid
979 382 3-(3-{4-[(furans-2-carbonyl)-amino]-phenyl }-thioureido)-phenylformic acid
980 408 N-{4-[3-(3-ethanoyl-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide
981 502 N-{4-[3-(3-butyl amino-sulfonyl-phenyl)-thioureido]-phenyl }-2-fluoro-benzamide
982 380 Furans-2-carboxylic acid 4-[3-(3-ethanoyl-phenyl)-thioureido]-phenyl }-acid amides
983 447 Furans-2-carboxylic acid (4-{3-[3-(2-hydroxyl-ethylsulfonyl)-phenyl]-thioureido }-phenyl)-acid amides
984 475 2-fluoro-N-(4-{3-[3-(2-hydroxyl-ethylsulfonyl)-phenyl]-thioureido }-phenyl)-benzamide
985 474 Furans-2-carboxylic acid 4-[3-(3-butyl amino-sulfonyl-phenyl)-thioureido]-phenyl }-acid amides
Embodiment 986 (method 57)
1-(4-fluoro-phenyl)-2-methyl-third-1-alcohol
In ether (40 milliliters) solution of 0 ℃ 4-fluorobenzaldehyde (2.0 gram), drip while stirring the bromination isopropyl-magnesium (2.0M, 9.6ml).1.5 after hour,, use extracted with diethyl ether with aqueous ammonium chloride solution cancellation reaction.Wash ethereal extract with saturated sodium-chloride, use anhydrous magnesium sulfate drying, filtration and evaporation obtain oil.With silica gel column chromatography purifying oil,, obtain yellow oil product (1.76 gram) with 10% methylene dichloride-hexane wash-out.
Embodiment 987 (method 58)
1-(4-fluoro-phenyl)-2-methyl-third-1-ketone
In acetone (10 milliliters) solution of 0 ℃ 1-(4-fluoro-phenyl)-2-methyl-third-1-alcohol (1.6 gram), drip Jones reagent (20ml) while stirring.After 10 minutes, add Virahol and destroy excessive Jones reagent.Add ether, add anhydrous magnesium then, filtering mixt, evaporation obtains yellow oil product (1.2 gram).
Embodiment 988 (method 59)
3-dimethylamino-5-trifluoromethyl-benzonitrile
At the N of 3-dimethylamino-5-methyl bromobenzene trifluoride (7.3 gram), add cuprous cyanide (2.7 gram) in dinethylformamide (20 milliliters) solution, reflux mixture 12 hours.Water (40 milliliters) diluting reaction thing adds methylene dichloride.Use dense ammonium hydroxide, wash the methylene dichloride component then with water.Use anhydrous magnesium sulfate drying solution, concentrate, obtain yellow solid,, obtain yellow solid (4.7 gram) its recrystallization in hexane.
Tested the activity of above-claimed cpd as the simplexvirus inhibitor.
Human cytomegalic inclusion disease virus
Volume analysis.With HCMV wild-type (usually to be equivalent to 0.2 infection multiplicity) infection human foreskin fibroblast monolayer culture thing under inhibitor compound (different concns).Infected back 3 days, and, be determined at the viral total amount that produces in these cultures in the 12-well culture plate by the human foreskin fibroblast virus (in the presence of the unrestraint agent, carrying out) of collecting and titration is cultivated.Infect the quantitative plaque in 2 week backs.By existing under the situation of compound and not having the minimizing that the titre in the presence of the compound compares the viral yield titre, identify the inhibitor of HCMV.In this test, a kind of HCMV-of antagonism mutually of inhibitor is active usually by calculating IC 50Or IC 90Value (that is, respectively viral yield being reduced by 50% or 90% required compound amount) is determined.Table I has been described the IC of the compound of measuring at HCMV 50Data.
The microtiter plate test.In the presence of inhibitor compound, (its genome contains protokaryon beta-Glucuronidase gene (Jefferson with a kind of HCMV recombination mutation virus, R.A., S.M.Burgess, and D.Hirsh, 1986, from intestinal bacteria, as the beta-Glucuronidase of gene fusion mark, Proc.Natl.Acad.Sci.USA83:8447-8451), its expression is controlled by viral promotors), the fibroblastic 96-orifice plate of infected person foreskin culture.An example of this virus be RV145 virus (Jones, T.R., V.P.Muzithras and Y.Gluzman1991, the displacement mutagenesis of human cytomegalovirus gene group: US10 and US11 gene product are nonessential, J.Virol.65:5860-5872).Because it is in the control of viral promotors, it is the indirect index that HCMV grows and duplicates that beta-Glucuronidase is expressed in this test.In infection back 96 hours, the cell lysate that preparation is infected is (with 50mM sodium phosphate [pH7.0], contain 0.1%Triton X-100 and 0.1% sodium lauryl sulphate), measure the beta-Glucuronidase activity with enzyme substrates (when cutting, obtaining under spectrophotometer, to measure or under microfluorimeter, using the product of fluoroscopic examination) with development process.The example of these substrates is respectively p-nitrophenyl-β-D-glucuronide and methyl Umbrella shape base glucuronide.The existence of the minimizing indication antiviral compound of comparing when residing the beta-Glucuronidase expression of gene with the unrestraint agent with the HCMV genome.Like this, the corresponding minimizing of generation of chromophoric group or fluorophore product in this test.The data that this test uses the inhibitor compound of different amounts to produce also are used for estimating the IC of inhibitor compound 50
HSV antiviral (ELISA) test
In the tissue culturing plate of 96-hole, replenished the tissue culture medium (TCM) DMEM (the improvement Eale substratum of Dulbecco) of 2% foetal calf serum (FBS) with every hole 100 microlitres, wherein contain 3.5 * 10 4Vero cell (ATCC#CCL-81).37 ℃ of overnight incubation are (at 5%CO 2In) after, infected preceding 30 minutes with HSV-1 (infection multiplicity is equivalent to 0.006), do not handle, or with the standard drug control treatment cell of test compounds (different concns) or reference.Infect the back at 37 ℃ (at 5%CO 2In) incubation is after about 24 hours, fixed cell is used for the ELISA test.First antibody is mouse anti-HSV glycoprotein D mono-clonal first antibody, and two anti-be that the goat that is connected with beta-galactosidase enzymes resists-mouse IgG.Therefore, after adding methyl Umbrella shape base β-D-galactoside (Sigma#M1633) substrate, go up quantitative 4-methylumbelliferone fluorescence cleaved products, measure the virus replication degree at microfluorimeter (excite 365 nanometers, launch 450 nanometers).Fluorescence that obtains when relatively not having compound and the fluorescence that obtains when compound is arranged are determined the antiviral activity (IC of test compounds 50).Table I has shown data.
VZV antiviral (ELISA) test
In order to produce the original seed VZV that uses in test, infect human foreskin fibroblast (HFF) cell with VZV strain Ellen (ATCC#VR-1367) with low infection multiplicity (less than 0.1), and at 37 ℃ of (5%CO 2) in be incubated overnight.Spend the night behind the incubation, collect the mixture of the HFF cells infected that has not infected and infected VZV, and be added in each hole of 96-well culture plate and go that (100 microlitres are supplemented with among the DMEM of 2%FBS and contain 3.5 * 10 4Individual cell), the standard drug contrast (100 microlitres in every hole have replenished among the DMEM of 2%FBS) of test compounds or reference is contained in each hole.At 37 ℃ of (5%CO 2) cultivated these cells 3, be fixed for the ELISA test then.First antibody be mouse anti-VZV glycoprotein I I monoclonal antibody (Applied Biosystems, Inc.#13-145-100), two anti-be that the goat that is connected with beta-galactosidase enzymes resists-mouse IgG.Therefore, after adding methyl Umbrella shape base β-D-galactoside (Sigma#M1633) substrate, go up quantitative 4-methylumbelliferone fluorescence cleaved products, measure the virus replication degree at microfluorimeter (excite 365 nanometers, launch 450 nanometers).Fluorescence that obtains when relatively not having compound and the fluorescence that obtains when compound is arranged are determined the antiviral activity (IC of test compounds 50).Table I has shown data.
Table 1 has been described the IC of the compound of test at simplexvirus 50Data.
Example I C50 IC50 suppresses % IC50
μg/ml??(μg/ml)?10μg/ml???(μg/ml)
HCMV??????HSV?????VZV????????VZV
283???????7?????????0.6?????17???????＞10
284???????0.4???????3???????100??????＞15
289???????＞10??????0.6?????30???????＞10
498???????0.14??????6???????14???????＞10
499???????3?????????5???????25???????＞10
506???????＞10??????＞10????68???????＞10
507???????1.2???????10??????90???????4
512???????0.7???????0.5?????70???????4
514???????1.2???????4???????62???????＞10
515???????＞10??????＞10????30???????＞10
815???????0.0024?????????????????????＞7.5
816???????0.0015?????????????????????＞7.5
817???????0.001??????????????????????＞7.5
818???????0.0022?????????????????????＞7.5
819???????0.0022?????????????????????＞7.5
820???????0.0013?????????????????????3.4
821???????0.014??????????????????????＞7.5
822???????0.05???????????????????????＞7.5
823???????0.05???????????????????????＞7.5
824???????0.004??????????????????????3.20
825???????0.003??????????????????????6.12
826???????0.020??????????????????????0.86
827???????0.026
828???????0.45???????????????????????＞7.5
829???????0.08???????????????????????＞7.5
Therefore, compound of the present invention is the potent inhibitor that simplexvirus (comprising HCMV, VZV and HSV) grows and duplicates, and effectively suppresses viral yield.
According to the present invention, compound of the present invention can be applied to the patient who infects simplexvirus (comprising HCMV, VZV and HSV) with significant quantity, suppress virus.Therefore, compound of the present invention can be used for improving or eliminating the herpesvirus infection symptom of Mammals (including but not limited to the people).
Compound of the present invention can be pure or and conventional medicine learn carrier and be applied to patient together.
Spendable solid carrier comprises one or more materials, and they are also as perfume compound, lubricant, solubilizing agent, suspension agent, filler, glidant, compression auxiliary material, tackiness agent or tablet-disintegrating agent or encapsulated materials.With powder type, carrier can be superfine solid, and it mixes with superfine activeconstituents.With tablet form, the carrier with required compression performance of activeconstituents and proper ratio mixes, and is pressed into desired shape and size.Powder and tablet preferably contain and reach 99% activeconstituents.Suitable solid-state carrier for example comprises: calcium phosphate, Magnesium Stearate, talcum, sugar, lactose, dextrin, starch, gelatin, Mierocrystalline cellulose, methylcellulose gum, carboxylic acid methyl sodium cellulosate, polyvinylpyrrolidone/, low melt wax and ion exchange resin.
Liquid vehicle can be used for preparing solution, suspension, emulsion, syrup and elixir.Activeconstituents of the present invention dissolves in or is suspended in acceptable carrier on the pharmacology, as water, organic solvent, both mixture or pharmacology in acceptable oil or the fat.Liquid vehicle can contain other suitable pharmacology additive, as solubilizing agent, emulsifying agent, buffer reagent, sanitas, sweeting agent, reodorant, suspension agent, thickening material, pigment, viscosity modifier, stablizer or Osmolyte regulator.Liquid vehicle oral or that the parenteral dispenser is suitable comprises that water (particularly contains above-mentioned additive, as derivatived cellulose, the preferably carboxymethyl cellulose sodium solution), alcohol (comprising monohydroxy-alcohol and polyvalent alcohol) and derivative thereof as glycol, and oil (as fractionated Oleum Cocois and peanut oil).For the parenteral dispenser, carrier can also be a grease, as ethyl oleate and Isopropyl myristate.Sterile liquid carrier is used for the sterile liquid form composition that parenteral is used.
But the liquid medicine composition of sterile liquid or suspensions is used in intramuscular, intraperitoneal or subcutaneous injection.Also but intravenously is used sterile solution.Oral dispenser can be liquid state or solid-state composition form.
Preferred pharmaceutical compositions is single agent form, as tablet or capsule.The composition of this form is divided into the unitary dose that contains an amount of activeconstituents again; Unit dosage form can be a packaged composition, as powder, tubule, ampoule, prepackage syringe of packing or the pouch that contains liquid.Unit dosage for example can be: capsule or tablet itself maybe can be these compositions of an amount of any packaged form.
Must in the treatment of herpesvirus infection, determine the used effective dosage of treatment according to the personal considerations by the doctor who participates in.Relevant factor comprises patient's situation, age and body weight.The novel method that the present invention treats herpesvirus infection comprises the compound of using (comprising the mankind) at least a formula I of significant quantity to individual, or it is nontoxic, acceptable salt on the pharmacology.But these compounds are used in oral cavity, rectum, parenteral or external application (to skin or mucous membrane).General consumption every day is determined by particular compound, methods of treatment and patient.General every day consumption for oral be 0.01-1000 milligram/kilogram, preferred 0.5-500 milligram/kilogram, using for parenteral is 0.1-100 milligram/kilogram, preferably 0.5-50 milligram/kilogram.

Claims (28)

1. a compound is characterized in that, this compound has following formula:
Figure A9981580700021
Wherein
R 1-R 5Be selected from respectively cycloalkyl, a 3-10 carbon atom of perhaloalkyl radical, a 3-10 carbon atom of alkynyl, a 1-6 carbon atom of alkenyl, a 2-6 carbon atom of alkyl, a 2-6 carbon atom of hydrogen, a 1-6 carbon atom Heterocyclylalkyl, aryl, heteroaryl, halogen ,-CN ,-NO 2,-CO 2R 6,-COR 6,-OR 6,-SR 6,-SOR 6,-SO 2R 6,-CONR 7R 8,-NR 6N (R 7R 8) ,-N (R 7R 8) or W-Y-(CH 2) n-Z; Or R 2And R 3, or R 3And R 4Form 3-7 unit's Heterocyclylalkyl or 3-7 unit heteroaryl altogether;
R 6And R 7Be respectively the alkyl of hydrogen, a 1-6 carbon atom, the perhaloalkyl radical of a 1-6 carbon atom, or aryl;
R 8Be the alkyl of hydrogen, a 1-6 carbon atom, the perhaloalkyl radical of a 1-6 carbon atom, cycloalkyl, 3-10 unit Heterocyclylalkyl, aryl or the heteroaryl of a 3-10 carbon atom, or
R 7And R 8Can form 3-7 unit Heterocyclylalkyl altogether;
A is a heteroaryl;
W is O, NR 6, or do not exist;
Y is-(CO)-or-(CO 2)-, or do not exist;
Z be 1-4 carbon atom alkyl ,-CN ,-CO 2R 6, COR 6,-CONR 7R 8,-OCOR 6,-NR 6COR 7,-OCONR 6,-OR 6,-SR 6,-SOR 6,-SO 2R 6, SR 6N (R 7R 8) ,-N (R 7R 8) or phenyl;
G is aryl or heteroaryl;
X be a key ,-alkylamino of the alkoxyl group of the alkyl of NH, a 1-6 carbon atom, the alkenyl of a 1-6 carbon atom, a 1-6 carbon atom, the alkylthio of a 1-6 carbon atom, a 1-6 carbon atom or (CH) J;
J is the alkyl of 1-6 carbon atom, cycloalkyl, phenyl or the benzyl of a 3-7 carbon atom; With
N is the integer of 1-6;
Or the salt on its pharmacology.
2. compound as claimed in claim 1 is characterized in that R 1-R 5In at least one is not a hydrogen.
3. compound as claimed in claim 1 is characterized in that R 1-R 5Be selected from hydrogen respectively, be the alkoxyl group of 1-6 carbon atom, the perhaloalkyl radical and the halogen of a 1-6 carbon atom.
4. compound as claimed in claim 1 is characterized in that, X is CH (J), and J is the alkyl of 1-6 carbon atom.
5. compound as claimed in claim 4 is characterized in that J is a methyl.
6. compound as claimed in claim 1 is characterized in that A is not substituted.
7. compound as claimed in claim 1 is characterized in that A is a pyridyl.
8. compound as claimed in claim 1 is characterized in that, G is unsubstituted 5 or 6 yuan of heteroaryls.
9. compound as claimed in claim 8 is characterized in that, G is furyl, thiazolyl or thiadiazolyl group.
10. compound as claimed in claim 8 is characterized in that, G is the 2-furyl.
11. compound as claimed in claim 8 is characterized in that, G is 1,2, the 3-thiadiazolyl group.
12. compound as claimed in claim 8 is characterized in that, G is the 1,3-thiazoles base.
13. compound as claimed in claim 1 is characterized in that, G is a phenyl.
14. compound as claimed in claim 1 is characterized in that, G is the phenyl that replaces.
15. compound as claimed in claim 14 is characterized in that, G is replaced by one or more substituting groups that are selected from the alkoxyl group of halogen or 1-6 carbon atom.
16. compound as claimed in claim 1 is characterized in that, X is CH (J), and J is a methyl, and A is that pyridyl and G are thiazolyls.
17. compound as claimed in claim 1 is characterized in that, this compound is selected from:
Furans-2-carboxylic acid 5-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridine-2-yl }-acid amides
[1,2,3] thiadiazoles-4-carboxylic acid 5-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridine-2-yl }-acid amides
Pyridine-2-carboxylic acids 5-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridine-2-yl }-acid amides
Pyridine-2-carboxylic acids 6-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-3-yl }-acid amides
Furans-2-carboxylic acid 6-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-3-yl }-acid amides
[1,2,3] thiadiazoles-4-carboxylic acid 6-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-3-yl }-acid amides
[1,2,3] thiadiazoles-4-carboxylic acid 5-[3-(3,5-two chloro-phenyl)-thioureido]-pyridine-2-yl }-acid amides
N-[5-[[[(5-chloro-2, the 4-Dimethoxyphenyl) amino] sulphomethyl] amino]-the 2-pyridyl]-the 2-methyl benzamide
N-{5-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridine-2-yl }-2-fluoro-benzamide
N-{6-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-3-yl }-2-fluoro-benzamide
Furans-2-carboxylic acid 6-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-3-yl }-acid amides
[1,2,3] thiadiazoles-4-carboxylic acid 6-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-3-yl }-acid amides
[1,2,3] thiadiazoles-4-carboxylic acid 5-[3-(3,5-two chloro-phenyl)-thioureido]-pyridine-2-yl }-acid amides
N-[5-[[[(5-chloro-2, the 4-Dimethoxyphenyl) amino] sulphomethyl] amino]-pyridine-2-yl]-the 2-methyl benzamide
N-{5-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridine-2-yl }-2-fluoro-benzamide
N-{6-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-3-yl }-2-fluoro-benzamide
N-{5-[({[3,5-two (trifluoromethyl) benzyl] amino } thiocarbonyl) amino]-the 2-pyridyl }-1,2,3-thiadiazoles-4-carboxylic acid amides
N-(5-{[({ (1S)-1-[3,5-two (trifluoromethyl) phenyl] ethyl } amino) thiocarbonyl] amino }-the 2-pyridyl)-1,2,3-thiadiazoles-4-carboxylic acid amides
N-(5-{[({ (1S)-1-[3,5-two (trifluoromethyl) phenyl] ethyl } amino) thiocarbonyl] amino }-the 2-pyridyl)-1,3-thiazoles-4-carboxylic acid amides
N-(5-{[({1-[2-fluoro-5-(trifluoromethyl) phenyl] ethyl } amino) thiocarbonyl] amino }-the 2-pyridyl)-1,3-thiazoles-4-carboxylic acid amides
N-(5-{[({1-[2-fluoro-4-(trifluoromethyl) phenyl] ethyl } amino) thiocarbonyl] amino }-the 2-pyridyl)-1,3-thiazoles-4-carboxylic acid amides
N-(5-{[({1-[3-fluoro-5-(trifluoromethyl) phenyl] ethyl } amino) thiocarbonyl] amino }-the 2-pyridyl)-1,3-thiazoles-4-carboxylic acid amides
N-(5-{[({ (1S)-1-[3,5-two (trifluoromethyl) phenyl] ethyl } amino) carbonyl] amino }-the 2-pyridyl)-1,3-thiazoles-4-carboxylic acid amides
N-{5-[([1-(3-bromophenyl) ethyl] amino } thiocarboxyl group) amino]-the 2-pyridyl }-1,3-thiazoles-4-carboxylic acid amides
N-{5-[({[1-(2-bromophenyl) ethyl] amino } thiocarboxyl group) amino]-the 2-pyridyl }-1,3-thiazoles-4-carboxylic acid amides
N-(5-{[({1-[3-(trifluoromethyl) phenyl] ethyl } amino) thiocarbonyl] amino }-the 2-pyridyl)-1,3-thiazoles-4-carboxylic acid amides
N-(5-{[({1-[4-chloro-3-(trifluoromethyl) phenyl] ethyl } amino) thiocarbonyl] amino }-the 2-pyridyl)-1,3-thiazoles-4-carboxylic acid amides
N-{5-[({[1-(4-chloro-3-fluorophenyl) ethyl] amino } thiocarbonyl) amino]-the 2-pyridyl }-1,3-thiazoles-4-carboxylic acid amides
N-{5-[([1-(4-chloro-2-fluorophenyl) ethyl] amino } thiocarbonyl) amino]-the 2-pyridyl }-1,3-thiazoles-4-carboxylic acid amides
N-{6-[({[1-(4-fluorophenyl) ethyl] amino } thiocarbonyl) amino]-the 3-pyridyl }-1,2,3-thiadiazoles-4-carboxylic acid amides
N-(6-{[({1S)-1-[3,5-two (trifluoromethyl) phenyl] ethyl } amino) thiocarbonyl] amino }-the 3-pyridyl)-1,2,3-thiadiazoles-4-carboxylic acid amides; With the salt on its pharmacology.
18. a pharmaceutical composition is characterized in that, this pharmaceutical composition contains the compound of following formula:
Figure A9981580700051
Wherein
R 1-R 5Be selected from respectively cycloalkyl, a 3-10 carbon atom of perhaloalkyl radical, a 3-10 carbon atom of alkynyl, a 1-6 carbon atom of alkenyl, a 2-6 carbon atom of alkyl, a 2-6 carbon atom of hydrogen, a 1-6 carbon atom Heterocyclylalkyl, aryl, heteroaryl, halogen ,-CN ,-NO 2,-CO 2R 6,-COR 6,-OR 6,-SR 6,-SOR 6,-SO 2R 6,-CONR 7R 8,-NR 6N (R 7R 8) ,-N (R 7R 8) or W-Y-(CH 2) n-Z; Or R 2And R 3, or R 3And R 4Form 3-7 unit's Heterocyclylalkyl or 3-7 unit heteroaryl altogether;
R 6And R 7Be respectively the alkyl of hydrogen, a 1-6 carbon atom, the perhaloalkyl radical of a 1-6 carbon atom, or aryl;
R 8Be the alkyl of hydrogen, a 1-6 carbon atom, the perhaloalkyl radical of a 1-6 carbon atom, cycloalkyl, 3-10 unit Heterocyclylalkyl, aryl or the heteroaryl of a 3-10 carbon atom, or
R 7And R 8Can form 3-7 unit Heterocyclylalkyl altogether;
A is a heteroaryl;
W is O, NR 6, or do not exist;
Y is-(CO)-or-(CO 2)-, or do not exist;
Z be 1-4 carbon atom alkyl ,-CN ,-CO 2R 6, COR 6,-CONR 7R 8,-OCOR 6,-NR 6COR 7,-OCONR 6,-OR 6,-SR 6,-SOR 6,-SO 2R 6, SR 6N (R 7R 8) ,-N (R 7R 8) or phenyl;
G is aryl or heteroaryl;
X be a key ,-alkylamino of the alkoxyl group of the alkyl of NH, a 1-6 carbon atom, the alkenyl of a 1-6 carbon atom, a 1-6 carbon atom, the alkylthio of a 1-6 carbon atom, a 1-6 carbon atom or (CH) J;
J is the alkyl of 1-6 carbon atom, cycloalkyl, phenyl or the benzyl of a 3-7 carbon atom; With
N is the integer of 1-6;
Or acceptable carrier or thinner on salt on its pharmacology and the pharmacology.
19. a method that suppresses herpes virus replication is characterized in that, this method comprises the compound that makes following formula: Wherein
R 1-R 5Be selected from respectively cycloalkyl, a 3-10 carbon atom of perhaloalkyl radical, a 3-10 carbon atom of alkynyl, a 1-6 carbon atom of alkenyl, a 2-6 carbon atom of alkyl, a 2-6 carbon atom of hydrogen, a 1-6 carbon atom Heterocyclylalkyl, aryl, heteroaryl, halogen ,-CN ,-NO 2,-CO 2R 6,-COR 6,-OR 6,-SR 6,-SOR 6,-SO 2R 6,-CONR 7R 8,-NR 6N (R 7R 8) ,-N (R 7R 8) or W-Y-(CH 2) n-Z; Or R 2And R 3, or R 3And R 4Form 3-7 unit's Heterocyclylalkyl or 3-7 unit heteroaryl altogether;
R 6And R 7Be respectively the alkyl of hydrogen, a 1-6 carbon atom, the perhaloalkyl radical of a 1-6 carbon atom, or aryl;
R 8Be the alkyl of hydrogen, a 1-6 carbon atom, the perhaloalkyl radical of a 1-6 carbon atom, cycloalkyl, 3-10 unit Heterocyclylalkyl, aryl or the heteroaryl of a 3-10 carbon atom, or
R 7And R 8Can form 3-7 unit Heterocyclylalkyl altogether;
A is a heteroaryl;
W is O, NR 6, or do not exist;
Y is-(CO)-or-(CO 2)-, or do not exist;
Z be 1-4 carbon atom alkyl ,-CN ,-CO 2R 6, COR 6,-CONR 7R 8,-OCOR 6,-NR 6COR 7,-OCONR 6,-OR 6,-SR 6,-SOR 6,-SO 2R 6, SR 6N (R 7R 8) ,-N (R 7R 8) or phenyl;
G is aryl or heteroaryl;
X be a key ,-alkylamino of the alkoxyl group of the alkyl of NH, a 1-6 carbon atom, the alkenyl of a 1-6 carbon atom, a 1-6 carbon atom, the alkylthio of a 1-6 carbon atom, a 1-6 carbon atom or (CH) J;
J is the alkyl of 1-6 carbon atom, cycloalkyl, phenyl or the benzyl of a 3-7 carbon atom; With
N is the integer of 1-6;
Or the salt on the pharmacology contacts with simplexvirus.
20. method as claimed in claim 19 is characterized in that, described simplexvirus is a human cytomegalic inclusion disease virus.
21. method as claimed in claim 19 is characterized in that, described simplexvirus is a hsv.
22. method as claimed in claim 19 is characterized in that, described simplexvirus is a varicella zoster virus.
23. method as claimed in claim 22 is characterized in that, with pure substantially (S) optical isomer treatment varicella zoster virus.
24. a method for the treatment of the patient who suffers from herpesvirus infection is characterized in that this method comprises the compound with following formula that is applied to the patient significant quantity: Wherein
R 1-R 5Be selected from respectively cycloalkyl, a 3-10 carbon atom of perhaloalkyl radical, a 3-10 carbon atom of alkynyl, a 1-6 carbon atom of alkenyl, a 2-6 carbon atom of alkyl, a 2-6 carbon atom of hydrogen, a 1-6 carbon atom Heterocyclylalkyl, aryl, heteroaryl, halogen ,-CN ,-NO 2,-CO 2R 6,-COR 6,-OR 6,-SR 6,-SOR 6,-SO 2R 6,-CONR 7R 8,-NR 6N (R 7R 8) ,-N (R 7R 8) or W-Y-(CH 2) n-Z; Or R 2And R 3, or R 3And R 4Form 3-7 unit's Heterocyclylalkyl or 3-7 unit heteroaryl altogether;
R 6And R 7Be respectively the alkyl of hydrogen, a 1-6 carbon atom, the perhaloalkyl radical of a 1-6 carbon atom, or aryl;
R 8Be the alkyl of hydrogen, a 1-6 carbon atom, the perhaloalkyl radical of a 1-6 carbon atom, cycloalkyl, 3-10 unit Heterocyclylalkyl, aryl or the heteroaryl of a 3-10 carbon atom, or
R 7And R 8Can form 3-7 unit Heterocyclylalkyl altogether;
A is a heteroaryl;
W is O, NR 6, or do not exist;
Y is-(CO)-or-(CO 2)-, or do not exist;
Z be 1-4 carbon atom alkyl ,-CN ,-CO 2R 6, COR 6,-CONR 7R 8,-OCOR 6,-NR 6COR 7,-OCONR 6,-OR 6,-SR 6,-SOR 6,-SO 2R 6, SR 6N (R 7R 8) ,-N (R 7R 8) or phenyl;
G is aryl or heteroaryl;
X be a key ,-alkylamino of the alkoxyl group of the alkyl of NH, a 1-6 carbon atom, the alkenyl of a 1-6 carbon atom, a 1-6 carbon atom, the alkylthio of a 1-6 carbon atom, a 1-6 carbon atom or (CH) J;
J is the alkyl of 1-6 carbon atom, cycloalkyl, phenyl or the benzyl of a 3-7 carbon atom; With
N is the integer of 1-6;
Or the salt on its pharmacology.
25. method as claimed in claim 24 is characterized in that, described simplexvirus is a human cytomegalic inclusion disease virus.
26. method as claimed in claim 24 is characterized in that, described simplexvirus is a hsv.
27. method as claimed in claim 24 is characterized in that, described simplexvirus is a varicella zoster virus.
28. method as claimed in claim 27 is characterized in that, with pure substantially (S) optical isomer treatment varicella zoster virus.
CN99815807A 1998-12-09 1999-12-06 Thiourea inhibitors of herpes viruses Pending CN1335843A (en)

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