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ES2255971T3 - DIFENIL-UREAS REPLACED WITH OMEGA-CARBOXIARILO AS INHIBITORS OF THE QUINASA RAF. - Google Patents

DIFENIL-UREAS REPLACED WITH OMEGA-CARBOXIARILO AS INHIBITORS OF THE QUINASA RAF.

Info

Publication number
ES2255971T3
ES2255971T3 ES00903239T ES00903239T ES2255971T3 ES 2255971 T3 ES2255971 T3 ES 2255971T3 ES 00903239 T ES00903239 T ES 00903239T ES 00903239 T ES00903239 T ES 00903239T ES 2255971 T3 ES2255971 T3 ES 2255971T3
Authority
ES
Spain
Prior art keywords
phenyl
trifluoromethyl
chloro
urea
pyridyloxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
ES00903239T
Other languages
Spanish (es)
Inventor
Bernd Riedl
Jacques Dumas
Uday Khire
Timothy B. Lowinger
William J. Scott
Roger A. Smith
Jill E. Wood
Mary-Katherine Monahan
Reina Natero
Joel Renick
Robert N. Sibley
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharmaceuticals Corp
Original Assignee
Bayer Pharmaceuticals Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=27381740&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=ES2255971(T3) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Bayer Pharmaceuticals Corp filed Critical Bayer Pharmaceuticals Corp
Application granted granted Critical
Publication of ES2255971T3 publication Critical patent/ES2255971T3/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/78—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
    • A01N43/42—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
    • A01N47/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having one or more single bonds to nitrogen atoms
    • A01N47/28—Ureas or thioureas containing the groups >N—CO—N< or >N—CS—N<
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    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
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    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
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    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4453—Non condensed piperidines, e.g. piperocaine only substituted in position 1, e.g. propipocaine, diperodon
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
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    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/30—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by halogen atoms, or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/32—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
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    • C07C275/32—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms
    • C07C275/34—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C275/36—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with at least one of the oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. N-aryloxyphenylureas
    • C—CHEMISTRY; METALLURGY
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    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
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    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
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    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/16—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C317/22—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
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Abstract

Un compuesto seleccionado del grupo constituido por las 4-cloro-3-(trifluorometil)fenil-ureas: N-(4-cloro-3-(trifluorometil)fenil)-N¿-(3-(2-carbamoil-4-piridiloxi)fenil)urea, N-(4-cloro-3-(trifluorometil)fenil-N¿-(3-(2-(N-metilcarbamoil)-4-piridiloxi)fenil)-urea, N-(4-cloro-3-(trifluorometil)fenil)-N¿-(4-(2-carbamoil-4-piridiloxi)fenil)-urea, N-(4-cloro-3-(trifluorometil)fenil)-N¿-(4-(2-(N-metilcarbamoil)-4-piridiloxi)fenil)-urea y N-(4-cloro-3-(trifluorometil)fenil-N¿-(2-cloro-4-(2-(N-metilcarbamoil)(4-piridiloxi))fenil)-urea, las 4-bromo-3(trifluorometil)fenil-ureas: N-(4-bromo-3-(trifluorometil)fenil)-N¿-(3-(2-(N-metilcarbamoil)-4-piridiloxi)fenil)-urea, N-(4-bromo-3-(trifluorometil)fenil)-N¿-(4-(2-(N-metilcarbamoil)-4-piridiloxi)-fenil-urea, N-(4-bromo-3-(trifluorometilfenil)-N¿-(3-(2-(N-metilcarbamoil)-4-piridiltio)fenil)-urea, N-(4-bromo-3-(trifluorometil)fenil)-N¿-(2-cloro-4-(2-(N-metilcarbamoil)(4-piridiloxi))fenil)-urea y N-(4-bromo-3-(trifluorometil)fenil)-N¿-(3-cloro-4-(2-(N-metilcarbamoil)(4-piridiloxi))fenil)-urea, las 2-metoxi-4-cloro-5-(trifluorometil)fenil-ureas: N-(2-metoxi-4-cloro-5-(trifluorometil)fenil)-N¿-(4-(2-(N-metilcarbamoil)-4-piridiloxi)fenil)-urea, N-(2-metoxi-4-cloro-5-(trifluorometil)fenil)-N¿-(2-cloro-4-(2-(N-metilcarbamoil)(4-piridiloxi))fenil)-urea o una de sus sales farmacéuticamente aceptables.A compound selected from the group consisting of 4-chloro-3- (trifluoromethyl) phenyl ureas: N- (4-chloro-3- (trifluoromethyl) phenyl) -N¿- (3- (2-carbamoyl-4-pyridyloxy) ) phenyl) urea, N- (4-chloro-3- (trifluoromethyl) phenyl-N¿- (3- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) -urea, N- (4-chloro- 3- (trifluoromethyl) phenyl) -N¿- (4- (2-carbamoyl-4-pyridyloxy) phenyl) -urea, N- (4-chloro-3- (trifluoromethyl) phenyl) -N¿- (4- ( 2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) -urea and N- (4-chloro-3- (trifluoromethyl) phenyl-N¿- (2-chloro-4- (2- (N-methylcarbamoyl) ( 4-pyridyloxy)) phenyl) -urea, 4-bromo-3 (trifluoromethyl) phenyl ureas: N- (4-bromo-3- (trifluoromethyl) phenyl) -N¿- (3- (2- (N- methylcarbamoyl) -4-pyridyloxy) phenyl) -urea, N- (4-bromo-3- (trifluoromethyl) phenyl) -N¿- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -phenyl-urea , N- (4-bromo-3- (trifluoromethylphenyl) -N¿- (3- (2- (N-methylcarbamoyl) -4-pyridylthio) phenyl) -urea, N- (4-bromo-3- (trifluoromethyl) phenyl) -N¿- (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) -urea and N- (4-bromo-3- (trifluoromethyl) phenyl) -N¿- (3-clo ro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) -urea, 2-methoxy-4-chloro-5- (trifluoromethyl) phenyl ureas: N- (2-methoxy-4- Chloro-5- (trifluoromethyl) phenyl) -N¿- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) -urea, N- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N¿- (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) -urea or a pharmaceutically acceptable salt thereof.

Description

Difenil-ureas sustituidas con \omega-carboxiarilo como inhibidores de la quinasa raf.Diphenyl ureas substituted with ? -carboxaryl as inhibitors of raf kinase

Campo de la invenciónField of the Invention

Esta invención se refiere al uso de un grupo de aril-ureas en el tratamiento de enfermedades mediadas por raf, y composiciones farmacéuticas para la producción de medicamentos en dicha terapia.This invention relates to the use of a group of aryl ureas in the treatment of diseases raf mediated, and pharmaceutical compositions for production of medications in such therapy.

Antecedentes de la invenciónBackground of the invention

El oncogén p21^{ras} es un contribuidor importante para el desarrollo y la progresión de los cánceres sólidos humanos y está mutado en el 30% de todos los cánceres humanos (Bolton et al. Ann. Rep. Med. Chem. 1994, 29, 165-74; Bos. Cancer Res. 1989, 49, 4682-9). En su forma normal, no mutada, la proteína ras es un elemento clave de la cascada de transducción de señales dirigida por receptores de factores de crecimiento en casi todos los tejidos (Avruch et al. Trends Biochem. Sci. 1994, 19, 279-83). Bioquímicamente, ras es una proteína de fijación de nucleótidos de guanina, y la ciclación entre una forma activada combinada con GTP y una forma inactiva combinada con GDP está controlada estrictamente por la actividad de la GTPasa endógena de ras y otras proteínas reguladoras. En los mutantes ras en las células de cáncer, la actividad de la GTPasa endógena está atenuada y, por esta razón, la proteína suministra señales constitutivas de crecimiento a efectores situados aguas abajo tales como la enzima quinasa raf. Esto conduce al crecimiento canceroso de las células portadoras de estos mutantes (Magnuson et al. Semin. Cancer Biol. 1994, 5, 247-53). Se ha demostrado que la inhibición del efecto de ras activa por inhibición del camino de señalización de la quinasa raf mediante administración de anticuerpos desactivadores para la quinasa raf o por co-expresión de quinasa raf dominante negativa o MEK dominante negativa, el sustrato de la quinasa raf, conduce a la reversión de las células transformadas al fenotipo normal de crecimiento (véase: Daum et al. Trends Biochem. Sci. 1994, 19, 474-80; Fridman et al. J. Biol. Chem. 1994, 269, 30105-8. Kolch et al. (Nature 1991, 349, 426-28) han indicado ulteriormente que la inhibición de la expresión de raf por RNA antisentido bloquea la proliferación celular en oncogenes asociados a la membrana. Análogamente, la inhibición de la quinasa raf (por oligodesoxinucleótidos antisentido) se ha correlacionado in vitro e in vivo con la inhibición del crecimiento de una diversidad de tipos de tumores humanos (Monia et al., Nat. Med. 1996, 2, 668-75).The p21 ras oncogene is an important contributor to the development and progression of human solid cancers and is mutated in 30% of all human cancers (Bolton et al. Ann. Rep. Med. Chem. 1994 , 29 , 165-74; Bos. Cancer Res. 1989 , 49 , 4682-9). In its normal, non-mutated form, the ras protein is a key element of the signal transduction cascade directed by growth factor receptors in almost all tissues (Avruch et al. Trends Biochem. Sci. 1994 , 19 , 279- 83). Biochemically, ras is a guanine nucleotide binding protein, and the cyclization between an activated form combined with GTP and an inactive form combined with GDP is strictly controlled by the activity of the endogenous GTPase of ras and other regulatory proteins. In ras mutants in cancer cells, the activity of endogenous GTPase is attenuated and, for this reason, the protein supplies constituent growth signals to downstream effectors such as the enzyme kinase raf. This leads to the cancerous growth of the carrier cells of these mutants (Magnuson et al. Semin. Cancer Biol. 1994 , 5 , 247-53). It has been shown that the inhibition of the active ras effect by inhibition of the raf kinase signaling pathway by administration of deactivating antibodies to the raf kinase or by co-expression of negative dominant raf kinase or negative dominant MEK, the kinase substrate raf, leads to the reversal of transformed cells to the normal growth phenotype (see: Daum et al. Trends Biochem. Sci. 1994 , 19 , 474-80; Fridman et al. J. Biol. Chem. 1994 , 269 , 30105 -8.Kolch et al. ( Nature 1991 , 349 , 426-28) have further indicated that inhibition of raf expression by antisense RNA blocks cell proliferation in membrane-associated oncogenes. Similarly, inhibition of raf kinase (by antisense oligodeoxynucleotides) has been correlated in vitro and in vivo with the inhibition of the growth of a variety of human tumor types (Monia et al., Nat. Med. 1996 , 2 , 668-75).

Sumario de la invenciónSummary of the invention

La presente invención proporciona compuestos que son inhibidores de la enzima quinasa raf. Dado que la enzima es un efector aguas abajo de p21^{ras}, los inhibidores son útiles en composiciones farmacéuticas para uso humano o veterinario donde la inhibición del camino de la quinasa raf está indicada, v.g., en el tratamiento de tumores y/o crecimiento de células cancerosas mediado por la quinasa raf. En particular, los compuestos son útiles en la producción de medicamentos para el tratamiento de cánceres sólidos humanos o animales, v.g., cáncer murino, dado que la progresión de estos cánceres depende de la cascada de transducción de señales de la proteína ras y es por consiguiente susceptible de tratamiento por interrupción de la cascada, es decir, por inhibición de la quinasa raf. De acuerdo con ello, los compuestos de la invención son útiles en la preparación de medicamentos para tratamiento de cánceres, con inclusión de cánceres sólidos, tales como, por ejemplo, carcinomas (v.g., de los pulmones, páncreas, tiroides, vejiga o colon), trastornos mieloides (v.g. leucemia mieloide) o adenomas (v.g. adenoma velloso de colon).The present invention provides compounds that they are inhibitors of the enzyme kinase raf. Since the enzyme is a effector downstream of p21 ras, inhibitors are useful in pharmaceutical compositions for human or veterinary use where the inhibition of the raf kinase pathway is indicated, e.g., in the treatment of tumors and / or mediated cancer cell growth for the kinase raf. In particular, the compounds are useful in the production of medicines for the treatment of solid cancers humans or animals, e.g., murine cancer, since the progression of these cancers depend on the signal transduction cascade of the ras protein and is therefore susceptible to treatment by cascade disruption, that is, by kinase inhibition raf. Accordingly, the compounds of the invention are useful. in the preparation of medicines for the treatment of cancers, with inclusion of solid cancers, such as, for example, carcinomas (e.g., from the lungs, pancreas, thyroid, bladder or colon), myeloid disorders (e.g. myeloid leukemia) or adenomas (e.g. hairy colon adenoma).

La presente invención proporciona por tanto compuestos descritos generalmente como aril-ureas, que incluyen análogos tanto de arilo como de heteroarilo, que inhiben el camino de la quinasa raf. Así pues, la invención está dirigida a compuestos que inhiben la enzima quinasa raf y también a compuestos, composiciones y métodos para el tratamiento del crecimiento de células cancerosas mediado por la quinasa raf en los cuales un compuesto de la invención es una sal aceptable de aquéllos.The present invention therefore provides compounds generally described as aryl ureas, which include both aryl and heteroaryl analogs, which inhibit the raf kinase path. Thus, the invention is directed to compounds that inhibit the enzyme kinase raf and also to compounds, compositions and methods for the treatment of cancer cell growth mediated by raf kinase in which a compound of the invention is an acceptable salt of those.

Un compuesto de la invención se selecciona del grupo constituido por las 4-cloro-3-(trifluorometil)fenil-ureas:A compound of the invention is selected from group consisting of 4-Chloro-3- (trifluoromethyl) phenyl ureas:

N-(4-cloro-3-(trifluorometil)fenil)-N'-(3-(2-carbam-oil-4-piridiloxi)fenil)urea,N- (4-Chloro-3- (trifluoromethyl) phenyl) -N '- (3- (2-carbam-oil-4-pyridyloxy) phenyl) urea,

N-(4-cloro-3-(trifluorometil)fenil-N'-(3-(2-(N-metilcarbamoil)-4-piridiloxi)-fenil)-urea,N- (4-Chloro-3- (trifluoromethyl) phenyl-N '- (3- (2- (N-methylcarbamoyl) -4-pyridyloxy) -phenyl) -urea,

N-(4-cloro-3-(trifluorometil)fenil)-N'-(4-(2-carbamoil-4-piridiloxi)fenil)-urea,N- (4-Chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2-carbamoyl-4-pyridyloxy) phenyl) -urea,

N-(4-cloro-3-(trifluorometil)fenil)-N'-(4-(2-(N-metilcarbamoil)-4-piridiloxi)-fenil)-urea yN- (4-Chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -phenyl) -urea Y

N-(4-cloro-3-(trifluorometil)fenil-N'-(2-cloro-4-(2-(N-metilcarbamoil)(4-piridiloxi))fenil)-urea,N- (4-chloro-3- (trifluoromethyl) phenyl-N '- (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) -urea,

las 4-bromo-3(trifluorometil)fenil-ureas:the 4-Bromo-3 (trifluoromethyl) phenyl ureas:

N-(4-bromo-3-(trifluorometil)fenil)-N'-(3-(2-(N-metilcarbamoil)-4-piridiloxi)-fenil)-urea,N- (4-Bromo-3- (trifluoromethyl) phenyl) -N '- (3- (2- (N-methylcarbamoyl) -4-pyridyloxy) -phenyl) -urea,

N-(4-bromo-3-(trifluorometil)fenil)-N'-(4-(2-(N-metilcarbamoil)-4-piridiloxi)-fenil)-urea,N- (4-Bromo-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -phenyl) -urea,

N-(4-bromo-3-(trifluorometilfenil)-N'-(3-(2-(N-metilcarbamoil)-4-piridiltio)-fenil)-urea,N- (4-Bromo-3- (trifluoromethylphenyl) -N '- (3- (2- (N-methylcarbamoyl) -4-pyridylthio) -phenyl) -urea,

N-(4-bromo-3-(trifluorometil)fenil)-N'-(2-cloro-4-(2-(N-metilcarbamoil)(4-piridiloxi))fenil)-urea yN- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) -urea Y

N-(4-bromo-3-(trifluorometil)fenil)-N'-(3-cloro-4-(2-(N-metilcarbamoil)(4-piridiloxi))fenil)-urea,N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (3-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) -urea,

las 2-metoxi-4-cloro-5-(trifluorometil)fenil-ureas:the 2-methoxy-4-chloro-5- (trifluoromethyl) phenyl ureas:

N-(2-metoxi-4-cloro-5-(trifluorometil)fenil)-N'-(4-(2-(N-metilcarbamoil)-4-piridiloxi)fenil)-urea,N- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) -urea,

N-(2-metoxi-4-cloro-5-(trifluorometil)fenil)-N'-(2-cloro-4-(2-(N-metilcarbamoil)(4-piridiloxi))fenil)-ureaN- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) -urea

o una sal farmacéuticamente aceptable de las mismas.or a pharmaceutically acceptable salt of the same.

La presente invención está dirigida también a sales farmacéuticamente aceptables de un compuesto de la invención.The present invention is also directed to pharmaceutically acceptable salts of a compound of the invention.

Sales farmacéuticamente aceptables adecuadas son bien conocidas por los expertos en la técnica e incluyen sales básicas de ácidos inorgánicos y orgánicos, tales como ácido clorhídrico, ácido bromhídrico, ácido sulfúrico, ácido fosfórico, ácido metanosulfónico, ácido trifluorometanosulfónico, ácido bencenosulfónico, ácido p-toluenosulfónico, ácido 1-naftalenosulfónico, ácido 2-naftalenosulfónico, ácido acético, ácido trifluoroacético, ácido málico, ácido tartárico, ácido cítrico, ácido láctico, ácido oxálico, ácido succínico, ácido fumárico, ácido maleico, ácido benzoico, ácido salicílico, ácido fenilacético, y ácido mandélico. Adicionalmente, sales farmacéuticamente aceptables incluyen sales ácidas de bases inorgánicas, tales como sales que contienen cationes alcalinos (v.g., Li^{+}, Na^{+} o K^{+}), cationes alcalino-térreos (v.g., Mg^{+2}, Ca^{+2} o Ba^{+2}), el catión amonio, así como sales ácidas de bases orgánicas, que incluyen amonio con sustituyentes alifáticos y aromáticos, y cationes amonio cuaternarios, tales como los que se originan por protonación o peralquilación de trietilamina, N,N-dietilamina, N,N-diciclohexilamina, lisina, piridina, N,N-dimetilamino-piridina (DMAP), 1,4-diazabiciclo[2.2.2]octano (DABCO), 1,5-diazabiciclo[4.3.0]non-5-eno (DBN) y 1,8-diazabi-ciclo[5.4.0]undec-7-eno (DBU).Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid , 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid. Additionally, pharmaceutically acceptable salts include acidic salts of inorganic bases, such as salts containing alkali cations (eg, Li +, Na + or K +), alkaline earth cations (eg, Mg ^ {+2, Ca +2 or Ba +2), the ammonium cation, as well as acid salts of organic bases, which include ammonium with aliphatic and aromatic substituents, and quaternary ammonium cations, such as those originate from protonation or peralkylation of triethylamine, N, N- diethylamine, N, N -decyclohexylamine, lysine, pyridine, N, N- dimethylamino-pyridine (DMAP), 1,4-diazabicyclo [2.2.2] octane (DABCO) , 1,5-diazabicyclo [4.3.0] non-5-eno (DBN) and 1,8-diazabi-cycle [5.4.0] undec-7-eno (DBU).

Cierto número de dichos compuestos poseen carbonos asimétricos y pueden existir por tanto en formas racémicas y ópticamente activas. Métodos de separación de mezclas enantiómeras y diastereoisómeras son bien conocidos por los expertos en la técnica. La presente invención abarca cualquier forma aislada racémica u ópticamente activa de los compuestos descritos en la invención que poseen actividad inhibidora de raf.A certain number of said compounds have asymmetric carbons and can therefore exist in racemic forms and optically active. Methods of separation of enantiomeric mixtures and diastereoisomers are well known to experts in the technique. The present invention encompasses any isolated form. racemic or optically active compounds described in the invention possessing raf inhibitory activity.

Métodos generales de preparaciónGeneral Preparation Methods

Los compuestos de la invención se pueden preparar por el uso de reacciones químicas y procedimientos conocidos, algunos a partir de materias primas que están disponibles comercialmente. Sin embargo, se proporcionarán a continuación métodos generales de preparación para ayudar a los expertos en la técnica en la síntesis de estos compuestos, proporcionándose ejemplos más detallados en la sección experimental que sigue.The compounds of the invention can be prepared by the use of known chemical reactions and procedures, some from raw materials that are available commercially However, they will be provided below. General methods of preparation to assist experts in the technique in the synthesis of these compounds, providing more detailed examples in the experimental section that follows.

Las anilinas sustituidas pueden producirse utilizando métodos estándar (March, Advanced Organic Chemistry, 3ª edición; John Wiley: Nueva York (1985). Larock, Comprehensive Organic Transformations; VCH Publishers: Nueva York (1989)). Como se muestra en el Esquema I, las aril-aminas se sintetizan generalmente por reducción de nitroarilos utilizando un catalizador metálico, tal como Ni, Pd, o Pt, y H_{2} o un agente de transferencia de hidruro, tal como formiato, ciclohexadieno, o un borohidruro (Rylander, Hydrogenation Methods; Academic Press: Londres, UK (1985)). Los nitroarilos pueden reducirse también directamente utilizando una fuente de hidruro potente, tal como LiAlH_{4} (Seyden-Penne, Reductions by the Alumino- and Borohydrides in Organic Synthesis; VCH Publishers: Nueva York (1991)), o utilizando un metal de valencia cero, tal como Fe, Sn o Ca, a menudo en medios ácidos. Existen muchos métodos para la síntesis de nitroarilos (March, Advanced Organic Chemistry, 3ª edición; John Wiley: Nueva York (1985). Larock, Comprehensive Organic Transformations; VCH Publishers: Nueva York (1989)).Substituted anilines can be produced using standard methods (March, Advanced Organic Chemistry , 3rd edition; John Wiley: New York (1985). Larock, Comprehensive Organic Transformations ; VCH Publishers: New York (1989)). As shown in Scheme I, aryl amines are generally synthesized by reduction of nitroaryls using a metal catalyst, such as Ni, Pd, or Pt, and H2 or a hydride transfer agent, such as formate, cyclohexadiene, or a borohydride (Rylander, Hydrogenation Methods ; Academic Press: London, UK (1985)). Nitroaryls can also be directly reduced using a potent hydride source, such as LiAlH4 (Seyden-Penne, Reductions by the Alumino- and Borohydrides in Organic Synthesis ; VCH Publishers: New York (1991)), or using a metal of zero valence, such as Fe, Sn or Ca, often in acidic media. There are many methods for nitroaryl synthesis (March, Advanced Organic Chemistry , 3rd edition; John Wiley: New York (1985). Larock, Comprehensive Organic Transformations ; VCH Publishers: New York (1989)).

1one 

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Esquema IScheme I

Reducción de Nitroarilos a Aril-AminasReduction of Nitroaryls to Aril-Amines

Los nitroarilos se forman generalmente por nitración electrófila de compuestos aromáticos utilizando HNO_{3}, o una fuente alternativa de NO_{2}^{-}. Los nitroarilos pueden elaborarse adicionalmente antes de la reducción. Así, los nitroarilos sustituidos conNitroaryls are usually formed by electrophilic nitration of aromatic compounds using HNO3,  or an alternative source of NO_ {2} -. Nitroaryls can be elaborated further before reduction. So, the nitroaryls substituted with

Ar-H \xrightarrow{{\textstyle{HNO_{3}}}} ArNO_{2}Ar-h \ xrightarrow {{\ textstyle {HNO_ {3}}}} ArNO_ {2}

grupos potencialmente lábiles (v.g. F, Cl, Br, etc.) pueden sufrir reacciones de sustitución por tratamiento con nucleófilos, tales como tiolato (ilustrado en el Esquema II) o fenóxido. Los nitroarilos pueden sufrir también reacciones de acoplamiento de tipo Ullman (Esquema II).potentially labile groups (e.g. F, Cl, Br, etc.) may undergo substitution reactions by nucleophilic treatment, such as thiolate (illustrated in Scheme II) or phenoxide. Nitroaryls may also suffer Ullman type coupling reactions (Scheme II). 

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22 

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Esquema IIScheme II

Sustitución Aromática Nucleófila Seleccionada Utilizando NitroarilosNucleophilic Aromatic Substitution Selected Using Nitroaryls

Los nitroarilos pueden sufrir también reacciones de acoplamiento cruzado mediadas por metales de transición. Por ejemplo, los electrófilos de nitroarilo, tales como nitroaril-bromuros, -yoduros o -triflatos, sufren reacciones de acoplamiento cruzado mediadas por paladio con aril-nucleófilos, tales como ácidos arilborónicos (reacciones de Suzuki, ilustradas más adelante), arilestaños (reacciones de Stille) o arilcincs (reacción de Negishi) para proporcionar el biarilo (5).Nitroaryls may also suffer reactions of cross coupling mediated by transition metals. By example, nitroaryl electrophiles, such as nitroaryl bromides, iodides or triflates, suffer Palladium-mediated cross-coupling reactions with aryl nucleophiles, such as arylboronic acids (Suzuki reactions, illustrated below), Arilestaños (Stille reactions) or arilcincs (Negishi reaction) to provide the biaryl (5). 

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33 

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Cualesquiera nitroarilos o anilinas pueden convertirse en el cloruro de arenosulfonilo correspondiente (7) por tratamiento con ácido clorosulfónico. La reacción del cloruro de sulfonilo con una fuente de fluoruro, tal como KF, proporciona luego el fluoruro de sulfonilo (8). La reacción del fluoruro de sulfonilo (8) con trimetilsilil-trifluorometano en presencia de una fuente de fluoruro, tal como difluorotrimetilsiliconato de tris(dimetil-amino)sulfonio (TASF) conduce a la trifluorometilsulfona correspondiente (9). Alternativamente, el cloruro de sulfonilo (7) puede reducirse al arenotiol (10), por ejemplo con amalgama de cinc. La reacción del tiol (10) con CHClF_{2} en presencia de base da el difluorometil-mercaptano (11), que puede oxidarse a la sulfona (12) con cualquiera de una diversidad de oxidantes, que incluyen CrO_{3}-anhídrido acético (Sedova et al. Zh. Org. Khim. 1970, 6, (568).Any nitroaryls or anilines can be converted into the corresponding arenesulfonyl chloride ( 7 ) by treatment with chlorosulfonic acid. Reaction of sulfonyl chloride with a fluoride source, such as KF, then provides sulfonyl fluoride ( 8 ). The reaction of sulfonyl fluoride ( 8 ) with trimethylsilyl-trifluoromethane in the presence of a fluoride source, such as tris (dimethyl-amino) sulfonium difluorotrimethylsilylonate (TASF) leads to the corresponding trifluoromethylsulfone ( 9 ). Alternatively, sulfonyl chloride ( 7 ) can be reduced to arenotiol ( 10 ), for example with zinc amalgam. The reaction of thiol ( 10 ) with CHClF 2 in the presence of base gives difluoromethyl mercaptan ( 11 ), which can be oxidized to sulfone ( 12 ) with any of a variety of oxidants, including CrO 3 -anhydride acetic (Sedova et al. Zh. Org. Khim. 1970 , 6, (568).

44

Esquema IIIScheme III

Métodos Seleccionados de Síntesis de Aril-Sulfonas FluoradasSelected Methods of Synthesis of Fluorinated Aryl-Sulfones

Como se muestra en el Esquema IV, la formación de ureas asimétricas puede implicar la reacción de un aril-isocianato (14) con una aril-amina (13). El heteroaril-isocianato puede sintetizarse a partir de una heteroaril-amina por tratamiento con fosgeno o un equivalente de fosgeno, tal como cloroformiato de triclorometilo (difosgeno), carbonato de bis(triclorometilo) (trifosgeno), o N,N'-carbonildiimidazol (CDI). El isocianato puede derivarse también de un derivado de ácido carboxílico heterocíclico, tal como un éster, un haluro de ácido o un anhídrido por una transposición de tipo Curtius. Así, la reacción del derivado de ácido (16) con una fuente de azida, seguida por transposición, proporciona el isocianato. El ácido carboxílico (17) correspondiente puede someterse también a transposiciones de tipo Curtius utilizando difenilfosforil-azida (DPPA) o un reactivo similar.As shown in Scheme IV, the formation of asymmetric ureas may involve the reaction of an aryl isocyanate ( 14 ) with an aryl amine ( 13 ). The heteroaryl isocyanate can be synthesized from a heteroaryl amine by treatment with phosgene or a phosgene equivalent, such as trichloromethyl chloroformate (diphosgene), bis (trichloromethyl) carbonate (triphosgene), or N, N'- carbonyldiimidazole ( CDI). The isocyanate can also be derived from a heterocyclic carboxylic acid derivative, such as an ester, an acid halide or an anhydride by a Curtius type transposition. Thus, the reaction of the acid derivative (16) with an azide source, followed by transposition, provides the isocyanate. The corresponding carboxylic acid (17) can also be subjected to Curtius type transpositions using diphenylphosphoryl azide (DPPA) or a similar reagent.

55

Esquema IVScheme IV

Métodos Seleccionados de Formación de Ureas AsimétricasSelected Methods of Asymmetric Urea Formation

Por último, las ureas pueden manipularse ulteriormente utilizando métodos familiares para los expertos en la técnica.Finally, ureas can be manipulated subsequently using familiar methods for experts in the technique.

La invención incluye también composiciones farmacéuticas que incluyen un compuesto de la invención y un vehículo fisiológicamente aceptable.The invention also includes compositions pharmaceuticals that include a compound of the invention and a physiologically acceptable vehicle.

Los compuestos se pueden administrar por vías oral, tópica, parenteral, por inhalación o pulverización o por vía rectal en formulaciones de dosificación unitaria. El término "administración por inyección" incluye inyecciones intravenosas, intramusculares, subcutáneas y parenterales, así como el uso de técnicas de infusión. Pueden estar presentes uno o más compuestos en asociación con uno o más vehículos no tóxicos farmacéuticamente aceptables y, en caso deseado, otros ingredientes activos.The compounds can be administered via oral, topical, parenteral, by inhalation or spraying or by route rectal in unit dosage formulations. The term "administration by injection" includes injections intravenous, intramuscular, subcutaneous and parenteral, as well as the use of infusion techniques. One or more may be present compounds in association with one or more non-toxic vehicles pharmaceutically acceptable and, if desired, other ingredients assets.

Las composiciones destinadas a uso oral pueden prepararse de acuerdo con cualquier método adecuado conocido en la técnica para la fabricación de composiciones farmacéuticas. Tales composiciones pueden contener uno o más agentes seleccionados del grupo constituido por diluyente, agentes edulcorantes, agentes saborizantes, agentes colorantes y agentes conservantes a fin de proporcionar preparaciones agradables al paladar. Las tabletas contienen el ingrediente activo en mezcla con excipientes no tóxicos farmacéuticamente aceptables que son adecuados para la fabricación de tabletas. Estos excipientes pueden ser, por ejemplo, diluyentes inertes, tales como carbonato de calcio, carbonato de sodio, lactosa, fosfato de calcio o fosfato de sodio; agentes granuladores y desintegradores, por ejemplo, almidón de maíz, o ácido algínico; y agentes aglomerantes, por ejemplo estearato de magnesio, ácido esteárico o talco. Las tabletas pueden carecer de recubrimiento o pueden estar recubiertas por técnicas conocidas para retardar la desintegración y adsorción en el tracto gastrointestinal y proporcionar con ello una acción sostenida durante un período prolongado. Por ejemplo, puede emplearse un material de retardo temporal tal como monoestearato de glicerilo o diestearato de glicerilo. Estos compuestos pueden prepararse también en forma sólida que se libera rápidamente.Compositions intended for oral use may be prepared according to any suitable method known in the technique for the manufacture of pharmaceutical compositions. Such compositions may contain one or more agents selected from the group consisting of diluent, sweetening agents, agents flavorings, coloring agents and preservatives in order to provide pleasant preparations to the palate. The tablets contain the active ingredient in admixture with non-toxic excipients pharmaceutically acceptable that are suitable for manufacturing of tablets. These excipients may be, for example, diluents. inert, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrators, for example, corn starch, or alginic acid; Y binding agents, for example magnesium stearate, acid stearic or talc. The tablets may be uncoated or they may be coated by known techniques to retard the disintegration and adsorption in the gastrointestinal tract and thereby provide sustained action over a period dragged on. For example, a delay material can be used temporary such as glyceryl monostearate or distearate glyceryl These compounds can also be prepared in the form solid that releases quickly.

Las formulaciones para uso oral pueden presentarse también como cápsulas de gelatina dura en las cuales el ingrediente activo está mezclado con un diluyente sólido inerte, por ejemplo, carbonato de calcio, fosfato de calcio o caolín, o como cápsulas de gelatina blanda en las cuales el ingrediente activo está mezclado con agua o con un medio aceitoso, por ejemplo aceite de cacahuete, aceite de parafina o aceite de oliva.Formulations for oral use may also present as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, by example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oily medium, for example peanut, paraffin oil or olive oil.

Las suspensiones acuosas contienen los materiales activos en mezcla con excipientes adecuados para la fabricación de suspensiones acuosas. Tales excipientes son agentes de suspensión, por ejemplo carboximetilcelulosa sódica, metilcelulosa, hidroxipropil-metilcelulosa, alginato de sodio, polivinilpirrolidona, goma tragacanto y goma arábiga; agentes dispersantes o humectantes pueden ser un fosfátido existente naturalmente, por ejemplo, lecitina, o productos de condensación o un óxido de alquileno con ácidos grasos, por ejemplo poli(estearato de oxietileno), o productos de condensación de óxido de etileno con alcoholes alifáticos de cadena larga, por ejemplo heptadecaetileno-oxicetanol, o productos de condensación de óxido de etileno con ésteres parciales derivados de ácidos grasos y hexitol tales como monooleato de poli(oxietilen-sorbitol), o productos de condensación de óxido de etileno con ésteres parciales derivados de ácidos grasos y anhídridos de hexitol, por ejemplo monooleato de poli(etilen-sorbitán). Las suspensiones acuosas pueden contener también uno o más conservantes, por ejemplo p-hidroxibenzoato de etilo o de n-propilo, uno o más agentes colorantes, uno o más agentes saborizantes, y uno o más agentes edulcorantes tales como sacarosa o sacarina.Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth and gum arabic; dispersing or wetting agents may be a naturally occurring phosphatide, for example, lecithin, or condensation products or an alkylene oxide with fatty acids, for example poly (oxyethylene stearate), or condensation products of ethylene oxide with aliphatic alcohols of long chain, for example heptadecaethylene-oxyethanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol such as poly (oxyethylene sorbitol) monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example poly (ethylene sorbitan) monooleate. Aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl p -hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents such as sucrose or saccharin.

Los polvos y gránulos dispersables adecuados para preparación de una suspensión acuosa por adición de agua proporcionan el ingrediente activo en mezcla con un agente dispersante o humectante, agente de suspensión y uno o más conservantes. Agentes dispersantes o humectantes adecuados y agentes de suspensión se ilustran por los ya mencionados anteriormente. También pueden estar presentes excipientes adicionales, por ejemplo, agentes edulcorantes, saborizantes y colorantes.The dispersible powders and granules suitable for preparation of an aqueous suspension by adding water provide the active ingredient in admixture with an agent dispersant or humectant, suspending agent and one or more preservatives Suitable dispersing or wetting agents and agents Suspension are illustrated by those already mentioned above. Additional excipients may also be present, for example,  sweetening, flavoring and coloring agents.

Los compuestos pueden encontrarse también en la forma de formulaciones líquidas no acuosas, v.g., suspensiones aceitosas que pueden formularse por suspensión de los ingredientes activos en un aceite vegetal, por ejemplo aceite de cacahuete ("arachis oil"), aceite de oliva, aceite de sésamo o aceite de cacahuete ("peanut oil"), o en un aceite mineral tal como aceite de parafina. Las suspensiones aceitosas pueden contener un agente espesante, por ejemplo cera de abejas, parafina dura o alcohol cetílico. Pueden añadirse agentes edulcorantes tales como los arriba indicados, y agentes saborizantes para proporcionar preparaciones orales agradables al paladar. Estas composiciones pueden conservarse por adición de un anti-oxidante tal como ácido ascórbico.The compounds can also be found in the form of non-aqueous liquid formulations, e.g. suspensions Oils that can be formulated by suspending the ingredients active in a vegetable oil, for example peanut oil ("arachis oil"), olive oil, sesame oil or peanut ("peanut oil"), or in a mineral oil such as paraffin oil Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol Sweetening agents such as the above, and flavoring agents to provide oral preparations pleasant to the palate. These compositions can be preserved by adding an anti-oxidant such as ascorbic acid.

Las composiciones farmacéuticas de la invención pueden encontrarse también en la forma de emulsiones de aceite en agua. La fase aceitosa puede ser un aceite vegetal, por ejemplo aceite de oliva o aceite de cacahuete, o un aceite mineral, por ejemplo un aceite de parafina o mezclas de éstos. Agentes emulsionantes adecuados pueden ser gomas existentes naturalmente, por ejemplo goma arábiga o goma tragacanto, fosfátidos existentes naturalmente, por ejemplo soja, lecitina, y ésteres o ésteres parciales derivados de ácidos grasos y anhídridos de hexitol, por ejemplo monooleato de sorbitán, y productos de condensación de dichos ésteres parciales con óxido de etileno, por ejemplo monooleato de poli(oxietilen-sorbitán). Las emulsiones pueden contener también agentes edulcorantes y saborizantes.The pharmaceutical compositions of the invention they can also be found in the form of oil emulsions in Water. The oily phase can be a vegetable oil, for example olive oil or peanut oil, or a mineral oil, for example a paraffin oil or mixtures thereof. Agents Suitable emulsifiers can be naturally occurring gums, eg gum arabic or gum tragacanth, existing phosphatides naturally, for example soy, lecithin, and esters or esters partial derivatives of fatty acids and hexitol anhydrides, by example sorbitan monooleate, and condensation products of said partial esters with ethylene oxide, for example poly (oxyethylene sorbitan) monooleate. The emulsions may also contain sweetening agents and flavorings

Pueden formularse jarabes y elixires con agentes edulcorantes, por ejemplo glicerol, propilenglicol, sorbitol y sacarosa. Tales formulaciones pueden contener también un demulcente, un conservante y agentes saborizantes y colorantes.Syrups and elixirs can be formulated with agents sweeteners, for example glycerol, propylene glycol, sorbitol and saccharose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.

Los compuestos se pueden administrar también en la forma de supositorios para administración rectal del fármaco. Estas composiciones se pueden preparar por mezcla del fármaco con un excipiente no irritante adecuado que es sólido a las temperaturas ordinarias pero líquido a la temperatura rectal, y por consiguiente fundirá en el recto para liberar el fármaco. Tales materiales incluyen manteca de cacao y polietilenglicoles.The compounds can also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at temperatures ordinary but liquid at rectal temperature, and therefore It will melt in the rectum to release the drug. Such materials They include cocoa butter and polyethylene glycols.

Para todos los regímenes de uso descritos en esta memoria para los compuestos de la invención, el régimen de dosificación diaria oral será preferiblemente desde 0,01 a 200 mg/kg de peso corporal total. La dosificación diaria para administración por inyección, con inclusión de inyecciones intravenosas, intramusculares, subcutáneas y parenterales, y uso de técnicas de infusión será preferiblemente desde 0,01 a 200 mg/kg de peso corporal total. El régimen de dosificación diaria rectal será preferiblemente desde 0,01 a 200 mg/kg de peso corporal total. El régimen de dosificación diaria tópica será con preferencia desde 0,1 a 200 mg, administrados entre 1 y 4 veces al día. El régimen de dosificación diaria por inhalación será preferiblemente desde 0,01 a 10 mg/kg de peso corporal total.For all the use regimes described in this memory for the compounds of the invention, the regimen of Daily oral dosage will preferably be from 0.01 to 200 mg / kg of total body weight. The daily dosage for administration by injection, including intravenous injections, intramuscular, subcutaneous and parenteral, and use of techniques infusion will preferably be from 0.01 to 200 mg / kg of weight total body The daily rectal dosing regimen will be preferably from 0.01 to 200 mg / kg of total body weight. He Topical daily dosage regimen will preferably be from 0.1 at 200 mg, administered 1 to 4 times a day. The regime of Daily dosage by inhalation will preferably be from 0.01 to 10 mg / kg total body weight.

Será apreciado por los expertos en la técnica que el método particular de administración dependerá de una diversidad de factores, todos los cuales se consideran rutinariamente cuando se administran tratamientos terapéuticos. Será apreciado también por un experto en la técnica que el nivel de dosis específico para un paciente dado depende de una diversidad de factores, que incluyen la actividad específica del compuesto administrado, la edad, el peso corporal, la salud, el sexo, la dieta, el tiempo y la vía de administración, la tasa de excreción, etc. Será apreciado adicionalmente por los expertos en la técnica que el curso óptimo del tratamiento, es decir, el modo de tratamiento y el número de diario de dosis de un compuesto de la invención o una sal farmacéuticamente aceptable del mismo durante un número definido de días, puede ser determinado por los expertos en la técnica utilizando ensayos de tratamiento convencionales.It will be appreciated by those skilled in the art who the particular method of administration will depend on a diversity of factors, all of which are routinely considered when They administer therapeutic treatments. It will also be appreciated by one skilled in the art that the specific dose level for a given patient depends on a variety of factors, which include the specific activity of the compound administered, age, weight body, health, sex, diet, time and route of administration, excretion rate, etc. It will be appreciated additionally by those skilled in the art that the optimal course of the treatment, that is, the mode of treatment and the number of daily dose of a compound of the invention or a salt pharmaceutically acceptable thereof for a defined number of days, can be determined by those skilled in the art using conventional treatment trials.

Se comprenderá, sin embargo, que el nivel específico de dosis para cualquier paciente particular dependerá de una diversidad de factores, que incluyen la actividad del compuesto específico empleado, la edad, el peso corporal, el estado general de salud, el sexo, la dieta, el tiempo de administración, la vía de administración y la tasa de excreción, la combinación de fármacos y la gravedad de la afección sometida a terapia.It will be understood, however, that the level Specific dose for any particular patient will depend on a variety of factors, which include the activity of the compound specific employee, age, body weight, general condition health, sex, diet, administration time, route of administration and excretion rate, the combination of drugs and the severity of the condition undergoing therapy.

Los compuestos se pueden producir a partir de compuestos conocidos (o de materias primas que, a su vez, pueden producirse a partir de compuestos conocidos), v.g., por los métodos generales de preparación que se muestran más adelante. La actividad de un compuesto dado para inhibir la quinasa raf puede ensayarse rutinariamente, v.g., de acuerdo con procedimientos descritos más adelante. Los ejemplos siguientes se proporcionan únicamente para propósitos ilustrativos y no tienen por objeto limitar en modo alguno la invención, ni deben interpretarse en dicho sentido.Compounds can be produced from known compounds (or raw materials that, in turn, can produced from known compounds), e.g., by the methods General preparation shown below. Activity of a given compound to inhibit raf kinase can be tested routinely, e.g., according to procedures described further ahead. The following examples are provided only for illustrative purposes and are not intended to limit in mode some of the invention, nor should they be interpreted in that sense.

Ejemplos Examples

Todas las reacciones se realizaron en material de vidrio secado a la llama o secado a la estufa bajo una presión positiva de argón seco o nitrógeno seco, y se agitaron magnéticamente a no ser que se indique otra cosa. Los líquidos y soluciones sensibles se transfirieron mediante jeringuilla o cánula, y se introdujeron en los recipientes de reacción a través de tapones de caucho. A no ser que se indique otra cosa, el término "concentración a presión reducida" se refiere al uso de un evaporador rotativo Buchi a aproximadamente 15 mmHg. A no ser que se indique otra cosa, el término "a alto vacío" se refiere a un vacío de 0,4-1,0 mmHg.All reactions were performed on material flame dried glass or stove dried under pressure positive of dry argon or dry nitrogen, and stirred magnetically unless otherwise indicated. Liquids and Sensitive solutions were transferred by syringe or cannula, and were introduced into the reaction vessels through rubber plugs Unless otherwise indicated, the term "concentration under reduced pressure" refers to the use of a Buchi rotary evaporator at approximately 15 mmHg. Unless I know state otherwise, the term "high vacuum" refers to a 0.4-1.0 mmHg vacuum.

Todas las temperaturas se expresan en grados Celsius (ºC) sin corregir. A no ser que se indique otra cosa, todas las partes y porcentajes se expresan en peso.All temperatures are expressed in degrees Celsius (ºC) uncorrected. Unless otherwise indicated, all Parts and percentages are expressed by weight.

Se utilizaron reactivos y disolventes de calidad comercial sin purificación ulterior. La N-ciclohexil-N'-(metilpo-
liestireno)carbodiimida se adquirió de Calbiochem-Novabiochem Corp. 3-terc-Butilanilina, 5-terc-butil-2-metoxianilina, 4-bromo-3-(trifluorometil)anilina, 4-cloro-3-(trifluorometil)anilina, 2-metoxi-5-(trifluorometil)anilina, 4-terc-butil-2-nitroanilina, 3-amino-2-naftol, 4-isocianatobenzoato de etilo, N-acetil-4-cloro-2-metoxi-5-(trifluorometil)anilina e isocianato de 4-cloro-3-(trifluorometil)fenilo se adquirieron y utilizaron sin purificación ulterior. Las síntesis de 3-amino-2-metoxiquinolina (E. Cho et al., documento WO 98/00402; A. Cordi et al., documento EP 542.609; IBID Bioorg. Med. Chem., 3, 1995, 129), 4-(3-carbamoilfenoxi)-1-nitrobenceno (K. Ikawa Yakugaku Zasshi 79, 1959, 760; Chem. Abstr. 53, 1959, 12761b), isocianato de 3-terc-butilfenilo (O. Rohr et al., documento DE 2.436.108) e isocianato de 2-metoxi-5-(trifluorometil)fenilo (K. Inukai et al., documento JP 42.025.067; IBID Kogyo Kagaku Zasshi 70, 1967, 491) han sido descritas previamente.Commercial grade reagents and solvents were used without further purification. N -cyclohexyl- N '- (methylpo-
Liestirene) carbodiimide was purchased from Calbiochem-Novabiochem Corp. 3- tert -Butilaniline, 5- tert -butyl-2-methoxyaniline, 4-bromo-3- (trifluoromethyl) aniline, 4-chloro-3- (trifluoromethyl) aniline, 2 -methoxy-5- (trifluoromethyl) aniline, 4- tert -butyl-2-nitroaniline, ethyl 3-amino-2-naphthol, 4-isocyanatobenzoate, N- acetyl-4-chloro-2-methoxy-5- (trifluoromethyl ) 4-Chloro-3- (trifluoromethyl) phenyl aniline and isocyanate were purchased and used without further purification. The synthesis of 3-amino-2-methoxyquinoline (E. Cho et al. , WO 98/00402; A. Cordi et al. , EP 542,609; IBID Bioorg. Med. Chem. , 3 , 1995 , 129), 4- (3-carbamoylphenoxy) -1-nitrobenzene (K. Ikawa Yakugaku Zasshi 79 , 1959 , 760; Chem. Abstr. 53 , 1959 , 12761b), 3- tert -butylphenyl isocyanate (O. Rohr et al. , Document DE 2,436,108) and 2-methoxy-5- (trifluoromethyl) phenyl isocyanate (K. Inukai et al. , JP 42,025,067; IBID Kogyo Kagaku Zasshi 70 , 1967 , 491) have been previously described.

La cromatografía en capa delgada (TLC) se realizó utilizando placas Whatman® de 250 \mum de gel de sílice 60A F-254 con respaldo de vidrio y recubiertas previamente. La visualización de las placas se efectuó por una o más de las técnicas siguientes: (a) iluminación ultravioleta, (b) exposición a vapor de yodo, (c) inmersión de la placa en una solución al 10% de ácido fosfomolíbdico en etanol seguida por calentamiento, (d) inmersión de la placa en una solución de sulfato de cerio seguida por calentamiento, y/o (e) inmersión de la placa en una solución etanólica ácida de 2,4-dinitrofenilhidrazina seguida por calentamiento. La cromatografía en columna (cromatografía súbita) se realizó utilizando gel de sílice EM Science® de mallas 230-400.Thin layer chromatography (TLC) was performed using Whatman® 250 µm silica gel 60A plates F-254 with glass and coated back previously. The plates were visualized by one or more of the following techniques: (a) ultraviolet lighting, (b) iodine vapor exposure, (c) immersion of the plate in a 10% solution of phosphomolibic acid in ethanol followed by heating, (d) immersion of the plate in a sulfate solution of cerium followed by heating, and / or (e) immersion of the plate in  an ethanolic acid solution of 2,4-dinitrophenylhydrazine followed by heating. Column chromatography (sudden chromatography) was performed using EM Science® mesh silica gel 230-400

Los puntos de fusión (pf) se determinaron utilizando un aparato de punto de fusión Thomas-Hoover o un aparato automático del punto de fusión Mettler FP66, y están sin corregir. Los espectros infrarrojos según la transformada de Fourier se obtuvieron utilizando un espectrofotómetro Mattson 4020 Galaxy Series. Los espectros de resonancia magnética nuclear (NMR) del protón (^{1}H) se midieron con un espectrómetro General Electric GN-Omega 300 (300 MHz) con Me_{4}Si (\delta 0,00) o disolvente residual protonizado (CHCl_{3}, \delta 7,26; MeOH \delta 3,30; DMSO \delta 2,49) como patrón. Los espectros NMR del carbono (^{13}C) se midieron con un espectrómetro General Electric GN-Omega 300 (75 MHz) con disolvente (CDCl_{3} \delta 77,0; MeOD-d_{3}; \delta 49,0; DMSO-d_{6} \delta 39,5) como patrón. Los espectros de masas (MS) de baja resolución y espectros de masas de alta resolución (HRMS) se obtuvieron como espectros de masas con impacto de electrones (EI) o como espectros de masas con bombardeo de átomos rápidos (FAB). Los espectros de masas con impacto de electrones (EI-MS) se obtuvieron con un espectrómetro de masas Hewlett Packard 5989A, equipado con una Sonda de Ionización Química por Desorción Vacumetrics para introducción de la muestra. La fuente de iones se mantuvo a 250ºC. La ionización por impacto de electrones se realizó con energía electrónica de 70 eV y una corriente de atrapamiento de 300 \muA. Los espectros de masas de ion secundario con cesio líquido (FAB-MS), una versión actualizada del bombardeo con átomos rápidos se obtuvieron utilizando un espectrómetro Kratos Concept 1-H. Los espectros de masas por ionización química (CI-MS) se obtuvieron utilizando un equipo Hewlett Packard MS-Engine (5989A) con metano o amoníaco como el gas reactivo (1 x 10^{-4} torr a 2,5 x 10^{-4} torr). La sonda de ionización química por desorción (DCI) de inserción directa (Vaccumetrics, Inc.) se intensificó desde 0 a 1,5 amps en 10 s y se mantuvo a 10 amps hasta que se separaron totalmente las trazas de la muestra (\sim1-2 min). Los espectros se escanearon desde 50 a 800 amu a 2 s por escaneo. Los espectros de masas HPLC-pulverización electrónica (HPLC ES-MS) se obtuvieron utilizando un instrumento Hewlett-Packard 1100 HPLC equipado con una bomba cuaternaria, un detector de longitud de onda variable, una columna C-18, y un espectrómetro de masas por atrapamiento de iones Finnigan LCQ con ionización por pulverización electrónica. Los espectros se escanearon desde 120 a 800 amu utilizando un tiempo de ionización variable de acuerdo con el número de iones en la fuente. Los espectros de masas con cromatografía de gases de iones selectivos (GC-MS) se obtuvieron con un cromatógrafo de gases Hewlett Packard 5890 equipado con una columna de metil-silicona HP-1 (recubrimiento 0,33 mM; 25 m x 0,2 mm) y un Detector Selectivo de Masas Hewlett Packard 5971 (energía de ionización 70 eV). Los análisis elementales fueron realizados por Robertson Microlit Labs, Madison, NJ.Melting points (mp) were determined using a melting point apparatus Thomas-Hoover or an automatic point device Mettler FP66 fusion, and are uncorrected. Infrared spectra according to the Fourier transform they were obtained using a Mattson 4020 Galaxy Series spectrophotometer. The spectra of Nuclear magnetic resonance imaging (NMR) of the proton (1 H) was measured with a General Electric GN-Omega 300 spectrometer (300 MHz) with Me 4 Si (δ 0.00) or residual solvent protonized (CHCl 3, δ 7.26; MeOH δ 3.30; DMSO δ 2.49) as standard. NMR spectra of carbon (13 C) were measured with a General Electric spectrometer GN-Omega 300 (75 MHz) with solvent (CDCl3) δ 77.0; MeOD-d 3; δ 49.0; DMSO-d_ {6} δ 39.5) as a standard. The Low resolution mass spectra (MS) and mass spectra of High resolution (HRMS) were obtained as mass spectra with electron impact (EI) or as mass spectra with bombardment of fast atoms (FAB). Mass spectra with impact of electrons (EI-MS) were obtained with a Hewlett Packard 5989A mass spectrometer, equipped with a Probe of Chemical Ionization by Desorption Vacumetrics for introduction of the sample. The ion source was maintained at 250 ° C. Ionization Electron impact was performed with 70 electronic energy eV and a trap current of 300 µA. The spectra of Secondary ion masses with liquid cesium (FAB-MS), an updated version of rapid atom bombardment will obtained using a Kratos Concept spectrometer 1 HOUR. Mass spectra by chemical ionization (CI-MS) were obtained using a Hewlett equipment Packard MS-Engine (5989A) with methane or ammonia as the reactive gas (1 x 10-4 torr at 2.5 x 10-4 torr). The chemical desorption ionization probe (DCI) insertion Direct (Vaccumetrics, Inc.) intensified from 0 to 1.5 amps in 10 s and kept at 10 amps until the sample traces (sim1-2 min). The specters They were scanned from 50 to 800 amu at 2 s per scan. The spectra of HPLC masses-electronic spray (HPLC ES-MS) were obtained using an instrument Hewlett-Packard 1100 HPLC equipped with a pump quaternary, a variable wavelength detector, a column C-18, and a entrapment mass spectrometer of Finnigan LCQ ions with electronic spray ionization. The spectra were scanned from 120 to 800 amu using a variable ionization time according to the number of ions in the fountain. Mass spectra with gas chromatography of Selective ions (GC-MS) were obtained with a Hewlett Packard 5890 gas chromatograph equipped with a column HP-1 methyl silicone (0.33 mM coating; 25 m x 0.2 mm) and a Selective Detector Hewlett Packard 5971 masses (ionization energy 70 eV). The Elemental analyzes were performed by Robertson Microlit Labs, Madison, NJ

Todos los compuestos exhibían espectros NMR, LRMS y análisis elementales o HRMS consistentes con las estructuras asignadas.All compounds exhibited NMR, LRMS spectra and elementary analysis or HRMS consistent with the structures assigned.

Lista de abreviaturas y acrónimosList of abbreviations and acronyms

AcOH AcOH
ácido acéticoacetic acid

anhanh
anhidroanhydrous

atmatm
atmósfera(s)atmosphere (s)

BOCBOC
terc-butoxicarbonilo tert -butoxycarbonyl

CDICDI
1,1'-carbonil-diimidazol1,1'-carbonyl diimidazole

concconc
concentradoconcentrated

dd
día(s)days)

DescDesc
descomposicióndecomposition

DMACDMAC
N,N-dimetilacetamida N, N- dimethylacetamide

DMPUDMPU
1,3-dimetil-3,4,5,6-tetrahidro-2(1H)-pirimidinona1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone

DMFDMF
N,N-dimetilformamida N, N- dimethylformamide

DMSODMSO
dimetilsulfóxidodimethylsulfoxide

DPPADPPA
difenilfosforil-azidadiphenylphosphoryl azide

EDCIEDCI
1-(3-dimetilaminopropil)-3-etilcarbodiimida1- (3-dimethylaminopropyl) -3-ethylcarbodiimide

EtOAcEtOAc
acetato de etiloethyl acetate

EtOHEtOH
etanol (100%)ethanol (100%)

Et_{2}OEt 2 O
dietil-éterdiethyl ether

Et_{3}NEt 3 N
trietilaminatriethylamine

hh
hora(s)hours)

HOBTHOBT
1-hidroxibenzotriazol1-hydroxybenzotriazole

m-CPBA m -CPBA
ácido 3-cloroperoxibenzoicoacid 3-chloroperoxybenzoic

MeOHMeOH
metanolmethanol

éter pet.pet ether
éter de petróleo (intervalo de ebullición 30-60ºCpetroleum ether (boiling range 30-60ºC

temp.temp.
temperaturatemperature

THFTHF
tetrahidrofuranotetrahydrofuran

TFATFA
ácido trifluoroacéticotrifluoroacetic acid

TfTf
trifluorometanosulfonilotrifluoromethanesulfonyl
A. Métodos Generales para la Síntesis de Anilinas SustituidasA. General Methods for Synthesis of Anilines Replaced A1. Método General para Formación de Aril-Aminas por Formación de Éter Seguida por Saponificación de Éster, Transposición de Curtius y Desprotección de Carbamato. Síntesis de 2-Amino-3-metoxinaftalenoA1. General Method for Training Aril-Amines by Ether Formation Followed by Saponification of Ester, Curtius Transposition and Deprotection of Carbamate Synthesis of 2-Amino-3-methoxynaphthalene

66

Paso 1He passed one

3-Metoxi-2-naftoato de metilo3-Methoxy-2-naphthoate of methyl

Una suspensión de 3-hidroxi-2-naftoato de metilo (10,1 g, 50,1 mmol) y K_{2}CO_{3} (7,96 g, 57,6 mmol) en DMF (200 ml) se agitó a la temperatura ambiente durante 15 min, y se trató luego con yodometano (3,43 ml, 55,1 mmol). La mezcla se dejó en agitación a la temperatura ambiente durante una noche, y se trató luego con agua (200 ml). La mezcla resultante se extrajo con EtOAc (2 x 200 ml). Las capas orgánicas reunidas se lavaron con una solución saturada de NaCl (100 ml), se secaron (MgSO_{4}), y se concentraron a presión reducida (aproximadamente 0,4 mmHg durante una noche) para dar 3-metoxi-2-naftoato de metilo como un aceite ambarino (10,30 g): ^{1}H-NMR (DMSO-d_{6}) \delta 2,70 (s, 3H), 2,85 (s, 3H), 7,38 (t app, J = 8,09 Hz, 1H), 7,44 (s, 1H), 7,53 (t app, J = 8,09 Hz, 1H), 7,84 (d, J = 8,09 Hz, 1H), 7,90 (s, 1H), 8,21 (s, 1H).A suspension of methyl 3-hydroxy-2-naphthoate (10.1 g, 50.1 mmol) and K 2 CO 3 (7.96 g, 57.6 mmol) in DMF (200 ml) is stirred at room temperature for 15 min, and then treated with iodomethane (3.43 ml, 55.1 mmol). The mixture was allowed to stir at room temperature overnight, and then treated with water (200 ml). The resulting mixture was extracted with EtOAc (2 x 200 ml). The combined organic layers were washed with a saturated NaCl solution (100 ml), dried (MgSO4), and concentrated under reduced pressure (approximately 0.4 mmHg overnight) to give 3-methoxy-2- methyl naphthoate as an amber oil (10.30 g): 1 H-NMR (DMSO-d 6) δ 2.70 (s, 3H), 2.85 (s, 3H), 7 , 38 (t app, J = 8.09 Hz, 1H), 7.44 (s, 1H), 7.53 (t app, J = 8.09 Hz, 1H), 7.84 (d, J = 8.09 Hz, 1H), 7.90 (s, 1H), 8.21 (s, 1H).

77

Paso 2He passed 2

Ácido 3-metoxi-2-naftoicoAcid 3-methoxy-2-naphthoic

Una solución de 3-metoxi-2-naftoato de metilo (6,28 g, 29,10 mmol) y agua (10 ml) en MeOH (100 ml) a la temperatura ambiente se trató con una solución 1N de NaOH (33,4 ml, 33,4 mmol). La mezcla se calentó a la temperatura de reflujo durante 3 h, se enfrió a la temperatura ambiente, y se acidificó con una solución de ácido cítrico al 10%. La solución resultante se extrajo con EtOAc (2 x 100 ml). Las capas orgánicas reunidas se lavaron con una solución saturada de NaCl, se secaron (MgSO_{4}), y se concentraron a presión reducida. El residuo se trituró con hexano y se lavó luego varias veces con hexano para dar ácido 3-metoxi-2-naftoico como un sólido blanco (5,40 g, 92%): ^{1}H-NMR (DMSO-d_{6}) \delta 3,88 (s, 3H), 7,34-7,41 (m, 2H), 7,49-7,54 (m, 1H), 7,83 (d, J = 8,09 Hz, 1H), 7,91 (d, J = 8,09 Hz, 1H), 8,19 (s, 1H), 12,83 (br s, 1H).A solution of methyl 3-methoxy-2-naphthoate (6.28 g, 29.10 mmol) and water (10 ml) in MeOH (100 ml) at room temperature was treated with a 1N solution of NaOH (33, 4 ml, 33.4 mmol). The mixture was heated at reflux temperature for 3 h, cooled to room temperature, and acidified with a 10% citric acid solution. The resulting solution was extracted with EtOAc (2 x 100 ml). The combined organic layers were washed with a saturated NaCl solution, dried (MgSO4), and concentrated under reduced pressure. The residue was triturated with hexane and then washed several times with hexane to give 3-methoxy-2-naphthoic acid as a white solid (5.40 g, 92%): 1 H-NMR (DMSO-d_ { 6}) δ 3.88 (s, 3H), 7.34-7.41 (m, 2H), 7.49-7.54 (m, 1H), 7.83 (d, J = 8, 09 Hz, 1H), 7.91 (d, J = 8.09 Hz, 1H), 8.19 (s, 1H), 12.83 (br s, 1H).

88

Paso 3He passed 3

2-(N-(Carbobenciloxi)amino-3-metoxinaftaleno 2- ( N - (Carbobenzyloxy) amino-3-methoxynaphthalene

Una solución de ácido 3-metoxi-2-naftoico (3,36 g, 16,6 mmol) y Et_{3}N (2,59 ml, 18,6 mmol) en tolueno anh (70 ml) se agitó a la temperatura ambiente durante 15 min, y se trató luego con una solución de DPPA (5,12 g, 18,6 mmol) en tolueno (10 ml) por la vía de una pipeta. La mezcla resultante se calentó a 80ºC durante 2 h. Después de enfriar la mezcla a la temperatura ambiente, se añadió alcohol bencílico (2,06 ml, 20 mmol) mediante una jeringuilla. La mezcla se calentó luego a 80ºC durante una noche. La mezcla resultante se enfrió a la temperatura ambiente, se extinguió con una solución de ácido cítrico al 10%, y se extrajo con EtOAc (2 x 100 ml). Las capas orgánicas reunidas se lavaron con una solución saturada de NaCl, se secaron (MgSO_{4}) y se concentraron a presión reducida. El residuo se purificó por cromatografía en columna (14% EtOAc/86% hexano) para dar 2-(N-(carbobenciloxi)amino-3-metoxinaftaleno como un aceite amarillo pálido (5,1 g, 100%): ^{1}H-NMR (DMSO-d_{6}) \delta 3,89 (s, 3H), 5,17 (s, 2H), 7,27-7,44 (m, 8H), 7,72-7,75 (m, 2H), 8,20 (s, 1H), 8,76 (s, 1H).A solution of 3-methoxy-2-naphthoic acid (3.36 g, 16.6 mmol) and Et 3 N (2.59 ml, 18.6 mmol) in toluene anh (70 ml) was stirred at room temperature for 15 min, and then treated with a solution of DPPA (5.12 g, 18.6 mmol) in toluene (10 ml) via a pipette. The resulting mixture was heated at 80 ° C for 2 h. After cooling the mixture to room temperature, benzyl alcohol (2.06 ml, 20 mmol) was added by syringe. The mixture was then heated at 80 ° C overnight. The resulting mixture was cooled to room temperature, quenched with a 10% citric acid solution, and extracted with EtOAc (2 x 100 ml). The combined organic layers were washed with a saturated NaCl solution, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by column chromatography (14% EtOAc / 86% hexane) to give 2- ( N - (carbobenzyloxy) amino-3-methoxynaphthalene as a pale yellow oil (5.1 g, 100%): 1 } H-NMR (DMSO-d6) δ 3.89 (s, 3H), 5.17 (s, 2H), 7.27-7.44 (m, 8H), 7.72-7 , 75 (m, 2H), 8.20 (s, 1H), 8.76 (s, 1H).

99

Paso 4He passed 4

2-Amino-3-metoxinaftaleno 2-Amino-3-methoxynaphthalene

Una suspensión de 2-(N-(carbobenciloxi)amino-3-metoxinaftaleno (5,0 g, 16,3 mmol) y Pd/C al 10% (0,5 g) en EtOAc (70 ml) se mantuvo bajo una atm de H_{2} (balón) a la temperatura ambiente durante una noche. La mezcla resultante se filtró a través de Celite® y se concentró a presión reducida para dar 2-amino-3-metoxinaftaleno como un polvo de color rosa pálido (2,40 g, 85%): ^{1}H-NMR (DMSO-d_{6}) \delta 3,86 (s, 3H), 6,86 (s, 2H), 7,04-7,16 (m, 2H), 7,43 (d, J = 8,0 Hz, 1H), 7,56 (d, J = 8,0, 1H); EI-MS m/z 173 (M^{+}).A suspension of 2- ( N - (carbobenzyloxy) amino-3-methoxynaphthalene (5.0 g, 16.3 mmol) and 10% Pd / C (0.5 g) in EtOAc (70 ml) was kept under atm of H2 (balloon) at room temperature overnight The resulting mixture was filtered through Celite® and concentrated under reduced pressure to give 2-amino-3-methoxynaphthalene as a pale pink powder ( 2.40 g, 85%): 1 H-NMR (DMSO-d 6) δ 3.86 (s, 3H), 6.86 (s, 2H), 7.04-7, 16 (m, 2H), 7.43 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 8.0, 1H); EI-MS m / z 173 (M + }).

A2. Síntesis de \omega-Carbamil-Anilinas por Formación de una Carbamilpiridina Seguida por Acoplamiento Nucleófilo con una Aril-Amina. Síntesis de 4-(2-N-Metilcarbamil-4-piridiloxi)AnilinaA2. Synthesis of?-Carbamil-Anilines by Formation of a Carbamilpiridine Followed by Nucleophilic Coupling with an Aryl-Amine. Synthesis of 4- (2- N- Methylcarbamil-4-pyridyloxy) Aniline

1010

Paso 1aHe passed 1st

Síntesis de 4-Cloro-N-metil-2-piridinacarboxamida por la reacción de MenisciSynthesis of 4-Chloro- N -methyl-2-pyridinecarboxamide by the Menisci reaction

Precaución: Ésta es una reacción muy peligrosa, potencialmente explosiva. A una solución mantenida en agitación de 4-cloropiridina (10,0 g) en N-metilformamida (250 ml) a la temperatura ambiente, se añadió H_{2}SO_{4} conc. (3,55 ml) para generar una exotermia. Se añadió a esta mezcla H_{2}O_{2} (al 30% en peso en H_{2}O, 17 ml) seguido por FeSO_{4}·7H_{2}O (0,56 g) para generar otra exotermia. La mezcla resultante se agitó en la oscuridad a la temperatura ambiente durante 1 h, y se calentó luego lentamente durante 4 h a 45ºC. Cuando hubo disminuido el borboteo, se calentó la mezcla de reacción a 60ºC durante 16 h. La solución resultante opaca de color pardo se diluyó con H_{2}O (700 ml) seguido por una solución de NaOH al 10% (250 ml). La mezcla resultante se extrajo con EtOAc (3 x 500 ml). Las fases orgánicas se lavaron por separado con una solución saturada de NaCl (3 x 150 ml), se combinaron luego, se secaron (MgSO_{4}) y se filtraron a través de un taco de gel de sílice con ayuda de EtOAc. El aceite pardo resultante se purificó por cromatografía en columna (gradiente desde 50% EtOAc/50% hexano a 80% EtOAc/20% hexano). El aceite amarillo resultante cristalizó a 0ºC durante 72 h para dar 4-cloro-N-metil-2-piridinacarboxamida (0,61 g, 5,3%): TLC (50% EtOAc/50% hexano) R_{f} 0,50; ^{1}H-NMR (CDCl_{3}) \delta 3,04 (d, J = 5,1 Hz, 3H), 7,43 (dd, J = 5,4, 2,4 Hz, 1H), 7,96 (br s, 1H), 8,21 (s, 1H), 8,44 (d, J = 5,1 Hz, 1H); CI-MS m/z 171 ((M+H)^{+}). Caution : This is a very dangerous, potentially explosive reaction. To a stirred solution of 4-chloropyridine (10.0 g) in N- methylformamide (250 ml) at room temperature, conc. H 2 SO 4 was added. (3.55 ml) to generate an exotherm. H2O2 (30% by weight in H2O, 17 ml) was added to this mixture followed by FeSO4 · 7H2O (0.56 g) to generate another exotherm The resulting mixture was stirred in the dark at room temperature for 1 h, and then slowly heated for 4 h at 45 ° C. When the bubbling had decreased, the reaction mixture was heated at 60 ° C for 16 h. The resulting opaque brown solution was diluted with H2O (700 ml) followed by a 10% NaOH solution (250 ml). The resulting mixture was extracted with EtOAc (3 x 500 ml). The organic phases were washed separately with a saturated solution of NaCl (3 x 150 ml), then combined, dried (MgSO 4) and filtered through a pad of silica gel with the aid of EtOAc. The resulting brown oil was purified by column chromatography (gradient from 50% EtOAc / 50% hexane to 80% EtOAc / 20% hexane). The resulting yellow oil crystallized at 0 ° C for 72 h to give 4-chloro- N- methyl-2-pyridinecarboxamide (0.61 g, 5.3%): TLC (50% EtOAc / 50% hexane) R f 0 ,fifty; 1 H-NMR (CDCl 3) δ 3.04 (d, J = 5.1 Hz, 3H), 7.43 (dd, J = 5.4, 2.4 Hz, 1H) , 7.96 (br s, 1H), 8.21 (s, 1H), 8.44 (d, J = 5.1 Hz, 1H); CI-MS m / z 171 ((M + H) +).

11eleven

Paso 1bHe passed 1 B

Síntesis de la sal cloruro de 4-cloropiridina-2-carbonilo.HCl por la vía del ácido picolínicoSynthesis of the chloride salt of 4-chloropyridine-2-carbonyl.HCl via picolinic acid

Se añadió lentamente DMF anhidra (6,0 ml) a SOCl_{2} (180 ml) entre 40º y 50ºC. La solución se agitó en dicho intervalo de temperatura durante 10 min, y se añadió luego ácido picolínico (60,0 g, 487 mmol) en porciones durante 30 min. La solución resultante se calentó a 72ºC (desprendimiento enérgico de SO_{2}) durante 16 h para generar un precipitado sólido amarillo. La mezcla resultante se enfrió a la temperatura ambiente, se diluyó con tolueno (500 ml) y se concentró a 200 ml. El proceso de adición de tolueno/concentración se repitió dos veces. El residuo prácticamente seco resultante se filtró y los sólidos se lavaron con tolueno (2 x 200 ml) y se secaron a alto vacío durante 4 h para proporcionar la sal cloruro de 4-cloropiridina-2-carbonilo.HCl como un sólido amarillo-anaranjado (92,0 g, 89%).Anhydrous DMF (6.0 ml) was added slowly to SOCl 2 (180 ml) between 40 ° and 50 ° C. The solution was stirred in said temperature range for 10 min, and then acid was added picolinic (60.0 g, 487 mmol) in portions for 30 min. The resulting solution was heated to 72 ° C (vigorous release of SO2) for 16 h to generate a yellow solid precipitate. The resulting mixture was cooled to room temperature, diluted with toluene (500 ml) and concentrated to 200 ml. The addition process of toluene / concentration was repeated twice. The residue The resulting practically dry was filtered and the solids washed with toluene (2 x 200 ml) and dried under high vacuum for 4 h to provide the chloride salt of 4-chloropyridine-2-carbonyl.HCl  as a yellow-orange solid (92.0 g, 89%).

1212

Paso 2He passed 2

Síntesis de la sal 4-cloropiridina-2-carboxilato de metilo.HClSalt Synthesis 4-chloropyridine-2-carboxylate methyl.HCl

Se añadió lentamente DMF anh (10,0 ml) a SOCl_{2} (300 ml) a 40-48ºC. La solución se agitó en dicho intervalo de temperatura durante 10 min, y se añadió luego ácido picolínico (100 g, 812 mmol) durante 30 min. La solución resultante se calentó a 72ºC (desprendimiento enérgico de SO_{2}) durante 16 h para generar un sólido amarillo. La mezcla resultante se enfrió a la temperatura ambiente, se diluyó con tolueno (500 ml) y se concentró a 200 ml. El proceso de adición de tolueno/concentración se repitió dos veces. El residuo prácticamente seco resultante se filtró, y los sólidos se lavaron con tolueno (50 ml) y se secaron a alto vacío durante 4 horas para proporcionar la sal cloruro de 4-cloropiridina-2-carbonilo.HCl como un sólido blanquecino (27,2 g, 16%). Este material se dejó aparte.DMF anh (10.0 ml) was slowly added to SOCl 2 (300 ml) at 40-48 ° C. The solution was stirred. in said temperature range for 10 min, and then added picolinic acid (100 g, 812 mmol) for 30 min. The solution resulting was heated to 72 ° C (strong release of SO2) for 16 h to generate a yellow solid. The resulting mixture cooled to room temperature, diluted with toluene (500 ml) and concentrated to 200 ml. The process of adding Toluene / concentration was repeated twice. The residue practically  The resulting dry was filtered, and the solids were washed with toluene (50 ml) and dried under high vacuum for 4 hours to provide the chloride salt 4-chloropyridine-2-carbonyl.HCl as an off-white solid (27.2 g, 16%). This material was left apart.

El filtrado de color rojo se añadió a MeOH (200 ml) a una tasa tal que mantenía la temperatura interna por debajo de 55ºC. Los contenidos se agitaron a la temperatura ambiente durante 45 min, se enfriaron a 5ºC y se trataron con Et_{2}O (200 ml) gota a gota. Los sólidos resultantes se filtraron, se lavaron con Et_{2}O (200 ml) y se secaron a presión reducida a 35ºC para proporcionar la sal 4-cloropiridina-2-carboxilato.HCl como un sólido blanco (110 g, 65%): pf 108-112ºC; ^{1}H-NMR (DMSO-d_{6}) \delta 3,88 (s, 3H); 7,82 (dd, J = 5,5, 2,2 Hz, 1H), 8,08 (d, J = 2,2 Hz, 1H), 8,68 (d, J = 5,5 Hz, 1H); 10,63 (br s, 1H); HPLC ES-MS m/z 172 ((M+H)^{+}).The red filtrate was added to MeOH (200 ml) at a rate that kept the internal temperature below 55 ° C. The contents were stirred at room temperature for 45 min, cooled to 5 ° C and treated with Et2O (200 ml) dropwise. The resulting solids were filtered, washed with Et2O (200 ml) and dried under reduced pressure at 35 ° C to provide the 4-chloropyridine-2-carboxylate.HCl salt as a white solid (110 g, 65%) : mp 108-112 ° C; 1 H-NMR (DMSO-d 6) δ 3.88 (s, 3H); 7.82 (dd, J = 5.5, 2.2 Hz, 1H), 8.08 (d, J = 2.2 Hz, 1H), 8.68 (d, J = 5.5 Hz, 1H ); 10.63 (br s, 1 H); HPLC ES-MS m / z 172 ((M + H) +).

1313

Paso 3aHe passed 3rd

Síntesis de 4-cloro-N-metil-2-piridinacarboxamida a partir de 4-cloropiridina-2-carboxilato de metiloSynthesis of methyl 4-chloro- N -methyl-2-pyridinecarboxamide from 4-chloropyridine-2-carboxylate

Una suspensión de sal 4-cloropiridina-2-carboxilato de metilo.HCl (89,0 g, 428 mmol) en MeOH (75 ml) a 0ºC se trató con una solución 2,00 M de metilamina en THF (1 l) a una tasa que mantenía la temperatura interna por debajo de 5ºC. La mezcla resultante se guardó a 3ºC durante 5 h, y se concentró luego a presión reducida. Los sólidos resultantes se suspendieron en EtOAc (1 l) y se filtraron. El filtrado se lavó con una solución saturada de NaCl (500 ml), se secó (Na_{2}SO_{4}) y se concentró a presión reducida para proporcionar 4-cloro-N-metil-2-piridinacarboxamida como cristales de color amarillo pálido (71,2 g, 97%): pf 41-42ºC; ^{1}H-NMR (DMSO-d_{6}) \delta 2,81 (s, 3H), 7,74 (dd, J = 5,1, 2,2 Hz, 1H), 8,00 (d, J = 2,2, 1H), 8,61 (d, J = 5,1 Hz, 1H), 8,85 (br d, 1H); CI-MS m/z 171 ((M+H)^{+}).A suspension of methyl 4-chloropyridine-2-carboxylate salt. HCl (89.0 g, 428 mmol) in MeOH (75 mL) at 0 ° C was treated with a 2.00 M solution of methylamine in THF (1 L) at a rate that kept the internal temperature below 5 ° C. The resulting mixture was stored at 3 ° C for 5 h, and then concentrated under reduced pressure. The resulting solids were suspended in EtOAc (1 L) and filtered. The filtrate was washed with a saturated NaCl solution (500 ml), dried (Na2SO4) and concentrated under reduced pressure to provide 4-chloro- N- methyl-2-pyridinecarboxamide as colored crystals. pale yellow (71.2 g, 97%): mp 41-42 ° C; 1 H-NMR (DMSO-d 6) δ 2.81 (s, 3H), 7.74 (dd, J = 5.1, 2.2 Hz, 1H), 8.00 ( d, J = 2.2, 1H), 8.61 (d, J = 5.1 Hz, 1H), 8.85 (br d, 1H); CI-MS m / z 171 ((M + H) +).

1414

Paso 3bHe passed 3b

Síntesis de 4-cloro-N-metil-2-piridinacarboxamida a partir de cloruro de 4-cloropiridina-2-carboniloSynthesis of 4-chloro- N- methyl-2-pyridinecarboxamide from 4-chloropyridine-2-carbonyl chloride

Se añadió sal cloruro de 4-cloropiridina-2-carbo-nilo.HCl (7,0 g, 32,95 mmol) en porciones a una mezcla de una solución 2,0 M de metilamina en THF (100 ml) y MeOH (20 ml) a 0ºC. La mezcla resultante se guardó a 3ºC durante 4 h y se concentró luego a presión reducida. Los sólidos prácticamente secos resultantes se suspendieron en EtOAc (100 ml) y se filtraron. El filtrado se lavó con una solución saturada de NaCl (2 x 100 ml), se secó (Na_{2}SO_{4}) y se concentró a presión reducida para proporcionar 4-cloro-N-metil-2-piridinacarboxamida como un sólido amarillo cristalino (4,95 g, 88%): pf 37-40ºC.Salt of 4-chloropyridine-2-carbo-nyl chloride.HCl (7.0 g, 32.95 mmol) was added portionwise to a mixture of a 2.0 M solution of methylamine in THF (100 ml) and MeOH ( 20 ml) at 0 ° C. The resulting mixture was stored at 3 ° C for 4 h and then concentrated under reduced pressure. The resulting practically dry solids were suspended in EtOAc (100 ml) and filtered. The filtrate was washed with a saturated NaCl solution (2 x 100 ml), dried (Na2SO4) and concentrated under reduced pressure to provide 4-chloro- N- methyl-2-pyridinecarboxamide as a crystalline yellow solid (4.95 g, 88%): mp 37-40 ° C.

15fifteen

Paso 4He passed 4

Síntesis de 4-(2-(N-metilcarbamoil)-4-piridiloxi)anilinaSynthesis of 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) aniline

Una solución de 4-aminofenol (9,60 g, 88,0 mmol) en DMF anh. (150 ml) se trató con terc-butóxido de potasio (10,29 g, 91,7 mmol), y la mezcla de color pardo rojizo se agitó a la temperatura ambiente durante 2 h. El contenido se trató con 4-cloro-N-metil-2-piridinacarboxamida (15,0 g, 87,9 mmol) y K_{2}CO_{3} (6,50 g, 47,0 mmol) y se calentó luego a 80ºC durante 8 h. La mezcla se enfrió a la temperatura ambiente y se separó entre EtOAc (500 ml) y una solución saturada de NaCl (500 ml). La fase acuosa se extrajo de nuevo con EtOAc (300 ml). Las capas orgánicas reunidas se lavaron con una solución saturada de NaCl (4 x 1000 ml), se secaron (Na_{2}SO_{4}) y se concentraron a presión reducida. Los sólidos resultantes se secaron a presión reducida a 35ºC durante 3 h para proporcionar 4-(2-(N-metilcarbamoil)-4-piridiloxi)anilina como un sólido de color pardo claro, (17,9 g, 84%): ^{1}H-NMR (DMSO-d_{6}) \delta 2,77 (d, J = 4,8 Hz, 3H), 5,17 (br s, 2H), 6,64-6,86 (cuartete AA'BB', J = 8,4 Hz, 4H), 7,06 (dd, J = 5,5, 2,5 Hz, 1H), 7,33 (d, J = 2,5 Hz, 1H), 8,44 (d, J = 5,5 Hz, 1H), 8,73 (br d, 1H); HPLC ES-MS m/z 244 ((M+H)^{+}).A solution of 4-aminophenol (9.60 g, 88.0 mmol) in DMF anh. (150 ml) was treated with potassium tert -butoxide (10.29 g, 91.7 mmol), and the reddish brown mixture was stirred at room temperature for 2 h. The content was treated with 4-chloro- N- methyl-2-pyridinecarboxamide (15.0 g, 87.9 mmol) and K 2 CO 3 (6.50 g, 47.0 mmol) and heated then at 80 ° C for 8 h. The mixture was cooled to room temperature and separated between EtOAc (500 ml) and a saturated NaCl solution (500 ml). The aqueous phase was extracted again with EtOAc (300 ml). The combined organic layers were washed with a saturated NaCl solution (4 x 1000 ml), dried (Na2SO4) and concentrated under reduced pressure. The resulting solids were dried under reduced pressure at 35 ° C for 3 h to provide 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline as a light brown solid, (17.9 g, 84%): ^ {1} H-NMR (DMSO-d6) δ 2.77 (d, J = 4.8 Hz, 3H), 5.17 (br s, 2H), 6.64-6.86 ( Quartet AA'BB ', J = 8.4 Hz, 4H), 7.06 (dd, J = 5.5, 2.5 Hz, 1H), 7.33 (d, J = 2.5 Hz, 1H ), 8.44 (d, J = 5.5 Hz, 1H), 8.73 (br d, 1H); HPLC ES-MS m / z 244 ((M + H) +).

A3. Método General para la Síntesis de Anilinas por Adición Aromática Nucleófila Seguida por Reducción de Nitroareno. Síntesis de 5-(4-aminofenoxi)isoindolina-1,3-dionaA3. General Method for the Synthesis of Anilines by Nucleophilic Aromatic Addition Followed by Nitroarene Reduction. Synthesis of 5- (4-aminophenoxy) isoindoline-1,3-dione

1616

Paso 1He passed one

Síntesis de 5-hidroxiisoindolina-1,3-dionaSynthesis of 5-hydroxyisoindoline-1,3-dione

A una mezcla de carbonato de amonio (5,28 g, 54,9 mmol) en AcOH conc. (25 ml) se añadió lentamente ácido 4-hidroxiftálico (5,0 g, 27,45 mmol). La mezcla resultante se calentó a 120ºC durante 45 min, y a continuación la mezcla clara de color amarillo brillante se calentó a 160ºC durante 2 h. La mezcla resultante se mantuvo a 160ºC y se concentró a aproximadamente 15 ml, se enfrió luego a la temp. ambiente y se ajustó a pH 10 con una solución 1N de NaOH. Esta mezcla se enfrió a 0ºC y se acidificó lentamente a pH 5 utilizando una solución 1N de HCl. El precipitado resultante se recogió por filtración y se secó a presión reducida para dar 5-hidroxiisoindolina-1,3-diona como un polvo de color amarillo pálido como producto (3,24 g, 72%): ^{1}H-NMR (DMSO-d_{6}) \delta 7,00-7,03 (m, 2H), 7,56 (d, J = 9,3 Hz, 1H).To a mixture of ammonium carbonate (5.28 g, 54.9 mmol) in conc. AcOH. (25 ml) 4-hydroxyxtalic acid (5.0 g, 27.45 mmol) was added slowly. The resulting mixture was heated at 120 ° C for 45 min, and then the clear bright yellow mixture was heated at 160 ° C for 2 h. The resulting mixture was maintained at 160 ° C and concentrated to approximately 15 ml, then cooled to temp. ambient and adjusted to pH 10 with a 1N NaOH solution. This mixture was cooled to 0 ° C and slowly acidified to pH 5 using a 1N HCl solution. The resulting precipitate was collected by filtration and dried under reduced pressure to give 5-hydroxyisoindoline-1,3-dione as a pale yellow powder as product (3.24 g, 72%): 1 H-NMR (DMSO-d 6) δ 7.00-7.03 (m, 2H), 7.56 (d, J = 9.3 Hz, 1H).

1717

Paso 2He passed 2

Síntesis de 5-(4-nitrofenoxi)isoindolina-1,3-dionaSynthesis of 5- (4-nitrophenoxy) isoindoline-1,3-dione

A una suspensión de NaH (1,1 g, 44,9 mmol) en DMF (40 ml) mantenida en agitación a 0ºC se añadió una solución de 5-hidroxiisoindolina-1,3-diona (3,2 g, 19,6 mmol) en DMF (40 ml) gota a gota. La mezcla brillante de color amarillo-verde se dejó volver a la temperatura ambiente y se agitó durante 1 h, después de lo cual se añadió 1-fluoro-4-nitrobenceno (2,67 g, 18,7 mmol) mediante una jeringuilla en 3-4 porciones. La mezcla resultante se calentó a 70ºC durante una noche, se enfrió luego a la temp. ambiente y se diluyó lentamente con agua (150 ml), después de lo cual se extrajo con EtOAc (2 x 100 ml). Las capas orgánicas reunidas se secaron (MgSO_{4}) y se concentraron a presión reducida para dar 5-(4-nitrofenoxi)-isoindolina-1,3-diona como un sólido amarillo (3,3 g, 62%): TLC (30% EtOAc/70% hexano) R_{f} 0,28; ^{1}H-NMR (DMSO-d_{6}) \delta 7,32 (d, J = 12 Hz, 2H), 7,52-7,57 (m, 2H), 7,89 (d, J = 7,8 Hz, 1H), 8,29 (d, J = 9 Hz, 2H), 11,43 (br s, 1H); CI-MS m/z 285 ((M+H)^{+}, 100%).To a suspension of NaH (1.1 g, 44.9 mmol) in DMF (40 ml) maintained under stirring at 0 ° C was added a solution of 5-hydroxyisoindoline-1,3-dione (3.2 g, 19.6 mmol) in DMF (40 ml) dropwise. The bright yellow-green mixture was allowed to return to room temperature and stirred for 1 h, after which 1-fluoro-4-nitrobenzene (2.67 g, 18.7 mmol) was added by syringe into 3-4 servings The resulting mixture was heated at 70 ° C overnight, then cooled to temp. ambient and slowly diluted with water (150 ml), after which it was extracted with EtOAc (2 x 100 ml). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to give 5- (4-nitrophenoxy) -isoindoline-1,3-dione as a yellow solid (3.3 g, 62%): TLC (30% EtOAc / 70% hexane) R f 0.28; 1 H-NMR (DMSO-d 6) δ 7.32 (d, J = 12 Hz, 2H), 7.52-7.57 (m, 2H), 7.89 (d, J = 7.8 Hz, 1H), 8.29 (d, J = 9 Hz, 2H), 11.43 (br s, 1H); CI-MS m / z 285 ((M + H) +, 100%).

1818

Paso 3He passed 3

Síntesis de 5-(4-aminofenoxi)isoindolina-1,3-dionaSynthesis of 5- (4-aminophenoxy) isoindoline-1,3-dione

Una solución de 5-(4-nitrofenoxi)isoindolina-1,3-diona (0,6 g, 2,11 mmol) en AcOH conc. (12 ml) y agua (0,1 ml) se agitó en corriente de argón mientras se añadía lentamente hierro en polvo (0,59 g, 55,9 mmol). Esta mezcla se agitó a la temperatura ambiente durante 72 h, se diluyó luego con agua (25 ml) y se extrajo con EtOAc (3 x 50 ml). Las capas orgánicas reunidas se secaron (MgSO_{4}) y se concentraron a presión reducida para dar 5-(4-aminofenoxi)isoindolina-1,3-diona como un sólido pardusco (0,4 g, 75%): TLC (50% EtOAc/50% hexano) R_{f} 0,27; ^{1}H-NMR (DMSO-d_{6}) \delta 5,14 (br s, 2H), 6,62 (d, J = 8,7 Hz, 2H), 6,84 (d, J = 8,7 Hz, 2H), 7,03 (d, J = 2,1 Hz, 1H), 7,23 (dd, 1H), 7,75 (d, J = 8,4 Hz, 1H), 11,02 (s, 1H); HPLC ES-MS m/z 255 ((M+H)^{+}, 100%).A solution of 5- (4-nitrophenoxy) isoindoline-1,3-dione (0.6 g, 2.11 mmol) in conc. AcOH. (12 ml) and water (0.1 ml) was stirred under argon while slowly adding powdered iron (0.59 g, 55.9 mmol). This mixture was stirred at room temperature for 72 h, then diluted with water (25 ml) and extracted with EtOAc (3 x 50 ml). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to give 5- (4-aminophenoxy) isoindoline-1,3-dione as a brownish solid (0.4 g, 75%): TLC ( 50% EtOAc / 50% hexane) R f 0.27; 1 H-NMR (DMSO-d 6) δ 5.14 (br s, 2H), 6.62 (d, J = 8.7 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H), 7.03 (d, J = 2.1 Hz, 1H), 7.23 (dd, 1H), 7.75 (d, J = 8.4 Hz, 1H), 11.02 (s, 1 H); HPLC ES-MS m / z 255 ((M + H) +, 100%).

A4. Método General para la Síntesis de Pirrolilanilinas. Síntesis de 5-terc-butil-2-(2,5-dimetilpirrolil)-anilinaA4. General Method for the Synthesis of Pyrrolylanilines. Synthesis of 5- tert -butyl-2- (2,5-dimethylpyrrolyl) -aniline

1919

Paso 1He passed one

Síntesis de 1-(4-terc-butil-2-nitrofenil)-2,5-dimetilpirrolSynthesis of 1- (4- tert -butyl-2-nitrophenyl) -2,5-dimethylpyrrole

A una solución de 2-nitro-4-terc-butilanilina (0,5 g, 2,57 mmol) mantenida en agitación en ciclohexano (10 ml) se añadieron AcOH (0,1 ml) y acetonilacetona (0,299 g, 2,63 mmol) por medio de una jeringuilla. La mezcla de reacción se calentó a 120ºC durante 72 h con separación azeotrópica de las materias volátiles. La mezcla de reacción se enfrió a la temperatura ambiente, se diluyó con CH_{2}Cl_{2} (10 ml) y se lavó secuencialmente con una solución 1N de HCl (15 ml), una solución 1N de NaOH (15 ml) y una solución saturada de NaCl (15 ml), se secó (MgSO_{4}) y se concentró a presión reducida. Los sólidos de color pardo anaranjado resultantes se purificaron por cromatografía en columna (60 g de SiO_{2}; gradiente desde 6% EtOAc/94% hexano a 25% EtOAc/75% hexano) para dar 1-(4-terc-butil-2-nitrofenil)-2,5-dimetilpirrol como un sólido anaranjado-amarillo (0,34 g, 49%): TLC (15% EtOAc/85% hexano) R_{f} 0,67; ^{1}H-NMR (CDCl_{3}) \delta 1,34 (s, 9H), 1,89 (s, 6H), 5,84 (s, 2H), 7,19-7,24 (m, 1H), 7,62 (dd, 1H), 7,88 (d, J = 2,4 Hz, 1H); CI-MS m/z 273 ((M+H)^{+}, 50%).To a solution of 2-nitro-4- tert -butylaniline (0.5 g, 2.57 mmol) maintained under stirring in cyclohexane (10 ml) were added AcOH (0.1 ml) and acetonylacetone (0.299 g, 2, 63 mmol) by means of a syringe. The reaction mixture was heated at 120 ° C for 72 h with azeotropic separation of volatile materials. The reaction mixture was cooled to room temperature, diluted with CH2Cl2 (10 ml) and washed sequentially with a 1N solution of HCl (15 ml), a 1N solution of NaOH (15 ml) and a saturated solution of NaCl (15 ml), dried (MgSO4) and concentrated under reduced pressure. The resulting orange-brown solids were purified by column chromatography (60 g of SiO2; gradient from 6% EtOAc / 94% hexane to 25% EtOAc / 75% hexane) to give 1- (4- tert -butyl) -2-nitrophenyl) -2,5-dimethylpyrrole as an orange-yellow solid (0.34 g, 49%): TLC (15% EtOAc / 85% hexane) R f 0.67; 1 H-NMR (CDCl 3) δ 1.34 (s, 9H), 1.89 (s, 6H), 5.84 (s, 2H), 7.19-7.24 ( m, 1H), 7.62 (dd, 1H), 7.88 (d, J = 2.4 Hz, 1H); CI-MS m / z 273 ((M + H) +, 50%).

20twenty

Paso 2He passed 2

Síntesis de 5-terc-butil-2-(2,5-dimetilpirrolil)-anilinaSynthesis of 5- tert -butyl-2- (2,5-dimethylpyrrolyl) -aniline

Una suspensión de 1-(4-terc-butil-2-nitrofenil)-2,5-dimetilpirrol (0,341 g, 1,25 mmol), Pd/C al 10% (0,056 g) y EtOAc (50 ml) en atmósfera de H_{2} (balón) se agitó durante 72 h, y se filtró luego a través de un taco de Celite®. El filtrado se concentró a presión reducida para dar 5-terc-butil-2-(2,5-dimetilpirrolil)anilina como sólidos amarillentos (0,30 g, 99%): TLC (10% EtOAc/90% hexano) R_{f} 0,43; ^{1}H-NMR (CDCl_{3}) \delta 1,28 (s, 9H), 1,87-1,91 (m, 8H), 5,85 (br s, 2H), 6,73-6,96 (m, 3H), 7,28 (br s, 1H).A suspension of 1- (4- tert -butyl-2-nitrophenyl) -2,5-dimethylpyrrole (0.341 g, 1.25 mmol), 10% Pd / C (0.056 g) and EtOAc (50 ml) in atmosphere of H2 (balloon) was stirred for 72 h, and then filtered through a plug of Celite®. The filtrate was concentrated under reduced pressure to give 5- tert -butyl-2- (2,5-dimethylpyrrolyl) aniline as yellowish solids (0.30 g, 99%): TLC (10% EtOAc / 90% hexane) R_ { f} 0.43; 1 H-NMR (CDCl 3) δ 1.28 (s, 9H), 1.87-1.91 (m, 8H), 5.85 (br s, 2H), 6.73 -6.96 (m, 3H), 7.28 (br s, 1H).

A5. Método General para la Síntesis de Anilinas a Partir de Anilinas por Sustitución Aromática Nucleófila. Síntesis de la Sal 4-(2-(N-metilcarbamoil)-4-piridiloxi)-2-metilanilina.HClTO 5. General Method for the Synthesis of Anilines from Anilines by Nucleophilic Aromatic Substitution. Synthesis of Salt 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) -2-methylaniline. HCl

21twenty-one

Una solución de 4-amino-3-metilfenol (5,45 g, 44,25 mmol) en dimetilacetamida seca (75 ml) se trató con terc-butóxido de potasio (10,86 g, 96,77 mmol) y la mezcla de color negro se agitó a la temperatura ambiente hasta que el matraz hubo alcanzado la temperatura ambiente. El contenido se trató luego con 4-cloro-N-metil-2-piridinacarboxamida (Método A2, Paso 3b; 7,52 g, 44,2 mmol) y se calentó a 110ºC durante 8 h. La mezcla se enfrió a la temperatura ambiente y se diluyó con agua (75 ml). La capa orgánica se extrajo con EtOAc (5 x 100 ml). Las capas orgánicas reunidas se lavaron con una solución saturada de NaCl (200 ml), se secaron (MgSO_{4}) y se concentraron a presión reducida. El aceite negro residual se trató con Et_{2}O (50 ml) y se sometió a ultrasonidos. La solución se trató luego con HCl (1 M en Et_{2}O; 100 ml) y se agitó a la temperatura ambiente durante 5 min. El sólido de color rosa oscuro resultante (7,04 g, 24,1 mmol) se separó por filtración de la solución y se guardó en condiciones anaerobias a 0ºC antes de utilizarlo: ^{1}H-NMR (DMSO-d_{6}) \delta 2,41 (s, 3H), 2,78 (d, J = 4,4 Hz, 3H), 4,93 (br s, 2H), 7,19 (dd, J = 8,5, 2,6 Hz, 1H), 7,23 (dd, J = 5,5, 2,6 Hz, 1H), 7,26 (d, J = 2,6 Hz, 1H), 7,55 (d, J = 2,6 Hz, 1H), 7,64 (d, J = 8,8 Hz, 1H), 8,55 (d, J = 5,9 Hz, 1H), 8,99 (q, J = 4,8 Hz, 1H).A solution of 4-amino-3-methylphenol (5.45 g, 44.25 mmol) in dry dimethylacetamide (75 ml) was treated with potassium tert -butoxide (10.86 g, 96.77 mmol) and the mixture The black color was stirred at room temperature until the flask had reached room temperature. The content was then treated with 4-chloro-N-methyl-2-pyridinecarboxamide (Method A2, Step 3b; 7.52 g, 44.2 mmol) and heated at 110 ° C for 8 h. The mixture was cooled to room temperature and diluted with water (75 ml). The organic layer was extracted with EtOAc (5 x 100 ml). The combined organic layers were washed with a saturated NaCl solution (200 ml), dried (MgSO4) and concentrated under reduced pressure. The residual black oil was treated with Et2O (50 ml) and subjected to ultrasound. The solution was then treated with HCl (1 M in Et2O; 100 ml) and stirred at room temperature for 5 min. The resulting dark pink solid (7.04 g, 24.1 mmol) was filtered off the solution and stored under anaerobic conditions at 0 ° C before use: 1 H-NMR (DMSO-d 6 }) δ 2.41 (s, 3H), 2.78 (d, J = 4.4 Hz, 3H), 4.93 (br s, 2H), 7.19 (dd, J = 8.5 , 2.6 Hz, 1H), 7.23 (dd, J = 5.5, 2.6 Hz, 1H), 7.26 (d, J = 2.6 Hz, 1H), 7.55 (d , J = 2.6 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 8.55 (d, J = 5.9 Hz, 1H), 8.99 (q, J = 4.8 Hz, 1H).

A6. Método General para la Síntesis de Anilinas a Partir de Hidroxianilinas por Protección en N, Sustitución Aromática Nucleófila y Desprotección. Síntesis de 4-(2-(N-Metilcarbamoil)-4-piridiloxi)-2-cloroanilinaA6 General Method for the Synthesis of Anilines from Hydroxyanilines by N Protection, Nucleophilic Aromatic Substitution and Deprotection. Synthesis of 4- (2- ( N- Methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline

2222

Paso 1He passed one

Síntesis de 3-Cloro-4-(2,2,2-trifluoroacetil-amino)fenolSynthesis of 3-Chloro-4- (2,2,2-trifluoroacetyl-amino) phenol

Se añadió hierro (3,24 g, 58,00 mmol) a TFA en agitación (200 ml). Se añadieron a esta suspensión 2-cloro-4-nitrofenol (10,0 g, 58,0 mmol) y anhídrido trifluoroacético (20 ml). Esta suspensión de color gris se agitó a la temperatura ambiente durante 6 d. Se separó el hierro de la solución por filtración y el material restante se concentró a presión reducida. El sólido gris resultante se disolvió en agua (20 ml). A la solución amarilla resultante se añadió una solución saturada de NaHCO_{3} (50 ml). El sólido que precipitó de la solución se separó. El filtrado se extinguió lentamente con la solución de bicarbonato de sodio hasta que el producto se separó visiblemente de la solución (lo que se determinó utilizando un vial de mini-tratamiento). La solución amarilla ligeramente turbia se extrajo con EtOAc (3 x 125 ml). Las capas orgánicas reunidas se lavaron con una solución saturada de NaCl (125 ml) se secaron (MgSO_{4}) y se concentraron a presión reducida. La ^{1}H-NMR (DMSO-d_{6}) indicó una relación 1:1 del material de partida nitrofenol y el producto 3-cloro-4-(2,2,2-trifluoroacetilamino)fenol deseado. El material bruto se llevó al paso siguiente sin purificación ulterior.Iron (3.24 g, 58.00 mmol) was added to TFA in stirring (200 ml). They were added to this suspension 2-chloro-4-nitrophenol  (10.0 g, 58.0 mmol) and trifluoroacetic anhydride (20 ml). This Gray suspension was stirred at room temperature for 6 d. The iron was separated from the solution by filtration and the material The remaining was concentrated under reduced pressure. The resulting gray solid It was dissolved in water (20 ml). The resulting yellow solution is added a saturated solution of NaHCO3 (50 ml). The solid that precipitated from the solution separated. The filtrate was extinguished slowly with sodium bicarbonate solution until the product was visibly separated from the solution (which was determined using a mini-treatment vial). The solution Slightly cloudy yellow was extracted with EtOAc (3 x 125 ml). The The combined organic layers were washed with a saturated solution of NaCl (125 ml) was dried (MgSO4) and concentrated under pressure reduced 1 H-NMR (DMSO-d6) indicated a 1: 1 ratio of the material Nitrophenol starting and product 3-Chloro-4- (2,2,2-trifluoroacetylamino) phenol  wanted. The raw material was taken to the next step without further purification.

232. 3

Paso 2He passed 2

Síntesis de 4-(2-(N-metilcarbamoil)-4-piridiloxi)-2-clorofenil-(2,2,2-trifluoro)acetamidaSynthesis of 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) -2-chlorophenyl- (2,2,2-trifluoro) acetamide

Una solución de 3-cloro-4-(2,2,2-trifluoroacetilamino)fenol bruto (5,62 g, 23,46 mmol) en dimetilacetamida seca (50 ml) se trató con terc-butóxido de potasio (5,16 g, 45,98 mmol) y la mezcla de color negro parduzco se agitó a la temperatura ambiente hasta que el matraz de hubo enfriado a la temperatura ambiente. La mezcla resultante se trató con 4-cloro-N-metil-2-piridinacarboxamida (Método A2, Paso 3b; 1,99 g, 11,7 mmol) y se calentó a 100ºC bajo argón durante 4 d. La mezcla de reacción negra se enfrió a la temperatura ambiente y se vertió luego en agua fría (100 ml). La mezcla se extrajo con EtOAc (3,75 ml) y las capas orgánicas reunidas se concentraron a presión reducida. El aceite pardo residual se precipitó por cromatografía en columna (gradiente desde 20% EtOAc/éter pet. a 40% EtOAc/éter pet.) para dar 4-(2-(N-metilcarbamoil)-4-piridiloxi)-2-clorofenil-(2,2,2-trifluoro)-acetamida como un sólido amarillo (8,59 g, 23,0 mmol).A solution of crude 3-chloro-4- (2,2,2-trifluoroacetylamino) phenol (5.62 g, 23.46 mmol) in dry dimethylacetamide (50 ml) was treated with potassium tert -butoxide (5.16 g, 45.98 mmol) and the brownish black mixture was stirred at room temperature until the flask had cooled to room temperature. The resulting mixture was treated with 4-chloro- N- methyl-2-pyridinecarboxamide (Method A2, Step 3b; 1.99 g, 11.7 mmol) and heated at 100 ° C under argon for 4 d. The black reaction mixture was cooled to room temperature and then poured into cold water (100 ml). The mixture was extracted with EtOAc (3.75 ml) and the combined organic layers were concentrated under reduced pressure. The residual brown oil was precipitated by column chromatography (gradient from 20% EtOAc / pet. Ether to 40% EtOAc / pet. Ether) to give 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) -2-chlorophenyl - (2,2,2-trifluoro) -acetamide as a yellow solid (8.59 g, 23.0 mmol).

2424

Paso 3He passed 3

Síntesis de 4-(2-(N-metilcarbamoil)-4-piridiloxi)-2-cloroanilinaSynthesis of 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline

Una solución de 4-(2-(N-metilcarbamoil)-4-piridiloxi)-2-clorofenil-(2,2,2-trifluoro)acetamida bruta (8,59 g, 23,0 mmol) en 4-dioxano seco (20 ml) se trató con una solución 1N de NaOH (20 ml). Esta solución parda se mantuvo en agitación durante 8 h. Se añadió a esta solución EtOAc (40 ml). La capa orgánica de color verde se extrajo con EtOAc (3 x 40 ml) y el disolvente se concentró para dar 4-(2-(N-metilcarbamoil)-4-piridiloxi)-2-cloroanilina como un aceite verde que solidificó al dejarlo en reposo (2,86 g, 10,30 mmol): ^{1}H-NMR (DMSO-d_{6}) \delta 2,77 (d, J = 4,8 Hz, 3H), 5,51 (s, 2H), 6,60 (dd, J = 8,5, 2,6 Hz, 1H), 6,76 (d, J = 2,6 Hz, 1H), 7,03 (d, J = 8,5 Hz, 1H), 7,07 (dd, J = 5,5, 2,6 Hz, 1H), 7,27 (d, J = 2,6 Hz, 1H), 8,46 (d, J = 5,5 Hz, 1H), 8,75 (q, J = 4,8 Hz, 1H).A solution of 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) -2-chlorophenyl- (2,2,2-trifluoro) acetamide crude (8.59 g, 23.0 mmol) in dry 4-dioxane (20 ml) was treated with a 1N solution of NaOH (20 ml). This brown solution was kept under stirring for 8 h. EtOAc (40 ml) was added to this solution. The green organic layer was extracted with EtOAc (3 x 40 mL) and the solvent was concentrated to give 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline as a green oil that solidified upon leaving. at rest (2.86 g, 10.30 mmol): 1 H-NMR (DMSO-d 6) δ 2.77 (d, J = 4.8 Hz, 3H), 5.51 (s, 2H), 6.60 (dd, J = 8.5, 2.6 Hz, 1H), 6.76 (d, J = 2.6 Hz, 1H), 7.03 (d, J = 8.5 Hz, 1H), 7.07 (dd, J = 5.5, 2.6 Hz, 1H), 7.27 (d, J = 2.6 Hz, 1H), 8.46 (d, J = 5.5 Hz, 1H), 8.75 (q, J = 4.8 Hz, 1H).

A7. Método General para la Desprotección de una Anilina Acilada. Síntesis de 4-Cloro-2-Metoxi-5-(Trifluorometil)AnilinaA7 General Method for the Deprotection of an Aniline Acylated Synthesis of 4-Chloro-2-Methoxy-5- (Trifluoromethyl) Aniline

2525

Una suspensión de 3-cloro-6-(N-acetil)-4-(trifluorometil)anisol (4,00 g, 14,95 mmol) en una solución 6 M de HCl (24 ml) se calentó a la temperatura de reflujo durante 1 h. La solución resultante se dejó enfriar a la temperatura ambiente, durante cuyo tiempo solidificó ligeramente. La mezcla resultante se diluyó con agua (20 ml), y se trató luego con una combinación de NaOH sólido y una solución saturada de NaHCO_{3} hasta que la solución adquirió carácter básico. La capa orgánica se extrajo con CH_{2}Cl_{2} (3 x 50 ml). Las capas orgánicas reunidas se secaron (MgSO_{4}) y se concentraron a presión reducida para dar 4-cloro-2-metoxi-5-(trifluorometil)anilina como un aceite pardo (3,20 g, 14,2 mmol): ^{1}H-NMR (DMSO-d_{6}) \delta 3,84 (s, 3H), 5,30 (s, 2H), 7,01 (s, 2H).A suspension of 3-chloro-6- ( N -acetyl) -4- (trifluoromethyl) anisole (4.00 g, 14.95 mmol) in a 6 M solution of HCl (24 ml) was heated to reflux temperature for 1 h. The resulting solution was allowed to cool to room temperature, during which time it solidified slightly. The resulting mixture was diluted with water (20 ml), and then treated with a combination of solid NaOH and a saturated NaHCO 3 solution until the solution became basic. The organic layer was extracted with CH2Cl2 (3 x 50 ml). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to give 4-chloro-2-methoxy-5- (trifluoromethyl) aniline as a brown oil (3.20 g, 14.2 mmol): 1 H-NMR (DMSO-d 6) δ 3.84 (s, 3H), 5.30 (s, 2H), 7.01 (s, 2H).

A8. Método General para la Síntesis de \omega-Alcoxi-\omega-Carboxifenil-Anilinas. Síntesis de 4-(3-(N-Metilcarbamoil)-4-Metoxifenoxi)anilinaA8 General Method for the Synthesis of? -Alkoxy-? -Carboxyphenyl-Anilines. Synthesis of 4- (3- ( N- Methylcarbamoyl) -4-Methoxyphenoxy) aniline

2626

Paso 1He passed one

4-(3-Metoxicarbonil-4-metoxifenoxi)-1-nitrobenceno 4- (3-Methoxycarbonyl-4-methoxyphenoxy) -1-nitrobenzene

A una solución de 4-(3-carboxi-4-hidroxifenoxi)-1-nitrobenceno (preparado a partir de ácido 2,5-hidroxibenzoico de manera análoga a la descrita en el método A13, Paso 1, 12 mmol) en acetona (50 ml) se añadieron K_{2}CO_{3} (5 g) y sulfato de dimetilo (3,5 ml). La mezcla resultante se calentó a la temperatura de reflujo durante una noche, se enfrió luego a la temperatura ambiente y se filtró a través de un taco de Celite®. La solución resultante se concentró a presión reducida, se absorbió sobre SiO_{2}, y se purificó por cromatografía en columna (50% EtOAc/50% hexano) para dar 4-(3-metoxicarbonil-4-metoxifenoxi)-1-nitrobenceno como un polvo amarillo (3 g): pf. 115-118ºC.To a solution of 4- (3-carboxy-4-hydroxyphenoxy) -1-nitrobenzene (prepared from 2,5-hydroxybenzoic acid of analogously to that described in method A13, Step 1, 12 mmol) in acetone (50 ml) K2CO3 (5 g) and sulfate were added dimethyl (3.5 ml). The resulting mixture was heated to the temperature of reflux overnight, then cooled to the temperature ambient and filtered through a plug of Celite®. The solution resulting was concentrated under reduced pressure, absorbed on SiO2, and was purified by column chromatography (50% EtOAc / 50% hexane) to give 4- (3-methoxycarbonyl-4-methoxyphenoxy) -1-nitrobenzene as a yellow powder (3 g): mp. 115-118 ° C.

2727

Paso 2He passed 2

4-(3-Carboxi-4-metoxifenoxi)-1-nitrobenceno 4- (3-Carboxy-4-methoxyphenoxy) -1-nitrobenzene

Una mezcla de 4-(3-metoxicarbonil-4-metoxifenoxi)-1-nitrobenceno (1,2 g), KOH (0,33 g) y agua (5 ml) en MeOH (45 ml) se agitó a la temperatura ambiente durante una noche y se calentó luego a la temperatura de reflujo durante 4 h. La mezcla resultante se enfrió a la temperatura ambiente y se concentró a presión reducida. El residuo se disolvió en agua (50 ml), y la mezcla acuosa se acidificó con una solución 1N de HCl. La mezcla resultante se extrajo con EtOAc (50 ml). La capa orgánica se secó (MgSO_{4}) y se concentró a presión reducida para dar 4-(3-carboxi-4-metoxifenoxi)-1-nitrobenceno (1,04 g).A mix of 4- (3-methoxycarbonyl-4-methoxyphenoxy) -1-nitrobenzene (1.2 g), KOH (0.33 g) and water (5 ml) in MeOH (45 ml) was stirred at room temperature overnight and then heated to the reflux temperature for 4 h. The resulting mixture was cooled. at room temperature and concentrated under reduced pressure. He residue was dissolved in water (50 ml), and the aqueous mixture was acidified with a 1N solution of HCl. The resulting mixture was extracted with EtOAc (50 ml). The organic layer was dried (MgSO4) and concentrated under reduced pressure to give 4- (3-carboxy-4-methoxyphenoxy) -1-nitrobenzene (1.04 g).

2828

Paso 3He passed 3

4-(3-(N-Metilcarbamoil)-4-metoxifenoxi)-1-nitrobenceno 4- (3- ( N- Methylcarbamoyl) -4-methoxyphenoxy) -1-nitrobenzene

A una solución de 4-(3-carboxi-4-metoxifenoxi)-1-nitrobenceno (0,50 g, 1,75 mmol) en CH_{2}Cl_{2} (12 ml) se añadió SOCl_{2} (0,64 ml, 8,77 mmol) en porciones. La solución resultante se calentó a la temperatura de reflujo durante 18 h, se enfrió a la temperatura ambiente y se concentró a presión reducida. Los sólidos amarillos resultantes se disolvieron en CH_{2}Cl_{2} (3 ml) y a continuación se trató la solución con una solución de metilamina (2,0 M en THF, 3,5 ml, 7,02 mmol) en porciones (PRECAUCIÓN: desprendimiento de gas), y se agitó a la temperatura ambiente durante 4 h. La mezcla resultante se trató con una solución 1N de NaOH, y se extrajo luego con CH_{2}Cl_{2} (25 ml). La capa orgánica se secó (Na_{2}SO_{4}) y se concentró a presión reducida para dar 4-(3-(N-metilcarbamoil)-4-metoxifenoxi)-1-nitrobenceno como un sólido amarillo (0,50 g, 95%).To a solution of 4- (3-carboxy-4-methoxyphenoxy) -1-nitrobenzene (0.50 g, 1.75 mmol) in CH2Cl2 (12 mL) SOCl2 ( 0.64 ml, 8.77 mmol) in portions. The resulting solution was heated at reflux temperature for 18 h, cooled to room temperature and concentrated under reduced pressure. The resulting yellow solids were dissolved in CH2Cl2 (3 ml) and then the solution was treated with a solution of methylamine (2.0 M in THF, 3.5 ml, 7.02 mmol) in portions (CAUTION: gas evolution), and stirred at room temperature for 4 h. The resulting mixture was treated with a 1N solution of NaOH, and then extracted with CH 2 Cl 2 (25 ml). The organic layer was dried (Na2SO4) and concentrated under reduced pressure to give 4- (3- ( N- methylcarbamoyl) -4-methoxyphenoxy) -1-nitrobenzene as a yellow solid (0.50 g, 95%).

2929

Paso 4He passed 4

4-(3-(N-Metilcarbamoil)-4-metoxifenoxi)anilina 4- (3- ( N- Methylcarbamoyl) -4-methoxyphenoxy) aniline

Una suspensión de 4-(3-(N-metilcarbamoil)-4-metoxi-fenoxi)-1-nitrobenceno (0,78 g, 2,60 mmol) y Pd/C al 10% (0,20 g) en EtOH (55 ml) se agitó bajo 1 atm de H_{2} (balón) durante 2,5 d, y se filtró luego a través de un taco de Celite®. La solución resultante se concentró a presión reducida para proporcionar 4-(3-(N-metilcarbamoil)-4-metoxifenoxi)anilina como un sólido blanquecino (0,68 g, 96%): TLC (0,1% Et_{3}N/99,9% EtOAc) R_{f} 0,36.A suspension of 4- (3- ( N- methylcarbamoyl) -4-methoxy-phenoxy) -1-nitrobenzene (0.78 g, 2.60 mmol) and 10% Pd / C (0.20 g) in EtOH (55 ml) was stirred under 1 atm of H2 (balloon) for 2.5 d, and then filtered through a plug of Celite®. The resulting solution was concentrated under reduced pressure to provide 4- (3- ( N- methylcarbamoyl) -4-methoxyphenoxy) aniline as an off-white solid (0.68 g, 96%): TLC (0.1% Et3) N / 99.9% EtOAc) R f 0.36.

A9. Método General para Preparación de Anilinas que Contienen \omega-Alquilftalimidas. Síntesis de 5-(4-Aminofenoxi)-2-metilisoindol-1,3-DionaA9 General Method for Preparation of Anilines that They contain? -Alkylphthalimides. Synthesis of 5- (4-Aminophenoxy) -2-methylisoindole-1,3-Dione

3030

Paso 1He passed one

Síntesis de 5-(4-nitrofenoxi)-2-metilisoindolina-1,3-dionaSynthesis of 5- (4-nitrophenoxy) -2-methylisoindoline-1,3-dione

Una suspensión de 5-(4-nitrofenoxi)-isoindolina-1,3-diona (A3, Paso 2; 1,0 g, 3,52 mmol) y NaH (0,13 g, 5,27 mmol) en DMF (15 ml) se agitó a la temperatura ambiente durante 1 h, y se trató luego con yoduro de metilo (0,3 ml, 4,57 mmol). La mezcla resultante se agitó a la temperatura ambiente durante una noche, se enfrió luego a 0ºC y se trató con agua (10 ml). Los sólidos resultantes se recogieron y se secaron a presión reducida para dar 5-(4-nitrofenoxi)-2-metilisoindolina-1,3-diona como un sólido amarillo brillante (0,87 g, 83%): TLC (35% EtOAc/65% hexano) R_{f} 0,61.A suspension of 5- (4-nitrophenoxy) -isoindoline-1,3-dione (A3, Step 2; 1.0 g, 3.52 mmol) and NaH (0.13 g, 5.27 mmol) in DMF (15 ml) was stirred at room temperature for 1 h, and then treated with methyl iodide (0.3 ml, 4.57 mmol). The resulting mixture is stirred at room temperature overnight, then cooled at 0 ° C and treated with water (10 ml). The resulting solids are collected and dried under reduced pressure to give 5- (4-nitrophenoxy) -2-methylisoindoline-1,3-dione as a bright yellow solid (0.87 g, 83%): TLC (35% EtOAc / 65% hexane) R f 0.61.

3131

Paso 2He passed 2

Síntesis de 5-(4-aminofenoxi)-2-metilisoindolina-1,3-dionaSynthesis of 5- (4-aminophenoxy) -2-methylisoindoline-1,3-dione

Una suspensión de nitrofenoxi)-2-metilisoindolina-1,3-diona (0,87 g, 2,78 mmol) y Pd/C al 10% (0,10 g) en MeOH se agitó bajo 1 atm de H_{2} (balón) durante una noche. La mezcla resultante se filtró a través de un taco de Celite® y se concentró a presión reducida. Los sólidos amarillos resultantes se disolvieron en EtOAc (3 ml) y se filtraron a través de un taco de SiO_{2} (60% EtOAc/40% hexano) para proporcionar 5-(4-aminofenoxi)-2-metilisoindolina-1,3-diona como un sólido amarillo (0,67 g, 86%): TLC (40% EtOAc/60% hexano) R_{f} 0,27.A suspension of nitrophenoxy) -2-methylisoindoline-1,3-dione (0.87 g, 2.78 mmol) and 10% Pd / C (0.10 g) in MeOH was stirred under 1 atm of H2 (balloon) overnight. The resulting mixture is filtered through a plug of Celite® and concentrated under pressure reduced The resulting yellow solids were dissolved in EtOAc (3 ml) and filtered through a plug of SiO2 (60% EtOAc / 40% hexane) to provide 5- (4-aminophenoxy) -2-methylisoindoline-1,3-dione  as a yellow solid (0.67 g, 86%): TLC (40% EtOAc / 60% hexane) R f 0.27.

A10. Método General para la síntesis de \omega-Carbamoilaril-Anilinas por Reacción de Precursores de \omega-Alcoxicarbonilarilo con Aminas. Síntesis de 4-(2-(N-(2-morfolin-4-iletil)carbamoil)piridiloxi)-anilinaA10 General Method for the synthesis of? -Carbamoylaryl-Anilines by Reaction of? -Alkoxycarbonylaryl Precursors with Amines. Synthesis of 4- (2- ( N - (2-morpholin-4-ylethyl) carbamoyl) pyridyloxy) -aniline

3232

Paso 1He passed one

Síntesis de 4-cloro-2-(N-(2-morfolin-4-iletil)-carbamoil)piridinaSynthesis of 4-chloro-2- ( N - (2-morpholin-4-ylethyl) -carbamoyl) pyridine

A una solución de sal 4-cloropiridina-2-carboxilato de metilo.HCl (Método A2, Paso 2; 1,01 g, 4,86 mmol) en THF (20 ml) se añadió 4-(2-aminometil)morfolina (2,55 ml, 19,4 mmol) gota a gota y la solución resultante se calentó a la temperatura de reflujo durante 20 h, se enfrió a la temperatura ambiente, y se trató con agua (50 ml). La mezcla resultante se extrajo con EtOAc (50 ml). La capa orgánica se secó (MgSO_{4}) y se concentró a presión reducida para proporcionar 4-cloro-2-(N-(2-morfolin-4-iletil)carbamoil)piridina como un aceite amarillo (1,25 g, 95%): TLC (10% MeOH/90 EtOAc) R_{f} 0,50.To a solution of methyl 4-chloropyridine-2-carboxylate salt.HCl (Method A2, Step 2; 1.01 g, 4.86 mmol) in THF (20 ml) was added 4- (2-aminomethyl) morpholine ( 2.55 ml, 19.4 mmol) dropwise and the resulting solution was heated at reflux temperature for 20 h, cooled to room temperature, and treated with water (50 ml). The resulting mixture was extracted with EtOAc (50 ml). The organic layer was dried (MgSO 4) and concentrated under reduced pressure to provide 4-chloro-2- ( N - (2-morpholin-4-ylethyl) carbamoyl) pyridine as a yellow oil (1.25 g, 95%): TLC (10% MeOH / 90 EtOAc) R f 0.50.

3333

Paso 2He passed 2

Síntesis de 4-(2-(N-(2-morfolin-4-iletil)-carbamoil)piridiloxi)anilinaSynthesis of 4- (2- ( N - (2-morpholin-4-ylethyl) -carbamoyl) pyridyloxy) aniline

Una solución de 4-aminofenol (0,49 g, 4,52 mmol) y terc-butóxido de potasio (0,53 g, 4,75 mmol) en DMF (8 ml) se agitó a la temperatura ambiente durante 2 h, y se trató luego sucesivamente con 4-cloro-2-(N-(2-morfolin-4-iletil)carbamoil)piridina (1,22 g, 4,52 mmol) y K_{2}CO_{3} (0,31 g, 2,26 mmol). La mezcla resultante se calentó a 75ºC durante una noche, se enfrió a la temperatura ambiente, y se separó entre EtOAc (25 ml) y una solución saturada de NaCl (25 ml). La capa acuosa se extrajo de nuevo con EtOAc (25 ml). Las capas orgánicas reunidas se lavaron con una solución saturada de NaCl (3 x 25 ml) y se concentraron a presión reducida. Los sólidos de color pardo resultantes se purificaron por cromatografía en columna (58 g; gradiente desde 100% EtOAc a 25% MeOH/75% EtOAc) para proporcionar 4-(2-(N-(2-morfolin-4-iletil)carbamoil)piridiloxi)anilina (1,0 g, 65%): TLC (10% MeOH/90 EtOAc) R_{f} 0,32.A solution of 4-aminophenol (0.49 g, 4.52 mmol) and potassium tert -butoxide (0.53 g, 4.75 mmol) in DMF (8 ml) was stirred at room temperature for 2 h, and then treated successively with 4-chloro-2- ( N - (2-morpholin-4-ylethyl) carbamoyl) pyridine (1.22 g, 4.52 mmol) and K 2 CO 3 (0, 31 g, 2.26 mmol). The resulting mixture was heated at 75 overnight, cooled to room temperature, and separated between EtOAc (25 mL) and a saturated NaCl solution (25 mL). The aqueous layer was extracted again with EtOAc (25 ml). The combined organic layers were washed with a saturated NaCl solution (3 x 25 ml) and concentrated under reduced pressure. The resulting brown solids were purified by column chromatography (58 g; gradient from 100% EtOAc to 25% MeOH / 75% EtOAc) to provide 4- (2- ( N - (2-morpholin-4-ylethyl) carbamoyl ) pyridyloxy) aniline (1.0 g, 65%): TLC (10% MeOH / 90 EtOAc) R f 0.32.

A11. Método General para la Reducción de Nitroarenos a Arilaminas. Síntesis de 4-(3-carboxifenoxi)-anilinaA11 General Method for the Reduction of Nitroarenos a Arylamines Synthesis of 4- (3-carboxyphenoxy) -aniline 

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343. 4 

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Una suspensión de 4-(3-carboxifenoxi)-1-nitrobenceno (5,38 g, 20,7 mmol) y Pd/C al 10% (0,50 g) en MeOH (120 ml) se agitó en atmósfera de H_{2} (balón) durante 2 d. La mezcla resultante se filtró a través de un taco de Celite®, y se concentró luego a presión reducida para proporcionar 4-(3-carboxifenoxi)anilina como un sólido pardo (2,26 g, 48%): TLC (10% MeOH/90 CH_{2}Cl_{2}) R_{f} 0,44 (veteado).A suspension of 4- (3-carboxyphenoxy) -1-nitrobenzene (5.38 g, 20.7 mmol) and 10% Pd / C (0.50 g) in MeOH (120 ml) was stirred under H2 (balloon) for 2 d. Mix resulting was filtered through a plug of Celite®, and concentrated then under reduced pressure to provide 4- (3-carboxyphenoxy) aniline as a solid brown (2.26 g, 48%): TLC (10% MeOH / 90 CH 2 Cl 2) R f 0.44 (veined)

A12. Método General para la Síntesis de Anilinas que Contienen Isoindolinona. Síntesis de 4-(1-oxoisoindolin-5-iloxi)anilinaA12 General Method for the Synthesis of Anilines that They contain Isoindolinone. Synthesis of 4- (1-Oxoisoindolin-5-yloxy) aniline 

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3535 

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Paso 1He passed one

Síntesis de 5-hidroxiisoindolin-1-onaSynthesis of 5-hydroxyisoindolin-1-one

A una solución de 5-hidroxiftalimida (19,8 g, 121 mmol) en AcOH (500 ml) se añadió lentamente cinc en polvo (47,6 g, 729 mmol) en porciones, y la mezcla se calentó luego a la temperatura de reflujo durante 40 min, se filtró en caliente, y se concentró a presión reducida. La reacción se repitió en la misma escala y el residuo aceitoso reunido se purificó por cromatografía en columna (1,1 kg SiO_{2}; gradiente desde 60% EtOAc/40% hexano a 25% MeOH/75% EtOAc) para dar 5-hidroxiisoindolin-1-ona (3,77 g): TLC (100% EtOAc) R_{f} 0,17; HPLC ES-MS m/z 150 ((M+H)^{+}).To a solution of 5-hydroxyphthalimide (19.8 g, 121 mmol) in AcOH (500 ml) zinc powder (47.6 g, 729 mmol) was added slowly in portions, and the mixture was then heated to the temperature of reflux for 40 min, filtered hot, and concentrated under reduced pressure. The reaction was repeated on the same scale and the combined oily residue was purified by column chromatography (1.1 kg SiO2; gradient from 60% EtOAc / 40% hexane to 25% MeOH / 75% EtOAc) to give 5 -hydroxyisoindolin-1-one (3.77 g): TLC (100% EtOAc) R f 0.17; HPLC ES-MS m / z 150 ((M + H) +). 

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3636 

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Paso 2He passed 2

Síntesis de 4-(1-isoindolinon-5-iloxi)-1-nitrobencenoSynthesis of 4- (1-Isoindolinon-5-yloxy) -1-nitrobenzene

A una suspensión de NaH (0,39 g, 16,1 mmol) en DMF a 0ºC se añadió 5-hidroxiisoindolin-1-ona (2,0 g, 13,4 mmol) en porciones. La suspensión resultante se dejó calentar a la temperatura ambiente y se agitó durante 45 min, se añadieron luego 4-fluoro-1-nitrobenceno y la mezcla se calentó después a 70ºC durante 3 h. Se enfrió la mezcla a 0ºC y se trató con agua gota a gota hasta que se formó un precipitado. Los sólidos resultantes se recogieron para dar 4-(1-isoindolinon-5-iloxi)-1-nitrobenceno como un sólido amarillo oscuro (3,23 g, 89%): TLC (100% EtOAc) R_{f} 0,35.To a suspension of NaH (0.39 g, 16.1 mmol) in DMF at 0 ° C was added 5-hydroxyisoindolin-1-one (2.0 g, 13.4 mmol) in portions. The resulting suspension was left heat to room temperature and stirred for 45 min, it they added later 4-fluoro-1-nitrobenzene and the mixture was then heated at 70 ° C for 3 h. It cooled mixture at 0 ° C and treated with water dropwise until a precipitate. The resulting solids were collected to give 4- (1-Isoindolinon-5-yloxy) -1-nitrobenzene as a dark yellow solid (3.23 g, 89%): TLC (100% EtOAc) R f 0.35.

3737

Paso 3He passed 3

Síntesis de 4-(1-oxoisoindolin-5-iloxi)anilinaSynthesis of 4- (1-Oxoisoindolin-5-yloxy) aniline

Una suspensión de 4-(1-isoindolinon-5-iloxi)-1-nitrobenceno (2,12 g, 7,8 mmol) y Pd/C al 10% (0,20 g) en EtOH (50 ml) se agitó en atmósfera de H_{2} (balón) durante 4 h, y se filtró luego a través de un taco de Celite®. El filtrado se concentró a presión reducida para proporcionar 4-(1-oxoisoindolin-5-iloxi)anilina como un sólido amarillo oscuro: TLC (100% EtOAc) R_{f} 0,15.A suspension of 4- (1-Isoindolinon-5-yloxy) -1-nitrobenzene (2.12 g, 7.8 mmol) and 10% Pd / C (0.20 g) in EtOH (50 ml) was stirred under H2 atmosphere (balloon) for 4 h, and then filtered at through a wad of Celite®. The filtrate was concentrated under pressure. reduced to provide 4- (1-Oxoisoindolin-5-yloxy) aniline  as a dark yellow solid: TLC (100% EtOAc) R f 0.15.

A13. Método General Para la Síntesis de \omega-Carbamoil-Anilinas por Formación de Amidas Mediada por EDCI, Seguida por Reducción del Nitroareno. Síntesis de 4-(3-N-metilcarbamoilfenoxi)anilinaA13 General Method for the Synthesis of?-Carbamoyl-Anilines by EDCI Mediated Amide Formation, Followed by Nitroarene Reduction. Synthesis of 4- (3- N -methylcarbamoylphenoxy) aniline

3838

Paso 1He passed one

Síntesis de 4-(3-etoxicarbonilfenoxi)-1-nitrobencenoSynthesis of 4- (3-ethoxycarbonylphenoxy) -1-nitrobenzene

Una mezcla de 4-fluoro-1-nitrobenceno (16 ml, 150 mmol)-3-hidroxibenzoato de etilo (25 g, 150 mmol) y K_{2}CO_{3} (41 g, 300 mmol) en DMF (125 ml) se calentó a la temperatura de reflujo durante una noche, se enfrió a la temperatura ambiente y se trató con agua (250 ml). La mezcla resultante se extrajo con EtOAc (3 x 150 ml). Las fases orgánicas reunidas se lavaron sucesivamente con agua (3 x 100 ml) y una solución saturada de NaCl (2 x 100 ml), se secaron (Na_{2}SO_{4}) y se concentraron a presión reducida. El residuo se purificó por cromatografía en columna (10% EtOAc/90% hexano) para proporcionar 4-(3-etoxi-carbonilfenoxi)-1-nitrobenceno como un aceite (38 g).A mix of 4-fluoro-1-nitrobenzene (16 ml, 150 mmol) -3-hydroxybenzoate of ethyl (25 g, 150 mmol) and K 2 CO 3 (41 g, 300 mmol) in DMF (125 ml) was heated at reflux temperature overnight, It was cooled to room temperature and treated with water (250 ml). The The resulting mixture was extracted with EtOAc (3 x 150 ml). Phases The combined organics were washed successively with water (3 x 100 ml) and a saturated solution of NaCl (2 x 100 ml), dried (Na2SO4) and concentrated under reduced pressure. The residue purified by column chromatography (10% EtOAc / 90% hexane) to provide 4- (3-ethoxycarbonylphenoxy) -1-nitrobenzene  as an oil (38 g).

3939

Paso 2He passed 2

Síntesis de 4-(3-carboxifenoxi)-1-nitrobencenoSynthesis of 4- (3-carboxyphenoxy) -1-nitrobenzene

A una mezcla agitada enérgicamente de 4-(3-etoxicarbonilfenoxi)-1-nitrobenceno (5,14 g, 17,9 mmol) en una solución THF/agua 3:1 (75 ml) se añadió una solución LiOH·H_{2}O (1,50 g, 35,8 mmol) en agua (36 ml). La mezcla resultante se calentó a 50ºC durante una noche, se enfrió luego a la temperatura ambiente, se concentró a presión reducida, y se ajustó a pH 2 con una solución 1M de HCl. Los sólidos de color amarillo brillante resultantes se separaron por filtración y se lavaron con hexano para dar 4-(3-carboxifenoxi)-1-nitrobenceno (4,40 g, 95%).To a vigorously stirred mixture of 4- (3-ethoxycarbonylphenoxy) -1-nitrobenzene (5.14 g, 17.9 mmol) in a 3: 1 THF / water solution (75 ml) was added a solution LiOH · H 2 O (1.50 g, 35.8 mmol) in water (36 ml). The resulting mixture was heated at 50 ° C overnight, cooled then at room temperature, it was concentrated under reduced pressure, and it was adjusted to pH 2 with a 1M solution of HCl. Color solids resulting bright yellow were filtered off and washed with hexane to give 4- (3-carboxyphenoxy) -1-nitrobenzene  (4.40 g, 95%).

4040

Paso 3He passed 3

Síntesis de 4-(3-(N-metilcarbamoil)fenoxi)-1-nitrobencenoSynthesis of 4- (3- ( N- methylcarbamoyl) phenoxy) -1-nitrobenzene

Una mezcla de 4-(3-carboxifenoxi)-1-nitrobenceno (3,72 g, 14,4 mmol), EDCI.HCl (3,63 g, 18,6 mmol), N-metilmorfolina (1,6 ml, 14,5 mmol) y metilamina (2,0 M en THF; 8 ml, 16 mmol) en CH_{2}Cl_{2} (45 ml) se agitó a la temperatura ambiente durante 3 d, y se concentró luego a presión reducida. El residuo se disolvió en EtOAc (50 ml) y la mezcla resultante se extrajo con una solución 1M de HCl (50 ml). La capa acuosa se extrajo de nuevo con EtOAc (2 x 50 ml). Las fases orgánicas reunidas se lavaron con una solución saturada de NaCl (50 ml), se secaron (Na_{2}SO_{4}), y se concentraron a presión reducida para dar 4-(3-(N-metilcarbamoil)fenoxi)-1-nitrobenceno como un aceite (1,89 g).A mixture of 4- (3-carboxyphenoxy) -1-nitrobenzene (3.72 g, 14.4 mmol), EDCI.HCl (3.63 g, 18.6 mmol), N- methylmorpholine (1.6 ml, 14.5 mmol) and methylamine (2.0 M in THF; 8 ml, 16 mmol) in CH 2 Cl 2 (45 ml) was stirred at room temperature for 3 d, and then concentrated under pressure reduced The residue was dissolved in EtOAc (50 ml) and the resulting mixture was extracted with a 1M solution of HCl (50 ml). The aqueous layer was extracted again with EtOAc (2 x 50 ml). The combined organic phases were washed with a saturated NaCl solution (50 ml), dried (Na2SO4), and concentrated under reduced pressure to give 4- (3- ( N- methylcarbamoyl) phenoxy) -1-nitrobenzene as an oil (1.89 g).

4141

Paso 4He passed 4

Síntesis de 4-(3-(N-metilcarbamoil)fenoxi)anilinaSynthesis of 4- (3- ( N- methylcarbamoyl) phenoxy) aniline

Una suspensión de 4-(3-(N-metilcarbamoil)fenoxi)-1-nitrobenceno (1,89 g, 6,95 mmol) y Pd/C al 5% (0,24 g) en EtOAc (20 ml) se agitó en una atmósfera de H_{2} (balón) durante una noche. La mezcla resultante se filtró a través de un taco de Celite® y se concentró a presión reducida. El residuo se purificó por cromatografía en columna (5% MeOH/95% CH_{2}Cl_{2}). El aceite resultante solidificó a vacío durante una noche para dar 4-(3-(N-metilcarbamoil)-fenoxi)anilina como un sólido amarillo (0,95 g, 56%).A suspension of 4- (3- ( N- methylcarbamoyl) phenoxy) -1-nitrobenzene (1.89 g, 6.95 mmol) and 5% Pd / C (0.24 g) in EtOAc (20 ml) is stirred in an atmosphere of H2 (balloon) overnight. The resulting mixture was filtered through a plug of Celite® and concentrated under reduced pressure. The residue was purified by column chromatography (5% MeOH / 95% CH2Cl2). The resulting oil solidified in vacuo overnight to give 4- (3- ( N- methylcarbamoyl) -phenoxy) aniline as a yellow solid (0.95 g, 56%).

A14. Método General Para la Síntesis de \omega-Carbamoil-Anilinas por Formación de Amidas Mediada por EDCI Seguida por Reducción del Nitroareno. Síntesis de 4-(3-(5-Metilcarbamoil)piridiloxi)anilinaA14 General Method for the Synthesis of ? -carbamoyl-anilines by Formation of Amides Mediated by EDCI Followed by Reduction of Nitroarene Synthesis of 4- (3- (5-Methylcarbamoyl) pyridyloxy) aniline

4242

Paso 1He passed one

Síntesis de 4-(3-(5-metoxicarbamoil)piridiloxi)-1-nitrobencenoSynthesis of 4- (3- (5-methoxycarbamoyl) pyridyloxy) -1-nitrobenzene

A una suspensión de NaH (0,63 g, 26,1 mmol) en DMF (20 ml) se añadió una solución de 5-hidroxinicotinato de metilo (2,0 g, 13,1 mmol) en DMF (10 ml). La mezcla resultante se añadió a una solución de 4-fluoronitrobenceno (1,4 ml, 13,1 mmol) en DMF (10 ml) y la mezcla resultante se calentó a 70ºC durante una noche, se enfrió a la temperatura ambiente, y se trató con MeOH (5 ml) seguido por agua (50 ml). La mezcla resultante se extrajo con EtOAc (100 ml). La base orgánica se concentró a presión reducida. El residuo se purificó por cromatografía en columna (30% EtOAc/70% hexano) para proporcionar 4-(3-(5-metoxicarbonil)piridiloxi)-1-nitrobenceno (0,60 g).To a suspension of NaH (0.63 g, 26.1 mmol) in DMF (20 ml) was added a solution of Methyl 5-hydroxynicotinate (2.0 g, 13.1 mmol) in DMF (10 ml). The resulting mixture was added to a solution of 4-fluoronitrobenzene (1.4 ml, 13.1 mmol) in DMF (10 ml) and the resulting mixture was heated at 70 overnight, cooled to room temperature, and treated with MeOH (5 ml) followed by water (50 ml). The resulting mixture was extracted with EtOAc (100 ml). The organic base was concentrated under reduced pressure. He residue was purified by column chromatography (30% EtOAc / 70% hexane) to provide 4- (3- (5-methoxycarbonyl) pyridyloxy) -1-nitrobenzene (0.60 g). 

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4343 

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Paso 2He passed 2

Síntesis de 4-(3-(5-metoxicarbonil)piridiloxi)anilinaSynthesis of 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline

Una suspensión de 4-(3-(5-metoxicarbonil)piridiloxi)-1-nitrobenceno (0,60 g, 2,20 mmol) y Pd/C al 10% en MeOH/EtOAc se agitó en atmósfera de H_{2} (balón) durante 72 h. La mezcla resultante se filtró y el filtrado se concentró a presión reducida. El residuo se purificó por cromatografía en columna (gradiente desde 10% EtOAC/90% hexano a 30% EtOAc/70% hexano a 50% EtOAc/50% hexano) para proporcionar 4-(3-(5-metoxicarbonil)piridiloxi)anilina (0,28 g, 60%): ^{1}H NMR (CDCl_{3}) \delta 3,92 (s, 3H), 6,71 (d, 2H), 6,89 (d, 2H), 7,73 (, 1H), 8,51 (d, 1H), 8,87 (d, 1H).A suspension of 4- (3- (5-methoxycarbonyl) pyridyloxy) -1-nitrobenzene (0.60 g, 2.20 mmol) and 10% Pd / C in MeOH / EtOAc was stirred in atmosphere of H2 (balloon) for 72 h. The resulting mixture is filtered and the filtrate was concentrated under reduced pressure. The residue is purified by column chromatography (gradient from 10% EtOAC / 90% hexane to 30% EtOAc / 70% hexane to 50% EtOAc / 50% hexane) to provide 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline  (0.28 g, 60%): 1 H NMR (CDCl 3) δ 3.92 (s, 3H), 6.71 (d, 2H), 6.89 (d, 2H), 7.73 (, 1H), 8.51 (d, 1H), 8.87 (d, 1H).

A15. Síntesis de una Anilina por Nitración Electrófila Seguida por Reducción. Síntesis de 4-(3-Metilsulfamoilfenoxi)anilinaA15 Synthesis of an Aniline by Electrophilic Nitration Followed by Reduction. Synthesis of 4- (3-Methylsulfamoylphenoxy) aniline

4444

Paso 1He passed one

Síntesis de N-metil-3-bromobencenosulfonamidaSynthesis of N- methyl-3-bromobenzenesulfonamide

A una solución de cloruro de 3-bromobencenosulfonilo (2,5 g, 11,2 mmol) en THF (15 ml) a 0ºC se añadió metilamina (2,0 M en THF; 28 ml, 56 mmol). La solución resultante se dejó calentar a la temperatura ambiente y se agitó a la temperatura ambiente durante una noche. La mezcla resultante se separó entre EtOAc (25 ml) y una solución 1M de HCl (25 ml). La fase acuosa se extrajo de nuevo con EtOAc (2 x 25 ml). Las fases orgánicas reunidas se lavaron sucesivamente con agua (2 x 25 ml) y una solución saturada de NaCl (25 ml), se secaron (MgSO_{4}) y se concentraron a presión reducida para dar N-metil-3-bromobencenosulfonamida como un sólido blanco (2,8 g, 99%).To a solution of 3-bromobenzenesulfonyl chloride (2.5 g, 11.2 mmol) in THF (15 ml) at 0 ° C was added methylamine (2.0 M in THF; 28 ml, 56 mmol). The resulting solution was allowed to warm to room temperature and stirred at room temperature overnight. The resulting mixture was separated between EtOAc (25 ml) and a 1M solution of HCl (25 ml). The aqueous phase was extracted again with EtOAc (2 x 25 ml). The combined organic phases were washed successively with water (2 x 25 ml) and a saturated NaCl solution (25 ml), dried (MgSO 4) and concentrated under reduced pressure to give N- methyl-3-bromobenzenesulfonamide as a white solid (2.8 g, 99%).

45Four. Five

Paso 2He passed 2

Síntesis de 4-(3-(N-metilsulfamoil)feniloxi)-bencenoSynthesis of 4- (3- ( N- Methylsulfamoyl) phenyloxy) -benzene

A una suspensión de fenol (1,9 g, 20 mmol), K_{2}CO_{3} (6,0 g, 40 mmol), y CuI (4 g, 20 mmol) en DMF (25 ml) se añadió N-metil-3-bromobencenosulfonamida (2,5 g, 10 mmol), y la mezcla resultante se agitó a la temperatura de reflujo durante una noche, se enfrió a la temperatura ambiente, y se separó entre EtOAc (50 ml) y una solución 1N de HCl (50 ml). La capa acuosa se extrajo de nuevo con EtOAc (2 x 50 ml). Las fases orgánicas reunidas se lavaron sucesivamente con agua (2 x 50 ml) y una solución saturada de NaCl (50 ml), se secaron (MgSO_{4}), y se concentraron a presión reducida. El aceite residual se purificó por cromatografía en columna (30% EtOAc/70% hexano) para dar 4-(3-(N-metilsulfamoil)feniloxi)benceno (0,30 g).To a suspension of phenol (1.9 g, 20 mmol), K 2 CO 3 (6.0 g, 40 mmol), and CuI (4 g, 20 mmol) in DMF (25 ml) was added N -methyl-3-bromobenzenesulfonamide (2.5 g, 10 mmol), and the resulting mixture was stirred at reflux temperature overnight, cooled to room temperature, and separated between EtOAc (50 ml) and a 1N HCl solution (50 ml). The aqueous layer was extracted again with EtOAc (2 x 50 ml). The combined organic phases were washed successively with water (2 x 50 ml) and a saturated NaCl solution (50 ml), dried (MgSO4), and concentrated under reduced pressure. The residual oil was purified by column chromatography (30% EtOAc / 70% hexane) to give 4- (3- ( N- methylsulfamoyl) phenyloxy) benzene (0.30 g).

4646

Paso 3He passed 3

Síntesis de 4-(3-N-metilsulfamoil)feniloxi)-1-nitrobencenoSynthesis of 4- (3- N -methylsulfamoyl) phenyloxy) -1-nitrobenzene

A una solución de 4-(3-N-metilsulfamoil)feniloxi)-benceno (0,30 g, 1,14 mmol) en TFA (6 ml) a -10ºC se añadió NaNO_{2} (0,097 g, 1,14 mmol) en porciones durante 5 min. La solución resultante se agitó a -10ºC durante 1 h, se dejó calentar luego a la temperatura ambiente, y se concentró a presión reducida. El residuo se separó entre EtOAc (10 ml) y agua (10 ml). La fase orgánica se lavó sucesivamente con agua (10 ml) y una solución saturada de NaCl (10 ml), se secó (MgSO_{4}) y se concentró a presión reducida para dar 4-(3-(N-metilsulfamoil)feniloxi)-1-nitrobenceno (0,20 g). Este material se llevó al paso siguiente sin purificación ulterior.To a solution of 4- (3- N -methylsulfamoyl) phenyloxy) -benzene (0.30 g, 1.14 mmol) in TFA (6 ml) at -10 ° C was added NaNO2 (0.097 g, 1.14 mmol) in portions for 5 min. The resulting solution was stirred at -10 ° C for 1 h, then allowed to warm to room temperature, and concentrated under reduced pressure. The residue was separated between EtOAc (10 ml) and water (10 ml). The organic phase was washed successively with water (10 ml) and a saturated NaCl solution (10 ml), dried (MgSO 4) and concentrated under reduced pressure to give 4- (3- ( N- methyl sulfamoyl) phenyloxy ) -1-nitrobenzene (0.20 g). This material was taken to the next step without further purification.

4747

Paso 4He passed 4

Síntesis de 4-(3-(N-metilsulfamoil)feniloxi)-anilinaSynthesis of 4- (3- ( N- Methylsulfamoyl) phenyloxy) -aniline

Una suspensión de 4-(3-(N-metilsulfamoil)feniloxi)-1-nitrobenceno (0,30 g) y Pd/C al 10% (0,030 g) en EtOAc (20 ml) se agitó en atmósfera de H_{2} (balón) durante una noche. La mezcla resultante se filtró a través de un taco de Celite®. El filtrado se concentró a presión reducida. El residuo se purificó por cromatografía en columna (30% EtOAc/70% hexano) para dar 4-(3-(N-metilsulfamoil)feniloxi)anilina (0,070 g).A suspension of 4- (3- ( N- methylsulfamoyl) phenyloxy) -1-nitrobenzene (0.30 g) and 10% Pd / C (0.030 g) in EtOAc (20 ml) was stirred under H 2 atmosphere } (ball) overnight. The resulting mixture was filtered through a plug of Celite®. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (30% EtOAc / 70% hexane) to give 4- (3- ( N- methylsulfamoyl) phenyloxy) aniline (0.070 g).

A16. Modificación de \omega-Cetonas. Síntesis de la sal 4-(4-(1-(N-metoxi)iminoetil)fenoxianilina.HClA16 Modification of ga-Ketones. Synthesis of salt 4- (4- (1- ( N -methoxy) iminoethyl) phenoxyaniline. HCl

4848

A una suspensión de sal 4-(4-acetilfenoxi)anilina.HCl (preparada de una manera análoga al Método A13, Paso 4; 1,0 g, 3,89 mmol) en una mezcla de EtOH (10 ml) y piridina (1,0 ml) se añadió sal O-metilhidroxilamina.HCl (0,65 g, 7,78 mmol, 2,0 equiv.). La solución resultante se calentó a la temperatura de reflujo durante 30 min, se enfrió a la temperatura ambiente y se concentró a presión reducida. Los sólidos resultantes se trituraron con agua (10 ml) y se lavaron con agua para dar la sal 4-(4-(1-(N-metoxi)iminoetil)fenoxianilina.HCl como un sólido amarillo (0,85 g): TLC (50% EtOAc/50% éter pet.) R_{f} 0,78. ^{1}H NMR (DMSO-d_{6}) \delta 3,90 (s, 3H), 5,70 (s, 3H); HPLC-MS m/z 257 ((M+H)^{+}).To a suspension of 4- (4-acetylphenoxy) aniline.HCl salt (prepared in a manner analogous to Method A13, Step 4; 1.0 g, 3.89 mmol) in a mixture of EtOH (10 ml) and pyridine ( 1.0 ml) O- methylhydroxylamine.HCl salt (0.65 g, 7.78 mmol, 2.0 equiv.) Was added. The resulting solution was heated at reflux temperature for 30 min, cooled to room temperature and concentrated under reduced pressure. The resulting solids were triturated with water (10 ml) and washed with water to give the salt 4- (4- (1- ( N -methoxy) iminoethyl) phenoxyaniline.HCl as a yellow solid (0.85 g): TLC (50% EtOAc / 50% pet ether.) R f 0.78. 1 H NMR (DMSO-d 6) δ 3.90 (s, 3H), 5.70 (s, 3H); HPLC-MS m / z 257 ((M + H) +).

A17. Síntesis de N-(\omega-Sililoxialquil)amidas. Síntesis de 4-(4-(2-(N-(2-Triisopropilsililoxi)etilcarbamoil)piridiloxianilinaA17 Synthesis of N - (ome-Sililoxyalkyl) amides. Synthesis of 4- (4- (2- ( N - (2-Triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyaniline

4949

Paso 1He passed one

4-Cloro-N-(2-triisopropilsililoxi)etilpiridina-2-carboxamida 4-Chloro- N - (2-triisopropylsilyloxy) ethylpyridine-2-carboxamide

A una solución de 4-cloro-N-(2-hidroxietil)piridina-2-carboxamida (preparada de una manera análoga al Método A2, Paso 3b; 1,5 g, 7,4 mmol) en DMF anh (7 ml) se añadió cloruro de triisopropilsililo (1,59 g, 8,2 mmol, 1,1 equiv.) e imidazol (1,12 g, 16,4 mmol, 2,2 equiv.). La solución amarilla resultante se agitó durante 3 h a la temperatura ambiente, y se concentró luego a presión reducida. El residuo se separó entre agua (10 ml) y EtOAc (10 ml). La capa acuosa se extrajo con EtOAc (3 x 10 ml). Las fases orgánicas reunidas se secaron (MgSO_{4}), y se concentraron a presión reducida para proporcionar 4-cloro-2-(N-(2-triisopropilsililoxi)etil)piridinacarboxamida como un aceite anaranjado (2,32 g, 88%). Este material se utilizó en el paso siguiente sin purificación ulterior.To a solution of 4-chloro- N - (2-hydroxyethyl) pyridine-2-carboxamide (prepared in a manner analogous to Method A2, Step 3b; 1.5 g, 7.4 mmol) in DMF anh (7 ml) Triisopropylsilyl chloride (1.59 g, 8.2 mmol, 1.1 equiv.) and imidazole (1.12 g, 16.4 mmol, 2.2 equiv.) were added. The resulting yellow solution was stirred for 3 h at room temperature, and then concentrated under reduced pressure. The residue was separated between water (10 ml) and EtOAc (10 ml). The aqueous layer was extracted with EtOAc (3 x 10 ml). The combined organic phases were dried (MgSO 4), and concentrated under reduced pressure to provide 4-chloro-2- ( N - (2-triisopropylsilyloxy) ethyl) pyridinecarboxamide as an orange oil (2.32 g, 88% ). This material was used in the next step without further purification. 

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50fifty 

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Paso 2He passed 2

4-(4-(2-(N-(2-Triisopropilsililoxi)etilcarbamoil)piridiloxianilina 4- (4- (2- ( N - (2-Triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyaniline

A una solución de 4-hidroxianilina (0,70 g, 6,0 mmol) en DMF anh (8 ml) se añadió terc-butóxido de potasio (0,67 g, 6,0 mmol, 1,0 equiv.) en una sola porción causando una exotermia. Cuando esta mezcla se hubo enfriado a la temperatura ambiente, se añadió una solución de 4-cloro-2-(N-(2-triisopropilsililoxi)etil)piridinacarboxamida (2,32 g, 6 mmol, 1 equiv.) en DMF (4 ml), seguida por K_{2}CO_{3} (0,42 g, 3,0 mmol, 0,50 equiv.). La mezcla resultante se calentó a 80ºC durante una noche. Se añadió luego una porción adicional de terc-butóxido de potasio (0,34 g, 3 mmol, 0,5 equiv.) y la mezcla se agitó a 80ºC durante 4 h más. La mezcla se enfrió a 0ºC con un baño hielo/agua, y se añadió luego agua (aprox. 1 ml) lentamente gota a gota. La capa orgánica se extrajo con EtOAc (3 x 10 ml). Las capas orgánicas reunidas se lavaron con una solución saturada de NaCl (20 ml), se secaron (MgSO_{4}) y se concentraron a presión reducida. El residuo aceitoso pardo se purificó por cromatografía en columna (SiO_{2}; 30% EtOAc/70% éter pet.) para proporcionar 4-(4-(2-(N-(2-triisopropilsililoxi)etilcarbamoil)piridiloxianilina como un aceite transparente pardo claro (0,99 g, 38%).To a solution of 4-hydroxyaniline (0.70 g, 6.0 mmol) in DMF anh (8 ml) was added potassium tert -butoxide (0.67 g, 6.0 mmol, 1.0 equiv.) In a single portion causing an exotherm. When this mixture had cooled to room temperature, a solution of 4-chloro-2- ( N - (2-triisopropylsilyloxy) ethyl) pyridinecarboxamide (2.32 g, 6 mmol, 1 equiv.) In DMF (4 ml), followed by K 2 CO 3 (0.42 g, 3.0 mmol, 0.50 equiv.). The resulting mixture was heated at 80 ° C overnight. An additional portion of potassium tert -butoxide (0.34 g, 3 mmol, 0.5 equiv.) Was then added and the mixture was stirred at 80 ° C for a further 4 h. The mixture was cooled to 0 ° C with an ice / water bath, and then water (approx. 1 ml) was added slowly dropwise. The organic layer was extracted with EtOAc (3 x 10 ml). The combined organic layers were washed with a saturated NaCl solution (20 ml), dried (MgSO4) and concentrated under reduced pressure. The brown oily residue was purified by column chromatography (SiO2; 30% EtOAc / 70% pet. Ether) to provide 4- (4- (2- ( N - (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyaniline as an oil light brown transparent (0.99 g, 38%).

A18. Síntesis de Ésteres de 2-Piridinacarboxilato por Oxidación de 2-Metilpiridinas. Síntesis de 4-(5-(2-metoxicarbonil)piridiloxi)anilinaA18 Synthesis of Esters of 2-Pyridinecarboxylate by Oxidation of 2-Methylpyridines. Synthesis of 4- (5- (2-methoxycarbonyl) pyridyloxy) aniline

5151

Paso 1He passed one

4-(5-(2-Metil)piridiloxi)-1-nitrobenceno 4- (5- (2-Methyl) pyridyloxy) -1-nitrobenzene

Una mezcla de 5-hidroxi-2-metilpiridina (10,0 g, 91,6 mmol), 1-fluoro-4-nitrobenceno (9,8 ml, 91,6 mmol, 1,0 equiv.), K_{2}CO_{3} (25 g, 183 mmol, 2,0 equiv.) en DMF (100 ml) se calentó a la temperatura de reflujo durante una noche. La mezcla resultante se enfrió a la temperatura ambiente, se trató con agua (200 ml), y se extrajo con EtOAc (3 x 100 ml). Las capas orgánicas reunidas se lavaron sucesivamente con agua (2 x 100 ml) y una solución saturada de NaCl (100 ml), se secaron (MgSO_{4}) y se concentraron a presión reducida para dar 4-(5-(2-metil)piridiloxi)-1-nitrobenceno como un sólido pardo (12,3 g).A mix of 5-hydroxy-2-methylpyridine (10.0 g, 91.6 mmol), 1-fluoro-4-nitrobenzene (9.8 ml, 91.6 mmol, 1.0 equiv.), K 2 CO 3 (25 g, 183 mmol, 2.0 equiv.) In DMF (100 ml) was heated to reflux temperature during one night The resulting mixture was cooled to temperature ambient, treated with water (200 ml), and extracted with EtOAc (3 x 100 ml) The combined organic layers were washed successively with water (2 x 100 ml) and a saturated solution of NaCl (100 ml), dried (MgSO 4) and concentrated under reduced pressure to give 4- (5- (2-methyl) pyridyloxy) -1-nitrobenzene as a brown solid (12.3 g).

5252

Paso 2He passed 2

Síntesis de 4-(5-(2-Metoxicarbonil)piridiloxi)-1-nitrobencenoSynthesis of 4- (5- (2-Methoxycarbonyl) pyridyloxy) -1-nitrobenzene

Una mezcla de 4-(5-(2-metil)piridiloxi)-1-nitrobenceno (1,70 g, 7,39 mmol) y dióxido de selenio (2,50 g, 22,2 mmol, 3,0 equiv.) en piridina (20 ml) se calentó a la temperatura de reflujo durante 5 h, y se enfrió luego a la temperatura ambiente. La suspensión resultante se filtró, y se concentró luego a presión reducida. El residuo se disolvió en MeOH (100 ml). La solución se trató con una solución concentrada de HCl (7 ml), se calentó luego a la temperatura de reflujo durante 3 h, se enfrió a la temperatura ambiente y se concentró a presión reducida. El residuo se separó entre EtOAc (50 ml) y una solución 1N de NaOH (50 ml). La capa acuosa se extrajo con EtOAc (2 x 50 ml). Las capas orgánicas reunidas se lavaron sucesivamente con agua (2 x 50 ml) y una solución saturada de NaCl,(50 ml) se secaron (MgSO_{4}) y se concentraron a presión reducida. El residuo se purificó por cromatografía en columna (SiO_{2}; 50% EtOAc/50% hexano) para proporcionar 4-(5-(2-metoxicarbonil)piridiloxi)-1-nitrobenceno (0,70 g).A mix of 4- (5- (2-methyl) pyridyloxy) -1-nitrobenzene (1.70 g, 7.39 mmol) and selenium dioxide (2.50 g, 22.2 mmol, 3.0 equiv.) in pyridine (20 ml) was heated to reflux temperature for 5 h, and then cooled to room temperature. The resulting suspension was filtered, and then concentrated under pressure reduced The residue was dissolved in MeOH (100 ml). The solution is treated with a concentrated solution of HCl (7 ml), then heated at the reflux temperature for 3 h, it was cooled to the temperature ambient and concentrated under reduced pressure. The residue was separated. between EtOAc (50 ml) and a 1N solution of NaOH (50 ml). The layer Aqueous was extracted with EtOAc (2 x 50 ml). Organic layers together they were washed successively with water (2 x 50 ml) and a saturated NaCl solution, (50 ml) dried (MgSO 4) and dried concentrated under reduced pressure. The residue was purified by column chromatography (SiO2; 50% EtOAc / 50% hexane) to provide 4- (5- (2-methoxycarbonyl) pyridyloxy) -1-nitrobenzene  (0.70 g). 

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5353 

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Paso 3He passed 3

Síntesis de 4-(5-(2-metoxicarbonil)piridiloxi)anilinaSynthesis of 4- (5- (2-methoxycarbonyl) pyridyloxy) aniline

Una suspensión de 4-(5-(2-metoxicarbonil)piridiloxi)-1-nitrobenceno (0,50 g) y Pd/C al 10% (0,050 g) en una mezcla de EtOAc (20 ml) y MeOH (5 ml) se puso bajo una atmósfera de H_{2} (balón) durante una noche. La mezcla resultante se filtró a través de un taco de Celite®, y el filtrado se concentró a presión reducida. El residuo se purificó por cromatografía en columna (SiO_{2}; 70% EtOAc/30% hexano) para dar 4-(5-(2-metoxicarbonil)-piridiloxi)anilina (0,40 g).A suspension of 4- (5- (2-methoxycarbonyl) pyridyloxy) -1-nitrobenzene (0.50 g) and 10% Pd / C (0.050 g) in a mixture of EtOAc (20 ml) and MeOH (5 ml) was placed under an atmosphere of H2 (balloon) during one night. The resulting mixture was filtered through a plug of Celite®, and the filtrate was concentrated under reduced pressure. The residue purified by column chromatography (SiO2; 70% EtOAc / 30% hexane) to give 4- (5- (2-methoxycarbonyl) -pyridyloxy) aniline  (0.40 g).

A19. Síntesis de \omega-Sulfonilfenil-Anilinas. Síntesis de 4-(4-Metilsulfonilfenoxi)anilinaA19 Synthesis of ? -Sulfonylphenyl-Anilines. Synthesis of 4- (4-Methylsulfonylphenoxy) aniline

5454

Paso 1He passed one

4-(4-Metilsulfonilfenoxi)-1-nitrobenceno 4- (4-Methylsulfonylphenoxy) -1-nitrobenzene

A una solución de 4-(4-metiltiofenoxi)-1-nitrobenceno (2,0 g, 7,7 mmol) en CH_{2}Cl_{2} (75 ml) a 0ºC se añadió lentamente m-CPBA (57-86%, 4,0 g), y la mezcla de reacción se agitó a la temperatura ambiente durante 5 h. Se trató la mezcla de reacción con una solución 1N de NaOH (25 ml). La capa orgánica se lavó sucesivamente con una solución 1N de NaOH (25 ml), agua (25 ml) y una solución saturada de NaCl (25 ml), se secó (MgSO_{4}), y se concentró a presión reducida para dar 4-(4-metilsulfonilfenoxi)-1-nitrobenceno como un sólido (2,1 g).To a solution of 4- (4-methylthiophenoxy) -1-nitrobenzene (2.0 g, 7.7 mmol) in CH 2 Cl 2 (75 ml) at 0 ° C was added slowly m-CPBA (57-86%, 4.0 g), and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was treated with a 1N NaOH solution (25 ml) The organic layer was washed successively with a 1N solution of NaOH (25 ml), water (25 ml) and a saturated NaCl solution (25 ml), dried (MgSO 4), and concentrated under reduced pressure to give 4- (4-Methylsulfonylphenoxy) -1-nitrobenzene as a solid (2.1 g).

Paso 2He passed 2

4-(4-Metilsulfonilfenoxi)-1-anilina 4- (4-Methylsulfonylphenoxy) -1-aniline

Se redujo 4-(4-metilsulfonilfenoxi)-1-nitrobenceno a la anilina de manera análoga a la descrita en el Método A18, Paso 3.Decreased 4- (4-Methylsulfonylphenoxy) -1-nitrobenzene to aniline analogously to that described in Method A18, Step 3.

B. Síntesis de Precursores de UreasB. Synthesis of Urea Precursors B1. Método General para la Síntesis de Isocianatos a Partir de Anilinas Utilizando CDI. Síntesis de Isocianato de 4-Bromo-3-(trifluorometil)feniloB1. General Method for Synthesis of Isocyanates a Starting from Anilines Using CDI. Synthesis of Isocyanate 4-Bromo-3- (trifluoromethyl) phenyl

5555

Paso 1He passed one

Síntesis de la sal 4-bromo-3-(trifluorometil)-anilina.HClSalt Synthesis 4-Bromo-3- (trifluoromethyl) -aniline.HCl

A una solución de 4-bromo-3-(trifluorometil)anilina (64 g, 267 mmol) en Et_{2}O (500 ml) se añadió una solución de HCl (1M en Et_{2}O; 300 ml) gota a gota y la mezcla resultante se agitó a la temperatura ambiente durante 16 h. El precipitado blanco-rosado resultante se separó por filtración y se lavó con Et_{2}O (50 ml) para proporcionar la sal 4-bromo-3-(trifluorometil)anilina.HCl (73 g, 98%).To a solution of 4-Bromo-3- (trifluoromethyl) aniline (64 g, 267 mmol) in Et2O (500 ml) a solution of HCl (1M in Et2O; 300 ml) dropwise and the resulting mixture is stirred at room temperature for 16 h. The precipitate resulting white-pink was filtered off and washed with Et2O (50 ml) to provide the salt 4-Bromo-3- (trifluoromethyl) aniline.HCl (73 g, 98%). 

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5656 

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Paso 2He passed 2

Síntesis de isocianato de 4-bromo-3-(trifluorometil)feniloSynthesis of isocyanate from 4-Bromo-3- (trifluoromethyl) phenyl

Una suspensión de sal 4-bromo-3-(trifluorometil)-anilina.HCl (36,8 g, 133 mmol) en tolueno (278 ml) se trató con cloroformiato de triclorometilo gota a gota y la mezcla resultante se calentó a la temperatura de reflujo durante 18 h. La mezcla resultante se concentró a presión reducida. El residuo se trató con tolueno (500 ml), y se concentró luego a presión reducida. El residuo se trató con CH_{2}Cl_{2} (500 ml), y se concentró luego a presión reducida. Se repitió el protocolo de tratamiento con CH_{2}Cl_{2}/concentración y el aceite de color ámbar resultante se guardó a -20ºC durante 16 h, para proporcionar isocianato de 4-bromo-3-(trifluorometil)fenilo como un sólido de color canela (35,1 g, 86%): GC-MS m/z 265 (M)^{+}.A suspension of 4-bromo-3- (trifluoromethyl) -aniline.HCl salt (36.8 g, 133 mmol) in toluene (278 ml) was treated with trichloromethyl chloroformate dropwise and the resulting mixture was heated to temperature of reflux for 18 h. The resulting mixture was concentrated under reduced pressure. The residue was treated with toluene (500 ml), and then concentrated under reduced pressure. The residue was treated with CH 2 Cl 2 (500 ml), and then concentrated under reduced pressure. The treatment protocol with CH 2 Cl 2 / concentration was repeated and the resulting amber oil was stored at -20 ° C for 16 h, to provide 4-bromo-3- (trifluoromethyl) phenyl isocyanate as a solid. cinnamon color (35.1 g, 86%): GC-MS m / z 265 (M) +.

C. Métodos de Formación de UreasC. Ureas Formation Methods C1a. Método General para la Síntesis de Ureas por Reacción de un Isocianato con una Anilina. Síntesis de N-(4-Cloro-3-(trifluorometil)fenil)-N'-(4-(2-(N-metilcarbamoil)-4-piridiloxi)fenil)ureaC1a. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of N - (4-Chloro-3- (trifluoromethyl) phenyl) - N '- (4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) phenyl) urea

5757

Una solución de isocianato de 4-cloro-3-(trifluorometil)fenilo (14,60 g, 65,90 mmol) en CH_{2}Cl_{2} (35 ml) se añadió gota a gota a una suspensión de 4-(2-(N-metilcarbamoil)-4-piridiloxi)anilina (Método A2, Paso 4; 16,0 g, 65,77 mmol) en CH_{2}Cl_{2} (35 ml) a 0ºC. La mezcla resultante se agitó a la temperatura ambiente durante 22 h. Los sólidos de color amarillo resultantes se separaron por filtración, se lavaron luego con CH_{2}Cl_{2} (2 x 30 ml) y se secaron a presión reducida (aproximadamente 1 mm Hg) para proporcionar N-(4-cloro-3-(trifluorometil)fenil)-N'-(4-(2-(N-metilcabamoil)-4-piridiloxi)fenil)urea como un sólido blanquecino (28,5 g, 93%): pf 207-209ºC; ^{1}H-NMR (DMSO-d_{6}) \delta 2,77 (d, J = 4,8 Hz, 3H), 7,16 (m, 3H), 7,37 (d, J = 2,5 Hz, 1H), 7,62 (m, 4H), 8,11 (d, J = 2,5 Hz, 1H), 8,49 (d, J = 5,5 Hz, 1H), 8,77 (br d, 1H), 8,99 (s, 1H), 9,21 (s, 1H); HPLC ES-MS m/z 465 ((M+H)^{+}).A solution of 4-chloro-3- (trifluoromethyl) phenyl isocyanate (14.60 g, 65.90 mmol) in CH2Cl2 (35 mL) was added dropwise to a suspension of 4- (2- ( N -methylcarbamoyl) -4-pyridyloxy) aniline (Method A2, Step 4; 16.0 g, 65.77 mmol) in CH 2 Cl 2 (35 ml) at 0 ° C. The resulting mixture was stirred at room temperature for 22 h. The resulting yellow solids were filtered off, then washed with CH 2 Cl 2 (2 x 30 ml) and dried under reduced pressure (approximately 1 mm Hg) to provide N - (4-chloro- 3- (trifluoromethyl) phenyl) - N '- (4- (2- ( N- methylcabamoyl) -4-pyridyloxy) phenyl) urea as an off-white solid (28.5 g, 93%): mp 207-209 ° C; 1 H-NMR (DMSO-d 6) δ 2.77 (d, J = 4.8 Hz, 3H), 7.16 (m, 3H), 7.37 (d, J = 2.5 Hz, 1H), 7.62 (m, 4H), 8.11 (d, J = 2.5 Hz, 1H), 8.49 (d, J = 5.5 Hz, 1H), 8 , 77 (br d, 1H), 8.99 (s, 1H), 9.21 (s, 1H); HPLC ES-MS m / z 465 ((M + H) +).

C1b. Método General para la Síntesis de Ureas por Reacción de un Isocianato con una Anilina. Síntesis de N-(4-Bromo-3-(trifluorometil)fenil)-N'-(4-(2-N-metilcarbamoil)-4-piridiloxi)fenil)-ureaC1b. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of N - (4-Bromo-3- (trifluoromethyl) phenyl) - N '- (4- (2- N -methylcarbamoyl) -4-pyridyloxy) phenyl) -urea

5858

Una solución de isocianato de 4-bromo-3-(trifluorometil)fenilo (Método B1, Paso 2; 8,0 g, 30,1 mmol) en CH_{2}Cl_{2} (80 ml) se añadió gota a gota a una solución de 4-(2-(N-metilcarbamoil)-4-piridiloxi)anilina (Método A2, Paso 4; 7,0 g, 28,8 mmol) en CH_{2}Cl_{2} (40 ml) a 0ºC. La mezcla resultante se agitó a la temperatura ambiente durante 16 h. Los sólidos de color amarillo resultantes se separaron por filtración, se lavaron luego con CH_{2}Cl_{2} (2 x 50 ml) y se secaron a presión reducida (aproximadamente 1 mmHg) a 40ºC para proporcionar N-(4-bromo-3-(trifluorometil)fenil)-N'-(4-(2-(N-metilcarbamoil)-4-piridiloxi)fenil-urea como un sólido amarillo pálido (3,2 g, 90%): pf 203-205ºC; ^{1}H-NMR (DMSO-d_{6}) \delta 2,77 (d, J = 4,8 Hz, 3H), 7,16 (m, 3H), 7,37 (d, J = 2,5 Hz, 1H), 7,58 (m, 3H), 7,77 (d, J = 8,8 Hz, 1H), 8,11 (d, J = 2,5 Hz, 1H), 8,49 (d, J = 5,5 Hz, 1H), 8,77 (br d, 1H), 8,99 (s, 1H), 9,21 (s, 1H); HPLC ES-MS m/z 509 ((M+H)^{+}).A solution of 4-bromo-3- (trifluoromethyl) phenyl isocyanate (Method B1, Step 2; 8.0 g, 30.1 mmol) in CH 2 Cl 2 (80 ml) was added dropwise to a solution of 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) aniline (Method A2, Step 4; 7.0 g, 28.8 mmol) in CH 2 Cl 2 (40 ml) at 0 ° C. The resulting mixture was stirred at room temperature for 16 h. The resulting yellow solids were filtered off, then washed with CH 2 Cl 2 (2 x 50 ml) and dried under reduced pressure (approximately 1 mm Hg) at 40 ° C to provide N - (4-bromine -3- (trifluoromethyl) phenyl) - N '- (4- (2- ( N -methylcarbamoyl) -4-pyridyloxy) phenyl-urea as a pale yellow solid (3.2 g, 90%): mp 203-205 ° C ; 1 H-NMR (DMSO-d 6) δ 2.77 (d, J = 4.8 Hz, 3H), 7.16 (m, 3H), 7.37 (d, J = 2.5 Hz, 1H), 7.58 (m, 3H), 7.77 (d, J = 8.8 Hz, 1H), 8.11 (d, J = 2.5 Hz, 1H), 8.49 (d, J = 5.5 Hz, 1H), 8.77 (br d, 1H), 8.99 (s, 1H), 9.21 (s, 1H); HPLC ES-MS m / z 509 ((M + H) +).

C1c. Método General para la Síntesis de Ureas por Reacción de un Isocianato con una Anilina. Síntesis de N-(4-Cloro-3-(trifluorometil)fenil)-N'-(2-metil-4-(2-(N-metilcarbamoil)(4-piridiloxi))-fenil-ureaC1c. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of N - (4-Chloro-3- (trifluoromethyl) phenyl) - N '- (2-methyl-4- (2- ( N- methylcarbamoyl) (4-pyridyloxy)) - phenyl-urea 

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5959 

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Una solución de 2-metil-4-(2-(N-metilcarbamoil)(4-piridiloxi))anilina (Método A5; 0,11 g, 0,45 mmol) en CH_{2}Cl_{2} (1 ml) se trató con Et_{3}N (0,16 ml) e isocianato de 4-cloro-3-(trifluorometil)fenilo (0,10 g, 0,45 mmol). La solución parda resultante se agitó a la temperatura ambiente durante 6 d, y se trató luego con agua (5 ml). La capa acuosa se extrajo de nuevo con EtOAc (3 x 5 ml). Las capas orgánicas reunidas se secaron (MgSO_{4}) y se concentraron a presión reducida para proporcionar N-(4-cloro-3-(trifluorometil)fenil)-N'-(2-metil-4-(2-(N-metilcarbamoil)(4-piridiloxi))fenil)-urea como un aceite pardo (0,11 g, 0,22 mmol): ^{1}H-NMR (DMSO-d_{6}) \delta 2,27 (s, 3H), 2,77 (d, J = 4,8 Hz, 3H), 7,03 (dd, J = 8,5, 2,6 Hz, 1H), 7,11 (d, J = 2,9 Hz, 1H), 7,15 (dd, J = 5,5, 2,6 Hz, 1H), 7,38 (d, J = 2,6 Hz, 1H), 7,62 (d app, J = 2,6 Hz, 2H), 7,84 (d, J = 8,8 Hz, 1H), 8,12 (s, 1H), 8,17 (s, 1H), 8,50 (d, J = 5,5 Hz, 1H), 8,78 (q, J = 5,2, 1H), 9,52 (s, 1H); HPLC ES-MS m/z 479 ((M+H)^{+}).A solution of 2-methyl-4- (2- ( N- methylcarbamoyl) (4-pyridyloxy)) aniline (Method A5; 0.11 g, 0.45 mmol) in CH2Cl2 (1 ml ) was treated with Et3N (0.16 ml) and 4-chloro-3- (trifluoromethyl) phenyl isocyanate (0.10 g, 0.45 mmol). The resulting brown solution was stirred at room temperature for 6 d, and then treated with water (5 ml). The aqueous layer was extracted again with EtOAc (3 x 5 ml). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to provide N - (4-chloro-3- (trifluoromethyl) phenyl) - N '- (2-methyl-4- (2- ( N -methylcarbamoyl) (4-pyridyloxy)) phenyl) -urea as a brown oil (0.11 g, 0.22 mmol): 1 H-NMR (DMSO-d 6) δ 2.27 ( s, 3H), 2.77 (d, J = 4.8 Hz, 3H), 7.03 (dd, J = 8.5, 2.6 Hz, 1H), 7.11 (d, J = 2 , 9 Hz, 1H), 7.15 (dd, J = 5.5, 2.6 Hz, 1H), 7.38 (d, J = 2.6 Hz, 1H), 7.62 (d app, J = 2.6 Hz, 2H), 7.84 (d, J = 8.8 Hz, 1H), 8.12 (s, 1H), 8.17 (s, 1H), 8.50 (d, J = 5.5 Hz, 1H), 8.78 (q, J = 5.2, 1H), 9.52 (s, 1H); HPLC ES-MS m / z 479 ((M + H) +).

C1d. Método General para la Síntesis de Ureas por Reacción de un Isocianato con una Anilina. Síntesis de N-(4-Cloro-3-(trifluorometil)fenil)-N'-(4-aminofenil)-ureaC1d. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of N - (4-Chloro-3- (trifluoromethyl) phenyl) - N '- (4-aminophenyl) -urea

6060

A una solución de isocianato de 4-cloro-3-(trifluorometil)fenilo (2,27 g, 10,3 mmol) en CH_{2}Cl_{2} (308 ml) se añadió p-fenilenodiamina (3,32 g, 30,7 mmol) en una sola parte. La mezcla resultante se agitó a la temperatura ambiente durante 1 h, se trató con CH_{2}Cl_{2} (100 ml), y se concentró a presión reducida. Los sólidos de color rosa resultantes se disolvieron en una mezcla de EtOAc (110 ml) y MeOH (15 ml), y la solución clara se lavó con una solución 0,05 N de HCl. La capa orgánica se concentró a presión reducida para proporcionar N-(4-cloro-3-(trifluorometil)fenil)-N'-(4-aminofenil)-urea impura (3,3 g; TLC (100% EtOAc) R_{f} 0,72.To a solution of 4-chloro-3- (trifluoromethyl) phenyl isocyanate (2.27 g, 10.3 mmol) in CH 2 Cl 2 (308 ml) was added p- phenylenediamine (3.32 g , 30.7 mmol) in one part. The resulting mixture was stirred at room temperature for 1 h, treated with CH 2 Cl 2 (100 ml), and concentrated under reduced pressure. The resulting pink solids were dissolved in a mixture of EtOAc (110 ml) and MeOH (15 ml), and the clear solution was washed with a 0.05 N solution of HCl. The organic layer was concentrated under reduced pressure to provide impure N - (4-chloro-3- (trifluoromethyl) phenyl) - N ' - (4-aminophenyl) -urea (3.3 g; TLC (100% EtOAc) R_ { f} 0.72.

C1e. Método General para la Síntesis de Ureas por Reacción de un Isocianato con una Anilina. Síntesis de N-(4-(Cloro-3-(trifluorometil)fenil)-N'-(4-etoxicarbonilfenil)-ureaC1e. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of N - (4- (Chloro-3- (trifluoromethyl) phenyl) - N '- (4-ethoxycarbonylphenyl) -urea

6161

A una solución de 4-isocianatobenzoato de etilo (3,14 g, 16,4 mmol) en CH_{2}Cl_{2} (30 ml) se añadió 4-cloro-3-(trifluorometil)anilina (3,21 g, 16,4 mmol), y la solución se agitó a la temperatura ambiente durante una noche. La suspensión resultante se diluyó con CH_{2}Cl_{2} (50 ml) y se filtró para proporcionar N-(4-cloro-3-(trifluorometil)fenil)-N'-(4-etoxicarbonilfenil)-urea como un sólido blanco (5,93 g, 97%): TLC (40% EtOAc/60% hexano) R_{f} 0,44.To a solution of ethyl 4-isocyanatobenzoate (3.14 g, 16.4 mmol) in CH 2 Cl 2 (30 ml) was added 4-chloro-3- (trifluoromethyl) aniline (3.21 g , 16.4 mmol), and the solution was stirred at room temperature overnight. The resulting suspension was diluted with CH 2 Cl 2 (50 ml) and filtered to provide N - (4-chloro-3- (trifluoromethyl) phenyl) - N ' - (4-ethoxycarbonylphenyl) -urea as a white solid (5.93 g, 97%): TLC (40% EtOAc / 60% hexane) R f 0.44.

C1f. Método General para la Síntesis de Ureas por Reacción de un Isocianato con una Anilina. Síntesis de N-(4-Cloro-3-(trifluorometil)fenil)-N'-(3-carboxifenil)-ureaC1f. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of N - (4-Chloro-3- (trifluoromethyl) phenyl) - N '- (3-carboxyphenyl) -urea

6262

A una solución de isocianato de 4-cloro-3-(trifluorometil)fenilo (1,21 g, 5,46 mmol) en CH_{2}Cl_{2} (8 ml) se añadió 4-(3-carboxifenoxi)anilina (Método A11; 0,81 g, 5,76 mmol) y la mezcla resultante se agitó a la temperatura ambiente durante una noche, se trató luego con MeOH (8 ml), y se agitó durante 2 horas más. La mezcla resultante se concentró a presión reducida. Los sólidos de color pardo resultantes se trituraron con una solución EtOAc/hexano 1:1 para dar N-(4-cloro-3-(trifluorometil)fenil)-N'-(3-carboxifenil)-urea como un sólido blanquecino (1,21 g, 76%).To a solution of 4-chloro-3- (trifluoromethyl) phenyl isocyanate (1.21 g, 5.46 mmol) in CH 2 Cl 2 (8 ml) was added 4- (3-carboxyphenoxy) aniline (Method A11; 0.81 g, 5.76 mmol) and the resulting mixture was stirred at room temperature overnight, then treated with MeOH (8 ml), and stirred for a further 2 hours. The resulting mixture was concentrated under reduced pressure. The resulting brown solids were triturated with a 1: 1 EtOAc / hexane solution to give N - (4-chloro-3- (trifluoromethyl) phenyl) - N '- (3-carboxyphenyl) -urea as an off-white solid (1 , 21 g, 76%).

C2a. Método General para la Síntesis de Ureas por Reacción de una Anilina con N,N'-Carbonil-Diimidazol Seguida por Adición de una Segunda Anilina. Síntesis de N-(2-Metoxi-5-(trifluorometil)fenil)-N'-(4-(2-(N-metilcarbamoil)-4-piri-diloxi)fenil)-ureaC2a. General Method for the Synthesis of Ureas by Reaction of an Aniline with N, N '-Carbonyl-Diimidazole Followed by Addition of a Second Aniline. Synthesis of N - (2-Methoxy-5- (trifluoromethyl) phenyl) - N '- (4- (2- ( N- methylcarbamoyl) -4-piri-diloxy) phenyl) -urea

6363 

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A una solución de 2-metoxi-5-(trifluorometil)anilina (0,15 g) en CH_{2}Cl_{2} anh (15 ml) a 0ºC se añadió CDI (0,13 g). La solución resultante se dejó calentar a la temperatura ambiente durante 1 h, se agitó a la temperatura ambiente durante 16 h, y se trató luego con 4-(2-(N-metilcarbamoil)-4-piridiloxi)anilina (0,18 g). La solución amarilla resultante se agitó a la temperatura ambiente durante 72 h, y se trató luego con H_{2}O (125 ml). La mezcla acuosa resultante se extrajo con EtOAc (2 x 150 ml). Las fases orgánicas reunidas se lavaron con una solución saturada de NaCl (100 ml), se secaron (MgSO_{4}) y se concentraron a presión reducida. El residuo se trituró (90% EtOAc/10% hexano). Los sólidos blancos resultantes se recogieron por filtración y se lavaron con EtOAc. El filtrado se concentró a presión reducida y el aceite residual se purificó por cromatografía en columna (gradiente desde 33% EtOAc/67% hexano a 50% EtOAC/50% hexano a 100% EtOAc) para dar N-(2-metoxi-5-(trifluorometil)-fenil)-N'-(4-(2-(N-metilcarbamoil)-4-piridiloxi)fenil-urea como un sólido de color canela claro (0,098 g, 30%): TLC (100% EtOAc) R_{f} 0,62; ^{1}H NMR (DMSO-d_{6}) \delta 2,76 (d, J = 4,8 Hz, 3H), 3,96 (s, 3H), 7,1-7,6 y 8,4-8,6 (m, 11H), 8,75 (d, J = 4,8 Hz, 1H), 9,55 (s, 1H); FAB-MS m/z 461 ((M+H)^{+}).To a solution of 2-methoxy-5- (trifluoromethyl) aniline (0.15 g) in CH 2 Cl 2 anh (15 ml) at 0 ° C was added CDI (0.13 g). The resulting solution was allowed to warm to room temperature for 1 h, stirred at room temperature for 16 h, and then treated with 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) aniline (0.18 g ). The resulting yellow solution was stirred at room temperature for 72 h, and then treated with H2O (125 ml). The resulting aqueous mixture was extracted with EtOAc (2 x 150 ml). The combined organic phases were washed with a saturated NaCl solution (100 ml), dried (MgSO4) and concentrated under reduced pressure. The residue was triturated (90% EtOAc / 10% hexane). The resulting white solids were collected by filtration and washed with EtOAc. The filtrate was concentrated under reduced pressure and the residual oil was purified by column chromatography (gradient from 33% EtOAc / 67% hexane to 50% EtOAC / 50% hexane to 100% EtOAc) to give N - (2-methoxy-5 - (trifluoromethyl) -phenyl) - N ' - (4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) phenyl-urea as a light tan solid (0.098 g, 30%): TLC (100% EtOAc ) R f 0.62; 1 H NMR (DMSO-d 6) δ 2.76 (d, J = 4.8 Hz, 3H), 3.96 (s, 3H), 7.1-7.6 and 8.4-8.6 (m, 11H), 8.75 (d, J = 4.8 Hz, 1H), 9.55 (s, 1H); FAB-MS m / z 461 ((M + H) +).

C2b. Método General para la Síntesis de Ureas por Reacción de una Anilina con N,N'-Carbonil-Diimidazol Seguida por Adición de una Segunda Anilina. Ureas Simétricas como Productos Secundarios de un Procedimiento de Reacción con N,N'-Carbonil-Diimidazol. Síntesis de Bis(4-(2-(N-Metilcarbamoil)-4-piridiloxi)fenil)-ureaC2b General Method for the Synthesis of Ureas by Reaction of an Aniline with N, N '-Carbonyl-Diimidazole Followed by Addition of a Second Aniline. Symmetric Areas as Secondary Products of a Reaction Procedure with N, N '-Carbonyl-Diimidazole. Synthesis of Bis (4- (2- ( N- Methylcarbamoyl) -4-pyridyloxy) phenyl) -urea

6464

A una solución en agitación de 3-amino-2-metoxi-quinolina (0,14 g) en CH_{2}Cl_{2} anhidro (15 ml) a 0ºC se añadió CDI (0,13 g). La solución resultante se dejó calentar a la temperatura ambiente durante 1 h y se agitó luego a la temperatura ambiente durante 16 h. La mezcla resultante se trató con 4-(2-(N-metilcarbamoil)-4-piridiloxi)anilina (0,18 g). La solución amarilla resultante se agitó a la temperatura ambiente durante 72 h, y se trató luego con agua (125 ml). La mezcla acuosa resultante se extrajo con EtOAc (2 x 150 ml). Las fases orgánicas reunidas se lavaron con una solución saturada de NaCl (100 ml), se secaron (MgSO_{4}) y se concentraron a presión reducida. El residuo se trituró (90% EtOAc/10% hexano). Los sólidos blancos resultantes se recogieron por filtración y se lavaron con EtOAc para dar bis(4-(2-(N-metilcarbamoil)-4-piridiloxi)fenil)urea (0,081 g, 44%): TLC (100% EtOAc) R_{f} 0,50; ^{1}H NMR (DMSO-d_{6}) \delta 2,76 (d, J = 5,1 Hz, 6H), 7,1-7,6 (m, 12H), 8,48 (d, J = 5,4 Hz, 1H), 8,75 (d, J = 4,8 Hz, 2H), 8,86 (s, 2H); HPLC ES-MS m/z 513 ((M+H)^{+}).To a stirring solution of 3-amino-2-methoxyquinoline (0.14 g) in anhydrous CH 2 Cl 2 (15 ml) at 0 ° C was added CDI (0.13 g). The resulting solution was allowed to warm to room temperature for 1 h and then stirred at room temperature for 16 h. The resulting mixture was treated with 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) aniline (0.18 g). The resulting yellow solution was stirred at room temperature for 72 h, and then treated with water (125 ml). The resulting aqueous mixture was extracted with EtOAc (2 x 150 ml). The combined organic phases were washed with a saturated NaCl solution (100 ml), dried (MgSO4) and concentrated under reduced pressure. The residue was triturated (90% EtOAc / 10% hexane). The resulting white solids were collected by filtration and washed with EtOAc to give bis (4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) phenyl) urea (0.081 g, 44%): TLC (100% EtOAc) R_ {f} 0.50; 1 H NMR (DMSO-d 6) δ 2.76 (d, J = 5.1 Hz, 6H), 7.1-7.6 (m, 12H), 8.48 (d , J = 5.4 Hz, 1H), 8.75 (d, J = 4.8 Hz, 2H), 8.86 (s, 2H); HPLC ES-MS m / z 513 ((M + H) +).

C2c. Método General para la Síntesis de Ureas por Reacción de un Isocianato con una Anilina. Síntesis de N-(2-Metoxi-5-(trifluorometil)fenil-N'-(4-(1,3-dioxoisoindolin-5-iloxi)fenil)-ureaC2c General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of N - (2-Methoxy-5- (trifluoromethyl) phenyl- N '- (4- (1,3-dioxoisoindolin-5-yloxy) phenyl) -urea

6565

A una solución agitada de isocianato de 2-metoxi-5-(trifluorometil)fenilo (0,10 g, 0,47 mmol) en CH_{2}Cl_{2} (1,5 ml) se añadió 5-(4-aminofenoxi)isoindolina-1,3-diona (Método A3, Paso 3, 0,12 g 0,47 mmol) en una sola porción. La mezcla resultante se agitó durante 12 h, y se trató luego con CH_{2}Cl_{2} (10 ml) y MeOH (5 ml). La mezcla resultante se lavó sucesivamente con una solución 1N de HCl (15 ml) y una solución saturada de NaCl (15 ml), se secó (MgSO_{4}) y se concentró a presión reducida para proporcionar N-(2-metoxi-5-(trifluorometil)fenil-N'-(4-(1,3-dioxo-isoindolin-5-iloxi)fenil)-urea como un sólido blanco (0,2 g, 96%): TLC (70% EtOAc/30% hexano) R_{f} 0,50; ^{1}H NMR (DMSO-d_{6}) \delta 3,95 (s, 3H), 7,31-7,10 (m, 6H), 7,57 (d, J = 9,3 Hz, 2H), 7,80 (d, J = 8,7 Hz, 1H), 8,53 (br s, 2H), 9,57 (s, 1H), 11,27 (br s, 1H); HPLC ES-MS 472,0 ((M+H)^{+}, 100%).To a stirred solution of 2-methoxy-5- (trifluoromethyl) phenyl isocyanate (0.10 g, 0.47 mmol) in CH 2 Cl 2 (1.5 ml) was added 5- (4- aminophenoxy) isoindoline-1,3-dione (Method A3, Step 3, 0.12 g 0.47 mmol) in a single portion. The resulting mixture was stirred for 12 h, and then treated with CH 2 Cl 2 (10 ml) and MeOH (5 ml). The resulting mixture was washed successively with a 1N HCl solution (15 ml) and a saturated NaCl solution (15 ml), dried (MgSO 4) and concentrated under reduced pressure to provide N - (2-methoxy- 5- (trifluoromethyl) phenyl- N ' - (4- (1,3-dioxo-isoindolin-5-yloxy) phenyl) -urea as a white solid (0.2 g, 96%): TLC (70% EtOAc / 30% hexane) R f 0.50; 1 H NMR (DMSO-d 6) δ 3.95 (s, 3H), 7.31-7.10 (m, 6H), 7.57 (d, J = 9.3 Hz, 2H), 7.80 (d, J = 8.7 Hz, 1H), 8.53 (br s, 2H), 9.57 (s, 1H) , 11.27 (br s, 1H); HPLC ES-MS 472.0 ((M + H) +, 100%).

C2d. Método General para la Síntesis de Ureas por Reacción de una Anilina con N,N'-Carbonil-Diimidazol Seguida por Adición de una Segunda Anilina. Síntesis de N-(5-(terc-Butil)-2-(2,5-dimetilpirrolil)fenil)-N'-(4-(2-(N-metilcarbamoil)-4-piridiloxi)fenil)-ureaC2d General Method for the Synthesis of Ureas by Reaction of an Aniline with N, N '-Carbonyl-Diimidazole Followed by Addition of a Second Aniline. Synthesis of N - (5- ( tert- Butyl) -2- (2,5-dimethylpyrrolyl) phenyl) - N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) -urea

6666

A una solución agitada de CDI (0,21 g, 1,30 mmol) en CH_{2}Cl_{2} (2 ml) se añadió 5-(terc-butil)-2-(2,5-dimetil-pirrolil)anilina (Método A4, Paso 2; 0,30 g, 1,24 mmol) en una sola porción. La mezcla resultante se agitó a la temperatura ambiente durante 4 h, y se añadió luego 4-(2-(N-metilcarbamoil)-4-piridiloxi)anilina (0,065 g, 0,267 mmol) en una sola porción. La mezcla resultante se calentó a 36ºC durante una noche, se enfrió luego a la temperatura ambiente y se diluyó con EtOAc (5 ml). La mezcla resultante se lavó sucesivamente con agua (15 ml) y con una solución 1N de HCl (15 ml), se secó (MgSO_{4}), y se filtró a través de un taco de gel de sílice (50 g) para proporcionar N-(5-(terc-butil)-2-(2,5-dimetilpirrolil)-fenil)-N'-(4-(2-(N-metilcarbamoil)-4-piridiloxi)fenil)-urea como un sólido amarillento (0,033 g, 24%): TLC (40% EtOAc/60% hexano) R_{f} 0,24; ^{1}H NMR (acetona-d_{6}) \delta 1,37 (s, 9H), 1,89 (s, 6H), 2,89 (d, J = 4,8 Hz, 3H), 5,83 (s, 2H), 6,87-7,20 (m, 6H), 7,17 (dd, 1H), 7,51-7,58 (m, 3H), 8,43 (d, J = 5,4 Hz, 1H), 8,57 (d, J = 2,1 Hz, 1H), 8,80 (br s, 1H); HPLC ES-MS 512 ((M+H)^{+}, 100%).To a stirred solution of CDI (0.21 g, 1.30 mmol) in CH 2 Cl 2 (2 ml) was added 5- ( tert -butyl) -2- (2,5-dimethyl-pyrrolyl) ) aniline (Method A4, Step 2; 0.30 g, 1.24 mmol) in a single portion. The resulting mixture was stirred at room temperature for 4 h, and 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) aniline (0.065 g, 0.267 mmol) was added in a single portion. The resulting mixture was heated at 36 ° C overnight, then cooled to room temperature and diluted with EtOAc (5 ml). The resulting mixture was washed successively with water (15 ml) and with a 1N solution of HCl (15 ml), dried (MgSO 4), and filtered through a plug of silica gel (50 g) to provide N - (5- ( tert -butyl) -2- (2,5-dimethylpyrrolyl) -phenyl) - N ' - (4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) phenyl) -urea as a yellowish solid (0.033 g, 24%): TLC (40% EtOAc / 60% hexane) R f 0.24; 1 H NMR (acetone-d 6) δ 1.37 (s, 9H), 1.89 (s, 6H), 2.89 (d, J = 4.8 Hz, 3H), 5.83 (s, 2H), 6.87-7.20 (m, 6H), 7.17 (dd, 1H), 7.51-7.58 (m, 3H), 8.43 (d, J = 5.4 Hz, 1H), 8.57 (d, J = 2.1 Hz, 1H), 8.80 (br s, 1H); HPLC ES-MS 512 ((M + H) +, 100%).

C3. Método Combinatorio para la Síntesis de Difenil-Ureas Utilizando TrifosgenoC3 Combinatorial Method for the Synthesis of Diphenyl Ureas Using Triphosgene

Una de las anilinas a acoplar se disolvió en dicloroetano (0,10 M). Esta solución se añadió a un vial de 8 ml (0,5 ml) que contenía dicloroetano (1 ml). Se añadió a esto una solución de carbonato de bis(triclorometilo) (0,12 M en dicloroetano, 0,2 ml, 0,4 equiv.), seguido por diisopropiletilamina (0,35 M en dicloroetano, 0,2 ml, 1,2 equiv.). El vial se tapó y se calentó a 80ºC durante 5 h, después de lo cual se dejo enfriar a la temperatura ambiente durante aproximadamente 10 h. Se añadió la segunda anilina (0,10 M en dicloroetano, 0,5 ml, 1,0 equiv.), seguida por diisopropiletilamina (0,35 M en dicloroetano, 0,2 ml, 1,2 equiv.). La mezcla resultante se calentó a 80ºC durante 4 h, se enfrió a la temperatura ambiente, y se trató con MeOH (0,5 ml). La mezcla resultante se concentró a presión reducida y los productos se purificaron por HPLC en fase inversa.One of the anilines to be coupled dissolved in dichloroethane (0.10 M). This solution was added to an 8 ml vial. (0.5 ml) containing dichloroethane (1 ml). Added to this a bis (trichloromethyl) carbonate solution (0.12 M in dichloroethane, 0.2 ml, 0.4 equiv.), followed by diisopropylethylamine (0.35 M in dichloroethane, 0.2 ml, 1.2 equiv.). The vial was covered and heated at 80 ° C for 5 h, after which it was allowed to cool to room temperature for about 10 h. The second aniline (0.10 M in dichloroethane, 0.5 ml, 1.0 equiv.), followed by diisopropylethylamine (0.35 M in dichloroethane, 0.2 ml, 1.2 equiv.). The resulting mixture was heated at 80 ° C for 4 h, cooled to room temperature, and treated with MeOH (0.5 ml). The resulting mixture was concentrated under reduced pressure and the products were purified by reverse phase HPLC.

C4. Método General para la Síntesis de Ureas por Reacción de una Anilina con Fosgeno Seguida por Adición de una Segunda Anilina. Síntesis de N-(2-Metoxi-5-(trifluorometil)fenil)-N'-(4-(2-(N-metilcarbamoil)-4-piridiloxi)fenil)-ureaC4 General Method for the Synthesis of Ureas by Reaction of an Aniline with Phosgene Followed by Addition of a Second Aniline. Synthesis of N - (2-Methoxy-5- (trifluoromethyl) phenyl) - N '- (4- (2- ( N -methylcarbamoyl) -4-pyridyloxy) phenyl) -urea

6767

A una solución agitada de fosgeno (1,9 M en tolueno; 2,07 ml, 0,21 g, 1,30 mmol) en CH_{2}Cl_{2} (20 ml) a 0ºC se añadió piridina anh (0,32 ml) seguida por 2-metoxi-5-(trifluorometil)anilina (0,75 g). La solución amarilla se dejó calentar a la temperatura ambiente en cuyo transcurso se formó un precipitado. La mezcla amarilla se agitó durante 1 h, y se concentró luego a presión reducida. El sólido resultante se trató con tolueno anh (20 ml) seguido por 4-(2-(N-metilcarbamoil)-4-piridiloxi)anilina (preparada como se describe en el Método A2; 0,30 g) y la suspensión resultante se calentó a 80ºC durante 20 h, y se dejó enfriar luego a la temperatura ambiente. La mezcla resultante se diluyó con agua (100 ml), y se alcalinizó luego con una solución saturada de NaHCO_{3} (2-3 ml). La solución básica se extrajo con EtOAc (2 x 250 ml). Las capas orgánicas se lavaron por separado con una solución saturada de NaCl, se reunieron, se secaron (MgSO_{4}), y se concentraron a presión reducida. El residuo pardo-rosado resultante se disolvió en MeOH y se absorbió sobre SiO_{2} (100 g). La cromatografía en columna (300 g SiO_{2}; gradiente desde 1% Et_{3}N/33% EtOAc/66% hexano a 1% Et_{3}N/99% EtOAc a 1% Et_{3}N/20% MeOH/79% EtOAc) seguida por concentración a presión reducida a 45ºC proporcionó una solución concentrada caliente en EtOAc, que se trató con hexano (10 ml) para formar lentamente cristales de N-(2-metoxi-5-(trifluorometil)fenil)-N'-(4-(2-(N-metilcarbamoil)-4-piridiloxi)fenil)-urea (0,44 g): TLC (1% Et_{3}N/99% EtOAc) R_{f} 0,40.To a stirred solution of phosgene (1.9 M in toluene; 2.07 ml, 0.21 g, 1.30 mmol) in CH 2 Cl 2 (20 ml) at 0 ° C was added pyridine anh (0 , 32 ml) followed by 2-methoxy-5- (trifluoromethyl) aniline (0.75 g). The yellow solution was allowed to warm to room temperature during which a precipitate formed. The yellow mixture was stirred for 1 h, and then concentrated under reduced pressure. The resulting solid was treated with toluene anh (20 ml) followed by 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) aniline (prepared as described in Method A2; 0.30 g) and the resulting suspension was heated at 80 ° C for 20 h, and then allowed to cool to room temperature. The resulting mixture was diluted with water (100 ml), and then made alkaline with a saturated solution of NaHCO3 (2-3 ml). The basic solution was extracted with EtOAc (2 x 250 ml). The organic layers were washed separately with a saturated NaCl solution, combined, dried (MgSO4), and concentrated under reduced pressure. The resulting brown-pink residue was dissolved in MeOH and absorbed on SiO2 (100 g). Column chromatography (300 g SiO 2; gradient from 1% Et 3 N / 33% EtOAc / 66% hexane to 1% Et 3 N / 99% EtOAc to 1% Et 3 N / 20% MeOH / 79% EtOAc) followed by concentration under reduced pressure at 45 ° C provided a hot concentrated solution in EtOAc, which was treated with hexane (10 ml) to slowly form crystals of N - (2-methoxy-5- (trifluoromethyl) phenyl) - N ' - (4- (2- ( N -methylcarbamoyl) -4-pyridyloxy) phenyl) -urea (0.44 g): TLC (1% Et 3 N / 99% EtOAc) R f } 0.40.

D. Interconversión de UreasD. Ureas Interconversion D1a. Conversión de \omega-Aminofenil-Ureas en \omega-(Aril-amino)Fenil-Ureas. Síntesis de N-(4-Cloro-3-((trifluorometil)fenil)-N'-(4-(3-metoxicarbonilfenil)carboxilaminofenil)-ureaDay 1 Conversion of ga-Aminophenyl-Ureas to ome- (Aryl-amino) Phenyl-Ureas. Synthesis of N - (4-Chloro-3 - ((trifluoromethyl) phenyl) - N '- (4- (3-methoxycarbonylphenyl) carboxylaminophenyl) -urea

6868

A una solución de N-(4-cloro-3-((trifluorometil)-fenil)-N'-(4-aminofenil)-urea (Método C1d; 0,050 g, 1,52 mmol), isoftalato de mono-metilo (0,25 g, 1,38 mmol), HOBT\cdotH_{2}O (0,41 g, 3,03 mmol) y N-metilmorfolina (0,33 ml, 3,03 mmol) en DMF (8 ml) se añadió EDCI.HCl (0,29 g, 1,52 mmol). La mezcla resultante se agitó a la temperatura ambiente durante una noche, se diluyó con EtOAc (25 ml) y se lavó sucesivamente con agua (25 ml) y una solución saturada de NaHCO_{3} (25 ml). La capa orgánica se secó (Na_{2}SO_{4}), y se concentró a presión reducida. Los sólidos resultantes se trituraron con una solución de EtOAc (80% EtOAc/20% hexano) para dar N-(4-cloro-3-((trifluorometil)fenil-N'-(4-(3-metoxicarbonilfenil)carboxilamino-fenil)-urea (0,27 g, 43%): pf 121-122; TLC (80% EtOAc/20% hexano) R_{f} 0,75.To a solution of N - (4-chloro-3 - ((trifluoromethyl) -phenyl) - N ' - (4-aminophenyl) -urea (Method C1d; 0.050 g, 1.52 mmol), mono-methyl isophthalate ( 0.25 g, 1.38 mmol), HOBT • H 2 O (0.41 g, 3.03 mmol) and N- methylmorpholine (0.33 ml, 3.03 mmol) in DMF (8 ml) EDCI.HCl (0.29 g, 1.52 mmol) was added.The resulting mixture was stirred at room temperature overnight, diluted with EtOAc (25 ml) and washed successively with water (25 ml) and a saturated NaHCO3 solution (25 ml). The organic layer was dried (Na2SO4), and concentrated under reduced pressure. The resulting solids were triturated with an EtOAc solution (80% EtOAc / 20% hexane) to give N - (4-chloro-3 - ((trifluoromethyl) phenyl- N ' - (4- (3-methoxycarbonylphenyl) carboxylamino-phenyl) -urea (0.27 g, 43%): mp 121 -122; TLC (80% EtOAc / 20% hexane) R f 0.75.

D1b. Conversión de \omega-Carboxifenil-Ureas en \omega-(Aril-carbamoil)fenil-Ureas. Síntesis de N-(4-Cloro-3-((trifluorome- til)fenil)-N'-(4-(3-metilcarbamoil-fenil)carbamoilfenil)-ureaD1b. Conversion of ga-Carboxyphenyl-Ureas into en- (Aryl-carbamoyl) phenyl-Ureas. Synthesis of N - (4-Chloro-3 - ((trifluoromethyl) phenyl) - N '- (4- (3-methylcarbamoyl-phenyl) carbamoylphenyl) -urea

6969

A una solución de N-(4-cloro-3-((trifluorometil)-fenil)-N'-(4-(3-metilcarbamoilfenil)-carboxiaminofenil)-urea
(0,14 g, 0,48 mmol), 3-metilcarbamoilanilina (0,080 g, 0,53 mmol), HOBT·H_{2}O (0,14 g, 1,07 mmol), y N-metilmor-
folina (0,5 ml, 1,07 mmol) en DMF (3 ml) a 0ºC se añadió EDCI.HCl (0,10 g, 0,53 mmol). La mezcla resultante se dejó calentar a la temperatura ambiente y se agitó durante una noche. La mezcla resultante se trató con agua (10 ml), y se extrajo con EtOAc (25 ml). La fase orgánica se concentró a presión reducida. Los sólidos amarillos resultantes se disolvieron en EtOAc (3 ml), y se filtraron luego a través de un taco de gel de sílice (17 g, gradiente desde 70% EtOAc/30% hexano a 10% MeOH/90% EtOAc) para dar N-(4-cloro-3-((trifluorometil)fenil)-N'-(4-(3-metilcarbamoilfenil)carbamoilfenil)-urea como un sólido blanco (0,097 g, 41%): pf 225-229; TLC (100% EtOAc) R_{f} 0,23.To a solution of N - (4-chloro-3 - ((trifluoromethyl) -phenyl) - N ' - (4- (3-methylcarbamoylphenyl) -carboxiaminophenyl) -urea
(0.14 g, 0.48 mmol), 3-methylcarbamoylaniline (0.080 g, 0.53 mmol), HOBT · H 2 O (0.14 g, 1.07 mmol), and N- methylmor-
folin (0.5 ml, 1.07 mmol) in DMF (3 ml) at 0 ° C EDCI.HCl (0.10 g, 0.53 mmol) was added. The resulting mixture was allowed to warm to room temperature and stirred overnight. The resulting mixture was treated with water (10 ml), and extracted with EtOAc (25 ml). The organic phase was concentrated under reduced pressure. The resulting yellow solids were dissolved in EtOAc (3 ml), and then filtered through a plug of silica gel (17 g, gradient from 70% EtOAc / 30% hexane to 10% MeOH / 90% EtOAc) to give N - (4-Chloro-3 - ((trifluoromethyl) phenyl) - N ' - (4- (3-methylcarbamoylphenyl) carbamoylphenyl) -urea as a white solid (0.097 g, 41%): mp 225-229; TLC ( 100% EtOAc) R f 0.23.

D1c. Enfoque Combinatorio a la Conversión de \omega-Carboxifenil-Ureas en \omega-(Arilcarbamoil)fenil-Ureas. Síntesis de N-(4-Cloro-3-((trifluorometil)fenil)-N'-(4-(N-(3-N(3-piridil)carbamoil)-fenil)carbamoil)fenil)-ureaD1c. Combinatorial Approach to the Conversion of? -Carboxyphenyl-Ureas into \ omega- (Arylcarbamoyl) phenyl-Ureas. Synthesis of N - (4-Chloro-3 - ((trifluoromethyl) phenyl) - N '- (4- ( N - (3- N (3-pyridyl) carbamoyl) -phenyl) carbamoyl) phenyl) -urea

7070

Una mezcla de N-(4-cloro-3-((trifluorometil)fenil)-N'-(3-carboxifenil)-urea (Método C1f; 0,030 g, 0,067 mmol) y N-ciclohexil-N'-(metilpoliestireno)carbodiimida (55 mg) en 1,2 dicloroetano (1 ml) se trató con una solución de 3-aminopiridina en CH_{2}Cl_{2} (1M; 0,074 ml, 0,074 mmol). (En casos de insolubilidad o turbidez, se añadió también una pequeña cantidad de DMSO.) La mezcla resultante se calentó a 36ºC durante una noche. Las mezclas de reacción turbias se trataron luego con THF (1 ml) y se continuó el tratamiento durante 18 h. Las mezclas resultantes se trataron con poli(4-(isocianatometil)estireno) (0,040 g) y la mezcla resultante se agitó a 36ºC durante 72 h, se enfrió luego a la temperatura ambiente y se filtró. La solución resultante se filtró a través de un taco de gel de sílice (1 g). La concentración a presión reducida proporcionó N-(4-cloro-3-((trifluorometil)fenil)-N'-(4-(N-(3-(N-(3-piridil)carbamoil)fenil)carbamoil)fenil)-urea (0,024 g, 59%): TLC (70% EtOAc/30% hexano) R_{f} 0,12.A mixture of N - (4-chloro-3 - ((trifluoromethyl) phenyl) - N ' - (3-carboxyphenyl) -urea (Method C1f; 0.030 g, 0.067 mmol) and N -cyclohexyl- N' - (methyl polystyrene) Carbodiimide (55 mg) in 1.2 dichloroethane (1 ml) was treated with a solution of 3-aminopyridine in CH2Cl2 (1M; 0.074 ml, 0.074 mmol). (In cases of insolubility or turbidity, a small amount of DMSO was also added.) The resulting mixture was heated at 36 ° C overnight. The cloudy reaction mixtures were then treated with THF (1 ml) and the treatment was continued for 18 h. The resulting mixtures were treated with poly (4- (isocyanatomethyl) styrene) (0.040 g) and the resulting mixture was stirred at 36 ° C for 72 h, then cooled to room temperature and filtered.The resulting solution was filtered through a plug of silica gel (1 g) Concentration under reduced pressure provided N - (4-chloro-3 - ((trifluoromethyl) phenyl) - N ' - (4- ( N - (3- ( N - (3-pyridyl) carbamoyl) phenyl) ) carbamoyl) phenyl) -urea (0.024 g, 59%): TLC (70% EtOAc / 30% hexane) R f 0.12.

D2. Conversión de \omega-Carboalcoxiaril-Ureas en \omega-Carbamoilaril-Ureas. Síntesis de N-(4-Cloro-3-((trifluorometil)fenil)-N'-(4-(3-metilcarbamoilfenil)-carboxiaminofenil)-ureaD2 Conversion of ome-Carboalkoxyaryl-Ureas into ome-Carbamoylaryl-Ureas. Synthesis of N - (4-Chloro-3 - ((trifluoromethyl) phenyl) - N '- (4- (3-methylcarbamoylphenyl) -carboxiaminophenyl) -urea

7171

A una muestra de N-(4-cloro-3-((trifluorometil)-fenil)-N'-(4-(3-carbometoxifenil)carboxiaminofenil)-urea (0,17 g, 0,34 mmol) se añadió metilamina (2 M en THF; 1 ml, 1,7 mmol) y la mezcla resultante se agitó a la temperatura ambiente durante una noche, y se concentró luego a presión reducida para dar N-(4-cloro-3-((trifluorometil)fenil)-N'-(4-(3-metilcarbamoilfenil)carboxiaminofenil)-urea como un sólido blanco: pf 247; TLC (100% EtOAc) R_{f} 0,35.To a sample of N - (4-chloro-3 - ((trifluoromethyl) -phenyl) - N ' - (4- (3-carbomethoxyphenyl) carboxyminophenyl) -urea (0.17 g, 0.34 mmol) methylamine was added (2 M in THF; 1 ml, 1.7 mmol) and the resulting mixture was stirred at room temperature overnight, and then concentrated under reduced pressure to give N - (4-chloro-3 - ((trifluoromethyl) phenyl) - N ' - (4- (3-methylcarbamoylphenyl) carboxyminophenyl) -urea as a white solid: mp 247; TLC (100% EtOAc) R f 0.35.

D3. Conversión de \omega-Carboalcoxiaril-Ureas en \omega-Carboxiaril-Ureas. Síntesis de N-(4-Cloro-3-((trifluorometil)fenil)-N'-(4-carboxifenil)-ureaD3 Conversion of \ omega-Carboalkoxyaryl-Ureas into \ omega-Carboxaryl-Ureas. Synthesis of N - (4-Chloro-3 - ((trifluoromethyl) phenyl) - N '- (4-carboxyphenyl) -urea

7272

A una suspensión de N-(4-cloro-3-((trifluorometil)-fenil)-N'-(4-etoxicarbonilfenil)-urea (Método C1e; 5,93 g, 15,3 mmol) en MeOH (75 ml) se añadió una solución acuosa de KOH (2,5 N, 10 ml, 23 mmol). La mezcla resultante se calentó a la temperatura de reflujo durante 12 h, se enfrió a la temperatura ambiente, y se concentró a presión reducida. El residuo se diluyó con agua (50 ml), y se trató luego con una solución 1N de HCl para ajustar el pH a un valor comprendido entre 2 y 3. El sólido resultante se recogió y se secó a presión reducida para dar N-(4-cloro-3-((trifluorometil)fenil)-N'-(4-carboxifenil)-urea como un sólido blanco (5,05 g, 92%).To a suspension of N - (4-chloro-3 - ((trifluoromethyl) -phenyl) - N ' - (4-ethoxycarbonylphenyl) -urea (Method C1e; 5.93 g, 15.3 mmol) in MeOH (75 ml ) an aqueous solution of KOH (2.5 N, 10 ml, 23 mmol) was added.The resulting mixture was heated at reflux temperature for 12 h, cooled to room temperature, and concentrated under reduced pressure. The residue was diluted with water (50 ml), and then treated with a 1N HCl solution to adjust the pH to a value between 2 and 3. The resulting solid was collected and dried under reduced pressure to give N - (4 -chloro-3 - ((trifluoromethyl) phenyl) -N '- (4-carboxyphenyl) -urea as a white solid (5.05 g, 92%).

D4. Método General para la Conversión de \omega-Alcoxi-Ésteres en \omega-Alquil-Amidas. Síntesis de N-(4-Cloro-3-((trifluo- rometil)fenil)-N'-((4-(3-(5-(2-dimetilaminoetil)-carbamoil)piridil)oxifenil)-ureaD4 General Method for the Conversion of ome-Alkoxy-Esters into Al-Alkyl-Amides. Synthesis of N - (4-Chloro-3 - ((trifluoromethyl) phenyl) - N '- ((4- (3- (5- (2-dimethylaminoethyl) -carbamoyl) pyridyl) oxyphenyl) -urea

7373

Paso 1He passed one

Síntesis de N-(4-cloro-3-(trifluorometil)fenil)-N'-((4-(3-(5-carboxipiridil)oxifenil)-ureaSynthesis of N - (4-Chloro-3- (trifluoromethyl) phenyl) - N '- ((4- (3- (5-carboxypyridyl) oxyphenyl) -urea

Se sintetizó N-(4-cloro-3-(trifluorometil)fenil)-N'-((4-(3-(5-metoxicarbonilpiridil)oxifenil)-urea a partir de isocianato de 4-cloro-3-(trifluorometil)fenilo y 4-(3-(5-metoxicarbonilpiridil)-oxianilina (Método A14, Paso 2) de una manera análoga al Método C1a. Una suspensión de N-(4-cloro-3-(trifluorometil)fenil)-N'-((4-(3-(5-metoxi-carbonilpiridil)oxifenil)-urea (0,26 g, 0,56 mmol) en MeOH (10 ml) se trató con una solución de KOH (0,14 g, 2,5 mmol) en agua (1 ml) y se agitó a la temperatura ambiente durante 1 h. La mezcla resultante se ajustó a pH 5 con una solución 1N de HCl. El precipitado resultante se separó por filtración y se lavó con agua. Los sólidos resultantes se disolvieron en EtOAc (10 ml) y la solución resultante se concentró a presión reducida. Se repitió dos veces el procedimiento de EtOH/concentración para dar N-(4-cloro-3-(trifluorometil)fenil)-N'-((4-(3-(5-carboxipiridil)oxifenil)-urea (0,18 g, 71%). N - (4-Chloro-3- (trifluoromethyl) phenyl) - N ' - ((4- (3- (5-methoxycarbonylpyridyl) oxyphenyl) -urea was synthesized from 4-chloro-3- (trifluoromethyl) isocyanate phenyl and 4- (3- (5-methoxycarbonylpyridyl) -oxyaniline (Method A14, Step 2) in a manner analogous to Method C1a. A suspension of N - (4-chloro-3- (trifluoromethyl) phenyl) - N ' - ((4- (3- (5-Methoxycarbonylpyridyl) oxyphenyl) -urea (0.26 g, 0.56 mmol) in MeOH (10 ml) was treated with a solution of KOH (0.14 g, 2, 5 mmol) in water (1 ml) and stirred at room temperature for 1 h The resulting mixture was adjusted to pH 5 with a 1N HCl solution.The resulting precipitate was filtered off and washed with water. The resulting were dissolved in EtOAc (10 ml) and the resulting solution was concentrated under reduced pressure The EtOH / concentration procedure was repeated twice to give N- (4-chloro-3- (trifluoromethyl) phenyl) -N ' - ( (4- (3- (5-carboxypyridyl) oxyphenyl) -urea (0.18 g, 71%). 

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7474 

       \newpage\ newpage

Paso 2He passed 2

Síntesis de N-(4-cloro-3-(trifluorometil)fenil)-N'-((4-(3-(5-(2-dimetilaminoetil)carbamoil)-piridil)oxifenil)-ureaSynthesis of N - (4-Chloro-3- (trifluoromethyl) phenyl) - N '- ((4- (3- (5- (2-dimethylaminoethyl) carbamoyl) -pyridyl) oxyphenyl) -urea

Una mezcla de N-(4-cloro-3-(trifluorometil)fenil)-N'-((4-(3-(5-(carboxipiridil)oxifenil)-urea (0,050 g, 0,011
mmol), N,N-dimetiletilenodiamina (0,22 mg, 0,17 mmol), HOBT (0,028 g, 0,17 mmol), N-metilmorfolina (0,035 g, 0,28 mmol), y EDCI.HCl (0,032 g, 0,17 mmol) en DMF (2,5 ml) se agitó a la temperatura ambiente durante una noche. La solución resultante se separó entre EtOAc (50 ml) y agua (50 ml). La fase orgánica se lavó con agua (35 ml), se secó (MgSO_{4}) y se concentró a presión reducida. El residuo se disolvió en una cantidad mínima de CH_{2}Cl_{2} (aproximadamente 2 ml). La solución resultante se trató con Et_{2}O gota a gota para dar N-(4-cloro-3-(trifluorometil)fenil)-N'-((4-(3-(5-(2-dimetilaminoetil)carbamoil)-piridil)oxifenil)-urea como un precipitado blanco (0,48 g, 84%): ^{1}H NMR (DMSO-d_{6}) \delta 2,10 (s, 6H), 3,26 (s, H), 7,03 (d, 2H), 7,52 (d, 2H), 7,60 (m, 3H), 8,05 (s, 1H), 8,43 (s, 1H), 8,58 (t, 1H), 8,69 (s, 1H), 8,90 (s, 1H), 9,14 (s, 1H); HPLC ES-MS m/z 522 ((M+H)^{+}).A mixture of N - (4-chloro-3- (trifluoromethyl) phenyl) - N ' - ((4- (3- (5- (carboxypyridyl) oxyphenyl) -urea (0.050 g, 0.011
mmol), N, N- dimethylethylenediamine (0.22 mg, 0.17 mmol), HOBT (0.028 g, 0.17 mmol), N- methylmorpholine (0.035 g, 0.28 mmol), and EDCI.HCl (0.032 g, 0.17 mmol) in DMF (2.5 ml) was stirred at room temperature overnight. The resulting solution was separated between EtOAc (50 ml) and water (50 ml). The organic phase was washed with water (35 ml), dried (MgSO 4) and concentrated under reduced pressure. The residue was dissolved in a minimum amount of CH 2 Cl 2 (approximately 2 ml). The resulting solution was treated with Et2O dropwise to give N - (4-chloro-3- (trifluoromethyl) phenyl) - N ' - ((4- (3- (5- (2-dimethylaminoethyl)) carbamoyl ) -pyridyl) oxyphenyl) -urea as a white precipitate (0.48 g, 84%): 1 H NMR (DMSO-d 6) δ 2.10 (s, 6H), 3.26 (s, H), 7.03 (d, 2H), 7.52 (d, 2H), 7.60 (m, 3H), 8.05 (s, 1H), 8.43 (s, 1H) , 8.58 (t, 1H), 8.69 (s, 1H), 8.90 (s, 1H), 9.14 (s, 1H); HPLC ES-MS m / z 522 ((M + H ) +).

D5. Método General para la Desprotección de N-(\omega-sililoxialquil)amidas. Síntesis de N-(4-Cloro-3-((trifluorometil)fenil)-N'-(4-(4-(2-(N-(2-hidroxi)-etilcarbamoil)piridiloxifenil)-ureaD5 General Method for the Deprotection of N - (ome-silyloxyalkyl) amides. Synthesis of N - (4-Chloro-3 - ((trifluoromethyl) phenyl) - N '- (4- (4- (2- ( N - (2-hydroxy) -ethylcarbamoyl) pyridyloxyphenyl) -urea

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A una solución de N-(4-cloro-3-((trifluorometil)-fenil)-N'-(4-(4-(2-(N-(2-triisopropilsililoxi)-etilcar-bamoil)piridiloxifenil)-urea (preparada de una manera análoga al Método C1a; 0,25 g, 0,37 mmol) en THF anh (2 ml) se añadió fluoruro de tetrabutilamonio (1,0 M en THF; 2 ml). La mezcla se agitó a la temperatura ambiente durante 5 min, y se trató luego con agua (10 ml). La mezcla acuosa se extrajo con EtOAc (3 x 10 ml). Las capas orgánicas reunidas se secaron (MgSO_{4}) y se concentraron a presión reducida. El residuo se purificó por cromatografía en columna (SiO_{2}; gradiente desde 100% hexano a 40% EtOAc/60% hexano) para dar N-(4-cloro-((trifluorometil)fenil)N-(4-(4-(2-(N-(2-hidroxi)etilcarbamoil)-piridiloxifenil)-urea como un sólido blanco (0,019 g, 10%).To a solution of N - (4-chloro-3 - ((trifluoromethyl) -phenyl) -N '- (4- (4- (2- ( N - (2-triisopropylsilyloxy) -ethylcar-bamoyl) pyridyloxyphenyl) -urea (prepared in a manner analogous to Method C1a; 0.25 g, 0.37 mmol) in THF anh (2 ml) tetrabutylammonium fluoride (1.0 M in THF; 2 ml) was added. The mixture was stirred at room temperature for 5 min, and then treated with water (10 ml) The aqueous mixture was extracted with EtOAc (3 x 10 ml) The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2; gradient from 100% hexane to 40% EtOAc / 60% hexane) to give N - (4-chloro - ((trifluoromethyl) phenyl) N - (4- (4 - (2- ( N - (2-hydroxy) ethylcarbamoyl) -pyridyloxyphenyl) -urea as a white solid (0.019 g, 10%).

A continuación se enumeran compuestos enumerados en las Tablas siguientes que se han sintetizado de acuerdo con los Procedimientos Experimentales Detallados dados anteriormente. En este caso, las entradas de los compuestos 42-45, 49, 85-87, 89, 93, 95 y 96 se refieren a los compuestos de acuerdo con la presente invención. Los compuestos restantes son compuestos de referencia.Listed compounds are listed below. in the following Tables that have been synthesized according to the Detailed Experimental Procedures given above. In this case, the entries of compounds 42-45, 49, 85-87, 89, 93, 95 and 96 refer to the compounds according to the present invention. The compounds Remaining are reference compounds.

Síntesis de los Compuestos Citados como EjemplosSynthesis of Compounds Cited as Examples

(Véanse las Tablas para caracterización de compuestos)(See Tables for characterization of compounds)

Entrada 1: Se preparó 4-(3-N-metilcarbamoilfenoxi)-anilina de acuerdo con el Método A13. De acuerdo con el Método C3, se hizo reaccionar, 3-(terc-butilanilina con carbonato de bis(triclorometilo) seguido por 4-(3-N-metilcarba-
moilfenoxi)anilina para proporcionar la urea.Entry 1: 4- (3- N -methylcarbamoylphenoxy) -aniline was prepared according to Method A13. According to Method C3, 3- ( tert -butylaniline with bis (trichloromethyl) carbonate was reacted followed by 4- (3- N -methylcarba-
moylphenoxy) aniline to provide urea.

Entrada 2: Se hicieron reaccionar 4-fluoro-1-nitrobenceno y p-hidroxiacetofenona de acuerdo con el método A13, Paso 1 para proporcionar el 4-(4-acetilfenoxi)-1-nitrobenceno. Se redujo el 4-(4-acetoxifenoxi)-1-nitrobenceno de acuerdo con el método A13, Paso 4 para proporcionar 4-(4-acetilfenoxi)anilina. De acuerdo con el método C3, se hizo reaccionar 3-terc-butilanilina con carbonato de bis(triclorometilo) seguido por 4-(4-acetilfenoxi)anilina para proporcionar la urea.Entry 2: 4-Fluoro-1-nitrobenzene and p- hydroxyacetophenone were reacted according to method A13, Step 1 to provide 4- (4-acetylphenoxy) -1-nitrobenzene. 4- (4-Acetoxyphenoxy) -1-nitrobenzene was reduced according to method A13, Step 4 to provide 4- (4-acetylphenoxy) aniline. According to method C3, 3- tert -butylaniline was reacted with bis (trichloromethyl) carbonate followed by 4- (4-acetylphenoxy) aniline to provide urea.

Entrada 3: De acuerdo con el Método C2d, se trató 3-terc-butilanilina con CDI, seguido por 4-(3-N-metilcarbamoil)-4-metoxifenoxi)anilina, que se había preparado de acuerdo con el método A8, para proporcionar la urea.Entry 3: According to Method C2d, 3- tert -butylaniline was treated with CDI, followed by 4- (3- N -methylcarbamoyl) -4-methoxyphenoxy) aniline, which had been prepared according to method A8, for provide urea.

Entrada 4: Se convirtió 5-terc-butil-2-metoxianilina en isocianato de 5-terc-butil-2-metoxifenilo de acuerdo con el Método B1. Se hizo reaccionar 4-(3-N-metilcarbamoilfenoxi)anilina, preparada de acuerdo con el Método A13, con el isocianato de acuerdo con el Método C1a para proporcionar la urea.Entry 4: 5- tert -butyl-2-methoxyaniline was converted into 5- tert -butyl-2-methoxyphenyl isocyanate according to Method B1. 4- (3- N -methylcarbamoylphenoxy) aniline, prepared according to Method A13, was reacted with the isocyanate according to Method C1a to provide urea.

Entrada 5: De acuerdo con el Método C2d, se hizo reaccionar 5-terc-butil-2-metoxianilina con CDI seguido por 4-(3-N-metilcarbamoil)-4-metoxifenoxi)anilina, que se había preparado de acuerdo con el Método A8, para proporcionar la urea.Entry 5: According to Method C2d, 5- tert -butyl-2-methoxyaniline was reacted with CDI followed by 4- (3- N -methylcarbamoyl) -4-methoxyphenoxy) aniline, which had been prepared according to Method A8, to provide urea.

Entrada 6: Se preparó 5-(4-aminofenoxi)isoindolina-1,3-diona de acuerdo con el Método A3. De acuerdo con el Método 2d, se hizo reaccionar 5-terc-butil-2-metoxianilina con CDI seguido por 5-(4-aminofenoxi)isoindolina-1,3-diona para proporcionar la urea.Entry 6: 5- (4-Aminophenoxy) isoindoline-1,3-dione was prepared according to Method A3. According to Method 2d, 5- tert -butyl-2-methoxyaniline was reacted with CDI followed by 5- (4-aminophenoxy) isoindoline-1,3-dione to provide urea.

Entrada 7: Se sintetizó 4-(1-oxoindolin-5-iloxi)anilina de acuerdo con el método A12. De acuerdo con el Método 2d, se hizo reaccionar 5-terc-butil-2-metoxianilina con CDI seguido por 4-(1-oxoisoindolin-5-iloxi)anilina para proporcionar la urea.Entry 7: 4- (1-Oxoindolin-5-yloxy) aniline was synthesized according to method A12. According to Method 2d, 5- tert -butyl-2-methoxyaniline was reacted with CDI followed by 4- (1-oxoisoindolin-5-yloxy) aniline to provide urea.

Entrada 8: Se sintetizó 4-(3-N-metilcarbamoil-fenoxi)anilina de acuerdo con el Método A13. De acuerdo con el Método C2a, se hizo reaccionar 2-metoxi-5-(trifluorometil)anilina con CDI seguido por 4-(3-N-metilcarbamoilfenoxi)anilina para proporcionar la urea.Entry 8: 4- (3- N -methylcarbamoyl-phenoxy) aniline was synthesized according to Method A13. According to Method C2a, 2-methoxy-5- (trifluoromethyl) aniline was reacted with CDI followed by 4- (3- N -methylcarbamoylphenoxy) aniline to provide urea.

Entrada 9: Se hizo reaccionar 4-hidroxiacetofenona con 2-cloro-5-nitropiridina para dar 4-(4-acetilfenoxi)-5-nitropiridina de acuerdo con el Método A3, Paso 2. De acuerdo con el Método A8, Paso 4, se redujo 4-(4-acetilfenoxi)-5-nitropiridina a 4-(4-acetilfenoxi)-5-aminopiridina. Se convirtió 2-metoxi-5-(trifluorometil)-anilina en isocianato de 2-metoxi-5-(trifluorometil)-fenilo de acuerdo con el Método B1. El isocianato se hizo reaccionar con 4-(4-acetilfenoxi)-5-aminopiridina de acuerdo con el Método C1a para proporcionar la urea.Entry 9: Reacted 4-hydroxyacetophenone with 2-chloro-5-nitropyridine to give 4- (4-acetylphenoxy) -5-nitropyridine  according to Method A3, Step 2. According to Method A8, Step 4, was reduced 4- (4-acetylphenoxy) -5-nitropyridine  to 4- (4-acetylphenoxy) -5-aminopyridine. He turned 2-methoxy-5- (trifluoromethyl) -aniline in isocyanate 2-methoxy-5- (trifluoromethyl) -phenyl  according to Method B1. The isocyanate was reacted with 4- (4-acetylphenoxy) -5-aminopyridine according to Method C1a to provide urea.

Entrada 10: Se hicieron reaccionar 4-fluoro-1-nitrobenceno y p-hidroxiacetofenona de acuerdo con el Método A13, Paso 1 para proporcionar 4-(4-acetilfenoxi)-1-nitrobenceno. Se redujo el 4-(4-acetilfenoxi)-1-nitrobenceno de acuerdo con el Método A13, Paso 4 para proporcionar 4-(4-acetilfenoxi)anilina. De acuerdo con el Método C3, se hizo reaccionar 5-(trifluorometil)-2-metoxibutilanilina con carbonato de bis(triclorometilo) seguido por 4-(4-acetilfenoxi)anilina para proporcionar la urea.Entry 10: 4-Fluoro-1-nitrobenzene and p- hydroxyacetophenone were reacted according to Method A13, Step 1 to provide 4- (4-acetylphenoxy) -1-nitrobenzene. 4- (4-Acetylphenoxy) -1-nitrobenzene was reduced according to Method A13, Step 4 to provide 4- (4-acetylphenoxy) aniline. According to Method C3, 5- (trifluoromethyl) -2-methoxybutylaniline was reacted with bis (trichloromethyl) carbonate followed by 4- (4-acetylphenoxy) aniline to provide urea.

Entrada 11: 4-(Cloro-N-metil-2-piridinacarboxamida, que se sintetizó de acuerdo con el Método A2, Paso 3a, se hizo reaccionar con 3-aminofenol de acuerdo con el Método A2, Paso 4 utilizando DMAC en lugar de DMF para dar 3-(2-(N-metilcarbamoil)-4-piridiloxi)anilina. De acuerdo con el Método C4, se hizo reaccionar 2-metoxi-5-(trifluorometil)anilina con fosgeno, seguido por 3-(2-(N-metilcarbamoil)-4-piridiloxi)anilina para proporcionar la urea.Entry 11: 4- (Chloro- N -methyl-2-pyridinecarboxamide, which was synthesized according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 using DMAC instead of DMF to give 3- (2- ( N- methylcarbamoyl) -4-pyridyloxy) aniline According to Method C4, 2-methoxy-5- (trifluoromethyl) aniline was reacted with phosgene, followed by 3- (2- ( N- methylcarbamoyl) -4-pyridyloxy) aniline to provide urea.

Entrada 12: Se hizo reaccionar la sal cloruro de 4-cloropiridina-2-carbonilo.HCl con amoníaco de acuerdo con el Método A2, Paso 3b para formar 4-cloro-2-piridinacarboxamida. La 4-cloro-2-piridinacarboxamida se hizo reaccionar con 3-aminofenol de acuerdo con el Método A2, Paso 4 utilizando DMAC en lugar de DMF para dar 3-(2-carbamoil-4-piridiloxi)anilina. De acuerdo con el Método C2a, se hizo reaccionar 2-metoxi-5-(trifluorometil)-anilina con fosgeno seguido por 3-(2-carbamoil-4-piridiloxianilina para proporcionar la urea.Entry 12: The chloride salt of was reacted 4-chloropyridine-2-carbonyl.HCl with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. The 4-chloro-2-pyridinecarboxamide was reacted with 3-aminophenol according to Method A2, Step 4 using DMAC instead of DMF to give 3- (2-carbamoyl-4-pyridyloxy) aniline.  According to Method C2a, it was reacted 2-methoxy-5- (trifluoromethyl) -aniline with phosgene followed by 3- (2-carbamoyl-4-pyridyloxyaniline to provide urea.

Entrada 13: Se sintetizó 4-cloro-N-metil-2-piridinacarboxamida de acuerdo con el Método A2, Paso 3b. Se hizo reaccionar 4-cloro-N-metil-2-piridinacarboxamida con 4-aminofenol de acuerdo con el Método A2, Paso 4 utilizando DMAC en lugar de DMF para dar 4-(2-(N-metilcarbamoil)-4-piridiloxi)anilina. De acuerdo con el Método C2a, se hizo reaccionar 2-metoxi-5-(trifluorometil)anilina con CDI seguido por 4-(2-(N-metilcarbamoil)-4-piridiloxi)anilina para proporcionar la urea.Entry 13: 4-Chloro- N- methyl-2-pyridinecarboxamide was synthesized according to Method A2, Step 3b. 4-Chloro- N- methyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 using DMAC instead of DMF to give 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) aniline. According to Method C2a, 2-methoxy-5- (trifluoromethyl) aniline was reacted with CDI followed by 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) aniline to provide urea.

Entrada 14: Se hizo reaccionar la sal cloruro de 4-cloropiridina-2-carbonilo.HCl con amoníaco de acuerdo con el Método A2, Paso 3b para formar 4-cloro-2-piridinacarboxamida. Se hizo reaccionar la 4-cloro-2-piridinacarboxamida con 4-aminofenol de acuerdo con el Método A2, Paso 4 utilizando DMAC en lugar de DMF para dar 4-(2-carbamoil-4-piridiloxi)anilina. De acuerdo con el Método C4, se hizo reaccionar 2-metoxi-5-(trifluorometil)anilina con fosgeno seguido por 4-(2-carbamoil)-4-piridiloxi)-anilina para proporcionar la urea.Entry 14: The chloride salt of was reacted 4-chloropyridine-2-carbonyl.HCl with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. He reacted the 4-chloro-2-pyridinecarboxamide  with 4-aminophenol according to Method A2, Step 4 using DMAC instead of DMF to give 4- (2-carbamoyl-4-pyridyloxy) aniline.  According to Method C4, it was reacted 2-methoxy-5- (trifluoromethyl) aniline with phosgene followed by 4- (2-carbamoyl) -4-pyridyloxy) -aniline to provide urea.

Entrada 15: De acuerdo con el Método C2d, se hizo reaccionar 5-(trifluorometil)-2-metoxianilina con CDI seguido por 4-(3-N-metilcarbamoil)-4-metoxifenoxi)anilina, que se había preparado de acuerdo con el Método A8, para proporcionar la urea.Entry 15: According to Method C2d, 5- (trifluoromethyl) -2-methoxyaniline was reacted with CDI followed by 4- (3- N -methylcarbamoyl) -4-methoxyphenoxy) aniline, which had been prepared according to Method A8, to provide urea.

Entrada 16: Se sintetizó 4-(2-(N-metilcarbamoil)-4-piridiloxi)-2-metilanilina de acuerdo con el Método A5. Se convirtió 5-(trifluorometil)-2-metoxianilina en isocianato de 5-(trifluorometil)-2-metoxifenilo de acuerdo con el Método B1. El isocianato se hizo reaccionar con 4-(2-(N-metilcarbamoil)-4-piridiloxi)-2-metilanilina de acuerdo con el Método C1c para proporcionar la urea.Entry 16: 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) -2-methylaniline was synthesized according to Method A5. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. The isocyanate was reacted with 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) -2-methylaniline according to Method C1c to provide urea.

Entrada 17: Se sintetizó 4-(2-(N-metilcarbamoil)-4-piridiloxi)-2-cloroanilina de acuerdo con el Método A6. Se convirtió 5-(trifluorometil)-2-metoxianilina en isocianato de 5-(trifluorometil)-2-metoxifenilo de acuerdo con el Método B1. El isocianato de 5-(trifluorometil)-2-metoxifenilo se hizo reaccionar con 4-(2-(N-metilcarbamoil)-4-piridiloxi)-2-cloroanilina de acuerdo con el Método C1a para proporcionar la urea.Entry 17: 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline was synthesized according to Method A6. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. The 5- (trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline according to Method C1a to provide urea.

Entrada 18: De acuerdo con el Método A2, Paso 4, se hizo reaccionar 5-amino-2-metilfenol con 4-cloro-N-metil-2-piridinacarboxamida, que se había sintetizado de acuerdo con el Método A2, Paso 3b, para dar 3-(2-(N-metilcarbamoil)-4-piridiloxi)-4-metilanilina. Se convirtió 5-(trifluorometil)-2-metoxianilina en isocianato de 5-(tri-
fluorometil)-2-metoxifenilo de acuerdo con el Método B1. El isocianato de 5-(trifluorometil)-2-metoxifenilo se hizo reaccionar con 3-(2-(N-metilcarbamoil)-4-piridiloxi)-4-metilanilina de acuerdo con el Método C1a para proporcionar la urea.Entry 18: According to Method A2, Step 4, 5-amino-2-methylphenol was reacted with 4-chloro- N -methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 3- (2- ( N- methylcarbamoyl) -4-pyridyloxy) -4-methylaniline. 5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (tri-
fluoromethyl) -2-methoxyphenyl according to Method B1. The 5- (trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 3- (2- ( N- methylcarbamoyl) -4-pyridyloxy) -4-methylaniline according to Method C1a to provide urea.

Entrada 19: Se hizo reaccionar cloruro de 4-cloropiridina-2-carbonilo con etilamina de acuerdo con el Método A2, Paso 3b. La 4-cloro-N-etil-2-piridinacarboxamida resultante se hizo reaccionar con 4-aminofenol de acuerdo con el Método A2, Paso 4 para dar 4-(2-(N-etilcarbamoil)-4-piridiloxi)anilina. Se convirtió 5-(trifluorometil)-2-metoxianilina en isocianato de 5-(trifluorometil)-2-metoxifenilo de acuerdo con el Método B1. Se hizo reaccionar el isocianato de 5-(trifluorometil)-2-metoxifenilo con 4-(2-(N-etilcarbamoil)-4-piridiloxi)anilina de acuerdo con el Método C1a para proporcionar la urea.Entry 19: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro- N- ethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4- (2- ( N -ethylcarbamoyl) -4-pyridyloxy) aniline. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. The 5- (trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (2- ( N- ethylcarbamoyl) -4-pyridyloxy) aniline according to Method C1a to provide urea.

Entrada 20: De acuerdo con el Método A2, Paso 4, se hizo reaccionar 4-amino-2-clorofenol con 4-cloro-N-metil-2-piridinacarboxamida, que se había sintetizado de acuerdo con el Método A2, Paso 3b, para dar 4-(2-(N-metilcarbamoil)-4-piridiloxi)-3-cloroanilina. Se convirtió 5-(trifluorometil)-2-metoxianilina en isocianato de 5-(tri-
fluorometil)-2-metoxifenilo de acuerdo con el Método B1. El isocianato de 5-(trifluorometil)-2-metoxifenilo se hizo reaccionar con 4-(2-(N-metilcarbamoil)-4-piridiloxi)-3-cloroanilina de acuerdo con el Método C1a para proporcionar la urea.Entry 20: According to Method A2, Step 4, 4-amino-2-chlorophenol was reacted with 4-chloro- N- methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline. 5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (tri-
fluoromethyl) -2-methoxyphenyl according to Method B1. The 5- (trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline according to Method C1a to provide urea.

Entrada 21: Se oxidó 4-(4-metiltiofenoxi)-1-nitrobenceno de acuerdo con el Método A19, Paso 1 para dar 4-(4-metilsulfonilfenoxi)-1-nitrobenceno. El nitrobenceno se redujo de acuerdo con el Método A19, Paso 2 para dar 4-(4-metilsulfonilfenoxi)-1-anilina. De acuerdo con el Método C1a, el isocianato de 5-(trifluorometil)-2-metoxifenilo se hizo reaccionar con 4-(4-metilsulfonilfenoxi)-1-anilina para proporcionar la urea.Entry 21: Rusted 4- (4-methylthiophenoxy) -1-nitrobenzene According to Method A19, Step 1 to give 4- (4-Methylsulfonylphenoxy) -1-nitrobenzene. Nitrobenzene was reduced according to Method A19, Step 2 to give 4- (4-Methylsulfonylphenoxy) -1-aniline. According to Method C1a, the isocyanate of 5- (trifluoromethyl) -2-methoxyphenyl was reacted with 4- (4-Methylsulfonylphenoxy) -1-aniline to provide urea.

Entrada 22: Se redujo 4-(3-carbamoilfenoxi)-1-nitrobenceno a 4-(3-carbamoilfenoxi)anilina de acuerdo con el Método A15, Paso 4. De acuerdo con el Método C1a, se hizo reaccionar isocianato de 5-(trifluorometil)-2-metoxifenilo con 4-(3-carbamoilfenoxi)anilina para proporcionar la urea.Entry 22: Reduced 4- (3-carbamoylphenoxy) -1-nitrobenzene to 4- (3-carbamoylphenoxy) aniline according to  Method A15, Step 4. According to Method C1a, it was done react isocyanate from 5- (trifluoromethyl) -2-methoxyphenyl with 4- (3-carbamoylphenoxy) aniline for provide urea.

Entrada 23: Se sintetizó 5-(4-(aminofenoxi)-isoindolina-1,3-diona de acuerdo con el Método A3. Se convirtió 5-(trifluorometil)-2-metoxianilina en isocianato de 5-(trifluorometil)-2-metoxifenilo de acuerdo con el Método B1. El isocianato de 5-(trifluorometil)-2-metoxifenilo se hizo reaccionar con 5-(4-aminofenoxi)isoindolina-1,3-diona de acuerdo con el Método C1a para proporcionar la urea.Entry 23: It was synthesized 5- (4- (aminophenoxy) -isoindoline-1,3-dione according to Method A3. He turned 5- (trifluoromethyl) -2-methoxyaniline in isocyanate 5- (trifluoromethyl) -2-methoxyphenyl of according to Method B1. Isocyanate 5- (trifluoromethyl) -2-methoxyphenyl se he reacted with 5- (4-aminophenoxy) isoindoline-1,3-dione  according to Method C1a to provide urea.

Entrada 24: Se hizo reaccionar cloruro de 4-cloropiridina-2-carbonilo con dimetilamina de acuerdo con el Método A2, Paso 3b. La 4-cloro-N,N-dimetil-2-piridinacarboxamida resultante se hizo reaccionar con 4-aminofenol de acuerdo con el Método A2, Paso 4 para dar 4-(2-(N,N-dimetilcarbamoil)-4-piridiloxi)anilina. Se convirtió 5-(trifluorometil)-2-metoxianilina en isocianato de 5-(trifluorometil)-2-metoxifenilo de acuerdo con el Método B1. El isocianato de 5-(trifluorometil)-2-metoxifenilo se hizo reaccionar con 4-(2-(N,N-dimetilcarbamoil)-4-piridiloxi)anilina de acuerdo con el Método C1a para proporcionar la urea.Entry 24: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro- N, N- dimethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4- (2- ( N, N- dimethylcarbamoyl) -4-pyridyloxy) aniline. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. The 5- (trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (2- ( N, N- dimethylcarbamoyl) -4-pyridyloxy) aniline according to Method C1a to provide urea.

Entrada 25: Se sintetizó 4-(1-oxoisoindolin-5-iloxi)anilina de acuerdo con el Método A12. Se trató 5-(trifluoro-
metil)-2-metoxianilina con CDI, seguido por 4-(1-oxoisoindolin-5-iloxi)anilina de acuerdo con el Método C2d para proporcionar la urea.Entry 25: 4- (1-Oxoisoindolin-5-yloxy) aniline was synthesized according to Method A12. It was treated 5- (trifluoro-
methyl) -2-methoxyaniline with CDI, followed by 4- (1-oxoisoindolin-5-yloxy) aniline according to Method C2d to provide urea.

Entrada 26: Se hizo reaccionar 4-hidroxiacetofenona con 4-fluoronitrobenceno de acuerdo con el Método A13, Paso 1 para dar 4-(4-acetilfenoxi)nitrobenceno. El nitrobenceno se redujo de acuerdo con el Método A13, Paso 4 para proporcionar 4-(4-acetilfenoxi)anilina, que se convirtió en la sal 4-(4-(1-(N-metoxi)iminoetil)fenoxi-anilina.HCl de acuerdo con el Método A16. Se convirtió 5-(trifluorometil)-2-metoxianilina en isocianato de 5-(trifluorometil)-2-metoxifenilo de acuerdo con el Método B1. El isocianato de 5-(trifluorometil)-2-metoxifenilo se hizo reaccionar con la sal 4-(4-(1-(N-metoxi)imino-etil)fenoxianilina.HCl de acuerdo con el Método C1a para proporcionar la urea.Entry 26: 4-Hydroxyacetophenone was reacted with 4-fluoronitrobenzene according to Method A13, Step 1 to give 4- (4-acetylphenoxy) nitrobenzene. Nitrobenzene was reduced according to Method A13, Step 4 to provide 4- (4-acetylphenoxy) aniline, which became the salt 4- (4- (1- ( N -methoxy) iminoethyl) phenoxy-aniline. HCl according to Method A16. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 5- (Trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with the salt 4- (4- (1- ( N -methoxy) imino-ethyl) phenoxyaniline.HCl according to Method C1a to provide urea.

Entrada 27: Se sintetizó 4-cloro-N-metilpiridinacarboxamida como se describe en el Método A2, Paso 3b. La cloropiridina se hizo reaccionar con 4-aminotiofenol de acuerdo con el Método A2, Paso 4 para dar 4-(4-(2-(N-metilcarbamoil)feniltio)anilina. Se convirtió 5-(trifluorometil)-2-metoxianilina en isocianato de 5-(trifluorometil)-2-metoxifenilo de acuerdo con el Método B1. El isocianato de 5-(trifluorometil)-2-metoxifenilo se hizo reaccionar con 4-(4-(2-(N-metilcarbamoil)feniltio)anilina de acuerdo con el Método C1a para proporcionar la urea.Entry 27: 4-Chloro- N- methylpyridinecarboxamide was synthesized as described in Method A2, Step 3b. Chloropyridine was reacted with 4-aminothiophenol according to Method A2, Step 4 to give 4- (4- (2- ( N- methylcarbamoyl) phenylthio) aniline.) 5- (Trifluoromethyl) -2-methoxyaniline was converted to isocyanate of 5- (trifluoromethyl) -2-methoxyphenyl according to Method B1. The 5- (trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (4- (2- ( N- methylcarbamoyl) phenylthio) aniline according to Method C1a to provide urea.

Entrada 28: Se sintetizó 5-(4-aminofenoxi)-2-metilisoindolina-1,3-diona de acuerdo con el Método A9. Se convirtió 5-(trifluorometil)-2-metoxianilina en isocianato de 5-(trifluorometil)-2-metoxifenilo de acuerdo con el Método B1. Se hizo reaccionar el isocianato de 5-(trifluorometil)-2-metoxifenilo con 5-(4-aminofenoxi)-2-metilisoindolina-1,3-diona de acuerdo con el Método C1a para proporcionar la urea.Entry 28: It was synthesized 5- (4-aminophenoxy) -2-methylisoindoline-1,3-dione according to Method A9. He turned 5- (trifluoromethyl) -2-methoxyaniline in isocyanate 5- (trifluoromethyl) -2-methoxyphenyl of according to Method B1. The isocyanate was reacted from 5- (trifluoromethyl) -2-methoxyphenyl with 5- (4-aminophenoxy) -2-methylisoindoline-1,3-dione  according to Method C1a to provide urea.

Entrada 29: Se sintetizó 4-cloro-N-metilpiridinacarboxamida como se describe en el Método A2, Paso 3b. La cloropiridina se hizo reaccionar con 3-aminotiofenol de acuerdo con el Método A2, Paso 4 para dar 3-(4-(2-(N-metilcarbamoil)feniltio)anilina. Se convirtió 5-(trifluorometil)-2-metoxianilina en isocianato de 5-(trifluorometil)-2-metoxifenilo de acuerdo con el Método B1. El isocianato de 5-(trifluorometil)-2-metoxifenilo se hizo reaccionar con 3-(4-(2-(N-metilcarbamoil)feniltio)-anilina de acuerdo con el Método C1a para proporcionar la urea.Entry 29: 4-Chloro- N- methylpyridinecarboxamide was synthesized as described in Method A2, Step 3b. Chloropyridine was reacted with 3-aminothiophenol according to Method A2, Step 4 to give 3- (4- (2- ( N- methylcarbamoyl) phenylthio) aniline.) 5- (Trifluoromethyl) -2-methoxyaniline was converted to isocyanate of 5- (trifluoromethyl) -2-methoxyphenyl according to Method B. 1. The 5- (trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 3- (4- (2- ( N- methylcarbamoyl) phenylthio) -aniline according to Method C1a to provide urea.

Entrada 30: Se hizo reaccionar cloruro de 4-cloropiridina-2-carbonilo con isopropilamina de acuerdo con el Método A2, Paso 3b. La 4-cloro-N-isopropil-2-piridinacarboxamida resultante se hizo reaccionar con 4-aminofenol de acuerdo con el Método A2, Paso 4 para dar 4-(2-(N-isopropilcarbamoil)-4-piridiloxi)anilina. Se convirtió 5-(trifluorometil)-2-metoxianilina en isocianato de 5-(trifluorometil)-2-metoxifenilo de acuerdo con el Método B1. El 5-(trifluorometil)-2-metoxifenilo se hizo reaccionar con 4-(2-(N-isopropilcarbamoil)-4-piridiloxi)-anilina de acuerdo con el Método C1a para proporcionar la urea.Entry 30: 4-Chloropyridine-2-carbonyl chloride was reacted with isopropylamine according to Method A2, Step 3b. The resulting 4-chloro- N- isopropyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4- (2- ( N- isopropylcarbamoyl) -4-pyridyloxy) aniline. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. The 5- (trifluoromethyl) -2-methoxyphenyl was reacted with 4- (2- ( N -isopropylcarbamoyl) -4-pyridyloxy) -aniline according to Method C1a to provide urea. 

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Entrada 31: Se sintetizó 4-(3-(5-metoxicarbonil)-piridiloxi)anilina de acuerdo con el Método A14. Se convirtió 5-(trifluorometil)-2-metoxianilina en isocianato de 5-(trifluorometil)-2-metoxifenilo de acuerdo con el Método B1. El isocianato de 5-(trifluorometil)-2-metoxifenilo se hizo reaccionar con 4-(3-(5-metoxicarbonil)piridiloxi)anilina de acuerdo con el Método C1a para proporcionar la urea. Se saponificó N-(5-(trifluorometil)-2-metoxifenil)-N'-(4-(3-(5-metoxicarbonilpiridil)oxi)fenil)-urea de acuerdo con el método D4, Paso 1, y el ácido correspondiente se acopló con 4-(2-aminoetil)morfolina para proporcionar la amida de acuerdo con el Método D4, Paso 2.Entry 31: 4- (3- (5-Methoxycarbonyl) -pyridyloxy) aniline was synthesized according to Method A14. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. The 5- (trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to Method C1a to provide urea. N - (5- (trifluoromethyl) -2-methoxyphenyl) - N ' - (4- (3- (5-methoxycarbonylpyridyl) oxy) phenyl) -urea was saponified according to method D4, Step 1, and the corresponding acid was coupled with 4- (2-aminoethyl) morpholine to provide the amide according to Method D4, Step 2.

Entrada 32: Se sintetizó 4-(3-(5-metoxicarbonil)-piridiloxi)anilina de acuerdo con el Método A14. Se convirtió 5-(trifluorometil)-2-metoxianilina en isocianato de 5-(trifluorometil)-2-metoxifenilo de acuerdo con el Método B1. Se hizo reaccionar el isocianato de 5-(trifluorometil)-2-metoxifenilo con 4-(3-(5-metoxicarbonil)piridiloxi)anilina de acuerdo con el Método C1a para proporcionar la urea. Se saponificó N-(5-(trifluorometil)-2-metoxifenil)-N'-(4-(3-(5-metoxicarbonilpiridil)-oxi)fenil)-urea de acuerdo con el método D4, Paso 1, y el ácido correspondiente se acopló con metilamina de acuerdo con el Método D4, Paso 2 para proporcionar la amida.Entry 32: 4- (3- (5-Methoxycarbonyl) -pyridyloxy) aniline was synthesized according to Method A14. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. The 5- (trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to Method C1a to provide urea. N - (5- (trifluoromethyl) -2-methoxyphenyl) - N ' - (4- (3- (5-methoxycarbonylpyridyl) -oxy) phenyl) -urea was saponified according to method D4, Step 1, and the acid corresponding was coupled with methylamine according to Method D4, Step 2 to provide the amide.

Entrada 33: Se sintetizó 4-(3-(5-metoxicarbonil)-piridiloxi)anilina de acuerdo con el Método A14. Se convirtió 5-(trifluorometil)-2-metoxianilina en isocianato de 5-(trifluorometil)-2-metoxifenilo de acuerdo con el Método B1. El isocianato de 5-(trifluorometil)-2-metoxifenilo se hizo reaccionar con 4-(3-(5-metoxicarbonil)piridiloxi)anilina de acuerdo con el Método C1a para proporcionar la urea. Se saponificó N-(5-(trifluorometil)-2-metoxifenil)-N'-(4-(3-(5-metoxicarbonilpiridil)oxi)fenil)-urea de acuerdo con el método D4, Paso 1, y el ácido correspondiente se acopló con N,N-dimetiletilenodiamina de acuerdo con el Método D4, Paso 2 para proporcionar la amida.Entry 33: 4- (3- (5-Methoxycarbonyl) -pyridyloxy) aniline was synthesized according to Method A14. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. The 5- (trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to Method C1a to provide urea. N - (5- (trifluoromethyl) -2-methoxyphenyl) - N ' - (4- (3- (5-methoxycarbonylpyridyl) oxy) phenyl) -urea was saponified according to method D4, Step 1, and the corresponding acid It was coupled with N, N- dimethylethylenediamine according to Method D4, Step 2 to provide the amide.

Entrada 34: Se sintetizó 4-(3-carboxifenoxi)anilina de acuerdo con el Método A11. Se convirtió 5-(trifluorometil)-2-metoxianilina en isocianato de 5-(trifluorometil)-2-metoxifenilo de acuerdo con el Método B1. Se hizo reaccionar 4-(3-carboxifenoxi)anilina con isocianato de 5-(trifluorometil)-2-metoxifenilo de acuerdo con el Método C1f para proporcionar N-(5-(trifluorometil)-2-metoxifenil)-N'-(3-carboxifenil)-urea, que se acopló con 3-aminopiridina de acuerdo con el Método D1c.Entry 34: 4- (3-Carboxyphenoxy) aniline was synthesized according to Method A11. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 4- (3-Carboxyphenoxy) aniline was reacted with 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method C1f to provide N - (5- (trifluoromethyl) -2-methoxyphenyl) - N ' - (3 -carboxyphenyl) -urea, which was coupled with 3-aminopyridine according to Method D1c.

Entrada 35: Se sintetizó 4-(3-carboxifenoxi)anilina de acuerdo con el Método A11. Se convirtió 5-(trifluorometil)-2-metoxianilina en isocianato de 5-(trifluorometil)-2-metoxifenilo de acuerdo con el Método B1. Se hizo reaccionar 4-(3-carboxifenoxi)anilina con isocianato de 5-(trifluorometil)-2-metoxifenilo de acuerdo con el Método C1f para proporcionar N-(5-(trifluorometil)-2-metoxifenil)-N'-(3-carboxifenil)-urea, que se acopló con N-(4-fluorofenil)piperazina de acuerdo con el Método D1c.Entry 35: 4- (3-Carboxyphenoxy) aniline was synthesized according to Method A11. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 4- (3-Carboxyphenoxy) aniline was reacted with 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method C1f to provide N - (5- (trifluoromethyl) -2-methoxyphenyl) - N ' - (3 -carboxyphenyl) -urea, which was coupled with N - (4-fluorophenyl) piperazine according to Method D1c.

Entrada 36: Se sintetizó 4-(3-carboxifenoxi)anilina de acuerdo con el Método A11. Se convirtió 5-(trifluorometil)-2-metoxianilina en isocianato de 5-(trifluorometil)-2-metoxifenilo de acuerdo con el Método B1. Se hizo reaccionar 4-(3-carboxifenoxi)anilina con el isocianato de 5-(trifluorometil)-2-metoxifenilo de acuerdo con el Método C1f para proporcionar N-(5-(trifluorometil)-2-metoxifenil)-N'-(3-carboxifenil)-urea, que se acopló con 4-fluoroanilina de acuerdo con el Método D1c.Entry 36: 4- (3-Carboxyphenoxy) aniline was synthesized according to Method A11. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 4- (3-Carboxyphenoxy) aniline was reacted with the 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method C1f to provide N - (5- (trifluoromethyl) -2-methoxyphenyl) - N ' - ( 3-carboxyphenyl) -urea, which was coupled with 4-fluoroaniline according to Method D1c.

Entrada 37: Se sintetizó 4-(3-carboxifenoxi)anilina de acuerdo con el Método A11. Se convirtió 5-(trifluorometil)-2-metoxianilina en isocianato de 5-(trifluorometil)-2-metoxifenilo de acuerdo con el Método B1. Se hizo reaccionar 4-(3-carboxifenoxi)anilina con el isocianato de 5-(trifluorometil)-2-metoxifenilo de acuerdo con el Método C1f para proporcionar N-(5-(trifluorometil)-2-metoxifenil)-N'-(3-carboxifenil)-urea, que se acopló con 4-(dimetilamino)anilina de acuerdo con el Método D1c.Entry 37: 4- (3-Carboxyphenoxy) aniline was synthesized according to Method A11. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 4- (3-Carboxyphenoxy) aniline was reacted with the 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method C1f to provide N - (5- (trifluoromethyl) -2-methoxyphenyl) - N ' - ( 3-carboxyphenyl) -urea, which was coupled with 4- (dimethylamino) aniline according to Method D1c.

Entrada 38: Se sintetizó 4-(3-carboxifenoxi)anilina de acuerdo con el Método A11. Se convirtió 5-(trifluorometil)-2-metoxianilina en isocianato de 5-(trifluorometil)-2-metoxifenilo de acuerdo con el Método B1. Se hizo reaccionar 4-(3-carboxifenoxi)anilina con el isocianato de 5-(trifluorometil)-2-metoxifenilo de acuerdo con el Método C1f para proporcionar N-(5-(trifluorometil)-2-metoxifenil)-N'-(3-carboxifenil)-urea, que se acopló con 5-amino-2-metoxipiridina de acuerdo con el Método D1c.Entry 38: 4- (3-Carboxyphenoxy) aniline was synthesized according to Method A11. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 4- (3-Carboxyphenoxy) aniline was reacted with the 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method C1f to provide N - (5- (trifluoromethyl) -2-methoxyphenyl) - N ' - ( 3-carboxyphenyl) -urea, which was coupled with 5-amino-2-methoxypyridine according to Method D1c.

Entrada 39: Se sintetizó 4-(3-carboxifenoxi)anilina de acuerdo con el Método A11. Se convirtió 5-(trifluorometil)-2-metoxianilina en isocianato de 5-(trifluorometil)-2-metoxifenilo de acuerdo con el Método B1. Se hizo reaccionar 4-(3-carboxifenoxi)anilina con el isocianato de 5-(trifluorometil)-2-metoxifenilo de acuerdo con el Método C1f para proporcionar N-(5-(trifluorometil)-2-metoxifenil)-N'-(3-carboxifenil)-urea, que se acopló con 4-morfolinoanilina de acuerdo con el Método D1c.Entry 39: 4- (3-Carboxyphenoxy) aniline was synthesized according to Method A11. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 4- (3-Carboxyphenoxy) aniline was reacted with the 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method C1f to provide N - (5- (trifluoromethyl) -2-methoxyphenyl) - N ' - ( 3-carboxyphenyl) -urea, which was coupled with 4-morpholinoaniline according to Method D1c.

Entrada 40: Se sintetizó 4-(3-carboxifenoxi)anilina de acuerdo con el Método A11. Se convirtió 5-(trifluorometil)-2-metoxianilina en isocianato de 5-(trifluorometil)-2-metoxifenilo de acuerdo con el Método B1. Se hizo reaccionar 4-(3-carboxifenoxi)anilina con el isocianato de 5-(trifluorometil)-2-metoxifenilo de acuerdo con el Método C1f para proporcionar N-(5-(trifluorometil)-2-metoxifenil)-N'-(3-carboxifenil)-urea, que se acopló con N-(2-piridil)piperazina de acuerdo con el Método D1c.Entry 40: 4- (3-Carboxyphenoxy) aniline was synthesized according to Method A11. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 4- (3-Carboxyphenoxy) aniline was reacted with the 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method C1f to provide N - (5- (trifluoromethyl) -2-methoxyphenyl) - N ' - ( 3-carboxyphenyl) -urea, which was coupled with N - (2-pyridyl) piperazine according to Method D1c.

Entrada 41: Se sintetizó 4-(3-N-metilcarbamoil)-fenoxi)anilina de acuerdo con el Método A13. De acuerdo con el Método C3, se convirtió 4-cloro-3-(trifluorometil)anilina en el isocianato, y se hizo reaccionar luego con 4-(3-N-metilcarbamoil)-fenoxi)anilina para proporcionar la urea.Entry 41: 4- (3- N -methylcarbamoyl) -phenoxy) aniline was synthesized according to Method A13. According to Method C3, 4-chloro-3- (trifluoromethyl) aniline was converted into the isocyanate, and then reacted with 4- (3- N -methylcarbamoyl) -phenoxy) aniline to provide urea.

Entrada 42: Se sintetizó 4-(2-N-metilcarbamoil-4-piridiloxi)anilina de acuerdo con el Método A2. Se hizo reaccionar isocianato de 4-cloro-3-(trifluorometil)fenilo con 4-(2-N-metilcarbamil-4-piridiloxi)anilina de acuerdo con el Método C1a para proporcionar la urea.Entry 42: 4- (2- N -methylcarbamoyl-4-pyridyloxy) aniline was synthesized according to Method A2. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- N -methylcarbamyl-4-pyridyloxy) aniline according to Method C1a to provide urea.

Entrada 43: Se hizo reaccionar la sal cloruro de 4-cloropiridina-2-carbonilo.HCl con amoníaco de acuerdo con el Método A2, Paso 3b para formar 4-cloro-2-piridinacarboxamida. Se hizo reaccionar la 4-cloro-2-piridinacarboxamida con 4-aminofenol de acuerdo con el Método A2, Paso 4 para formar 4-(2-carbamoil-4-piridiloxi)anilina. De acuerdo con el Método C1a, se hizo reaccionar isocianato de 4-cloro-3-(trifluorometil)fenilo con 4-(2-carbamoil-4-piridiloxi)anilina para proporcionar la urea.Entry 43: The chloride salt of was reacted 4-chloropyridine-2-carbonyl.HCl with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. He reacted the 4-chloro-2-pyridinecarboxamide  with 4-aminophenol according to Method A2, Step 4 to form 4- (2-carbamoyl-4-pyridyloxy) aniline. According to Method C1a, isocyanate was reacted from 4-chloro-3- (trifluoromethyl) phenyl with 4- (2-carbamoyl-4-pyridyloxy) aniline  to provide urea.

Entrada 44: Se hizo reaccionar la sal cloruro de 4-cloropiridina-2-carbonilo.HCl con amoníaco de acuerdo con el Método A2, Paso 3b para formar 4-cloro-2-piridinacarboxamida. Se hizo reaccionar la 4-cloro-2-piridinacarboxamida con 3-aminofenol de acuerdo con el Método A2, Paso 4 para formar 3-(2-carbamoil-4-piridiloxi)anilina. De acuerdo con el Método C1a, se hizo reaccionar isocianato de 4-cloro-3-(trifluorometil)fenilo con 3-(2-carbamoil-4-piridiloxi)anilina para proporcionar la urea.Entry 44: The chloride salt of was reacted 4-chloropyridine-2-carbonyl.HCl with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. He reacted the 4-chloro-2-pyridinecarboxamide  with 3-aminophenol according to Method A2, Step 4 to form 3- (2-carbamoyl-4-pyridyloxy) aniline. According to Method C1a, isocyanate was reacted from 4-chloro-3- (trifluoromethyl) phenyl with 3- (2-carbamoyl-4-pyridyloxy) aniline  to provide urea.

Entrada 45: 4-Cloro-N-metil-2-piridinacarboxamida, que se sintetizó de acuerdo con el Método A2, Paso 3a, se hizo reaccionar con 3-aminofenol de acuerdo con el Método A2, Paso 4 para formar 3-(2-N-metilcarbamoil)-4-piridiloxi)anilina. De acuerdo con el Método C1a, se hizo reaccionar isocianato de 4-cloro-3-(trifluorometil)fenilo con 3-(2-N-metilcarbamoil)-4-piridiloxi)anilina para proporcionar la urea.Entry 45: 4-Chloro- N -methyl-2-pyridinecarboxamide, which was synthesized according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 to form 3- (2 - N -methylcarbamoyl) -4-pyridyloxy) aniline. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 3- (2- N -methylcarbamoyl) -4-pyridyloxy) aniline to provide urea.

Entrada 46: Se sintetizó 5-(4-aminofenoxi)iso-indolina-1,3-diona de acuerdo con el Método A3. De acuerdo con el Método C1a, se hizo reaccionar isocianato de 4-cloro-3-(trifluorometil)fenilo con 5-(4-aminofenoxi)isoindolina-1,3-diona para proporcionar la urea.Entry 46: It was synthesized 5- (4-aminophenoxy) iso-indoline-1,3-dione according to Method A3. According to Method C1a, it was done react isocyanate from 4-chloro-3- (trifluoromethyl) phenyl with 5- (4-aminophenoxy) isoindoline-1,3-dione  to provide urea.

Entrada 47: Se sintetizó 4-(2-(N-metilcarbamoil)-4-piridiloxi)-2-metilanilina de acuerdo con el Método A5. De acuerdo con el Método C1c, se hizo reaccionar isocianato de 4-cloro-3-(trifluorometil)fenilo con 5-(4-aminofenoxi)isoindolina-1,3-diona para proporcionar la urea.Entry 47: 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) -2-methylaniline was synthesized according to Method A5. According to Method C1c, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 5- (4-aminophenoxy) isoindoline-1,3-dione to provide urea.

Entrada 48: Se sintetizó 4-(3-N-metilsulfamoil)-feniloxi)anilina de acuerdo con el Método A15. De acuerdo con el Método C1a, se hizo reaccionar isocianato de 4-cloro-3-(trifluorometil)fenilo con 4-(3-N-metilsulfamoil)feniloxi)anilina para proporcionar la urea.Entry 48: 4- (3- N- Methylsulfamoyl) -phenyloxy) aniline was synthesized according to Method A15. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3- N -methylsulfamoyl) phenyloxy) aniline to provide urea.

Entrada 49: Se sintetizó 4-(2-(N-metilcarbamoil)-4-piridiloxi)-2-cloroanilina de acuerdo con el Método A6. De acuerdo con el Método C1a, se hizo reaccionar isocianato de 4-cloro-3-(trifluorometil)fenilo con 4-(2-(N-metilcarba-
moil)-4-piridiloxi)-2-cloroanilina para proporcionar la urea.Entry 49: 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline was synthesized according to Method A6. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- ( N- methylcarba)
moil) -4-pyridyloxy) -2-chloroaniline to provide urea.

Entrada 50: De acuerdo con el Método A2, Paso 4, se hizo reaccionar 5-amino-2-metilfenol con 4-cloro-N-metil-2-piridinacarboxamida, que se había sintetizado de acuerdo con el Método A2, paso 3b, para dar 3-(2-(N-metilcarbamoil)-4-piridiloxi)-4-metilanilina. De acuerdo con el Método C1a, se hizo reaccionar isocianato de 4-cloro-3-(trifluorometil)fenilo con 3-(2-(N-metilcarbamoil)-4-piridiloxi)-4-metilanilina para proporcionar la urea.Entry 50: According to Method A2, Step 4, 5-amino-2-methylphenol was reacted with 4-chloro- N -methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, step 3b, to give 3- (2- ( N- methylcarbamoyl) -4-pyridyloxy) -4-methylaniline. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 3- (2- ( N- methylcarbamoyl) -4-pyridyloxy) -4-methylaniline to provide urea.

Entrada 51: Se hizo reaccionar cloruro de 4-cloropiridina-2-carbonilo con etilamina de acuerdo con el Método A2, Paso 3b. La 4-cloro-N-etil-2-piridinacarboxamida resultante se hizo reaccionar con 4-aminofenol de acuerdo con el Método A2, Paso 4 para dar 4-(2-(N-etilcarbamoil)-4-piridiloxi)anilina. De acuerdo con el Método C1a, se hizo reaccionar isocianato de 4-cloro-3-(trifluorometil)fenilo con 4-(2-N-etilcarbamoil)-4-piridiloxi)anilina para proporcionar la urea.Entry 51: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro- N- ethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4- (2- ( N -ethylcarbamoyl) -4-pyridyloxy) aniline. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- N -ethylcarbamoyl) -4-pyridyloxy) aniline to provide urea.

Entrada 52: De acuerdo con el Método A2, Paso 4, se hizo reaccionar 4-amino-2-clorofenol con 4-cloro-N-metil-2-piridinacarboxamida, que se había sintetizado de acuerdo con el Método A2, Paso 3b, para dar 4-(2-(N-metilcarbamoil)-4-piridiloxi)-3-cloroanilina. De acuerdo con el Método C1a, se hizo reaccionar isocianato de 4-cloro-3-(trifluorometil)fenilo con 4-(2-(N-metilcarbamoil)-4-piridiloxi)-3-cloroanilina para proporcionar la urea.Entry 52: According to Method A2, Step 4, 4-amino-2-chlorophenol was reacted with 4-chloro- N- methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline to provide urea.

Entrada 53: Se oxidó 4-(4-metiltiofenoxi)-1-nitrobenceno de acuerdo con el Método A19, Paso 1 para dar 4-(4-metilsulfonilfenoxi)-1-nitrobenceno. El nitrobenceno se redujo de acuerdo con el Método A19, Paso 2 para dar 4-(4-metilsulfonilfenoxi)-1-anilina. De acuerdo con el Método C1a, se hizo reaccionar isocianato de 4-cloro-3-(trifluorometil)fenilo con 4-(4-metilsulfonilfenoxi)-1-anilina para proporcionar la urea.Entry 53: Rusted 4- (4-methylthiophenoxy) -1-nitrobenzene According to Method A19, Step 1 to give 4- (4-Methylsulfonylphenoxy) -1-nitrobenzene.  Nitrobenzene was reduced according to Method A19, Step 2 to give 4- (4-Methylsulfonylphenoxy) -1-aniline.  According to Method C1a, isocyanate was reacted from 4-chloro-3- (trifluoromethyl) phenyl with 4- (4-Methylsulfonylphenoxy) -1-aniline  to provide urea.

Entrada 54: Se hizo reaccionar cloruro de 4-bromobencenosulfonilo con metilamina de acuerdo con el Método A15, Paso 1 para proporcionar N-metil-4-bromobencenosulfonamida. Se acopló la N-metil-4-bromobencenosulfonamida con fenol de acuerdo con el Método A15, Paso 2 para proporcionar 4-(4-(N-metilsulfamoil)-fenoxi)benceno. Se convirtió el 4-(4-(N-metilsulfamoil)-fenoxi)benceno en 4-(4-(N-metilsulfamoil)fenoxi)-1-nitrobenceno de acuerdo con el Método A15, Paso 3. El 4-(4-(N-metilsulfamoil)fenoxi)-1-nitrobenceno se redujo a 4-(4-N-metilsulfamoil)feniloxi)anilina de acuerdo con el Método A15, Paso 4. De acuerdo con el Método C1a, se hizo reaccionar isocianato de 4-cloro-3-(trifluorometil)fenilo con 4-(3-N-metilsulfamoil)feniloxi)anilina para proporcionar la urea.Entry 54: 4-Bromobenzenesulfonyl chloride was reacted with methylamine according to Method A15, Step 1 to provide N- methyl-4-bromobenzenesulfonamide. The N- methyl-4-bromobenzenesulfonamide was coupled with phenol according to Method A15, Step 2 to provide 4- (4- ( N- methylsulfamoyl) -phenoxy) benzene. 4- (4- ( N- Methylsulfamoyl) -phenoxy) benzene was converted to 4- (4- ( N- methylsulfamoyl) phenoxy) -1-nitrobenzene according to Method A15, Step 3. 4- (4- ( N- Methylsulfamoyl) phenoxy) -1-nitrobenzene was reduced to 4- (4- N -methylsulfamoyl) phenyloxy) aniline according to Method A15, Step 4. According to Method C1a, isocyanate was reacted 4- Chloro-3- (trifluoromethyl) phenyl with 4- (3- N -methylsulfamoyl) phenyloxy) aniline to provide urea.

Entrada 55: Se acopló 5-hidroxi-2-metilpiridina con 1-fluoro-4-nitrobenceno de acuerdo con el Método A18, Paso 1 para dar 4-(5-(2-metil)piridiloxi)-1-nitrobenceno. La metilpiridina se oxidó de acuerdo con el ácido carboxílico, y se esterificó luego de acuerdo con el Método A18, Paso 2 para dar 4-(5-(2-metoxicarbonil)piridiloxi)-1-nitrobenceno. Se redujo el nitrobenceno de acuerdo con el Método A18, Paso 3 para dar 4-(5-(2-metoxicarbonil)piridiloxi)anilina. La anilina se hizo reaccionar con isocianato de 4-cloro-3-(trifluorometil)-fenilo de acuerdo con el Método C1a para proporcionar la urea.Entry 55: Docked 5-hydroxy-2-methylpyridine with 1-fluoro-4-nitrobenzene According to Method A18, Step 1 to give 4- (5- (2-methyl) pyridyloxy) -1-nitrobenzene. The methylpyridine was oxidized according to the carboxylic acid, and was then esterified according to Method A18, Step 2 to give 4- (5- (2-methoxycarbonyl) pyridyloxy) -1-nitrobenzene.  Nitrobenzene was reduced according to Method A18, Step 3 to give 4- (5- (2-methoxycarbonyl) pyridyloxy) aniline.  The aniline was reacted with isocyanate of 4-chloro-3- (trifluoromethyl) -phenyl according to Method C1a to provide urea.

Entrada 56: Se acopló 5-hidroxi-2-metilpiridina con 1-fluoro-4-nitrobenceno de acuerdo con el Método A18, Paso 1 para dar 4-(5-(2-metil)piridiloxi)-1-nitrobenceno. La metilpiridina se oxidó de acuerdo con el ácido carboxílico, y se esterificó luego de acuerdo con el Método A18, Paso 2 para dar 4-(5-(2-metoxicarbonil)piridiloxi)-1-nitrobenceno. Se redujo el nitrobenceno de acuerdo con el Método A18, Paso 3 para dar 4-(5-(2-metoxi-carbonil)piridiloxi)anilina. La anilina se hizo reaccionar con isocianato de 4-cloro-3-(trifluorometil)-fenilo de acuerdo con el Método C1a para dar N-(4-cloro-3-(trifluorometil)fenil)-N'-(4-(2-(metoxicarbonil)-5-piridiloxi)fenil)-urea. El éster metílico se hizo reaccionar con metilamina de acuerdo con el Método D2 para proporcionar N-(4-cloro-3-(trifluorometil)fenil)-N'-(4-(2-(N'-metilcarbamoil)-5-piridiloxi)fenil)-urea.Entry 56: 5-Hydroxy-2-methylpyridine was coupled with 1-fluoro-4-nitrobenzene according to Method A18, Step 1 to give 4- (5- (2-methyl) pyridyloxy) -1-nitrobenzene. The methylpyridine was oxidized according to the carboxylic acid, and then esterified according to Method A18, Step 2 to give 4- (5- (2-methoxycarbonyl) pyridyloxy) -1-nitrobenzene. Nitrobenzene was reduced according to Method A18, Step 3 to give 4- (5- (2-methoxycarbonyl) pyridyloxy) aniline. The aniline was reacted with 4-chloro-3- (trifluoromethyl) -phenyl isocyanate according to Method C1a to give N - (4-chloro-3- (trifluoromethyl) phenyl) - N ' - (4- (2 - (methoxycarbonyl) -5-pyridyloxy) phenyl) -urea. The methyl ester was reacted with methylamine according to Method D2 to provide N - (4-chloro-3- (trifluoromethyl) phenyl) - N ' - (4- (2- ( N' -methylcarbamoyl) -5-pyridyloxy ) phenyl) -urea.

Entrada 57: Se preparó N-(4-cloro-3-(trifluorometil)fenil)-N'-(4-aminofenil)-urea de acuerdo con el Método C1d. Se acopló N-(4-cloro-3-(trifluorometil)fenil)-N'-(4-aminofenil)-urea con isoftalato de mono-metilo de acuerdo con el Método D1a para proporcionar la urea.Entry 57: N - (4-Chloro-3- (trifluoromethyl) phenyl) - N ' - (4-aminophenyl) -urea was prepared according to Method C1d. N - (4-Chloro-3- (trifluoromethyl) phenyl) - N ' - (4-aminophenyl) -urea was coupled with mono-methyl isophthalate according to Method D1a to provide urea.

Entrada 58: Se preparó N-(4-cloro-3-(trifluorometil)fenil-N'-(4-aminofenil)-urea de acuerdo con el Método C1d. Se acopló N-(4-cloro-3-(trifluorometil)fenil)-N'-(4-aminofenil)-urea con isoftalato de mono-metilo de acuerdo con el Método D1a para proporcionar N-(4-cloro-3-(trifluorometil)fenil-N'-(4-(3-metoxicarbonilfenil)carboxiaminofenil)-urea. De acuerdo con el Método D2, se hizo reaccionar N-(4-cloro-3-(trifluorometil)-fenil-N'-(4-(3-metoxicarbonilfenil)carboxiaminofenil)-urea con metilamina para proporcionar la metil-amida correspondiente.Entry 58: N - (4-Chloro-3- (trifluoromethyl) phenyl- N ' - (4-aminophenyl) -urea was prepared according to Method C1d. N - (4-Chloro-3- (trifluoromethyl) was coupled phenyl) - N ' - (4-aminophenyl) -urea with mono-methyl isophthalate according to Method D1a to provide N - (4-chloro-3- (trifluoromethyl) phenyl- N' - (4- (3- Methoxycarbonylphenyl) carboxiaminophenyl) -urea According to Method D2, N - (4-chloro-3- (trifluoromethyl) -phenyl- N ' - (4- (3-methoxycarbonylphenyl) carboxyminophenyl) -urea was reacted with methylamine for provide the corresponding methyl amide.

Entrada 59: Se hizo reaccionar cloruro de 4-cloropiridina-2-carbonilo con dimetilamina de acuerdo con el Método A2, Paso 3b. La 4-cloro-N,N-dimetil-2-piridinacarboxamida resultante se hizo reaccionar con 4-aminofenol de acuerdo con el Método A2, Paso 4 para dar 4-(2-(N,N-dimetilcarbamoil)-4-piridiloxi)anilina. De acuerdo con el Método C1a, se hizo reaccionar isocianato de 4-cloro-3-(trifluorometil)fenilo con 4-(2-(N,N-dimetilcarbamoil)-4-piridiloxi)anilina para proporcionar la urea.Entry 59: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro- N, N- dimethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4- (2- ( N, N- dimethylcarbamoyl) -4-pyridyloxy) aniline. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- ( N, N- dimethylcarbamoyl) -4-pyridyloxy) aniline to provide urea.

Entrada 60: Se hizo reaccionar 4-hidroxiacetofenona con 4-fluoronitrobenceno de acuerdo con el Método A13, Paso 1 para dar 4-(4-acetilfenoxi)nitrobenceno. El nitrobenceno se redujo de acuerdo con el Método 13, Paso 4 para proporcionar 4-(4-acetilfenoxi)anilina, que se convirtió en la sal 4-(4-(1-(N-metoxi)iminoetil)-fenoxianilina.HCl de acuerdo con el Método A16. De acuerdo con el Método C1a, se hizo reaccionar isocianato de 4-cloro-3-(trifluorometil)fenilo con 4-(4-acetilfenoxi)-anilina para proporcionar la urea.Entry 60: 4-Hydroxyacetophenone was reacted with 4-fluoronitrobenzene according to Method A13, Step 1 to give 4- (4-acetylphenoxy) nitrobenzene. Nitrobenzene was reduced according to Method 13, Step 4 to provide 4- (4-acetylphenoxy) aniline, which was converted to the 4- (4- (1- ( N -methoxy) iminoethyl) -phenoxyaniline salt. according to Method A 16. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (4-acetylphenoxy) -aniline to provide urea.

Entrada 61: Se sintetizó 4-(3-carboxifenoxi)-1-nitrobenceno de acuerdo con el Método A13, Paso 2. Se acopló 4-(3-carboxifenoxi)-1-nitrobenceno con 4-(2-aminoetil)morfolina de acuerdo con el Método A13, Paso 3 para dar 4-(3-(N-(2-morfoliniletil)carbamoil)fenoxi)-1-nitrobenceno. De acuerdo con el Método A13, Paso 4, se redujo 4-(3-(N-(2-morfoliniletil)carbamoil)fenoxi)-1-nitrobenceno a 4-(3-(N-(2-morfoliniletil)carbamoil)-fenoxi)anilina. De acuerdo con el Método C1a, se hizo reaccionar isocianato de 4-cloro-3-(trifluorometil)fenilo con 4-(3-(N-(2-morfoliniletil)carbamoil)fenoxi)anilina para proporcionar la urea.Entry 61: 4- (3-Carboxyphenoxy) -1-nitrobenzene was synthesized according to Method A13, Step 2. 4- (3-Carboxyphenoxy) -1-nitrobenzene was coupled with 4- (2-aminoethyl) morpholine according with Method A13, Step 3 to give 4- (3- ( N - (2-morpholinylethyl) carbamoyl) phenoxy) -1-nitrobenzene. According to Method A13, Step 4 : 4- (3- (N - (2-morpholinylethyl) carbamoyl) phenoxy) -1-nitrobenzene 4- (3- (N - (2-morpholinylethyl) carbamoyl) - phenoxy) aniline. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3- ( N - (2-morpholinylethyl) carbamoyl) phenoxy) aniline to provide urea.

Entrada 62: Se sintetizó 4-(3-carboxifenoxi)-1-nitrobenceno de acuerdo con el Método A13, Paso 2. Se acopló 4-(3-carboxifenoxi)-1-nitrobenceno con 1-(2-aminoetil)piperidina de acuerdo con el Método A13, Paso 3 para dar 4-(3-(N-(2-piperidiletil)carbamoil)fenoxi)-1-nitrobenceno. De acuerdo con el Método A13, Paso 4, se redujo 4-(3-(N-(2-piperidiletil)carbamoil)fenoxi)-1-nitrobenceno a 4-(3-(N-(2-piperidiletil)carbamoil)-fenoxi)anilina. De acuerdo con el Método C1a, se hizo reaccionar isocianato de 4-cloro-3-(trifluorometil)fenilo con 4-(3-(N-(2-piperidiletil)carbamoil)fenoxi)anilina para proporcionar la urea.Entry 62: 4- (3-Carboxyphenoxy) -1-nitrobenzene was synthesized according to Method A13, Step 2. 4- (3-Carboxyphenoxy) -1-nitrobenzene was coupled with 1- (2-aminoethyl) piperidine according with Method A13, Step 3 to give 4- (3- ( N - (2-piperidylethyl) carbamoyl) phenoxy) -1-nitrobenzene. According to Method A13, Step 4, 4- (3- ( N - (2-piperidylethyl) carbamoyl) phenoxy) -1-nitrobenzene was reduced to 4- (3- ( N - (2-piperidylethyl) carbamoyl) - phenoxy) aniline. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3- ( N - (2-piperidylethyl) carbamoyl) phenoxy) aniline to provide urea.

Entrada 63: Se sintetizó 4-(3-carboxifenoxi)-1-nitrobenceno de acuerdo con el Método A13, Paso 2. Se acopló 4-(3-carboxifenoxi)-1-nitrobenceno con tetrahidrofurfurilamina de acuerdo con el Método A13, Paso 3 para dar 4-(3-(N-(tetrahidrofurilmetil)carbamoil)fenoxi)-1-nitrobenceno. De acuerdo con el Método A13, Paso 4, se redujo 4-(3-(N-(tetrahidrofurilmetil)carbamoil)fenoxi)-1-nitrobenceno a 4-(3-(N-(tetrahidrofurilmetil)carbamoil)-fenoxi)anilina. De acuerdo con el Método C1a, se hizo reaccionar isocianato de 4-cloro-3-(trifluorometil)fenilo con 4-(3-(N-(tetrahidrofurilmetil)carbamoil)-fenoxi)-anilina para proporcionar la urea.Entry 63: 4- (3-Carboxyphenoxy) -1-nitrobenzene was synthesized according to Method A13, Step 2. 4- (3-Carboxyphenoxy) -1-nitrobenzene was coupled with tetrahydrofurfurylamine according to Method A13, Step 3 to give 4- (3- ( N - (tetrahydrofurylmethyl) carbamoyl) phenoxy) -1-nitrobenzene. According to Method A13, Step 4, 4- (3- ( N - (tetrahydrofurylmethyl) carbamoyl) phenoxy) -1-nitrobenzene was reduced to 4- (3- ( N - (tetrahydrofurylmethyl) carbamoyl) -phenoxy) aniline. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3- ( N - (tetrahydrofurylmethyl) carbamoyl) -phenoxy) -aniline to provide urea.

Entrada 64: Se sintetizó 4-(3-carboxifenoxi)-1-nitrobenceno de acuerdo con el Método A13, Paso 2. Se acopló 4-(3-carboxifenoxi)-1-nitrobenceno con 2-aminometil-1-etilpirrolidina de acuerdo con el Método A13, Paso 3 para dar 4-(3-(N-((1-metilpirrolidinil)-metil)carbamoil)fenoxi)-1-nitrobenceno. De acuerdo con el Método A13, Paso 4, se redujo 4-(3-(N-((1-metilpirrol-idinil)metil)carbamoil)fenoxi)-1-nitrobenceno a 4-(3-(N-((1-metilpirrolidinil)metil)carbamoil)fenoxi)anilina. De acuerdo con el Método C1a, se hizo reaccionar isocianato de 4-cloro-3-(trifluorometil)fenilo con 4-(3-(N-((1-metilpirrolidinil)metil)carbamoil)fenoxi)anilina para proporcionar la urea.Entry 64: 4- (3-Carboxyphenoxy) -1-nitrobenzene was synthesized according to Method A13, Step 2. 4- (3-Carboxyphenoxy) -1-nitrobenzene was coupled with 2-aminomethyl-1-ethylpyrrolidine according to Method A13, Step 3 to give 4- (3- ( N - ((1-methylpyrrolidinyl) -methyl) carbamoyl) phenoxy) -1-nitrobenzene. According to Method A13, Step 4, 4- (3- ( N - ((1-methylpyrrol-idinyl) methyl) carbamoyl) phenoxy) -1-nitrobenzene was reduced to 4- (3- ( N - ((1 -methylpyrrolidinyl) methyl) carbamoyl) phenoxy) aniline. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3- ( N - ((1-methylpyrrolidinyl) methyl) carbamoyl) phenoxy) aniline to provide urea.

Entrada 65: Se sintetizó 4-cloro-N-metilpiridinacarboxamida como se describe en el Método A2, Paso 3b. Se hizo reaccionar la cloropiridina con 4-aminotiofenol de acuerdo con el Método A2, Paso 4 para dar 4-(4-(2-(N-metilcarbamoil)feniltio)anilina. De acuerdo con el Método C1a, se hizo reaccionar isocianato de 4-cloro-3-(trifluoro-
metil)fenilo con 4-(4-(2-(N-metilcarbamoil)-feniltio)anilina para proporcionar la urea.Entry 65: 4-Chloro- N- methylpyridinecarboxamide was synthesized as described in Method A2, Step 3b. Chloropyridine was reacted with 4-aminothiophenol according to Method A2, Step 4 to give 4- (4- (2- ( N- methylcarbamoyl) phenylthio) aniline. According to Method C1a, 4-isocyanate was reacted -chloro-3- (trifluoro-
methyl) phenyl with 4- (4- (2- ( N- methylcarbamoyl) -phenylthio) aniline to provide urea.

Entrada 66: Se hizo reaccionar cloruro de 4-cloropiridina-2-carbonilo con isopropilamina de acuerdo con el Método A2, Paso 3b. Se hizo reaccionar la 4-cloro-N-isopropil-2-piridinacarboxamida resultante con 4-aminofenol de acuerdo con el Método A2, Paso 4 para dar 4-(2-(N-isopropilcarbamoil)-4-piridiloxi)anilina. De acuerdo con el Método C1a, se hizo reaccionar isocianato de 4-cloro-3-(trifluorometil)fenilo con 4-(2-(N-isopropilcarbamoil)-4-piridiloxi)anilina para proporcionar la urea.Entry 66: 4-Chloropyridine-2-carbonyl chloride was reacted with isopropylamine according to Method A2, Step 3b. The resulting 4-chloro- N- isopropyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4- (2- ( N- isopropylcarbamoyl) -4-pyridyloxy) aniline. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- ( N -isopropylcarbamoyl) -4-pyridyloxy) aniline to provide urea.

Entrada 67: Se sintetizó N-(4-cloro-3-(trifluorometil)fenil-N'-(4-etoxicarbonilfenil)-urea de acuerdo con el Método C1e. Se saponificó N-(4-cloro-3-(trifluorometil)fenil-N'-(4-etoxicarbonilfenil)-urea de acuerdo con el Método D3 para dar N-(4-cloro-3-(trifluorometil)fenil-N'-(4-carboxifenil)-urea. Se acopló N-(4-cloro-3-(trifluorometil)fenil-N'-(4-carboxifenil)-urea con 3-metilcarbamoilanilina de acuerdo con el Método D1b para dar N-(4-cloro-3-(trifluorometil)fenil-N'-(4-(3-metilcarbamoilfenil)carbamoilfenil)-urea.Entry 67: N - (4-Chloro-3- (trifluoromethyl) phenyl- N ' - (4-ethoxycarbonylphenyl) -urea was synthesized according to Method C1e. N- (4-Chloro-3- (trifluoromethyl) was saponified Phenyl- N ' - (4-ethoxycarbonylphenyl) -urea according to Method D3 to give N - (4-chloro-3- (trifluoromethyl) phenyl- N' - (4-carboxyphenyl) -urea. N - ( 4-Chloro-3- (trifluoromethyl) phenyl- N ' - (4-carboxyphenyl) -urea with 3-methylcarbamoylaniline according to Method D1b to give N - (4-chloro-3- (trifluoromethyl) phenyl- N' - (4- (3-methylcarbamoylphenyl) carbamoylphenyl) -urea.

Entrada 68: Se sintetizó 5-(4-aminofenoxi)-2-metilisoindolina-1,3-diona de acuerdo con el Método A9. De acuerdo con el Método C1a, se hizo reaccionar isocianato de 4-cloro-3-(trifluorometil)fenilo con 5-(4-aminofenoxi)-2-metilisoindolina-1,3-diona para proporcionar la urea.Entry 68: It was synthesized 5- (4-aminophenoxy) -2-methylisoindoline-1,3-dione according to Method A9. According to Method C1a, it was done react isocyanate from 4-chloro-3- (trifluoromethyl) phenyl with 5- (4-aminophenoxy) -2-methylisoindoline-1,3-dione  to provide urea.

Entrada 69: Se sintetizó 4-cloro-N-metilpiridinacarboxamida como se describe en el Método A2, Paso 3b. Se hizo reaccionar la cloropiridina con 3-aminotiofenol de acuerdo con el Método A2, Paso 4 para dar 3-(4-(2-(N-metilcarbamoil)feniltio)anilina. De acuerdo con el Método C1a, se hizo reaccionar 4-cloro-3-(trifluorometil)fenilo con 3-(4-(2-N-metilcarbamoil)feniltio)anilina para proporcionar la urea.Entry 69: 4-Chloro- N- methylpyridinecarboxamide was synthesized as described in Method A2, Step 3b. Chloropyridine was reacted with 3-aminothiophenol according to Method A2, Step 4 to give 3- (4- (2- ( N- methylcarbamoyl) phenylthio) aniline. According to Method C1a, 4-chloro was reacted -3- (trifluoromethyl) phenyl with 3- (4- (2- N -methylcarbamoyl) phenylthio) aniline to provide urea.

Entrada 70: Se sintetizó 4-(2-N-(2-morfolin-4-iletil)carbamoil)piridiloxi)anilina de acuerdo con el Método A10. De acuerdo con el Método C1a, se hizo reaccionar isocianato de 4-cloro-3-(trifluorometil)fenilo con 4-(2-(N-(2-morfolin-4-iletil)carbamoil)piridiloxi)anilina para proporcionar la urea.Entry 70: 4- (2- N - (2-morpholin-4-ylethyl) carbamoyl) pyridyloxy) aniline was synthesized according to Method A10. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- ( N - (2-morpholin-4-ylethyl) carbamoyl) pyridyloxy) aniline to provide urea.

Entrada 71: Se sintetizó 4-(3-(5-metoxicarbonil)-piridiloxi)anilina de acuerdo con el Método A14. Se hizo reaccionar isocianato de 4-cloro-3-(trifluorometil)-2-metoxifenilo con 4-(3-(5-metoxicarbonil)piridiloxi)-anilina de acuerdo con el Método C1a para proporcionar la urea. Se saponificó N-(4-cloro-3-(trifluorometil)fenil)-N'-(4-(3-(5-metoxicarbonilpiridil)oxi)fenil)-urea de acuerdo con el Método D4, Paso 1, y el ácido correspondiente se acopló con 4-(2-aminoetil)morfolina para proporcionar la amida.Entry 71: 4- (3- (5-Methoxycarbonyl) -pyridyloxy) aniline was synthesized according to Method A14. 4-Chloro-3- (trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (3- (5-methoxycarbonyl) pyridyloxy) -aniline according to Method C1a to provide urea. N - (4-Chloro-3- (trifluoromethyl) phenyl) - N ' - (4- (3- (5-methoxycarbonylpyridyl) oxy) phenyl) -urea was saponified according to Method D4, Step 1, and the acid corresponding was coupled with 4- (2-aminoethyl) morpholine to provide the amide.

Entrada 72: Se sintetizó 4-(3-(5-metoxicarbonil)-piridiloxi)anilina de acuerdo con el Método A14. Se hizo reaccionar isocianato de 4-cloro-3-(trifluorometil)fenilo con 4-(3-(5-metoxicarbonil)piridiloxi)anilina de acuerdo con el Método C1a para proporcionar la urea. Se saponificó N-(5-(trifluorometil)-2-metoxifenil)-N'-(4-(3-(5-metoxicarbonilpiridil)oxi)fenil)-urea de acuerdo con el Método D4, Paso 1, y el ácido correspondiente se acopló con metilamina de acuerdo con el Método D4, Paso 2, para proporcionar la amida.Entry 72: 4- (3- (5-Methoxycarbonyl) -pyridyloxy) aniline was synthesized according to Method A14. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to Method C1a to provide urea. N - (5- (trifluoromethyl) -2-methoxyphenyl) - N ' - (4- (3- (5-methoxycarbonylpyridyl) oxy) phenyl) -urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with methylamine according to Method D4, Step 2, to provide the amide.

Entrada 73: Se sintetizó 4-(3-(5-metoxicarbonil)-piridiloxi)anilina de acuerdo con el Método A14. Se hizo reaccionar isocianato de 4-cloro-3-(trifluorometil)fenilo con 4-(3-(5-metoxicarbonil)piridiloxi)anilina de acuerdo con el Método C1a para proporcionar la urea. Se saponificó N-(5-(trifluorometil)-2-metoxifenil)-N'-(4-(3-(5-metoxicarbonilpiridil)oxi)fenil)-urea de acuerdo con el Método D4, Paso 1, y el ácido correspondiente se acopló con N,N-dimetiletilenodiamina de acuerdo con el Método D4, Paso 2, para proporcionar la amida.Entry 73: 4- (3- (5-Methoxycarbonyl) -pyridyloxy) aniline was synthesized according to Method A14. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to Method C1a to provide urea. N - (5- (trifluoromethyl) -2-methoxyphenyl) - N ' - (4- (3- (5-methoxycarbonylpyridyl) oxy) phenyl) -urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with N, N- dimethylethylenediamine according to Method D4, Step 2, to provide the amide.

Entrada 74: Se hizo reaccionar la sal cloruro de 4-cloropiridina-2-carbonilo.HCl con 2-hidroxietilamina de acuerdo con el Método A2, Paso 3b para formar 4-cloro-N-(2-triisopropilsililoxi)etilpiridina-2-carboxamida. Se hizo reaccionar la 4-cloro-N-(2-triisopropilsililoxi)-etilpiridina-2-carboxamida con cloruro de triisopropilsililo, seguido por 4-aminofenol de acuerdo con el Método A17 para formar 4-(4-(2-(N-(2-triisopropilsililoxi)-etilcarbamoil)piridiloxianilina. De acuerdo con el Método C1a, se hizo reaccionar isocianato de 4-cloro-3-(trifluorometil)fenilo con 4-(4-(2-(N-(2-triisopropil-sililoxi)etilcarbamoil)piridiloxianilina para proporcionar N-(4-cloro-3-((trifluorometil)fenil)-N'-(4-(4-(2-(N-(2-triisopropilsililoxi)-etilcarbamoil)piridiloxifenil)-urea.Entry 74: The salt of 4-chloropyridine-2-carbonyl chloride.HCl was reacted with 2-hydroxyethylamine according to Method A2, Step 3b to form 4-chloro- N - (2-triisopropylsilyloxy) ethylpyridine-2-carboxamide . 4-Chloro- N - (2-triisopropylsilyloxy) -ethylpyridine-2-carboxamide was reacted with triisopropylsilyl chloride, followed by 4-aminophenol according to Method A17 to form 4- (4- (2- ( N - (2-Triisopropylsilyloxy) -ethylcarbamoyl) pyridyloxyaniline According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (4- (2- ( N - (2-triisopropyl-silyloxy) ) ethylcarbamoyl) pyridyloxyaniline to provide N - (4-chloro-3 - ((trifluoromethyl) phenyl) - N ' - (4- (4- (2- ( N - (2-triisopropylsilyloxy) -ethylcarbamoyl) pyridyloxyphenyl) -urea.

Entrada 75: Se sintetizó 4-(3-carboxifenoxi)anilina de acuerdo con el Método A11. Se hizo reaccionar isocianato de 4-cloro-3-(trifluorometil)fenilo con 4-(3-(5-metoxicarbonil)piridiloxi)anilina de acuerdo con el Método C1f para proporcionar la urea, que se acopló con 3-aminopiridina de acuerdo con el Método D1c.Entry 75: It was synthesized 4- (3-carboxyphenoxy) aniline according to the Method A11 Isocyanate was reacted from 4-chloro-3- (trifluoromethyl) phenyl with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to Method C1f to provide urea, which is coupled with 3-aminopyridine according to the Method D1c.

Entrada 76: Se sintetizó 4-(3-carboxifenoxi)anilina de acuerdo con el Método A11. Se hizo reaccionar isocianato de 4-cloro-3-(trifluorometil)fenilo con 4-(3-carboxifenoxi)anilina de acuerdo con el Método C1f para proporcionar la urea, que se acopló con N-(4-acetilfenil)piperazina de acuerdo con el Método D1c.Entry 76: 4- (3-Carboxyphenoxy) aniline was synthesized according to Method A11. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3-carboxyphenoxy) aniline according to Method C1f to provide urea, which was coupled with N - (4-acetylphenyl) piperazine according to Method D1c.

Entrada 77: Se sintetizó 4-(3-carboxifenoxi)anilina de acuerdo con el Método A11. Se hizo reaccionar isocianato de 4-cloro-3-(trifluorometil)fenilo con 4-(3-carboxifenoxi)anilina de acuerdo con el Método C1f para proporcionar la urea, que se acopló con 4-fluoroanilina de acuerdo con el Método D1c.Entry 77: It was synthesized 4- (3-carboxyphenoxy) aniline according to the Method A11 Isocyanate was reacted from 4-chloro-3- (trifluoromethyl) phenyl with 4- (3-carboxyphenoxy) aniline according to Method C1f to provide urea, which was coupled with 4-fluoroaniline according to Method D1c.

Entrada 78: Se sintetizó 4-(3-carboxifenoxi)anilina de acuerdo con el Método A11. Se hizo reaccionar isocianato de 4-cloro-3-(trifluorometil)fenilo con 4-(3-carboxifenoxi)anilina de acuerdo con el Método C1f para proporcionar la urea, que se acopló con 4-(dimetilamino)anilina de acuerdo con el Método D1c.Entry 78: It was synthesized 4- (3-carboxyphenoxy) aniline according to the Method A11 Isocyanate was reacted from 4-chloro-3- (trifluoromethyl) phenyl with 4- (3-carboxyphenoxy) aniline according to Method C1f to provide urea, which was coupled with 4- (dimethylamino) aniline according to Method D1c. 

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Entrada 79: Se sintetizó 4-(3-carboxifenoxi)anilina de acuerdo con el Método A11. Se hizo reaccionar isocianato de 4-cloro-3-(trifluorometil)fenilo con 4-(3-carboxifenoxi)anilina de acuerdo con el Método C1f para proporcionar la urea, que se acopló con N-feniletilenodiamina de acuerdo con el Método D1c.Entry 79: 4- (3-Carboxyphenoxy) aniline was synthesized according to Method A11. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3-carboxyphenoxy) aniline according to Method C1f to provide urea, which was coupled with N- phenylethylene diamine according to Method D1c.

Entrada 80: Se sintetizó 4-(3-carboxifenoxi)anilina de acuerdo con el Método A11. Se hizo reaccionar isocianato de 4-cloro-3-(trifluorometil)fenilo con 4-(3-carboxifenoxi)anilina de acuerdo con el Método C1f para proporcionar la urea, que se acopló con 2-metoxietilamina de acuerdo con el Método D1c.Entry 80: It was synthesized 4- (3-carboxyphenoxy) aniline according to the Method A11 Isocyanate was reacted from 4-chloro-3- (trifluoromethyl) phenyl with 4- (3-carboxyphenoxy) aniline according to Method C1f to provide urea, which was coupled with 2-methoxyethylamine according to Method D1c.

Entrada 81: Se sintetizó 4-(3-carboxifenoxi)anilina de acuerdo con el Método A11. Se hizo reaccionar isocianato de 4-cloro-3-(trifluorometil)fenilo con 4-(3-carboxifenoxi)anilina de acuerdo con el Método C1f para proporcionar la urea, que se acopló con 5-amino-2-metoxipiridina de acuerdo con el Método D1c.Entry 81: It was synthesized 4- (3-carboxyphenoxy) aniline according to the Method A11 Isocyanate was reacted from 4-chloro-3- (trifluoromethyl) phenyl with 4- (3-carboxyphenoxy) aniline according to Method C1f to provide urea, which was coupled with 5-amino-2-methoxypyridine according to Method D1c.

Entrada 82: Se sintetizó 4-(3-carboxifenoxi)anilina de acuerdo con el Método A11. Se hizo reaccionar isocianato de 4-cloro-3-(trifluorometil)fenilo con 4-(3-carboxifenoxi)anilina de acuerdo con el Método C1f para proporcionar la urea, que se acopló con 4-morfolinoanilina de acuerdo con el Método D1c.Entry 82: It was synthesized 4- (3-carboxyphenoxy) aniline according to the Method A11 Isocyanate was reacted from 4-chloro-3- (trifluoromethyl) phenyl with 4- (3-carboxyphenoxy) aniline according to Method C1f to provide urea, which was coupled with 4-morpholinoaniline according to Method D1c.

Entrada 83: Se sintetizó 4-(3-carboxifenoxi)anilina de acuerdo con el Método A11. Se hizo reaccionar isocianato de 4-cloro-3-(trifluorometil)fenilo con 4-(3-carboxifenoxi)anilina de acuerdo con el Método C1f para proporcionar la urea, que se acopló con N-(2-piridil)piperazina de acuerdo con el Método D1c.Entry 83: 4- (3-Carboxyphenoxy) aniline was synthesized according to Method A11. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3-carboxyphenoxy) aniline according to Method C1f to provide urea, which was coupled with N - (2-pyridyl) piperazine according to Method D1c.

Entrada 84: Se hizo reaccionar la sal cloruro de 4-cloropiridina-2-carbonilo.HCl con 2-hidroxietilamina de acuerdo con el Método A2, Paso 3b para formar 4-cloro-N-(2-triisopropilsililoxi)etilpiridina-2-carboxamida. Se hizo reaccionar la 4-cloro-N-(2-triisopropilsililoxi)-etilpiridina-2-carboxamida con cloruro de triisopropilsililo, seguido por 4-aminofenol de acuerdo con el Método A17 para formar 4-(4-(2-(N-(2-triisopropilsililoxi)-etilcarbamoil)piridiloxianilina. De acuerdo con el Método C1a, se hizo reaccionar isocianato de 4-cloro-3-(trifluorometil)fenilo con 4-(4-(2-(N-(2-triisopropil-sililoxi)etilcarbamoil)piridiloxianilina para dar N-(4-cloro-3-((trifluorometil)fenil)-N'-(4-(4-(2-(N-(2-triisopropilsililoxi)etilcarbamoil)piridiloxifenil)-urea. La urea se desprotegió de acuerdo con el Método D5 para proporcionar N-(4-cloro-3-((trifluorometil)fenil)-N'-(4-(4-(2-(N-(2-hidroxi)etilcarbamoil)piridiloxifenil)-urea.Entry 84: The salt of 4-chloropyridine-2-carbonyl chloride.HCl was reacted with 2-hydroxyethylamine according to Method A2, Step 3b to form 4-chloro- N - (2-triisopropylsilyloxy) ethylpyridine-2-carboxamide . 4-Chloro- N - (2-triisopropylsilyloxy) -ethylpyridine-2-carboxamide was reacted with triisopropylsilyl chloride, followed by 4-aminophenol according to Method A17 to form 4- (4- (2- ( N - (2-Triisopropylsilyloxy) -ethylcarbamoyl) pyridyloxyaniline According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (4- (2- ( N - (2-triisopropyl-silyloxy) ) ethylcarbamoyl) pyridyloxyaniline to give N - (4-chloro-3 - ((trifluoromethyl) phenyl) - N ' - (4- (4- (2- ( N - (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyphenyl) -urea. urea was deprotected according to Method D5 to provide N - (4-chloro-3 - ((trifluoromethyl) phenyl) - N ' - (4- (4- (2- ( N - (2-hydroxy) ethylcarbamoyl) pyridyloxyphenyl) )-urea.

Entrada 85: Se sintetizó 4-(2-(N-metilcarbamoil)-4-piridiloxi)anilina de acuerdo con el Método A2. Se convirtió 4-bromo-3-(trifluorometil)anilina en isocianato de 4-bromo-3-(trifluorometil)fenilo de acuerdo con el Método B1. De acuerdo con el Método C1a, se hizo reaccionar isocianato de 4-bromo-3-(trifluorometil)fenilo con 4-(2-(N-metilcarbamoil)-4-piridiloxi)anilina para proporcionar la urea.Entry 85: 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) aniline was synthesized according to Method A2. 4-Bromo-3- (trifluoromethyl) aniline was converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to Method B1. According to Method C1a, 4-bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) aniline to provide urea.

Entrada 86: Se sintetizó 4-(2-(N-metilcarbamoil)-4-piridiloxi)-2-cloroanilina de acuerdo con el Método A6. Se convirtió 4-bromo-3-(trifluorometil)anilina en isocianato de 4-bromo-3-(trifluorometil)fenilo de acuerdo con el Método B1. De acuerdo con el Método C1a, se hizo reaccionar isocianato de 4-bromo-3-(trifluorometil)fenilo con 4-(2-(N-metilcarbamoil)-4-piridiloxi)-2-cloroanilina para proporcionar la urea.Entry 86: 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline was synthesized according to Method A6. 4-Bromo-3- (trifluoromethyl) aniline was converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to Method B1. According to Method C1a, 4-bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline to provide urea.

Entrada 87: De acuerdo con el Método A2, Paso 4, se hizo reaccionar 4-amino-2-clorofenol con 4-cloro-N-metil-2-piridinacarboxamida, que se había sintetizado de acuerdo con el Método A2, Paso 3b, para dar 4-(2-(N-metilcarbamoil)-4-piridiloxi)-3-cloroanilina. Se convirtió 4-bromo-3-(trifluorometil)anilina en isocianato de 4-bromo-3-(trifluorometil)fenilo de acuerdo con el Método B1. De acuerdo con el Método C1a, el isocianato de 4-bromo-3-(trifluorometil)fenilo se hizo reaccionar con 4-(2-(N-metilcarbamoil)-4-piridiloxi)-3-cloroanilina para proporcionar la urea.Entry 87: According to Method A2, Step 4, 4-amino-2-chlorophenol was reacted with 4-chloro- N- methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline. 4-Bromo-3- (trifluoromethyl) aniline was converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to Method B1. According to Method C1a, the 4-bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline to provide urea.

Entrada 88: Se hizo reaccionar cloruro de 4-cloropiridina-2-carbonilo con etilamina de acuerdo con el Método A2, Paso 3b. La 4-cloro-N-etil-2-piridinacarboxamida resultante se hizo reaccionar con 4-aminofenol de acuerdo con el Método A2, Paso 4, para dar 4-(2-(N-etilcarbamoil)-4-piridiloxi)anilina. Se convirtió 4-bromo-3-(trifluorometil)anilina en isocianato de 4-bromo-3-(trifluorometil)fenilo de acuerdo con el Método B1. De acuerdo con el Método C1a, se hizo reaccionar el isocianato de 4-bromo-3-(trifluorometil)fenilo con 4-(2-(N-etilcarbamoil)-4-piridiloxi)anilina para proporcionar la urea.Entry 88: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro- N- ethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4, to give 4- (2- ( N- ethylcarbamoyl) -4-pyridyloxy) aniline. 4-Bromo-3- (trifluoromethyl) aniline was converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to Method B1. According to Method C1a, the 4-bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- ( N- ethylcarbamoyl) -4-pyridyloxy) aniline to provide urea.

Entrada 89: 4-Cloro-N-metil-2-piridinacarboxamida, que se sintetizó de acuerdo con el Método A2, Paso 3a, se hizo reaccionar con 3-aminofenol de acuerdo con el Método A2, Paso 4, para formar 3-(2-(N-metilcarbamoil)-4-piridiloxi)anilina. Se convirtió 4-bromo-3-(trifluorometil)anilina en isocianato de 4-bromo-3-(trifluorometil)fenilo de acuerdo con el Método B1. De acuerdo con el Método C1a, se hizo reaccionar el isocianato de 4-bromo-3-(trifluorometil)fenilo con 3-(2-(N-metilcarbamoil)-4-piridiloxi)anilina para proporcionar la urea.Entry 89: 4-Chloro- N -methyl-2-pyridinecarboxamide, which was synthesized according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4, to form 3- ( 2- ( N- methylcarbamoyl) -4-pyridyloxy) aniline. 4-Bromo-3- (trifluoromethyl) aniline was converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to Method B1. According to Method C1a, the 4-bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 3- (2- ( N- methylcarbamoyl) -4-pyridyloxy) aniline to provide urea.

Entrada 90: De acuerdo con el Método A2, Paso 4, se hizo reaccionar 5-amino-2-metilfenol con 4-cloro-N-metil-2-piridinacarboxamida, que se había sintetizado de acuerdo con el Método A2, Paso 3b, para dar 3-(2-(N-metilcarbamoil)-4-piridiloxi)-4-metilanilina. Se convirtió 4-bromo-3-(trifluorometil)anilina en isocianato de 4-bromo-3-(trifluorometil)fenilo de acuerdo con el Método B1. De acuerdo con el Método C1a, se hizo reaccionar el isocianato de 4-bromo-3-(trifluorometil)fenilo con 3-(2-(N-metilcarbamoil)-4-piridiloxi)-4-metilanilina para proporcionar la urea.Entry 90: According to Method A2, Step 4, 5-amino-2-methylphenol was reacted with 4-chloro- N -methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 3- (2- ( N- methylcarbamoyl) -4-pyridyloxy) -4-methylaniline. 4-Bromo-3- (trifluoromethyl) aniline was converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to Method B1. According to Method C1a, the 4-bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 3- (2- ( N- methylcarbamoyl) -4-pyridyloxy) -4-methylaniline to provide urea.

Entrada 91: Se hizo reaccionar cloruro de 4-cloropiridina-2-carbonilo con dimetilamina de acuerdo con el Método A2, Paso 3b. La 4-cloro-N,N-dimetil-2-piridinacarboxamida resultante se hizo reaccionar con 4-aminofenol de acuerdo con el Método A2, Paso 4, para dar 4-(2-(N,N-dimetilcarbamoil)-4-piridiloxi)anilina. Se convirtió 4-bromo-3-(trifluorometil)anilina en isocianato de 4-bromo-3-(trifluorometil)fenilo de acuerdo con el Método B1. De acuerdo con el Método C1a, el isocianato de 4-bromo-3-(trifluorometil)fenilo se hizo reaccionar con 4-(2-(N,N-dimetilcarbamoil)-4-piridiloxi)anilina para proporcionar la urea.Entry 91: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro- N, N- dimethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4, to give 4- (2- ( N, N- dimethylcarbamoyl) -4-pyridyloxy )aniline. 4-Bromo-3- (trifluoromethyl) aniline was converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to Method B1. According to Method C1a, the 4-bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- ( N, N- dimethylcarbamoyl) -4-pyridyloxy) aniline to provide urea.

Entrada 92: Se sintetizó 4-cloro-N-metilpiridinacarboxamida como se describe en el Método A2, Paso 3b. Se hizo reaccionar la cloropiridina con 4-aminofenol de acuerdo con el Método A2, Paso 4 para dar 4-(4-(2-(N-metilcarbamoil)feniltio)anilina. Se convirtió 4-bromo-3-(trifluorometil)anilina en isocianato de 4-bromo-3-(trifluorometil)fenilo de acuerdo con el Método B1. De acuerdo con el Método C1a, el isocianato de 4-bromo-3-(trifluorometil)fenilo se hizo reaccionar con 4-(4-(2-(N-metilcarbamoil)feniltio)anilina para proporcionar la urea.Entry 92: 4-Chloro- N- methylpyridinecarboxamide was synthesized as described in Method A2, Step 3b. Chloropyridine was reacted with 4-aminophenol according to Method A2, Step 4 to give 4- (4- (2- ( N- methylcarbamoyl) phenylthio) aniline.) 4-Bromo-3- (trifluoromethyl) aniline was converted into 4-Bromo-3- (trifluoromethyl) phenyl isocyanate according to Method B. 1. According to Method C1a, 4-bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (4- (2 ( - ( N- methylcarbamoyl) phenylthio) aniline to provide urea.

Entrada 93: Se sintetizó 4-cloro-N-metilpiridinacarboxamida como se describe en el Método A2, Paso 3b. La cloropiridina se hizo reaccionar con 3-aminofenol de acuerdo con el Método A2, Paso 4 para dar 3-(4-(2-(N-metilcarbamoil)feniltio)anilina. Se convirtió 4-bromo-3-(trifluorometil)anilina en isocianato de 4-bromo-3-(trifluorometil)fenilo de acuerdo con el Método B1. De acuerdo con el Método C1a, se hizo reaccionar el isocianato de 4-bromo-3-(trifluoro-
metil)fenilo con 3-(4-(2-(N-metilcarbamoil)feniltio)anilina para proporcionar la urea.Entry 93: 4-Chloro- N- methylpyridinecarboxamide was synthesized as described in Method A2, Step 3b. The chloropyridine was reacted with 3-aminophenol according to Method A2, Step 4 to give 3- (4- (2- ( N- methylcarbamoyl) phenylthio) aniline.) 4-Bromo-3- (trifluoromethyl) aniline was converted into 4-Bromo-3- (trifluoromethyl) phenyl isocyanate according to Method B1. According to Method C1a, the 4-bromo-3- (trifluoro-) isocyanate was reacted
methyl) phenyl with 3- (4- (2- ( N- methylcarbamoyl) phenylthio) aniline to provide urea.

Entrada 94: Se sintetizó 4-(2-(N-(2-morfolin-4-iletil)carbamoil)piridiloxi)anilina de acuerdo con el Método A10. Se convirtió 4-bromo-3-(trifluorometil)anilina en isocianato de 4-bromo-3-(trifluorometil)fenilo de acuerdo con el Método B1. De acuerdo con el Método C1a, se hizo reaccionar el isocianato de 4-bromo-3-(trifluorometil)fenilo con 4-(2-(N-(2-morfolin-4-iletil)carbamoil)piridiloxi)anilina para proporcionar la urea.Entry 94: 4- (2- ( N - (2-morpholin-4-ylethyl) carbamoyl) pyridyloxy) aniline was synthesized according to Method A10. 4-Bromo-3- (trifluoromethyl) aniline was converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to Method B1. According to Method C1a, the 4-bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- ( N - (2-morpholin-4-ylethyl) carbamoyl) pyridyloxy) aniline to provide the urea .

Entrada 95: Se sintetizó 4-(2-(N-metilcarbamoil)-4-piridiloxi)anilina de acuerdo con el Método A2. Se sintetizó 4-cloro-2-metoxi-5-(trifluorometil)anilina de acuerdo con el Método A7. Se convirtió la 4-cloro-2-metoxi-5-(trifluorometil)anilina en isocianato de 4-cloro-2-metoxi-5-(trifluorometil)fenilo de acuerdo con el Método B1. De acuerdo con el Método C1a, el isocianato de 4-cloro-2-metoxi-5-(trifluorometil)fenilo se hizo reaccionar con 4-(2-(N-metilcarbamoil)-4-piridiloxi)anilina para proporcionar la urea.Entry 95: 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) aniline was synthesized according to Method A2. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline was synthesized according to Method A7. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline was converted to 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate according to Method B1. According to Method C1a, the 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) aniline to provide urea.

Entrada 96: Se sintetizó 4-(2-(N-metilcarbamoil)-4-piridiloxi)-2-cloroanilina de acuerdo con el Método A6. Se sintetizó 4-cloro-2-metoxi-5-(trifluorometil)anilina de acuerdo con el Método A7. La 4-cloro-2-metoxi-5-(trifluorometil)anilina se convirtió en isocianato de 4-cloro-2-metoxi-5-(trifluorometil)fenilo de acuerdo con el Método B1. De acuerdo con el Método C1a, el isocianato de 4-cloro-2-metoxi-5-(trifluorometil)fenilo se hizo reaccionar con 4-(2-(N-metilcarbamoil)-4-piridiloxi)-2-cloroanilina para proporcionar la urea.Entry 96: 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline was synthesized according to Method A6. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline was synthesized according to Method A7. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline was converted to 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate according to Method B1. According to Method C1a, the 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline to provide the urea.

Entrada 97: De acuerdo con el Método A2, Paso 4, Se hizo reaccionar 4-amino-2-clorofenol con 4-cloro-N-metil-2-piridinacarboxamida, que se había sintetizado de acuerdo con el Método A2, Paso 3b, para dar 4-(2-(N-metilcarbamoil)-4-piridiloxi)-3-cloroanilina. Se sintetizó 4-cloro-2-metoxi-5-(trifluorometil)anilina de acuerdo con el Método A7. La 4-cloro-2-metoxi-5-trifluorometil)anilina se convirtió en isocianato de 4-cloro-2-metoxi-5-trifluorometil)fenilo de acuerdo con el Método B1. De acuerdo con el Método C1a, el isocianato de 4-cloro-2-metoxi-5-(trifluorometil)fenilo se hizo reaccionar con 4-(2-(N-metilcarbamoil)-4-piridiloxi)-3-cloro-anilina para proporcionar la urea.Entry 97: According to Method A2, Step 4, 4-amino-2-chlorophenol was reacted with 4-chloro- N- methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline was synthesized according to Method A7. The 4-chloro-2-methoxy-5-trifluoromethyl) aniline was converted to 4-chloro-2-methoxy-5-trifluoromethyl) phenyl isocyanate according to Method B1. According to Method C1a, the 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) -3-chloro-aniline for provide urea.

Entrada 98: 4-Cloro-N-metil-2-piridinacarboxamida, que se sintetizó de acuerdo con el Método A2, Paso 3a, se hizo reaccionar con 3-aminofenol de acuerdo con el Método A2, Paso 4 para formar 3-(2-(N-metilcarbamoil)-4-piridiloxi)anilina. Se sintetizó 4-cloro-2-metoxi-5-(trifluorometil)anilina de acuerdo con el Método A7. La 4-cloro-2-metoxi-5-(trifluorometil)anilina se convirtió en isocianato de 4-cloro-2-metoxi-5-(trifluorometil)-fenilo de acuerdo con el Método B1. De acuerdo con el Método C1a, el isocianato de 4-cloro-2-metoxi-5-(trifluorometil)fenilo se hizo reaccionar con 3-(2-(N-metilcarbamoil)-4-piridiloxi)anilina para proporcionar la urea.Entry 98: 4-Chloro- N -methyl-2-pyridinecarboxamide, which was synthesized according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 to form 3- (2 - ( N- methylcarbamoyl) -4-pyridyloxy) aniline. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline was synthesized according to Method A7. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline was converted to 4-chloro-2-methoxy-5- (trifluoromethyl) -phenyl isocyanate according to Method B1. According to Method C1a, the 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate was reacted with 3- (2- ( N- methylcarbamoyl) -4-pyridyloxy) aniline to provide urea.

Entrada 99: Se hizo reaccionar cloruro de 4-cloropiridina-2-carbonilo con etilamina de acuerdo con el Método A2, Paso 3b. La 4-cloro-N-etil-2-piridinacarboxamida resultante se hizo reaccionar con 4-aminofenol de acuerdo con el Método A2, Paso 4, para dar 4-(2-(N-etilcarbamoil)-4-piridiloxi)anilina. Se sintetizó 4-cloro-2-metoxi-5-(trifluorometil)anilina de acuerdo con el Método A7. La 4-cloro-2-metoxi-5-(trifluorometil)-anilina se convirtió en isocianato de 4-cloro-2-metoxi-5-(trifluorometil)fenilo de acuerdo con el Método B1. De acuerdo con el Método C1a, el isocianato de 4-cloro-2-metoxi-5-(trifluorometil)fenilo se hizo reaccionar con 4-(2-(N-etilcarbamoil)-4-piridiloxi)anilina para proporcionar la urea.Entry 99: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro- N- ethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4, to give 4- (2- ( N- ethylcarbamoyl) -4-pyridyloxy) aniline. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline was synthesized according to Method A7. 4-Chloro-2-methoxy-5- (trifluoromethyl) -aniline was converted to 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate according to Method B1. According to Method C1a, the 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- ( N- ethylcarbamoyl) -4-pyridyloxy) aniline to provide urea.

Entrada 100: Se hizo reaccionar cloruro de 4-cloropiridina-2-carbonilo con dimetilamina de acuerdo con el Método A2, Paso 3b. La 4-cloro-N,N-dimetil-2-piridinacarboxamida resultante se hizo reaccionar con 4-aminofenol de acuerdo con el Método A2, Paso 4, para dar 4-(2-(N,N-dimetilcarbamoil)-4-piridiloxi)anilina. Se sintetizó 4-cloro-2-metoxi-5-(trifluorometil)anilina de acuerdo con el Método A7. La 4-cloro-2-metoxi-5-(trifluorometil)anilina se convirtió en isocianato de 4-cloro-2-metoxi-5-(trifluorometil)fenilo de acuerdo con el Método B1. De acuerdo con el Método C1a, el isocianato de 4-cloro-2-metoxi-5-(trifluorometil)fenilo se hizo reaccionar con 4-(2-(N,N-dimetilcarbamoil)-4-piridiloxi)-anilina para proporcionar la urea.Entry 100: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro- N, N- dimethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4, to give 4- (2- ( N, N- dimethylcarbamoyl) -4-pyridyloxy )aniline. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline was synthesized according to Method A7. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline was converted to 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate according to Method B1. According to Method C1a, the 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- ( N, N- dimethylcarbamoyl) -4-pyridyloxy) -aniline to provide the urea.

Entrada 101: 4-Cloro-N-metil-2-piridinacarboxamida, que se sintetizó de acuerdo con el Método A2, Paso 3a, se hizo reaccionar con 3-aminofenol de acuerdo con el Método A2, Paso 4 para formar 3-(2-N-metilcarbamoil)-4-piridiloxi-anilina. Se sintetizó 2-amino-3-metoxi-naftaleno como se describe en el Método A1. De acuerdo con el Método C3, se hizo reaccionar 2-amino-3-metoxinaftaleno con carbonato de bis(triclorometilo) seguido por 3-(2-(N-metilcarbamoil)-4-piridiloxi)anilina para formar la urea.Entry 101: 4-Chloro- N -methyl-2-pyridinecarboxamide, which was synthesized according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 to form 3- (2 - N -methylcarbamoyl) -4-pyridyloxy-aniline. 2-Amino-3-methoxy-naphthalene was synthesized as described in Method A1. According to Method C3, 2-amino-3-methoxynaphthalene was reacted with bis (trichloromethyl) carbonate followed by 3- (2- ( N- methylcarbamoyl) -4-pyridyloxy) aniline to form urea.

Entrada 102: Se sintetizó 4-(2-(N-metilcarbamoil)-4-piridiloxi)anilina de acuerdo con el Método A2. Se sintetizó 5-terc-butil-2-(2,5-dimetilpirrolil)anilina de acuerdo con el Método A4. Se hizo reaccionar 5-terc-butil-2-(2,5-dimetilpirrolil)anilina con CDI seguida por 4-(2-(N-metilcarbamoil-4-piridiloxi)anilina de acuerdo con el Método C2d para proporcionar la urea.Entry 102: 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) aniline was synthesized according to Method A2. 5- tert -butyl-2- (2,5-dimethylpyrrolyl) aniline was synthesized according to Method A4. 5- tert -butyl-2- (2,5-dimethylpyrrolyl) aniline was reacted with CDI followed by 4- (2- ( N- methylcarbamoyl-4-pyridyloxy) aniline according to Method C2d to provide urea.

Entrada 103: Se sintetizó 4-cloro-N-metil-2-piridinacarboxamida de acuerdo con el Método A2, Paso 3b. Se hizo reaccionar 4-cloro-N-metil-2-piridinacarboxamida con 4-aminofenol de acuerdo con el método A2, Paso 4 utilizando DMAC en lugar de DMF para dar 4-(2-(N-metilcarbamoil)-4-piridiloxi)anilina. De acuerdo con el Método C2b, la reacción de 3-amino-2-metoxiquinolina con CDI seguida por 4-(2-(N-metilcarbamoil)4-piridiloxi)anilina proporcionó bis(4-(2-(N-metilcarbamoil)-4-piridiloxi)fenil)urea.Entry 103: 4-Chloro- N- methyl-2-pyridinecarboxamide was synthesized according to Method A2, Step 3b. 4-Chloro- N- methyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to method A2, Step 4 using DMAC instead of DMF to give 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) aniline. According to Method C2b, the reaction of 3-amino-2-methoxyquinoline with CDI followed by 4- (2- ( N- methylcarbamoyl) 4-pyridyloxy) aniline provided bis (4- (2- ( N- methylcarbamoyl)) - 4-pyridyloxy) phenyl) urea.

En las Tablas siguientes se enumeran compuestos que se han sintetizado de acuerdo con los Procedimientos Experimentales Detallados proporcionados anteriormente:Compounds are listed in the following Tables that have been synthesized according to the Procedures Detailed Experimental provided above:

Tablas Boards

Los compuestos enumerados en las Tablas 1-6 siguientes se sintetizaron de acuerdo con los métodos generales expuestos anteriormente, y los procedimientos ilustrativos más detallados se encuentran en los listados de entrada anteriores, indicándose las caracterizaciones en las Tablas.The compounds listed in the Tables 1-6 following were synthesized according to the general methods set forth above, and procedures More detailed illustrative are found in the listings of previous entry, indicating the characterizations in the Boards. 

       \vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
TABLA 1TABLE 1 3-terc-Butilfenil-Ureas3- tert -Butylphenyl-Ureas

7676

TABLA 2TABLE 2 5-terc-Butil-2-metoxifenil-Ureas5- tert -Butyl-2-methoxyphenyl-Ureas

7777

TABLA 3TABLE 3 5-(Trifluorometil)-2-metoxifenil-Ureas5- (Trifluoromethyl) -2-methoxyphenyl-Ureas

7979

8080

8181

8282 

       \newpage\ newpage
TABLA 4TABLE 4 3-(Trifluorometil)-4-clorofenil-Ureas3- (Trifluoromethyl) -4-chlorophenyl-Ureas

8383

8484

8585

8686

8787

8888 

       \newpage\ newpage
TABLA 5TABLE 5 3-(Trifluorometil)-4-bromofenil-Ureas3- (Trifluoromethyl) -4-bromophenyl-Ureas

8989

9090

TABLA 6TABLE 6 5-(Trifluorometil)-4-cloro-2-metoxifenil-Ureas5- (Trifluoromethyl) -4-chloro-2-methoxyphenyl-Ureas

9292

TABLA 7TABLE 7 Ureas adicionalesAdditional areas

9393

Los ejemplos que anteceden pueden repetirse con éxito similar empleando las sustancias reaccionantes y/o las condiciones de operación descritas genérica o específicamente de esta invención en sustitución de las utilizadas en los ejemplos que anteceden.The preceding examples can be repeated with similar success using the reactants and / or the operating conditions described generically or specifically of this invention replacing those used in the examples that precede

Claims (18)

1. Un compuesto seleccionado del grupo constituido por1. A compound selected from the group Constituted by las 4-cloro-3-(trifluorometil)fenil-ureas:the 4-Chloro-3- (trifluoromethyl) phenyl ureas: N-(4-cloro-3-(trifluorometil)fenil)-N'-(3-(2-carbamoil-4-piridiloxi)fenil)urea,N- (4-Chloro-3- (trifluoromethyl) phenyl) -N '- (3- (2-carbamoyl-4-pyridyloxy) phenyl) urea, N-(4-cloro-3-(trifluorometil)fenil-N'-(3-(2-(N-metilcarbamoil)-4-piridiloxi)fenil)-urea,N- (4-Chloro-3- (trifluoromethyl) phenyl-N '- (3- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) -urea, N-(4-cloro-3-(trifluorometil)fenil)-N'-(4-(2-carbamoil-4-piridiloxi)fenil)-urea,N- (4-Chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2-carbamoyl-4-pyridyloxy) phenyl) -urea, N-(4-cloro-3-(trifluorometil)fenil)-N'-(4-(2-(N-metilcarbamoil)-4-piridiloxi)fenil)-urea yN- (4-Chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) -urea Y N-(4-cloro-3-(trifluorometil)fenil-N'-(2-cloro-4-(2-(N-metilcarbamoil)(4-piridiloxi))fenil)-urea,N- (4-chloro-3- (trifluoromethyl) phenyl-N '- (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) -urea, las 4-bromo-3(trifluorometil)fenil-ureas:the 4-Bromo-3 (trifluoromethyl) phenyl ureas: N-(4-bromo-3-(trifluorometil)fenil)-N'-(3-(2-(N-metilcarbamoil)-4-piridiloxi)fenil)-urea,N- (4-Bromo-3- (trifluoromethyl) phenyl) -N '- (3- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) -urea, N-(4-bromo-3-(trifluorometil)fenil)-N'-(4-(2-(N-metilcarbamoil)-4-piridiloxi)-fenil-urea,N- (4-Bromo-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -phenyl-urea, N-(4-bromo-3-(trifluorometilfenil)-N'-(3-(2-(N-metilcarbamoil)-4-piridiltio)fenil)-urea,N- (4-bromo-3- (trifluoromethylphenyl) -N '- (3- (2- (N-methylcarbamoyl) -4-pyridylthio) phenyl) -urea, N-(4-bromo-3-(trifluorometil)fenil)-N'-(2-cloro-4-(2-(N-metilcarbamoil)(4-piridiloxi))fenil)-urea yN- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) -urea Y N-(4-bromo-3-(trifluorometil)fenil)-N'-(3-cloro-4-(2-(N-metilcarbamoil)(4-piridiloxi))fenil)-urea,N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (3-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) -urea, las 2-metoxi-4-cloro-5-(trifluorometil)fenil-ureas:the 2-methoxy-4-chloro-5- (trifluoromethyl) phenyl ureas: N-(2-metoxi-4-cloro-5-(trifluorometil)fenil)-N'-(4-(2-(N-metilcarbamoil)-4-piridiloxi)fenil)-urea,N- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) -urea, N-(2-metoxi-4-cloro-5-(trifluorometil)fenil)-N'-(2-cloro-4-(2-(N-metilcarbamoil)(4-piridiloxi))fenil)-ureaN- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) -urea o una de sus sales farmacéuticamente aceptables.or one of its salts pharmaceutically acceptable. 2. Un compuesto de la reivindicación 1, que es una sal farmacéuticamente aceptable del mismo seleccionada del grupo constituido por2. A compound of claim 1, which is a pharmaceutically acceptable salt thereof selected from the group consisting of
a)to)
sales básicas de ácidos orgánicos y ácidos inorgánicos seleccionados del grupo constituido por ácido clorhídrico, ácido bromhídrico, ácido sulfúrico, ácido fosfórico, ácido metanosulfónico, ácido trifluorosulfónico, ácido bencenosulfónico, ácido p-toluenosulfónico (sal tosilato), ácido 1-naftalenosulfónico, ácido 2-naftalenosulfónico, ácido acético, ácido trifluoroacético, ácido málico, ácido tartárico, ácido cítrico, ácido láctico, ácido oxálico, ácido succínico, ácido fumárico, ácido maleico, ácido benzoico, ácido salicílico, ácido fenilacético y ácido mandélico; y Basic salts of organic acids and selected inorganic acids from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acid trifluorosulfonic acid, benzenesulfonic acid, acid p-toluenesulfonic acid (tosylate salt), acid 1-naphthalenesulfonic acid 2-Naphthalenesulfonic acid, acetic acid, acid trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid; Y
b)b)
sales ácidas de bases orgánicas e inorgánicas que contienen cationes seleccionados del grupo constituido por cationes alcalinos, cationes alcalino-térreos, el catión amonio, cationes amonio con sustituyentes alifáticos y cationes amonio con sustituyentes aromáticos. acid salts of organic and inorganic bases containing cations selected from the group consisting of alkaline cations, alkaline earth cations, the ammonium cation, ammonium cations with aliphatic substituents and ammonium cations with aromatic substituents
3. Una composición farmacéutica que comprende un compuesto de la reivindicación 1 o una sal farmacéuticamente aceptable del mismo y un vehículo fisiológicamente aceptable.3. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically salt acceptable thereof and a physiologically acceptable vehicle. 4. Un compuesto de acuerdo con la reivindicación 1, seleccionado del grupo constituido por4. A compound according to claim 1, selected from the group consisting of N-(4-cloro-3-(trifluorometil)fenil)-N'-(4-(2-(N-metilcarbamoil)-4-piridiloxi)fenil)-urea,N- (4-Chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) -urea, N-(4-cloro-3-(trifluorometil)fenil)-N'-(4-(2-carbamoil-4-piridiloxi)fenil)-urea,N- (4-Chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2-carbamoyl-4-pyridyloxy) phenyl) -urea, N-(4-cloro-3-(trifluorometil)fenil-N'-(2-cloro-4-(2-(N-metilcarbamoil)(4-piridiloxi))fenil)-urea,N- (4-chloro-3- (trifluoromethyl) phenyl-N '- (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) -urea, N-(4-bromo-3-(trifluorometil)fenil)-N'-(4-(2-(N-metilcarbamoil)-4-piridiloxi)fenil)-urea,N- (4-Bromo-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) -urea, N-(2-metoxi-4-cloro-5-(trifluorometil)fenil)-N'-(4-(2-(Nmetilcarbamoil)-4-piridiloxi)fenil)-urea,N- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N '- (4- (2- (Nmethylcarbamoyl) -4-pyridyloxy) phenyl) -urea, N-(2-metoxi-4-cloro-5-(trifluorometil)fenil)-N'-(2-cloro-4-(2-(N-metilcarbamoil)(4-piridiloxi))fenil)-ureaN- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) -urea o una de sus sales farmacéuticamente aceptables.or one of its salts pharmaceutically acceptable. 5. Un compuesto de la reivindicación 4 que es una sal farmacéuticamente aceptable del mismo seleccionada del grupo constituido por5. A compound of claim 4 which is a pharmaceutically acceptable salt thereof selected from the group Constituted by
a)to)
sales básicas de ácidos orgánicos y ácidos inorgánicos seleccionadas del grupo constituido por ácido clorhídrico, ácido bromhídrico, ácido sulfúrico, ácido fosfórico, ácido metanosulfónico, ácido trifluorosulfónico, ácido bencenosulfónico, ácido p-toluenosulfónico (sal tosilato), ácido 1-naftalenosulfónico, ácido 2-naftalenosulfónico, ácido acético, ácido trifluoroacético, ácido málico, ácido tartárico, ácido cítrico, ácido láctico, ácido oxálico, ácido succínico, ácido fumárico, ácido maleico, ácido benzoico, ácido salicílico, ácido fenilacético y ácido mandélico; y Basic salts of organic acids and selected inorganic acids from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acid trifluorosulfonic acid, benzenesulfonic acid, acid p-toluenesulfonic acid (tosylate salt), acid 1-naphthalenesulfonic acid 2-Naphthalenesulfonic acid, acetic acid, acid trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid; Y
b)b)
sales ácidas de bases orgánicas e inorgánicas que contienen cationes seleccionados del grupo constituido por cationes alcalinos, cationes alcalino-térreos, el catión amonio, cationes amonio con sustituyentes alifáticos y cationes amonio con sustituyentes aromáticos. acid salts of organic and inorganic bases containing cations selected from the group consisting of alkaline cations, alkaline earth cations, the ammonium cation, ammonium cations with aliphatic substituents and ammonium cations with aromatic substituents
6. Una composición farmacéutica que comprende un compuesto de la reivindicación 4 o una sal farmacéuticamente aceptable del mismo y un vehículo fisiológicamente aceptable.6. A pharmaceutical composition comprising a compound of claim 4 or a pharmaceutically salt acceptable thereof and a physiologically acceptable vehicle. 7. Uso de un compuesto de acuerdo con la reivindicación 1 seleccionado del grupo constituido por las 4-cloro-3-(trifluorometil)fenil-ureas:7. Use of a compound in accordance with the claim 1 selected from the group consisting of the 4-Chloro-3- (trifluoromethyl) phenyl ureas: N-(4-cloro-3-(trifluorometil)fenil)-N'-(3-(2-carbamoil-4-piridiloxi)fenil)urea,N- (4-Chloro-3- (trifluoromethyl) phenyl) -N '- (3- (2-carbamoyl-4-pyridyloxy) phenyl) urea, N-(4-cloro-3-(trifluorometil)fenil)N'-(3-(2-(N-metilcarbamoil)-4-piridiloxi)fenil)-urea,N- (4-Chloro-3- (trifluoromethyl) phenyl) N '- (3- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) -urea, N-(4-cloro-3-(trifluorometil)fenil)-N'-(4-(2-carbamoil-4-piridiloxi)fenil)-urea,N- (4-Chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2-carbamoyl-4-pyridyloxy) phenyl) -urea, N-(4-cloro-3-(trifluorometil)fenil)-N'-(4-(2-(N-metilcarbamoil)-4-piridiloxi)fenil)-urea yN- (4-Chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) -urea Y N-(4-cloro-3-(trifluorometil)fenil-N'-(2-cloro-4-(2-(N-metilcarbamoil)(4-piridiloxi))fenil)-urea,N- (4-chloro-3- (trifluoromethyl) phenyl-N '- (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) -urea, las 4-bromo-3(trifluorometil)fenil-ureas:the 4-Bromo-3 (trifluoromethyl) phenyl ureas: N-(4-bromo-3-(trifluorometil)fenil)-N'-(3-(2-(N-metilcarbamoil)-4-piridiloxi)fenil)-urea,N- (4-Bromo-3- (trifluoromethyl) phenyl) -N '- (3- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) -urea, N-(4-bromo-3-(trifluorometil)fenil)-N'-(4-(2-(N-metilcarbamoil)-4-piridiloxi)fenil-urea,N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl-urea, N-(4-bromo-3-(trifluorometilfenil)-N'-(3-(2-(N-metilcarbamoil)-4-piridiltio)fenil)-urea,N- (4-bromo-3- (trifluoromethylphenyl) -N '- (3- (2- (N-methylcarbamoyl) -4-pyridylthio) phenyl) -urea, N-(4-bromo-3-(trifluorometil)fenil)-N'-(2-cloro-4-(2-(N-metilcarbamoil)(4-piridiloxi))fenil)-urea yN- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) -urea Y N-(4-bromo-3-(trifluorometil)fenil)-N'-(3-cloro-4-(2-(N-metilcarbamoil)(4-piridiloxi))fenil)-urea,N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (3-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) -urea, las 2-metoxi-4-cloro-5-(trifluorometil)fenil-ureas:the 2-methoxy-4-chloro-5- (trifluoromethyl) phenyl ureas: N-(2-metoxi-4-cloro-5-(trifluorometil)fenil)-N'-(4-(2-(N-metilcarbamoil)-4-piridiloxi)fenil)-urea,N- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) -urea, N-(2-metoxi-4-cloro-5-(trifluorometil)fenil)-N'-(2-cloro-4-(2-(N-metilcarbamoil)(4-piridiloxi))fenil)-ureaN- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) -urea o una sal farmacéuticamente aceptable del mismo para la fabricación de un medicamento para el tratamiento del crecimiento de una célula cancerosa mediado por la quinasa raf.or a pharmaceutically salt acceptable for the manufacture of a medicament for treatment of the growth of a cancer cell mediated by kinase raf. 8. Uso de un compuesto de acuerdo con la reivindicación 1, seleccionado del grupo constituido por las 4-cloro-3-(trifluorometil)fenil-ureas:8. Use of a compound in accordance with the claim 1, selected from the group consisting of the 4-Chloro-3- (trifluoromethyl) phenyl ureas: N-(4-cloro-3-(trifluorometil)fenil)-N'-(3-(2-carbamoil-4-piridiloxi)fenil)urea,N- (4-Chloro-3- (trifluoromethyl) phenyl) -N '- (3- (2-carbamoyl-4-pyridyloxy) phenyl) urea, N-(4-cloro-3-(trifluorometil)fenil)-N'-(3-(2-(N-metilcarbamoil)-4-piridiloxi)fenil)-urea,N- (4-Chloro-3- (trifluoromethyl) phenyl) -N '- (3- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) -urea, N-(4-cloro-3-(trifluorometil)fenil)-N'-(4-(2-carbamoil-4-piridiloxi)fenil)-urea,N- (4-Chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2-carbamoyl-4-pyridyloxy) phenyl) -urea, N-(4-cloro-3-(trifluorometil)fenil)-N'-(4-(2-(N-metilcarbamoil)-4-piridiloxi)-fenil)-urea yN- (4-Chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -phenyl) -urea Y N-(4-cloro-3-(trifluorometil)fenil)-N'-(2-cloro-4-(2-(N-metilcarbamoil)(4-piridiloxi))fenil)-urea,N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) -urea, las 4-bromo-3(trifluorometil)fenil-ureas:the 4-Bromo-3 (trifluoromethyl) phenyl ureas: N-(4-bromo-3-(trifluorometil)fenil)-N'-(3-(2-(N-metilcarbamoil)-4-piridiloxi)fenil)-urea,N- (4-Bromo-3- (trifluoromethyl) phenyl) -N '- (3- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) -urea, N-(4-bromo-3-(trifluorometil)fenil)-N'-(4-(2-(N-metilcarbamoil)-4-piridiloxi)fenil-urea,N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl-urea, N-(4-bromo-3-(trifluorometil)fenil)-N'-(3-(2-(N-metilcarbamoil)-4-piridiltio)fenil)-urea,N- (4-Bromo-3- (trifluoromethyl) phenyl) -N '- (3- (2- (N-methylcarbamoyl) -4-pyridylthio) phenyl) -urea, N-(4-bromo-3-(trifluorometil)fenil)-N'-(2-cloro-4-(2-(N-metilcarbamoil)(4-piridiloxi))fenil)-urea yN- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) -urea Y N-(4-bromo-3-(trifluorometil)fenil)-N'-(3-cloro-4-(2-(N-metilcarbamoil)(4-piridiloxi))fenil)-urea,N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (3-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) -urea, las 2-metoxi-4-cloro-5-(trifluorometil)fenil-ureas:the 2-methoxy-4-chloro-5- (trifluoromethyl) phenyl ureas: N-(2-metoxi-4-cloro-5-(trifluorometil)fenil)-N'-(4-(2-(N-metilcarbamoil)-4-piridiloxi)fenil)-urea,N- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) -urea, N-(2-metoxi-4-cloro-5-(trifluorometil)fenil)-N'-(2-cloro-4-(2-(N-metilcarbamoil)(4-piridiloxi))fenil)-ureaN- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) -urea o una sal farmacéuticamente aceptable del mismo para la fabricación de un medicamento para el tratamiento deor a pharmaceutically salt acceptable for the manufacture of a medicament for treatment from i) carcinoma de pulmón, páncreas, tiroides, vejiga, colon,i) carcinoma of the lung, pancreas, thyroid, bladder, colon, ii) leucemia mieloide oii) myeloid leukemia or iii) adenoma velloso de colon.iii) villous colon adenoma. 9. Uso de un compuesto de acuerdo con la reivindicación 1 seleccionado del grupo constituido por las 4-cloro-3-(trifluorometil)fenil-ureas:9. Use of a compound in accordance with the claim 1 selected from the group consisting of the 4-Chloro-3- (trifluoromethyl) phenyl ureas: N-(4-cloro-3-(trifluorometil)fenil)-N'-(3-(2-carbamoil-4-piridiloxi)fenil)urea,N- (4-Chloro-3- (trifluoromethyl) phenyl) -N '- (3- (2-carbamoyl-4-pyridyloxy) phenyl) urea, N-(4-cloro-3-(trifluorometil)fenil)-N'-(3-(2-(N-metilcarbamoil)-4-piridiloxi)fenil)-urea,N- (4-Chloro-3- (trifluoromethyl) phenyl) -N '- (3- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) -urea, N-(4-cloro-3-(trifluorometil)fenil)-N'-(4-(2-carbamoil-4-piridiloxi)fenil)-urea,N- (4-Chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2-carbamoyl-4-pyridyloxy) phenyl) -urea, N-(4-cloro-3-(trifluorometil)fenil)-N'-(4-(2-(N-metilcarbamoil)-4-piridiloxi)fenil)-urea yN- (4-Chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) -urea Y N-(4-cloro-3-(trifluorometil)fenil)-N'-(2-cloro-4-(2-(N-metilcarbamoil)(4-piridiloxi))fenil)-urea,N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) -urea, las 4-bromo-3(trifluorometil)fenil-ureas:the 4-Bromo-3 (trifluoromethyl) phenyl ureas: N-(4-bromo-3-(trifluorometil)fenil)-N'-(3-(2-(N-metilcarbamoil)-4-piridiloxi)fenil)-urea,N- (4-Bromo-3- (trifluoromethyl) phenyl) -N '- (3- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) -urea, N-(4-bromo-3-(trifluorometil)fenil)-N'-(4-(2-(N-metilcarbamoil)-4-piridiloxi)fenil-urea,N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl-urea, N-(4-bromo-3-(trifluorometil)fenil)-N'-(3-(2-(N-metilcarbamoil)-4-piridiltio)fenil)-urea,N- (4-Bromo-3- (trifluoromethyl) phenyl) -N '- (3- (2- (N-methylcarbamoyl) -4-pyridylthio) phenyl) -urea, N-(4-bromo-3-(trifluorometil)fenil)-N'-(2-cloro-4-(2-(N-metilcarbamoil)(4-piridiloxi))fenil)-urea yN- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) -urea Y N-(4-bromo-3-(trifluorometil)fenil)-N'-(3-cloro-4-(2-(N-metilcarbamoil)(4-piridiloxi))fenil)-urea,N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (3-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) -urea, las 2-metoxi-4-cloro-5-(trifluorometil)fenil-ureas:the 2-methoxy-4-chloro-5- (trifluoromethyl) phenyl ureas: N-(2-metoxi-4-cloro-5-(trifluorometil)fenil)-N'-(4-(2-(N-metilcarbamoil)-4-piridiloxi)fenil)-urea,N- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) -urea, N-(2-metoxi-4-cloro-5-(trifluorometil)fenil)-N'-(2-cloro-4-(2-(N-metilcarbamoil)(4-piridiloxi))fenil)-ureaN- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) -urea o una sal farmacéuticamente aceptable del mismo para la fabricación de un medicamento para el tratamiento de tumores.or a pharmaceutically salt acceptable for the manufacture of a medicament for treatment of tumors 10. Uso de un compuesto de acuerdo con la reivindicación 4, seleccionado del grupo constituido por10. Use of a compound in accordance with the claim 4, selected from the group consisting of N-(4-cloro-3-(trifluorometil)fenil)-N'-(4-(2-N-metilcarbamoil)-4-piridiloxi)fenil)-urea,N- (4-Chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2-N-methylcarbamoyl) -4-pyridyloxy) phenyl) -urea, N-(4-cloro-3-(trifluorometil)fenil)-N'-(4-(2-(carbamoil)-4-piridiloxi)fenil)-urea,N- (4-Chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2- (carbamoyl) -4-pyridyloxy) phenyl) -urea, N-(4-cloro-3-(trifluorometil)feni)l-N'-(2-cloro-4-(2-(N-metilcarbamoil)(4-piridiloxi))fenil)-urea,N- (4-Chloro-3- (trifluoromethyl) pheny) l-N '- (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) -urea, N-(4-bromo-3-(trifluorometil)fenil)-N'-(4-(2-(N-metilarbamoil)-4-piridiloxi)fenil)-urea,N- (4-Bromo-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylabamoyl) -4-pyridyloxy) phenyl) -urea, N-(2-metoxi-4-cloro-5-(trifluorometil)fenil)-N'-(4-(2-(N-metilcarbamoil)-4-piridiloxi)fenil)-urea,N- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) -urea, N-(2-metoxi-4-cloro-5-(trifluorometil)fenil)-N'-(2-cloro-4-(2-(N-metilcarbamoil)(4-piridiloxi))fenil)-ureaN- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) -urea o una sal farmacéuticamente aceptable del mismo para la fabricación de un medicamento para el tratamiento del crecimiento de una célula cancerosa mediado por la quinasa raf.or a pharmaceutically salt acceptable for the manufacture of a medicament for treatment of the growth of a cancer cell mediated by kinase raf. 11. Uso de un compuesto de acuerdo con la reivindicación 4, seleccionado del grupo constituido por11. Use of a compound in accordance with the claim 4, selected from the group consisting of N-(4-cloro-3-(trifluorometil)fenil)-N'-(4-(2-N-metilcarbamoil)-4-piridiloxi)fenil)-urea,N- (4-Chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2-N-methylcarbamoyl) -4-pyridyloxy) phenyl) -urea, N-(4-cloro-3-(trifluorometil)fenil)-N'-(4-(2-carbamoil-4-piridiloxi)fenil)-urea,N- (4-Chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2-carbamoyl-4-pyridyloxy) phenyl) -urea, N-(4-cloro-3-(trifluorometil)fenil)-N'-(2-cloro-4-(2-(N-metilcarbamoil)(4-piridiloxi))fenil)-urea,N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) -urea, N-(4-bromo-3-(trifluorometil)fenil)-N'-(4-(2-(N-metilcarbamoil)-4-piridiloxi)fenil)-urea,N- (4-Bromo-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) -urea, N-(2-metoxi-4-cloro-5-(trifluorometil)fenil)-N'-(4-(2-(N-metilcarbamoil)-4-piridiloxi)fenil)-urea,N- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) -urea, N-(2-metoxi-4-cloro-5-(trifluorometil)fenil)-N'-(2-cloro-4-(2-(N-metilcarbamoil)(4-piridiloxi))fenil)-ureaN- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) -urea o una sal farmacéuticamente aceptable del mismo para la fabricación de un medicamento para el tratamiento deor a pharmaceutically salt acceptable for the manufacture of a medicament for treatment from i) carcinoma de pulmón, páncreas, tiroides, vejiga, colon,i) carcinoma of the lung, pancreas, thyroid, bladder, colon, ii) leucemia mieloide oii) myeloid leukemia or iii) adenoma velloso de colon.iii) villous colon adenoma. 12. Uso de un compuesto de acuerdo con la reivindicación 4 seleccionado del grupo constituido por12. Use of a compound in accordance with the claim 4 selected from the group consisting of N-(4-cloro-3-(trifluorometil)fenil)-N'-(4-(2-N-metilcarbamoil)-4-piridiloxi)fenil)-urea,N- (4-Chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2-N-methylcarbamoyl) -4-pyridyloxy) phenyl) -urea, N-(4-cloro-3-(trifluorometil)fenil)-N'-(4-(2-carbamoil-4-piridiloxi)fenil)-urea,N- (4-Chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2-carbamoyl-4-pyridyloxy) phenyl) -urea, N-(4-cloro-3-(trifluorometil)fenil-N'-(2-cloro-4-(2-(N-metilcarbamoil)(4-piridiloxi))fenil)-urea,N- (4-chloro-3- (trifluoromethyl) phenyl-N '- (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) -urea, N-(4-bromo-3-(trifluorometil)fenil)-N'-(4-(2-(N-metilcarbamoil)-4-piridiloxi)fenil)-urea,N- (4-Bromo-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) -urea, N-(2-metoxi-4-cloro-5-(trifluorometil)fenil)-N'-(4-(2-(N-metilcarbamoil)-4-piridiloxi)fenil)-urea,N- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) -urea, N-(2-metoxi-4-cloro-5-(trifluorometil)fenil)-N'-(2-cloro-4-(2-(N-metilcarbamoil)(4-piridiloxi))fenil)-ureaN- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) -urea o una sal farmacéuticamente aceptable del mismo para la fabricación de un medicamento para el tratamiento de tumores.or a pharmaceutically salt acceptable for the manufacture of a medicament for treatment of tumors 13. Un compuesto de la reivindicación 1 que es N-(4-cloro-3-(trifluorometil)fenil)-N'-(4-(2-carbamoil-4-piridiloxi)fenil)-urea.13. A compound of claim 1 which is N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2-carbamoyl-4-pyridyloxy) phenyl) -urea. 14. Un compuesto de la reivindicación 1 que es N-(4-cloro-3-(trifluorometil)fenil)-N'-(4-(2-(N-metilcarbamoil)-4-piridiloxi)fenil)-urea.14. A compound of claim 1 which is N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) -urea. 15. Una composición farmacéutica que comprende N-(4-cloro-3-(trifluorometil)fenil)-N'-(4-(2-carbamoil-4-piridiloxi)fenil)-urea o una sal farmacéuticamente aceptable de la misma y un vehículo fisiológicamente aceptable.15. A pharmaceutical composition comprising N- (4-Chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2-carbamoyl-4-pyridyloxy) phenyl) -urea  or a pharmaceutically acceptable salt thereof and a vehicle Physiologically acceptable. 16. Una composición farmacéutica que comprende N-(4-cloro-3-(trifluorometil)fenil)-N'-(4-(2-(N-metilcarba-
moil)-4-piridiloxi)fenil)-urea o una sal farmacéuticamente aceptable de la misma y un vehículo fisiológicamente aceptable.16. A pharmaceutical composition comprising N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarba)
moyl) -4-pyridyloxy) phenyl) -urea or a pharmaceutically acceptable salt thereof and a physiologically acceptable carrier. 17. Uso de N-(4-cloro-3-(trifluorometil)fenil)-N'-(4-(2-carbamoil-4-piridiloxi)fenil)-urea o una sal farmacéuticamente aceptable de la misma para la fabricación de un medicamento para el tratamiento del crecimiento de una célula cancerosa mediado por la quinasa raf.17. Use of N- (4-Chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2-carbamoyl-4-pyridyloxy) phenyl) -urea or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for growth treatment of a cancer cell mediated by raf kinase. 18. Uso de N-(4-cloro-3-(trifluorometil)fenil)-N'-(4-(2-(N-metilcarbamoil)-4-piridiloxi)fenil)-urea o una sal farmacéuticamente aceptable de la misma para la fabricación de un medicamento para el tratamiento del crecimiento de una célula cancerosa mediado por la quinasa raf.18. Use of N- (4-Chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) -urea or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for growth treatment of a cancer cell mediated by raf kinase.
ES00903239T 1999-01-13 2000-01-12 DIFENIL-UREAS REPLACED WITH OMEGA-CARBOXIARILO AS INHIBITORS OF THE QUINASA RAF. Expired - Lifetime ES2255971T3 (en)

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